Bright light therapy for CPAP-resistant OSA symptoms.

STUDY OBJECTIVES: Sleep fragmentation and daytime sleepiness often persist in patients with sleep apnea despite correctly administered continuous positive airway pressure (CPAP). Our proof-of-concept study tested the acceptability and efficacy of morning bright light therapy (BLT) to improve sleep, circadian rhythms, and CPAP-resistant daytime symptoms in patients with sleep apnea. METHODS: In this within-subject crossover study, 14 individuals completed 4 weeks of BLT and sham BLT in randomized order. Outcomes included actigraphy-based objective sleep measures, sleepiness, depressive symptoms, and sleep-related functional impairment, analyzed with multilevel models. RESULTS: Patients experienced greater reductions in wake after sleep onset and increased amplitude of rest-activity rhythms in a shorter photoperiod with BLT compared with sham. Patients also reported reductions in self-reported sleepiness and depressive symptoms with BLT compared with sham only during the early stages of treatment and shorter photoperiod. CONCLUSIONS: These results suggest the potential for novel applications for existing chronotherapeutic interventions for improving symptoms and quality of life for those patients who experience residual symptoms with current available treatments. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Bright Light Therapy for Residual Daytime Symptoms Associated With Obstructive Sleep Apnea; URL: https://clinicaltrials.gov/ct2/show/NCT04299009; Identifier: NCT04299009. CITATION: Soreca I, Arnold N, Dombrovski AY. Bright light therapy for CPAP-resistant OSA symptoms. J Clin Sleep Med. 2024;20(2):211-219.

Hypoglossal Nerve Stimulation and Cardiovascular Outcomes for Patients With Obstructive Sleep Apnea: A Randomized Clinical Trial.

Importance: Sham-controlled trials are needed to characterize the effect of hypoglossal nerve stimulation (HGNS) therapy on cardiovascular end points in patients with moderate-severe obstructive sleep apnea (OSA). Objective: To determine the effect of therapeutic levels of HGNS, compared to sham levels, on blood pressure, sympathetic activity, and vascular function. Design, Setting, and Participants: This double-blind, sham-controlled, randomized crossover therapy trial was conducted from 2018 to 2022 at 3 separate academic medical centers. Adult patients with OSA who already had an HGNS device implanted and were adherent and clinically optimized to HGNS therapy were included. Participants who had fallen asleep while driving within 1 year prior to HGNS implantation were excluded from the trial. Data analysis was performed from January to September 2022. Interventions: Participants underwent a 4-week period of active HGNS therapy and a 4-week period of sham HGNS therapy in a randomized order. Each 4-week period concluded with collection of 24-hour ambulatory blood pressure monitoring (ABPM), pre-ejection period (PEP), and flow-mediated dilation (FMD) values. Main Outcomes and Measures: The change in mean 24-hour systolic blood pressure was the primary outcome, with other ABPM end points exploratory, and PEP and FMD were cosecondary end points. Results: Participants (n = 60) were older (mean [SD] age, 67.3 [9.9] years), overweight (mean [SD] body mass index, calculated as weight in kilograms divided by height in meters squared, 28.7 [4.6]), predominantly male (38 [63%]), and had severe OSA at baseline (mean [SD] apnea-hypopnea index, 33.1 [14.9] events/h). There were no differences observed between active and sham therapy in 24-hour systolic blood pressure (mean change on active therapy, -0.18 [95% CI, -2.21 to 1.84] mm Hg), PEP (mean change on active therapy, 0.11 [95% CI, -5.43 to 5.66] milliseconds), or FMD (mean change on active therapy, -0.17% [95% CI, -1.88% to 1.54%]). Larger differences between active and sham therapy were observed in a per-protocol analysis set (n = 20) defined as experiencing at least a 50% reduction in apnea-hypopnea index between sham and active treatment. Conclusions and Relevance: In this sham-controlled HGNS randomized clinical trial, mean 24-hour systolic blood pressure and other cardiovascular measures were not significantly different between sham and active HGNS therapy. Several methodologic lessons can be gleaned to inform future HGNS randomized clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT03359096.

Advances in the Use of Hypoglossal Nerve Stimulator in Adolescents With Down Syndrome and Persistent Obstructive Sleep Apnea-A Systematic Review.

