Extracorporeal Membrane Oxygenation and Reperfusion Strategies in High-Risk Pulmonary Embolism Hospitalizations.

OBJECTIVES: To investigate the contemporary use of extracorporeal membrane oxygenation (ECMO) in conjunction with reperfusion strategies in high-risk pulmonary embolism (PE). DESIGN: Observational epidemiological analysis. SETTING: The U.S. Nationwide Inpatient Sample (NIS) (years 2016-2020). PATIENTS: High-risk PE hospitalizations. MEASUREMENTS AND MAIN RESULTS: Use of ECMO in conjunction with thrombolysis-based reperfusion (systemic thrombolysis or catheter-directed thrombolysis) or mechanical reperfusion (surgical embolectomy or catheter-based thrombectomy) with regards to in-hospital mortality and major bleeding. We identified high-risk PE hospitalizations in the NIS (years 2016-2020) and investigated the use of ECMO in conjunction with thrombolysis-based (systemic thrombolysis or catheter-directed thrombolysis) and mechanical (surgical embolectomy or catheter-based thrombectomy) reperfusion strategies with regards to in-hospital mortality and major bleeding. Among 122,735 hospitalizations for high-risk PE, ECMO was used in 2,805 (2.3%); stand-alone in 1.4%, thrombolysis-based reperfusion in 0.4%, and mechanical reperfusion in 0.5%. Compared with neither reperfusion nor ECMO, ECMO plus thrombolysis-based reperfusion was associated with reduced in-hospital mortality (adjusted odds ratio [aOR] 0.61; 95% CI, 0.38-0.98), whereas no difference was found with ECMO plus mechanical reperfusion (aOR 1.03; 95% CI, 0.67-1.60), and ECMO stand-alone was associated with increased in-hospital mortality (aOR 1.60; 95% CI, 1.22-2.10). In the cardiac arrest subgroup, ECMO was associated with reduced in-hospital mortality (aOR 0.71; 95% CI, 0.53-0.93). Among all patients on ECMO, thrombolysis-based reperfusion was significantly associated (aOR 0.55; 95% CI, 0.33-0.91), and mechanical reperfusion showed a trend (aOR 0.75; 95% CI, 0.47-1.19) toward reduced in-hospital mortality compared with no reperfusion, without increases in major bleeding. CONCLUSIONS: In patients with high-risk PE and refractory hemodynamic instability, ECMO may be a valuable supportive treatment in conjunction with reperfusion treatment but not as a stand-alone treatment especially for patients suffering from cardiac arrest.

Comparative Analysis of Mitochondria Surrounding the Intercalated Discs in Heart Diseases-An Ultrastructural Pilot Study.

BACKGROUND: Mitochondria play a crucial role in adapting to fluctuating energy demands, particularly in various heart diseases. This study investigates mitochondrial morphology near intercalated discs in left ventricular (LV) heart tissues, comparing samples from patients with sinus rhythm (SR), atrial fibrillation (AF), dilated cardiomyopathy (DCM), and ischemic cardiomyopathy (ICM). METHODS: Transmission electron microscopy was used to analyze mitochondria within 0-3.5 µm and 3.5-7 µm of intercalated discs in 9 SR, 10 AF, 9 DCM, and 8 ICM patient samples. Parameters included mean size in µm2 and elongation, count, percental mitochondrial area in the measuring frame, and a conglomeration score. RESULTS: AF patients exhibited higher counts of small mitochondria in the LV myocardium, resembling SR. DCM and ICM groups had fewer, larger, and often hydropic mitochondria. Accumulation rates and percental mitochondrial area were similar across groups. Significant positive correlations existed between other defects/size and hydropic mitochondria and between count/area and conglomeration score, while negative correlations between count and size/other defects and between hydropic mitochondria and count could be seen as well. CONCLUSION: Mitochondrial parameters in the LV myocardium of AF patients were similar to those of SR patients, while DCM and ICM displayed distinct changes, including a decrease in number, an increase in size, and compromised mitochondrial morphology. Further research is needed to fully elucidate the pathophysiological role of mitochondrial morphology in different heart diseases, providing deeper insights into potential therapeutic targets and interventions.

