bluuebunny/crossref_metadata_2025_split huggingface dataset:
Markers of blood-brain barrier disruption increase early and persistently in COVID-19 patients with neurological manifestations
Authors: Bonetto Valentina , Pasetto Laura , Lisi Ilaria , Carbonara Marco , Zangari Rosalia , Ferrari Erica , Punzi Veronica , Luotti Silvia , Bottino Nicola , Biagianti Bruno , Moglia Cristina , Fuda Giuseppe , Gualtierotti Roberta , Blasi Francesco , Canetta Ciro , Montano Nicola , Tettamanti Mauro , Camera Giorgia , Grimoldi Maria , Negro Giulia , Rifino Nicola , Calvo Andrea , Brambilla Paolo , Biroli Francesco , Bandera Alessandra , Nobili Alessandro , Stocchetti Nino , Sessa Maria , Zanier Elisa R. 
Published: December 2022

BackgroundCoronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is associated with disorders affecting the peripheral and the central nervous system. A high number of patients develop post-COVID-19 syndrome with the persistence of a large spectrum of symptoms, including neurological, beyond 4 weeks after infection. Several potential mechanisms in the acute phase have been hypothesized, including damage of the blood-brain-barrier (BBB). We tested weather markers of BBB damage in association with markers of brain injury and systemic inflammation may help in identifying a blood signature for disease severity and neurological complications.MethodsBlood biomarkers of BBB disruption (MMP-9, GFAP), neuronal damage (NFL) and systemic inflammation (PPIA, IL-10, TNFα) were measured in two COVID-19 patient cohorts with high disease severity (ICUCovid; n=79) and with neurological complications (NeuroCovid; n=78), and in two control groups free from COVID-19 history, healthy subjects (n=20) and patients with amyotrophic lateral sclerosis (ALS; n=51). Samples from COVID-19 patients were collected during the first and the second wave of COVID-19 pandemic in Lombardy, Italy. Evaluations were done at acute and chronic phases of the COVID-19 infection.ResultsBlood biomarkers of BBB disruption and neuronal damage are high in COVID-19 patients with levels similar to or higher than ALS. NeuroCovid patients display lower levels of the cytokine storm inducer PPIA but higher levels of MMP-9 than ICUCovid patients. There was evidence of different temporal dynamics in ICUCovid compared to NeuroCovid patients with PPIA and IL-10 showing the highest levels in ICUCovid patients at acute phase. On the contrary, MMP-9 was higher at acute phase in NeuroCovid patients, with a severity dependency in the long-term. We also found a clear severity dependency of NFL and GFAP levels, with deceased patients showing the highest levels.DiscussionThe overall picture points to an increased risk for neurological complications in association with high levels of biomarkers of BBB disruption. Our observations may provide hints for therapeutic approaches mitigating BBB disruption to reduce the neurological damage in the acute phase and potential dysfunction in the long-term.
Specificity of CD200/CD200R pathway in LPS-induced lung inflammation
Authors: Patoine Dany , Bouchard Karine , Lemay Anne-Marie , Bissonnette Elyse Y. , Lauzon-Joset Jean-Francois 
Published: December 2022

IntroductionAt lung mucosal surfaces, immune cells must initiate inflammatory response against pathogen without inducing tissue damage. Loss of this equilibrium can lead to acute respiratory distress syndrome (ARDS), a severe lung inflammatory disease characterized by excessive inflammation and dysregulation of anti-inflammatory pathways.MethodsTo investigate the role of anti-inflammatory pathway CD200/CD200R in lung inflammatory response, we administered LPS intratracheally in CD200 KO and wild type (WT) rats. Inflammation was evaluated using bronchoalveolar lavage (BAL) cellularity. Lung injury was measured by total protein level in BAL fluid, and levels of proinflammatory cytokines (TNF, IL-6) and chemokines (CXCL2, CCL2) were determined in BAL supernatants. In a second series of experiments, recombinant CD200Fc was administered to KO rats to restore the anti-inflammatory response.ResultsAt baseline, CD200 KO rats did not show sign of inflammation, however KO rats had lower number of alveolar macrophages. In addition, LPS administration induced greater pulmonary edema in CD200 KO rats. This was accompanied with a higher recruitment of neutrophils as well as levels of TNF, IL-6, CXCL2, and CCL2 in BAL compared to WT rats. CD200Fc administration in KO rats reduced neutrophil accumulation and TNF and CXCL2 levels in BAL. Interestingly, the increased inflammatory response of CD200 KO rats could be attributed to greater activation potential of alveolar macrophages with higher levels of ERK and P-ERK MAPK.ConclusionThis study shows that lung inflammatory response is exacerbated in absence of CD200 in an experimental model of ARDS in rats. In addition, CD200/CD200R pathway shows selective regulation of acute lung inflammation and cannot completely abrogate the complex LPS-induced inflammatory response. However, addition of CD200 agonist in a multi-target therapy strategy could have beneficial impacts.
Comparison of different gene addition strategies to modify placental derived-mesenchymal stromal cells to produce FVIII
Authors: Ramamurthy Ritu M. , Rodriguez Martin , Ainsworth Hannah C. , Shields Jordan , Meares Diane , Bishop Colin , Farland Andrew , Langefeld Carl D. , Atala Anthony , Doering Christopher B. , Spencer H. Trent , Porada Christopher D. , Almeida-Porada Graça 
Published: December 2022

