Machine Learning Model Combining Ventilatory, Hypoxic, Arousal Domains Across Sleep Better Predicts Adverse Consequences of Obstructive Sleep Apnea.

Obstructive sleep apnea(OSA) severity is currently assessed clinically using the apnea-hypopnea index (AHI), which is inconsistently associated with short- and long-term outcomes. Ventilatory, hypoxic, and arousal domains are known to exhibit abnormalities in OSA. Using the same set of features across these three domains, albeit using different models, we show that a physiology-guided ML approach can better predict adverse consequences of OSA compared to the AHI.

EEG slow oscillations and overnight spatial navigational memory performance in CPAP-treated obstructive sleep apnea.

Obstructive sleep apnea (OSA) exerts pathogenic effects through a combination of sleep fragmentation (SF) and intermittent hypoxia (IH). The mechanisms through which sleep disruption impacts memory might arise by investigating disruption of specific sleep stages and, when such disruption occurs through OSA, by evaluating the individual contributions of SF and IH. Given region-specific EEG slow activity during non-REM sleep has been associated with overnight declarative, motor and spatial memory formation, we investigated the effects of disrupting slow wave sleep (SWS) on a virtual maze navigation task.

The stability of slow-wave sleep and EEG oscillations across two consecutive nights of laboratory polysomnography in cognitively normal older adults.

Laboratory polysomnography provides gold-standard measures of sleep physiology, but multi-night investigations are resource intensive. We assessed the night-to-night stability via reproducibility metrics for sleep macrostructure and electroencephalography oscillations in a group of cognitively normal adults attending two consecutive polysomnographies. Electroencephalographies were analysed using an automatic algorithm for detection of slow-wave activity, spindle and K-complex densities.

Tenecteplase With Concomitant Anticoagulation for Acute Respiratory Failure in Patients With COVID-19: A Randomized Controlled Trial.

Background Pulmonary thrombosis and thromboembolism play a significant role in the physiologic derangements seen in COVID-19 acute respiratory failure. The effect of thrombolysis with tenecteplase on patient outcomes is unknown. Methods We conducted a randomized, controlled, double-blind, phase II trial comparing tenecteplase versus placebo in patients with COVID-19 acute respiratory failure (NCT04505592).

Ventilatory Burden as a Measure of Obstructive Sleep Apnea Severity Is Predictive of Cardiovascular and All-Cause Mortality.

The apnea-hypopnea index (AHI), used for the diagnosis of obstructive sleep apnea, captures only the frequency of respiratory events and has demonstrable limitations. We propose a novel automated measure, termed "ventilatory burden" (VB), that represents the proportion of overnight breaths with less than 50% normalized amplitude, and we show its ability to overcome limitations of AHI. Data from two epidemiological cohorts (EPISONO [Sao Paolo Epidemiological Study] and SHHS [Sleep Heart Health Study]) and two retrospective clinical cohorts (DAYFUN; New York University Center for Brain Health) were used in this study to ) derive the normative range of VB, ) assess the relationship between degree of upper airway obstruction and VB, and ) assess the relationship between VB and all-cause and cardiovascular disease (CVD) mortality with and without hypoxic burden that was derived using an in-house automated algorithm.

Night-to-night reliability and agreement of obstructive sleep apnea pathophysiologic mechanisms estimated with phenotyping using polysomnography in cognitively normal elderly participants.

Study Objectives: Phenotyping using polysomnography (PUP) is an algorithmic method to quantify physiologic mechanisms underlying obstructive sleep apnea (OSA): loop gain (LG1), arousal threshold (ArTH), and upper airway collapsibility (Vpassive) and muscular compensation (Vcomp). The consecutive-night test-retest reliability and agreement of PUP-derived estimates are unknown. From a cohort of elderly (age ≥55 years), largely non-sleepy, community-dwelling volunteers who underwent in-lab polysomnography (PSG) on 2 consecutive nights, we determined the test-retest reliability and agreement of PUP-estimated physiologic factors.

Night-to-Night Variability of Polysomnography-Derived Physiologic Endotypic Traits in Patients With Moderate to Severe OSA.

Background: Emerging data suggest that determination of physiologic endotypic traits (eg, loop gain) may enable precision medicine in OSA.

Research Question: Does a single-night assessment of polysomnography-derived endotypic traits provide reliable estimates in moderate to severe OSA?

Study Design And Methods: Two consecutive in-lab polysomnography tests from a clinical trial (n = 67; male, 69%; mean ± SD age, 61 ± 10 years; apnea-hypopnea index [AHI] 53 ± 22 events/h) were used for the reliability analysis. Endotypic traits, reflecting upper airway collapsibility (ventilation at eupneic drive [V]), upper airway dilator muscle tone (ventilation at the arousal threshold [V]), loop gain (stability of ventilatory control, LG1), and arousal threshold (ArTh) were determined.

Selective Continuous Positive Airway Pressure Withdrawal With Supplemental Oxygen During Slow-Wave Sleep as a Method of Dissociating Sleep Fragmentation and Intermittent Hypoxemia-Related Sleep Disruption in Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) is considered to impair memory processing and increase the expression of amyloid-β (Aβ) and risk for Alzheimer's disease (AD). Given the evidence that slow-wave sleep (SWS) is important in both memory and Aβ metabolism, a better understanding of the mechanisms by which OSA impacts memory and risk for AD can stem from evaluating the role of disruption of SWS specifically and, when such disruption occurs through OSA, from evaluating the individual contributions of sleep fragmentation (SF) and intermittent hypoxemia (IH). In this study, we used continuous positive airway pressure (CPAP) withdrawal to recapitulate SWS-specific OSA during polysomnography (PSG), creating conditions of both SF and IH in SWS only.

Quantification of airway conductance from noninvasive ventilatory drive in patients with sleep apnea.

