Pulse Wave Amplitude Drops Index: A Biomarker of Cardiovascular Risk in Obstructive Sleep Apnea.

Rationale: It is currently unclear which patients with obstructive sleep apnea (OSA) are at increased cardiovascular risk. Objective: To investigate the value of pulse wave amplitude drops (PWADs), reflecting sympathetic activations and vasoreactivity, as a biomarker of cardiovascular risk in OSA. Methods: PWADs were derived from pulse oximetry-based photoplethysmography signals in three prospective cohorts: HypnoLaus (N = 1,941), the Pays-de-la-Loire Sleep Cohort (PLSC; N = 6,367), and "Impact of Sleep Apnea syndrome in the evolution of Acute Coronary syndrome. Effect of intervention with CPAP" (ISAACC) (N = 692). The PWAD index was the number of PWADs (>30%) per hour during sleep. All participants were divided into subgroups according to the presence or absence of OSA (defined as ⩾15 or more events per hour or <15/h, respectively, on the apnea-hypopnea index) and the median PWAD index. Primary outcome was the incidence of composite cardiovascular events. Measurements and Main Results: Using Cox models adjusted for cardiovascular risk factors (hazard ratio; HR [95% confidence interval]), patients with a low PWAD index and OSA had a higher incidence of cardiovascular events compared with the high-PWAD and OSA group and those without OSA in the HypnoLaus cohort (HR, 2.16 [1.07-4.34], P = 0.031; and 2.35 [1.12-4.93], P = 0.024) and in the PLSC (1.36 [1.13-1.63], P = 0.001; and 1.44 [1.06-1.94], P = 0.019), respectively. In the ISAACC cohort, the low-PWAD and OSA untreated group had a higher cardiovascular event recurrence rate than that of the no-OSA group (2.03 [1.08-3.81], P = 0.028). In the PLSC and HypnoLaus cohorts, every increase of 10 events per hour in the continuous PWAD index was negatively associated with incident cardiovascular events exclusively in patients with OSA (HR, 0.85 [0.73-0.99], P = 0.031; and HR, 0.91 [0.86-0.96], P < 0.001, respectively). This association was not significant in the no-OSA group and the ISAACC cohort. Conclusions: In patients with OSA, a low PWAD index reflecting poor autonomic and vascular reactivity was independently associated with a higher cardiovascular risk.

Integrity of Corpus Callosum Is Essential for theCross-Hemispheric Propagation of Sleep Slow Waves:A High-Density EEG Study in Split-Brain Patients.

The slow waves of non-rapid eye movement (NREM) sleep reflect experience-dependent plasticity and play a direct role in the restorative functions of sleep. Importantly, slow waves behave as traveling waves, and their propagation is assumed to occur through cortico-cortical white matter connections. In this light, the corpus callosum (CC) may represent the main responsible for cross-hemispheric slow-wave propagation. To verify this hypothesis, we performed overnight high-density (hd)-EEG recordings in five patients who underwent total callosotomy due to drug-resistant epilepsy (CPs; two females), in three noncallosotomized neurologic patients (NPs; two females), and in a sample of 24 healthy adult subjects (HSs; 13 females). In all CPs slow waves displayed a significantly reduced probability of cross-hemispheric propagation and a stronger inter-hemispheric asymmetry. In both CPs and HSs, the incidence of large slow waves within individual NREM epochs tended to differ across hemispheres, with a relative overall predominance of the right over the left hemisphere. The absolute magnitude of this asymmetry was greater in CPs relative to HSs. However, the CC resection had no significant effects on the distribution of slow-wave origin probability across hemispheres. The present results indicate that CC integrity is essential for the cross-hemispheric traveling of slow waves in human sleep, which is in line with the assumption of a direct relationship between white matter integrity and slow-wave propagation. Our findings also revealed a residual cross-hemispheric slow-wave propagation that may rely on alternative pathways, including cortico-subcortico-cortical loops. Finally, these data indicate that the lack of the CC does not lead to differences in slow-wave generation across brain hemispheres.SIGNIFICANCE STATEMENT The slow waves of NREM sleep behave as traveling waves, and their propagation has been suggested to reflect the integrity of white matter cortico-cortical connections. To directly assess this hypothesis, here we investigated the role of the corpus callosum in the cortical spreading of NREM slow waves through the study of a rare population of totally callosotomized patients. Our results demonstrate a causal role of the corpus callosum in the cross-hemispheric traveling of sleep slow waves. Additionally, we found that callosotomy does not affect the relative tendency of each hemisphere at generating slow waves. Incidentally, we also found that slow waves tend to originate more often in the right than in the left hemisphere in both callosotomized and healthy adult individuals.

