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Introduction: Obstructive sleep apnoea (OSA) and type 2 diabetes mellitus (T2DM) often occur concurrently, and untreated OSA may potentially amplify the high risk of cardiovascular disease in T2DM. Compliance with continuous positive airway pressure (CPAP), the conventional treatment for OSA, can be poor and considering weight loss is the most effective treatment for OSA. This trial examines whether the glucagon-like peptide-1 receptor agonist liraglutide, a glucose-lowering therapy associated with significant weight loss used in T2DM, can improve the severity and symptoms of OSA., Methods and Analysis: This is an outpatient, single-centred, open-labelled, prospective, phase IV randomised controlled trial in a two-by-two factorial design. One hundred and thirty-two patients with newly diagnosed OSA (apnoea-hypopnoea index (AHI) ≥15 events/hour), and existing obesity and T2DM (glycated haemoglobin (HbA 1c ) ≥47 mmol/mol), will be recruited from diabetes and sleep medicine outpatient clinics in primary and secondary care settings across Liverpool. Patients will be allocated equally, using computer-generated random, permuted blocks of unequal sizes, to each of the four treatment arms for 26 weeks: (i) liraglutide (1.8 mg once per day) alone, (ii) liraglutide 1.8 mg once per day with CPAP, (iii) CPAP alone (conventional care) or (iv) no treatment (control). The primary outcome measure is change in OSA severity, determined by AHI. Secondary outcome measures include effects on glycaemic control (glycated haemoglobin (HbA1c)), body weight and quality of life measures. Exploratory measures include measures of physical activity, MRI-derived measures of regional body composition including fat mass (abdominal subcutaneous, visceral, neck and liver fat) and skeletal muscle mass (cross-sectional analysis of thigh), indices of cardiac function (using transthoracic echocardiography) and endothelial function., Ethical Approval: The study has been approved by the North West Liverpool Central Research Ethics Committee (14/NW/1019) and it is being conducted in accordance with the Declaration of Helsinki and Good Clinical Practice., Trial Registration Numbers: ISRCTN16250774. EUDRACT No. 2014-000988-41. UTN U1111-1139-0677., Competing Interests: Competing interests: DJC has competing interests with AstraZeneca, Boehringer Ingelheim, Janssen Pharmaceuticals and Lilly & Novo Nordisk. JW has acted as a consultant, received institutional grants and given lectures on behalf of pharmaceutical companies developing or marketing medicines used for the treatment of diabetes, specifically AstraZeneca, Boehringer Ingelheim, Janssen Pharmaceuticals, Lilly, Novo Nordisk and Sanofi & Takeda., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Obstructive sleep apnea (OSA) is characterized by intermittent obstruction of the airways during sleep. Cerebrovascular reactivity (CVR) is an index of cerebral vessels' ability to respond to a vasoactive stimulus, such as increased CO 2 . We hypothesized that OSA alters CVR, expressed as a breath-hold index (BHI) defined as the rate of change in CBF or BOLD signal during a controlled breath-hold stimulus mimicking spontaneous apneas by being both hypercapnic and hypoxic. In 37 OSA and 23 matched non sleep apnea (NSA) subjects, we obtained high temporal resolution CBF and BOLD MRI data before, during, and between five consecutive BH stimuli of 24 s, each averaged to yield a single BHI value. Greater BHI was observed in OSA relative to NSA as derived from whole-brain CBF (78.6 ± 29.6 vs. 60.0 ± 20.0 mL/min 2 /100 g, P  = 0.010) as well as from flow velocity in the superior sagittal sinus (0.48 ± 0.18 vs. 0.36 ± 0.10 cm/s 2 , P  = 0.014). Similarly, BOLD-based BHI was greater in OSA in whole brain (0.19 ± 0.08 vs. 0.15 ± 0.03%/s, P  = 0.009), gray matter (0.22 ± 0.09 vs. 0.17 ± 0.03%/s, P  = 0.011), and white matter (0.14 ± 0.06 vs. 0.10 ± 0.02%/s, P  = 0.010). The greater CVR is not currently understood but may represent a compensatory mechanism of the brain to maintain oxygen supply during intermittent apneas.

Study Objectives: This study evaluated differences in upper airway, soft tissues and craniofacial structures between Asians from China and Europeans from Iceland with OSA using three-dimensional magnetic resonance imaging (MRI)., Methods: Airway sizes, soft tissue volumes, and craniofacial dimensions were compared between Icelandic (N = 108) and Chinese (N = 57) patients with oxygen desaturation index (ODI) ≥ 10 events/h matched for age, gender, and ODI. Mixed effects models adjusting for height or BMI and residual differences in age and ODI were utilized., Results: In our matched sample, compared to Icelandic OSA patients, Chinese patients had smaller BMI (p < 0.0001) and neck circumference (p = 0.011). In covariate adjusted analyses, Chinese showed smaller retropalatal airway size (p ≤ 0.002), and smaller combined soft tissues, tongue, fat pads, and pterygoid (all p ≤ 0.0001), but male Chinese demonstrated a larger soft palate volume (p ≤ 0.001). For craniofacial dimensions, Chinese demonstrated bigger ANB angle (p ≤ 0.0196), differently shaped mandibles, including shorter corpus length (p < 0.0001) but longer ramus length (p < 0.0001), and a wider (p < 0.0001) and shallower (p ≤ 0.0001) maxilla., Conclusions: Compared to Icelandic patients of similar age, gender and ODI, Chinese patients had smaller retropalatal airway and combined soft tissue, but bigger soft palate volume (in males), and differently shaped mandible and maxilla with more bony restrictions. Results support an ethnic difference in upper airway anatomy related to OSA, which may inform targeted therapies., (© Sleep Research Society 2019. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Background : Evidence-based guidelines for the management of type 2 diabetes (T2D) consist of blood glucose monitoring, medication adherence, and lifestyle modifications that may particularly benefit from reminders, consultation, education, and behavioral reinforcements through remote patient monitoring (RPM). Objectives : To identify predictors of weight loss and to examine the association between weight loss and hemoglobin A1C (HbA1C) outcomes for T2D patients who were enrolled in an RPM program for diabetes management. Materials and Methods : The study applied logistic and ordinary least-squares regression models to examine the relationship between baseline characteristics and the likelihood of weight loss during the RPM, and how the magnitude of weight loss was related to changes in HbA1C outcomes for 1,103 T2D patients who went through 3 months of RPM from 2014 to 2017. Results : Older patients were 3% more likely to have weight loss (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.02-1.05), whereas patients with higher baseline HbA1C had 9% reduced odds (OR, 0.91; 95% CI, 0.85-0.97) of experiencing weight loss. For every pound of weight lost, there was a 0.02-point (95% CI, 0.01-0.03) reduction on the HbA1C measured at the end of the RPM. Moreover, compared with those who had weight loss of ≤3%, participants who had lost 5-7%, or >7% of their baseline weight had a 0.37- and 0.58-point reduction in HbA1C, respectively. Conclusions : This study revealed a notable relationship between weight loss and positive HbA1C outcomes for T2D patients in an RPM-facilitated diabetes management program, which pointed to the potential of integrating evidence-based lifestyle modification programs into future telemedicine programs to improve diabetes management outcomes.

Rationale: Obesity is the primary risk factor for obstructive sleep apnea (OSA). Tongue fat is increased in obese persons with OSA, and may explain the relationship between obesity and OSA. Weight loss improves OSA, but the mechanism is unknown. Objectives: To determine the effect of weight loss on upper airway anatomy in subjects with obesity and OSA. We hypothesized that weight loss would decrease soft tissue volumes and tongue fat, and that these changes would correlate with reductions in apnea-hypopnea index (AHI). Methods: A total of 67 individuals with obesity and OSA (AHI ≥ 10 events/h) underwent a sleep study and upper airway and abdominal magnetic resonance imaging before and after a weight loss intervention (intensive lifestyle modification or bariatric surgery). Airway sizes and soft tissue, tongue fat, and abdominal fat volumes were quantified. Associations between weight loss and changes in these structures, and relationships to AHI changes, were examined. Measurements and Main Results: Weight loss was significantly associated with reductions in tongue fat and pterygoid and total lateral wall volumes. Reductions in tongue fat were strongly correlated with reductions in AHI (Pearson's rho = 0.62, P  < 0.0001); results remained after controlling for weight loss (Pearson's rho = 0.36, P  = 0.014). Reduction in tongue fat volume was the primary upper airway mediator of the relationship between weight loss and AHI improvement. Conclusions: Weight loss reduced volumes of several upper airway soft tissues in subjects with obesity and OSA. Improved AHI with weight loss was mediated by reductions in tongue fat. New treatments that reduce tongue fat should be considered for patients with OSA.