Upper airway conductance, the ratio of inspiratory airflow to inspiratory effort, quantifies the degree of airway obstruction in hypopneas observed in sleep apnea. We evaluated the ratio of ventilation to noninvasive ventilatory drive as a surrogate of conductance. Furthermore, we developed and tested a refinement of noninvasive drive to incorporate the interactions of inspiratory flow, pressure, and drive to better estimate conductance.

Endotyping Sleep Apnea One Breath at a Time: An Automated Approach for Separating Obstructive from Central Sleep-disordered Breathing.

Determining whether an individual has obstructive or central sleep apnea is fundamental to selecting the appropriate treatment. Here we derive an automated breath-by-breath probability of obstruction, as a surrogate of gold-standard upper airway resistance, using hallmarks of upper airway obstruction visible on clinical sleep studies. From five nocturnal polysomnography signals (airflow, thoracic and abdominal effort, oxygen saturation, and snore), nine features were extracted and weighted to derive the breath-by-breath probability of obstruction (P).

Cardiac index is associated with oxygenation in COVID-19 acute respiratory distress syndrome.

Eleven participants with COVID-19 acute respiratory distress syndrome requiring mechanical ventilation underwent pulmonary artery catheterization for clinical indications. Clinical interventions or events concurrent with hemodynamic were recorded. Increased cardiac index was associated with worse hypoxemia.

COVID-19 Critical Illness Pathophysiology Driven by Diffuse Pulmonary Thrombi and Pulmonary Endothelial Dysfunction Responsive to Thrombolysis.

Patients with severe COVID-19 disease have been characterized as having the acute respiratory distress syndrome (ARDS). Critically ill COVID-19 patients have relatively well-preserved lung mechanics despite severe gas exchange abnormalities, a feature not consistent with classical ARDS but more consistent with pulmonary vascular disease. Patients with severe COVID-19 also demonstrate markedly abnormal coagulation, with elevated D-dimers and higher rates of venous thromboembolism.

COVID-19 critical illness pathophysiology driven by diffuse pulmonary thrombi and pulmonary endothelial dysfunction responsive to thrombolysis.

Patients with severe COVID-19 disease have been characterized as having the acute respiratory distress syndrome (ARDS). Critically ill COVID-19 patients have relatively well-preserved lung mechanics despite severe gas exchange abnormalities, a feature not consistent with classical ARDS but more consistent with pulmonary vascular disease. Many patients with severe COVID-19 also demonstrate markedly abnormal coagulation, with elevated d-dimers and higher rates of venous thromboembolism.

Effects of Glycan Structure on the Stability and Receptor Binding of an IgG4-Fc.

A series of well-defined N-glycosylated IgG4-Fc variants were utilized to investigate the effect of glycan structure on their physicochemical properties (conformational stability and photostability) and interactions with an Fc γ receptor IIIA (FcγRIIIA). High mannose (HM, GlcNAcMan [n = 0-4]), Man (GlcNAcMan), GlcNAc, and N297Q IgG4-Fc were prepared in good quality. The physical stability of these IgG4-Fc variants was examined with differential scanning calorimetry and intrinsic fluorescence spectroscopy.

Photoinduced Tyrosine Side Chain Fragmentation in IgG4-Fc: Mechanisms and Solvent Isotope Effects.

Immunoglobulin gamma (IgG) monoclonal antibodies (mAbs) are glycoproteins that have emerged as powerful and promising protein therapeutics. During the process of production, storage and transportation, exposure to ambient light is inevitable, which can cause protein physical and chemical degradation. For mechanistic studies of photodegradation, we have exposed IgG4-Fc to UV light.

Impact of Glycosylation on the Local Backbone Flexibility of Well-Defined IgG1-Fc Glycoforms Using Hydrogen Exchange-Mass Spectrometry.

We have used hydrogen exchange-mass spectrometry to characterize local backbone flexibility of 4 well-defined IgG1-Fc glycoforms expressed and purified from Pichia pastoris, 2 of which were prepared using subsequent in vitro enzymatic treatments. Progressively decreasing the size of the N-linked N297 oligosaccharide from high mannose (Man8-Man12), to Man5, to GlcNAc, to nonglycosylated N297Q resulted in progressive increases in backbone flexibility. Comparison of these results with recently published physicochemical stability and Fcγ receptor binding data with the same set of glycoproteins provide improved insights into correlations between glycan structure and these pharmaceutical properties.

Structural characterization of the Man5 glycoform of human IgG3 Fc.

Immunoglobulin G (IgG) consists of four subclasses in humans: IgG1, IgG2, IgG3 and IgG4, which are highly conserved but have unique differences that result in subclass-specific effector functions. Though IgG1 is the most extensively studied IgG subclass, study of other subclasses is important to understand overall immune function and for development of new therapeutics. When compared to IgG1, IgG3 exhibits a similar binding profile to Fcγ receptors and stronger activation of complement.

Biosimilarity under stress: A forced degradation study of Remicade® and Remsima™.

Remsima™ (infliximab) is the first biosimilar monoclonal antibody (mAb) approved by the European Medical Agency and the US Food and Drug Administration. Remsima™ is highly similar to its reference product, Remicade®, with identical formulation components. The 2 products, however, are not identical; Remsima™ has higher levels of soluble aggregates, C-terminal lysine truncation, and fucosylated glycans.

Synthesis of a Bifunctional Peptide Inhibitor-IgG1 Fc Fusion That Suppresses Experimental Autoimmune Encephalomyelitis.

Multiple sclerosis (MS) is a neurodegenerative disease that is estimated to affect over 2.3 million people worldwide. The exact cause for this disease is unknown but involves immune system attack and destruction of the myelin protein surrounding the neurons in the central nervous system.