Sleep Enforces the Temporal Order in Memory

BACKGROUND: Temporal sequence represents the main principle underlying episodic memory. The storage of temporal sequence information is thought to involve hippocampus-dependent memory systems, preserving temporal structure possibly via chaining of sequence elements in heteroassociative networks. Converging evidence indicates that sleep enhances the consolidation of recently acquired representations in the hippocampus-dependent declarative memory system. Yet, it is unknown if this consolidation process comprises strengthening of the temporal sequence structure of the representation as well, or is restricted to sequence elements independent of their temporal order. To address this issue we tested the influence of sleep on the strength of forward and backward associations in word-triplets. METHODOLOGY/PRINCIPAL FINDINGS: Subjects learned a list of 32 triplets of unrelated words, presented successively (A-B-C) in the center of a screen, and either slept normally or stayed awake in the subsequent night. After two days, retrieval was assessed for the triplets sequentially either in a forward direction (cueing with A and B and asking for B and C, respectively) or in a backward direction (cueing with C and B and asking for B and A, respectively). Memory was better for forward than backward associations (p<0.01). Sleep did not affect backward associations, but enhanced forward associations, specifically for the first (AB) transitions (p<0.01), which were generally more difficult to retrieve than the second transitions. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate that consolidation during sleep strengthens the original temporal sequence structure in memory, presumably as a result of a replay of new representations during sleep in forward direction. Our finding suggests that the temporally directed replay of memory during sleep, apart from strengthening those traces, could be the key mechanism that explains how temporal order is integrated and maintained in the trace of an episodic memory

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&lt;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 (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;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

Time Course of Induced Astigmatism After Canaloplasty

Purpose:To study the changes in astigmatism after canaloplasty and to analyze its correlation with long-term intraocular pressure (IOP) results.Methods:Twenty-six eyes of 26 consecutive patients with primary open-angle glaucoma (n=14) and pseudoexfoliative glaucoma (n=12) undergoing canaloplasty were included in this retrospective study. Canaloplasty comprised of 360-degree catheterisation of Schlemm canal by means of a flexible microcatheter with distension of the canal by 2 tensioning 10-0 polypropylene sutures. Primary outcome measures included IOP, glaucoma medication usage, astigmatism, and adverse events at 2, 4, 12, and 24 weeks postoperatively.Results:The mean preoperative IOP was 21.15.8 mm Hg. The mean IOP decreased to 14.25 +/- 4.3 mm Hg at 6 months. Mean astigmatism preoperatively was 0.77 +/- 0.5 D, which increased to 3.3 +/- 1.7 D at 2 weeks postoperatively (P0.05; Wilcoxon-test). Thereafter, the astigmatism underwent a spontaneous decline, reaching 1.9 +/- 0.8 D at 4 weeks and 1.2 +/- 0.74 D at 12 weeks postoperatively. Best-corrected visual acuity did not change significantly. Six months after canaloplasty, mean astigmatism reached the preoperative range of 0.86 +/- 0.52 D. Astigmatism at 2 weeks correlated significantly and inversely with IOP at 6 months (r=0.59, P=0.005; Spearman).Conclusions:The change of astigmatism after canaloplasty follows a clear time course with a maximum at 2 weeks reaching preoperative values at 6 months. The amount of surgically induced astigmatism might be helpful to predict outcome of canaloplasty in terms of IOP reduction

Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer : outcomes from the CONKO-003 trial

PURPOSE: To assess the efficacy of a second-line regimen of oxaliplatin and folinic acid-modulated fluorouracil in patients with advanced pancreatic cancer who have experienced progression while receiving gemcitabine monotherapy. PATIENTS AND METHODS: A randomized, open-label, phase III study was conducted in 16 institutions throughout Germany. Recruitment ran from January 2004 until May 2007, and the last follow-up concluded in December 2012. Overall, 168 patients age 18 years or older who experienced disease progression during first-line gemcitabine therapy were randomly assigned to folinic acid and fluorouracil (FF) or oxaliplatin and FF (OFF). Patients were stratified according to the presence of metastases, duration of first-line therapy, and Karnofsky performance status. RESULTS: Median follow-up was 54.1 months, and 160 patients were eligible for the primary analysis. The median overall survival in the OFF group (5.9 months; 95% CI, 4.1 to 7.4) versus the FF group (3.3 months; 95% CI, 2.7 to 4.0) was significantly improved (hazard ratio [HR], 0.66; 95% CI, 0.48 to 0.91; log-rank P = .010). Time to progression with OFF (2.9 months; 95% CI, 2.4 to 3.2) versus FF (2.0 months; 95% CI, 1.6 to 2.3) was significantly extended also (HR, 0.68; 95% CI, 0.50 to 0.94; log-rank P = .019). Rates of adverse events were similar between treatment arms, with the exception of grades 1 to 2 neurotoxicity, which were reported in 29 patients (38.2%) and six patients (7.1%) in the OFF and FF groups, respectively (P < .001). CONCLUSION: Second-line OFF significantly extended the duration of overall survival when compared with FF alone in patients with advanced gemcitabine-refractory pancreatic cancer

Clofarabine/busulfan-based reduced intensity conditioning regimens provides very good survivals in acute myeloid leukemia patients in complete remission at transplant: a retrospective study on behalf of the SFGM-TC

International audienceBackground: Clofarabine has been proved to have higher anti-leukemic myeloid activity compared to fludarabine, a drug extensively used as part of reduced intensity conditioning (RIC) for allogeneic stem cell transplantation (allo-SCT).Results: Eighty-four patients were included. The majority of patients had acute myeloid leukemia (AML, = 63). Sixty-one patients were in complete remission (AML = 55). With a median follow up of 31 months (range: 5.7-74.1), 2-year overall (OS) and disease-free (DFS) survivals, relapse incidence (RI), non-relapse mortality (NRM) and graft-versus-host disease (GVHD)/relapse free survival (GRFS) were 64.5% (53.8-75.2); 57.2% (46.2-68.2); 27.7% (18.2-37.9); 15.1% (8.2-23.9) and 43.6% (32.5-54.7), respectively. Considering AML in remission, 2-year OS, DFS, RI, NRM and GRFS were 74.2% (62-86.5); 66.8% (53.6-79.9); 23.4% (12.7-36); 9.8% (3.5-19.9) and 50.9% (36.9-64.9), respectively. Two-year outcomes were similar between CloB2A1 and CloB2A2 sub-groups. In multivariate analysis, active disease at transplant was the only factor adversely impacting 2 years outcomes.Conclusions: CloB2A2/A1 RIC regimen provides very good results for AML patients allografted in CR and could be retained as a new RIC platform for these patients.>Materials and Methods: This was a retrospective study including all patients who received a clofarabine/busulfan based RIC allo-SCT for myeloid malignancies and reported within the SFGM-TC registry. RIC regimen consisted of clofarabine 30 mg/m/day 4 to 5 days (Clo), busulfan 3.2 mg/kg/day 2 days (B2) and 2.5 mg/kg/day of rabbit anti-thymocyte globulin 1 or 2 days (A1 or A2). The primary objective of the study was to report the main outcomes of the whole cohort at 2 years