Molecular mechanisms of atherosclerosis in metabolic syndrome: role of reduced IRS2-dependent signaling

OBJECTIVE: The mechanisms underlying accelerated atherosclerosis in metabolic syndrome (MetS) patients remain poorly defined. In the mouse, complete disruption of insulin receptor substrate-2 (Irs2) causes insulin resistance, MetS-like manifestations, and accelerates atherosclerosis. Here, we performed human, mouse, and cell culture studies to gain insight into the contribution of defective Irs2 signaling to MetS-associated alterations. METHODS AND RESULTS: In circulating leukocytes from insulin-resistant MetS patients, Irs2 and Akt2 mRNA levels inversely correlate with plasma insulin levels and HOMA index and are reduced compared to insulin-sensitive MetS patients. Notably, a moderate reduction in Irs2 expression in fat-fed apolipoprotein E-null mice lacking one allele of Irs2 (apoE(-/-)Irs2(+/-)) accelerates atherosclerosis compared to apoE-null controls, without affecting plaque composition. Partial Irs2 inactivation also increases CD36 and SRA scavenger receptor expression and modified LDL uptake in macrophages, diminishes Akt2 and Ras expression in aorta, and enhances expression of the proatherogenic cytokine MCP1 in aorta and primary vascular smooth muscle cells (VSMCs) and macrophages. Inhibition of AKT or ERK1/2, a downstream target of RAS, upregulates Mcp1 in VSMCs. CONCLUSIONS: Enhanced levels of MCP1 resulting from reduced IRS2 expression and accompanying defects in AKT2 and Ras/ERK1/2 signaling pathways may contribute to accelerated atherosclerosis in MetS states

INDIGO-DataCloud: a Platform to Facilitate Seamless Access to E-Infrastructures

[EN] This paper describes the achievements of the H2020 project INDIGO-DataCloud. The project has provided e-infrastructures with tools, applications and cloud framework enhancements to manage the demanding requirements of scientific communities, either locally or through enhanced interfaces. The middleware developed allows to federate hybrid resources, to easily write, port and run scientific applications to the cloud. In particular, we have extended existing PaaS (Platform as a Service) solutions, allowing public and private e-infrastructures, including those provided by EGI, EUDAT, and Helix Nebula, to integrate their existing services and make them available through AAI services compliant with GEANT interfederation policies, thus guaranteeing transparency and trust in the provisioning of such services. Our middleware facilitates the execution of applications using containers on Cloud and Grid based infrastructures, as well as on HPC clusters. Our developments are freely downloadable as open source components, and are already being integrated into many scientific applications.INDIGO-Datacloud has been funded by the European Commision H2020 research and innovation program under grant agreement RIA 653549.Salomoni, D.; Campos, I.; Gaido, L.; Marco, J.; Solagna, P.; Gomes, J.; Matyska, L.... (2018). INDIGO-DataCloud: a Platform to Facilitate Seamless Access to E-Infrastructures. Journal of Grid Computing. 16(3):381-408. https://doi.org/10.1007/s10723-018-9453-3S381408163García, A.L., Castillo, E.F.-d., Puel, M.: Identity federation with VOMS in cloud infrastructures. In: 2013 IEEE 5Th International Conference on Cloud Computing Technology and Science, pp 42–48 (2013)Chadwick, D.W., Siu, K., Lee, C., Fouillat, Y., Germonville, D.: Adding federated identity management to OpenStack. Journal of Grid Computing 12(1), 3–27 (2014)Craig, A.L.: A design space review for general federation management using keystone. 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A Cloud-Based Framework for Machine Learning Workloads and Applications

[EN] In this paper we propose a distributed architecture to provide machine learning practitioners with a set of tools and cloud services that cover the whole machine learning development cycle: ranging from the models creation, training, validation and testing to the models serving as a service, sharing and publication. In such respect, the DEEP-Hybrid-DataCloud framework allows transparent access to existing e-Infrastructures, effectively exploiting distributed resources for the most compute-intensive tasks coming from the machine learning development cycle. Moreover, it provides scientists with a set of Cloud-oriented services to make their models publicly available, by adopting a serverless architecture and a DevOps approach, allowing an easy share, publish and deploy of the developed models.This work was supported by the project DEEP-Hybrid-DataCloud ``Designing and Enabling E-infrastructures for intensive Processing in a Hybrid DataCloud'' that has received funding from the European Union's Horizon 2020 Research and Innovation Programme under Grant 777435Lopez Garcia, A.; Marco De Lucas, J.; Antonacci, M.; Zu Castell, W.; David, M.; Hardt, M.; Lloret Iglesias, L.... (2020). A Cloud-Based Framework for Machine Learning Workloads and Applications. IEEE Access. 8:18681-18692. https://doi.org/10.1109/ACCESS.2020.2964386S1868118692

