RESUMEN
Regulatory elements activate promoters by recruiting transcription factors (TFs) to specific motifs. Notably, TF-DNA interactions often depend on cooperativity with colocalized partners, suggesting an underlying cis-regulatory syntax. To explore TF cooperativity in mammals, we analyze â¼500 mouse and human primary cells by combining an atlas of TF motifs, footprints, ChIP-seq, transcriptomes, and accessibility. We uncover two TF groups that colocalize with most expressed factors, forming stripes in hierarchical clustering maps. The first group includes lineage-determining factors that occupy DNA elements broadly, consistent with their key role in tissue-specific transcription. The second one, dubbed universal stripe factors (USFs), comprises â¼30 SP, KLF, EGR, and ZBTB family members that recognize overlapping GC-rich sequences in all tissues analyzed. Knockouts and single-molecule tracking reveal that USFs impart accessibility to colocalized partners and increase their residence time. Mammalian cells have thus evolved a TF superfamily with overlapping DNA binding that facilitate chromatin accessibility.
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Cromatina , Factores de Transcripción , Animales , Sitios de Unión , Cromatina/genética , ADN/genética , Humanos , Mamíferos/genética , Mamíferos/metabolismo , Ratones , Ratones Noqueados , Unión Proteica , Factores de Transcripción/metabolismoRESUMEN
Transcription factors (TFs) regulate gene expression by binding to specific consensus motifs within the local chromatin context. The mechanisms by which TFs navigate the nuclear environment as they search for binding sites remain unclear. Here, we used single-molecule tracking and machine-learning-based classification to directly measure the nuclear mobility of the glucocorticoid receptor (GR) in live cells. We revealed two distinct and dynamic low-mobility populations. One accounts for specific binding to chromatin, while the other represents a confinement state that requires an intrinsically disordered region (IDR), implicated in liquid-liquid condensate subdomains. Further analysis showed that the dwell times of both subpopulations follow a power-law distribution, consistent with a broad distribution of affinities on the GR cistrome and interactome. Together, our data link IDRs with a confinement state that is functionally distinct from specific chromatin binding and modulates the transcriptional output by increasing the local concentration of TFs at specific sites.
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Proteínas Intrínsecamente Desordenadas/química , Receptores de Glucocorticoides/química , Factores de Transcripción/química , Animales , Femenino , Proteínas Intrínsecamente Desordenadas/genética , Proteínas Intrínsecamente Desordenadas/metabolismo , Ratones , Ratas , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Genes are transcribed in a discontinuous pattern referred to as RNA bursting, but the mechanisms regulating this process are unclear. Although many physiological signals, including glucocorticoid hormones, are pulsatile, the effects of transient stimulation on bursting are unknown. Here we characterize RNA synthesis from single-copy glucocorticoid receptor (GR)-regulated transcription sites (TSs) under pulsed (ultradian) and constant hormone stimulation. In contrast to constant stimulation, pulsed stimulation induces restricted bursting centered around the hormonal pulse. Moreover, we demonstrate that transcription factor (TF) nuclear mobility determines burst duration, whereas its bound fraction determines burst frequency. Using 3D tracking of TSs, we directly correlate TF binding and RNA synthesis at a specific promoter. Finally, we uncover a striking co-bursting pattern between TSs located at proximal and distal positions in the nucleus. Together, our data reveal a dynamic interplay between TF mobility and RNA bursting that is responsive to stimuli strength, type, modality, and duration.
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Glucocorticoides/farmacología , Regiones Promotoras Genéticas , ARN/biosíntesis , Receptores de Glucocorticoides/metabolismo , Sitio de Iniciación de la Transcripción , Transcripción Genética/efectos de los fármacos , Animales , Ratones , ARN/genéticaRESUMEN
As climatic variation re-shapes global biodiversity, understanding eco-evolutionary feedbacks during species range shifts is of increasing importance. Theory on range expansions distinguishes between two different forms: "pulled" and "pushed" waves. Pulled waves occur when the source of the expansion comes from low-density peripheral populations, while pushed waves occur when recruitment to the expanding edge is supplied by high-density populations closer to the species' core. How extreme events shape pushed/pulled wave expansion events, as well as trailing-edge declines/contractions, remains largely unexplored. We examined eco-evolutionary responses of a marine invertebrate (the owl limpet, Lottia gigantea) that increased in abundance during the 2014-2016 marine heatwaves near the poleward edge of its geographic range in the northeastern Pacific. We used whole-genome sequencing from 19 populations across >11 degrees of latitude to characterize genomic variation, gene flow, and demographic histories across the species' range. We estimated present-day dispersal potential and past climatic stability to identify how contemporary and historical seascape features shape genomic characteristics. Consistent with expectations of a pushed wave, we found little genomic differentiation between core and leading-edge populations, and higher genomic diversity at range edges. A large and well-mixed population in the northern edge of the species' range is likely a result of ocean current anomalies increasing larval settlement and high-dispersal potential across biogeographic boundaries. Trailing-edge populations have higher differentiation from core populations, possibly driven by local selection and limited gene flow, as well as high genomic diversity likely as a result of climatic stability during the Last Glacial Maximum. Our findings suggest that extreme events can drive poleward range expansions that carry the adaptive potential of core populations, while also cautioning that trailing-edge extirpations may threaten unique evolutionary variation. This work highlights the importance of understanding how both trailing and leading edges respond to global change and extreme events.
