Low-Dose Morphine Does Not Cause Sleepiness in COPD: A Secondary Analysis of a Randomized Trial.

RATIONALE: Regular, low-dose, sustained-release morphine is frequently prescribed for persistent breathlessness in chronic obstructive pulmonary disease (COPD). However, effects on daytime sleepiness, perceived sleep quality and daytime function have not been rigorously investigated. OBJECTIVES: Determine the effects of regular, low-dose, sustained-release morphine on sleep parameters in COPD. METHODS: Pre-specified secondary analyses of validated sleep questionnaire data from a randomized trial of daily, low-dose, sustained -release morphine versus placebo over four weeks commencing at 8mg or 16mg/day with blinded up-titration over two weeks to a maximum of 32mg/day. Primary outcomes for these analyses were week-1 Epworth Sleepiness Scale (ESS) and Karolinska Sleepiness Scale (KSS) responses on morphine versus placebo. Secondary outcomes included Leeds Sleep Evaluation Questionnaire (LSEQ) scores (end of weeks 1 and 4), KSS and ESS beyond week-1 and associations between breathlessness, morphine, and questionnaire scores. MEASUREMENTS AND MAIN RESULTS: 156 people were randomized. Week-1 sleepiness scores were not different on morphine versus placebo (∆ESS [95%CI] versus placebo: 8mg group: -0.59 [-1.99, 0.81], p=0.41; 16mg group: -0.72 [-2.33, 0.9], p=0.38; ∆KSS versus placebo: 8mg group: 0.11 [-0.7, 0.9], p=0.78; 16mg group: -0.41 [-1.31, 0.49], p=0.37). This neutral effect persisted at later timepoints. In addition, participants who reported reduced breathlessness with morphine at 4 weeks also had improvement in LSEQ domain scores including perceived sleep quality and daytime function. CONCLUSIONS: Regular, low-dose morphine does not worsen sleepiness when used for breathlessness in COPD. Individual improvements in breathlessness with morphine may be related to improvements in sleep.

Effects of the antipsychotic quetiapine on sleep and breathing: a review of clinical findings and potential mechanisms.

Quetiapine is an antipsychotic medication indicated for schizophrenia and bipolar disorder. However, quetiapine also has hypnotic properties and as such is increasingly being prescribed at low doses 'off-label' in people with insomnia symptoms. Pharmacologically, in addition to its dopaminergic properties, quetiapine also modulates multiple other transmitter systems involved in sleep/wake modulation and potentially breathing. However, very little is known about the impact of quetiapine on obstructive sleep apnoea (OSA), OSA endotypes including chemosensitivity, and control of breathing. Given that many people with insomnia also have undiagnosed OSA, it is important to understand the effects of quetiapine on OSA and its mechanisms. Accordingly, this concise review covers the existing knowledge on the effects of quetiapine on sleep and breathing. Further, we highlight the pharmacodynamics of quetiapine and its potential to alter key OSA endotypes to provide potential mechanistic insight. Finally, an agenda for future research priorities is proposed to fill the current key knowledge gaps.

Multinight Prevalence, Variability, and Diagnostic Misclassification of Obstructive Sleep Apnea.

Rationale: Recent studies suggest that obstructive sleep apnea (OSA) severity can vary markedly from night to night, which may have important implications for diagnosis and management. Objectives: This study aimed to assess OSA prevalence from multinight in-home recordings and the impact of night-to-night variability in OSA severity on diagnostic classification in a large, global, nonrandomly selected community sample from a consumer database of people that purchased a novel, validated, under-mattress sleep analyzer. Methods: A total of 67,278 individuals aged between 18 and 90 years underwent in-home nightly monitoring over an average of approximately 170 nights per participant between July 2020 and March 2021. OSA was defined as a nightly mean apnea-hypopnea index (AHI) of more than 15 events/h. Outcomes were multinight global prevalence and likelihood of OSA misclassification from a single night's AHI value. Measurements and Main Results: More than 11.6 million nights of data were collected and analyzed. OSA global prevalence was 22.6% (95% confidence interval, 20.9-24.3%). The likelihood of misdiagnosis in people with OSA based on a single night ranged between approximately 20% and 50%. Misdiagnosis error rates decreased with increased monitoring nights (e.g., 1-night F1-score = 0.77 vs. 0.94 for 14 nights) and remained stable after 14 nights of monitoring. Conclusions: Multinight in-home monitoring using novel, noninvasive under-mattress sensor technology indicates a global prevalence of moderate to severe OSA of approximately 20%, and that approximately 20% of people diagnosed with a single-night study may be misclassified. These findings highlight the need to consider night-to-night variation in OSA diagnosis and management.

