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Jia-Meng Shao,&ast; Bing Shen,&ast; Zhi-Xiang Zhou, Lucia D’Angelo, Shea Michaela James, Jia-Feng Lin, Cheng Zheng Department of Cardiology, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Cheng Zheng; Jia-Feng Lin, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, East Section of Wenzhou Avenue, No. 1111, Wenzhou, Zhejiang Province, 325000, People’s Republic of China, Tel +86-13587688177 ; +86-13806685498, Email zhengcheng_wzmufey@163.com; linjiafeng_wzmcfey@163.comBackground: The role of total bilirubin (TBIL) in cardiovascular disease has been increasingly recognized in recent decades. Studies have shown a correlation between total bilirubin levels and the prognosis of patients after heart surgery. This study aimed to investigate the clinical significance of bilirubin elevation in persistent atrial fibrillation (PAF) patients who received radiofrequency catheter ablation (RFCA).Methods and Results: A total of 184 patients with PAF who received RFCA were retrospectively studied. Laboratory examinations and demographic data were analyzed to identify independent predictors of TBIL elevation. The relationship between TBIL and prognosis was further investigated. Our results indicated that TBIL increased significantly after RFCA. Multiple linear regression analysis showed that TBIL elevation owned a negative correlation with the percentile of low voltage areas (LVAs) in left atria (β=− 0.490, P< 0.001). In contrast, a positive correlation was observed with the white blood cell (WBC) ratio (β=0.153, P=0.042) and left atrial diameter (LAD) (β=0.232, P=0.025). It was found that postoperative TBIL levels increased and then gradually decreased to baseline within 5 days without intervention. The bilirubin ratio < 1.211 indicated the possibility of 1-year AF recurrence after ablation with a predictive value of 0.743 (specificity = 75.00%, sensitivity = 66.67%).Conclusion: Bilirubin elevation post PAF RFCA was a common phenomenon and was associated with 1-year recurrence of AF in PAF patients after RFCA.Keywords: bilirubin, atrial fibrillation, radiofrequency catheter ablation, oxidative stress, prognosis

Some proteins perform their biological functions by changing their material states through liquid-liquid phase separation. Upon phase separation, the protein condenses into a concentrated liquid phase and sometimes into a gel phase, changing its dynamic properties and intermolecular interactions, thereby regulating cellular functions. Although the biological significance of this phenomenon has been widely recognized by researchers, there is still a lack of a comprehensive understanding of the structural and dynamic properties of the protein in the condensed phase. In this phase, molecules usually contain domains with varied dynamic properties and undergo intermediate exchanges. Magic angle spinning (MAS) solid-state NMR (SSNMR) experiments are very powerful in studying rigid protein polymers such as amyloid. The incorporation of solution-like experiments into SSNMR and the development of J-coupling based MAS SSNMR techniques extend its ability to study partially mobile segments of proteins in a condensed liquid or gel phase which are not visible by solution NMR or dipolar-coupling based SSNMR. Therefore, it has been applied in studying protein condensation and has provided very important information that is hard to obtain by other techniques.

ObjectiveTo determine if methotrexate or folic acid prescription was associated with differential risk for COVID-19 diagnosis or mortality.DesignCase-control analysis.SettingThe population-based UK Biobank (UKBB) cohort.ParticipantsData from 380 380 UKBB participants with general practice prescription data for 2019-2021. Updated medical information was retrieved on 13 December 2021.Primary and secondary outcome measuresThe outcomes of COVID-19 diagnosis and COVID-19-related mortality were analysed by multivariable logistic regression. Exposures evaluated were prescription of folic acid and/or methotrexate. Criteria for COVID-19 diagnosis were (1) a positive SARS-CoV-2 test or (2) ICD-10 code for confirmed COVID-19 (U07.1) or probable COVID-19 (U07.2) in hospital records, or death records. By these criteria, 26 003 individuals were identified with COVID-19 of whom 820 were known to have died from COVID-19. Logistic regression statistical models were adjusted for age sex, ethnicity, Townsend deprivation index, body mass index, smoking status, presence of rheumatoid arthritis, sickle cell disease, use of anticonvulsants, statins and iron supplements.ResultsCompared with people prescribed neither folic acid nor methotrexate, people prescribed folic acid supplementation had increased risk of diagnosis of COVID-19 (OR 1.51 (1.42-1.61)). The prescription of methotrexate with or without folic acid was not associated with COVID-19 diagnosis (p≥0.18). People prescribed folic acid supplementation had positive association with death after a diagnosis of COVID-19 (OR 2.64 (2.15-3.24)) in a fully adjusted model. The prescription of methotrexate in combination with folic acid was not associated with an increased risk for COVID-19-related death (1.07 (0.57-1.98)).ConclusionsWe report an association of increased risk for COVID-19 diagnosis and COVID-19-related death in people prescribed folic acid supplementation. Our results also suggest that methotrexate might attenuate these associations.

