A snapshot of cancer-associated thromboembolic disease in 2018-2019: First data from the TESEO prospective registry

BACKGROUND: The ever-growing complexity of cancer-associated thrombosis (CAT), with new antineoplastic drugs and anticoagulants, distinctive characteristics, and decisions with low levels of evidence, justifies this registry. METHOD: TESEO is a prospective registry promoted by the Spanish Society of Medical Oncology to which 34 centers contribute cases. It seeks to provide an epidemiological description of CAT in Spain. RESULTS: Participants (N=939) with CAT diagnosed between July 2018 and December 2019 were recruited. Most subjects had advanced colon (21.4%), non-small cell lung (19.2%), and breast (11.1%) cancers, treated with dual-agent chemotherapy (28.4%), monochemotherapy (14.4%), or immune checkpoint inhibitors (3.6%). Half (51%) were unsuspected events, albeit only 57.1% were truly asymptomatic. Pulmonary embolism (PE) was recorded in 571 (58.3%); in 120/571 (21.0%), there was a concurrent deep venous thromboembolism (VTE). Most initially received low molecular weight heparin (89.7%). Suspected and unsuspected VTE had an OS rate of 9.9 (95% CI, 7.3-non-computable) and 14.4 months (95% CI, 12.6-non-computable) (p=0.00038). Six-month survival was 80.9%, 55.9%, and 55.5% for unsuspected PE, unsuspected PE admitted for another reason, and suspected PE, respectively (p<0.0001). The 12-month cumulative incidence of venous rethrombosis was 7.1% (95% CI, 4.7-10.2) in stage IV vs 3.0% (95% CI, 0.9-7.1) in stages I-III. The 12-month cumulative incidence of major/clinically relevant bleeding was 9.6% (95% CI, 6.1-14.0) in the presence of risk factors. CONCLUSION: CAT continues to be a relevant problem in the era of immunotherapy and targeted therapies. The initial TESEO data highlight the evolution of CAT, with new agents and thrombotic risk factors

A two-scale damage model for high cycle fatigue delamination in laminated composites

In this paper a model for predicting fatigue delamination growth in laminated composites under high cycle fatigue is proposed. The model uses the cohesive zone approach and a two-scale continuum damage mechanics model. The behavior of the interface material is considered quasi-brittle at the macro scale while plastic deformations are allowed at the scale of micro-defects. The validity of the proposed model is investigated through several standard tests using experimental data from literature. Good agreement between the numerical and experimental results is observed. The model is also capable of simulating fatigue under variable amplitude loading. This feature of model is shown through several sample simulations

Annexin A6 Is Critical to Maintain Glucose Homeostasis and Survival During Liver Regeneration in Mice

Background and Aims: Liver regeneration requires the organized and sequential activation of events that lead to restoration of hepatic mass. During this process, other vital liver functions need to be preserved, such as maintenance of blood glucose homeostasis, balancing the degradation of hepatic glycogen stores, and gluconeogenesis (GNG). Under metabolic stress, alanine is the main hepatic gluconeogenic substrate, and its availability is the rate‐limiting step in this pathway. Na+‐coupled neutral amino acid transporters (SNATs) 2 and 4 are believed to facilitate hepatic alanine uptake. In previous studies, we demonstrated that a member of the Ca2+‐dependent phospholipid binding annexins, Annexin A6 (AnxA6), regulates membrane trafficking along endo‐ and exocytic pathways. Yet, although AnxA6 is abundantly expressed in the liver, its function in hepatic physiology remains unknown. In this study, we investigated the potential contribution of AnxA6 in liver regeneration. Approach and Results: Utilizing AnxA6 knockout mice (AnxA6−/−), we challenged liver function after partial hepatectomy (PHx), inducing acute proliferative and metabolic stress. Biochemical and immunofluorescent approaches were used to dissect AnxA6−/− mice liver proliferation and energetic metabolism. Most strikingly, AnxA6−/− mice exhibited low survival after PHx. This was associated with an irreversible and progressive drop of blood glucose levels. Whereas exogenous glucose administration or restoration of hepatic AnxA6 expression rescued AnxA6−/− mice survival after PHx, the sustained hypoglycemia in partially hepatectomized AnxA6−/− mice was the consequence of an impaired alanine‐dependent GNG in AnxA6−/− hepatocytes. Mechanistically, cytoplasmic SNAT4 failed to recycle to the sinusoidal plasma membrane of AnxA6−/− hepatocytes 48 hours after PHx, impairing alanine uptake and, consequently, glucose production. Conclusions: We conclude that the lack of AnxA6 compromises alanine‐dependent GNG and liver regeneration in mice