COVID-19 infection and its impact on case fatality in patients with pulmonary embolism.

BACKGROUND: Although a high prevalence of pulmonary embolism (PE) has been reported in association with coronavirus disease 2019 (COVID-19) in critically ill patients, nationwide data on the outcome of hospitalised patients with COVID-19 and PE are still limited. Thus, we investigated seasonal trends and predictors of in-hospital death in patients with COVID-19 and PE in Germany. METHODS: We used a German nationwide inpatient sample to analyse data on hospitalisations among COVID-19 patients with and without PE during 2020, and to detect changes in PE prevalence and case fatality in comparison with 2019. RESULTS: We analysed 176 137 COVID-19 hospitalisations in 2020; PE was recorded in 1.9% (n=3362) of discharge certificates. Almost one-third of patients with COVID-19 and PE died during the in-hospital course (28.7%) compared with COVID-19 patients without PE (17.7%). Between 2019 and 2020, numbers of PE-related hospitalisations were largely unchanged (98 485 versus 97 718), whereas the case fatality rate of PE increased slightly in 2020 (from 12.7% to 13.1%; p<0.001). Differences in case fatality were found between PE patients with and without COVID-19 in 2020 (28.7% versus 12.5%; p<0.001), corresponding to a 3.1-fold increased risk of PE-related death (OR 3.16, 95% CI 2.91-3.42; p<0.001) in the presence of COVID-19. CONCLUSIONS: In Germany, the prevalence of PE events during hospitalisations was similar in 2019 and 2020. However, the fatality rate among patients with both COVID-19 and PE was substantially higher than that in those with only one of these diseases, suggesting a life-threatening additive prognostic impact of the COVID-19-PE combination.

Cardiopulmonary exercise testing during follow-up after acute pulmonary embolism.

BACKGROUND: Cardiopulmonary exercise testing (CPET) may provide prognostically valuable information during follow-up after pulmonary embolism (PE). Our objective was to investigate the association of patterns and degree of exercise limitation, as assessed by CPET, with clinical, echocardiographic and laboratory abnormalities and quality of life (QoL) after PE. METHODS: In a prospective cohort study of unselected consecutive all-comers with PE, survivors of the index acute event underwent 3- and 12-month follow-ups, including CPET. We defined cardiopulmonary limitation as ventilatory inefficiency or insufficient cardiocirculatory reserve. Deconditioning was defined as peak O2 uptake (V'O2 ) <80% with no other abnormality. RESULTS: Overall, 396 patients were included. At 3 months, prevalence of cardiopulmonary limitation and deconditioning was 50.1% (34.7% mild/moderate; 15.4% severe) and 12.1%, respectively; at 12 months, it was 44.8% (29.1% mild/moderate; 15.7% severe) and 14.9%, respectively. Cardiopulmonary limitation and its severity were associated with age (OR per decade 2.05, 95% CI 1.65-2.55), history of chronic lung disease (OR 2.72, 95% CI 1.06-6.97), smoking (OR 5.87, 95% CI 2.44-14.15) and intermediate- or high-risk acute PE (OR 4.36, 95% CI 1.92-9.94). Severe cardiopulmonary limitation at 3 months was associated with the prospectively defined, combined clinical-haemodynamic end-point of "post-PE impairment" (OR 6.40, 95% CI 2.35-18.45) and with poor disease-specific and generic health-related QoL. CONCLUSIONS: Abnormal exercise capacity of cardiopulmonary origin is frequent after PE, being associated with clinical and haemodynamic impairment as well as long-term QoL reduction. CPET can be considered for selected patients with persisting symptoms after acute PE to identify candidates for closer follow-up and possible therapeutic interventions.

Incidence and risk factors of myocarditis in hospitalized patients with COVID-19.

