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Background: Probabilistic causality (PC) is a framework for checking that the occurrence of a cause raises the probability of the effect by comparing the probability of the effect conditioned and unconditioned to the cause. Even though it is less frequently utilized with respect to the more traditional model-based Wiener-Granger causality (WGC) that is based on the predictability improvement of an effect resulting from the inclusion of the presumed cause in the multivariate linear regression model, PC has the advantage of being model-free., Objective: The aim of the study is to apply the PC framework to assess the evolution of cardiac baroreflex control with age from spontaneous fluctuations of heart period (HP) and systolic arterial pressure (SAP) and to compare it to the more common WGC approach., Approach: We studied 100 healthy humans (54 males, age: 21-70 years, 20 subjects for each 10 years bin). HP and SAP were extracted on a beat-to-beat basis from 5 min recordings of electrocardiogram and plethysmographic arterial pressure at rest in supine position (REST) and during active standing (STAND) under spontaneous breathing. The WGC ratio (WGCR) was computed as the log ratio of the prediction error variance of the autoregressive model on HP to that on HP with exogenous SAP. The PC ratio (PCR) was computed as the probability of observing an HP ramp given an associated parallel SAP variation divided by the probability of observing an HP ramp., Main Results: The WGCR and PCR suggested the gradual impairment of cardiac baroreflex with age, especially during STAND. Moreover, they were significantly associated both at REST and during STAND but the degree of the PCR-WGCR association was weak., Significance: PC can be effectively exploited to assess modification of the cardiovascular control during senescence even though a limited agreement was observed with WGC.

CHIKV has become an emerging public health concern in the temperate regions of the Northern Hemisphere as a consequenceof the expansion of the endemic areas of its vectors (mainly Aedes aegypti and Aedes albopictus ). In 2017, a new outbreak of CHIKV was detected in Italy with three clusters of autochthonous transmission in the Lazio Region (central Italy), in the cities of Anzio, Rome, and Latina and a secondary cluster in the Calabria Region (south Italy). Given the climate characteristics of Italy, sporadic outbreaks mostly driven by imported cases followed by autochthonous transmission could occur during the summer season. This highlights the importance of a well-designed surveillance system, which should promptly identify autochthonous transmission. The use of a surveillance system integrating different surveillance tools, including entomological surveillance in a one health approach, together with education of the health care professionals should facilitate the detection, response, and control of arboviruses spreading.

The study compares a recently proposed shortterm model-based linear multiscale complexity approach to a single-scale application of the same method and to a model-free nonlinear one based on the computation of conditional entropy with the aim at assessing the complementary information. Comparison was carried out over 24 hours Holter recordings of heart period variability during daytime and nighttime in 12 healthy men (age: 34-55 years). Single-scale methods were able to detect the increased complexity of the cardiac control during nighttime. Multiscale complexity analysis showed that this increase was due to an increase of complexity in the low frequency band (from 0.04 to 0.15 Hz), while complexity in the range of frequencies typical of the respiratory rate was unmodified. Regardless of the method (i.e. linear or nonlinear) single-scale complexity indexes were uncorrelated to the multiscale ones. We conclude that short-term model-based linear multiscale complexity approach provides complementary information to single-scale methods in an application devoted to the analysis of cardiac control from 24 hours Holter recordings.

The analysis of short-term cardiovascular and cardiorespiratory regulation during altered conscious states, such as those induced by anesthesia, requires to employ time series analysis methods able to deal with the multivariate and multiscale nature of the observed dynamics. To meet this requirement, the present study exploits the extension to multiscale analysis of recently proposed information decomposition methods which allow to quantify, from short realizations, the amounts of joint, unique, redundant and synergistic information transferred within multivariate time series. These methods were applied to the spontaneous variability of heart period (HP), systolic arterial pressure (SAP) and respiration (RESP) in patients undergoing coronary artery bypass graft monitored before and after the induction of general anesthesia. We found that, after anesthesia induction, information is processed within the cardiovascular network in a scale-dependent way: at short time scales, a shift from synergistic to redundant information transferred from SAP and RESP to HP occurs, which is associated with enhanced baroreflex-mediated respiratory effects on arterial pressure; at longer time scales, the increased information transfer from SAP to HP denotes an enhancement of the baroreflex coupling related to slow cardiovascular oscillations.

Cardiac baroreflex (cBR) is activated by both arterial pressure (AP) increases and decreases. Sequence method, a widely utilized tool assessing cBR sensitivity (cBRS) from spontaneous heart period (HP) and systolic AP (SAP) variations, allows the separated computation of cBRS from positive and negative SAP variations. The recently proposed phase-rectified signal averaging (PRSA) method has the same feature but it has been applied so far solely to positive SAP variations. We adapted the PRSA method to compute cBRS over negative SAP variations and we compared the results with those derived from sequence method over two protocols: (i) graded head-up tilt (HUT) at 15, 30, 45, 60, and 75° in 19 healthy subjects and (ii) general anesthesia induction in 118 patients undergoing coronary artery bypass graft surgery. Regardless of the sign of SAP changes and method, cBRS moved toward 0 during HUT. Only sequence method detected the cBRS decrease after general anesthesia induction. In both protocols, the correlation between the PRSA-based cBRSs derived from positive and negative SAP changes was higher than that obtained from analogous sequence-based cBRSs and correlation between equivalent cBRSs derived from different methods might be absent. We conclude that the two methods are not interchangeable in assessing cBRS. Graphical abstract Graphical representation of the baroreflex sensitivity (BRS) estimation procedures carried out using sequence (SEQ) and phase-rectified signal averaging (PRSA) techniques over spontaneous fluctuations of heart period (HP) and systolic arterial pressure (SAP). BRS SEQ and BRS PRSA was separately computed over positive (+) and negative (-) SAP variations.

Baroreflex sensitivity (BRS) can be noninvasively assessed from heart period (HP) and arterial pressure (AP) variability series via the estimation of the gain of the transfer function (TF) in the low frequency (LF, 0.04-0.15 Hz) band. However, different strategies can be adopted to pick the value of the TF gain and different fiducial AP values can be considered. In this study we compared different strategies to reduce the TF gain into a unique maker: i) sampling the TF gain in correspondence of the maximum of the HP-AP squared coherence; ii) sampling the TF gain at the weighted average of the central frequencies of AP spectral components; iii) calculating the average of the TF gain in the LF band. Indexes were computed using alternatively systolic AP (SAP) or diastolic AP (DAP) series in combination with HP. Results were obtained in 129 patients undergoing coronary artery bypass graft surgery before (PRE) and after (POST) the induction of general anesthesia with propofol and remifentanil. The reduction of BRS during general anesthesia is expected as a result of overall depression of the cardiovascular control even in this group of pathological subjects already featuring a low BRS before general anesthesia induction. We found that the expected decrease of BRS was observed regardless of the strategy using DAP. Moreover, regardless of series (i.e., SAP or DAP), the sampling of TF gain at the weighted average of the central frequencies of the AP spectral components has the greatest statistical power in distinguishing the two experimental conditions. We recommend the use of this strategy in assessing BRS via TF analysis and a more frequent exploitation of the DAP series.

