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Background: The association between heart rate (HR) and pulmonary embolism (PE) outcomes has not been well studied. Furthermore, optimal cutoffs to identify low-risk and intermediate- to high-risk patients are not well known. Research Question: Does an association exist between baseline HR and PE outcome across the continuum of HR values? Study Design and Methods: The current study included 44,331 consecutive nonhypotensive patients with symptomatic PE from the Registro Informatizado de la Enfermedad TromboEmbólica registry between 2001 and 2021. Outcomes included 30-day all-cause and PE-specific mortality. We used hierarchical logistic regression to assess the association between admission HR and outcomes. Results: A positive relationship was found between admission HR and 30-day all-cause and PE-related mortality. Considering an HR of 80 to 99 beats/min as a reference, patients in the higher HR strata showed higher rates of all-cause death (adjusted OR, 1.5 for HR of 100-109 beats/min; adjusted OR, 1.7 for HR of 110-119 beats/min; adjusted OR, 1.9 for HR of 120-139 beats/min; and adjusted OR, 2.4 for HR of ≥ 140 beats/min). Patients in the lower strata of HR showed significantly lower rates of 30-day all-cause mortality compared with the same reference group (adjusted OR, 0.6 for HR of 60-79 beats/min; and adjusted OR, 0.5 for HR of < 60 beats/min). The findings for 30-day PE-related mortality were similar. For identification of low-risk patients, a cutoff value of 80 beats/min (vs 110 beats/min) increased the sensitivity of the simplified Pulmonary Embolism Severity Index (sPESI) from 93.4% to 98.8%. For identification of intermediate- to high-risk patients, a cutoff value of 140 beats/min (vs 110 beats/min) increased the specificity of the Bova score from 93.2% to 98.0%. Interpretation: In nonhypotensive patients with acute symptomatic PE, a high HR portends an increased risk of all-cause and PE-related mortality. Modifying the HR cutoff in the sPESI and the Bova score improves prognostication of patients with PE.

Hospitalized patients with COVID-19 are at increased risk of thrombosis, acute respiratory distress syndrome and death. The optimal dosage of thromboprophylaxis is unknown. The aim was to evaluate the efficacy and safety of tinzaparin in prophylactic, intermediate, and therapeutic doses in non-critical patients admitted for COVID-19 pneumonia. PROTHROMCOVID is a randomized, unblinded, controlled, multicenter trial enrolling non-critical, hospitalized adult patients with COVID-19 pneumonia. Patients were randomized to prophylactic (4500 IU), intermediate (100 IU/kg), or therapeutic (175 IU/kg) groups. All tinzaparin doses were administered once daily during hospitalization, followed by 7 days of prophylactic tinzaparin at discharge. The primary efficacy outcome was a composite endpoint of symptomatic systemic thrombotic events, need for invasive or non-invasive mechanical ventilation, or death within 30 days. The main safety outcome was major bleeding at 30 days. Of the 311 subjects randomized, 300 were included in the prespecified interim analysis (mean [SD] age, 56.7 [14.6] years; males, 182 [60.7%]). The composite endpoint at 30 days from randomization occurred in 58 patients (19.3%) of the total population; 19 (17.1 %) in the prophylactic group, 20 (22.1%) in the intermediate group, and 19 (18.5%) in the therapeutic dose group (p = 0.72). No major bleeding event was reported; non-major bleeding was observed in 3.7% of patients, with no intergroup differences. Due to these results and the futility analysis, the trial was stopped. In non-critically ill COVID-19 patients, intermediate or full-dose tinzaparin compared to standard prophylactic doses did not appear to affect the risk of thrombotic event, non-invasive ventilation, or mechanical ventilation or death. Trial RegistrationClinicalTrials.gov Identifier (NCT04730856). Edura-CT registration number: 2020-004279-42.

