Effects of vitamin family members on insulin resistance and diabetes complications.

The following letter to the editor highlights the article "Effects of vitamin D supplementation on glucose and lipid metabolism in patients with type 2 diabetes mellitus and risk factors for insulin resistance" in World J Diabetes 2023 Oct 15; 14 (10): 1514-1523. It is necessary to explore the role of vitamin family members in insulin resistance and diabetes complications.

Enhancing Iodine Capture of Porous Organic Cages through N-Heteroatom Engineering.

Iodine radioisotopes, produced or released during nuclear-related activities, severely affect human health and the environment. The efficient removal of radioiodine from both aqueous and vapor phases is crucial for the sustainable development of nuclear energy. In this study, we propose an "N-heteroatom engineering" strategy to design three porous organic cages with N-containing functional groups for efficient iodine capture. Among the molecular cages investigated, FT-Cage incorporating tertiary amine groups and RT-Cage with secondary amine groups show higher adsorption capacity and much faster iodine release compared to IT-Cage with imine groups. Detailed investigations demonstrate the superiority of amine groups, along with the influence of crystal structures and porosity, for iodine capture. These findings provide valuable insights for the design of porous organic cages with enhanced capabilities for capturing iodine.

Modification of Endotypic Traits in OSA by the Carbonic Anhydrase Inhibitor Sulthiame.

BACKGROUND: The carbonic anhydrase inhibitor sulthiame reduces OSA severity, increases overnight oxygenation, and improves sleep quality. Insights into how sulthiame modulates OSA pathophysiologic features (endotypic traits) adds to our understanding of the breathing disorder itself, as well as the effects of carbonic anhydrases in respiratory regulation. RESEARCH QUESTION: How does sulthiame treatment modify endotypic traits in OSA? STUDY DESIGN AND METHODS: Per-protocol tertiary analysis of a randomized controlled trial with the inclusion criteria as follow: BMI, ≥ 20 to ≤ 35 kg/m2; age, 18-75 years; apnea-hypopnea index (AHI) ≥ 15 events/h; Epworth sleepiness scale score, ≥ 6; as well as nonacceptance or nontolerance of positive airway pressure treatment. Patients were randomized to receive placebo (n = 22), sulthiame 200 mg (n = 12), or sulthiame 400 mg (n = 24) during 4 weeks of treatment. Polysomnography was applied twice at baseline and follow-up. Endotypic traits were determined from polysomnography tracings (PUPBeta). Sulthiame plasma concentration was analyzed. Differences from baseline to follow-up (Δs) were analyzed with the analysis of covariance or Kruskal-Wallis H test and Pearson (r) or Spearman correlations (rs). RESULTS: Sulthiame (200-mg and 400-mg groups) consistently reduced loop gain (response to a 1-cycle/min disturbance, LG1; mean, -0.16 [95% CI, -0.18 to -0.13]; P < .05) in addition to increased ventilation at lowest decile of ventilatory drive (Vmin; median, +12 [95% CI, 4-20]; P < .05) and median ventilation at eupneic ventilatory drive (Vpassive; median, +4 [95% CI, 0-5]; P < .05). ΔLG1 correlated with ΔAHI percentage (200 mg: r = 0.65; P < .05). Vmin and Vpassive correlated with ΔAHI (all sulthiame: rs = -0.59 and rs = -0.65; P < .05 for all). The reduction of LG1 was seen already in the lower sulthiame concentration range, whereas changes in Vmin peaked in the higher range. INTERPRETATION: The effect of sulthiame in OSA may be explained by a reduction of ventilatory instability (LG1) as well as upper airway collapsibility (Vmin and Vpassive). TRIAL REGISTRY: European Union Drug Regulating Authorities Clinical Trials Database; No.: EudraCT 2017-004767-13; URL: https://www.clinicaltrialsregister.eu.

Eveningness is associated with coronary artery calcification in a middle-aged Swedish population.