Human predecidual stromal cells are mesenchymal stromal/stem cells and have a therapeutic effect in an immune-based mouse model of recurrent spontaneous abortion

Human decidual stromal cells (DSCs) are involved in the maintenance and development of pregnancy, in which they play a key role in the induction of immunological maternal–fetal tolerance. Precursors of DSCs (preDSCs) are located around the vessels, and based on their antigen phenotype, previous studies suggested a relationship between preDSCs and mesenchymal stromal/stem cells (MSCs). This work aimed to further elucidate the MSC characteristics of preDSCs. Under the effect of P4 and cAMP, the preDSC lines and clones decidualized in vitro: the cells became rounder and secreted PRL, a marker of physiological decidualization. PreDSC lines and clones also exhibited MSC characteristics. They differentiated into adipocytes, osteoblasts, and chondrocytes, and preDSC lines expressed stem cell markers OCT- 4, NANOG, and ABCG2; exhibited a cloning efficiency of 4 to 15%; significantly reduced the embryo resorption rate (P < 0.001) in the mouse model of abortion; and survived for prolonged periods in immunocompetent mice. The fact that 3 preDSC clones underwent both decidualization and mesenchymal differentiation shows that the same type of cell exhibited both DSC and MSC characteristics. Together, our results confirm that preDSCs are decidual MSCs and suggest that these cells are involved in the mechanisms of maternal–fetal immune toleranceThis work was supported by the Plan Estatal de Investigación Científica y Técnica y de Innovación 2013–2016, ISCIII-Subdirección General de Evaluación y Fomento de la Investigación, the Ministerio de Economía y Competitividad, Spain (Grant PI16/01642) and European Regional Development Fund (ERDF/ FEDER funding), the European Community, and the Cátedra de Investigación Anto nio Chamorro–Alejandro Otero, Universidad de Granada (CACH2017-1)

A personalized intervention to prevent depression in primary care: cost-effectiveness study nested into a clustered randomized trial

Background: Depression is viewed as a major and increasing public health issue, as it causes high distress in the people experiencing it and considerable financial costs to society. Efforts are being made to reduce this burden by preventing depression. A critical component of this strategy is the ability to assess the individual level and profile of risk for the development of major depression. This paper presents the cost-effectiveness of a personalized intervention based on the risk of developing depression carried out in primary care, compared with usual care. Methods: Cost-effectiveness analyses are nested within a multicentre, clustered, randomized controlled trial of a personalized intervention to prevent depression. The study was carried out in 70 primary care centres from seven cities in Spain. Two general practitioners (GPs) were randomly sampled from those prepared to participate in each centre (i.e. 140 GPs), and 3326 participants consented and were eligible to participate. The intervention included the GP communicating to the patient his/her individual risk for depression and personal risk factors and the construction by both GPs and patients of a psychosocial programme tailored to prevent depression. In addition, GPs carried out measures to activate and empower the patients, who also received a leaflet about preventing depression. GPs were trained in a 10- to 15-h workshop. Costs were measured from a societal and National Health care perspective. Qualityadjustedlife years were assessed using the EuroQOL five dimensions questionnaire. The time horizon was 18 months. Results: With a willingness-to-pay threshold of (sic)10, 000 ((sic)8568) the probability of cost-effectiveness oscillated from 83% (societal perspective) to 89% (health perspective). If the threshold was increased to (sic)30, 000 ((sic)25, 704), the probability of being considered cost-effective was 94% (societal perspective) and 96%, respectively (health perspective). The sensitivity analysis confirmed these results. Conclusions: Compared with usual care, an intervention based on personal predictors of risk of depression implemented by GPs is a cost-effective strategy to prevent depression. This type of personalized intervention in primary care should be further developed and evaluated