BACKGROUND: Atrial fibrillation (AF) increases the risk of thromboembolism. We investigate the efficacy and safety of oral anticoagulation (OAC) therapy and explored the number needed to treat for net effect (NNTnet) of OAC in the Spanish cohort of the EURObservational Research Programme-AF (EORP-AF) Long-term General Registry. METHODS: The EORP-AF General Registry is a prospective, multicentre registry conducted in ESC countries, including consecutive AF patients. For the present analysis, we used the Spanish cohort, and the primary outcome was any thromboembolism (TE)/acute coronary syndrome (ACS)/cardiovascular death during the first year of follow-up. RESULTS: 729 AF patients were included (57.1% male, median age 75 [IQR 67-81] years, median CHA(2) DS(2) -VASc and HAS-BLED of 3 [IQR 2-5] and 2 [IQR 1-2], respectively). 548 (75.2%) patients received OAC alone (318 [43.6%] on VKAs and 230 [31.6%] on DOACs). After 1 year, the use of OAC alone showed lower rates of any TE/ACS/cardiovascular death (3.0%/year; p

People’s eating habits and lifestyle can have a negative impact on health. In situations of difficulty or socioeconomic crisis, these habits tend to be modified, leading to unhealthy dietary patterns that result in an increase of chronic non-communicable diseases (NCDs). Previous studies have indicated that, due to the state of alarm imposed in Spain to combat the spread of COVID-19, an increase in the purchase of non-core products occurred, along with a decrease in the daily physical activity of the population. This could be a risk factor for COVID-19 infection. The objective of this observational study was to analyze the dietary pattern of the Spanish population during home confinement and to compare it with the pattern of habitual consumption collected in the last National Health Survey, analyzing the possible changes. More than half of the respondents in the sample increased their consumption of sweets and snacks during confinement, while the consumption of fresh products decreased. Most claimed to be emotionally hungry, leading to an increase in their daily energy intake. The stress and anxiety generated by confinement could be the cause of the increased consumption of products rich in sugars and saturated fats, which are associated with greater stress and anxiety.

Background Atrial fibrillation (AF) may exist before or occur early in the course of pulmonary embolism (PE). We determined the PE outcomes based on the presence and timing of AF. Methods and Results Using the data from a multicenter PE registry, we identified 3 groups: (1) those with preexisting AF, (2) patients with new AF within 2 days from acute PE (incident AF), and (3) patients without AF. We assessed the 90‐day and 1‐year risk of mortality and stroke in patients with AF, compared with those without AF (reference group). Among 16 497 patients with PE, 792 had preexisting AF. These patients had increased odds of 90‐day all‐cause (odds ratio [OR], 2.81; 95% CI, 2.33–3.38) and PE‐related mortality (OR, 2.38; 95% CI, 1.37–4.14) and increased 1‐year hazard for ischemic stroke (hazard ratio, 5.48; 95% CI, 3.10–9.69) compared with those without AF. After multivariable adjustment, preexisting AF was associated with significantly increased odds of all‐cause mortality (OR, 1.91; 95% CI, 1.57–2.32) but not PE‐related mortality (OR, 1.50; 95% CI, 0.85–2.66). Among 16 497 patients with PE, 445 developed new incident AF within 2 days of acute PE. Incident AF was associated with increased odds of 90‐day all‐cause (OR, 2.28; 95% CI, 1.75–2.97) and PE‐related (OR, 3.64; 95% CI, 2.01–6.59) mortality but not stroke. Findings were similar in multivariable analyses. Conclusions In patients with acute symptomatic PE, both preexisting AF and incident AF predict adverse clinical outcomes. The type of adverse outcomes may differ depending on the timing of AF onset.

Current guidelines suggest treating cancer patients with incidental pulmonary embolism (PE) similarly to those with clinically suspected and confirmed PE. However, the natural history of these presentations has not been thoroughly compared.We used the data from the RIETE (Registro Informatizado de Enfermedad TromboEmbólica) registry to compare the 3-month outcomes in patients with active cancer and incidental PEFrom July 2012 to January 2019, 946 cancer patients with incidental asymptomatic PE and 2274 with clinically suspected and confirmed PE were enrolled. Most patients (95%Cancer patients with incidental PE had a lower mortality rate than those with clinically suspected and confirmed PE. Further studies are required to validate these findings, and to explore optimal management strategies in these patients.

