Machine learning to predict major bleeding during anticoagulation for venous thromboembolism: possibilities and limitations.

Predictive tools for major bleeding (MB) using machine learning (ML) might be advantageous over traditional methods. We used data from the Registro Informatizado de Enfermedad TromboEmbólica (RIETE) to develop ML algorithms to identify patients with venous thromboembolism (VTE) at increased risk of MB during the first 3 months of anticoagulation. A total of 55 baseline variables were used as predictors. New data prospectively collected from the RIETE were used for further validation. The RIETE and VTE-BLEED scores were used for comparisons. External validation was performed with the COMMAND-VTE database. Learning was carried out with data from 49 587 patients, of whom 873 (1.8%) had MB. The best performing ML method was XGBoost. In the prospective validation cohort the sensitivity, specificity, positive predictive value and F1 score were: 33.2%, 93%, 10%, and 15.4% respectively. F1 value for the RIETE and VTE-BLEED scores were 8.6% and 6.4% respectively. In the external validation cohort the metrics were 10.3%, 87.6%, 3.5% and 5.2% respectively. In that cohort, the F1 value for the RIETE score was 17.3% and for the VTE-BLEED score 9.75%. The performance of the XGBoost algorithm was better than that from the RIETE and VTE-BLEED scores only in the prospective validation cohort, but not in the external validation cohort.

Machine Learning to Predict Outcomes in Patients with Acute Pulmonary Embolism Who Prematurely Discontinued Anticoagulant Therapy.

BACKGROUND: Patients with pulmonary embolism (PE) who prematurely discontinue anticoagulant therapy (<90 days) are at an increased risk for death or recurrences. METHODS: We used the data from the RIETE (Registro Informatizado de Pacientes con Enfermedad TromboEmbólica) registry to compare the prognostic ability of five machine-learning (ML) models and logistic regression to identify patients at increased risk for the composite of fatal PE or recurrent venous thromboembolism (VTE) 30 days after discontinuation. ML models included decision tree, k-nearest neighbors algorithm, support vector machine, Ensemble, and neural network [NN]. A "full" model with 70 variables and a "reduced" model with 23 were analyzed. Model performance was assessed by confusion matrix metrics on the testing data for each model and a calibration plot. RESULTS: Among 34,447 patients with PE, 1,348 (3.9%) discontinued therapy prematurely. Fifty-one (3.8%) developed fatal PE or sudden death and 24 (1.8%) had nonfatal VTE recurrences within 30 days after discontinuation. ML-NN was the best method for identification of patients experiencing the composite endpoint, predicting the composite outcome with an area under receiver operating characteristic (ROC) curve of 0.96 (95% confidence interval [CI]: 0.95-0.98), using either 70 or 23 variables captured before discontinuation. Similar numbers were obtained for sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. The discrimination of logistic regression was inferior (area under ROC curve, 0.76 [95% CI: 0.70-0.81]). Calibration plots showed similar deviations from the perfect line for ML-NN and logistic regression. CONCLUSION: The ML-NN method very well predicted the composite outcome after premature discontinuation of anticoagulation and outperformed traditional logistic regression.

Thirty-day outcomes in patients with proximal deep vein thrombosis who discontinued anticoagulant therapy prematurely.

INTRODUCTION: In patients receiving anticoagulation for deep vein thrombosis (DVT), a variety of reasons (including active bleeding or high-risk for bleeding) may lead into premature discontinuation of therapy (prior to completing 90 days). The relative frequency and clinical consequences of premature discontinuation in contemporary patients remain unknown. METHODS: We used the data from RIETE, an international registry of patients with venous thromboembolism (VTE), to identify patients with proximal (above knee) lower limb DVT who prematurely discontinued anticoagulation. We assessed the incidence of the composite outcome: pulmonary embolism (PE)-related death, sudden death, or recurrent VTE within the subsequent 30 days after discontinuation and compared the risk of these events vs. the risk in patients without premature discontinuation, once adjusted for demographics and clinical factors. RESULTS: Of 26,335 patients with proximal DVT recruited from 2001 to 2018, 1322 (5.02%) prematurely discontinued anticoagulation. Thirty days after discontinuation, 12 (0.91%) patients suffered fatal PE (n = 8) or sudden death (n = 4) and 33 (2.50%) had non-fatal recurrent VTE (PE = 15; recurrent DVT = 18). In patients with premature discontinuation, the 30-day incidence of the composite outcome was 1.62 per 1000 patient-days (95%CI: 0.00-3.80). During the first week after discontinuation, the incidence rate was 4.09 per 1000 patient-days (95%CI: 0.65-7.52). The adjusted odds of the composite outcome was 7.88 times (95%CI: 6.39-9.72) higher in patients who discontinued prematurely than in those without premature discontinuation. CONCLUSION: Premature discontinuation of anticoagulation occurred in 5% of patients with proximal DVT, and was associated an 8-fold increased odds for the composite outcome.