INTRODUCTION: The Hypoglossal Nerve Stimulator (HNS) is a novel therapy that has been extensively studied in adults and more recently, it has been incorporated in children with Down Syndrome (DS) with persistent obstructive sleep apnea after adenotonsillectomy and trial of continuous positive airway pressure treatment. This systematic review article aims to examine the existing literature on HNS use in children to explore the benefits, efficacy, and parental experiences. METHODS: MEDLINE, Web of Science and EMBASE were searched to include all studies published up to March 2nd, 2023, on the topic of HNS use in pediatric population under 21 years old. RESULTS: A total of 179 studies were initially identified from which 10 articles were consistent with the inclusion criteria. Nine articles addressed outcomes after implantation of the HNS device in children with DS and 1 article explored the parental experiences. Findings were similar across studies where after implantation of HNS, there was marked improvement in polysomnographic outcomes and quality of life scores with high level of compliance. CONCLUSIONS: HNS holds promise as an effective treatment option for pediatric patients with DS and persistent OSA after AT and CPAP trials. It significantly improves sleep-disordered breathing, quality of life, and neurocognitive measures, leading to substantial and sustained benefits for these children. While the findings are encouraging, further research is needed to explore the potential of HNS in other pediatric populations without DS and to raise awareness among healthcare providers about this treatment option. Overall, HNS may offer significant long-term benefits for the overall well-being and health of pediatric patients with DS and persistent OSA.

Anaerobic pathogens associated with OSA may contribute to pathophysiology via amino-acid depletion.

BACKGROUND: The human microbiome is linked to multiple metabolic disorders such as obesity and diabetes. Obstructive sleep apnoea (OSA) is a common sleep disorder with several metabolic risk factors. We investigated the associations between the gut microbiome composition and function, and measures of OSA severity in participants from a prospective community-based cohort study: the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). METHODS: Bacterial-Wide Association Analysis (BWAS) of gut microbiome measured via metagenomics with OSA measures was performed adjusting for clinical, lifestyle and co-morbidities. This was followed by functional analysis of the OSA-enriched bacteria. We utilized additional metabolomic and transcriptomic associations to suggest possible mechanisms explaining the microbiome effects on OSA. FINDINGS: Several uncommon anaerobic human pathogens were associated with OSA severity. These belong to the Lachnospira, Actinomyces, Kingella and Eubacterium genera. Functional analysis revealed enrichment in 49 processes including many anaerobic-related ones. Severe OSA was associated with the depletion of the amino acids glycine and glutamine in the blood, yet neither diet nor gene expression revealed any changes in the production or consumption of these amino acids. INTERPRETATION: We show anaerobic bacterial communities to be a novel component of OSA pathophysiology. These are established in the oxygen-poor environments characteristic of OSA. We hypothesize that these bacteria deplete certain amino acids required for normal human homeostasis and muscle tone, contributing to OSA phenotypes. Future work should test this hypothesis as well as consider diagnostics via anaerobic bacteria detection and possible interventions via antibiotics and amino-acid supplementation. FUNDING: Described in methods.

Posttraumatic sleep disturbances in veterans: A pilot randomized controlled trial of cognitive behavioral therapy for insomnia and imagery rehearsal therapy.

OBJECTIVES: Posttraumatic stress disorder (PTSD) is associated with sleep disturbances including insomnia and nightmares. This study compared cognitive behavioral therapy for insomnia (CBT-I) with CBT-I combined with imagery rehearsal therapy (IRT) for nightmares to evaluate if the combined treatment led to greater reductions in trauma-related sleep disturbances in Australian veterans. METHODS: Veterans with diagnosed PTSD, high insomnia symptom severity, and nightmares (N = 31) were randomized to eight group CBT-I sessions or eight group CBT-I + IRT sessions. Self-reported sleep, nightmare, and psychological measures (primary outcome: Pittsburgh Sleep Quality Index), and objective actigraphy data were collected; the effect of obstructive sleep apnea (OSA) risk on treatment outcomes was also examined. RESULTS: No treatment condition effects were detected for the combined treatment compared to CBT-I alone, and no moderating effect of OSA risk was detected. On average, participants from both groups improved on various self-report measures over time (baseline to 3 months posttreatment). Despite the improvements, mean scores for sleep-specific measures remained indicative of poor sleep quality. There were also no significant differences between the groups on the actigraphy indices. CONCLUSIONS: The findings indicate that there is potential to optimize both treatments for veterans with trauma-related sleep disturbances.

