Propuesta de mejora de una férula convencional

Los dispositivos inmovilizadores u ortopédicos usados en el tratamiento de lesiones presentan las mismas características e inconvenientes desde hace años. Aunque surgen novedades con el paso del tiempo, ninguna consigue asentarse en el mercado y competir contra las ya anticuadas escayolas y yesos. El objetivo principal de este proyecto es diseñar un catálogo de tres modelos de férula de rápida colocación para lesiones ubicadas en la región comprendida por el antebrazo, la muñeca y la palma de la mano. El principio básico de dichos dispositivos es la adaptación personalizada al usuario y la fijación del producto mediante materiales fotopolimerizables, los cuales solidifican al aplicar luz UV sobre ellos. Inicialmente se ha realizado una fase de estudio con el fin de conocer y definir toda la información necesaria para poder abordar el tratamiento de las lesiones pertinentes, además de los precedentes ya existentes y la información legal a aplicar, entre otros. Se han realizado entrevistas a traumatólogos, fisioterapeutas y enfermeras con tal de poder obtener la información más precisa y veraz posible. Una vez definidos todos los parámetros y habiendo realizado una previa fase de diseño, se han obtenido un total de tres modelos de férula. Estos modelos finales, los cuales se basan en el mismo principio de uso y cuya diferencia es su propuesta estética, han sido validados por el personal sanitario entrevistado. También han superado una serie de ensayos y pruebas ante esfuerzos físicos. Los tres modelos de férula presentan mejoras notables ante los dispositivos inmovilizadores ya conocidos. También cuentan con una marca asociada, embalaje propio, documentación técnica reglamentaria y consideraciones ecológicas a lo largo de su ciclo de vida, entre otros.Els dispositius inmobilitzadors o ortopèdics usats en el tractament de lesions presenten les mateixes característiques i inconvenients de de fa anys. Encara que sorgeixen novetats amb el pas del temps, cap aconsegueix assentar-se en el mercat i competir contra les ja antiquades escaioles i guixos. L'objectiu principal d'aquest projecte és dissenyar un catàleg de tres models de fèrula de ràpida col·locació per a lesions situades a la regió compresa per l'avantbraç, el canell i el palmell de la mà. El principi bàsic d'aquests dispositius és l'adaptació personalitzada a l'usuari i la fixació del producte mitjançant materials fotopolimeritzables, els quals solidifiquen en aplicar llum UV sobre ells. Inicialment s'ha realitzat una fase d'estudi amb la finalitat de conèixer i definir tota la informació necessària per a poder abordar el tractament de les lesions pertinents, a més dels precedents ja existents i la informació legal a aplicar, entre altres. S'han realitzat entrevistes a traumatòlegs, fisioterapeutes i infermeres amb l’objectiu de poder obtenir la informació més precisa i veraç possible. Una vegada definits tots els paràmetres i havent realitzat una prèvia fase de disseny, s'han obtingut un total de tres models de fèrula. Aquests models finals, els quals es basen en el mateix principi d'ús diferenciant-se per la seva proposta estètica, han estat validats pel personal sanitari entrevistat. També han superat una sèrie d'assajos i proves davant esforços físics. Els tres models de fèrula presenten millores notables davant els dispositius immobilitzadors ja coneguts. També compten amb una marca associada, embalatge propi, documentació tècnica reglamentària i consideracions ecològiques al llarg del seu cicle de vida, entre altres.The immobilizing or orthopedic devices used in the treatment of injuries have exhibited the same characteristics and drawbacks for years. Although new developments emerge over time, none manage to establish themselves in the market and compete against the already outdated casts and plaster. The main objective of this project is to design a catalog featuring three models of quickly applicable splints for injuries located in the region comprising the forearm, wrist, and palm of the hand. The fundamental principle of these devices lies in personalized adaptation to the user and securing the product using photosensitive materials, which solidify upon exposure to UV light. Initially, a study phase was conducted to understand and define all the necessary information required to address the treatment of relevant injuries, in addition to existing precedents and the legal information to be applied, among other aspects. Interviews were conducted with orthopedic surgeons, physiotherapists, and nurses to obtain the most precise and accurate information possible. Once all parameters were defined and a preliminary design phase was completed, a total of three splint models were obtained. These final models, based on the same principle of use and differing in their aesthetic proposal, were validated by the interviewed healthcare professionals. They also successfully passed a series of tests and trials involving physical exertion. The three splint models exhibit significant improvements over the known immobilizing devices. They also come with an associated brand, their own packaging, regulatory technical documentation, and ecological considerations throughout their lifecycle, among other features

