El depósito de armas del bronce final de «Los Cascajos», Grañón (La Rioja)

The until now unpublished hoard of weapons from «Los Cascajos» is exceptional in its geographical context, since it is the only one recovered in the province of La Rioja, and it is also exceptional at the Peninsular level for the pieces that make it up: number, typology, origin and conservation. It’s a set of metal pieces from the transit of the Late Bronze Age I to the Late Bronze Age II (1200-1000 B.C.), some of them unpublished in the Peninsula, since they are not of local manufacture but imported from other territories of the Atlantic Bronze Age. The formal characteristics of some pieces point to the Thames Valley as place of origin, although it is not possible to dismiss the Gallic origin of others.El hasta ahora inédito depósito de armas de «Los Cascajos» es excepcional dentro de su contexto geográfico, ya que es el único recuperado en la provincia de La Rioja, pero también a nivel peninsular por las piezas que lo integran: por su número, tipología, origen y conservación. Se trata de un conjunto de metales del tránsito del BFI al BFII (1200-1000 a.C.), algunos de ellos inéditos en la Península, ya que no son de factura local, sino importados de otros territorios del Bronce Atlántico. Las características formales de algunas piezas señalan el Valle del Támesis como lugar de procedencia, aunque sin descartar el origen galo de otras

Entrar y salir de la ciudad medieval: datos arqueológicos sobre las puertas de San Juan y San Martín de Burgos, y su muralla

Historical information about the chronology of Burgos’s medieval wall has never been ratified by urban archaeology in the city, while its construction was neither linear nor took place at a single time. This article presents the archaeological study carried out at the gates of San Juan and San Martín, the entrance and exit of the French Way of St James in the medieval city. The funerary use of the former came to an end in the late Middle Ages, when a section of the wall was built. At the latter, at least three building phases are known and supported by the stratigraphic sequence, the mineralogical comparison of the mortars and a 14C AMS date. Profound renovation of the urban plan in the fourteenth century has been demonstrated at both sites.Las noticias históricas sobre la cronología de la muralla medieval de Burgos no han sido aún ratificadas por la arqueología urbana de la ciudad, al tiempo que su evolución constructiva no fue ni lineal ni unitaria. Se presentan los resultados de las intervenciones arqueológicas realizadas en las puertas de San Juan y de San Martín, entrada y salida del Camino de Santiago francés en esta ciudad medieval. En la primera desaparece el uso funerario del espacio a comienzos de la Baja Edad Media, cuando se edifica un tramo de muralla. En la segunda se constatan al menos tres fases constructivas avaladas por la secuencia estratigráfica, los resultados químico-mineralógicos del estudio de morteros de cal y la datación 14C AMS. En ambos contextos queda demostrada la profunda renovación del urbanismo en el siglo XIV

Compositional Characterization and Chronology of Roman Mortars from the Archaeological Site of Arroyo De La Dehesa De Velasco (Burgo De Osma- Ciudad De Osma, Soria, Spain)

This study characterises the mortar materials used in the construction of walls and floors at the Arroyo de la Dehesa de Velasco site, located near the Roman city of Uxama Argaela (the modern Burgo de Osma—Ciudad de Osma, Soria, Spain). Multilayer mortars have been characterised by petrographic, mineralogical (X-ray diffraction and scanning electron microscopy with energy dispersive analyses and geochemical analysis (X-ray fluorescence). Additionally, radiocarbon dating of the mortar binder fraction was performed in order to establish the chronology of the building in the absence of other archaeological chronological records. The results showed that similar siliceous aggregates and lime binders were used in the fabrication of multilayer system mortars. Some multilayer wall mortars show ceramic fragments or brick powder to produce hydraulic mortars and improve the resistance to moisture. The raw materials used for the construction of the site were of local origin and the construction was built during the first century BC, according to radiocarbon dating.This study was partially supported by the T1193-13 project of the Basque Country Government

Strontium and oxygen isotopes to trace mobility routes during the Bell Beaker period in the north of Spain

[EN]Strontium and oxygen isotopes of individuals from El Hundido and Valdescusa (north of Spain) sites, corresponding to the Bell Beaker culture, were analysed in order to determine mobility patterns and provenance areas. Strontium and oxygen isotope ratios in three teeth from two individuals at El Hundido and two teeth from the five individuals at Valdescusa were studied. The analyses were performed in both dentine and enamel fractions. Sr-87/Sr-86 ratios of El Hundido individuals indicate one was of foreign origin and the other was local whereas at Valdescusa were all of foreign provenance. Calculated delta O-18(w) values of El Hundido suggest a provenance from the geographical area close to the site while the Valdescusa would come from a warmer region. The comparison of oxygen and strontium isotope signatures indicate the west of the Iberian Peninsula (Zamora or the east of Leon regions) as the provenance area for the foreign individual at El Hundido and southwest France (Garonne basin) as the region of provenance for the Valdescusa.This work has been supported financially by Research Group IT1193-19 and PIBA 2018_1_0053 research projects of the Government of the Basque Country

