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Rates of cannabis initiation among teenagers and young adults are increasing. Further, the use of various forms of cannabis (smoked or vaped) with nicotine (dual use) is increasingly common among young people. The health effects of dual use are lesser known, particularly in the context of high-potency cannabis products and across different routes of administration, which is ominous in terms of predicting future health outcomes. There is a long history of cannabis use being associated with decreased activity and increased snacking, both of which could portend an increased risk of metabolic and cardiovascular disease, particularly when these habits begin during formative years. However, modern forms of cannabis may not have these same effects. Here, we assess whether cannabis use alone and dual use of cannabis with nicotine impact dietary and exercise habits in young people. An anonymous, social media-based survey was designed based on the UC San Diego Inhalant Questionnaire and published diet and exercise questionnaires. A total of 457 surveys were completed. Young sole cannabis users represented 29% of responders, 16% were dual users of cannabis and nicotine, and 55% were non-users of either drug. Although the sole use of cannabis was not associated with dietary or activity differences relative to non-users, dual users of cannabis and nicotine reported higher consumption of unhealthy sugars. This novel finding of dual use being associated with increased sugar intake in young people raises concerns for an increased risk of metabolic syndrome and cardiovascular disease in this population.

BackgroundPeople with serious mental illnesses (SMIs) have three-fold higher rates of comorbid insomnia than the general population, which has downstream effects on cognitive, mental, and physical health. Cognitive Behavioral Therapy for Insomnia (CBT-i) is a safe and effective first-line treatment for insomnia, though the therapy's effectiveness relies on completing nightly sleep diaries which can be challenging for some people with SMI and comorbid cognitive deficits. Supportive technologies such as mobile applications and sleep sensors may aid with completing sleep diaries. However, commercially available CBT-i apps are not designed for individuals with cognitive deficits. To aid with this challenge, we have developed an integrated mobile application, named "Sleep Catcher," that will automatically incorporate data from a wearable fitness tracker and a bed sensor to track nightly sleep duration, overnight awakenings, bed-times, and wake-times to generate nightly sleep diaries for CBT-i.MethodsThe application development process will be described-writing algorithms to generating useful data, creating a clinician web portal to oversee patients and the mobile application, and integrating sleep data from device platforms and user input.ResultsThe mobile and web applications were developed using Flutter, IBM Code Engine, and IBM Cloudant database. The mobile application was developed with a user-centered approach and incremental changes informed by a series of beta tests. Special user-interface features were considered to address the challenges of developing a simple and effective mobile application targeting people with SMI.ConclusionThere is strong potential for synergy between engineering and mental health expertise to develop technologies for specific clinical populations. Digital health technologies allow for the development of multi-disciplinary solutions to existing health disparities in vulnerable populations, particularly in people with SMI.

BackgroundObstructive sleep apnea (OSA) contributes to the generation, recurrence, and perpetuation of atrial fibrillation, and it is associated with worse outcomes. Little is known about the economic impact of OSA therapy in atrial fibrillation. This retrospective cohort study assessed the impact of positive airway pressure (PAP) therapy adherence on health care resource use and costs in patients with OSA and atrial fibrillation.Methods and resultsInsurance claims data for ≥1 year before sleep testing and 2 years after device setup were linked with objective PAP therapy use data. PAP adherence was defined from an extension of the US Medicare 90-day definition. Inverse probability of treatment weighting was used to create covariate-balanced PAP adherence groups to mitigate confounding. Of 5867 patients (32% women; mean age, 62.7 years), 41% were adherent, 38% were intermediate, and 21% were nonadherent. Mean±SD number of all-cause emergency department visits (0.61±1.21 versus 0.77±1.55 [P=0.023] versus 0.95±1.90 [P

Rationale: Oral appliances are second-line treatments after continuous positive airway pressure for obstructive sleep apnea (OSA) management. However, the need for oral appliance titration limits their use as a result of monitoring challenges to assess the treatment effect on OSA. Objectives: To assess the validity of mandibular jaw movement (MJM) automated analysis compared with polysomnography (PSG) and polygraphy (PG) in evaluating the effect of oral appliance treatment and the effectiveness of MJM monitoring for oral appliance titration at home in patients with OSA. Methods: This observational, prospective study included 135 patients with OSA eligible for oral appliance therapy. The primary outcome was the apnea-hypopnea index (AHI), measured through in-laboratory PSG/PG and MJM-based technology. Additionally, MJM monitoring at home was conducted at regular intervals during the titration process. The agreement between PSG/PG and MJM automated analysis was revaluated using Bland-Altman analysis. Changes in AHI during the home-based oral appliance titration process were evaluated using a generalized linear mixed model and a generalized estimating equation model. Results: The automated MJM analysis demonstrated strong agreement with PG in assessing AHI at the end of titration, with a median bias of 0.24/h (limits of agreement, -11.2 to 12.8/h). The improvement of AHI from baseline in response to oral appliance treatment was consistent across three evaluation conditions: in-laboratory PG (-59.6%; 95% confidence interval, -59.8% to -59.5%), in-laboratory automated MJM analysis (-59.2%; -65.2% to -52.2%), and at-home automated MJM analysis (-59.7%; -67.4% to -50.2%). Conclusions: Incorporating MJM automated analysis into the oral appliance titration process has the potential to optimize oral appliance therapy outcomes for OSA.

ObjectivePrevious studies have shown that treatment of obstructive sleep apnea (OSA) with positive airway pressure (PAP) therapy in patients with depression may improve depression symptoms and response to antidepressant therapy. We investigated the association between PAP therapy adherence, self-harm events, healthcare resource utilization (HCRU), and costs over 2 years in a national sample of patients with pre-existing depression and newly diagnosed comorbid OSA.MethodsAdministrative claims data were linked to objective PAP therapy usage. Inverse probability treatment weighting was used to compare outcomes over 2 years across PAP adherence levels. The predicted numbers of emergency room (ER) visits and hospitalizations by adherence level were assessed using risk-adjusted generalized linear models.Results37,459 patients were included. Relative to non-adherent patients, consistently adherent patients had fewer self-harm events (0.04 vs 0.05, p

Hypoxia-inducible factor pathway genes are linked to adaptation in both human and nonhuman highland species. EPAS1, a notable target of hypoxia adaptation, is associated with relatively lower hemoglobin concentration in Tibetans. We provide evidence for an association between an adaptive EPAS1 variant (rs570553380) and the same phenotype of relatively low hematocrit in Andean highlanders. This Andean-specific missense variant is present at a modest frequency in Andeans and absent in other human populations and vertebrate species except the coelacanth. CRISPR-base-edited human cells with this variant exhibit shifts in hypoxia-regulated gene expression, while metabolomic analyses reveal both genotype and phenotype associations and validation in a lowland population. Although this genocopy of relatively lower hematocrit in Andean highlanders parallels well-replicated findings in Tibetans, it likely involves distinct pathway responses based on a protein-coding versus noncoding variants, respectively. These findings illuminate how unique variants at EPAS1 contribute to the same phenotype in Tibetans and a subset of Andean highlanders despite distinct evolutionary trajectories.

BackgroundContinuation of continuous positive airway pressure (CPAP) therapy after initial prescription has been shown to reduce all-cause mortality versus therapy termination. However, there is a lack of data on the rates and impact of resuming CPAP in patients with obstructive sleep apnoea (OSA). This analysis determined the prevalence of CPAP resumption in the year after termination, characterised determinants of CPAP resumption, and examined the impact of CPAP resumption on all-cause mortality.MethodsFrench national health insurance reimbursement system data for adults aged ≥18 years were used. CPAP prescription was identified by specific treatment codes. Patients who resumed CPAP after first therapy termination and continued to use CPAP for 1 year were matched with those who resumed CPAP then terminated therapy for a second time.ResultsOut of 103 091 individuals with a first CPAP termination, 26% resumed CPAP over the next 12 months, and 65% of these were still using CPAP 1 year later. Significant predictors of CPAP continuation after resumption included male sex, hypertension and CPAP prescription by a pulmonologist. In the matched population, the risk of all-cause death was 38% lower in individuals who continued using CPAP after therapy resumption versus those who had a second therapy discontinuation (hazard ratio 0.62, 95% CI 0.48-0.79; p=0.0001).ConclusionThese data suggest that individuals with OSA who fail initial therapy with CPAP should be offered a second trial with the device to ensure that effective therapy is not withheld from those who might benefit.

