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This paper focuses on the use of web-based discourse by three Spanish undergraduate students in Computer Engineering. Key lexico-grammatical features in Computer English have been analysed by means of corpus linguistics techniques, for which word statistics and collocation functions in the WordSmith concordancer have been highly useful. The information was then used to compare the students' results. The students' reading skills have been evaluated in the documentation process of the three final projects, required prior to their graduation as engineers. Overall observations point to code-switching, re-wording, and key vocabulary identification as strategies that the students demonstrate to be able to operate with significantly after on-line reading. The students also rely more on Internet discourse as a main source of feedback for their projects and useful tool for work. Two of the projects have dealt with the design and use of interactive platforms for language learning (via two different approaches), while the third project has focused on the management of e-learning with the use of Squeak, a special language for programming. The assessment of the three students' reading / interpretation skills has taken place by means of written tasks and personal interviews.

Estimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Gaucher disease (GD) is a rare autosomal recessive disorder arising from bi-allelic variants in the GBA1 gene, encoding glucocerebrosidase. Deficiency of this enzyme leads to progressive accumulation of the sphingolipid glucosylsphingosine (lyso-Gb1). The international, multicenter, observational "Lyso-Gb1 as a Long-term Prognostic Biomarker in Gaucher Disease"-LYSO-PROOF study succeeded in enrolling a cohort of 160 treatment-naïve GD patients from diverse geographic regions and evaluated the potential of lyso-Gb1 as a specific biomarker for GD. Using genotypes based on established classifications for clinical presentation, patients were stratified into type 1 GD ( n = 114) and further subdivided into mild ( n = 66) and severe type 1 GD ( n = 48). Due to having previously unreported genotypes, 46 patients could not be classified. Though lyso-Gb1 values at enrollment were widely distributed, they displayed a moderate and statistically highly significant correlation with disease severity measured by the GD-DS3 scoring system in all GD patients (r = 0.602, p < 0.0001). These findings support the utility of lyso-Gb1 as a sensitive biomarker for GD and indicate that it could help to predict the clinical course of patients with undescribed genotypes to improve personalized care in the future.

Introduction: Active surveillance (AS) is considered a suitable management practice for those patients with low-risk prostate cancer (PCa). At present, however, the role of multiparametric magnetic resonance imaging (mpMRI) in AS protocols has not yet been clearly established., Outcomes: To determine the role of mpMRI and its ability to detect significant prostate cancer (SigPCa) in PCa patients enrolled in AS protocols., Materials and Methods: There were 229 patients enrolled in an AS protocol between 2011 and 2020 at Reina Sofía University Hospital. MRI interpretation was based on PIRADS v.1 or v.2/2.1 classification. Demographics, clinical, and analytical data were collected and analyzed. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for mpMRI in different scenarios. We defined SigPCa and reclassification/progression as a Gleason score (GS) ≥ 3 + 4, a clinical stage ≥T2b, or an increase in PCa volume. Kaplan-Meier and log-rank tests were used to estimate progression-free survival time., Results: Median age was 69.02 (±7.73) at diagnosis, with a 0.15 (±0.08) PSA density (PSAD). Eighty-six patients were reclassified after confirmatory biopsy, with a suspicious mpMRI an indication for a clear reclassification and risk-predictor factor in disease progression (p < 0.05). During follow-up, 46 patients were changed from AS to active treatment mainly due to disease progression. Ninety patients underwent ≥2mpMRI during follow-up, with a median follow-up of 29 (15-49) months. Thirty-four patients had a baseline suspicious mpMRI (at diagnostic or confirmatory biopsy): 14 patients with a PIRADS 3 and 20 patients with ≥PIRADS 4. From 14 patients with a PIRADS 3 baseline mpMRI, 29% progressed radiologically, with a 50% progression rate versus 10% (1/10 patients) for those with similar or decreased mpMRI risk. Of the 56 patients with a non-suspicious baseline mpMRI (PIRADS < 2), 14 patients (25%) had an increased degree of radiological suspicion, with a detection rate of SigPCa of 29%. The mpMRI NPV during follow-up was 0.91., Conclusion: A suspicious mpMRI increases the reclassification and disease progression risk during follow-up and plays an important role in monitoring biopsies. In addition, a high NPV at mpMRI follow-up can help to decrease the need to monitor biopsies during AS., (© 2023 The Authors. The Prostate published by Wiley Periodicals LLC.)