Generation of periventricular reactive astrocytes overexpressing aquaporin 4 Is stimulated by mesenchymal stem cell therapy

Aquaporin-4 (AQP4) plays a crucial role in brain water circulation and is considered a therapeutic target in hydrocephalus. Congenital hydrocephalus is associated with a reaction of astrocytes in the periventricular white matter both in experimental models and human cases. A previous report showed that bone marrow-derived mesenchymal stem cells (BM-MSCs) transplanted into the lateral ventricles of hyh mice exhibiting severe congenital hydrocephalus are attracted by the periventricular astrocyte reaction, and the cerebral tissue displays recovery. The present investigation aimed to test the effect of BM-MSC treatment on astrocyte reaction formation. BM-MSCs were injected into the lateral ventricles of four-day-old hyh mice, and the periventricular reaction was detected two weeks later. A protein expression analysis of the cerebral tissue differentiated the BM-MSC-treated mice from the controls and revealed effects on neural development. In in vivo and in vitro experiments, BM-MSCs stimulated the generation of periventricular reactive astrocytes overexpressing AQP4 and its regulatory protein kinase D-interacting substrate of 220 kDa (Kidins220). In the cerebral tissue, mRNA overexpression of nerve growth factor (NGF), vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1 (HIF1α), and transforming growth factor beta 1 (TGFβ1) could be related to the regulation of the astrocyte reaction and AQP4 expression. In conclusion, BM-MSC treatment in hydrocephalus can stimulate a key developmental process such as the periventricular astrocyte reaction, where AQP4 overexpression could be implicated in tissue recovery.The present work was supported by grants PI15/00619 and PI19/00778 (to A.J.J. and P.P.-G.), PI21/000914 (to J.V.) and PI21/000915 (to A.G.) from the Instituto de Salud Carlos III, Spain, co-financed by FEDER funds from the European Union; PI18-RT-2233 from Junta de Andalucía (to A.G.) co-financed by Programa Operativo FEDER 2014–2020; PID2020-115218RB-I00 to T.I., funded by MCIN/AEI/10.13039/501100011033; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED, Instituto de Salud Carlos III, Spain) to J.V., T.I. and A.G.; FPU13/02906 to MG-B from the Ministerio de Educación, Cultura y Deporte, Spain; RYC-2014-16980 to P.P.-G. from the Ministerio de Economía y Competitividad, Spain; UMA18-FEDERJA-277 from Plan Operativo FEDER Andalucía 2014–2020 and Universidad de Málaga to P.P.-G.; Proyectos dirigidos por jóvenes investigadores from Universidad de Málaga to P.P.-G. The cost of this publication has been paid in art by “ERDF A way of making Europe” funds. Partial funding for open access charge: Universidad de Málaga

Importance of Timely Treatment Initiation in Infantile-Onset Pompe Disease, a Single-Centre Experience

Abstract Classic infantile Pompe disease (IPD) is a rare lysosomal storage disorder characterized by severe hypertrophic cardiomyopathy and profound muscle weakness. Without treatment, death occurs within the first 2 years of life. Although enzyme replacement therapy (ERT) with alglucosidase alfa has improved survival, treatment outcome is not good in many cases and is largely dependent on age at initiation. The objective of the study was (a) to analyse the different stages in the diagnosis and specific treatment initiation procedure in IPD patients, and (b) to compare clinical and biochemical outcomes depending on age at ERT initiation (<1 month of age vs. <3 months of age). Here, we show satisfactory clinical and biochemical outcomes in two IPD patients after early treatment initiation before 3 months of life with immunomodulatory therapy in the ERT-naïve setting, with a high ERT dose from the beginning. Despite the overall good evolution, the patient who initiated treatment <1 month of life presented even better outcomes than the patient who started treatment <3 months of life, with an earlier normalization of hypertrophic cardiomyopathy, along with CK normalization, highlighting the importance of early treatment initiation in this progressive disease before irreversible muscle damage has occurred.This work was partially funded by the Basque Department of Education (IT1281-19)

Differences in saliva ACE2 activity among infected and non-infected adult and pediatric population exposed to SARS-CoV-2

