The negative effects of short-term extreme thermal events on the seagrass Posidonia oceanica are exacerbated by ammonium additions

Global warming is increasingly affecting our biosphere. However, in addition to global warming, a panoply of local stressors caused by human activities is having a profound impact on our environment. The risk that these local stressors could modify the response of organisms to global warming has attracted interest and fostered research on their combined effect, especially with a view to identifying potential synergies. In coastal areas, where human activities are heavily concentrated, this scenario is particularly worrying, especially for foundation species such as seagrasses. In this study we explore these potential interactions in the seagrass Posidonia oceanica. This species is endemic to the Mediterranean Sea. It is well known that the Mediterranean is already experiencing the effects of global warming, especially in the form of heat waves, whose frequency and intensity are expected to increase in the coming decades. Moreover, this species is especially sensitive to stress and plays a key role as a foundation species. The aim of this work is thus to evaluate plant responses (in terms of photosynthetic efficiency and growth) to the combined effects of short-term temperature increases and ammonium additions.To achieve this, we conducted a mesocosm experiment in which plants were exposed to three thermal treatments (20°C, 30°C and 35°C) and three ammonium concentrations (ambient, 30 μM and 120 μM) in a full factorial experiment. We assessed plant performance by measuring chlorophyll fluorescence variables (maximum quantum yield (Fv/Fm), effective quantum yield of photosystem II (ΔF/Fm'), maximum electron transport rate (ETRmax) and non-photochemical quenching (NPQ)), shoot growth rate and leaf necrosis incidence. At ambient ammonium concentrations, P. oceanica tolerates short-term temperature increases up to 30°C. However, at 35°C, the plant loses functionality as indicated by a decrease in photosynthetic performance, an inhibition of plant growth and an increase of the necrosis incidence in leaves. On the other hand, ammonium additions at control temperatures showed only a minor effect on seagrass performance. However, the combined effects of warming and ammonium were much worse than those of each stressor in isolation, given that photosynthetic parameters and, above all, leaf growth were affected. This serves as a warning that the impact of global warming could be even worse than expected (based on temperature-only approaches) in environments that are already subject to eutrophication, especially in persistent seagrass species living in oligotrophic environments

A geometrically defined stiffness contact for finite element models of wood joints

Finite element models tend to overestimate the actual elastic response of structural timber connections. The paper shows how such overprediction relates to the modelling of the contact between fasteners and timber. The use of a control parameter called stiffness contact is proposed. After an experimental campaign, a method to determine it, based only on the geometry of a rectangular contact area, is proposed. The modeling adequacy is demonstrated by applying it to dowel embedment and moment resistant wood joint tests. The obtained results show good agreement with the experimental test series

Matryoshka-type gastro-resistant microparticles for the oral treatment of Mycobacterium tuberculosis

Aim: Production of Matryoshka-type gastroresistant microparticles containing antibiotic-loaded poly lactic-co-glycolic acid (PLGA) nanoparticles (NP) against Mycobacterium tuberculosis. Materials & methods: The emulsification and evaporation methods were followed for the synthesis of PLGA–NPs and methacrylic acid-ethyl acrylate-based coatings to protect rifampicin from degradation under simulated gastric conditions. Results & conclusion: The inner antibiotic-loaded NPs here reported can be released under simulated intestinal conditions whereas their coating protects them from degradation under simulated gastric conditions. The encapsulation does not hinder the antituberculosis action of the encapsulated antibiotic rifampicin. A sustained antibiotic release could be obtained when using the drug-loaded encapsulated NPs. Compared with the administration of the free drug, a more effective elimination of M. tuberculosis was observed when applying the NPs against infected macrophages. The antibiotic-loaded PLGA–NPs were also able to cross an in vitro model of intestinal barrier. Matryoshka-type gastroresistant microparticles containing antibiotic-loaded poly lactic-co-glycolic acid nanoparticles against M. tuberculosis were produced to protect the antibiotic from degradation under simulated gastric conditions. The antibiotic-loaded poly lactic-co-glycolic acid nanoparticles were able to cross an in vitro model of intestinal barrier, being more effective in the elimination of M. tuberculosis when applied against infected macrophages compared with the use of the free drug

The immunotherapy potential of agonistic anti-CD137 (4-1BB) monoclonal antibodies for malignancies and chronic viral diseases

