Diverse cytomegalovirus US11 antagonism and MHC-A evasion strategies reveal a tit-for-tat coevolutionary arms race in hominids.

Recurrent, ancient arms races between viruses and hosts have shaped both host immunological defense strategies as well as viral countermeasures. One such battle is waged by the glycoprotein US11 encoded by the persisting human cytomegalovirus. US11 mediates degradation of major histocompatibility class I (MHC-I) molecules to prevent CD8+ T-cell activation. Here, we studied the consequences of the arms race between US11 and primate MHC-A proteins, leading us to uncover a tit-for-tat coevolution and its impact on MHC-A diversification. We found that US11 spurred MHC-A adaptation to evade viral antagonism: In an ancestor of great apes, the MHC-A A2 lineage acquired a Pro184Ala mutation, which confers resistance against the ancestral US11 targeting strategy. In response, US11 deployed a unique low-complexity region (LCR), which exploits the MHC-I peptide loading complex to target the MHC-A2 peptide-binding groove. In addition, the global spread of the human HLA-A*02 allelic family prompted US11 to employ a superior LCR strategy with an optimally fitting peptide mimetic that specifically antagonizes HLA-A*02. Thus, despite cytomegaloviruses low pathogenic potential, the increasing commitment of US11 to MHC-A has significantly promoted diversification of MHC-A in hominids.

A new class of biological ion-driven rotary molecular motors with 5:2 symmetry.

Several new structures of three types of protein complexes, obtained by cryo-electron microscopy (cryo-EM) and published between 2019 and 2021, identify a new family of natural molecular wheels, the "5:2 rotary motors." These span the cytoplasmic membranes of bacteria, and their rotation is driven by ion flow into the cell. They consist of a pentameric wheel encircling a dimeric axle within the cytoplasmic membrane of both Gram-positive and gram-negative bacteria. The axles extend into the periplasm, and the wheels extend into the cytoplasm. Rotation of these wheels has never been observed directly; it is inferred from the symmetry of the complexes and from the roles they play within the larger systems that they are known to power. In particular, the new structure of the stator complex of the Bacterial Flagellar Motor, MotA5B2, is consistent with a "wheels within wheels" model of the motor. Other 5:2 rotary motors are believed to share the core rotary function and mechanism, driven by ion-motive force at the cytoplasmic membrane. Their structures diverge in their periplasmic and cytoplasmic parts, reflecting the variety of roles that they perform. This review focuses on the structures of 5:2 rotary motors and their proposed mechanisms and functions. We also discuss molecular rotation in general and its relation to the rotational symmetry of molecular complexes.

Accrual and retention of diverse patients in psychosocial cancer clinical trials.

Background: Minority and older adult patients remain underrepresented in cancer clinical trials (CCTs). The current study sought to examine sociodemographic inequities in CCT interest, eligibility, enrollment, decline motivation, and attrition across two psychosocial CCTs for gynecologic, gastrointestinal, and thoracic cancers. Methods: Patients were approached for recruitment to one of two interventions: (1) a randomized control trial (RCT) examining effects of a cognitive-behavioral intervention targeting sleep, pain, mood, cytokines, and cortisol following surgery, or (2) a yoga intervention to determine its feasibility, acceptability, and effects on mitigating distress. Prospective RCT participants were queried about interest and screened for eligibility. All eligible patients across trials were offered enrollment. Patients who declined yoga intervention enrollment provided reasons for decline. Sociodemographic predictors of enrollment decisions and attrition were explored. Results: No sociodemographic differences in RCT interest were observed, and older patients were more likely to be ineligible. Eligible Hispanic patients across trials were significantly more likely to enroll than non-Hispanic patients. Sociodemographic factors predicted differences in decline motivation. In one trial, individuals originating from more urban areas were more likely to prematurely discontinue participation. Discussion: These results corroborate evidence of no significant differences in CCT interest across minority groups, with older adults less likely to fulfill eligibility criteria. While absolute Hispanic enrollment was modest, Hispanic patients were more likely to enroll relative to non-Hispanic patients. Additional sociodemographic trends were noted in decline motivation and geographical prediction of attrition. Further investigation is necessary to better understand inequities, barriers, and best recruitment practices for representative CCTs.