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Evolución Biológica , Cambio Climático , Animales , Flujo Génico , Dinámica Poblacional , Distribución Animal , Variación GenéticaRESUMEN
Beauveria bassiana has potential for Aedes aegypti biological control. However, its efficacy depends on the strain's geographic location, host susceptibility, and virulence. The present study aimed to evaluate the effectiveness of B. bassiana strain BBPTG4 conidia in controlling Ae. aegypti adults and its detection via introns profile on exposed mosquito corpses. Morphologic characteristics among strains were highly similar. Comprehensive testing of these strains demonstrated that BBPT4 exhibited the ideal biological activity for Ae. aegypti control, with a median lethal time (TL50) of 7.5 d compared to ~3 d and ~10 d for BB01 and BB37 strains, respectively. Infected mosquitoes died after GHA and BBPTG4 exposure, and corpses were analyzed for infecting strains detection. Differences among the seven evaluated strains were determined, assessing five different insertion group I intron profiles in BBTG4, BB01, GHA, BB37, and BB02 strains. Mosquitoes infected by BBPTG4 and non-exposed (negative control) intron profiles were obtained. We detected the presence of introns in the BBPTG4 strain, which were not present in non-exposed mosquitoes. In conclusion, B. bassiana strains showed similarities in terms of their cultural and microscopic morphological characteristics and biologicals virulence level, but different intron profiles. BBPTG4 strain-infected Ae. aegypti adult corpses, showing specific amplicons, enabled us to identify B. bassiana at the strain level among infected mosquitoes. However, monitoring and detection of field-infected insects is essential for further verification.
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Aedes , Beauveria , Beauveria/genética , Beauveria/patogenicidad , Animales , Aedes/microbiología , Intrones/genética , Fenotipo , Genotipo , Variación Genética , Control Biológico de Vectores , Control de Mosquitos/métodos , Virulencia/genética , Mosquitos Vectores/microbiologíaRESUMEN
BACKGROUND: There are no randomized data evaluating the safety or efficacy of apixaban for stroke prevention in patients with end-stage kidney disease on hemodialysis and with atrial fibrillation (AF). METHODS: The RENAL-AF trial (Renal Hemodialysis Patients Allocated Apixaban Versus Warfarin in Atrial Fibrillation) was a prospective, randomized, open-label, blinded-outcome evaluation (PROBE) of apixaban versus warfarin in patients receiving hemodialysis with AF and a CHA2DS2-VASc score ≥2. Patients were randomly assigned 1:1 to 5 mg of apixaban twice daily (2.5 mg twice daily for patients ≥80 years of age, weight ≤60 kg, or both) or dose-adjusted warfarin. The primary outcome was time to major or clinically relevant nonmajor bleeding. Secondary outcomes included stroke, mortality, and apixaban pharmacokinetics. Pharmacokinetic sampling was day 1, day 3, and month 1. RESULTS: From January 2017 through January 2019, 154 patients were randomly assigned to apixaban (n=82) or warfarin (n=72). The trial stopped prematurely because of enrollment challenges. Time in therapeutic range (international normalized ratio, 2.0-3.0) for warfarin-treated patients was 44% (interquartile range, 23%-59%). The 1-year rates for major or clinically relevant nonmajor bleeding were 32% and 26% in apixaban and warfarin groups, respectively (hazard ratio, 1.20 [95% CI, 0.63-2.30]), whereas 1-year rates for stroke or systemic embolism were 3.0% and 3.3% in apixaban and warfarin groups, respectively. Death was the most common major event in the apixaban (21 patients [26%]) and warfarin (13 patients [18%]) arms. The pharmacokinetic substudy enrolled the target 50 patients. Median steady-state 12-hour area under the curve was 2475 ng/mL×h (10th to 90th percentiles, 1342-3285) for 5 mg of apixaban twice daily and 1269 ng/mL×h (10th to 90th percentiles, 615-1946) for 2.5 mg of apixaban twice daily. There was substantial overlap between minimum apixaban blood concentration, 12-hour area under the curve, and maximum apixaban blood concentration for patients with and without a major or clinically relevant nonmajor bleeding event. CONCLUSIONS: There was inadequate power to draw any conclusion regarding rates of major or clinically relevant nonmajor bleeding comparing apixaban and warfarin in patients with AF and end-stage kidney disease on hemodialysis. Clinically relevant bleeding events were ≈10-fold more frequent than stroke or systemic embolism among this population on anticoagulation, highlighting the need for future randomized studies evaluating the risks versus benefits of anticoagulation among patients with AF and end-stage kidney disease on hemodialysis. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02942407.
