Sex differences of post-Covid patients undergoing outpatient pulmonary rehabilitation.

BACKGROUND: Following years of pandemic severe acute respiratory syndrome coronavirus 2 infections labelled Covid-19, long lasting impairment summarized as post-Covid syndrome (PCS) challenges worldwide healthcare. Patients benefit from rehabilitation programs, but sex specific aspects of improvement remain little understood. The aim of the study was to assess whether women and men differ in response to outpatient pulmonary rehabilitation for PCS. METHODS: 263 (54.4% female) patients partaking in outpatient pulmonary rehabilitation (OPR) due to PCS between March 2020 and July 2022 were included in a prospective observational cohort study. Outcomes were assessed at baseline and before discharge from OPR and included six-minute walking distance (6MWD), 1-second forced expiratory volume (FEV1), diffusion capacity for carbon monoxide, maximal inspiratory pressure (MIP), dyspnea (medical research council scale), and post-Covid functional status scale (PCFS). Sexspecific changes in outcomes following OPR were assessed by linear mixed model and presented as mean differences (MD) with 95% confidence intervals. Linear regression was applied to test whether 6MWD correlates with PCFS and the minimal clinically important difference (MCID) in 6MWD regarding an improvement of at least one point in PCFS was computed with logistic regression. RESULTS: Significant improvement throughout OPR was observed for all outcomes (all p < 0.0001). Despite less severe Covid-19 infections, PCFS scores remained higher in females after OPR (p = 0.004) and only 19.4% of women compared to 38.5% of men achieved remission of functional impairment. At baseline as well as after OPR, females showed higher symptom load compared to men in dyspnea (p = 0.0027) and scored lower in FEV1 (p = 0.009) and MIP (p = 0.0006) assessment. Performance in 6MWD was comparable between men and women. An increase of 35 m in 6MWD was computed as minimal clinically important difference to improve functional impairment. CONCLUSION: Both subjective symptoms such as fatigue and dyspnea and objective impairment in performance in pulmonary function were more frequently observed among women. Despite improvement throughout OPR in both women and men, the sex-gap in symptom load could not be closed as women less often achieved remission from functional impairment due to PCS. Intensified treatment of these symptoms should be considered in women undergoing rehabilitation for PCS.

While female sex is protective during the acute infection of Covid-19, women are at increased risk of developing post-Covid syndrome (PCS) even after only mild Covid-19 infections. Severity and frequency of symptoms such as fatigue and shortness of breath are known to be higher in women compared to men. Many different rehabilitation protocols are used for PCS, but a knowledge gap regarding sex related differences in rehabilitation success remains.Both female and male patients with PCS undergoing outpatient pulmonary rehabilitation improved in the maximum walking distance achieved within 6 min and selfrated impairment in everyday living. Although women less frequently required inpatient treatment for acute Covid-19 infection, female patients with PCS showed higher impairment in everyday living, lower capacity of physical exercise and more frequent shortness of breath, fatigue and breathing muscle weakness. Only 19.4% of women compared to 38.5% of men achieved complete remission of impairment in everyday living. Our results show that women treated for PCS retain greater symptom burden and are at risk of unsuccessful rehabilitation, calling for more targeted treatment in female patients after Covid-19 infection.

Impact of thrombosis location on walking capacity: a cohort study of patients with acute deep vein thrombosis.

Background: Data on walking impairment during the acute phase of deep vein thrombosis (DVT) are limited. Objectives: This study aimed to assess the degree of walking impairment in patients with acute DVT, with a particular focus on the relation to the DVT's anatomical location. Methods: Patients with sonographically confirmed DVT were eligible for inclusion in this cohort study. Pain-free walking distance (PWD) and maximum walking distance (MWD) were determined using standardized treadmill ergometer tests and analyzed in relation to DVT location. The impact of previous DVT on walking capacity was evaluated in an exploratory analysis. Results: The study included 64 patients (31% women; median age, 55 years). The median (IQR) time from diagnosis to exercise test was 3 (1-5) days. Patients with suprainguinal DVT demonstrated significantly shorter median (IQR) MWD than those with infrainguinal DVT (130 (61-202) m vs 565 (128-750) m; P < .01), while PWD did not significantly differ (PWD: 20 (0-30) m vs 40 (0-222) m; P = .14). The proportion of patients who had to terminate treadmill tests prematurely was higher in patients with suprainguinal DVT (91.7% vs 57.7%; P = .04). PWD and MWD seemed to be similar in patients with and without a history of DVT. Premature test termination and suprainguinal DVT location were associated with reduced quality of life, as measured by the EuroQoL Group 5-Dimension 5-Level questionnaire and visual analog scale. Conclusion: Suprainguinal DVT was linked to a more pronounced walking impairment compared with infrainguinal DVT. Limited walking capacity was associated with a reduced quality of life.