IntroductionPlacenta-derived mesenchymal cells (PLCs) endogenously produce FVIII, which makes them ideally suited for cell-based fVIII gene delivery. We have previously reported that human PLCs can be efficiently modified with a lentiviral vector encoding a bioengineered, expression/secretion-optimized fVIII transgene (ET3) and durably produce clinically relevant levels of functionally active FVIII. The objective of the present study was to investigate whether CRISPR/Cas9 can be used to achieve location-specific insertion of a fVIII transgene into a genomic safe harbor, thereby eliminating the potential risks arising from the semi-random genomic integration inherent to lentiviral vectors. We hypothesized this approach would improve the safety of the PLC-based gene delivery platform and might also enhance the therapeutic effect by eliminating chromatin-related transgene silencing.MethodsWe used CRISPR/Cas9 to attempt to insert the bioengineered fVIII transgene “lcoET3” into the AAVS1 site of PLCs (CRISPR-lcoET3) and determined their subsequent levels of FVIII production, comparing results with this approach to those achieved using lentivector transduction (LV-lcoET3) and plasmid transfection (Plasmid-lcoET3). In addition, since liver-derived sinusoidal endothelial cells (LSECs) are the native site of FVIII production in the body, we also performed parallel studies in human (h)LSECs).ResultsPLCs and hLSECs can both be transduced (LV-lcoET3) with very high efficiency and produce high levels of biologically active FVIII. Surprisingly, both cell types were largely refractory to CRISPR/Cas9-mediated knockin of the lcoET3 fVIII transgene in the AAVS1 genome locus. However, successful insertion of an RFP reporter into this locus using an identical procedure suggests the failure to achieve knockin of the lcoET3 expression cassette at this site is likely a function of its large size. Importantly, using plasmids, alone or to introduce the CRISPR/Cas9 “machinery”, resulted in dramatic upregulation of TLR 3, TLR 7, and BiP in PLCs, compromising their unique immune-inertness.DiscussionAlthough we did not achieve our primary objective, our results validate the utility of both PLCs and hLSECs as cell-based delivery vehicles for a fVIII transgene, and they highlight the hurdles that remain to be overcome before primary human cells can be gene-edited with sufficient efficiency for use in cell-based gene therapy to treat HA.
Transcriptome profiling of osteoclast subsets associated with arthritis: A pathogenic role of CCR2hi osteoclast progenitors
Authors: Filipović Maša , Flegar Darja , Aničić Sara , Šisl Dino , Kelava Tomislav , Kovačić Nataša , Šućur Alan , Grčević Danka 
Published: December 2022