The arm of the baroreflex (BR) controlling peripheral resistances (PR), labeled as BR of PR (prBR), was characterized through an extension of the cardiac BR (cBR) sequence analysis. The method exploits recordings of skin blood flow (SBF) from the palm of the non-dominant hand via a laser Doppler flowmeter and of arterial pressure (AP) from the middle finger of the same hand via a plethysmographic device. PR was estimated beat-by-beat as the ratio of mean AP to mean SBF computed over the same heart period (HP). Peripheral resistances-diastolic arterial pressure (PR-DAP) sequences featuring simultaneous increases of PR and decreases of diastolic AP (DAP) or vice versa were identified and the slope of the regression line in the (DAP, PR) plane was taken as an estimate of prBR sensitivity (BRS prBR ). The percentage of prBR sequences (SEQ% prBR ) was taken as a measure of prBR involvement and the prBR effectiveness index (EI prBR ) was computed as the fraction of DAP sequences capable to drive antiparallel PR variations. Analogous markers were computed over cBR from HP and systolic AP (SAP) variability [i.e., cBR sensitivity (BRS cBR ), percentage of cBR sequences (SEQ% cBR ) , and effectiveness index of the cBR (EI cBR )]. prBR and cBR were typified during incremental light-to-moderate bicycle ergometer exercise at 10, 20, and 30% of the maximum effort in 16 healthy subjects (aged from 22 to 58 years, six males). We found that: (i) BRS cBR decreased gradually with the challenge, while BRS prBR declined only at the heaviest workload; (ii) SEQ% cBR decreased solely at the lightest workload, while the decline of SEQ% prBR was significant regardless of the intensity of the challenge; (iii) EI prBR and EI cBR were not affected by exercise; (iv) after pooling together all the data regardless of the experimental conditions, BRS prBR and BRS cBR were uncorrelated, while SEQ% cBR and SEQ% prBR as well as EI cBR and EI prBR , were significantly and positively correlated; (v) when the correlation between SEQ% cBR and SEQ% prBR and between EI cBR and EI prBR was assessed separately in each experimental condition, it was not systematically detected. This study suggests that prBR characterization provides information complementary to cBR that might be fruitfully exploited to improve patients' risk stratification.

Background: Postoperative atrial fibrillation (AF) might be favored by cardiovascular control impairment. We hypothesize that cardiovascular regulation indexes derived from directional model-based analysis of the spontaneous fluctuations of heart period (HP) and systolic arterial pressure (SAP) can identify subjects at risk to develop AF after coronary artery bypass graft (CABG) surgery., Methods: Beat-to-beat HP and SAP series were derived from electrocardiogram (ECG) and invasive arterial pressure recorded for 5 min just before CABG surgery in conscious condition. The group comprised subjects who did develop AF (AF, n = 37, 71 ± 8 years, 27 males) or did not (noAF, n = 92, 65 ± 10 years, 85 males). From HP and SAP variabilities we computed classical time-domain, spectral, cross-spectral and complexity indexes characterizing autonomic function and cardiac baroreflex control. Moreover, we performed model-based directional analysis assessing the gain and strength of the relations from SAP to HP along cardiac baroreflex feedback and from HP to SAP along the feedforward pathway while disambiguating the effect of respiration as estimated from respiratory-related ECG modulations., Results: Classical HP and SAP variability indexes and baroreflex sensitivity could not separate AF from noAF individuals. Causality markers, and more specifically, the strength of the dynamical interactions from SAP to HP and vice versa, could distinguish the two groups: indeed, AFs have a lower degree of association from SAP to HP and vice versa., Conclusions: An impairment of the feedforward and feedback arms of the HP-SAP closed loop relation predisposes subjects undergoing CABG surgery to develop postoperative AF., Perspectives: Competency in medical knowledge: Atrial fibrillation (AF) is a frequent complication after coronary artery bypass graft (CABG) surgery lengthening hospitalization duration and increasing healthcare system costs. Translational outlook 1: CABG patients who developed AF had a less preserved cardiovascular interactions due to less active physiological control mechanisms as resulting from the lower degree of dependence of systolic arterial pressure on heart period and vice versa before CABG surgery. Translational outlook 2: Cardiovascular control markers improve stratification of the AF risk after CABG surgery above and beyond more traditional demographic and clinical indexes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

This study checks whether autonomic markers derived from spontaneous fluctuations of heart period (HP) and systolic arterial pressure (SAP) and from their interactions with spontaneous or mechanical respiration (R) are associated with mortality in patients admitted to intensive care unit (ICU). Three-hundred consecutive HP, SAP and R values were recorded during the first day in ICU in 123 patients. Population was divided into survivors (SURVs, n = 83) and non-survivors (NonSURVs, n = 40) according to the outcome. SURVs and NonSURVs were aged- and gender-matched. All subjects underwent modified head-up tilt (MHUT) by tilting the bed back rest segment to 60°. Autonomic control indexes were computed using time-domain, spectral, cross-spectral, complexity, symbolic and causality techniques via univariate, bivariate and conditional approaches. SAP indexes derived from time-domain, model-free complexity and symbolic approaches were associated with the endpoint, while none of HP variability markers was. The association was more powerful during MHUT. Linear cross-spectral and causality indexes were useless to separate SURVs from NonSURVs, while nonlinear bivariate symbolic markers were successful. When indexes were combined with clinical scores, only SAP variance provided complementary information. Cardiovascular control variability indexes, especially when derived after an autonomic challenge such as MHUT, can improve mortality risk stratification in ICU.

An aqueous process for the recovery of oil bodies from rapeseed using sodium bicarbonate-based soaking and grinding media (pH 9.5) was investigated. The effect of the ratio between seed and mass of media during grinding and molarity of the medium used on oil body integrity, purity and storage stability have been studied. The grinding of seeds in solution at a ratio of 1:7 (w/w) significantly improved the quality of oil body suspension to a size more in-line with that seen in vivo (average D 4,3 of 1.19µm). The purity and the composition of the recovered oil bodies depends on the molarity of medium used; the use of a sodium bicarbonate solution (pH 9.5, 0.1M) in the grinding and washing steps produced oil body preparations with the same purity as that resulting from washing a crude preparation with 9M urea. The resultant emulsion had improved physical stability over a storage period of one month., (Copyright © 2017. Published by Elsevier Ltd.)

[This corrects the article DOI: 10.1371/journal.pone.0175008.].

Background: Cardiac surgery with cardiopulmonary bypass is associated with important changes in the microcirculation, usually attributed to endothelial dysfunction. Another common finding of cardiac surgery is postoperative thrombocytopenia and platelet loss of function., Objective: To investigate the association between microvascular flow pattern and postoperative changes in platelet count and function in cardiac surgery patients., Methods: Twelve adult cardiac surgery patients received microvascular circulation (sidestream darkfield sublingual mucosa analysis) and platelet count and function (multiple electrode aggregometry ADPtest and TRAPtest) assessment before and after cardiopulmonary bypass., Results: After cardiopulmonary bypass, sublingual microcirculation showed a significantly (P = 0.001) decreased microvascular flow index and increased heterogeneity index (P = 0.006). Platelet function significantly decrease after cardiopulmonary bypass both at ADPtest (P = 0.011) and TRAPtest (P = 0.002). Preoperative patterns of poor microvascular perfusion (low perfused vessels density and total vessels density) were significantly associated with lower values of post-cardiopulmonary bypass platelet function (ADPtest, P = 0.009, TRAPtest, P = 0.031) and count (P = 0.048)., Conclusions: A preoperative disturbance of the microcirculation is associated with a greater postoperative platelet dysfunction. Endothelial damage, chemical and mechanical stimuli are the possible link between the two patterns.

The hepatitis A virus (HAV) is mainly transmitted through the faecal-oral route. In industrialized countries HAV infection generally occurs as either sporadic cases in travelers from endemic areas, local outbreak within closed/semi-closed population and as foodborne community outbreak. Recently, an increasing number of HAV infection clusters have been reported among young men-who-have-sex-with-men (MSM). The Lazio Regional Service for the epidemiology and control for infectious diseases (SeRESMI) has noticed an increase of acute hepatitis A (AHA) since September 2016. Temporal analysis carried out with a discrete Poisson model using surveillance data between January 2016 and March 2017 evidenced an ongoing outbreak of AHA that started at the end of August. Molecular investigation carried out on 130 out of 513 cases AHA reported until March 2017 suggests that this outbreak is mainly supported by an HAV variant which is currently spreading within MSM communities across Europe (VRD_521_2016). The report confirms that AHA is an emerging issue among MSM. In addition through the integration of standard (case based) surveillance with molecular investigation we could discriminate, temporally concomitant but epidemiologically unrelated, clusters due to different HAV variants. As suggested by the WHO, in countries with low HAV circulation, vaccination programmes should be tailored on the local epidemiological patterns to prevent outbreaks among high risk groups and eventual spillover of the infection in the general population.