Background: The choice of the imaging modality for diagnosis of pulmonary embolism (PE) could be influenced by provider, patient or hospital characteristics, or over time. However, little is known about the choice of the diagnostic modalities in practice. The aim of this study was to evaluate the variations in the use of imaging modalities for patients with acute PE. Methods: Using the data from Registro Informatizado Enfermedad TromboEmbolica (RIETE), a prospective international registry of patients with venous thromboembolism (March 2001–January 2019), we explored the imaging modalities used in patients with acute PE. The imaging modalities included computed tomography pulmonary angiography, ventilation/perfusion scanning, pulmonary angiography, a combination of these tests, or PE signs and symptoms plus imaging-confirmed proximal deep vein thrombosis but no chest imaging. Results: Among 38 025 patients with confirmed PE (53.1% female, age: 67.3±17 years), computed tomography pulmonary angiography was the dominant modality of diagnosis in all RIETE enrollees (78.2% [99% CI, 77.6–78.7]); including pregnant patients (58.9% [99% CI, 47.7%–69.4%]) and patients with severe renal insufficiency (62.5% [99% CI, 59.9–65.0]). A greater proportion of patients underwent ventilation/perfusion scanning in larger hospitals compared with smaller hospitals (13.1% versus 7.3%, P P Conclusions: In a large multinational PE registry, variations were observed in the use of imaging modalities according to patient or institutional factors and over time. However, computed tomography pulmonary angiography was the dominant modality of diagnosis, even in pregnancy and severe renal insufficiency. The safety, costs, and downstream effects of these tests on PE-related and non-PE-related outcomes warrant further investigation.

Registro Informatizado de Enfermedad Tromboembólica Investigators., [Objective] Overlap exists between the risk factors for coronary artery disease and venous thromboembolism (VTE). However, a paucity of data is available on the incidence of major acute cardiovascular events (MACE) and major adverse limb events (MALE) among patients presenting with VTE. Moreover, it is unknown whether the rate of cardiovascular outcomes differs among patients with unprovoked vs provoked VTE., [Methods] We analyzed the data from 2009 to 2017 in the Registro Informatizado de Enfermedad Tromboembólica registry, an ongoing, multicenter, international registry of consecutive patients with a diagnosis of objectively confirmed VTE. The query was restricted it to patients with data entry for the arterial outcomes. The baseline prevalence of coronary artery disease risk factors was compared between patients with provoked (ie, immobility, cancer, surgery, travel >6 hours, hormonal causes) and unprovoked VTE. After the initial VTE event, we followed up patients for the composite primary outcome of incident MACE (ie, stroke, myocardial infarction, unstable angina) and/or MALE (ie, major limb events). We used the χ2 test for baseline associations and a Cox proportional hazard for multivariate analysis. We used IBM SPSS, version 24 (IBM Corp, Armonk, NY) for statistical analysis. A P value of, [Results] We analyzed the data from 41,259 patients with VTE, of whom 22,633 (55.6%) had experienced a provoked VTE. During follow-up, the patients with provoked VTE were more likely to develop MACE or MALE than were patients with unprovoked VTE (hazard ratio [HR], 1.3; 95% confidence interval [CI], 1.1-1.5). The association of arterial events with recent immobility (HR, 1.4; 95% CI, 1.5-12.1) and cancer (HR, 1.7; 95% CI, 1.4-1.9) was strong. After adjusting for multiple conventional cardiovascular risk factors, provoked VTE, compared with unprovoked VTE, was significantly associated with an increased hazard for MACE (HR, 1.4; 95% CI, 1.1-1.7). Cancer remained a significant adjusted predictor for both MACE (HR, 1.7; 95% CI, 1.4-2.1) and MALE (HR, 2.1; 95% CI 1.01-4.6) in those with provoked VTE., [Conclusions] Among patients with VTE, provoked cases, specifically those with cancer-associated VTE, have an increased risk of major arterial events.

[Background]: Improved prediction of the risk of major bleeding in patients with acute pulmonary embolism (PE) receiving systemic thrombolysis is crucial to guide the choice of therapy. [Methods]: The study included consecutive patients with acute PE who received systemic thrombolysis in the RIETE registry. We used multivariable logistic regression analysis to create a risk score to predict 30-day major bleeding episodes. We externally validated the risk score in patients from the COMMAND VTE registry. In addition, we compared the newly created risk score against the Kuijer and RIETE scores., [Results]: Multivariable logistic regression identified four predictors for major bleeding: recent major bleeding (3 points), age >75 years (1 point), active cancer (1 point) and syncope (1 point) (BACS). Among 1172 patients receiving thrombolytic therapy in RIETE, 446 (38%) were classified as having low risk (none of the variables present, 0 points) of major bleeding according to the BACS score, and the overall 30-day major bleeding rate of this group was 2.9% (95% CI 1.6–4.9%), compared with 44% (95% CI 14–79%) in the high-risk group (>3 points). In the validation cohort, 51% (149 out of 290) of patients were classified as having low risk, and the overall 30-day major bleeding rate of this group was 1.3%. In RIETE, the 30-day major bleeding event rates in the Kuijer and RIETE low-risk strata were 5.3% and 4.4%, respectively., [Conclusions]: The BACS score is an easily applicable aid for prediction of the risk of major bleeding in the population of PE patients who receive systemic thrombolysis.