IntroductionThe existence of different osteoclast progenitor (OCP) subsets has been confirmed by numerous studies. However, pathological inflammation-induced osteoclastogenesis remains incompletely understood. Detailed characterization of OCP subsets may elucidate the pathophysiology of increased osteoclast activity causing periarticular and systemic bone resorption in arthritis. In our study, we rely on previously defined OCP subsets categorized by the level of CCR2 expression as circulatory-like committed CCR2hi OCPs, which are substantially expanded in arthritis, and marrow-resident CCR2lo OCPs of immature phenotype and behavior.MethodsIn order to perform transcriptome characterization of those subsets in the context of collagen-induced arthritis (CIA), we sorted CCR2hi and CCR2lo periarticular bone marrow OCPs of control and arthritic mice, and performed next-generation RNA sequencing (n=4 for each group) to evaluate the differential gene expression profile using gene set enrichment analysis with further validation.ResultsA disparity between CCR2hi and CCR2lo subset transcriptomes (863 genes) was detected, with the enrichment of pathways for osteoclast differentiation, chemokine and NOD-like receptor signaling in the CCR2hi OCP subset, and ribosome biogenesis in eukaryotes and ribosome pathways in the CCR2lo OCP subset. The effect of intervention (CIA) within each subset was greater in CCR2hi (92 genes) than in CCR2lo (43 genes) OCPs. Genes associated with the osteoclastogenic pathway (Fcgr1, Socs3), and several genes involved in cell adhesion and migration (F11r, Cd38, Lrg1) identified the CCR2hi subset and distinguish CIA from control group, as validated by qPCR (n=6 for control mice, n=9 for CIA mice). The latter gene set showed a significant positive correlation with arthritis clinical score and frequency of CCR2hi OCPs. Protein-level validation by flow cytometry showed increased proportion of OCPs expressing F11r/CD321, CD38 and Lrg1 in CIA, indicating that they could be used as disease markers. Moreover, osteoclast pathway-identifying genes remained similarly expressed (Fcgr1) or even induced by several fold (Socs3) in preosteoclasts differentiated in vitro from CIA mice compared to pre-cultured levels, suggesting their importance for enhanced osteoclastogenesis of the CCR2hi OCPs in arthritis.ConclusionOur approach detected differentially expressed genes that could identify distinct subset of OCPs associated with arthritis as well as indicate possible therapeutic targets aimed to modulate osteoclast activity.
Preoperative anxiety during COVID-19 pandemic: A single-center observational study and comparison with a historical cohort
Authors: Buonanno Pasquale , Marra Annachiara , Iacovazzo Carmine , Vargas Maria , Nappi Serena , de Siena Andrea Uriel , Servillo Giuseppe 
Published: December 2022

BackgroundPreoperative anxiety is a common sensation experienced by patients undergoing surgical interventions. It can influence intraoperative and postoperative management through the activation of the neuroendocrine system, leading to tachycardia, hypertension, pulmonary complications, higher consumption of anesthetic drugs, and increased postoperative pain. Our aim was to investigate the level of preoperative anxiety during the COVID-19 pandemic; we also compared it to the preoperative anxiety of a historical cohort before the outbreak.MethodsThis is a single-center observational study. We enrolled 314 patients during the pandemic from May 2021 to November 2021, and our historical cohort consisted of 122 patients enrolled from July 2015 to May 2016 in the university hospital “Federico II” of Naples. The Amsterdam Preoperative Anxiety and Information Scale (APAIS) and the State-Trait Anxiety Inventory (STAI) were used to evaluate preoperative anxiety. In particular, APAIS measures preoperative anxiety and the need for information, and STAI assesses state and trait anxiety through STAI-Y1 and STAI-Y2, respectively. We analyzed APAIS and STAI scores in our population stratified on the basis of age, gender, marital status, previous surgical experiences, and type of surgery, and we compared them to our historical cohort. Statistical analysis was performed through a t-test and ANOVA for parametric data, and the Mann–Whitney and Kruskal–Wallis tests for non-parametric data. Linear regression was used to investigate the correlation between demographic data and the scores of STAI and APAIS in both groups.ResultsOur results showed that state and preoperative anxiety remained stable, whereas trait anxiety increased in all the subgroups analyzed.DiscussionEven if state anxiety is considered a variable characteristic of the emotional sphere and trait anxiety a stable element, our findings suggested that COVID-19 deeply influenced trait anxiety, thus altering the patients’ psychological foundations.
A novel dual-task paradigm with story recall shows significant differences in the gait kinematics in older adults with cognitive impairment: A cross-sectional study
Authors: Ali Nawab , Liu Jin , Tian Huifang , Pan Wei , Tang Yao , Zhong Qian , Gao Yaxin , Xiao Ming , Wu Han , Sun Cuiyun , Wu Ting , Yang Xi , Wang Tong , Zhu Yi 
Published: December 2022