Objective: Indexes assessing the balance between redundancy and synergy were hypothesized to be helpful in characterizing cardiovascular control from spontaneous beat-to-beat variations of heart period (HP), systolic arterial pressure (SAP), and respiration (R). Methods: Net redundancy/synergy indexes were derived according to predictability and transfer entropy decomposition strategies via a multivariate linear regression approach. Indexes were tested in two protocols inducing modifications of the cardiovascular regulation via baroreflex loading/unloading (i.e., head-down tilt at -25° and graded head-up tilt at 15°, 30°, 45°, 60°, 75°, and 90°, respectively). The net redundancy/synergy of SAP and R to HP and of HP and R to SAP were estimated over stationary sequences of 256 successive values. Results: We found that: 1) regardless of the target (i.e., HP or SAP) redundancy was prevalent over synergy and this prevalence was independent of type and magnitude of the baroreflex challenge; 2) the prevalence of redundancy disappeared when decoupling inputs from output via a surrogate approach; 3) net redundancy was under autonomic control given that it varied in proportion to the vagal withdrawal during graded head-up tilt; and 4) conclusions held regardless of the decomposition strategy. Conclusion: Net redundancy indexes can monitor changes of cardiovascular control from a perspective completely different from that provided by more traditional univariate and multivariate methods. Significance: Net redundancy measures might provide a practical tool to quantify the reservoir of effective cardiovascular regulatory mechanisms sharing causal influences over a target variable. Objective: Indexes assessing the balance between redundancy and synergy were hypothesized to be helpful in characterizing cardiovascular control from spontaneous beat-to-beat variations of heart period (HP), systolic arterial pressure (SAP), and respiration (R). Methods: Net redundancy/synergy indexes were derived according to predictability and transfer entropy decomposition strategies via a multivariate linear regression approach. Indexes were tested in two protocols inducing modifications of the cardiovascular regulation via baroreflex loading/unloading (i.e., head-down tilt at -25° and graded head-up tilt at 15°, 30°, 45°, 60°, 75°, and 90°, respectively). The net redundancy/synergy of SAP and R to HP and of HP and R to SAP were estimated over stationary sequences of 256 successive values. Results: We found that: 1) regardless of the target (i.e., HP or SAP) redundancy was prevalent over synergy and this prevalence was independent of type and magnitude of the baroreflex challenge; 2) the prevalence of redundancy disappeared when decoupling inputs from output via a surrogate approach; 3) net redundancy was under autonomic control given that it varied in proportion to the vagal withdrawal during graded head-up tilt; and 4) conclusions held regardless of the decomposition strategy. Conclusion: Net redundancy indexes can monitor changes of cardiovascular control from a perspective completely different from that provided by more traditional univariate and multivariate methods. Significance: Net redundancy measures might provide a practical tool to quantify the reservoir of effective cardiovascular regulatory mechanisms sharing causal influences over a target variable.

An outbreak of chickenpox occurred between December 2015 and May 2016 among asylum seekers in a reception centre in Latium, Italy. We describe the epidemiological and laboratory investigations, control measures and validity of reported history of chickenpox infection. Serological screening of all residents and incoming asylum seekers was performed, followed by vaccine offer to all susceptible individuals without contraindication. Forty-six cases were found and 41 were associated with the outbreak. No complications, hospitalisations or deaths occurred. Serological testing was performed in 1,278 individuals and 169 were found to be susceptible, with a seroprevalence of 86.8%. A questionnaire was administered to 336 individuals consecutively attending the CARA health post to collect their serological result. The sensitivity, specificity and the positive and negative predictive value (PPV and NPV) of the reported history of chickenpox were 45.0%, 76.1%, 88.3% and 25.6%, respectively. We observed an increasing trend for the PPV and decreasing trend for the NPV with increasing age. Our report confirms that, in the asylum seeker population, chickenpox history is not the optimal method to identify susceptible individuals. Our experience supports the need for additional prevention and control measures and highlights the importance of national and local surveillance systems for reception centres.

Carotid artery intima media thickness estimation is a well-established way of cardio vascular disease evaluation. The purpose of this cross-sectional study was to develop normal carotid intima media thickness percentile values for a Pakistani cohort. Data was collected at the Departments of Radiology and Family Medicine, The Aga Khan University Hospital, Karachi, from April 2014 to August 2015. High frequency ultrasound of carotid was done in 257 patients [97 male (38%), 160 female (62%)] without any known carotid artery disease. Reference ranges (90% range between 5th and 95th centiles) were constructed for each common carotid and internal carotid artery measurement and displayed in graph form. The mean difference was found in left common carotid artery (0.55 ±0.13) and left internal carotid artery thickness (0.50 ±0.10) significant at p=0.031 and p=0.014, respectively. The IMTpercentile graphs developed in this study for internal and common carotid arteries are exclusive for this population and can be used to assess vascular health from ultrasound measurements.

We propose a multiscale complexity (MSC) method assessing irregularity in assigned frequency bands and being appropriate for analyzing the short time series. It is grounded on the identification of the coefficients of an autoregressive model, on the computation of the mean position of the poles generating the components of the power spectral density in an assigned frequency band, and on the assessment of its distance from the unit circle in the complex plane. The MSC method was tested on simulations and applied to the short heart period (HP) variability series recorded during graded head-up tilt in 17 subjects (age from 21 to 54 years, median = 28 years, 7 females) and during paced breathing protocols in 19 subjects (age from 27 to 35 years, median = 31 years, 11 females) to assess the contribution of time scales typical of the cardiac autonomic control, namely in low frequency (LF, from 0.04 to 0.15 Hz) and high frequency (HF, from 0.15 to 0.5 Hz) bands to the complexity of the cardiac regulation. The proposed MSC technique was compared to a traditional model-free multiscale method grounded on information theory, i.e., multiscale entropy (MSE). The approach suggests that the reduction of HP variability complexity observed during graded head-up tilt is due to a regularization of the HP fluctuations in LF band via a possible intervention of sympathetic control and the decrement of HP variability complexity observed during slow breathing is the result of the regularization of the HP variations in both LF and HF bands, thus implying the action of physiological mechanisms working at time scales even different from that of respiration. MSE did not distinguish experimental conditions at time scales larger than 1. Over a short time series MSC allows a more insightful association between cardiac control complexity and physiological mechanisms modulating cardiac rhythm compared to a more traditional tool such as MSE.

The study proposes an extension of cardiac baroreflex (cBR) sequence analysis, traditionally performed over spontaneous fluctuations of heart period and systolic arterial pressure, to typify peripheral resistance baroreflex (prBR) from spontaneous variations of peripheral resistances and diastolic arterial pressure. The prBR baroreflex sensitivity (BRS prBR ) and percentage of prBR sequences (SEQ% prBR ) were computed along with analogous quantities assessed over cBR (i.e. BRS cBR and SEQ% cBR ). The cBR and prBR were typified in healthy subjects at rest (REST) and during light bicycle ergometer exercise at 10 percent of the maximal effort (EXE). Both cBR and prBR were affected by EXE: indeed, BRS cBR and SEQ% prBR were significantly reduced. Moreover, while BRS cBR and BRS prBR were not significantly associated, SEQ% cBR and SEQ% prBR were, and the correlation coefficient was positive. This study suggests that prBR can be typified from spontaneous variabilities along with the more traditional cBR, thus enlarging the possibility of monitoring human cardiovascular control mechanisms.

The assessment of cardiovascular control complexity as derived from spontaneous heart period (HP) fluctuations can be improved by exploiting a multivariate (MV) approach. This work proposes the assessment of a normalized complexity index (NCI) of HP variability according to a k-nearest-neighbor approach based on local predictability performed in a MV nonuniform embedding space. The method allows the selection of the past components of HP, systolic arterial pressure (SAP) and respiration (R) most useful for the prediction of HP fluctuations. The NCI derived from the MV approach (NCIMV) was compared to a NCI computed via the same technique applied in a univariate (UV) embedding space (NCIUV) formed exclusively by HP past samples. Indexes were computed in 130 patients undergoing coronary artery bypass graft (CABG) surgery before and after the induction of general anesthesia. Thirty-eight subjects developed atrial fibrillation (AF) after surgery, while the remaining ones did not (noAF, n=92). Both NCIUV and NCIMV could separate AF from noAF patients and revealed a larger complexity of the AF subjects. However, the statistical power of the NCIMV was superior given that the probability of type I error was smaller than that of NCIUV. The assessment of cardiac control complexity could improve risk stratification of patients at risk of developing AF after CABG surgery.