Background: Diabetes prevention remains a top public health priority; digital approaches are potential solutions to existing scalability and accessibility challenges. There remains a gap in our understanding of the relationship between effectiveness, costs, and potential for sustained implementation of digital diabetes prevention strategies within typical healthcare settings., Purpose: To describe the methods and design of a type 1 hybrid effectiveness-implementation trial of a digital diabetes prevention program (DPP) using the iPARIHS and RE-AIM frameworks., Methods: The trial will contrast the effects of two DPP interventions: (1) small group, in-person class, and (2) a digital DPP consisting of small group support, personalized health coaching, digital tracking tools, and weekly behavior change curriculum. Each intervention includes personal action planning with a focus on key elements of the lifestyle intervention from the CDC National DPP. Adults at risk for diabetes (BMI ≥25 and 5.7% ≤ HbA1c ≤ 6.4) will be randomly assigned to either the intervention group (n = 241) or the small group (n = 241). Assessment of primary (HbA1c) and secondary (weight loss, costs, cardiovascular risk factors) outcomes will occur at baseline, 4, and 12 months. Additionally, the trial will explore the potential for future adoption, implementation, and sustainability of the digitally-based intervention within a regional healthcare system based on key informant interviews and assessments of organizational administrators and primary care physicians., Conclusion: This trial of a digital DPP will allow the research team to determine the relationships between reach, effectiveness, implementation, and costs., (Copyright © 2019. Published by Elsevier Inc.)

Aims: To examine gender differences in program completion and glycemic outcomes for patients with type 2 diabetes (T2D) in a remote patient monitoring (RPM) program for diabetes management., Methods: Based on data from an RPM program that enrolled post-discharge T2D patients (n = 1645) in 2014-2017, logistic regression models were estimated to assess gender difference in the likelihood of completing the three-month RPM program; whereas ordinary least squares (OLS) regression models were used to examine gender difference in post-RPM hemoglobin A1c (HbA1c), controlling for demographics, baseline health status, including HbA1c, patient activation scores, and physiological data upload frequency for patients who had completed the program., Results: Among enrolled participants, men had lower odds of completing the three-month RPM program than women (adjusted odds ratio, 0.61; 95% confidence interval [CI], 0.39-0.95). However, among those who completed the program, men had lower post-RPM HbA1c than women (-0.18; 95% CI, -0.33, -0.03) after controlling for baseline HbA1c and other covariates., Conclusions: While female patients with T2D were more likely to complete the RPM program, they showed a higher glycemic level at the end of the program compared to male patients. To close gender disparities in health, interventions through telemedicine tailored towards women's diabetes outcomes and men's engagement level are warranted., Competing Interests: Declaration of Competing Interest No competing financial interests exist., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Rationale: A model for stratifying progression of respiratory muscle weakness in amyotrophic lateral sclerosis (ALS) would identify disease mechanisms and phenotypes suitable for future investigations. This study sought to categorize progression of FVC after presentation to an outpatient ALS clinic. Objectives: To identify clinical phenotypes of ALS respiratory progression based on FVC trajectories over time. Methods: We derived a group-based trajectory model from a single-center cohort of 837 patients with ALS who presented between 2006 and 2015. We applied our model to the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database with 7,461 patients with ALS. Baseline characteristics at first visit were used as predictors of trajectory group membership. The primary outcome was trajectory of FVC over time in months. Measurements and Main Results: We found three trajectories of FVC over time, termed "stable low," "rapid progressor," and "slow progressor." Compared with the slow progressors, the rapid progressors had shorter diagnosis delay, more bulbar-onset disease, and a lower ALS Functional Rating Scale-Revised (ALSFRS-R) total score at baseline. The stable low group had a shorter diagnosis delay, lower body mass index, more bulbar-onset disease, lower ALSFRS-R total score, and were more likely to have an ALSFRS-R orthopnea score lower than 4 compared with the slow progressors. We found that projected group membership predicted respiratory insufficiency in the PRO-ACT cohort (concordance statistic = 0.78, 95% CI, 0.76-0.79). Conclusions: We derived a group-based trajectory model for FVC progression in ALS, which validated against the outcome of respiratory insufficiency in an external cohort. Future studies may focus on patients predicted to be rapid progressors.

Many patients with obstructive sleep apnea (OSA), but not all, have a reduction in blood pressure (BP) with positive airway pressure (PAP) treatment. Our objective was to determine whether the BP response following PAP treatment is related to obesity. A total of 188 adults with OSA underwent 24-hour BP monitoring and 24-hour urinary norepinephrine collection at baseline. Obesity was assessed by waist circumference, body mass index, and abdominal visceral fat volume. Participants adherent to PAP treatment were reassessed after 4 months. Primary outcomes were 24-hour mean arterial pressure (MAP) and 24-hour urinary norepinephrine level. Obstructive sleep apnea participants had a significant reduction in 24-hour MAP following PAP treatment (-1.22 [95% CI: -2.38, -0.06] mm Hg; P = .039). No significant correlations were present with any of the 3 obesity measures for BP or urinary norepinephrine measures at baseline in all OSA participants or for changes in BP measures in participants adherent to PAP treatment. Changes in BP measures following treatment were not correlated with baseline or change in urinary norepinephrine. Similar results were obtained when BP or urinary norepinephrine measures were compared between participants dichotomized using the sex-specific median of each obesity measure. Greater reductions in urinary norepinephrine were correlated with higher waist circumference (rho = -0.21, P = .037), with a greater decrease from baseline in obese compared to non-obese participants (-6.26 [-8.82, -3.69] vs -2.14 [-4.63, 0.35] ng/mg creatinine; P = .027). The results indicate that the BP response to PAP treatment in adults with OSA is not related to obesity or urinary norepinephrine levels., (©2019 Wiley Periodicals, Inc.)

Background: The documented efficacy and promise of telemedicine in diabetes management does not necessarily mean that it can be easily translated into clinical practice. An important barrier concerns patient activation and engagement with telemedicine technology. Objective: To assess the importance of patient activation and engagement with remote patient monitoring technology in diabetes management among patients with type 2 diabetes. Methods: Ordinary least squares and logistic regression analyses were used to examine how patient activation and engagement with remote patient monitoring technology were related to changes in hemoglobin A1c (HbA1c) for 1,354 patients with type 2 diabetes monitored remotely for 3 months between 2015 and 2017. Results: Patients with more frequent and regular participation in remote monitoring had lower HbA1c levels at the end of the program. Compared to patients who uploaded their biometric data every 2 days or less frequently, patients who maintained an average frequency of one upload per day were less likely to have a postmonitoring HbA1c > 9% after adjusting for selected covariates on baseline demographics and health conditions. Conclusions: Higher levels of patient activation and engagement with remote patient monitoring technology were associated with better glycemic control outcomes. Developing targeted interventions for different groups of patients to promote their activation and engagement levels would be important to improve the effectiveness of remote patient monitoring in diabetes management.

A clinically useful model to prognose onset of respiratory insufficiency in amyotrophic lateral sclerosis (ALS) would inform disease interventions, communication and clinical trial design. We aimed to derive and validate a clinical prognostic model for respiratory insufficiency within 6 months of presentation to an outpatient ALS clinic.We used multivariable logistic regression and internal cross-validation to derive a clinical prognostic model using a single-centre cohort of 765 ALS patients who presented between 2006 and 2015. External validation was performed using the multicentre Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database with 7083 ALS patients. Predictors included baseline characteristics at first outpatient visit. The primary outcome was respiratory insufficiency within 6 months, defined by initiation of noninvasive ventilation, forced vital capacity (FVC) <50% predicted, tracheostomy, or death.Of 765 patients in our centre, 300 (39%) had respiratory insufficiency or death within 6 months. Six baseline characteristics (diagnosis age, delay between symptom onset and diagnosis, FVC, symptom onset site, amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R) total score and ALSFRS-R dyspnoea score) were used to prognose the risk of the primary outcome. The derivation cohort c-statistic was 0.86 (95% CI 0.84-0.89) and internal cross-validation produced a c-statistic of 0.86 (95% CI 0.85-0.87). External validation of the model using the PRO-ACT cohort produced a c-statistic of 0.74 (95% CI 0.72-0.75).We derived and externally validated a clinical prognostic rule for respiratory insufficiency in ALS. Future studies should investigate interventions on equivalent high-risk patients., Competing Interests: Conflict of interest: J. Ackrivo has nothing to disclose. Conflict of interest: J. Hansen-Flaschen has nothing to disclose. Conflict of interest: E.P. Wileyto has nothing to disclose. Conflict of interest: R.J. Schwab has nothing to disclose. Conflict of interest: L. Elman has nothing to disclose. Conflict of interest: S.M. Kawut has nothing to disclose., (Copyright ©ERS 2019.)