Early discharge and home treatment of patients with acute pulmonary embolism in the tertiary care setting.

Acute pulmonary embolism (PE) is a potentially life-threatening disease. Current guidelines suggest risk-adapted management. Hospitalization is required for intermediate- and high-risk patients. Early discharge and home treatment are considered safe in the majority of low-risk patients. In this study, we describe characteristics, discharge, and outcome of outpatients diagnosed with acute PE at a tertiary care center. All outpatients undergoing computed tomography pulmonary angiography or ventilation/perfusion lung scan between 01.01.2016 and 31.12.2019 at the University Hospital Vienna, Austria, were screened for a PE diagnosis. Electronic patient charts were used to extract characteristics, clinical course, and outcomes. Within the 4-year period, 709 outpatients (median age: 62 years, 50% women) were diagnosed with PE. Thirty-three (5%) patients were classified as high-risk, 159 (22%) as intermediate-high, 332 (47%) as intermediate-low, and 185 (26%) as low-risk PE according to the European Society of Cardiology risk stratification. In total, 156 (22%) patients (47% with low-risk and 20% with intermediate-low-risk PE) were discharged as outpatients and received home treatment. Rates for home treatment increased 2.4-fold during the study period. Thirty-day mortality in the entire population was 4.9%. All low-risk patients and all but one patient with home treatment survived the first 30 days. Home treatment significantly increased over time and seems to be safe in routine clinical practice. Notably, one in five intermediate-low-risk patients was discharged immediately, suggesting that a subpopulation of intermediate-low-risk patients may also be eligible for home treatment.

Hemostatic biomarkers associated with postpartum hemorrhage: a systematic review and meta-analysis.

Postpartum hemorrhage (PPH) is a leading cause of maternal morbi-mortality. Although obstetric risk factors are well described, the impact of predelivery hematologic and hemostatic biomarkers remains incompletely understood. In this systematic review, we aimed to summarize the available literature on the association between predelivery hemostatic biomarkers and PPH/severe PPH. Searching MEDLINE, EMBASE, and CENTRAL databases from inception to October 2022, we included observational studies on unselected pregnant women without bleeding disorder reporting on PPH and on predelivery hemostatic biomarkers. Two review authors independently performed title, abstract and full-text screening, upon which quantitative syntheses of studies reporting on the same hemostatic biomarker were conducted, calculating the mean difference (MD) between women with PPH/severe PPH and controls. A search on 18 October 2022 yielded 81 articles fitting our inclusion criteria. The heterogeneity between studies was considerable. With regard to PPH, the estimated average MD in the investigated biomarkers (platelets, fibrinogen, hemoglobin, Ddimer, activated partial thromboplastin time, and prothrombin time) were not statistically significant. Women who developed severe PPH had lower predelivery platelets than controls (MD = -26.0 109/L; 95% confidence interval, -35.8 to -16.1), whereas differences in predelivery fibrinogen concentration (MD = -0.31 g/L; 95% confidence interval, -0.75 to 0.13) and levels of factor XIII or hemoglobin were not statistically significant in women with and without severe PPH. Predelivery platelet counts were, on average, lower in women with severe PPH compared with controls, suggesting the potential usefulness of this biomarker for predicting severe PPH. This trial was registered at the International Prospective Register of Systematic Reviews as CRD42022368075.

Growth differentiation factor-15 and prediction of cancer-associated thrombosis and mortality: a prospective cohort study.

