It is unclear if direct oral anticoagulants (DOACs) are effective and safe alternatives to low-molecular-weight heparin (LMWHs) for the treatment of cancer-associated venous thromboembolism (VTE). We ...aim to synthesize existing literature that compared DOACs versus LMWHs in this high-risk population.
We conducted a systematic review using EMBASE, MEDLINE and CENTRAL for all observational studies and randomized controlled trials (RCTs) (PROSPERO: CRD42017080898). Two authors independently reviewed study eligibility, extracted data, and assessed bias. Primary outcomes included 6-month recurrent VTE and major bleeding. Secondary outcomes included clinically relevant non-major bleeding (CRNMB) and mortality.
We screened 426 articles, reviewed 25 in full-text, and selected 13 and 2 for qualitative and quantitative synthesis, respectively. Based on a meta-analysis of the 2 RCTs, DOACs had lower 6-month recurrent VTE (42/725) when compared to LMWH (64/727) (RR: 0.65 (0.42–1.01)). However, DOACs had higher major bleeding (40/725) when compared to LMWH (23/727) (RR 1.74 (1.05–2.88)). Similarly, CRNMB was higher (RR 2.31 (0.85–6.28)) for patients receiving DOACs. There was no difference in mortality (RR 1.03 (0.85–1.26)). Observational studies were heterogeneous with high risks of bias but showed recurrent VTE rates consistent with the meta-analysis.
DOACs were more effective than LMWHs to prevent recurrent VTE but were associated with a significantly increased risk of major bleeding as well as a trend toward more CRNMB. The absolute risk differences were small (2–3%) for both primary outcomes and may reflect better compliance with DOACs than LMWHs.
•LMWHs have been the treatment of choice for cancer associated VTE.•DOACs are more effective than LMWHs to prevent recurrent VTE in cancer patients.•DOACs are associated with a higher risk of major bleeding compared to LMWHs.•Effectiveness and safety may reflect better compliance with DOACs compared to LMWHs.
Abstract Background Non–vitamin K oral anticoagulants (NOACs) do not require routine laboratory monitoring. However, laboratory measurement may be desirable in special situations and populations. ...Objectives This study’s objective was to systematically review and summarize current evidence regarding laboratory measurement of the anticoagulant activity of dabigatran, rivaroxaban, and apixaban. Methods We searched PubMed and Web of Science for studies that reported a relationship between drug levels of dabigatran, rivaroxaban, and apixaban and coagulation assay results. Study quality was evaluated using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2). Results We identified 17 eligible studies for dabigatran, 15 for rivaroxaban, and 4 for apixaban. For dabigatran, a normal thrombin time excludes clinically relevant drug concentrations. The activated partial thromboplastin time (APTT) and prothrombin time (PT) are less sensitive and may be normal at trough drug levels. The dilute thrombin time (R2 = 0.92 to 0.99) and ecarin-based assays (R2 = 0.92 to 1.00) show excellent linearity across on-therapy drug concentrations and may be used for drug quantification. For rivaroxaban and apixaban, anti-Xa activity is linear (R2 = 0.89 to 1.00) over a wide range of drug levels and may be used for drug quantification. Undetectable anti-Xa activity likely excludes clinically relevant drug concentrations. The PT is less sensitive (especially for apixaban); a normal PT may not exclude clinically relevant levels. The APTT demonstrates insufficient sensitivity and linearity for quantification. Conclusions Dabigatran, rivaroxaban, and apixaban exhibit variable effects on coagulation assays. Understanding these effects facilitates interpretation of test results in NOAC-treated patients. More information on the relationship between drug levels and clinical outcomes is needed.