Thirty-day outcomes in patients with acute pulmonary embolism who discontinued anticoagulant therapy before 90 days.

BACKGROUND: The contemporary natural history of patients with acute pulmonary embolism (PE) not receiving (or early discontinuing) anticoagulant therapy has not been consistently evaluated. OBJECTIVE: To assess the rate of the composite outcome of PE-related death, sudden death, or recurrent thromboembolism (VTE) within 30 days in all PE patients in whom anticoagulation was not administered or discontinued prematurely (<90 days of anticoagulation). METHODS: We used the RIETE database to assess the incidence rates (per 100 person-days) of the composite outcome within the subsequent 30 days. The risk of these events was compared to PE patients who were anticoagulated for ≥90 days. RESULTS: Of 34,447 PE recruited from 2001 to 2017, 47 (0.14%) did not receive anticoagulants and 1348 (3.91%) discontinued it before 90 days. Fatal PE developed in 25 (53%) of those without any anticoagulation and in 45 (3.33%) with premature discontinuations. Sudden death or non-fatal recurrent VTE occurred in 6 (0.45%) and 24 (1.48%) patients, respectively. The incidence of the primary outcome declined logarithmically from 6.36 per 100 patient-days in untreated patients to 0.32-0.13 in those treated for 8-90 days. During the first week of follow-up, the incidence rate was 13.9 and 0.60-0.31 per 100 patient-days, respectively. The adjusted odds of the primary outcome was 27 fold higher in untreated than in treated patients, and progressively decreased to 2.5-7 fold higher in patients treated for at least 7 days. CONCLUSION: The incidence of the composite outcome was highest during the first week, and inversely and logarithmically correlated with the duration of anticoagulant therapy.

Clinical outcomes during anticoagulant therapy in fragile patients with venous thromboembolism.

BACKGROUND: Subgroup analyses from randomized trials suggested favorable results for the direct oral anticoagulants in fragile patients with venous thromboembolism (VTE). The frequency and natural history of fragile patients with VTE have not been studied yet. OBJECTIVES: To compare the clinical characteristics, treatment and outcomes during the first 3 months of anticoagulation in fragile vs non-fragile patients with VTE. METHODS: Retrospective study using consecutive patients enrolled in the RIETE (Registro Informatizado Enfermedad TromboEmbolica) registry. Fragile patients were defined as those having age ≥75 years, creatinine clearance (CrCl) levels ≤50 mL/min, and/or body weight ≤50 kg. RESULTS: From January 2013 to October 2016, 15 079 patients were recruited. Of these, 6260 (42%) were fragile: 37% were aged ≥75 years, 20% had CrCl levels ≤50 mL/min, and 3.6% weighed ≤50 kg. During the first 3 months of anticoagulant therapy, fragile patients had a lower risk of VTE recurrences (0.78% vs 1.4%; adjusted odds ratio [OR]: 0.52; 95% confidence intervals [CI]: 0.37-0.74) and a higher risk of major bleeding (2.6% vs 1.4%; adjusted OR: 1.41; 95% CI: 1.10-1.80), gastrointestinal bleeding (0.86% vs 0.35%; adjusted OR: 1.84; 95% CI: 1.16-2.92), haematoma (0.51% vs 0.07%; adjusted OR: 5.05; 95% CI: 2.05-12.4), all-cause death (9.2% vs 3.5%; adjusted OR: 2.02; 95% CI: 1.75-2.33), or fatal PE (0.85% vs 0.35%; adjusted OR: 1.77; 95% CI: 1.10-2.85) than the non-fragile. CONCLUSIONS: In real life, 42% of VTE patients were fragile. During anticoagulation, they had fewer VTE recurrences and more major bleeding events than the non-fragile.

Short-term effects on antioxidant enzymes and long-term genotoxic and carcinogenic potential of CuO nanoparticles compared to bulk CuO and ionic copper in mussels Mytilus galloprovincialis.

The aim of this work was to study short-term effects on antioxidant enzyme activities and long-term genotoxic and carcinogenic potential of CuO nanoparticles (NPs) in comparison to bulk CuO and ionic copper in mussels Mytilus galloprovincialis after 21 days exposure to 10 µg Cu L(-1). Then, mussels were kept for up to 122 days in clean water. Cu accumulation depended on the form of the metal and on the exposure time. CuO NPs were localized in lysosomes of digestive cells, as confirmed by TEM and X ray microanalysis. CuO NPs, bulk CuO and ionic copper produced different effects on antioxidant enzyme activities in digestive glands, overall increasing antioxidant activities. CuO NPs significantly induced catalase and superoxide dismutase activities. Fewer effects were observed in gills. Micronuclei frequency increased significantly in mussels exposed to CuO NPs and one organism treated with CuO NPs showed disseminated neoplasia. However, transcription levels of cancer-related genes did not vary significantly. Thus, short-term exposure to CuO NPs provoked oxidative stress and genotoxicity, but further studies are needed to determine whether these early events can lead to cancer development in mussels.