BACKGROUND: Patients with cancer are at increased risk of venous thromboembolism (VTE) and arterial thromboembolic/thrombotic events (ATEs). Growth differentiation factor-15 (GDF-15) improves cardiovascular risk assessment, but its predictive utility in patients with cancer remains undefined. OBJECTIVES: To investigate the association of GDF-15 with the risks of VTE, ATE, and mortality in patients with cancer and its predictive utility alongside established models. METHODS: The Vienna Cancer and Thrombosis Study (CATS)-a prospective, observational cohort study of patients with newly diagnosed or recurrent cancer-which was followed for 2 years, served as the study framework. Serum GDF-15 levels at study inclusion were measured, and any association with VTE, ATE, and death was determined using competing risk (VTE/ATE) or Cox regression (death) modeling. The added value of GDF-15 to established VTE risk prediction models was assessed using the Khorana and Vienna CATScore. RESULTS: Among 1531 included patients with cancer (median age, 62 years; 53% men), median GDF-15 levels were 1004 ng/L (IQR, 654-1750). Increasing levels of GDF-15 were associated with the increased risks of VTE, ATE, and all-cause death ([subdistribution] hazard ratio per doubling, 1.16 [95% CI, 1.03-1.32], 1.30 [95% CI, 1.11-1.53], and 1.57 [95% CI, 1.46-1.69], respectively). After adjustment for clinically relevant covariates, the association only prevailed for all-cause death (hazard ratio, 1.21; 95% CI, 1.10-1.33) and GDF-15 did not improve the performance of the Khorana or Vienna CATScore. CONCLUSION: GDF-15 is strongly associated with survival in patients with cancer, independent of the established risk factors. While an association with ATE and VTE was identified in univariable analysis, GDF-15 was not independently associated with these outcomes and failed to improve established VTE prediction models.

Atrial fibrillation and cancer: prevalence and relative risk from a nationwide study.

Background: Atrial fibrillation (AF) is an increasingly recognized codiagnosis in patients with cancer. Objectives: This study aimed to provide a robust and contemporary estimate on the coprevalence and relative risk of AF in patients with cancer. Methods: We conducted a nationwide analysis, utilizing diagnosis codes from the Austrian Association of Social Security Providers dataset. Estimates of the coprevalence of cancer and AF and the relative risk of AF in patients with cancer compared with individuals without cancer were obtained as point prevalences with binomial exact confidence intervals and summarized across age groups and cancer types with random-effects models. Results: Overall, 8,306,244 persons were included in the present analysis, of whom 158,675 (prevalence estimate, 1.91%; 95% CI, 1.90-1.92) had a cancer diagnosis code and 112,827 (1.36%; 95% CI, 1.35-1.36) an AF diagnosis code, respectively. The prevalence estimate for AF in patients with cancer was 9.77% (95% CI, 9.63-9.92) and 1.19% (95% CI, 1.19-1.20) in the noncancer population. Conversely, 13.74% (95% CI, 13.54-13.94) of patients with AF had a concurrent cancer diagnosis. The corresponding age-stratified random-effects relative risk ratio for AF in patients with cancer compared with no cancer diagnosis was 10.45 (95% CI, 7.47-14.62). The strongest associations between cancer and AF were observed in younger persons and patients with hematologic malignancies. Conclusion: Cancer and AF have a substantial coprevalence in the population. This finding corroborates the concept that cancer and AF have common risk factors and pathophysiology.

Effect of Hydrogen Sulfide on Essential Functions of Polymorphonuclear Leukocytes.