The study assesses the strength of the causal relation along baroreflex (BR) in humans during an incremental postural challenge soliciting the BR. Both cardiac BR (cBR) and sympathetic BR (sBR) were characterized via BR sequence approaches from spontaneous fluctuations of heart period (HP), systolic arterial pressure (SAP), diastolic arterial pressure (DAP) and muscle sympathetic nerve activity (MSNA). A model-based transfer entropy method was applied to quantify the strength of the coupling from SAP to HP and from DAP to MSNA. The confounding influences of respiration were accounted for. Twelve young healthy subjects (20-36 years, nine females) were sequentially tilted at 0°, 20°, 30° and 40°. We found that (i) the strength of the causal relation along the cBR increases with tilt table inclination, while that along the sBR is unrelated to it; (ii) the strength of the causal coupling is unrelated to the gain of the relation; (iii) transfer entropy indexes are significantly and positively associated with simplified causality indexes derived from BR sequence analysis. The study proves that causality indexes are complementary to traditional characterization of the BR and suggests that simple markers derived from BR sequence analysis might be fruitfully exploited to estimate causality along the BR.This article is part of the themed issue 'Mathematical methods in medicine: neuroscience, cardiology and pathology'., (© 2017 The Author(s).)

Objective: A network physiology approach to evaluate the strength of the directed interactions among cardiac controls at sinoatrial and ventricular levels and respiration (R) is proposed., Approach: The network is composed of three nodes (i.e. sinoatrial and ventricular cardiac controls and R) and their activity is exemplified by the variability of heart period (HP), the variability of the duration of the electrical activity of the heart approximated as the temporal distance between Q-wave onset and T-wave end or apex (i.e. QTe or QTa) and thoracic movements respectively. Model-based transfer entropy provided the estimate of the strength of the causal link from the source to the destination conditioned on the remaining node activity. The interactions were monitored in 15 healthy subjects aged from 24 to 54 years (9 males). Increasing levels of sympathetic activity were induced by graded head-up tilt with table inclination of 0, 15, 30, 45, 60, 75°., Main Results: We found that: (i) the strength of the causal link from HP to QTe gradually decreases with tilt table angle, while that in the reverse direction is weak, even though significant, and constant; (ii) the action of R on HP is stronger than that from R to QTe; (iii) the strength of the relation from R to HP is weakly related to tilt table inclination, while that from R to QTe does not depend on it; (iv) while QTe cannot affect R, a weak causal dependence of R on HP is detected; (v) the network computed over QTa is qualitatively similar to that over QTe, even though the strength of the causal relations might be different., Significance: The proposed network physiology approach provides a comprehensive picture of the directed links among relevant cardiac regulatory mechanisms and their evolution with sympathetic tone usable to identify pathological conditions.

Objective: We test the hypothesis that the linear model-based (MB) approach for the estimation of conditional entropy (CE) can be utilized to assess the complexity of the cardiac control in healthy individuals., Methods: An MB estimate of CE was tested in an experimental protocol (i.e., the graded head-up tilt) known to produce a gradual decrease of cardiac control complexity as a result of the progressive vagal withdrawal and concomitant sympathetic activation. The MB approach was compared with traditionally exploited nonlinear model-free (MF) techniques such as corrected approximate entropy, sample entropy, corrected CE, two k -nearest-neighbor CE procedures and permutation CE. Electrocardiogram was recorded in 17 healthy subjects at rest in supine position and during head-up tilt with table angles of 15°, 30°, 45°, 60°, and 75°. Heart period (HP) was derived as the temporal distance between two consecutive R-wave peaks and analysis was carried out over stationary sequences of 256 successive HPs., Results: The performance of the MB method in following the progressive decrease of HP complexity with tilt table angles was in line with those of MF approaches and the MB index was remarkably correlated with the MF ones., Conclusion: The MB approach can be utilized to monitor the changes of the complexity of the cardiac control, thus speeding up dramatically the CE calculation., Significance: The remarkable performance of the MB approach challenges the notion, generally assumed in cardiac control complexity analysis based on CE, about the need of MF techniques and could allow real-time applications.

Objective: We exploited a model-based Wiener-Granger causality method in the information domain for the evaluation of the transfer entropy (TE) and interaction TE (ITE), the latter taken as a measure of the net balance between redundancy and synergy, to describe the interactions between the spontaneous variability of heart period (HP) and systolic arterial pressure (SAP) and the effect of respiration (R) on both variables., Approach: Cardiac control was typified via the genuine TE from SAP to HP, that from R to HP, and the ITE from SAP and R to HP, while vascular control was characterized via the genuine TE from HP to SAP, that from R to SAP, and the ITE from HP and R to SAP. The approach was applied to study age-related modifications of cardiac and vascular controls in a cohort of 100 healthy humans (age from 21 to 70 years, 54 males) recorded at supine rest (REST) and during active standing (STAND). A surrogate approach was exploited to test the significance of the computed quantities., Main Results: Trends of the genuine information transfer with age, already present in literature, were here confirmed. We originally found that: (i) at REST redundancy was predominant over synergy in both vascular and cardiac controls; (ii) the predominance of redundancy of the cardiac control was not affected by postural challenge, while STAND reduced redundancy of vascular control; (iii) the net redundancy of the cardiac control at REST gradually decreased with age, while that of vascular control remained stable; (iv) during STAND net redundancy of both cardiac and vascular controls was stable with age., Significance: The study confirms the relevance of computing genuine information transfer in cardiovascular control analysis and stresses the importance of evaluating the ITE to quantify the degree of redundancy of physiological mechanisms operating to maintain cardiovascular homeostasis.

Objective: A model-based conditional transfer entropy approach was exploited to quantify the information transfer in cerebrovascular (CBV) and cardiovascular (CV) systems in subjects prone to develop postural syncope., Approach: Spontaneous beat-to-beat variations of mean cerebral blood flow velocity (MCBFV) derived from a transcranial Doppler device, heart period (HP) derived from surface electrocardiogram, mean arterial pressure (MAP) and systolic arterial pressure (SAP) derived from finger plethysmographic arterial pressure device were monitored at rest in supine position (REST) and during 60° head-up tilt (TILT) in 13 individuals (age mean  ±  standard deviation: 28  ±  9 years, min-max range: 18-44 years, 5 males) with a history of recurrent episodes of syncope (SYNC) and in 13 age- and gender-matched controls (NonSYNC). Respiration (R) obtained from a thoracic belt was acquired as well and considered as a conditioning signal in transfer entropy assessment. Synchronous sequences of 250 consecutive MCBFV, HP, MAP, SAP and R values were utilized to estimate the information genuinely transferred from MAP to MCBFV (i.e. disambiguated from R influences) and vice versa. Analogous indexes were computed from SAP to HP and vice versa. Traditional time and frequency domain analyses were carried out as well., Main Results: SYNC subjects showed an increased genuine information transfer from MAP to MCBFV during TILT, while they did not exhibit the expected rise of the genuine information transfer from SAP to HP., Significance: We conclude that SYNC individuals featured an impaired cerebral autoregulation visible during TILT and were unable to activate cardiac baroreflex to cope with the postural challenge. Traditional frequency domain markers based on transfer function modulus, phase and coherence functions were less powerful or less specific in typifying the CBV and CV controls of SYNC individuals. Conditional transfer entropy approach can identify the impairment of CBV and CV controls and provide specific clues to identify subjects prone to develop postural syncope.