Rivaroxaban in the treatment of venous thromboembolism and the prevention of recurrences: a practical approach.

Anticoagulation therapy is the standard treatment of patients with symptomatic venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism. Until recently, treatment of VTE was based on parenteral or low-molecular-weight heparin for initial therapy (5-10 days) and oral vitamin K antagonists for long-term therapy. Those treatments have some limitations, including parenteral administration (heparins), the need for frequent monitoring and dose adjustments, interactions with several medications, and dietary restrictions (vitamin K antagonists). Rivaroxaban is a new oral direct factor Xa inhibitor with a wide therapeutic window, predictable anticoagulant effect, no food interactions, and few drug interactions. Consequently, no periodic monitoring of anticoagulation is needed, and fixed doses can be prescribed. EINSTEIN program demonstrated that rivaroxaban was as effective as and significantly safer than standard therapy for treatment of VTE. Rivaroxaban was recently authorized so doubts exist about how to use it in daily clinical practice. This document aims to clarify common questions formulated by clinicians regarding the use of this new drug.

Venous thromboembolism prophylaxis in acutely ill hospitalized medical patients. A retrospective multicenter study.

OBJECTIVE: To analyze the incidence of VTE in hospitalized medical patients and prophylaxis applied in accordance with the 8th ACCP guidelines and the National PRETEMED guide for thromboprophylaxis. METHODS: Discharge lists were reviewed to select the first consecutive 20 patients, aged ≥ 40 years and admitted ≥ 4 days to the Internal Medicine Departments of 79 Spanish hospitals. Exclusion criteria were: admission for diagnostic procedures, VTE or surgical illness, or care during hospitalization provided by the local investigator. RESULTS: From September 2011 to July 2012, 2845 discharge reports were evaluated and 1623 were considered eligible for the study. Overall 930 (57.3%) patients of this group were at risk of VTE according to the ACCP guidelines, 759 (81.6%) received VTE prophylaxis (mechanical or pharmacological) and 159 (17.1%) had at least one risk factor that might contraindicate anticoagulant use. The proportion of patients at VTE risk according to the ACCP and National PRETEMED guidelines with no risk factors of bleeding that did not receive prophylaxis was 16.3% and 17.2%, respectively. During hospitalization, there were 14 (0.9%) episodes of symptomatic VTE, 12 (86%) of which occurred in patients receiving prophylaxis. VTE rate was 1.3% among patients with VTE risk that received prophylaxis and 3.5% in patients that also had one risk factor that might contraindicate anticoagulant use. CONCLUSIONS: In a setting characterized by high thromboprophylaxis compliance most of the episodes occurred in patients receiving pharmacological prophylaxis. Patients with combined VTE and bleeding risk factors showed the highest rate of both symptomatic VTE and prophylaxis failure.

Risk of venous thromboembolism associated with single and combined effects of Factor V Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls.

Genetic and environmental factors interact in determining the risk of venous thromboembolism (VTE). The risk associated with the polymorphic variants G1691A of factor V (Factor V Leiden, FVL), G20210A of prothrombin (PT20210A) and C677T of methylentetrahydrofolate reductase (C677T MTHFR) genes has been investigated in many studies. We performed a pooled analysis of case-control and cohort studies investigating in adults the association between each variant and VTE, published on Pubmed, Embase or Google through January 2010. Authors of eligible papers, were invited to provide all available individual data for the pooling. The Odds Ratio (OR) for first VTE associated with each variant, individually and combined with the others, were calculated with a random effect model, in heterozygotes and homozygotes (dominant model for FVL and PT20210A; recessive for C677T MTHFR). We analysed 31 databases, including 11,239 cases and 21,521 controls. No significant association with VTE was found for homozygous C677T MTHFR (OR: 1.38; 95 % confidence intervals [CI]: 0.98-1.93), whereas the risk was increased in carriers of either heterozygous FVL or PT20210 (OR = 4.22; 95 % CI: 3.35-5.32; and OR = 2.79;95 % CI: 2.25-3.46, respectively), in double heterozygotes (OR = 3.42; 95 %CI 1.64-7.13), and in homozygous FVL or PT20210A (OR = 11.45; 95 %CI: 6.79-19.29; and OR: 6.74 (CI 95 % 2.19-20.72), respectively). The stratified analyses showed a stronger effect of FVL on individuals ≤ 45 years (p value for interaction = 0.036) and of PT20210A in women using oral contraceptives (p-value for interaction = 0.045). In this large pooled analysis, inclusive of large studies like MEGA, no effect was found for C677T MTHFR on VTE; FVL and PT20210A were confirmed to be moderate risk factors. Notably, double carriers of the two genetic variants produced an impact on VTE risk significantly increased but weaker than previously thought.

