Oral appliance therapy and hypoglossal nerve stimulation as non-positive airway pressure treatment alternatives for obstructive sleep apnea: a narrative expert review.

This perspective on alternatives to positive airway pressure (PAP) therapy for the treatment of obstructive sleep apnea (OSA) summarizes the proceedings of a focus group that was conducted by the Sleep Research Society Foundation. This perspective is from a multidisciplinary panel of experts from sleep medicine, dental sleep medicine, and otolaryngology that aims to identify the current role of oral appliance therapy and hypoglossal nerve stimulation for the treatment of OSA with emphasis on the US practice arena. A secondary aim is to identify-from an implementation science standpoint-the various barriers and facilitators for adoption of non-PAP treatment that includes access to care, multidisciplinary expertise, reimbursement, regulatory aspects, current treatment guidelines, health policies, and other factors related to the delivery of care. The panel has contextualized the review with recent events-such as a large-scale PAP device recall compounded by supply chain woes of the pandemic-and emerging science in the field of OSA and offers solutions for multidisciplinary approaches while identifying knowledge gaps and future research opportunities.

A Facile NMR Method for Pre-MRI Evaluation of Trigger-Responsive T1 Contrast Enhancement.

There is a growing interest in developing paramagnetic nanoparticles as responsive magnetic resonance imaging (MRI) contrast agents, which feature switchable T1 image contrast of water protons upon biochemical cues for better discerning diseases. However, performing an MRI is pragmatically limited by its cost and availability. Hence, a facile, routine method for measuring the T1 contrast is highly desired in early-stage development. This work presents a single-point inversion recovery (IR) nuclear magnetic resonance (NMR) method that can rapidly evaluate T1 contrast change by employing a single, optimized IR pulse sequence that minimizes water signal for "off-state" nanoparticles and allows for sensitively measuring the signal change with "switch-on" T1 contrast. Using peptide-induced liposomal gadopentetic acid (Gd3+ -DTPA) release and redox-sensitive manganese oxide (MnO2 ) nanoparticles as a demonstration of generality, this method successfully evaluates the T1 shortening of water protons caused by liposomal Gd3+ -DTPA release and Mn2+ formation from MnO2 reduction. Furthermore, the NMR measurement is highly correlated to T1 -weighted MRI scans, suggesting its feasibility to predict the MRI results at the same field strength. This NMR method can be a low-cost, time-saving alternative for pre-MRI evaluation for a diversity of responsive T1 contrast systems.

Strengths, weaknesses, opportunities, and threats of using AI-enabled technology in sleep medicine: a commentary.

Over the past few years, artificial intelligence (AI) has emerged as a powerful tool used to efficiently automate several tasks across multiple domains. Sleep medicine is perfectly positioned to leverage this tool due to the wealth of physiological signals obtained through sleep studies or sleep tracking devices and abundance of accessible clinical data through electronic medical records. However, caution must be applied when utilizing AI, due to intrinsic challenges associated with novel technology. The Artificial Intelligence in Sleep Medicine Committee of the American Academy of Sleep Medicine reviews advancements in AI within the sleep medicine field. In this article, the Artificial Intelligence in Sleep Medicine committee members provide a commentary on the scope of AI technology in sleep medicine. The commentary identifies 3 pivotal areas in sleep medicine that can benefit from AI technologies: clinical care, lifestyle management, and population health management. This article provides a detailed analysis of the strengths, weaknesses, opportunities, and threats associated with using AI-enabled technologies in each pivotal area. Finally, the article broadly reviews barriers and challenges associated with using AI-enabled technologies and offers possible solutions. CITATION: Bandyopadhyay A, Oks M, Sun H, et al. Strengths, weaknesses, opportunities, and threats of using AI-enabled technology in sleep medicine: a commentary. J Clin Sleep Med. 2024;20(7):1183-1191.

Cost-effectiveness of a 3-year tele-messaging intervention for positive airway pressure use.