Statins Restore Endothelial Protection against Complement Activity in Obstructive Sleep Apnea: A Randomized Clinical Trial.

Rationale: Increased cardiovascular risk in obstructive sleep apnea (OSA) persists after continuous positive airway pressure (CPAP) and alternative therapies are needed. Impaired endothelial protection against complement is a cholesterol-dependent process that initiates endothelial inflammation in OSA, which increases cardiovascular risk. Objectives: To investigate directly whether lowering cholesterol improves endothelial protection against complement and its proinflammatory effects in OSA. Methods: Newly diagnosed patients with OSA (n = 87) and OSA-free controls (n = 32) participated. Endothelial cells and blood were collected at baseline, after 4 weeks of CPAP therapy, and again after 4 weeks of 10 mg atorvastatin versus placebo using a randomized, double-blind, parallel-group design. Primary outcome was the proportion of a complement inhibitor, CD59, on the endothelial cell plasma membrane in OSA patients after 4 weeks of statins versus placebo. Secondary outcomes were complement deposition on endothelial cells and circulating levels of its downstream proinflammatory factor, angiopoietin-2, after statins versus placebo. Results: Baseline expression of CD59 was lower, whereas complement deposition on endothelial cells and levels of angiopoietin-2 were greater, in patients with OSA compared with controls. CPAP did not affect expression of CD59 or complement deposition on endothelial cells in patients with OSA, regardless of adherence. Compared with placebo, statins increased expression of endothelial complement protector CD59 and lowered complement deposition in patients with OSA. Good CPAP adherence was associated with increased angiopoietin-2 levels, which was reversed by statins. Conclusions: Statins restore endothelial protection against complement and reduce its downstream proinflammatory effects, suggesting a potential approach to reduce residual cardiovascular risk after CPAP in patients with OSA. Clinical trial registered with www.clinicaltrials.gov (NCT03122639).

Is obstructive sleep apnea a circadian rhythm disorder?

Obstructive sleep apnea is the most common sleep-related breathing disorder worldwide and remains underdiagnosed. Its multiple associated comorbidities contribute to a decreased quality of life and work performance as well as an increased risk of death. Standard treatment seems to have limited effects on cardiovascular and metabolic aspects of the disease, emphasising the need for early diagnosis and additional therapeutic approaches. Recent evidence suggests that the dysregulation of circadian rhythms, processes with endogenous rhythmicity that are adjusted to the environment through various cues, is involved in the pathogenesis of comorbidities. In patients with obstructive sleep apnea, altered circadian gene expression patterns have been demonstrated. Obstructive respiratory events may promote circadian dysregulation through the effects of sleep disturbance and intermittent hypoxia, with subsequent inflammation and disruption of neural and hormonal homeostasis. In this review, current knowledge on obstructive sleep apnea, circadian rhythm regulation, and circadian rhythm sleep disorders is summarised. Studies that connect obstructive sleep apnea to circadian rhythm abnormalities are critically evaluated. Furthermore, pathogenetic mechanisms that may underlie this association, most notably hypoxia signalling, are presented. A bidirectional relationship between obstructive sleep apnea and circadian rhythm dysregulation is proposed. Approaching obstructive sleep apnea as a circadian rhythm disorder may prove beneficial for the development of new, personalised diagnostic, therapeutic and prognostic tools. However, further studies are needed before the clinical approach to obstructive sleep apnea includes targeting the circadian system.

Relationship of obstructive sleep apnea with periodontal condition and its local and systemic risk factors.

OBJECTIVE: Obstructive sleep apnea (OSA) and periodontitis share risk factors, such as age, obesity, stress, and cardiovascular events, which have a bidirectional cause-effect relationship through systemic inflammation. Our objective was to determine the relationship between OSA and the periodontal condition and its associated local and systemic risk factors. MATERIAL AND METHODS: This was an observational case-control study involving 60 patients. Local oral risk factors and the systemic condition of each patient were evaluated. All patients underwent polysomnography for the diagnosis of OSA. Chi-squared, one-way ANOVA, and Bonferroni's tests were performed. RESULTS: A higher percentage of patients with periodontitis had severe OSA (66.66%); however, no statistically significant association was found between the two pathologies (p = 0.290). In terms of systemic risk factors, an association was found between arterial hypertension and severe OSA (p = 0.038), and in terms of local factors, an association was found between the use of removable prostheses and severe OSA (p = 0.0273). CONCLUSION: In the general population, patients with periodontitis showed a higher prevalence of severe OSA. Obesity and hypothyroidism were the most prevalent systemic findings in patients with OSA and periodontitis. Arterial hypertension and osteoarthritis were found to be associated with severe OSA. The local risk factors associated with periodontitis and severe OSA were removable partial dentures and misfit resins. CLINICAL RELEVANCE: To study the factors that can facilitate the progression of OSA and periodontitis, physicians and dentists should be advised to provide comprehensive care for patients with both pathologies.