Introduction: Despite the fact that the Sincope is an alarming symptom that always forces us to suspect significant cardiac dysfunction, the most recommended Clinical Scales for the prognostic evaluation of the PE do not include it as a risk parameter, for the refusal on the part of the classic studies to observe an association with the clinical outcome. Among patients who, due to their clinical profile of Low Risk, would be candidates for extrahospital management, its prognostic significance is especially necessary to clarify. Objective: Considere if the presence of Sincope is associated with mortality in a large cohort of patients with PE and a low risk clinical profile according to the sPESI scale. Material and Methods: Patients included in the RIETE Registry until March 2017 and who presented a score of 0 on the sPESI scale. The Student and Mann-Whitney tests were used to compare the continuous variables, and the Chi-square test for qualitative ones. Univariate logistic regression analyzes were performed and a predictive model was constructed using multivariate logistic regression with the selected variables. Conclusion: In patients with a low risk clinical profile according to the sPESI scale, the presence of Sincope increases significantly the probability of short-term death. When making decisions about the initial outpatient management of PE its presence should be taken into account.

Background The natural history of patients with lung cancer and venous thromboembolism (VTE) has not been consistently evaluated. Methods We used the RIETE (Registro Informatizado Enfermedad TromboEmbólica) database to assess the clinical characteristics, time course, and outcomes during anticoagulation of lung cancer patients with acute, symptomatic VTE. Results As of May 2017, a total of 1,725 patients were recruited: 1,208 (70%) presented with pulmonary embolism (PE) and 517 with deep vein thrombosis (DVT). Overall, 865 patients (50%) were diagnosed with cancer Conclusion Active surveillance on early signs and/or symptoms of VTE in patients with recently diagnosed lung cancer and prescription of prophylaxis in those undergoing surgery or during periods of immobilization might likely help prevent VTE better, detect it earlier, and treat it more efficiently.

International audience; BACKGROUND:The prognostic value of D-dimer testing in patients with acute pulmonary embolism (PE) has not been thoroughly studied.METHODS:We used the RIETE Registry data to assess the 90-day prognostic value of increased IL Test D-dimer levels at baseline in patients with PE, according to the presence or absence of cancer.RESULTS:As of May 2013, 3,283 patients with acute PE underwent D-dimer testing using IL Test D-dimer. Among 2,588 patients without cancer, those with D-dimer levels in the highest quartile had a higher rate of fatal PE (2.6% vs. 0.9%; p=0.002), fatal bleeding (1.1% vs. 0.3%; p=0.017) and all-cause death (9.1% vs. 4.4%; p

The debate concerning the use of single-use vs reusable devices, such as laryngoscopes, in order to prevent cross-contamination of medical equipment between patients remains a major issue in clinical practice. There are several points to consider before taking a clinical decision, the most important one being patient safety. With that priority in mind, other issues can be discussed, for example, the financial implications (in terms of budget allowance). While it might appear that single-use devices are the best option—due to the lowered risk of cross-contamination, and a consequent reduction in the cost of sterilisation—patient safety is not solely concerned with cross-contamination; it is also about the appropriateness of the tool being used and the reliability it offers. This paper will focus on laryngoscopes and will assess safety—understood as cross-contamination, light quality and blade rigidity—and cost, enabling the reader to take action on evidence-based practice when considering laryngoscopes and their fitness for purpose. This article is informed by a literature review and, as such, no ethical approval was required.