Studies over the past decade have highlighted the key role of liquid–liquid phase separation in cellular organization and function. Dynamic compartmentalization of transcription factors and ...coactivators by such phase-separated condensates regulates the assembly of transcriptional machinery at genomic loci. Although rapid advances in microscopy have demonstrated the ubiquity of such condensates, a rigorous characterization of the physics of phase separation in transcription remains to be carried out. In this review, we discuss theoretical and experimental evidence for biomolecular condensates as dynamic regulators of transcription. Looking beyond, we highlight functional consequences for transcription factor dynamics and gene expression and discuss potential pitfalls of misclassifying biomolecular condensates as liquid droplets in the absence of a rigorous physical description.
•Liquid–liquid phase separation provides a mechanism for transcriptional regulation•Transcriptional machinery can spontaneously assemble into condensates•Phase separation may regulate genomic organization at all length scales•Liquid condensates can age into gels or solids with different physical properties•Careful characterization of condensates is essential to understand their function
Physical activity (PA) protects against a wide range of diseases. Habitual PA appears to be heritable, motivating the search for specific genetic variants that may inform efforts to promote PA and ...target the best type of PA for each individual.
We used data from the UK Biobank to perform the largest genome-wide association study of PA to date, using three measures based on self-report (n
= 377,234) and two measures based on wrist-worn accelerometry data (n
= 91,084). We examined genetic correlations of PA with other traits and diseases, as well as tissue-specific gene expression patterns. With data from the Atherosclerosis Risk in Communities (ARIC; n = 8,556) study, we performed a meta-analysis of our top hits for moderate-to-vigorous PA (MVPA).
We identified ten loci across all PA measures that were significant in both a basic and a fully adjusted model (p < 5 × 10
). Upon meta-analysis of the nine top hits for MVPA with results from ARIC, eight were genome-wide significant. Interestingly, among these, the rs429358 variant in the APOE gene was the most strongly associated with MVPA, whereby the allele associated with higher Alzheimer's risk was associated with greater MVPA. However, we were not able to rule out possible selection bias underlying this result. Variants in CADM2, a gene previously implicated in obesity, risk-taking behavior and other traits, were found to be associated with habitual PA. We also identified three loci consistently associated (p < 5 × 10
) with PA across both self-report and accelerometry, including CADM2. We found genetic correlations of PA with educational attainment, chronotype, psychiatric traits, and obesity-related traits. Tissue enrichment analyses implicate the brain and pituitary gland as locations where PA-associated loci may exert their actions.
These results provide new insight into the genetic basis of habitual PA, and the genetic links connecting PA with other traits and diseases.
Long-range synchronization of neural oscillations correlates with distinct behaviors, yet its causal role remains unproven. In mice, tests of avoidance behavior evoke increases in theta-frequency ...(∼8 Hz) oscillatory synchrony between the ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC). To test the causal role of this synchrony, we dynamically modulated vHPC-mPFC terminal activity using optogenetic stimulation. Oscillatory stimulation at 8 Hz maximally increased avoidance behavior compared to 2, 4, and 20 Hz. Moreover, avoidance behavior was selectively increased when 8-Hz stimulation was delivered in an oscillatory, but not pulsatile, manner. Furthermore, 8-Hz oscillatory stimulation enhanced vHPC-mPFC neurotransmission and entrained neural activity in the vHPC-mPFC network, resulting in increased synchrony between vHPC theta activity and mPFC spiking. These data suggest a privileged role for vHPC-mPFC theta-frequency communication in generating avoidance behavior and provide direct evidence that synchronized oscillations play a role in facilitating neural transmission and behavior.
•Oscillatory, not pulsatile, stimulation of vHPC-mPFC at 8 Hz increased avoidance•Oscillatory stimulation of vHPC-mPFC at 2 or 20 Hz did not increase avoidance•Oscillatory stimulation of vHPC-mPFC facilitated neural transmission in this pathway•8-Hz oscillatory stimulation increased vHPC-mPFC theta synchrony during the EPM
Padilla-Coreano et al. investigated the role of vHPC-mPFC theta synchrony in avoidance behavior. They demonstrate that, compared to other frequencies, oscillatory optogenetic stimulation of vHPC terminals in mPFC at 8 Hz maximally increases avoidance, enhances neural transmission, and increases synchrony in this pathway.