OBJECTIVES: To evaluate the cost-effectiveness of a 3-year tele-messaging intervention for positive airway pressure (PAP) use in obstructive sleep apnea (OSA). STUDY DESIGN: A post hoc cost-effectiveness analysis (from US payers' perspective) of data from a 3-month tele-OSA trial, augmented with 33 months of epidemiologic follow-up. METHODS: Cost-effectiveness was compared among 3 groups of participants with an apnea-hypopnea index of at least 15 events/hour: (1) no messaging (n = 172), (2) messaging for 3 months (n = 124), and (3) messaging for 3 years (n = 46). We report the incremental cost (2020 US$) per incremental hour of PAP use and the fraction probability of acceptability based on a willingness-to-pay threshold of $1825 per year ($5/day). RESULTS: The use of 3 years of messaging had similar mean annual costs ($5825) compared with no messaging ($5889; P = .89) but lower mean cost compared with 3 months of messaging ($7376; P = .02). Those who received messaging for 3 years had the highest mean PAP use (4.11 hours/night), followed by no messaging (3.03 hours/night) and 3 months of messaging (2.84 hours/night) (all P < .05). The incremental cost-effectiveness ratios indicated that 3 years of messaging showed lower costs and greater hours of PAP use compared with both no messaging and 3 months of messaging. Based on a willingness-to-pay threshold of $1825, there is a greater than 97.5% chance (ie, 95% confidence) that 3 years of messaging is acceptable compared with the other 2 interventions. CONCLUSIONS: Long-term tele-messaging is highly likely to be cost-effective compared with both no and short-term messaging, with an acceptable willingness-to-pay threshold. Future long-term cost-effectiveness studies in a randomized controlled trial setting are warranted.

Association Between Positive Airway Pressure Adherence and Health Care Costs Among Individuals With OSA.

BACKGROUND: The impact of positive airway pressure (PAP) therapy for OSA on health care costs is uncertain. RESEARCH QUESTION: Are 3-year health care costs associated with PAP adherence in participants from the Tele-OSA clinical trial? STUDY DESIGN AND METHODS: Participants with OSA and prescribed PAP in the Tele-OSA study were stratified into three PAP adherence groups based on usage patterns over 3 years: (1) high (consistently ≥ 4 h/night), (2) moderate (2-3.9 h/night or inconsistently ≥ 4 h/night), and (3) low (< 2 h/night). Using data from 3 months of the Tele-OSA trial and 33 months of posttrial follow up, average health care costs (2020 US dollars) in 6-month intervals were derived from electronic health records and analyzed using multivariable generalized linear models. RESULTS: Of 543 participants, 25% were categorized as having high adherence, 22% were categorized as having moderate adherence, and 52% were categorized as having low adherence to PAP therapy. Average PAP use mean ± SD was 6.5 ± 1.0 h, 3.7 ± 1.2 h, and 0.5 ± 0.5 h for the high, moderate, and low adherence groups, respectively. The high adherence group had the lowest average covariate-adjusted 6-month health care costs ± SE ($3,207 ± $251) compared with the moderate ($3,638 ± $363) and low ($4,040 ± $304) adherence groups. Significant cost differences were observed between the high and low adherence groups ($832; 95% CI, $127 to $1,538); differences between moderate and low adherence were nonsignificant ($401; 95% CI, -$441 to $1,243). INTERPRETATION: In participants with OSA, better PAP adherence was associated with significantly lower health care costs over 3 years. Findings support the importance of strategies to enhance long-term PAP adherence.

Collagen-binding peptides for the enhanced imaging, lubrication and regeneration of osteoarthritic articular cartilage.