Coronary artery calcification (CAC) is an established imaging biomarker of subclinical atherosclerosis, but its relationship to diurnal preference is not well studied. We investigated the association between chronotype and CAC in the Swedish CArdioPulmonary bioImage Study (SCAPIS) pilot cohort. Participants aged 50-64 years were randomly recruited and underwent extensive examination including imaging and accelerometry-assessed physical activity. 771 participants (47.3 % male, 57.6 ± 4.4 years) were included in this cross-sectional analysis. CAC was assessed by non-contrast computed tomography, and a CAC score > 10 was considered significant calcification. Self-assessed chronotype was classified as extreme morning, moderate morning, intermediate, moderate evening, or extreme evening. 10-year risk of first-onset cardiovascular disease was estimated by the Systemic Coronary Risk Evaluation 2 (SCORE2). Significant CAC was present in 29 % of the cohort. CAC prevalence increased from extreme morning to extreme evening type (22 %, 28 %, 29 %, 27 %, 41 % respectively, p = 0.018). In a multivariate logistic regression model controlling for confounders, extreme evening chronotype was independently associated with increased CAC prevalence compared to extreme morning type (OR 1.90, [95%CI 1.04-3.46], p = 0.037). When stratified by SCORE2 risk category (low: <5 %; moderate: 5 to <10 %; high: ≥10 %), significant CAC was most prevalent among extreme evening chronotypes in the low and moderate-risk groups, while chronotype seemed less important in the high-risk group (p = 0.011, p = 0.023, p = 0.86, respectively). Our findings suggest circadian factors may play an important role in atherosclerosis and should be considered in early cardiovascular prevention.

Blood pressure control in hypertensive sleep apnoea patients of the European Sleep Apnea Database cohort - effects of positive airway pressure and antihypertensive medication.

Aims: We analysed longitudinal blood pressure (BP) data from hypertensive obstructive sleep apnoea (OSA) patients in the European Sleep Apnea Database cohort. The study investigated the interaction between positive airway pressure (PAP)-induced BP change and antihypertensive treatment (AHT). Methods and results: Hypertensive patients with AHT [monotherapy/dual therapy n = 1283/652, mean age 59.6 ± 10.7/60.6 ± 10.3 years, body mass index (BMI) 34.2 ± 6.5/34.8 ± 7.0 kg/m2, apnoea-hypopnoea index 46 ± 25/46 ± 24 n/h, proportion female 29/26%, respectively] started PAP treatment. Office BP at baseline and 2- to 36-month follow-up were assessed. The interaction between AHT drug classes and PAP on BP was quantified and the influences of age, gender, BMI, co-morbidities, BP at baseline, and study site were evaluated. Following PAP treatment (daily usage, 5.6 ± 1.6/5.7 ± 1.9 h/day), systolic BP was reduced by -3.9 ± 15.5/-2.8 ± 17.7 mmHg in mono/dual AHT and diastolic BP by -3.0 ± 9.8/-2.7 ± 10.8 mmHg, respectively, all P < 0.0001. Systolic and diastolic BP control was improved following PAP treatment (38/35% to 54/46% and 67/67% to 79/74%, mono/dual AHT, respectively). PAP treatment duration predicted a larger BP improvement in the monotherapy group. Intake of renin-angiotensin blockers [angiotensin converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB)] alone or in any AHT combination was associated with better BP control. The AHT-dependent BP improvement was independent of confounders. Conclusion: In this pan-European OSA patient cohort, BP control improved following initiation of PAP. Longer PAP treatment duration, was associated with a favourable effect on BP. Our study suggests that ACEI/ARB, alone or in combination with other drug classes, provides a particularly strong reduction of BP and better BP control when combined with PAP in OSA.

Perspective: Systematic review and meta-analysis in obstructive sleep apnea - What is lacking?