Abstract Background Glioblastoma (GBM) is the most malignant among gliomas with an inevitable lethal outcome. The elucidation of the physiology and regulation of this tumor is mandatory to unravel novel target and effective therapeutics. Emerging concepts show that the minor subset of glioblastoma stem cells (GSCs) accounts for tumorigenicity, representing the true target for innovative therapies in GBM. Methods Here, we isolated and established functionally stable and steadily expanding GSCs lines from a large cohort of GBM patients. The molecular, functional and antigenic landscape of GBM tissues and their derivative GSCs was highlited in a side-by-side comprehensive genomic and transcriptomic characterization by ANOVA and Fisher’s exact tests. GSCs’ physio-pathological hallmarks were delineated by comparing over time in vitro and in vivo their expansion, self-renewal and tumorigenic ability with hierarchical linear models for repeated measurements and Kaplan–Meier method. Candidate biomarkers performance in discriminating GBM patients’ classification emerged by classification tree and patients’ survival analysis. Results Here, distinct biomarker signatures together with aberrant functional programs were shown to stratify GBM patients as well as their sibling GSCs population into TCGA clusters. Of importance, GSCs cells were demonstrated to fully resemble over time the molecular features of their patient of origin. Furthermore, we pointed out the existence of distinct GSCs subsets within GBM classification, inherently endowed with different self-renewal and tumorigenic potential. Particularly, classical GSCs were identified by more undifferentiated biological hallmarks, enhanced expansion and clonal capacity as compared to the more mature, relatively slow-propagating mesenchymal and proneural cells, likely endowed with a higher potential for infiltration either ex vivo or in vivo. Importantly, the combination of DCX and EGFR markers, selectively enriched among GSCs pools, almost exactly predicted GBM patients’ clusters together with their survival and drug response. Conclusions In this study we report that an inherent enrichment of distinct GSCs pools underpin the functional inter-cluster variances displayed by GBM patients. We uncover two selectively represented novel functional biomarkers capable of discriminating GBM patients’ stratification, survival and drug response, setting the stage for the determination of patient-tailored diagnostic and prognostic strategies and, mostly, for the design of appropriate, patient-selective treatment protocols.

Abstract Background Extracellular vesicles (EVs) are membrane-enclosed particles released systemically by all cells, including tumours. Tumour EVs have been shown to manipulate their local environments as well as distal targets to sustain the tumour in a variety of tumours, including glioblastoma (GBM). We have previously demonstrated the dual role of the glial water channel aquaporin-4 (AQP4) protein in glioma progression or suppression depending on its aggregation state. However, its possible role in communication mechanisms in the microenvironment of malignant gliomas remains to be unveiled. Results Here we show that in GBM cells AQP4 is released via EVs that are able to affect the GBM microenvironment. To explore this role, EVs derived from invasive GBM cells expressing AQP4-tetramers or apoptotic GBM cells expressing orthogonal arrays of particles (AQP4-OAPs) were isolated, using a differential ultracentrifugation method, and were added to pre-seeded GBM cells. Confocal microscopy analysis was used to visualize the interaction and uptake of AQP4-containing EVs by recipient cells. Chemoinvasion and Caspase3/7 activation assay, performed on recipient cells after EVs uptake, revealed that EVs produced by AQP4-tetramers expressing cells were able to drive surrounding tumour cells toward the migratory phenotype, whereas EVs produced by AQP4-OAPs expressing cells drive them toward the apoptosis pathway. Conclusion This study demonstrates that the different GBM cell phenotypes can be transferred by AQP4-containing EVs able to influence tumour cell fate toward invasiveness or apoptosis. This study opens a new perspective on the role of AQP4 in the brain tumour microenvironment associated with the EV-dependent communication mechanism. Graphical Abstract