Impaired polymorphonuclear leukocyte (PMNL) functions contribute to increased infections and cardiovascular diseases in chronic kidney disease (CKD). Uremic toxins reduce hydrogen sulfide (H2S) levels and the anti-oxidant and anti-inflammatory effects of H2S. Its biosynthesis occurs as a side process of transsulfuration and in the disposal of adenosylhomocysteine, a transmethylation inhibitor and proposed uremic toxin. PMNL chemotaxis was measured by the under-agarose method, phagocytosis, and oxidative burst by flow cytometry in whole blood and apoptosis by determining DNA content by flow cytometry and morphological features by fluorescence microscopy. Sodium hydrogen sulfide (NaHS), diallyl trisulphide (DATS) and diallyl disulphide (DADS), cysteine, and GYY4137 were used as H2S-producing substances. Increased H2S concentrations did not affect chemotaxis and phagocytosis. NaHS primed PMNL oxidative burst activated by phorbol 12-myristate 13-acetate (PMA) or E. coli. Both DATS and cysteine significantly decreased E. coli-activated oxidative burst but had no effect on PMA stimulation. While NaHS, DADS, and cysteine attenuated PMNL apoptosis, GYY4137 decreased their viability. Experiments with signal transduction inhibitors suggest that the intrinsic apoptosis pathway is mainly involved in GYY4137-induced PMNL apoptosis and that GYY4137 and cysteine target signaling downstream of phosphoinositide 3-kinase.

Association of telomere length and mitochondrial DNA copy number, two biomarkers of biological aging, with the risk of venous thromboembolism.

BACKGROUND: Venous thromboembolism (VTE) is the third most common cardiovascular disease and occurs in all age groups, albeit the risk increases considerably with age. Previous research indicates mitochondrial dysfunction and telomere shortening in cardiovascular aging. However, in the context of VTE this has not been investigated in detail. AIM: We aimed to explore biomarkers reflecting biological aging (i.e. human mitochondrial DNA copy number (mtDNA) and telomere length) and their association with VTE. METHODS: mtDNA and telomere length were measured in a case-control study of 116 patients with a history of VTE and 128 age- and sex-matched healthy individuals from isolated blood using a qPCR-based assay kit. Cases had at least one unprovoked VTE event and were enrolled no earlier than 3 months after the last VTE event. RESULTS: The mtDNA copy number was significantly lower in VTE cases compared to controls (median [IQR]: 663 per diploid cells [78.75-2204.5] vs. 2832 per diploid cells [724-4350]; p < 0.001). After adjustment for age, sex, BMI, and smoking, mtDNA copy number was independently associated with VTE risk (odds ratio per increase in 400 mtDNA per diploid cell: 0.889, 95%CI 0.834-0.947). mtDNA copy numbers were significantly different between women and men (2375 [455-3737] women vs. 893 [152-3154] men; p < 0.001). The analysis of telomere length showed no significant difference between patients and healthy controls. CONCLUSION: Lower mtDNA levels were found in patients with VTE compared to controls, indicating an association of biological aging with risk of VTE.

Circulatory miR-411-5p as a Novel Prognostic Biomarker for Major Adverse Cardiovascular Events in Patients with Atrial Fibrillation.

The risk stratification of patients with atrial fibrillation (AF) for subsequent cardiovascular events could help in guiding prevention strategies. In this study, we aimed at investigating circulating microRNAs as prognostic biomarkers for major adverse cardiovascular events (MACE) in AF patients. We conducted a three-stage nested case-control study within the framework of a prospective registry, including 347 AF patients. First, total small RNA-sequencing was performed in 26 patients (13 cases with MACE) and the differential expression of microRNAs was analyzed. Seven candidate microRNAs with promising results in a subgroup analysis on cardiovascular death were selected and measured via using RT-qPCR in 97 patients (42 cases with cardiovascular death). To further validate our findings and investigate broader clinical applicability, we analyzed the same microRNAs in a subsequent nested case-control study of 102 patients (37 cases with early MACE) by using Cox regression. In the microRNA discovery cohort (n = 26), we detected 184 well-expressed microRNAs in circulation without overt differential expression between the cases and controls. A subgroup analysis on cardiovascular death revealed 26 microRNAs that were differentially expressed at a significance level < 0.05 (three of which with an FDR-adjusted p-value <0.05). We, therefore, proceeded with a nested case-control approach (n = 97) focusing on patients with cardiovascular death and selected, in total, seven microRNAs for further RT-qPCR analysis. One microRNA, miR-411-5p, was significantly associated with cardiovascular death (adjusted HR (95% CI): 1.95 (1.04-3.67)). Further validation (n = 102) in patients who developed early MACE showed similar results (adjusted HR (95% CI) 2.35 (1.17-4.73)). In conclusion, circulating miR-411-5p could be a valuable prognostic biomarker for MACE in AF patients.