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Fibrilación Atrial , Embolia , Fallo Renal Crónico , Accidente Cerebrovascular , Humanos , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/complicaciones , Warfarina/efectos adversos , Anticoagulantes/uso terapéutico , Estudios Prospectivos , Resultado del Tratamiento , Hemorragia/epidemiología , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Embolia/prevención & control , Diálisis Renal/efectos adversos , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/terapiaRESUMEN
The flexibility to associate with more than one symbiont may considerably expand a host's niche breadth. Coral animals and dinoflagellate micro-algae represent one of the most functionally integrated and widespread mutualisms between two eukaryotic partners. Symbiont identity greatly affects a coral's ability to cope with extremes in temperature and light. Over its broad distribution across the Eastern Pacific, the ecologically dominant branching coral, Pocillopora grandis, depends on mutualisms with the dinoflagellates Durusdinium glynnii and Cladocopium latusorum. Measurements of skeletal growth, calcification rates, total mass increase, calyx dimensions, reproductive output and response to thermal stress were used to assess the functional performance of these partner combinations. The results show both host-symbiont combinations displayed similar phenotypes; however, significant functional differences emerged when exposed to increased temperatures. Negligible physiological differences in colonies hosting the more thermally tolerant D. glynnii refute the prevailing view that these mutualisms have considerable growth tradeoffs. Well beyond the Eastern Pacific, pocilloporid colonies with D. glynnii are found across the Pacific in warm, environmentally variable, near shore lagoonal habitats. While rising ocean temperatures threaten the persistence of contemporary coral reefs, lessons from the Eastern Pacific indicate that co-evolved thermally tolerant host-symbiont combinations are likely to expand ecologically and spread geographically to dominate reef ecosystems in the future.
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Antozoos , Dinoflagelados , Animales , Antozoos/fisiología , Ecosistema , Arrecifes de Coral , Temperatura , Dinoflagelados/fisiología , Simbiosis/fisiologíaRESUMEN
Heparin-induced thrombocytopenia (HIT) is a life-threatening, prothrombotic, antibody-mediated disorder. To maximize the likelihood of recovery, early and accurate diagnosis is critical. Widely available HIT assays, such as the platelet factor 4 (PF4) heparin enzyme-linked immunosorbent assay (ELISA) lack specificity, and the gold-standard carbon 14-labeled serotonin release assay (SRA) is of limited value for early patient management because it is available only through reference laboratories. Recent studies have demonstrated that pathogenic HIT antibodies selectively activate PF4-treated platelets and that a technically simpler assay, the PF4-dependent P-selectin expression assay (PEA), may provide an option for rapid and conclusive results. Based upon predefined criteria that combined 4Ts scores and HIT ELISA results, 409 consecutive adults suspected of having HIT were classified as disease positive, negative, or indeterminate. Patients deemed HIT indeterminate were considered disease negative in the primary analysis and disease positive in a sensitivity analysis. The ability of PEA and SRA to identify patients judged to have HIT was compared using receiver operating characteristic curve statistics. Using these predefined criteria, the diagnostic accuracy of PEA was high (area under the curve [AUC], 0.94; 95% confidence interval [CI], 0.87-1.0) and similar to that of SRA (AUC, 0.91; 95% CI, 0.82-1.0). In sensitivity analysis, the AUCs of PEA and SRA were also similar at 0.88 (95% CI, 0.78-0.98) and 0.86 (95% CI, 0.77-0.96), respectively. The PEA, a technically simple nonradioactive assay that uses â¼20-fold fewer platelets compared with the SRA, had high accuracy for diagnosing HIT. Widespread use of the PEA may facilitate timely and more effective management of patients with suspected HIT.
