Extending the spectral decomposition of Granger causality to include instantaneous influences: application to the control mechanisms of heart rate variability.

Assessing Granger causality (GC) intended as the influence, in terms of reduction of variance of surprise, that a driver variable exerts on a given target, requires a suitable treatment of 'instantaneous' effects, i.e. influences due to interactions whose time scale is much faster than the time resolution of the measurements, due to unobserved confounders or insufficient sampling rate that cannot be increased because the mechanism of generation of the variable is inherently slow (e.g. the heartbeat). We exploit a recently proposed framework for the estimation of causal influences in the spectral domain and include instantaneous interactions in the modelling, thus obtaining (i) a novel index of undirected instantaneous causality and (ii) a novel measure of GC including instantaneous effects. An effective procedure to speed up the optimization of parameters in this frame is also presented. After illustrating the proposed formalism in a theoretical example, we apply it to two datasets of cardiovascular and respiratory time series and compare the values obtained within the frequency bands of physiological interest by the proposed total measure of causality with those derived from the standard GC analysis. We find that the inclusion of instantaneous causality allows us to correctly disentangle the baroreflex mechanism from the effects related to cardiorespiratory interactions. Moreover, studying how controlling the respiratory rhythm acts on cardiovascular interactions, we document an increase of the direct (non-baroreflex mediated) influence of respiration on the heart rate in the respiratory frequency band when switching from spontaneous to paced breathing. This article is part of the theme issue 'Advanced computation in cardiovascular physiology: new challenges and opportunities'.

Impact of the COVID-19 outbreak on acute stroke pathways - insights from the Alsace region in France.

BACKGROUND AND PURPOSE: To date, no study has attempted to quantify the impact of the COVID-19 outbreak on the incidence and treatment of acute stroke. METHODS: This was a retrospective review of acute stroke pathway parameters in all three stroke units in the Alsace region during the first month of the outbreak (1-31 March 2020), using the similar period from 2019 as a comparator. A secondary detailed analysis of all stroke alerts and stroke unit admissions was performed in the centre with the largest case volume. RESULTS: Compared to the same period in 2019, in March 2020 there were 39.6% fewer stroke alerts and 33.3% fewer acute revascularization treatments [40.9% less intravenous thrombolysis (IVT) and 27.6% less mechanical thrombectomy (MT)]. No marked variation was observed in the number of stroke unit admissions (-0.6%). The proportion of patients with acute revascularization treatments (IVT or MT) out of the total number of stroke unit admissions was significantly lower in March 2020 (21.3%) compared to 2019 (31.8%), P = 0.034. There were no significant differences in time delays or severity of clinical symptoms for patients treated by IVT or MT, nor in the distribution of final diagnosis amongst stroke alerts and stroke unit admissions. CONCLUSION: These results suggest that the overall incidence of stroke remained the same, but fewer patients presented within the therapeutic time window. Increased public awareness and corrective measures are needed to mitigate the deleterious effects of the COVID-19 outbreak on acute stroke care.

Updated Summation Model: An Improved Agreement with the Daya Bay Antineutrino Fluxes.

A new summation method model of the reactor antineutrino energy spectrum is presented. It is updated with the most recent evaluated decay databases and with our total absorption gamma-ray spectroscopy measurements performed during the last decade. For the first time, the spectral measurements from the Daya Bay experiment are compared with the antineutrino energy spectrum computed with the updated summation method without any renormalization. The results exhibit a better agreement than is obtained with the Huber-Mueller model in the 2-5 MeV range, the region that dominates the detected flux. A systematic trend is found in which the antineutrino flux computed with the summation model decreases with the inclusion of more pandemonium-free data. The calculated flux obtained now lies only 1.9% above that detected in the Daya Bay experiment, a value that may be reduced with forthcoming new pandemonium-free data, leaving less room for a reactor anomaly. Eventually, the new predictions of individual antineutrino spectra for the ^{235}U, ^{239}Pu, ^{241}Pu, and ^{238}U are used to compute the dependence of the reactor antineutrino spectral shape on the fission fractions.

