Novel Germline TET2 Mutations in Two Unrelated Patients with Autoimmune Lymphoproliferative Syndrome-Like Phenotype and Hematologic Malignancy.

Somatic mutations in the ten-eleven translocation methylcytosine dioxygenase 2 gene (TET2) have been associated to hematologic malignancies. More recently, biallelic, and monoallelic germline mutations conferring susceptibility to lymphoid and myeloid cancer have been described. We report two unrelated autoimmune lymphoproliferative syndrome-like patients who presented with T-cell lymphoma associated with novel germline biallelic or monoallelic mutations in the TET2 gene. Both patients presented a history of chronic lymphoproliferation with lymphadenopathies and splenomegaly, cytopenias, and immune dysregulation. We identified the first compound heterozygous patient for TET2 mutations (P1) and the first ALPS-like patient with a monoallelic TET2 mutation (P2). P1 had the most severe form of autosomal recessive disease due to TET2 loss of function resulting in absent TET2 expression and profound increase in DNA methylation. Additionally, the immunophenotype showed some alterations in innate and adaptive immune system as inverted myeloid/plasmacytoid dendritic cells ratio, elevated terminally differentiated effector memory CD8 + T-cells re-expressing CD45RA, regulatory T-cells, and Th2 circulating follicular T-cells. Double-negative T-cells, vitamin B12, and IL-10 were elevated according to the ALPS-like suspicion. Interestingly, the healthy P1's brother carried a TET2 mutation and presented some markers of immune dysregulation. P2 showed elevated vitamin B12, hypergammaglobulinemia, and decreased HDL levels. Therefore, novel molecular defects in TET2 confirm and expand both clinical and immunological phenotype, contributing to a better knowledge of the bridge between cancer and immunity.

Risk scores for predicting incident heart failure admission in patients with chronic coronary syndromes: Validation in a prospective, monocentric, long-term, cohort study.

BACKGROUND: Heart failure (HF) admission in chronic coronary syndrome (CCS) patients has a prognostic impact. Stratification schemes have been described for predicting this endpoint, but none of them has been externally validated. OBJECTIVES: Our aim was to develop point scores for predicting incident HF admission with data from previous studies, to perform an external validation in an independent prospective cohort and to compare their discriminative ability for this event. METHODS: Independent predictive variables of HF admission in CCS patients without baseline HF were selected from four previous prospective studies (CARE, PEACE, CORONOR and CLARIFY), generating scores based on the relative magnitude of the coefficients of Cox of each variable. Finally, the scores were validated and compared in a monocentric prospective cohort. RESULTS: The validation cohort included 1212 patients followed for up to 17 years, with 171 patients suffering at least one HF admission in the follow-up. Discriminative ability for predicting HF admission was statistically significant for all, and paired comparisons among them were all nonsignificant except for CORONOR score was superior to CLARIFY score (C-statistic 0.73, 95%CI 0.69-0.76 vs. 0.69, 95% CI 0.65-0.73; p = 0.03). CONCLUSION: All tested scores showed significant discriminative ability for predicting incident HF admission in this independent validation study. Their discriminative ability was similar, with significant differences only between the two scores with higher and lower performance.

Combining familial hypercholesterolemia and statin genetic studies as a strategy for the implementation of pharmacogenomics. A multidisciplinary approach.

The diagnostic process of familial hypercholesterolemia frequently involves the use of genetic studies. Patients are treated with lipid-lowering drugs, frequently statins. Although pharmacogenomic clinical practice guidelines focusing on genotype-based statin prescription have been published, their use in routine clinical practice remains very modest.We have implemented a new NGS strategy that combines a panel of genes related to familial hypercholesterolemia with genomic regions related to the pharmacogenomics of lipid-lowering drugs described in clinical practice guidelines and in EMA and FDA drug labels. A multidisciplinary team of doctors, biologists, and pharmacists creates a clinical report that provides diagnostic and therapeutic findings using a knowledge management and clinical decision support system, as well as an algorithm for treatment selection.For 12 months, a total of 483 genetic diagnostic studies for familial hypercholesterolemia were carried out, of which 221 (45.8%) requested a complementary pharmacogenomic test. Of these 221 patients, 66.5% were carriers of actionable variants in any of the studied pharmacogenomic pathways: 46.6% of patients in one pathway, 19.0% in two pathways, and 0.9% in three pathways. 45.7% of patients could have a response to atorvastatin different from that of the reference population, 45.7% for simvastatin and lovastatin, 29.0% for fluvastatin, and 6.7% patients for pitavastatin.This implementation approach facilitates the incorporation of pharmacogenomic studies in clinical care practice, it does not add complexity nor additional steps to laboratory processes, and improves the pharmacotherapeutic process of patients.

Role of obesity and blood pressure in epicardial adipose tissue thickness in children.

BACKGROUND: Elevated body mass index (BMI) has been associated with cardiac changes, such as higher epicardial adipose tissue (EAT) thickness. This fat has been identified as a predictive factor of cardiovascular diseases during adulthood. However, few studies have tested the association of multiple cardiovascular risk factors (high weight or blood pressure) with EAT in adolescents and children. Therefore, the main objective of this current research was to determine the impact of BMI, overweight, obesity, and blood pressure on EAT thickness in children. METHODS: A descriptive cross-sectional study focused on elementary and high school students aged 6-16 years was carried out by utilizing diverse measurements and instruments, such as echocardiography. RESULTS: EAT thickness (N = 228) was linked to sex (more predominant in boys 2.3 ± 0.6; p = 0.044), obesity (2.3 ± 0.6; p < 0.001), and hypertension (2.6 ± 0.6; p = 0.036). The logistic regression indicated that age, sex, and BMI seemed to be more relevant factors in EAT thickness in children (adjusted R square = 0.22; p < 0.001). CONCLUSIONS: This paper examined the associations of sex, age, and cardiovascular risk factors (arthrometric measures and blood pressure) with EAT thickness, indicating that it is necessary to assess whether the findings are associated with future events. IMPACT: Excessive weight gain and blood pressure in the early stages of life have been associated with adipose tissue. This increase in weight and blood pressure has been attributed to alterations in the epicardial adipose tissue linked to anthropometric markers in adults, but no related study has been implemented in Spanish children. This study revealed how higher epicardial adipose tissue is linked to body mass index, other anthropometric parameters, and blood pressure in Spanish children. These measurements are related to high epicardial adipose tissue thickness, which in early stages does not imply pathology but increases the risk of developing cardiovascular diseases.

Variables affecting the quality of anticoagulation in atrial fibrillation patients newly initiating vitamin K antagonists: insights from the national and multicentre SULTAN registry.

AIMS: Vitamin K antagonists (VKAs) are effective drugs reducing the risk for stroke in atrial fibrillation (AF), but the benefits derived from such therapy depend on the international normalized ratio (INR) maintenance in a narrow therapeutic range. Here, we aimed to determine independent variables driving poor anticoagulation control [defined as a time in therapeutic range (TTR) <65%] in a 'real world' national cohort of AF patients. METHODS AND RESULTS: The SULTAN registry is a multicentre, prospective study, involving patients with non-valvular AF from 72 cardiology units expert in AF in Spain. At inclusion, all patients naïve for oral anticoagulation were started with VKAs for the first time. For the analysis, the first month of anticoagulation and those patients with <3 INR determinations were disregarded. Patients were followed up during 1 year. A total of 870 patients (53.9% male, the mean age of 73.6 ± 9.2 years, mean CHA2DS2-VASc and HAS-BLED of 3.3 ± 1.5 and 1.4 ± 0.9, respectively) were included in the full analysis set. In overall, 7889 INR determinations were available. At 1-year, the mean TTR was 63.1 ± 22.1% and 49.2% patients had a TTR < 65%. Multivariate Cox regression analysis showed that coronary artery disease [odds ratio (OR) 1.81, 95% confidence interval (CI) 1.14-2.87; P = 0.012] and amiodarone use (OR 1.54, 95% CI 1.01-2.34; P = 0.046) were independently associated with poor quality of anticoagulation (TTR <65%). CONCLUSION: This study demonstrated that the quality of anticoagulation in AF patients newly starting VKAs is sub-optimal. Previous coronary artery disease and concomitant use of amiodarone were identified as independent variables affecting the poor quality of VKA therapy during the first year.

Relationship between overweight and obesity and cardiac dimensions and function in a paediatric population.

Obesity in adults is associated with left ventricular hypertrophy, dilatation, and myocardial fibrosis, as well as heart failure and coronary heart disease. These associations have been studied to a lesser extent in the paediatric population. This study aims to investigate the relationship between obesity and cardiac structure and function in the paediatric population. In a southern Spanish village, we selected all inhabitants aged 6-17 years stratifying by age, gender, and educational centres. We performed a complete transthoracic echocardiogram evaluating all the cardiac morphological and functional parameters commonly measured in an echocardiographic study. There were 212 children and adolescents included. Of them, 48.1% were males. The mean age was 10.9 ± 3.0 years. A total of 106 (50%) were normal weight, 57 (26.9%) overweight, and 49 (23.1%) obese. Sex and age were similar in all three groups. Overweight and obesity were associated with larger left ventricular end-diastolic and end-systolic volumes (p < 0.0005), greater left ventricular mass (p < 0.0005), and smaller ejection fraction (p < 0.0005). They were also associated with larger atrial, aortic, and right ventricular size. Lateral and mean E/e' ratios were higher (p = 0.007 and p = 0.01 respectively). Body mass index was independently associated with all cavity size variables as well as left ventricular ejection fraction. CONCLUSION: Childhood obesity is independently associated with larger heart chambers, greater left ventricle mass, and smaller left ventricle ejection fraction. WHAT IS KNOWN: • Childhood obesity is related to the development of cardiovascular risk factors and is considered an epidemic of the twenty-first century; its prevalence is rising. WHAT IS NEW: • Childhood overweight and obesity lead to changes in cardiac structure and function which, although not considered clinically pathological, are significant and a result of obesity, and which behave as unfavourable incipient alterations at an early age.

Impact on daily clinical practice of the latest evidence on percutaneous closure of patent foramen ovale after cryptogenic stroke: a single-center experience.

INTRODUCTION AND OBJECTIVES: At the end of 2017, three clinical trials demonstrated that, in selected patients, percutaneous closure of patent foramen ovale (PFO) after cryptogenic stroke (CS) reduces the risk of recurrence. Our aim was to determine the impact of these findings on routine clinical practice in a tertiary hospital. METHODS: Patients with CS and percutaneous closure of PFO during 2001-2020 were included. The clinical characteristics of the patient and the anatomical characteristics of the foramen were analyzed. Based on both, the closure indications were classified into three groups according to the latest European recommendations and were analyzed in two periods, before and after the publication date of the clinical trials. RESULTS: A total of 293 patients were included. The mean age was 49 ± 11 years, and 15% were older than 60 years. The median RoPE score was 6 [p25-75, 5-7] and 75% had complex anatomy (CA). After the publication of the studies, the frequency of CA and the mean age of the patients were significantly higher (89% vs. 69% p < 0.0005 and 51 ± 11 vs. 48 ± 11 years, p = 0.02, respectively), and the RoPE score, significantly lower (5 [5-7] versus 6 [5-7], p = 0.02). Inadequate closure indications were significantly reduced (8% vs. 18%, p = 0.02). CONCLUSION: After the publication of clinical trials that have shown benefit of PFO closure after CS, the number of inappropriate indications for closure has decreased significantly in our institution, with a higher percentage of CA, despite a clinical profile suggestive of lower causal probability of PFO.

Incidence and outcomes of hospital treated acute myocarditis from 2003 to 2015 in Spain.

BACKGROUND: There are no data on population-based epidemiological changes in acute myocarditis in Europe. Our aim was to evaluate temporal trends in incidence, clinical features and outcomes of hospital treated acute myocarditis (AM) in Spain from 2003 to 2015. METHODS: We conducted a retrospective longitudinal study using information of all hospital discharges of the Spanish National Health System. All episodes with a discharge diagnosis of AM from 1 January 2003 to 31 December 2015 were included. The risk-standardized in-hospital mortality ratio (RSMR) was calculated using a multilevel risk-adjustment model developed by the Medicare and Medicaid Services. Temporal trends for in-hospital mortality were modelled using Poisson regression analysis. RESULTS: A total of 11 147 episodes of AM were analysed, most of them idiopathic (94.7%). The rate of AM discharges increased along the period, from 13 to 30/million inhabitants/year (2003-2015), and this increase was statistically significant when weighted by age and sex (incidence rate ratio, IRR 1.06, 95% CI 1.04-1.08, P = .001). In-hospital crude mortality rate was 3.1%, diminishing significantly along 2003-2015 (IRR 0.95, 95% CI 0.92-0.99, P = .02). RSMR also significantly diminished along the period (IRR 0.95, 95% CI 0.92-0.99, P = .01). Renal failure (OR 7.03, 5.38-9.18, P = .001), liver disease (OR 4.61, 2.59-8.21, P = .001), pneumonia (OR 4.13, 2.75-6.20, P = .001) and heart failure (OR 1.91, 95% CI 1.47-2.47, P = .001) were the strongest independent factors associated with in-hospital mortality. CONCLUSIONS: Acute myocarditis is an uncommon entity, although hospital discharges have increased in Spain along the study period. Most of AM were idiopathic. Adjusted mortality was low and seemed to decrease from 2003 to 2015, suggesting an improvement in AM management.

Thirteen-year trends in hospitalization and outcomes of patients with heart failure in Spain.

BACKGROUND: Heart failure is one of the most pressing current public health concerns. However, in Spain there is a lack of population data. We aimed to examine thirteen-year nationwide trends in heart failure hospitalization, in-hospital mortality and 30-day readmission rates in Spain. METHODS: We conducted a retrospective observational study of patients discharged with the principal diagnosis of heart failure from The National Health System' acute hospitals during 2003-2015. The source of the data was the Minimum Basic Data Set. Temporal trends were modelled using Poisson regression analysis. The risk-standardized in-hospital mortality ratio was calculated using a multilevel risk adjustment logistic regression model. RESULTS: A total of 1 254 830 episodes of heart failure were selected. Throughout 2003-2015, the number of hospital discharges with principal diagnosis of heart failure increased by 61%. Discharge rates weighted by age and sex increased during the period [incidence rate ratio (IRR): 1.03; 95% confidence interval (95% CI): 1.03-1.03; P < .001)], although this increase was motivated by the increase in older age groups (≥75 years old). The crude mortality rate diminished (IRR: 0.99; 95% CI: 0.98-1, P < .001), but 30-day readmission rate increased (IRR: 1.05; 95% CI: 1.04-1.06; P < .001). The risk-standardized in-hospital mortality ratio did not change throughout the study period (IRR: 0.997; 95% CI: 0.992-1; P = .32). CONCLUSIONS: From 2003 to 2015, heart failure admission rates increased significantly in Spain as a consequence of the sustained increase of hospitalization in the population ≥75 years. 30-day readmission rates increased, but the risk-standardized in-hospital mortality ratio did not significantly change for the same period.

Peripheral artery disease and clinical outcomes in patients with atrial fibrillation: A report from the FANTASIIA registry.

BACKGROUND: Atrial fibrillation (AF) and peripheral artery disease (PAD) are common conditions that increase cardiovascular risk. We determined the association between PAD and prognosis in a cohort of real-world patients receiving oral anticoagulant therapy for nonvalvular AF. METHODS: We prospectively included 1956 patients (mean age 73.8 ± 9.5 years, 44.0% women) receiving oral anticoagulant therapy for AF. Clinical characteristics were collected at baseline. Patients were followed for a period of 3 years. Survival analysis and multivariable regression analyses were performed to assess variables related to death, stroke, bleeding, myocardial infarction and major adverse cardiovascular events (MACE). RESULTS: Patients with PAD (n = 118; 6%) exhibited higher rates of cardiovascular risk factors and cardiovascular diseases. After 3 years of follow-up, there were a total of 255 deaths (no PAD 233, vs PAD 22), 45 strokes (43 vs 2), 146 major bleedings (136 vs 10) and 168 MACE (148 vs 20). On univariate analysis, there was a higher risk of cardiovascular mortality (2.02%/year no PAD vs 4.08%/year PAD, P = .02), myocardial infarction (0.99%/year no PAD vs 2.43%/year PAD, P = .02) and MACE (3.18%/year no PAD vs 6.99%/year PAD, P < .01). There was no statistically significant association with these events after multivariable adjustment. CONCLUSIONS: In a large cohort of anticoagulated patients with AF, the presence of PAD represents a higher risk subgroup and is associated with worse crude outcomes. The exact contribution of the PAD independently of other cardiovascular diseases or risk factors requires further investigation.

Rationale and design of the rigorous atrial analysis in advanced interatrial block (ARABIA) prospective study.