Background: Neurological manifestations associated with COVID-19 remain partially described, mainly in low- and middle-income countries where diagnostic tools are limited. To address this, we assembled medical centers in Brazil with the goal of describing neurological syndromes associated with COVID-19 during the first wave of the pandemic. Methods: From June 1st, 2020 to June 1st, 2021, non-consecutive adult patients with new onset of six neurological syndromes up to 60 days after confirmed COVID-19 were included. Data were compiled from four tertiary centers and compared with general local COVID-19 data, as well as with a previous cohort focused on vascular syndrome. Results: 197 patients were included, presenting with vascular syndromes (81), encephalopathy (68), encephalitis (19), Guillain-Barré syndrome (13), other neuropathies (12), and myelitis (4). The incidence curve of neurocovid mirrored that of COVID-19. Neurological syndromes were present regardless of COVID-19 severity. The median time from COVID-19 to onset of neurological symptoms was 14 days, suggesting a post-infectious immune-mediated mechanism. Patients were 10 times more likely to die (χ2 (1) = 356.55, p < 0.01, OR = 10.89) and 38 times more likely to be hospitalized than other COVID-19 patients (χ2 (1) = 1167.9, p < 0.01, OR = 38.22). Those developing vascular syndromes patients were 3 times more likely to require ICU (χ2 (1) = 37.12, p < 0.01, OR = 3.78) and 4 times more likely to die (χ2 (1) = 58.808, p < 0.01, OR = 4.73) than patients with vascular syndromes due to different etiologies. Conclusions: Our study corroborates the association of neurological syndromes with COVID-19. The incidence correlated with local waves of COVID-19, and patients with neurocovid exhibited a higher susceptibility to adverse outcomes compared to other COVID-19 patients. Among all neurological syndromes, vascular syndromes were the most common, and their severity surpassed that of vascular syndromes not attributed to COVID-19. [ABSTRACT FROM AUTHOR]

Construction is known as one of the most dangerous industries in terms of worker safety. Collisions due the excessive proximity of workers to moving construction vehicles are one of the leading causes of fatal and non-fatal accidents on construction sites internationally. Proximity warning systems (PWS) have been proposed in the literature as a solution to detect the risk for collision and to alert workers and equipment operators in time to prevent collisions. Although the role of sensing technologies for situational awareness has been recognised in previous studies, several factors still need to be considered. This paper describes the design of a prototype sensor-based PWS, aimed mainly at small and medium-sized construction companies, to collect real-time data directly from construction sites and to warn workers of a potential risk of collision accidents. It considers, in an integrated manner, factors such as cost of deployment, the actual nature of a construction site as an operating environment and data protection. A low-cost, ultra-wideband (UWB)-based proximity detection system has been developed that can operate with or without fixed anchors. In addition, the PWS is compliant with the General Data Protection Regulation (GDPR) of the European Union. A privacy-by-design approach has been adopted and privacy mechanisms have been used for data protection. Future work could evaluate the PWS in real operational conditions and incorporate additional factors for its further development, such as studies on the timely interpretation of data.