An active tectonic field for CO2 storage management: the Hontomín onshore case study (Spain)

One of the concerns of underground CO2 onshore storage is the triggering of induced seismicity and fault reactivation by the pore pressure increasing. Hence, a comprehensive analysis of the tectonic parameters involved in the storage rock formation is mandatory for safety management operations. Unquestionably, active faults and seal faults depicting the storage bulk are relevant parameters to be considered. However, there is a lack of analysis of the active tectonic strain field affecting these faults during the CO2 storage monitoring. The advantage of reconstructing the tectonic field is the possibility to determine the strain trajectories and describing the fault patterns affecting the reservoir rock. In this work, we adapt a methodology of systematic geostructural analysis to underground CO2 storage, based on the calculation of the strain field from kinematics indicators on the fault planes (ey and ex for the maximum and minimum horizontal shortening, respectively). This methodology is based on a statistical analysis of individual strain tensor solutions obtained from fresh outcrops from the Triassic to the Miocene. Consequently, we have collected 447 fault data in 32 field stations located within a 20 km radius. The understanding of the fault sets’ role for underground fluid circulation can also be established, helping further analysis of CO2 leakage and seepage. We have applied this methodology to Hontomín onshore CO2 storage facilities (central Spain). The geology of the area and the number of high-quality outcrops made this site a good candidate for studying the strain field from kinematics fault analysis. The results indicate a strike-slip tectonic regime with maximum horizontal shortening with a 160 and 50◦ E trend for the local regime, which activates NE–SW strike-slip faults. A regional extensional tectonic field was also recognized with a N–S trend, which activates N–S extensional faults, and NNE–SSW and NNW– SSE strike-slip faults, measured in the Cretaceous limestone on top of the Hontomín facilities. Monitoring these faults within the reservoir is suggested in addition to the possibility of obtaining a focal mechanism solutions for microearthquakes (M < 3)This work has been partially supported by the European Project ENOS: ENabling Onshore CO2 Storage in Europe, H2020 Project ID: 653718 and the Spanish project 3GEO, CGL2017-83931-C3-2-P, MICIU-FEDE

Memòria personal : una altra manera de llegir la història

El llibre proposa el consens assolit entre les diverses fórmules que s'han afirmat amb més o menys fortuna els darrers temps al voltant de la literatura personal, aquella del "jo", autobiogràfica, dietarística. Memòria personal entre històri

Angiotensin II type 1/adenosine A2A receptor oligomers: a novel target for tardive dyskinesia

Tardive dyskinesia (TD) is a serious motor side effect that may appear after long-term treatment with neuroleptics and mostly mediated by dopamine D2 receptors (D2Rs). Striatal D2R functioning may be finely regulated by either adenosine A2A receptor (A2AR) or angiotensin receptor type 1 (AT1R) through putative receptor heteromers. Here, we examined whether A2AR and AT1R may oligomerize in the striatum to synergistically modulate dopaminergic transmission. First, by using bioluminescence resonance energy transfer, we demonstrated a physical AT1R-A2AR interaction in cultured cells. Interestingly, by protein-protein docking and molecular dynamics simulations, we described that a stable heterotetrameric interaction may exist between AT1R and A2AR bound to antagonists (i.e. losartan and istradefylline, respectively). Accordingly, we subsequently ascertained the existence of AT1R/A2AR heteromers in the striatum by proximity ligation in situ assay. Finally, we took advantage of a TD animal model, namely the reserpine-induced vacuous chewing movement (VCM), to evaluate a novel multimodal pharmacological TD treatment approach based on targeting the AT1R/A2AR complex. Thus, reserpinized mice were co-treated with sub-effective losartan and istradefylline doses, which prompted a synergistic reduction in VCM. Overall, our results demonstrated the existence of striatal AT1R/A2AR oligomers with potential usefulness for the therapeutic management of TD