BACKGROUND: Advanced interatrial block (IAB) is present in 10% of subjects ≥75 years and is associated with the risk of clinical events. METHODS AND RESULTS: Prospective multicenter study that will include subjects ≥75 years without exclusion criteria (indication for anticoagulation, cardiac devices, severe valve disease, systolic dysfunction, moderate or severe cognitive impairment, poor echocardiographic window, non-sinus rhythm or partial IAB, stroke, and life expectancy <2 years). A total of 356 subjects, 178 patients with advanced IAB (exposed) and 178 matched individuals with normal P-wave (non-exposed) will be included. Electrocardiogram and advanced transthoracic echocardiography will be performed. Two substudies will include magnetic resonance imaging: cardiac (86 subjects, 43 exposed, and 43 non-exposed) and brain (86 subjects, 43 exposed, and 43 non-exposed). The follow-up will be 2 years. Our main objective is to determine the association of advanced IAB, P-wave duration, and atrial imaging parameters (I] atrial global longitudinal strain, II] maximal left atrial volume index, III] left atrial ejection fraction, IV] left atrial fibrosis - % total left atrial area V] inter- and intra-atrial asynchrony/dyssynchrony) with clinical events (atrial fibrillation, stroke, cognitive impairment, and mortality). The secondary objective is to assess the association of the P-wave duration with atrial imaging parameters and of both with cerebral microemboli in magnetic resonance imaging. CONCLUSION: Our study will provide data regarding the association of advanced IAB, P-wave duration, and atrial imaging parameters with clinical events. We will also assess the association P-wave duration-atrial imaging parameters-cerebral microemboli.

Myocardial deformation and acute cellular rejection after heart transplantation: Impact of inter-vendor variability in diagnostic effectiveness.

PURPOSE: Our objective was to investigate the impact of inter-vendor variability in the ability of myocardial strain analysis to detect acute cellular rejection (ACR) in heart transplant recipients. METHODS: We performed serial echocardiographic examinations in 18 consecutive adult heart transplanted patients, in their first year post-transplantation, within 3 hours of the routine surveillance endomyocardial biopsies (EMB) in a single center. Myocardial strain was analyzed using two software in two different institutions, and inter-vendor variability of strain values and its association with ACR (any grade or grade ≥2R) was investigated. The parameter of comparison was the peak value of the average curve of strain during the entire cardiac cycle. RESULTS: A total of 147 pairs of EMB-echocardiogram were performed, 65 with no ACR, 63 with ACR grade 1R, and 19 with ACR grade ≥2R. Intra-class correlation coefficients for left ventricle longitudinal, radial, and circumferential strain were 0.38, 0.39, and 0.77, respectively, and 0.32 for right ventricular longitudinal strain. Neither software found significant association of left ventricular longitudinal strain with rejection. Grade ≥2R ACR was associated with left ventricular circumferential strain measured with the first software and with left ventricular radial strain with the other; and ACR of any grade was only significantly associated with right ventricle longitudinal strain measured with the first software. CONCLUSIONS: Inter-vendor reproducibility of strain values was low in this study. Some strain parameters were associated to ACR, although these results were inconsistent between two commercially available software. Specific validation of each software is warranted for this clinical indication.

Reproductive biology of a viviparous lizard (Mabuya dorsivittata) from the subtropical Wet Chaco of Argentina: geographical variations in response to local environmental pressures.

Herein we studied the reproductive biology of a viviparous lizard (Mabuya dorsivittata) from the Wet Chaco region (northeastern Argentina) and compared the results with other populations from the Espinal (central Argentina) and the Atlantic Forest (southeastern Brazil), and with other Neotropical species of Mabuya to better understand the possible causes of its reproductive phenotype variation. Males and females of M. dorsivittata from the Wet Chaco exhibited associated, seasonal, and annual reproductive cycles. Spermatogenic activity related positively to a lengthening photoperiod reaching maximum activity in late spring (December). Females displayed an extended gestation period of 11 months, from mid-summer (February) to late spring or early summer (December) when births occur. Embryonic development was associated with temperature and historical rainfall. Litter size ranged from 3 to 8 (mean = 5.3 ± 1.3 SD) and increased with body size and body mass of females. Fat-body mass varied seasonally and was inversely correlated with spermatogenesis and to embryonic development. Females were larger in body size and interlimb length, and smaller in head length than males. We observed interpopulational differences in minimum body size, litter size, and timing of birth, probably as a result of phenotypic plasticity, genetic divergence or both.

