Tranexamic acid reduces the risk of bleeding among patients undergoing cardiac surgery, but it is unclear whether this leads to improved outcomes. Furthermore, there are concerns that tranexamic acid ...may have prothrombotic and proconvulsant effects.
In a trial with a 2-by-2 factorial design, we randomly assigned patients who were scheduled to undergo coronary-artery surgery and were at risk for perioperative complications to receive aspirin or placebo and tranexamic acid or placebo. The results of the tranexamic acid comparison are reported here. The primary outcome was a composite of death and thrombotic complications (nonfatal myocardial infarction, stroke, pulmonary embolism, renal failure, or bowel infarction) within 30 days after surgery.
Of the 4662 patients who were enrolled and provided consent, 4631 underwent surgery and had available outcomes data; 2311 were assigned to the tranexamic acid group and 2320 to the placebo group. A primary outcome event occurred in 386 patients (16.7%) in the tranexamic acid group and in 420 patients (18.1%) in the placebo group (relative risk, 0.92; 95% confidence interval, 0.81 to 1.05; P=0.22). The total number of units of blood products that were transfused during hospitalization was 4331 in the tranexamic acid group and 7994 in the placebo group (P<0.001). Major hemorrhage or cardiac tamponade leading to reoperation occurred in 1.4% of the patients in the tranexamic acid group and in 2.8% of the patients in the placebo group (P=0.001), and seizures occurred in 0.7% and 0.1%, respectively (P=0.002 by Fisher's exact test).
Among patients undergoing coronary-artery surgery, tranexamic acid was associated with a lower risk of bleeding than was placebo, without a higher risk of death or thrombotic complications within 30 days after surgery. Tranexamic acid was associated with a higher risk of postoperative seizures. (Funded by the Australian National Health and Medical Research Council and others; ATACAS Australia New Zealand Clinical Trials Registry number, ACTRN12605000557639 .).
Saccadic eye movements enable us to search for the target of interest in a crowded scene or, in the case of goal-directed saccades, to simply bring the image of the peripheral target to the very ...centre of the fovea. This mechanism extends the use of the superior image processing performance of the fovea over a large visual field. We know that visual information is processed quickly at the end of each saccade but estimates of the times involved remain controversial. This study aims to investigate the processing of visual information during post fixation oscillations of the eyeball. A new psychophysical test measures the combined eye movement response latencies, including fixation duration and visual processing times. When the test is used in conjunction with an eye tracker, each component that makes up the 'integrated saccade latency' time, from the onset of the peripheral stimulus to the correct interpretation of the information carried by the stimulus, can be measured and the discrete components delineated. The results show that the time required to process and encode the stimulus attribute of interest at the end of a saccade is longer than the time needed to carry out the same task in the absence of an eye movement. We propose two principal hypotheses, each of which can account for this finding. 1. The known inhibition of afferent retinal signals during fast eye movements extends beyond the end point of the saccade. 2. The extended visual processing times measured when saccades are involved are caused by the transient loss of spatial resolution due to eyeball instability during post-saccadic oscillations. The latter can best be described as retinal image smear with greater loss of spatial resolution expected for stimuli of low luminance contrast.
We report the preparation and X‐ray crystallographic characterization of the first crystalline homoatomic polymer chain, which is part of a semiconducting pyrroloperylene–iodine complex. The crystal ...structure contains infinite polyiodide I∞δ−. Interestingly, the structure of iodine within the insoluble, blue starch–iodine complex has long remained elusive, but has been speculated as having infinite chains of iodine. Close similarities in the low‐wavenumber Raman spectra of the title compound and starch–iodine point to such infinite polyiodide chains in the latter as well.
The crystal structure of the pyrroloperylene–iodine complex (with a formula close to pyrroloperylene–I2.2) has been solved. The structure contains infinite polyiodide chains, the Raman spectrum of which resembles that of the famous starch–iodine complex, thus casting light on a historical puzzle (see picture). The complex displays nearly metallic conductivity and some signatures of a Peierls distortion of the chains at 150 K.
The 2013-2016 West African epidemic caused by the Ebola virus was of unprecedented magnitude, duration and impact. Here we reconstruct the dispersal, proliferation and decline of Ebola virus ...throughout the region by analysing 1,610 Ebola virus genomes, which represent over 5% of the known cases. We test the association of geography, climate and demography with viral movement among administrative regions, inferring a classic 'gravity' model, with intense dispersal between larger and closer populations. Despite attenuation of international dispersal after border closures, cross-border transmission had already sown the seeds for an international epidemic, rendering these measures ineffective at curbing the epidemic. We address why the epidemic did not spread into neighbouring countries, showing that these countries were susceptible to substantial outbreaks but at lower risk of introductions. Finally, we reveal that this large epidemic was a heterogeneous and spatially dissociated collection of transmission clusters of varying size, duration and connectivity. These insights will help to inform interventions in future epidemics.