Obstructive sleep apnea (OSA) affects nearly one billion of the global adult population. It is associated with substantial burden in terms of quality of life, cognitive function, and cardiovascular health. Positive airway pressure (PAP) therapy, commonly considered the first-line treatment, is limited by low compliance and lacking efficacy on long-term cardiovascular outcomes. A substantial body of research has been produced investigating (novel) non-PAP treatments. With increased understanding of OSA pathogenesis, promising therapeutic approaches are emerging. There is an imperative need of high-quality synthesis of evidence; however, current systematic reviews and meta-analyses (SR/MA) on the topic demonstrate important methodological limitations and are seldom based on research questions that fully reflect the complex intricacies of OSA management. Here, we discuss the current challenges in management of OSA, the need of treatable traits based OSA treatment, the methodological limitations of existing SR/MA in the field, potential remedies, as well as future perspectives.

Beneficial Effects of Early Intervention Telemedicine-based Follow-Up in Sleep Apnea: A Randomized Controlled Multicenter Trial.

Rationale: Positive airway pressure (PAP) is standard treatment for obstructive sleep apnea. Telemedicine has been introduced for improved PAP follow-up. Objectives: Our study aim was to evaluate the clinical utility of and patient satisfaction with PAP follow-up with an early intervention telemedical protocol. Methods: A randomized controlled trial was conducted at four sleep clinics of the same county. Treatment-naive patients with obstructive sleep apnea were randomized to standard PAP follow-up (203 patients, fixed follow-up procedures) or early intervention telemedical follow-up (AirView, ResMed; 206 patients, continuous follow-up) for 3 months. Evaluated variables included PAP adherence at 3 months, patient-reported outcome measures (Epworth Sleepiness Scale, 36-item Short Form Health Survey, Insomnia Severity Index, Hospital Anxiety and Depression Scale), and staff time. Group differences were analyzed with linear mixed regression models adjusted for age, body mass index, apnea-hypopnea index, and study center. Results: The study groups were comparable at baseline (N = 409; mean age, 59 ± 12 yr; body mass index, 31.9 ± 6 kg/m2, apnea-hypopnea index, 41.5 ± 21 events/h). PAP adherence was higher in the proactive telemedicine group than in the control group (4.3 ± 2.4 and 4.1 ± 2.6 h/night; P = 0.01, respectively), and mean mask pressure at follow-up was significantly lower in the telemedicine group than in the control group (8.7 ± 2.1 cm H2O vs. 9.2 ± 2.5 cm H2O; P = 0.028). In post hoc analysis, the difference in PAP adherence between groups was most pronounced in patients with depression (4.8 ± 2.6 h/night vs. 2.7 ± 2.3 h/night; P = 0.03). Relevant mask leakage (>24 L/min) was lower in the telemedicine group (5.4% vs. 12.1%, P = 0.024). Improvement of patient-reported outcome measures and patient satisfaction was equivalent between groups. Conclusions: Proactive telemedical management of the initial follow-up of PAP treatment compared favorably with conventional follow-up in terms of adherence, pressure level, and mask leakage. Patients with depression may particularly benefit from telemedical follow-up. Specific clinical routines are required to establish this practice in sleep clinics. Clinical trial registered with www.clinicaltrials.gov (NCT03446560).

Clinical impact of routine sleep assessment by peripheral arterial tonometry in patients with COPD.

Background: Coexisting obstructive sleep apnoea (OSA) in patients with COPD, defined as overlap syndrome (OVS), is prevalent and underdiagnosed. Routine assessment of OSA is not common practice in COPD care. Our study assessed the clinical impact of sleep assessment by peripheral arterial tonometry (PAT) in COPD patients. Methods: 105 COPD patients (mean age 68.1±9 years, body mass index (BMI) 28.3±6.0 kg·m-2, 44% males, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages I to IV in 2%, 40%, 42% and 16%, respectively) underwent assessment at an outpatient COPD clinic including anthropometrics, arterial blood gas (ABG) and spirometry in this clinical cohort study. PAT-based sleep studies were performed. Predictors of OVS and ABG were determined. Rapid eye movement (REM) sleep-related OSA (REM-OSA) was analysed in OVS. Results: 49 COPD patients (47%) suffered from moderate to severe OSA (OVS group, mean apnoea-hypopnoea index 30.8±18 events·h-1, REM-oxygen desaturation index (REM-ODI) 26.9±17 events·h-1). OVS was more prevalent in males compared to females (59% and 37%, p=0.029, respectively). Age (70.1±8 versus 66.3±10 years), BMI (30.0±6 versus 26.4±7 kg·m-2) and hypertension prevalence (71% versus 45%) were elevated (all p<0.03, respectively), while deep sleep (12.7±7% and 15.4±6%, p=0.029) and mean overnight oxygenation (90.6±3% and 92.3±2%, p=0.003) were lower in OVS compared to COPD alone. REM-ODI was independently associated with daytime arterial carbon dioxide tension (P aCO2 ) (ß=0.022, p<0.001). REM-OSA was associated with an elevated prevalence of atrial fibrillation compared to no REM-OSA (25% and 3%, p=0.022). Conclusions: OVS was highly prevalent, specifically in obese males. REM-related OSA showed strong association with elevated daytime P aCO2 and prevalent cardiovascular disease. PAT was feasible for sleep assessment in COPD.