BackgroundAchieving equitable access to medications for opioid use disorder (MOUD) such as buprenorphine is a pressing issue. Evidence suggests disparities in MOUD access based on race and socioeconomic status, further exacerbated by the COVID-19 pandemic. However, the drivers behind this access gap remain poorly understood. This study explores barriers to treatment access among individuals with opioid use disorder (OUD) experiencing homelessness.MethodsWe interviewed 28 individuals in and around the Boston Public Health Commission (BPHC) Engagement Center, an area known for its high density of active substance use and homelessness. We asked about people's experiences, perceptions, and attitudes toward OUD treatment. We conducted a thematic analysis of our interview data.ResultsFifty-four percent of participants sampled were not prescribed MOUD. None of the participants reported having an active prescription of sublingual buprenorphine or buprenorphine/naloxone. White participants were more likely to have been prescribed buprenorphine in the past compared to participants of other races even in this socioeconomically homogeneous sample. Themes that emerged in our data included challenges to accessing MOUD due to reduced services during the COVID-19 pandemic, lost or stolen medications, fewer inpatient withdrawal management beds for women, transportation challenges, fear of adverse effects of MOUD, the perception that taking MOUD replaces one addiction for another, and community disapproval of MOUD. Participants also reported stigma and discrimination based on race, gender, and socioeconomic status.ConclusionSystems and individual-level factors contribute to the MOUD treatment gap across race and socioeconomic status. The COVID-19 pandemic posed additional access challenges. This study provides important, actionable insights about the barriers faced by a particularly vulnerable population of individuals with OUD experiencing homelessness.

IntroductionIn high-burden settings, low-complexity screening tests for tuberculosis (TB) could expand the reach of community-based case-finding efforts. The potential costs and cost-effectiveness of approaches incorporating these tests are poorly understood.MethodsWe developed a microsimulation model assessing 3 approaches to community-based case-finding in hypothetical populations (India-, South Africa-, The Philippines-, Uganda-, and Vietnam-like settings) with TB prevalence 4 times that of national estimates: (1) screening with a point-of-care C-reactive protein (CRP) test, (2) screening with a more sensitive "Hypothetical Screening test" (95% sensitive for Xpert Ultra-positive TB, 70% specificity; equipment/labor costs similar to Xpert Ultra, but using a $2 cartridge) followed by sputum Xpert Ultra if positive, or (3) testing all individuals with sputum Xpert Ultra. Costs are expressed in 2023 US dollars and include treatment costs.ResultsUniversal Xpert Ultra was estimated to cost a mean $4.0 million (95% uncertainty range: $3.5 to $4.6 million) and avert 3200 (2600 to 3900) TB-related disability-adjusted life years (DALYs) per 100 000 people screened ($670 [The Philippines] to $2000 [Vietnam] per DALY averted). CRP was projected to cost $550 (The Philippines) to $1500 (Vietnam) per DALY averted but with 44% fewer DALYs averted. The Hypothetical Screening test showed minimal benefit compared to universal Xpert Ultra, but if specificity were improved to 95% and per-test cost to $4.5 (all-inclusive), this strategy could cost $390 (The Philippines) to $940 (Vietnam) per DALY averted.ConclusionsScreening tests can meaningfully improve the cost-effectiveness of community-based case-finding for TB but only if they are sensitive, specific, and inexpensive.

Sepsis remains a major cause of mortality and morbidity worldwide. Algorithms that assist with the early recognition of sepsis may improve outcomes, but relatively few studies have examined their impact on real-world patient outcomes. Our objective was to assess the impact of a deep-learning model (COMPOSER) for the early prediction of sepsis on patient outcomes. We completed a before-and-after quasi-experimental study at two distinct Emergency Departments (EDs) within the UC San Diego Health System. We included 6217 adult septic patients from 1/1/2021 through 4/30/2023. The exposure tested was a nurse-facing Best Practice Advisory (BPA) triggered by COMPOSER. In-hospital mortality, sepsis bundle compliance, 72-h change in sequential organ failure assessment (SOFA) score following sepsis onset, ICU-free days, and the number of ICU encounters were evaluated in the pre-intervention period (705 days) and the post-intervention period (145 days). The causal impact analysis was performed using a Bayesian structural time-series approach with confounder adjustments to assess the significance of the exposure at the 95% confidence level. The deployment of COMPOSER was significantly associated with a 1.9% absolute reduction (17% relative decrease) in in-hospital sepsis mortality (95% CI, 0.3%-3.5%), a 5.0% absolute increase (10% relative increase) in sepsis bundle compliance (95% CI, 2.4%-8.0%), and a 4% (95% CI, 1.1%-7.1%) reduction in 72-h SOFA change after sepsis onset in causal inference analysis. This study suggests that the deployment of COMPOSER for early prediction of sepsis was associated with a significant reduction in mortality and a significant increase in sepsis bundle compliance.

Sleep health is an essential component to overall health. Because of numerous societal, economic, and biological factors, obtaining adequate sleep poses a unique challenge to aging women. Yet, women have been traditionally understudied in sleep research. An increasing body of research supports abnormal sleep duration as a risk factor for obesity, cardiovascular disease, and mortality. This review focuses specifically on 3 areas of the discussion of insufficient sleep in women: (1) the mysterious poor health of long sleepers, (2) the potential underlying mechanisms linking abnormal sleep duration and cardiometabolic health, and (3) the need to investigate multiple levels of social determinants driving sleep disparities.

ObjectiveIn an earlier study, several tested International Pharmaceutical Federation (FIP) pictograms did not achieve validity among older adults in Singapore. In this study, for 27 unvalidated FIP pictograms, we (1) developed variants of each pictogram, (2) elicited the most-preferred variant, and (3) assessed the validity of the most-preferred variant among older Singaporeans.MethodsIn phase 1, up to three variants of the 27 pictograms were developed, based on older adults' feedback from a previous study. In phase 2, the most-preferred variant of 26 pictograms, which had two or three variants, was selected by 100 older participants. In phase 3, the 27 most-preferred variants (including the pictogram with only one variant) were assessed for validity - transparency and translucency - among 278 older participants (10 pictograms per participant). To evaluate transparency, participants were first asked: "If you see this picture on a medicine label, what do you think it means?" for each assigned pictogram. If they responded, they were asked, "How do you know?", and if not, they were told, "Tell me everything you see in this picture". Then, participants were shown their assigned pictograms again, one by one, and the pictogram's intended meaning was revealed to evaluate translucency. Pictograms were classified as valid (≥66% participants interpreted its intended meaning correctly [transparency criterion] and ≥85% participants rated its representativeness as ≥ 5 [translucency criterion]), partially valid (only transparency criterion fulfilled) or not valid.ResultsIn phase 1, 77 variants of the 27 pictograms were developed. In phase 2, a majority of the most-preferred variants were selected by >50% participants. In phase 3, 10 (37.0%) of the 27 pictograms tested were considered valid, and five (18.5%) were partially valid. A higher proportion of pictograms portraying dose and route of administration and precautions were valid or partially valid, versus those depicting indications or side effects.ConclusionContextual redesigning and selection of pharmaceutical pictograms, which initially failed to achieve validity in a population, contributed to their validation.InnovationThe redesigned validated pictograms from this study can be incorporated into relevant patient information materials in clinical practice.

IntroductionRetrospective studies report that angiotensin-converting enzyme inhibitors (ACEIs) may reduce the severity of COVID-19, but prospective data on de novo treatment with ACEIs are limited. The RAMIC trial was a randomized, multicenter, placebo-controlled, double-blind, allocation-concealed clinical trial to examine the efficacy of de novo ramipril versus placebo for the treatment of COVID-19.MethodsEligible participants were aged 18 years and older with a confirmed diagnosis of SARS-CoV-2 infection, recruited from urgent care clinics, emergency departments, and hospital inpatient wards at eight sites in the USA. Participants were randomly assigned to daily ramipril 2.5 mg or placebo orally in a 2:1 ratio, using permuted block randomization. Analyses were conducted on an intention-to-treat basis. The primary outcome was a composite of mortality, intensive care unit (ICU) admission, or invasive mechanical ventilation by day 14.ResultsBetween 27 May 2020 and 19 April 2021, a total of 114 participants (51% female) were randomized to ramipril (n = 79) or placebo (n = 35). The overall mean (± SD) age and BMI were 45 (± 15) years and 33 (± 8) kg/m2. Two participants in the ramipril group required ICU admission and one died, compared with none in the placebo group. There were no significant differences between ramipril and placebo in the primary endpoint (ICU admission, mechanical ventilation, or death) (3% versus 0%, p = 1.00) or adverse events (27% versus 29%, p = 0.82). The study was terminated early because of a low event rate and subsequent Emergency Use Authorization of therapies for COVID-19.ConclusionDe novo ramipril was not different compared with placebo in improving or worsening clinical outcomes from COVID-19 but appeared safe in non-critically ill patients with COVID-19.Trial registrationClinicaltrials.gov NCT04366050.

Obesity is a chronic disease affecting over 670 million adults globally, with multiple complications including obstructive sleep apnea (OSA). Substantial weight loss in patients with obesity-related OSA can reduce or even eliminate OSA as well as reduce sleepiness and improve cardio-metabolic health. Evidence suggests that these improvements exceed those that occur with device-based OSA therapies like continuous positive airway pressure which continue to be the first-line of therapy. Resistance to weight management as a first-line strategy to combat OSA could arise from the complexities in delivering and maintaining adequate weight management, particularly in sleep clinic settings. Recently, incretin-based pharmacotherapies including glucagon-like peptide 1 (GLP-1) receptor agonists alone or combined with glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have been developed to target glycemic control in type 2 diabetes. These medications also slow gastric emptying and reduce energy intake. In randomized, placebo-controlled trials of these medications in diabetic and non-diabetic populations with obesity, participants on active medication lost up to 20% of their body weight, with corresponding improvements in blood pressure, lipid levels, physical functioning, and fat mass loss. Their adverse effects are predominantly gastrointestinal-related, mild, and transient. There are trials currently underway within individuals with obesity-related OSA, with a focus on reduction in weight, OSA severity, and cardio-metabolic outcomes. These medications have the potential to substantially disrupt the management of OSA. Pending coming data, we will need to consider pharmacological weight loss as a first-line therapy and how that influences training and management guidelines.

