Effectiveness and safety of self-managed oral anticoagulant therapy compared with direct oral anticoagulants in patients with atrial fibrillation

Abstract We compared the effectiveness and safety of direct oral anticoagulants (DOAC) vs patient self-managed warfarin therapy (PSM) in patients with atrial fibrillation. We linked prospectively registered data from university hospital clinics to nationwide Danish health registries. Primary effectiveness and safety outcomes were ischaemic stroke (incl. systemic embolism) and major bleeding. All-cause mortality and all-cause stroke were secondary outcomes. An inverse probability of treatment propensity-weighted approach was applied to adjust for potential confounding. The study cohorts included 534 patients treated with PSM and 2,671 patients treated with DOAC. Weighted rates of ischaemic stroke were 0.46 and 1.30 percent per year with PSM vs DOAC, hazard ratio (HR) 0.27 (95% confidence interval 0.11–0.68) with 2.5 years follow-up. Rates of major bleeding were 2.32 and 2.13 percent per year (HR 1.06 [0.69–1.63]). All-cause mortality was not statistically different (HR 0.67 [0.39–1.17]), whereas the incidence of all-cause stroke was significantly lower among patients treated with PSM with rates of 0.61 vs 1.45 percent per year (HR 0.36 [0.16–0.78]). In patients with atrial fibrillation, self-managed oral anticoagulant treatment was associated with a significantly lower risk of all-cause and ischaemic stroke compared to treatment with DOAC, whereas no significant differences were observed for major bleeding and mortality

Management of Cancer-Associated Venous Thrombosis:A Nationwide Survey among Danish Oncologists

Background  Treatment patterns for cancer-associated venous thrombosis (CAT) has been shown to be nonconsistent with contemporary guideline recommendations, resulting in poor patient outcomes. Objectives  The study aimed to describe contemporary CAT management in Danish oncology departments and identify knowledge gaps and inconsistencies between guidelines and clinical practice. Patients and Methods  A survey questionnaire in Danish was developed based on contemporary national guidelines. Using an open recruitment strategy, invitations to participate in the electronic survey were sent to physicians employed at oncology departments in Denmark in winter of 2018/2019. The questionnaire was based on current national guidelines and included 10 items with multiple choices and a free-text option to specify or comment. The questionnaire was pilot-tested by a junior and senior oncologist. Results  A total of 142 physicians completed the survey, representing all Danish geographical regions and various seniority. The majority reported that CAT was treated and followed up in oncology departments. However, 36.6% of the physicians were unaware of the existence of designated cancer thrombosis guidelines. Risk of venous thrombosis was generally assessed without diagnostic scores. Almost all (98.6%) reported low-molecular-weight heparin to be first-line treatment for CAT. Treatment duration seemed wrongly influenced by subtype of venous thrombosis, and 44.5% responded that thromboprophylaxis among hospitalized patients was substantially underused. Conclusion  The variability in the daily clinical management of CAT demonstrated through this survey indicates a potential to increase awareness of available guidelines, standardized use of inpatient thromboprophylaxis, and organized treatment and follow-up in a multidisciplinary setting, which would potentially improve management of CAT in Denmark

Risk of recurrent cancer-associated venous thromboembolism: A Danish nationwide cohort study

Background Predictive factors for recurrent cancer-associated venous thromboembolism have been inconsistent across previous studies. To provide data for improved risk stratification, we described the risk of recurrent venous thromboembolism overall and across age, sex, calendar period, cancer type, Ottawa risk score, cancer stage, and cancer treatment in a nationwide cohort of patients with active cancer. Methods Using Danish administrative registries, we identified a cohort of all adult patients with active cancer and a first-time diagnosis of venous thromboembolism during 2003–2018. We accounted for the competing risk of death and calculated absolute risks of recurrent venous thromboembolism at six months. Results The population included 34,072 patients with active cancer and venous thromboembolism. Recurrence risks at six months were higher for patients with genitourinary cancer (6.5%), lung cancer (6.1%), gastrointestinal cancer (5.6%), brain cancer (5.2%), and hematological cancer (5.1%) than for patients with gynecological cancer (4.7%), breast cancer (4.1%), and other cancer types (4.8%). Recurrence risks were similar for men (5.2%) and women (4.9%), with and without chemotherapy (5.1%), across Ottawa risk score group (low: 5.0%; high: 5.1%) and across calendar periods but increased with increasing cancer stage. The overall six-month all-cause mortality risk was 26%, and highest for patients with lung cancer (49%) and lowest among breast cancer patients (4.1%). Conclusions Six-month recurrence risk after first-time cancer-associated venous thromboembolism was high and varied by cancer type and patient characteristics. Refining risk stratification for recurrence may improve decision-making regarding treatment duration after cancer-associated thromboembolism