Cortical and subcortical hemodynamic changes during sleep slow waves in human light sleep.

EEG slow waves, the hallmarks of NREM sleep are thought to be crucial for the regulation of several important processes, including learning, sensory disconnection and the removal of brain metabolic wastes. Animal research indicates that slow waves may involve complex interactions within and between cortical and subcortical structures. Conventional EEG in humans, however, has a low spatial resolution and is unable to accurately describe changes in the activity of subcortical and deep cortical structures. To overcome these limitations, here we took advantage of simultaneous EEG-fMRI recordings to map cortical and subcortical hemodynamic (BOLD) fluctuations time-locked to slow waves of light sleep. Recordings were performed in twenty healthy adults during an afternoon nap. Slow waves were associated with BOLD-signal increases in the posterior brainstem and in portions of thalamus and cerebellum characterized by preferential functional connectivity with limbic and somatomotor areas, respectively. At the cortical level, significant BOLD-signal decreases were instead found in several areas, including insula and somatomotor cortex. Specifically, a slow signal increase preceded slow-wave onset and was followed by a delayed, stronger signal decrease. Similar hemodynamic changes were found to occur at different delays across most cortical brain areas, mirroring the propagation of electrophysiological slow waves, from centro-frontal to inferior temporo-occipital cortices. Finally, we found that the amplitude of electrophysiological slow waves was positively related to the magnitude and inversely related to the delay of cortical and subcortical BOLD-signal changes. These regional patterns of brain activity are consistent with theoretical accounts of the functions of sleep slow waves.

Risk factors of excessive daytime sleepiness in a prospective population-based cohort.

Although excessive daytime sleepiness is commonly evaluated in clinical and research settings using the Epworth Sleepiness Scale, few studies have assessed the factors associated with its incidence in the general population. We prospectively investigated the predictors of incident and persistent excessive daytime sleepiness in 2,751 subjects (46.1% men, mean age 56.0 ± 9.8 years) from the CoLaus-PsyCoLaus population-based cohort (Lausanne, Switzerland) over 5 years. Participants completed the Epworth Sleepiness Scale and the Pittsburgh Sleep Quality Index, and underwent a full clinical evaluation at baseline and 5 years afterwards. Ambulatory polysomnography was performed at baseline in a sub-sample of 1,404 subjects. Among the 2,438 subjects without excessive daytime sleepiness (Epworth Sleepiness Scale ≤ 10) at baseline, the 5-year incidence of excessive daytime sleepiness was 5.1% (n = 124). Multivariate logistic regression revealed that male sex, depressive symptoms, reported poor sleep quality and moderate to severe obstructive sleep apnea were independent predictors of incident excessive daytime sleepiness, while older age, moderate coffee consumption, periodic leg movement during sleep and hypertension were independent protective factors. Stratified analysis according to sex and age showed some distinctive associations. Among the 313 patients with excessive daytime sleepiness at baseline, 137 (43.8%) had persistent excessive daytime sleepiness 5 years later. Our findings provide new insights into the predictors of incident excessive daytime sleepiness, but interventional studies are needed to understand the impact of treating these risk factors on the incidence of excessive daytime sleepiness.

Regional Delta Waves In Human Rapid Eye Movement Sleep.