Isocitrate dehydrogenase 1 (IDH1) variations occur in up to approximately 20% of patients with intrahepatic cholangiocarcinoma. In the ClarIDHy trial, progression-free survival as determined by ...central review was significantly improved with ivosidenib vs placebo.
To report the final overall survival (OS) results from the ClarIDHy trial, which aimed to demonstrate the efficacy of ivosidenib (AG-120)-a first-in-class, oral, small-molecule inhibitor of mutant IDH1-vs placebo for patients with unresectable or metastatic cholangiocarcinoma with IDH1 mutation.
This multicenter, randomized, double-blind, placebo-controlled, clinical phase 3 trial was conducted from February 20, 2017, to May 31, 2020, at 49 hospitals across 6 countries among patients aged 18 years or older with cholangiocarcinoma with IDH1 mutation whose disease progressed with prior therapy.
Patients were randomized 2:1 to receive ivosidenib, 500 mg, once daily or matched placebo. Crossover from placebo to ivosidenib was permitted if patients had disease progression as determined by radiographic findings.
The primary end point was progression-free survival as determined by blinded independent radiology center (reported previously). Overall survival was a key secondary end point. The primary analysis of OS followed the intent-to-treat principle. Other secondary end points included objective response rate, safety and tolerability, and quality of life.
Overall, 187 patients (median age, 62 years range, 33-83 years) were randomly assigned to receive ivosidenib (n = 126; 82 women 65%; median age, 61 years range, 33-80 years) or placebo (n = 61; 37 women 61%; median age, 63 years range, 40-83 years); 43 patients crossed over from placebo to ivosidenib. The primary end point of progression-free survival was reported elsewhere. Median OS was 10.3 months (95% CI, 7.8-12.4 months) with ivosidenib vs 7.5 months (95% CI, 4.8-11.1 months) with placebo (hazard ratio, 0.79 95% CI, 0.56-1.12; 1-sided P = .09). When adjusted for crossover, median OS with placebo was 5.1 months (95% CI, 3.8-7.6 months; hazard ratio, 0.49 95% CI, 0.34-0.70; 1-sided P < .001). The most common grade 3 or higher treatment-emergent adverse event (≥5%) reported in both groups was ascites (11 patients 9% receiving ivosidenib and 4 patients 7% receiving placebo). Serious treatment-emergent adverse events considered ivosidenib related were reported in 3 patients (2%). There were no treatment-related deaths. Patients receiving ivosidenib reported no apparent decline in quality of life compared with placebo.
This randomized clinical trial found that ivosidenib was well tolerated and resulted in a favorable OS benefit vs placebo, despite a high rate of crossover. These data, coupled with supportive quality of life data and a tolerable safety profile, demonstrate the clinical benefit of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation.
ClinicalTrials.gov Identifier: NCT02989857.
Oats are a rich source of β-glucan, a viscous, soluble fibre recognised for its cholesterol-lowering properties, and are associated with reduced risk of CVD. Our objective was to conduct a systematic ...review and meta-analysis of randomised-controlled trials (RCT) investigating the cholesterol-lowering potential of oat β-glucan on LDL-cholesterol, non-HDL-cholesterol and apoB for the risk reduction of CVD. MEDLINE, Embase, CINAHL and Cochrane CENTRAL were searched. We included RCT of ≥3 weeks of follow-up, assessing the effect of diets enriched with oat β-glucan compared with controlled diets on LDL-cholesterol, non-HDL-cholesterol or apoB. Two independent reviewers extracted data and assessed study quality and risk of bias. Data were pooled using the generic inverse-variance method with random effects models and expressed as mean differences with 95 % CI. Heterogeneity was assessed by the Cochran's Q statistic and quantified by the I 2-statistic. In total, fifty-eight trials (n 3974) were included. A median dose of 3·5 g/d of oat β-glucan significantly lowered LDL-cholesterol (-0·19; 95 % CI -0·23, -0·14 mmol/l, P<0·00001), non-HDL-cholesterol (-0·20; 95 % CI -0·26, -0·15 mmol/l, P<0·00001) and apoB (-0·03; 95 % CI -0·05, -0·02 g/l, P<0·0001) compared with control interventions. There was evidence for considerable unexplained heterogeneity in the analysis of LDL-cholesterol (I 2=79 %) and non-HDL-cholesterol (I 2=99 %). Pooled analyses showed that oat β-glucan has a lowering effect on LDL-cholesterol, non-HDL-cholesterol and apoB. Inclusion of oat-containing foods may be a strategy for achieving targets in CVD reduction.