The changes of AHI after long-term CPAP in patients with comorbid OSA and cardiovascular disease.

PURPOSE: To evaluate the effect of long-term continuous positive airway pressure (CPAP) treatment on disease severity of obstructive sleep apnea (OSA). METHODS: We analyzed results from the Sleep Apnea and Cardiovascular Events (SAVE) study involving participants recruited at the Guangdong Provincial People's Hospital, China. Participants were aged 45-75 years with a history of cardiac or cerebrovascular disease. OSA was confirmed by home sleep apnea testing (HSAT). Participants were randomized to receive CPAP plus standard cardiovascular care (CPAP group) or standard care alone (UC group) and followed for several years. At the study conclusion, surviving participants were invited to repeat HSAT. Changes in OSA indicators were compared by independent samples t-tests and subgroup analysis was implied among groups stratified by OSA severity. RESULTS: One hundred two adults were recruited (51 per group) and followed for 48.0 ± 14.5 months. Daily CPAP usage in the CPAP group was 4.1 ± 1.9 h. AHI decreased from baseline to end-of-study in both CPAP and UC groups (- 5.0 (- 12.5,2.0), P = 0.000; - 4.0 (- 12.5,1.5), P = 0.007, respectively), with no between-group difference (P = 0.453). An improvement in nadir SpO2 showed from baseline to end-of-study in the CPAP but not UC group (2.3% ± 6.1%, P = 0.011 and - 0.7% ± 7.6%, P = 0.511, respectively; between-group difference P = 0.032). Subgroup analysis shows that CPAP could improve AHI in patients with moderate OSA (- 8.0 (- 11.8, - 2.8) in CPAP group, - 2.0 (- 0.8,6.0) in UC group, P = 0.022) and improve nadir SpO2 in patients with severe OSA (5.0 (- 0.8, - 0.8,7.0) in CPAP group, 0.0 (- 8.5,2.5) in UC group, P = 0.032). CONCLUSION: Long-term CPAP use did not result in clinically significant changes in AHI or ODI overall but showed variable effects stratified by OSA severity. CLINICAL TRIAL REGISTRATION: Registry: Clinical Trials.gov, title: Continuous Positive Airway Pressure Treatment of Obstructive Sleep Apnea to Prevent Cardiovascular Disease (SAVE), URL: www. CLINICALTRIALS: gov , identifier: NCT00738179.

Adherence to CPAP Treatment and the Risk of Recurrent Cardiovascular Events: A Meta-Analysis.

Importance: The effect of continuous positive airway pressure (CPAP) on secondary cardiovascular disease prevention is highly debated. Objective: To assess the effect of CPAP treatment for obstructive sleep apnea (OSA) on the risk of adverse cardiovascular events in randomized clinical trials. Data Sources: PubMed (MEDLINE), EMBASE, Current Controlled Trials: metaRegister of Controlled Trials, ISRCTN Registry, European Union clinical trials database, CENTRAL (Cochrane Central Register of Controlled Trials), and ClinicalTrials.gov databases were systematically searched through June 22, 2023. Study Selection: For qualitative and individual participant data (IPD) meta-analysis, randomized clinical trials addressing the therapeutic effect of CPAP on cardiovascular outcomes and mortality in adults with cardiovascular disease and OSA were included. Data Extraction and Synthesis: Two reviewers independently screened records, evaluated potentially eligible primary studies in full text, extracted data, and cross-checked errors. IPD were requested from authors of the selected studies (SAVE [NCT00738179], ISAACC [NCT01335087], and RICCADSA [NCT00519597]). Main Outcomes and Measures: One-stage and 2-stage IPD meta-analyses were completed to estimate the effect of CPAP treatment on risk of recurrent major adverse cardiac and cerebrovascular events (MACCEs) using mixed-effect Cox regression models. Additionally, an on-treatment analysis with marginal structural Cox models using inverse probability of treatment weighting was fitted to assess the effect of good adherence to CPAP (≥4 hours per day). Results: A total of 4186 individual participants were evaluated (82.1% men; mean [SD] body mass index, 28.9 [4.5]; mean [SD] age, 61.2 [8.7] years; mean [SD] apnea-hypopnea index, 31.2 [17] events per hour; 71% with hypertension; 50.1% receiving CPAP [mean {SD} adherence, 3.1 {2.4} hours per day]; 49.9% not receiving CPAP [usual care], mean [SD] follow-up, 3.25 [1.8] years). The main outcome was defined as the first MACCE, which was similar for the CPAP and no CPAP groups (hazard ratio, 1.01 [95% CI, 0.87-1.17]). However, an on-treatment analysis by marginal structural model revealed a reduced risk of MACCEs associated with good adherence to CPAP (hazard ratio, 0.69 [95% CI, 0.52-0.92]). Conclusions and Relevance: Adherence to CPAP was associated with a reduced MACCE recurrence risk, suggesting that treatment adherence is a key factor in secondary cardiovascular prevention in patients with OSA.