Although the EEG slow wave of sleep is typically considered to be a hallmark of nonrapid eye movement (NREM) sleep, recent work in mice has shown that slow waves can also occur in REM sleep. Here, we investigated the presence and cortical distribution of negative delta (1-4 Hz) waves in human REM sleep by analyzing high-density EEG sleep recordings obtained in 28 healthy subjects. We identified two clusters of delta waves with distinctive properties: (1) a frontal-central cluster characterized by ∼2.5-3.0 Hz, relatively large, notched delta waves (so-called "sawtooth waves") that tended to occur in bursts, were associated with increased gamma activity and rapid eye movements (EMs), and upon source modeling displayed an occipital-temporal and a frontal-central component and (2) a medial-occipital cluster characterized by more isolated, slower (<2 Hz), and smaller waves that were not associated with rapid EMs, displayed a negative correlation with gamma activity, and were also found in NREM sleep. Therefore, delta waves are an integral part of REM sleep in humans and the two identified subtypes (sawtooth and medial-occipital slow waves) may reflect distinct generation mechanisms and functional roles. Sawtooth waves, which are exclusive to REM sleep, share many characteristics with ponto-geniculo-occipital waves described in animals and may represent the human equivalent or a closely related event, whereas medial-occipital slow waves appear similar to NREM sleep slow waves.SIGNIFICANCE STATEMENT The EEG slow wave is typically considered a hallmark of nonrapid eye movement (NREM) sleep, but recent work in mice has shown that it can also occur in REM sleep. By analyzing high-density EEG recordings collected in healthy adult individuals, we show that REM sleep is characterized by prominent delta waves also in humans. In particular, we identified two distinctive clusters of delta waves with different properties: a frontal-central cluster characterized by faster, activating "sawtooth waves" that share many characteristics with ponto-geniculo-occipital waves described in animals and a medial-occipital cluster containing slow waves that are more similar to NREM sleep slow waves. These findings indicate that REM sleep is a spatially and temporally heterogeneous state and may contribute to explaining its known functional and phenomenological properties.

Visual imagery and visual perception induce similar changes in occipital slow waves of sleep.

Previous studies have shown that regional slow-wave activity (SWA) during non-rapid eye movement (NREM) sleep is modulated by prior experience and learning. Although this effect has been convincingly demonstrated for the sensorimotor domain, attempts to extend these findings to the visual system have provided mixed results. In this study we asked whether depriving subjects of external visual stimuli during daytime would lead to regional changes in slow waves during sleep and whether the degree of "internal visual stimulation" (spontaneous imagery) would influence such changes. In two 8-h sessions spaced 1 wk apart, 12 healthy volunteers either were blindfolded while listening to audiobooks or watched movies (control condition), after which their sleep was recorded with high-density EEG. We found that during NREM sleep, the number of small, local slow waves in the occipital cortex decreased after listening with blindfolding relative to movie watching in a way that depended on the degree of visual imagery subjects reported during blindfolding: subjects with low visual imagery showed a significant reduction of occipital sleep slow waves, whereas those who reported a high degree of visual imagery did not. We also found a positive relationship between the reliance on visual imagery during blindfolding and audiobook listening and the degree of correlation in sleep SWA between visual areas and language-related areas. These preliminary results demonstrate that short-term alterations in visual experience may trigger slow-wave changes in cortical visual areas. Furthermore, they suggest that plasticity-related EEG changes during sleep may reflect externally induced ("bottom up") visual experiences, as well as internally generated ("top down") processes. NEW & NOTEWORTHY Previous work has shown that slow-wave activity, a marker of sleep depth, is linked to neural plasticity in the sensorimotor cortex. We show that after short-term visual deprivation, subjects who reported little visual imagery had a reduced incidence of occipital slow waves. This effect was absent in subjects who reported strong spontaneous visual imagery. These findings suggest that visual imagery may "substitute" for visual perception and induce similar changes in non-rapid eye movement slow waves.

Perspectives on optimal control of varicella and herpes zoster by mass routine varicella vaccination.