Cardioventilatory phase synchronization was studied in ten critically ill patients admitted in intensive care unit (ICU) for acute respiratory failure under two mechanical ventilatory modes: (i) pressure controlled ventilation (PCV); (ii) pressure support ventilation (PSV). The two modalities were administered to the same patient in different times in a random order. Cardioventilatory phase interactions were typified by plotting the relative position of a heartbeat, detected from the electrocardiogram and collected in n groups, within m ventilatory cycles as a function of the progressive cardiac beat number via the synchrogram. n:m phase synchronized patterns were detected by computing the variability of each phase group. The percent duration of the recording featuring phase synchronization was assessed as a measure of the strength of phase synchrony and tested against situations of full phase desynchronization between cardiac and ventilatory rhythms. Indexes quantifying the variability of the cardiac and ventilatory activities were computed as well. Findings proved that: (i) a significant presence of n:m phase synchronized patterns was detected in PCV; (ii) the strength of n:m phase synchronization was stronger during PCV than PSV; (iii) different strengths of cardioventilatory phase synchronization detected during PCV and PSV were found in presence of similar heart and ventilatory rates and alike variability. We conclude that mechanical ventilation can induce a significant presence of cardioventilatory phase synchronized patterns and this amount depends on the mode of mechanical ventilation. Future studies should test the eventual link of the level of phase coordination between heart and mechanical ventilation to a clinical outcome to understand whether featuring a certain degree of cardioventilatory phase synchronization is beneficial for the critical patient in ICU.

Postoperative atrial fibrillation, acute kidney dysfunction and low cardiac output following coronary surgery are associated with morbidity and mortality. The purpose of this study is to determine if the preoperative autonomic control is a determinant of these postoperative complications. This is a prospective cohort study on 150 adult patients undergoing surgical coronary revascularization with cardiopulmonary bypass. The patients received an autonomic control assessment after the induction of anesthesia. Baroreflex sensitivity was computed by spectral analysis and expressed as BRSαHF and BRSαLF for measure respectively in the high and low frequency domains. Atrial fibrillation was adjudicated at any postoperative time during the hospital stay. Acute kidney dysfunction was defined as any increase of serum creatinine levels from preoperative values within the first 48 hours after surgery, and acute kidney injury was adjudicated at a 50% increase. Low cardiac ouput syndrome was defined as the need for inotropic support > 48 hours. Thirty-eight (26.4%) patients experienced postoperative atrial fibrillation; 32 (22.2%) had acute kidney dysfunction and 5 (3.5%) acute kidney injury; 14(10%) had a low cardiac output state. No indices of baroreflex sensitivity were associated with atrial fibrillation or acute kidney injury. A low value of BRSαLF was associated with acute kidney dysfunction and low cardiac output state. A BRSαLF < 3 msec/mmHg was an independent risk factor for acute kidney dysfunction (odds ratio 3.0, 95% confidence interval 1.02-8.8, P = 0.045) and of low cardiac output state (odds ratio 17.0, 95% confidence interval 2.9-99, P = 0.002). Preoperative baroreflex sensitivity is linked to postoperative complications through a number of possible mechanisms, including an autonomic nervous system-mediated vasoconstriction, a poor response to hypotension, and an increased inflammatory reaction.

Background: Semi-quantitative evaluation of Modic changes (MCs) has recently been proposed as a way to standardise and increase repeatability of clinical studies. This study is aimed at developing semi-quantitative measures of enhancement, given by contrast agent injection, on T1-weighted images in MCs, and to investigate their reliability and relation with MC types., Methods: Thirty-seven subjects suffering from low back pain underwent T1-weighted and T2-weighted turbo spin-echo sequences. Five minutes after the injection of a paramagnetic contrast agent, a second T1-weighted sequence was acquired. Regions of interest (ROIs) corresponding to MCs were selected manually on the unenhanced image; control ROIs in the "healthy" bone marrow were selected. For each ROI, the mean signal intensity (SI) of unenhanced pixels and the mean absolute and normalised difference in SI between unenhanced and contrast-enhanced pixels values were calculated., Results: A total of 103 MCs were recognised and 61 were semi-quantitatively analysed: 16 type I, 34 type II and 11 type I/II. Regarding controls, MCs I showed a lower SI on the unenhanced T1-weighted images and a marked contrast enhancement (CE); MCs II showed a higher SI than controls on unenhanced images and a lower or comparable CE; and MCs I/II presented an intermediate SI on the unenhanced images and a marked CE. Inter-rater and intra-rater agreements were found to be excellent or substantial., Conclusions: Semi-quantitative measurements could differentiate MC types in terms of unenhanced SI and of CE with respect to "healthy" bone marrow.

Objective: To compare carotid Intima media thickness and atherosclerosis burden amongst healthy, diabetic and hypertensive Pakistani patients., Methods: A cross-sectional study was carried out at the Department of radiology and family medicine, Aga Khan University Hospital Karachi from April 2014 to July 2015. Bilateral carotid ultrasound was done in 133 healthy adults, 65 hypertensive, 31 type-2 diabetic and 37 hypertensive with type-2 diabetes patients. Normal adults were matched for age and gender. Mean intimal media thickness was measured for common and internal carotid arteries. Presence or absence of atherosclerotic plaque was also identified. Height, weight, ethnicity, socioeconomic status and other risk factors were also assessed. Ultrasound findings were compared between healthy and diseased patients through statistical tests., Results: A total of 266 patients participated (Controls=133, Hypertensive=65, Diabetic=31, and Diabetes with Hypertension=37). There was no significant difference in the baseline characteristics between the four patients' groups for age (p>0.05) and gender (p>0.05). The mean carotid intima media thickenss of right common carotid artery was significantly higher in patients with diabetes along with hypertension as compared to the control group (p=0.03). For (RICA) Right Internal Carotid Artery, (LCCA) Left Common Carotid Artery and (LICA) Left Internal Carotid Artery, there was a significantly higher thickness among patients with hypertension as compared to the control group with p=0.011, p=0.002, and p=0.039 respectively., Conclusions: Increased CIMT is most likely associated with underlying chronic diseases. Ultrasound is a non-invasive, easily available and useful modality for early detection and prevention of vascular atherosclerosis.

We propose a sympathetic baroreflex (sBR) sequence method for characterizing sBR from spontaneous beat-to-beat fluctuations of muscle sympathetic nerve activity (MSNA) and diastolic arterial pressure (DAP). The method exploits a previously defined MSNA variability quantifying the fluctuations of MSNA burst rate. The method is based on the detection of MSNA and DAP sequences characterized by the contemporaneous DAP increase and MSNA decrease or vice versa . The percentage of sBR sequences (SEQ% sBR ) was taken as an indication of the degree of sBR solicitation and the average slope of the regression lines in the (DAP, MSNA) plane was taken as sBR sensitivity (sBRS SEQ ) and expressed in bursts . s -1. mmHg -1 . sBRS SEQ was compared to a more traditional estimate based on the baroreflex threshold analysis (sBRS BTA ). An incremental head-up tilt protocol, carried out in 12 young healthy subjects (age: 20-36 yr, median = 22.5 yr, 9 females) sequentially tilted at 0, 20, 30, 40, 60° table inclinations, was utilized to set the sBR sequence method parameters. Traditional sequence analysis was exploited to estimate cardiac baroreflex (cBR) sensitivity (cBRS SEQ ) and percentage of cBR sequences (SEQ% cBR ). The head-up tilt induced the progressive increase of SEQ% sBR and SEQ% cBR and gradual decrease of both sBRS SEQ and cBRS SEQ , thus suggesting the gradual rise of the sBR and cBR solicitations and the progressive reduction of their effectiveness with the stimulus. sBRS SEQ was significantly associated with sBRS BTA . sBRS SEQ and cBRS SEQ were significantly correlated as well as SEQ% sBR and SEQ% cBR , even though the correlation was not strong, thus suggesting a certain degree of independence between the baroreflex arms. The proposed sBR sequence approach provides a dynamical characterization of the sBR alternative to more traditional static pharmacological and nonpharmacological methods and fully homogenous with the cBR sequence technique.

The study evaluates the k-nearest-neighbor (KNN) strategy for the assessment of complexity of the cardiac neural control from spontaneous fluctuations of heart period (HP). Two different procedures were assessed: i) the KNN estimation of the conditional entropy (CE) proposed by Porta et al; ii) the KNN estimation of mutual information proposed by Kozachenko-Leonenko, refined by Kraskov-Stögbauer-Grassberger and here adapted for the CE estimation. The two procedures were compared over HP variability recordings obtained at rest in supine position and during head-up tilt (HUT) in amyotrophic lateral sclerosis patients and healthy subjects. We found that the indexes derived from the two procedures were significantly correlated and both methods were able to detect the effect of HUT on HP complexity within the same group and distinguish the two populations within the same experimental condition. We recommend the use of the KNN strategy to quantify the dynamical complexity of cardiac neural control in addition to more traditional approaches.