Effect of Obstructive Sleep Apnea Treatment on Renal Function in Patients with Cardiovascular Disease.

RATIONALE: Obstructive sleep apnea (OSA) is associated with impaired renal function, but uncertainty exists over whether OSA treatment can influence renal outcomes. OBJECTIVES: To determine the effects of continuous positive airway pressure (CPAP) on renal function in subjects with coexisting OSA and cardiovascular disease. METHODS: This was a substudy of the international SAVE (Sleep Apnea Cardiovascular Endpoints) trial, in which 2,717 patients with moderate to severe OSA and established coronary or cerebrovascular disease were randomized to receive either CPAP plus usual care or usual care alone. Renal function and adverse renal events were compared between the CPAP (n = 102) and usual care (n = 98) groups. Glomerular filtration rate was estimated at randomization and at the end of follow-up, and the urinary albumin-to-creatinine ratio was measured at study exit. MEASUREMENTS AND MAIN RESULTS: In 200 substudy participants (mean age, 64 yr; median, 4% oxygen desaturation index; 20 events/h; mean estimated glomerular filtration rate at baseline, 82 ml/min/1.73 m2), the median (interquartile range) changes in estimated glomerular filtration rate (ml/min/1.73 m2/yr) were -1.64 (-3.45 to -0.740) in the CPAP group and -2.30 (-4.53 to -0.71) in the usual care group (P = 0.21) after a median of 4.4 years. There were no between-group differences in end-of-study urinary albumin-to-creatinine ratio or in the occurrence of serious renal or urinary adverse events during the trial. The level of CPAP adherence did not influence the findings. CONCLUSIONS: CPAP treatment of OSA in patients with cardiovascular disease does not alter renal function or the occurrence of renal adverse events. Clinical trial registered with www.clinicaltrials.gov (NCT00738179).

Identification of the CIMP-like subtype and aberrant methylation of members of the chromosomal segregation and spindle assembly pathways in esophageal adenocarcinoma.

The incidence of esophageal adenocarcinoma (EAC) has risen significantly over recent decades. Although survival has improved, cure rates remain poor, with <20% of patients surviving 5 years. This is the first study to explore methylome, transcriptome and ENCODE data to characterize the role of methylation in EAC. We investigate the genome-wide methylation profile of 250 samples including 125 EAC, 19 Barrett's esophagus (BE), 85 squamous esophagus and 21 normal stomach. Transcriptome data of 70 samples (48 EAC, 4 BE and 18 squamous esophagus) were used to identify changes in methylation associated with gene expression. BE and EAC showed similar methylation profiles, which differed from squamous tissue. Hypermethylated sites in EAC and BE were mainly located in CpG-rich promoters. A total of 18575 CpG sites associated with 5538 genes were differentially methylated, 63% of these genes showed significant correlation between methylation and mRNA expression levels. Pathways involved in tumorigenesis including cell adhesion, TGF and WNT signaling showed enrichment for genes aberrantly methylated. Genes involved in chromosomal segregation and spindle formation were aberrantly methylated. Given the recent evidence that chromothripsis may be a driver mechanism in EAC, the role of epigenetic perturbation of these pathways should be further investigated. The methylation profiles revealed two EAC subtypes, one associated with widespread CpG island hypermethylation overlapping H3K27me3 marks and binding sites of the Polycomb proteins. These subtypes were supported by an independent set of 89 esophageal cancer samples. The most hypermethylated tumors showed worse patient survival.

Diagnosis and management of sleep disorders in shift workers, with patient informed solutions to improve health services research and practice.