Pharmacological intervention on the immune system to achieve more intense lymphocyte responses has potential application in tumour immunology and in the treatment of chronic viral diseases. Immunostimulating monoclonal antibodies are defined as a new family of drugs that augment cellular immune responses. They interact as artificial ligands with functional proteins of the immune system, either activating or inhibiting their functions. There are humanized monoclonal antibodies directed to the inhibitory receptor CD152 (CTLA-4) that are being tested in clinical trials with evidence of antitumoural activity. As a drawback, anti-CTLA-4 monoclonal antibodies induce severe autoimmunity reactions in a fraction of the patients. Anti-CD137 monoclonal antibodies have the ability to induce potent immune responses mainly mediated by cytotoxic lymphocytes with the result of frequent complete tumour eradications in mice. Comparative studies in experimental models indicate that the antitumour activity of anti-CD137 monoclonal antibodies is superior to that of anti-CD152. CD137 (4-1BB) is a leukocyte differentiation antigen selectively expressed on the surface of activated T and NK lymphocytes, as well as on dendritic cells. Monoclonal antibodies acting as artificial stimulatory ligands of this receptor (anti-CD137 agonist antibodies) enhance cellular antitumoural and antiviral immunity in a variety of mouse models. Paradoxically, anti-CD137 monoclonal antibodies are therapeutic or preventive in the course of model autoimmune diseases in mice. In light of these experimental results, a number of research groups have humanized antibodies against human CD137 and early clinical trials are about to start

Effectiveness of a Structured Group Intervention Based on Pain Neuroscience Education for Patients with Fibromyalgia in Primary Care: a Multicentre Randomized Open-Label Controlled Trial

Background There has been increased interest in pain neuroscience education (PNE) as a therapeutic approach for the management of fibromyalgia (FM). Methods A multicentre randomized, open-label, controlled trial was conducted to assess the effectiveness of a structured group intervention based on PNE in patients with FM. A total of 139 patients were included in the study and randomized to the intervention group (7 group sessions of education in neurobiology of pain) or to the control group (treatment as usual only). The primary outcome was the improvement of functional status and pain measured with the Fibromyalgia Impact Questionnaire (FIQ), and secondary outcomes were the reduction in the impact of pain and other symptoms (catastrophizing, anxiety and depression) and number of patients reaching no worse than moderate functional impairment (FIQ score <39). Differences between groups were calculated by linear mixed-effects (intention-to-treat approach) and mediational models through path analyses. Results At 1 year, improvements in FIQ scores were higher in the intervention group with moderate or high effect size, and decreases of >= 20% in 69.1% of patients (20.9% in the control group) and of >= 50% in 39.7% (4.5% in the control group). Also, 52.9% of patients had a FIQ <39 points (13.4% in the control group). Conclusions In this sample of patients with FM, the improvement in quality of life and control of symptoms obtained by adding a PNE intervention showed promising results, equalling or surpassing previously reported outcomes. Significance A structured group intervention based on pain neuroscience education for 1 year in patients with fibromyalgia was associated with significant amelioration of the impact of the disease on scores of the Fibromyalgia Impact Questionnaire, the Health Assessment Questionnaire, the Hospital Anxiety and Depression Scale, the Pain Catastrophizing Scale and the Polysymptomatic Distress Scale as compared with only treatment as usual. These findings are clinically relevant considering the challenges posed by fibromyalgia to clinicians and patients alike.Partial reduction of routine work tasks of the principal investigator, MJ Barrenengoa-Cuadra, was supported by a grant from OSI Bilbao Basurto Osakidetza, Basque country, Spain (the grant was paid to the Health Service to substitute MJ Barrenengoa-Cuadra while research work)

Recombinant adenoviral vectors turn on the type I interferon system without inhibition of transgene expression and viral replication

Recombinant adenovirus administration gives rise to transgene-independent effects caused by the ability of the vector to activate innate immunity mechanisms. We show that recombinant adenoviruses encoding reporter genes trigger IFN-alpha and IFN-beta transcription from both plasmacytoid and myeloid mouse dendritic cells. Interestingly, IFN-beta and IFN-alpha5 are the predominant transcribed type I IFN genes both in vitro and in vivo. In human peripheral blood leukocytes type I IFNs are induced by adenoviral vectors, with a preponderance of IFN-beta together with IFN-alpha1 and IFN-alpha5 subtypes. Accordingly, functional type I IFN is readily detected in serum samples from human cancer patients who have been treated intratumorally with a recombinant adenovirus encoding thymidine kinase. Despite inducing functional IFN-alpha release in both mice and humans, gene transfer by recombinant adenoviruses is not interfered with by type I IFNs either in vitro or in vivo. Moreover, IFN-alpha does not impair replication of wild-type adenovirus. As a consequence, cancer gene therapy strategies with defective or replicative-competent adenoviruses are not expected to be hampered by the effect of the type I IFNs induced by the vector itself. However, type I IFN might modulate antitumor and antiadenoviral immune responses and thus influence the outcome of gene immunotherapy

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients

Background: Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. Methods: Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. Results: Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0-171.2] to 180.0 [135.4-227.9] mmHg and the ventilatory ratio from 1.73 [1.33-2.25] to 1.96 [1.61-2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01-1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01-1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93-1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). Conclusions: Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation

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