Dabigatran, rivaroxaban and apixaban versus enoxaparin for thomboprophylaxis after total knee or hip arthroplasty: pool-analysis of phase III randomized clinical trials.

OBJECTIVES: To compare the main efficacy and safety endpoints of the pivotal randomised clinical trials (RCTs) on venous thromboembolism (VTE) prevention after total hip (THR) or knee (TKR) replacement with the new oral anticoagulants (NAs) versus enoxaparin. METHODS: A pool-analysis of 10 RCTs that included 32.144 randomised patients was performed. Efficacy outcomes were total VTE and all-cause mortality, major VTE, and proximal DVT. Safety outcomes were major bleeding, and clinically relevant (major or non-major) bleeding. RESULTS: Overall, a significant effect favouring NAs was found for the primary efficacy outcome (RR 0.71; 95%CI 0.56-0.90), major VTE (RR 0.59; 95%CI 0.41-0.84), and proximal DVT (RR 0.51; 95%CI 0.35-0.76). Compared to enoxaparin 40 mg QD, rivaroxaban showed superiority (RR 0.50; 95%CI 0.34-0.73), followed by apixaban (RR 0.63; 95%CI 0.36-1.01) and dabigatran (RR 1.02; 95%CI 0.86-1.20). There was significant heterogeneity among trials and subgroups analysed for these efficacy outcomes. Major bleeding (RR 1.04; 95% CI 0.74-1.46) and clinically relevant bleeding (RR 1.03; 95%CI 0.88-1.21) was similar with NAs or enoxaparin. Rivaroxaban showed a trend toward more major bleeding episodes than enoxaparin (RR 1.88; 95%CI 0.92-3.82) and apixaban showed the lowest clinically relevant bleeding risk (RR 0.81; 95%CI 0.64-1.01). CONCLUSIONS: Overall, NAs showed more efficacy and same safety when compared to the recommended dose of enoxaparin after THR and TKR. There are little differences in efficacy and bleeding risk among NAs and the type of prophylaxis that should be analysed further.

Otology versus Otosociology.

Otology concerns the biological study of ear alterations and diseases, solely. So, the diagnosis of audiovestibular diseases tends to be idiopathic or is based on theoretical concepts such as idiopathic sudden deafness, Ménière disease, benign paroxysmal positional vertigo, tinnitus, hyperacusis, or idiopathic facial paralysis. The treatment for these pathologies is symptomatic. Otosociology takes the aetiology and pathogenesis of the ear and situates them within the social and cultural environment of the patient. Then, audiovestibular disease is based on evidence, and the treatment options seek to solve the causes and consequences produced. Otosociology should be considered as a new discipline. Otosociology came into being since otology does not provide definitive solutions for the audiovestibular alterations produced from the point of view of the ear, whereas otosociology finds these solutions within the social/cultural environment of the patient. Where otology emphasises the diseases of the ear, otosociology deals with social manifestations. Where otology deals with idiopathic diseases, otosociology deals with causes and pathogeny produced by interactions in the social and cultural surroundings of the patient. Where otology offers symptomatic treatment, otosociology offers treatment of causes and consequences. Otosociology can fill significant voids in audiovestibular processes from the perspective of the patient's social environment.

Evaluation of seven tests for diagnosis of human brucellosis in an area where the disease is endemic.

The results of seven serologic tests for diagnosis of human brucellosis were evaluated. The titrated Rose Bengal test, microagglutination test, microtiter-adapted Coombs test, and immunocapture-agglutination test (Brucellacapt) were positive for all sera from patients with acute brucellosis. The immunoglobulin G (IgG), IgM, and IgA commercial enzyme immunoassays (ELISAs) failed to show specific antibodies in 3 patients, 10 patients, and 1 patient, respectively. The sensitivity of ELISA is not higher than that of conventional tests.

Tromboembolia pulmonar. Luces y sombras / Pulmonary thromboembolism. Light and shadows

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Children and adolescents as sexual beings: cross-cultural perspectives.

This article offers a broad perspective on child and adolescent behaviors, which are seen by different Western definitions as associated with sexual/erotic implications. This article also demonstrates that basic definitions or meanings that many modern Western societies consider important are viewed as unimportant in other societies. Topics such as masturbation, child-adult sexual activities or cross-generational marriages, same-sex activities, and sexual indoctrination are viewed differently among many groups.