Assigned the universe of knowledge Ω as composed by one target and two exogenous signals, the conditional joint transfer entropy (CJTE), assessing the amount of information jointly transferred from the two sources to the target that can be uniquely linked to one of the two sources, was found useful to study cardiovascular control. We propose the assessment of CJTE from systolic arterial pressure (SAP) and respiration (R) to heart period (HP) conditioned on R (CJTESAP, R→HP|R) along the baroreflex, and from HP and R to SAP conditioned on R (CJTEHP, R→SAP|R) along the feedforward mechanical pathway, in 134 patients undergoing coronary artery bypass graft surgery before (PRE) and after (POST) the induction of general anesthesia. In this group 38 patients developed atrial fibrillation (AF) after surgery, while the remaining individuals did not (noAF, n=96). Both CJTESAP, R→HP|R and CJTEHP, R→SAP|R distinguished AF from noAF individuals in the PRE condition, suggesting an impairment of HP-SAP closed-loop regulation in AF group and the possibility to identify subjects at higher risk to develop post-surgery AF.

OBJECTIVE To provide an overview of the economic aspects of needlestick and sharps injury (NSI) management among healthcare personnel (HCP) within a Health Technology Assessment project to evaluate the impact of safety-engineered devices on health care METHODS A systematic review of economic analyses related to NSIs was performed in accordance with the PRISMA statement and by searching PubMed and Scopus databases (January 1997-February 2015). Mean costs were stratified by study approach (modeling or data driven) and type of cost (direct or indirect). Costs were evaluated using the CDC operative definition and converted to 2015 International US dollars (Int$). RESULTS A total of 14 studies were retrieved: 8 data-driven studies and 6 modeling studies. Among them, 11 studies provided direct and indirect costs and 3 studies provided only direct costs. The median of the means for aggregate (direct + indirect) costs was Int$747 (range, Int$199-Int$1,691). The medians of the means for disaggregated costs were Int$425 (range, Int$48-Int$1,516) for direct costs (9 studies) and Int$322 (range, Int$152-Int$413) for indirect costs (6 studies). When compared with data-driven studies, modeling studies had higher disaggregated and aggregated costs, but data-driven studies showed greater variability. Indirect costs were consistent between studies, mostly referring to lost productivity, while direct costs varied widely within and between studies according to source infectivity, HCP susceptibility, and post-exposure diagnostic and prophylactic protocols. Costs of treating infections were not included, and intangible costs could equal those associated with NSI medical evaluations. CONCLUSIONS NSIs generate significant direct, indirect, potential, and intangible costs, possibly increasing over time. Economic efforts directed at preventing occupational exposures and infections, including provision of safety-engineered devices, may be offset by the savings from a lower incidence of NSIs. Infect Control Hosp Epidemiol 2016;37:635-646.

Muscle sympathetic nerve activity (MSNA) variability is traditionally computed through a low-pass filtering procedure that requires normalization. We proposed a new beat-to-beat MSNA variability computation that preserves dimensionality typical of an integrated neural discharge (i.e., bursts per unit of time). The calibrated MSNA (cMSNA) variability technique is contrasted with the traditional uncalibrated MSNA (ucMSNA) version. The powers of cMSNA and ucMSNA variabilities in the low-frequency (LF, from 0.04 to 0.15 Hz) band were computed with those of the heart period (HP) of systolic and diastolic arterial pressure (SAP and DAP, respectively) in seven healthy subjects (age, 20-28 years; median, 22 years; 5 women) during a graded head-up tilt. Subjects were sequentially tilted at 0°, 20°, 30°, 40°, and 60° table inclinations. The LF powers of ucMSNA and HP variabilities were expressed in normalized units (LFnu), whereas all remaining spectral markers were expressed in absolute units. We found that 1) the LF power of cMSNA variability was positively correlated with tilt angle, whereas the LFnu power of the ucMSNA series was uncorrelated; 2) the LF power of cMSNA variability was correlated with LF powers of SAP and DAP, LFnu power of HP and noradrenaline concentration, whereas the relationship of the LFnu power of ucMSNA variability to LF powers of SAP and DAP was weaker and that to LFnu power of HP was absent; and 3) the stronger relationship of cMSNA variability to SAP and DAP spectral markers compared with the ucMSNA series was confirmed individually. The cMSNA variability appears to be more suitable in describing sympathetic control in humans than traditional ucMSNA variability., (Copyright © 2016 the American Physiological Society.)

Cardiovascular and cerebrovascular regulatory systems are vital control mechanisms responsible for guaranteeing homeostasis and are affected by respiration. This work proposes the investigation of cardiovascular and cerebrovascular control systems and the nonlinear influences of respiration on both regulations through joint symbolic analysis (JSA), conditioned or unconditioned on respiration. Interactions between cardiovascular and cerebrovascular regulatory systems were evaluated as well by performing correlation analysis between JSA indexes describing the two control systems. Heart period, systolic and mean arterial pressure, mean cerebral blood flow velocity and respiration were acquired on a beat-to-beat basis in 13 subjects experiencing recurrent syncope episodes (SYNC) and 13 healthy individuals (non-SYNC) in supine resting condition and during head-up tilt test at 60° (TILT). Results showed that JSA distinguished conditions and groups, whereas time domain parameters detected only the effect of TILT. Respiration affected cardiovascular and cerebrovascular regulatory systems in a nonlinear way and was able to modulate the interactions between the two control systems with different outcome in non-SYNC and SYNC groups, thus suggesting that the analysis of the impact of respiration on cardiovascular and cerebrovascular regulatory systems might improve our understanding of the mechanisms underpinning the development of postural-related syncope., (© 2016 The Author(s).)

We hypothesized that Wiener-Granger causality (WGC) indexes might have different abilities in coping with modifications of the complexity of the target variable in the context of the assessment of the cardiovascular control from spontaneous fluctuations of heart period (HP), systolic arterial pressure (SAP) and respiratory activity (R). After having defined the universe of knowledge as the set Ω = {HP, SAP, R} and the unpredictability decrement (UPD) as the difference between the prediction error variances of the target signal computed in Ω after excluding the presumed cause (i.e. the restricted Ω) and in Ω, we computed the following frequently utilized WGC indexes: (i) the plain UPD; (ii) the fractional UPD (FUPD) by dividing UPD by the prediction error variance in the restricted Ω; (iii) the normalized UPD (NUPD) by dividing UPD by the prediction error variance in Ω; (iv) the log-unpredictability decrement (LUPD) by applying the logarithm transformation to the prediction error variances before computing the UPD. The hypothesis was tested over two experimental protocols known to produce modifications of the complexity of HP variability: graded head-up tilt (HUT) inducing a gradual decrease of the HP complexity with tilt table inclination and head-down tilt (HDT) inducing the opposite trend. We demonstrated that: (1) when the strength of the causal relations from SAP to HP during HUT and from R to HP during HDT is assessed in Ω, WGC indexes reach different conclusions; (2) UPD is biased by modifications of the complexity of HP dynamics; (3) FUPD, NUPD and LUPD are less sensitive to changes of the complexity of the target dynamic, even though they have slightly different statistical power, being the NUPD the weakest one and FUPD and LUPD the strongest ones. We conclude that UPD should be avoided when assessing WGC and FUPD and LUPD should be privileged over NUPD.

