Background
Balancing the risk of bleeding and thrombosis after acute myocardial infarction (AMI) is challenging, and the optimal antithrombotic therapy remains uncertain. The potential of non‐vitamin ...K antagonist oral anticoagulants (NOACs) to prevent ischaemic cardiovascular events is promising, but the evidence remains limited.
Objectives
To evaluate the efficacy and safety of non‐vitamin‐K‐antagonist oral anticoagulants (NOACs) in addition to background antiplatelet therapy, compared with placebo, antiplatelet therapy, or both, after acute myocardial infarction (AMI) in people without an indication for anticoagulation (i.e. atrial fibrillation or venous thromboembolism).
Search methods
We searched CENTRAL, MEDLINE, Embase, the Conference Proceedings Citation Index – Science, and two clinical trial registers in September 2022 with no language restrictions. We checked the reference lists of included studies for any additional trials.
Selection criteria
We searched for randomised controlled trials (RCTs) that evaluated NOACs plus antiplatelet therapy versus placebo, antiplatelet therapy, or both, in people without an indication for anticoagulation after an AMI.
Data collection and analysis
Two review authors independently checked the results of searches to identify relevant studies, assessed each included study, and extracted study data. We conducted random‐effects pairwise analyses using Review Manager Web, and network meta‐analysis using the R package 'netmeta'. We ranked competing treatments by P scores, which are derived from the P values of all pairwise comparisons and allow ranking of treatments on a continuous 0‐to‐1 scale.
Main results
We identified seven eligible RCTs, including an ongoing trial that we could not include in the analysis. Of the six RCTs involving 33,039 participants, three RCTs compared rivaroxaban with placebo, two RCTs compared apixaban with placebo, and one RCT compared dabigatran with placebo. All participants in the six RCTs received concomitant antiplatelet therapy.
The available evidence suggests that rivaroxaban compared with placebo reduces the rate of all‐cause mortality (risk ratio (RR) 0.82, 95% confidence interval (CI) 0.69 to 0.98; number needed to treat for an additional beneficial outcome (NNTB) 250; 3 studies, 21,870 participants; high certainty) and probably reduces cardiovascular mortality (RR 0.83, 95% CI 0.69 to 1.01; NNTB 250; 3 studies, 21,870 participants; moderate certainty). There is probably little or no difference between apixaban and placebo in all‐cause mortality (RR 1.09, 95% CI 0.88 to 1.35; number needed to treat for an additional harmful outcome (NNTH) 334; 2 studies, 8638 participants; moderate certainty) and cardiovascular mortality (RR 0.99, 95% CI 0.77 to 1.27; number needed to treat not applicable; 2 studies, 8638 participants; moderate certainty). Dabigatran may reduce the rate of all‐cause mortality compared with placebo (RR 0.57, 95% CI 0.31 to 1.06; NNTB 63; 1 study, 1861 participants; low certainty). Dabigatran compared with placebo may have little or no effect on cardiovascular mortality, although the point estimate suggests benefit (RR 0.72, 95% CI 0.34 to 1.52; NNTB 143; 1 study, 1861 participants; low certainty).
Two of the investigated NOACs were associated with an increased risk of major bleeding compared to placebo: apixaban (RR 2.41, 95% CI 1.44 to 4.06; NNTH 143; 2 studies, 8544 participants; high certainty) and rivaroxaban (RR 3.31, 95% CI 1.12 to 9.77; NNTH 125; 3 studies, 21,870 participants; high certainty). There may be little or no difference between dabigatran and placebo in the risk of major bleeding (RR 1.74, 95% CI 0.22 to 14.12; NNTH 500; 1 study, 1861 participants; low certainty).
The results of the network meta‐analysis were inconclusive between the different NOACs at all individual doses for all primary outcomes. However, low‐certainty evidence suggests that apixaban (combined dose) may be less effective than rivaroxaban and dabigatran for preventing all‐cause mortality after AMI in people without an indication for anticoagulation.