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 transition to the American Academy of Sleep Medicine-recommended hypopnea definition in adults: initiatives of the Hypopnea Scoring Rule Task Force.

The American Academy of Sleep Medicine (AASM) recommends that hypopneas be identified using a definition that is based on a ≥ 30% decrease in airflow associated with a ≥ 3% reduction in the oxygen saturation or an arousal (H3A) for diagnosis of obstructive sleep apnea (OSA) in adults. This conflicts with the Centers for Medicare & Medicaid Services definition, which requires a ≥ 4% decrease in the oxygen saturation to identify a hypopnea (H4) and does not acknowledge arousals. In 2018, the AASM Board of Directors constituted a Hypopnea Scoring Rule Task Force with a mandate to "create a strategy for adoption and implementation of the AASM recommended adult hypopnea scoring criteria among members, payers and device manufacturers." The task force initiated several activities including a survey of AASM-accredited sleep facilities and discussions with polysomnography software vendors. Survey results indicated that most sleep facilities scored polysomnograms using only the Centers for Medicare & Medicaid Services definition. Vendors indicated that they could easily support dual scoring. Informal testing among task force members' sleep facilities confirmed there would be little additional work if dual scoring was performed. The task force convened several meetings of a working group of OSA content experts and interested parties, with the purpose of creating research recommendations to study the impact on relevant clinical outcomes using the different definitions of hypopnea. Several possible prospective and retrospective approaches were discussed with emphasis on the group of patients diagnosed with OSA based on an apnea-hypopnea index using H3A but not H4. Based on the deliberations of the working group, the Hypopnea Scoring Rule Task Force submitted recommendations to the AASM Foundation concerning research project strategies for potential grant funding. Further discussions within the Hypopnea Scoring Rule Task Force focused on developing advocacy initiatives among patient stakeholder groups to change payer policy. CITATION: Berry RB, Abreu AR, Krishnan V, Quan SF, Strollo PJ Jr, Malhotra RK. A transition to the American Academy of Sleep Medicine-recommended hypopnea definition in adults: initiatives of the Hypopnea Scoring Rule Task Force. J Clin Sleep Med. 2022;18(5):1419-1425.

Incorporation of Polymer-Grafted Cellulose Nanocrystals into Latex-Based Pressure-Sensitive Adhesives.

While the improvement of water-based adhesives with renewable additives is important as industry shifts toward more sustainable practices, a complete understanding of how the compatibility between additives and polymers affects adhesive performance is currently lacking. To elucidate these links, cellulose nanocrystals (CNCs) were first functionalized via surface-initiated atom-transfer radical polymerization with the hydrophobic polymers poly(butyl acrylate) (PBA) and poly(methyl methacrylate) (PMMA) to facilitate their incorporation into latex-based pressure-sensitive adhesives (PSAs). Next, PBA latexes were synthesized using seeded semibatch emulsion polymerization with unmodified or polymer-grafted CNCs added in situ at a loading of 0.5 or 1 phm (parts per hundred parts of monomer). Viscosity and electron microscopy suggested that the polymer-grafted CNCs were incorporated inside or on the latex particles. PSAs containing any CNC type had one or more improved properties (compared to the no-CNC "base case"); CNCs with a low degree of polymerization (DP) grafts exhibited improved tack (up to 2.5-fold higher) and peel strength (up to 6-fold higher) relative to PSAs with unmodified CNCs. The best performing PSA contained the low DP PMMA-grafted CNCs, which is attributed to the higher glass transition temperature and the higher wettability of the PMMA grafts compared to PBA, and the more uniform dispersion of polymer-grafted CNCs throughout the PSA film. In contrast, PSAs containing CNCs with high DP grafts resulted in reduced tack and peel strength (compared to low DP grafts) due to enhanced CNC aggregation. Unfortunately, all PSAs containing polymer-grafted CNCs exhibited inferior shear strength relative to PSAs with unmodified CNCs (and comparable shear strength to the no-CNC "base case"). Collectively, these results provide guidelines for future optimization of more sustainable latex-based PSAs.

Elucidation of obstructive sleep apnoea related blood pressure surge using a novel continuous beat-to-beat blood pressure monitoring system.