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Anticoagulantes/efectos adversos , Heparina/efectos adversos , Factor Plaquetario 4/inmunología , Trombocitopenia/inducido químicamente , Trombocitopenia/diagnóstico , Adulto , Anciano , Anticuerpos/inmunología , Anticoagulantes/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Heparina/inmunología , Humanos , Inmunoensayo , Masculino , Persona de Mediana Edad , Selectina-P/inmunología , Estudios Prospectivos , Trombocitopenia/inmunologíaRESUMEN
Single-molecule tracking (SMT) allows the study of transcription factor (TF) dynamics in the nucleus, giving important information regarding the diffusion and binding behavior of these proteins in the nuclear environment. Dwell time distributions obtained by SMT for most TFs appear to follow bi-exponential behavior. This has been ascribed to two discrete populations of TFs-one non-specifically bound to chromatin and another specifically bound to target sites, as implied by decades of biochemical studies. However, emerging studies suggest alternate models for dwell-time distributions, indicating the existence of more than two populations of TFs (multi-exponential distribution), or even the absence of discrete states altogether (power-law distribution). Here, we present an analytical pipeline to evaluate which model best explains SMT data. We find that a broad spectrum of TFs (including glucocorticoid receptor, oestrogen receptor, FOXA1, CTCF) follow a power-law distribution of dwell-times, blurring the temporal line between non-specific and specific binding, suggesting that productive binding may involve longer binding events than previously believed. From these observations, we propose a continuum of affinities model to explain TF dynamics, that is consistent with complex interactions of TFs with multiple nuclear domains as well as binding and searching on the chromatin template.
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Factores de Transcripción/metabolismo , Animales , Línea Celular Tumoral , Cinética , Ratones , Modelos Biológicos , Fotoblanqueo , Unión Proteica , Receptores de Glucocorticoides/metabolismo , Imagen Individual de MoléculaRESUMEN
SOURCE CITATION: Spyropoulos AC, Goldin M, Giannis D, et al. Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: the HEP-COVID randomized clinical trial. JAMA Intern Med. 2021;181:1612-20. 34617959.
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COVID-19 , Tromboembolia Venosa , Anticoagulantes/efectos adversos , Heparina/efectos adversos , Humanos , Pacientes Internos , SARS-CoV-2 , Tromboembolia Venosa/inducido químicamenteRESUMEN
SOURCE CITATION: Sholzberg M, Tang GH, Rahhal H, et al. Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial. BMJ. 2021;375:n2400. 34649864.
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COVID-19 , Heparina , Anticoagulantes/efectos adversos , Heparina/efectos adversos , Hospitalización , Humanos , Unidades de Cuidados Intensivos , SARS-CoV-2RESUMEN
BACKGROUND: Ambulatory patients receiving systemic cancer therapy are at varying risk for venous thromboembolism. However, the benefit of thromboprophylaxis in these patients is uncertain. METHODS: In this double-blind, randomized trial involving high-risk ambulatory patients with cancer (Khorana score of ≥2, on a scale from 0 to 6, with higher scores indicating a higher risk of venous thromboembolism), we randomly assigned patients without deep-vein thrombosis at screening to receive rivaroxaban (at a dose of 10 mg) or placebo daily for up to 180 days, with screening every 8 weeks. The primary efficacy end point was a composite of objectively confirmed proximal deep-vein thrombosis in a lower limb, pulmonary embolism, symptomatic deep-vein thrombosis in an upper limb or distal deep-vein thrombosis in a lower limb, and death from venous thromboembolism and was assessed up to day 180. In a prespecified supportive analysis involving the same population, the same end point was assessed during the intervention period (first receipt of trial agent to last dose plus 2 days). The primary safety end point was major bleeding. RESULTS: Of 1080 enrolled patients, 49 (4.5%) had thrombosis at screening and did not undergo randomization. Of the 841 patients who underwent randomization, the primary end point occurred in 25 of 420 patients (6.0%) in the rivaroxaban group and in 37 of 421 (8.8%) in the placebo group (hazard ratio, 0.66; 95% confidence interval [CI], 0.40 to 1.09; P = 0.10) in the period up to day 180. In the prespecified intervention-period analysis, the primary end point occurred in 11 patients (2.6%) in the rivaroxaban group and in 27 (6.4%) in the placebo group (hazard ratio, 0.40; 95% CI, 0.20 to 0.80). Major bleeding occurred in 8 of 405 patients (2.0%) in the rivaroxaban group and in 4 of 404 (1.0%) in the placebo group (hazard ratio, 1.96; 95% CI, 0.59 to 6.49). CONCLUSIONS: In high-risk ambulatory patients with cancer, treatment with rivaroxaban did not result in a significantly lower incidence of venous thromboembolism or death due to venous thromboembolism in the 180-day trial period. During the intervention period, rivaroxaban led to a substantially lower incidence of such events, with a low incidence of major bleeding. (Funded by Janssen and others; CASSINI ClinicalTrials.gov number, NCT02555878.).