Combination CPAP and bilateral hypoglossal nerve stimulation for obstructive sleep apnea in Treacher Collins syndrome: first case report.

We report the first case of bilateral hypoglossal nerve stimulator implantation in a patient with Treacher Collins syndrome and very severe obstructive sleep apnea, who was initially intolerant of continuous positive airway pressure (CPAP) treatment. Novel bilateral hypoglossal nerve stimulation in combination with CPAP allowed near obliteration of snoring, improved sleep quality, and ability to maintain the CPAP mask in position in the setting of craniofacial changes associated with this condition. CITATION: Wong ACL, Jones A, Stone A, MacKay SG. Combination CPAP and bilateral hypoglossal nerve stimulation for obstructive sleep apnea in Treacher Collins syndrome: first case report. J Clin Sleep Med. 2023;19(1):197-199.

Parental experience of hypoglossal nerve stimulator implantation in adolescents with Down Syndrome and obstructive sleep apnea.

PURPOSE: The purpose of this study is to explore the experience of parents in deciding whether to participate in a clinical trial of the insertion of the Hypoglossal Nerve Stimulator (HNS) to treat their adolescent with Down Syndrome (DS) and Obstructive Sleep Apnea (OSA). DESIGN AND METHODS: A qualitative descriptive design with interviews was used to gather parental experiences from those who consented to HNS for their adolescent with DS and OSA. Interviews were conducted, audiotaped, and transcribed. Basic content analysis was followed to interpret the data. Using a process of data debriefing/engagement, codes were generated, and field/reflective notes were used to assure trustworthiness of the data. RESULTS: Parents, 13 mothers/2 fathers, participated. Three themes were identified: Parents experience desperation about acceptance of standard of care for their adolescent with DS and OSA. This desperation led parents to seek information/insights from social media and they came to rely on those sites to explore options, ultimately leading them to HNS clinical trial. Finally, parents had a desire to share experience with HNS implantation. CONCLUSIONS: Parents described being desperate at acceptance of standards of care for OSA. They shifted reliance on experts and parents by searching social media pages to explore options for treatment of OSA. Parents wished to share experiences with the HNS implantation. PRACTICE IMPLICATIONS: Nurses play a role in preparing for the HNS by instructing/educating parents. Nurses can identify supportive social media sites for parents during the HNS decision and suggest ways to measure outcomes of HNS.

Assessing the causal associations of obstructive sleep apnea with serum uric acid levels and gout: a bidirectional two-sample Mendelian randomization study.

OBJECTIVE: Multiple observational studies have reported the close associations of obstructive sleep apnea (OSA) with serum uric acid (SUA) levels and gout. However, the causal nature and direction remains unclear. METHODS: A bidirectional two-sample Mendelian randomization (MR) study was performed, based on publicly available genome-wide association studies (GWAS) summary statistics, to investigate whether OSA is causally related to SUA levels, gout and vice versa. The inverse-variance weighted (IVW) was used as the primary analysis approach, supplemented with four sensitive analysis methods applied to assess the robustness of the results. Moreover, multivariable MR (MVMR) was utilized to evaluate the independent causal effect of OSA on SUA and gout after adjusting for body mass index (BMI), hypertension, type 2 diabetes (T2D), coronary artery disease (CAD), and chronic kidney disease (CKD). RESULTS: Genetically predicted OSA liability was significantly associated with increased levels of SUA (IVW method: ß = 0.19, 95% CI = 0.11 - 0.26, P = 7.24 × 10-7) and risk of gout [IVW method: odds ratio (OR) = 1.75 95% CI = 1.13 - 2.69, P = 0.01] in univariable MR. The MVMR results suggested that OSA retained its significant association with increased SUA levels, whereas the significant association between OSA and gout was attenuated to null after adjusting for BMI and T2D. No causal effect of OSA on SUA levels and gout was found in the reverse direction. CONCLUSIONS: Our findings suggest that OSA was causally associated with increased levels of SUA, but was not independently associated with gout risk.

