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Background: Traditional methods for the quantification of OSA severity may not encapsulate potential relationships between hypoxemia in OSA and cardiovascular risk., Research Question: Do novel nocturnal oxygen saturation (Spo 2 ) metrics have prognostic value in patients with OSA and high cardiovascular event risk?, Study Design and Methods: We conducted post hoc analyses of the Sleep Apnea Cardiovascular Endpoints (SAVE) trial. In 2687 individuals, Cox proportional hazards models that were stratified for treatment allocation were used to determine the associations between clinical characteristics, pulse oximetry-derived metrics that were designed to quantify sustained and episodic features of hypoxemia, and cardiovascular outcomes. Metrics included oxygen desaturation index, time <90% Spo 2 , average Spo 2 for the entire recording (mean Spo 2 ), average Spo 2 during desaturation events (desaturation Spo 2 ), average baseline Spo 2 interpolated across episodic desaturation events (baseline Spo 2 ), episodic desaturation event duration and desaturation/resaturation-time ratio, and mean and SD of pulse rate., Results: Neither apnea-hypopnea index, oxygen desaturation index, nor any of the novel Spo 2 metrics were associated with the primary SAVE composite cardiovascular outcome. Mean and baseline Spo 2 were associated with heart failure (hazard ratio [HR], 0.81; 95% CI, 0.69-0.95; P = .009; and HR, 0.78; 95% CI, 0.67-0.90; P = .001, respectively) and myocardial infarction (HR, 0.86; 95% CI, 0.77-0.95; P = .003; and HR, 0.81; 95% CI, 0.73-0.90; P < .001, respectively). Desaturation duration and desaturation/resaturation time ratio, with established risk factors, predicted future heart failure (area under the curve, 0.86; 95% CI, 0.79-0.93)., Interpretation: Apnea-hypopnea index and oxygen desaturation index were not associated with cardiovascular outcomes. In contrast, the pattern of oxygen desaturation was associated with heart failure and myocardial infarction. However, concomitant risk factors remained the predominant determinants for secondary cardiovascular events and thus deserve the most intensive management., (Copyright © 2020. Published by Elsevier Inc.)

Objective: This study seeks to decompose QT variability (QTV) into physiological sources and assess their role for risk stratification in patients post myocardial infarction (MI). We hypothesize that the magnitude of QTV that cannot be explained by heart rate or respiration carries important prognostic information., Background: Elevated beat-to-beat QTV is predictive of cardiac mortality, but the underlying mechanisms, and hence its interpretation, remain opaque., Methods: We decomposed the QTV of 895 patients post MI into contributions by heart rate, respiration, and unexplained sources., Results: Cox proportional hazard analysis demonstrates that augmented oscillations in QTV and their level of dissociation from heart rate are associated with a higher 5-year mortality rate (18.4% vs. 4.7%, p < 0.0001). In patients with left ventricular ejection fraction (LVEF) > 35%, a higher QTV risk score was associated with a significantly higher 5-year mortality rate (16% vs. 4%, p < 0.0001). In patients with a GRACE score ≥ 120, a higher QTV risk score was associated with a significantly higher 5-year mortality (25% vs. 11%, p < 0.001)., Conclusion: Augmented oscillations in QTV and discordance from heart rate, possibly indicative of excessive sympathetic outflow to the ventricular myocardium, predict high risk in patients post MI independent from established risk markers., Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT00196274., (Copyright © 2020 El-Hamad, Bonabi, Müller, Steger, Schmidt and Baumert.)

Study Objectives: Restless sleep disorder (RSD) is a newly recognized condition characterized by motor movements involving large muscle groups with frequent repositioning or bed sheets disruption. We analyzed cyclic alternating pattern (CAP) in these children, a marker of sleep instability that might be associated with the motor episodes of RSD and may play a role in their daytime symptoms., Methods: Polysomnographic recordings from thirty-eight children who fulfilled RSD diagnostic criteria (23 boys and 15 girls), 23 children with restless legs syndrome (RLS, 18 boys and 5 girls) and 19 controls (10 boys and 9 girls) were included. For CAP analysis, a previously developed, highly precise automated system, based on a deep learning recurrent neural network, was used., Results: Age and gender were not statistically different between groups. RSD patients showed a lower percentage of A3 CAP subtypes than controls (median 9.8 vs. 18.2, p = 0.0089), accompanied by shorter duration of the B phase of the CAP cycle (median 28.2 vs. 29.8 in controls, 30.2 in RLS, p = 0.005) and shorter CAP cycle duration than both controls and RLS subjects (median 33.8 vs. 35.0 in controls, 35.8 in RLS, p = 0.002). Finally, RSD children also showed a longer duration of CAP cycle sequences, when compared to controls (median 172.7 vs. 141.9, p = 0.0063)., Conclusions: In conclusion, our study indicates that NREM sleep EEG shows an increased instability in RSD; these findings add to the current knowledge on the mechanisms of this newly recognized sleep disorder and suggest that sleep instability might be a favoring mechanism for the emergence of the motor episodes characterizing RSD., Competing Interests: Disclosure statement This was not an industry-supported study and was partially supported by a fund from the Italian Ministry of Health “Ricerca Corrente” (RC n. 22751598) (R.F.) and by a grant from the Australian Research Council (DP0663345) (S.H., M.B.)., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Study Objectives: To assess the microstructural architecture of non-rapid eye movement (NREM) sleep known as cyclic alternating pattern (CAP) in relation to the age, gender, self-reported sleep quality, and the degree of sleep disruption in large community-based cohort studies of older people., Methods: We applied a high-performance automated CAP detection system to characterize CAP in 2,811 men from the Osteoporotic Fractures in Men Sleep Study (MrOS) and 426 women from the Study of Osteoporotic Fractures (SOF). CAP was assessed with respect to age and gender and correlated to obstructive apnea-hypopnea index, arousal index (AI-NREM), and periodic limb movements in sleep index. Further, we evaluated CAP across levels of self-reported sleep quality measures using analysis of covariance., Results: Age was significantly associated with the number of CAP sequences during NREM sleep (MrOS: p = 0.013, SOF = 0.051). CAP correlated significantly with AI-NREM (MrOS: ρ = 0.30, SOF: ρ = 0.29). CAP rate, especially the A2+A3 index, was inversely related to self-reported quality of sleep, independent of age and sleep disturbance measures. Women experienced significantly fewer A1-phases compared to men, in particular, in slow-wave sleep (N3)., Conclusions: We demonstrate that automated CAP analysis of large-scale databases can lead to new findings on CAP and its subcomponents. We show that sleep disturbance indices are associated with the CAP rate. Further, the CAP rate is significantly linked to subjectively reported sleep quality, independent from traditionally scored markers of sleep fragmentation. Finally, men and women show differences in the microarchitecture of sleep as identified by CAP, despite similar macro-architecture., (© Sleep Research Society 2020. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Results: There were no differences found in the HE4 levels determined for the mothers' blood samples and umbilical cord blood samples in all investigated groups. In comparison with healthy children, the elevated HE4 levels were observed in neonates with TTN. Significant positive correlation between HE4 and CRP as well as PCT levels was observed in all investigated neonates. The receiver operating characteristic (ROC) curve analysis demonstrated the cut-off value for the serum HE4 in the researched neonates at the level of 318.5 pmol/L, yielding the sensitivity of 73.9% and specificity of 66.7% for the early diagnosis of TTN., Conclusions: Serum HE4 could be considered as a candidate biomarker for the early diagnosis of pulmonary dysfunction in the newborns., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2020 Piotr Surmiak et al.)