Study Objectives: Obstructive sleep apnea (OSA) is a global health issue and is associated with obesity and oropharyngeal crowding. Global data are limited on the effect of ethnicity and sex on these relationships. We compare associations between the apnea-hypopnea index (AHI) and these risk factors across ethnicities and sexes within sleep clinics., Methods: This is a cross-sectional, multicenter study of patients with OSA from eight sleep centers representing the Sleep Apnea Global Interdisciplinary Consortium (SAGIC). Four distinct ethnic groups were analyzed, using a structured questionnaire: Caucasians (Australia, Iceland, Germany, United States), African Americans (United States), Asians (Taiwan), and South Americans (Brazil). Regression analyses and interaction tests were used to assess ethnic and sex differences in relationships between AHI and anthropometric measures (body mass index [BMI], neck circumference, waist circumference) or Mallampati score., Results: Analyses included 1,585 individuals from four ethnic groups: Caucasian (60.6%), African American (17.5%), Asian (13.1%), and South American (8.9%). BMI was most strongly associated with AHI in South Americans (7.8% increase in AHI per 1 kg/m 2 increase in BMI; P < .0001) and most weakly in African Americans (1.9% increase in AHI per 1 kg/m 2 increase in BMI; P = .002). In Caucasians and South Americans, associations were stronger in males than females. Mallampati score differed between ethnicities but did not influence AHI differently across groups., Conclusions: We demonstrate ethnic and sex variations in associations between obesity and OSA. For similar BMI increases, South American patients show greatest AHI increases compared to African Americans. Findings highlight the importance of considering ethnicity and sex in clinical assessments of OSA risk., (© 2019 American Academy of Sleep Medicine.)

Rationale: Obesity is a major risk factor for obstructive sleep apnea. Although greater dimensional changes in the upper airway during wake respiration have been noted in patients with apnea compared with control subjects, whether these differences remain in the presence of obesity is unknown., Objectives: To evaluate upper airway anatomic characteristics and airway compliance (distensibility) in obese subjects with obstructive sleep apnea compared with obese control subjects., Methods: Dynamic magnetic resonance imaging was performed in 157 obese subjects with apnea and 46 obese control subjects during wakefulness in the midsagittal and three axial upper airway regions (retropalatal, retroglossal, epiglottal). Differences in measurements between subjects with apnea and control subjects, and correlations with apnea-hypopnea index among subjects with apnea, were examined., Measurements and Main Results: Measurements included airway areas and linear dimensions. Subject-specific coefficients of variation were calculated to examine variability in airway size. Controlling for covariates, the retropalatal area during respiration was significantly smaller in subjects with apnea than control subjects, based on the average (P = 0.003), maximum (P = 0.004), and minimum (P = 0.001) airway area. Airway narrowing was observed in anteroposterior and lateral dimensions (adjusted P < 0.05). Results were similar in an age, sex, and body mass index-matched subsample. There were significant correlations between apnea-hypopnea index and dynamic measures of airway caliber in the retropalatal and retroglossal regions among subjects with apnea., Conclusions: Upper airway caliber during respiration was significantly narrower in obese subjects with apnea than obese control subjects in the retropalatal region. These findings provide further evidence that retropalatal airway narrowing plays an important role in the pathogenesis of obstructive sleep apnea in obese subjects.

The objective of this study was to evaluate changes in clinical outcomes for patients with type 2 diabetes (T2D) after a 3-month remote patient monitoring (RPM) program, and examine the relationship between hemoglobin A1c (HbA1c) outcomes and participant characteristics. The study sample included 955 patients with T2D who were admitted to an urban Midwestern medical center for any reason from 2014 to 2017, and used RPM for 3 months after discharge. Clinical outcomes included HbA1c, weight, body mass index (BMI), and patient activation scores. Logistic regression was used to estimate the likelihood of having a postintervention HbA1c <9% by patient characteristics, among those who had baseline HbA1c >9%. Most patients experienced decreases in HbA1c (67%) and BMI (58%), and increases in patient activation scores (67%) (P < 0.001 in all 3 cases) at the end of RPM. Logistic regression analyses revealed that among patients who had HbA1c >9% at baseline, men (odds ratio [OR] = 3.72; 95% confidence interval [CI], 1.43-9.64), those who had increased patient activation scores after intervention (OR = 1.05; 95% CI, 1.01-1.09), those who had higher baseline patient activation scores, and those who had a greater number of biometric data uploads during the intervention (OR = 1.02; 95% CI, 1.00-1.04) were more likely to have reduced their HbA1c to <9% at the end of RPM. RPM for postdischarge patients with T2D might be a promising approach for HbA1c control with increased patient engagement. Future studies with study designs that include a control group should provide more robust evidence.

Purpose: Obesity is associated with both obstructive sleep apnea (OSA) and obesity hypoventilation. Differences in adipose tissue distribution are thought to underlie the development of both OSA and hypoventilation. We explored the relationships between the distribution of upper airway, neck, chest, abdominal and muscle fat in very obese individuals., Methods: We conducted a cross-sectional cohort study of individuals presenting to a tertiary sleep clinic or for assessment for bariatric surgery. Individuals underwent magnetic resonance (MR) imaging of their upper airway, neck, chest, abdomen and thighs; respiratory polygraphy; 1 week of autotitrating CPAP; and morning arterial blood gas to determine carbon dioxide partial pressure and base excess., Results: Fifty-three individuals were included, with mean age of 51.6 ± 8.4 years and mean BMI of 44.3 ± 7.9 kg/m 2 ; there were 27 males (51%). Soft palate, tongue and lateral wall volumes were significantly associated with the AHI in univariable analyses (p < 0.001). Gender was a significant confounder in these associations. No significant associations were found between MRI measures of adiposity and hypoventilation., Conclusions: In very obese individuals, our results indicate that increased volumes of upper airway structures are associated with increased severity of OSA, as previously reported in less obese individuals. Increasingly large upper airway structures that reduce pharyngeal lumen size are likely to lead to OSA by increasing the collapsibility of the upper airway. However, we did not show any significant association between regional fat distribution and propensity for hypoventilation, in this population.

Study Objectives: Upper airway stimulation has been shown to be an effective treatment for some patients with obstructive sleep apnea. However, the mechanism by which hypoglossal nerve stimulation increases upper airway caliber is not clear. Therefore, the objective of this study was to identify the mechanism of action of upper airway stimulation. We hypothesized that, with upper airway stimulation, responders would show greater airway opening in the retroglossal (base of the tongue) region, greater hyoid movement toward the mandible, and greater anterior motion in the posterior, inferior region of the tongue compared with nonresponders., Methods: Seven participants with obstructive sleep apnea who had been successfully treated with upper airway stimulation (responders) and six participants who were not successfully treated (nonresponders) underwent computed tomography imaging during wakefulness with and without hypoglossal nerve stimulation. Responders reduced their apnea-hypopnea index (AHI) by 22.63 ± 6.54 events per hour, whereas nonresponders had no change in their AHI (0.17 ± 14.04 events per hour). We examined differences in upper airway caliber, the volume of the upper airway soft tissue structures, craniofacial relationships, and centroid tongue and soft palate movement between responders and nonresponders with and without hypoglossal nerve stimulation., Results: Our data indicate that compared with nonresponders, responders had a smaller baseline soft palate volume and, with stimulation, had (1) a greater increase in retroglossal airway size; (2) increased shortening of the mandible-hyoid distance; and (3) greater anterior displacement of the tongue., Conclusions: These results suggest that smaller soft palate volumes at baseline and greater tongue movement anteriorly with stimulation improve the response to upper airway stimulation.

Study Objectives: A recent study of patients with moderate-severe obstructive sleep apnea (OSA) in Iceland identified three clinical clusters based on symptoms and comorbidities. We sought to verify this finding in a new cohort in Iceland and examine the generalizability of OSA clusters in an international ethnically diverse cohort., Methods: Using data on 972 patients with moderate-severe OSA (apnea-hypopnea index [AHI] ≥ 15 events per hour) recruited from the Sleep Apnea Global Interdisciplinary Consortium (SAGIC), we performed a latent class analysis of 18 self-reported symptom variables, hypertension, cardiovascular disease, and diabetes., Results: The original OSA clusters of disturbed sleep, minimally symptomatic, and excessively sleepy replicated among 215 SAGIC patients from Iceland. These clusters also generalized to 757 patients from five other countries. The three clusters had similar average AHI values in both Iceland and the international samples, suggesting clusters are not driven by OSA severity; differences in age, gender, and body mass index were also generally small. Within the international sample, the three original clusters were expanded to five optimal clusters: three were similar to those in Iceland (labeled disturbed sleep, minimal symptoms, and upper airway symptoms with sleepiness) and two were new, less symptomatic clusters (labeled upper airway symptoms dominant and sleepiness dominant). The five clusters showed differences in demographics and AHI, although all were middle-aged (44.6-54.5 years), obese (30.6-35.9 kg/m2), and had severe OSA (42.0-51.4 events per hour) on average., Conclusions: Results confirm and extend previously identified clinical clusters in OSA. These clusters provide an opportunity for a more personalized approach to the management of OSA.