Treatments for osteoarthritis would benefit from the enhanced visualization of injured articular cartilage and from the targeted delivery of disease-modifying drugs to it. Here, by using ex vivo human osteoarthritic cartilage and live rats and minipigs with induced osteoarthritis, we report the application of collagen-binding peptides, identified via phage display, that are home to osteoarthritic cartilage and that can be detected via magnetic resonance imaging when conjugated with a superparamagnetic iron oxide. Compared with the use of peptides with a scrambled sequence, hyaluronic acid conjugated with the collagen-binding peptides displayed enhanced retention in osteoarthritic cartilage and better lubricated human osteoarthritic tissue ex vivo. Mesenchymal stromal cells encapsulated in the modified hyaluronic acid and injected intra-articularly in rats showed enhanced homing to osteoarthritic tissue and improved its regeneration. Molecular docking revealed WXPXW as the consensus motif that binds to the α1 chain of collagen type XII. Peptides that specifically bind to osteoarthritic tissue may aid the diagnosis and treatment of osteoarthritic joints.

MRI Detection of Hepatic N-Acetylcysteine Uptake in Mice.

This proof-of-concept study looked at the feasibility of using a thiol-water proton exchange (i.e., CEST) MRI contrast to detect in vivo hepatic N-acetylcysteine (NAC) uptake. The feasibility of detecting NAC-induced glutathione (GSH) biosynthesis using CEST MRI was also investigated. The detectability of the GSH amide and NAC thiol CEST effect at B0 = 7 T was determined in phantom experiments and simulations. C57BL/6 mice were injected intravenously (IV) with 50 g L-1 NAC in PBS (pH 7) during MRI acquisition. The dynamic magnetisation transfer ratio (MTR) and partial Z-spectral data were generated from the acquisition of measurements of the upfield NAC thiol and downfield GSH amide CEST effects in the liver. The 1H-NMR spectroscopy on aqueous mouse liver extracts, post-NAC-injection, was performed to verify hepatic NAC uptake. The dynamic MTR and partial Z-spectral data revealed a significant attenuation of the mouse liver MR signal when a saturation pulse was applied at -2.7 ppm (i.e., NAC thiol proton resonance) after the IV injection of the NAC solution. The 1H-NMR data revealed the presence of hepatic NAC, which coincided strongly with the increased upfield MTR in the dynamic CEST data, providing strong evidence that hepatic NAC uptake was detected. However, this MTR enhancement was attributed to a combination of NAC thiol CEST and some other upfield MT-generating mechanism(s) to be identified in future studies. The detection of hepatic GSH via its amide CEST MRI contrast was inconclusive based on the current results.

Detection of Common Arrhythmias by the Watch-PAT: Expression of Electrical Arrhythmias by Pulse Recording.

Background: The WatchPAT (WP) device was shown to be accurate for the diagnosis of sleep apnea and is widely used worldwide as an ambulatory diagnostic tool. While it records peripheral arterial tone (PAT) and not electrocardiogram (ECG), the ability of it to detect arrhythmias is unknown and was not studied previously. Common arrhythmias such as atrial fibrillation (AF) or premature beats may be uniquely presented while recording PAT/pulse wave. Purpose: To examine the potential detection of common arrhythmias by analyzing the PAT amplitude and pulse rate/volume changes. Patients and Methods: Patients with suspected sleep disordered breathing (SDB) were recruited with preference for patients with previously diagnosed AF or congestive heart failure (CHF). They underwent simultaneous WP and PSG studies in 11 sleep centers. A novel algorithm was developed to detect arrhythmias while measuring PAT and was tested on these patients. Manual scoring of ECG channel (recorded as part of the PSG) was blinded to the automatically analyzed WP data. Results: A total of 84 patients aged 57±16 (54 males) participated in this study. Their BMI was 30±5.7Kg/m2. Of them, 41 had heart failure (49%) and 17 (20%) had AF. The sensitivity and specificity of the WP to detect AF segments (of at least 60 seconds) were 0.77 and 0.99, respectively. The correlation between the WP derived detection of premature beats (events/min) to that of the PSG one was 0.98 (p<0.001). Conclusion: The novel automatic algorithm of the WP can reasonably detect AF and premature beats. We suggest that when the algorithm raises a flag for arrhythmia, the patients should shortly undergo ECG and/or Holter ECG study.

A Gadolinium DO3A Amide m-Phenyl Boronic Acid MRI Probe for Targeted Imaging of Sialated Solid Tumors.