BACKGROUND: The combination of shift work and an unmanaged sleep disorder carries health and safety risks. Yet, diagnosis rates for sleep disorders are low in shift workers. The aim of this study was to understand the experience of sleep disorder diagnosis and treatment in shift workers, and consider patient informed solutions to improve access to health services. METHODS: Semi-structured interviews were conducted with 16 Australian shift workers with a diagnosed sleep disorder. Patient journey mapping and reflexive thematic analysis were used to understand diagnosis and management experiences. RESULTS: There were highly variable experiences with diagnosis and management, often taking >5 years to seek help from a health care provider (HCP) after noticing symptoms of a sleep disorder. Three themes were constructed, including 'the cause of the problem', 'prioritising work', and '(dis)satisfaction and (dis)connection'. Extent of patient and HCP awareness of sleep disorders, and a prevailing attitude of shift work being 'the problem' impacted diagnosis, as did organisational needs (including rostering, which had both positive and negative influences on help seeking). Relationships with HCPs were important, and living on non-standard time was both a barrier and an enabler to sleep disorder care. Participants identified the need for education and awareness, prompts and easy access to screening and referral pathways, and tailored models of care. CONCLUSION: Education and awareness initiatives for shift workers, their employers and HCPs, together with development of a model of care for shift workers with sleep disorders may address some of the unique barriers to diagnosis and management.

Sex differences in response to cognitive behavioural therapy for insomnia: A chart review of 455 patients with chronic insomnia.

BACKGROUND: Insomnia is more prevalent in females, however studies examining sex differences in response to insomnia treatment are scarce. This study assessed sex-specific differences in cognitive behavioural therapy for insomnia (CBT-I)-related changes in insomnia symptoms in a large clinical cohort. METHODS: A chart review was conducted of a clinical cohort (females n = 305, males n = 150) referred to a sleep clinic. Participants had a registered psychologist confirm diagnosis of chronic insomnia according to DSM-IV/V criteria and a Level 1 or 2 sleep study. Daily sleep diaries and questionnaires including the Insomnia Severity Index (ISI), Flinders Fatigue Scale (FFS), the Daytime Feelings and Functioning Scale (DFFS), and the Depression, Anxiety and Stress Scale-21 items (DASS), were administered at baseline, post-treatment, and three-month follow-up. Linear mixed models determined interactions between sex and timepoint on symptoms. RESULTS: Mean (SD) age was 51.7 yrs (15.7, range = 18-90 yrs), and mean BMI was 26.3 kg/m2 (4.9), neither of which differed by sex. At pre-treatment, females demonstrated higher objective total sleep time (min) [343.5 (97.6) vs 323.8 min (92.1), p = 0.044], ISI [19.7 (4.2) vs 18.6 (4.4), p = 0.033], and FFS scores [19.2 (6.0) vs 16.9 (7.2), p = 0.003]. Compared to males, females experienced a greater reduction in FFS and DFFS scores and DASS depressive symptoms (p for interaction: 0.017, 0.043, 0.016 respectively) from baseline to follow-up. The greater reduction in depressive symptoms did not persist after controlling for age, BMI, and sleep apnea severity. Subjective total sleep time similarly increased across treatment for both males [baseline: 335.7 (15.1), post: 357.9 (15.5)] and females [baseline: 318.3 (10.4), post: 354.4 (10.7)], p for interaction: 0.22. CONCLUSION: Females and males experience similar, substantial benefits from CBT-I after accounting for comorbidities, suggesting the same treatment can resolve insomnia in both sexes.

Content Comparison of Quality-of-Life Instruments Used in Economic Evaluations of Sleep Disorder Interventions: A Systematic Review.

BACKGROUND: Assessment of quality of life (QoL) in people living with sleep disorders using questionnaires is necessary to compare intervention benefits. Knowledge of the content and concepts covered by specific QoL instruments is essential to determine which instruments are best suited for conducting economic evaluations of sleep-related interventions. OBJECTIVES: This review aims to identify the QoL instruments that have been applied in economic evaluations of sleep disorder interventions and compare their conceptual overlap and content coverage using the framework of the International Classification of Functioning, Disability and Health (ICF). METHODS: A systematic review of full economic evaluations in sleep published in peer-reviewed journals from conception to 30 May, 2023 was conducted. MEDLINE, PsychInfo, ProQuest, Cochrane, Scopus, CINAHL, Web of Science and Emcare were searched for eligible studies. Studies incorporating either generic or sleep-specific QoL instruments as the primary or secondary measures of effectiveness within a full economic evaluation were included. Quality appraisal against the JBI Critical Appraisal Checklist for Economic Evaluations and EURONHEED checklists and mapping of QoL items to ICF categories were performed by two reviewers, with a third helping settle any potential differences. RESULTS: Sixteen instruments were identified as having been used in sleep health economic evaluations. The EQ-5D-3L, Epworth Sleepiness Scale, and Insomnia Severity Index were the most widely used, but the latter two are predominantly diagnostic tools and not specifically designed to guide economic evaluations. Other instruments with broader ICF content coverage have been least used, and these include the Sleep Apnea Quality of Life Index, Functional Outcomes of Sleep Questionnaire, 15 Dimensions, Short-Form 6 Dimensions, 12-item Short Form Survey, 36-item Short Form Survey and the GRID Hamilton Rating Scale for Depression. CONCLUSIONS: This study provides an overview of current QoL instruments used in economic evaluations of sleep with respect to their content coverage. A combination of generic and sleep-specific instruments with broader ICF content coverage is recommended for such evaluations.