The placebo effect in pharmacological treatment of obstructive sleep apnea, a systematic review and meta-analysis.

OBJECTIVE: New drug treatments are under development in obstructive sleep apnea (OSA). The placebo effect is well recognized in various conditions, but its relevance in OSA is debated. In the current study we determined the influence of a placebo effect in studies of drug therapy in OSA. METHODS: A systematic review and meta-analysis (PROSPERO CRD42021229410) with searches in MEDLINE, Scopus, Web of Science and Cochrane CENTRAL from inception to 2021-01-19. Inclusion criteria were (i) RCTs of adults with OSA, (ii) drug intervention with placebo baseline and follow-up sleep study (iii) outcomes: apnea hypopnea index (AHI), mean oxygen saturation (mSaO2), oxygen desaturation index (ODI) and/or Epworth Sleepiness Scale (ESS). Risk-of-bias was assessed with Cochrane RoB 2. RESULTS: 7436 articles were identified and 29 studies included (n = 413). Studies were generally small (median n = 14), with 78% men, baseline AHI range 9-74 events/h and treatment duration range 1-120 days. Meta-analyses were conducted for main outcomes. Mean change of the primary outcome, AHI, was -0.84 (95% CI -2.98 to 1.30); mSaO2 and ODI estimations were also non-significant. ESS showed a trend towards a reduction of -1 unit. Subgroup analysis did not show significant differences. Risk-of-bias assessment indicated mostly low risk but studies were small with wide confidence intervals. CONCLUSIONS: In this meta-analysis we did not identify systematic placebo effects on the AHI, ODI or mSaO2 while ESS score showed a trend for a small reduction. These results have an impact on the design and interpretation of drug trials in OSA.

Molecular Cage with Dual Outputs of Photochromism and Luminescence Both in Solution and the Solid State.

The rational design of stimuli-responsive materials requires a deep understanding of the structure-activity relationship. Herein, we proposed an intramolecular conformation-locking strategy─incorporating flexible tetraphenylethylene (TPE) luminogens into the rigid scaffold of a molecular cage─to produce a molecular photoswitch with dual outputs of luminescence and photochromism in solution and in the solid states at once. The molecular cage scaffold, which restricts the intramolecular rotations of the TPE moiety, not only helps to preserve the luminescence of TPE in a dilute solution but facilitates the reversible photochromism on account of the intramolecular cyclization/cycloreversion reactions. Furthermore, we demonstrate assorted applications of this multiresponsive molecular cage, e.g., photo-switchable patterning, anticounterfeiting, and selective vapochromism sensing.

Night-to-Night Variability of Polysomnography-Derived Physiologic Endotypic Traits in Patients With Moderate to Severe OSA.

