bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapeutic Targeting of Neutrophil Extracellular Traps Improves Primary and Secondary Intention Wound Healing in Mice
Authors: Heuer Annika , Stiel Carolin , Elrod Julia , Königs Ingo , Vincent Deirdre , Schlegel Patrick , Trochimiuk Magdalena , Appl Birgit , Reinshagen Konrad , Raluy Laia Pagerols , Boettcher Michael 
Published: February 2021

BackgroundNeutrophils are the first responders in wound healing after injury that mediate pro- and anti-inflammatory activities i.a. through the formation of extracellular traps (NETs). However, excessive NETs presence in wound tissue can cause local hyperinflammation and -coagulation resulting in delayed wound healing. To improve wound healing, we aimed to examine the role of NETs and DNase1 on primary and secondary wound healing.MethodsThe study included 93 C57BL/6 mice, with 3 different genotypes: wildtype, Pad4-, and DNase1-Knockout (KO). Pad4-KO mice show limited NETs formation, while DNase1-KO mice cannot disintegrate them. All 3 genotypes were included in (1) a laparotomy group and (2) a thermal injury group. Animals in both groups either received DNase1 or a vehicle i.p. post wound induction and wound assessment and euthanasia were conducted. Laparotomy and burn scars were assessed using the stony brook scar evaluation scale and modified Yeong scale respectively. Tissue was analyzed histologically using H&amp;E staining. Ly6g, Collagen I and III, SMA, and Fibrinogen were visualized and neutrophils activation (NE, MPO) and NETs (H3cit) formation assessed.ResultsAll animals survived with no complications. DNase1 treatment led to a significantly improved scar appearance in both groups, which was also seen in Pad4-KO mice. In the laparotomy group DNase1 improved collagen deposition and fibrin concentration was significantly reduced by DNase1 treatment. Markers of neutrophil activation were significantly reduced in the treatment and Pad4-KO group. In the thermal injury group wound closure time was significantly reduced after DNase1 treatment and in the Pad4-KO group. Even though inflammation remained high in the thermal injury model over time, neutrophil activation and NETs formation were significantly reduced by DNase1 treatment compared to controls.DiscussionPrimary and secondary intention wound healing is improved by targeting NETs through DNase1 treatment or genetic KO, as assessed by wound closure time and scar appearances. Additionally, wound stability was not affected by DNASE treatment. The results suggest that overall wound healing is accelerated and DNase1 appears to be a promising option to reduce scar formation; which should be evaluated in humans.
Better Together: Current Insights Into Phagosome-Lysosome Fusion
Authors: Nguyen Jenny A. , Yates Robin M. 
Published: February 2021

Following phagocytosis, the nascent phagosome undergoes maturation to become a phagolysosome with an acidic, hydrolytic, and often oxidative lumen that can efficiently kill and digest engulfed microbes, cells, and debris. The fusion of phagosomes with lysosomes is a principal driver of phagosomal maturation and is targeted by several adapted intracellular pathogens. Impairment of this process has significant consequences for microbial infection, tissue inflammation, the onset of adaptive immunity, and disease. Given the importance of phagosome-lysosome fusion to phagocyte function and the many virulence factors that target it, it is unsurprising that multiple molecular pathways have evolved to mediate this essential process. While the full range of these pathways has yet to be fully characterized, several pathways involving proteins such as members of the Rab GTPases, tethering factors and SNAREs have been identified. Here, we summarize the current state of knowledge to clarify the ambiguities in the field and construct a more comprehensive phagolysosome formation model. Lastly, we discuss how other cellular pathways help support phagolysosome biogenesis and, consequently, phagocyte function.
Incidence and Associated Risk Factors for Lactic Acidosis Induced by Linezolid Therapy in a Case–Control Study in Patients Older Than 85 Years
Authors: Liu Tingting , Hu Chao , Wu Jionghe , Liu Miao , Que Yifan , Wang Jiang , Fang Xiangqun , Xu Guogang , Li Hongxia 
Published: February 2021