Myocarditis as cardiac involvement in coronavirus disease 2019 (COVID-19)-infection is well known. Real-world data about incidence in hospitalized COVID-19-patients and risk factors for myocarditis in COVID-19-patients are sparse. We used the German nationwide inpatient sample to analyze all hospitalized patients with confirmed COVID-19-diagnosis in Germany in 2020 and stratified them for myocarditis. Overall, 176 137 hospitalizations (52.3% males, 53.6% aged ≥70 years) with confirmed COVID-19-infection were coded in Germany in 2020 and among them, 226 (0.01%) had myocarditis (incidence: 1.28 per 1000 hospitalization-cases). Absolute numbers of myocarditis increased, while relative numbers decreased with age. COVID-19-patients with myocarditis were younger (64.0 [IQR: 43.0/78.0] vs. 71.0 [56.0/82.0], p < 0.001). In-hospital case-fatality was 1.3-fold higher in COVID-19-patients with than without myocarditis (24.3% vs. 18.9%, p = 0.012). Myocarditis was independently associated with increased case-fatality (OR: 1.89 [95% CI: 1.33-2.67], p < 0.001). Independent risk factors for myocarditis were age <70 years (OR: 2.36 [95% CI: 1.72-3.24], p < 0.001), male sex (1.68 [95% CI: 1.28-2.23], p < 0.001), pneumonia (OR: 1.77 [95% CI: 1.30-2.42], p < 0.001), and multisystemic inflammatory COVID-19-infection (OR: 10.73 [95% CI: 5.39-21.39], p < 0.001). The incidence of myocarditis in hospitalized COVID-19-patients in Germany was 1.28 cases per 1000 hospitalizations in 2020. Risk factors for myocarditis in COVID-19 were young age, male sex, pneumonia, and multisystemic inflammatory COVID-19-infection. Myocarditis was independently associated with increased case-fatality.

From acute pulmonary embolism to post-pulmonary embolism sequelae.

Aim of this narrative review is to summarize the functional and hemodynamic implications of acute PE and PE sequelae, namely the post-PE syndrome. Briefly, we will first describe the epidemiology, diagnostic procedures, and therapeutic approaches of acute PE. Then, we will provide a definition of the post-PE syndrome and present the so far accumulated evidence regarding its epidemiology and the implications that arise for further diagnosis and treatment. Lastly, we will explore the most devastating long-term complication of PE, namely chronic thromboembolic pulmonary hypertension (CTEPH), and recent advances in its management.

Structural Analysis of Mitochondrial Dynamics-From Cardiomyocytes to Osteoblasts: A Critical Review.

Mitochondria play a crucial role in cell physiology and pathophysiology. In this context, mitochondrial dynamics and, subsequently, mitochondrial ultrastructure have increasingly become hot topics in modern research, with a focus on mitochondrial fission and fusion. Thus, the dynamics of mitochondria in several diseases have been intensively investigated, especially with a view to developing new promising treatment options. However, the majority of recent studies are performed in highly energy-dependent tissues, such as cardiac, hepatic, and neuronal tissues. In contrast, publications on mitochondrial dynamics from the orthopedic or trauma fields are quite rare, even if there are common cellular mechanisms in cardiovascular and bone tissue, especially regarding bone infection. The present report summarizes the spectrum of mitochondrial alterations in the cardiovascular system and compares it to the state of knowledge in the musculoskeletal system. The present paper summarizes recent knowledge regarding mitochondrial dynamics and gives a short, but not exhaustive, overview of its regulation via fission and fusion. Furthermore, the article highlights hypoxia and its accompanying increased mitochondrial fission as a possible link between cardiac ischemia and inflammatory diseases of the bone, such as osteomyelitis. This opens new innovative perspectives not only for the understanding of cellular pathomechanisms in osteomyelitis but also for potential new treatment options.

Predictors of short- and long-term outcomes of patients undergoing transcatheter mitral valve edge-to-edge repair.