BACKGROUND: Emerging data suggest that determination of physiologic endotypic traits (eg, loop gain) may enable precision medicine in OSA. RESEARCH QUESTION: Does a single-night assessment of polysomnography-derived endotypic traits provide reliable estimates in moderate to severe OSA? STUDY DESIGN AND METHODS: Two consecutive in-lab polysomnography tests from a clinical trial (n = 67; male, 69%; mean ± SD age, 61 ± 10 years; apnea-hypopnea index [AHI] 53 ± 22 events/h) were used for the reliability analysis. Endotypic traits, reflecting upper airway collapsibility (ventilation at eupneic drive [Vpassive]), upper airway dilator muscle tone (ventilation at the arousal threshold [Vactive]), loop gain (stability of ventilatory control, LG1), and arousal threshold (ArTh) were determined. Reliability was expressed as an intraclass correlation coefficient (ICC). Minimal detectable differences (MDDs) were computed to provide an estimate of maximum spontaneous variability. Further assessment across four repeated polysomnography tests was performed in a subcohort (n = 22). RESULTS: Reliability of endotypic traits between the two consecutive nights was moderate to good (ICC: Vpassive = 0.82, Vactive = 0.76, LG1 = 0.72, ArTh = 0.83). Variability in AHI, but not in body position or in sleep stages, was associated with fluctuations in Vpassive and Vactive (r = -0.49 and r = -0.41, respectively; P < .001 for both). MDDs for single-night assessments were: Vpassive = 22, Vactive = 34, LG1 = 0.17, and ArTh = 21. Multiple assessments (mean of two nights, n = 22) further reduced MDDs by approximately 20% to 30%. INTERPRETATION: Endotypic trait analysis using a single standard polysomnography shows acceptable reliability and reproducibility in patients with moderate to severe OSA. The reported MDDs of endotypic traits may facilitate the quantification of relevant changes and may guide future evaluation of interventions in OSA.

Arterial bicarbonate is associated with hypoxic burden and uncontrolled hypertension in obstructive sleep apnea - The ESADA cohort.

OBJECTIVE: Blood bicarbonate concentration plays an important role for obstructive sleep apnea (OSA) patients to maintain acid-base balance. We investigated the association between arterial standard bicarbonate ([HCO3-]) and nocturnal hypoxia as well as comorbid hypertension in OSA. METHODS: A cross-sectional analysis of 3329 patients in the European Sleep Apnea Database (ESADA) was performed. Arterial blood gas analysis and lung function test were performed in conjunction with polysomnographic sleep studies. The 4% oxygen desaturation index (ODI), mean and minimum oxygen saturation (SpO2), and percentage of time with SpO2 below 90% (T90%) were used to reflect nocturnal hypoxic burden. Arterial hypertension was defined as a physician diagnosis of hypertension with ongoing antihypertensive medication. Hypertensive patients with SBP/DBP below or above 140/90 mmHg were classified as controlled-, uncontrolled hypertension, respectively. RESULTS: The [HCO3-] level was normal in most patients (average 24.0 ± 2.5 mmol/L). ODI, T90% increased whereas mean and minimum SpO2 decreased across [HCO3-] tertiles (ANOVA, p = 0.030, <0.001, <0.001, and <0.001, respectively). [HCO3-] was independently associated with ODI, mean SpO2, minimum SpO2, and T90% after adjusting for confounders (ß value [95%CI]: 1.21 [0.88-1.54], -0.16 [-0.20 to -0.11], -0.51 [-0.64 to -0.37], 1.76 [1.48-2.04], respectively, all p < 0.001). 1 mmol/L elevation of [HCO3-] was associated with a 4% increased odds of uncontrolled hypertension (OR: 1.04 [1.01-1.08], p = 0.013). CONCLUSION: We first demonstrated an independent association between [HCO3-] and nocturnal hypoxic burden as well as uncontrolled hypertension in OSA patients. Bicarbonate levels as an adjunctive measure provide insight into the pathophysiology of hypertension in OSA.

Hypertension treatment in patients with sleep apnea from the European Sleep Apnea Database (ESADA) cohort - towards precision medicine.