Background: Serum lactic acid is considered a prognostic indicator in critically ill patients. However, studies on linezolid-induced lactic acidosis (LILA) are still limited. Individuals older than 85 years old (very elderly) have limited capacity for organ compensation, and LILA data from these patients are lacking. In this study, we evaluated the risk factors for LILA in patients older than 85 years and established a risk prediction model for geriatric practice.Methods: In this retrospective cohort study, blood gas analysis data and arterial lactate levels were monitored in patients older than 85 years during the use of teicoplanin or linezolid. After propensity score matching analyses, we compared the incidence of lactic acidosis between the teicoplanin and linezolid therapy groups and identified the risk factors of LILA.Results: The incidence of lactic acidosis was found to be much lower in the group receiving teicoplanin than those receiving linezolid therapy (0 vs. 35.7%; p &lt; 0.0001). A duration of linezolid therapy ≥ 9 days [odds ratio (OR), 3.541; 95% confidence interval (CI), 1.161–10.793; p = 0.026], an arterial blood glucose level ≥ 8 mmol/L (OR, 4.548; 95% CI, 1.507–13.725; p = 0.007), and a high sequential organ failure assessment score (OR, 1.429; 95% CI, 1.213–1.685; p &lt; 0.0001) were risk factors for LILA. The constructed risk model could be used to predict LILA (area under the curve, 0.849; specificity, 65.1%; sensitivity, 91.4%, with a negative predictive value of 93.2% and a positive predictive value of 59.3%).Conclusions: LILA can occur in patients older than 85 years after a relatively shorter duration of linezolid therapy. Therefore, close monitoring of blood gas and arterial lactate levels during linezolid therapy in the very elderly population is necessary.
Systemic Bone Density at Disease Onset Is Associated With Joint Erosion Progression in Early Naive to Treatment Rheumatoid Arthritis: A Prospective 12-Month Follow-Up Open-Label Study
Authors: Bruno Dario , Fedele Anna Laura , Tolusso Barbara , Barini Angelina , Petricca Luca , Di Mario Clara , Barini Antonella , Mirone Luisa , Ferraccioli Gianfranco , Alivernini Stefano , Gremese Elisa 
Published: February 2021

Objectives:Osteoporosis and bone erosions are hallmarks of rheumatoid arthritis (RA) since disease onset is underpinned by the inflammatory burden. In this observational study, we aimed to dissect the putative RA-related parameters and bone-derived biomarkers associated with systemic and focal bone loss at disease onset and with their progression.Methods:One-hundred twenty-eight patients with early rheumatoid arthritis (ERA) were recruited at disease onset. At study entry, demographic, clinical, and immunological parameters were recorded. Each ERA patient underwent plain X-rays of the hands and feet at study entry and after 12 months to assess the presence of erosions. After enrollment, each patient was treated according to the recommendations for RA management and followed up based on a treat-to-target (T2T) strategy. At baseline, blood samples for soluble biomarkers were collected from each patient, and plasma levels of osteoprotegerin (OPG), receptor activator of nuclear factor κB ligand (RANKL), Dickkopf-1 (DKK1), and interleukin 6 (IL-6) were assessed by enzyme-linked immunosorbent assay (ELISA). Seventy-one ERA patients underwent bone mineral density (BMD) measurement at the left femoral neck and second to fourth lumbar spine vertebrae (L2–L4) by dual-energy X-ray absorptiometry (DXA).Results:Among the whole cohort, 34 (26.6%) ERA patients with bone erosions at study entry had a higher disease activity (p= 0.02) and IL-6 plasma levels (p= 0.03) than non-erosive ones. Moreover, at DXA, 33 (46.5%) ERA patients had osteopenia, and 16 (22.5%) had osteoporosis; patients with baseline bone erosions were more likely osteopenic/osteoporotic than non-erosive ones (p= 0.03), regardless of OPG, RANKL, and DKK1 plasma levels. Obese ERA patients were less likely osteopenic/osteoporotic than normal weight ones (p= 0.002), whereas anti-citrullinated protein antibodies (ACPA) positive ERA patients were more likely osteopenic/osteoporotic than ACPA negative ones (p= 0.034). At logistic regression analysis, baseline Disease Activity Score measured on 44 joints (DAS44) [OR: 2.46 (1.11–5.44)] and osteopenic/osteoporosis status [OR: 7.13 (1.27–39.94)] arose as independent factors of erosiveness. Baseline osteopenic/osteoporotic status and ACPA positivity were associated with bone damage progression during the follow-up.Conclusions:Bone erosions presence is associated with systemic bone loss since the earliest phases of RA, suggesting that the inflammatory burden and autoimmune biology, underpinning RA, represent crucial enhancers of bone remodeling either locally as at systemic level.
Factors Influencing the Live Birth Rate Following Fresh Embryo Transfer Cycles in Infertile Women After Endometrioma Cystectomy
Authors: Liu Wei , Sha Tongye , Huang Yuzhen , Guo Zizhen , Yan Lei , Ma Jinlong 
Published: February 2021