Background: The obstructive sleep apnoea syndrome (OSAS) results from a combination of structural and neuromotor factors; however, the relative contributions of these factors have not been studied during the important developmental phase of adolescence. We hypothesised that adenotonsillar volume (ATV), nasopharyngeal airway volume (NPAV), upper airway critical closing pressure (Pcrit) in the hypotonic and activated neuromotor states, upper airway electromyographic response to subatmospheric pressure and the ventilatory response to CO 2 during sleep would be major predictors of OSAS risk., Methods: 42 obese adolescents with OSAS and 37 weight-matched controls underwent upper airway MRI, measurements of Pcrit, genioglossal electromyography and ventilatory response to CO 2 during wakefulness and sleep., Results: ATV, NPAV, activated and hypotonic Pcrit, genioglossal electromyography and ventilatory response to CO 2 during sleep were all associated with OSAS risk. Multivariate models adjusted for age, gender, body mass index and race indicated that ATV, NPAV and activated Pcrit each independently affected apnoea risk in adolescents; genioglossal electromyography was independently associated in a reduced sample. There was significant interaction between NPAV and activated Pcrit (p=0.021), with activated Pcrit more strongly associated with OSAS in adolescents with larger NPAVs and NPAV more strongly associated with OSAS in adolescents with more negative activated closing pressure., Conclusions: OSAS in adolescents is mediated by a combination of anatomic (ATV, NPAV) and neuromotor factors (activated Pcrit). This may have important implications for the management of OSAS in adolescents., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: OSA is associated with changes in pharyngeal anatomy. The goal of this study was to objectively and reproducibly quantify pharyngeal anatomy by using digital morphometrics based on a laser ruler and to assess differences between subjects with OSA and control subjects and associations with the apnea-hypopnea index (AHI). To the best of our knowledge, this study is the first to use digital morphometrics to quantify intraoral risk factors for OSA., Methods: Digital photographs were obtained by using an intraoral laser ruler and digital camera in 318 control subjects (mean AHI, 4.2 events/hour) and 542 subjects with OSA (mean AHI, 39.2 events/hour)., Results: The digital morphometric paradigm was validated and reproducible over time and camera distances. A larger modified Mallampati score and having a nonvisible airway were associated with a higher AHI, both unadjusted (P < .001) and controlling for age, sex, race, and BMI (P = .015 and P = .018, respectively). Measures of tongue size were larger in subjects with OSA vs control subjects in unadjusted models and controlling for age, sex, and race but nonsignificant controlling for BMI; similar results were observed with AHI severity. Multivariate regression suggests photography-based variables capture independent associations with OSA., Conclusions: Measures of tongue size, airway visibility, and Mallampati scores were associated with increased OSA risk and severity. This study shows that digital morphometrics is an accurate, high-throughput, and noninvasive technique to identify anatomic OSA risk factors. Morphometrics may also provide a more reproducible and standardized measurement of the Mallampati score. Digital morphometrics represent an efficient and cost-effective method of examining intraoral crowding and tongue size when examining large populations, genetics, or screening for OSA., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

The tongue is a highly innervated and vascularized muscle hydrostat on the floor of the mouth of most vertebrates. Its primary functions include supporting mastication and deglutition, as well as taste-sensing and phonetics. Accordingly, the strength and volume of the tongue can impact the ability of vertebrates to accomplish basic activities such as feeding, communicating, and breathing. Human patients with sleep apnea have enlarged tongues, characterized by reduced muscle tone and increased intramuscular fat that can be visualized and quantified by magnetic resonance imaging (MRI). The abilities to measure force generation and viscoelastic properties of the tongue constitute important tools for obtaining functional information to correlate with imaging data. Here, we present techniques for measuring tongue force production in anesthetized Zucker rats via electrical stimulation of the hypoglossal nerves and for determining the viscoelastic properties of the tongue by applying passive Lissajous force/deformation curves.

As upper airway stimulation (UAS) surgical implantation is a new procedure, the authors thought it would be instructive to describe a single-institution's experience with the inception of a UAS program. The description of our experience at the University of Pennsylvania may be useful for planning purposes when surgeons and sleep medicine physicians are considering program development. Laryngoscope, 126:S17-S19, 2016 Laryngoscope, 126:S17-S19, 2016., (© 2016 The American Laryngological, Rhinological and Otological Society, Inc.)

Study Objectives: The goal of this study was to examine different paradigms for determining critical closing pressures (Pcrit). Methods of determining Pcrit were compared, including direct observation of occluded (no flow) breaths versus inferring Pcrit from extrapolated data, and Pcrit generated by aggregating pressure-flow data from multiple runs versus Pcrit averaged across individual pressure-flow runs. The relationship between Pcrit and obstructive sleep apnea (OSA) was examined., Methods: A total of 351 participants with and without OSA underwent overnight polysomnography with pressure-flow measurements to determine Pcrit. A series of filters were applied to raw data to provide consistent, objective criteria for determining which data to include in Pcrit calculations. Observed Pcrit values were computed as the mean nasal pressure level at which a subject had at least two breaths with peak inspiratory flow < 50 mL/sec. Extrapolated Pcrit was calculated in two ways: (1) separately for each individual run and then averaged; and (2) using all valid data from individual runs combined into one plot., Results: Observed Pcrit was calculated in 67% to 69% of participants, a similar or higher proportion of study subjects compared to extrapolated Pcrit values using a ± 3 cm H2O filter. Although raw (unfiltered) extrapolated Pcrit measures were able to be calculated among a greater proportion of participants than filtered, extrapolated Pcrit values, and thus had fewer missing values, they had larger variability. Both extrapolated and observed Pcrit were higher among individuals with OSA compared to those without OSA., Conclusions: Observed Pcrit provides a reliable descriptor of hypotonic upper airway collapsibility. Different methods for determining Pcrit were able to distinguish subjects with and without OSA., (© 2016 Associated Professional Sleep Societies, LLC.)

Obstructive sleep apnea (OSA) is associated with extensive neurologic comorbidities. It is hypothesized that the repeated nocturnal apneas experienced in patients with OSA may inhibit the normal apneic response, resulting in hypoxic brain injury and subsequent neurologic dysfunction. In this study, we applied the recently developedOxFlowMRI method for rapid quantification of cerebral metabolic rate of oxygen (CMRO2) during a volitional apnea paradigm. MRI data were analyzed in 11 OSA subjects and 10 controls (mean ± SD apnea-hypopnea index (AHI): 43.9 ± 18.1 vs. 2.9 ± 1.6 events/hour,P < 0.0001; age: 53.8 ± 8.2 vs. 45.3 ± 8.5 years,P = 0.027; BMI: 36.6 ± 4.4 vs. 31.9 ± 2.2 kg/m(2),P = 0.0064). Although total cerebral blood flow and arteriovenous oxygen difference were not significantly different between apneics and controls (P > 0.05), apneics displayed reduced baseline CMRO2(117.4 ± 37.5 vs. 151.6 ± 29.4 µmol/100 g/min,P = 0.013). In response to apnea, CMRO2decreased more in apneics than controls (-10.9 ± 8.8 % vs. -4.0 ± 6.7 %,P = 0.036). In contrast, group differences in flow-based cerebrovascular reactivity were not significant. Results should be interpreted with caution given the small sample size, and future studies with larger independent samples should examine the observed associations, including potential independent effects of age or BMI. Overall, these data suggest that dysregulation of the apneic response may be a mechanism for OSA-associated neuropathology., (© The Author(s) 2015.)

Objectives/hypothesis: To quantitatively measure volumetric changes in upper airway soft tissue structures using magnetic resonance imaging (MRI) pre- and post transoral robotic surgery for obstructive sleep apnea (OSA-TORS)., Study Design: Prospective, nonrandomized, institutional board-approved study., Methods: Apneics undergoing OSA-TORS, which included bilateral posterior hemiglossectomy with limited pharyngectomy and uvulopalatopharyngoplasty, had upper airway MRIs pre- and postoperatively. Changes (percent and absolute values) in upper airway and surrounding soft tissue volumes were calculated. We assessed whether there were significant volumetric changes and if changes correlated with apnea-hypopnea index (AHI) changes., Results: Nineteen MRIs and 18 polysomnograms were analyzed pre- and postoperation. Total airway volume increased by 19.4% (P = 0.030). Soft palate and tongue volumes decreased by 18.3% (P = 0.002) and 5.8% (P = 0.013), respectively. Retropalatal and total lateral wall volumes decreased by 49.8% (P = 0.0001) and 17.9% (P = 0.008), respectively. Changes in other structures were not significant. Eleven patients had surgical success, with a mean AHI decrease of 52.9; six were nonsuccesses with a mean AHI decrease of 4.5 (P =0.006). Decreased retropalatal lateral wall volume correlated with decreased AHI., Conclusion: Airway, tongue, soft palate, and lateral wall volumes change significantly after OSA-TORS. Changes in the volume of the lateral walls correlated with changes in AHI. Volumetric upper airway MRI may be a helpful tool to better understand reasons for surgical success., Level of Evidence: 4., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

