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.

Engineered Paramagnetic Graphene Quantum Dots with Enhanced Relaxivity for Tumor Imaging.

Nano contrast agents (Nano CA) are nanomaterials used to increase contrast in the medical magnetic resonance imaging (MRI). However, the related relaxation mechanism of the Nano CA is not clear yet and little significant breakthrough in relaxivity enhancement has been achieved. Herein, a new hydrophilic Gd-DOTA complex functionalized with different chain length of PEG was synthesized and incorporated into graphene quantum dots (GQD) to obtain paramagnetic graphene quantum dots (PGQD). We performed a variable-temperature and variable-field intensity NMR study in aqueous solution on the water exchange and rotational dynamics of three different chain lengths of PGQD. The optimal GQD with paramagnetic chain length shows a great improvement in performance on 1H NMR relaxometric studies. In vitro results demonstrated that the relaxivity of the designed PGQD could be controlled by regulating the PEG length, and its relaxivity was ∼16 times higher than that of current commercial MRI contrast agents (e.g., Gd-DTPA), on a "per Gd" basis. The relaxivity of the Nano CA can be rationally tuned to obtain unmatched potentials in MR imaging, exemplified by preparation of the paramagnetic GQD with the enhanced T1 relaxivity. The fabricated PGQDs with suitable PEG length got the best relaxivity at 1.5 T. After intravenous injection, its feeding process by solid tumor could even be monitored by clinically used 1.5 T MRI scanners. This research will also provide an excellent platform for the design and synthesis of highly effective MR contrast agents.

Effect of Telemedicine Education and Telemonitoring on Continuous Positive Airway Pressure Adherence. The Tele-OSA Randomized Trial.

RATIONALE: Automated telemedicine interventions could potentially improve adherence to continuous positive airway pressure (CPAP) therapy. OBJECTIVES: Examining the effects of telemedicine-delivered obstructive sleep apnea (OSA) education and CPAP telemonitoring with automated patient feedback messaging on CPAP adherence. METHODS: This four-arm, randomized, factorial design clinical trial enrolled 1,455 patients (51.0% women; age, 49.1 ± 12.5 yr [mean ± SD]) referred for suspected OSA. Nine hundred and fifty-six underwent home sleep apnea testing, and 556 were prescribed CPAP. Two telemedicine interventions were implemented: 1) web-based OSA education (Tel-Ed) and 2) CPAP telemonitoring with automated patient feedback (Tel-TM). Patients were randomized to 1) usual care, 2) Tel-Ed added, 3) Tel-TM added, or 4) Tel-Ed and Tel-TM added (Tel-both). MEASUREMENTS AND MAIN RESULTS: The primary endpoint was 90-day CPAP usage. Secondary endpoints included attendance to OSA evaluation, and change in Epworth Sleepiness Scale score. CPAP average daily use at 90 days was 3.8 ± 2.5, 4.0 ± 2.4, 4.4 ± 2.2, and 4.8 ± 2.3 hours in usual care, Tel-Ed, Tel-TM, and Tel-both groups. Usage was significantly higher in the Tel-TM and Tel-both groups versus usual care (P = 0.0002 for both) but not for Tel-Ed (P = 0.10). Medicare adherence rates were 53.5, 61.0, 65.6, and 73.2% in usual care, Tel-Ed, Tel-TM, and Tel-both groups (Tel-both vs. usual care, P = 0.001; Tel-TM vs. usual care, P = 0.003; Tel-Ed vs. usual care, P = 0.07), respectively. Telemedicine education improved clinic attendance compared with no telemedicine education (show rate, 68.5 vs. 62.7%; P = 0.02). CONCLUSIONS: The use of CPAP telemonitoring with automated feedback messaging improved 90-day adherence in patients with OSA. Telemedicine-based education did not significantly improve CPAP adherence but did increase clinic attendance for OSA evaluation. Clinical trial registered with www.clinicaltrials.gov (NCT02279901).

Does Providing Positive Airway Pressure for Sleep Apnea Change Health Care Utilization?