The norepinephrine reuptake inhibitor reboxetine alone reduces obstructive sleep apnea severity: a double-blind, placebo-controlled, randomized crossover trial.

STUDY OBJECTIVES: Recent findings indicate that noradrenergic and muscarinic processes are crucial for pharyngeal muscle control during sleep. However, to date, reductions in obstructive sleep apnea (OSA) severity have only been detected when noradrenergic agents are combined with an antimuscarinic. Accordingly, this study aimed to determine if reboxetine alone and combined with oxybutynin reduces OSA severity. The pathophysiological mechanisms underpinning the effects of these agents were also investigated via endotyping analysis. METHODS: Sixteen people (6 women) with OSA completed 3 polysomnograms (∼1-week washout) according to a double-blind, placebo-controlled, three-way crossover design across 2 sites. Single doses of 4 mg reboxetine, placebo, or 4 mg reboxetine + 5 mg oxybutynin were administered before sleep (order randomized). RESULTS: Reboxetine reduced the apnea-hypopnea index (primary outcome) by 5.4 (95% confidence interval -10.4 to -0.3) events/h, P = .03 (-24 ± 27% in men; -0.7 ± 32% in women). Oxybutynin did not cause additional reductions in apnea-hypopnea index. Reboxetine alone reduced the 4% oxygen desaturation index by (mean ± standard deviation) 5.2 ± 7.2 events/h and reboxetine+oxybutynin by 5.1 ± 10.6 events/h vs placebo, P = .02. Nadir oxygen saturation also increased by 7 ± 11% with reboxetine and 5 ± 9% with reboxetine+oxybutynin vs placebo, P = .01. Mechanistically, reboxetine and reboxetine+oxybutynin improved pharyngeal collapsibility and respiratory control (loop gain). Larger reductions in apnea-hypopnea index with reboxetine in men were associated with higher baseline loop gain. CONCLUSIONS: These findings show the first evidence that reboxetine alone reduces OSA severity. The data provide novel insight into the role of norepinephrine reuptake inhibitors on upper airway stability during sleep and are important to inform future pharmacotherapy development for OSA. CLINICAL TRIAL REGISTRATION: Registry: Australian New Zealand Clinical Trials Registry; Name: Reboxetine and Combination Therapy with AD128 in Sleep Apnoea Trial: A Double-Blind, 3-Way Cross-Over Study; URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374614&isReview=true; Identifier: ACTRN12620000662965. CITATION: Altree TJ, Aishah A, Loffler KA, Grunstein RR, Eckert DJ. The norepinephrine reuptake inhibitor reboxetine alone reduces obstructive sleep apnea severity: a double-blind, placebo-controlled, randomized crossover trial. J Clin Sleep Med. 2023;19(1):85-96.

Single-Night Diagnosis of Sleep Apnea Contributes to Inconsistent Cardiovascular Outcome Findings.

BACKGROUND: Single-night disease misclassification of OSA due to night-to-night variability may contribute to inconsistent findings in OSA trials. RESEARCH QUESTION: Does multinight quantification of OSA severity provide more precise estimates of associations with incident hypertension? STUDY DESIGN AND METHODS: A total of 3,831 participants without hypertension at baseline were included in simulation analyses. Included participants had ≥ 28 days of nightly apnea-hypopnea index (AHI) recordings via an under-mattress sensor and ≥ three separate BP measurements over a 3-month baseline period followed by ≥ three separate BP measurements 6 to 9 months postbaseline. Incident hypertension was defined as a mean systolic BP ≥ 140 mm Hg or a mean diastolic BP ≥ 90 mm Hg. Simulated trials (1,000) were performed, using bootstrap methods to investigate the effect of variable numbers of nights (x = 1-56 per participant) to quantify AHI and the ability to detect associations between OSA and incident hypertension via logistic regression adjusted for age, sex, and BMI. RESULTS: Participants were middle-aged (mean ± SD, 52 ± 12 y), mostly male (91%), and overweight (BMI, 28 ± 5 kg/m2). Single-night quantification of OSA failed to detect an association with hypertension risk in 42% of simulated trials (α = .05). Conversely, 100% of trials detected an association when AHI was quantified over ≥ 28 nights. Point estimates of hypertension risk were also 50% higher and uncertainty was five times lower during multinight vs single-night simulation trials. INTERPRETATION: Multinight monitoring of OSA allows for better estimates of hypertension risk and potentially other adverse health outcomes associated with OSA. These findings have important implications for clinical care and OSA trial design.