Current guidelines suggest treating cancer patients with incidental pulmonary embolism comparably to patients with symptomatic pulmonary embolism.We used the Registro Informatizado de Enfermedad TromboEmbólica (RIETE) registry to compare the rate of major bleeding and symptomatic pulmonary embolism during the course of anticoagulation and after its discontinuation in cancer patients with incidental pulmonary embolism.As of March 2016, 715 cancer patients with incidental pulmonary embolism had been enrolled in RIETE. During the course of anticoagulant therapy (mean 235 days), the rate of major bleeding was higher than the rate of symptomatic pulmonary embolism (10.1 (95% CI 7.48–13.4) versus 3.17 (95% CI 1.80–5.19) events per 100 patient–years, respectively), and the rate of fatal bleeding was higher than the rate of fatal pulmonary embolism (2.66 (95% CI 1.44–4.52) versus 0.66 (95% CI 0.17–1.81) deaths per 100 patient-years, respectively). After discontinuing anticoagulation (mean follow-up 117 days), the rate of major bleeding was lower than the rate of symptomatic pulmonary embolism (3.00 (95% CI 1.10–6.65) versus 8.37 (95% CI 4.76–13.7) events per 100 patient-years, respectively); however, there were no differences in the rate of fatal events at one death each.The risk/benefit ratio of anticoagulant therapy in cancer patients with incidental pulmonary embolism is uncertain and must be evaluated in further studies.

Background Patients with venous thromboembolism (VTE) treated with anticoagulants are at risk of death from pulmonary embolism (PE) and/or bleeding. However, whether patients who develop VTE in hospital have a higher complication rate than those who develop VTE in an outpatient setting is unclear. Patients and methods RIETE is an ongoing, prospective registry of consecutive patients with acute, objectively confirmed, symptomatic VTE. We compared the 3-month incidence of fatal PE and fatal bleeding in patients in whom the VTE had developed while in hospital for another medical condition (inpatients) with those who presented to the emergency ward because of VTE (outpatients). Results Up to April 2008, 22,133 patients with acute VTE were enrolled: 10,461 (47%) presented with PE, 11,672 with deep vein thrombosis. Overall, 6445 (29%) were inpatients. During the study period, those who developed VTE as inpatients had a significantly higher incidence of fatal PE (2.1% vs. 1.5%; odds ratio: 1.4; 95% CI: 1.1–1.7), overall death (7.0% vs. 5.4%; odds ratio: 1.3; 95% CI: 1.2–1.5), and major bleeding (2.9% vs. 2.1%; odds ratio: 1.4; 95% CI: 1.1–1.6) than outpatients. The incidence of fatal bleeding was not significantly increased (0.7% vs. 0.5%; odds ratio: 1.2; 95% CI: 0.9–1.8). In multivariable analysis, inpatient status was significantly associated with a higher risk for fatal PE (odds ratio: 1.3; 95% CI: 1.1–1.7). Conclusions VTE occurring in hospitalized patients carries a significantly higher risk for death of PE than in outpatients, underscoring the importance of VTE prevention strategies in the hospital setting.

In recent decades, the growing incidence of patients with heart failure who have preserved systolic function, underlines the need to differentiate between heart failure due to diastolic dysfunction and that due to systolic dysfunction.To develop a prediction profile of clinical parameters that enables clinicians to differentiate between patients with systolic and diastolic heart failure.164 patients admitted for congestive heart failure to the cardiology department of an academic tertiary care hospital, whose left ventricular systolic and diastolic function had been evaluated echocardiographically and who satisfied the Framingham criteria for heart failure, were prospectively recruited. All patients answered a questionnaire which included, in addition to other clinical variables, the Framingham criteria.Patients with diastolic heart failure (61.6%) were more likely to be older, female, and to present left ventricular hypertrophy (LVH), with a lower proportion of smokers, alcohol drinkers, coronary disease, q wave and left bundle branch block (all p0.005). The predicting model obtained on the logistic regression analysis was very significant, with three variables and 72.3% of correct predictions (x(2) value=40,457, p0.001). These three variables, predictors of diastolic as opposed to systolic heart failure, were female sex (OR=3.546), left ventricle hypertrophy (OR=4.011) and absence of coronary disease (OR=3.547).Three variables which can be easily evaluated, female sex, left ventricular hypertrophy and presence or absence of coronary disease, may enable clinicians to differentiate between patients with systolic or diastolic heart failure.