Herpes zoster arises from reactivation of the varicella-zoster virus (VZV), causing varicella in children. As reactivation occurs when cell-mediated immunity (CMI) declines, and there is evidence that re-exposure to VZV boosts CMI, mass varicella immunization might increase the zoster burden, at least for some decades. Fear of this natural zoster boom is the main reason for the paralysis of varicella immunization in Europe. We apply optimal control to a realistically parametrized age-structured model for VZV transmission and reactivation to investigate whether feasible varicella immunization paths that are optimal in controlling both varicella and zoster exist. We analyse the optimality system numerically focusing on the role of the cost functional, of the relative zoster-varicella cost and of the planning horizon length. We show that optimal programmes will mostly be unfeasible for public health owing to their complex temporal profiles. This complexity is the consequence of the intrinsically antagonistic nature of varicella immunization programmes when aiming to control both varicella and zoster. However, we show that gradually increasing-hence feasible-vaccination schedules can perform better than routine programmes with constant vaccine uptake. Finally, we show the optimal profiles of feasible programmes targeting mitigation of the post-immunization natural zoster boom with priority.

Maturation-dependent changes in cortical and thalamic activity during sleep slow waves: Insights from a combined EEG-fMRI study.

INTRODUCTION: Studies using scalp EEG have shown that slow waves (0.5-4 Hz), the most prominent hallmark of NREM sleep, undergo relevant changes from childhood to adulthood, mirroring brain structural modifications and the acquisition of cognitive skills. Here we used simultaneous EEG-fMRI to investigate the cortical and subcortical correlates of slow waves in school-age children and determine their relative developmental changes. METHODS: We analyzed data from 14 school-age children with self-limited focal epilepsy of childhood who fell asleep during EEG-fMRI recordings. Brain regions associated with slow-wave occurrence were identified using a voxel-wise regression that also modelled interictal epileptic discharges and sleep spindles. At the group level, a mixed-effects linear model was used. The results were qualitatively compared with those obtained from 2 adolescents with epilepsy and 17 healthy adults. RESULTS: Slow waves were associated with hemodynamic-signal decreases in bilateral somatomotor areas. Such changes extended more posteriorly relative to those in adults. Moreover, the involvement of areas belonging to the default mode network changes as a function of age. No significant hemodynamic responses were observed in subcortical structures. However, we identified a significant correlation between age and thalamic hemodynamic changes. CONCLUSIONS: Present findings indicate that the somatomotor cortex may have a key role in slow-wave expression throughout the lifespan. At the same time, they are consistent with a posterior-to-anterior shift in slow-wave distribution mirroring brain maturational changes. Finally, our results suggest that slow-wave changes may not reflect only neocortical modifications but also the maturation of subcortical structures, including the thalamus.

Cross-participant prediction of vigilance stages through the combined use of wPLI and wSMI EEG functional connectivity metrics.

Functional connectivity (FC) metrics describe brain inter-regional interactions and may complement information provided by common power-based analyses. Here, we investigated whether the FC-metrics weighted Phase Lag Index (wPLI) and weighted Symbolic Mutual Information (wSMI) may unveil functional differences across four stages of vigilance-wakefulness (W), NREM-N2, NREM-N3, and REM sleep-with respect to each other and to power-based features. Moreover, we explored their possible contribution in identifying differences between stages characterized by distinct levels of consciousness (REM+W vs. N2+N3) or sensory disconnection (REM vs. W). Overnight sleep and resting-state wakefulness recordings from 24 healthy participants (27 ± 6 years, 13F) were analyzed to extract power and FC-based features in six classical frequency bands. Cross-validated linear discriminant analyses (LDA) were applied to investigate the ability of extracted features to discriminate (1) the four vigilance stages, (2) W+REM vs. N2+N3, and (3) W vs. REM. For the four-way vigilance stages classification, combining features based on power and both connectivity metrics significantly increased accuracy relative to considering only power, wPLI, or wSMI features. Delta-power and connectivity (0.5-4 Hz) represented the most relevant features for all the tested classifications, in line with a possible involvement of slow waves in consciousness and sensory disconnection. Sigma-FC, but not sigma-power (12-16 Hz), was found to strongly contribute to the differentiation between states characterized by higher (W+REM) and lower (N2+N3) probabilities of conscious experiences. Finally, alpha-FC resulted as the most relevant FC-feature for distinguishing among wakefulness and REM sleep and may thus reflect the level of disconnection from the external environment.