Dysregulated cholesterol metabolism is implicated in a number of neurological disorders. Many sterols, including cholesterol and its precursors and metabolites, are biologically active and important for proper brain function. However, spatial cholesterol metabolism in brain and the resulting sterol distributions are poorly defined. To better understand cholesterol metabolism in situ across the complex functional regions of brain, we have developed on-tissue enzyme-assisted derivatization in combination with microliquid extraction for surface analysis and liquid chromatography-mass spectrometry to locate sterols in tissue slices (10 µm) of mouse brain. The method provides sterolomic analysis at 400-µm spot diameter with a limit of quantification of 0.01 ng/mm 2 It overcomes the limitations of previous mass spectrometry imaging techniques in analysis of low-abundance and difficult-to-ionize sterol molecules, allowing isomer differentiation and structure identification. Here we demonstrate the spatial distribution and quantification of multiple sterols involved in cholesterol metabolic pathways in wild-type and cholesterol 24S-hydroxylase knockout mouse brain. The technology described provides a powerful tool for future studies of spatial cholesterol metabolism in healthy and diseased tissues., Competing Interests: Competing interest statement: Y.W. and W.J.G. are listed as inventors on the patent “Kit and method for quantitative detection of steroids” US9851368B2., (Copyright © 2020 the Author(s). Published by PNAS.)

Background: It remains unclear whether brain fog is related to impaired cerebral blood flow (CBF) in postural tachycardia syndrome (POTS) patients., Methods: We assessed CBF in the posterior cerebral artery (PCA) using transcranial Doppler with visual stimuli in 11 POTS and 8 healthy subjects in the seated position, followed by neurocognitive testing., Results: CBF parameters were similar between the two groups. POTS patients demonstrated significantly longer latency in delayed match to sample response time and greater errors in attention switching task., Conclusions: Impaired short-term memory and alertness may underlie the symptom of brain fog in POTS patients, despite normal CBF., Competing Interests: The University of Adelaide reports having received on behalf of Dr Lau lecture and/or consulting fees from Abbott Medical, Bayer, Boehringer Ingelheim, Biotronik, BMS Pfizer, and Medtronic., (© 2020 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Heart Rhythm Society.)

Context: Standardized description of external genitalia is needed in the assessment of children with atypical genitalia., Objectives: To validate the External Genitalia Score (EGS), to present reference values for preterm and term babies up to 24 months and correlate obtained scores with anogenital distances (AGDs)., Design, Setting: A European multicenter (n = 8) validation study was conducted from July 2016 to July 2018., Patients and Methods: EGS is based on the external masculinization score but uses a gradual scale from female to male (range, 0-12) and terminology appropriate for both sexes. The reliability of EGS and AGDs was determined by the interclass correlation coefficient (ICC). Cross-sectional data were obtained in 686 term babies (0-24 months) and 181 preterm babies, and 111 babies with atypical genitalia., Results: The ICC of EGS in typical and atypical genitalia is excellent and good, respectively. Median EGS (10th to 90th centile) in males < 28 weeks gestation is 10 (8.6-11.5); in males 28-32 weeks 11.5 (9.2-12); in males 33-36 weeks 11.5 (10.5-12) and in full-term males 12 (10.5-12). In all female babies, EGS is 0 (0-0). The mean (SD) lower/upper AGD ratio (AGDl/u) is 0.45 (0.1), with significant difference between AGDl/u in males 0.49 (0.1) and females 0.39 (0.1) and intermediate values in differences of sex development (DSDs) 0.43 (0.1). The AGDl/u correlates with EGS in males with typical genitalia and in atypical genitalia., Conclusions: EGS is a reliable and valid tool to describe external genitalia in premature and term babies up to 24 months. EGS correlates with AGDl/u in males. It facilitates standardized assessment, clinical decision-making and multicenter research., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Cardiac function is modulated by multiple factors including exogenous (circadian rhythm) and endogenous (ultradian 90-110 min sleep cycle) factors. By evaluating heart rate variability (HRV) during sleep, we will better understand their influence on cardiac activity. The aim of this study was to evaluate HRV in the dark phase of the circadian rhythm during sleep in healthy children and adolescents. Methods: One 3 min segment of pre-sleep electrocardiography (EEG) and 3, 6 min segments of electrocardiography recorded during polysomnography from 75 healthy children and adolescents were sampled during progressive cycles of slow wave sleep (SWS1, SWS2, SWS3). Three, 3 min segments of rapid eye movement sleep (REM) were also assessed, with REM1 marked at the last REM period before awakening. Studies that recorded REM3 prior to SWS3 were used for assessment. HRV variables include the following time domain values: mean NN (average RR intervals over given time), SDNN (Standard Deviation of RR intervals), and RMSSD (root Mean Square of beat-to-beat Differences). Frequency domain values include: low frequency (LF), high frequency (HF), and LF:HF. Results: Mixed linear effects model analysis revealed a significant difference in time and frequency domain values between sleep cycles and stages. Mean NN was lowest (highest heart rate) during pre-sleep then significantly increased across SWS1-3. Mean NN in SWS1 was similar to all REM periods which was significantly lower than both SWS2 and SWS3. SDNN remained at pre-sleep levels until SWS3, and then significantly increased in REM1&2. There was a large drop in LF from pre-sleep to SWS1. As cycles progressed through the night, LF remains lower than awake but increases to awake like levels by REM2. RMSSD and HF were lowest in pre-sleep and increased significantly by SWS1 and remain high and stable across stages and cycles except during the REM3 period where RMSSD decreased. Conclusion: Our results demonstrate that there are considerable changes in the spectral analysis of cardiac function occurring during different sleep stages and between sleep cycles across the night. Hence, time of night and sleep stage need to be considered when reporting any HRV differences., (Copyright © 2020 Kontos, Baumert, Lushington, Kennedy, Kohler, Cicua-Navarro, Pamula and Martin.)

Aims: To investigate the composition of nocturnal hypoxaemic burden and its prognostic value for cardiovascular (CV) mortality in community-dwelling older men., Methods and Results: We analysed overnight oximetry data from polysomnograms obtained in 2840 men from the Outcomes of Sleep Disorders in Older Men (MrOS Sleep) study (ClinicalTrials.gov Identifier: NCT00070681) to determine the number of acute episodic desaturations per hour (oxygen desaturation index, ODI) and time spent below 90% oxygen saturation (T90) attributed to acute desaturations (T90desaturation) and to non-specific drifts in oxygen saturation (T90non-specific), respectively, and their relationship with CV mortality. After 8.8 ± 2.7 years follow-up, 185 men (6.5%) died from CV disease. T90 [hazard ratio (HR) 1.21, P < 0.001], but not ODI (HR 1.13, P = 0.06), was significantly associated with CV death in univariate analysis. T90 remained significant when adjusting for potential confounders (HR 1.16, P = 0.004). Men with T90 > 12 min were at an elevated risk of CV mortality (HR 1.59; P = 0.006). Approximately 20.7 (5.7-48.5) percent of the variation in T90 could be attributed to non-specific drifts in oxygen saturation. T90desaturation and T90non-specific were individually associated with CV death but combining both variables did not improve the prediction., Conclusion: In community-dwelling older men, T90 is an independent predictor of CV mortality. T90 is not only a consequence of frank desaturations, but also reflects non-specific drifts in oxygen saturation, both contributing towards the association with CV death. Whether T90 can be used as a risk marker in the clinical setting and whether its reduction may constitute a treatment target warrants further study., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Brain computer interfaces (BCI) for the rehabilitation of motor impairments exploit sensorimotor rhythms (SMR) in the electroencephalogram (EEG). However, the neurophysiological processes underpinning the SMR often vary over time and across subjects. Inherent intra- and inter-subject variability causes covariate shift in data distributions that impede the transferability of model parameters amongst sessions/subjects. Transfer learning includes machine learning-based methods to compensate for inter-subject and inter-session (intra-subject) variability manifested in EEG-derived feature distributions as a covariate shift for BCI. Besides transfer learning approaches, recent studies have explored psychological and neurophysiological predictors as well as inter-subject associativity assessment, which may augment transfer learning in EEG-based BCI. Here, we highlight the importance of measuring inter-session/subject performance predictors for generalized BCI frameworks for both normal and motor-impaired people, reducing the necessity for tedious and annoying calibration sessions and BCI training., (Copyright © 2020 Saha and Baumert.)