Background Variations in the ACE2 activity in saliva could explain the striking differences of susceptibility to infection and risk of severe disease. Methods We analyze the activity of ACE2 in saliva in different population groups across a wide age range and disease status during April to June 2020, before SARS-CoV-2 vaccine implementation, and we establish differences between infected people and participants considered resistant (highly exposed healthcare workers and children who cohabited with parents with COVID-19 without isolation and remain IgG negative). Results We included 74 adults, of which 47 (64%) were susceptible and 27 (36%) were resistant, and 79 children, of which 41 (52%) were susceptible and 38 (48%) were resistant. Resistant adults have significantly lower ACE2 activity in saliva than susceptible adults and non-significant higher values than susceptible and resistant children. ACE2 activity is similar in the susceptible and resistant pediatric population (p = 0.527). In contrast, we observe an increase in activity as the disease's severity increases among the adult population (mild disease vs. severe disease, 39 vs. 105 FU, p = 0.039; severe disease vs. resistant, 105 vs. 31 FU, p < 0.001). Conclusions using an enzymatic test, we show that ACE2 activity in saliva correlates with the susceptibility to SARS-Cov-2 infection and disease severity. Children and adults with low-susceptibility to SARS-Cov-2 infection showed the lowest ACE2 activity. These findings could inform future strategies to identify at-risk individuals.This work was supported by Instituto de Salud Carlos III (AC17/00019, PI18/00154, COV20/00349, ICI20/00058), CRUE-Supera COVID, cofinanced by the European Development Regional Fund ‘‘A way to achieve Europe’’ (ERDF), Merck, Sharp & Dohme Investigator Studies Program (code MISP# IIS 60257), Fondo Supera COVID-19 (2020-001), and SEIMC (becas SEIMC).Peer reviewe

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Effectiveness, safety/tolerability of OBV/PTV/r ± DSV in patients with HCV genotype 1 or 4 with/without HIV-1 co-infection, chronic kidney disease (CKD) stage IIIb-V and dialysis in Spanish clinical practice - Vie-KinD study

Limited data are available on the effectiveness and tolerability of direct-acting antivirals (DAAs) therapies in the real world for HCV-infected patients with comorbidities. This study aimed to describe the effectiveness of OBV/PTV/r ± DSV (3D/2D regimen) with or without ribavirin (RBV) in HCV or HCV/HIV co-infected patients with GT1/GT4 and CKD (IIIb-V stages), including those under hemodialysis and peritoneal dialysis in routine clinical practice in Spain in 2015.Non-interventional, retrospective, multicenter data collection study in 31 Spanish sites. Socio-demographic, clinical variables, study treatment characteristics, effectiveness and tolerability data were collected from medical records.Data from 135 patients with a mean age (SD) of 58.3 (11.4) years were analyzed: 92.6% GT1 (81.6% GT1b and 17.6% GT1a) and 7.4% GT4, 14 (10.4%) HIV/HCV co-infected, 19.0% with fibrosis F3 and 28.1% F4 by FibroScan®, 52.6% were previously treated with pegIFN and RBV. 11.1%, 14.8% and 74.1% of patients had CKD stage IIIb, IV and V respectively. 68.9% of patients were on hemodialysis; 8.9% on peritoneal dialysis and 38.5% had history of renal transplant. A total of 125 (96.2%) of 135 patients were treated with 3D, 10 (7.4%) with 2D and 30.4% received RBV. The overall intention-to-treat (ITT) sustained virologic response at week 12 (SVR12) was 92.6% (125/135) and the overall modified-ITT (mITT) SVR12 was 99.2% (125/126). The SVR12 rates (ITT) per sub-groups were: HCV mono-infected (91.7%), HCV/HIV co-infected (100%), GT1 (92.0%), GT4 (100%), CKD stage IIIb (86.7%), stage IV (95%) and stage V (93%). Among the 10 non-SVR there was only 1 virologic failure (0.7%); 4 patients had missing data due lost to follow up (3.0%) and 5 patients discontinued 3D/2D regimen (3.7%): 4 due to severe adverse events (including 3 deaths) and 1 patient´s decision.These results have shown that 3D/2D regimens are effective and tolerable in patients with advanced CKD including those in dialysis with GT 1 or 4 chronic HCV mono-infection and HIV/HCV coinfection in a real-life cohort. The overall SVR12 rates were 92.6% (ITT) and 99.2% (mITT) without clinically relevant changes in eGFR until 12 weeks post-treatment. These results are consistent with those reported in clinical trials

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality