Non-Invasive Identification of Atrial Fibrillation Driver Location Using the 12-lead ECG: Pulmonary Vein Rotors vs. other Locations.

Atrial fibrillation (AF) is an irregular heart rhythm due to disorganized atrial electrical activity, often sustained by rotational drivers called rotors. In the present work, we sought to characterize and discriminate whether simulated single stable rotors are located in the pulmonary veins (PVs) or not, only by using non-invasive signals (i.e., the 12-lead ECG). Several features have been extracted from the signals, such as Hjort descriptors, recurrence quantification analysis (RQA), and principal component analysis. All the extracted features have shown significant discriminatory power, with particular emphasis to the RQA parameters. A decision tree classifier achieved 98.48% accuracy, 83.33% sensitivity, and 100% specificity on simulated data.Clinical Relevance-This study might guide ablation procedures, suggesting doctors to proceed directly in some patients with a pulmonary veins isolation, and avoiding the prior use of an invasive atrial mapping system.

Low incidence of factor VIII inhibitors in previously untreated patients with severe haemophilia A treated with octanate® : Final report from a prospective study.

INTRODUCTION: Octanate® is a human, plasma-derived, von Willebrand factor-stabilized coagulation factor VIII (FVIII) concentrate with demonstrated haemostatic efficacy in previously treated patients with haemophilia A. AIM: This prospective, open-label study aimed to assess the immunogenicity of octanate® in previously untreated patients (PUPs). METHODS: The study monitored development of FVIII inhibitors in 51 PUPs. Tolerability, viral safety, FVIII recovery and efficacy of octanate® for the prevention and treatment of bleeds and in surgical procedures were also assessed. RESULTS: Five (9.8%) of the 51 patients developed inhibitors during the study, 4 of which (7.8%) were high titre. Three inhibitor cases (5.9%) were considered clinically relevant; 2 were transient inhibitors that disappeared during regular octanate® treatment without a change in dose or treatment frequency. Amongst 45 patients with FVIII:C <1% at baseline and who received ≥20 exposure days (EDs) or had <20 EDs but developed an inhibitor, inhibitor incidence was 11.1% (6.7% clinically relevant). All clinically relevant inhibitors developed within 20 EDs of on-demand treatment. No inhibitors developed in PUPs receiving prophylaxis. All patients who developed inhibitors had either intron 22 inversions or large deletions. Irrespective of the reason for administration, haemostatic efficacy was rated as "excellent" in 99.6% of all infusions (4700 of 4717 infusions), and no complications were reported in 23 surgical procedures. Mean incremental in vivo recovery was 2.0%/IU/kg (±0.7) and 1.9%/IU/kg (±0.5) for the first and second assessments, respectively. Tolerability was rated "very good" in 99.9% of infusions. CONCLUSION: In PUPs with severe haemophilia A, octanate® demonstrated haemostatic efficacy with a low rate of inhibitor development.

Measuring ventricular repolarisation dynamics from ambulatory electrocardiography as non-invasive cardiac risk indices / Medición de la dinámica de repolarización ventricular mediante electrocardiografía ambulatoria, como índices de riesgo cardiaco no invasivos

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Identification of patients prone to hypotension during hemodialysis based on the analysis of cardiovascular signals.

Intradialytic hypotension (IDH) is a major complication during hemodialysis treatment, and therefore it is highly desirable to identify, at an early stage during treatment, whether the patient is prone to IDH. Heart rate variability (HRV), blood pressure variability (BPV) and baroreflex sensitivity (BRS) were analyzed during the first 30 min of treatment to assess information on the autonomic nervous system. Using the sequential floating forward selection method and linear classification, the set of features with the best discriminative power was selected, resulting in an accuracy of 92.1%. Using a classifier based on the HRV features only, thereby avoiding that continuous blood pressure has to be recorded, accuracy decreased to 90.2%. The results suggest that an HRV-based classifier is useful for determining whether a patient is prone to IDH at the beginning of the treatment.

Evaluation of T-wave alternans activity under stress conditions after 5 d and 21 d of sedentary head-down bed rest.

It is well known that prolonged microgravity leads to cardiovascular deconditioning, inducing significant changes in autonomic control of the cardiovascular system. This may adversely influence cardiac repolarization, and provoke cardiac rhythm disturbances. T-wave alternans (TWA), reflecting temporal and spatial repolarization heterogeneity, could be affected. The aim of this work was to test the hypothesis that 5 d and 21 d head-down (-6°) bed rest (HDBR) increases TWA, thus suggesting a higher underlying electrical instability and related arrhythmogenic risk. Forty-four healthy male volunteers were enrolled in the experiments as part of the European Space Agency's HDBR studies. High-fidelity ECG was recorded during orthostatic tolerance (OT) and aerobic power (AP) tests, before (PRE) and after HDBR (POST). A multilead scheme for TWA amplitude estimation was used, where non-normalized and T-wave amplitude normalized TWA indices were computed. In addition, spectral analysis of heart rate variability during OT was assessed. Both 5 d and 21 d HDBR induced a reduction in orthostatic tolerance time (OTT), as well as a decrease in maximal oxygen uptake and reserve capacity, thus suggesting cardiovascular deconditioning. However, TWA indices were found not to increase. Interestingly, subjects with lower OTT after 5 d HDBR also showed higher TWA during recovery after OT testing, associated with unbalanced sympathovagal response, even before the HDBR. In contrast with previous observations, augmented ventricular heterogeneity related to 5 d and 21 d HDBR was not sufficient to increase TWA under stress conditions.

ECG-based estimation of dispersion of APD restitution as a tool to stratify sotalol-induced arrhythmic risk.

BACKGROUND: Increased spatial dispersion of restitution properties has been associated to arrhythmic risk. An ECG-based index quantifying restitution dispersion, DRest, is evaluated in patients who experienced Torsades de Pointes (TdP) under sotalol challenge and compared with the response in healthy subjects. METHODS AND RESULTS: ECG recordings were analyzed for quantification of DRest and QTc, among others biomarkers. DRest provides improved discrimination following sotalol administration between TdP and healthy subjects ([min-max]: [0.18-0.22] vs [0.02-0.12]), compared to other biomarkers including QTc ([436-548ms] vs [376-467ms]). Results in healthy subjects are in agreement with simulations of sotalol effects on a human tissue electrophysiological model. CONCLUSIONS: This case study supports the potential of DRest for improved arrhythmia risk stratification even with QTc values below 450ms.

[Ischemia is not an independent predictive factor of chronic renal failure after partial nephrectomy in a solitary kidney in patients without pre-operative renal insufficiency]. / L'ischémie a un impact limité sur la fonction rénale après néphrectomie partielle sur rein unique chez les patients sans insuffisance rénale préopératoire.

OBJECTIVE: To assess the influence of vascular clamping and ischemia time on long-term post-operative renal function following partial nephrectomy (PN) for cancer in a solitary kidney. PATIENTS AND METHODS: This is a retrospective study including 259 patients managed by PN between 1979 and 2010 in 13 centers. Clamping use, technique choice (pedicular or parenchymal clamping), ischemia time, and peri-operative data were collected. Pre-operative and last follow-up glomerular filtration rates were compared. A multivariate analysis using a Cox model was performed to assess the impact of ischemia on post-operative chronic renal failure risk. RESULTS: Mean tumor size was 4.0±2.3cm and mean pre-operative glomerular filtration rate was 60.8±18.9mL/min. One hundred and six patients were managed with warm ischemia (40.9%) and 53 patients with cold ischemia (20.5%). Thirty patients (11.6%) have had a chronic kidney disease. In multivariate analysis, neither vascular clamping (P=0.44) nor warm ischemia time (P=0.1) were associated with a pejorative evolution of renal function. Pre-operative glomerular filtration rate (P<0.0001) and blood loss volume (P=0.02) were significant independent predictive factors of long-term renal failure. CONCLUSION: Renal function following PN in a solitary kidney seems to depend on non-reversible factors such as pre-operative glomerular filtration rate. Our findings minimize the role of vascular clamping and ischemia time, which were not significantly associated with chronic renal failure risk in our study. LEVEL OF EVIDENCE: 5.

Modeling and quantification of repolarization feature dependency on heart rate.

INTRODUCTION: This article is part of the Focus Theme of Methods of Information in Medicine on "Biosignal Interpretation: Advanced Methods for Studying Cardiovascular and Respiratory Systems". OBJECTIVES: This work aims at providing an efficient method to estimate the parameters of a non linear model including memory, previously proposed to characterize rate adaptation of repolarization indices. METHODS: The physiological restrictions on the model parameters have been included in the cost function in such a way that unconstrained optimization techniques such as descent optimization methods can be used for parameter estimation. The proposed method has been evaluated on electrocardiogram (ECG) recordings of healthy subjects performing a tilt test, where rate adaptation of QT and Tpeak-to-Tend (Tpe) intervals has been characterized. RESULTS: The proposed strategy results in an efficient methodology to characterize rate adaptation of repolarization features, improving the convergence time with respect to previous strategies. Moreover, Tpe interval adapts faster to changes in heart rate than the QT interval. CONCLUSIONS: In this work an efficient estimation of the parameters of a model aimed at characterizing rate adaptation of repolarization features has been proposed. The Tpe interval has been shown to be rate related and with a shorter memory lag than the QT interval.

Predictive factors of chronic kidney disease stage V after partial nephrectomy in a solitary kidney: a multi-institutional study.

OBJECTIVE: Partial Nephrectomy (PN) in a solitary kidney is at risk of chronic kidney disease (CKD) stage V and/or haemodialysis (HD). Our objective was to determine predictive factors of CKD stage V in this population. MATERIAL & METHODS: Data from 300 patients were retrospectively collected from 16 tertiary centres. Clinical and operative parameters, tumor characteristics and renal function before surgery were analyzed. Patients with and without CKD stage V (defined as MDRD<1 5 ml/min) were compared using χ2 and Student-t tests for qualitative and quantitative variables, respectively. Predictive factors of CKD stage V were evaluated with a multivariable analysis using a Cox regression model. RESULTS: Median age and BMI were 63 years old and 26 kg/m², respectively. Most of the patients (65%) were male with an anatomic solitary kidney (88.3%). Median tumor size was 4 cm and 98% were malignant tumors. Median operative time, blood loss and clamping time were 180 min, 350 ml and 20 min respectively. Renal cooling was used in 19.3% and clamping of the pedicle was performed in 61.6%. Twenty five patients (8.5%) presented post operative CKD stage V at last follow-up and 18 underwent HD (6%) post-operatively because of acute renal insufficiency. There was no difference between CKD stage V and non CKD stage V patients concerning Charlson index, operative time (180 min vs 179 min, p = 0.39), blood loss (475 ml vs 350 ml, p = 0.51), use of renal cooling and type of clamping. Patients with CKD stage V were older (70 vs 63 years old, p = 0.005), had a lower baseline renal function (clearance MDRD 41 vs. 62 ml/min, p<0.0001) and an increased tumor size (p = 0.02). Complications occurred in 91 patients (30%) with 16% of minor (Clavien 1-2) and 14% of major (Clavien > 2) complications, respectively. In multivariable analysis, baseline MDRD, BMI, and the occurrence of a minor complication were independent predictive factors of post operative CKD stage V. CONCLUSION: PN in a solitary kidney is at risk of post-operative CKD stage V and HD. Pre-operative altered renal function and post operative complications are the main predictive factors of permanent CKD stage V.

Assessing real-time RR-QT frequency-domain measures of coupling and causality through inhomogeneous point-process bivariate models.

Ventricular repolarization instability is known to be related to arrhythmogenesis and increased risk of sudden cardiac death. These repolarization dynamics are linked to the distance between T-wave and Q-wave occurrences (QT) on the ECG, and they are coupled with R-wave to R-wave interval variability (RRV). Several efforts have been dedicated to the analysis of QT-RR interactions in order to provide both a quantification of the coupling and estimates of intrinsic repolarization dynamics. However, a methodology able to quantify dynamic changes in repolarization variability unrelated to RRV dynamics is still needed. In this study, we propose a bivariate model embedded within a multiple inhomogeneous point-process framework to obtain time-varying tracking of (causal) interactions between QT variability (QTV), a marker of repolarization variability, and RRV. Data from 15 healthy subjects undergoing a tilt table test were analyzed. Our results demonstrate that the model effectively captures the time-varying mutual QTV-RRV interactions. The analysis of time-varying coherence confirms that head-up tilt is associated with a decrease in linear QTV-RRV coupling, while time-varying directed coherence shows that intrinsic QTV becomes more prominent during head-up tilt.

Results from a large multinational clinical trial (guardian™3) using prophylactic treatment with turoctocog alfa in paediatric patients with severe haemophilia A: safety, efficacy and pharmacokinetics.

Recombinant factor VIII (rFVIII) products provide a safe and efficacious replacement therapy for prophylaxis and treatment of bleeding episodes in patients with severe haemophilia A. This multinational, open-label, non-controlled trial investigated the safety, efficacy and pharmacokinetics (PK) of turoctocog alfa, a new rFVIII product, in a paediatric population. The primary objective was to evaluate safety. A total of 31 younger children (0-5 years) and 32 older children (6-11 years), with ≥ 50 exposure days to any factor VIII (FVIII) product and no history of inhibitors, received prophylaxis with turoctocog alfa (25-50 IU kg(-1) every second day or 25-60 IU kg(-1) three times weekly). PK assessments of turoctocog alfa and the patients' previous FVIII product were performed in 28 patients. Mean exposure to turoctocog alfa was 60 exposure days per patient. This corresponds to approximately 4.5 months in the trial. None of the patients developed inhibitors (≥ 0.6 BU) and no safety concerns were raised. A total of 120 bleeding episodes (95%) were controlled with 1-2 infusions of turoctocog alfa. Based on patient reports, the success rate (defined as 'excellent' or 'good' haemostatic response) for treatment of bleeding episodes was 92%. Overall, the median annualized bleeding rate was 3.0 (interquartile range: 8.5) bleeds patient(-1) year(-1) . PK parameters were comparable between the two age groups. In conclusion, the present large global clinical trial showed that turoctocog alfa was safe, effective in treatment of bleeding episodes and had a prophylactic effect in paediatric patients.

Head-to-head comparison of the pharmacokinetic profiles of a high-purity factor IX concentrate (AlphaNine®) and a recombinant factor IX (BeneFIX®) in patients with severe haemophilia B.

Head-on comparative studies of factor IX (FIX) concentrates performed under standardized conditions are rarely conducted regardless of being a valuable instrument guiding health care providers towards better informed and cost-effective decisions. This study is an extension of a multicentre study that assessed the efficacy, safety and pharmacokinetics (PK) of AlphaNine(®) in 25 previously treated patients with severe haemophilia B (FIX:C ≤ 2%). After a washout period ≥ 7 days following the last PK performed with AlphaNine(®) after a dose of 65-75 IU kg(-1) , an identical PK study was performed with BeneFIX(®) on 22 of the same patients. Venous blood samples for analysis were taken at baseline and at 0.25, 0.5, 1, 3, 6, 9, 24, 48, 72 and 74 h post infusion. The outcomes of the comparison of the PK parameters were as follows: Mean (± SD) in vivo recovery (IVR) was 1.3 ± 0.4 IU dL(-1) per IU kg(-1) for AlphaNine(®) and 1.0 ± 0.3 IU dL(-1) per IU kg(-1) for BeneFIX(®) (P < 0.01). Mean terminal half-life, mean residence time, area under the curve, clearance and volume of distribution of BeneFIX(®) were 36.0 ± 12.8 h, 39.3 ± 13.9 h, 1631 ± 467 IU h dL(-1) , 0.046 ± 0.01 dL kg(-1) min(-1) and 1.75 ± 0.52 mL kg(-1) respectively. These values were not significantly different to those observed in AlphaNine(®), although BeneFIX(®) displayed higher than expected IVR values and lower than expected clearance values. In conclusion, AlphaNine(®) showed a comparable half-life, but an IVR significantly higher than that of BeneFIX(®). This dissimilarity may have implications on dosing requirements for on-demand treatment regimes affecting optimal resource allocation.

The use of mannitol in partial and live donor nephrectomy: an international survey.