BACKGROUND: Obstructive sleep apnoea (OSA) episode related blood pressure (BP) surge may mediate the association of OSA with cardiovascular disease. However, BP is not measured during a clinical sleep study. METHOD: We tested the feasibility of incorporating the Caretaker physiological monitor, which utilizes a novel continuous beat-to-beat (b-b) BP monitoring technology, into polysomnography (PSG) and aimed to characterize BP surges related to obstructive respiratory events. B-b BP was concurrently collected and merged with PSG data on a posthoc basis. We compared BP surge between mean respiratory (apnoea, hypopnea and desaturation-alone events) and nonrespiratory events (spontaneous or leg movement-related arousals). We examined the association of the degree of oxygen desaturation with BP surge in a given respiratory event combining all events. A total of 17 consecutive patients (12 men, mean 52 years old, nine diagnostic and eight split-night PSGs) undergoing clinically indicated PSG were included after excluding one patient with poor signal quality due to excessive movement. RESULTS: Caretaker was well tolerated. Mean respiratory BP surge ranged from 5 to 19 mmHg [Median (IQR) = 13.9 (9.5--16.2)]. Mean BP surge between the respiratory and nonrespiratory events was similar [13.8 (4.5) vs. 14.9 (5.3) mmHg, P = 0.13]. Accounting for the count distribution of desaturation/BP surge data pair events, there was a linear correlation between the degree of oxygen desaturation and BP surge (R = 0.57, P < 0.001). In eight patients undergoing split-night sleep studies, the number of BP surge events (≥10 mmHg/h) decreased during continuous positive airway pressure in all but one patient. CONCLUSION: We demonstrated highly variable OSA-related BP surge patterns using the Caretaker's b-b BP monitoring technology that has the potential to be integrated into sleep studies.

Impacts of Cognitive Behavioral Therapy for Insomnia and Pain on Sleep in Women with Gynecologic Malignancies: A Randomized Controlled Trial.

Insomnia is an adverse cancer outcome impacting mood, pain, quality of life, and mortality in cancer patients. Cognitive Behavioral Therapy (CBT) is an evidence-based treatment for diverse psychophysiological disorders, including pain and insomnia. Primarily studied in breast cancer, there is limited research on CBT within gynecology oncology. This study examined CBT effects on subjective and behavioral sleep outcomes: Sleep Efficiency (SE), Sleep Quality (SQ), Total Wake Time (TWT), Sleep Onset Latency (SOL), and Wake After Sleep Onset (WASO). Thirty-five women with insomnia status/post-surgery for gynecologic cancer were randomized to CBT for insomnia and pain (CBTi.p., N = 18) or Psychoeducation (N = 17). Sleep was assessed via sleep diaries and wrist-worn actigraphy at baseline (T1), post-intervention (T2), and two-month follow-up (T3). Intent-to-treat analyses utilizing mixed linear modeling examined longitudinal group differences on sleep controlling for age and advanced cancer. All participants demonstrated improved (1) subjective SE (0.5, p < .01), SOL (-1.2, p < .01), TWT (-1.2, p < .01), and (2) behavioral SE (0.1, p = .02), TWT (-1.2, p = .03), WASO (-0.8, p < .01) across time. Group-level time trends were indicative of higher subjective SE (6.8, p = .02), lower TWT (-40.3, p = .01), and lower SOL (-13.0, p = .05) in CBTi.p. compared to Psychoeducation. Supplemental analyses examining clinical significance and acute treatment effects demonstrated clinical improvements in SE (T1), TWT (T2, T3), and SOL (T3). Remaining effects were not significant. Despite lacking power to detect interaction effects, CBTi.p. clinically improved sleep in women with gynecologic cancers and insomnia during the active treatment phase. Future research will focus on developing larger trials within underserved populations.

Neural activation changes in response to pain following cognitive behavioral therapy for patients with comorbid fibromyalgia and insomnia: a pilot study.