The balance between stem cell quiescence and proliferation in skeletal muscle is tightly controlled, but perturbed in a variety of disease states. Despite progress in identifying activators of stem ...cell proliferation, the niche factor(s) responsible for quiescence induction remain unclear. Here we report an in vivo imaging-based screen which identifies Oncostatin M (OSM), a member of the interleukin-6 family of cytokines, as a potent inducer of muscle stem cell (MuSC, satellite cell) quiescence. OSM is produced by muscle fibers, induces reversible MuSC cell cycle exit, and maintains stem cell regenerative capacity as judged by serial transplantation. Conditional OSM receptor deletion in satellite cells leads to stem cell depletion and impaired regeneration following injury. These results identify Oncostatin M as a secreted niche factor responsible for quiescence induction, and for the first time establish a direct connection between induction of quiescence, stemness, and transplantation potential in solid organ stem cells.
Background.Acute gastroenteritis is commonly associated with norovirus genogroup II (GII) infection. Norovirus GII has 17 classified genotypes (GII.1–GII.17), but only 1 norovirus genotype (GII.4) is ...associated with global epidemics of gastroenteritis. In 2006, an increase in global norovirus activity was observed. Methods.During the period from December 2005 through August 2006, a total of 231 fecal samples were obtained from patients with acute gastroenteritis from Australia and New Zealand. Norovirus RNA was amplified and sequenced to determine norovirus genotype and relatedness to known epidemic norovirus GII.4 variants. Results.Two GII.4 variants, designated 2006a and 2006b, were identified in 61.8% and 11.3%, respectively, of the 186 cases investigated. Norovirus 2006a and 2006b have also been implicated as the predominant causes of norovirus-associated gastroenteritis across Europe in 2006. Conclusions.The global increase in norovirus-associated gastroenteritis in 2006 was linked to the emergence of 2 novel GII.4 variants, 2006a and 2006b.
Global increases in atmospheric CO2 and temperature are associated with changes in ocean chemistry and circulation, altering light and nutrient regimes. Resulting changes in phytoplankton community ...structure are expected to have a cascading effect on primary and export production, food web dynamics and the structure of the marine food web as well the biogeochemical cycling of carbon and bio-limiting elements in the sea. A review of current literature indicates cell size and elemental stoichiometry often respond predictably to abiotic conditions and follow biophysical rules that link environmental conditions to growth rates, and growth rates to food web interactions, and consequently to the biogeochemical cycling of elements. This suggests that cell size and elemental stoichiometry are promising ecophysiological traits for modelling and tracking changes in phytoplankton community structure in response to climate change. In turn, these changes are expected to have further impacts on phytoplankton community structure through as yet poorly understood secondary processes associated with trophic dynamics.
Varus and valgus alignment increase medial and lateral tibiofemoral load. Alignment was associated with tibiofemoral osteoarthritis progression in previous studies; an effect on incident ...osteoarthritis risk is less certain. This study tested whether alignment influences the risk of incident and progressive radiographic tibiofemoral osteoarthritis.
In an observational, longitudinal study of the Multicenter Osteoarthritis Study cohort, full-limb x-rays to measure alignment were acquired at baseline and knee x-rays were acquired at baseline and knee x-rays at baseline and 30 months. Varus alignment was defined as ≤178° and valgus ≥182°. Using logistic regression and generalised estimating equations, the associations of baseline alignment and incident osteoarthritis at 30 months (in knees without baseline osteoarthritis) and alignment and osteoarthritis progression (in knees with osteoarthritis) were examined, adjusting. For age, gender, body mass index, injury, laxity and strength, with neutral knees as referent.
2958 knees (1752 participants) were without osteoarthritis at baseline. Varus (adjusted OR 1.49, 95% CI 1.06 to 2.10) but not valgus alignment was associated with incident osteoarthritis. 1307 knees (950 participants) had osteoarthritis at baseline. Varus alignment was associated with a greater risk of medial osteoarthritis progression (adjusted OR 3.59, 95% CI 2.62 to 4.92) and a reduced risk of lateral progression, and valgus with a greater risk of lateral progression (adjusted OR 4.85, 95% CI 3.17 to 7.42) and a reduced risk of medial progression.
Varus but not valgus alignment increased the risk of incident tibiofemoral osteoarthritis. In knees with osteoarthritis, varus and valgus alignment each increased the risk of progression in the biomechanically stressed compartment.
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