The aim of this study was to determine the feasibility, concerning compliance to protocol and recommended clinical practice guidelines, as well as efficacy results of multidisciplinary treatment (surgery, radiotherapy and chemotherapy) of resectable rectal cancer in a third-level hospital devoid of radiotherapy and clinical oncology units.A retrospective, single-institution analysis was completed for 45 consecutive patients diagnosed with resectable rectal cancer who entered an officially proposed multidisciplinary treatment protocol from October 1998 to September 2003. Adequacy of patient inclusion, according to clinical stage, was reviewed. Neoadjuvant radiotherapy schedule, surgery procedures and adjuvant chemotherapy indication were assessed. All treatment time intervals were analysed. Finally, efficacy results are discussed and contextualised by comparison with results of clinical trials which support this treatment strategy.According to an independent board review, 3 patients (6.7%) with stage I rectal cancer, 31 patients (68.9%) with stage II and 11 patients (24.4%) with stage III rectal cancer were included. Radiotherapy dosage, volume and schedule were as planned. Median time from diagnosis to start of radiotherapy was 26.36 days (24.26- 28.57; CI 95%). Median duration of radiotherapy was 6.00 days (5.56-6.44; CI 95%). Median time from start of radiotherapy to surgery was 15.67 days (14.47-16.87; CI 95%). Median time from completion of radiotherapy to surgery was 10.67 days (9.53-11.81; CI 95%). Most of the patients underwent low anterior resection [23 patients (51.2%)] and abdominoperineal resection [16 patients (35.6%)]. Correlation between clinical and pathologic staging was as expected. Twenty-nine patients (64.4%) of the 45 that were initially included started adjuvant chemotherapy. A statistically significant relationship between pathologic stage (grouped I-II vs. III) and the use of adjuvant chemotherapy was found (p=0.033; chi-square test). Radiotherapy- and chemotherapy-induced toxicity did not differ from that previously reported. With a median follow-up of 65.46 months, a total of 10 recurrences have been diagnosed, all of them in stage III patients. Overall survival rate at five years was 76% for the complete population included.Multidisciplinary treatment of resectable rectal cancer in a third-level hospital is feasible. Although efficacy results are comparable to those previously reported in the literature, further improvements in clinical staging as well as in adjuvant chemotherapy indication are desirable.

An estimated 50 million dengue virus (DENV) infections occur annually and more than forty percent of the human population is currently at risk of developing dengue fever (DF) or dengue hemorrhagic fever (DHF). Despite the prevalence and potential severity of DF and DHF, there are no approved vaccines or antiviral therapeutics available. An improved understanding of DENV immune evasion is pivotal for the rational development of anti-DENV therapeutics. Antagonism of type I interferon (IFN-I) signaling is a crucial mechanism of DENV immune evasion. DENV NS5 protein inhibits IFN-I signaling by mediating proteasome-dependent STAT2 degradation. Only proteolytically-processed NS5 can efficiently mediate STAT2 degradation, though both unprocessed and processed NS5 bind STAT2. Here we identify UBR4, a 600-kDa member of the N-recognin family, as an interacting partner of DENV NS5 that preferentially binds to processed NS5. Our results also demonstrate that DENV NS5 bridges STAT2 and UBR4. Furthermore, we show that UBR4 promotes DENV-mediated STAT2 degradation, and most importantly, that UBR4 is necessary for efficient viral replication in IFN-I competent cells. Our data underscore the importance of NS5-mediated STAT2 degradation in DENV replication and identify UBR4 as a host protein that is specifically exploited by DENV to inhibit IFN-I signaling via STAT2 degradation.

Background Current guidelines make no specific recommendations for venous thromboembolism (VTE) treatment in patients with renal insufficiency, but some experts recommend some reduction in heparin dose. Methods Registro Informatizado de Enfermedad TromboEmbolica (RIETE) is an ongoing, prospective registry of consecutively enrolled patients with objectively confirmed, symptomatic, acute VTE. In this analysis we retrospectively analyzed the effect of renal insufficiency on the incidence of fatal pulmonary embolism (PE) and fatal bleeding within 15 days of diagnosis. Results Up to March 2005, 10,526 patients with acute VTE were enrolled in RIETE, of whom 9234 (88%) had a creatinine clearance (CrCl) greater than 60 mL/min, 704 (6.7%) had a CrCl 30 to 60 mL/min, and 588 (5.6%) had a CrCl less than 30 mL/min. The incidence of fatal PE during the study period was 1.0%, 2.6%, and 6.6%, respectively. Fatal bleeding occurred in 0.2%, 0.3%, and 1.2% of the patients, respectively. On multivariate analysis, patients with a CrCl less than 30 mL/min were independently associated with an increased risk for fatal PE and fatal bleeding. In addition, initial diagnosis of PE, immobility for 4 days or more, cancer, and initial therapy with unfractionated heparin were independent predictors of fatal PE; whereas immobility for 4 days or more and cancer were independent predictors of fatal bleeding. Conclusions Patients with VTE who have renal insufficiency had an increased incidence of both fatal PE and fatal bleeding, but the risk of fatal PE far exceeded that of fatal bleeding. Our data support the use of full-dose anticoagulant therapy, even in patients with a CrCl less than 30 mL/min.