Objective: This study had two specific objectives, 1) to investigate the impact of being on-call on overnight heart rate variability during sleep and; 2) to examine whether being on-call overnight impacted next-day salivary cortisol concentrations., Methods: Data are reported from three within-subject laboratory studies (n = 24 in each study) that assessed varying on-call conditions. Healthy male participants (n = 72 total) completed a four-night laboratory protocol, comprising an adaptation night, a control night, and two counterbalanced on-call nights with varying on-call conditions. These on-call conditions were designed to determine the impact of, Study 1: the likelihood of receiving a call (definitely, maybe), Study 2: task stress (high-stress, low-stress), and Study 3: chance of missing the alarm (high-chance, low-chance), on measures of physiological stress. Overnight heart rate variability (HRV) (during sleep) was measured using two-lead electrocardiography, and time- and frequency-domain variables were analysed. Saliva samples were collected at 15-min time intervals from 0700-0800 h to determine cortisol awakening response outcomes and at four daily time points (0930 h, 1230 h, 1430 h, and 1730 h) to assess diurnal cortisol profiles., Results: There were few differences in HRV measures during sleep across all three studies. The only exception was in Study 1 where the standard deviation of the time interval between consecutive heartbeats and the root mean square of consecutive differences between heartbeats were lower across all sleep stages in the definitely condition, when compared to control. Across all three studies, being on-call overnight also had little impact on next-day cortisol awakening response (CAR), with the exception of Study 2 where the 1) CAR area under the curve with respect to increase was blunted in the high-stress condition, compared to the control and low-stress conditions and, 2) CAR reactivity was higher in low-stress condition, compared with the high-stress condition. In Study 1, diurnal cortisol area under the curve with respect to ground was lower in the on-call conditions (definitely and maybe) when compared to control. There were no differences in diurnal cortisol measures in Study 3., Conclusion: This is the first study to investigate how different aspects of being on-call affect physiological stress responses. Overall, relatively little differences in measures of overnight heart rate variability and next-day cortisol response were recorded in all three studies. Further research utilising real on-call work tasks, not just on-call expectations (as in the current study) will help determine the impact of on-call work on the physiological stress response., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

In patients with atrial fibrillation (AF), the prevalence of moderate-to-severe sleep-disordered breathing (SDB) ranges between 21% and 72% and observational studies have demonstrated that SDB reduces the efficacy of rhythm control strategies, while treatment with continuous positive airway pressure lowers the rate of AF recurrence. Currently, the number of apneas and hypopneas per hour (apnea-hypopnea-index, AHI) determined during a single overnight sleep study is clinically used to assess the severity of SDB. However, recent studies suggest that SDB-severity in an individual patient is not stable over time but exhibits a considerable night-to-night variability which cannot be detected by only one overnight sleep assessment. Nightly SDB-severity assessment rather than the single-night diagnosis by one overnight sleep study may better reflect the exposure to SDB-related factors and yield a superior metric to determine SDB-severity in the management of AF. In this review we discuss mechanisms of night-to-night SDB variability, arrhythmogenic consequences of night-to-night SDB variability, strategies for longitudinal assessment of nightly SDB-severity and clinical implications for screening and management of SDB in AF patients., (© 2019 The Author(s).)

The identification of recurrent, transient perturbations in brain activity during sleep, so called cyclic alternating patterns (CAP), is of significant interest as they have been linked to neurological pathologies. CAP sequences comprise multiple, consecutive cycles of phasic activation (A-phases). Here, we propose a novel, automated system exploiting the dynamical, temporal information in electroencephalography (EEG) recordings for the classification of A-phases and their subtypes. Using recurrent neural networks (RNN), crucial information in the temporal behavior of the EEG is extracted. The automatic classification system is equipped to deal with the biasing issue of imbalanced data sets and uses state-of-the-art signal processing methods to reduce inter-subject variation. To evaluate our system, we applied recordings from the publicly available CAP Sleep Database on Physionet. Our results show that the RNN improved the detection accuracy by 3-5% and the F 1 -score by approximately 7% on two data sets compared to a normal feed-forward neural network. Our system achieves a sensitivity of approximately 76-78% and F 1 -score between 63-68%, significantly outperforming existing technologies. Moreover, its sensitivity for subtype classification of 60-63% (A1), 42-45% (A2), and 71-74% (A3) indicates superior multi-class classification performance for CAP detection. In conclusion, we have developed a fully automated high performance CAP scoring system that includes A-phase subtype classification. RNN classifiers yield a significant improvement in accuracy and sensitivity compared to previously proposed systems.

Rationale: We describe a novel method for preparing milk samples and profiling their triglyceride (TG) fractions. This method was used to explore how the TG profile of milk modulates as lactation progresses and how the TG profile differs between breasts., Methods: Fresh milk was spotted onto Whatman filter paper and air-dried. Liquid Extraction Surface Analysis coupled to Fourier Transform Mass Spectrometry (LESA-MS) was adapted for molecular profiling. Collision-Induced Dissociation (CID) was used to profile fatty acid residues., Results: LESA-MS produced the relative abundances of all isobaric TGs described and showed that mammary glands within one individual can produce a different profile of TGs. CID was used to uncover the configuration of isobaric triglycerides, indicating the relative amounts of the fatty acids contributing to that triglyceride's mass. This also indicated the presence of very long chain fatty acids (C26:0 and C26:1) that have not been reported before in human breast milk., Conclusions: We conclude that spotting on paper and the use of LESA-MS and CID on milk spots is not only a means for analysing milk in unprecedented detail for this preparation time, but is also amenable to conditions in which collecting and storing fresh milk samples for detailed profiling is prohibitively difficult., (© 2019 The Authors Rapid Communications in Mass Spectrometry Published by John Wiley & Sons, Ltd.)

The fraction of repolarization variability independent of RR interval variability is of clinical interest. It has been linked to direct autonomic nervous system (ANS) regulation of the ventricles in healthy subjects and seems to reflect the instability of the ventricular repolarization process in heart disease. In this study, we sought to identify repolarization measures that best reflect the sympathetic influences on the ventricles independent of the RR interval. ECG was recorded in 46 young subjects during supine and then following 45 degrees head-up tilt. RR intervals and five repolarization features (QTend, QTpeak, RTend, RTpeak, and TpTe) were extracted from the ECG recordings. Repolarization variability was separated into RR-dependent and RR-independent variability using parametric spectral analysis. Results show that LF power of TpTe is independent of RR in both supine and tilt, while the LF power of QTend and RTend independent of RR and respiration increases following tilt. We conclude that TpTe is independent of RR and is highly affected by respiration. QTend and RTend LF power might reflect the sympathetic influences on the ventricles elicited by tilt. Graphical abstract.