Authors' conclusions
Compared with placebo, rivaroxaban reduces all‐cause mortality and probably reduces cardiovascular mortality after AMI in people without an indication for anticoagulation. Dabigatran may reduce the rate of all‐cause mortality and may have little or no effect on cardiovascular mortality. There is probably no meaningful difference in the rate of all‐cause mortality and cardiovascular mortality between apixaban and placebo. Moreover, we found no meaningful benefit in efficacy outcomes for specific therapy doses of any investigated NOACs following AMI in people without an indication for anticoagulation. Evidence from the included studies suggests that rivaroxaban and apixaban increase the risk of major bleeding compared with placebo. There may be little or no difference between dabigatran and placebo in the risk of major bleeding. Network meta‐analysis did not show any superiority of one NOAC over another for our prespecified primary outcomes.
Although the evidence suggests that NOACs reduce mortality, the effect size or impact is small; moreover, NOACs may increase major bleeding. Head‐to‐head trials, comparing NOACs against each other, are required to provide more solid evidence.
We report protein fold prediction using deep-learning artificial intelligence (AI) has transformed the field of protein structure prediction. By combining physical and geometric constraints—and ...especially patterns extracted from the Protein Data Bank —these machine learning algorithms can predict protein structures at or near atomic resolution and do so in seconds. Today, these computational methods have now solved more than 200 million protein structures, which are accessible from the AlphaFold Protein Structure Database. This accomplishment seems all the more remarkable because few thought it possible or saw it coming. Deservedly, deep-learning AI was named Science magazine’s 2021 “breakthrough of the year”. Clearly, deep-learning AI represents a major advance in protein fold prediction.
Through exomic sequencing of 32 intrahepatic cholangiocarcinomas, we discovered frequent inactivating mutations in multiple chromatin-remodeling genes (including BAP1, ARID1A and PBRM1), and mutation ...in one of these genes occurred in almost half of the carcinomas sequenced. We also identified frequent mutations at previously reported hotspots in the IDH1 and IDH2 genes encoding metabolic enzymes in intrahepatic cholangiocarcinomas. In contrast, TP53 was the most frequently altered gene in a series of nine gallbladder carcinomas. These discoveries highlight the key role of dysregulated chromatin remodeling in intrahepatic cholangiocarcinomas.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The design of PROteolysis-TArgeting Chimeras (PROTACs) requires bringing an E3 ligase into proximity with a target protein to modulate the concentration of the latter through its ubiquitination and ...degradation. Here, we present a method for generating high-accuracy structural models of E3 ligase–PROTAC–target protein ternary complexes. The method is dependent on two computational innovations: adding a “silent” convolution term to an efficient protein–protein docking program to eliminate protein poses that do not have acceptable linker conformations and clustering models of multiple PROTACs that use the same E3 ligase and target the same protein. Results show that the largest consensus clusters always have high predictive accuracy and that the ensemble of models can be used to predict the dissociation rate and cooperativity of the ternary complex that relate to the degrading activity of the PROTAC. The method is demonstrated by applications to known PROTAC structures and a blind test involving PROTACs against BRAF mutant V600E. The results confirm that PROTACs function by stabilizing a favorable interaction between the E3 ligase and the target protein but do not necessarily exploit the most energetically favorable geometry for interaction between the proteins.
We investigate water desorption from hydrophobic surfaces using two curved Ag single crystals centered at (111) and (001) apices. On these types of crystals the step density gradually increases along ...the curvature, allowing us to probe large ranges of surface structures in between the (001), (111) and (110) planes. Subtle differences in desorption of submonolayer water coverages point toward structure dependencies in water cluster nucleation. The B-type step on hydrophobic Ag binds water structures more strongly than adjacent (111) planes, leading to preferred desorption from steps. This driving force is smaller for A-type steps on (111) terraces. The A'-type step flanked by (001) terraces shows no indication of preferred desorption from steps. Extrapolation to the (311) surface, not contained within either curved surface, demonstrates that both A- and A'-type steps can be regarded chemically identical for water desorption. The different trends in desorption temperature on the two crystals can thus be attributed to stronger water adsorption at (001) planes than at (111) planes and identical to adsorption at the step. These results show that our approach to studying the structure dependence of water desorption is sensitive to variations in desorption energy smaller than 'chemical accuracy', i.e. 1 kcal mol-1.