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Inhibidores del Factor Xa/uso terapéutico , Neoplasias/tratamiento farmacológico , Rivaroxabán/uso terapéutico , Tromboembolia Venosa/prevención & control , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Método Doble Ciego , Inhibidores del Factor Xa/efectos adversos , Femenino , Hemorragia/inducido químicamente , Humanos , Incidencia , Análisis de Intención de Tratar , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasias/complicaciones , Factores de Riesgo , Rivaroxabán/efectos adversos , Resultado del Tratamiento , Tromboembolia Venosa/etiologíaRESUMEN
Anthozoan cnidarians (corals and sea anemones) include some of the world's most important foundation species, capable of building massive reef complexes that support entire ecosystems. Although previous molecular phylogenetic analyses have revealed widespread homoplasy of the morphological characters traditionally used to define orders and families of anthozoans, analyses using mitochondrial genes or rDNA have failed to resolve many key nodes in the phylogeny. With a fully resolved, time-calibrated phylogeny for 234 species constructed from hundreds of ultraconserved elements and exon loci, we explore the evolutionary origins of the major clades of Anthozoa and some of their salient morphological features. The phylogeny supports reciprocally monophyletic Hexacorallia and Octocorallia, with Ceriantharia as the earliest diverging hexacorals; two reciprocally monophyletic clades of Octocorallia; and monophyly of all hexacoral orders with the exception of the enigmatic sea anemone Relicanthus daphneae. Divergence dating analyses place Anthozoa in the Cryogenian to Tonian periods (648-894 Ma), older than has been suggested by previous studies. Ancestral state reconstructions indicate that the ancestral anthozoan was a solitary polyp that had bilateral symmetry and lacked a skeleton. Colonial growth forms and the ability to precipitate calcium carbonate evolved in the Ediacaran (578 Ma) and Cambrian (503 Ma) respectively; these hallmarks of reef-building species have subsequently arisen multiple times independently in different orders. Anthozoans formed associations with photosymbionts by the Devonian (383 Ma), and photosymbioses have been gained and lost repeatedly in all orders. Together, these results have profound implications for the interpretation of the Precambrian environment and the early evolution of metazoans.[Bilateral symmetry; coloniality; coral; early metazoans; exon capture; Hexacorallia; Octocorallia photosymbiosis; sea anemone; ultraconserved elements.].
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Antozoos , Anémonas de Mar , Animales , Antozoos/genética , Ecosistema , Genes Mitocondriales , Filogenia , Anémonas de Mar/genéticaRESUMEN
BACKGROUND: Anticoagulation requires urgent reversal in cases of life-threatening bleeding or invasive procedures. STUDY DESIGN AND METHODS: Network meta-analysis for comparing the safety and efficacy of warfarin reversal strategies including plasma and prothrombin complex concentrates (PCCs). RESULTS: Seven studies including 594 subjects using reversal agents plasma, 3-factor-PCC (Uman Complex and Konyne), and 4-factor-PCC (Beriplex/KCentra, Octaplex, and Cofact) met inclusion criteria. Compared with plasma, patients receiving Cofact probably have a higher rate of international normalized ratio (INR) correction (risk difference [RD] 499 more per 1000 patients, 95% confidence interval [CI], 176-761, low certainty[LC]); higher reversal of bleeding (323 more per 1000 patients, 11-344 more, LC); and fewer transfusion requirements (0.96 fewer units, 1.65-0.27 fewer, LC). Patients receiving Beriplex/KCentra probably have a higher rate of INR correction (476 more per 1000 patients, 332-609 more, LC); higher reversal of bleeding (127 more per 1000 patients, 43 fewer to 236 more); and similar transfusion requirements (0.01 fewer units, 0.31 fewer to 0.28 more, high/moderate certainty). Patients receiving Octaplex probably have a higher rate of INR correction (RD 579 more per 1000 patients, 189-825 more, LC). CONCLUSIONS: PCCs probably provide an advantage in INR reversal compared to plasma. There was no added risk of adverse events with PCCs.