International audience; OBJECTIVE:Patients with acute venous thromboembolism (VTE) are at increased risk for the development of subsequent arterial ischemic events unrelated to the diagnosis of VTE. Accurate identification of VTE patients at increased risk for ischemic events during the course of anticoagulation may help to select those who would potentially benefit from concomitant therapy with anticoagulants and antiplatelets.METHODS:We used the Registro Informatizado de Enfermedad TromboEmbólica (RIETE) Registry to assess the rate and severity of subsequent ischemic events (ie, stroke, myocardial infarction, lower limb amputation, or mesenteric ischemia) appearing during the course of anticoagulant therapy and tried to identify risk factors for these events.RESULTS:From February 2009 to March 2014, 23,370 patients were recruited: 12,397 initially presenting with pulmonary embolism (PE) and 10,973 with deep venous thrombosis. During the course of anticoagulation (mean, 9.2 months), 597 patients developed recurrent VTE, 652 bled, 162 had ischemic events (stroke, 86; myocardial infarction, 53; limb amputation, 13; mesenteric ischemia, 11), and 2063 died. Of these, 29 patients died of recurrent PE, 83 of bleeding, and 53 of the ischemic events. On multivariable analysis, cancer (hazard ratio [HR], 1.77; 95% confidence interval [CI], 1.21-2.61), chronic lung disease (HR, 1.54; 95% CI, 1.05-2.26), renal insufficiency (HR, 1.72; 95% CI, 1.25-2.36), anemia (HR, 1.54; 95% CI, 1.11-2.14), prior artery disease (HR, 1.84; 95% CI, 1.29-2.64), and diabetes (HR, 1.58; 95% CI, 1.10-2.27) independently predicted the risk for ischemic events. Most of these variables also predicted major bleeding (cancer, chronic lung disease, renal insufficiency, anemia, and prior artery disease) or recurrent PE (cancer, chronic lung disease, anemia, and prior artery disease).CONCLUSIONS:In patients receiving anticoagulation for VTE, the mortality due to PE recurrences was lower than the mortality due to ischemic events. Most independent predictors for ischemic events were also predictors for major bleeding and for recurrent PE.

Fundamento El objetivo de este estudio fue valorar el efecto de la vacunacion antigripal sobre la carga viral plasmatica del virus de la inmunodeficiencia humana (VIH) y los linfocitos T CD4 en pacientes con infeccion por el VIH en fase avanzada. Pacientes y metodo Estudio observacional en pacientes con titulo de linfocitos T CD4 inferior a 200 × 106/l en tratamiento antirretroviral. Se practicaron vacunacion antigripal voluntaria y determinacion de la carga viral y de los linfocitos T CD4 basalmente y a las 4 y 12 semanas de la visita inicial en vacunados y en no vacunados. Resultados Se analizo a 16 pacientes, de los que 10 recibieron la vacuna. En los vacunados se observo un descenso de los linfocitos T CD4 a las 4 semanas (p = 0,025), asi como una tendencia ascendente en la carga viral. Los cambios se observaron exclusivamente en los 6 enfermos que tenian la carga viral elevada en el momento de la vacunacion. El descenso de los linfocitos T CD4 en este subgrupo fue significativo tambien a las 12 semanas (p = 0,043). La media del descenso de los linfocitos T CD4 fue del 49,8% de los valores basales. En tres pacientes la reduccion supero el 60%. Conclusiones La vacunacion antigripal podria acompanarse de un empeoramiento de la situacion inmunologica en los pacientes con infeccion por el VIH con inmunodepresion grave que estan en situacion de fracaso virologico.

