Impact of Disease-Modifying Therapies on Gut–Brain Axis in Multiple Sclerosis

Multiple sclerosis is a chronic, autoimmune-mediated, demyelinating disease whose pathogenesis remains to be defined. In past years, in consideration of a constantly growing number of patients diagnosed with multiple sclerosis, the impacts of different environmental factors in the pathogenesis of the disease have been largely studied. Alterations in gut microbiome composition and intestinal barrier permeability have been suggested to play an essential role in the regulation of autoimmunity. Thus, increased efforts are being conducted to demonstrate the complex interplay between gut homeostasis and disease pathogenesis. Numerous results confirm that disease-modifying therapies (DMTs) used for the treatment of MS, in addition to their immunomodulatory effect, could exert an impact on the intestinal microbiota, contributing to the modulation of the immune response itself. However, to date, the direct influence of these treatments on the microbiota is still unclear. This review intends to underline the impact of DMTs on the complex system of the microbiota–gut–brain axis in patients with multiple sclerosis

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Extracellular vesicles produced by irradiated endothelial or Glioblastoma stem cells promote tumor growth and vascularization modulating tumor microenvironment

BackgroundGlioblastoma (GBM) is the most lethal primary brain tumor in adult, characterized by highly aggressive and infiltrative growth. The current therapeutic management of GBM includes surgical resection followed by ionizing radiations and chemotherapy. Complex and dynamic interplay between tumor cells and tumor microenvironment drives the progression and contributes to therapeutic resistance. Extracellular vesicles (EVs) play a crucial role in the intercellular communication by delivering bioactive molecules in the surrounding milieu modulating tumor microenvironment.MethodsIn this study, we isolated by ultracentrifugation EVs from GBM stem-like cell (GSC) lines and human microvascular endothelial cells (HMVECs) exposed or not to ionizing irradiation. After counting and characterization, we evaluated the effects of exposure of GSCs to EVs isolated from endothelial cells and vice versa. The RNA content of EVs isolated from GSC lines and HMVECs exposed or not to ionizing irradiation, was analyzed by RNA-Seq. Periostin (POSTN) and Filamin-B (FLNB) emerged in gene set enrichment analysis as the most interesting transcripts enriched after irradiation in endothelial cell-derived EVs and GSC-derived EVs, respectively. POSTN and FLNB expression was modulated and the effects were analyzed by in vitro assays.ResultsWe confirmed that ionizing radiations increased EV secretion by GSCs and normal endothelial cells, affected the contents of and response to cellular secreted EVs. Particularly, GSC-derived EVs decreased radiation-induced senescence and promoted migration in HMVECs whereas, endothelial cell-derived EVs promoted tumorigenic properties and endothelial differentiation of GSCs. RNA-Seq analysis of EV content, identified FLNB and POSTN as transcripts enriched in EVs isolated after irradiation from GSCs and HMVECs, respectively. Assays performed on POSTN overexpressing GSCs confirmed the ability of POSTN to mimic the effects of endothelial cell-derived EVs on GSC migration and clonogenic abilities and transdifferentiation potential. Functional assays performed on HMVECs after silencing of FLNB supported its role as mediator of the effects of GSC-derived EVs on senescence and migration.ConclusionIn this study, we identified POSTN and FLNB as potential mediators of the effects of EVs on GSC and HMVEC behavior confirming that EVs play a crucial role in the intercellular communication by delivering bioactive molecules in the surrounding milieu modulating tumor microenvironment

Thalassaemia is paradoxically associated with a reduced risk of in-hospital complications and mortality in COVID-19: Data from an international registry

