Targeting Hypercapnia in Chronic Lung Disease and Obesity Hypoventilation: Benefits and Challenges.

Hypoventilation is a complication that is not uncommon in chronic obstructive pulmonary disease and calls for both medical treatment of the underlying disease and, frequently, noninvasive ventilation either during exacerbations requiring hospitalization or in a chronic state in the patient at home. Obesity hypoventilation syndrome by definition is associated with ventilatory failure and hypercapnia. It may or may not be accompanied by obstructive sleep apnea, which when detected becomes an additional target for positive airway pressure treatment. Intensive research has not completely resolved the best choice of treatment, and the simplest modality, continuous positive airway pressure, may still be entertained.

Efficient Estimation of the Human Circadian Phase via Kalman Filtering.

Circadian rhythms play a vital role in maintaining a person's well-being but remain difficult to quantify accurately. Numerous approaches exist to measure these rhythms, but they often suffer from performance issues on the individual level. This work implements a Steady-State Kalman Filter as a method for estimating the circadian phase shifts from biometric signals. Our framework can automatically fit the filter's parameters to biometric data obtained for each individual, and we were able to consistently estimate the phase shift within 1 hour of melatonin estimates on 100% of all subjects in this study. The estimation method opens up the possibility of real-time control and assessment of the circadian system, as well as chronotherapeutic intervention.Clinical relevance- This establishes a near real-time alternative to melatonin measurements for the estimation of circadian phase shifts, with potential applications in feedback circadian control and chronotherapeutics.

Fast tuning of observer-based circadian phase estimator using biometric data.

Circadian rhythms play a vital role in maintaining an individual's well-being, and they have been shown to be the product of the master oscillator in the suprachiasmatic nuclei (SCN) located in the brain. The SCN however, is inaccessible for assessment, so existing standards for circadian phase estimation often focus on the use of indirect measurements as proxies for the circadian state. These methods often suffer from severe delays due to invasive methods of sample collection, making online estimation impossible. In this paper, we propose a linear state observer as an elegant solution for continuous phase estimation. This observer-based filter is used in isolating the frequency components of input biometric signals, which are then taken to be the circadian state. We start the design process by fixing the observer's oscillatory frequency at 24 hours, and then we tune its gains using an evolutionary optimization algorithm to extract the target components from individuals' data. The resulting filter was able to provide phase estimates with an average absolute error within 1.5 hours on all test subjects, given their minute-to-minute actigraphy data collected in ambulatory conditions.

A Life-threatening Complication of Multiple System Atrophy.

CASE PRESENTATION: A 50-year-old woman was initially seen in 2016 for sleep disorders consultation, referred by Neurology because of progressive cerebellar ataxia syndrome with possible autonomic involvement and sleep-disordered breathing described as having stridorous sounds during her sleep. She had initially presented to Neurology because of issues with balance, and she had frequent falls at home. In 2016, her speech was clear, and she was able to ambulate steadily with a cane. She underwent a diagnostic polysomnogram that did not demonstrate clinically significant sleep apnea. However, the study demonstrated rapid eye movement (REM) sleep without atonia in 62% of REM epochs (normal, up to 27%) and a soft inspiratory stridor during non-REM and REM sleep. The patient was lost to follow-up until she presented to us for reevaluation 3 years later. In the interim, she had been diagnosed with multiple system atrophy-cerebellar type (MSA-C) at another health-care institution.

Actigraphy-based parameter tuning process for adaptive notch filter and circadian phase shift estimation.

We report herein the application of an adaptive notch filter (ANF) algorithm to minute-by-minute actigraphy data to estimate the continuous circadian phase of eight healthy adults. As the adaptation rates and damping factor of the ANF algorithm have large impacts on the ANF states and circadian phase estimation results, we propose a method for optimizing these parameters. The ANF with optimal parameters is further used to estimate the circadian phase shift from the actigraphy data. Dim light melatonin onset (DLMO), considered the "gold standard" method for identification of circadian phase, was determined by a serial collection of salivary samples analyzed for melatonin per standard protocol simultaneously with the collection of actigraphic data. We demonstrate our ANF algorithm, when applied to the actigraphy data, is able to estimate the circadian phase as determined by the DLMO. These results demonstrate that applying our ANF with a well-defined parameter tuning process to actigraphic data can provide accurate measurements of the circadian phase and its shift without resorting to salivary melatonin collections.

Update on Apneas of Heart Failure With Reduced Ejection Fraction: Emphasis on the Physiology of Treatment: Part 2: Central Sleep Apnea.