Large Impact of the Decay of Niobium Isomers on the Reactor ν[over ¯]_{e} Summation Calculations.

Even mass neutron-rich niobium isotopes are among the principal contributors to the reactor antineutrino energy spectrum. They are also among the most challenging to measure due to the refractory nature of niobium, and because they exhibit isomeric states lying very close in energy. The ß-intensity distributions of ^{100gs,100m}Nb and ^{102gs,102m}Nb ß decays have been determined using the total absorption γ-ray spectroscopy technique. The measurements were performed at the upgraded Ion Guide Isotope Separator On-Line facility at the University of Jyväskylä. Here, the double Penning trap system JYFLTRAP was employed to disentangle the ß decay of the isomeric states. The new data obtained in this challenging measurement have a large impact in antineutrino summation calculations. For the first time the discrepancy between the summation model and the reactor antineutrino measurements in the region of the shape distortion has been reduced.

Anomalies in the Charge Yields of Fission Fragments from the

Fast-neutron-induced fission of ^{238}U at an energy just above the fission threshold is studied with a novel technique which involves the coupling of a high-efficiency γ-ray spectrometer (MINIBALL) to an inverse-kinematics neutron source (LICORNE) to extract charge yields of fission fragments via γ-γ coincidence spectroscopy. Experimental data and fission models are compared and found to be in reasonable agreement for many nuclei; however, significant discrepancies of up to 600% are observed, particularly for isotopes of Sn and Mo. This indicates that these models significantly overestimate the standard 1 fission mode and suggests that spherical shell effects in the nascent fission fragments are less important for low-energy fast-neutron-induced fission than for thermal neutron-induced fission. This has consequences for understanding and modeling the fission process, for experimental nuclear structure studies of the most neutron-rich nuclei, for future energy applications (e.g., Generation IV reactors which use fast-neutron spectra), and for the reactor antineutrino anomaly.

Enhanced γ-Ray Emission from Neutron Unbound States Populated in ß Decay.

Total absorption spectroscopy is used to investigate the ß-decay intensity to states above the neutron separation energy followed by γ-ray emission in (87,88)Br and (94)Rb. Accurate results are obtained thanks to a careful control of systematic errors. An unexpectedly large γ intensity is observed in all three cases extending well beyond the excitation energy region where neutron penetration is hindered by low neutron energy. The γ branching as a function of excitation energy is compared to Hauser-Feshbach model calculations. For (87)Br and (88)Br the γ branching reaches 57% and 20%, respectively, and could be explained as a nuclear structure effect. Some of the states populated in the daughter can only decay through the emission of a large orbital angular momentum neutron with a strongly reduced barrier penetrability. In the case of neutron-rich (94)Rb the observed 4.5% branching is much larger than the calculations performed with standard nuclear statistical model parameters, even after proper correction for fluctuation effects on individual transition widths. The difference can be reconciled by introducing an enhancement of 1 order of magnitude in the photon strength to neutron strength ratio. An increase in the photon strength function of such magnitude for very neutron-rich nuclei, if it proves to be correct, leads to a similar increase in the (n,γ) cross section that would have an impact on r process abundance calculations.

Total Absorption Spectroscopy Study of (92)Rb Decay: A Major Contributor to Reactor Antineutrino Spectrum Shape.

The antineutrino spectra measured in recent experiments at reactors are inconsistent with calculations based on the conversion of integral beta spectra recorded at the ILL reactor. (92)Rb makes the dominant contribution to the reactor antineutrino spectrum in the 5-8 MeV range but its decay properties are in question. We have studied (92)Rb decay with total absorption spectroscopy. Previously unobserved beta feeding was seen in the 4.5-5.5 region and the GS to GS feeding was found to be 87.5(25)%. The impact on the reactor antineutrino spectra calculated with the summation method is shown and discussed.

A checklist for critical appraisal of indirect comparisons.