We developed a new probe, Gd-DO3A-Am-PBA, for imaging tumors. Our results showed active targeting of Gd-DO3A-Am-PBA to sialic acid (SA) moieties, with increased cellular labeling in vitro and enhanced tumor accumulation and retention in vivo, compared to the commercial Gadovist. The effectiveness of our newly synthesized probe lies in its adequate retention phase, which is expected to provide a suitable time window for tumor diagnosis and a faster renal clearance, which will reduce toxicity risks when translated to clinics. Hence, this study can be extended to other tumor types that express SA on their surface. Targeting and MR imaging of any type of tumors can also be achieved by conjugating the newly synthesized contrast agent with specific antibodies. This study thus opens new avenues for drug delivery and tumor diagnosis via imaging.

Personalized and Patient-Centered Strategies to Improve Positive Airway Pressure Adherence in Patients with Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA), a common sleep disorder characterized by repeated pauses in breathing during sleep, is effectively treated with positive airway pressure (PAP) therapy. The magnitude of improvements in daily functioning and reduced negative health risks are dependent on maintaining PAP adherence, which is a significant challenge. Evidence-based interventions to improve PAP use are not easily translated to clinical practice because they are labor-intensive and require specialty expertise. Further, to date, individualized care, inclusive of personalized medicine and patient- and person-centered care have been marginally incorporated in the field's understanding of OSA and PAP adherence. This integrative review describes current PAP adherence assessment processes, interventions to improve adherence, and outlines future opportunities to advance the field, particularly as it relates to individualizing care and the use of implementation science to apply evidence to practice.

A population health approach to insomnia using internet-based cognitive behavioral therapy for insomnia.

STUDY OBJECTIVES: To determine if a population health approach to insomnia using internet-based cognitive behavioral therapy for insomnia (ICBT-I) affects dispensed medications and provider encounters compared with usual care. METHODS: A pragmatic hybrid study design was used to evaluate both the implementation strategy and the long-term effects of ICBT-I on health care utilization in an integrated health system. Adult members with insomnia (a diagnosis or insomnia medication dispensation) or at high risk of insomnia (a diagnosis of depression or anxiety) were randomized to receive information on either an ICBT-I program (intervention arm) or in-person classes on insomnia (usual-care arm). Outcomes included dispensed insomnia medications and provider encounters over 12 months. The effectiveness of our implementation of ICBT-I on the target population was determined by an intention-to-treat analysis and by regression models comparing those who engaged in ICBT-I with matched usual-care arm controls. RESULTS: A total of 136,630 participants were randomized. Six hundred thirty-eight (0.96%) accessed the ICBT-I program while 431 (0.66%) attended 1 or more usual-care insomnia classes. Dispensed insomnia medications and provider encounters were no different in the ICBT-I arm vs the usual-care arm (intention-to-treat) or among those who engaged in ICBT-I vs matched usual-care arm controls. CONCLUSIONS: Since ICBT-I program engagement was low, additional strategies to improve engagement should be explored. ICBT-I did not result in a reduction in several measures of health care utilization; nevertheless, it offers an alternative and accessible approach to managing population insomnia. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Trial of Internet-Based Cognitive Behavioral Therapy for Insomnia in Patients Prescribed Insomnia Medications; URL: https://clinicaltrials.gov/ct2/show/NCT03313466; Identifier: NCT03313466. CITATION: Derose SF, Rozema E, Chen A, Shen E, Hwang D, Manthena P. A population health approach to insomnia using internet-based cognitive behavioral therapy for insomnia. J Clin Sleep Med. 2021;17(8):1675-1684.

PHIP hyperpolarized [1-13C]pyruvate and [1-13C]acetate esters via PH-INEPT polarization transfer monitored by 13C NMR and MRI.