Gaucher disease is a rare inherited disorder caused by a deficiency of the lysosomal acid beta-glucocerebrosidase enzyme. Metabolomic studies by our group targeted several new potential urinary biomarkers. Apart from lyso-Gb 1 , these studies highlighted lyso-Gb 1 analogs -28, -26, -12 (A/B), +2, +14, +16 (A/B), +30, and +32 Da, and polycyclic lyso-Gb 1 analogs 362, 366, 390, and 394 Da. The main objective of the current study was to develop and validate a robust UPLC-MS/MS method to study the urine distribution of these biomarkers in patients., Method: Urine samples were purified using solid-phase extraction. A 12 min UPLC-MS/MS method was developed., Results: Validation assays revealed high precision and accuracy for creatinine and lyso-Gb 1 . Most lyso-Gb 1 analogs had good recovery rates and high intra- and interday precision assays. Biomarker-estimated LOD and LOQ levels ranged from 56-109 pM to 186-354 pM, respectively. Comparison between GD patients and healthy controls showed significant differences in most biomarker levels. Typically, treated GD patients presented lower biomarker levels compared to untreated patients., Conclusions: These data suggest that the metabolites investigated might be interesting GD biomarkers. More studies with a larger cohort of patients will be needed to better understand the clinical significance of these GD biomarkers.

Gaucher disease (GD) is a lysosomal storage disorder resulting from a biallelic mutation in the gene GBA1 , leading to deficiencies in the enzyme β-glucocerebrosidase (Gcase). Inabilities of the Gcase to catabolize its substrate result in the accumulation of sphingolipids in macrophages, which impairs the cell functions and ultimately leads to multisystemic clinical manifestations. Important variability in symptoms and manifestations may lead to challenging diagnosis and patient care. Plasma glucosylsphingosine (lyso-Gb 1 ) is a biomarker frequently used for prognosis, monitoring, and patient follow-up. While lyso-Gb 1 appears to be a valid biomarker, few studies have investigated other matrices for potential GD biomarkers. The main objective of this study was to investigate the urine matrix as a potential source of new GD biomarkers by performing a metabolomic study using time-of-flight mass spectrometry. Our study highlighted a significant increase of eight urinary lyso-Gb 1 analogues. Moreover, a novel class of biomarkers, named polycyclic lyso-Gb 1 analogues, was identified. These four new molecules were more elevated than lyso-Gb 1 and related analogues in urine specimens of GD patients. Further investigations are warranted to validate the efficiency of these newly found biomarkers on a larger cohort of Gaucher patients and to compare them with plasma biomarkers currently quantified in clinical laboratories.

Background: Sphingolipidoses are caused by a defective sphingolipid catabolism, leading to an accumulation of several glycolipid species in tissues and resulting in neurotoxicity and severe systemic manifestations. Methods & results: Urine samples from controls and patients were purified by solid-phase extraction prior to the analysis by ultra-high-performance liquid chromatography (UPLC) combined with MS/MS. A UPLC-MS/MS method for the analysis of 21 urinary creatinine-normalized biomarkers for eight diseases was developed and validated. Conclusion: Considering the growing demand to identify patients with different sphingolipidoses early and reliably, this methodology will be applied for high-risk screening to target efficiently patients with various sphingolipidoses.

Aim: Gaucher disease (GD) is caused by a deficiency of the lysosomal enzyme acid β-glucocerebrosidase. Recent metabolomic studies highlighted several new metabolites increased in the plasma of GD patients. We aimed to develop and validate a UPLC-MS/MS method allowing a relative quantitation of lyso-Gb 1 and lyso-Gb 1 analogs -28, -12, -2, +14, +16 and +18 Da in addition to sphingosylphosphorylcholine, N -palmitoyl- O -phosphocholine to study potential correlations with clinical manifestations. Methodology & results: Following solid-phase extraction, plasma samples were evaporated and resuspended in 100 μl of resuspension solution. Three microliter is injected into the UPLC-MS/MS for analysis. Conclusion: All biomarkers studied were increased in GD patients. Significant correlations were observed between specific analogs and hematological, and visceral complications, as well as overall disease severity.