OBJECTIVES: Transcatheter mitral valve repair (TMVR) by edge-to-edge therapy is an established treatment for severe mitral valve regurgitation (MR). BACKGROUND: Symptomatic and prognostic benefit in functional MR has been shown recently; nevertheless, data on long-term outcomes are sparse. METHODS AND RESULTS: We analyzed survival of patients treated with isolated edge-to-edge repair from June 2010 to March 2018 (primarily combined edge-to-edge repair with other mitral valve interventions was excluded) in a retrospective monocentric study. Overall, 627 consecutive patients (47.0% females, 78.6 years in mean) were included. Leading etiology was functional MR (57.4%). Follow-up regarding survival was available in 97.0%. While 97.6% were discharged alive, 75.7% were alive after a 1-year, 54.5% after 3-year, 37.6% after 5-year and 21.7% after 7-year follow-up. Higher logistic Euroscores and comorbidities such as COPD and renal insufficiency were associated with higher in-hospital and 1-year mortality. Importantly, in-hospital survival increased over the years. CONCLUSIONS: With the present study we established high survival rates at discharge and after 1 year of patients treated with TMVR. This goes along with high implantation numbers, increased interventional experience and a better in-hospital survival over the years. Long-term mortality in turn was substantially influenced by comorbidities.

Trends in thrombolytic treatment and outcomes of acute pulmonary embolism in Germany.

AIMS: Pulmonary embolism (PE) is the third most common cardiovascular cause of death; systemic thrombolysis is potentially lifesaving treatment in patients presenting with haemodynamic instability. We investigated trends in the use of systemic thrombolysis and the outcome of patients with acute PE. METHODS AND RESULTS: We analysed data on the characteristics, comorbidities, treatment, and in-hospital outcome of 885 806 PE patients in Germany between 2005 and 2015. Incidence of acute PE was 99/100 000 population/year and increased from 85/100 000 in 2005 to 109/100 000 in 2015 [ß 0.32 (0.26-0.38), P < 0.001]. During the same period, in-hospital case fatality rates decreased from 20.4% to 13.9% [ß -0.51 (-0.52 to -0.49), P < 0.001]. The overall proportion of patients treated with systemic thrombolysis increased from 3.1% in 2005 to 4.4% in 2015 [ß 0.28 (0.25-0.31), P < 0.001]. Thrombolysis was associated with lower in-hospital mortality rates in patients with haemodynamic instability, both in those with shock not necessitating cardiopulmonary resuscitation (CPR) or mechanical ventilation [odds ratio (OR) 0.42 (0.37-0.48), P < 0.001], and in those who underwent CPR [OR 0.92 (0.87-0.97), P = 0.002]. This association was independent from age, sex, and comorbidities. However, systemic thrombolysis was administered to only 23.1% of haemodynamically unstable patients. CONCLUSION: Although the proportion of PE patients treated with systemic thrombolysis increased slightly in Germany between 2005 and 2015, only the minority of haemodynamically unstable patients currently receive this treatment. In the nationwide inpatient cohort, thrombolytic therapy was associated with reduced in-hospital mortality rates in PE patients with shock, and also in those who underwent CPR.

Entropy Measures for Data Analysis II: Theory, Algorithms and Applications.

Entropies and entropy-like quantities are playing an increasing role in modern non-linear data analysis [...].

Generalized Ordinal Patterns and the KS-Entropy.

Ordinal patterns classifying real vectors according to the order relations between their components are an interesting basic concept for determining the complexity of a measure-preserving dynamical system. In particular, as shown by C. Bandt, G. Keller and B. Pompe, the permutation entropy based on the probability distributions of such patterns is equal to Kolmogorov-Sinai entropy in simple one-dimensional systems. The general reason for this is that, roughly speaking, the system of ordinal patterns obtained for a real-valued "measuring arrangement" has high potential for separating orbits. Starting from a slightly different approach of A. Antoniouk, K. Keller and S. Maksymenko, we discuss the generalizations of ordinal patterns providing enough separation to determine the Kolmogorov-Sinai entropy. For defining these generalized ordinal patterns, the idea is to substitute the basic binary relation ≤ on the real numbers by another binary relation. Generalizing the former results of I. Stolz and K. Keller, we establish conditions that the binary relation and the dynamical system have to fulfill so that the obtained generalized ordinal patterns can be used for estimating the Kolmogorov-Sinai entropy.