Risk of venous thromboembolism in patients with stage III and IV non-small cell lung cancer: Nationwide descriptive cohort study

Objectives Venous thromboembolism (VTE) is a common complication in patients starting cancer therapies for non-small cell lung cancer (NSCLC). We examined the risk and timing of VTE in patients with stage IIIA, IIIB-C, and stage IV NSCLC according to received cancer treatments. Materials and Methods A nationwide registry-based cohort study of patients recorded in the Danish Lung Cancer Registry (2010-2021) followed for 1 year after entry into the registry to assess the incidence of VTE. The Aalen-Johansen estimator was used to calculate the risk of VTE after treatment commencement with chemotherapy, radiotherapy, chemoradiation, immunotherapy, and targeted therapy. Results Among the 3,475 patients with stage IIIA, 4,047 with stage IIIB-C, and 18,082 patients with stage IV cancer, the 1-year risk of VTE was highest in the first six months and varied markedly by cancer stage and cancer treatment. In stage IIIA, VTE risk was highest with chemotherapy (3.9%) and chemoradiation (4.1%). In stage IIIB-C, risks increased with chemotherapy (5.2%), immunotherapy (9.4%) and targeted therapy (6.0%). Stage IV NSCLC showed high risk with targeted therapy (12.5%) and immunotherapy (12.2%). The risk was consistently higher for pulmonary embolism than deep vein thrombosis. Conclusion VTE risks vary substantially according to cancer treatments and cancer stages. The highest risk was observed in the initial six months of therapy initiation. These insights emphasize the need for tailored risk assessment and vigilance in managing VTE complications in patients with NSCLC. Further research is needed to optimize individual thromboprophylaxis strategies for patients with unresectable and metastatic NSCLC. Micro abstract This nationwide cohort study highlights the significant risk of VTE in patients undergoing cancer therapies for NSCLC. The 1-year risk of VTE was highest within the initial six months of treatment and demonstrated substantial variability on cancer stage and the specific treatments received. These findings emphasize the importance of a nuanced risk assessment tailored to both cancer stage and the specific cancer therapies employed. Such insights contribute to the ongoing efforts to optimize patient care

Defects in Mitochondrial Dynamics and Metabolomic Signatures of Evolving Energetic Stress in Mouse Models of Familial Alzheimer's Disease

The identification of early mechanisms underlying Alzheimer's Disease (AD) and associated biomarkers could advance development of new therapies and improve monitoring and predicting of AD progression. Mitochondrial dysfunction has been suggested to underlie AD pathophysiology, however, no comprehensive study exists that evaluates the effect of different familial AD (FAD) mutations on mitochondrial function, dynamics, and brain energetics.We characterized early mitochondrial dysfunction and metabolomic signatures of energetic stress in three commonly used transgenic mouse models of FAD. Assessment of mitochondrial motility, distribution, dynamics, morphology, and metabolomic profiling revealed the specific effect of each FAD mutation on the development of mitochondrial stress and dysfunction. Inhibition of mitochondrial trafficking was characteristic for embryonic neurons from mice expressing mutant human presenilin 1, PS1(M146L) and the double mutation of human amyloid precursor protein APP(Tg2576) and PS1(M146L) contributing to the increased susceptibility of neurons to excitotoxic cell death. Significant changes in mitochondrial morphology were detected in APP and APP/PS1 mice. All three FAD models demonstrated a loss of the integrity of synaptic mitochondria and energy production. Metabolomic profiling revealed mutation-specific changes in the levels of metabolites reflecting altered energy metabolism and mitochondrial dysfunction in brains of FAD mice. Metabolic biomarkers adequately reflected gender differences similar to that reported for AD patients and correlated well with the biomarkers currently used for diagnosis in humans.Mutation-specific alterations in mitochondrial dynamics, morphology and function in FAD mice occurred prior to the onset of memory and neurological phenotype and before the formation of amyloid deposits. Metabolomic signatures of mitochondrial stress and altered energy metabolism indicated alterations in nucleotide, Krebs cycle, energy transfer, carbohydrate, neurotransmitter, and amino acid metabolic pathways. Mitochondrial dysfunction, therefore, is an underlying event in AD progression, and FAD mouse models provide valuable tools to study early molecular mechanisms implicated in AD

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion