Acutely decompensated heart failure (ADHF) presents high morbidity andmortality in spite of therapeutic advance. Identifying factors of worstprognosis is important to improve assistance during the hospital phase andfollow-up after discharge. The use of echocardiography for diagnosis andtherapeutic guidance has been of great utility in clinical practice.However, it is not clear if it could also be useful for risk determinationand classification in patients with ADHF and if it is capable of addingprognostic value to a clinical score (OPTIMIZE-HF).To identify the echocardiographic variables with independent prognostic valueand to test their incremental value to a clinical score.Prospective cohort of patients consecutively admitted between January 2013and January 2015, with diagnosis of acutely decompensated heart failure,followed up to 60 days after discharge. Inclusion criteria were raisedplasma level of NT-proBNP (> 450 pg/ml for patients under 50 years of ageor NT-proBNP > 900 pg/ml for patients over 50 years of age) and at leastone of the signs and symptoms: dyspnea at rest, low cardiac output or signsof right-sided HF. The primary outcome was the composite of death andreadmission for decompensated heart failure within 60 days.Study participants included 110 individuals with average age of 68 ±16 years, 55% male. The most frequent causes of decompensation (51%) weretransgression of the diet and irregular use of medication. Reduced ejectionfraction (<40%) was present in 47% of cases, and the NT-proBNP median was3947 (IIQ = 2370 to 7000). In multivariate analysis, out of the 16echocardiographic variables studied, only pulmonary artery systolic pressureremained as an independent predictor, but it did not significantly incrementthe C-statistic of the OPTMIZE-HF score.The addition of echocardiographic variables to the OPTIMIZE-HF score, withthe exception of left ventricular ejection fraction, did not improve itsprognostic accuracy concerning cardiovascular events (death or readmission)within 60 days In those patients withNYHA functional class IV, it can reach 80% within 2 years.3 The firsthospitalization constitutes an important step in the clinical evolution, modifyingthe quality of life and survival of patients with heart failure.4 In spite of the advances intherapeutics, readmission rates due to recurrence of symptoms are high. NorthAmerican studies in patients over the age of 70 years reveal readmission rates of upto 25%, within 30 days, and 50% within 6 months.6 Thus, thestratification of patients based on their risk profile for adverse events  is a crucial task, with a view to improvetherapeutic planning and identification of the higher risk subgroup which maybenefit from closer monitoring and/or more advanced therapies.8Acutely decompensated heart failure (ADHF) is a complex and heterogeneous syndromecharacterized by the sudden or gradual onset of the signs or symptoms of heartfailure, requiring immediate medical attention and treatment.12 Among them is a large registry, theOPTIMIZE-HF13 , whichprovided data on hospital mortality and rehospitalization/death within 60 days afterhospitalization using clinical and laboratory variables. In this prognostic model,the only echocardiographic variable tested was left ventricular ejection fraction,computed dichotomously. Other traditional echocardiographic parameters, such ascavity dimensions, left ventricular diastolic function, right ventricular diastolicfunction, valvular and hemodynamic changes have not been analysed. The associationbetween echocardiographic variables and cardiovascular outcomes, in otherstudies,15generates the hypothesis that they may add value to the traditional prognosticmodels.Several probabilistic risk models, using clinical variables, have been proposed topredict events in the short and long run.As a result, we conducted a study which tests the hypothesis that multipleechocardiographic variables increment the prognostic accuracy of traditional riskprediction by using the OPTIMIZE-HF score.Individuals consecutively hospitalized for ADHF were selected in the cardiac unitof a tertiary hospital, from January 2013 to January 2015. The inclusioncriteria for this Registry included individuals with 18 years of age or more andelevated plasma levels of NT-proBNP , whose hospitalizationoccurred due to: dyspnea at rest or in the last 15 days; signs of low cardiacoutput  or signs of right heart failure . Pregnant women, patients who did notpresent adequate acoustic window and those who did not consent to participate inthe study were excluded. The protocol is in conformity with the declaration ofHelsinki, it was approved by the Research Ethics Committee of the institutionand all patients signed a free and clarified consent term.bioMerieuxVIDAS® NT-proBNP assay. The dosage of NT-proBNP was performed on a blood sample collected immediatelyafter the arrival of the patient to the emergency departament, a procedure whichaims to ensure the shortest possible time between the beginning of the symptomsand the collection of material. The measurement was performed in serum using theELFA technique (Enzyme-Linked Fluorescent Assay) and the 17 The patients who did not havesuboptimal acoustic window, which did not allow satisfactory analysis of theechocardiographic parameters, would not be included in the Registry.All the exams have been performed in the first 24 hours after admission in thehospital unit, by only one examiner, blind to clinical and laboratoryinformation. The parameters were obtained in digital format and stored forfurther analysis, using the GE Vivid 7 machine and the Vivid I system with a M4Ssector transducer with frequencies of 1.5 - 3.6MHz. Another trained andqualified observer reviewed the archieved images in 15% of the exams in order totest the interobserver agreement. The patients were studied in left lateraldecubitus with sequential analysis of the parasternal, apical, suprasternal andsubxiphoid windows. Echocardiographic parameters were assessed in conformitywith the recomemndations of the American Society of Echocardiography(ASE).The echocardiographic predictor variables analized were: the left ventriclediastolic diameter, left ventricle systolic diameter, right ventricle diameter,left atrial diameter, left atrial volume (indexed to body surface), tissueDoppler imaging of the tricuspid annulus (S' wave), tricuspid annular planesystolic excursion (TAPSE), left ventricular ejection fraction (Simpson'smethod), pulsed Doppler analysis of mitral flow ,lateral and septal mitral annular tissue Doppler , E/e´relation, systolic pulmonary artery pressure and mitralinsufficiency (moderate/severe).13The OPTIMIZE-HF predictive model, assessed in all patients to admission, involvesthe collection of clinical and laboratory variables, such as: age, urea, sodium,heart rate, systolic blood pressure and left ventricular systolic dysfunction,in addition to antecedent history of hepatic dysfunction, depression and airwayhyperactivity.The primary outcome variable was defined by the composite of death (sudden deathor due to HF decompensation) and readmission for ADHF within 60 days.The numerical variables tested were expressed as mean and standard deviationor median and interquartile interval according to normality(Kolmogorov-Smirnov and Shapiro Wilk test), and compared between patientswith or without outcome using the unpaired t-test or the Mann-Whitney test.The correlations between the dichotomous variables were performed with thechi-square test. Once outcome-associated variables were identified (p <0.10), they were inserted into a multivariate logistic regression model, andadjusted according to the OPTIMIZE-HF score. In the final model, variablesthat proved to be independent predictors (p < 0.05) were added to theOPTIMIZE-HF score. The evaluation of the incremental value ofechocardiographic variables was performed by comparing the C-statistic ofthe model, containing echocardiographic and clinical variables(ECO+OPTIMIZE-HF), with an exclusively clinical model (OPTIMIZE-HF). Theareas under the ROC curve were compared using the DeLong test. To evaluatethe calibration of the model, the Hosmer-Lemeshow test was performed.SPSS Statistical Software and MedCalc Software  were used fordata analysis, the latter for comparison between the ROC curves.The sample was sized to provide a power of 80% and an alpha of 5%, for thepre-established analysis. To construct a new probabilistic model, in thelogistic regression, 1 variable was included for every 5 outcomes. Samplesize was calculated to detect a ROC curve with statistical significance,estimating an AUC of 0.75 and an events rate of 25%. A pilot study wascarried out with 30 patients and an events rate of 36% of combined outcomeswas noted. 110 patients were included, thus allowing for the inclusion of upto 8 echocardiographic variables in a logistic regression model.During the period covered by the study, 110 patients diagnosed with ADHF wereincluded. Most patients were elderly people, with an average age of 68 ± 16years, 55% of them male. Dyspnea was the main symptom in 92% of patients, followedby lower limb edema in 5%. The most common identifiable cause for clinicaldecompensation was poor drug adherence and/or diet transgression (51%), followed byinfection and arrhythmia (21% and 5% respectively). The most common HF etiology wasthe hypertensive (47%), followed by ischemic heart failure (37%) and Chagas disease(7.2%). The median value of admission NT-proBNP was 3947 (IIQ = 2370 to 7000). Theprimary outcome occurred in 37 patients (34% of the sample), corresponding to 14deaths and 23 readmissions within 60 days. The general characteristics are presentedin 2).The echocardiographic analysis has shown that most patients did not presentsevere left ventricular dilatation, with left ventricular diastolic diameteraverage of 55.5 ± 11.5 mm. On the other hand, left atrial volume indexwas significantly raised , grade I dysfunction  wasobserved in 28.6% of cases and grades II and III dysfunction (reducedcomplacency) in 71.4%. However, the estimation of the left ventricular fillingpressures was evaluated in all patients using the septal E/e' ratio, and a meanof 23.7±15 was obtained. Estimation of systolic pulmonary arterypressure, through analysis of tricuspid regurgitation, was calculated in allpatients, and a mean of 44.4 ± 14.8mmHg was obtained. versus 41.8 ± 6 p = 0.05)and the indexed volume of the left atrium  were significantlyhigher in the events group. With regard to the ejection fraction, there was nostatistically significant difference between the groups , however when it was examined as adichotomous, rather than a continuous variable, there was higher prevalence ofLVEF < 40% in the outcome group and with statistical significance (61%versus 52% p = 0.04). The estimation of left ventricularfilling, evaluated through the analysis of the E/e´ relation, did not differbetween the two groups . However, pulmonary artery systolic pressure was higher in theevents group . The degree of the diastolic dysfunction did not differ significantlybetween the groups; neither did the presence of moderate/severe mitralinsufficiency.The exploratory analysis of 16 variables, which reflected morphological,functional and hemodynamic changes, was performed, as shown in versus 89 ± 25; p =0.04). Lower creatinine level on admission was also noted , but with nostatistically significant difference. The OPTIMIZE-HF score was higher in theevents group .Comparing the non-events group with the events group (death or readmission), nostatiscally significant difference was seen in relation to age, sex and systolicblood pressure at admission, as shown in In the exploratory analysis, the left atrial volume index and the systolicpulmonary artery pressure (sPAP) were predictors of the primary outcome, andthus selected for multivariate analysis. In the logistic regression, using theOPTIMIZE-HF score and echocardiographic predictor variables, it was observedthat the left atrial volume index lost statistical significance, and only thesPAP (p = 0.01) and the OPTIMIZE score (p = 0.002) remained in the final model,as shown in The accuracy of the sPAP echocardiographic variable was evaluated using the areaunder the ROC curve (C-statistic), which resulted in 0.66 ,while the area under the curve of the clinical model (OPTIMIZE-HF score) was0.69 . After sPAP was included in the model, it was observedan increase in the area under the ROC curve to 0.75 .However, this increase was not significant (p = 0.17), which suggests that theechocardiographic variables used did not improve the prediction of eventscompared to the clinical model, as shown in The results of this study indicate that routinely measurable echocardiographicparameters, during a standard transthoracic echocardiography, do not seem to improvethe risk stratification in patients with ADHF when associated with a clinical scorethat already uses left ventricular ejection fraction. Only the measurement ofpulmonary artery systolic pressure was an independent predictor of death orreadmission within 60 days in patients with acutely decompensated HF, but it did notadd incremental value to the OPTIMIZE-HF clinical score.13 is one of thetools recommended by the Brazilian Guidelines on Acute Heart Failure,18 as well as by other internationalguidelines19 for riskstratification in patients with ADHF. It was developed to evaluate the risk ofcardiovascular outcomes in hospital and after discharge (death and readmission). Inour sample, the referred score presented regular performance with an area under thecurve (AUC) of 0.69 . However, this performance wasnot significantly improved when echocardiographic variables were added to the score(independent predictor of outcomes), and an AUC of 0.75  was obtained. This suggests that not all information provided by a negativeechocardiogram, or that apparently could indicate a worsen evolution, may improverisk prediction, when evaluated within the context of a clinical score.There are several validated prognostic models, each of which combining differentvariables, which suggests how difficult it is to estimate risks in patients withADHF. The efforts towards developing and improving such probabilistic models arejustified because risk of in-hospital mortality, mortality after discharge andreadmission are still elevated in spite of the evolution of specific treatment. TheOPTIMIZE-HF score20 For the first time, in a population-based study, it wasdemonstrated that patients with HF who received echocardiographic evaluation hadimproved survival and were more willing to be treated with angiotensin convertingenzyme inhibitors (ACE inhibitors) compared to those patients who were not evaluatedby echocardiography. Since then, innumerable echocardiographic variables have beenstudied and identified as predictors of morbidity and mortality in acute heartfailure.28 Left ventricular ejection fraction is probably themost researched variable and it has been shown to be a predictor of short29 and long31 termmortality in patients with ADHF. In our study, we observed that in those patientswho had LVEF < 40%, there were more outcomes when compared to those with LVEF> 40%. However, when we compared the absolute value of LVEF, it did not predictevents, which suggests that qualifying the systolic function  is more important for risk stratification than thenumerical value of ejection fraction. Hemodynamic analysis of left ventricularcompliance and filling pressures have also been largely studied, based onnon-invasive hemodynamic analysis using conventional echocardiography.32 The assessment of mitral flow andtissue Doppler allows to infer the therapeutic response in patients with ADHF, sincethese ratings are directly related to ventricular preload and afterload, which varyconsiderably in the acute phase of decompensation.33 However, available data on the E/e’ relation andits prognostic meaning in the ADHF scenario are few and often conflicting. Somestudies assert that this variable is not capable of providing prognostic informationon these patients, when admission is evaluated in the emergency unit,34 and others suggest that, when itis associated with LVEF, it is possible to identify those patients with higher riskof death and readmission.30 Inthis study, the degree of diastolic dysfunction at admission, in both E/A and E/e´relations , were not capable of identifying those patients whohad more or less events. Other important component of the echocardiographic analysisof patients with ADHF is the estimation of pulmonary artery systolic pressure. Mostof these patients suffer from passive or mixed pulmonary hypertension, that is, acombination of passively elevated pressures and pulmonary vasoreactivity response.These types may improve acutely with blood volume normalization.35 Several studies have shown thesPAP as an independent predictor of cardiovascular outcomes.37 In this study, itwas observed that sPAP remained as an independent predictor of combined outcomes,even after it was adjusted to the clinical variables that composed the clinicalscore.The hypothesis according to which echocardiography could have prognostic impact inpatients with acutely decompensated heart failure took shape in the late 1990’s,based on a study by Sennim et al.38 whichevaluated retrospectively the incremental value of the echocardiography to theADHERE score, demonstrating that the sPAP added independent prognostic informationand allowed a modest increment in the score’s C-statistic, around 0.07, inpredicting in-hospital mortality. However, there were no reports that this increasepresented statistical significance.However, the statistical significance in multivariate analysis is not a sufficientrequirement to state clinical relevance of the prognostic evaluation. Theincremental value in relation to a usual predictive model must also be demonstratedand few studies have incorporated echocardiographic variables to a clinicalpredictive model and evaluated their performance using the C-statistic increment.Our study has demonstrated that the addition of the 16 (sixteen) echocardiographicvariables tested did not improve the prognostic accuracy of the clinical score in predictingcardiovascular events within 60 days. Among the variables tested, the sPAP, with aC-statistic of 0.66  and with p = 0.01 in the logisticregression analysis, was the only one which predicted cardiovascular events within60 days. However, when it was added to the OPTIMIZE-HF score, the C-statisticincrement was not significant. As a result, in spite of its statistical significancein the multivariate analysis, the sPAP was not enough to assert the incrementalprognostic value and clinical relevance of the prognostic evaluation in patientswith acutely decompensated heart failure. In the review of the literature carriedout, we did not find any scientific work that has examined the incremental value ofconventional echocardiography to the OPTIMIZE-HF score. A small number of researcheshas incorporated echocardiographic variables into a clinical predictive model,aiming to evaluate the performance of these variables and their incremental value onthe C-statistics of the score tested. Among them, we highlight the researchpublished by Gripp et al.,The main limitation of this study is its sample size and the fact that it was carriedout in only one center, which means that our data cannot be generalized, norconsidered definitive in relation to the lack of prognostic increment in theechocardiographic variables. Another point to highlight is the absence of a secondcontrol echocardiography in all the patients, so that the variables could have beencompared before and after therapeutic optimization. Echocardiographic variations mayoccur, such as sPAP decrease in more than 10 mmHg, increase in LVEF from 5 to 10%,reduced degree of mitral insufficiency and/or tricuspid, as well as improveddiastolic dysfunction and pericardial stroke. Furthermore, new technologies, such asspeckle tracking and three-dimensional echocardiography, were not used, which couldhave improved the analysis of the biventricular systolic function as well as thecardiac chamber real volumes.The addition of echocardiographic variables, except for left ventricular ejectionfraction, to the OPTIMIZE-HF score, did not improve its prognostic accuracy inrelation to cardiovascular events (death or readmission) within 60 days.


The prevalence of high blood pressure in children is increasing worldwide, largely, but not entirely, driven by the concurrent childhood obesity epidemic. The aims of this study were to examine the prevalence of prehypertension and hypertension in 4-to-6-year-old Spanish schoolchildren, and to evaluate the association between different blood pressure (BP) components with different adiposity indicators.Cross-sectional study including a sample of 1.604 schoolchildren aged 4-to-6-years belonging to 21 schools from the provinces of Ciudad Real and Cuenca, Spain. We measured height, weight, body mass index (BMI), fat mass percentage (%FM), triceps skinfold thickness (TST), waist circumference (WC), systolic and diastolic BP, mean arterial pressure and pulse pressure.The estimates of prevalence of prehypertension and hypertension were 12.3% and 18.2%, respectively. In both sexes, adiposity indicators were positively and significantly associated with all BP components (p<0.001), thus schoolchildren in the higher adiposity categories had significantly higher BP levels (p<0.001).Our results show a high prevalence of high blood pressure in Spanish children. Moreover, high levels of adiposity are associated with high blood pressure in early childhood, which support that it could be related to cardiovascular risk later in life. A reTraditionally, BP measurements only include systolic blood pressure (SBP) and diastolic blood pressure (DBP) values, but other indices, such as mean arterial blood pressure (MAP) or pulse pressure (PP), have also been shown to be independent predictors of cardiovascular events in both normotensive and hypertensive adult individuals , 17.Because the current estimates of overweight/obesity prevalence in Spanish children are one of the highest in the world, estimates of high blood pressure prevalence in Spanish children might represent an indirect indicator of the impact of the obesity epidemic on BP levels. Thus, the aims of this study were to examine in 4-to-6 years old Spanish schoolchildren: 1) the prevalence of prehypertension and hypertension and 2) the association between adiposity indicators  with traditional  and alternative  blood pressure components.NCT01971840) aimed at assessing the effectiveness of a multidimensional physical activity intervention (Movi-Kids) for preventing obesity, improving fitness and reducing cardiovascular risk in schoolchildren belonging in the third grade of preschool and the first grade of primary school (aged 4-to-6 years) [This was a cross-sectional analysis of baseline data (collected September–November 2013) from a cross-over randomized cluster trial NCT019740 aimed Measurement procedures have been extensively described elsewhere . To mini® 861, Vogel and Halke, Hamburg, Germany) and height was measured using a wall stadiometer  with the child upright and with the sagittal midline touching the backboard. The mean of the two measurements of weight and height was used to calculate BMI (kg/m2). %FM was estimated using an eight-electrode Tanita® Segmental-418 bioimpedance analysis system . Two readings were obtained in the morning, under controlled temperature and humidity conditions, with the child being barefoot, fasting and after urination and 15 minutes of rest. Triceps skinfold thickness (TST) was measured three times at the triceps using a Holtain Ltd. caliber . Waist circumference (WC) was calculated as the average of three measurements using a flexible tape at the midpoint between the last rib and the iliac crest at the end of a normal breathe .Weight, height and %FM were measured twice with the child barefoot and in light clothing. Weight was measured with a scale  and stage 2 (>99th percentile plus 5 mm Hg).SBP and DBP were measured twice, taken at an interval of five minutes, with the subject resting for at least five minutes before the first measurement, using an OMRON-M5-I automatic tensiometer , in a quiet, calm environment, with the child seated and the right arm placed in a semi-flexed position at heart level and choosing the most appropriate size of the cuff according to recommendations of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents . The meaThe distribution of continuous variables was checked for normality using both graphical  and statistical (Kolmogorov—Smirnov test) procedures. All variables had a normal distribution, thus we used parametric test in the analysis. Anthropometrical and BP variables were presented as mean and standard deviation (SD). Sex differences on the quantitative variables were tested using a Student T-test.Partial correlation coefficients were estimated to examine the relationship between each BP component  and indicators of adiposity , controlling for age, by sex.We categorized %FM, TST and WC as low (first quartile), medium (second and third quartiles) and high (fourth quartile). Children were classified as underweight, normal weight, overweight and obese according to the BMI cut-offs proposed by Cole and Lobstein .post hoc hypotheses were tested using the Bonferroni correction for multiple comparisons.ANCOVA models were used to assess mean differences in each component of BP  among BMI, %FM, WC and TST categories controlling for age in the total sample and also separately by sex. Pairwise All statistical analyses were performed using the IBM SPSS 22 Statistic software; the criterion for statistical significance was set at p ≤ 0.05.Of the 2.407 schoolchildren invited to participate in the study, 1.604 (66.63%) agreed to participate. Out of these, 788 were girls (49.10%). No significant differences were observed between the mean age of the girls and boys. Summary statistics of all variables are shown in Partial correlation coefficients between BP and adiposity indicators, controlling for age, are shown in post hoc tests were statistically significant. Similar results were also found when data were analyzed separately by sex (p<0.001) (data not shown).Mean differences in all BP components  by categories of BMI and %FM, controlling for age, are shown in Studies estimating prevalence of high blood pressure in children ≤ 6 years old are scarce across the world, and none have been performed in Spain. This study shows that high blood pressure prevalence in children aged 4-to-6 years from Castilla-La Mancha, Spain, was 27.5% and 30.6% in boys and girls, respectively. Furthermore, the prevalence of prehypertension and hypertension in the total sample was 12.3% and 18.2%, respectively. Likewise, a positive relationship between adiposity categories and BP levels has been found.th percentile) prevalence has been reported in different population-based studies in the same age-range groups of children across the world; some of them were similar to our results: 23% in China [A significant variability of hypertension  were moderately and positively correlated with SBP, DBP and MAP , as foun–Our findings also suggest that children in the higher categories of BMI and %FM have higher levels of SBP, DBP, MAP and PP in both boys and girls, as reported in other studies in the same age group and different ethnicities –37. HoweIt has been suggested that cardiovascular risk attributable to hemodynamic factors may be assessed more accurately considering physiological  rather than traditional  components of BP, using PP as an indicator of large artery stiffness (pulsatile load) and MAP as an indicator of peripheral resistance and cardiac output (steady flow load) . It has The association between overweight/obesity with physiologic BP components (MAP and PP) at such an early ages might have an impact on the large arteries, which would need to adjust their size to a higher blood volume, increasing their diameter. This enlarged arterial stiffness might determine higher risk of future hypertension and cardiovascular disease, but longitudinal studies are needed to assess this association in adulthood .This study has some limitations that should be noted. First, the cross-sectional design which prevents us from making cause-effect inferences. Second, potential overestimation of the prevalence of high BP due to the determination of BP in a single occasion, compared to others studies that reported two more screenings of BP in those individuals classified as prehypertensive and hypertensive , 46. AccOur data show a high prevalence of prehypertension and hypertension in Spanish children younger than 6 years. These findings are important from a clinical and public health point of view because they support the idea that early detection of a prehypertensive and hypertensive status in young children may help to prevent the cardiovascular disease in adulthood in Spanish population.


Objective: It is well-known that initiation of fingolimod induces a transient decrease of heart rate. However, the underlying cardiac autonomic regulation is poorly understood. We aimed to investigate the changes of autonomic activity caused by the first dose of fingolimod using a long-term multiple trigonometric spectral analysis for the first time. In addition, we sought to use the continuous Holter ECG recording to find predictors for fingolimod induced bradycardia.Methods: Seventy-eight patients with relapsing-remitting multiple sclerosis (RRMS) were included. As a part of the START study (NCT01585298), continuous electrocardiogram was recorded before fingolimod initiation, and until no <6 h post medication. Time domain and frequency domain heart rate variability (HRV) parameters were computed hourly to assess cardiac autonomic regulation. A long-term multiple trigonometric regressive spectral (MTRS) analysis was applied on successive 1-h-length electrocardiogram recordings. Decision tree analysis was used to find predictors for bradycardia following fingolimod initiation.Results: Most of the HRV parameters representing parasympathetic activities began to increase since the second hour after fingolimod administration. These changes of autonomic regulations were in accordance with the decline of heart rate. Baseline heart rate was highly correlated with nadir heart rate, and was the only significant predicting factor for fingolimod induced bradycardia among various demographic, clinical and cardiovascular variables in the decision tree analysis.Conclusions: The first dose application of fingolimod enhances the cardiac parasympathetic activity during the first 6 h post medication, which might be the underlying autonomic mechanism of reduced heart rate. Baseline heart rate is a powerful predictor for bradycardia caused by fingolimod. Fingolimod is highly effective for the treatment of relapsing-remitting multiple sclerosis  is a valuable tool for the quantitative evaluation of the fluctuations of HR, and can reflect the parasympathetic activities of cardiac autonomic function . However, RRIs are non-equidistant and therefore interpolation is needed. The interpolation for the fast Fourier transform can affect the accuracy of spectral analysis  and HR were measured before medication and every hour for at least 6 h after medication. Continuous 12-lead ECG recording was performed using CardioMed CM3000-12  since 1 h before medication, and until no <6 h post medication. In general, the patients were in a sedentary state in the waiting room of our hospital during the ECG monitoring, although their physical activity was not restricted and they breathed freely. All the ECG recordings were checked by a cardiology expert for any abnormalities.Mean HR was computed from mean RRI of each hour, and bradycardia was defined as a HR < 60 bpm  in the range of 20–60 s. The regression function in TRS has a general form: Reg (t) = A*sin(ωt+ψ); A is the amplitude, ωt is the angular frequency, and ψ is the phase shift of the trigonometric regression function Reg (t). To determine the function Reg (t), we need to make the deviations of Reg (t) from the original values minimal: F = Σ (RRI (t) –Reg (t))2 = Min and /or dF = 0. By pursuing a minimal deviation of Reg (t), we can determine the variables A, ω, and ψ with the help of partial differential quotients through the following equations: dF/dA = 0; df/dω = 0; df/d ψ = 0. Then optimal oscillations can be found by variation of the frequency for a maximal adaption to the original RR intervals . In this case TRS analysis is called MTRS analysis. This procedure guarantees a statistically representative spectral analysis for the global data segment . Data are presented as mean ± standard error of the mean (SEM) unless stated otherwise. Normality of variables was assessed by the Kolmogorov–Smirnov test. Logarithmic (ln) transformation was used in right-skewed variables if applicable. Changes of the measurements across different time points were tested by the repeated measures ANOVA. Greenhouse-Geisser correctional adjustment was applied if the assumption of sphericity was violated. To explore potential modifying factors, sex was included as a between-subjects factor, while age and EDSS were added as covariates. For variables with a non-normal distribution, Friedman test was performed to assess the changes between different time points. p < 0.05.Based on the data distribution, Pearson  or Spearman's  correlation was used to explore the associations between demographic and clinical variables, cardiovascular parameters and the nadir HR. Decision tree analysis is a powerful statistical tool for prediction, and can effectively subdivide continuous variables into subgroups . One patient underwent an extended monitoring of 2 h due to delayed HR recovery. There was no rebound arrhythmia in the included participants. All the patients' concomitant diseases were in a stable state. Patients with depression were mainly treated by selective serotonin reuptake inhibitors or serotonin norepinephrine reuptake inhibitors. Three patients with hypertension underwent angiotensin-converting enzyme inhibitor monotherapy, one hypertensive patient took Ramipril and hydrochlorothiazide, and the other hypertensive patient took telmisartan and amlodipine. The patients diagnosed with hypothyroidism were treated with L-thyroxin. There was no patient with diabetes mellitus.Three of the recruited patients lacked part of the required time window of continuous ECG monitoring and were excluded for further analyses. Finally, 78 patients with RRMS were included for the analyses. Their demographic and clinical characteristics are shown in Table Post-hoc pairwise comparison did not reveal a significant decrease of systolic blood pressure after medication, while diastolic blood pressure during the third and fifth hour was significantly lower than baseline. Absolute LF power increased after fingolimod initiation, with a significant difference from baseline at the third and fourth hour. Absolute HF power also increased after fingolimod administration, with a significant difference from baseline at the third, fourth, and fifth hour. Sex, age, and EDSS had no significant interaction with the effect of fingolimod in these parameters. Sex had a significant main effect in frequency domain parameters, female patients had a lower relative value of LF power and LF/HF ratio than male patients , and a higher relative value of HF than male patients (p = 0.002; Figure The changes of HR, systolic and diastolic blood pressure, SDNN, pNN50, RMSSD, absolute and relative values of LF and HF powers, and LF/HF ratio were presented in Figures The results of the correlation analyses between nadir HR during the 6 h after fingolimod administration and various demographic, clinical, and cardiovascular parameters are shown in Table In the decision tree analysis, the demographic, clinical, and cardiovascular variables in Table This is the first study which implemented long-term MTRS analysis in successive 1-h-length ECG segments analysis. Our results disclosed the consistent changes of HR and HRV parameters after fingolimod initiation, and indicated that baseline HR was the strongest predictor for nadir HR among various cardiovascular parameters.Because the changes of cardiac parameters after fingolimod intake is a dynamic process over several hours, manually choosing or recording a several-minute-length ECG segment from each hour for analysis might be affected by subjectivity of the selection and inconsistency of the exact position of chosen segments between patients, thus could increase systematic bias. This is also the case for delineating slower alterations such as circadian changes of cardiac autonomic regulation (Parati et al., The present study showed that parameters reflecting parasympathetc function such as RMSSD, pNN50, and HF power increased after fingolimod intake, while HR, LF power and LF/HF ratio decreased after medication. This phenominan can be explained by the vagomimetic effect of fingolimod. During the first several hours after fingolimod administration, this medication activates the S1P G protein-gated potassium channels in the myocytes, which is a vagomimetic effect and similar to the action of acetylcholine on muscarinic receptors (Camm et al., post-hoc multiple pairwise comparisons were not corrected. Since we enrolled a much larger sample size, and used the Bonfferoni correction during pairwise comparisons to avoid false positivities, our results of this concordant change of the above cardiac parameters are more trustworthy.In the present study, heart rate and most of the HRV parameters showed a consistent deviation from baseline since the second hour after fingolimod application. This is incompatible with the study by Simula et al. . In theiHilz et al.  showed tIt is noteworthy that the decrease of SDNN in the first hour after fingolimod intake was not consistent with other parameters in the present study. In the study by Simula et al. , SDNN waThe diastolic blood pressure decreased significantly in the third and fifth hour after fingolimod administration in our study. Previous studies including very large patient samples demonstrated that fingolimod could slightly decrease blood pressure in the first several hours (Camm et al., A previous study showed that pNN50 might predict the HR decrease caused by fingolimod (Simula et al., In the present study, we found that female patients with RRMS had a higher relative value of HF, and a lower relative value of LF and LF/HF ratio than male patients. Thus, the female patients had higher parasympathetic activity compared with the male patients. As far as we know, our study is the first to report this sex difference in RRMS. It has been reported that healthy females had a higher HF, as well as lower LF and LF/HF ratio compared with healthy males. This gender difference in autonomic balance may be attributed to several factors: estrogen, oxytocin, and neuro controls (Koenig and Thayer, Our study has several limitations. Firstly, respiration was not controlled in the study, and the patients' activity was not strictly restricted. Although the patients were generally in a sedentary state and breathed peacefully, physical activity and breathing rate/tidal volume can potentially affect both time and frequency domain HRV parameters, and this could be a confounding factor in the analysis of the effects of fingolimod and gender on the HRV parameters (Yamamoto et al., In conclusion, the present study showed that long-term MTRS was a useful tool for the determination of the dynamic change of HRV. Our findings demonstrated the consistent changes of cardiovascular parasympathetic activity and HR after fingolimod administration. Furthermore, among various demographic, clinical, and cardiovascular parameters, baseline HR was the strongest predictor for nadir HR after fingolimod initiation.Conception and design of the study: TZ, UK, KA. Recruiting the patients and collecting demographic and clinical information: TZ, UK, KA. Acquisition, analysis and interpretation of data: KL, RH, HR, MR. Drafting the manuscript: KL, TZ, all the other authors critically revised the draft and approved the final version.KA received personal compensation from Novartis, Biogen Idec, and Roche for the consulting service. TZ received personal compensation from Biogen Idec, Bayer, Novartis, Sanofi, Teva, and Synthon for the consulting services. TZ received additional financial support for the research activities from Bayer, Biogen Idec, Novartis, Teva, and Sanofi Aventis. UK received travel support by Teva. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Acute kidney injury (AKI) is a serious post-surgery complication; however, few preoperative risk models for AKI have been developed for hypertensive patients undergoing general surgery. Thus, in this study involving a large Chinese cohort, we developed and validated a risk model for surgery-related AKI using preoperative risk factors.This retrospective cohort study included 24,451 hypertensive patients aged ≥18 years who underwent general surgery between 2007 and 2015. The endpoints for AKI classification utilized by the KDIGO  system were assessed. The most discriminative predictor was selected using Fisher scores and was subsequently used to construct a stepwise multivariate logistic regression model, whose performance was evaluated via comparisons with models used in other published works using the net reclassification index (NRI) and integrated discrimination improvement (IDI) index.Surgery-related AKI developed in 1994 hospitalized patients (8.2%). The predictors identified by our Xiang-ya Model were age, gender, eGFR, NLR, pulmonary infection, prothrombin time, thrombin time, hemoglobin, uric acid, serum potassium, serum albumin, total cholesterol, and aspartate amino transferase. The area under the receiver-operating characteristic curve (AUC) for the validation set and cross validation set were 0.87 (95% CI 0.86–0.89) and , respectively, and was therefore similar to the AUC for the training set . The optimal cutoff value was 0.09. Our model outperformed that developed by Kate et al., which exhibited an NRI of 31.38% (95% CI 25.7%-37.1%) and an IDI of 8% (95% CI 5.52%-10.50%) for patients who underwent cardiac surgery (n = 2101).We developed an AKI risk model based on preoperative risk factors and biomarkers that demonstrated good performance when predicting events in a large cohort of hypertensive patients who underwent general surgery. Acute kidney injury (AKI) is a serious post-surgery complication and a strong predictor of various long-term adverse outcomes –6, incluHypertension is a worldwide public health problem affecting billions of people of all races and ethnicities. According to the 2015 Report on the Status of Nutrition and Chronic Diseases in China , approxiA few risk prediction models have been used to identify high-risk individuals and thus improve patient prognoses through aggressive interventions; however, no preoperative risk models for AKI have been developed for hypertensive patients undergoing general surgery. Thus, in this study, we analyzed preoperative risk factors in a large cohort of hypertensive patients and developed and validated a risk model for surgery-related AKI.rd Xiangya Hospital , which serves as the sole portal for clinical data entry for all public inpatient settings across different regions of China and provides the complete patient health record information, including information regarding age, sex, race, body mass index (BMI), blood pressure (BP), hospital service type , International Classification of Disease (ICD-10) clinical diagnosis, surgery date, surgical sites, and laboratory data. Information regarding comorbidities, including cardiovascular risk factors and medical conditions, such as “pulmonary infection”, “chronic kidney disease”, “diabetes” or “impaired glucose tolerance”, “malignant tumor”, “viral hepatitis”, and “heart failure”, was extracted from the system using ICD-10 codes. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki, and the provision of informed consent was not necessary because all patients were anonymized. The Institutional Review Board of Third Xiangya Hospital approved this study  of the 3Patients who underwent only one elective surgery during hospitalization and had a discharge diagnosis of “hypertension” between October 2007 and June 2015 were considered potential candidates  for inclusion in this study. All candidates were adults (aged ≥18 years). Patients with missing data regarding age and pre- or postoperative blood creatinine levels (n = 5087) were excluded. Thus, 24,451 eligible patients were randomly classified into either a derivation dataset  or a validation dataset .All included patients were followed up until the development of surgery-related AKI was confirmed based on the KDIGO  AKI classification system  (a serumThe estimated glomerular filtration rate (eGFR) was derived from the serum creatinine nadir recorded during hospitalization using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation . AdditioAll covariates were included to compute Fisher scores to identify prognostic factors, and less significant clinical or statistical variables were subsequently excluded one by one during the model-building process. Several candidate models were developed thereafter and compared with respect to their ability to predict AKI using stepwise multivariate logistic regression. Variation inflation factors (VIF) were computed to detect multicollinearity between selected variables, and multicollinearity was determined to be present in cases in which these factors were ≥5. Variables could be evaluated on the basis of subject knowledge. The likelihood-ratio chi-square test was used to examine the linearity assumption for the predictors used in the multivariable model. Akaike information criterion (AIC) values were also determined after fitting several candidate markers. Over-fitting was assessed using cross validation error and training error, although over-fitting may not have been present in this large cohort. A model was considered over-fitted if the training error was far greater than the validation error, and the value of the training error was small.mean, receiver operating characteristic (ROC) curves, and areas under the ROC curve (AUC) were calculated to evaluate the performance of the model developed based on the imbalanced data. In a two-class problem, the confusion matrix has two rows and two columns specifying the number of false positives (FPs), false negatives (FNs), true positives (TPs), and true negatives (TNs), and the above measures are defined as follows: Sensitivity = TP/(TP + FN), Specificity = TN/(TN + FP), Youden index = Sensitivit + Specificity − 1, and Sensitivity, specificity, Youden's index, GPredicted probabilities were calculated using published equations, and the net reclassification index (NRI) and integrated discrimination improvement (IDI) were estimated to compare the performances of the new models to those of previously published models. A systematic literature search of Medline (1950-) was performed in February 2016 by professional document retrieval personnel from the Xiang-Ya Medical Library of Central South University using the following search terms: ‘predict’, ‘forecast’, ‘surgery’, ‘operation’, ‘forecasting’, ‘acute kidney injury’, and ‘Surgical Procedures, Operative’, and the reference lists of relevant papers were subsequently reviewed. There were no language restrictions. Studies were included if they utilized a model for predicting adult (≥18 years old) AKI based on the KDIGO  AKI classification system after any type of surgery was performed and reported outcomes using scoring systems or algorithms. Studies were also included if they reported external validation of a primary risk model. However, studies were excluded if their model was not performed clearly enough to be used in a clinical setting or if the utilized models including intraoperative or pro-operative variables, models predicting AKI requiring dialysis and models predicting AKI independent of the need for dialysis. Unpublished conference abstracts were also excluded.All analyses were performed using IBM SPSS version 22.0  and SAS version 9.3 . Continuous variables were presented as the mean ± standard deviation (SD) or as the median and interquartile range (IQR) when the data exhibited a skewed distribution. Analysis of variance (ANOVA) or post-hoc analysis of the least significant difference (LSD) were used to compare means between normally distributed continuous variables; otherwise, the Kruskal-Wallis test was used. Categorical variables were expressed as proportions and tested using chi-squared tests. P values of 0.05 (two-tailed) were established as the threshold for statistical significance.2, 137.95±19.70 mmHg, 80.88±12.22 mmHg, and 77.80±32.28 mL/min/1.73 m2, respectively, and CKD, diabetes mellitus, heart failure, pulmonary infection, and respiratory failure were observed in 23.0%, 20.4%, 12.0%, 10.4%, and 0.6% of patients, respectively, before surgery.Surgery-related AKI developed in 1994 hospitalized patients (8.2%). The baseline characteristics of the study population are shown in Sixty-six potential variables were evaluated in the training set used for model inclusion, and variable significance scores were computed using Fisher’s linear discriminant analysis method. The top 31 variables with weights greater than 0.99 were selected . eGFR haThe validation set consisted of 7362 hypertensive patients who underwent surgery, 598 of whom developed AKI. The AUC for the validation set was 0.87 (95% CI 0.86–0.89), which was similar to the AUC for the training set  . Cross vA total of 1550 studies were identified and screened, and we identified 18 relevant articles  containiAKI is a serious and frequent post-surgery complication, and many factors are associated with the risk of AKI development. A common feature of a larger number of the processes causing AKI is a reduction in regional renal oxygen delivery, leading to inflammation, ischemia and necrosis . HyperteAlthough the addition of intra- and early postoperative information substantially improved our ability to predict AKI, preoperative risk stratification tools would allow the identification of high-risk patients and enable prevention strategies to be implemented earlier, thereby improving quality of care, patient management, and resource allocation. Hence, it is essential to evaluate and predict AKI before surgery in hypertensive patients.We selected and analyzed 24,451 hypertensive patients to develop a risk prediction model for surgery-related AKI. The main findings of this study are as follows: (1) hypertensive patients who underwent general surgery exhibited a high incidence of postoperative AKI (8.2%); (2) preoperative renal function was the factor most strongly associated with AKI; and (3) our model, which was based on thirteen preoperative risk factors and biomarkers, feasibly predicted AKI in hypertensive patients who underwent general surgery.rd Xiangya Hospital, which serves as the sole portal for clinical data entry for all public inpatient settings across different regions of China and provides quality-controlled and reliable data. Another strength of our study was that it focused on all types of operations and nonetheless achieved better discriminatory ability in patients undergoing cardiac surgery. Most other AKI risk prediction models have not been adequately tested in this population. Furthermore, we applied a well-established KDIGO definition to enhance the applicability of this model for other studies, as well as the comparability of its data with those from other studies. We identified only one existing risk prediction tool [2, as well as other definitions based on various absolute or relative increases in serum creatinine concentrations.One strength of our study was that AKI events could be detected using the structured HIS of the 3ion tool  that preThe important covariates in our prediction model were age, gender, eGFR, NLR, pulmonary infection, PT, TT, hemoglobin, uric acid, serum potassium, serum albumin, total cholesterol, and AST. To increase the predictive ability of our model, we adopted continuous variables as often as possible rather than defining cutoffs. The incorporated data indicated that the overall renal function and the general condition  of the patient were predictive of AKI events. It is not surprising that age and hypercholesterolemia were risk factors identified in our model because they have a remarkable effect on the arterial system and markedly increases the risk of cardiovascular events, such as atherosclerosis, stroke, and myocardial infarction. In addition, the NLR (an inflammatory marker) and preoperative pulmonary infection were independently significantly associated with AKI in our model. These variables are considered markers of sepsis, which is the leading cause of AKI in clinical practice, and can be controlled before elective surgery ,41. ThesThe optimal cutoff value was 0.09, indicating that 34.29%  of participants with a score >0.09 were diagnosed with AKI, whereas 97.84%  of participants with a score <0.09 were not diagnosed with AKI. From a clinical point of view, however, the cutoff value should be chosen according to prevention strategies.2, hypertensive patients had a higher risk of AKI at than those without hypertension. However, hypertension has little impact on the risk of AKI when eGFRs<60 mL/min/1.73 m2 [The potential limitations of our study should be mentioned. First, this study was conducted in a single center and may therefore be weaker in methodology than studies using randomly sampled populations. Second, the patients in our study who developed AKI were not classified according to AKI severity . Third, although predictable intraoperative variables  and novel biomarkers, such as microRNAs , urine n/1.73 m2 . TherefoIn summary, we developed an AKI risk model based on preoperative risk factors and biomarkers and demonstrated that it provides an acceptable level of performance for predicting events in a large cohort of hypertensive patients who underwent general surgery. However, the applicability of this proposed risk model should be evaluated in additional studies.S1 FigCKD, chronic kidney disease; DM, diabetes mellitus; HF, heart failure; HTN, hypertension; PVD, peripheral vascular disease.(EPS)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S1 Text(PDF)Click here for additional data file.S2 Text(PDF)Click here for additional data file.


The factors influencing three major outcomes–death, stroke/systemic embolism (SE), and major bleeding–have not been investigated in a large international cohort of unselected patients with newly diagnosed atrial fibrillation (AF).2DS2-VASc score was 3.0 (2.0 to 4.0); 63.3% of patients were on anticoagulants (ACs) with or without antiplatelet (AP) therapy, 24.5% AP monotherapy, and 12.2% no antithrombotic therapy. At 2 years, rates (95% CI) of death, stroke/SE, and major bleeding were 3.84 , 1.27 , and 0.71  per 100 person-years. Age, history of stroke/SE, vascular disease (VascD), and chronic kidney disease (CKD) were associated with the risks of all three outcomes. Congestive heart failure (CHF) was associated with the risks of death and stroke/SE. Smoking, non-paroxysmal forms of AF, and history of bleeding were associated with the risk of death, female sex and heavy drinking with the risk of stroke/SE. Asian race was associated with lower risks of death and major bleeding versus other races. AC treatment was associated with 30% and 28% lower risks of death and stroke/SE, respectively, compared with no AC treatment. Rates of prescription of guideline-recommended drugs were suboptimal in patients with CHF, VascD, or CKD.In 28,628 patients prospectively enrolled in the GARFIELD-AF registry with 2-year follow-up, we aimed at analysing: (1) the variables influencing outcomes; (2) the extent of implementation of guideline-recommended therapies in comorbidities that strongly affect outcomes. Median (IQR) age was 71.0 (63.0 to 78.0) years, 44.4% of patients were female, median (IQR) CHAOur data show that several variables are associated with the risk of one or more outcomes, in terms of death, stroke/SE, and major bleeding. Comprehensive management of AF should encompass, besides anticoagulation, improved implementation of guideline-recommended therapies for comorbidities strongly associated with outcomes, namely CHF, VascD, and CKD.NCT01090362ClinicalTrials.gov  Atrial fibrillation (AF), the most frequent of all sustained cardiac arrhythmias, is associated with increased risk of death, stroke/systemic embolism (SE), and bleeding. Currently recommended management approaches include rhythm and/or rate control, and anticoagulation for the prevention of stroke/SE in at-risk patients without contraindication , 2. We pIn this report, we analyse at 2-year follow-up the outcomes of 28,628 patients with newly diagnosed AF recruited in the first three cohorts of GARFIELD-AF, with two objectives. The primary objective was to identify the variables associated with the risks of all three major outcome measures, namely death, stroke/SE and bleeding, particularly those linked to modifiable risk factors. The secondary objective was to assess compliance with guidelines as regards drug prescription in comorbidities identified to strongly affect outcomes, namely congestive heart failure (CHF), vascular disease (VascD), and chronic kidney disease (CKD) –6.The design of the GARFIELD-AF registry was reported previously , 8. BriePatients were enrolled prospectively and consecutively. Investigator sites were selected randomly (apart from 18 sites) and represent the different care settings in each participating country  , 8.Independent ethics committee and hospital-based institutional review board approvals were obtained. A list of central ethics committees and regulatory authorities that provided approval can be found in S2 File. Additional approvals were obtained from individual study sites. The registry is being conducted in accordance with the principles of the Declaration of Helsinki, local regulatory requirements, and the International Conference on Harmonisation–Good Pharmacoepidemiological and Clinical Practice guidelines. Written informed consent is obtained from all study participants. Confidentiality and anonymity of all patients recruited into this registry are maintained.2DS2-VASc and HAS-BLED risk stratification schemes were collected to assess the risks of stroke and bleeding retrospectively. HAS-BLED scores were calculated excluding fluctuations in international normalised ratio.Baseline characteristics collected at inclusion in the registry included medical history, care setting, type of AF, date and method of diagnosis, symptoms, antithrombotic treatment , as well as all cardiovascular drugs. Race was classified by the investigator in agreement with the patient . Data onCollection of follow-up data occurred at 4-monthly intervals up to 24 months , 8. StanData for the analysis in this report were extracted from the study database on 28 July 2016.VascD included peripheral artery disease or coronary artery disease with a history of acute coronary syndromes (ACS). CKD was classified according to National Kidney Foundation guidelines into two groups: moderate-to-severe (stages 3–5), or mild (stages 1 and 2) or none . CHF wasGuideline-recommended therapies included angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), betablockers, aldosterone blockade, and loop diuretics for CHF; aspirin (ASA), statins, ACE inhibitors/ARBs, and betablockers for VascD; and ACE inhibitors/ARBs for CKD.Continuous variables are expressed as median  and categorical variables as frequency and percentage. Baseline rates of prescription of guideline-recommended drugs in CHF, VascD, and CKD are displayed with the baseline rate of prescription of anticoagulants (ACs).Differences in medians were tested using the Wilcoxon rank-sum (Mann-Whitney) test. Differences in proportions were tested using the two-sample test of proportion. Trends were assessed using an extension of the Wilcoxon rank-sum test.Occurrence of major clinical outcomes is expressed as person-time event rates (per 100 person-years) and 95% confidence intervals (CIs). Person-year rates were estimated using a Poisson model with the number of events as the dependent variable and the log of time as an offset, i.e., a covariate with a known coefficient of 1. Only the first occurrence of events was taken into account. Hazard ratios (HRs) and 95% CIs were estimated using a proportional hazards Cox model based on five imputed datasets. The imputed datasets were created by the Multiple Imputation by Chained Equations (MICE) algorithm . The proData analysis was performed with SAS version 9.4  and Stata Statistical Software: Release 14.2 . Forest plots were created in R 3.3.1 .2DS2-VASc and HAS-BLED scores were 3.0 (2.0 to 4.0) and 1.0 (1.0 to 2.0), respectively. Other baseline characteristics are shown in The study population comprised 28,628 prospective patients with AF enrolled in GARFIELD-AF between March 2010 and October 2014 and followed for 2 years. Patients came from 1048 study sites representative of routine practice in each of 32 countries. Two-year follow-up was achieved in 91% of patients. At baseline, the median (IQR) age was 71.0 (63.0 to 78.0) years and 44.4% of patients were female. The median (IQR) CHAIn patients with CHF, the rates of prescription of guideline-recommended therapies were no drug in 11.7%, one drug in 25.1%, two drugs in 33.6%, three drugs in 23.3%, and four drugs in 6.4% of patients . These fIn patients with VascD, the rates of prescription of guideline-recommended therapies were no drug in 6.0%, one drug in 17.0%, two drugs in 28.9%, three drugs in 31.7%, and four drugs in 16.4% .Details about guideline-recommended drugs for both CHF and VascD are in Of the patients with CKD, 36.1% were prescribed ACE inhibitors/ARBs, drugs that may slow the rate of kidney function deterioration.During 2-year follow-up, the rates 95% CI) of all-cause mortality, stroke/SE, and major bleeding (first occurrences) were 3.84 , 1.27 , and 0.71  per 100 person-years, respectively . Cardiov% CI of aOf the strokes occurring during follow-up, 70.6% were primary ischaemic, 10.6% were primary intracerebral haemorrhages, and 18.9% were undetermined . BleedinThe rates (95% CI) of myocardial infarction/ACS and of new onset or worsening of CHF during follow-up were 0.68  and 1.96  per 100 person-years, respectively .After adjustment, the following baseline variables were found to be significantly associated with a higher risk of death: age, ‘other race’ (vs Caucasian/Hispanic/Latino), smoking, diabetes mellitus, history of stroke/TIA/SE, history of bleeding, cardiac failure, VascD, moderate-to-severe renal disease, and non-paroxysmal forms of AF . The varAsians had significantly lower risks of death and major bleeding compared with Caucasian/Hispanic/Latino patients, but they also had a lower rate of comorbidities, particularly CKD , and a significantly lower age . AC treatment was associated with lower risks of death and stroke/SE and a higher risk of major bleeding. History of hypertension and pattern of AF were not associated with a higher risk of stroke/SE.2DS2-VASc scoring scheme . This subset of patients had a higher risk of stroke/SE but not of death or bleeding compared to patients without high blood pressure .AC was associated with substantially lower risks of all-cause death (30% lower risk in AC patients compared with non-AC patients) and stroke/SE (28% lower risk in patients receiving AC compared with those not receiving AC), and with a 52% higher risk of bleeding compared with no AC treatment. Reduction in mortality in association with anticoagulation may have been due, in part, to prevention of thromboembolism in patients with CHF, sepsis, respiratory failure, or cancer [2DS2-VASc score. In addition, in some Asian countries, physicians routinely target a lower INR than in other regions, resulting in a significantly lower risk of bleeding compared with non-Asian patients, yet with no excess risk of stroke/SE [In contrast, Asian race was associated with lower risks of death and bleeding, without an excess of stroke/SE compared with non-Asian races. Conflicting observations were previously reported on this issue with the risks of death, stroke/SE, and bleeding found to be identical or higher in Asians compared to non-Asians , 28. In troke/SE , 30.2DS2-VASc and HAS-BLED. Biomarker-based scores like the recently described ABC score [Overall, two messages arise from this report. Firstly, several variables are linked to the risk of one or more outcome measures. So far, the therapeutic approach recommended for the management of AF emphasises rhythm and/or rate control and anticoagulation administered in at-risk patients without contraindication. The decision for treatment is based on clinical judgment and assessment of the risks of stroke/SE and bleeding using clinical risk scores, most commonly CHABC score  cannot bSecondly, this study shows that the comorbidities that strongly affect outcomes are undertreated in at least one-third of patients with newly diagnosed AF. All comorbidities shown to have an impact on outcomes should be addressed. In this regard, aggressive management of CHF, CKD, and VascD and their risk factors, as well as smoking and drinking cessation, should be strongly advocated. Strikingly, patients with comorbidities associated with the risk of two or all three outcome measures, namely CHF, VascD, and CKD, are undertreated if we consider the rates of prescription of guideline-recommended therapies. In patients with CHF, depending on the New York Heart Association (NYHA) class, up to four drugs may be needed . Our datWe focused on three variables only when assessing the prescription rates of guideline-recommended therapies. We cannot assume that our observations are valid for other variables. We did not differentiate between CHF with preserved or reduced ejection fraction. In addition, the collection of data on drug prescriptions in patients with CHF, VascD, and CKD may be suboptimal since GARFIELD-AF is a study on patients with AF, and not specifically on these entities.Death is the most frequent adverse event in newly diagnosed AF, occurring at threefold the rate of stroke/SE and fivefold the rate of major bleeding. Many modifiable variables have an influence on the risk of one or more major outcome measures, particularly CHF, VascD, and CKD, whose management seems suboptimal as regards the prescription of guideline-recommended drugs in routine practice. Based upon these observations, we advocate for comprehensive management of newly diagnosed AF, particularly the implementation of guideline-recommended therapies in CHF, VascD, and CKD, in addition to anticoagulation. Registries like GARFIELD-AF may help to elucidate the causes of under treatment and to assess the impact on outcomes of aggressive management of the most influential comorbidities.S1 Appendix(DOCX)Click here for additional data file.S2 Appendix(XLSX)Click here for additional data file.


Asthma patients are enrolled in multimodal pulmonary rehabilitation (PR) programs. However, available data for the effectiveness of PR in asthma are sparse. Therefore, the primary aim of this randomized control trial (RCT) is to evaluate short-term (end of rehabilitation) and intermediate-term effectiveness (3 months after rehabilitation) of PR for patients with asthma regarding asthma control (primary outcome) and other outcomes. Secondly, moderator effects of gender, age, baseline asthma control, quality of life, and anxiety will be examined. Thirdly, a longitudinal follow-up study will explore the course of the outcomes over one year and the annual costs.The EPRA study is a single-center randomized controlled waiting-list trial in the Bad Reichenhall Clinic. Inclusion criteria include a referral diagnosis for uncontrolled asthma, no cognitive impairment and no very severe co-morbidities that indicate significantly greater illness morbidity than asthma alone. In the intervention group (IG), participants will start PR within 4 weeks after randomization; participants of the control group (CG) will start PR 20 weeks after randomization. Data will be assessed at randomization (T0), after 4 weeks , 7 weeks , and 20 weeks . The primary outcome is asthma control at T2/T3. Secondary outcomes are health-related quality of life, functional exercise capacity, dyspnea, anxiety, depression, subjective self-management skills, illness perceptions, sick leave and subjective work ability. Outcomes will be analyzed with analysis of covariance, including baseline values of the respective outcomes as covariates. Healthcare costs will be analyzed with a gamma model with a log-link.A longitudinal follow-up study will generate additional data at 3/6/9/12 months after PR for both IG and CG. Latent change models will be used to analyze the course of the primary and secondary outcomes. Annual cost differences before and after rehabilitation will be compared by paired t-test.This RCT will determine the effectiveness of a complex inpatient PR for asthma patients concerning asthma control. Furthermore, important medical and economic information regarding the effectiveness of PR as part of the long-term management of patients with uncontrolled asthma will be generated.DRKS00007740, May 15, 2015). Protocol version: 1.0 .German Clinical Trials Register ( Asthma is one of the most common chronic diseases worldwide with an estimated 300 million affected individuals . Asthma Pulmonary rehabilitation (PR) is widely accepted as an effective treatment for patients with chronic respiratory diseases, especially for chronic obstructive pulmonary disease (COPD) . In EuroHowever, the effectiveness of the essential individual components of PR, such as patient education , 10, resBesides the two RCTs , 8, a liThis lack of evidence is of particular relevance since asthma is a common indication for PR in Europe and in the US , and is The primary aim of this RCT is to evaluate the effectiveness of PR for patients with asthma on short (end of rehabilitation) and intermediate-term (3 months after rehabilitation) outcomes as compared to a waiting-list control group. We hypothesize that pulmonary inpatient rehabilitation is superior regarding mean change in AC at 3 months after rehabilitation (primary outcome). Furthermore, we expect superior effectiveness of the pulmonary rehabilitation regarding health related quality of life (HRQoL), functional exercise capacity, dyspnea, anxiety, depression, subjective self-management skills, illness perceptions, sick leave, as well as subjective work ability (secondary outcomes). In addition, moderator effects of (a) gender, (b) age, (c) baseline AC, (d) baseline HRQoL and (e) baseline anxiety will be examined. Moreover, in a longitudinal follow-up study, the course of primary and secondary outcomes over one year and the annual costs before and after rehabilitation will be explored.We use a two part-study design, combining a randomized controlled trial (RCT) and a longitudinal follow-up design.The main study is a randomized control superiority trial, comparing the intervention group (IG) with a waiting-list control group (CG). For legal reasons, any insurant of the statutory German Pension Insurance (GPI) whose application for medical rehabilitation was approved by the GPI will receive a rehabilitative intervention. Therefore, it is not possible to use an entirely untreated CG, but a waiting-list CG can be realized. After inpatient rehabilitation in the Bad Reichenhall Clinic has been approved by the GPI, patients receive a letter informing about the study and screening for their eligibility. If no response is received within 14 days, a reminder will be sent to the patients. If patients meet the inclusion criteria, they are asked to participate. After consent has been obtained, participants will be randomized to the IG or CG. In the IG, participants will start inpatient rehabilitation within 4 weeks after randomization. Data will be assessed at randomization (T0), at the beginning (T1), the end (T2), and three months after inpatient rehabilitation (T3). The CG will start inpatient rehabilitation five months (i.e. 20 weeks) after randomization. CG data will be assessed at randomization (T0), at four weeks (T1), at seven weeks (T2) and at 20 weeks  after randomization. The crucial reference intervals for the primary research questions are T0 to T2 and T0 to T3 for both IG and the CG. Since CG starts PR 19 to 20 weeks after T0, which is 3 months after the discharge time-point of IG, it will be possible to compare the results of IG with those of the (still) untreated CG during these initial 19 to 20 weeks. However, it may be possible that for the CG, arrival at the rehabilitation clinic (at T3) already has an effect on several outcome parameters. To estimate this “arrival effect”, an additional measurement time point (T3a) for the CG at 10 (+/-3) days before T3 has been included.The second part of the study is a longitudinal cohort study. In addition to the data collected in the first part of the study (RCT), data at 6, 9 and 12 months after inpatient rehabilitation in the IG and data at the end of and at 3, 6, 9 and 12 months after inpatient rehabilitation in the CG will be collected. Longitudinal data from both groups will be combined to one sample. Fig. Patients are eligible for the study if they are approved for PR, have a physician diagnosis of asthma ICD-10: J45) at T0 and have uncontrolled asthma based on an Asthma Control Test (ACT) <20 0: J45 at, 30. PatParticipants will be recruited consecutively. All patients meeting the inclusion criteria and providing informed consent are randomly assigned to the IG or CG by a study nurse at the time of their PR approval. Randomization will be stratified according to age. The randomization list (with computer-generated random numbers) is created by the Department of Medical Psychology and Psychotherapy, Medical Sociology and Rehabilitation Sciences at the University of Würzburg .Patients themselves cannot be blinded due to the time-point of the start of their inpatient rehabilitation. However, those who deliver the rehabilitation treatment are unaware whether the patient is a study participant, a participant of the IG or the CG, or a regular inpatient outside the study.Calculation of sample size is based on our primary outcome, the ACT, assessed three months after the inpatient rehabilitation. A previous longitudinal study of asthma patients in the Bad Reichenhall Clinic (without a CG) showed changes between start of inpatient rehabilitation and three months after inpatient rehabilitation of (Cohen’s) d > 0.5 . HoweverLatent curve models will be used to analyze the course of the primary outcome in the longitudinal follow-up study. As a rule of thumb, N > 100 cases should be included in the computation of these models. Even with a conservatively estimated drop-out rate of 50% until T6 for IG and T8 for CG, N = 152 patients would remain in the study, which is sufficient.As shown in Fig. Physical training (O) consisting of three obligatory components: a) endurance training scheduled for 5 units per week for 45–60 min each, during which outdoor sports and training in water  are performed. Exercise intensity is controlled by BORG Scale and heart rate; b) strength training scheduled for 3 sessions per week of 45–60 min each and c) whole-body vibration-training scheduled 7 times per week. In addition, inspiratory muscle training (F) is provided for patients with inspiratory muscle weakness and is scheduled for 7 sessions per week, each for 21 min, of which 2 per week are supervised.Comprehensive patient education (O) consisting of two obligatory components: a.) patient education regarding asthma for one week with 7 units of 45 min; b.) one session of practical medical inhalation training and/or peak flow meter use for 60 min. In addition, patients also receive allergy awareness and trigger avoidance training (F) if required (one 60-min session).Respiratory physiotherapy (O) consisting of 3 units of group respiratory physiotherapy per week with learning of pursed lips breathing (O) for 45 min each. If necessary, patients may also receive the following optional components (F) including: a) individual breathing training by physiotherapists; b) training of Buteyko breathing techniques  for patiPsychosocial support (F) such as social counseling, individual psychological counseling and/or group therapy will be offered if necessary  > 9 points, Generalized Anxiety Questionnaire (GAD-7) > 9 points or if indicated by their physicians).Comprehensive smoking cessation program (F) will be offered to all smokers.Comprehensive nutritional counseling (F) will be offered to patients with food intolerance or allergies or over- and underweight.The rehabilitation program includes the following non-drug therapy components :In addition, patients will receive a routine check-up and if necessary, current asthma medications will be optimized according to the current guidelines. This is an obligatory part of the rehabilitation in Germany. Any changes to medications will be documented. Adverse events and complications during rehabilitation are recorded by the physicians on a standardized basis in the medical survey sheet at the end of rehabilitation.The primary outcome is the mean change in AC, assessed by ACT. Secondary outcomes include mean changes in HRQoL, 6-min walk distance (6-MWD) and Sit-to-stand-test, lung function parameters, Eosinophils, dyspnea, depression, anxiety, smoking habits, illness representations, self-management skills, work ability, subjective prognosis of return to work, sick leave, medication beliefs and medication adherence. Measurement instruments for all outcomes and measurement occasions can be found in Table Asthma Control will be assessed by using the Asthma Control Test (ACT) , 33. TheSymptoms, Activity and Impacts as well as a Total scale. All scales are computed by weighted sums of the respective items. The scores range from 0 (no impairment) to 100 (maximum impairment). A minimal important difference (MID) of 4 is established for COPD, a MID for asthma has not been reported up to now. The standardized version Asthma Quality of Life Questionnaire (AQLQ) contains 32 questions to capture the four domains Symptoms, Activity limitation, Emotional function and Environmental stimuli to measure the functional problems that are most troublesome to adults with asthma. The survey period covers the past 2 weeks. Each question is answered on a 7-point scale . The overall AQLQ score is the mean of all 32 responses and the individual domain scores are the means of the items from those domains.Asthma specific HRQoL will be assessed by both, the Saint George’s Respiratory Questionnaire (SGRQ)  and the Generic HRQoL of patients is measured using the Euroqol questionnaire (EQ-5D-5L) and the EQ visual analogue scale (VAS). The EQ-5D-5L  is a staGlobal rating of change (GRC)  in subjeSeverity of dyspnea, cough, sputum and pain will be assessed with response to seven 11-point numeric rating scales . Scale vThe Brief Fatigue Inventory (BFI) will be used to measure fatigue. This short questionnaire assesses severity of and impairment from fatigue with ten questions. The subscales and the total score range from 0 to 10, with higher values indicating higher severity/impairment. A German version exists and has been proven reliable and valid .The PHQ-9 and the GAD-7 will be used to assess depression  and anxiillness representations   will be Skill and technique acquisition scale from the Health Education Impact Questionnaire . ThNecessity assesses patients’ beliefs about the necessity of prescribed instruments and the scale Concern assesses patients’ concerns about prescribed medications. Both scales range from 5 to 25 points with higher values indicating higher belief of necessity/higher concerns.Patients will complete the Medication Adherence Report Scale (MARS-D) . This is1), vital capacity (VC), residual volume (RV) and total specific resistance (SRtot) are determined using spirometry and body plethysmography  before and after bronchodilation with a short-acting bronchodilator in accordance with recommendations of the national guidelines   66] & SAAsthma is one of the most common chronic diseases worldwide with an estimated 300 million affected individuals . AlthougThe findings of this study will be published in peer-reviewed journals and conference presentations.