Four different classes of new 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) inhibitors were synthesized, in order to lower the cytotoxicity exhibited by the lead compound A, via disrupting the linearity and the aromaticity of the biphenyl moiety. Compounds 3, 4, 7a and 8 displayed comparable or better inhibitory activity and selectivity, as well as a lower cytotoxic effect, compared to the reference compound A. The best compound 4 (IC50=160nM, selectivity factor=168, LD50≈25μM) turned out as new lead compound for inhibition of 17β-HSD2., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

A full decomposition of the predictive entropy (PE) of the spontaneous variations of the heart period (HP) given systolic arterial pressure (SAP) and respiration (R) is proposed. The PE of HP is decomposed into the joint transfer entropy (JTE) from SAP and R to HP and self-entropy (SE) of HP. The SE is the sum of three terms quantifying the synergistic/redundant contributions of HP and SAP, when taken individually and jointly, to SE and one term conditioned on HP and SAP denoted as the conditional SE (CSE) of HP given SAP and R. The JTE from SAP and R to HP is the sum of two terms attributable to SAP or R plus an extra term describing the redundant/synergistic contribution to the JTE. All quantities were computed during cardiopulmonary loading induced by -25° head-down tilt (HDT) via a multivariate linear regression approach. We found that: (i) the PE of HP decreases during HDT; (ii) the decrease of PE is attributable to a lessening of SE of HP, while the JTE from SAP and R to HP remains constant; (iii) the SE of HP is dominant over the JTE from SAP and R to HP and the CSE of HP given SAP and R is prevailing over the SE of HP due to SAP and R both in supine position and during HDT; (iv) all terms of the decompositions of JTE from SAP and R to HP and SE of HP due to SAP and R were not affected by HDT; (v) the decrease of the SE of HP during HDT was attributed to the reduction of the CSE of HP given SAP and R; (vi) redundancy of SAP and R is prevailing over synergy in the information transferred into HP both in supine position and during HDT, while in the HP information storage synergy and redundancy are more balanced. The approach suggests that the larger complexity of the cardiac control during HDT is unrelated to the baroreflex control and cardiopulmonary reflexes and may be related to central commands and/or modifications of the dynamical properties of the sinus node.

The study exploits a Wiener-Granger causality (WGC) approach in the time domain to assess directionality of the dynamical interactions between QT interval and heart period (HP) during a graded head-up tilt protocol challenging the cardiovascular control as a function of the tilt table inclination. QT interval and HP are approximated from the surface ECG as the temporal distance between the R-wave apex and T-wave offset and between two consecutive R-wave peaks respectively. The adopted WGC approach accounts for the confounding effect of respiration (RESP) affecting both QT and HP. Causality ratios (CRs) from HP to QT given RESP (CRHP→QT|RESP) and from QT to HP given RESP (CRQT→HP|RESP) were computed and their significance was tested via F-test. We found that, regardless of the tilt table angle, CRHP→QT|RESP is significant, while CRQT→HP|RESP is negligible. CRHP→QT|RESP showed a trend towards a decrease with tilt table angle. These findings suggested that the causal direction from HP over QT is dominant compared to the reverse one and sympathetic activation induced a QT-HP uncoupling.

The study demonstrates the ability of an information-theoretic measure, such as the transfer entropy (TE), in detecting the depression of the cardiac baroreflex control and circulatory-cardio mechanical feedforward link during propofol-induced general anesthesia. TE was computed from spontaneous variability of heart period (HP) and systolic arterial pressure (SAP) in patients undergoing coronary artery bypass graft (CABG). TE from SAP to HP and from HP to SAP were evaluated by accounting for the confounding effect of respiration (R) affecting both HP and SAP (i.e. TESAP→HP|R and TEHP→SAP|R respectively). Both TESAP→HP|R and TEHP→SAP|R decreased during general anesthesia, thus suggesting that the strength of the causal relation diminished over both arms of the closed loop HP-SAP control. The squared coherence function between HP and SAP confirmed the decreased HP-SAP coupling during general anesthesia, even though it could not distinguish directionality.

Self-entropy (SE) and transfer entropy (TE) are widely utilized in biomedical signal processing to assess the information stored into a system and transferred from a source to a destination respectively. The study proposes a more specific definition of the SE, namely the conditional SE (CSE), and a more flexible definition of the TE based on joint TE (JTE), namely the conditional JTE (CJTE), for the analysis of information dynamics in multivariate time series. In a protocol evoking a gradual sympathetic activation and vagal withdrawal proportional to the magnitude of the orthostatic stimulus, such as the graded head-up tilt, we extracted the beat-to-beat spontaneous variability of heart period (HP), systolic arterial pressure (SAP) and respiratory activity (R) in 19 healthy subjects and we computed SE of HP, CSE of HP given SAP and R, JTE from SAP and R to HP, CJTE from SAP and R to HP given SAP and CJTE from SAP and R to HP given R. CSE of HP given SAP and R was significantly smaller than SE of HP and increased progressively with the amplitude of the stimulus, thus suggesting that dynamics internal to HP and unrelated to SAP and R, possibly linked to sympathetic activation evoked by head-up tilt, might play a role during the orthostatic challenge. While JTE from SAP and R to HP was independent of tilt table angle, CJTE from SAP and R to HP given R and from SAP and R to HP given SAP showed opposite trends with tilt table inclination, thus suggesting that the importance of the cardiac baroreflex increases and the relevance of the cardiopulmonary pathway decreases during head-up tilt. The study demonstrates the high specificity of CSE and the high flexibility of CJTE over real data and proves that they are particularly helpful in disentangling physiological mechanisms and in assessing their different contributions to the overall cardiovascular regulation.

Introduction: Needlesticks and cuts are the most common occupational injuries in healthcare workers (HCWs). Directive 2010/32/EU defines principles and preventive interventions., Objectives: To assess, in hospitals participating in the Italian Study on Occupational Risk of HIV (SIROH) project, which are very active in prevention, the degree of application of the measures provided for by the Directive, prior to its incorporation into Italian law., Methods: An open questionnaire covering the 9 focal points of the Directive, as a guide for a presentation at the SIROH meeting in 2013., Results: Of 100 SIROH hospitals, 97% and 96% respectively provide specific information and education initiatives (54% and 73% of which expressly for new employees). All centres reinforce the ban on recapping, and 30 monitor its application by inspecting sharps containers; all hospitals place containers on mobile trolleys and 78 provide operating procedures for their replacement; all introduced at least one needlestick-prevention device (NPD; 4 on average, range 1-11), most frequently intravenous catheters (91%) and winged needles (87%), but 39% only in selected units; 14 centres implemented initiatives to eliminate unnecessary needles. Regarding hepatitis B, all centres screen and vaccinate HCWs but only 78% monitor their response: 89% of HCWs were immunized. Post-exposure management protocols, although based on the same rationale, differ significantly causing considerable differences in  costs., Conclusions: Most of the preventive interventions covered by the Directive were implemented in SIROH hospitals. It is necessary to invest in NPD availability and dissemination, elimination of unnecessary needles, and streamline post-exposure protocols. The situation in the remaining Italian facilities should be investigated.

The study compares permutation-based and coarse-grained entropy approaches for the assessment of complexity of short heart period (HP) variability recordings. Shannon permutation entropy (SPE) and conditional permutation entropy (CPE) are computed as examples of permutation-based entropies, while the k-nearest neighbor conditional entropy (KNNCE) is calculated as an example of coarse-grained conditional entropy. SPE, CPE and KNNCE were applied to ad-hoc simulated autoregressive processes corrupted by increasing amounts of broad band noise and to real HP variability series recorded after complete vagal blockade obtained via administration of a high dose of atropine (AT) in nine healthy volunteers and during orthostatic challenge induced by 90° head-up tilt (T90) in 15 healthy individuals. Over the simulated series the performances of SPE and CPE degraded more rapidly with the amplitude of the superimposed broad band noise than those of KNNCE. Over real data KNNCE identified the expected decrease of the HP variability complexity both after AT and during T90. Conversely SPE and CPE detected the decrease of HP variability complexity solely during T90 as a likely result of the more favorable signal-to-noise ratio during T90 than after AT. Results derived from both simulations and real data indicated that permutation-based entropies had a larger susceptibility to broad band noise than KNNCE. We recommend caution in applying permutation-based entropies in presence of short HP variability series characterized by a low signal-to-noise ratio.

Two diverse complexity metrics quantifying time irreversibility and local prediction, in connection with a surrogate data approach, were utilized to detect nonlinear dynamics in short heart period (HP) variability series recorded in fetuses, as a function of the gestational period, and in healthy humans, as a function of the magnitude of the orthostatic challenge. The metrics indicated the presence of two distinct types of nonlinear HP dynamics characterized by diverse ranges of time scales. These findings stress the need to render more specific the analysis of nonlinear components of HP dynamics by accounting for different temporal scales.