Abstract Background Glioblastoma multiforme (GBM) is an incurable tumor, with a median survival rate of only 14–15 months. Along with heterogeneity and unregulated growth, a central matter in dealing with GBMs is cell invasiveness. Thus, improving prognosis requires finding new agents to inhibit key multiple pathways, even simultaneously. A subset of GBM stem-like cells (GSCs) may account for tumorigenicity, representing, through their pathways, the proper cellular target in the therapeutics of glioblastomas. GSCs cells are routinely enriched and expanded due to continuous exposure to specific growth factors, which might alter some of their intrinsic characteristic and hide therapeutically relevant traits. Methods By removing exogenous growth factors stimulation, here we isolated and characterized a subset of GSCs with a “mitogen-independent” phenotype (I-GSCs) from patient’s tumor specimens. Differential side-by-side comparative functional and molecular analyses were performed either in vitro or in vivo on these cells versus their classical growth factor (GF)-dependent counterpart (D-GSCs) as well as their tissue of origin. This was performed to pinpoint the inherent GSCs’ critical regulators, with particular emphasis on those involved in spreading and tumorigenic potential. Transcriptomic fingerprints were pointed out by ANOVA with Benjamini-Hochberg False Discovery Rate (FDR) and association of copy number alterations or somatic mutations was determined by comparing each subgroup with a two-tailed Fisher’s exact test. The combined effects of interacting in vitro and in vivo with two emerging GSCs’ key regulators, such as Wnt5a and EphA2, were then predicted under in vivo experimental settings that are conducive to clinical applications. In vivo comparisons were carried out in mouse-human xenografts GBM model by a hierarchical linear model for repeated measurements and Dunnett’s multiple comparison test with the distribution of survival compared by Kaplan–Meier method. Results Here, we assessed that a subset of GSCs from high-grade gliomas is self-sufficient in the activation of regulatory growth signaling. Furthermore, while constitutively present within the same GBM tissue, these GF-independent GSCs cells were endowed with a distinctive functional and molecular repertoire, defined by highly aggressive Wnt5aHigh/EphA2Low profile, as opposed to Wnt5aLow/EphA2High expression in sibling D-GSCs. Regardless of their GBM subtype of origin, I-GSCs, are endowed with a raised in vivo tumorigenic potential than matched D-GSCs, which were fast-growing ex-vivo but less lethal and invasive in vivo. Also, the malignant I-GSCs’ transcriptomic fingerprint faithfully mirrored the original tumor, bringing into evidence key regulators of invasiveness, angiogenesis and immuno-modulators, which became candidates for glioma diagnostic/prognostic markers and therapeutic targets. Particularly, simultaneously counteracting the activity of the tissue invasive mediator Wnt5a and EphA2 tyrosine kinase receptor addictively hindered GSCs’ tumorigenic and invasive ability, thus increasing survival. Conclusion We show how the preservation of a mitogen-independent phenotype in GSCs plays a central role in determining the exacerbated tumorigenic and high mobility features distinctive of GBM. The exploitation of the I-GSCs' peculiar features shown here offers new ways to identify novel, GSCs-specific effectors, whose modulation can be used in order to identify novel, potential molecular therapeutic targets. Furthermore, we show how the combined use of PepA, the anti-Wnt5a drug, and of ephrinA1-Fc to can hinder GSCs’ lethality in a clinically relevant xenogeneic in vivo model thus being conducive to perspective, novel combinatorial clinical application.

Abstract Shedding synchrotron light on microfluidic systems, exploring several contrasts in situ/operando at the nanoscale, like X-ray fluorescence, diffraction, luminescence, and absorption, has the potential to reveal new properties and functionalities of materials across diverse areas, such as green energy, photonics, and nanomedicine. In this work, we present the micro-fabrication and characterization of a multifunctional polyester/glass sealed microfluidic device well-suited to combine with analytical X-ray techniques. The device consists of smooth microchannels patterned on glass, where three gold electrodes are deposited into the channels to serve in situ electrochemistry analysis or standard electrical measurements. It has been efficiently sealed through an ultraviolet-sensitive sticker-like layer based on a polyester film, and The burst pressure determined by pumping water through the microchannel(up to 0.22 MPa). Overall, the device has demonstrated exquisite chemical resistance to organic solvents, and its efficiency in the presence of biological samples (proteins) is remarkable. The device potentialities, and its high transparency to X-rays, have been demonstrated by taking advantage of the X-ray nanoprobe Carnaúba/Sirius/LNLS, by obtaining 2D X-ray nanofluorescence maps on the microchannel filled with water and after an electrochemical nucleation reaction. To wrap up, the microfluidic device characterized here has the potential to be employed in standard laboratory experiments as well as in in situ and in vivo analytical experiments using a wide electromagnetic window, from infrared to X-rays, which could serve experiments in many branches of science.