PURPOSE: Animal studies have shown the potential benefits of mannitol as renoprotective during warm ischemia; it may have antioxidant and anti-inflammatory properties and is sometimes used during partial nephrectomy (PN) and live donor nephrectomy (LDN). Despite this, a prospective study on mannitol has never been performed. The aim of this study is to document patterns of mannitol use during PN and LDN. MATERIALS AND METHODS: A survey on the use of mannitol during PN and LDN was sent to 92 high surgical volume urological centers. Questions included use of mannitol, indications for use, physician responsible for administration, dosage, timing and other renoprotective measures. RESULTS: Mannitol was used in 78 and 64 % of centers performing PN and LDN, respectively. The indication for use was as antioxidant (21 %), as diuretic (5 %) and as a combination of the two (74 %). For PN, the most common dosages were 12.5 g (30 %) and 25 g (49 %). For LDN, the most common doses were 12.5 g (36.3 %) and 25 g (63.7 %). Overall, 83 % of centers utilized mannitol, and two (percent or centers??) utilized furosemide for renoprotection. CONCLUSIONS: A large majority of high-volume centers performing PN and LDN use mannitol for renoprotection. Since there are no data proving its value nor standardized indication and usage, this survey may provide information for a randomized prospective study.

What is the added value of combined core biopsy and fine needle aspiration in the diagnostic process of renal tumours?

PURPOSE: Non-diagnostic results still hinder the routine use of core biopsy (CB) and fine needle aspiration (FNA) in the diagnostic process of renal tumours. Furthermore, substantial interobserver variability has been reported. We assessed the added value of combining the results of CB and FNA by five pathologists in the ex vivo diagnosis of renal mass. METHODS: Two ex vivo core biopsies were taken followed by two FNA passes from extirpated tumours. All samples were evaluated by five blinded pathologists. A consensus diagnosis of the surgical specimen was the index for comparison. For each pathologist, the number of non-diagnostic (non-conclusive or undetermined biology and failed biopsies), correct and incorrect scored cases of each technique was assessed. When a non-diagnostic CB or FNA had a correct diagnostic counterpart, this was considered as of added value. RESULTS: Of the 57 assessed tumours, 53 were malignant. CB was non-diagnostic in 4-10 cases (7-17.5%). FNA established the correct diagnosis in 1-7 of these cases. FNA was non-diagnostic in 2-6 cases (3.5-10.5%), and the counterpart CB established the correct diagnosis in 1-6 of these cases. For the 5 pathologists, accuracy of CB and FNA varied between 82.5-93% and 89.5-96.5%, respectively. Combination of both types of biopsy resulted in 55-57 correct results (accuracy 96.5-100%), i.e., an increase in accuracy of 3.5-14%. CONCLUSION: Combining the result of CB and FNA in renal mass biopsy leads to a higher diagnostic accuracy. Recommendations on which technique used should be adapted to local expertise and logistic possibilities.

Lymphoscintigraphy for differential diagnosis of peripheral edema: diagnostic yield of different scintigraphic patterns.

UNLABELLED: Edema of the limbs is a common reason for medical consultation, for which the lymphoscintigraphy is considered to be a reliable method for its differential diagnosis. OBJECTIVE: To evaluate the usefulness of radionuclide studies in the differential diagnosis of edema, and the diagnostic yield of different scintigraphic patterns. MATERIAL AND METHODS: A total of 61 patients, mean age 43 years, referred to our Department in the last three years for suspected lymphoedema, were considered. One patient was discarded due to lack of diagnosis, 56 had lower limb edema and 4 upper limb edema. After intradermal injection of two doses of (99m)Tc-nanocolloid, scintigraphic scans were made at 30 and 120minutes. The final diagnosis was based on imaging tests, clinical course, and response to treatment. We calculated the parameters of the diagnostic yield of four different scintigraphic patterns (presence of dermal backflow, asymmetry-alteration in inguinal/axillary nodes, presence of collateral pathways, and visualization of intermediate lymph nodes), considering them individually and jointly. RESULTS: The best diagnostic yield was achieved by considering dermal backflow and asymmetry in inguinal/axillary nodes (accuracy 88.9%, specificity 96.4%, PPV 95.5%). Evaluation of intermediate lymph nodes and presence of collateral pathways contributed little to the diagnostic yield, showing poor sensitivity and high false positive rates. CONCLUSION: The lymphoscintigraphy had high diagnostic yield, allowing early treatment of lymphœdema. The dermal backflow and asymmetry in inguinal/axillary nodes had the greatest diagnostic accuracy. Evaluation of intermediate lymph nodes and visualization of collateral pathways contributed little to improving the diagnosis.

