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.

Epidemiology of Sleep-Disordered Breathing and Heart Failure: What Drives What.

PURPOSE OF REVIEW: The bidirectional relationships that have been demonstrated between heart failure (HF) and central sleep apnea (CSA) demand further exploration with respect to the implications that each condition has for the other. This review discusses the body of literature that has accumulated on these relationships and how CSA and its potential treatment may affect outcomes in patients with CSA. RECENT FINDINGS: Obstructive sleep apnea (OSA) can exacerbate hypertension, type 2 diabetes, obesity, and atherosclerosis, which are known predicates of HF. Conversely, patients with HF more frequently exhibit OSA partly due to respiratory control system instability. These same mechanisms are responsible for the frequent association of HF with CSA with or without a Hunter-Cheyne-Stokes breathing (HCSB) pattern. Just as is the case with OSA, patients with HF complicated by CSA exhibit more severe cardiac dysfunction leading to increased mortality; the increase in severity of HF can in turn worsen the degree of sleep disordered breathing (SDB). Thus, a bidirectional relationship exists between HF and both phenotypes of SDB; moreover, an individual patient may exhibit a combination of these phenotypes. Both types of SDB remain significantly underdiagnosed in patients with HF and hence undertreated. Appropriate screening for, and treatment of, OSA is clearly a significant factor in the comprehensive management of HF, while the relevance of CSA remains controversial. Given the unexpected results of the Treatment of Sleep-Disordered Breathing with Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients with Heart Failure trial, it is now of paramount importance that additional analysis of these data be expeditiously reported. It is also critical that ongoing and proposed prospective studies of this issue proceed without delay.

Relationships between obstructive sleep apnea and anxiety.

PURPOSE OF REVIEW: To summarize recent research investigating the interaction between obstructive sleep apnea (OSA) and anxiety, and contextualize their bidirectional relationship. RECENT FINDINGS: Recent investigations corroborate the bidirectional relationship between sleep-disordered breathing (SDB) and anxiety, evaluate the etiological and clinical manifestations through different mechanisms, and provide insight into clinical implications of this interaction. Much of the literature about anxiety as it relates to SDB is from small samples, using different tools of symptom measurement that are often subjectively quantified. The objective severity of OSA does not appear to be associated with subjectively reported sleepiness and fatigue, whereas physiological manifestations of anxiety are associated with the severity of subjective symptoms reported. Recent findings support that women are more likely to have comorbid SDB and anxiety than men. SDB may precipitate and perpetuate anxiety, whereas anxiety in OSA negatively impacts quality-of-life. Treating SDB may improve anxiety symptoms, whereas anxiety symptoms can be an obstacle and deterrent to appropriate treatment. SUMMARY: The interaction between anxiety and SDB is still poorly elucidated. Being aware of the clinical associations, risk factors, and treatment implications for SDB as related to anxiety disorders in different populations can help clinicians with the diagnosis and management of both SDB and anxiety.

Obesity hypoventilation syndrome: current theories of pathogenesis.

PURPOSE OF REVIEW: To summarize recent primary publications and discuss the impact these finding have on current understanding on the development of hypoventilation in obesity hypoventilation syndrome (OHS), also known as Pickwickian syndrome. RECENT FINDINGS: As a result of the significant morbidity and mortality associated with OHS, evidence is building for pre-OHS intermediate states that can be identified earlier and treated sooner, with the goal of modifying disease course. Findings of alterations in respiratory mechanics with obesity remain unchanged; however, elevated metabolism and CO2 production may be instrumental in OHS-related hypercapnia. Ongoing positive airway pressure trials continue to demonstrate that correction of nocturnal obstructive sleep apnea and hypoventilation improves diurnal respiratory physiology, metabolic profiles, quality of life, and morbidity/mortality. Finally, CNS effects of leptin on respiratory mechanics and chemoreceptor sensitivity are becoming better understood; however, characterization remains incomplete. SUMMARY: OHS is a complex multiorgan system disease process that appears to be driven by adaptive changes in respiratory physiology and compensatory changes in metabolic processes, both of which are ultimately counter-productive. The diurnal hypercapnia and hypoxia induce pathologic effects that further worsen sleep-related breathing, resulting in a slowly progressive worsening of disease. In addition, leptin resistance in obesity and OHS likely contributes to blunting of ventilatory drive and inadequate chemoreceptor response to hypercarbia and hypoxemia.