Rationale: Structural risk factors for obstructive sleep apnea syndrome (OSAS) in adolescents have not been well characterized. Because many adolescents with OSAS are obese, we hypothesized that the anatomic OSAS risk factors would be more similar to those in adults than those in children., Objectives: To investigate the anatomic risk factors in adolescents with OSAS compared with obese and lean control subjects using magnetic resonance imaging (MRI)., Methods: Three groups of adolescents (age range: 12-16 yr) underwent MRI: obese individuals with OSAS (n = 49), obese control subjects (n = 38), and lean control subjects (n = 50)., Measurements and Main Results: We studied 137 subjects and found that (1) obese adolescents with OSAS had increased adenotonsillar tissue compared with obese and lean control subjects; (2) obese OSAS adolescents had a smaller nasopharyngeal airway than control subjects; (3) the size of other upper airway soft tissue structures (volume of the tongue, parapharyngeal fat pads, lateral walls, and soft palate) was similar between subjects with OSAS and obese control subjects; (4) although there were no major craniofacial abnormalities in most of the adolescents with OSAS, the ratio of soft tissue to craniofacial space surrounding the airway was increased; and (5) there were sex differences in the pattern of lymphoid proliferation., Conclusions: Increased size of the pharyngeal lymphoid tissue, rather than enlargement of the upper airway soft tissue structures, is the primary anatomic risk factor for OSAS in obese adolescents. These results are important for clinical decision making and suggest that adenotonsillectomy should be considered as the initial treatment for OSAS in obese adolescents, a group that has poor continuous positive airway pressure adherence and difficulty in achieving weight loss.

Sleep is an important physiologic process, and lack of sleep is associated with a host of adverse outcomes. Basic and clinical research has documented the important role circadian rhythm plays in biologic function. Critical illness is a time of extreme vulnerability for patients, and the important role sleep may play in recovery for intensive care unit (ICU) patients is just beginning to be explored. This concise clinical review focuses on the current state of research examining sleep in critical illness. We discuss sleep and circadian rhythm abnormalities that occur in ICU patients and the challenges to measuring alterations in circadian rhythm in critical illness and review methods to measure sleep in the ICU, including polysomnography, actigraphy, and questionnaires. We discuss data on the impact of potentially modifiable disruptors to patient sleep, such as noise, light, and patient care activities, and report on potential methods to improve sleep in the setting of critical illness. Finally, we review the latest literature on sleep disturbances that persist or develop after critical illness.

Background: Elevated levels of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) may contribute to cardiovascular disease and are associated with obstructive sleep apnea (OSA) and obesity. The relationship between OSA and obesity in determining ICAM-1 and VCAM-1 levels, and the effect of treatment, is unclear., Objective: Our aim was to study whether positive airway pressure (PAP) usage resulted in changes in ICAM-1 and VCAM-1 after 2 years within 309 OSA patients from the Icelandic Sleep Apnea Cohort, and determine how obesity affected such changes., Subjects/methods: The mean body mass index (BMI) was 32.4±5.1 kg m(-2); subjects had moderate-to-severe OSA (apnea-hypopnea index=45.0±20.2) and 79% were male. There were 177 full PAP users (⩾4 h per night and ⩾20 of last 28 nights), 44 partial (<4 h per night or <20 nights) and 88 nonusers., Results: ICAM-1 (P<0.001) and VCAM-1 (P=0.012) change was significantly different among the PAP groups. The largest ICAM-1 differences were among the most obese subjects (P<0.001). At follow-up, nonusers had increased ICAM-1 compared with decreased levels in full users. All groups had increased VCAM-1, but nonusers had a significantly larger increase than full users., Conclusions: Within moderate-to-severe OSA patients, PAP usage prevents increases in adhesion molecules observed in nonusers after 2 years. For ICAM-1, the largest effect is in the most obese subjects. As OSA and obesity commonly coexist, the usage of PAP to limit increases in adhesion molecules may decrease the rate of progression of OSA-related cardiovascular disease.

Rationale: Body habitus is a major determinant of obstructive sleep apnea (OSA). However, many individuals do not have OSA despite being overweight/obese (body mass index > 25 kg/m(2)) for reasons that are not fully elucidated., Objectives: To determine the key physiologic traits (upper-airway anatomy/collapsibility, upper-airway muscle responsiveness, chemoreflex control of ventilation, arousability from sleep) responsible for the absence of OSA in overweight/obese individuals., Methods: We compared key physiologic traits in 18 overweight/obese subjects without apnea (apnea-hypopnea index < 15 events per hour) with 25 overweight/obese matched patients with OSA (apnea-hypopnea index ≥ 15 events per hour) and 11 normal-weight nonapneic control subjects. Traits were measured by repeatedly lowering continuous positive airway pressure to subtherapeutic levels for 3 minutes during non-REM sleep., Measurements and Main Results: Overweight/obese subjects without apnea exhibited a less collapsible airway than overweight/obese patients with apnea (critical closing pressure: -3.7 ± 1.9 vs. 0.6 ± 1.2 cm H2O; P = 0.003; mean ± 95% confidence interval), but a more collapsible airway relative to normal-weight control subjects (-8.8 ± 3.1 cm H2O; P < 0.001). Notably, overweight/obese subjects without apnea exhibited a threefold greater upper-airway muscle responsiveness than both overweight/obese patients with apnea (Δgenioglossus EMG/Δepiglottic pressure: -0.49 [-0.22 to -0.79] vs. -0.15 [-0.09 to -0.22] %max/cm H2O; P = 0.008; mean [95% confidence interval]) and normal-weight control subjects (-0.16 [-0.04 to -0.30] %max/cm H2O; P = 0.02). Loop gain was elevated (more negative) in both overweight/obese groups and normal-weight control subjects (P = 0.02). Model-based analysis demonstrated that overweight/obese individuals without apnea rely on both more favorable anatomy and collapsibility and enhanced upper-airway dilator muscle responses to avoid OSA., Conclusions: Overweight/obese individuals without apnea have a moderately compromised upper-airway structure that is mitigated by highly responsive upper-airway dilator muscles to avoid OSA. Elucidating the mechanisms underlying enhanced muscle responses in this population may provide clues for novel OSA interventions.

Background: Sleep disordered breathing (SDB) is associated with significant cardiovascular sequelae and positive airway pressure (PAP) has been shown to improve heart failure and prevent the recurrence of atrial fibrillation in cardiac patients with sleep apnea. Patients who are hospitalized with cardiac conditions frequently have witnessed symptoms of SDB but often do not have a diagnosis of sleep apnea. We implemented a clinical paradigm to perform unattended sleep studies and initiate treatment with PAP in hospitalized cardiac patients with symptoms consistent with SDB. We hypothesized that PAP adherence in cardiac patients with SDB would reduce readmission rates 30 days after discharge., Methods: 106 consecutive cardiac patients hospitalized for heart failure, arrhythmias, and myocardial infarction and who reported symptoms of SDB were evaluated. Patients underwent a type III portable sleep study and those patients diagnosed with sleep apnea were started on PAP. Demographic data, SDB type, PAP adherence, and data regarding 30-day hospital readmission/ED visits were collected., Results: Of 106 patients, 104 had conclusive diagnostic studies using portable monitoring systems. Seventy-eight percent of patients (81/104) had SDB (AHI ≥ 5 events/h). Eighty percent (65/81) had predominantly obstructive sleep apnea, and 20% (16/81) had predominantly central sleep apnea. None of 19 patients (0%) with adequate PAP adherence, 6 of 20 (30%) with partial PAP use, and 5 of 17 (29%) of patients who did not use PAP were readmitted to the hospital or visited the emergency department (ED) for a cardiac issue within 30 days from discharge (p = 0.025)., Conclusions: Performing diagnostic unattended sleep studies and initiating PAP treatment in hospitalized cardiac patients was feasible and provided important clinical information. Our data indicate that hospital readmission and ED visits 30 days after discharge were significantly lower in patients with cardiac disease and SDB who adhered to PAP treatment than those who were not adherent., Commentary: A commentary on this article appears in this issue on page 1067.

Study Objectives: The objective of this study was to determine whether tongue fat is increased in obese sleep apneics compared to obese subjects without sleep apnea. We hypothesized that excess fat is deposited in the tongue in obese patients with sleep apnea., Design: Case-control design., Setting: Academic medical center., Patients: We examined tongue fat in 31 obese controls (apnea-hypopnea index, 4.1 ± 2.7 events/h) and 90 obese apneics (apnea-hypopnea index, 43.2 ± 27.3 events/h). Analyses were repeated in a subsample of 18 gender-, race-, age-, and BMI-matched case-control pairs., Interventions: All subjects underwent a MRI with three-point Dixon magnetic resonance imaging. We used sophisticated volumetric reconstruction algorithms to study the size and distribution of upper airway fat deposits in the tongue and masseter muscles within apneics and obese controls., Measurements and Results: The data supported our a priori hypotheses that after adjustment for age, BMI, gender, and race, the tongue in apneics was significantly larger (P = 0.001) and had an increased amount of fat (P = 0.002) compared to controls. Similar results were seen in our matched sample. Our data also demonstrate that within the apneic and normal tongue, there are regional differences in fat distribution, with larger fat deposits at the base of the tongue., Conclusions: There is increased tongue volume and deposition of fat at the base of tongue in apneics compared to controls. Increased tongue fat may begin to explain the relationship between obesity and obstructive sleep apnea., (© 2014 Associated Professional Sleep Societies, LLC.)