Genetic and clinical characterization of a novel FH founder mutation in families with hereditary leiomyomatosis and renal cell cancer syndrome

Hereditary leiomyomatosis and renal cell cancer syndrome is a rare autosomal dominant hereditary syndrome. Previously, we published the largest cohort of FH mutation carriers in Spain and observed a highly recurrent missense heterozygous variant, FH(NM_000143.4):c.1118A > G p.(Asn373Ser), in 104 individuals from 31 apparently unrelated families. Here, we aimed to establish its founder effect and characterize the associated clinical phenotype. Results Haplotype analysis confirmed that families shared a common haplotype (32/38 markers) spanning 0.61-0.82 Mb, indicating this recurrent variant was inherited from a founder ancestor. Cutaneous and uterine leiomyomatosis were diagnosed in 64.6% (64/99) and 98% (50/51) of patients, respectively, and renal cell cancer was present in 10.4% (10/96). The pathogenic FH_c.1118A > G variant is a Spanish founder mutation that originated 12-26 generations ago. We estimate that the variant may have appeared between 1370 and 1720. Individuals carrying this founder mutation had similar frequency of renal cell cancer and a higher frequency of renal cysts and leiomyomas than those in other cohorts of this syndrome. Conclusions In the Spanish province of Alicante there is a high prevalence of HLRCC because of the founder mutation FH c.1118A > G; p.(Asn373Ser). The characterization of founder mutations provides accurate and specific information regarding their penetrance and expressivity. In individuals with suspected HLRCC from the province of Alicante, genetic testing by direct analysis of the founder FH c.1118A > G; p.(Asn373Ser) mutation may be a faster and more efficient diagnostic tool compared with complete gene sequencing

Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome in Spain: Clinical and Genetic Characterization

Simple Summary Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is a very rare hereditary disorder characterized by cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs), renal cysts (RCys) and renal cell cancer (RCC), with no data on its prevalence worldwide. No genotype-phenotype associations have been described. The aim of our study was to describe the genotypic and phenotypic features of the largest series of patients with HLRCC from Spain reported to date. Of 27 FH germline pathogenic variants, 12 were not previously reported in databases. Patients with missense pathogenic variants showed higher frequencies of CLMs, ULMs and RCys, than those with loss-of-function variants. The frequency of RCCs (10.9%) was lower than those reported in the previously published series. Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) is a very rare hereditary disorder characterized by cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs), renal cysts (RCys) and renal cell cancers (RCCs). We aimed to describe the genetics, clinical features and potential genotype-phenotype associations in the largest cohort of fumarate hydratase enzyme mutation carriers known from Spain using a multicentre, retrospective study of individuals with a genetic or clinical diagnosis of HLRCC. We collected clinical information from medical records, analysed genetic variants and looked for genotype-phenotype associations. Analyses were performed using R 3.6.0. software. We included 197 individuals: 74 index cases and 123 relatives. CLMs were diagnosed in 65% of patients, ULMs in 90% of women, RCys in 37% and RCC in 10.9%. Twenty-seven different pathogenic variants were detected, 12 (44%) of them not reported previously. Patients with missense pathogenic variants showed higher frequencies of CLMs, ULMs and RCys, than those with loss-of-function variants (p = 0.0380, p = 0.0015 and p = 0.024, respectively). This is the first report of patients with HLRCC from Spain. The frequency of RCCs was lower than those reported in the previously published series. Individuals with missense pathogenic variants had higher frequencies of CLMs, ULMs and RCys