We recruited 5,970 hypertensive patients with obstructive sleep apnea (OSA) on current antihypertensive treatment from the European Sleep Apnea Database (ESADA) cohort. The group was subdivided into those receiving monotherapy (n = 3,594) and those receiving dual combined therapy (n = 2,376). We studied how major OSA confounders like age, gender, and body mass index as well as the degree of sleep apnea modified office systolic and diastolic blood pressure. Beta-blockers alone or in combination with a diuretic were compared with other antihypertensive drug classes. Monotherapy with beta-blocker was associated with lower systolic blood pressure, particularly in non-obese middle-aged males with hypertension. Conversely, the combination of a beta-blocker and a diuretic was associated with lower systolic and diastolic blood pressure in hypertensive patients with moderate-severe OSA. Systolic blood pressure was better controlled in female patients using this combined treatment. Our cross-sectional data suggest that specific clinical characteristics and type of antihypertensive medication influence the degree of blood pressure control in hypertensive OSA patients. Controlled trials are warranted.

Baseline clusters and the response to positive airway pressure treatment in obstructive sleep apnoea patients: longitudinal data from the European Sleep Apnea Database cohort.

Introduction: The European Sleep Apnea Database was used to identify distinguishable obstructive sleep apnoea (OSA) phenotypes and to investigate the clinical outcome during positive airway pressure (PAP) treatment. Method: Prospective OSA patient data were recruited from 35 sleep clinics in 21 European countries. Unsupervised cluster analysis (anthropometrics, clinical variables) was performed in a random sample (n=5000). Subsequently, all patients were assigned to the clusters using a conditional inference tree classifier. Responses to PAP treatment change in apnoea severity and Epworth sleepiness scale (ESS) were assessed in relation to baseline patient clusters and at short- and long-term follow-up. Results: At baseline, 20 164 patients were assigned (mean age 54.1±12.2 years, 73% male, median apnoea-hypopnoea index (AHI) 27.3 (interquartile range (IQR) 14.1-49.3) events·h-1, and ESS 9.8±5.3) to seven distinct clusters based on anthropometrics, comorbidities and symptoms. At PAP follow-up (median 210 [IQR 134-465] days), the observed AHI reduction (n=1075) was similar, whereas the ESS response (n=3938) varied: largest reduction in cluster 3 (young healthy symptomatic males) and 6 (symptomatic males with psychiatric disorders, -5.0 and -5.1 units, respectively (all p<0.01), limited reduction in clusters 2 (obese males with systemic hypertension) and 5 (elderly multimorbid obese males, -4.2 (p<0.05) and -3.7 (p<0.001), respectively). Residual sleepiness in cluster 5 was particularly evident at long-term follow-up (p<0.05). Conclusion: OSA patients can be classified into clusters based on clinically identifiable features. Importantly, these clusters may be useful for prediction of both short- and long-term responses to PAP intervention.

Turning Over a New Leaf-Pharmacologic Therapy in Obstructive Sleep Apnea.

Despite extensive research, there is currently no approved drug for obstructive sleep apnea (OSA) treatment. OSA is a heterogeneous condition that involves multiple dominating pathophysiological traits. Drug development in this field needs to address both pathophysiological mechanisms and associated comorbid conditions in order to meet requirements for long-term therapy in OSA. Several drug candidates have been proposed and ongoing phase II trials that target various forms of sleep-disordered breathing have been initiated. The field is moving toward tailored therapeutic approaches in patients with OSA.

New pharmacologic agents for obstructive sleep apnoea: what do we know and what can we expect?

PURPOSE OF REVIEW: This review provides a condensed description of pharmacological remedies explored in patients with obstructive sleep apnoea (OSA) as well as projections of what we might expect in terms of clinical performance of these drugs. RECENT FINDINGS: Conventional drug therapies explored in OSA have generally produced disappointing results and there is a shortage of pharmacological treatment alternatives in this disorder. Recent insights into pathophysiological mechanisms potentially involved in OSA suggest that the condition may be divided into distinct subgroups based on clusters or defined by means of unique functional endotypic criteria. In fact, positive outcomes in clinical trials have now resulted in several drug candidates that show a convincing reduction of sleep disordered breathing in both short and intermediate term. Such drugs may be particularly useful in certain variants of OSA but not in others. These insights have also raised the ambition to create personalized therapies in OSA. Another recent development is the insight that OSA-linked conditions such as obesity, daytime somnolence and various forms of cardiovascular/metabolic disease may provide drug-based targets. For instance, pharmacological obesity therapy may provide not only positive metabolic effects but may also be a way to eliminate the anatomic component in obese OSA patients. SUMMARY: Recent insights into the pathophysiology of OSA have opened possibilities to develop personalized therapy. Drugs addressing fundamental aspects of the sleep and breathing disorder provide a particularly promising avenue for development of novel forms of treatment in OSA.