In the architecture, engineering and construction industry, site management during construction is a key phase. Scheduling activities and monitoring their progress allow any deviations from the schedule to be identified so that timely action can be taken. Until now, the monitoring phase has mainly been characterised by inspections in which the construction site manager manually collects data and produces a summary report. This proves to be a time-consuming process and is prone to errors. The authors propose an innovative construction progress monitoring method that combines BIM-based construction scheduling (4D BIM) with periodic geometric surveying using an indoor mobile mapping system (iMMS). Ten surveys were carried out on a real case study, producing point clouds to be compared with the 4D BIM, thereby comparing the as-built with the as-planned. The comparison was carried out using Sitemotion exploiting a custom class, the work breakdown structure (WBS), added to the BIM to associate each element with its scheduled construction date. The results show how the proposed method can effectively support the evaluation of construction progress, allowing the monitoring to be performed digitally and linked to the BIM. The paper details the proposed methodology, highlighting the problems encountered and suggesting adjustments for future implementation.

Abstract Gout flare prophylaxis and therapy use in people with underlying chronic kidney disease (CKD) is challenging, given limited treatment options and risk of worsening renal function with inappropriate treatment dosing. This literature review aimed to describe the current literature on the efficacy and safety of gout flare prophylaxis and therapy use in people with CKD stages 3–5. A literature search via PubMed, the Cochrane Library, and EMBASE was performed from 1 January 1959 to 31 January 2018. Inclusion criteria were studies with people with gout and renal impairment (i.e. estimated glomerular filtration rate (eGFR) or creatinine clearance (CrCl)

Objective To determine if methotrexate or folic acid prescription was associated with differential risk for COVID-19 diagnosis or mortality.Design Case–control analysis.Setting The population-based UK Biobank (UKBB) cohort.Participants Data from 380 380 UKBB participants with general practice prescription data for 2019–2021. Updated medical information was retrieved on 13 December 2021.Primary and secondary outcome measures The outcomes of COVID-19 diagnosis and COVID-19-related mortality were analysed by multivariable logistic regression. Exposures evaluated were prescription of folic acid and/or methotrexate. Criteria for COVID-19 diagnosis were (1) a positive SARS-CoV-2 test or (2) ICD-10 code for confirmed COVID-19 (U07.1) or probable COVID-19 (U07.2) in hospital records, or death records. By these criteria, 26 003 individuals were identified with COVID-19 of whom 820 were known to have died from COVID-19. Logistic regression statistical models were adjusted for age sex, ethnicity, Townsend deprivation index, body mass index, smoking status, presence of rheumatoid arthritis, sickle cell disease, use of anticonvulsants, statins and iron supplements.Results Compared with people prescribed neither folic acid nor methotrexate, people prescribed folic acid supplementation had increased risk of diagnosis of COVID-19 (OR 1.51 (1.42–1.61)). The prescription of methotrexate with or without folic acid was not associated with COVID-19 diagnosis (p≥0.18). People prescribed folic acid supplementation had positive association with death after a diagnosis of COVID-19 (OR 2.64 (2.15–3.24)) in a fully adjusted model. The prescription of methotrexate in combination with folic acid was not associated with an increased risk for COVID-19-related death (1.07 (0.57–1.98)).Conclusions We report an association of increased risk for COVID-19 diagnosis and COVID-19-related death in people prescribed folic acid supplementation. Our results also suggest that methotrexate might attenuate these associations.