Background: Reproductive outcomes after fresh in vitro fertilization/intracytoplasmic sperm injection–embryo transfer (IVF/ICSI–ET) cycles are diverse in infertile women with a history of ovarian cystectomy for endometriomas. We aimed to develop a logistic regression model based on patients' characteristics including number of embryos transferred and stimulation protocols to predict the live birth rate in fresh IVF/ICSI–ET cycles for such patients.Methods: We recruited 513 infertile women with a history of ovarian cystectomy for endometriomas who underwent their first fresh ET with different stimulation protocols following IVF/ICSI cycles in our unit from January 2014 to December 2018. One or two embryo are implanted. Clinical and laboratory parameters potentially affecting the live birth rate following fresh ET cycles were analyzed. Univariable and multivariable analyses were performed to assess the relationship between predictive factors and live birth rate.Results: The overall live birth rate was 240/513 (46.8%). Multivariable modified Poisson regression models showed that two factors were significantly lowers the probability of live birth: female age ≥ 5 years (aOR 0.603; 95% CI 0.389–0.933; P = 0.023); BMI range 21–24.99 kg/m2 compared with BMI &lt;21 kg/m2 (aOR 0.572; 95% CI 0.372–0.881, P = 0.011). And two factors significantly increased the probability of live birth: AFC &gt;7 (aOR 1.591; 95% CI 1.075–2.353; P = 0.020); two embryos transferred (aOR 1.607; 95% CI 1.089–2.372; P = 0.017).Conclusions: For these infertile women who had undergone ovarian cystectomy for endometriosis, female age &lt;35 years, AFC &gt; 7, and two embryos transferred might achieve better clinical fresh IVF/ICSI–ET outcomes. BMI &lt;21 kg/m2 or ≥25 kg/m2 might also have positive effects on the live birth rate, but different ovarian stimulation protocols had no significant effects. However, a larger sample size may be needed for further study.
Comparative Genomics of Emerging Lineages and Mobile Resistomes of Contemporary Broiler Strains of Salmonella Infantis and E. coli
Authors: Szmolka Ama , Wami Haleluya , Dobrindt Ulrich 
Published: February 2021

IntroductionCommensal and pathogenic strains of multidrug-resistant (MDR)Escherichia coliand non-typhoid strains ofSalmonellarepresent a growing foodborne threat from foods of poultry origin. MDR strains ofSalmonellaInfantis andE. coliare frequently isolated from broiler chicks and the simultaneous presence of these two enteric bacterial species would potentially allow the exchange of mobile resistance determinants.ObjectivesIn order to understand possible genomic relations and to obtain a first insight into the potential interplay of resistance genes between enteric bacteria, we compared genomic diversity and mobile resistomes ofS. Infantis andE. colifrom broiler sources.ResultsThe core genome MLST analysis of 56S. Infantis and 90E. colicontemporary strains revealed a high genomic heterogeneity of broilerE. coli.It also allowed the first insight into the genomic diversity of the MDR clone B2 ofS. Infantis, which is endemic in Hungary. We also identified new MDR lineages forS. Infantis (ST7081 and ST7082) and forE. coli(ST8702 and ST10088). Comparative analysis of antibiotic resistance genes and plasmid types revealed a relatively narrow interface between the mobile resistomes ofE. coliandS. Infantis. The mobile resistance genestet(A),aadA1, andsul1were identified at an overall high prevalence in both species. This gene association is characteristic to the plasmid pSI54/04 of the epidemic clone B2 ofS. Infantis. Simultaneous presence of these genes and of IncI plasmids of the same subtype in cohabitant caecal strains ofE. coliandS. Infantis suggests an important role of these plasmid families in a possible interplay of resistance genes betweenS. Infantis andE. coliin broilers.ConclusionThis is the first comparative genomic analysis of contemporary broiler strains ofS. Infantis andE. coli. The diversity of mobile resistomes suggests that commensalE. colicould be potential reservoirs of resistance forS. Infantis, but so far only a few plasmid types and mobile resistance genes could be considered as potentially exchangeable between these two species. Among these, IncI1 plasmids could make the greatest contribution to the microevolution and genetic interaction betweenE. coliandS. Infantis.
Thalamic Structural Connectivity Abnormalities in Minimal Hepatic Encephalopathy
Authors: Chen Hua-Jun , Zhang Xiao-Hong , Shi Jia-Yan , Jiang Shao-Fan , Sun Yi-Fan , Zhang Ling , Li Dan , Chen Rong 
Published: February 2021