Respiratory frequency ( f R ) predicts in-hospital and short-term mortality in patients with a variety of pathophysiological conditions, but its predictive value for long-term cardiovascular and all-cause mortality in the general population is unknown. Here, we investigated the relationship between mean nocturnal f R and mortality in community-dwelling older men and women.We measured mean nocturnal f R during sleep from overnight polysomnography in 2686 men participating in the Osteoporotic Fractures in Men Study (MrOS) Sleep study and 406 women participating in the Study of Osteoporotic Fractures (SOF) to investigate the relationship between mean nocturnal f R and long-term cardiovascular and all-cause mortality.166 (6.1%) men in the MrOS cohort (8.9±2.6 years' follow-up) and 46 (11.2%) women in the SOF cohort (6.4±1.6 years' follow-up) died from cardiovascular disease. All-cause mortality was 51.2% and 26.1% during 13.7±3.7 and 6.4±1.6 years' follow-up in the MrOS Sleep study and the SOF cohorts, respectively. Multivariable Cox regression analysis adjusted for significant covariates demonstrated that f R dichotomised at 16 breaths·min -1 was independently associated with cardiovascular mortality (MrOS: hazard ratio (HR) 1.57, 95% CI 1.14-2.15; p=0.005; SOF: HR 2.58, 95% CI 1.41-4.76; p=0.002) and all-cause mortality (MrOS: HR 1.18, 95% CI 1.04-1.32; p=0.007; SOF: HR 1.50, 95% CI 1.02-2.20; p=0.04).In community-dwelling older men and women, polysomnography-derived mean nocturnal f R ≥16 breaths·min -1 is an independent predictor of long-term cardiovascular and all-cause mortality. Whether nocturnal mean f R can be used as a risk marker warrants further prospective studies., Competing Interests: Conflict of interest: M. Baumert has nothing to disclose. Conflict of interest: D. Linz reports having served on the advisory board of LivaNova, and has received lecture and/or consulting fees from LivaNova and ResMed. Conflict of interest: K. Stone has nothing to disclose. Conflict of interest: R.D. McEvoy has nothing to disclose. Conflict of interest: S. Cummings has nothing to disclose. Conflict of interest: S. Redline has nothing to disclose. Conflict of interest: R. Mehra has nothing to disclose. Conflict of interest: S. Immanuel has nothing to disclose., (Copyright ©ERS 2019.)

We propose event-related cortical sources estimation from subject-independent electroencephalography (EEG) recordings for motor imagery brain computer interface (BCI). By using wavelet-based maximum entropy on the mean (wMEM), task-specific EEG channels are selected to predict right hand and right foot sensorimotor tasks, employing common spatial pattern (CSP) and regularized common spatial pattern (RCSP). EEG from five healthy individuals (Dataset IVa, BCI Competition III) were evaluated by a cross-subject paradigm. Prediction performance was evaluated via a two-layer feed-forward neural network, where the classifier was trained and tested by data from two subjects independently. On average, the overall mean prediction accuracies obtained using all 118 channels are (55.98±6.53) and (71.20±5.32) in cases of CSP and RCSP, respectively, which are slightly lower than the accuracies obtained using only the selected channels, i.e., (58.95±6.90) and (71.41±6.65), respectively. The highest mean prediction accuracy achieved for a specific subject pair by using selected EEG channels was on average (90.36±5.59) and outperformed that achieved by using all available channels (86.07 ± 10.71). Spatially projected cortical sources approximated using wMEM may be useful for capturing inter-subject associative sensorimotor brain dynamics and pave the way toward an enhanced subject-independent BCI.

Bipolar electrograms (EGM) are widely used to assess intracardiac electrical activity and to find the atrial fibrillation-related sources. However, the interpretation of bipolar EGM is not straightforward. Variables including bipolar lead (vector) orientation relative to the wave propagation dynamics significantly impact the EGM and EGM-derived measures, which are clinically used to select target sources for catheter ablation. In this study, left atrial unipolar EGM were recorded using a 4 × 4 grid of 16 unipolar electrodes. A set (node) of 4 unipolar EGM were used to construct possible 6 bipolar EGM to evaluate the measurement uncertainty within a particular node. A novel beamforming-inspired spatial filtering (BiSF) method is proposed to reduce the potential measurement uncertainty inevitable in bipolar EGM. A set of three bipolar lead orientations that were constructed using a common unipolar electrode towards three different directions at 45°s, were added to form beamforming EGM. Finally, two beamforming EGM were intertwined to acquire BiSF EGM for a node. Results show greater signal power gain (at least around 10dB) for all BiSF EGM with better or similar signal-to-noise ratio as compared to their respective bipolar counterparts. In conclusion, reduced uncertainty in BiSF EGM improve the interpretation of EGM and EGM-derived measures used in clinical practice after further validation on a larger dataset.

Sleep arousal is generally defined as an abrupt shift in EEG frequency with a duration of 3-16 seconds. Arousal from sleep expected to cause sudden changes in the cardiovascular system that can manifest as cardiac responses. In this paper, our objective was to investigate how cardiac characteristics change due to arousal. We focused on the QT interval fluctuations in ECG during the occurrence of arousals. We analysed 7373 sleep arousals collected from 50 males that were older than 65 years. We analysed the ECG signal 5 seconds prior to and 10 seconds after each arousal onset (Pre and Post-Onset). Q and T waves were detected for all Pre and Post-Onset windows to estimate their time intervals. To find out whether the QT interval, a marker of ventricular activation, is modulated by arousal onset, we have applied graphical and statistical analysis. Our observations indicate that in 47 out of 50 subjects (94%), the average QT interval of all arousal significantly shortened at arousal onset. We observed similar outcomes for different types of arousals, indicating that the shortening in average QT interval is independent of the type of arousal. We also studied the relative QT interval change during arousal. The distribution of relative QT interval changes demonstrates that around 60% of arousals increase or decrease QT interval by a maximum of 20%. The probability of QT time interval shortening was twice that of QT interval lengthening.

In recent years, machine learning algorithms have become increasingly popular for analyzing biomedical signals. This includes the detection of cyclic alternating pattern (CAP) in electroencephalography recordings. Here, we investigate the performance gain of a recurrent neural network (RNN) for CAP scoring in comparison to standard classification methods. We analyzed 15 recordings (n1-n15) from the publicly available CAP Sleep Database on Physionet to evaluate each machine learning method. A long short-term memory (LSTM) network increases the accuracy and F 1 -score by 0.5-3.5% and 3.5-8%, respectively, compared to commonly used classification algorithms such as linear discriminant analysis, k-nearest neighbour or feed-forward neural network. Our results show that by using a LSTM classifier the quantity of correctly detected CAP events can be increased and the number of wrongly classified periods reduced. RNNs significantly improve the precision in CAP scoring by taking advantage of available information from the past for deciding current classification.

Sleep disordered breathing (SDB) is a common pediatric disorder, which results in increasing respiratory workload during sleep, restless night time sleep and excessive daytime sleepiness. It has significant negative effects on children with SDB on their physical growth and cognitive related developments. Chronic autonomic activation was suggested to be one of the possible key drivers causing cardiovascular structural changes in SDB children and increasing the risk of developing cardiovascular disease in their future. The aim of this study was to investigate the effect of SDB on autonomic activation changes in children, by analyzing the pulse wave amplitude (PWA) dynamics using a simple envelope estimation method extracting PWA from PPG signal.Children with SDB (n = 40) showed a significantly a wider dynamic distribution in PWA compare to matched controls (n = 40), which suggests a higher and stronger level of autonomic response in SDB children.In conclusion, the PWA dynamic is altered in children with SDB during sleep and indicate changes in autonomic activation.

Increased beat-to-beat QT interval variability in electrocardiograms is a robust descriptor of ventricular depolarization and repolarization lability. Variability analysis of the depolarization and repolarization intervals in vectorcardiogram has indicated potential diagnostic abilities. Here, we describe an inhomogeneous signal adaptation technique for vectorcardiogram. We propose a novel global-to-local adaptation method that yields robust results even when dealing with noisy vectorcardiogram signals. We evaluated several vectorcardiogram features using the proposed adaptation technique on the PTB database to demonstrate its potential diagnostic prowess for myocardial infarction.