Risk of cancer in family members of patients with lynch-like syndrome

Lynch syndrome (LS) is a common cause of hereditary colorectal cancer (CRC). Some CRC patients develop mismatch repair deficiency without germline pathogenic mutation, known as Lynch-like syndrome (LLS). We compared the risk of CRC in first-degree relatives (FDRs) in LLS and LS patients. LLS was diagnosed when tumors showed immunohistochemical loss of MSH2, MSH6, and PMS2; or loss of MLH1 with BRAF wild type; and/or no MLH1 methylation and absence of pathogenic mutation in these genes. CRC and other LS-related neoplasms were followed in patients diagnosed with LS and LLS and among their FDRs. Standardized incidence ratios (SIRs) were calculated for CRC and other neoplasms associated with LS among FDRs of LS and LLS patients. In total, 205 LS (1205 FDRs) and 131 LLS families (698 FDRs) had complete pedigrees. FDRs of patients with LLS had a high incidence of CRC (SIR, 2.08; 95% confidence interval (CI), 1.56-2.71), which was significantly lower than that in FDRs of patients with LS (SIR, 4.25; 95% CI, 3.67-4.90; p < 0.001). The risk of developing other neoplasms associated with LS also increased among FDR of LLS patients (SIR, 2.04; 95% CI, 1.44-2.80) but was lower than that among FDR of patients with LS (SIR, 5.01, 95% CI, 4.26-5.84; p < 0.001). FDRs with LLS have an increased risk of developing CRC as well as LS-related neoplasms, although this risk is lower than that of families with LS. Thus, their management should take into account this increased risk

Computational tools for splicing defect prediction in breast/ovarian cancer genes: how efficient are they at predicting RNA alterations?

In silico tools for splicing defect prediction have a key role to assess the impact of variants of uncertain significance. Our aim was to evaluate the performance of a set of commonly used splicing in silico tools comparing the predictions against RNA in vitro results. This was done for natural splice sites of clinically relevant genes in hereditary breast/ovarian cancer (HBOC) and Lynch syndrome. A study divided into two stages was used to evaluate SSF-like, MaxEntScan, NNSplice, HSF, SPANR, and dbscSNV tools. A discovery dataset of 99 variants with unequivocal results of RNA in vitro studies, located in the 10 exonic and 20 intronic nucleotides adjacent to exon-intron boundaries of BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, ATM, BRIP1, CDH1, PALB2, PTEN, RAD51D, STK11, and TP53, was collected from four Spanish cancer genetic laboratories. The best stand-alone predictors or combinations were validated with a set of 346 variants in the same genes with clear splicing outcomes reported in the literature. Sensitivity, specificity, accuracy, negative predictive value (NPV) and Mathews Coefficient Correlation (MCC) scores were used to measure the performance. The discovery stage showed that HSF and SSF-like were the most accurate for variants at the donor and acceptor region, respectively. The further combination analysis revealed that HSF, HSF+SSF-like or HSF+SSF-like+MES achieved a high performance for predicting the disruption of donor sites, and SSF-like or a sequential combination of MES and SSF-like for predicting disruption of acceptor sites. The performance confirmation of these last results with the validation dataset, indicated that the highest sensitivity, accuracy, and NPV (99.44%, 99.44%, and 96.88, respectively) were attained with HSF+SSF-like or HSF+SSF-like+MES for donor sites and SSF-like (92.63%, 92.65%, and 84.44, respectively) for acceptor sites. We provide recommendations for combining algorithms to conduct in silico splicing analysis that achieved a high performance. The high NPV obtained allows to select the variants in which the study by in vitro RNA analysis is mandatory against those with a negligible probability of being spliceogenic. Our study also shows that the performance of each specific predictor varies depending on whether the natural splicing sites are donors or acceptors

Computational Tools for Splicing Defect Prediction in Breast/Ovarian Cancer Genes: How Efficient Are They at Predicting RNA Alterations?