The Relationship Between Volume Overload in End-Stage Renal Disease and Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) is common, underdiagnosed, and undertreated among patients with end-stage renal disease (ESRD). As in all cases, pathogenesis of OSA is related to repeated upper airway (UA) occlusion or narrowing, but in ESRD, additional contributory factors likely include uremic destabilization of central respiratory control and anatomic changes in the UA related to fluid status. Pulmonary congestion is common in acute and chronic kidney failure and is a consequence of cardiomyopathy and fluid overload, two potentially reversible risk factors. Emerging evidence suggests that volume overload also reduces the UA caliber. The diminution in UA area as well as destabilization of ventilatory control in ESRD have been postulated as causes of increased OSA prevalence and severity in these patients, and creates a vicious cycle wherein OSA exacerbates fluid overload disorders such as in congestive heart failure (CHF) and ESRD, which then further worsen OSA. Dialysis modalities may differ in their effects on volume status, the accumulation of uremic toxins, and acid-base status, and as a consequence, on the emergence and severity of OSA. Given the contribution of excess fluid to both the severity of nocturnal hypoxia and UA narrowing, establishing and maintaining dry weight is of particular importance when managing OSA in ESRD. Clinical trials to determine the extent to which more aggressive fluid removal in ESRD patients may alleviate OSA are needed.

Adaptive servo-ventilation for the treatment of central sleep apnea in congestive heart failure: what have we learned?

PURPOSE OF REVIEW: Positive airway pressure devices for the noninvasive treatment of sleep-disordered breathing are being marketed that have substantially expanded capabilities. Most recently, adaptive servo-ventilation devices have become available that are capable of measuring patient ventilation continuously and use that information to adjust expiratory positive airway pressure and pressure support levels to abolish central and obstructive apneas and hypopneas, including central sleep-disordered breathing of the Hunter-Cheyne-Stokes variety. Patients with congestive heart failure are particularly prone to developing central sleep apnea and/or Hunter-Cheyne-Stokes breathing, and studies have shown that suppression of these abnormal breathing patterns may improve cardiac function and, ultimately, mortality. RECENT FINDINGS: Over the last approximately 18 months, increasing numbers of studies have appeared demonstrating improvement in cardiac function and other important outcomes after both acute application of adaptive servo-ventilation as well as 3 to 6 months of use in patients with congestive heart failure and central sleep apnea/Hunter-Cheyne-Stokes breathing. Several of these studies are randomized controlled trials and several include assessment of cardiac event-free survival showing an advantage to treating with adaptive servo-ventilation. SUMMARY: As an adjunct to optimal pharmacological management, adaptive servo-ventilation shows considerable promise as a means to improve outcomes in patients with congestive heart failure complicated by central sleep apnea/Hunter-Cheyne-Stokes breathing. Larger randomized controlled trials will be necessary to demonstrate the ultimate role of this therapeutic modality in such patients.

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.

Exploring Decisional Conflict Experienced by Individuals Considering Metoidioplasty and Phalloplasty Gender-affirming Surgery.

Background: Metoidioplasty and phalloplasty gender-affirming surgery (MaPGAS) is increasingly performed and requires patients to make complex decisions that may lead to decisional uncertainty. This study aimed to evaluate decisional conflict in individuals considering MaPGAS. Methods: We administered a cross-sectional survey to adult participants assigned female sex at birth and considering MaPGAS, recruited via social media platforms and community health centers. We collected data on demographics, medical and surgical history, MaPGAS type considered, and the Decisional Conflict Scale (DCS). DCS scores range from 0 to 100 (>37.5 indicates greater decisional conflict). Demographic characteristics and DCS scores were compared between subgroups, using descriptive and chi-square statistics. Participants commented on MaPGAS uncertainty, and their comments were evaluated and thematically analyzed. Results: Responses from 264 participants were analyzed: mean age 29 years; 64% (n = 168) trans men, 80% (n = 210) White, 78% (n = 206) nonrural, 45% (n = 120) privately insured, 56% (n = 148) had 4 or more years of college, 23% (n = 84) considering metoidioplasty, 24% (n = 87) considering phalloplasty, and 26% (n = 93) considering metoidioplasty and phalloplasty. DCS total scores were significantly higher (39.8; P < 0.001) among those considering both MaPGAS options, as were mean ratings on the Uncertainty subscale [64.1 (SD 25.5; P < 0.001)]. Concerns surrounding complications were the top factor contributing to uncertainty and decisional conflict. Conclusions: In a cross-sectional national sample of individuals seeking MaPGAS, decisional uncertainty was the highest for those considering both MaPGAS options compared with metoidioplasty or phalloplasty alone. This suggests this cohort would benefit from focused decision support.