Hysteresis of the baroreflex (BR) is the result of the different BR sensitivity (BRS) when arterial pressure (AP) rises or falls. This phenomenon has been poorly studied and almost exclusively examined by applying pharmacological challenges and static approaches disregarding causal relations. This study inspects the asymmetry of the cardiac BR (cBR) and vascular sympathetic BR (sBR) in physiological closed loop conditions from spontaneous fluctuations of physiological variables, namely heart period (HP) and systolic AP (SAP) leading to the estimation of cardiac BRS (cBRS) and muscle sympathetic nerve activity (MSNA) and diastolic AP (DAP) leading to the estimation of vascular sympathetic BRS (sBRS). The assessment was carried out in 12 young healthy subjects undergoing incremental head-up tilt with table inclination gradually increased from 0 to 60°. Two analytical methods were exploited and compared, namely the sequence (SEQ) and phase-rectified signal averaging (PRSA) methods. SEQ analysis is based on the detection of joint causal schemes representing the HP and MSNA burst rate delayed responses to spontaneous SAP and DAP modifications, respectively. PRSA analysis averages HP and MSNA burst rate patterns after aligning them according to the direction of SAP and DAP changes, respectively. Since cBRSs were similar when SAP went up or down, hysteresis of cBR was not detected. Conversely, hysteresis of sBR was evident with sBRS more negative when DAP was falling than rising. sBR hysteresis was no longer visible during sympathetic activation induced by the orthostatic challenge. These results were obtained via the SEQ method, while the PRSA technique appeared to be less powerful in describing the BR asymmetry due to the strong association between BRS estimates computed over positive and negative AP variations. This study suggests that cBR and sBR provide different information about the BR control, sBR exhibits more relevant non-linear features that are evident even during physiological changes of AP, and the SEQ method can be fruitfully exploited to characterize the BR hysteresis with promising applications to BR branches different from cBR and sBR.

The objective of the present study was to quantify repolarization lability and its association with sex, sleep stage, and cardiovascular mortality. We analyzed polysomnographic recordings of 2,263 participants enrolled in the Sleep Heart Health Study (SHHS-2). Beat-to-beat QT interval variability (QTV) was quantified for consecutive epochs of 5 min according to the dominant sleep stage [wakefulness, nonrapid eye movement stage 2 (NREM2), nonrapid eye movement stage 3 (NREM3), and rapid eye movement (REM)]. To explore the effect of sleep stage and apnea-hypopnea index (AHI) on QT interval parameters, we used a general linear mixed model and mixed ANOVA. The Cox proportional hazards model was used for cardiovascular disease (CVD) death prediction. Sex-related differences in T wave amplitude ( P < 0.001) resulted in artificial QTV differences. Hence, we corrected QTV parameters by T wave amplitude for further analysis. Sleep stages showed a significant effect ( P < 0.001) on QTV. QTV was decreased in deep sleep compared with wakefulness, was higher in REM than in NREM, and showed a distinct relation to AHI in all sleep stages. The T wave amplitude-corrected QTV index (cQTVi) in REM sleep was predictive of CVD death (hazard ratio: 2.067, 95% confidence interval: 1.105-3.867, P < 0.05) in a proportional hazards model. We demonstrated a significant impact of sleep stages on ventricular repolarization variability. Sex differences in QTV are due to differences in T wave amplitude, which should be corrected for. Independent characteristics of QTV measures to sleep stages and AHI showed different behaviors of heart rate variability and QTV expressed as cQTVi. cQTVi during REM sleep predicts CVD death. NEW & NOTEWORTHY We demonstrate here, for the first time, a significant impact of sleep stages on ventricular repolarization variability, quantified as QT interval variability (QTV). We showed that QTV is increased in rapid eye movement sleep, reflective of high sympathetic drive, and predicts death from cardiovascular disease. Sex-related differences in QTV are shown to be owing to differences in T wave amplitude, which should be corrected for.

Background: Sleep-disordered breathing (SDB) is highly prevalent in patients with atrial fibrillation (AF) and its treatment can improve rhythm control. Polysomnography (PSG) is the gold standard for the diagnosis of SDB but its high cost and limited availability constrain its role as a standard SDB screening tool. We sought to assess the diagnostic utility of overnight oximetry in predicting SDB in AF patients., Methods: We analyzed prospectively collected data on 439 patients with documented AF (62% paroxysmal AF) who underwent PSG. Overnight oximetry was used to determine the oxygen desaturation index (ODI, number of desaturation/h) by a novel automated computer algorithm. ODI was validated against PSG derived apnea-hypopnea index (AHI)., Results: The sample consisted of 69% men with a mean age of 59.9 ± 11.3 years and body mass index of 30 ± 5 kg/m 2 . The median AHI was 9.5 [3.6-21.0]/h and the prevalence of moderate (AHI 15-29/h) and severe SDB (AHI ≥ 30/h) was 17.3% and 16.6% respectively. The ODI was able to detect moderate-to-severe SDB (AHI ≥ 15/h; area under the receiver-operating-characteristic curve (AUC): 0.951, 95% CI: 0.929-0.972) and severe SDB (AHI ≥ 30/h; 0.932, 95% CI: 0.895-0.968) with high diagnostic accuracy. An ODI cut-off of 4.1/h resulted in a 91% sensitivity and 83% specificity in discriminating between patients with and without AHI ≥ 15/h. An ODI of 7.6/h yielded a sensitivity and specificity for AHI ≥ 30/h of 89% and 83%, respectively., Conclusions: ODI derived from a simple and low-cost overnight oximetry can be used as an accessible and reliable screening tool, particularly to rule out SDB., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Sleep disordered breathing (SDB) is highly prevalent in patients with atrial fibrillation, heart failure and hypertension and is associated with increased risk of mortality, cardiovascular (CV) events and arrhythmias. Current assessment of the severity of SDB is mainly based on the apnea-hypopnea index (AHI) representing the number of hypopneas and apneas per hour of sleep. However, this event-based parameter alone may not sufficiently reflect the complex pathophysiological mechanisms underlying SDB potentially contributing to CV outcome risk. In this review article, we highlight important limitations and pitfalls of current assessment, quantification and interpretation of SDB-severity in patients with CV disease and will discuss pathophysiological considerations from preclinical and clinical mechanistic studies and possible clinical implications., (Copyright © 2018 Elsevier B.V. All rights reserved.)

There is evidence that 15-30% of the general population cannot effectively operate brain-computer interfaces (BCIs). Thus the BCI performance predictors are critically required to pre-screen participants. Current neurophysiological and psychological tests either require complicated equipment or suffer from subjectivity. Thus, a simple and objective BCI performance predictor is desirable. Neurofeedback (NFB) training involves performing a cognitive task (motor imagery) instructed via sensory stimuli and re-adjusted through ongoing real-time feedback. A simple reaction time (SRT) test reflects the time required for a subject to respond to a defined stimulus. Thus, we postulated that individuals with shorter reaction times operate a BCI with rapidly updated feedback better than individuals with longer reaction times. Furthermore, we investigated how changing the feedback update interval (FUI), i.e., modification of the feedback provision frequency, affects the correlation between the SRT and BCI performance. Ten participants attended four NFB sessions with FUIs of 16, 24, 48, and 96 ms in a randomized order. We found that: 1) SRT is correlated with the BCI performance with FUIs of 16 and 96 ms; 2) good and poor performers elicit stronger ERDs and control BCIs more effectively (i.e., produced larger information transfer rates) with 16 and 96 ms FUIs, respectively. Our findings suggest that SRT may be used as a simple and objective surrogate for BCI aptitude with FUIs of 16 and 96 ms. It also implies that the FUI customization according to participants SRT measure may enhance the BCI performance.

Study Objectives: To assess the effect of adenotonsillectomy for relieving obstructive sleep apnea syndrome (OSAS) symptoms in children on cardiac autonomic modulation., Methods: In 354 children enrolled in the Childhood Adenotonsillectomy Trial, randomized to undergo either early adenotonsillectomy (eAT; N = 181) or a strategy of watchful waiting with supportive care (WWSC; N = 173), nocturnal heart rate control was analyzed during quiet, event-free sleep at baseline and at 7 months using overnight polysomnography (PSG). The relative frequency of patterns indicating monotonous changes in heart rate was quantified., Results: Children who underwent eAT demonstrated a significantly greater reduction in heart rate patterns postsurgery than the WWSC group. On assessing those heart rate patterns regarding normalization of clinical PSG, heart patterns were reduced to a similar level in both groups. In children whose AHI normalized spontaneously, heart rate patterns were already significantly less frequent at baseline, suggesting that upper airway obstruction was milder in this group at the outset., Conclusions: Adenotonsillectomy reduces monotonous heart rate patterns throughout quiet event-free sleep, reflecting a reduction in cardiac autonomic modulation. Heart rate pattern analysis may help quantifying the effect of OSAS on autonomic nervous system activity in children. Clinical Trial Registration: The study was registered at Clinicaltrials.gov (#NCT00560859).