Speech is our most natural and efficient form of communication and offers a strong potential to improve how we interact with machines. However, speech communication can sometimes be limited by environmental (e.g., ambient noise), contextual (e.g., need for privacy), or health conditions (e.g., laryngectomy), preventing the consideration of audible speech. In this regard, silent speech interfaces (SSI) have been proposed as an alternative, considering technologies that do not require the production of acoustic signals (e.g., electromyography and video). Unfortunately, despite their plentitude, many still face limitations regarding their everyday use, e.g., being intrusive, non-portable, or raising technical (e.g., lighting conditions for video) or privacy concerns. In line with this necessity, this article explores the consideration of contactless continuous-wave radar to assess its potential for SSI development. A corpus of 13 European Portuguese words was acquired for four speakers and three of them enrolled in a second acquisition session, three months later. Regarding the speaker-dependent models, trained and tested with data from each speaker while using 5-fold cross-validation, average accuracies of 84.50% and 88.00% were respectively obtained from Bagging (BAG) and Linear Regression (LR) classifiers, respectively. Additionally, recognition accuracies of 81.79% and 81.80% were also, respectively, achieved for the session and speaker-independent experiments, establishing promising grounds for further exploring this technology towards silent speech recognition.

Background: Genetic stratification of Parkinson's disease (PD) patients facilitates gene-tailored research studies and clinical trials. The objective of this study was to describe the design of and the initial data from the Rostock International Parkinson's Disease (ROPAD) study, an epidemiological observational study aiming to genetically characterize ~10,000 participants., Methods: Recruitment criteria included (1) clinical diagnosis of PD, (2) relative of participant with a reportable LRRK2 variant, or (3) North African Berber or Ashkenazi Jew. DNA analysis involved up to 3 successive steps: (1) variant (LRRK2) and gene (GBA) screening, (2) panel sequencing of 68 PD-linked genes, and (3) genome sequencing., Results: Initial data based on the first 1360 participants indicated that the ROPAD enrollment strategy revealed a genetic diagnostic yield of ~14% among a PD cohort from tertiary referral centers., Conclusions: The ROPAD screening protocol is feasible for high-throughput genetic characterization of PD participants and subsequent prioritization for gene-focused research efforts and clinical trials. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

The Coronavirus disease 2019 (COVID-19) pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has resulted in economic and social lockdowns in most countries all over the globe. Early identification of infected individuals is regarded as one of the most important prerequisites for fighting the pandemic and for returning to a 'New Normal'. Large-scale testing is therefore crucial, but is facing several challenges including shortage of sample collection tools and of molecular biological reagents, and the need for safe electronic communication of medical reports. We present the successful establishment of a holistic SARS-CoV-2 testing platform that covers proband registration, sample collection and shipment, sample testing, and report issuing. The RT-PCR-based virus detection, being central to the platform, was extensively validated: sensitivity and specificity were defined as 96.8% and 100%, respectively; intra-run and inter-run precision were <3%. A novel type of sample swab and an in-house-developed RNA extraction system were shown to perform as good as commercially available products. The resulting flexibility guarantees independence from the current bottlenecks in SARS-CoV-2 testing. Based on our technology, we offered testing at local, national, and global levels. In the present study, we report the results from approx. 18,000 SARS-CoV-2 tests in almost 10,000 individuals from a low-frequency SARS-CoV-2 pandemic area in a homogenous geographical region in north-eastern Germany for a period of 10 weeks (21 March to 31 May 2020). Among the probands, five SARS-CoV-2 positive cases were identified. Comparative analysis of corresponding virus genomes revealed a diverse origin from three of the five currently recognized SARS-CoV-2 phylogenetic clades. Our study exemplifies how preventive SARS-CoV-2 testing can be set up in a rapid and flexible manner. The application of our test has enabled a safe maintenance/resume of critical local infrastructure, e.g., nursing homes where more than 5000 elderlies and caretakers got tested. The strategy outlined by the present study may serve as a blueprint for the implementation of large-scale preventive SARS-CoV-2 testing elsewhere.