AimTo determine the association between total sleep time (TST) spent in increased respiratory effort (RE) and the prevalence of type 2 diabetes in a large cohort of individuals with suspected obstructive sleep apnoea (OSA) referred for in-laboratory polysomnography (PSG).Materials and methodsWe conducted a retrospective cross-sectional study using the clinical data of 1128 patients. Non-invasive measurements of RE were derived from the sleep mandibular jaw movements (MJM) bio-signal. An explainable machine-learning model was built to predict prevalent type 2 diabetes from clinical data, standard PSG indices, and MJM-derived parameters (including the proportion of TST spent with increased respiratory effort [REMOV [%TST]).ResultsOriginal data were randomly assigned to training (n = 853) and validation (n = 275) subsets. The classification model based on 18 input features including REMOV showed good performance for predicting prevalent type 2 diabetes (sensitivity = 0.81, specificity = 0.89). Post hoc interpretation using the Shapley additive explanation method found that a high value of REMOV was the most important risk factor associated with type 2 diabetes after traditional clinical variables (age, sex, body mass index), and ahead of standard PSG metrics including the apnoea-hypopnea and oxygen desaturation indices.ConclusionsThese findings show for the first time that the proportion of sleep time spent in increased RE (assessed through MJM measurements) is an important predictor of the association with type 2 diabetes in individuals with OSA.

Syndromic conditions, such as sepsis, are commonly encountered in the intensive care unit. Although these conditions are easy for clinicians to grasp, these conditions may limit the performance of machine-learning algorithms. Individual hospital practice patterns may limit external generalizability. Data missingness is another barrier to optimal algorithm performance and various strategies exist to mitigate this. Recent advances in data science, such as transfer learning, conformal prediction, and continual learning, may improve generalizability of machine-learning algorithms in critically ill patients. Randomized trials with these approaches are indicated to demonstrate improvements in patient-centered outcomes at this point.

Study objectivesObstructive sleep apnea is a prevalent disease with well-known complications when left untreated. Advances in sleep-disordered breathing diagnosis may increase detection and appropriate treatment. The Wesper device is a recently developed portable system with specialized wearable patches that can measure respiratory effort, derived airflow, estimated air pressure, and body position. This study sought to compare the diagnostic ability of the novel Wesper device with the gold standard of polysomnography.MethodsPatients enrolled in the study underwent simultaneous polysomnography and Wesper device testing in a sleep laboratory setting. Data were collected and scored by readers blinded to all patient information, and the primary reader was blinded to testing method. The accuracy of the Wesper device was determined by calculation of the Pearson correlation and Bland-Altman limits of agreement of apnea-hypopnea indices between testing methods. Adverse events were also recorded.ResultsA total of 53 patients were enrolled in the study and 45 patients were included in the final analysis. Pearson correlation between polysomnography and Wesper device apnea-hypopnea index determinations was 0.951, which met the primary endpoint goal (P = .0003). The Bland-Altman 95% limits of agreement were -8.05 and 6.38, which also met the endpoint goal (P < .001). There were no adverse events or serious adverse events noted.ConclusionsThe Wesper device compares favorably with gold-standard polysomnography. Given the lack of safety concerns, we advocate for further study regarding its utility in diagnosis and management of sleep apnea in the future.CitationRaphelson JR, Ahmed IM, Ancoli-Israel S, et al. Evaluation of a novel device to assess obstructive sleep apnea and body position. J Clin Sleep Med. 2023;19(9):1643-1649.

PurposeFollowing curative-intent therapy of lung cancer, many survivors experience dyspnea and physical inactivity. We investigated the feasibility, acceptability, safety, and potential efficacy of inspiratory muscle training (IMT) and walking promotion to disrupt a postulated "dyspnea-inactivity" spiral.MethodsBetween January and December 2022, we recruited lung cancer survivors from Kaiser Permanente Colorado who completed curative-intent therapy within 1-6 months into a phase-IIb, parallel-group, pilot randomized trial (1:1 allocation). The 12-week intervention, delivered via telemedicine, consisted of exercise training (IMT + walking), education, and behavior change support. Control participants received educational materials on general exercise. We determined feasibility a priori: enrollment of ≥ 20% eligible patients, ≥ 75% retention, study measure completion, and adherence. We assessed acceptability using the Telemedicine-Satisfaction-and-Usefulness-Questionnaire and safety events that included emergency department visits or hospitalizations. Patient-centered outcome measures (PCOMs) included dyspnea (University-of-California-San-Diego-Shortness-of-Breath-Questionnaire), physical activity (activPAL™ steps/day), functional exercise capacity (mobile-based-six-minute-walk-test), and health-related quality of life (HRQL, St.-George's-Respiratory-Questionnaire). We used linear mixed-effects models to assess potential efficacy.ResultsWe screened 751 patients, identified 124 eligible, and consented 31 (25%) participants. Among 28 participants randomized (14/group), 22 (11/group) completed the study (79% retention). Intervention participants returned > 90% of self-reported activity logs, completed > 90% of PCOMs, and attended > 90% of tele-visits; 75% of participants performed IMT at the recommended dose. Participants had high satisfaction with tele-visits and found the intervention useful. There was no statistically significant difference in safety events between groups. Compared to control participants from baseline to follow-up, intervention participants had statistically significant and clinically meaningful improved HRQL (SGRQ total, symptom, and impact scores) (standardized effect size: -1.03 to -1.30).ConclusionsAmong lung cancer survivors following curative-intent therapy, telemedicine-based IMT + walking was feasible, acceptable, safe, and had potential to disrupt the "dyspnea-inactivity" spiral. Future efficacy/effectiveness trials are warranted and should incorporate IMT and walking promotion to improve HRQL.Trial registrationClinicalTrials.gov NCT05059132.

Study objectivesThe coexistence of obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) in a single individual, also known as overlap syndrome (OVS), is associated with higher cardiovascular risk and mortality than either OSA or COPD alone. However, the underlying mechanisms remain unclear. We hypothesized that patients with OVS have elevated systemic inflammatory biomarkers relative to patients with either disease alone, which could explain greater cardiovascular risk observed in OVS.MethodsWe included 255 participants in the study, 55 with COPD alone, 100 with OSA alone, 50 with OVS, and 50 healthy controls. All participants underwent a home sleep study, spirometry, and a blood draw for high-sensitivity C-reactive protein and total blood count analysis. In a randomly selected subset of 186 participants, inflammatory protein profiling was performed using Bio-Rad Bio-Plex Pro Human Cytokine 27-Plex Assays. Biomarker level differences across groups were identified using a mixed linear model.ResultsLevels of interleukin 6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), and granulocyte colony stimulating factor (G-CSF) were higher in participants with OVS and COPD compared with healthy controls and participants with OSA. Furthermore, participants with OVS had higher circulating levels of leukocytes and neutrophils than those with COPD, OSA, and controls.ConclusionsCOPD and OVS are associated with higher systemic inflammation relative to OSA and healthy controls. This work proposes the potential utilization of interleukin 6, granulocyte colony stimulating factor, and high-sensitivity C-reactive protein as screening biomarkers for COPD in patients with OSA. Inflammatory pathways may not fully explain the higher cardiovascular risk observed in OVS, indicating the need for further investigation.CitationSanchez-Azofra A, Gu W, Masso-Silva JA, et al. Inflammation biomarkers in OSA, chronic obstructive pulmonary disease, and chronic obstructive pulmonary disease/OSA overlap syndrome. J Clin Sleep Med. 2023;19(8):1447-1456.