Objective: The aim of this study was to assess cardiovascular autonomic modulation in children with upper airway obstruction (UAO), to compare this modulation to that of non-snoring children and to investigate the effect of adenotonsillectomy (AT)., Methods: ECG and finger photoplethysmographic signals obtained from overnight polysomnographic (PSG) recordings of 31 children with mild-to-moderate UAO and 34 non-snoring children were analysed. The extent of autonomic modulation was assessed by symbolic analysis of heart period (HP), pulse wave amplitude (PWA), and their joint dynamics during non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep., Results: Children with UAO showed more frequent patterns of monotonically increasing and decreasing HP in NREM sleep and monotonically increasing and decreasing joint PWA-HP patterns in REM and NREM sleep at baseline compared to controls, even when considering only periods of sleep free of discrete respiratory events. Following AT, HP, and joint PWA-HP dynamics significantly altered towards levels observed in the control group., Conclusions: In children with mild-to-moderate UAO, cardiovascular autonomic modulation is more prevalent, even during quiet, event-free sleep. AT appears to reverse this pattern., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The objective of this study was to determine the response of heart rate and blood pressure variability (respiratory sinus arrhythmia, baroreflex sensitivity) to orthostatic and mental stress, focusing on causality and the mediating effect of respiration. Seventy-seven healthy young volunteers (46 women, 31 men) aged 18.4 ± 2.7 yr underwent an experimental protocol comprising supine rest, 45° head-up tilt, recovery, and a mental arithmetic task. Heart rate variability and blood pressure variability were analyzed in the time and frequency domain and modeled as a multivariate autoregressive process where the respiratory volume signal acted as an external driver. During head-up tilt, tidal volume increased while respiratory rate decreased. During mental stress, breathing rate increased and tidal volume was elevated slightly. Respiratory sinus arrhythmia decreased during both interventions. Baroreflex function was preserved during orthostasis but was decreased during mental stress. While sex differences were not observed during baseline conditions, cardiovascular response to orthostatic stress and respiratory response to mental stress was more prominent in men compared with women. The respiratory response to the mental arithmetic tasks was more prominent in men despite a significantly higher subjectively perceived stress level in women. In conclusion, respiration shows a distinct response to orthostatic versus mental stress, mediating cardiovascular variability; it needs to be considered for correct interpretation of heart rate and blood pressure phenomena.

Sleep-disordered breathing (SDB) is associated with cardiovascular disease and systemic inflammation in adults but this remains to be explored in children, especially in children with the most common form of SDB, i.e. primary snoring/mild SDB. This pilot study investigated the relationship between the cardiovascular function and inflammation in children with mild SDB. Nineteen participants aged 5-14 years underwent overnight polysomnography, cardiac magnetic resonance imaging (aortic blood flow velocity and left and right ventricular systolic function) and assessment for inflammatory markers (intracellular cytokine analysis of T cells by flow cytometry). Parents also completed the Sleep Disturbances Scale for Children (SDSC). Children with mild SDB exhibited increased ascending aortic peak systolic velocity compared to controls (SDB 119.95 m/s vs. control 101.49 m/s, p < 0.05). No significant group differences were observed for left and right ventricular ejection fraction or mean aortic blood flow velocity from either the ascending aorta or pulmonary artery. Children with mild SDB had increased inflammatory markers as demonstrated by elevated T cell interferon gamma (IFNγ) (SDB 52 ± 4% vs. control 25 ± 3% positive cells, p < 0.005) and tumour necrosis factor alpha (TNFα) (SDB 39 ± 4% vs. control 20 ± 2% positive cells, p < 0.005) expression from CD8 + cells. A strong positive correlation was observed between ascending aorta peak blood flow velocity and both TNFα and IFNγ (TNFα, r = 0.54, p < 0.03; IFNγ, r = 0.63, p < 0.005, respectively). Polysomnography revealed that oxygen saturation (SaO 2 ) nadir was significantly lower in children with mild SDB compared to controls (SDB 92.3 ± 2.7% vs. control 94.4 ± 1.6%, p < 0.05). A lower SaO 2 nadir was associated with an increased ascending aorta peak systolic velocity (r = - 0.48, p < 0.05). As well, both a lower SaO 2 nadir and an increased ascending aorta peak systolic velocity were associated with higher SDSC Sleep-Disordered Breathing and Disorder of Initiating and Maintaining Sleep subscale scores but not the polysomnographic-derived Obstructive Apnea-Hypopnea Index. The finding of elevated ascending aortic peak systolic blood flow velocity and its association with increased inflammatory markers suggests that the profile of cardiovascular changes noted in adult SDB may also occur in children with mild SDB.

The purpose of this study was to investigate the beat-to-beat variability of T-waves (TWV) and to assess the diagnostic capabilities of T-wave-based features for myocardial infarction (MI). A total of 148 recordings of standard 12-lead electrocardiograms (ECGs) from 79 MI patients (22 females, mean age 63±12 years; 57 males, mean age 57±10 years) and 69 recordings from healthy subjects (HS) (17 females, 42±18 years; 52 males, 40±13 years) were studied. For the quantification of beat-to-beat QT intervals in ECG signal, a template-matching algorithm was applied. To study the T-waves beat-to-beat, we measured the angle between T-wave max and T-wave end with respect to Q-wave (∠α) and T-wave amplitudes. We computed the standard deviation (SD) of beat-to-beat T-wave features and QT intervals as markers of variability in T-waves and QT intervals, respectively, for both patients and HS. Moreover, we investigated the differences in the studied features based on gender and age for both groups. Significantly increased TWV and QT interval variability (QTV) were found in MI patients compared to HS (p<0.05). No significant differences were observed based on gender or age. TWV may have some diagnostic attributes that may facilitate identifying patients with MI. In addition, the proposed beat-to-beat angle variability was found to be independent of heart rate variations. Moreover, the proposed feature seems to have higher sensitivity than previously reported feature (QT interval and T-wave amplitude) variability for identifying patients with MI.

Sleep disordered breathing (SDB) is highly prevalent in patients with high blood pressure (BP). Severity of SDB can be evaluated by the number of apneas and hypopneas per hour (AHI) or by measures of hypoxia. The objective of this study was to assess the association between different measures of SDB and BP. In 134 consecutive patients, polygraphy was performed to determine the AHI. Pulse oximetry was used to determine hypoxemic burden (time below 90% oxygen saturation [T90] and hypoxia load [HL], representing the integrated area above the curve of desaturation). AHI did not correlate with systolic and diastolic BP or pulse pressure. In contrast, HL correlated with pulse pressure during the day (P = .01) and night (P = .0034) before and after adjustment for body mass index. The correlation between systolic BP and HL at night disappeared following adjustment for body mass index. This study generates the hypothesis that nocturnal hypoxemic burden may represent a suitable marker of BP pattern and a potential treatment target in hypertensive patients., (©2018 Wiley Periodicals, Inc.)

