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.

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

Current concept of abdominal sepsis : WSES position paper

Peer reviewe

Identifying transport behavior of single-molecule trajectories.

Models of biological diffusion-reaction systems require accurate classification of the underlying diffusive dynamics (e.g., Fickian, subdiffusive, or superdiffusive). We use a renormalization group operator to identify the anomalous (non-Fickian) diffusion behavior from a short trajectory of a single molecule. The method provides quantitative information about the underlying stochastic process, including its anomalous scaling exponent. The classification algorithm is first validated on simulated trajectories of known scaling. Then it is applied to experimental trajectories of microspheres diffusing in cytoplasm, revealing heterogeneous diffusive dynamics. The simplicity and robustness of this classification algorithm makes it an effective tool for analysis of rare stochastic events that occur in complex biological systems

The nucleus does not significantly affect the migratory trajectories of amoeba in two-dimensional environments

For a wide range of cells, from bacteria to mammals, locomotion movements are a crucial systemic behavior for cellular life. Despite its importance in a plethora of fundamental physiological processes and human pathologies, how unicellular organisms efficiently regulate their locomotion system is an unresolved question. Here, to understand the dynamic characteristics of the locomotion movements and to quantitatively study the role of the nucleus in the migration of Amoeba proteus we have analyzed the movement trajectories of enucleated and non-enucleated amoebas on flat two-dimensional (2D) surfaces using advanced non-linear physical-mathematical tools and computational methods. Our analysis shows that both non-enucleated and enucleated amoebas display the same kind of dynamic migration structure characterized by highly organized data sequences, super-diffusion, non-trivial long-range positive correlations, persistent dynamics with trend-reinforcing behavior, and move-step fluctuations with scale invariant properties. Our results suggest that the presence of the nucleus does not significantly affect the locomotion of amoeba in 2D environments.We would like to thank Jose Gonzalez Romero and Jose Miguel Perez Perez from the Institute of Parasitology and Biomedicine "Lopez-Neyra" for their technical assistance, as well as the technical support provided by SGIker of UPV/EHU, European funding (ERDF and ESF), the Basque Government funding (IT1974-16, KK-2018/00090), and by the UPV/EHU and Basque Center of Applied Mathematics (US18/21)

Endoscopic Papillectomy for Ampullary Lesions of minor papilla

Background and aims: Ampullary lesions (AL) of the minor duodenal papilla are extremely rare. Endoscopic papillectomy (EP) is a routinely used treatment for AL of the major duodenal papilla but the role of EP for minor AL has not been accurately studied. Methods: We identified 20 patients with AL of minor duodenal papilla out of the multicentric database from the ESAP study that included 1422 EPs. We used the propensity score matching (nearest-neighbor method), to match these cases with ampullary lesions of the major duodenal papilla based on age, gender, histologic subtype and size of the lesion in a 1:2-ratio. Cohorts were compared by using Chi-square or Fisher's exact test as well as Mann-Whitney U test. Results: Propensity-score-based matching identified a cohort of 60 (minor papilla 20, major papilla 40) patients with similar baseline characteristics. The most common histological subtype of lesions of minor papilla was an ampullary adenoma in 12 Patients (3 low-grade dysplasia and 9 high-grade dysplasia). Five patients revealed non-neoplastic lesions. Invasive cancer (T1a), adenomyoma and neuroendocrine neoplasia each were found in one case. The rate of complete resection, en bloc resection and recurrences were comparable between both groups. There were no severe complications after EP of lesions of minor papilla. One patient had a delayed bleeding that could be treated by endoscopic hemostasis and two patients showed a recurrence in surveillance endoscopy after a median follow up of 21 months (IQR 12-50). Conclusions: EP is safe and effective in AL of the minor duodenal papilla. Such lesions could be managed according to guidelines for EP of major duodenal papilla

Endoscopic papillectomy for ampullary lesions of minor papilla

Background and Aims: Ampullary lesions (ALs) of the minor duodenal papilla are extremely rare. Endoscopic papillectomy (EP) is a routinely used treatment for AL of the major duodenal papilla, but the role of EP for minor AL has not been accurately studied. Methods: We identified 20 patients with ALs of minor duodenal papilla in the multicentric database from the Endoscopic Papillectomy vs Surgical Ampullectomy vs Pancreatitcoduodenectomy for Ampullary Neoplasm study, which included 1422 EPs. We used propensity score matching (nearest-neighbor method) to match these cases with ALs of the major duodenal papilla based on age, sex, histologic subtype, and size of the lesion in a 1:2 ratio. Cohorts were compared by means of chi-square or Fisher exact test as well as Mann-Whitney U test. Results: Propensity score–based matching identified a cohort of 60 (minor papilla 20, major papilla 40) patients with similar baseline characteristics. The most common histologic subtype of lesions of minor papilla was an ampullary adenoma in 12 patients (3 low-grade dysplasia and 9 high-grade dysplasia). Five patients revealed nonneoplastic lesions. Invasive cancer (T1a), adenomyoma, and neuroendocrine neoplasia were each found in 1 case. The rate of complete resection, en-bloc resection, and recurrences were similar between the groups. There were no severe adverse events after EP of lesions of minor papilla. One patient had delayed bleeding that could be treated by endoscopic hemostasis, and 2 patients showed a recurrence in surveillance endoscopy after a median follow-up of 21 months (interquartile range, 12-50 months). Conclusions: EP is safe and effective in ALs of the minor duodenal papilla. Such lesions could be managed according to guidelines for EP of major duodenal papilla.</p