BACKGROUND: Sleep apnea is underdiagnosed and thus undertreated. If therapy for sleep apnea results in reduced health care utilization in an entire treated population, then decision-makers will have key information for allocating limited health care resources. OBJECTIVES: To determine whether positive airway pressure (PAP) for sleep apnea was associated with reduced health care utilization in an entire treated population. RESEARCH DESIGN: This was a retrospective cohort; propensity score-matched cases and noncases; pre-post analyses of individual subject utilization. SUBJECTS: Electronic health records were used to identify adult subjects diagnosed with sleep apnea and dispensed PAP therapy (cases) and those without either diagnosed sleep apnea or dispensed PAP therapy (noncases). MEASURES: Acute care hospital days and dispensed medication days supply were compared in cases and noncases. Negative binomial regression was used to model utilization for up to 5 years before and 7 years after PAP dispensation (cases) or a random date (noncases). The association of PAP with changing annual utilization was estimated. RESULTS: There were 13,271 cases and 13,271 matched noncases from 2008 to 2012 for analyses. Trends in the annual rate of acute care utilization were no different between cases and noncases (rate ratio, 0.98, P=0.543). Trends in the annual rate of medication utilization were no different between cases and noncases (rate ratio, 1.008, P=0.112). CONCLUSIONS: PAP dispensation for sleep apnea did not appear to reduce the rate of acute care and medication utilization over several years of follow-up in a large integrated health care system.

Does remote monitoring change OSA management and CPAP adherence?

It is increasingly recognized that the high prevalence of obstructive sleep apnoea (OSA), and its associated cardio-metabolic morbidities make OSA a burden for society. Continuous positive airway pressure (CPAP), the gold standard treatment, needs to be used for more than 4 h/night to be effective, but suffers from relatively poor adherence. Furthermore, CPAP is likely to be more effective if combined with lifestyle changes. Thus, the remote telemonitoring (TM) of OSA patients in terms of CPAP use, signalling of device problems, following disease progression, detection of acute events and monitoring of daily physical activity is an attractive option. In the present review, we aim to summarize the recent scientific data on remote TM of OSA patients, and whether it meets expectations. We also look at how patient education and follow-up via telemedicine is used to improve adherence and we discuss the influence of the profile of the healthcare provider. Then, we consider how TM might be extended to encompass the patient's cardio-metabolic health in general. Lastly, we explore how TM and the deluge of data it potentially generates could be combined with electronic health records in providing personalized care and multi-disease management to OSA patients.

Guizhi Fuling Wan as a Novel Agent for Intravesical Treatment for Bladder Cancer in a Mouse Model.

Alternative intravesical agents are required to overcome the side effects currently associated with the treatment of bladder cancer. This study used an orthotopic bladder cancer mouse model to evaluate Guizhi Fuling Wan (GFW) as an intravesical agent. The effects of GFW were compared with those of mitomycin-C (Mito-C) and bacille Calmette-Guérin (BCG). We began by evaluating the response of the mouse bladder cancer cell line MB49 to GFW treatment, with regard to cell viability, cell cycle progression and apoptosis. MB49 cells were subsequently implanted into the urothelial walls of the bladder in female C57BL/6 mice. The success of the model was confirmed by the appearance of hematuria and tumor growth in the bladder. Intravesical chemotherapy was administered in accordance with a published protocol. In vitro data revealed that GFW arrested MB49 cell cycle in the G0/G1 phase, resulting in the suppression of cell proliferation and induced apoptosis. One possible mechanism underlying these effects is an increase in intracellular reactive oxygen species (ROS) levels leading to the activation of ataxia telangiectasia-mutated (ATM)/checkpoint kinase 2 (CHK2) and ATM/P53 pathways, thereby mediating cell cycle progression and apoptosis, respectively. This mouse model demonstrates the effectiveness of GFW in the tumor growth, with results comparable to those achieved by using BCG and Mito-C. Furthermore, GFW was shown to cause only mild hematuria. The low toxicity of the compound was confirmed by a complete lack of lesions on bladder tissue, even after 10 consecutive treatments using high concentrations of GFW. These results demonstrate the potential of GFW for the intravesical therapy of bladder cancer.

Sensitive imaging of magnetic nanoparticles for cancer detection by active feedback MR.