Interest in the effects of drugs on the heart rate-corrected JTpeak (JTpc) interval from the body-surface ECG has spawned an increasing number of scientific investigations in the field of regulatory sciences, and more specifically in the context of the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative. We conducted a novel initiative to evaluate the role of automatic JTpc measurement technologies by comparing their ability to distinguish multi- from single-channel blocking drugs. A set of 5232 ECGs was shared by the FDA (through the Telemetric and Holter ECG Warehouse) with 3 ECG device companies (AMPS, Mortara, and Philips). We evaluated the differences in drug-concentration effects on these measurements between the commercial and the FDA technologies. We provide a description of the drug-induced placebo-corrected changes from baseline for dofetilide, quinidine, ranolazine, and verapamil, and discuss the various differences across all technologies. The results revealed only small differences between measurement technologies evaluated in this study. It also confirms that, in this dataset, the JTpc interval distinguishes between multi- and single-channel (hERG) blocking drugs when evaluating the effects of dofetilide, quinidine, ranolazine, and verapamil. However, in the case of quinidine and dofetilide, we noticed a poor consistency across technologies because of the lack of standard definitions for the location of the peak of the T-wave (T-apex) when the T-wave morphology is abnormal., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Direct analysis by mass spectrometry (imaging) has become increasingly deployed in preclinical and clinical research due to its rapid and accurate readouts. However, when it comes to biomarker discovery or histopathological diagnostics, more sensitive and in-depth profiling from localized areas is required. We developed a comprehensive, fully automated online platform for high-resolution liquid extraction surface analysis (HR-LESA) followed by micro-liquid chromatography (LC) separation and a data-independent acquisition strategy for untargeted and low abundant analyte identification directly from tissue sections. Applied to tissue sections of rat pituitary, the platform demonstrated improved spatial resolution, allowing sample areas as small as 400 μm to be studied, a major advantage over conventional LESA. The platform integrates an online buffer exchange and washing step for removal of salts and other endogenous contamination that originates from local tissue extraction. Our carry over-free platform showed high reproducibility, with an interextraction variability below 30%. Another strength of the platform is the additional selectivity provided by a postsampling gas-phase ion mobility separation. This allowed distinguishing coeluted isobaric compounds without requiring additional separation time. Furthermore, we identified untargeted and low-abundance analytes, including neuropeptides deriving from the pro-opiomelanocortin precursor protein and localized a specific area of the pituitary gland (i.e., adenohypophysis) known to secrete neuropeptides and other small metabolites related to development, growth, and metabolism. This platform can thus be applied for the in-depth study of small samples of complex tissues with histologic features of ∼400 μm or more, including potential neuropeptide markers involved in many diseases such as neurodegenerative diseases, obesity, bulimia, and anorexia nervosa.

Jones-Roberts solitons are the only known class of stable dark solitonic solutions of the nonlinear Schrödinger equation in two and three dimensions. They feature a distinctive elongated elliptical shape that allows them to travel without change of form. By imprinting a triangular phase pattern, we experimentally generate two-dimensional Jones-Roberts solitons in a three-dimensional atomic Bose-Einstein condensate. We monitor their dynamics, observing that this kind of soliton is indeed not affected by dynamic (snaking) or thermodynamic instabilities, that instead make other classes of dark solitons unstable in dimensions higher than one. Our results confirm the prediction that Jones-Roberts solitons are stable solutions of the nonlinear Schrödinger equation and promote them for applications beyond matter wave physics, like energy and information transport in noisy and inhomogeneous environments.

Study Objectives: To assess cardiovascular control during sleep in children with sleep-disordered breathing (SDB) and the effect of adenotonsillectomy in comparison to healthy nonsnoring children., Methods: Cardiorespiratory signals obtained from overnight polysomnographic recordings of 28 children with SDB and 34 healthy nonsnoring children were analyzed. We employed an autoregressive closed-loop model with heart period (RR) and pulse transit time (PTT) as outputs and respiration as an external input to obtain estimates of respiratory gain and baroreflex gain., Results: Mean and variability of PTT were increased in children with SDB across all stages of sleep. Low frequency power of RR and PTT were attenuated during non-rapid eye movement (REM) sleep. Baroreflex sensitivity was reduced in children with SDB in stage 2 sleep, while respiratory gain was increased in slow wave sleep. After adenotonsillectomy, these indices normalized in the SDB group attaining values comparable to those of healthy children., Conclusions: In children with mild-to-moderate SDB, vasomotor activity is increased and baroreflex sensitivity decreased during quiet, event-free non-REM sleep. Adenotonsillectomy appears to reverse this effect., (© Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Restorative brain-computer interfaces (BCIs) have been proposed to enhance stroke rehabilitation. Restorative BCIs are able to close the sensorimotor loop by rewarding motor imagery (MI) with sensory feedback. Despite the promising results from early studies, reaching clinically significant outcomes in a timely fashion is yet to be achieved. This lack of efficacy may be due to suboptimal feedback provision. To the best of our knowledge, the optimal feedback update interval (FUI) during MI remains unexplored. There is evidence that sensory feedback disinhibits the motor cortex. Thus, in this study, we explore how shorter than usual FUIs affect behavioural and neurophysiological measures following BCI training for stroke patients using a single-case proof-of-principle study design. The action research arm test was used as the primary behavioural measure and showed a clinically significant increase (36%) over the course of training. The neurophysiological measures including motor evoked potentials and maximum voluntary contraction showed distinctive changes in early and late phases of BCI training. Thus, this preliminary study may pave the way for running larger studies to further investigate the effect of FUI magnitude on the efficacy of restorative BCIs. It may also elucidate the role of early and late phases of motor learning along the course of BCI training., Competing Interests: We have no competing interests.

Background: Acute kidney injury (AKI) is the most common complication of perinatal asphyxia. Recent research indicates that serum neutrophil gelatinase-associated lipocalin (NGAL) is an early marker for AKI, but there are the lacks of data about its use in term neonates with perinatal asphyxia., Methods: A prospective cohort study was conducted on 43 term neonates. Umbilical cord blood and 24 h after birth serum NGAL, copeptin, creatinine, and molality were measured in all asphyxiated and controls neonates., Results: During the study period, 8 of asphyxiated nenates (18.6 %) suffered from AKI, while 35 newborns have no signs of AKI and 30 healthy infants. We did not observe any differences in creatinine and copeptin levels, as well as serum osmolality in all three investigated groups (AKI, no-AKI, and controls) in cord blood, and 24 h after birth. Serum NGAL levels in umbilical cord blood were significantly higher in the AKI group (174.3 ng/mL) compared with no-AKI (88.5 ng/mL, p = 0.01) and control groups (28.5 ng/mL, p < 0.001), and 24 h after birth (respectively, AKI 152.5 ng/mL vs no-AKI 74.9 ng/mL, p = 0.02 vs controls 39.1 ng/mL, p < 0.001). NGAL concentration showed a strong negative correlation to umbilical artery pH (Rho = -0.42, p = 0.04), base excess (Rho = -0.31, p = 0.03), and Apgar score in 1st min (Rho = -0.41, p = 0.02) and 5th min of life (Rho = -0.20, p = 0.001). ROC curve analysis demonstrated a good predictive value for NGAL levels (>140.7 ng/mL) which allows to diagnose AKI in asphyxiated patients with 88.9 % sensitivity (95 % CI 75-95 %) and 95.0 % specificity (95 % CI 76-99 %)., Conclusion: NGAL seems to be a promising marker, even in subclinical AKI in neonates, due to its high specificity, but copeptin did not meet expectations.

Background: Sleep disordered breathing in children is associated with increased blood flow velocity and sympathetic overactivity. Sympathetic overactivity results in peripheral vasoconstriction and reduced systemic vascular compliance, which increases blood flow velocity during systole. Augmented blood flow velocity is recognized to promote vascular remodeling. Importantly, increased vascular sympathetic nerve fiber density and innervation in early life plays a key role in the development of early-onset hypertension in animal models. Examination of sympathetic nerve fiber density of the tonsillar arteries in children undergoing adenotonsillectomy for Sleep disordered breathing will address this question in humans., Methods and Results: Thirteen children scheduled for adenotonsillectomy to treat sleep disordered breathing underwent pupillometry, polysomnography, flow-mediated dilation, resting brachial artery blood flow velocity (velocity time integral), and platelet aggregation. The dorsal lingual artery (tonsil) was stained and immunofluorescence techniques used to determine sympathetic nerve fiber density. Sympathetic nerve fiber density was correlated with increased resting velocity time integral ( r =0.63; P <0.05) and a lower Neuronal Pupillary Index ( r =-0.71, P <0.01), as well as a slower mean pupillary constriction velocity (mean, r =-0.64; P <0.05). A faster resting velocity time integral was associated with a slower peak pupillary constriction velocity ( r =-0.77; P <0.01) and higher platelet aggregation to collagen antigen ( r =0.64; P <0.05). Slower mean and peak pupillary constriction velocity were associated with higher platelet aggregation scores ( P <0.05; P <0.01, respectively)., Conclusions: These results indicate that sympathetic activity is associated with change in both the function and structure of systemic vasculature in children with sleep disordered breathing., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

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.