The aim of this study was to develop a user-friendly checklist for critical appraisal of indirect comparisons of drugs, considering clinical, methodological/statistical and quality aspects, mainly to be applied in drug evaluation in the decision-making context. After conducting a review of the literature, we used group consensus to establish the key points of the checklist, focusing mainly on indirect comparisons, but including topics related to network meta-analysis or multiple treatment comparisons. The coordinating group elaborated the first draft, which was reviewed by external experts, re-evaluated by the coordinating group and finally assessed by 23 drug evaluation experts trained in indirect comparisons, who applied the checklist to one study. The Kappa index of agreement was calculated and the final checklist was developed by group consensus including the external experts. The checklist has two parts. The first consists of three eliminatory key questions while the second includes 17 items: 5 regarding quality, 5 regarding clinical issues and 7 dealing with methodology/statistics. The median kappa values of the 23 evaluations were 0.83 (range 0.67-0.93), 0.61 (0.54-0.91) and 0.36 (0.22-1) with regard to quality, clinical aspects and methodology/statistics, respectively. A structured checklist was developed to facilitate critical appraisal of key issues in indirect comparisons, including comments for assessing the consequences of its application to drug evaluation in the decision-making context. Agreement between reviewers in clinical and quality items was good, but weaker in methodology/statistics ones.

In vitro fertilization: an unexpected finding in a cohort of patients with biliary atresia.

In biliary atresia (BA), efforts to prevent premature liver transplantation (LT) are aimed at early diagnosis, timing of Kasai-portoenterostomy (KPE), and centralization of care. This report presents the clinical picture, treatment strategies, and outcomes of BA patients with no previous treatment. A retrospective cohort study (Jan/2001 to Jan/2021) was conducted to evaluate the outcome of patients with BA referred to a single team. Study groups were: 1) Kasai-only group (K-only) n=9), 2) LT-only group (n=7), and 3) Kasai+LT group (K+LT) (n=23). Survival with native liver and overall survival were 22.9 and 94.8%, respectively, at 120 months of follow-up. There was no difference in age at KPE in the K-only group (46.8±21.8 days) vs K+LT (52.1±22 days), P=0.4. Ten (25.6%) patients were babies conceived through in vitro fertilization (IVF). Four IVF patients (40%) presented associated congenital heart disease vs 5 patients (17%) in the remaining group (P=0.14). Two of the IVF patients were premature (<37 weeks). Median maternal age at birth was 35 years (33 to 41 years). Excellent patient survival is expected for patients with BA with the available treatment strategies. IVF+BA was an unexpected prevalent association in this cohort, and further studies are required to better understand these findings.

New antineutrino energy spectra predictions from the summation of beta decay branches of the fission products.

In this Letter, we study the impact of the inclusion of the recently measured beta decay properties of the (102;104;105;106;107)Tc, (105)Mo, and (101)Nb nuclei in an updated calculation of the antineutrino energy spectra of the four fissible isotopes (235,238)U and (239,241)Pu. These actinides are the main contributors to the fission processes in pressurized water reactors. The beta feeding probabilities of the above-mentioned Tc, Mo, and Nb isotopes have been found to play a major role in the γ component of the decay heat of (239)Pu, solving a large part of the γ discrepancy in the 4-3000 s range. They have been measured by using the total absorption technique, insensitive to the pandemonium effect. The calculations are performed by using the information available nowadays in the nuclear databases, summing all the contributions of the beta decay branches of the fission products. Our results provide a new prediction of the antineutrino energy spectra of (235)U, (239,241)Pu, and, in particular, (238)U for which no measurement has been published yet. We conclude that new total absorption technique measurements are mandatory to improve the reliability of the predicted spectra.

IFNγ-dependent silencing of TFF1 during Helicobacter pylori infection.