A cost and performance comparison of Public Private Partnership and public hospitals in Spain

© 2016 Caballer-Tarazona and Vivas-Consuelo. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The Erratum to this article has been published in Health Economics Review 2016 6:20[EN] Public-private partnership (PPP) initiatives are extending around the world, especially in Europe, as an innovation to traditional public health systems, with the intention of making them more efficient. There is a varied range of PPP models with different degrees of responsibility from simple public sector contracts with the private, up to the complete privatisation of the service. As such, we may say the involvement of the private sector embraces the development, financing and provision of public infrastructures and delivery services. In this paper, one of the oldest PPP initiatives developed in Spain and transferred to other European and Latin American countries is evaluated for first time: the integrated healthcare delivery Alzira model. Through a comparison of public and PPP hospital performance, cost and quality indicators, the efficiency of the PPP experience in five hospitals is evaluated to identify the influence of private management in the results. Regarding the performance and efficiency analysis, it is seen that the PPP group obtains good results, above the average, but not always better than those directly managed. It is necessary to conduct studies with a greater number of PPP hospitals to obtain conclusive results.Caballer Tarazona, M.; Vivas Consuelo, DJJ. (2016). 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Measurement of health-related quality by multimorbidity groups in primary health care

[EN] Background: Increased life expectancy in Western societies does not necessarily mean better quality of life. To improve resources management, management systems have been set up in health systems to stratify patients according to morbidity, such as Clinical Risk Groups (CRG). The main objective of this study was to evaluate the effect of multimorbidity on health-related quality of life (HRQL) in primary care. Methods: An observational cross-sectional study, based on a representative random sample (n = 306) of adults from a health district (N = 32,667) in east Spain (Valencian Community), was conducted in 2013. Multimorbidity was measured by stratifying the population with the CRG system into nine mean health statuses (MHS). HRQL was assessed by EQ-5D dimensions and the EQ Visual Analogue Scale (EQ VAS). The effect of the CRG system, age and gender on the utility value and VAS was analysed by multiple linear regression. A predictive analysis was run by binary logistic regression with all the sample groups classified according to the CRG system into the five HRQL dimensions by taking the ¿healthy¿ group as a reference. Multivariate logistic regression studied the joint influence of the nine CRG system MHS, age and gender on the five EQ-5D dimensions. Results: Of the 306 subjects, 165 were female (mean age of 53). The most affected dimension was pain/discomfort (53%), followed by anxiety/depression (42%). The EQ-5D utility value and EQ VAS progressively lowered for the MHS with higher morbidity, except for MHS 6, more affected in the five dimensions, save self-care, which exceeded MHS 7 patients who were older, and MHS 8 and 9 patients, whose condition was more serious. The CRG system alone was the variable that best explained health problems in HRQL with 17%, which rose to 21% when associated with female gender. Age explained only 4%. Conclusions: This work demonstrates that the multimorbidity groups obtained by the CRG classification system can be used as an overall indicator of HRQL. These utility values can be employed for health policy decisions based on cost-effectiveness to estimate incremental quality-adjusted life years (QALY) with routinely e-health data. Patients under 65 years with multimorbidity perceived worse HRQL than older patients or disease severity. Knowledge of multimorbidity with a stronger impact can help primary healthcare doctors to pay attention to these population groups.The authors would like to thank the Conselleria de Sanitat Universal i Sanitat Pública of the Generalitat Valenciana (the Regional Valencian Health Government) for providing the study data. We would also like to thank Helen Warbuton for editing the English.Milá-Perseguer, M.; Guadalajara Olmeda, MN.; Vivas-Consuelo, D.; Usó-Talamantes, R. (2019). 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Ruxolitinib in refractory acute and chronic graft-versus-host disease : a multicenter survey study