Eveningness is associated with sedentary behavior and increased 10-year risk of cardiovascular disease: the SCAPIS pilot cohort.

Chronotype reflects individual preferences for timing activities throughout the day, determined by the circadian system, environment and behavior. The relationship between chronotype, physical activity, and cardiovascular health has not been established. We studied the association between chronotype, physical activity patterns, and an estimated 10-year risk of first-onset cardiovascular disease (CVD) in the Swedish CArdioPulmonary bioImage Study (SCAPIS) pilot cohort. A cross-sectional analysis was performed in a middle-aged population (n = 812, 48% male). Self-assessed chronotype was classified as extreme morning, moderate morning, intermediate, moderate evening, or extreme evening. Time spent sedentary (SED) and in moderate to vigorous physical activity (MVPA) were derived from hip accelerometer. The newly introduced Systematic COronary Risk Evaluation 2 (SCORE2) model was used to estimate CVD risk based on gender, age, smoking status, systolic blood pressure, and non-HDL cholesterol. Extreme evening chronotypes exhibited the most sedentary lifestyle and least MVPA (55.3 ± 10.2 and 5.3 ± 2.9% of wear-time, respectively), with a dose-dependent relationship between chronotype and SED/MVPA (p < 0.001 and p = 0.001, respectively). In a multivariate generalized linear regression model, extreme evening chronotype was associated with increased SCORE2 risk compared to extreme morning type independent of confounders (ß = 0.45, SE = 0.21, p = 0.031). Mediation analysis indicated SED was a significant mediator of the relationship between chronotype and SCORE2. Evening chronotype is associated with unhealthier physical activity patterns and poorer cardiovascular health compared to morning chronotype. Chronotype should be considered in lifestyle counseling and primary prevention programs as a potential modifiable risk factor.

A Randomized Controlled Clinical Trial Exploring Safety and Tolerability of Sulthiame in Sleep Apnea.

Rationale: Current therapies for obstructive sleep apnea (OSA) are limited by insufficient efficacy, compliance, or tolerability. An effective pharmacological treatment for OSA is warranted. Carbonic anhydrase inhibition has been shown to ameliorate OSA. Objectives: To explore safety and tolerability of the carbonic anhydrase inhibitor sulthiame (STM) in OSA. Methods: A 4-week double-blind, randomized, placebo-controlled dose-guiding trial was conducted in patients with moderate and/or severe OSA not tolerating positive airway pressure treatment. Measurements and Main Results: Intermittent paresthesia was reported by 79%, 67%, and 18% of patients receiving 400 mg STM (n = 34), 200 mg STM (n = 12), and placebo (n = 22), respectively. Dyspnea was reported after 400 mg STM (18%). Six patients in the higher dose group withdrew because of adverse events. There were no serious adverse events. STM reduced the apnea-hypopnea index from 55.2 to 33.0 events/h (-41.0%) in the 400-mg group and from 61.1 to 40.6 events/h (-32.1%) after 200 mg (P < 0.001 for both). Corresponding placebo values were 53.9 and 50.9 events/h (-5.4%). The apnea-hypopnea index reduction threshold of ⩾50% was reached in 40% of patients after 400 mg, 25% after 200 mg, and 5% after placebo. Mean overnight oxygen saturation improved by 1.1% after 400 and 200 mg (P < 0.001 and P = 0.034, respectively). Patient-related outcomes were unchanged. Conclusions: STM showed a satisfactory safety profile in moderate and/or severe OSA. STM reduced OSA, on average, by more than 20 events/h, one of the strongest reductions reported in a drug trial in OSA. Larger scale clinical studies of STM in OSA are justified. Clinical trial registered with www.clinicaltrialsregister.eu (2017-004767-13).