Heart rate variability (HRV) modulates dynamics of ventricular repolarization. A diminishing value of HRV is associated with increased vulnerability to life-threatening ventricular arrhythmias, however the causal relationship is not well-defined. We evaluated if fixed-rate atrial pacing that abolishes the effect of physiological HRV, will alter ventricular repolarization wavefronts and is relevant to ventricular arrhythmogenesis. The study was performed in 16 subjects: 8 heart failure patients with spontaneous ventricular tachycardia [HFVT], and 8 subjects with structurally normal hearts (H Norm ). The T-wave heterogeneity descriptors [total cosine angle between QRS and T-wave loop vectors (TCRT, negative value corresponds to large difference in the 2 loops), T-wave morphology dispersion, T-wave loop dispersion] and QT intervals were analyzed in a beat-to-beat manner on 3-min records of 12-lead surface ECG at baseline and during atrial pacing at 80 and 100 bpm. The global T-wave heterogeneity was expressed as mean values of each of the T-wave morphology descriptors and variability in QT intervals (QTV) as standard deviation of QT intervals. Baseline T-wave morphology dispersion and QTV were higher in HFVT compared to H Norm subjects (p ≤ 0.02). While group differences in T-wave morphology dispersion and T-wave loop dispersion remained unaltered with atrial pacing, TCRT tended to fall more in HFVT patients compared to H Norm subjects (interaction p value = 0.086). Atrial pacing failed to reduce QTV in both groups, however group differences were augmented (p < 0.0001). Atrial pacing and consequent loss of HRV appears to introduce unfavorable changes in ventricular repolarization in HFVT subjects. It widens the spatial relationship between wavefronts of ventricular depolarization and repolarization. This may partly explain the concerning relation between poorer HRV and the risk of ventricular arrhythmias.

Estimating interactions between physiological systems is an important challenge in modern biomedical research. Here, we explore a new concept for quantifying information common in two time series by cross-compressibility. Cross-compression entropy (CCE) exploits the ZIP data compression algorithm extended to bivariate data analysis. First, time series are transformed into symbol vectors. Symbols of the target time series are coded by the symbols of the source series. Uncoupled and linearly coupled surrogates were derived from cardiovascular recordings of 36 healthy controls obtained during rest to demonstrate suitability of this method for assessing physiological coupling. CCE at rest was compared to that of isometric handgrip exercise. Finally, spontaneous baroreflex interaction assessed by CCE BRS was compared between 21 patients suffering from acute schizophrenia and 21 matched controls. The CCE BRS of original time series was significantly higher than in uncoupled surrogates in 89% of the subjects and higher than in linearly coupled surrogates in 47% of the subjects. Handgrip exercise led to sympathetic activation and vagal inhibition accompanied by reduced baroreflex sensitivity. CCE BRS decreased from 0.553 ± 0.030 at rest to 0.514 ± 0.035 during exercise ( p < 0.001). In acute schizophrenia, heart rate, and blood pressure were elevated. Heart rate variability indicated a change of sympathovagal balance. The CCE BRS of patients with schizophrenia was reduced compared to healthy controls (0.546 ± 0.042 vs. 0.507 ± 0.046, p < 0.01) and revealed a decrease of blood pressure influence on heart rate in patients with schizophrenia. Our results indicate that CCE is suitable for the investigation of linear and non-linear coupling in cardiovascular time series. CCE can quantify causal interactions in short, noisy and non-stationary physiological time series.

Motor imagery (MI) activates the sensorimotor system independent of actual movements and might be facilitated by neurofeedback. Knowledge on the interaction between feedback modality and the involved frequency bands during MI-related brain self-regulation is still scarce. Previous studies compared the cortical activity during the MI task with concurrent feedback (MI with feedback condition) to cortical activity during the relaxation task where no feedback was provided (relaxation without feedback condition). The observed differences might, therefore, be related to either the task or the feedback. A proper comparison would necessitate studying a relaxation condition with feedback and a MI task condition without feedback as well. Right-handed healthy subjects performed two tasks, i.e., MI and relaxation, in alternating order. Each of the tasks (MI vs. relaxation) was studied with and without feedback. The respective event-driven oscillatory activity, i.e., sensorimotor desynchronization (during MI) or synchronization (during relaxation), was rewarded with contingent feedback. Importantly, feedback onset was delayed to study the task-related cortical activity in the absence of feedback provision during the delay period. The reward modality was alternated every 15 trials between proprioceptive and visual feedback. Proprioceptive input was superior to visual input to increase the range of task-related spectral perturbations in the α- and β-band, and was necessary to consistently achieve MI-related sensorimotor desynchronization (ERD) significantly below baseline. These effects occurred in task periods without feedback as well. The increased accuracy and duration of learned brain self-regulation achieved in the proprioceptive condition was specific to the β-band. MI-related operant learning of brain self-regulation is facilitated by proprioceptive feedback and mediated in the sensorimotor β-band.

The efficacy of adenotonsillectomy for treating obstructive sleep apnoea syndrome (OSAS) in children has been established, but its precise effects on inspiratory effort are not well documented.In 353 children enrolled in the Childhood Adenotonsillectomy Trial, randomised to undergo either early adenotonsillectomy (n=182) or a strategy of watchful waiting with supportive care (WWSC) (n=171), thoraco-abdominal asynchrony (TAA) was analysed during quiet, non-apnoeic and non-hypopnoeic breathing during sleep at baseline and at 7 months using overnight polysomnography.Children who underwent early adenotonsillectomy demonstrated a reduction in TAA post-surgery while the WWSC arm showed no change. On assessing TAA with regard to normalisation of clinical polysomnography findings at follow-up, TAA was reduced in children who had surgical resolution of OSAS (based on apnoea-hypopnoea index), but not in children who displayed spontaneous normalisation of apnoea-hypopnoea index. In the latter group, TAA was inversely correlated with quality of life.We conclude that adenotonsillectomy reduces TAA during quiet sleep. Monitoring of instantaneous TAA may yield additional insight in the dynamic changes of inspiratory effort. In combination with traditional indices of obstruction, TAA may more accurately characterise the degree of sleep-disordered breathing in children., (Copyright ©ERS 2017.)

Objectives: The etiology of conotruncal heart defects (CHD) remains unknown; however relation between homocysteine, folate levels, and congenital heart disease was found. With this perspective in mind, the aim of the study was to investigate biomarkers of homosyteine metabolism pathway in mothers and their neonates with CHD., Material and Methods: Forty-three pairs of mothers and their neonates with CHD and forty pairs of mothers and neonates with nonconotruncal heart defects (non-CHD) were enrolled. The control group (CG) consisted of fifty-nine pairs of mothers and their healthy neonates. For estimating the plasma total homocysteine (tHcy), serum folates, and cobalamin levels, mothers' venous blood samples and umbilical cord blood were taken in all groups., Results: We observed higher tHcy levels in newborns with CHD in comparison to their mothers and to neonates with non-CHD. Cobalamin levels were significantly lower in neonates with CHD compared to other children. Folates and cobalamin levels were lower in CHD mothers compared to their children., Conclusions: Elevated homocysteine levels in neonates with CHD and folate metabolism disturbances in their mothers were noticed. The observed differences in homocysteine and cobalamin levels between neonates with CHD suggest the influence of various agents disturbing homocysteine metabolic pathways.