The post-VTE functional status scale for assessment of functional limitations in patients with venous thromboembolism: Construct validity and responsiveness in a prospective cohort study.

BACKGROUND: A large proportion of patients experience functional limitations after an acute episode of venous thromboembolism (VTE). Recently, the post-VTE functional status (PVFS) scale was proposed to capture these limitations. We performed a prospective cohort study to validate this scale. METHODS: The PVFS scale, PROMIS physical function 10a, EQ-5D-5L, and disease-specific quality of life (VEINES-QOL/Sym, PEmb-QoL) were assessed within three weeks of VTE diagnosis and after a median (IQR) follow-up of 13.4 (12.7-15.9) weeks. To evaluate construct validity of the PVFS scale, we determined correlations of PVFS scale with the other health measurements and investigated differences in patients above/below 70 years. Responsiveness was evaluated with a linear regression model, predicting change in PROMIS with change in PVFS scale. RESULTS: We included 211 patients (median (IQR) age: 55.1 (44.1-67.6) years, 40 % women). Pulmonary embolism was diagnosed in 105 (49.8 %) patients and 62.6 % of events were unprovoked. The PVFS scale correlated with PROMIS physical function (Spearman's rho (r): -0.67 and -0.63, p < 0.001) and EQ-5D-5L index (r = -0.61 and -0.61, p < 0.001) at baseline and follow-up. Furthermore, PVFS correlated moderately to strongly with disease-specific quality of life. Patients >70 years had significantly higher PVFS grades at follow-up (median (IQR): 2 (0-3) vs. 1 (0-2), p = 0.010). Changes in PVFS scale over time were significantly associated with changes in PROMIS physical function. CONCLUSIONS: The PVFS scale showed adequate construct validity and responsiveness in a prospective cohort study of patients with VTE, suggesting that it can be incorporated as additional health measurement and outcome parameter in research and clinical practice.

Growth differentiation factor-15 predicts major bleeding, major adverse cardiac events and mortality in patients with end-stage kidney disease on haemodialysis: findings from the VIVALDI study.

BACKGROUND: Patients with end-stage kidney disease (ESKD) are at high risk of cardiovascular events and bleeding. Optimizing risk assessment of ESKD patients regarding the risk of thromboembolism and bleeding complications in comorbid conditions, including atrial fibrillation and coronary heart disease, is challenging. To improve risk prediction we investigated growth differentiation factor-15 (GDF-15), a promising cardiovascular biomarker, and its relation to adverse outcomes. METHODS: In this prospective, multicentre, population-based cohort study, GDF-15 was measured in 594 ESKD patients on haemodialysis (median age 66 years, 38% female), who were followed up for a median of 3.5 years. The association of GDF-15 with major bleeding, arterial thromboembolism, major adverse cardiac events (MACE) and death was analysed within a competing risk framework. Further, we evaluated the additive predictive value of GDF-15 to cardiovascular and death risk assessment. RESULTS: GDF-15 levels were in median 5475 ng/l (25th-75th percentile 3964-7533) and independently associated with major bleeding {subdistribution hazard ratio [SHR] 1.31 per double increase [95% confidence interval (CI) 1.00-1.71]}, MACE [SHR 1.47 (95% CI 1.11-1.94)] and all-cause mortality [SHR 1.58 (95% CI 1.28-1.95)] but not arterial thromboembolism [SHR 0.91 (95% CI 0.61-1.36)]. The addition of GDF-15 to the HAS-BLED score significantly improved discrimination and calibration for predicting major bleeding [C-statistics increased from 0.61 (95% CI 0.52-0.70) to 0.68 (95% CI 0.61-0.78)]. Furthermore, we established an additive predictive value of GDF-15 beyond current risk models for predicting MACE and death. CONCLUSION: GDF-15 predicts the risk of major bleeding, cardiovascular events and death in ESKD patients on haemodialysis and might be a valuable marker to guide treatment decisions in this challenging patient population.

Antithrombin Activity and Association with Risk of Thrombosis and Mortality in Patients with Cancer.