One Month Dosing of Atomoxetine plus Oxybutynin in Obstructive Sleep Apnea: A Randomized, Placebo-controlled Trial.

Rationale: The combination of noradrenergic and antimuscarinic agents has recently been shown to improve upper-airway function and reduce obstructive sleep apnea (OSA) severity in short-term (⩽1 wk) proof-of-concept studies. Objectives: To determine the safety, tolerability, and potential efficacy of longer term use of different doses of the noradrenergic agent atomoxetine combined with the antimuscarinic oxybutynin (ato-oxy). Methods: Thirty-nine people with predominantly severe OSA received 80/5 mg ato-oxy, 40/5 mg ato-oxy, 40/2.5 mg ato-oxy, or placebo nightly for 30 days in a double-blind, randomized, parallel design. Participants completed three in-laboratory sleep studies (baseline, Night 1, and Night 30) to assess efficacy. Vital signs and objective measures of alertness and memory were assessed. In men, potential effects on prostate function were assessed using the International Prostate Symptom Score at baseline and Night 30. Potential adverse events were assessed during in-laboratory visits and via weekly phone calls. Results: Side effects were generally mild and consistent with known side-effect profiles of each individual drug (i.e., dose-dependent increases in dry mouth with oxybutynin). Heart rate increased by Night 30 in two active drug arms (mean ± standard deviation 8 ± 10 beats/min [P = 0.01] with 80/5 mg and 9 ± 14 beats/min [P = 0.02] with 40/2.5 mg vs. placebo). No clinically relevant changes in blood pressure, International Prostate Symptom Score, and measures of alertness and memory were observed between conditions. Apnea-hypopnea index (AHI) with 4% oxygen desaturation and hypoxic burden decreased by ∼50% with 80/5 mg ato-oxy from baseline but not versus placebo (e.g., AHI with 3% oxygen desaturation and AHI with 4% oxygen desaturation difference at Night 30 was -8.2 [95% confidence interval, -22.5 to 6.2] and -8.5 [95% confidence interval, -18.3 to 1.3] events/h, respectively). Conclusions: One month of nightly noradrenergic and antimuscarinic combination therapy was generally well tolerated, with a side-effect profile consistent with each agent alone, and was associated with an ∼50% reduction from baseline in a key OSA severity metric, the hypoxic burden with the highest dose combination. These findings highlight the potential to target noradrenergic and antimuscarinic mechanisms for OSA pharmacotherapy development. Clinical trial registered with www.anzctr.org.au (ACTRN 12619001153101).

High night-to-night variability in sleep apnea severity is associated with uncontrolled hypertension.

Obstructive sleep apnea (OSA) severity can vary markedly from night-to-night. However, the impact of night-to-night variability in OSA severity on key cardiovascular outcomes such as hypertension is unknown. Thus, the primary aim of this study is to determine the effects of night-to-night variability in OSA severity on hypertension likelihood. This study uses in-home monitoring of 15,526 adults with ~180 nights per participant with an under-mattress sleep sensor device, plus ~30 repeat blood pressure measures. OSA severity is defined from the mean estimated apnea-hypopnoea index (AHI) over the ~6-month recording period for each participant. Night-to-night variability in severity is determined from the standard deviation of the estimated AHI across recording nights. Uncontrolled hypertension is defined as mean systolic blood pressure ≥140 mmHg and/or mean diastolic blood pressure ≥90 mmHg. Regression analyses are performed adjusted for age, sex, and body mass index. A total of 12,287 participants (12% female) are included in the analyses. Participants in the highest night-to-night variability quartile within each OSA severity category, have a 50-70% increase in uncontrolled hypertension likelihood versus the lowest variability quartile, independent of OSA severity. This study demonstrates that high night-to-night variability in OSA severity is a predictor of uncontrolled hypertension, independent of OSA severity. These findings have important implications for the identification of which OSA patients are most at risk of cardiovascular harm.