BackgroundMany cellular processes are controlled by sleep. Therefore, alterations in sleep might be expected to stress biological systems that could influence malignancy risk.Research questionWhat is the association between polysomnographic measures of sleep disturbances and incident cancer, and what is the validity of cluster analysis in identifying polysomnography phenotypes?Study design and methodsWe conducted a retrospective multicenter cohort study using linked clinical and provincial health administrative data on consecutive adults free of cancer at baseline with polysomnography data collected between 1994 and 2017 in four academic hospitals in Ontario, Canada. Cancer status was derived from registry records. Polysomnography phenotypes were identified by k-means cluster analysis. A combination of validation statistics and distinguishing polysomnographic features was used to select clusters. Cox cause-specific regressions were used to assess the relationship between identified clusters and incident cancer.ResultsAmong 29,907 individuals, 2,514 (8.4%) received a diagnosis of cancer over a median of 8.0 years (interquartile range, 4.2-13.5 years). Five clusters were identified: mild (mildly abnormal polysomnography findings), poor sleep, severe OSA or sleep fragmentation, severe desaturations, and periodic limb movements of sleep (PLMS). The associations between cancer and all clusters compared with the mild cluster were significant while controlling for clinic and year of polysomnography. When additionally controlling for age and sex, the effect remained significant only for PLMS (adjusted hazard ratio [aHR], 1.26; 95% CI, 1.06-1.50) and severe desaturations (aHR, 1.32; 95% CI, 1.04-1.66). Further controlling for confounders, the effect remained significant for PLMS, but was attenuated for severe desaturations.InterpretationIn a large cohort, we confirmed the importance of polysomnographic phenotypes and highlighted the role that PLMS and oxygenation desaturation may play in cancer. Using this study's findings, we also developed an Excel (Microsoft) spreadsheet (polysomnography cluster classifier) that can be used to validate the identified clusters on new data or to identify which cluster a patient belongs to.Trial registryClinicalTrials.gov; Nos.: NCT03383354 and NCT03834792; URL: www.Clinicaltrialsgov.

PurposeCardiac rehabilitation (CR) improves clinical outcomes in patients with cardiovascular disease (CDV). Patients with CVD often have multiple comorbidities, including obstructive sleep apnea (OSA), potentially affecting their ability to participate and achieve functional improvement during CR. We aimed to test the hypothesis that OSA reduces peak exercise capacity (EC) in patients undergoing CR and to explore if OSA treatment modifies this relationship.MethodsData from a retrospective cohort of CR patients was analyzed. OSA was defined as a respiratory event index > 5/h or physician diagnosis. Patients with OSA were considered "treated" if using continuous positive airway pressure regularly during the CR period. Change in METs was the primary study outcome.ResultsAmong 312 CR patients, median age of 67 years, 103 (33%) had known OSA (30 treated, 73 untreated). Patients with OSA vs. those with no OSA were more likely to be obese and male; otherwise, groups were similar. Compared with the no OSA group, patients with OSA had lower pre-CR METs (3.3 [2.9-4.5] vs. 3.9 [3.1-5], P = .01) and lower post-CR METs (5.3 [4-7] vs. 6 [4.6-7.6], P = .04), but achieved a similar increase in METs post-CR (1.8 [0.6-2.6] vs. 2.0 [0.9-3], P = .22). Furthermore, compared to no OSA, pre-CR and post-CR METs tended to be similar in patients with treated OSA, but lower in untreated patients, with similar increases in METs across all groups, even when adjusting for covariates via multivariable regression.ConclusionOSA is prevalent in patients with CVD undergoing CR. CR substantially improves exercise capacity independent of OSA status, but screening for-and treatment of-OSA may improve the absolute exercise capacity achieved through CR.

PurposeTo assess if a novel automated method to spatially delineate and quantify the extent of hypoperfusion on multienergy CT angiograms can aid the evaluation of chronic thromboembolic pulmonary hypertension (CTEPH) disease severity.Materials and methodsMultienergy CT angiograms obtained between January 2018 and December 2020 in 51 patients with CTEPH (mean age, 47 years ± 17 [SD]; 27 women) were retrospectively compared with those in 110 controls with no imaging findings suggestive of pulmonary vascular abnormalities (mean age, 51 years ± 16; 81 women). Parenchymal iodine values were automatically isolated using deep learning lobar lung segmentations. Low iodine concentration was used to delineate areas of hypoperfusion and calculate hypoperfused lung volume (HLV). Receiver operating characteristic curves, correlations with preoperative and postoperative changes in invasive hemodynamics, and comparison with visual assessment of lobar hypoperfusion by two expert readers were evaluated.ResultsGlobal HLV correctly separated patients with CTEPH from controls (area under the receiver operating characteristic curve = 0.84; 10% HLV cutoff: 90% sensitivity, 72% accuracy, and 64% specificity) and correlated moderately with hemodynamic severity at time of imaging (pulmonary vascular resistance [PVR], ρ = 0.67; P < .001) and change after surgical treatment (∆PVR, ρ = -0.61; P < .001). In patients surgically classified as having segmental disease, global HLV correlated with preoperative PVR (ρ = 0.81) and postoperative ∆PVR (ρ = -0.70). Lobar HLV correlated moderately with expert reader lobar assessment (ρHLV = 0.71 for reader 1; ρHLV = 0.67 for reader 2).ConclusionAutomated quantification of hypoperfused areas in patients with CTEPH can be performed from clinical multienergy CT examinations and may aid clinical evaluation, particularly in patients with segmental-level disease.Keywords: CT-Spectral Imaging (Multienergy), Pulmonary, Pulmonary Arteries, Embolism/Thrombosis, Chronic Thromboembolic Pulmonary Hypertension, Multienergy CT, Hypoperfusion© RSNA, 2023.

BackgroundEvaluation and interpretation of the literature on obstructive sleep apnea (OSA) allows for consolidation and determination of the key factors important for clinical management of the adult OSA patient. Toward this goal, an international collaborative of multidisciplinary experts in sleep apnea evaluation and treatment have produced the International Consensus statement on Obstructive Sleep Apnea (ICS:OSA).MethodsUsing previously defined methodology, focal topics in OSA were assigned as literature review (LR), evidence-based review (EBR), or evidence-based review with recommendations (EBR-R) formats. Each topic incorporated the available and relevant evidence which was summarized and graded on study quality. Each topic and section underwent iterative review and the ICS:OSA was created and reviewed by all authors for consensus.ResultsThe ICS:OSA addresses OSA syndrome definitions, pathophysiology, epidemiology, risk factors for disease, screening methods, diagnostic testing types, multiple treatment modalities, and effects of OSA treatment on multiple OSA-associated comorbidities. Specific focus on outcomes with positive airway pressure (PAP) and surgical treatments were evaluated.ConclusionThis review of the literature consolidates the available knowledge and identifies the limitations of the current evidence on OSA. This effort aims to create a resource for OSA evidence-based practice and identify future research needs. Knowledge gaps and research opportunities include improving the metrics of OSA disease, determining the optimal OSA screening paradigms, developing strategies for PAP adherence and longitudinal care, enhancing selection of PAP alternatives and surgery, understanding health risk outcomes, and translating evidence into individualized approaches to therapy.

Cannabis use is growing among older adults to manage medical concerns including poor sleep. In this study, we characterized how patients seen at a geriatrics clinic use cannabis to address sleep disturbance. Specifically, we conducted an anonymous survey of 568 adults, including 83 who reported cannabis use within the past 3 years, to inquire about such use. We compared cannabis use characteristics between those using it for sleep disturbance versus all other conditions. We considered a p-value

Purpose of reviewTo synthesize the existing literature regarding the complex interplay between sleep disturbance, obesity, and diabetes. The review emphasizes the three pillars of health being diet, exercise, and sleep, with the notion that if one is ignored, then the other two could suffer.Recent findingsSleep deprivation is associated with incident obesity, perhaps mediated by dysregulation in leptin and ghrelin - hormones important in regulation of appetite. Sleep apnea is very common particularly among obese people with type 2 diabetes mellitus. Treatment of sleep apnea has clear symptomatic benefits although its impact on long-term cardiometabolic health is less clear. Sleep disturbance may be an important modifiable risk for patients at risk of cardiometabolic disease. An assessment of sleep health may be an important component of the comprehensive care of patients with obesity and diabetes mellitus.

Study objectivesSleep-disordered breathing (SDB) is common in patients with congestive heart failure and has important implications regarding symptoms and prognosis. However, the burden of SDB on those with heart failure has not been well characterized in developing countries, including Mozambique in sub-Saharan Africa. Diagnosing SDB in individuals with congestive heart failure is important because treatment of SDB may improve outcomes.MethodsBetween September 2014 and April 2017, patients hospitalized in a specialized cardiology unit in Maputo, Mozambique with decompensated congestive heart failure were recruited using convenience sampling. We determined the prevalence of SDB and associated risk factors.ResultsA total of 165 patients were recruited, of which 145 had evaluable sleep study data. The overall prevalence of SDB in patients with decompensated congestive heart failure was 72%, and of these 46% had Cheyne-Stokes respirations. Male sex, higher body mass index, and lower left ventricular ejection fraction were all associated with a higher likelihood of SDB and more severe SDB. Cheyne-Stokes respirations were associated with male sex, lower ejection fraction, and larger left atrial size.ConclusionsWe conclude that in sub-Saharan Africa SDB is common in decompensated congestive heart failure and strongly predicted by demographic and echocardiographic parameters. This study highlights the need for the development of diagnostic tools and management strategies for patients with severe heart failure in resource-limited settings.CitationLo S, Mbanze I, Orr JE, et al. The prevalence of sleep-disordered breathing and associated risk factors in patients with decompensated congestive heart failure in Mozambique. J Clin Sleep Med. 2023;19(6):1103-1110.