Venous and arterial thromboembolism (VTE/ATE) are common complications in cancer patients. Antithrombin deficiency is a risk factor for thrombosis in the general population, but its connection to risk of cancer-associated thrombosis is unclear. We investigated the association of antithrombin activity levels with risk of cancer-associated VTE/ATE and all-cause mortality in an observational cohort study including patients with cancer, the Vienna Cancer and Thrombosis Study. In total, 1127 patients were included (45% female, median age: 62 years). Amongst these subjects, 110 (9.7%) patients were diagnosed with VTE, 32 (2.8%) with ATE, and 563 (49.9%) died. Antithrombin was not associated with a risk of VTE (subdistribution hazard ratio (SHR): 1.00 per 1% increase in antithrombin level; 95% CI: 0.99-1.01) or ATE (SHR: 1.00; 95% CI: 0.98-1.03). However, antithrombin showed a u-shaped association with the risk of all-cause death, i.e., patients with very low but also very high levels had poorer overall survival. In the subgroup of patients with brain tumors, higher antithrombin levels were associated with ATE risk (SHR: 1.02 per 1% increase; 95% CI: 1.00-1.04) and mortality (HR: 1.01 per 1% increase; 95% CI: 1.00-1.02). Both high and low antithrombin activity was associated with the risk of death. However, no association with cancer-associated VTE and ATE across all cancer types was found, with the exception of in brain tumors.

Diabetes mellitus is associated with a higher relative risk for venous thromboembolism in females than in males.

AIMS: The risk for developing venous thromboembolism (VTE) is about equal in both sexes. Research suggests diabetes mellitus (DM) is a risk factor for pulmonary embolism and deep vein thrombosis, both forms of VTE. We aimed at investigating the sex-specific impact of DM on VTE risk. MATERIALS AND METHODS: Medical claims data were analyzed in a retrospective, population-level cohort study in Austria between 1997 and 2014. 180,034 patients with DM were extracted and compared to 540,102 sex and age-matched controls without DM in terms of VTE risk and whether specific DM medications might modulate VTE risk. RESULTS: The risk to develop VTE was 1.4 times higher amongst patients with DM than controls (95% CI 1.36-1.43, p < 0.001). The association of DM with newly diagnosed VTE was significantly greater in females (OR = 1.52, 95% CI 1.46-1.58, p < 0.001) resulting in a relative risk increase of 1.17 (95% CI 1.11-1.23) across all age groups with a peak of 1.65 (95% CI 1.43-1.89) between 50 and 59 years. Dipeptidyl peptidase 4 inhibitors were associated with a higher risk for VTE amongst female DM patients (OR = 2.3, 95% CI 1.3-4.3, p = 0.0096). CONCLUSION: Amongst DM patients, females appear to be associated with a higher relative risk increase in VTE than males, especially during perimenopause.

Epidemiology, risk profile, management, and outcome in geriatric patients with atrial fibrillation in two long-term care hospitals.

Aim of this study was investigate the prevalence and incidence of atrial fibrillation (AF) and to describe the clinical characteristics, risk profiles, and types of anticoagulant therapy for stroke prevention and the clinical outcomes in persons admitted to a long-term care hospital. We conducted a retrospective cohort study using data from the electronic medical records of patients aged 65 years or older living in two long-term care hospitals between January 1, 2014 and October 31, 2017. Overall data from 1148 patients (mean age 84.1 ± 7.9 years, 74.2% women) were analyzed. At baseline, the median CHA2DS2-VASc score was 4 (IQR 3-5) and the HAS-BLED score 2 (IQR 2-3). We observed patients over a median period of 3.7 years. The point prevalence of AF was 29.6% (95% CI 25.8-33.7) on January 1, 2014. The 1-year cumulative incidence of de novo AF was 4.0% (2.8-5.6). Oral anticoagulants were prescribed in 48% of patients with AF. The cumulative incidence at 1 year for a composite outcome of TIA, stroke, or systemic arterial embolism was 0.6% (0.1-3.1) and 1.7% (0.5-4.6) and for bleeding 2.6% (0.9-6.2) and 1.8% (0.5-4.8) in patients with AF and oral anticoagulants or no oral anticoagulants, respectively. In long-term care hospital patients, we observed a high burden of AF. However, only about half of patients with AF received oral anticoagulation for stroke prevention.