Chronic Helicobacter pylori infection is the leading cause of intestinal-type adenocarcinoma, as prolonged Helicobacter colonization triggers chronic active gastritis, which may evolve into adenocarcinoma of the intestinal type. In this environment, cytokines play a significant role in determining the evolution of the infection. In combination with other factors (genetic, environmental and nutritional), the pro-inflammatory response may trigger pro-oncogenic mechanisms that lead to the silencing of tumour-suppressor genes, such as trefoil factor 1 (TFF1). The latter is known to play a protective role by maintaining the gastric mucosa integrity and retaining H. pylori in the mucus layer, preventing the progression of infection and, consequently, the development of gastric cancer (GC). Since TFF1 expression is reduced during chronic Helicobacter infection with a loss of gastric mucosa protection, we investigated the molecular pathways involved in this reduction. Specifically, we evaluated the effect of some pro-inflammatory cytokines on TFF1 regulation in GC and primary gastric cells by RT-qPCR and luciferase reporter assay analyses and the repressor role of the transcription factor C/EBPß, overexpressed in gastric-intestinal cancer. Our results show that, among several cytokines, IFNγ stimulates C/EBPß expression, which acts as a negative regulator of TFF1 by binding its promoter at three different sites.

Intracranial compliance in type 2 diabetes mellitus and its relationship with the cardiovascular autonomic nervous control.

The intracranial compliance in type 2 diabetes mellitus (T2DM) patients and the association with cardiovascular autonomic control have not been fully elucidated. The aim of this study was to assess intracranial compliance using the noninvasive intracranial pressure (niICP) and the monitoring of waveform peaks (P1, P2, and P3) and the relationship with cardiovascular autonomic control in T2DM patients. Thirty-two men aged 40-60 years without cardiovascular autonomic neuropathy (CAN) were studied: T2DMG (n=16) and control group CG (n=16). The niICP was evaluated by a noninvasive extracranial sensor placed on the scalp. Cardiovascular autonomic control was evaluated by indices of the baroreflex sensitivity (BRS), from temporal series of R-R intervals of electrocardiogram and systolic arterial pressure, during supine and orthostatic positions. The participants remained in the supine position for 15 min and then 15 min more in orthostatism. T2DMG presented a decrease of the P2/P1 ratio during the orthostatic position (P<0.001). There was a negative moderate correlation between the P2 peak with cardiovascular coupling (K2HP-SAPLF) in supine (r=-0.612, P=0.011) and orthostatic (r=-0.568, P=0.020) positions in T2DMG. We concluded that T2DM patients without CAN and cardiovascular complications presented intracranial compliance similar to healthy subjects. Despite preserved intracranial adjustments, T2DM patients had a response of greater magnitude in orthostatism. In addition, the decoupling between the heart period and blood pressure signal oscillations in low frequency appeared to be related to the worsening of intracranial compliance due to the increased P2 peak.

Topsoil radiological characterisation of L-54M reactor surroundings preliminary to decommissioning operations.

The radiological characterization of the topsoil of the L-54M reactor surroundings carried out in this work aims at obtaining the reference blank point for the forthcoming decommissioning operations and ascertain if unexpected radionuclide release occurred during the operational life of the plant. Standardised methods have been employed in order to collect representative samples and reliable results. Suitable sample pre-treatment procedures were applied. Gamma and beta spectrometric analyses were carried out to measure the activity concentrations of 60Co 137Cs, 152Eu, 241Am and 90Sr. These have been considered as representative radionuclides that could have been originated from reactor operations and that could still be present at four decades post reactor shutdown.

Baroreflex sensitivity in frailty syndrome.

Frailty is related to a decrease in the physiological reserves, which causes difficulties in maintaining homeostasis. An example of physiological mechanisms for cardiovascular homeostasis is the baroreflex. The aim of this study was to compare baroreflex among frail, prefrail, and nonfrail individuals, in supine and orthostatic positions. Community-dwelling older adults were evaluated and categorized into frail, prefrail, or nonfrail groups, according to frailty phenotype. The RR interval (RRi) and systolic blood pressure (SBP) series were recorded for 15 min in the supine and 15 min in the orthostatic positions. Mean and variance of RRi and SBP, and baroreflex evaluated by phase, gain (α), and coherence (K2) were determined. A two-way repeated measures ANOVA, with Tukey's post hoc, was applied for group, position, and their interaction effects. The significance level established was 5%. Prefrail and frail participants did not present a significant decrease in mean values of RRi after postural challenge (893.43 to 834.20 ms and 925.99 to 857.98 ms, respectively). Frail participants showed a reduction in RRi variance in supine to orthostatic (852.04 to 232.37 ms2). Prefrail and frail participants showed a decrease in K2 after postural change (0.69 to 0.52 and 0.54 to 0.34, respectively). Frail participants exhibited lower values of K2 (0.34) compared to nonfrail and prefrail participants (0.61 and 0.52, respectively). Baroreflex indicated the presence of decoupling between heart period and SBP in frail and prefrail. Thus, reduced K2 might be a marker of the frailty process.