On Rényi Permutation Entropy.

Among various modifications of the permutation entropy defined as the Shannon entropy of the ordinal pattern distribution underlying a system, a variant based on Rényi entropies was considered in a few papers. This paper discusses the relatively new concept of Rényi permutation entropies in dependence of non-negative real number q parameterizing the family of Rényi entropies and providing the Shannon entropy for q=1. Its relationship to Kolmogorov-Sinai entropy and, for q=2, to the recently introduced symbolic correlation integral are touched.

Impact of obesity on adverse in-hospital outcomes in patients undergoing percutaneous mitral valve edge-to-edge repair using MitraClip® procedure - Results from the German nationwide inpatient sample.

BACKGROUND AND AIM: The number of percutaneous edge-to-edge mitral regurgitation (MR) valve repairs with MitraClip® implantations increased exponentially in recent years. Studies have suggested an obesity survival paradox in patients with cardiovascular diseases. We investigated the influence of obesity on adverse in-hospital outcomes in patients with MitraClip® implantation. METHODS AND RESULTS: We analyzed data on characteristics of patients and in-hospital outcomes for all percutaneous mitral valve repairs using the edge-to-edge MitraClip®-technique in Germany 2011-2015 stratified for obesity vs. normal-weight/over-weight. The nationwide inpatient sample comprised 13,563 inpatients undergoing MitraClip® implantations. Among them, 1017 (7.5%) patients were coded with obesity. Obese patients were younger (75 vs.77 years,P < 0.001), more often female (45.4% vs.39.5%,P < 0.001), had more often heart failure (87.1% vs.79.2%,P < 0.001) and renal insufficiency (67.0% vs.56.4%,P < 0.001). Obese and non-obese patients were comparable regarding major adverse cardiac and cerebrovascular events (MACCE) and in-hospital death. The combined endpoint of cardio-pulmonary resuscitation (CPR), mechanical ventilation and death was more often reached in non-obese than in obese patients with a trend towards significance (20.6%vs.18.2%,P = 0.066). Obesity was an independent predictor of reduced events regarding the combined endpoint of CPR, mechanical ventilation and death (OR 0.75, 95%CI 0.64-0.89,P < 0.001), but not for reduced in-hospital mortality (P = 0.355) or reduced MACCE rate (P = 0.108). Obesity class III was associated with an elevated risk for pulmonary embolism (OR 5.66, 95%CI 1.35-23.77,P = 0.018). CONCLUSIONS: We observed an obesity paradox regarding the combined endpoint of CPR, mechanical ventilation and in-hospital death in patients undergoing MitraClip® implantation, but our results failed to confirm an impact of obesity on in-hospital survival or MACCE.

Feasibility of a MPR-based 3DTEE guidance protocol for transcatheter direct mitral valve annuloplasty.

OBJECTIVES: Several interventional approaches have been established for the treatment of severe mitral regurgitation (MR) in patients at elevated risk for surgery. Direct annuloplasty is a relatively novel option in transcatheter mitral valve repair dedicated to reverse pathology in specific subsets of MR. With regard to echocardiographic guidance, this procedure presents with higher efforts in comparison with edge-to-edge therapy to enable safe and exact positioning of the device's anchors; evidence on optimal peri-interventional imaging is sparse. We tested a specific 3D-echo-guidance protocol implementing single-beat multiplanar reconstruction (MPR) and evaluated its feasibility. METHODS: Overall, 16 patients consecutively treated with transcatheter direct annuloplasty for severe MR (87.5% functional/6.3% degenerative/6.3% mixed pathology) were entered in this monocentric analysis. Of these, two patients received a combined procedure including edge-to-edge repair. For all implantations, a 3D-echo-guidance protocol inheriting MPR was employed. RESULTS: Periprocedural device time decreased continuously (overall mean 140 ± 55.1 minutes, 213 ± 38 minutes in the first 4 vs 108 ± 33 minutes in the last 4 procedures, P = .018) using the MPR-based echo protocol, going along with reduced fluoroscopy times and doses. Technical success rate was high (93.8%) without any serious cardiac-related adverse events. MR could be relevantly improved. CONCLUSION: Echocardiographic guidance of transcatheter direct annuloplasty using a real time MPR-based protocol is feasible and safe. Optimized imaging might enable reduced implantation times and potentially increases safety.