ObjectiveCognitive and motor dysfunctions in older people become more evident while dual-tasking. Several dual-task paradigms have been used to identify older individuals at the risk of developing Alzheimer’s disease and dementia. This study evaluated gait kinematic parameters for dual-task (DT) conditions in older adults with mild cognitive impairment (MCI), subjective cognitive decline (SCD), and normal cognition (NC).MethodThis is a cross-sectional, clinical-based study carried out at the Zhongshan Rehabilitation Branch of First Affiliated Hospital of Nanjing Medical University, China.ParticipantsWe recruited 83 community-dwelling participants and sorted them into MCI (n = 24), SCD (n = 33), and NC (n = 26) groups based on neuropsychological tests. Their mean age was 72.0 (5.55) years, and male–female ratio was 42/41 (p = 0.112). Each participant performed one single-task walk and four DT walks: DT calculation with subtracting serial sevens; DT naming animals; DT story recall; and DT words recall.Outcome and measuresKinematic gait parameters of speed, knee peak extension angle, and dual-task cost (DTC) were obtained using the Vicon Nexus motion capture system and calculated by Visual 3D software. A mixed-effect linear regression model was used to analyze the data.ResultsThe difference in gait speed under DT story recall and DT calculation was −0.099 m/s and − 0.119 m/s (p = 0.04, p = 0.013) between MCI and SCD, respectively. Knee peak extension angle under DT story recall, words recall, and single task was bigger in the MCI group compared to the NC group, respectively (p = 0.001, p = 0.001, p = 0.004). DTC was higher in the DT story recall test than all other DT conditions (p &lt; 0.001).ConclusionKinematic gait parameters of knee peak extension angle for the DT story recall were found to be sensitive enough to discriminate MCI individuals from NC group. DTC under DT story recall was higher than the other DT conditions.
Automated quantification of atrophy and acute ischemic volume for outcome prediction in endovascular thrombectomy
Authors: Kis Balázs , Neuhaus Ain A. , Harston George , Joly Olivier , Carone Davide , Gerry Stephen , Chadaide Zoltán , Pánczél András , Czifrus Eszter , Csike Viktória , Surányi Ágnes , Szikora István , Erőss Loránd 
Published: December 2022

BackgroundShort- and long-term outcomes from endovascular thrombectomy (EVT) for large vessel occlusion stroke remain variable. Numerous relevant predictors have been identified, including severity of neurological deficits, age, and imaging features. The latter is typically defined as acute changes (most commonly Alberta Stroke Programme Early CT Score, ASPECTS, at presentation), but there is little information on the impact of imaging assessment of premorbid brain health as a determinant of outcome.AimsTo examine the impact of automated measures of stroke severity and underlying brain frailty on short- and long-term outcomes in acute stroke treated with EVT.MethodsIn 215 patients with anterior circulation stroke, who subsequently underwent EVT, automated analysis of presenting non-contrast CT scans was used to determine acute ischemic volume (AIV) and e-ASPECTS as markers of stroke severity, and cerebral atrophy as a marker of brain frailty. Univariate and multivariate logistic regression were used to identify significant predictors of NIHSS improvement, modified Rankin scale (mRS) at 90 and 30 days, mortality at 90 days and symptomatic intracranial hemorrhage (sICH) following successful EVT.ResultsFor long-term outcome, atrophy and presenting NIHSS were significant predictors of mRS 0–2 and death at 90 days, whereas age did not reach significance in multivariate analysis. Conversely, for short-term NIHSS improvement, AIV and age were significant predictors, unlike presenting NIHSS. The interaction between age and NIHSS was similar to the interaction of AIV and atrophy for mRS 0–2 at 90 days.ConclusionCombinations of automated software-based imaging analysis and clinical data can be useful for predicting short-term neurological outcome and may improve long-term prognostication in EVT. These results provide a basis for future development of predictive tools built into decision-aiding software in stroke.
The clinical efficacy and safety of acupuncture intervention on cancer-related insomnia: A systematic review and meta-analysis
Authors: Yu HaiXin , Liu CaiYun , Chen Bo , Zhai JingBo , Ba DongSheng , Zhu Zheng , Li NingCen , Loh PeiYong , Chen AoXiang , Wang Bin , Guo Yi , Liu YangYang , Chen ZeLin 
Published: December 2022

ObjectiveTo evaluate the efficacy and safety of acupuncture in treating symptoms for Cancer-related Insomnia(CRI) patients.MethodsSeven databases were searched from the time of database establishment to 31 March 2022. Randomized Controlled Trials (RCTs) on acupuncture intervention for CRI were collected. Literature screening and data extraction were performed independently by two researchers. Meta-analysis was performed using RevMan 5.4 software.ResultsA total of 13 articles with 1,109 participants were included. Five hundred and seventeen in the treatment group and 592 in the control group. Ten of the RCTs used the PSQI rating scale and four randomized controlled trials used the ISI rating scale, and the PSQI and ISI were analyzed together as continuous data. The results of the meta-analysis were: MD = −1.83, 95%CI = [−2.71, −0.94], P &lt; 0.0001, indicating a significant improvement in PSQI scores in patients with CRI by acupuncture intervention; MD = 0.79, 95%CI = [−0.46, 2.03], P = 0.22. Acupuncture was not statistically significant on ISI scores for patients with CRI compared to controls, which does not yet indicate that acupuncture is effective for symptoms in patients with CRI. The results of the meta-analysis of the other 4 items using sleep disorder logs as efficacy analysis data were as follow, relative risk RR = 0.47, 95%CI = [0.33, 0.66], P &lt; 0.0001. The difference was statistically significant, indicating that acupuncture can improve the symptoms of CRI patients compared to control group.ConclusionAcupuncture can improve the symptoms of patients with CRI to some extent, but due to the relatively small number and low quality of the included literature in this study, more high-quality clinical trials are needed as supplement the evidences in future.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/.
Cellulose degradation products and high ionic strength enhance the retardation of strontium in hydrated cement paste
Authors: Hinchliff J. , Felipe-Sotelo M. , Drury D. , Evans N.D.M. , Read D. 
Published: December 2022