Electroencephalographic changes associated with subjective under- and overestimation of sleep duration.

Feeling awake although sleep recordings indicate clear-cut sleep sometimes occurs in good sleepers and to an extreme degree in patients with so-called paradoxical insomnia. It is unknown what underlies sleep misperception, as standard polysomnographic (PSG) parameters are often normal in these cases. Here we asked whether regional changes in brain activity could account for the mismatch between objective and subjective total sleep times (TST). To set cutoffs and define the norm, we first evaluated sleep perception in a population-based sample, consisting of 2,092 individuals who underwent a full PSG at home and estimated TST the next day. We then compared participants with a low mismatch (normoestimators, n = 1,147, ±0.5 SD of mean) with those who severely underestimated (n = 52, <2.5th percentile) or overestimated TST (n = 53, >97.5th percentile). Compared with normoestimators, underestimators displayed higher electroencephalographic (EEG) activation (beta/delta power ratio) in both rapid eye movement (REM) and non-rapid eye movement (NREM) sleep, while overestimators showed lower EEG activation (significant in REM sleep). To spatially map these changes, we performed a second experiment, in which 24 healthy subjects and 10 insomnia patients underwent high-density sleep EEG recordings. Similarly to underestimators, patients displayed increased EEG activation during NREM sleep, which we localized to central-posterior brain areas. Our results indicate that a relative shift from low- to high-frequency spectral power in central-posterior brain regions, not readily apparent in conventional PSG parameters, is associated with underestimation of sleep duration. This challenges the concept of sleep misperception, and suggests that instead of misperceiving sleep, insomnia patients may correctly perceive subtle shifts toward wake-like brain activity.

Pulse wave amplitude drops during sleep: clinical significance and characteristics in a general population sample.

STUDY OBJECTIVES: To explore the clinical significance of pulse wave amplitude (PWA)-drops during sleep as a biomarker for cardiometabolic disorders and describe their main characteristics in a general population sample. METHODS: Cross-sectional study of HypnoLaus cohort, in which 2162 individuals underwent clinical assessment and in-home full polysomnography. PWA-drops were derived from photoplethysmography and processed using a validated automated algorithm. Associations between PWA-drop features (index, mean duration, and mean area under the curve [AUC]) with hypertension, diabetes, and previous cardiovascular (CV) event were analyzed using multivariable-adjusted logistic regression. RESULTS: Two thousand one hundred forty-nine participants (59 ± 11 years, 51% women, 9.9% diabetes, 41.3% hypertension, 4.4% CV event) were included. Mean ± standard deviation (SD) of PWA-drop index, duration, and AUC during sleep were 51.0 ± 20.3 events/hour, 14.0 ± 2.7 seconds, and 527±115 %seconds, respectively. PWA-drop index was lower in women and decreased with age, while its mean duration and AUC increased in men and elderly. Overall, lower PWA-drop index, longer duration and greater AUC were associated with increased odds of hypertension, diabetes, or CV event after adjustment for confounders. Participants in the lowest quartile of mean duration-normalized PWA-drop index had a significantly higher odds ratio (OR) of hypertension (OR = 1.60 [1.19-2.16]), CV event (OR = 3.26 [1.33-8.03]), and diabetes (OR = 1.71 [1.06-2.76]) compared to those in the highest quartile. Similar results were observed for mean AUC-normalized PWA-drop index regarding hypertension (OR = 1.59 [1.19-2.13]), CV event (OR = 2.45 [1.14-5.26]) and diabetes (OR = 1.76 [1.10-2.83]). CONCLUSIONS: PWA-drop features during sleep seem to be an interesting biomarker independently associated with cardiometabolic outcomes in the general population.

Models for optimally controlling varicella and herpes zoster by varicella vaccination: a comparative study.