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Anticoagulantes , Factores de Coagulación Sanguínea , Anticoagulantes/efectos adversos , Factores de Coagulación Sanguínea/uso terapéutico , Factor IX , Factor X , Fibrinolíticos , Hemorragia/inducido químicamente , Hemorragia/tratamiento farmacológico , Humanos , Relación Normalizada Internacional , Metaanálisis en Red , Protrombina , Estudios Retrospectivos , Vitamina K/uso terapéutico , WarfarinaRESUMEN
In patients undergoing hematopoietic cell transplantation (HCT), venous thromboembolism (VTE) remains a serious complication that lacks validated risk assessment models (RAMs) to guide thromboprophylaxis. To address this dilemma, we performed a temporal and external validation study of the recently derived HIGH-2-LOW RAM. We selected adult patients undergoing allogeneic HCT from Fred Hutchinson Cancer Research Center (FHCRC) and MD Anderson Cancer Center (MDACC). Patients who died, received anticoagulation, or did not engraft platelets by day 30 were excluded. Primary outcomes were defined as overall VTE and pulmonary embolism ± lower-extremity deep venous thromboembolism (PE/LE-DVT) by day 180. Covariates were weighted according to the original model, except that grade 2-4 GVHD was substituted for grade 3-4. Discrimination and calibration were assessed. A total of 765 patients from FHCRC and 954 patients from MDACC were included. Incident VTE by day 180 was 5.1% at FHCRC and 6.8% at MDACC. The HIGH-2-LOW score had a c-statistic of 0.67 (0.59-0.75) for VTE and 0.75 (0.64-0.81) for PE/LE-DVT at FHCRC and 0.62 (0.55-0.70) for VTE and 0.70 (0.56-0.83) for PE/LE-DVT at MDACC. Twenty-five percent and 23% of patients were classified as high risk (2+ points) in the two cohorts, respectively. High versus low-risk was associated with odds ratio (OR) of 2.80 (1.46-5.38) for VTE and 4.21 (1.82-9.77) for PE/LE-DVT at FHCRC and OR of 3.54 (2.12-5.91) for VTE and 6.82 (2.30-20.16) for PE-LE-DVT at MDACC. The HIGH-2-LOW RAM identified allogeneic HCT recipients at high risk for VTE in both validation cohorts. It can improve evidence-based decision-making for thromboprophylaxis post-transplant.
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Embolia Pulmonar , Tromboembolia Venosa , Anticoagulantes/uso terapéutico , Humanos , Embolia Pulmonar/inducido químicamente , Factores de Riesgo , Trasplante Homólogo/efectos adversos , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/epidemiología , Tromboembolia Venosa/etiologíaRESUMEN
The epidemiology of cancer-associated thrombosis (CAT) among uninsured and vulnerable populations in the US is not well-characterized. We performed a retrospective cohort study for patients with newly diagnosed cancer from 2011 to 2020 at Harris Health System, which cares for uninsured residents in the Houston metropolitan area. Patient demographics, NCI comorbidity index, area of deprivation index (ADI), cancer histology, staging, and systemic therapy data were extracted. CAT included overall venous thromboembolism (VTE) or pulmonary embolism +/- lower extremity deep vein thrombosis (PE/LE-DVT) within 1 year of diagnosis. We used multivariable Fine-Gray models to assess the associations with CAT accounting for death as a competing risk. Among 15 342 patients, 74% were uninsured and 84% lived in socioeconomically disadvantaged neighborhoods. There were 16% Non-Hispanic White (NHW), 28% Non-Hispanic Black (NHB), 50% Hispanic (27% Mexican), and 6% Asian/Pacific Islanders (API). The 1-year CAT incidence rate was 14.6%. Overall VTE was lower for Hispanics versus NHW (SHR 0.87 [0.76-0.99]) and API versus NHW (SHR 0.58 [0.44-0.77]). PE/LE-DVT was higher for NHB versus NHW (SHR 1.18 [1.01-1.39]). CAT was also associated with chemotherapy-based regimens (+/- immunotherapy), age, obesity, cancer type/staging, VTE history, and recent hospitalization. NCI comorbidity and ADI scores were associated with mortality but not CAT. In a large cohort of underserved patients with cancer, we identified an elevated incidence of CAT with known and novel risk predictors. Hispanics had lower adjusted rates of CAT and mortality. Our findings highlight the need to investigate and incorporate vulnerable populations in clinical trials.