Relation of quality of anticoagulation control with different management systems among patients with atrial fibrillation: Data from FANTASIIA Registry.

BACKGROUND: Anticoagulation control in patients with atrial fibrillation (AF) has a multidisciplinary approach although is usually managed by general practitioners (GP) or haematologists. The aim of our study was to assess the quality of anticoagulation control with vitamin K antagonists (VKAs) in relation to the responsible specialist in a "real-world" AF population. METHODS: We consecutively enrolled VKA anticoagulated patients included in the FANTASIIA Registry from 2013 to 2015. We analysed demographical, clinical characteristics and the quality of anticoagulation control according to the specialist responsible (ie GPs or haematologists). RESULTS: Data on 1584 patients were included (42.5% females, mean age 74.0 ± 9.4 years): 977 (61.7%) patients were controlled by GPs and 607 (38.3%) by haematologists. Patients managed by GPs had higher previous heart disease (53.2% vs 43.3%, P < .001), heart failure (32.9% vs 26.5%, P < .008) and dilated cardiomyopathy (15.2% vs 8.7%, P < .001) with better renal function (69.3 ± 24.7 vs 63.1 ± 21.4 mL/min, P < .001) compared to patients managed by haematologists. There was no difference between groups in the type of AF, CHA2 DS2 -VASc or HAS-BLED scores, but patients with electrical cardioversion were more prevalent in GP group. The overall mean time in therapeutic range (TTR) assessed by Rosendaal method was 61.5 ± 24.9%; 52.6% of patients had TTR<65% and 60% of patients had TTR<70%. TTR was significantly lower in patients controlled by haematologists than by GPs (63 ± 24.4 vs 59.2 ± 25.6, P < .005). CONCLUSIONS: About 60% of AF patients anticoagulated with VKAs had poor anticoagulation control (ie TTR<70%), and their management was only slightly better than when it is managed by general practitioners.

Inappropriate doses of direct oral anticoagulants in real-world clinical practice: prevalence and associated factors. A subanalysis of the FANTASIIA Registry.

Aims: To describe the prevalence and associated factors of inappropriate doses of direct oral anticoagulants (DOAC) in a national registry of patients of real clinical practice. Methods and results: Five hundred and thirty outpatients with atrial fibrillation treated with DOAC were included in a prospective, national, multicentre study. The appropriateness of the doses of DOAC was defined according to the recommendations of the European Heart Rhythm Association. Mean age was 73 ± 9 years, with a 46% of women. Two hundred and sixty-seven patients were prescribed dabigatran, 190 rivaroxaban, and 73 apixaban. A total of 172 patients (32%) did not receive the appropriate dose: 93 patients received a lower dose (18%) and 79 patients a higher dose (15%). In the comparisons among the subgroups of inappropriately low, appropriate, and inappropriately high dose, we observed significant trends to older age (69 ± 8 years vs. 73 ± 10 years vs. 77 ± 6 years), more frequent female sex (37% vs. 46% vs. 59%), antiplatelet drugs (5% vs. 8% vs. 25%), rivaroxaban (14% vs. 38% vs. 53%), and apixaban use (5% vs. 15% vs. 19%), higher CHAD2DS2-VASc (3.00 ± 1.38 vs. 3.58 ± 1.67 vs. 4.59 ± 1.44) and HAS-BLED scores (1.83 ± 0.87 vs. 1.92 ± 1.07 vs. 2.47 ± 1.13), lower body mass index (30 ± 6 kg/m2 vs. 29 ± 4 kg/m2 vs. 28 ± 4 kg/m2) and glomerular filtration rate (74 ± 27 mL/min vs. 70 ± 22 mL/min vs. 63 ± 16 mL/min), and lower frequency of dabigatran use (81% vs. 47% vs. 28%) (all comparisons P ≤ 0.01). Conclusion: In this real-life study, 32% of patients received an inappropriate dose of DOAC. Several clinical factors can identify patients at risk of this situation.

Quality of oral anticoagulation with vitamin K antagonists in 'real-world' patients with atrial fibrillation: a report from the prospective multicentre FANTASIIA registry.