PURPOSE: Sensitive imaging of superparamagnetic nanoparticles or aggregates is of great importance in MR molecular imaging and medical diagnosis. For this purpose, a conceptually new approach, termed active feedback magnetic resonance, was developed. METHODS: In the presence of the Zeeman field, a dipolar field is induced by the superparamagnetic nanoparticles or aggregates. Such dipolar field creates spatial and temporal (due to water diffusion) variations to the precession frequency of the nearby water 1 H magnetization. Sensitive imaging of magnetic nanoparticles or aggregates can be achieved by manipulating the intrinsic spin dynamics by selective self-excitation and fixed-point dynamics under active feedback fields. RESULTS: Phantom experiments of superparamagnetic nanoparticles; in vitro experiments of brain tissue with blood clots; and in vivo mouse images of colon cancers, with and without labeling by magnetic nanoparticles, suggest that this new approach provides enhanced, robust, and positive contrast in imaging magnetic nanoparticles or aggregates for cancer detection. CONCLUSION: The spin dynamics originated from selective self-excitation and fixed-point dynamics under active feedback fields have been shown to be sensitive to dipolar fields generated by magnetic nanoparticles. Magn Reson Med 74:33-41, 2015. © 2014 Wiley Periodicals, Inc.

Multi-chromatic magnetic resonance imaging using frequency lock-in suppression.

This study developed a multi-chromatic MR contrast using the frequency lock-in technique. An electronic feedback device that generates a specific narrow-frequency-bandwidth RF field is presented. The effects of this RF field on MR images are assessed both theoretically and experimentally. Spectroscopy and imaging experiments were performed. Frequency tuning allowed the selected spectral peak to be suppressed. Phantom tests using methanol, ethanol, and water showed different contrasts using different feedback RF field frequencies. The frequency lock-in was also found to help differentiate among the small structural variations in biological tissues. The contrast achieved in in vivo mouse brain imaging using the lock-in suppressed technique indicated a better spatial discrimination when compared with that achieved using conventional imaging methods, especially in the hippocampus region. Selective lock-in suppressed imaging is a new approach to provide frequency information in MRI; rather than determining the evolution of image contrast over time, this approach allows small susceptibility variations to be distinguished by tuning the frequency of the narrow-bandwidth lock-in RF field. A new and enhanced contrast can be achieved using this technique.

Gd-DTPA-Dopamine-Bisphytanyl Amphiphile: Synthesis, Characterisation and Relaxation Parameters of the Nanoassemblies and Their Potential as MRI Contrast Agents.

Here, a new amphiphilic magnetic resonance imaging (MRI) contrast agent, a Gd(III)-chelated diethylenetriaminepentaacetic acid conjugated to two branched alkyl chains via a dopamine spacer, Gd-DTPA-dopamine-bisphytanyl (Gd-DTPA-Dop-Phy), which is readily capable of self-assembling into liposomal nanoassemblies upon dispersion in an aqueous solution, is reported. In vitro relaxivities of the dispersions were found to be much higher than Magnevist, a commercially available contrast agent, at 0.47 T but comparable at 9.40 T. Analysis of variable temperature (17)O NMR transverse relaxation measurements revealed the water exchange of the nanoassemblies to be faster than that previously reported for paramagnetic liposomes. Molecular reorientation dynamics were probed by (1)H NMRD profiles using a classical inner and outer sphere relaxation model and a Lipari-Szabo "model-free" approach. High payloads of Gd(III) ions in the liposomal nanoassemblies made solely from the Gd-DTPA-Dop-Phy amphiphiles, in combination with slow molecular reorientation and fast water exchange makes this novel amphiphile a suitable candidate to be investigated as an advanced MRI contrast agent.

Novel MRI contrast development by lock-in suppression.

PURPOSE: The goal of this study is to develop novel MR contrast by frequency lock-in technique. METHODS: An electronic feedback device that can control the frequency and bandwidth of the feedback RF field is presented. In this study, the effects of lock-in suppressed imaging are discussed both theoretically and experimentally. RESULTS: Two important imaging experiments were performed. The first experiment used magnetizations with the same central frequency but different frequency distributions and was compared with MR images obtained with T2 contrast agents. Lock-in suppressed images showed an improvement in contrast relative to the conventional imaging method. The second experiment used magnetizations with small shifts in frequency and a broad frequency distribution. This is helpful for differentiating between small structural variations in biological tissues. The contrast achieved in in vivo tumor imaging using the lock-in suppressed technique provide higher spatial resolutions and discriminate the regimes of necrosis and activation consistent with pathologic results. CONCLUSION: Lock-in suppressed imaging introduces a conceptually new approach to MRI. Heightened sensitivity to underlying susceptibility variations and their relative contribution to total magnetization may thus be achieved to yield new and enhanced contrast.

Digital Measures Development: Lessons Learned from an Expert Workshop Addressing Cross-Therapeutic Area Measures of Sleep.