Effects of different classroom temperatures on cardiac autonomic control and cognitive performances in undergraduate students.

OBJECTIVE: Indoor microclimate may affect students' wellbeing, cardiac autonomic control and cognitive performance with potential impact on learning capabilities. To assess the effects of classroom temperature variations on the autonomic profile and students' cognitive capabilities. APPROACH: Twenty students attending Humanitas University School, (14M, age 21 ± 3 years) underwent a single-lead ECG continuous recording by a portable device during a 2 h lecture when classroom temperature was set 'neutral' (20 °C-22 °C, Day 1) and when classroom temperature was set to 24 °C-26 °C (Day 2). ECGs were sent by telemetry to a server for off-line analysis. Spectral analysis of RR variability provided indices of cardiac sympathetic (LFnu), vagal (HF, HFnu) and cardiac sympatho-vagal modulation (LF/HF). Symbolic analysis of RR variability provided the percentage of sequences of three heart periods with no significant change in RR interval (0V%) and with two significant variations (2V%) reflecting cardiac sympathetic and vagal modulation, respectively. Students' cognitive performance (memory, verbal comprehension and reasoning) was assessed at the end of each lecture using the Cambridge Brain Sciences cognitive evaluation tool. MAIN RESULTS: Classroom temperature and CO2 were assessed every 5 min. Classroom temperatures were 22.4 °C ± 0.1 °C (Day 1) and 26.2 °C ± 0.1 °C (Day 2). Student's thermal comfort was lower during Day 2 compared to Day 1. HR, LF/HF and 0V% were greater during Day 2 (79.5 ± 12.1 bpm, 6.9 ± 7.1 and 32.8% ± 10.3%) than during Day 1 (72.6 ± 10.8 bpm, 3.4 ± 3.7, 21.4% ± 9.2%). Conversely, 2V% was lower during Day 2 (23.1% ± 8.1%) than during Day 1 (32.3% ± 11.4%). Short-term memory, verbal ability and the overall cognitive C-score scores were lower during Day 2 (10.3 ± 0.3; 8.1 ± 1.2 and 10.9 ± 2.0) compared to Day 1 (11.7 ± 2.1; 10.7 ± 1.7 and 12.6 ± 1.8). SIGNIFICANCE: During Day 2, a shift of the cardiac autonomic control towards a sympathetic predominance was observed compared to Day 1, in the presence of greater thermal discomfort. Furthermore, during Day 2 reduced cognitive performances were found.

Univariate and multivariate conditional entropy measures for the characterization of short-term cardiovascular complexity under physiological stress.

OBJECTIVE: A defining feature of physiological systems under the neuroautonomic regulation is their dynamical complexity. The most common approach to assess physiological complexity from short-term recordings, i.e. to compute the rate of entropy generation of an individual system by means of measures of conditional entropy (CE), does not consider that complexity may change when the investigated system is part of a network of physiological interactions. This study aims at extending the concept of short-term complexity towards the perspective of network physiology, defining multivariate CE measures whereby multiple physiological processes are accounted for in the computation of entropy rates. APPROACH: Univariate and multivariate CE measures are computed using state-of-the-art methods for entropy estimation and applied to time series of heart period (H), systolic (S) and diastolic (D) arterial pressure, and respiration (R) variability measured in healthy subjects monitored in a resting state and during conditions of postural and mental stress. MAIN RESULTS: Compared with the traditional univariate metric of short-term complexity, multivariate measures provide additional information with plausible physiological interpretation, such as (i) the dampening of respiratory sinus arrhythmia and activation of the baroreflex control during postural stress; (ii) the increased complexity of heart period and blood pressure variability during mental stress, reflecting the effect of respiratory influences and upper cortical centers; (iii) the strong influence of D on S, mediated by left ventricular ejection fraction and vascular properties; (iv) the role of H in reducing the complexity of D, related to cardiac run-off effects; and (v) the unidirectional role of R in influencing cardiovascular variability. SIGNIFICANCE: Our results document the importance of employing a network perspective in the evaluation of the short-term complexity of cardiovascular and respiratory dynamics across different physiological states.