Background and Aims: Numerous studies have demonstrated thalamus-related structural, functional, and metabolic abnormalities in minimal hepatic encephalopathy (MHE). We conducted the first study to investigate thalamic structural connectivity alterations in MHE.MethodsDiffusion tensor imaging (DTI)-based probabilistic tractography was employed to determine the structural linkage between the thalamus and cortical/subcortical regions in 52 cirrhotic patients [22 with MHE; 30 without MHE (NHE)] and 30 controls. We measured these thalamic connections, which included connectivity strength (CS), fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), and then compared these among the three groups. Neurocognitive assessment was also performed. Correlation analysis was conducted to investigate the relationship between neurocognitive performance and the above measurements. Classification analysis was performed to determine whether thalamic connection measurements can distinguish MHE from NHE.ResultsThe probabilistic tractography revealed thalamic structural connections, which were disrupted in cirrhotic patients (as reflected by a decrease in CS/FA and an increase in MD/AD/RD). Abnormal thalamic connections primarily involved the prefrontal cortex, sensorimotor cortex, parietal cortex, medial temporal cortex and hippocampus, and striatum. Thalamic connectivity abnormalities deteriorated from NHE to MHE, and they were correlated with patients’ neurocognitive performance. The moderate classification accuracy was obtained using CS and MD as discriminating indexes.ConclusionOur results demonstrated the altered thalamic structural connectivity involving both cortical and subcortical regions in MHE, which could be regarded as representative of MHE-related widespread impairments in white matter pathways. The disturbed thalamic connectivity may underlie the mechanism of cognitive deficits in MHE and may potentially be utilized as a biomarker for diagnosing MHE and in monitoring disease progression. In addition to thalamic–cortical/subcortical connections, further studies are recommended to explore the structural alterations in other white matter pathways in MHE.
Sleep Spindle Characteristics in Obstructive Sleep Apnea Syndrome (OSAS)
Authors: Mohammadi Hiwa , Aarabi Ardalan , Rezaei Mohammad , Khazaie Habibolah , Brand Serge 
Published: February 2021

Background:We compared the density and duration of sleep spindles topographically in stage 2 and 3 of non-rapid eye movement sleep (N2 and N3) among adults diagnosed with Obstructive Sleep Apnea Syndrome (OSAS) and healthy controls.Materials and Methods:Thirty-one individuals with OSAS (mean age: 48.50 years) and 23 healthy controls took part in the study. All participants underwent a whole night polysomnography. Additionally, those with OSAS were divided into mild, moderate and severe cases of OSAS.Results:For N2, sleep spindle density did not significantly differ between participants with and without OSAS, or among those with mild, moderate and severe OSAS. For N3,post-hocanalyses revealed significantly higher spindle densities in healthy controls and individuals with mild OSAS than in those with moderate or severe OSAS. Last, in N2 a higher AHI was associated with a shorter sleep spindle duration.Conclusion:OSAS is associated with a significantly lower spindle density in N3 and a shorter spindle duration in N2. Our results also revealed that, in contrast to moderate and severe OSAS, the sleep spindle characteristics of individuals with mild OSAS were very similar to those of healthy controls.
Multimodal Assessment of Precentral Anodal TDCS: Individual Rise in Supplementary Motor Activity Scales With Increase in Corticospinal Excitability
Authors: Karabanov Anke Ninija , Shindo Keiichiro , Shindo Yuko , Raffin Estelle , Siebner Hartwig Roman 
Published: February 2021