Intracellular innate immune responses are essential to protect host cells against pathogens. Upon infection, pattern recognition receptors detect incoming microbes and trigger downstream signaling pathways leading to production of antiviral type-I interferons (IFNs).These signaling pathways are regulated by different posttranslational modifications including the ubiquitin (Ub) system. Proteins covalently attached to K48-linked polyUb are targeted for degradation by the proteasome, whereas protein modification with K63-linked polyUb may have non-proteolytic activating functions. Unanchored Ub chains that are not covalently attached to any protein are also important for kinase activation. Tripartite motif (TRIM) proteins, which function as E3-ubiquitin ligases, have been implicated in antiviral activity. We found that TRIM6 is important in the synthesis of unanchored K48-linked polyUb chains, which activate the IKKε kinase for STAT1 phosphorylation and induction of an antiviral response. These polyUb chains and IKKε interact in vivo in an IFN-I signaling dependent manner upon virus infection in mice. To better understand the physiological role of unanchored polyUb during virus infection, we developed a system to isolate ubiquitin-interacting proteins from the lungs of influenza-infected mice. Using a proteomics approach we identified new cellular factors that interact with unanchored polyUb chains in vivo and may be involved in the innate immune antiviral response.

Type-I interferons (IFN-I) are essential antiviral cytokines produced upon microbial infection. IFN-I elicits this activity through the upregulation of 100s of IFN-I stimulated genes (ISGs), many of which have known antiviral activity. The full breadth of ISG induction requires activation of a number of cellular factors including the IκB kinase epsilon (IKKϵ). However, the mechanism of IKKϵ activation upon viral infection or IFN receptor signaling remains elusive. Here we show that TRIM6, a member of the E3-ubiquitin ligase tripartite motif (TRIM) family of proteins, interacts with IKKϵ and promotes induction of IKKϵ-dependent ISGs. Some studies have suggested a role for unanchored K63-linked polyubiquitin chains, which are not conjugated to any protein, in regulation of kinase activity. However, no role has yet been established for unanchored K48-linked polyubiquitin chains in kinase activation. We show that TRIM6 and the E2-ubiquitin conjugase UbE2K cooperate in the synthesis of unanchored K48-linked polyubiquitin chains, which activate IKKϵ for subsequent STAT1 phosphorylation. Our work defines a previously unrecognized activating role of K48-linked unanchored polyubiquitin chains in kinase activation and identifies the UbE2K-TRIM6-ubiquitin axis as critical for IFN signaling and antiviral response.

An estimated 50 million dengue virus (DENV) infections occur annually and more than forty percent of the human population is currently at risk of developing dengue fever (DF) or dengue hemorrhagic fever (DHF). Despite the prevalence and potential severity of DF and DHF, there are no approved vaccines or antiviral therapeutics available. An improved understanding of DENV immune evasion is pivotal for the rational development of anti-DENV therapeutics. Antagonism of type I interferon (IFN-I) signaling is a crucial mechanism of DENV immune evasion. DENV NS5 protein inhibits IFN-I signaling by mediating proteasome-dependent STAT2 degradation. Only proteolytically-processed NS5 can efficiently mediate STAT2 degradation, though both unprocessed and processed NS5 bind STAT2. Here we identify UBR4, a 600-kDa member of the N-recognin family, as an interacting partner of DENV NS5 that preferentially binds to processed NS5. Our results also demonstrate that DENV NS5 bridges STAT2 and UBR4. Furthermore, we show that UBR4 promotes DENV-mediated STAT2 degradation, and most importantly, that UBR4 is necessary for efficient viral replication in IFN-I competent cells. Our data underscore the importance of NS5-mediated STAT2 degradation in DENV replication and identify UBR4 as a host protein that is specifically exploited by DENV to inhibit IFN-I signaling via STAT2 degradation., Author Summary Dengue virus (DENV) is the leading cause of mosquito-borne viral illness and death in humans. At present, there are no vaccines and no specific antiviral therapeutics to prevent or treat DENV infections. We previously described that the NS5 protein of DENV inhibits type I interferon signaling in virus-infected cells by mediating STAT2 degradation. This property allows DENV to overcome the antiviral effects of type I interferon, contributing to viral replication in the host. We have now obtained new insight into the mechanism by which DENV NS5 induces STAT2 degradation. NS5 bridges STAT2 with the cellular protein UBR4, a member of a family of predicted E3 ligases, resulting in UBR4-mediated STAT2 degradation. Elimination of UBR4 or mutations in NS5 that prevent its binding to UBR4 prevent NS5 from inducing STAT2 degradation. Importantly, UBR4 is required for optimal DENV replication in the presence of a competent type I interferon system. Our data demonstrate the requirement of a host factor, UBR4, for DENV to overcome the antiviral interferon response. This information might be important for the design of specific DENV inhibitors that prevent dengue virus from evading innate immunity.