STUDY OBJECTIVES: To examine whether cognitive behavioral treatments for insomnia (CBT-I) and pain (CBT-P) lead to neural activation changes in response to pain in fibromyalgia. METHODS: Thirty-two patients with fibromyalgia (mean age = 55.9, standard deviation = 12.2) underwent an experimental pain protocol during functional magnetic resonance imaging and completed 14-day diaries assessing total wake time, total sleep time, and pain intensity before and after CBT-I, CBT-P, or waitlist control. Random effects analysis of covariance identified regions with significant group (CBT-I, CBT-P, waitlist control) by time (baseline, post-treatment) interactions in blood oxygen level-dependent response to pain. Linear regressions using residualized change scores examined how changes in total wake time, total sleep time, and pain intensity were related to activation (blood oxygen level-dependent) changes. RESULTS: Twelve regions exhibited small to moderate effects with significant interactions Ps < .00; right hemisphere: inferior frontal, middle occipital, and superior temporal gyri, insula, lentiform nucleus; left hemisphere: angular, superior temporal, midfrontal, inferior occipital, midtemporal, and inferior frontal gyri. Blood oxygen level-dependent response to pain decreased in 8 regions following CBT-I, and in 3 regions following CBT-P (CBT-I effects > CBT-P). Blood oxygen level-dependent response also increased in 3 regions following CBT-P and in 6 regions following waitlist control. Improved total wake time and/or total sleep time, not pain intensity, predicted decreased blood oxygen level-dependence in 7 regions (Ps < .05), accounting for 18%-47% of the variance. CONCLUSIONS: CBT-I prompted greater decreases in neural activation in response to pain across more regions associated with pain and sleep processing than CBT-P. Reported sleep improvements may underlie those decreases. Future research examining the longer-term impact of CBT-I and improved sleep on central pain and sleep mechanisms is warranted. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Title: Sleep and Pain Interventions in Fibromyalgia (SPIN); Identifier: NCT02001077; URL: https://clinicaltrials.gov/ct2/show/NCT02001077. CITATION: McCrae CS, Craggs JG, Curtis AF, et al. Neural activation changes in response to pain following cognitive behavioral therapy for patients with comorbid fibromyalgia and insomnia: a pilot study. J Clin Sleep Med. 2022;18(1):203-215.

Recognition of the antigen-presenting molecule MR1 by a Vδ3+ γδ T cell receptor.

Unlike conventional αß T cells, γδ T cells typically recognize nonpeptide ligands independently of major histocompatibility complex (MHC) restriction. Accordingly, the γδ T cell receptor (TCR) can potentially recognize a wide array of ligands; however, few ligands have been described to date. While there is a growing appreciation of the molecular bases underpinning variable (V)δ1+ and Vδ2+ γδ TCR-mediated ligand recognition, the mode of Vδ3+ TCR ligand engagement is unknown. MHC class I-related protein, MR1, presents vitamin B metabolites to αß T cells known as mucosal-associated invariant T cells, diverse MR1-restricted T cells, and a subset of human γδ T cells. Here, we identify Vδ1/2- γδ T cells in the blood and duodenal biopsy specimens of children that showed metabolite-independent binding of MR1 tetramers. Characterization of one Vδ3Vγ8 TCR clone showed MR1 reactivity was independent of the presented antigen. Determination of two Vδ3Vγ8 TCR-MR1-antigen complex structures revealed a recognition mechanism by the Vδ3 TCR chain that mediated specific contacts to the side of the MR1 antigen-binding groove, representing a previously uncharacterized MR1 docking topology. The binding of the Vδ3+ TCR to MR1 did not involve contacts with the presented antigen, providing a basis for understanding its inherent MR1 autoreactivity. We provide molecular insight into antigen-independent recognition of MR1 by a Vδ3+ γδ TCR that strengthens an emerging paradigm of antibody-like ligand engagement by γδ TCRs.

Elucidating the Motif for CpG Oligonucleotide Binding to the Dendritic Cell Receptor DEC-205 Leads to Improved Adjuvants for Liver-Resident Memory.

DEC-205 is a cell-surface receptor that transports bound ligands into the endocytic pathway for degradation or release within lysosomal endosomes. This receptor has been reported to bind a number of ligands, including keratin, and some classes of CpG oligodeoxynucleotides (ODN). In this study, we explore in detail the requirements for binding ODNs, revealing that DEC-205 efficiently binds single-stranded, phosphorothioated ODN of ≥14 bases, with preference for the DNA base thymidine, but with no requirement for a CpG motif. DEC-205 fails to bind double-stranded phosphodiester ODN, and thus does not bind the natural type of DNA found in mammals. The ODN binding preferences of DEC-205 result in strong binding of B class ODN, moderate binding to C class ODN, minimal binding to P class ODN, and no binding to A class ODN. Consistent with DEC-205 binding capacity, induction of serum IL-12p70 or activation of B cells by each class of ODN correlated with DEC-205 dependence in mice. Thus, the greater the DEC-205 binding capacity, the greater the dependence on DEC-205 for optimal responses. Finally, by covalently linking a B class ODN that efficiently binds DEC-205, to a P class ODN that shows poor binding, we improved DEC-205 binding and increased adjuvancy of the hybrid ODN. The hybrid ODN efficiently enhanced induction of effector CD8 T cells in a DEC-205-dependent manner. Furthermore, the hybrid ODN induced robust memory responses, and was particularly effective at promoting the development of liver tissue-resident memory T cells.