Parahydrogen-induced polarization of 13C nuclei by side-arm hydrogenation (PHIP-SAH) for [1-13C]acetate and [1-13C]pyruvate esters with application of PH-INEPT-type pulse sequences for 1H to 13C polarization transfer is reported, and its efficiency is compared with that of polarization transfer based on magnetic field cycling (MFC). The pulse-sequence transfer approach may have its merits in some applications because the entire hyperpolarization procedure is implemented directly in an NMR or MRI instrument, whereas MFC requires a controlled field variation at low magnetic fields. Optimization of the PH-INEPT-type transfer sequences resulted in 13C polarization values of 0.66 ± 0.04% and 0.19 ± 0.02% for allyl [1-13C]pyruvate and ethyl [1-13C]acetate, respectively, which is lower than the corresponding polarization levels obtained with MFC for 1H to 13C polarization transfer (3.95 ± 0.05% and 0.65 ± 0.05% for allyl [1-13C]pyruvate and ethyl [1-13C]acetate, respectively). Nevertheless, a significant 13C NMR signal enhancement with respect to thermal polarization allowed us to perform 13C MR imaging of both biologically relevant hyperpolarized molecules which can be used to produce useful contrast agents for the in vivo imaging applications.

The use of telemedicine for the diagnosis and treatment of sleep disorders: an American Academy of Sleep Medicine update.

NONE: The COVID-19 pandemic led to widespread use of telemedicine and highlighted its importance in improving access to sleep care and advocating for sleep health. This update incorporates the lessons learned from such widespread utilization of telehealth to build on the American Academy of Sleep Medicine's 2015 position paper on the use of telemedicine for diagnosing and treating sleep disorders. Important key factors in this update include an emphasis on quality and value, privacy and safety, health advocacy through sleep telemedicine, and future directions.

A Polypeptide-Based, Membrane-Penetrating, Target-Specific Contrast Agent for Magnetic Resonance Molecular Imaging.

Molecular imaging based on magnetic resonance imaging (MRI) requires a contrast agent with high relaxivity and specificity. Much effort has been devoted to this goal over the past decades. In this work, we continue this endeavor by synthesizing an MRI contrast agent that can penetrate the cellular membrane and bind with specific proteins. It was characterized with one- and two-dimensional NMR spectroscopy, NMR micro-imaging, and mass spectroscopy. The target specificity has been further confirmed by both molecular dynamics simulation and micro-imaging on a living biological system. It is one of the largest of peptide-based bioactivated MRI contrast agents, and its relaxivity enhancement factor is among the highest of MRI contrast agents hitherto published. We envision interesting applications and extension of this smart MRI contrast agent with bio-specificity and high contrast for molecular imaging.

pH Mapping of Skeletal Muscle by Chemical Exchange Saturation Transfer (CEST) Imaging.

Magnetic resonance imaging (MRI) is extensively used in clinical and basic biomedical research. However, MRI detection of pH changes still poses a technical challenge. Chemical exchange saturation transfer (CEST) imaging is a possible solution to this problem. Using saturation transfer, alterations in the exchange rates between the solute and water protons because of small pH changes can be detected with greater sensitivity. In this study, we examined a fatigued skeletal muscle model in electrically stimulated mice. The measured CEST signal ratio was between 1.96 ppm and 2.6 ppm in the z-spectrum, and this was associated with pH values based on the ratio between the creatine (Cr) and the phosphocreatine (PCr). The CEST results demonstrated a significant contrast change at the electrical stimulation site. Moreover, the pH value was observed to decrease from 7.23 to 7.15 within 20 h after electrical stimulation. This pH decrease was verified by 31P magnetic resonance spectroscopy and behavioral tests, which showed a consistent variation over time.

Watch-PAT is Useful in the Diagnosis of Sleep Apnea in Patients with Atrial Fibrillation.