Although numerous patient-specific co-factors have been shown to be associated with worse outcomes in COVID-19, the prognostic value of thalassaemic syndromes in COVID-19 patients remains poorly understood. We studied the outcomes of 137 COVID-19 patients with a history of transfusion-dependent thalassaemia (TDT) and transfusion independent thalassaemia (TIT) extracted from a large international cohort and compared them with the outcomes from a matched cohort of COVID-19 patients with no history of thalassaemia. The mean age of thalassaemia patients included in our study was 41 ± 16 years (48.9% male). Almost 81% of these patients suffered from TDT requiring blood transfusions on a regular basis. 38.7% of patients were blood group O. Cardiac iron overload was documented in 6.8% of study patients, whereas liver iron overload was documented in 35% of study patients. 40% of thalassaemia patients had a history of splenectomy. 27.7% of study patients required hospitalization due to COVID-19 infection. Amongst the hospitalized patients, one patient died (0.7%) and one patient required intubation. Continuous positive airway pressure (CPAP) was required in almost 5% of study patients. After adjustment for age-, sex- and other known risk factors (cardiac disease, kidney disease and pulmonary disease), the rate of in-hospital complications (supplemental oxygen use, admission to an intensive care unit for CPAP therapy or intubation) and all-cause mortality was significantly lower in the thalassaemia group compared to the matched cohort with no history of thalassaemia. Amongst thalassaemia patients in general, the TIT group exhibited a higher rate of hospitalization compared to the TDT group (p = 0.001). In addition, the rate of complications such as acute kidney injury and need for supplemental oxygen was significantly higher in the TIT group compared to the TDT group. In the multivariable logistic regression analysis, age and history of heart or kidney disease were all found to be independent risk factors for increased in-hospital, all-cause mortality, whereas the presence of thalassaemia (either TDT or TIT) was found to be independently associated with reduced all-cause mortality. The presence of thalassaemia in COVID-19 patients was independently associated with lower in-hospital, all-cause mortality and few in-hospital complications in our study. The pathophysiology of this is unclear and needs to be studied in vitro and in animal models

Italian patients with hemoglobinopathies exhibit a 5-fold increase in age-standardized lethality due to SARS-CoV-2 infection.

Since the beginning of the COVID-19 pandemic, concerns have been expressed worldwide for patients with hemoglobinopathies and their vulnerability to SARS-CoV-2 infection. Data from Lebanon confirmed a role of underlying comorbidities on COVID-19 severity, but no deaths among a cohort of thalassemia patients.1 Patients with sickle cell disease (SCD) displayed a broad range of severity after SARS-CoV-2 infection, spanning from a favorable outcome unless pre-existing comorbidities (UK cohort)2 to high case mortality in US.3 History of pain, heart, lung, and renal comorbidities was identified as risk factors of worse COVID-19 outcomes by the US SECURE-SCD Registry.4 While Italy experienced a death rate in the general population among the highest in the world, preliminary data from the first wave of the pandemic showed a lower than expected number of infected thalassemia patients (updated up to April 10, 2020), likely due to earlier and more vigilant self-isolation compared to the general population.

Analisi e modellizzazione dell'effetto di agrotecniche sull'altezza della pianta : il progetto MIATA

L\u2019altezza delle piante \ue8 importante per determinarne il potenziale produttivo e la suscettibilit\ue0 nei confronti di avversit\ue0 abio-tiche. Nonostante questo, i modelli disponibili la ignorano o la simulano utilizzando semplici funzioni logistiche indipendenti dai reali processi bioLsici in gioco e dalle modalit\ue0 di gestione. Il progetto MIATA, condotto da studenti del corso di Sistemi Colturali dell\u2019Universit\ue0 degli Studi di Milano, ha affrontato la problematica, fornendo soluzioni modellistiche utili sia a scopo previsionale che di supporto alla gestione

Association between multimorbidity and postoperative mortality in patients undergoing major surgery: a prospective study in 29 countries across Europe

BackgroundMultimorbidity poses a global challenge to healthcare delivery. This study aimed to describe the prevalence of multimorbidity, common disease combinations and outcomes in a contemporary cohort of patients undergoing major abdominal surgery.MethodsThis was a pre-planned analysis of a prospective, multicentre, international study investigating cardiovascular complications after major abdominal surgery conducted in 446 hospitals in 29 countries across Europe. The primary outcome was 30-day postoperative mortality. The secondary outcome measure was the incidence of complications within 30 days of surgery.ResultsOf 24,227 patients, 7006 (28.9%) had one long-term condition and 10,486 (43.9%) had multimorbidity (two or more long-term health conditions). The most common conditions were primary cancer (39.6%); hypertension (37.9%); chronic kidney disease (17.4%); and diabetes (15.4%). Patients with multimorbidity had a higher incidence of frailty compared with patients <= 1 long-term health condition. Mortality was higher in patients with one long-term health condition (adjusted odds ratio 1.93 (95%CI 1.16-3.23)) and multimorbidity (adjusted odds ratio 2.22 (95%CI 1.35-3.64)). Frailty and ASA physical status 3-5 mediated an estimated 31.7% of the 30-day mortality in patients with one long-term health condition (adjusted odds ratio 1.30 (95%CI 1.12-1.51)) and an estimated 36.9% of the 30-day mortality in patients with multimorbidity (adjusted odds ratio 1.61 (95%CI 1.36-1.91)). There was no improvement in 30-day mortality in patients with multimorbidity who received pre-operative medical assessment.ConclusionsMultimorbidity is common and outcomes are poor among surgical patients across Europe. Addressing multimorbidity in elective and emergency patients requires innovative strategies to account for frailty and disease control. The development of such strategies, that integrate care targeting whole surgical pathways to strengthen current systems, is urgently needed for multimorbid patients. Interventional trials are warranted to determine the effectiveness of targeted management for surgical patients with multimorbidity