Ordinal Pattern Based Entropies and the Kolmogorov-Sinai Entropy: An Update.

Different authors have shown strong relationships between ordinal pattern based entropies and the Kolmogorov-Sinai entropy, including equality of the latter one and the permutation entropy, the whole picture is however far from being complete. This paper is updating the picture by summarizing some results and discussing some mainly combinatorial aspects behind the dependence of Kolmogorov-Sinai entropy from ordinal pattern distributions on a theoretical level. The paper is more than a review paper. A new statement concerning the conditional permutation entropy will be given as well as a new proof for the fact that the permutation entropy is an upper bound for the Kolmogorov-Sinai entropy. As a main result, general conditions for the permutation entropy being a lower bound for the Kolmogorov-Sinai entropy will be stated. Additionally, a previously introduced method to analyze the relationship between permutation and Kolmogorov-Sinai entropies as well as its limitations will be investigated.

Risk of venous thromboembolism after endoprosthetic surgeries: lower versus upper extremity endoprosthetic surgeries.

Venous thromboembolism (VTE) is a potentially fatal disease. Important risk factors of a provoked VTE are trauma, surgery or immobilization. Especially, patients who undergo hip and knee replacements are at high risk for postoperative VTE. We aimed to compare in-hospital VTE burden and other outcomes after upper and lower extremity endoprosthetic surgeries in Germany. The nationwide German inpatient sample of the years 2005-2015 was used for data analysis. Patients who underwent endoprosthetic joint/bone replacements of the extremities (OPS codes 5-820, 5-822, 5-824 and 5-826) were further stratified in those operated on lower (OPS codes 5-820, 5-822 and 5-826) or upper extremity (OPS code 5-824) joints. Patients operated at upper and lower extremity were compared and lower extremity endoprosthetic surgery was investigated as a predictor for adverse outcomes. Overall, 4,134,088 hospitalized patients with extremity joint endoprosthetic surgeries (64.3% females, 54.0% aged > 70 years) were included in our analysis. Of these, 3,950,668 patients (95.6%) undergo lower and 183,420 (4.4%) upper extremity endoprosthetic joint surgery. VTE [RR 2.60 (95% CI 2.41-2.79), P < 0.001] and all-cause death [RR 1.68 (95% CI 1.58-1.77), P < 0.001] were more common in patients with lower extremity joint surgery. Risk for VTE events [OR 2.69 (2.50-2.90), P < 0.001] and in-hospital death [OR 1.65 (1.56-1.75), P < 0.001] were both higher in lower than in upper extremity joint surgeries independently of age, sex and comorbidities. Patients who undergo lower extremity endoprosthetic joint surgeries, bear a higher risk for VTE and in-hospital death compared to those with upper extremity endoprosthetic joint surgeries.

Life Expectancy of Olympic Wrestling Champions in Comparison to the General Population.

Although it was presumed that moderate exercise is a healthy practice but long term high intensity exercise is not, studies observed a life expectancy benefit for both high-intensity endurance and fast power sports athlets, but the data for contact sports are conflicting. Therefore, the author aimed to investigate the life expectancy of Olympic wrestling champions in comparison to the general population. Characteristics, vital status and life-span of the male Olympic wrestling champions was collected (1896-2016). The life expectancy of Olympic champions was compared with matched individuals of the general population (by country, age, and year of birth) obtained from the human mortality database ( http://www.mortality.org ). Overall, 341 male Olympic wrestling champions with median age of 25 (IQR 24-28) years at their Olympic victory were included in this analysis. In total, 142 (41.6%) came of rich countries. The survival was not affected by weight class and country of origin. A significant life expectancy benefit for Olympic champions in comparison to the general population was observed. Male Olympic wrestling champions lived in mean 19.1 ± 19.1 years longer than the matched individuals of the general population (respectively of their country of origin). A substantially lower mortality in male Olympic wrestling champions, compared with the general male population was observed. However, the results do not allow us to draw conclusions about the causes of this survival benefit.