Background Direct oral anticoagulants (DOACs) are the treatment of choice for most patients with atrial fibrillation and/or noncancer-associated venous thromboembolic disease. Although routine ...monitoring of these agents is not required, assessment of anticoagulant effect may be desirable in special situations. The objective of this review was to summarize systematically evidence regarding laboratory assessment of the anticoagulant effects of dabigatran, rivaroxaban, apixaban, and edoxaban. Methods PubMed, Embase, and Web of Science were searched for studies reporting relationships between drug levels and coagulation assay results. Results We identified 109 eligible studies: 35 for dabigatran, 50 for rivaroxaban, 11 for apixaban, and 13 for edoxaban. The performance of standard anticoagulation tests varied across DOACs and reagents; most assays, showed insufficient correlation to provide a reliable assessment of DOAC effects. Dilute thrombin time (TT) assays demonstrated linear correlation ( r2 = 0.67-0.99) across a range of expected concentrations of dabigatran, as did ecarin-based assays. Calibrated anti-Xa assays demonstrated linear correlation ( r2 = 0.78-1.00) across a wide range of concentrations for rivaroxaban, apixaban, and edoxaban. Conclusions An ideal test, offering both accuracy and precision for measurement of any DOAC is not widely available. We recommend a dilute TT or ecarin-based assay for assessment of the anticoagulant effect of dabigatran and anti-Xa assays with drug-specific calibrators for direct Xa inhibitors. In the absence of these tests, TT or APTT is recommended over PT/INR for assessment of dabigatran, and PT/INR is recommended over APTT for detection of factor Xa inhibitors. Time since last dose, the presence or absence of drug interactions, and renal and hepatic function should impact clinical estimates of anticoagulant effect in a patient for whom laboratory test results are not available.
Approximately 20% of patients with
-mutant myelodysplastic syndromes (MDS) achieve complete remission (CR) with hypomethylating agents. Eprenetapopt (APR-246) is a novel, first-in-class, small ...molecule that restores wild-type p53 functions in
-mutant cells.
This was a phase Ib/II study to determine the safety, recommended phase II dose, and efficacy of eprenetapopt administered in combination with azacitidine in patients with
-mutant MDS or acute myeloid leukemia (AML) with 20%-30% marrow blasts (ClinicalTrials.gov identifier: NCT03072043).
Fifty-five patients (40 MDS, 11 AML, and four MDS/myeloproliferative neoplasms) with at least one
mutation were treated. The overall response rate was 71% with 44% achieving CR. Of patients with MDS, 73% (n = 29) responded with 50% (n = 20) achieving CR and 58% (23/40) a cytogenetic response. The overall response rate and CR rate for patients with AML was 64% (n = 7) and 36% (n = 4), respectively. Patients with only
mutations by next-generation sequencing had higher rates of CR (69%
25%;
= .006). Responding patients had significant reductions in
variant allele frequency and p53 expression by immunohistochemistry, with 21 (38%) achieving complete molecular remission (variant allele frequency < 5%). Median overall survival was 10.8 months with significant improvement in responding versus nonresponding patients by landmark analysis (14.6
7.5 months;
= .0005). Overall, 19/55 (35%) patients underwent allogeneic hematopoietic stem-cell transplant, with a median overall survival of 14.7 months. Adverse events were similar to those reported for azacitidine or eprenetapopt monotherapy, with the most common grade ≥ 3 adverse events being febrile neutropenia (33%), leukopenia (29%), and neutropenia (29%).
Combination treatment with eprenetapopt and azacitidine is well-tolerated yielding high rates of clinical response and molecular remissions in patients with
-mutant MDS and oligoblastic AML.