Objectives: Accumulating evidence has shown that there is a genetic contribution to obstructive sleep apnea (OSA).The objectives were to use magnetic resonance imaging (MRI) cephalometry to (1) confirm heritability of craniofacial risk factors for OSA previously shown by cephalometrics; and (2) examine the heritability of new craniofacial structures that are measurable with MRI., Design: A sib pair "quad" design examining apneics, apneic siblings, controls, and control siblings. The study design used exact matching on ethnicity and sex, frequency matching on age, and statistical control for differences in age, sex, ethnicity, height, and weight., Setting: Academic medical center., Patients: We examined 55 apneic probands (apnea-hypopnea index [AHI]: 46.8 ± 33.5 events/h), 55 proband siblings (AHI: 11.1 ± 15.9 events/h), 55 controls (AHI: 2.2 ± 1.7 events/h), and 55 control siblings (AHI: 4.1 ± 4.0 events/h)., Interventions: N/A., Measurements and Results: Five independent domains reflecting different aspects of the craniofacial structure were examined. We confirmed heritability of sella-nasion-subspinale (38%, P = 0.002), saddle angle (55%, P < 0.0001), mandibular length (24%, P = 0.02) and lower facial height (33%, P = 0.006) previously measured by cephalometry. In addition, the current study added new insights by demonstrating significant heritability of mandibular width (30%, P = 0.005), maxillary width (47%, P < 0.0001), distance from the hyoid bone to the retropogonion (36%, P = 0.0018) and size of the oropharyngeal space (31%, P = 0.004). Finally, our data indicate that heritability of the craniofacial structures is similar in normal patients and those with apnea., Conclusions: The data support our a priori hypothesis that the craniofacial structures that have been associated with obstructive sleep apnea (OSA) are heritable. We have demonstrated heritability for several intermediate craniofacial phenotypes for OSA. Thus, we believe that future studies should be able to identify genes associated with these intermediate craniofacial phenotypes., (© 2014 Associated Professional Sleep Societies, LLC.)

Obstructive sleep apnoea (OSA) is associated with cardiovascular disease. Dyslipidaemia has been implicated as a mechanism linking OSA with atherosclerosis, but no consistent associations with lipids exist for OSA or positive airway pressure treatment. We assessed the relationships between fasting lipid levels and obesity and OSA severity, and explored the impact of positive airway pressure treatment on 2-year fasting lipid level changes. Analyses included moderate-to-severe OSA patients from the Icelandic Sleep Apnoea Cohort. Fasting morning lipids were analysed in 613 untreated participants not on lipid-lowering medications at baseline. Patients were then initiated on positive airway pressure and followed for 2 years. Sub-classification using propensity score quintiles, which aimed to replicate covariate balance associated with randomised trials and, therefore, minimise selection bias and allow causal inference, was used to design the treatment group comparisons. 199 positive airway pressure adherent patients and 118 non-users were identified. At baseline, obesity was positively correlated with triglycerides and negatively correlated with total cholesterol, and low-density and high-density lipoprotein cholesterol. A small correlation was observed between the apnoea/hypopnoea index and high-density lipoprotein cholesterol. No effect of positive airway pressure adherence on 2-year fasting lipid changes was observed. Results do not support the concept of changes in fasting lipids as a primary mechanism for the increased risk of atherosclerotic cardiovascular disease in OSA., (©ERS 2014.)

Study Objectives: The objective of this study was to explore the mechanism of action of the oral pressure therapy (OPT) device, a new treatment for sleep apnea., Design: Case series., Setting: Academic medical center., Patients: Fifteen subjects with sleep apnea who had been successfully treated (responders) with the OPT device and 4 subjects who were not successfully treated (non-responders) with the OPT device., Interventions: All subjects underwent a MRI (without the device, with the device in place without vacuum and with the device in place with vacuum) to examine the biomechanical changes associated with the OPT device., Measurements and Results: Oral pressure therapy significantly (P = 0.002) increased the size of the retropalatal airway in both the lateral and anterior-posterior dimensions by moving the soft palate anteriorly and superiorly and the anterior-superior segment of the tongue forward, toward the teeth. The percentage and absolute increase in the cross-sectional area of the retropalatal region, the superior movement of the soft palate, and the anterior displacement of the tongue were significantly greater in the responders than in the non-responders. In responders, there were significant increases in the mean (P = 0.002), maximum (P = 0.0002), and minimum (P = 0.04) cross-sectional areas of the retropalatal region with the OPT device. However, in the retroglossal region, airway caliber decreased with the OPT device., Conclusions: In those who responded to oral pressure therapy, it increased airway caliber in the retropalatal region by moving the soft palate anteriorly and superiorly and the anterior-superior segment of the tongue forward., Citation: Schwab RJ, Kim C, Siegel L, Keenan BT, Black J, Farid-Moayer M, Podmore J, Vaska M. Examining the mechanism of action of a new device using oral pressure therapy for the treatment of obstructive sleep apnea.

Objectives: To compare the performance of the BD Onclarity HPV Assay (BD Diagnostics, Sparks, MD) in BD SurePath liquid-based cytology media with that of Hybrid Capture 2 (HC2, Qiagen, Germantown, MD) samples co-collected in specimen transport medium in an adjudicated patient cohort., Methods: The performance of the BD Onclarity HPV Assay using BD SurePath media was compared with that of HC2 samples co-collected in specimen transport medium using 541 archived samples from a multicenter US clinical trial with histologically adjudicated cervical biopsy specimens., Results: The sensitivity for cervical intraepithelial neoplasia (CIN) 2 positivity (n - 104) was 90.4% (95% confidence interval [CI], 83-95) and 93.3% (95% CI, 87-97) and specificity was 76.9% (95% CI, 73-81) and 77.8% (95% CI, 74-82) for the BD assay and HC2, respectively. Nine cases of CIN 2+ had results discordant with the high-risk HPV assay. All were found to have been correctly classified with the BD assay using a novel WAVE denaturing high-performance liquid chromatography double-stranded DNA sequencing method., Conclusions: The clinical performance of The BD Onclarity HPV Assay with respect to histology end points was similar to HC2. Moreover, discordant analysis revealed improved performance of the BD assay with respect to ability to provide extended genotyping information and lack of cross-reactivity with low-risk HPV types associated with cellular abnormalities. The relative risks for CIN 3 disease for HPV 31 and HPV 33/58 (combined) were comparable to that of HPV 18 in this population, suggesting that these genotypes may warrant monitoring in future studies., (Copyright© by the American Society for Clinical Pathology.)

Study Objectives: Obesity is the most important risk factor for obstructive sleep apnea (OSA), and the effects of obesity may be mediated by tongue fat. Our objective was to examine the effects of obesity on upper airway structures in obese (OBZ) and non-obese (NBZ) Zucker rats., Design: Animal study., Setting: Academic Medical Center., Participants: OBZ (638.2 ± 39 g; 14.9 ± 1.1 w) and age-matched NBZ Zucker (442.6 ± 37 g, 15.1 ± 1.5 w) rats., Interventions: TONGUE FAT AND VOLUME AND WERE ASSESSED USING: in vivo magnetic resonance spectroscopy (MRS), magnetic resonance imaging including Dixon imaging for tongue fat volume, ex vivo biochemistry (fat quantification; triglyceride (mg)/tissue (g), and histology (Oil Red O stain)., Measurements and Results: MRS: overall OBZ tongue fat/water ratio was 2.9 times greater than NBZ (P < 0.002) with the anterior OBZ tongue up to 3.3 times greater than NBZ (P < 0.002). Biochemistry: Triglyceride (TG) in the tongue was 4.4 times greater in OBZ versus NBZ (P < 0.0006). TG was greater in OBZ tongue (3.57 ± 1.7 mg/g) than OBZ masseter muscle (0.28 ± 0.1; P < 0.0001) but tongue and masseter TG were not different in NBZ rats (0.82 ± 0.3 versus 0.28 ± 0.1 mg/g, P = 0.67). Dixon fat volume was significantly increased in OBZ (56 ± 15 mm3) versus NBZ (34 ± 5 mm3, P < 0.004). Histology demonstrated a greater degree of intracellular muscle fat and extramuscular fat infiltration in OBZ versus NBZ rats., Conclusions: Genetically obese rats had a large degree of fat infiltration in the tongue compared to both skeletal muscle and tongue tissues of the non-obese age-matched littermates. The significant fat increase and sequestration in the obese tongue may play a role in altered tongue neuromuscular function, tongue stiffness or metabolic function.