Circulation, we assessed the association of day-to-day BPV on a home blood pressure basis with the risk of dementia in a prospective study of an elderly Japanese population [Dementia has become a worldwide public health and social care priority, as the number of patients with dementia has been rising mainly due to aging of population . Blood ppulation .In this study, a total of 1,674 community-dwelling Japanese elderly without dementia, aged 60 years or older, were followed up for 5 years (2007 to 2012). All participants measured their blood pressure in the morning for a median of 28 days  using a validated digital electronic blood pressure device. Day-to-day systolic (SBP) and diastolic blood pressure (DBP) variabilities were defined with the coefficients of variation (CoV), calculated as the standard deviation of the mean blood pressure divided by the mean blood pressure times 100, and were categorized into quartiles. Dementia diagnoses were adjudicated by expert stroke physicians and psychiatrists and were based on rigorous evaluation of clinical information, neuroimaging, and autopsy findings. During the 5-year follow-up period, 194 patients developed all-cause dementia, of whom 47 had vascular dementia (VaD) and 134 had Alzheimer’s disease (AD).P for trend <0.05). These associations remained significant even after adjustment for potential confounding factors, including mean home SBP values. Compared with subjects in the first quartile of CoV levels of home SBP, the risks of all-cause dementia, VaD, and AD increased significantly in those in the fourth quartile . Similar associations were observed for CoV levels of home DBP. When dividing the subjects into 4 groups according to the status of hypertension based on home SBP values and the CoV values of home SBP, both higher day-to-day BPV and home SBP values were significantly associated with the risk of VaD, whereas the risk of AD increased significantly in subjects with higher BPV irrespective of the home SBP values. There was no interaction between home SBP levels and CoV levels of home SBP on the risk of each subtype of dementia.The age- and sex-adjusted incidences of all-cause dementia, VaD, and AD increased significantly with increasing CoV levels of home SBP (all Previous observational studies have demonstrated a significant association between cognitive decline and long-term BPV, mainly assessed by monthly or yearly blood pressure measurements in the office -5, and oBPV has been known to promote oxidative stress, endothelial injury, impairment of vascular smooth muscle function, and vascular stiffening . TherefoThe novel finding of this study is that increased day-to-day blood pressure variability, independent of average home blood pressure, is a significant risk factor for the development of dementia, suggesting that measurement of day-to-day BPV on a home blood pressure basis may be useful for assessing future risk of dementia. If this finding were to be confirmed in clinical trials or larger cohort studies, BPV modification could become an effective medical strategy to reduce the burden of dementia.


Disruption of motor and autonomic pathways induced by spinal cord injury (SCI) often leads to persistent low arterial blood pressure and orthostatic intolerance. Spinal cord epidural stimulation (scES) has been shown to enable independent standing and voluntary movement in individuals with clinically motor complete SCI. In this study, we addressed whether scES configured to activate motor lumbosacral networks can also modulate arterial blood pressure by assessing continuous, beat-by-beat blood pressure and lower extremity electromyography during supine and standing in seven individuals with C5-T4 SCI. In three research participants with arterial hypotension, orthostatic intolerance, and low levels of circulating catecholamines (group 1), scES applied while supine and standing resulted in increased arterial blood pressure. In four research participants without evidence of arterial hypotension or orthostatic intolerance and normative circulating catecholamines (group 2), scES did not induce significant increases in arterial blood pressure. During scES, there were no significant differences in electromyographic (EMG) activity between group 1 and group 2. In group 1, during standing assisted by scES, blood pressure was maintained at 119/72 ± 7/14 mmHg (mean ± SD) compared with 70/45 ± 5/7 mmHg without scES. In group 2 there were no arterial blood pressure changes during standing with or without scES. These findings demonstrate that scES configured to facilitate motor function can acutely increase arterial blood pressure in individuals with SCI-induced cardiovascular deficits. Spinal cord injury (SCI) can be catastrophic with significant health and financial implications for patients, their families, and society  at the lumbosacral level enabled four individuals with chronic, motor complete SCI to stand and generate voluntary movement in their lower limbs , the neurological level and completeness of the spinal cord lesion were determined using the American Spinal Cord Injury Association Impairment Scale (AIS)  in combination with a 16-electrode array  were implanted at the T11-L1 vertebral levels over the spinal cord segments L1-S1 as previously described  laboratory. Participants were instructed to avoid caffeine, alcohol, and high-fat foods for 12 h prior to their examination. Beat-to-beat blood pressure from a finger cuff , calibrated to brachial blood pressure measurements   were recorded continuously, as previously described, while the individual was supine or standing over ground  software. The locations of the R waves in the ECG were identified to construct beat-to-beat heart rate and RR interval time series. The maximum and minimum values of blood pressure between two RR intervals were computed as beat-by-beat sampled systolic and diastolic blood pressure. Group hemodynamic variables (mean ± SD) during orthostatic stress test were calculated for 1-min intervals in the sitting position. Values obtained in the seated position were compared with the last 5 min of supine by calculating the difference. Data recorded during the initial 15 s of the sitting position were excluded from analysis because of movement artifacts. In supine experiments, means of blood pressure and heart rate data were calculated for periods during each 1 V increment; data are reported as percentage-change from baseline to normalize hemodynamic response to stimulation between participants. During standing experiments, blood pressure and heart rate were obtained continuously. Blood pressure and heart rate were averaged during sitting and standing during 3 consecutive minutes.EMG amplitude of motor evoked responses to rostral and caudal scES was quantified by peak to peak amplitude  included factors accounting for group and time (the primary covariate). The models of EMG activity investigated differences in EMG activity between groups during the supine experiment. Stimulation voltage was the primary covariate, with factors accounting for configuration  and group  with an interaction between them. Smoothing spline functions were included in each model, defined as functions of the primary covariate . We used a two-way, repeated measures ANOVA to test for significant between-group differences in blood pressure with and without scES, and catecholamines at rest and in response to orthostatic stress. For each model, an interaction between group and position was included. The models were fit using the open-source R software environment . Significance was set to α < 0.05.p < 0.001), diastolic blood pressure (p < 0.001), and heart rate (p < 0.01) during the orthostatic stress test  lower circulating catecholamines : regardless of configuration of the electrode array, each muscle demonstrated a gradual increase in EMG activity with increasing stimulator voltage  on cardiovascular outcomes are needed. Better understanding the mechanism of action may lead to development of scES into a therapeutic strategy for management of unstable blood pressure in persons with SCI.The concept and design of this study were developed by SH, AK, CA, SA, and YC. SA, BL, MP, CA, AO, AK, and SH were involved in data acquisition, analysis, and interpretation. The manuscript draft written by SA, BL, MP, AO, and SH was critically revised by all authors.MP has the following financial relationships to disclose: (1) Listed faculty for University of Minnesota Educational Partnership with Medtronic Inc., Minneapolis, MN, (2) Grant/Research support from: Medtronic Inc., Boston Scientific, Advanced Neuromodulation Systems, Inc.,—St. Jude Medical, St. Jude Medical. SH has the following financial relationships to disclose: (1) NeuroRecovery Education and PowerNeuroRecovery. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.