Switch between Morphospecies of Pocillopora Corals Paz-García, David A.; Hellberg, Michael E.; García-de-León, Francisco J. ...
The American naturalist,
09/2015, Letnik:
186, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Pocillopora corals are the main reef builders in the eastern tropical Pacific. The validity of Pocillopora morphospecies remains under debate because of disagreements between morphological and ...genetic data. To evaluate the temporal stability of morphospecies in situ, we monitored the shapes of individual colonies in three communities in the southern Gulf of California for 44 months. Twenty-three percent of tagged colonies of Pocillopora damicornis changed to Pocillopora inflata morphology during this time. This switch in identity coincided with a shift to a higher frequency of storms and lower water turbidity (i.e., lower chlorophyll a levels). Seven months after the switch, P. inflata colonies were recovering their original P. damicornis morphology. All colonies of both morphospecies shared a common mitochondrial identity, but most P. damicornis colonies undergoing change were at a site with low-flow conditions. This is the first in situ study to document switching between described morphospecies, and it elucidates the influence of temporal shifts in environmental conditions on morphologically plastic responses.
Potential moderators of effects in the actor–partner interdependence model (APIM) include variables that vary within dyads, between dyads, or both between and within dyads (i.e., mixed moderators). ...Another factor in the moderation of the APIM is whether dyads are indistinguishable (e.g., same‐sex friendship pairs) or distinguishable (e.g., heterosexual couples). For each possibility, what are the potential moderator effects (up to 8), how they might be estimated and tested, and how they can be interpreted are discussed. Submodels are also presented, based on patterns of moderation of the actor and partner effects, which are statistically simpler, more conceptually meaningful, and more powerful in testing moderator effects. Example analyses illustrate the recommended steps involved in an APIM moderation analysis.
Coral reefs worldwide are threatened by thermal stress caused by climate change. Especially devastating periods of coral loss frequently occur during El Niño‐Southern Oscillation (ENSO) events ...originating in the Eastern Tropical Pacific (ETP). El Niño‐induced thermal stress is considered the primary threat to ETP coral reefs. An increase in the frequency and intensity of ENSO events predicted in the coming decades threatens a pan‐tropical collapse of coral reefs. During the 1982–1983 El Niño, most reefs in the Galapagos Islands collapsed, and many more in the region were decimated by massive coral bleaching and mortality. However, after repeated thermal stress disturbances, such as those caused by the 1997–1998 El Niño, ETP corals reefs have demonstrated regional persistence and resiliency. Using a 44 year dataset (1970–2014) of live coral cover from the ETP, we assess whether ETP reefs exhibit the same decline as seen globally for other reefs. Also, we compare the ETP live coral cover rate of change with data from the maximum Degree Heating Weeks experienced by these reefs to assess the role of thermal stress on coral reef survival. We find that during the period 1970–2014, ETP coral cover exhibited temporary reductions following major ENSO events, but no overall decline. Further, we find that ETP reef recovery patterns allow coral to persist under these El Niño‐stressed conditions, often recovering from these events in 10–15 years. Accumulative heat stress explains 31% of the overall annual rate of change of living coral cover in the ETP. This suggests that ETP coral reefs have adapted to thermal extremes to date, and may have the ability to adapt to near‐term future climate‐change thermal anomalies. These findings for ETP reef resilience may provide general insights for the future of coral reef survival and recovery elsewhere under intensifying El Niño scenarios.
El Niño is the main threat to coral reefs in the Eastern Tropical Pacific (ETP), but it is unknown if the coral cover decreases in the long term due to El Niño‐induced thermal stress. Based on a 44 year time‐series analysis of live coral cover (1970–2014), we determine that, unlike in the Caribbean and the Indo‐Pacific, coral reefs in the ETP do not show a long‐term decline. Our analysis indicates that ETP coral reefs show recovery patterns of 10–15 years, allowing them to persist under El Niño‐stressed conditions. We explore some possible explanations for this resilience to thermal stress.
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