Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Συγκριτική επίδραση ευαίσθητων και πολυανθεκτικών στελεχών Escherichia coli στα κύτταρα της μη ειδικής ανοσίας

In order to study the influence of multi-drug resistance of bacteria to the survival of the host, under the light of the ability of E. coli isolates, susceptible and multi-drug resistant, to stimulate monocytes, ten susceptible and ten multi-drug resistant and ESBL-producing isolates of E. coli were applied to stimulate monocytes isolated from healthy human donors; mediators of inflammation (TNF-α, IL-6, IL-8, IL-10, IL-12 & sTREM-1) were estimated in supernatants. The multi-drug resistant E. coli species stimulated monocytes to a premature production of TNF-α, IL-6 & IL-8 during the first four hours after the exposition. The susceptible E. coli species stimulated monocytes to the premature production of IL-12. The differences in the cytokines production seized to exist after six hours. So as to interpret those differences, a similar experiment took place with the use of thermally inactivated isolates, which practically represented the extract of the cell wall. The multi-drug resistant E. coli isolates were able to provoke premature production of inflammation-promoting cytokines, and they also stimulated to the simultaneous release of sTREM-1. The results show that the susceptible and multi-drug resistant E. coli isolates stimulated the human monocytes to a different type of releasing inflammation-promoting cytokines.Για να μελετηθεί η επίδραση της πολυανθεκτικότητας των μικροβίων στα αντιμικροβιακά ως προς την επιβίωση του ξενιστή, υπό το φως της ικανότητας των ευαίσθητων και πολυανθεκτικών στελεχών E. coli να διεγείρουν τα μονοκύτταρα, χρησιμοποιήθηκαν 10 ευαίσθητα και 10 πολυανθεκτικά στελέχη E. Coli για να διεγείρουν μονοκύτταρα που απομονώθηκαν από υγιείς ανθρώπους, ενώ στα υπερκείμενα των μονοκυττάρων προσδιορίστηκαν οι TNF-α, IL-6, IL-8, IL-10, IL-12 και sTREM-1. Τα πολυανθεκτικά στελέχη E. coli διέγειραν προς μια πρώιμη παραγωγή των TNF-a, IL-6 και IL-8 κατά τις πρώτες τέσσερις ώρες μετά την έκθεση. Τα ευαίσθητα στελέχη E. coli διέγειραν την πρώιμη παραγωγή της IL-12. Οι διαφορές στην παραγωγή των κυτταροκινών έπαψαν να υπάρχουν μετά από έξι ώρες. Για να ερμηνευθούν αυτές οι διαφορές, έγινε αντίστοιχος πειραματισμός με χρήση θερμικά αδρανοποιηθέντων στελεχών τα οποία πρακτικά αντιστοιχούν στο εκχύλισμα του κυτταρικού τοιχώματός τους. Τα πολυανθεκτικά στελέχη E. coli φάνηκαν ικανά να προκαλέσουν πρώιμη επαγωγή σε κυτταροκίνες ευοδωτικές της φλεγμονώδους διεργασίας, ενώ διέγειραν προς την σύγχρονη απελευθέρωση του sTREM-1. Τα αποτελέσματα δείχνουν ότι τα ευαίσθητα και πολυανθεκτικά στελέχη E. coli διεγείρουν τα ανθρώπινα μονοκύτταρα προς ένα διαφορετικό τύπο απελευθέρωσης ευοδωτικών διαμεσολαβητών της διεργασίας της φλεγμονής

Progression into sepsis: an individualized process varying by the interaction of comorbidities with the underlying infection

Abstract Background Development of sepsis is a process with significant variation among individuals. The precise elements of this variation need to be defined. This study was designed to define the way in which comorbidities contribute to sepsis development. Methods Three thousand five hundred nine patients with acute pyelonephritis (AP), community-acquired pneumonia (CAP), intraabdominal infections (IAI) or primary bacteremia (BSI) and at least two signs of the systemic inflammatory response syndrome were analyzed. The study primary endpoint was to define how comorbidities as expressed in the Charlson’s comorbidity index (CCI) and the underlying type of infection contribute to development of organ dysfunction. The precise comorbidities that mediate sepsis development and risk for death among 18 comorbidities recorded were the secondary study endpoints. Results CCI more than 2 had an odds ratio of 5.67 for sepsis progression in patients with IAI between significantly higher than AP and BSI. Forward logistic regression analysis indicated seven comorbidities that determine transition into sepsis in patients with AP, four comorbidities in CAP, six comorbidities in IAI and one in BSI. The odds ratio both for progression to sepsis and death with one comorbidity or with two and more comorbidities was greater than in the absence of comorbidities. Conclusions The study described how different kinds of infection vary in the degree to which they lead to sepsis. The number of comorbidities that enhances the risk of sepsis and death varies depending on the underlying infections

Kinetics of circulating immunoglobulin M in sepsis: Relationship with final outcome

Introduction: The aim of this study was to investigate the kinetics of immunoglobulin M (IgM) during the different stages of sepsis. Methods: In this prospective multicenter study, blood sampling for IgM measurement was done within the first 24 hours from diagnosis in 332 critically ill patients; in 83 patients this was repeated upon progression to more severe stages. Among these 83 patients, 30 patients with severe sepsis progressed into shock and IgM was monitored daily for seven consecutive days. Peripheral blood mononuclear cells (PBMCs) were isolated from 55 patients and stimulated for IgM production. Results: Serum IgM was decreased in septic shock compared to patients with systemic inflammatory response syndrome (SIRS) and patients with severe sepsis. Paired comparisons at distinct time points of the sepsis course showed that IgM was decreased only when patients deteriorated from severe sepsis to septic shock. Serial measurements in these patients, beginning from the early start of vasopressors, showed that the distribution of IgM over time was significantly greater for survivors than for non-survivors. Production of IgM by PBMCs was significantly lower at all stages of sepsis compared with healthy controls. Conclusions: Specific changes of circulating IgM occur when patients with severe sepsis progress into septic shock. The distribution of IgM is lower among non-survivors. © 2013 Giamarellos-Bourboulis et al.; licensee BioMed Central Ltd

Additional file 1: of Progression into sepsis: an individualized process varying by the interaction of comorbidities with the underlying infection

Table S1. Comparison of comorbidities between patients with infection and sepsis developing in the field of acute pyelonephritis. (DOCX 21 kb

Additional file 4: of Progression into sepsis: an individualized process varying by the interaction of comorbidities with the underlying infection

Table S4. Comparison of comorbidities between patients with infection and sepsis developing in the field of primary bacteremia. (DOCX 21 kb