The effect of breathing exercise on daytime sleepiness and fatigue among patients with obstructive sleep apnea syndrome.

This study was conducted with randomized controlled and experimental design to examine the effect of breathing exercise on daytime sleepiness and fatigue on patients with obstructive sleep apnea syndrome. The first application was performed by teaching patients in the intervention group breathing exercises including diaphragmatic and pursed lip breathing via the face-to-face interview technique. Then, the researcher applied breathing exercises in the same patient group every morning/evening for 10-15 min and a total of 20-30 min for eight weeks via the online interview method. The data were collected via a questionnaire, Epworth sleepiness scale (ESS), and Piper Fatigue Scale (PFS). Chi-square, Student's t, Mann Whitney U, paired sample t-test, analysis of variance (ANOVA) and generalized estimating equations were used to assess the data. It was determined that PFS total mean score of the intervention group which was 6.15 ± 1.65 before the application decreased to 5.34 ± 1.94 in the eighth week (p> 0.05) and PFS total mean score of the control group which was 5.59 ± 1.76 before the application increased to 5.77 ± 1.81 in the eighth week (p> 0.05). ESS total mean score of the intervention group which was 12.13 ± 4.34 at the baseline decreased to 9.13 ± 4.71 in the eighth week (p> 0.05) and ESS total mean score of the control group which was 10.37 ± 2.77 at the baseline increased to 10.5 ± 2.85 in the eighth week (p> 0.05). It was concluded that breathing exercise performed in the intervention group decreased the fatigue and daytime sleepiness mean scores of the patients at the end of the fourth and eighth week. In addition, the group-time interaction was significant, which was associated with the intervention group.

Impact of common diseases and habits on daytime sleepiness in adults.

We aimed to investigate the impact of common diseases and habits on daytime sleepiness in adults. We retrospectively collected the clinical and overnight polysomnographic data of 2829 adults. The impact of common diseases and habits on the Epworth Sleepiness Scale (ESS) score was analyzed by univariate and multivariate linear regression analyses. The mean ESS score was 6.2 (standard deviation = 4.3; range = 0-24) for all adults. Multivariate linear regression analysis showed that dyslipidemia, acute myocardial infarction (AMI), liver cirrhosis, alcohol drinking, and tea consumption had a significantly positive association with ESS score for all adults after adjusting for age, sex, body mass index, apnea-hypopnea index, sleep efficiency, percentage of sleep N3 stage, and depression. Subgroup analysis by sex showed that AMI, liver cirrhosis, alcohol drinking, and tea consumption had significantly positive association with ESS scores in males, whereas only dyslipidemia had significantly positive association with ESS scores in females. Subgroup analysis by age showed that alcohol drinking had a significantly positive association with ESS scores in young adults. AMI had a significantly positive association with ESS scores, but chronic kidney disease had a significantly negative association with ESS scores in middle-aged adults. Furthermore, dyslipidemia, chronic kidney disease, and cancers had a significantly positive association with ESS scores in older adults. Dyslipidemia, AMI, liver cirrhosis, alcohol drinking, and tea consumption had a significantly positive association with daytime sleepiness in adults but differed by sex and age.

Effect of different treatments for obstructive sleep apnoea on blood pressure.

OBJECTIVE: Obstructive sleep apnoea (OSA) is a common cause of secondary hypertension. This network meta-analysis (NMA) assessed the effect of different OSA treatments on lowering blood pressure. METHODS: PubMed, EMBASE, Web of Science, and Cochrane Library databases were searched for relevant randomized controlled trials. The search strategies included the concepts of OSA, blood pressure, hypertension, and blood pressure-reducing treatments without language or data restriction (from inception to 1 June 2021). The outcomes included office SBP, office DBP, daytime SBP (dSBP) and DBP (dDBP), and night-time SBP (nSBP) and DBP (nDBP). A Bayesian network meta-analysis was performed, and mean differences with 95% credibility intervals were calculated. RESULTS: We reviewed 49 randomized controlled trials involving 4893 patients and the following interventions: continuous positive-airway pressure (CPAP), mandibular advancement devices, nocturnal supplemental oxygen, surgery, ß-blocker, angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs), renal sympathetic denervation (RDN), mineralocorticoid receptor antagonists (MRAs), calcium channel blockers. MRAs were significantly associated with blood pressure reduction followed by ACEI/ARB. RDN could reduce office SBP, office DBP, 24-h SBP, 24-h DBP, dSBP, and dDBP. CPAP also demonstrated modest blood pressure lowering. CONCLUSION: MRAs and ACEIs/ARBs can reduce blood pressure effectively in patients with OSA. RDN is a novel hypertension treatment that lowered blood pressure in such patients. CPAP was associated with mild but stable blood pressure reduction, and it might be helpful as an adjunctive therapy in OSA patients with hypertension. REVIEW REGISTRATION: This systematic review and meta-analysis was registered in PROSPERO: CRD42021240891.