Central sleep apnea/Hunter-Cheyne-Stokes breathing (CSA/HCSB) is prevalent in patients with heart failure with reduced ejection fraction (HFrEF). The acute pathobiologic consequences of CSA/HSCB eventually lead to sustained sympathetic overactivity, repeated hospitalization, and premature mortality. A few randomized controlled trials (RCTs) have shown statistically significant and clinically important reduction in sympathetic activity when CSA/HCSB is attenuated by oxygen or PAP therapy. Yet, the two largest PAP RCTs in patients with HFrEF, one with CPAP and the other with adaptive servoventilation (ASV), were negative with respect to their primary outcomes, and both were associated with excess mortality. However, both trials suffered from significant deficiencies, casting doubt on their results. A second RCT evaluating an ASV device with an advanced algorithm is ongoing. A new modality of therapy, unilateral phrenic nerve stimulation, has undergone an RCT that demonstrated an improvement in CSA that was associated with a reduction in arousals, improvement in sleepiness, and improvement in quality of life. However, a long-term mortality trial has not been performed with this modality. Most recently, the National Institutes of Health has funded a long-term, phase 3 RCT of low-flow oxygen vs sham for the treatment of CSA/HCSB in HFrEF. The composite primary outcome includes all-cause mortality and hospitalization for worsening HF. In this article, we focus on various therapeutic options for the treatment of CSA/HCSB and, when appropriate, emphasize the importance of identifying CSA/HCSB phenotypes to tailor treatment.

Apneas of Heart Failure and Phenotype-Guided Treatments: Part One: OSA.

Sleep-disordered breathing (SDB), including OSA and central sleep apnea, is highly prevalent in patients with heart failure (HF). Multiple studies have reported this high prevalence in asymptomatic as well as symptomatic patients with reduced left ventricular ejection fraction (HFrEF), as well as in those with HF with preserved ejection fraction. The acute pathobiologic consequences of OSA, including exaggerated sympathetic activity, oxidative stress, and inflammation, eventually could lead to progressive left ventricular dysfunction, repeated hospitalization, and excessive mortality. Large numbers of observational studies and a few small randomized controlled trials have shown improvement in various cardiovascular consequences of SDB with treatment. There are no long-term randomized controlled trials to show improved survival of patients with HF and treatment of OSA. One trial of positive airway pressure treatment of OSA included patients with HF and showed no improvement in clinical outcomes. However, any conclusions derived from this trial must take into account several important pitfalls that have been extensively discussed in the literature. With the role of positive airway pressure as the sole therapy for SDB in HF increasingly questioned, a critical examination of long-accepted concepts in this field is needed. The objective of this review was to incorporate recent advances in the field into a phenotype-based approach to the management of OSA in HF.

Smart Lighting Clinical Testbed Pilot Study on Circadian Phase Advancement.

OBJECTIVE: Lighting is a strong synchronizer for circadian rhythms, which in turn drives a wide range of biological functions. The objective of our work is a) to construct a clinical in-patient testbed with smartI lighting, and b) evaluate its feasibility for use in future clinical studies. METHODS: A feedback capable, variable spectrum lighting system was installed at the University of New Mexico Hospital. The system consists of variable spectrum lighting troffers, color sensors, occupancy sensors, and computing and communication infrastructure. We conducted a pilot study to demonstrate proof of principle, that 1) this new technology is capable of providing continuous lighting and sensing in an active clinical environment, 2) subject recruitment and retention is feasible for round-the-clock, multi-day studies, and 3) current techniques for circadian regulation can be deployed in this unique testbed. Unlike light box studies, only troffer-based lighting was used, and both lighting intensity and spectral content were varied. RESULTS: The hardware and software functioned seamlessly to gather biometric data and provide the desired lighting. Salivary samples that measure dim-light melatonin onset showed phase advancement for all three subjects. CONCLUSION: We executed a five-day circadian rhythm study that varied intensity, spectrum, and timing of lighting as proof-of-concept or future clinical studies with troffer-based, variable spectrum lighting. Clinical Impact: The ability to perform circadian rhythm experiments in more realistic environments that do not overly constrain the subject is important for translating lighting research into practice, as well as for further research on the health impacts of lighting.

Improving the Affordability of Prescription Medications for People with Chronic Respiratory Disease. An Official American Thoracic Society Policy Statement.

BACKGROUND: Mounting evidence indicates that out-of-pocket costs for prescription medications, particularly among low- and middle-income patients with chronic diseases, are imposing financial burden, reducing medication adherence, and worsening health outcomes. This problem is exacerbated by a paucity of generic alternatives for prevalent lung diseases, such as asthma and chronic obstructive pulmonary disease, as well as high-cost medicines for rare diseases, such as cystic fibrosis. Affordability and access challenges are especially salient in the United States, as citizens of many other countries pay lower prices for and have greater access to prescription medications. METHODS: The American Thoracic Society convened a multidisciplinary committee comprising experts in health policy pharmacoeconomics, behavioral sciences, and clinical care, along with individuals providing industry and patient perspectives. The report and its recommendation were iteratively developed over a year of in-person, telephonic, and electronic deliberation. RESULTS: The committee unanimously recommended the establishment of a publicly funded, politically independent, impartial entity to systematically draft evidence-based pharmaceutical policy recommendations. The goal of this entity would be to generate evidence and action steps to ensure people have equitable and affordable access to prescription medications, to maximize the value of public and private pharmaceutical expenditures on health, to support novel drug development within a market-based economy, and to preserve clinician and patient choice regarding personalized treatment. An immediate priority is to examine the evidence and make recommendations regarding the need to have essential medicines with established clinical benefit from each drug class in all Tier 1 formularies and propose recommendations to reduce barriers to timely generic drug availability. CONCLUSIONS: By making explicit, evidence-based recommendations, the entity can support the establishment of coherent national policies that expand access to affordable medications, improve the health of patients with chronic disease, and optimize the use of public and private resources.