Introduction: The Digital Measures Development: Core Measures of Sleep project, led by the Digital Medicine Society (DiMe), emphasizes the importance of sleep as a cornerstone of health and the need for standardized measurements of sleep and its disturbances outside the laboratory. This initiative recognizes the complex relationship between sleep and overall health, addressing it as both a symptom of underlying conditions and a consequence of therapeutic interventions. It aims to fill a crucial gap in healthcare by promoting the development of accessible, nonintrusive, and cost-effective digital tools for sleep assessment, focusing on factors important to patients, caregivers, and clinicians. Methods: A central feature of this project was an expert workshop conducted on April 19th, 2023. The workshop convened stakeholders from diverse backgrounds, including regulatory, payer, industry, academic, and patient groups, to deliberate on the project's direction. This gathering focused on discussing the challenges and necessities of measuring sleep across various therapeutic areas, aiming to identify broad areas for initial focus while considering the feasibility of generalizing these measures where applicable. The methodological emphasis was on leveraging expert consensus to guide the project's approach to digital sleep measurement. Results: The workshop resulted in the identification of seven key themes that will direct the DiMe Core Digital Measures of Sleep project and the broader field of sleep research moving forward. These themes underscore the project's innovative approach to sleep health, highlighting the complexity of omni-therapeutic sleep measurement and identifying potential areas for targeted research and development. The discussions and outcomes of the workshop serve as a roadmap for enhancing digital sleep measurement tools, ensuring they are relevant, accurate, and capable of addressing the nuanced needs of diverse patient populations. Conclusion: The Digital Medicine Society's Core Measures of Sleep project represents a pivotal effort to advance sleep health through digital innovation. By focusing on the development of standardized, patient-centric, and clinically relevant digital sleep assessment tools, the project addresses a significant need in healthcare. The expert workshop's outcomes underscore the importance of collaborative, multi-stakeholder engagement in identifying and overcoming the challenges of sleep measurement. This initiative sets a new precedent for the integration of digital tools into sleep health research and practice, promising to improve outcomes for patients worldwide by enhancing our understanding and measurement of sleep.

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.

Effects of cholesterol on membrane molecular dynamics studied by fast field cycling NMR relaxometry.

Biological membranes are complex structures composed of various lipids and proteins. Different membrane compositions affect viscoelastic and hydrodynamic properties of membranes, which are critical to their functions. Lipid bilayer vesicles inserted by cholesterol not only enhance membrane surface motional behavior but also strengthen vesicle stability. Cholesterol-rich vesicles are similar to cell membranes in structure and composition. Therefore, cholesterol-rich vesicles can represent a typical model for studying membrane dynamics and functions. In this study, nuclear magnetic relaxation dispersion was used to investigate the detailed molecular dynamics of membrane differences between vesicles and cholesterol vesicles in the temperature range of 278-298 K. Vesicles of two different sizes were prepared. The effect of cholesterol mainly affected the order fluctuation of membranes and the diffusional motion of lipid molecules. In addition, phase variations were also observed in liposomes that contained cholesterol from analyses of the distances between lipid molecules.

NMR relaxation study of water dynamics in superparamagnetic iron-oxide-loaded vesicles.

Superparamagnetic iron oxide (SPIO) nanoparticles have been introduced as contrast agents for clinical applications in magnetic resonance imaging. Recently, SPIO has been also used for tracking cells. However, NMR relaxation of water molecules behaves differently in a SPIO solution and SPIO-loaded cells. In this study, we used water-in-oil-in-water double emulsions to mimic cellular environments. The MR relaxation induced by the SPIO-loaded vesicles and SPIO solution indicates that T(2)* is sensitive to the iron concentration alone, and the behavior was very similar in both SPIO-loaded vesicles and SPIO solution. However, T(2) relaxation of water in SPIO-loaded vesicles was faster than that in a SPIO solution. In addition, the contribution of water inside and outside the vesicles was clarified by replacing H(2)O with D(2)O, and water inside the vesicles was found to cause a nonlinear iron concentration dependency. The studied dilution revealed that vesicle aggregation undergoes a structural transition upon dilution by a certain amount of water. R(2)* relaxation is sensitive to this structural change and shows an obvious nonlinear iron concentration dependency when the SPIO loading is sufficiently high. Random walk simulations demonstrated that in the assumed model, the vesicles aggregate structures causing the differences between R(2)* and R(2) relaxation of water in vesicles in the presence of SPIO particles.

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.

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.

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.

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.