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Neoplasias , Embolia Pulmonar , Tromboembolia Venosa , Humanos , Incidencia , Pacientes no Asegurados , Neoplasias/complicaciones , Neoplasias/epidemiología , Neoplasias/terapia , Embolia Pulmonar/etiología , Estudios Retrospectivos , Factores de Riesgo , Tromboembolia Venosa/tratamiento farmacológico , Tromboembolia Venosa/epidemiología , Tromboembolia Venosa/etiología , Poblaciones VulnerablesRESUMEN
BACKGROUND: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) with oral anticoagulants has been associated with an increased risk of bleeding. We investigated the risk of bleeding and major cardiovascular outcomes in patients with atrial fibrillation taking NSAIDs and apixaban or warfarin. METHODS: The ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; n=18 201) compared apixaban with warfarin in patients with atrial fibrillation at an increased risk of stroke. Patients in ARISTOTLE without severe renal (creatine clearance ≤30 mL/min) or liver disease were included in this analysis (n=17 423). NSAID use at baseline, NSAID use during the trial (incident NSAID use), and never users were described. The primary outcome was major bleeding. Secondary outcomes included clinically relevant nonmajor bleeding, gastrointestinal bleeding, heart failure hospitalization, stroke or systemic embolism, and all-cause mortality. NSAID use during the trial, and the interaction between randomized treatment, was analyzed using time-dependent Cox proportional hazards models. RESULTS: Those with baseline NSAID use (n=832 [4.8%]), incident NSAID use (n=2185 [13.2%]), and never users were similar in median age (age [25th, 75th]; 70 [64, 77] versus 70 [63, 75] versus 70 [62, 76]). Those with NSAID use at baseline and incident NSAID use were more likely to have a history of bleeding than never users (24.5% versus 21.0% versus 15.6%, respectively). During a median follow-up (25th, 75th) of 1.8 (1.4, 2.3) years and when excluding those taking NSAID at baseline, we found that incident NSAID use was associated with an increased risk of major bleeding (hazard ratio [HR], 1.61 [95% CI, 1.11-2.33]) and clinically relevant nonmajor bleeding (HR, 1.70 [95% CI, 1.16-2.48]), but not gastrointestinal bleeding. No significant interaction was observed between NSAID use and randomized treatment for any outcome. CONCLUSIONS: A substantial number of patients in the ARISTOTLE trial took NSAIDs. Incident NSAID use was associated with major and clinically relevant nonmajor bleeding, but not with gastrointestinal bleeding. The safety and efficacy of apixaban versus warfarin appeared not significantly to be altered by NSAID use. This study warrants more investigation of the effect of NSAIDs on the outcomes of patients treated with apixaban. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00412984.
Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Anticoagulantes/administración & dosificación , Fibrilación Atrial , Pirazoles/administración & dosificación , Piridonas/administración & dosificación , Warfarina/administración & dosificación , Administración Oral , Anciano , Antiinflamatorios no Esteroideos/efectos adversos , Anticoagulantes/efectos adversos , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/mortalidad , Fibrilación Atrial/fisiopatología , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pirazoles/efectos adversos , Piridonas/efectos adversos , Tasa de Supervivencia , Warfarina/efectos adversosRESUMEN
History of venous thromboembolism (VTE) is prevalent among patients undergoing hematopoietic cell transplantation (HCT). Management of anticoagulation is particularly challenging as most patients will have chemotherapy-induced thrombocytopenia while awaiting engraftment post-HCT. We conducted a retrospective study of autologous and allogeneic HCT recipients with prior VTE from 2006-2015 to 1) compare anticoagulant strategies on short-term VTE recurrence and bleeding and 2) assess predictors for VTE recurrence beyond 30 days. Patients with VTE were allocated to two cohorts based on anticoagulant strategy at thrombocytopenia onset and underwent inverse probability weighting to assess primary outcomes of VTE recurrence and bleeding within 30 days post-HCT. Subsequently, multivariable logistic regression model was used to assess the association of 100-day VTE recurrence by the HIGH-2-LOW VTE risk assessment score and whether patients resumed anticoagulation at platelet recovery. Thirteen percent of recipients had VTE prior to HCT; of those meeting inclusion criteria, 227 continued anticoagulation and 113 temporarily discontinued it. Anticoagulant strategy was not significantly associated with decreased risk of VTE recurrence within 30 days (3% vs 4%, p = 0.61); however, risk of overall bleeding was non-significantly higher in those who continued vs discontinued anticoagulation (41% vs 31%, p = 0.08). In a subgroup of 250 allogeneic HCT patients, every one-point increase of HIGH-2-LOW score was significantly associated with VTE recurrence at 100 days (OR 1.57 [95% CI 1.10-2.23]), while anticoagulation resumption upon platelet engraftment was associated with lower recurrent risk (OR 0.48 [0.20-1.14]). Temporarily withholding anticoagulation during thrombocytopenia may optimize risk-benefit tradeoffs, though additional strategies are essential to prevent VTE recurrence after hematopoietic recovery.