Optimal NIV Medicare Access Promotion: Patients With Central Sleep Apnea: A Technical Expert Panel Report From the American College of Chest Physicians, the American Association for Respiratory Care, the American Academy of Sleep Medicine, and the American Thoracic Society.

This document summarizes suggestions of the central sleep apnea (CSA) Technical Expert Panel working group. This paper shares our vision for bringing the right device to the right patient at the right time. For patients with CSA, current coverage criteria do not align with guideline treatment recommendations. For example, CPAP and oxygen therapy are recommended but not covered for CSA. On the other hand, bilevel positive airway pressure (BPAP) without a backup rate may be a covered therapy for OSA, but it may worsen CSA. Narrow coverage criteria that require near elimination of obstructive breathing events on CPAP or BPAP in the spontaneous mode, even if at poorly tolerated pressure levels, may preclude therapy with BPAP with backup rate or adaptive servoventilation, even when those devices provide demonstrably better therapy. CSA is a dynamic disorder that may require different treatments over time, sometimes switching from one device to another; an example is switching from BPAP with backup rate to an adaptive servoventilation with automatic end-expiratory pressure adjustments, which may not be covered. To address these challenges, we suggest several changes to the coverage determinations, including: (1) a single simplified initial and continuing coverage definition of CSA that aligns with OSA; (2) removal of hypoventilation terminology from coverage criteria for CSA; (3) all effective therapies for CSA should be covered, including oxygen and all PAP devices with or without backup rates or servo-mechanisms; and (4) patients shown to have a suboptimal response to one PAP device should be allowed to add oxygen or change to another PAP device with different capabilities if shown to be effective with testing.

How latex film formation and adhesion at the nanoscale correlate to performance of pressure sensitive adhesives with cellulose nanocrystals.

Emulsion polymerized latex-based pressure-sensitive adhesives (PSAs) are more environmentally benign because they are synthesized in water but often underperform compared to their solution polymerized counterparts. Studies have shown a simultaneous improvement in the tack, and peel and shear strength of various acrylic PSAs upon the addition of cellulose nanocrystals (CNCs). This work uses atomic force microscopy (AFM) to examine the role of CNCs in (i) the coalescence of hydrophobic 2-ethyl hexyl acrylate/n-butyl acrylate/methyl methacrylate (EHA/BA/MMA) latex films and (ii) as adhesion modifiers over multiple length scales. Thin films with varying solids content and CNC loading were prepared by spin coating. AFM revealed that CNCs lowered the solids content threshold for latex particle coalescence during film formation. This improved the cohesive strength of the films, which was directly reflected in the increased shear strength of the EHA/BA/MMA PSAs with increasing CNC loading. Colloidal probe AFM indicated that the nano-adhesion of thicker continuous latex films increased with CNC loading when measured over small contact areas where the effect of surface roughness was negligible. Conversely, the beneficial effects of the CNCs on macroscopic PSA tack and peel strength were outweighed by the effects of increased surface roughness with increasing CNC loading over larger surface areas. This highlights that CNCs can improve both cohesive and adhesive PSA properties; however, the effects are most pronounced when the CNCs interact favourably with the latex polymer and are uniformly dispersed throughout the adhesive film. This article is part of the theme issue 'Bio-derived and bioinspired sustainable advanced materials for emerging technologies (part 1)'.

Effect of Reaction Media on Grafting Hydrophobic Polymers from Cellulose Nanocrystals via Surface-Initiated Atom-Transfer Radical Polymerization.