Factor XI Inhibitors for Prevention and Treatment of Venous Thromboembolism: A Review on the Rationale and Update on Current Evidence.

Although anticoagulation therapy has evolved from non-specific drugs (i.e., heparins and vitamin K antagonists) to agents that directly target specific coagulation factors (i.e., direct oral anticoagulants, argatroban, fondaparinux), thrombosis remains a leading cause of death worldwide. Direct oral anticoagulants (i.e., factor IIa- and factor Xa-inhibitors) now dominate clinical practice because of their favorable pharmacological profile and ease of use, particularly in venous thromboembolism (VTE) treatment and stroke prevention in atrial fibrillation. However, despite having a better safety profile than vitamin K antagonists, their bleeding risk is not insignificant. This is true for all currently available anticoagulants, and a high bleeding risk is considered a contraindication to anticoagulation. As a result, ongoing research focuses on developing future anticoagulants with an improved safety profile. Several promising approaches to reduce the bleeding risk involve targeting the intrinsic (or contact activation) pathway of coagulation, with the ultimate goal of preventing thrombosis without impairing hemostasis. Based on epidemiological data on hereditary factor deficiencies and preclinical studies factor XI (FXI) emerged as the most promising candidate target. In this review, we highlight unmet clinical needs of anticoagulation therapy, outlay the rationale and evidence for inhibiting FXI, discuss FXI inhibitors in current clinical trials, conduct an exploratory meta-analysis on their efficacy and safety, and provide an outlook on the potential clinical application of these novel anticoagulants.

Modeling Players' Scanning Activity in Football.

The purpose of this study was to develop and test models of scanning activity in football. Gibson's ecological approach of visual perception and exploratory activity provided the theoretical framework for the models. The video-based data analysis consisted of 17 selected matches and 239 players of the Union of European Football Associations (UEFA) U17 and U19 European Championship 2018 and the UEFA U17 and U21 European Championship 2019. The results showed a positive relation between scanning frequency and successful passes, as well as changes in body orientation. Scanning frequency was also related to a player's appearances in national teams and to opponent pressure. Opponent pressure had a large effect on pass result and the player's body orientation. Previous research on the relation between scanning frequency and performance was extended by several contextual predictors. Future research should focus on gaining a deeper understanding of the relation between scanning frequency and further contextual variables related to scanning.

ABO blood group type and risk of venous thromboembolism in patients with cancer.

Venous thromboembolism (VTE) is common in patients with cancer. Although in the general population blood type non-O is associated with increased VTE risk, the impact of ABO blood type on risk of cancer-associated VTE has not been clarified. To determine the influence of ABO blood type on cancer-associated VTE risk, we conducted an analysis within the Vienna Cancer and Thrombosis Study, a prospective cohort study including patients with newly diagnosed or recurrent cancer observed for the primary outcome VTE. Restricted cubic spline analysis was performed and specific time-restricted subdistribution hazard ratios (SHR) were calculated to investigate the association between non-O blood type and VTE over time. One thousand, seven hundred and eight patients were included in the analysis (median follow-up time: 24 months; interquartile range: 10-24), and 151 patients developed VTE (8.8%). During the first 3 months of follow-up, there was no association between non-O blood type and VTE risk (SHR: 1.00; 95% confidence interval [CI]: 0.60-1.67). Thereafter, non-O blood type was associated with a higher VTE risk (SHR: 1.79; 95% CI: 1.12-2.85). Furthermore, non-O blood type was associated with increased VTE risk in patients with intermediate and low thrombotic risk tumor types (SHR: 1.73; 95% CI: 1.09-2.73) but not in very high-risk types (pancreatic, gastroesophageal, and brain cancer; SHR: 0.94; 95% CI: 0.55-1.61). This association was weakened after adjustment for factor VIII. Non-O blood type is a time-dependent predictor of VTE in patients with cancer. It is associated with increased VTE risk beyond 3 months of follow-up and in patients with intermediate- and low-risk tumor types.