Invadosomes are specialised actin-based dynamic microdomains of the plasma membrane. Their occurrence has been associated with cell adhesion, matrix degrading and mechanosensory functions that make them crucial regulators of cell migration and invasion. Monocytic, cancer cell and Src-transformed cell invadosomes have been extensively described. Less well defined are the structures which form in other cell types, i.e., non-haematopoietic and non-transformed cells, exposed to specific stimuli. We herein describe the specificities of podosomes induced in aortic endothelial cells stimulated with TGFβ in vitro and in conditions that more closely resemble the in vivo situation. These podosomes display the typical architecture of monocytic podosomes. They organise into large rosette-shape superstructures where they exhibit collective dynamic behavior consisting in cycles of formation and regression. At the ultrastructural level, microfilament arrangements in individual podosomes were revealed. Oxygen levels and hemodynamic forces, which are key players in endothelial cell biology, both influence the process. In 3D environment, podosomes appear as globular structures along cellular extensions. A better characterization of endothelial podosomes has far-reaching implications in the understanding and, possibly, in the treatment of some vascular diseases., Competing Interests: Declaration of Competing Interest The authors do not disclose any competing interests., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Objective: To describe the technique of transrectal biopsy with a new device that fuses multiparametric magnetic resonance (mpMRI) and ultrasound images in real time to guide target biopsies and to evaluate our initial experience., Methods: Patients with persistent suspicion of prostate cancer despite a previous negative biopsy and who had an mpMRI before the biopsy were selected. All patients underwent target biopsy plus standard systematic biopsy. Significant prostate cancer (sig PCa) was defined according to the Epstein criteria for standard biopsy and Gleason grade of ≥7 and a positive core length of ≥5 mm for target biopsy., Results: The first 40 patients were evaluated. The median age was 65 years old. In a sagittal isotropic sequence, the fusion process was started. The fusion can be improved by using different tools such as concordant points and Global Positioning System corrections tools. In the target biopsy, a median of 4 cores was taken, whereas in the standard biopsy, 12 cores were taken. Twenty-two patients were diagnosed with prostate cancer; of these patients, 17 were diagnosed with sig PCa. The fusion target biopsy diagnosed more sig PCa than the standard biopsy; however, it was not statistically significant (37.5% vs 25%, P=.08). The probability of being diagnosed with cancer increased in correlation with the Prostate Imaging Reporting and Data System score, without reaching statistical significance (k=0.45, P=.08)., Conclusions: This new device is a useful tool to guide biopsy in patients with target lesions in an mpMRI to increase the detection of sig PCa. A larger cohort would be required to show significant differences., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Protein kinase D (PKD) is a family of serine/threonine kinases that is required for the structural integrity and function of the Golgi complex. Despite its importance in the regulation of Golgi function, the molecular mechanisms regulating PKD activity are still incompletely understood. Using the genetically encoded PKD activity reporter G-PKDrep we now uncover a Rho signaling network comprising GEF-H1, the RhoGAP DLC3, and the Rho effector PLCε that regulate the activation of PKD at trans-Golgi membranes. We further show that this molecular network coordinates the formation of TGN-derived Rab6-positive transport carriers delivering cargo for localized exocytosis at focal adhesions., Competing Interests: SE, FC, GL, SS, MN, MS, MO, AH No competing interests declared, (© 2018, Eisler et al.)

Objective: To assess the effect of vision in three dimensions (3D) versus two dimensions (2D) on mental workload and laparoscopic performance during simulation-based training., Materials and Methods: A prospective, randomized crossover study on inexperienced students in operative laparoscopy was conducted. Forty-six candidates executed five standardized exercises on a pelvitrainer with both vision systems (3D and 2D). Laparoscopy performance was assessed using the total time (in seconds) and the number of failed attempts. For workload assessment, the validated NASA-TLX questionnaire was administered., Results: 3D vision improves the performance reducing the time (3D = 1006.08 ± 315.94 vs. 2D = 1309.17 ± 300.28; P < .001) and the total number of failed attempts (3D = .84 ± 1.26 vs. 2D = 1.86 ± 1.60; P < .001). For each exercise, 3D vision also shows better performance times: "transfer objects" (P = .001), "single knot" (P < .001), "clip and cut" (P < .05), and "needle guidance" (P < .001). Besides, according to the NASA-TLX results, less mental workload is experienced with the use of 3D (P < .001). However, 3D vision was associated with greater visual impairment (P < .01) and headaches (P < .05)., Conclusion: The incorporation of 3D systems in laparoscopic training programs would facilitate the acquisition of laparoscopic skills, because they reduce mental workload and improve the performance on inexperienced surgeons. However, some undesirable effects such as visual discomfort or headache are identified initially., (Copyright © 2014 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.)