Advances in ab-initio theory of Multiferroics. Materials and mechanisms: modelling and understanding

Within the broad class of multiferroics (compounds showing a coexistence of magnetism and ferroelectricity), we focus on the subclass of "improper electronic ferroelectrics", i.e. correlated materials where electronic degrees of freedom (such as spin, charge or orbital) drive ferroelectricity. In particular, in spin-induced ferroelectrics, there is not only a {\em coexistence} of the two intriguing magnetic and dipolar orders; rather, there is such an intimate link that one drives the other, suggesting a giant magnetoelectric coupling. Via first-principles approaches based on density functional theory, we review the microscopic mechanisms at the basis of multiferroicity in several compounds, ranging from transition metal oxides to organic multiferroics (MFs) to organic-inorganic hybrids (i.e. metal-organic frameworks, MOFs)Comment: 22 pages, 9 figure

Effective Rheology of Bubbles Moving in a Capillary Tube

We calculate the average volumetric flux versus pressure drop of bubbles moving in a single capillary tube with varying diameter, finding a square-root relation from mapping the flow equations onto that of a driven overdamped pendulum. The calculation is based on a derivation of the equation of motion of a bubble train from considering the capillary forces and the entropy production associated with the viscous flow. We also calculate the configurational probability of the positions of the bubbles.Comment: 4 pages, 1 figur

Long-term adherence to IFN beta-1a treatment when using rebismart1device in patients with relapsing-remitting multiple sclerosis

The effectiveness of disease-modifying drugs in the treatment of multiple sclerosis is associated with adherence. RebiSmart® electronic device provides useful information about adherence to the treatment with subcutaneous (sc) interferon (IFN) ß-1a (Rebif®). The aim of the study was to determine long-term adherence to this treatment in patients with relapsing- remitting multiple sclerosis (RRMS). This retrospective multicentre observational study analysed 258 patients with RRMS who were receiving sc IFN ß-1a (Rebif®) treatment by using RebiSmart® until replacement (36 months maximum lifetime) or treatment discontinuation. Adherence was calculated with data (injection dosage, time, and date) automatically recorded by RebiSmart®. Patients in the study had a mean age of 41 years with a female proportion of 68%. Mean EDSS score at start of treatment was 1.8 (95% CI, 1.6-1.9). Overall adherence was 92.6%(95% CI, 90.6-94.5%). A total of 30.2% of patients achieved an adherence rate of 100%, 80.6% at least 90%, and only 13.2% of patients showed a suboptimal adherence (<80%). A total of 59.9% of subjects were relapse-free after treatment initiation. Among 106 subjects (41.1%) who experienced, on average, 1.4 relapses, the majority were mild (40.6%) or moderate (47.2%). Having experienced relapses from the beginning of the treatment was the only variable significantly related to achieving an adherence of at least 80% (OR = 3.06, 1.28-7.31). Results of this study indicate that sc IFN ß-1a administration facilitated by RebiSmart® could lead to high rates of adherence to a prescribed dose regimen over 36 months

Long-term follow-up of certolizumab pegol in uveitis due to immune-mediated inflammatory diseases: multicentre study of 80 patients

ObjectivesTo evaluate effectiveness and safety of certolizumab pegol (CZP) in uveitis due to immune-mediated inflammatory diseases (IMID).MethodsMulticentre study of CZP-treated patients with IMID uveitis refractory to conventional immunosuppressant. Effectiveness was assessed through the following ocular parameters: best-corrected visual acuity, anterior chamber cells, vitritis, macular thickness and retinal vasculitis. These variables were compared between the baseline, and first week, first, third, sixth months, first and second year.ResultsWe studied 80 (33 men/47 women) patients (111 affected eyes) with a mean age of 41.6 +/- 11.7 years. The IMID included were: spondyloarthritis (n=43), Behcet's disease (n=10), psoriatic arthritis (n=8), Crohn's disease (n=4), sarcoidosis (n=2), juvenile idiopathic arthritis (n=1), reactive arthritis (n=1), rheumatoid arthritis (n=1), relapsing polychondritis (n=1),ConclusionsCZP seems to be effective and safe in uveitis related to different IMID, even in patients refractory to previous biological drugs