Linfogammagrafía en el diagnóstico diferencial del edema. Rendimiento diagnóstico de diferentes patrones gammagráficos / Lymphoscintigraphy for differential diagnosis of peripheral edema: diagnostic yield of different scintigraphic patterns

El edema de extremidades constituye un motivo frecuente de consulta médica, considerándose la linfogammagrafía un método fiable para su diagnóstico diferencial. Objetivo. Valorar la utilidad del estudio isotópico en el diagnóstico diferencial del edema y el rendimiento diagnóstico de diferentes patrones gammagráficos encontrados. Material y Métodos. Se consideraron 61 pacientes remitidos a nuestro Servicio en los últimos tres años por sospecha de linfedema, descartándose uno por falta de diagnóstico. La media de edad fue de 43 años. Cincuenta y seis pacientes presentaban edema en miembros inferiores y 4 en superiores. Tras inyección intradérmica de dos dosis de 99mTc-nanocoloide, se realizaron rastreos gammagráficos de extremidades a los 30 y 120 minutos de su administración. El diagnóstico definitivo se basó en pruebas de imagen, evolución clínica y respuesta a tratamiento. Se calculó el rendimiento diagnóstico de cuatro diferentes patrones gammagráficos (presencia de flujo dérmico, asimetría-alteración en ganglios inguinales/axilares, presencia de vías colaterales y visualización de ganglios intermedios) considerándose de manera individual y conjunta. Resultados. El mayor rendimiento diagnóstico se alcanzó considerando el flujo dérmico y la asimetría en ganglios inguinales/axilares (exactitud 88,9%, especificidad 96,4%, VPP 95,5%). La valoración de ganglios intermedios y presencia de vías colaterales aportó escaso rendimiento diagnóstico, con baja sensibilidad y elevada tasa de falsos positivos. Conclusión. La linfogammagrafía presentó un alto rendimiento diagnóstico, permitiendo un tratamiento precoz del linfedema. El flujo dérmico y asimetría en ganglios inguinales/axilares mostraron la mayor exactitud diagnóstica. La valoración de ganglios intermedios y visualización de vías colaterales no aportaron mejoría al diagnóstico(AU)

Edema of the limbs is a common reason for medical consultation, for which the lymphoscintigraphy is considered to be a reliable method for its differential diagnosis. Objective. To evaluate the usefulness of radionuclide studies in the differential diagnosis of edema, and the diagnostic yield of different scintigraphic patterns. Material and Methods. A total of 61 patients, mean age 43 years, referred to our Department in the last three years for suspected lymphoedema, were considered. One patient was discarded due to lack of diagnosis, 56 had lower limb edema and 4 upper limb edema. After intradermal injection of two doses of 99mTc-nanocolloid, scintigraphic scans were made at 30 and 120minutes. The final diagnosis was based on imaging tests, clinical course, and response to treatment. We calculated the parameters of the diagnostic yield of four different scintigraphic patterns (presence of dermal backflow, asymmetry-alteration in inguinal/axillary nodes, presence of collateral pathways, and visualization of intermediate lymph nodes), considering them individually and jointly. Results. The best diagnostic yield was achieved by considering dermal backflow and asymmetry in inguinal/axillary nodes (accuracy 88.9%, specificity 96.4%, PPV 95.5%). Evaluation of intermediate lymph nodes and presence of collateral pathways contributed little to the diagnostic yield, showing poor sensitivity and high false positive rates. Conclusion. The lymphoscintigraphy had high diagnostic yield, allowing early treatment of lymphœdema. The dermal backflow and asymmetry in inguinal/axillary nodes had the greatest diagnostic accuracy. Evaluation of intermediate lymph nodes and visualization of collateral pathways contributed little to improving the diagnosis(AU)