The introduction of mass vaccination against Varicella-Zoster-Virus (VZV) is being delayed in many European countries mainly because of the "fear" of a subsequent boom in natural herpes zoster (HZ) incidence in the first decades after the initiation of vaccination, caused by the expected decline in the protective effect of natural immunity boosting due to reduced virus circulation. Optimal control theory has proven to be a successful tool in understanding ways to curtail the spread of infectious diseases by devising the optimal disease intervention strategies. In this paper, we describe how a reduced 'toy' model can extract the essentials of the dynamics of the VZV transmission and reactivation in case of the study of optimal paths of varicella immunization programs. Results obtained using different optimization approaches are compared with the ones of a more realistic age-structured model. The reduced model shows some unreliable predictions in regards of model time scales about herpes zoster dynamic; nevertheless, it is able to reproduce the main qualitative dynamic of the more realistic model to the different optimization problems, while requiring a minimal number of parameters to be identified. Graphical abstract ᅟ.

Emotionotopy in the human right temporo-parietal cortex.

Humans use emotions to decipher complex cascades of internal events. However, which mechanisms link descriptions of affective states to brain activity is unclear, with evidence supporting either local or distributed processing. A biologically favorable alternative is provided by the notion of gradient, which postulates the isomorphism between functional representations of stimulus features and cortical distance. Here, we use fMRI activity evoked by an emotionally charged movie and continuous ratings of the perceived emotion intensity to reveal the topographic organization of affective states. Results show that three orthogonal and spatially overlapping gradients encode the polarity, complexity and intensity of emotional experiences in right temporo-parietal territories. The spatial arrangement of these gradients allows the brain to map a variety of affective states within a single patch of cortex. As this organization resembles how sensory regions represent psychophysical properties (e.g., retinotopy), we propose emotionotopy as a principle of emotion coding.

Formant Space Reconstruction From Brain Activity in Frontal and Temporal Regions Coding for Heard Vowels.

Classical studies have isolated a distributed network of temporal and frontal areas engaged in the neural representation of speech perception and production. With modern literature arguing against unique roles for these cortical regions, different theories have favored either neural code-sharing or cortical space-sharing, thus trying to explain the intertwined spatial and functional organization of motor and acoustic components across the fronto-temporal cortical network. In this context, the focus of attention has recently shifted toward specific model fitting, aimed at motor and/or acoustic space reconstruction in brain activity within the language network. Here, we tested a model based on acoustic properties (formants), and one based on motor properties (articulation parameters), where model-free decoding of evoked fMRI activity during perception, imagery, and production of vowels had been successful. Results revealed that phonological information organizes around formant structure during the perception of vowels; interestingly, such a model was reconstructed in a broad temporal region, outside of the primary auditory cortex, but also in the pars triangularis of the left inferior frontal gyrus. Conversely, articulatory features were not associated with brain activity in these regions. Overall, our results call for a degree of interdependence based on acoustic information, between the frontal and temporal ends of the language network.

Common spatiotemporal processing of visual features shapes object representation.

Biological vision relies on representations of the physical world at different levels of complexity. Relevant features span from simple low-level properties, as contrast and spatial frequencies, to object-based attributes, as shape and category. However, how these features are integrated into coherent percepts is still debated. Moreover, these dimensions often share common biases: for instance, stimuli from the same category (e.g., tools) may have similar shapes. Here, using magnetoencephalography, we revealed the temporal dynamics of feature processing in human subjects attending to objects from six semantic categories. By employing Relative Weights Analysis, we mitigated collinearity between model-based descriptions of stimuli and showed that low-level properties (contrast and spatial frequencies), shape (medial-axis) and category are represented within the same spatial locations early in time: 100-150 ms after stimulus onset. This fast and overlapping processing may result from independent parallel computations, with categorical representation emerging later than the onset of low-level feature processing, yet before shape coding. Categorical information is represented both before and after shape, suggesting a role for this feature in the refinement of categorical matching.

EEG functional connectivity metrics wPLI and wSMI account for distinct types of brain functional interactions.