This study investigates whether infants are sensitive to backward and forward transitional probabilities within temporal and spatial visual streams. Two groups of 8‐month‐old infants were ...familiarized with an artificial grammar of shapes, comprising backward and forward base pairs (i.e. two shapes linked by strong backward or forward transitional probability) and part‐pairs (i.e. two shapes with weak transitional probabilities in both directions). One group viewed the continuous visual stream as a temporal sequence, while the other group viewed the same stream as a spatial array. Following familiarization, infants looked longer at test trials containing part‐pairs than base pairs, although they had appeared with equal frequency during familiarization. This pattern of looking time was evident for both forward and backward pairs, in both the temporal and spatial conditions. Further, differences in looking time to part‐pairs that were consistent or inconsistent with the predictive direction of the base pairs (forward or backward) indicated that infants were indeed sensitive to direction when presented with temporal sequences, but not when presented with spatial arrays. These results suggest that visual statistical learning is flexible in infancy and depends on the nature of visual input.
In this study, we demonstrate that 8‐month‐old infants are sensitive to backward and forward transitional probabilities within temporal and spatial visual streams. In addition, differences in sensitivity to violations of the forward and backward relations provide evidence that infants may not encode or represent spatial and temporal visual regularities in the same way.
Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome (MDS)/myeloproliferative disorder most commonly seen in the elderly. We describe an adolescent with monosomy 7 CMML presenting as ...central diabetes insipidus (DI), who was treated with venetoclax and decitabine as a bridge to hematopoietic stem cell transplantation (HSCT). Central DI is a rare manifestation of monosomy 7‐associated MDS including CMML, itself a rare manifestation of GATA2 deficiency, particularly in children. Venetoclax/decitabine was effective for treatment of CMML as a bridge to HSCT.
: Assessment of the prothrombotic, proinflammatory, and functional status of a cohort of COVID-19 patients at least two years after the acute infection to identify parameters with potential ...therapeutic and prognostic value.
: We conducted a retrospective, descriptive study that included 117 consecutive patients admitted to Iasi Pulmonary Rehabilitation Clinic for reassessment and a rehabilitation program at least two years after a COVID-19 infection. The cohort was divided into two groups based on the presence (
= 49) or absence (
= 68) of pulmonary fibrosis, documented through high-resolution computer tomography.
: The cohort comprises 117 patients, 69.23% females, with a mean age of 65.74 ± 10.19 years and abnormal body mass index (31.42 ± 5.71 kg/m
). Patients with pulmonary fibrosis have significantly higher levels of C-reactive protein (CRP) (
< 0.05), WBC (7.45 ± 7.86/mm
vs. 9.18 ± 17.24/mm
,
= 0.053), neutrophils (4.68 ± 7.88/mm
vs. 9.07 ± 17.44/mm
,
< 0.05), mean platelet volume (MPV) (7.22 ± 0.93 vs. 10.25 ± 0.86 fL,
< 0.05), lactate dehydrogenase (
< 0.05), and D-dimers (
< 0.05), but not ferritin (
= 0.470), reflecting the chronic proinflammatory and prothrombotic status. Additionally, patients with associated pulmonary fibrosis had a higher mean heart rate (
< 0.05) and corrected QT interval (
< 0.05). D-dimers were strongly and negatively correlated with diffusion capacity corrected for hemoglobin (DLCO corr), and ROC analysis showed that the persistence of high D-dimers values is a predictor for low DLCO values (ROC analysis: area under the curve of 0.772,
< 0.001). The results of pulmonary function tests (spirometry, body plethysmography) and the 6-minute walk test demonstrated no significant difference between groups, without notable impairment within either group.
Patients with COVID-19-related pulmonary fibrosis have a persistent long-term proinflammatory, prothrombotic status, despite the functional recovery. The persistence of elevated D-dimer levels could emerge as a predictive factor associated with impaired DLCO.
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