Rationale: The metabolic activity of the tongue is unknown in patients with obstructive sleep apnea (OSA). Tongue electromyographic (EMG) activity is increased in patients with OSA. This increase in tongue EMG activity is thought to be related to either increased neuromuscular compensation or denervation with subsequent reinnervation of the muscle fibers. Increased glucose uptake in the tongue would support increased neuromuscular compensation, whereas decreased glucose uptake in the tongue would support denervation with subsequent reinnervation of the muscle fibers., Objectives: To investigate the metabolic activity of the genioglossus and control upper airway muscles in obese patients with sleep apnea compared with obese control subjects., Methods: Obese subjects with and without OSA underwent a standard overnight sleep study to determine an apnea-hypopnea index. Each subject had a positron emission tomography with [(18)F]-2-fluoro-2-deoxy-D-glucose scan in addition to noncontrast computed tomography or magnetic resonance imaging. Glucose uptake was quantified within upper airway tissues with the standardized uptake value., Measurements and Main Results: We recruited 30 obese control subjects (apnea-hypopnea index, 4.7 ± 3.1 events per hour) and 72 obese patients with sleep apnea (apnea-hypopnea index, 43.5 ± 28.0 events per hour). Independent of age, body mass index, sex, and race, patients with OSA had significantly reduced glucose uptake in the genioglossus (P = 0.03) in comparison with obese normal subjects. No differences in standardized uptake value were found in the control muscles (masseter [P = 0.38] and pterygoid [P = 0.70]) and subcutaneous fat deposits (neck [P = 0.44] and submental [P = 0.95]) between patients with OSA and control subjects., Conclusions: There was significantly reduced glucose uptake in the genioglossus of patients with sleep apnea in comparison with obese normal subjects with [(18)F]-2-fluoro-2-deoxy-D-glucose positron emission tomography imaging. The reduction in glucose uptake was likely secondary to alterations in tongue muscle fiber-type or secondary to chronic denervation. The reduced glucose uptake argues against the neuromuscular compensation hypothesis explaining the increase in tongue EMG activity in obese patients with OSA.

Study Objectives: (1) To determine whether facial phenotype, measured by quantitative photography, relates to underlying craniofacial obstructive sleep apnea (OSA) risk factors, measured with magnetic resonance imaging (MRI); (2) To assess whether these associations are independent of body size and obesity., Design: Cross-sectional cohort., Setting: Landspitali, The National University Hospital, Iceland., Participants: One hundred forty patients (87.1% male) from the Icelandic Sleep Apnea Cohort who had both calibrated frontal and profile craniofacial photographs and upper airway MRI. Mean ± standard deviation age 56.1 ± 10.4 y, body mass index 33.5 ± 5.05 kg/m(2), with on-average severe OSA (apnea-hypopnea index 45.4 ± 19.7 h(-1))., Interventions: N/A., Measurements and Results: Relationships between surface facial dimensions (photos) and facial bony dimensions and upper airway soft-tissue volumes (MRI) was assessed using canonical correlation analysis. Photo and MRI craniofacial datasets related in four significant canonical correlations, primarily driven by measurements of (1) maxillary-mandibular relationship (r = 0.8, P < 0.0001), (2) lower face height (r = 0.76, P < 0.0001), (3) mandibular length (r = 0.67, P < 0.0001), and (4) tongue volume (r = 0.52, P = 0.01). Correlations 1, 2, and 3 were unchanged when controlled for weight and neck and waist circumference. However, tongue volume was no longer significant, suggesting facial dimensions relate to tongue volume as a result of obesity., Conclusions: Significant associations were found between craniofacial variable sets from facial photography and MRI. This study confirms that facial photographic phenotype reflects underlying aspects of craniofacial skeletal abnormalities associated with OSA. Therefore, facial photographic phenotyping may be a useful tool to assess intermediate phenotypes for OSA, particularly in large-scale studies.

Rationale: Symptoms of sleep-disordered breathing (SDB) are common among pregnant women, and several studies link SDB symptoms with gestational hypertension and preeclampsia. However, few prospective studies objectively measuring SDB during pregnancy have been performed., Objectives: We performed a prospective cohort study examining risk factors for third trimester SDB in pregnant women., Measurements and Methods: 105 pregnant women from the Hospital of the University of Pennsylvania obstetrics practices completed first and third trimester overnight polysomnography studies. We examined whether the number of SDB events per hour of sleep increased during pregnancy. We performed unadjusted and multivariable logistic regression analyses to estimate the effects of usual and pregnancy-specific characteristics on development of third trimester obstructive sleep apnoea (OSA). In secondary analyses, we examined the relationship between objectively measured SDB, hypertensive disorders of pregnancy, and other adverse maternal-fetal outcomes., Main Results: Mean Apnoea-Hypopnoea Index increased from 2.07 (SD 3.01) events/h at baseline (first trimester) to 3.74 (SD 5.97) in the third trimester (p=0.009). 10.5% of women had OSA in the first trimester. By the third trimester, 26.7% of women had OSA. In multivariable analyses, first trimester body mass index (BMI) and maternal age were significantly associated with third trimester OSA., Conclusions: Third trimester OSA is common. Risk factors for third trimester OSA among women without baseline SDB include higher baseline BMI and maternal age.

Objective: Reproductive hormone levels are associated with body size, and the association between estradiol and body size varies over the menopausal transition. This study aims to delineate these relationships using quantitative measures of visceral and subcutaneous fat., Methods: Early follicular hormones (follicle stimulating hormone (FSH), estradiol, luteinizing hormone, dehydroepiandrosterone sulfate, testosterone) and T-1 weighted abdominal MRI images were obtained in a cross-sectional assessment of 77 women in the Penn Ovarian Aging Study. Fat volume (cm(3)) was quantified using validated software (Amira) and divided into tertiles of visceral and subcutaneous fat volume for analysis. Multivariable linear regression models compared hormone values between tertiles adjusting for race, age, and menopausal status., Results: In adjusted models, estradiol was positively associated with visceral fat tertiles (geometric mean (GM) estradiol (pg/ml): Low 13.0, Mid 17.5, High 26.7, p = 0.006) while FSH was inversely associated with visceral fat tertiles (GM FSH (mIU/ml): Low 42.8, Mid 43.2, High 30.8, p = 0.03). The association of estradiol with visceral and subcutaneous fat tertiles varied by menopausal status (p < 0.001). In the early transition, estradiol was similar across tertiles of fat; postmenopause, estradiol was positively associated with visceral fat. Other hormones were not associated with fat measures., Conclusions: Estradiol was associated with quantitative measures of visceral fat and varies by menopausal status. This finding suggests that visceral fat may be an important mediator in hormone changes over the menopausal transition.

Background: Continuous positive airway pressure (CPAP) is considered the treatment of choice for obstructive sleep apnea (OSA), and studies have shown that there is a correlation between patient adherence and treatment outcomes. Newer CPAP machines can track adherence, hours of use, mask leak, and residual apnea-hypopnea index (AHI). Such data provide a strong platform to examine OSA outcomes in a chronic disease management model. However, there are no standards for capturing CPAP adherence data, scoring flow signals, or measuring mask leak, or for how clinicians should use these data., Methods: American Thoracic Society (ATS) committee members were invited, based on their expertise in OSA and CPAP monitoring. Their conclusions were based on both empirical evidence identified by a comprehensive literature review and clinical experience., Results: CPAP usage can be reliably determined from CPAP tracking systems, but the residual events (apnea/hypopnea) and leak data are not as easy to interpret as CPAP usage and the definitions of these parameters differ among CPAP manufacturers. Nonetheless, ends of the spectrum (very high or low values for residual events or mask leak) appear to be clinically meaningful., Conclusions: Providers need to understand how to interpret CPAP adherence tracking data. CPAP tracking systems are able to reliably track CPAP adherence. Nomenclature on the CPAP adherence tracking reports needs to be standardized between manufacturers and AHIFlow should be used to describe residual events. Studies should be performed examining the usefulness of the CPAP tracking systems and how these systems affect OSA outcomes.

Background: Patients in the ICU are thought to have abnormal circadian rhythms, but quantitative data are lacking., Methods: To investigate circadian rhythms in the ICU, we studied core body temperatures over a 48-h period in 21 patients (59 ± 11 years of age; eight men and 13 women)., Results: The circadian phase position for 17 of the 21 patients fell outside the published range associated with morningness/eveningness, which determines the normative range for variability among healthy normal subjects. In 10 patients, the circadian phase position fell earlier than the normative range; in seven patients, the circadian phase position fell later than the normative range. The mean ± SD of circadian displacement in either direction (advance or delay) was 4.44 ± 3.54 h. There was no significant day-to-day variation of the 24-h temperature profile within each patient. Stepwise linear regression was performed to determine if age, sex, APACHE (Acute Physiology and Chronic Health Evaluation) III score, or day in the ICU could predict the patient-specific magnitude of circadian displacement. The APACHE III score was found to be significantly predictive of circadian displacement., Conclusions: The findings indicate that circadian rhythms are present but altered in patients in the ICU, with the degree of circadian abnormality correlating with severity of illness.