Purpose: Simultaneous pancreas-kidney transplantation is the gold standard treatment for patients with end-stage renal failure secondary to insulin-dependent diabetes mellitus. This kind of transplantation is a complex operation associated with a high incidence of surgical complications and mortality risk which could influence graft survival. The aim of this study was to establish the influence of different grades of postoperative complications, classified according to Clavien-Dindo, on the rate of kidney graft loss., Methods: We performed an observational retrospective review of all simultaneous transplantations performed between February 1989 and May 2012. Factors examined were related to recipient and donor characteristics, surgical procedures, and postoperative outcomes. For this purpose, Kaplan-Meier analyses and Cox-Regression tests are used., Results: One hundred thirty-nine transplantations were performed. Complications grades I, II, and IIIa were experienced in 81 (58.3%) patients, and grades IIIb and IVa-b in 55 (39.6%). Multivariate analysis showed an influence of panel reactive antibody (hazard ratio [HR]: 10.79; P = .003), incidence of acute rejection (HR: 2.55; P = .03), and complications grouped into grades IIIb and IVa-b (HR: 3.63; P = .02). Kaplan Meier analysis showed worse kidney graft survival rate in groups grades IIIb and IVa-b compared to grades I, II, and IIIa (86.6% vs 98.7% at 1 year and 81.8% vs 97.3% at 5 years; P = .001)., Conclusions: Despite being the gold standard treatment for these patients, pancreas and kidney transplantations have numerous complications which could influence the prognosis of graft kidney survival., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Transforming growth factor β (TGF-β) and related cytokines play a central role in the vascular system. In vitro, TGF-β induces aortic endothelial cells to assemble subcellular actin-rich structures specialized for matrix degradation called podosomes. To explore further this TGF-β-specific response and determine in which context podosomes form, ALK5 and ALK1 TGF-β receptor signaling pathways were investigated in bovine aortic endothelial cells. We report that TGF-β drives podosome formation through ALK5 and the downstream effectors Smad2 and Smad3. Concurrent TGF-β-induced ALK1 signaling mitigates ALK5 responses through Smad1. ALK1 signaling induced by BMP9 also antagonizes TGF-β-induced podosome formation, but this occurs through both Smad1 and Smad5. Whereas ALK1 neutralization brings ALK5 signals to full potency for TGF-β-induced podosome formation, ALK1 depletion leads to cell disturbances not compatible with podosome assembly. Thus, ALK1 possesses passive and active modalities. Altogether, our results reveal specific features of ALK1 and ALK5 signaling with potential clinical implications., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Background: Numerous factors have been associated with early delay in kidney function and thence the graft survival. However, few data are derived from different types of donation: single or multiorgan. Our goal was to analyze the association of type of retrieval with the early function of the renal graft., Methods: A retrospective analysis of transplantations performed in the Reina Sofia Hospital from January 2004 to June 2012 from local deceased donors was carried out. We performed a descriptive analysis of the variables and univariate and multivariate analyses with the use of logistic regression to determine the association of type of retrieval (kidney-only [KO], kidney-liver [KL], and multiorgan [MO]) with delayed graft function (DGF) and early graft failure (EGF)., Results: We analyzed 287 kidney transplantations from 182 deceased donors, of which 25 (13.7%) were KO, 80 (43.9%) KL, and 77 (42.3%) MO. DGF was higher in MO retrievals compared with KL and KO (25.8% vs 24% vs 20.5%), though without reaching significance (P = .81). EGF at 3 months was 17.6% in KO compared with 10.5% in KL and 5.3% in MO (P = .2). Regarding DGF, in the multivariate analysis, donor age (P = .049) and donor sex (P = .029) appeared to be related to DGF. There were no differences by type of retrieval. Multivariate logistic regression analysis established a significant relationship between KO retrieval and EGF at 3 months (P = .005) compared with MO., Conclusions: Early graft function at 3 months decreases when the allograft is from KO retrievals compared with MO, probably related to the more unfavorable characteristics of these donors and their corresponding recipients., (Copyright © 2013 Elsevier Inc. All rights reserved.)