Hydrophobic polymer-grafted cellulose nanocrystals (CNCs) were produced via surface-initiated atom-transfer radical polymerization (SI-ATRP) in two different solvents to examine the role of reaction media on the extent of surface modification. Poly(butyl acrylate)-grafted CNCs were synthesized in either dimethylformamide (DMF) (D-PBA-g-CNCs) or toluene (T-PBA-g-CNCs) alongside a free polymer from a sacrificial initiator. The colloidal stability of unmodified CNCs, initiator-modified CNCs, and PBA-g-CNCs in water, DMF, and toluene was evaluated by optical transmittance. The enhanced colloidal stability of initiator-modified CNCs in DMF led to improved accessibility to initiator groups during polymer grafting; D-PBA-g-CNCs had 30 times more grafted chains than T-PBA-g-CNCs, determined by thermogravimetric and elemental analysis. D-PBA-g-CNCs dispersed well in toluene and were hydrophobic with a water contact angle of 124° (for polymer grafts > 13 kDa) compared to 25° for T-PBA-g-CNCs. The cellulose crystal structure was preserved, and individual nanoparticles were retained when grafting was carried out in either solvent. This work highlights that optimizing CNC colloidal stability prior to grafting is more crucial than solvent-polymer compatibility to obtain high graft densities and highly hydrophobic CNCs via SI-ATRP.

Molecular structure of the intact bacterial flagellar basal body.

The bacterial flagellum is a macromolecular protein complex that enables motility in many species. Bacterial flagella self-assemble a strong, multicomponent drive shaft that couples rotation in the inner membrane to the micrometre-long flagellar filament that powers bacterial swimming in viscous fluids1-3. Here, we present structures of the intact Salmonella flagellar basal body4, encompassing the inner membrane rotor, drive shaft and outer-membrane bushing, solved using cryo-electron microscopy to resolutions of 2.2-3.7 Å. The structures reveal molecular details of how 173 protein molecules of 13 different types assemble into a complex spanning two membranes and a cell wall. The helical drive shaft at one end is intricately interwoven with the rotor component with both the export gate complex and the proximal rod forming interactions with the MS-ring. At the other end, the drive shaft distal rod passes through the LP-ring bushing complex, which functions as a molecular bearing anchored in the outer membrane through interactions with the lipopolysaccharide. The in situ structure of a protein complex capping the drive shaft provides molecular insights into the assembly process of this molecular machine.

Protocol for Digital Real-world Evidence trial for Adults with insomnia treated via Mobile (DREAM): an open-label trial of a prescription digital therapeutic for treating patients with chronic insomnia.

Background: Cognitive behavioral therapy for insomnia (CBT-I) is underused in healthcare settings and is challenging for people with insomnia to access because of uneven geographical distribution of behavioral sleep medicine providers. Prescription digital therapeutics can overcome these barriers. This study evaluates the effectiveness of a specific digital CBT-I therapeutic. Materials & methods:Digital Real-world Evidence trial for Adults with insomnia treated via Mobile (DREAM) is a 9-week, open-label, decentralized clinical trial to collect real-world evidence for a digital therapeutic (Somryst™) delivering CBT-I to patients with chronic insomnia. The primary objective is to examine the effectiveness of Somryst to reduce self-reported insomnia symptoms and severity in a real-world population (n = 350). Conclusion: This pragmatic study seeks to assess the potential benefits of treating insomnia with an asynchronous, mobile, tailored prescription digital therapeutic. Clinical trial registration: NCT04325464 (ClinicalTrials.gov).

Lay abstract Chronic insomnia is linked to a range of health problems, including heart disease, chronic pain, high blood pressure and depression. A behavioral treatment called cognitive behavioral therapy for insomnia (CBT-I) is considered the first choice for helping patients overcome insomnia and reduce their risks of insomnia-related problems. Although the benefits of CBT-I have been established, it can be difficult for patients to access trained CBT-I therapists. One possible solution is to use digital forms of CBT-I, which patients can access on mobile devices. Somryst™ is a prescription digital therapeutic, which means it is authorized by the US FDA and has been proven effective in carefully-controlled clinical trials. Less is known, however, about how well the prescription digital therapeutic works in real-world settings. The Digital Real-world Evidence trial for Adults with insomnia treated via Mobile study (DREAM) will explore this question by evaluating a range of symptoms and outcomes in at least 350 patients with chronic insomnia who will use Somryst and be followed for 1 year.