Aims: The efficacy and safety of oral anticoagulation (OAC) using the vitamin K antagonists (VKA) are closely associated with the quality of anticoagulation, reflected by time in therapeutic range (TTR). The SAMe-TT2R2 is a risk score developed to predict the quality of anticoagulation control among VKA users. To analyse the quality of anticoagulation and its clinical determinants based on different methods in a prospective cohort of atrial fibrillation patients on VKA treatment participating in the multicentre Spanish observational registry FANTASIIA. Methods and results: Estimated TTR was calculated from Rosendaal, direct method, international normalized ratio variability, and NICE criteria. Time in therapeutic range values were compared for those patients with a SAMe-TT2R2 score 0-2 and >2. One thousand four hundred and seventy patients were analysed (56.4% male, mean age 74.1 ± 9.5 years). Mean TTR was 61.5 ± 25.1 with Rosendaal and 64.7 ± 24.2 with direct method. There was a high correlation between both methods (ρ = 0.805). The prevalence of poor anticoagulation control was 55%. Diabetes mellitus [odds ratio (OR) 1.38; P = 0.008], peripheral artery disease (PAD, OR 1.62; P = 0.048), and HAS-BLED (OR 1.13; P = 0.022) were independently associated with TTR < 70%. SAMe-TT2R2 score 0-2 had a higher mean TTR than patients with SAMe-TT2R2 >2 (P = 0.044), with a specificity of > 90% for predicting TTR < 70%. Patients with TTR < 70% had higher risk of events (21.7 vs. 16.8%; P = 0.021). Conclusion: In a multicentre prospective registry, 55% of AF patients had poor anticoagulation control with diabetes mellitus, PAD, and HAS-BLED being independently associated with TTR < 70%. A high SAMe-TT2R2 scores had a high specificity for predicting a TTR < 70% as an indicator of poor quality anticoagulation.

Heartbeats Do Not Make Good Pseudo-Random Number Generators: An Analysis of the Randomness of Inter-Pulse Intervals.

The proliferation of wearable and implantable medical devices has given rise to an interest in developing security schemes suitable for these systems and the environment in which they operate. One area that has received much attention lately is the use of (human) biological signals as the basis for biometric authentication, identification and the generation of cryptographic keys. The heart signal (e.g., as recorded in an electrocardiogram) has been used by several researchers in the last few years. Specifically, the so-called Inter-Pulse Intervals (IPIs), which is the time between two consecutive heartbeats, have been repeatedly pointed out as a potentially good source of entropy and are at the core of various recent authentication protocols. In this work, we report the results of a large-scale statistical study to determine whether such an assumption is (or not) upheld. For this, we have analyzed 19 public datasets of heart signals from the Physionet repository, spanning electrocardiograms from 1353 subjects sampled at different frequencies and with lengths that vary between a few minutes and several hours. We believe this is the largest dataset on this topic analyzed in the literature. We have then applied a standard battery of randomness tests to the extracted IPIs. Under the algorithms described in this paper and after analyzing these 19 public ECG datasets, our results raise doubts about the use of IPI values as a good source of randomness for cryptographic purposes. This has repercussions both in the security of some of the protocols proposed up to now and also in the design of future IPI-based schemes.

Pharmacokinetics of vancomycin and dosing recommendations for trauma patients.

OBJECTIVES: The objectives of this study were to characterize the population pharmacokinetics of vancomycin in trauma patients and to propose dosing schemes to optimize therapy. PATIENTS AND METHODS: Trauma patients from Hospital Universitario Severo Ochoa (Spain) receiving intravenous vancomycin and routine therapeutic drug monitoring were included. Concentrations and time data were retrospectively collected, and population modelling was performed with NONMEM 7.2; internal and external validations were performed to probe the final model. Finally, several simulations were executed to propose dosing guidelines to reach expected vancomycin concentrations. RESULTS: A total of 118 trauma patients were included; the population was 45% males, with a mean age of 77 years (range 37-100 years) and a mean total body weight (TBW) of 72 kg (range 38-110 kg). The pharmacokinetics of vancomycin was best described by a two-compartment open model; creatinine clearance (CLCR) was related to vancomycin clearance (0.49 ± 0.04 L/h), being diminished by the presence of furosemide (0.34 ± 0.05 L/h). TBW influenced both the central volume of distribution (V1 = 0.74 ± 0.1 L/kg) and peripheral volume of distribution (V2 = 5.9 ± 2 L/kg), but patients with age >65 years showed a larger V1 (1.07 ± 0.1 L/kg). Bootstrapping was performed to internally validate the stability of the final model. External validation was developed using an alternate population of 40 patients with the same characteristics. The validated model was compared with population pharmacokinetic models previously published and showed better predictive performance for trauma patients than the current one. This final model allowed us to propose a new practical dose guideline to reach higher trough concentrations (15-20 mg/L) and AUC0-24/MIC ratios of more than 400 after 4 days of vancomycin treatment. CONCLUSIONS: A new population model was described for trauma patients to optimize vancomycin therapy, showing precise predictive performance to be applied for therapeutic drug monitoring and providing a new practical dose guideline that considers CLCR and concomitant administration of furosemide for these patients.