Sarcopenia.

Sarcopenia is a very common, but frequently overlooked and undertreated geriatric syndrome comprising pronounced muscle mass and strength/performance loss. Estimated prevalence is between 5 and 40% in the general population, accompanied by an exponential incline with increasing age. Sarcopenia is connected to atrophy and loss of muscle fibers and motor units, affecting primarily the fast-twitch muscle fibers und their motor units. Fast-twitch muscle fibers seem to be more prone to failure of function and loss over time. Main causes for the development of sarcopenia are hormonal changes (reduced release of testosterone, estrogen, and growth hormone), nutritional deficiencies, chronic inflammation, and particularly a decrease in physical activity due to sedentary lifestyle with advancing age. Treatment options for sarcopenia comprise an active lifestyle with physical activity and exercise training, modifications of nutritional intake, and pharmacological therapies. Strength training and an adequate nutritional intake form the basis of successful sarcopenia treatment.

Algorithmics, Possibilities and Limits of Ordinal Pattern Based Entropies.

The study of nonlinear and possibly chaotic time-dependent systems involves long-term data acquisition or high sample rates. The resulting big data is valuable in order to provide useful insights into long-term dynamics. However, efficient and robust algorithms are required that can analyze long time series without decomposing the data into smaller series. Here symbolic-based analysis techniques that regard the dependence of data points are of some special interest. Such techniques are often prone to capacity or, on the contrary, to undersampling problems if the chosen parameters are too large. In this paper we present and apply algorithms of the relatively new ordinal symbolic approach. These algorithms use overlapping information and binary number representation, whilst being fast in the sense of algorithmic complexity, and allow, to the best of our knowledge, larger parameters than comparable methods currently used. We exploit the achieved large parameter range to investigate the limits of entropy measures based on ordinal symbolics. Moreover, we discuss data simulations from this viewpoint.

Prognostic impact of copeptin in pulmonary embolism: a multicentre validation study.

To externally validate the prognostic impact of copeptin, either alone or integrated in risk stratification models, in pulmonary embolism (PE), we performed a post hoc analysis of 843 normotensive PE patients prospectively included in three European cohorts.Within the first 30 days, 21 patients (2.5%, 95% CI 1.5-3.8) had an adverse outcome and 12 (1.4%, 95% CI 0.7-2.5) died due to PE. Patients with copeptin ≥24 pmol·L-1 had a 6.3-fold increased risk for an adverse outcome (95% CI 2.6-15.5, p<0.001) and a 7.6-fold increased risk for PE-related death (95% CI 2.3-25.6, p=0.001). Risk classification according to the 2014 European Society of Cardiology (ESC) guideline algorithm identified 248 intermediate-high-risk patients (29.4%) with 5.6% (95% CI 3.1-9.3) at risk of adverse outcomes. A stepwise biomarker-based risk assessment strategy (based on high-sensitivity troponin T, N-terminal pro-brain natriuretic peptide and copeptin) identified 123 intermediate-high-risk patients (14.6%) with 8.9% (95% CI 4.5-15.4) at risk of adverse outcomes. The identification of patients at higher risk was even better when copeptin was measured on top of the 2014 ESC algorithm in intermediate-high-risk patients (adverse outcome OR 11.1, 95% CI 4.6-27.1, p<0.001; and PE-related death OR 13.5, 95% CI 4.2-43.6, p<0.001; highest risk group versus all other risk groups). This identified 85 patients (10.1%) with 12.9% (95% CI 6.6-22.0) at risk of adverse outcomes and 8.2% (95% CI 3.4-16.2) at risk of PE-related deaths.Copeptin improves risk stratification of normotensive PE patients, especially when identifying patients with an increased risk of an adverse outcome.