ImportanceEvidence is lacking from randomized clinical trials of hypoglossal nerve stimulation in obstructive sleep apnea (OSA).ObjectiveTo evaluate the safety and effectiveness of targeted hypoglossal nerve stimulation (THN) of the proximal hypoglossal nerve in patients with OSA.Design, setting, and participantsThis randomized clinical trial (THN3) was conducted at 20 centers and included 138 patients with moderate to severe OSA with an apnea-hypopnea index (AHI) of 20 to 65 events per hour and body mass index (calculated as weight in kilograms divided by height in meters squared) of 35 or less. The trial was conducted from May 2015 through June 2018. Data were analyzed from January 2022 through January 2023.InterventionImplant with THN system; randomized 2:1 to activation at month 1 (treatment) or month 4 (control). All received 11 months of THN with follow-up at months 12 and 15, respectively.Main outcomes and measuresPrimary effectiveness end points comprised AHI and oxygen desaturation index (ODI) responder rates (RRs). Treatment responses at months 4 and 12/15 were defined as a 50% or greater reduction in AHI to 20 or less per hour and an ODI decrease of 25% or greater. Coprimary end points comprised (1) month 4 AHI and ODI RR in the treatment greater than the control group and (2) month 12/15 AHI and ODI RR in the entire cohort exceeding 50%. Secondary end points included sleep apnea severity (AHI and ODI) and patient-reported outcomes (Epworth Sleepiness Scale, Functional Outcomes of Sleep Questionnaire, and EQ-5D visual analog scale).ResultsAmong 138 participants, the mean (SD) age was 56 (9) years, and 19 (13.8%) were women. Month 4 THN RRs were substantially greater in those in the treatment vs control group (AHI, 52.3% vs 19.6%; ODI, 62.5% vs 41.3%, respectively) with treatment-control standardized mean differences of 0.725 (95% CI, 0.360-1.163) and 0.434 (95% CI, 0.070-0.843) for AHI and ODI RRs, respectively. Months 12/15 RRs were 42.5% and 60.4% for AHI and ODI, respectively. Improvements in AHI, ODI, Epworth Sleepiness Scale, Functional Outcomes of Sleep Questionnaire, and EQ-5D visual analog scale scores were all clinically meaningful (medium to large effect size). Two serious adverse events and 100 nonserious related adverse events were observed from the implant procedure or study protocol.Conclusions and relevanceThis randomized clinical trial found that THN demonstrated improvements in sleep apnea, sleepiness, and quality of life in patients with OSAs over an extended AHI and body mass index range without prior knowledge of pharyngeal collapse pattern. Clinically meaningful improvements in AHI and patient-reported responses compared favorably with those of distal hypoglossal nerve stimulation trials, although clinically meaningful differences were not definitive for ODI.Trial registrationClinicalTrials.gov Identifier: NCT02263859.

IntroductionIn resource-limited settings, obstructive sleep apnea (OSA) often goes undiagnosed as polysomnography (PSG) is expensive, time-consuming, and not readily available. Imaging studies of upper airway have been tried as alternatives to PSG to screen for OSA. However, racial differences in upper airway anatomy preclude generalizability of such studies. We sought to test the hypothesis that ultrasonography (USG), an inexpensive, readily available tool to study soft tissue structures of the upper airway, would have predictive value for OSA in South Asian people.MethodsAdult patients with sleep-related complaints suspicious for OSA were taken for overnight PSG. After the PSG, consecutive patients with and without OSA were studied with submental ultrasonography to measure tongue base thickness (TBT) and lateral pharyngeal wall thickness (LPWT).ResultsAmong 50 patients with OSA and 25 controls, mean age was 43.9 ± 11.4 years, and 39 were men. Patients with OSA had higher TBT (6.77 ± 0.63 cm vs 6.34 ± 0.54 cm, P value = 0.004) and higher LPWT (2.47 ± 0.60 cm vs 2.12 ± 0.26 cm, P value = 0.006) compared to patients without OSA. On multivariate analysis, TBT, LPWT, and neck circumference were identified as independent factors associated with OSA. These variables could identify patients with severe OSA with a sensitivity of 72% and a specificity of 76%.ConclusionPatients with OSA have higher tongue base thickness and lateral pharyngeal wall thickness proportionate to the severity of the disease, independent of BMI and neck circumference. These findings suggest that sub-mental ultrasonography may be useful to identify patients with severe OSA in resource-limited settings.

ObjectivesObesity is a risk factor for obstructive sleep apnea (OSA) in children. Childhood obesity rates vary amongst different ethnic groups. Here the interaction of Hispanic ethnicity and obesity on OSA risk was evaluated.MethodsRetrospective cross-sectional analysis of consecutive children undergoing polysomnography and anthropometry using bioelectrical impedance from 2017 to 2020. Demographics obtained from the medical chart. Children who had also undergone cardiometabolic testing were identified and the relationship of cardiometabolic markers with OSA and anthropometry was assessed.ResultsData from 1217 children revealed Hispanic children were more likely to have moderate-severe OSA (36.0%) compared to Non-Hispanic children (26.5%), p

Rationale: Clear definition of optimal positive airway pressure therapy usage in patients with obstructive sleep apnea is not possible because of scarce data on the relationship between usage hours and major clinical outcomes. Objective: To investigate the dose-response relationship between positive airway pressure usage and healthcare resource utilization and determine the minimum device usage required for benefit. Methods: A linked data set combined deidentified payer-sourced administrative medical/pharmacy claims data from more than 100 U.S. health plans and individual patient positive airway pressure usage data. Eligible adults (age ⩾18 yr) had a new obstructive sleep apnea diagnosis between June 2014 and April 2018. All received positive airway pressure therapy (AirSense 10; ResMed) with claims data for ⩾1 year before, and 2 years after, device setup. Healthcare resource utilization was determined on the basis of the number of all-cause hospitalizations and emergency room visits over 3, 12, and 24 months after positive airway pressure initiation. Results: Data from 179,188 patients showed a clear dose-response relationship between daily positive airway pressure usage and healthcare utilization. Minimum device usage required for benefit was 1-3 hours per night. There was a statistically significant decrease in hospitalizations and emergency room visits at all time points (all Ps

PurposeObstructive sleep apnea (OSA) is underdiagnosed, partially from variable clinical presentations. Emphasis is often placed on Epworth Sleepiness Scale (ESS), a subjective measure of sleepiness, but variable in OSA. We hypothesized that daytime complaints measured with Language of Sleepiness Questionnaire (LOS) in OSA are not being captured by ESS.MethodsAdults referred to a tertiary sleep clinic undergoing sleep studies completed ESS and LOS questionnaires (20 items with various patient-reported descriptors). LOS was examined in patients who had or did not have OSA without sleepiness based on ESS

Background Obstructive sleep apnea (OSA) is a common comorbidity in patients with heart failure, although current evidence is equivocal regarding the potential benefits of treating OSA with positive airway pressure (PAP) therapy in patients with heart failure. This study assessed the impact of adherence to PAP therapy on health care resource utilization in patients with OSA and heart failure with reduced ejection fraction. Methods and Results Administrative insurance claims data linked with objective PAP therapy use data from patients with OSA and heart failure with reduced ejection fraction were used to determine associations between PAP adherence and a composite outcome of hospitalizations and emergency room visits. One-year PAP adherence was based on an adapted US Medicare definition. Propensity score methods were used to create groups with similar characteristics across PAP adherence levels. The study cohort included 3182 patients (69.9% male, mean age 59.7 years); 39% were considered adherent to PAP therapy (29% intermediate adherent, 31% nonadherent). One year after PAP initiation, adherent patients had fewer composite visits than matched nonadherent patients, driven by a 24% reduction in emergency room visits for adherent patients. Composite visit costs were lower in adherent versus nonadherent patients ($3500 versus $5879, P=0.031), although total health care costs were not statistically different ($13 028 versus $14 729, P=0.889). Conclusions PAP therapy adherence in patients with OSA with heart failure with reduced ejection fraction was associated with a reduction in health care resource utilization. This suggests that greater emphasis should be placed on diagnosing and effectively treating OSA with PAP in patients with heart failure with reduced ejection fraction.

PurposeObstructive sleep apnea (OSA)-related pulmonary hypertension (PH) can often be reversed with treatment of OSA via continuous positive airway pressure. We hypothesized that treatment of OSA would be associated with a greater improvement in exercise capacity (EC) with cardiac rehabilitation (CR), especially in patients with PH as compared with those who are untreated.MethodsWe reviewed medical records of 315 consecutive patients who participated in CR. Pulmonary hypertension status was assessed on the basis of peak tricuspid regurgitant velocity (>2.8 m/sec) on pre-CR echocardiograms. The OSA status (no, untreated, or treated OSA) was determined on the basis of results from sleep studies, continuous positive airway pressure device data, and physician notes. Exercise capacity was assessed by measuring metabolic equivalents (METs) using a treadmill stress test before and after CR.ResultsWe included 290 patients who participated in CR with available echocardiographic data: 44 (15%) had PH, and 102 (35%) had known OSA (30 treated and 72 untreated). Patients with OSA versus those with no OSA were more likely to have PH ( P = .06). Patients with PH versus no-PH were associated with significantly lower baseline METs in crude and adjusted analyses ( P ≤. 004). The PH and OSA status in isolation were not associated with changes in METs ( P > .2) with CR. There was a significant interaction between OSA treatment and PH in crude and adjusted analyses ( P ≤.01): treatment vs no treatment of OSA was associated with a clinically and statistically greater improvement in METs in patients who participated in CR with but not without PH.ConclusionBaseline PH was associated with decreased baseline EC but did not attenuate CR-related improvements in METs. However, in the subset of OSA patients with PH, OSA therapy was associated with improved EC after CR.