Sex differences in pain expressed by patients across diverse disease states: individual patient data meta-analysis of 33,957 participants in 10 randomized controlled trials.

ABSTRACT: The experience of pain is determined by many factors and has a significant impact on quality of life. This study aimed to determine sex differences in pain prevalence and intensity reported by participants with diverse disease states in several large international clinical trials. Individual participant data meta-analysis was conducted using EuroQol-5 Dimension (EQ-5D) questionnaire pain data from randomised controlled trials published between January 2000 and January 2020 and undertaken by investigators at the George Institute for Global Health. Proportional odds logistic regression models, comparing pain scores between females and males and fitted with adjustments for age and randomized treatment, were pooled in a random-effects meta-analysis. In 10 trials involving 33,957 participants (38% females) with EQ-5D pain score data, the mean age ranged between 50 and 74. Pain was reported more frequently by females than males (47% vs 37%; P < 0.001). Females also reported greater levels of pain than males (adjusted odds ratio 1.41, 95% CI 1.24-1.61; P < 0.001). In stratified analyses, there were differences in pain by disease group ( P for heterogeneity <0.001), but not by age group or region of recruitment. Females were more likely to report pain, and at a higher level, compared with males across diverse diseases, all ages, and geographical regions. This study reinforces the importance of reporting sex-disaggregated analysis to identify similarities and differences between females and males that reflect variable biology and may affect disease profiles and have implications for management.

C-reactive protein is a prognostic biomarker in pancreatic ductal adenocarcinoma patients.

AIM: The 5-year survival rate of pancreatic ductal adenocarcinoma (PDAC) is approximately 11% and has only improved marginally over the last three decades. For operable PDAC, resection and adjuvant FOLFIRINOX chemotherapy is standard of care. There is growing interest in perioperative regimens to improve outcomes. The non-randomized Phase II study "Gemcitabine and Abraxane for resectable Pancreatic cancer" (GAP) demonstrated the feasibility of perioperative gemcitabine/abraxane. Long-term survival in PDAC requires an effective immune response; hence, we undertook this translational study of the GAP trial cohort to identify immune-oncology biomarkers for clinical use. METHODS: We combined Nanostring nCounter technology with immunohistochemistry to investigate the correlation between gene expression and overall patient survival. Findings were investigated in samples from the International Cancer Genome Consortium (ICGC, n = 88) and the Australian Pancreatic Genome Initiative (APGI, n = 227). RESULTS: We confirmed that human equilibrative nucleoside transporter 1 (hENT1) expression was not a prognostic marker in PDAC but patients with high levels of hENT1 were more likely to live longer than 24 months post-surgery. Additionally, CD274 (PD-L1) and two novel biomarkers of survival, cathepsin W (CTSW) and C-reactive protein (CRP), were identified in the GAP cohort (n = 19). CRP expression was confirmed in data from the ICGC. Although PD-L1 and CTSW proteins were not significant across all three cohorts, results show that low CRP mRNA and protein expression are associated with longer overall survival in all three patient groups. CONCLUSION: PDAC patients with long survival have higher hENT1 expression levels. Furthermore, CRP expression is a biomarker of poor prognosis following perioperative chemotherapy and resection in PDAC patients and thus may be useful for identifying patients who could benefit from more aggressive adjuvant strategies.

Menin and p53 have non-synergistic effects on tumorigenesis in mice.

BACKGROUND: While it is now more than a decade since the first description of the gene mutation underlying the tumour predisposition syndrome multiple endocrine neoplasia type 1 (MEN1), the mechanism by which its protein product menin acts to prevent development of tumours is still poorly understood. METHODS: We undertook a genetic experiment to assess whether menin synergises with p53. Mice carrying various combinations of Men1 and Trp53 mutations were generated then survival and pathology assessed. RESULTS: While homozygous loss of Trp53 in mice resulted in early onset, aggressive tumours and profoundly reduced lifespan, heterozygous loss of either Trp53 or Men1 caused later onset disease, with a spectrum of tumours characteristic of each tumour suppressor gene. Loss of one copy of Men1 in animals also lacking both alleles of Trp53 did not exacerbate phenotype, based on survival, animal weight or sites of pathology, compared to Trp53 deletion alone. Dual heterozygous deletion of Men1 and Trp53 resulted in a small reduction in lifespan compared to the individual mutations, without new tumour sites. In the adrenal, we observed development of cortical tumours in dual heterozygous animals, as we have previously seen in Men1+/- animals, and there was loss of heterozygosity at the Men1 allele in these tumours. Median number of pathology observations per animal was increased in dual heterozygous animals compared with heterozygous loss of Trp53 alone. CONCLUSIONS: Simultaneous heterozygous deletion of Men1 in animals with either heterozygous or homozygous deletion of Trp53 did not result in formation of tumours at any new sites, implying additive rather than synergistic effects of these pathways. Mice that were Men1+/- in addition to Trp53+/- had tumours in endocrine as well as other sites, implying that increase in total tumour burden, at sites typically associated with either Men1 or Trp53 loss, contributed to the slight decrease in survival in Men1+/-: Trp53+/- animals in comparison with their littermates.