BACKGROUND: Early diagnosis and treatment of sleep apnea in patients with atrial fibrillation (AF) is critical. The WatchPAT (WP) device was shown to be accurate for the diagnosis of sleep apnea; however, studies using the WatchPAT device have thus far excluded patients with arrhythmias due to the potential effect of arrhythmias on the peripheral arterial tonometry (PAT) amplitude and pulse rate changes. PURPOSE: To examine the accuracy of the WP in detecting sleep apnea in patients with AF. PATIENTS AND METHODS: Patients with AF underwent simultaneous WP and PSG studies in 11 sleep centers. PSG scoring was blinded to the automatically analyzed WP data. RESULTS: A total of 101 patients with AF (70 males) were recruited. Forty-six had AF episodes during the overnight sleep study. A significant correlation was found between the PSG-derived AHI and the WP- derived AHI (r=0.80, p<0.0001). There was a good agreement between PSG-derived AHI and WP-derived AHI (mean difference of AHI: -0.02±13.2). Using a threshold of AHI ≥15 per hour of sleep, the sensitivity and specificity of the WP were 0.88 and 0.63, respectively. The overall accuracy in sleep staging between WP and PSG was 62% with Kappa agreement of 0.42. CONCLUSION: WP can detect sleep apnea events in patients with AF. AF should not be an exclusion criterion for using the device. This finding may be of even greater importance in the era of the COVID19 epidemic, when sleep labs were closed and most studies were home based.

Anti-apoptotic BCL-2 regulation by changes in dynamics of its long unstructured loop.

BCL-2, a key protein in inhibiting apoptosis, has a 65-residue-long highly flexible loop domain (FLD) located on the opposite side of its ligand-binding groove. In vivo phosphorylation of the FLD enhances the affinity of BCL-2 for pro-apoptotic ligands, and consequently anti-apoptotic activity. However, it remains unknown as to how the faraway, unstructured FLD modulates the affinity. Here we investigate the protein-ligand interactions by fluorescence techniques and monitor protein dynamics by DEER and NMR spectroscopy tools. We show that phosphomimetic mutations on the FLD lead to a reduction in structural flexibility, hence promoting ligand access to the groove. The bound pro-apoptotic ligands can be displaced by the BCL-2-selective inhibitor ABT-199 efficiently, and thus released to trigger apoptosis. We show that changes in structural flexibility on an unstructured loop can activate an allosteric protein that is otherwise structurally inactive.

Detecting central sleep apnea in adult patients using WatchPAT-a multicenter validation study.

STUDY OBJECTIVES: To assess the accuracy of WatchPAT (WP-Itamar-Medical, Caesarea, Israel) enhanced with a novel systolic upstroke analysis coupled with respiratory movement analysis derived from a dedicated snoring and body position (SBP) sensor, to enable automated algorithmic differentiation between central sleep apnea (CSA) and obstructive sleep apnea (OSA) compared with simultaneous in-lab sleep studies with polysomnography (PSG). METHODS: Eighty-four patients with suspected sleep-disordered breathing (SDB) underwent simultaneous WP and PSG studies in 11 sleep centers. PSG scoring was blinded to the automatically analyzed WP data. RESULTS: Overall WP apnea-hypopnea index (AHI; mean ± SD) was 25.2 ± 21.3 (range 0.2-101) versus PSG AHI 24.4 ± 21.2 (range 0-110) (p = 0.514), and correlation was 0.87 (p < 0.001). Using a threshold of AHI ≥ 15, the sensitivity and specificity of WP versus PSG for diagnosing sleep apnea were 85% and 70% respectively and agreement was 79% (kappa = 0.867). WP central AHI (AHIc) was 4.2 ± 7.7 (range 0-38) versus PSG AHIc 5.9 ± 11.8 (range 0-63) (p = 0.034), while correlation was 0.90 (p < 0.001). Using a threshold of AHI ≥ 15, the sensitivity and specificity of WP versus PSG for diagnosing CSA were 67% and 100% respectively with agreement of 95% (kappa = 0.774), and receiver operator characteristic (ROC) area under the curve of 0.866, (p < 0.01). Using a threshold of AHI ≥ 10 showed comparable overall sleep apnea and CSA diagnostic accuracies. CONCLUSIONS: These findings show that WP can accurately detect overall AHI and effectively differentiate between CSA and OSA.