In silico tools for splicing defect prediction have a key role to assess the impact of variants of uncertain significance. Our aim was to evaluate the performance of a set of commonly used splicing in silico tools comparing the predictions against RNA in vitro results. This was done for natural splice sites of clinically relevant genes in hereditary breast/ovarian cancer (HBOC) and Lynch syndrome. A study divided into two stages was used to evaluate SSF-like, MaxEntScan, NNSplice, HSF, SPANR, and dbscSNV tools. A discovery dataset of 99 variants with unequivocal results of RNA in vitro studies, located in the 10 exonic and 20 intronic nucleotides adjacent to exon–intron boundaries of BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, ATM, BRIP1, CDH1, PALB2, PTEN, RAD51D, STK11, and TP53, was collected from four Spanish cancer genetic laboratories. The best stand-alone predictors or combinations were validated with a set of 346 variants in the same genes with clear splicing outcomes reported in the literature. Sensitivity, specificity, accuracy, negative predictive value (NPV) and Mathews Coefficient Correlation (MCC) scores were used to measure the performance. The discovery stage showed that HSF and SSF-like were the most accurate for variants at the donor and acceptor region, respectively. The further combination analysis revealed that HSF, HSF+SSF-like or HSF+SSF-like+MES achieved a high performance for predicting the disruption of donor sites, and SSF-like or a sequential combination of MES and SSF-like for predicting disruption of acceptor sites. The performance confirmation of these last results with the validation dataset, indicated that the highest sensitivity, accuracy, and NPV (99.44%, 99.44%, and 96.88, respectively) were attained with HSF+SSF-like or HSF+SSF-like+MES for donor sites and SSF-like (92.63%, 92.65%, and 84.44, respectively) for acceptor sites.We provide recommendations for combining algorithms to conduct in silico splicing analysis that achieved a high performance. The high NPV obtained allows to select the variants in which the study by in vitro RNA analysis is mandatory against those with a negligible probability of being spliceogenic. Our study also shows that the performance of each specific predictor varies depending on whether the natural splicing sites are donors or acceptors

Genome-wide pathway analysis identifies VEGF pathway association with oral ulceration in systemic lupus erythematosus

Background: Systemic lupus erythematosus (SLE) is a genetically complex rheumatic disease characterized by heterogeneous clinical manifestations of unknown etiology. Recent studies have suggested the existence of a genetic basis for SLE heterogeneity. The objective of the present study was to identify new genetic variation associated with the clinically relevant phenotypes in SLE. Methods: A two-stage pathway-based approach was used to identify the genetic variation associated with the main clinical phenotypes in SLE. In the discovery stage, 482 SLE patients were genotyped using Illumina Human Quad610 microarrays. Association between 798 reference genetic pathways from the Molecular Signatures Database and 11 SLE phenotypes was tested using the set-based method implemented in PLINK software. Pathways significantly associated after multiple test correction were subsequently tested for replication in an independent cohort of 425 SLE patients. Using an in silico approach, we analyzed the functional effects of common SLE therapies on the replicated genetic pathways. The association of known SLE risk variants with the development of the clinical phenotypes was also analyzed. Results: In the discovery stage, we found a significant association between the vascular endothelial growth factor (VEGF) pathway and oral ulceration (P value for false discovery rate (P FDR) < 0.05), and between the negative regulation signaling pathway of retinoic acid inducible gene-I/melanoma differentiation associated gene 5 and the production of antinuclear antibodies (P FDR < 0.05). In the replication stage, we validated the association between the VEGF pathway and oral ulceration. Therapies commonly used to treat mucocutaneous phenotypes in SLE were found to strongly influence VEGF pathway gene expression (P = 4.60e-4 to 5.38e-14). Analysis of known SLE risk loci identified a strong association between PTPN22 and the risk of hematologic disorder and with the development of antinuclear antibodies. Conclusions: The present study has identified VEGF genetic pathway association with the risk of oral ulceration in SLE. New therapies targeting the VEGF pathway could be more effective in reducing the severity of this phenotype. These findings represent a first step towards the understanding of the genetic basis of phenotype heterogeneity in SLE