Factors affecting obstructive sleep apnea patients' use of upper airway stimulation treatment.

STUDY OBJECTIVES: Upper airway stimulation (UAS) is an alternative treatment for obstructive sleep apnea that must be activated nightly. Although the implanted device offsets the mask- or pressure-related side effects often associated with continuous positive airway pressure therapy, some UAS recipients do not use the therapy consistently. This study qualitatively explored factors associated with UAS usage in obstructive sleep apnea patients. METHODS: Semistructured interviews were conducted with 24 obstructive sleep apnea patients who received UAS treatment. Twelve patients were categorized as high users with mean usage of ≥ 4 hours/night and 12 were categorized as low users with < 4 hours/night or nonuse. Interviews explored patients' experiences regarding barriers and facilitators to UAS use and their advice for new UAS recipients. Demographic and clinical data including the Insomnia Severity Index and Generalized Anxiety Disorder Scale were collected. RESULTS: Compared to high users, low users had higher levels of insomnia (mean Insomnia Severity Index: 3.6 vs 15.2, respectively) and anxiety (mean Generalized Anxiety Disorder Scale: 3.4 vs 6.9). High users reported more positive experiences with UAS treatment, such as improvements in symptoms and convenience of treatment, as facilitators of use. Low users tended to focus on the negative aspects of treatment, particularly stimulation-related discomfort and associated sleep disturbance. CONCLUSIONS: Insomnia with or without anxiety contributes to differing patient-reported experiences in high vs low user groups, with increased insomnia symptoms among low users. Improved understanding of the specific barrier and facilitators of UAS adherence may drive better long-term use and more personalized management strategies, including concomitant insomnia treatment. CLINICAL TRIALS REGISTRATION: Registry: ClinicalTrials.gov; Name: Stimulation Therapy for Apnea: Reporting Thoughts (START); URL: https://clinicaltrials.gov/ct2/show/NCT04768543; Identifier: NCT04768543. CITATION: Luyster FS, Ni Q, Lee K, et al. Factors affecting obstructive sleep apnea patients' use of upper airway stimulation treatment. J Clin Sleep Med. 2022;18(9):2207-2215.

Banxia-Houpu decoction diminishes iron toxicity damage in heart induced by chronic intermittent hypoxia.

CONTEXT: Obstructive sleep apnoea (OSA) causes chronic intermittent hypoxia (CIH), which results in mitochondrial dysfunction and generates reactive oxygen species (ROS) in the heart. Excessive free iron could accelerate oxidative damage, which may be involved in this process. Banxia-Houpu decoction (BHD) was reported to improve the apnoea hypopnoea index in OSA patients, but the specific mechanism was still unclear. OBJECTIVE: To investigate whether BHD could reduce CIH-induced heart damage by regulating iron metabolism and mitochondrial function. MATERIALS AND METHODS: C57BL/6N mice were randomly divided into control, CIH and BHD groups. Mice were exposed to CIH (21 - 5% O2, 20 times/h, 8 h/d) and administered BHD (3.51, 7.01 and 14.02 g/kg, intragastrically) for 21 d. Cardiac and mitochondrial function, iron levels, apoptosis and mitophagy were determined. RESULTS: BHD (7.01 g/kg) significantly improved cardiac dysfunction, pathological change and mitochondrial structure induced by CIH. BHD increased the Bcl-2/Bax ratio (1.4-fold) and inhibited caspase 3 cleavage in CIH mice (0.45-fold). BHD activated mitophagy by upregulating Parkin (1.94-fold) and PINK1 (1.26-fold), inhibiting the PI3K-AKT-mTOR pathway. BHD suppressed ROS generation by decreasing NOX2 (0.59-fold) and 4-HNE (0.83-fold). BHD reduced the total iron in myocardial cells (0.72-fold) and mitochondrial iron by downregulating Mfrn2 (0.81-fold) and MtFt (0.78-fold) proteins, and upregulating ABCB8 protein (1.33-fold). Rosmarinic acid, the main component of Perilla Leaf in BHD, was able to react with Fe2+ and Fe3+ in vitro. DISCUSSION AND CONCLUSIONS: These findings encourage the use of BHD to resist cardiovascular injury and provide the theoretical basis for clinical treatment in OSA patients.

