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Malhotra, Atul

Progress in the treatment of acute respiratory distress syndrome (ARDS) has been slow, perhaps in part due to the heterogeneity in the biology underlying this syndrome. Open lung biopsy is a feasible approach to define various subcategories of underlying histology. In experienced hands, with careful selection of patients and close attention to details of critical care management, including mechanical ventilator settings, the procedure is safe even in patients with severe disease. However, further work is needed to define which patients, if any, experience a beneficial effect on outcome from this procedure. More research is needed on assessing efficacy of potential therapies within histologically defined subgroups. In the future, various biomarkers may be available to non-invasively classify ARDS patients from the standpoint of responsiveness to various therapies, such as gluco-corticoids.

Background: The detection of change in magnitude of directional coupling between two non-linear time series is a common subject of interest in the biomedical domain, including studies involving the respiratory chemoreflex system. Although transfer entropy is a useful tool in this avenue, no study to date has investigated how different transfer entropy estimation methods perform in typical biomedical applications featuring small sample size and presence of outliers. Methods: With respect to detection of increased coupling strength, we compared three transfer entropy estimation techniques using both simulated time series and respiratory recordings from lambs. The following estimation methods were analyzed: fixed-binning with ranking, kernel density estimation (KDE), and the Darbellay-Vajda (D-V) adaptive partitioning algorithm extended to three dimensions. In the simulated experiment, sample size was varied from 50 to 200, while coupling strength was increased. In order to introduce outliers, the heavy-tailed Laplace distribution was utilized. In the lamb experiment, the objective was to detect increased respiratory-related chemosensitivity to O2 and CO2 induced by a drug, domperidone. Specifically, the separate influence of end-tidal PO2 and PCO2 on minute ventilation (V_E) before and after administration of domperidone was analyzed. Results: In the simulation, KDE detected increased coupling strength at the lowest SNR among the three methods. In the lamb experiment, D-V partitioning resulted in the statistically strongest increase in transfer entropy post-domperidone for PO2→V_E. In addition, D-V partitioning was the only method that could detect an increase in transfer entropy for PCO2→V_E, in agreement with experimental findings. Conclusions: Transfer entropy is capable of detecting directional coupling changes in non-linear biomedical time series analysis featuring a small number of observations and presence of outliers. The results of this study suggest that fixed-binning, even with ranking, is too primitive, and although there is no clear winner between KDE and D-V partitioning, the reader should note that KDE requires more computational time and extensive parameter selection than D-V partitioning. We hope this study provides a guideline for selection of an appropriate transfer entropy estimation method.

Intra-abdominal hypertension is increasingly recognized to be both prevalent and clinically important in medical and surgical intensive care units. Intra-abdominal pressure (IAP) can impact organ function throughout the body, and it can also complicate standard measurements used in intensive care units. The article by Krebs and colleagues reports the effect of IAP on respiratory function, gas exchange and hemodynamic function. Their results show a relatively small effect of modestly elevated IAP on these variables in their patient population. However, their work raises several questions for clinicians and researchers regarding the pathophysiology and management of IAP.

A growing literature supports a role for sleep after training in long-term memory consolidation and enhancement. Consequently, interrupted sleep should result in cognitive deficits. Recent evidence from an animal study indeed showed that optimal memory consolidation during sleep requires a certain amount of uninterrupted sleep.

Sleep continuity is disrupted in various medical disorders. We compared performance on a motor sequence learning task (MST) in relatively young subjects with obstructive sleep apnea (n = 16; apnea-hypopnea index (17.1 \pm 2.6 / h ) [SEM]) to a carefully matched control group (n = 15, apnea-hypopnea index (3.7 \pm 0.4 / h), p<0.001. Apart from AHI, oxygen nadir and arousal index, there were no significant differences between groups in total sleep time, sleep efficiency and sleep architecture as well as subjective measures of sleepiness based on standard questionnaires. In addition performance on the psychomotor vigilance task (reaction time and lapses), which is highly sensitive to sleep deprivation showed no differences as well as initial learning performance during the training phase. However there was a significant difference in the primary outcome of immediate overnight improvement on the MST between the two groups (controls = (14.7 \pm 4 % ), patients = (1.1 \pm 3.6 % ); (P = 0.023) ) as well as plateau performance (controls = (24.0 \pm 5.3 % ), patients = (10.1 \pm 2.0 % ); (P = 0.017) ) and this difference was predicted by the arousal index (p = 0.02) rather than oxygen saturation (nadir and time below 90% saturation. Taken together, this outcome provides evidence that there is a clear minimum requirement of sleep continuity in humans to ensure optimal sleep dependent memory processes. It also provides important new information about the cognitive impact of obstructive sleep apnea and challenges its current definitions.