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.

Can sleep deprivation studies explain why human adults sleep?

PURPOSE OF REVIEW: This review will concentrate on the consequences of sleep deprivation in adult humans. These findings form a paradigm that serves to demonstrate many of the critical functions of the sleep states. RECENT FINDINGS: The drive to obtain food, water, and sleep constitutes important vegetative appetites throughout the animal kingdom. Unlike nutrition and hydration, the reasons for sleep have largely remained speculative. When adult humans are nonspecifically sleep-deprived, systemic effects may include defects in cognition, vigilance, emotional stability, risk-taking, and, possibly, moral reasoning. Appetite (for foodstuffs) increases and glucose intolerance may ensue. Procedural, declarative, and emotional memory are affected. Widespread alterations of immune function and inflammatory regulators can be observed, and functional MRI reveals profound changes in regional cerebral activity related to attention and memory. Selective deprivation of rapid eye movement (REM) sleep, on the contrary, appears to be more activating and to have lesser effects on immunity and inflammation. SUMMARY: The findings support a critical need for sleep due to the widespread effects on the adult human that result from nonselective sleep deprivation. The effects of selective REM deprivation appear to be different and possibly less profound, and the functions of this sleep state remain enigmatic.

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.

An official American thoracic society statement: position statement on ATS activities for the promotion of respiratory and sleep/wake health and the care of the critically ill in the United States.

BACKGROUND: The 1997 American Thoracic Society (ATS) statement "A Framework for Health Care Policy in the United States" outlined core principles for the Society's activities in the public health arena. In the succeeding 10 years, profound changes have taken place in the United States health care environment. In addition, the 2005 publication of the Society's Vision highlighted some differences between the original Statement and our current priorities. Therefore, the Health Policy Committee embarked on a re-analysis and re-statement of the Society's attitudes and strategies with respect to health and public policy. This Statement reflects the findings of the Committee. PURPOSE: To outline the key aspects of an internal ATS strategy for the promotion of respiratory and sleep/wake health and the care of the critically ill in the United States. METHODS: Committee discussion and consensus-building occurred both before and after individual members performed literature searches and drafted sections of the document. Comments were solicited on the draft document from ATS committee and assembly chairs and the Executive Committee, resulting in substantive revisions of the final document. RESULTS: Specific strategies are suggested for the ATS in the arenas of research, training and education, patient care, and advocacy so as to enhance the delivery of health care in the fields of respiratory medicine, sleep medicine, and critical care. CONCLUSIONS: The American Thoracic Society's Mission, Core Principles, and Vision provide clear guidance for the formulation of specific strategies that will serve to promote improved respiratory health and care of the critically ill in the United States.

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.

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.

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.

Nonrespiratory sleep disorders found in ICU patients.

Intensive care subjects the critically ill patient to a multitude of stressors caused by the severity of illness and the use of invasive treatment modalities and medications. The ICU environment contributes significant stress of its own related to noise, light, 24-hour patient care, and other factors that disturb sleep. Consequently, various sleep pathologies may emerge or worsen in the ICU patient. Some sleep disorder symptomatology may be confused with serious neurologic complications of critical illness and lead to inappropriate testing or treatment, particularly in the patient who has narcolepsy. Given the high prevalence of sleep disorders in the general population, it is essential that the ICU practitioner attain an adequate knowledge of sleep and its disorders.