The Combination of Betahistine and Oxybutynin Increases Respiratory Control Sensitivity (Loop Gain) in People with Obstructive Sleep Apnea: A Randomized, Placebo-Controlled Trial.

Rationale: There are widespread histaminergic projections throughout the brain, including hypoglossal nuclei, that modulate pharyngeal muscle tone and respiratory control. Hence, histaminergic stimulation pharmacologically may increase pharyngeal muscle tone and stabilize respiratory control (loop gain) to reduce obstructive sleep apnea (OSA) severity. Antimuscarinics also increase REM pharyngeal muscle tone in rats. Thus, a combination of histaminergic and anti-muscarinic drugs may be a novel target for OSA pharmacotherapy. However, this has not been investigated. Accordingly, we aimed to test the effects of betahistine (Beta), an H3-autoreceptor antagonist which thereby increases histamine levels, in combination with the antimuscarinic oxybutynin (Oxy), on OSA severity, OSA endotypes, polysomnography parameters and next-day sleepiness and alertness. Methods: Thirteen adults with OSA received either Beta-Oxy (96-5mg) or placebo according to a randomized, crossover, double-blind design, prior to polysomnography. Participants completed the Karolinska Sleep Scale and Leeds Sleep Evaluation Questionnaire and a driving simulation task to quantify next-day sleepiness and alertness. OSA endotypes were estimated through validated algorithms using polysomnography. Results: Compared to placebo, Beta-Oxy increased respiratory control sensitivity (loop gain) (0.52[0.24] vs 0.60[0.34], median [IQR], P = 0.021) without systematically changing OSA severity (34.4±17.2 vs 40.3±27.3 events/h, mean±SD, P = 0.124), sleep efficiency, arousal index or markers of hypoxemia. Beta-Oxy was well tolerated and did not worsen next-day sleepiness/alertness. Conclusion: Rather than stabilize breathing during sleep, Beta-Oxy increases loop gain, which is likely to be deleterious for most people with OSA. However, in certain conditions characterized by blunted respiratory control (eg, obesity hypoventilation syndrome), interventions to increase loop gain may be beneficial.

All-Cause Mortality in People with Co-Occurring Insomnia Symptoms and Sleep Apnea: Analysis of the Wisconsin Sleep Cohort.

Purpose: Insomnia symptoms and sleep apnea frequently co-occur and are associated with worse sleep, daytime function, mental health and quality of life, compared to either insomnia or obstructive sleep apnea (OSA) alone. This study aimed to investigate the association of symptoms of co-morbid insomnia and sleep apnea (COMISA) with all-cause mortality. Patients and Methods: Wisconsin Sleep Cohort data were analysed to assess potential associations between COMISA symptoms and all-cause mortality. Nocturnal insomnia symptoms were defined as difficulties initiating sleep, maintaining sleep, and/or early morning awakenings "often" or "almost always", and/or regular sedative-hypnotic medicine use. OSA was defined as an apnea-hypopnea index ≥5/hr sleep. Participants were classified as having neither insomnia symptoms nor OSA, insomnia symptoms alone, OSA alone, or COMISA symptoms. Associations between the four groups and all-cause mortality over 20 years of follow-up were examined via multivariable adjusted Cox regression models. Results: Among 1115 adult participants (mean ± SD age 55 ± 8 years, 53% males), 19.1% had COMISA symptoms. After controlling for sociodemographic and behavioral factors, COMISA symptoms were associated with an increased risk of all-cause mortality compared to no insomnia symptoms or OSA (HR [95% CI]; 1.71 [1.00-2.93]). OSA alone (0.91 [0.53, 1.57]) and insomnia symptoms alone (1.04 [0.55, 1.97]) were not associated with increased mortality risk. Conclusion: Co-morbid insomnia symptoms and sleep apnea is associated with increased all-cause mortality risk. Future research should investigate mechanisms underpinning COMISA and the effectiveness of different treatment approaches to reduce mortality risk for this common condition.