The genioglossus is a major upper airway dilator muscle thought to be important in obstructive sleep apnea pathogenesis. Aging is a risk factor for obstructive sleep apnea although the mechanisms are unclear and the effects of aging on motor unit remodeled in the genioglossus remains unknown. To assess possible changes associated with aging we compared quantitative parameters related to motor unit potential morphology derived from EMG signals in a sample of older (n = 11; >55 years) versus younger (n = 29; <55 years) adults. All data were recorded during quiet breathing with the subjects awake. Diagnostic sleep studies (Apnea Hypopnea Index) confirmed the presence or absence of obstructive sleep apnea. Genioglossus EMG signals were analyzed offline by automated software (DQEMG), which estimated a MUP template from each extracted motor unit potential train (MUPT) for both the selective concentric needle and concentric needle macro (CNMACRO) recorded EMG signals. 2074 MUPTs from 40 subjects (mean±95% CI; older AHI 19.6±9.9 events/hr versus younger AHI 30.1±6.1 events/hr) were extracted. MUPs detected in older adults were 32% longer in duration (14.7±0.5 ms versus 11.1±0.2 ms; P = 0.05), with similar amplitudes (395.2±25.1 µV versus 394.6±13.7 µV). Amplitudes of CNMACRO MUPs detected in older adults were larger by 22% (62.7±6.5 µV versus 51.3±3.0 µV; P<0.05), with areas 24% larger (160.6±18.6 µV.ms versus 130.0±7.4 µV.ms; P<0.05) than those detected in younger adults. These results confirm that remodeled motor units are present in the genioglossus muscle of individuals above 55 years, which may have implications for OSA pathogenesis and aging related upper airway collapsibility.

Untreated and long-lasting obstructive sleep apnea (OSA) may lead to important vascular abnormalities, including endothelial cell (EC) dysfunction, hypertension, and atherosclerosis. We observed a correlation between microcirculatory reactivity and endothelium-dependent release of nitric oxide in OSA patients. Therefore, we hypothesized that OSA affects (micro)vasculature and we aimed to identify vascular gene targets of OSA that could possibly serve as reliable biomarkers of severity of the disease and possibly of vascular risk. Using quantitative RT-PCR, we evaluated gene expression in skin biopsies of OSA patients, mouse aortas from animals exposed to 4-week intermittent hypoxia (IH; rapid oscillations in oxygen desaturation and reoxygenation), and human dermal microvascular (HMVEC) and coronary artery endothelial cells (HCAEC) cultured under IH. We demonstrate a significant upregulation of endothelial nitric oxide synthase (eNOS), tumor necrosis factor-alpha-induced protein 3 (TNFAIP3; A20), hypoxia-inducible factor 1 alpha (HIF-1α?? and vascular endothelial growth factor (VEGF) expression in skin biopsies obtained from OSA patients with severe nocturnal hypoxemia (nadir saturated oxygen levels [SaO2]<75%) compared to mildly hypoxemic OSA patients (SaO2 75%–90%) and a significant upregulation of vascular cell adhesion molecule 1 (VCAM-1) expression compared to control subjects. Gene expression profile in aortas of mice exposed to IH demonstrated a significant upregulation of eNOS and VEGF. In an in vitro model of OSA, IH increased expression of A20 and decreased eNOS and HIF-1α expression in HMVEC, while increased A20, VCAM-1 and HIF-1αexpression in HCAEC, indicating that EC in culture originating from distinct vascular beds respond differently to IH stress. We conclude that gene expression profiles in skin of OSA patients may correlate with disease severity and, if validated by further studies, could possibly predict vascular risk in OSA patients.