IntroductionObstructive sleep apnea (OSA) is a common disorder with major neurocognitive and cardiovascular sequelae. The treatment of symptomatic patients with mild OSA remains controversial given that adherence to positive airway pressure (PAP) has historically been suboptimal. With this notion in mind, we assessed a daily transoral neuromuscular electrical stimulation (NMES) device for individuals with mild OSA.MethodsThe sample represents a subset of participants with a baseline AHI 5-14.9 events/hour, drawn from a parent study which also included participants with primary snoring. Outcome measures for the current study included changes in apnea-hypopnea index (AHI), Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI) and snoring levels before and after use of the NMES.  RESULTS: Among 65 participants (68% men) with median age of 49 years (range 24 to 79) and median BMI of 27.7 kg/m2 (range 20 to 34), the NMES device was used daily for 6 weeks. We observed a significant improvement in the AHI from 10.2 to 6.8 events/hour among all participants and from 10.4 to 5.0 events/h among responders. Statistically significant improvements in the ESS, PSQI, objectively measured snoring, and bed partner-reported snoring were observed. Adherence among all participants was 85%.DiscussionThis NMES device has the benefit of being a treatment modality of daytime therapy which confers a high level of tolerability and patient acceptance. It alleviates the need for an in situ device during sleep and leads to improvements in OSA severity, snoring, and subjective sleep metrics, potentially crucial in mild OSA. Further studies are needed to define which individuals may benefit most from the device across the wider spectrum of OSA severity and assess long-term therapeutic outcomes.Trial registrationClinicalTrials.gov Identifier: NCT03829956.

PurposeSleep disordered breathing in decompensated heart failure has physiological consequences (e.g., intermittent hypoxemia) that may predispose to subclinical myocardial injury, yet a temporal relationship between sleep apnea and troponin elevation has not been established.MethodsWe assessed the feasibility of performing respiratory polygraphy and measuring overnight high-sensitivity cardiac troponin T change in adults admitted to the hospital with acutely decompensated heart failure. Repeat sleep apnea tests (SATs) were performed to determine response to optimal medical heart failure therapy. Multivariable logistic regression was used to identify associations between absolute overnight troponin change and sleep apnea characteristics.ResultsAmong the 19 subjects with acutely decompensated heart failure, 92% of SATs demonstrated sleep disordered breathing (apnea-hypopnea index [AHI] > 5 events/h). For those with repeat SATs, AHI increased in 67% despite medical management of heart failure. Overnight troponin increase was associated with moderate to severe sleep apnea (vs. no to mild sleep apnea, odds ratio (OR = 18.4 [1.51-224.18]), central apnea index (OR = 1.11 [1.01-1.22]), and predominantly central sleep apnea (vs. obstructive, OR = 22.9 [1.29-406.32]).ConclusionsSleep apnea severity and a central apnea pattern may be associated with myocardial injury. Respiratory polygraphy with serial biomarker assessment is feasible in this population, and combining this approach with interventions (e.g., positive airway pressure) may help establish if a link exists between sleep apnea and subclinical myocardial injury.

Study objectivesThere is a complex interplay between obstructive sleep apnea (OSA) and type 2 diabetes. There are minimal data regarding the effects of treating OSA with positive airway pressure (PAP) therapy on outcomes and health care resource utilization (HCRU) in patients with OSA and type 2 diabetes. We investigated the impact of PAP adherence on HCRU and costs in this population.MethodsA retrospective analysis was conducted with a cohort of OSA patient from a US administrative claims dataset linked to objective device data (AirView, ResMed Corp., San Diego, California). Propensity score matching was used to control for potential imbalance in baseline covariates between PAP-adherent and -nonadherent patients. Newly diagnosed patients with OSA aged ≥ 18 years with type 2 diabetes were included. PAP adherence was defined as meeting Centers for Medicare and Medicaid Services compliance criteria in all 8 90-day periods over 2 years. HCRU was based on the number of all-cause doctor visits, emergency room visits, inpatient hospitalizations, and PAP equipment and supplies.ResultsIn years 1 and 2 of PAP therapy, HCRU was significantly lower in adherent vs nonadherent patients (number/patient for emergency room visits 0.68 ± 1.47 vs 0.99 ± 1.91 [year 1], 0.69 ± 1.43 vs 0.95 ± 1.89 [year 2]; for hospitalizations 0.16 ± 0.58 vs 0.22 ± 0.62 [year 1], 0.15 ± 0.51 vs 0.21 ± 0.74 [year 2]; all P

BackgroundMechanisms underlying blood pressure changes in obstructive sleep apnoea (OSA) are incompletely understood. Increased respiratory effort is one of the main features of OSA and is associated with sympathetic overactivity, leading to increased vascular wall stiffness and remodelling. This study investigated associations between a new measure of respiratory effort (percentage of total sleep time spent with increased respiratory effort based on measurement of mandibular jaw movements (MJM): REMOV, %TST) and prevalent hypertension in adults referred for evaluation of suspected OSA.MethodsA machine learning model was built to predict hypertension from clinical data, conventional polysomnography (PSG) indices and MJM-derived parameters (including REMOV). The model was evaluated in a training subset and a test subset.ResultsThe analysis included 1127 patients: 901 (80%) in the training subset and 226 (20%) in the test subset. The prevalence of hypertension was 31% and 30%, respectively, in the training and test subsets. A risk stratification model based on 18 input features including REMOV had good accuracy for predicting prevalent hypertension (sensitivity 0.75 and specificity 0.83). Using the Shapley additive explanation method, REMOV was the best predictor of hypertension after clinical risk factors (age, sex, body mass index and neck circumference) and time with oxygen saturation

BackgroundPrescription medication labels (PMLs) predominantly dispensed in English, are an important adjunct to medication counselling. PMLs are routinely used by pharmacy staff to counsel older adults about their medications. This study sought to identify challenges that pharmacy staff observe older adults face in using their PMLs, and to identify and quantify solutions employed by pharmacy staff during medication counselling to address such challenges.MethodsTen in-depth interviews were done with primary care pharmacy staff to gather the range of challenges and solutions. Subsequently, a quantitative survey, informed by the qualitative findings, was administered to 121 pharmacy staff to assess if the reported solutions were commonly used.ResultsThe two main challenges were incongruity between PML language (English) and older adults' language proficiency, and poor PML legibility. The solutions, classified under three themes, were simplifying medication information on PMLs, supplementing PMLs with additional medication information and mitigating poor readability.ConclusionsPharmacy staff observed challenges faced by older adults in using PMLs during medication counselling. Ad-hoc improvisations by pharmacy staff to PMLs were pervasive. System-level PML improvements, such as provision of legible bilingual medication instructions, pharmaceutical pictograms and additional medication information, through patient information leaflets or using quick response (QR) codes on PMLs, should be considered. This will facilitate patient-provider communication, especially in settings with language dissonance between PMLs and patients.

ObjectivesTo determine in patients with acute respiratory distress syndrome (ARDS) on venovenous extracorporeal membrane oxygenation (VV ECMO) whether reducing driving pressure (ΔP) would decrease plasma biomarkers of inflammation and lung injury (interleukin-6 [IL-6], IL-8, and the soluble receptor for advanced glycation end-products sRAGE).DesignA single-center prospective physiologic study.SettingAt a single university medical center.ParticipantsAdult patients with severe COVID-19 ARDS on VV ECMO.InterventionsParticipants on VV ECMO had the following biomarkers measured: (1) pre-ECMO with low-tidal-volume ventilation (LTVV), (2) post-ECMO with LTVV, (3) during low-driving-pressure ventilation (LDPV), (4) after 2 hours of very low driving-pressure ventilation (V-LDPV, main intervention ΔP = 1 cmH2O), and (5) 2 hours after returning to LDPV.Main measurements and resultsTwenty-six participants were enrolled; 21 underwent V-LDPV. There was no significant change in IL-6, IL-8, and sRAGE from LDPV to V-LDPV and from V-LDPV to LDPV. Only participants (9 of 21) with nonspontaneous breaths had significant change (p < 0.001) in their tidal volumes (Vt) (mean ± SD), 1.9 ± 0.5, 0.1 ± 0.2, and 2.0 ± 0.7 mL/kg predicted body weight (PBW). Participants with spontaneous breathing, Vt were unchanged-4.5 ± 3.1, 4.7 ± 3.1, and 5.6 ± 2.9 mL/kg PBW (p = 0.481 and p = 0.065, respectively). There was no relationship found when accounting for Vt changes and biomarkers.ConclusionsBiomarkers did not significantly change with decreased ΔPs or Vt changes during the first 24 hours post-ECMO. Despite deep sedation, reductions in Vt during V-LDPV were not reliably achieved due to spontaneous breaths. Thus, patients on VV ECMO for ARDS may have higher Vt (ie, transpulmonary pressure) than desired despite low ΔPs or Vt.