The present concept for the disposal of some low- and all intermediate-level radioactive waste in the United Kingdom involves grouting with cement in steel drums and placement in a geological facility. The vaults would then be backfilled with low strength, high porosity cement-based materials designed to promote a pervasive, alkaline environment in which many of the radioactive species present are sparingly soluble. This work investigates the interaction of strontium with such a backfill under both diffusive and advective conditions given the potential significance of the fission product 90Sr. An important characteristic of the United Kingdom waste inventory is the abundance of organic compounds, including cellulosic materials; consequently, the experiments were repeated with products of alkaline cellulose degradation. Additional experiments were performed at high ionic strength simulating anticipated changes in the salinity of the groundwater. The effective diffusivity (De) of strontium in the absence of the organic compounds ranged between 5.5 × 10−11 and 8.5 × 10−11 m2 s−1, with a distribution coefficient (Rd) of between 2.8 × 10−3 and 3.1 × 10−3 m3 kg−1. The presence of organic compounds and/or an increase of ionic strength enhanced the retardation of strontium. The results indicate that the retention of strontium by hydrated cement paste occurs via a reversible ion exchange mechanism rather than mineralisation and is promoted by decalcification of the calcium silicate hydrate phases.
Non-classical phenotypes of mismatch repair deficiency and microsatellite instability in primary and metastatic tumors at different sites in Lynch syndrome
Authors: Li Zhiyu , Cheng Bo , Liu Shan , Ding Shanshan , Liu Jinhong , Quan Lanju , Hao Yanjiao , Xu Lin , Zhao Huan , Guo Jing , Sun Suozhu 
Published: December 2022

BackgroundLynch syndrome is a genetic disease characterized by abnormal DNA replication caused by germline variation in the mismatch repair (MMR) gene. There are rare non-classical phenotypes with loss of MMR protein expression and inconsistent microsatellite stability (MSS) in Lynch syndrome-related colorectal cancers. However, the difference between microsatellite instability (MSI) of extraintestinal tumors in a patient with Lynch syndrome has been closely studied. Herein, we reported the non-classical phenotypes of mismatch repair deficiency (dMMR) and MSI in four cases of Lynch syndrome in patients with colorectal cancer and other primary and metastatic tumors.MethodsA retrospective analysis was conducted on four patients diagnosed with Lynch syndrome between 2018 and 2022 in the Department of Pathology of the Rocket Forces Specialized Medical Center. A one-step immunohistochemical (IHC) assay was employed to detect loss in the expression of Lynch syndrome-associated MMR proteins (MLH1, PMS2, MSH2, and MSH6). MSI detection was performed in both primary and metastatic tumors at different sites in the four patients using NCI 2B3D (BAT25, BAT26, D2S123, D17S250, and D5S346) and single nucleotide site (BAT25, BAT26, NR21, NR24, NR27, and MONO27) methods. In addition, related MMR gene germline variation, somatic mutations, and MLH1 gene promoter methylation were analyzed using next-generation sequencing and TaqMan probe-based methylation-specific polymerase chain reaction (MethyLight).ResultsTwo of the four patients were heterozygous for MSH6 germline pathogenic variation, and the other two were heterozygous for MSH2 germline pathogenic variation. In all cases, IHC detection of protein expression of the MMR gene with germline variation was negative in all primary and metastatic tumors; non-classical phenotypes of dMMR and MSI were present between primary and metastatic tumors at different sites. dMMR in Lynch colorectal cancer demonstrated high MSI, whereas MSI in primary and metastatic tumors outside the intestine mostly exhibited MSS or low MSI.ConclusionsThe non-classical dMMR and MSI phenotype are mostly observed in Lynch syndrome, even in the context of MMR protein expression loss. Extraintestinal tumors infrequently present with a high degree of MSI and often exhibit a stable or low degree of MSI.