Background: Increasing age is associated with a decline in cognition and motor skills, while at the same time exacerbating one's risk of developing obstructive sleep apnea (OSA). OSA-related cognitive deficits are highly prevalent and can affect various memory systems including overnight memory consolidation on a motor sequence task. Thus, the aim of our study was to examine the effect of aging on sleep-dependent motor memory consolidation in patients with and without OSA. Methods: We studied 44 patients (19–68 years) who had been referred by a physician for a baseline polysomnography (PSG) evaluation. Based on their PSG, patients were assigned either to the OSA group (AHI>5/h), or control (Non-OSA) group (AHI<5/h). All subjects performed the Psychomotor Vigilance Task (PVT) and the Motor Sequence Learning Task (MST) in the evening and again in the morning after their PSG. Results: Despite similar learning in the evening, OSA subjects showed significantly less overnight improvement on the MST, both for immediate (OSA −2.7%±2.8% vs. controls 12.2%±3.5%; p = 0.002) and plateau improvement (OSA 4.9%±2.3% vs. controls 21.1%±4.0%; p = 0.001). Within the OSA group, there was a significant negative correlation between overnight MST improvement and age (r2 = 0.3; p = 0.01), an effect that was not observed in the Non-OSA group (r2 = 0.08; p = 0.23) Conclusions: Consistent with previous research, healthy sleepers demonstrated a higher degree of sleep-dependent overnight improvement on the MST, an effect not mitigated by increasing age. However, the presence of untreated obstructive sleep apnea is associated with an aging-related cognitive deficit, otherwise not present in individuals without OSA. As other research has linked the presence of OSA to a higher likelihood of developing dementia, future studies are necessary to examine if the inhibition of memory consolidation is tied to the onset of neurodegenerative disease.

Esophageal pressure can be used to approximate pleural pressure and might be clinically useful, particularly in the obese e.g to guide mechanical ventilator settings in critical illness. However, mediastinal artifact (the difference between true pleural pressure and esophageal pressure) may limit acceptance of the measurement, and reproducibility of esophageal pressure measurements remains unknown. Therefore, we aimed to assess the effect of body posture on esophageal pressure in a cohort of obese but healthy subjects, some of whom had multiple measurements, to address the clinical robustness of esophageal manometry. Twenty-five overweight and obese subjects (BMI>25kg/m2) and 11 control lean subjects (BMI<25kg/m2) underwent esophageal manometry with pressures measured seated and supine. Twenty overweight and obese subjects had measurements repeated after ~1-2 weeks. Anthropometric data and sitting and supine spirometry were recorded. The average end-expiratory esophageal pressures sitting and supine were greater in the overweight and obese group than the lean group (sitting −0.1±2.1 vs. −3.3±1.2cmH2O, supine 9.3±3.3 vs. 6.9±2.8cmH2O, respectively). The mean differences between repeated measurements were small (−0.3 ± 1.7cmH2O sitting and −0.1 ± 1.5cmH2O supine). Esophageal pressures correlated with a number of anthropometric and spirometric variables. In conclusion, esophageal pressures are slightly greater in overweight and obese subjects than lean subjects; but changes with position are similar in both groups. These data indicate that mediastinal weight and postural effects on esophageal pressure are within a clinically acceptable range, and suggest that esophageal manometry can be used to inform clinical decision making across wide range of body types.

Physiologic systems generate complex dynamics in their output signals that reflect the changing state of the underlying control systems. In this work, we used a switching vector autoregressive (switching VAR) framework to systematically learn and identify a collection of vital sign dynamics, which can possibly be recurrent within the same patient and shared across the entire cohort. We show that these dynamical behaviors can be used to characterize and elucidate the progression of patients' states of health over time. Using the mean arterial blood pressure time series of 337 ICU patients during the first 24 hours of their ICU stays, we demonstrated that the learned dynamics from as early as the first 8 hours of patients' ICU stays can achieve similar hospital mortality prediction performance as the well-known SAPS-I acuity scores, suggesting that the discovered latent dynamics structure may yield more timely insights into the progression of a patient's state of health than the traditional snapshot-based acuity scores.

Cardiovascular variables such as heart rate (HR) and blood pressure (BP) are robustly regulated by an underlying control system. Time series of HR and BP exhibit distinct dynamical patterns of interaction in response to perturbations (e.g., drugs or exercise) as well as in pathological states (e.g., excessive sympathetic activation). A question of interest is whether “similar” dynamical patterns can be identified across a heterogeneous patient cohort. In this work, we present a technique based on switching linear dynamical systems for identification of shared dynamical patterns in the time series of HR and BP recorded from a patient cohort. The technique uses a mixture of linear dynamical systems, the components of which are shared across all patients, to capture both nonlinear dynamics and non-Gaussian perturbations. We present exploratory results based on a simulation study of the cardiovascular system, and real recordings from 10 healthy subjects undergoing a tilt-table test. These results demonstrate the ability of the proposed technique to identify similar dynamical patterns present across multiple time series.