Introduction: The obstructive sleep apnea syndrome (OSAS) is associated with increased visceral adipose tissue (VAT) in adults; however, few studies have evaluated VAT in relation to upper airway function in adolescents. We hypothesized that increased neck circumference (NC) and VAT would be associated with increased upper airway collapsibility., Methods: Adolescents (24 obese patients with OSAS, 22 obese control patients, and 29 lean control patients) underwent abdominal magnetic resonance imaging, and measurement of upper airway pressure-flow relationships in the activated and hypotonic upper airway states., Results: Patients with OSAS had a greater activated slope of the pressure-flow relationship (SPF) than control groups (P < 0.001), whereas hypotonic SPF was greater in both obese groups compared with lean control patients (P = 0.01). NC and VAT were greater in obese control patients and those with OSAS than in lean control patients (P < 0.001), but did not differ between obese patients with OSAS and obese control patients. In lean control patients and those with OSAS, increased NC was associated with increased activated SPF, whereas in obese control patients it was associated with decreased activated SPF (P = 0.03). In contrast, increased NC was associated with increased hypotonic SPF in all groups (P < 0.001). There was no significant effect of VAT on either activated or hypotonic SPF for any of the three groups., Conclusions: Increased neck circumference was associated with increased upper airway collapsibility in adolescents in the hypotonic but not activated state. These data suggest that obese adolescents without OSAS, despite a narrowed upper airway from adipose tissue, are protected from developing OSAS by upper airway neuromotor activation. Neither neck circumference nor visceral adipose tissue is useful in predicting upper airway collapsibility in obese adolescents.

We evaluated the effect of storage at 2 to 8°C on the stability of human genomic and human papillomavirus (HPV) DNA stored in BD SurePath and Hologic PreservCyt liquid-based cytology media. DNA retained the ability to be extracted and PCR amplified for more than 2.5 years in both medium types. Prior inability to detect DNA in archived specimens may have been due to failure of the extraction method to isolate DNA from fixed cells.

Objectives: To assess whether sleep apnea severity has an independent relationship with leptin levels in blood after adjusting for different measures of obesity and whether the relationship between obstructive sleep apnea (OSA) severity and leptin levels differs depending on obesity level., Methods: Cross-sectional study of 452 untreated OSA patients (377 males and 75 females), in the Icelandic Sleep Apnea Cohort (ISAC), age 54.3±10.6 (mean±s.d.), body mass index (BMI) 32.7±5.3 kg m(-2) and apnea-hypopnea index 40.2±16.1 events per h. A sleep study and magnetic resonance imaging of abdominal visceral and subcutaneous fat volume were performed, as well as fasting serum morning leptin levels were measured., Results: Leptin levels were more highly correlated with BMI, total abdominal and subcutaneous fat volume than visceral fat volume per se. No relationship was found between sleep apnea severity and leptin levels, assessed within three BMI groups (BMI <30, BMI 30-35 and BMI > or =35 kg m(-2)). In a multiple linear regression model, adjusted for gender, BMI explained 38.7% of the variance in leptin levels, gender explained 21.2% but OSA severity did not have a significant role and no interaction was found between OSA severity and BMI on leptin levels. However, hypertension had a significant effect on the interaction between OSA severity and obesity (P=0.04). In post-hoc analysis for nonhypertensive OSA subjects (n=249), the association between leptin levels and OSA severity explained a minor but significant variance (3.2%) in leptin levels. This relationship was greatest for nonobese nonhypertensive subjects (significant interaction with obesity level). No relationship of OSA severity and leptin levels was found for hypertensive subjects (n=199)., Conclusion: Obesity and gender are the dominant determinants of leptin levels. OSA severity is not related to leptin levels except to a minor degree in nonhypertensive nonobese OSA subjects.

Objectives/hypothesis: To quantitatively measure changes in airway caliber at multiple anatomical levels during drug-induced sleep endoscopy (DISE) for evaluation of sleep apnea. We hypothesize that patients undergoing DISE will show: 1) collapse at multiple upper airway regions (retropalatal, retroglossal, and retroepiglottic), with greater collapse in the retropalatal region; and 2) greater anterior-posterior dimensional narrowing than the lateral., Study Design: Case series., Methods: Patients underwent DISE employing propofol as part of a nonrandomized prospective trial assessing candidacy for transoral robotic surgery intervention for sleep apnea. Images of the retropalatal, retroglossal, and retroepiglottic regions were captured during an initial period of light sedation and again in a period of deep sedation. Images were analyzed using software to measure the percent change in regional airway measurements as a result of DISE., Results: Thirty-seven sleep endoscopy videos were analyzed from patients with obstructive sleep apnea (apnea-hypopnea index: 42.9 ± 27.0 events/hour). Analyzable images were in the retropalatal (n = 24), retroglossal (n = 27), and retroepiglottic (n = 29) regions. The patients demonstrated mean reductions in airway area in the retropalatal (84.1 ± 18.7%), retroglossal (39.3 ± 37.5%), and retroepiglottic region (44.6 ± 42.8%). No statistically significant differences were found between lateral and anterior-posterior airway dimensional changes., Conclusions: Patients undergoing DISE had significant reductions in airway area at multiple regions under deep sedation with propofol. We conclude that collapse in the retropalatal region is greater than the hypopharyngeal region. This method can be used to quantitatively measure DISE upper airway changes, which could potentially be used as a means for understanding surgical outcomes in patients with sleep apnea., (Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.)

Visceral adipose tissue (VAT) is associated with abnormal cardiovascular and metabolic profiles. Total VAT volume of the abdominal compartment by magnetic resonance imaging (MRI) is the gold-standard measurement for VAT but is costly and time consuming. Prior studies suggest VAT area on a single slice MR image may serve as a surrogate for total VAT volume but it is unknown if this relationship is maintained in overweight and obese men and women. Untreated sleep apnea subjects enrolled into the Icelandic Sleep Apnea Cohort (ISAC) underwent abdominal MRI. VAT area and subcutaneous adipose tissue (SAT) area at the L2-L3 and L4-L5 interspaces and total VAT and SAT volumes were determined by manual examination using image analysis software; 539 men and 129 women with mean ages of 54.1 and 58.8 years and mean BMI of 32.2 kg/m(2) and 33.7 kg/m(2), respectively, were studied. Mean total VAT volume was 40% smaller and mean total SAT was 25% larger among females compared with males. The correlation with VAT volume was significantly larger for L2-L3 VAT area (r = 0.96) compared to L4-L5 VAT area (r = 0.83). The difference in correlation coefficients was statistically significant (nonparametric bootstrap P < 0.001 with 95% confidence interval (CI) for the difference from 0.11 to 0.15. VAT area at L2-L3 was also significantly better correlated with VAT volume than traditional anthropometric variables. Linear regression analyses demonstrated that L2-L3 area alone was sufficient for predicting total VAT volume and that the nature of the linear association was maintained across all levels of obesity and in both genders.

Study Objectives: To assess the relative roles and interaction of obstructive sleep apnea (OSA) severity and obesity on interleukin-6 (IL-6) and C-reactive protein (CRP) levels., Design: Cross-sectional cohort., Setting: The Icelandic Sleep Apnea Cohort., Participants: 454 untreated OSA patients (380 males and 74 females), mean ± standard deviation age 54.4 ± 10.6 yr., Interventions: N/A., Measurements and Results: Participants underwent a sleep study, abdominal magnetic resonance imaging to measure total abdominal and visceral fat volume, and had fasting morning IL-6 and CRP levels measured in serum. A significantly higher correlation was found for BMI than visceral fat volume with CRP and IL-6 levels. Oxygen desaturation index, hypoxia time, and minimum oxygen saturation (SaO₂) significantly correlated with IL-6 and CRP levels, but apnea-hypopnea index did not. When stratified by body mass index (BMI) category, OSA severity was associated with IL-6 levels in obese participants only (BMI > 30 kg/m²). A multiple linear regression model with interaction terms showed an independent association of OSA severity with IL-6 levels and an interaction between OSA severity and BMI, i.e., degree of obesity altered the relationship between OSA and IL-6 levels. An independent association of OSA severity with CRP levels was found for minimum SaO₂ only. A similar interaction of OSA severity and BMI on CRP levels was found for males and postmenopausal women., Conclusions: OSA severity is an independent predictor of levels of IL-6 and CRP but interacts with obesity such that this association is found only in obese patients.