Three-row versus two-row circular staplers for left-sided colorectal anastomosis: a propensity score-matched analysis of the iCral 2 and 3 prospective cohorts

Background: Since most anastomoses after left-sided colorectal resections are performed with a circular stapler, any technological change in stapling devices may influence the incidence of anastomotic adverse events. The aim of the present study was to analyze the effect of a three-row circular stapler on anastomotic leakage and related morbidity after left-sided colorectal resections. Materials and methods: A circular stapled anastomosis was performed in 4255 (50.9%) out of 8359 patients enrolled in two prospective multicenter studies in Italy, and, after exclusion criteria to reduce heterogeneity, 2799 (65.8%) cases were retrospectively analyzed through a 1:1 propensity score-matching model including 20 covariates relative to patient characteristics, to surgery and to perioperative management. Two well-balanced groups of 425 patients each were obtained: group (A) – true population of interest, anastomosis performed with a three-row circular stapler; group (B) – control population, anastomosis performed with a two-row circular stapler. The target of inferences was the average treatment effect in the treated (ATT). The primary endpoints were overall and major anastomotic leakage and overall anastomotic bleeding; the secondary endpoints were overall and major morbidity and mortality rates. The results of multiple logistic regression analyses for the outcomes, including the 20 covariates selected for matching, were presented as odds ratios (OR) and 95% confidence intervals (95% CI). Results: Group A versus group B showed a significantly lower risk of overall anastomotic leakage (2.1 vs. 6.1%; OR 0.33; 95% CI 0.15–0.73; P = 0.006), major anastomotic leakage (2.1 vs. 5.2%; OR 0.39; 95% CI 0.17–0.87; P = 0.022), and major morbidity (3.5 vs. 6.6% events; OR 0.47; 95% CI 0.24–0.91; P = 0.026). Conclusion: The use of three-row circular staplers independently reduced the risk of anastomotic leakage and related morbidity after left-sided colorectal resection. Twenty-five patients were required to avoid one leakage

Identification of hemodynamically stable patients with acute pulmonary embolism at high risk for death: external validation of different models

Background: The optimal strategy for identification of hemodynamically stable patients with acute pulmonary embolism (PE) at risk for death and clinical deterioration remains undefined. Objectives: We aimed to assess the performances of currently available models/scores for identifying hemodynamically stable patients with acute, symptomatic PE at risk of death and clinical deterioration. Methods: This was a prospective multicenter cohort study including patients with acute PE (NCT03631810). Primary study outcome was in-hospital death within 30 days or clinical deterioration. Other outcomes were in-hospital death, death, and PE-related death, all at 30 days. We calculated positive and negative predictive values, c-statistics of European Society of Cardiology (ESC)-2014, ESC-2019, Pulmonary Embolism Thrombolysis (PEITHO), Bova, Thrombo-embolism lactate outcome study (TELOS), fatty acid binding protein, syncope and tachicardia (FAST), and National Early Warning Scale 2 (NEWS2) for the study outcomes. Results: In 5036 hemodynamically stable patients with acute PE, positive predictive values for the evaluated models/scores were all below 10%, except for TELOS and NEWS2; negative predictive values were above 98% for all the models/scores, except for FAST and NEWS2. ESC-2014 and TELOS had good performances for in-hospital death or clinical deterioration (c-statistic of 0.700 and 0.722, respectively), in-hospital death (c-statistic of 0.713 and 0.723, respectively), and PE-related death (c-statistic of 0.712 and 0.777, respectively); PEITHO, Bova, and NEWS2 also had good performances for PE-related death (c-statistic of 0.738, 0.741, and 0.742, respectively). Conclusion: In hemodynamically stable patients with acute PE, the accuracy for identification of hemodynamically stable patients at risk for death and clinical deterioration varies across the available models/scores; TELOS seems to have the best performance. These data can inform management studies and clinical practice