Outpatient Pulmonary Rehabilitation in Patients with Long COVID Improves Exercise Capacity, Functional Status, Dyspnea, Fatigue, and Quality of Life.

BACKGROUND: COVID-19 survivors face the risk of long-term sequelae including fatigue, breathlessness, and functional limitations. Pulmonary rehabilitation has been recommended, although formal studies quantifying the effect of rehabilitation in COVID-19 patients are lacking. METHODS: We conducted a prospective observational cohort study including consecutive patients admitted to an outpatient pulmonary rehabilitation center due to persistent symptoms after COVID-19. The primary endpoint was change in 6-min walk distance (6MWD) after undergoing a 6-week interdisciplinary individualized pulmonary rehabilitation program. Secondary endpoints included change in the post-COVID-19 functional status (PCFS) scale, Borg dyspnea scale, Fatigue Assessment Scale, and quality of life. Further, changes in pulmonary function tests were explored. RESULTS: Of 64 patients undergoing rehabilitation, 58 patients (mean age 47 years, 43% women, 38% severe/critical COVID-19) were included in the per-protocol-analysis. At baseline (i.e., in mean 4.4 months after infection onset), mean 6MWD was 584.1 m (±95.0), and functional impairment was graded in median at 2 (IQR, 2-3) on the PCFS. On average, patients improved their 6MWD by 62.9 m (±48.2, p < 0.001) and reported an improvement of 1 grade on the PCFS scale. Accordingly, we observed significant improvements across secondary endpoints including presence of dyspnea (p < 0.001), fatigue (p < 0.001), and quality of life (p < 0.001). Also, pulmonary function parameters (forced expiratory volume in 1 s, lung diffusion capacity, inspiratory muscle pressure) significantly increased during rehabilitation. CONCLUSION: In patients with long COVID, exercise capacity, functional status, dyspnea, fatigue, and quality of life improved after 6 weeks of personalized interdisciplinary pulmonary rehabilitation. Future studies are needed to establish the optimal protocol, duration, and long-term benefits as well as cost-effectiveness of rehabilitation.

Bleeding Risk Assessment in End-Stage Kidney Disease: Validation of Existing Risk Scores and Evaluation of a Machine Learning-Based Approach.

BACKGROUND: Patients with end-stage kidney disease (ESKD) on hemodialysis (HD) are at increased risk for bleeding. However, despite relevant clinical implications regarding dialysis modalities or anticoagulation, no bleeding risk assessment strategy has been established in this challenging population. METHODS: Analyses on bleeding risk assessment models were performed in the population-based Vienna InVestigation of Atrial fibrillation and thromboemboLism in patients on hemoDialysIs (VIVALDI) study including 625 patients. In this cohort study, patients were prospectively followed for a median observation period of 3.5 years for the occurrence of major bleeding. First, performances of existing bleeding risk scores (i.e., HAS-BLED, HEMORR2HAGES, ATRIA, and four others) were evaluated in terms of discrimination and calibration. Second, four machine learning-based prediction models that included clinical, dialysis-specific, and laboratory parameters were developed and tested using Monte Carlo cross-validation. RESULTS: Of 625 patients (median age: 66 years, 37% women), 89 (14.2%) developed major bleeding, with a 1-year, 2-year, and 3-year cumulative incidence of 6.1% (95% confidence interval [CI]: 4.2-8.0), 10.3% (95% CI: 8.0-12.8), and 13.5% (95% CI: 10.8-16.2), respectively. C-statistics of the seven contemporary bleeding risk scores ranged between 0.54 and 0.59 indicating poor discriminatory performance. The HAS-BLED score showed the highest C-statistic of 0.59 (95% CI: 0.53-0.66). Similarly, all four machine learning-based predictions models performed poorly in internal validation (C-statistics ranging from 0.49 to 0.55). CONCLUSION: Existing bleeding risk scores and a machine learning approach including common clinical parameters fail to assist in bleeding risk prediction of patients on HD. Therefore, new approaches, including novel biomarkers, to improve bleeding risk prediction in patients on HD are needed.