Study of immobilized metal affinity chromatography sorbents for the analysis of peptides by on-line solid-phase extraction capillary electrophoresis-mass spectrometry.

Several commercial immobilized metal affinity chromatography sorbents were evaluated in this study for the analysis of two small peptide fragments of the amyloid ß-protein (Aß) (Aß(1-15) and Aß(10-20) peptides) by on-line immobilized metal affinity SPE-CE (IMA-SPE-CE). The performance of a nickel metal ion (Ni(II)) sorbent based on nitrilotriacetic acid as a chelating agent was significantly better than two copper metal ion (Cu(II)) sorbents based on iminodiacetic acid. A BGE of 25 mM phosphate (pH 7.4) and an eluent of 50 mM imidazole (in BGE) yielded a 25-fold and 5-fold decrease in the LODs by IMA-SPE-CE-UV for Aß(1-15) and Aß(10-20) peptides (0.1 and 0.5 µg/mL, respectively) with regard to CE-UV (2.5 µg/mL for both peptides). The phosphate BGE was also used in IMA-SPE-CE-MS, but the eluent needed to be substituted by a 0.5% HAc v/v solution. Under optimum preconcentration and detection conditions, reproducibility of peak areas and migration times was acceptable (23.2 and 12.0%RSD, respectively). The method was more sensitive for Aß(10-20) peptide, which could be detected until 0.25 µg/mL. Linearity for Aß(10-20) peptide was good in a narrow concentration range (0.25-2.5 µg/mL, R(2) = 0.93). Lastly, the potential of the optimized Ni(II)-IMA-SPE-CE-MS method for the analysis of amyloid peptides in biological fluids was evaluated by analyzing spiked plasma and serum samples.

Impact of asymptomatic acute cellular rejection on left ventricle myocardial function evaluated by means of two-dimensional speckle tracking echocardiography in heart transplant recipients.

BACKGROUND: Our objective was to evaluate the impact of asymptomatic acute cellular rejection (ACR) in left ventricular myocardial strain in heart transplant (HT) recipients by means of two-dimensional speckle tracking echocardiography (2DSTE). METHODS: From September 1, 2009 to December 15, 2010 a conventional echocardiography and 2DSTE exam was performed on all consecutive HT recipients in their first year posttransplantation within 3 hours of the surveillance endomyocardial biopsies, as well as on 14 healthy controls. The association of strain echocardiographic variables with different grades of ACR was investigated. RESULTS: Of the 78 studies performed 4 ± 3 months after HT in 20 patients, 32 studies were coincident with grade 0R rejection, 41 with grade 1R, and 5 with grade 2R. Significantly lower values of average radial strain were found with higher grades of ACR (29.1 ± 7.7%, 23.2 ± 8.5%, and 14.3 ± 8.8% for grades 0R, 1R, and 2R of ACR, P = 0.001). Average deformation was similar for controls versus transplanted patients, in the absence of acute rejection: radial 29.1 ± 10.0% versus 29.1 ± 7.7%, P = 0.98; circumferential -19.3 ± 3.2% versus -20.2 ± 5.9%, P = 0.62; and longitudinal -20.7 ± 4.1% versus -18.5 ± 5.4%, P = 0.19. An average radial strain <25% presented 100% sensitivity, 48% specificity, 6% positive predictive value, and 100% negative predictive value for the presence of 2R rejection (area under the curve 0.80, IC 95% 0.60-0.99, P = 0.048). CONCLUSION: In this study, HT recipients showed significantly lower values of average radial left ventricle strain, evaluated by means of 2DSTE, with the presence of ACR.