Association between anxiety, depression, and emotional distress and hypoglossal nerve stimulator adherence.

PURPOSE: To evaluate relationships between hypoglossal nerve stimulator (HNS) adherence and the presence of anxiety, depression, and emotional distress. METHODS: This is a cross-sectional study of subjects with moderate to severe obstructive sleep apnea (OSA), who had HNS implanted and activated at The Ohio State University Medical Center (OSUMC). Patient usage data from the previous 6 months was obtained from 33 patients. Adherence was defined as ≥28 h of use per week. Generalized Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9) were administered, and the Patient Health Questionnaire Anxiety and Depression Scale (PHQ-ADS) score was calculated for all subjects. RESULTS: Sixty-five percent were adherent with average usage of 46.5±11.7 h per week vs 7.7±7.5 h per week in the non-adherent group. The average GAD-7 were 3.90±3.98 in the adherent group vs. 8.27±6.69 in the non-adherent group (p=0.049). PHQ-9 score was 6.15±4.31 vs. 10.09±7.53 (p=0.118), and PHQ-ADS was 10.05±7.49 vs. 19.20±9.80 (p=0.035). There were no statistically significant differences in age, gender, pre-treatment AHI, and post-treatment AHI between the two groups, though there was a trend to higher age in the adherent group. CONCLUSIONS: This study demonstrated higher GAD-7 and PHQ-ADS scores in the non-adherent group compared to those who were adherent to HNS supporting that anxiety and emotional distress may contribute to HNS therapy adherence. To our knowledge, this is the first study evaluating the relationship between anxiety, depression, emotional distress, and HNS adherence. Screening patients with the GAD-7 and PHQ-9 prior to implantation may be helpful when evaluating patient adherence to therapy.

Pitolisant, a wake-promoting agent devoid of psychostimulant properties: Preclinical comparison with amphetamine, modafinil, and solriamfetol.

Several therapeutic options are currently available to treat excessive daytime sleepiness (EDS) in patients suffering from narcolepsy or obstructive sleep apnea. However, there are no comparisons between the various wake-promoting agents in terms of mechanism of action, efficacy, or safety. The goal of this study was to compare amphetamine, modafinil, solriamfetol, and pitolisant at their known primary pharmacological targets, histamine H3 receptors (H3R), dopamine, norepinephrine, and serotonin transporters, and in various in vivo preclinical models in relation to neurochemistry, locomotion, behavioral sensitization, and food intake. Results confirmed that the primary pharmacological effect of amphetamine, modafinil, and solriamfetol was to increase central dopamine neurotransmission, in part by inhibiting its transporter. Furthermore, solriamfetol increased levels of extracellular dopamine in the nucleus accumbens, and decreased the 3,4-dihydroxyphenyl acetic acid (DOPAC)/DA ratio in the striatum, as reported for modafinil and amphetamine. All these compounds produced hyperlocomotion, behavioral sensitization, and hypophagia, which are common features of psychostimulants and of compounds with abuse potential. In contrast, pitolisant, a selective and potent H3R antagonist/inverse agonist that promotes wakefulness, had no effect on striatal dopamine, locomotion, or food intake. In addition, pitolisant, devoid of behavioral sensitization by itself, attenuated the hyperlocomotion induced by either modafinil or solriamfetol. Therefore, pitolisant presents biochemical, neurochemical, and behavioral profiles different from those of amphetamine and other psychostimulants such as modafinil or solriamfetol. In conclusion, pitolisant is a differentiated therapeutic option, when compared with psychostimulants, for the treatment of EDS, as this agent does not show any amphetamine-like properties within in vivo preclinical models.

Study on the Improvement of Behavioral and Cognitive Dysfunction of Children with OSAHS by Vitamin D.