Risk analysis of technological hazards: Simulation of scenarios and application of a local vulnerability index.

The potential impact of a technological accident can be assessed by risk estimation. Taking this into account, the latent or potential condition can be warned and mitigated. In this work we propose a methodology to estimate risk of technological hazards, focused on two components. The first one is the processing of meteorological databases to define the most probably and conservative scenario of study, and the second one, is the application of a local social vulnerability index to classify the population. In this case of study, the risk was estimated for a hypothetical release of liquefied ammonia in a meat-packing industry in the city of La Plata, Argentina. The method consists in integrating the simulated toxic threat zone with ALOHA software, and the layer of sociodemographic classification of the affected population. The results show the areas associated with higher risks of exposure to ammonia, which are worth being addressed for the prevention of disasters in the region. Advantageously, this systemic approach is methodologically flexible as it provides the possibility of being applied in various scenarios based on the available information of both, the exposed population and its meteorology. Furthermore, this methodology optimizes the processing of the input data and its calculation.

In vitro fertilization: an unexpected finding in a cohort of patients with biliary atresia

In biliary atresia (BA), efforts to prevent premature liver transplantation (LT) are aimed at early diagnosis, timing of Kasai-portoenterostomy (KPE), and centralization of care. This report presents the clinical picture, treatment strategies, and outcomes of BA patients with no previous treatment. A retrospective cohort study (Jan/2001 to Jan/2021) was conducted to evaluate the outcome of patients with BA referred to a single team. Study groups were: 1) Kasai-only group (K-only) n=9), 2) LT-only group (n=7), and 3) Kasai+LT group (K+LT) (n=23). Survival with native liver and overall survival were 22.9 and 94.8%, respectively, at 120 months of follow-up. There was no difference in age at KPE in the K-only group (46.8±21.8 days) vs K+LT (52.1±22 days), P=0.4. Ten (25.6%) patients were babies conceived through in vitro fertilization (IVF). Four IVF patients (40%) presented associated congenital heart disease vs 5 patients (17%) in the remaining group (P=0.14). Two of the IVF patients were premature (<37 weeks). Median maternal age at birth was 35 years (33 to 41 years). Excellent patient survival is expected for patients with BA with the available treatment strategies. IVF+BA was an unexpected prevalent association in this cohort, and further studies are required to better understand these findings.

Dominant active alleles of RIM101 (PRR2) bypass the pH restriction on filamentation of Candida albicans.

Morphological development of the fungal pathogen Candida albicans is profoundly affected by ambient pH. Acidic pH restricts growth to the yeast form, whereas neutral pH permits development of the filamentous form. Superimposed on the pH restriction is a temperature requirement of approximately 37 degrees C for filamentation. The role of pH in development was investigated by selecting revertants of phr2Delta mutants that had gained the ability to grow at acid pH. The extragenic suppressors in two independent revertants were identified as nonsense mutations in the pH response regulator RIM101 (PRR2) that resulted in a carboxy-terminal truncation of the open reading frame. These dominant active alleles conferred the ability to filament at acidic pH, to express PHR1, an alkaline-expressed gene, at acidic pH, and to repress the acid-expressed gene PHR2. It was also observed that both the wild-type and mutant alleles could act as multicopy suppressors of the temperature restriction on filamentation, allowing extensive filamentation at 29 degrees C. The ability of the activated alleles to promote filamentation was dependent upon the developmental regulator EFG1. The results suggest that RIM101 is responsible for the pH dependence of hyphal development.