Asunto(s)
Anticoagulantes/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Hemorragia/inducido químicamente , Tromboembolia Venosa/prevención & control , Adulto , Anciano , Anticoagulantes/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Factores de Riesgo , Prevención Secundaria , Tromboembolia Venosa/etiologíaRESUMEN
BACKGROUND: Randomized controlled trials (RCTs) have demonstrated that low-dose direct oral anticoagulants (DOACs), including rivaroxaban and apixaban, may help reduce the incidence of cancer-associated venous thromboembolism (VTE). METHODS: A cost-utility analysis was performed from the health sector perspective using a Markov state-transition model in patients with cancer who are at intermediate-to-high risk for VTE. Transition probability, relative risk, cost, and utility inputs were obtained from a meta-analysis of the RCTs and relevant epidemiology studies. Differences in cost, quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER) per patient were calculated over a lifetime horizon. One-way, probabilistic, and scenario sensitivity analyses were conducted. RESULTS: In patients with cancer at intermediate-to-high risk for VTE, treatment with low-dose DOAC thromboprophylaxis for 6 months, compared with placebo, was associated with 32 per 1000 fewer VTE and 11 per 1000 more major bleeding episodes over a lifetime. The incremental cost and QALY increases were $1445 and 0.12, respectively, with an ICER of $11,947 per QALY gained. Key drivers of ICER variations included the relative risks of VTE and bleeding as well as drug cost. This strategy was 94% cost effective at the threshold of $50,000 per QALY. The selection of patients with Khorana scores ≥3 yielded the greatest value, with an ICER of $5794 per QALY gained. CONCLUSIONS: Low-dose DOAC thromboprophylaxis for 6 months appears to be cost-effective in patients with cancer who are at intermediate-to-high risk for VTE. The implementation of this strategy in patients with Khorana scores ≥3 may lead to the highest cost-benefit ratio.
Asunto(s)
Anticoagulantes/administración & dosificación , Anticoagulantes/economía , Análisis Costo-Beneficio , Trombosis/economía , Trombosis/prevención & control , Administración Oral , Humanos , Persona de Mediana Edad , Neoplasias/complicaciones , Neoplasias/economía , Años de Vida Ajustados por Calidad de Vida , Trombosis/etiología , Estados UnidosRESUMEN
OBJECTIVES: A history of gastrointestinal bleeding (GIB) in patients with atrial fibrillation (AF) may impact decisions about anticoagulation treatment. We sought to determine whether prior GIB in patients with AF taking anticoagulants was associated with an increased risk of stroke or major hemorrhage. METHODS: We analyzed key efficacy and safety outcomes in patients with prior GIB in ARISTOTLE. Centrally adjudicated outcomes according to GIB history were analyzed using Cox proportional hazards models adjusted for randomized treatment and established risk factors. RESULTS: A total of 784 (4.3%) patients had prior GIB events (321 [41%] lower, 463 [59%] upper); 215 (27%) occurred <1 year before study enrollment. Patients with prior GIB were older, had more comorbidities, and higher CHADS2 and HAS-BLED scores than those with no GIB. Major GIB occurred more frequently in those with prior GIB (lower: aHR 1.72, 95% CI 0.86-3.42; upper: aHR 3.13, 95% CI 1.97-4.96). This association with major GIB was more pronounced in patients with GIB <1 year before randomization versus no recent GIB (recent lower: aHR 2.58, 95% CI 0.95-7.01; recent upper: aHR 5.16, 95% CI 2.66-10.0). There was no association between prior GIB and risk of stroke/systemic embolism or all-cause death. In those with prior GIB, the apixaban versus warfarin relative risks for stroke/systemic embolism, hemorrhagic stroke, death, or major bleeding were consistent with the results of the overall trial. CONCLUSIONS: In patients with AF on oral anticoagulants, prior GIB was associated with an increased risk of subsequent major GIB but not stroke, intracranial bleeding, or all-cause mortality. For the key outcomes of stroke, hemorrhagic stroke, death, and major bleeding, we found no evidence that the treatment effect (apixaban vs. warfarin) was modified by a history of GIB.