OBJECTIVE: This study is aimed at exploring the role of vitamin D in the treatment of children with OSAHS by comparing the clinical symptoms, serum indicators, and behavioral changes of vitamin D intervention. METHOD: Healthy children who were examined physically in Rizhao People's Hospital were selected as the control group, and their sex, age, triglyceride, total cholesterol, high-density lipoprotein, low-density lipoprotein, serum 25-OHD levels, and Conners' parental scale were measured. In addition, children diagnosed as OSAHS in the otolaryngology department of Rizhao People's Hospital were selected as experimental subjects. Their body mass index, triglycerides, total cholesterol, high-density lipoprotein, low-density lipoprotein, serum 25-OHD levels, sleep apnea hypopnea index, minimum oxygen saturation, and Conners' parental scale were measured. The experimental subjects were treated with Rocaltrol intervention therapy (0.25 g/QD) for 4 weeks and reanalyzing their triglycerides, total cholesterol, high-density lipoprotein, low-density lipoprotein, serum 25-OHD levels, sleep apnea hypopnea index, minimum oxygen saturation, and Conners' parental scale. RESULT: OSAHS children commonly have the situation of obesity, dyslipidemia, and vitamin D deficiency. Behavioral and cognitive dysfunction is common in OSAHS children. There were no significant changes in body mass index, triglycerides, total cholesterol, high-density lipoprotein, low-density lipoprotein, sleep apnea, hypopnea index, and minimum oxygen saturation for OSAHS children after vitamin D treatment, but the serum 25-OHD level is significantly improved, and children with conduct problems, learning problems, and hyperactivity index decrease. CONCLUSION: (1) OSAHS children commonly have the situation of obesity, dyslipidemia, vitamin D deficiency, and behavioral and cognitive impairment. (2) Vitamin D supplementation has no therapeutic effect on obesity and dyslipidemia of OSAHS children, but has obvious protective and improving effects on neuron damage caused by hypoxia. Obstructive sleep apnea syndrome (OSAHS) is a common disease. Patients with OSAHS usually have many clinical features, such as obesity, metabolic syndrome, and cardiovascular disease. The decline of cognitive function and learning ability is one of the serious complications of OSAHS patients [1]. Vitamin D (VitD) deficiency is associated with many diseases. Recent studies have shown that the serum 25-OHD level of OSAHS patients is relatively insufficient and related to the disease severity. However, there are few reports on explaining whether vitamin D supplementation can alleviate the clinical symptoms and improve serum indicators and behavioral and cognitive dysfunction in children with OSAHS.

Drug-Induced Sleep Endoscopy and Hypoglossal Nerve Stimulation Outcomes: A Multicenter Cohort Study.

OBJECTIVES/HYPOTHESIS: To determine the association between findings of blinded reviews of preoperative drug-induced sleep endoscopy (DISE) and outcomes of hypoglossal nerve stimulation (HNS) for obstructive sleep apnea (OSA). STUDY DESIGN: Cohort study. METHODS: A retrospective, multicenter cohort study of 343 adults who underwent treatment of OSA with HNS from 10 academic medical centers was performed. Preoperative DISE videos were scored by four blinded reviewers using the VOTE Classification and evaluation of a possible primary structure contributing to airway obstruction. Consensus DISE findings were examined for an association with surgical outcomes based on therapy titration polysomnogram (tPSG). Treatment response was defined by a decrease of ≥50% in the apnea-hypopnea index (AHI) to <15 events/hour. RESULTS: Study participants (76% male, 60.4 ± 11.0 years old) had a body mass index of 29.2 ± 3.6 kg/m2 . AHI decreased (35.6 ± 15.2 to 11.0 ± 14.1 events/hour; P < .001) on the tPSG, with a 72.6% response rate. Complete palate obstruction (vs. none) was associated with the greatest difference in AHI improvement (-26.8 ± 14.9 vs. -19.2 ± 12.8, P = .02). Complete (vs. partial/none) tongue-related obstruction was associated with increased odds of treatment response (78% vs. 68%, P = .043). Complete (vs. partial/none) oropharyngeal lateral wall-related obstruction was associated with lower odds of surgical response (58% vs. 74%, P = .042). CONCLUSIONS: The DISE finding of primary tongue contribution to airway obstruction was associated with better outcomes, whereas the opposite was true for the oropharyngeal lateral walls. This study suggests that the role for DISE in counseling candidates for HNS extends beyond solely for excluding complete concentric collapse related to the velum. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:1676-1682, 2021.