Introduction The number of subjects infected with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) throughout the western hemisphere increased exponentially in the later months of 2020. With this increase in infection, the number of subjects requiring advanced ventilatory support increased concomitantly. We decided to compare the survival rates between coronavirus disease 2019 (COVID-19) subjects versus non-COVID-19 subjects undergoing intubation in the intensive care unit (ICU). We hypothesized that COVID-19 subjects would have lower rates of survival post-intubation. Methods We screened all subjects admitted to the adult critical care unit between January 2020 and June 2020 to determine if they met the inclusion criteria. These subjects were required to be spontaneously ventilating upon admission and eventually required intubation. Subjects were selected from our electronic health record (EHR) system EPIC© (Epic Systems, Verona, WI) through a retrospective ICU admission analysis. We identified and included 267 non-COVID-19 subjects and 56 COVID-19 subjects. Our primary outcome of interest was intubation-related mortality. We defined intubation mortality as unexpected death (within 48 hours of intubation). Our secondary outcomes were the length of stay in the ICU, length of time requiring ventilator support, and proportion of subjects requiring tracheostomy placement. Results Compared to non-coronavirus disease (COVID) subjects, COVID subjects were more likely to be intubated for acute respiratory distress. COVID subjects had longer stays in the ICU and longer ventilator duration than non-COVID subjects. COVID-positive subjects had a decreased hazard ratio for mortality (HR = 0.42, 95% CI: 0.20-0.87, P < 0.05) and increased chances of survival compared to non-COVID subjects. Conclusions We showed the rates of intubation survival were no different between the COVID and non-COVID groups. We attribute this finding to intubation preparation, a multidisciplinary team approach, and having the most experienced provider lead the intubation process.

Rationale: Obstructive sleep apnea (OSA)-induced endothelial cell (EC) dysfunction contributes to OSA-related cardiovascular sequelae. The mechanistic basis of endothelial impairment by OSA is unclear. Objectives: The goals of this study were to identify the mechanism of OSA-induced EC dysfunction and explore the potential therapies for OSA-accelerated cardiovascular disease. Methods: The experimental methods include data mining, bioinformatics, EC functional analyses, OSA mouse models, and assessment of OSA human subjects. Measurements and Main Results: Using mined microRNA sequencing data, we found that microRNA 210 (miR-210) conferred the greatest induction by intermittent hypoxia in ECs. Consistently, the serum concentration of miR-210 was higher in individuals with OSA from two independent cohorts. Importantly, miR-210 concentration was positively correlated with the apnea-hypopnea index. RNA sequencing data collected from ECs transfected with miR-210 or treated with OSA serum showed a set of genes commonly altered by miR-210 and OSA serum, which are largely involved in mitochondrion-related pathways. ECs transfected with miR-210 or treated with OSA serum showed reduced [Formula: see text]o2 rate, mitochondrial membrane potential, and DNA abundance. Mechanistically, intermittent hypoxia-induced SREBP2 (sterol regulatory element-binding protein 2) bound to the promoter region of miR-210, which in turn inhibited the iron-sulfur cluster assembly enzyme and led to mitochondrial dysfunction. Moreover, the SREBP2 inhibitor betulin alleviated intermittent hypoxia-increased systolic blood pressure in the OSA mouse model. Conclusions: These results identify an axis involving SREBP2, miR-210, and mitochondrial dysfunction, representing a new mechanistic link between OSA and EC dysfunction that may have important implications for treating and preventing OSA-related cardiovascular sequelae.

Rationale: A growing body of evidence suggests that sleep is critical for the adaptive processing and consolidation of emotional information into long-term memory. Previous research has indicated that emotional components of scenes particularly benefit from sleep in healthy groups, yet sleep-dependent emotional memory processes remain unexplored in clinical cohorts, including those with obstructive sleep apnea (OSA). This line of research is important as it will add to the understanding of how disrupted sleep in OSA contributes to both impaired cognition and emotion dysregulation. Objectives: To test the hypothesis that individuals with OSA will have impaired sleep-dependent memory consolidation, with the greatest impact being on memory for emotional content. Methods: In this study, a group of newly diagnosed patients with OSA (n = 26; 10 female; average age, 42.5 years) and a matched group of healthy control subjects (n = 24; 13 female; average age, 37 years) were enrolled in the study at Beth Israel Deaconess Medical Center. Participants encoded scenes with negative or neutral foreground objects placed on neutral backgrounds before a night of polysomnographically recorded sleep. In the morning, they completed a recognition test in which old and new scene objects and backgrounds, presented separately and one at a time, were judged as old, new, or similar compared with what had been previously viewed. Results: Patients with OSA had a deficit in recognition memory for the scenes. Overall recognition (the ability to recognize old items as either old or similar) was impaired across all scene elements, both negative and neutral objects and backgrounds, whereas specific recognition (correctly identifying old items as old) was impaired only for negative objects. Across all participants, successful overall recognition correlated positively with sleep efficiency and rapid eye movement (REM) sleep, whereas successful specific memory recognition correlated only with REM sleep. Conclusions: Our findings indicate that fragmented sleep and reduced REM sleep, both hallmarks of OSA, are associated with disruptions in general memory impairment and veridical memory for emotional content, which could alter emotional regulation and contribute to comorbid emotional distress in OSA.

As the mechanism for worse prognosis after cardiac resynchronization therapy (CRT) upgrades in heart failure patients with RVP dependence (RVP-HF) has clinical implications for patient selection and CRT implementation approaches, this study's objective was to evaluate prognostic implications of cardiac magnetic resonance (CMR) findings and clinical factors in 102 HF patients (23.5% female, median age 66.5 years old, median follow-up 4.8 years) with and without RVP dependence undergoing upgrade and de novo CRT implants. Compared with other CRT groups, RVP-HF patients had decreased survival (p = 0.02), more anterior late-activated LV pacing sites (p = 0.002) by CMR, more atrial fibrillation (p = 0.0006), and higher creatinine (0.002). CMR activation timing at the LV pacing site predicted post-CRT LV functional improvement (p < 0.05), and mechanical activation onset < 34 ms by CMR at the LVP site was associated with decreased post-CRT survival in a model with higher pre-CRT creatinine and B-type natriuretic peptide (AUC 0.89; p < 0.0001); however, only the higher pre-CRT creatinine partially mediated (37%) the decreased survival in RVP-HF patients. In conclusion, RVP-HF had a distinct CMR phenotype, which has important implications for the selection of LV pacing sites in CRT upgrades, and only chronic kidney disease mediated the decreased survival after CRT in RVP-HF.

BackgroundFollowing acute brain injury, patients in the intensive care unit often undergo hourly or every-other-hour exams ("neurochecks") to monitor for neurodeterioration. We assessed health care provider attitudes towards neurocheck frequency and evaluated providers' ideal neurocheck frequency.MethodsThis was a cross-sectional, online survey distributed in Spring 2021 at a tertiary care academic medical center. Providers from multiple intensive care unit and neuroscience clinical specialties including attending faculty, medical trainees, advanced practice providers, and bedside nurses were invited to participate.ResultsAmong 177 participants, 61 (34%) and 116 (66%) were self-identified as ordering and performing providers, respectively. The survey response rate was 58% among physicians and 51% among bedside nurses with neurological expertise. The most common medical and non-medical reasons for ordering hourly neurochecks were "a specific diagnosis with anticipated course" and "standard of care," respectively. Compared with ordering providers, performing providers felt guidelines regarding neurocheck frequency ( P

BackgroundAcute Kidney Injury (AKI) incidence has continued to rise and is recognized as a major risk factor for kidney disease progression and cardiovascular complications. Early recognition of factors associated with post-AKI complications is fundamental to stratifying patients that could benefit from closer follow-up and management after an episode of AKI. Recent studies have shown that proteinuria is a prevalent sequela after AKI and a strong predictor of complications post-AKI. This study aims to evaluate the frequency and timing of the development of de-novo proteinuria after an AKI episode in patients with known kidney function and no prior history of proteinuria.MethodsWe retrospectively analyzed data from adult AKI patients with pre- and post-kidney function information between Jan 2014 and March 2019. The presence of proteinuria determined before and after index AKI encounter was based on ICD-10 code and/or urine dipstick and UPCR during the follow-up period.ResultsOf 9697 admissions with AKI diagnoses between Jan 2014 and March 2019, 2120 eligible patients with at least one assessment of Scr and proteinuria before AKI index admission were included in the analysis. The median age was 64 (IQR 54-75) years, and 57% were male. 58% (n-1712) patients had stage 1 AKI, 19% (n = 567) stage 2 AKI, and 22% (n = 650) developed stage 3 AKI. De novo proteinúria was found in 62% (n = 472) of patients and was already present by 90 days post-AKI in 59% (209/354). After adjusting for age and comorbidities, severe AKI (stage 2/3 AKI) and diabetes, were independently associated with increased risk for De novo proteinuria.ConclusionSevere AKI is an independent risk factor for subsequent de novo proteinuria post-hospitalization. Further prospective studies are needed to determine whether strategies to detect AKI patients at risk of proteinuria and early therapeutics to modify proteinuria can delay the progression of kidney disease.