We propose a symbolic analysis framework for the quantitative characterization of complex dynamical systems. It allows the description of the time course of a single variable, the assessment of joint interactions and an analysis triggered by a conditioning input. The framework was applied to spontaneous variability of heart period (HP), systolic arterial pressure (SAP) and integrated muscle sympathetic nerve activity (MSNA) with the aim of characterizing cardiovascular control and nonlinear influences of respiration at rest in supine position, during orthostatic challenge induced by 80° head-up tilt (TILT) and about 3 min before evoked pre-syncope signs (PRESY). The approach detected (i) the exaggerated sympathetic modulation and vagal withdrawal from HP variability and the increased presence of fast MSNA variability components during PRESY compared with TILT; (ii) the increase of the SAP-HP coordination occurring at slow temporal scales and a decrease of that occurring at faster time scales during PRESY compared with TILT; (iii) the reduction of the coordination between fast MSNA and SAP patterns during TILT and PRESY; (iv) the nonlinear influences of respiration leading to an increased likelihood to observe the abovementioned findings during expiration compared with inspiration one. The framework provided simple, quantitative indexes able to distinguish experimental conditions characterized by different states of the autonomic nervous system and to detect the early signs of a life threatening situation such as postural syncope., (© 2014 The Author(s) Published by the Royal Society. All rights reserved.)

We studied the autonomic response to an orthostatic challenge (i.e. head-up tilt) in 52 amyotrophic lateral sclerosis (ALS) patients and 16 healthy subjects by means of power spectral analysis of heart period (HP) and systolic arterial pressure (SAP) variability. In addition, we verified the correlation of spectral indexes with clinical features of the ALS patients. Results showed that cardiovascular control of the ALS patients was impaired and this impairment was more evident from SAP series. While the revised Functional Rating Scale score, its bulbar subscore, and disease duration were uncorrelated with spectral indexes, the rate of the disease progression was positively correlated with the absolute low frequency power of SAP variability at rest and negatively correlated with the normalized high frequency power of HP variability during head-up tilt. We conclude that: i) spectral analysis of HP and SAP variability provides indexes helpful to quantify the impairment of the cardiovascular neural control in ALS patients; ii) patients with a faster disease progression are characterized by a higher vascular sympathetic drive and/or a depressed vagal cardiac regulation.

The study investigates the two different aspects of the baroreflex control resulting in two baroreflex sensitivity (BRS) indexes: i) sympathetic BRS (sBRS); ii) cardiac BRS (cBRS). sBRS was assessed as the slope of the regression line of the conditional probability of detecting a burst on the integrated muscle nerve sympathetic activity (MSNA) given an assigned diastolic arterial pressure (DAP) on DAP. cBRS was estimated from spontaneous heart period (HP) and systolic arterial pressure (SAP) via a spectral approach in the low (0.04-0-15 Hz) and high (0.15-0.5 Hz) frequency bands respectively. Both sBRS and cBRS were assessed in eight healthy subjects undergoing three experimental sessions: supine resting position (REST), 80 degrees head-up tilt test (TILT) and before the occurrence of pre-syncope symptoms (TILT&#95;PRE). Results showed a decrease of both sBRS and cBRS during TILT and a baroreflex impairment during TILT&#95;PRE. sBRS and cBRS were linearly correlated during TILT but became uncorrelated during TILT&#95;PRE. Findings suggest a failure of both "baroreflexes" and their disassociation during TILT&#95;PRE.

This study was designed to characterize in time, frequency and information domains heart period (HP) and QT interval variabilities in asymptomatic (ASYMP) long QT syndrome type 2 (LQT2) subjects. HP, approximated as the temporal distance between two consecutive R-wave peaks, and QT, approximated as the temporal distance between the R-wave peak and the T-wave offset, were automatically derived from 24h Holter recordings in 10 ASYMP LQT2 patients and 13 healthy non mutation carriers (NMC) subjects. All analyses were carried out during DAY (from 2 to 6 PM) and NIGHT (from 12 to 4 AM). Mean, variance, spectral power and complexity indices at short, medium and long time scales were assessed over HP and QT beat-to-beat series. Circadian rhythmicity was evident in both NMC and ASYMP LQT2 but ASYMP LQT2 subjects were characterized by higher HP, QT interval and HP variability during both DAY and NIGHT. In addition, multiscale complexity analysis was able to differentiate the groups by showing a higher HP complexity and a lower QT complexity at long time scales in ASYMP LQT2 during DAY. ASYMP LQT2 exhibited a different autonomic control compared to NMC and such a differentiation could be protective and assure them a lower risk profile.

17β-HSD2 is a promising new target for the treatment of osteoporosis. In this paper, a rational strategy to overcome the metabolic liability in the 2,5-thiophene amide class of 17β-HSD2 inhibitors is described, and the biological activity of the new inhibitors. Applying different strategies, as lowering the cLogP or modifying the structures of the molecules, compounds 27, 31 and 35 with strongly improved metabolic stability were obtained. For understanding biotransformation in the 2,5-thiophene amide class the main metabolic pathways of three properly selected compounds were elucidated., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) is responsible for the oxidation of the highly active estradiol (E2) and testosterone (T) into the less potent estrone (E1) and Δ(4)-androstene-3,17-dione (Δ(4)-AD), respectively. As 17β-HSD2 is present in bones and as estradiol and testosterone are able to induce bone formation and repress bone resorption, inhibition of this enzyme could be a new promising approach for the treatment of osteoporosis. Herein, we describe the design, the synthesis and the biological evaluation of 24 new 17β-HSD2 inhibitors in the 5-substituted thiophene-2-carboxamide class. Structure-activity and structure-selectivity relationships have been explored by variation of the sulfur atom position in the central core, exchange of the thiophene by a thiazole, substitution of the amide group with a larger moiety, exchange of the N-methylamide group with bioisosteres like N-methylsulfonamide, N-methylthioamide and ketone, and substitutions at positions 2 and 3 of the thiophene core with alkyl and phenyl groups leading to 2,3,5-trisubstituted thiophene derivatives. The compounds were evaluated on human and mouse enzymes. From this study, a novel highly potent and selective compound in both human and mouse 17β-HSD2 enzymes was identified, compound 21 (IC50(h17β-HSD2) = 235 nM, selectivity factor toward h17β-HSD1 = 95, IC50 (m17β-HSD2) = 54 nM). This new compound 21 could be used for an in vivo proof of principle to demonstrate the true therapeutic efficacy of 17β-HSD2 inhibitors in osteoporosis. New structural insights into the active sites of the human and mouse enzymes were gained., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

We tested the hypothesis that causality analysis, applied to the spontaneous beat-to-beat variability of heart period (HP) and systolic arterial pressure (SAP), can identify the improvement of autonomic control linked to plantar mechanical stimulation in patients with Parkinson's disease (PD). A causality index, measuring the strength of the association from SAP to HP variability, and derived according to the Granger paradigm (i.e. SAP causes HP if the inclusion of SAP into the set of signals utilized to describe cardiovascular interactions improves the prediction of HP series), was calculated using both linear model-based (MB) and nonlinear model-free (MF) approaches. Univariate HP and SAP variability indices in time and frequency domains, and bivariate descriptors of the HP-SAP variability interactions were computed as well. We studied ten PD patients (age range: 57-78 years; Hoehn-Yahr scale: 2-3; six males, four females) without orthostatic hypotension or symptoms of orthostatic intolerance and 'on-time' according to their habitual pharmacological treatment. PD patients underwent recordings at rest in a supine position and during a head-up tilt before, and 24 h after, mechanical stimulation was applied to the plantar surface of both feet. The MF causality analysis indicated a greater involvement of baroreflex in regulating HP-SAP variability interactions after mechanical stimulation. Remarkably, MB causality and more traditional univariate or bivariate techniques could not detect changes in cardiovascular regulation after mechanical stimulation, thus stressing the importance of accounting for nonlinear dynamics in PD patients. Due to the higher statistical power of MF causality we suggest its exploitation to monitor the baroreflex control improvement in PD patients, and we encourage the clinical application of the Granger causality approach to evaluate the modification of the autonomic control in relation to the application of a pharmacological treatment, a rehabilitation procedure or external intervention.