BackgroundTranscranial direct current stimulation (TDCS) targeting the primary motor hand area (M1-HAND) may induce lasting shifts in corticospinal excitability, but after-effects show substantial inter-individual variability. Functional magnetic resonance imaging (fMRI) can probe after-effects of TDCS on regional neural activity on a whole-brain level.ObjectiveUsing a double-blinded cross-over design, we investigated whether the individual change in corticospinal excitability after TDCS of M1-HAND is associated with changes in task-related regional activity in cortical motor areas.MethodsSeventeen healthy volunteers (10 women) received 20 min of real (0.75 mA) or sham TDCS on separate days in randomized order. Real and sham TDCS used the classic bipolar set-up with the anode placed over right M1-HAND. Before and after each TDCS session, we recorded motor evoked potentials (MEP) from the relaxed left first dorsal interosseus muscle after single-pulse transcranial magnetic stimulation(TMS) of left M1-HAND and performed whole-brain fMRI at 3 Tesla while participants completed a visuomotor tracking task with their left hand. We also assessed the difference in MEP latency when applying anterior-posterior and latero-medial TMS pulses to the precentral hand knob (AP-LM MEP latency).ResultsReal TDCS had no consistent aftereffects on mean MEP amplitude, task-related activity or motor performance. Individual changes in MEP amplitude, measured directly after real TDCS showed a positive linear relationship with individual changes in task-related activity in the supplementary motor area and AP-LM MEP latency.ConclusionFunctional aftereffects of classical bipolar anodal TDCS of M1-HAND on the motor system vary substantially across individuals. Physiological features upstream from the primary motor cortex may determine how anodal TDCS changes corticospinal excitability.
Predicting Metastasis Risk in Pancreatic Neuroendocrine Tumors Using Deep Learning Image Analysis
Authors: Klimov Sergey , Xue Yue , Gertych Arkadiusz , Graham Rondell P. , Jiang Yi , Bhattarai Shristi , Pandol Stephen J. , Rakha Emad A. , Reid Michelle D. , Aneja Ritu 
Published: February 2021

BackgroundThe prognosis of patients with pancreatic neuroendocrine tumors (PanNET), the second most common type of pancreatic cancer, varies significantly, and up to 15% of patients develop metastasis. Although certain morphological characteristics of PanNETs have been associated with patient outcome, there are no available morphology-based prognostic markers. Given that current clinical histopathology markers are unable to identify high-risk PanNET patients, the development of accurate prognostic biomarkers is needed. Here, we describe a novel machine learning, multiclassification pipeline to predict the risk of metastasis using morphological information from whole tissue slides.MethodsDigital images from surgically resected tissues from 89 PanNET patients were used. Pathologist-annotated regions were extracted to train a convolutional neural network (CNN) to identify tiles consisting of PanNET, stroma, normal pancreas parenchyma, and fat. Computationally annotated cancer or stroma tiles and patient metastasis status were used to train CNN to calculate a region based metastatic risk score. Aggregation of the metastatic probability scores across the slide was performed to predict the risk of metastasis.ResultsThe ability of CNN to discriminate different tissues was high (per-tile accuracy &gt;95%; whole slide cancer regions Jaccard index = 79%). Cancer and stromal tiles with high evaluated probability provided F1 scores of 0.82 and 0.69, respectively, when we compared tissues from patients who developed metastasis and those who did not. The final model identified low-risk (n = 76) and high-risk (n = 13) patients, as well as predicted metastasis-free survival (hazard ratio: 4.71) after adjusting for common clinicopathological variables, especially in grade I/II patients.ConclusionUsing slides from surgically resected PanNETs, our novel, multiclassification, deep learning pipeline was able to predict the risk of metastasis in PanNET patients. Our results suggest the presence of prognostic morphological patterns in PanNET tissues, and that these patterns may help guide clinical decision making.