BackgroundPathological evidence suggests that coronavirus disease 2019 (COVID-19) pulmonary infection involves both alveolar damage (causing shunt) and diffuse microvascular thrombus formation (causing alveolar dead space). We propose that measuring respiratory gas exchange enables detection and quantification of these abnormalities. We aimed to measure shunt and alveolar dead space in moderate COVID-19 during acute illness and recovery.MethodsWe studied 30 patients (22 males; mean±sd age 49.9±13.5 years) 3-15 days from symptom onset and again during recovery, 55±10 days later (n=17). Arterial blood (breathing ambient air) was collected while exhaled oxygen and carbon dioxide concentrations were measured, yielding alveolar-arterial differences for each gas (P A-aO2 and P a-ACO2 , respectively) from which shunt and alveolar dead space were computed.ResultsFor acute COVID-19 patients, group mean (range) for P A-aO2 was 41.4 (-3.5-69.3) mmHg and for P a-ACO2 was 6.0 (-2.3-13.4) mmHg. Both shunt (% cardiac output) at 10.4% (0-22.0%) and alveolar dead space (% tidal volume) at 14.9% (0-32.3%) were elevated (normal:

IntroductionInflammation is highly prevalent among patients with end-stage kidney disease and is associated with adverse outcomes. We aimed to investigate longitudinal changes in inflammatory markers in a diverse international incident hemodialysis patient population.MethodsThe MONitoring Dialysis Outcomes (MONDO) Consortium encompasses hemodialysis databases from 31 countries in Europe, North America, South America, and Asia. The MONDO database was queried for inflammatory markers (total white blood cell count [WBC], neutrophil count, lymphocyte count, serum albumin, and C-reactive protein [CRP]) and hemoglobin levels in incident hemodialysis patients. Laboratory parameters were measured every month. Patients were stratified by survival time (≤6 months, >6 to 12 months, >12 to 18 months, >18 to 24 months, >24 to 30 months, >30 to 36 months, and >36 months) following dialysis initiation. We used cubic B-spline basis function to evaluate temporal changes in inflammatory parameters in relationship with patient survival.ResultsWe studied 18,726 incident hemodialysis patients. Their age at dialysis initiation was 71.3 ± 11.9 years; 10,802 (58%) were males. Within the first 6 months, 2068 (11%) patients died, and 12,295 patients (67%) survived >36 months (survivor cohort). Hemodialysis patients who died showed a distinct biphasic pattern of change in inflammatory markers where an initial decline of inflammation was followed by a rapid rise that was consistently evident approximately 6 months before death. This pattern was similar in all patients who died and was consistent across the survival time intervals. In contrast, in the survivor cohort, we observed initial decline of inflammation followed by sustained low levels of inflammatory biomarkers.ConclusionOur international study of incident hemodialysis patients highlights a temporal relationship between serial measurements of inflammatory markers and patient survival. This finding may inform the development of prognostic models, such as the integration of dynamic changes in inflammatory markers for individual risk profiling and guiding preventive and therapeutic interventions.

BackgroundAlthough there is considerable interest in machine learning (ML) and artificial intelligence (AI) in critical care, the implementation of effective algorithms into practice has been limited.ObjectiveWe sought to understand physician perspectives of a novel intubation prediction tool. Further, we sought to understand health care provider and nonprovider perspectives on the use of ML in health care. We aim to use the data gathered to elucidate implementation barriers and determinants of this intubation prediction tool, as well as ML/AI-based algorithms in critical care and health care in general.MethodsWe developed 2 anonymous surveys in Qualtrics, 1 single-center survey distributed to 99 critical care physicians via email, and 1 social media survey distributed via Facebook and Twitter with branching logic to tailor questions for providers and nonproviders. The surveys included a mixture of categorical, Likert scale, and free-text items. Likert scale means with SD were reported from 1 to 5. We used student t tests to examine the differences between groups. In addition, Likert scale responses were converted into 3 categories, and percentage values were reported in order to demonstrate the distribution of responses. Qualitative free-text responses were reviewed by a member of the study team to determine validity, and content analysis was performed to determine common themes in responses.ResultsOut of 99 critical care physicians, 47 (48%) completed the single-center survey. Perceived knowledge of ML was low with a mean Likert score of 2.4 out of 5 (SD 0.96), with 7.5% of respondents rating their knowledge as a 4 or 5. The willingness to use the ML-based algorithm was 3.32 out of 5 (SD 0.95), with 75% of respondents answering 3 out of 5. The social media survey had 770 total responses with 605 (79%) providers and 165 (21%) nonproviders. We found no difference in providers' perceived knowledge based on level of experience in either survey. We found that nonproviders had significantly less perceived knowledge of ML (mean 3.04 out of 5, SD 1.53 vs mean 3.43, SD 0.941; P

BackgroundCoronavirus disease 2019 (COVID-19) is an immunoinflammatory and hypercoagulable state that contributes to respiratory distress, multi-organ dysfunction, and mortality. Dipyridamole, by increasing extracellular adenosine, has been postulated to be protective for COVID-19 patients through its immunosuppressive, anti-inflammatory, anti-coagulant, vasodilatory, and anti-viral actions. Likewise, low-dose aspirin has also demonstrated protective effects for COVID-19 patients. This study evaluated the effect of these two drugs formulated together as Aggrenox in hospitalized COVID-19 patients.MethodsIn an open-label, single site randomized controlled trial (RCT), hospitalized COVID-19 patients were assigned to adjunctive Aggrenox (Dipyridamole ER 200mg/ Aspirin 25mg orally/enterally) with standard of care treatment compared to standard of care treatment alone. Primary endpoint was illness severity according to changes on the eight-point COVID ordinal scale, with levels of 1 to 8 where higher scores represent worse illness. Secondary endpoints included all-cause mortality and respiratory failure. Outcomes were measured through days 14, 28, and/or hospital discharge.ResultsFrom October 1, 2020 to April 30, 2021, a total of 98 patients, who had a median [IQR] age of 57 [47, 62] years and were 53.1% (n = 52) female, were randomized equally between study groups (n = 49 Aggrenox plus standard of care versus n = 49 standard of care alone). No clinically significant differences were found between those who received adjunctive Aggrenox and the control group in terms of illness severity (COVID ordinal scale) at days 14 and 28. The overall mortality through day 28 was 6.1% (3 patients, n = 49) in the Aggrenox group and 10.2% (5 patients, n = 49) in the control group (OR [95% CI]: 0.40 [0.04, 4.01], p = 0.44). Respiratory failure through day 28 occurred in 4 (8.3%, n = 48) patients in the Aggrenox group and 7 (14.6%, n = 48) patients in the standard of care group (OR [95% CI]: 0.21 [0.02, 2.56], p = 0.22). A larger decrease in the platelet count and blood glucose levels, and larger increase in creatinine and sodium levels within the first 7 days of hospital admission were each independent predictors of 28-day mortality (p < 0.05).ConclusionIn this study of hospitalized patients with COVID-19, while the outcomes of COVID illness severity, odds of mortality, and chance of respiratory failure were better in the Aggrenox group compared to standard of care alone, the data did not reach statistical significance to support the standard use of adjuvant Aggrenox in such patients.

BackgroundThe prognosis and therapeutic responses are worse for pulmonary arterial hypertension associated with systemic sclerosis (SSc-PAH) compared with idiopathic pulmonary arterial hypertension (IPAH). This discrepancy could be driven by divergence in underlying metabolic determinants of disease.Research questionAre circulating bioactive metabolites differentially altered in SSc-PAH vs IPAH, and can this alteration explain clinical disparity between these PAH subgroups?Study design and methodsPlasma biosamples from 400 patients with SSc-PAH and 1,082 patients with IPAH were included in the study. Another cohort of 100 patients with scleroderma with no PH and 44 patients with scleroderma with PH was included for external validation. More than 700 bioactive lipid metabolites, representing a range of vasoactive and immune-inflammatory pathways, were assayed in plasma samples from independent discovery and validation cohorts using liquid chromatography/high-resolution mass spectrometry-based approaches. Regression analyses were used to identify metabolites that exhibited differential levels between SSc-PAH and IPAH and associated with disease severity.ResultsFrom hundreds of circulating bioactive lipid molecules, five metabolites were found to distinguish between SSc-PAH and IPAH, as well as associate with markers of disease severity. Relative to IPAH, patients with SSc-PAH carried increased levels of fatty acid metabolites, including lignoceric acid and nervonic acid, as well as eicosanoids/oxylipins and sex hormone metabolites.InterpretationPatients with SSc-PAH are characterized by an unfavorable bioactive metabolic profile that may explain the poor and limited response to therapy. These data provide important metabolic insights into the molecular heterogeneity underlying differences between subgroups of PAH.