The weighted Phase Lag Index (wPLI) and the weighted Symbolic Mutual Information (wSMI) represent two robust and widely used methods for MEG/EEG functional connectivity estimation. Interestingly, both methods have been shown to detect relative alterations of brain functional connectivity in conditions associated with changes in the level of consciousness, such as following severe brain injury or under anaesthesia. Despite these promising findings, it was unclear whether wPLI and wSMI may account for distinct or similar types of functional interactions. Using simulated high-density (hd-)EEG data, we demonstrate that, while wPLI has high sensitivity for couplings presenting a mixture of linear and nonlinear interdependencies, only wSMI can detect purely nonlinear interaction dynamics. Moreover, we evaluated the potential impact of these differences on real experimental data by computing wPLI and wSMI connectivity in hd-EEG recordings of 12 healthy adults during wakefulness and deep (N3-)sleep, characterised by different levels of consciousness. In line with the simulation-based findings, this analysis revealed that both methods have different sensitivity for changes in brain connectivity across the two vigilance states. Our results indicate that the conjoint use of wPLI and wSMI may represent a powerful tool to study the functional bases of consciousness in physiological and pathological conditions.

Contribution of the Lung to the Genesis of Cheyne-Stokes Respiration in Heart Failure: Plant Gain Beyond Chemoreflex Gain and Circulation Time.

Background The contribution of the lung or the plant gain ( PG ; ie, change in blood gases per unit change in ventilation) to Cheyne-Stokes respiration ( CSR ) in heart failure has only been hypothesized by mathematical models, but never been directly evaluated. Methods and Results Twenty patients with systolic heart failure (age, 72.4±6.4 years; left ventricular ejection fraction, 31.5±5.8%), 10 with relevant CSR (24-hour apnea-hypopnea index [ AHI ] ≥10 events/h) and 10 without ( AHI <10 events/h) at 24-hour cardiorespiratory monitoring underwent evaluation of chemoreflex gain (CG) to hypoxia ([Formula: see text]) and hypercapnia ([Formula: see text]) by rebreathing technique, lung-to-finger circulation time, and PG assessment through a visual system. PG test was feasible and reproducible (intraclass correlation coefficient, 0.98; 95% CI , 0.91-0.99); the best-fitting curve to express the PG was a hyperbola ( R2≥0.98). Patients with CSR showed increased PG , [Formula: see text] (but not [Formula: see text]), and lung-to-finger circulation time, compared with patients without CSR (all P<0.05). PG was the only predictor of the daytime AHI ( R=0.56, P=0.01) and together with the [Formula: see text] also predicted the nighttime AHI ( R=0.81, P=0.0003) and the 24-hour AHI ( R=0.71, P=0.001). Lung-to-finger circulation time was the only predictor of CSR cycle length ( R=0.82, P=0.00006). Conclusions PG is a powerful contributor of CSR and should be evaluated together with the CG and circulation time to individualize treatments aimed at stabilizing breathing in heart failure.

Procoagulant control strategies for the human blood clotting process.

This paper describes the comparison between two drug control strategies to hemophilia A. To emulate blood clotting and the pathological condition of hemophilia, a mathematical model composed by 14 ordinary differential equations is considered. We adopt a variable structure non-linear PID approach and a Model Predictive Control in order to control the dosage of procoagulant factor used in the treatment of hemophiliac patient. The two control actions are sampled for a practical application. Finally, we discuss and compare the results of the two control approaches, introducing a suited control index (eINR).

Combining pharmacological therapy and vaccination in Chronic Myeloid Leukemia via model predictive control.

This paper describes a simulation study which aims at optimizing the therapy for the control of Chronic Myeloid Leukemia according to the following objectives: the reduction of the administered drug and vaccine amounts, the establishment of a auto-immune response and the long-term control of disease without reducing the effective of therapy with respect to the full treatment. A therapy optimization method is developed defining and solving a Model Predictive Control algorithm, preceded by an accurate Initial Guess search based on Monte-Carlo like approach. Simulation results show that the suggested procedure achieves the proposed goals.