Graft-versus-host disease is the main cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. First-line treatment is based on the use of high doses of corticosteroids. Unfortunately, second-line treatment for both acute and chronic graft-versus-host disease, remains a challenge. Ruxolitinib has been shown as an effective and safe treatment option for these patients. Seventy-nine patients received ruxolitinib and were evaluated in this retrospective and multicenter study. Twenty-three patients received ruxolitinib for refractory acute graft-versus-host disease after a median of 3 (range 1-5) previous lines of therapy. Overall response rate was 69.5% (16/23) which was obtained after a median of 2 weeks of treatment, and 21.7% (5/23) reached complete remission. Fifty-six patients were evaluated for refractory chronic graft-versus-host disease. The median number of previous lines of therapy was 3 (range 1-10). Overall response rate was 57.1% (32/56) with 3.5% (2/56) obtaining complete remission after a median of 4 weeks. Tapering of corticosteroids was possible in both acute (17/23, 73%) and chronic graft-versus-host disease (32/56, 57.1%) groups. Overall survival was 47% (CI: 23-67%) at 6 months for patients with aGVHD (62 vs 28% in responders vs non-responders) and 81% (CI: 63-89%) at 1 year for patients with cGVHD (83 vs 76% in responders vs non-responders). Ruxolitinib in the real life setting is an effective and safe treatment option for GVHD, with an ORR of 69.5% and 57.1% for refractory acute and chronic graft-versus-host disease, respectively, in heavily pretreated patients

Disruption of the CCL1-CCR8 axis inhibits vascular Treg recruitment and function and promotes atherosclerosis in mice

The CC chemokine 1 (CCL1, also called I-309 or TCA3) is a potent chemoattractant for leukocytes that plays an important role in inflammatory processes and diseases through binding to its receptor CCR8. Here, we investigated the role of the CCL1-CCR8 axis in atherosclerosis. We found increased expression of CCL1 in the aortas of atherosclerosis-prone fat-fed apolipoprotein E (Apoe)-null mice; moreover, in vitro flow chamber assays and in vivo intravital microscopy demonstrated an essential role for CCL1 in leukocyte recruitment. Mice doubly deficient for CCL1 and Apoe exhibited enhanced atherosclerosis in aorta, which was associated with reduced plasma levels of the anti-inflammatory interleukin 10, an increased splenocyte Th1/Th2 ratio, and a reduced regulatory T cell (Treg) content in aorta and spleen. Reduced Treg recruitment and aggravated atherosclerosis were also detected in the aortas of fat-fed low-density lipoprotein receptor-null mice treated with CCR8 blocking antibodies. These findings demonstrate that disruption of the CCL1-CCR8 axis promotes atherosclerosis by inhibiting interleukin 10 production and Treg recruitment and function.This study was supported by the Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU, grants SAF2016-79490-R and SAF2014-57845-R) and the Instituto de Salud Carlos III (ISCIII, grants PI14/00526, PI17/01395, CP11/00145, and CPII16/00022) with co-funding from the European Regional Development Fund (ERDF, “Una manera de hacer Europa”), the Fundación Ramón Areces, European Union (EuroCellNet COST Action CA15214) and the INSERM. VZG is supported by the ISCIII, JMG-G by the ISCIII Miguel Servet Program and the Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), AdMM by the MCIU (predoctoral contract BES-2014-06779), and ZM by a British Heart Foundation Professorship. The CNIC is supported by the MCIU and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505).S

The bubble snails (Gastropoda, Heterobranchia) of Mozambique: an overlooked biodiversity hotspot

This first account, dedicated to the shallow water marine heterobranch gastropods of Mozambique is presented with a focus on the clades Acteonoidea and Cephalaspidea. Specimens were obtained as a result of sporadic sampling and two dedicated field campaigns between the years of 2012 and 2015, conducted along the northern and southern coasts of Mozambique. Specimens were collected by hand in the intertidal and subtidal reefs by snorkelling or SCUBA diving down to a depth of 33 m. Thirty-two species were found, of which 22 are new records to Mozambique and five are new for the Western Indian Ocean. This account raises the total number of shallow water Acteonoidea and Cephalaspidea known in Mozambique to 39 species, which represents approximately 50 % of the Indian Ocean diversity and 83 % of the diversity of these molluscs found in the Red Sea. A gap in sampling was identified in the central swamp/mangrove bio-region of Mozambique, and therefore, we suggest that future research efforts concentrate on or at least consider this region.publishedVersio