A systematic scoping review of primary health care service outreach for homeless populations.

BACKGROUND: Homeless populations (HPs) have difficulties obtaining necessary medical care, and primary health care service outreach (PHSO) might be useful to bridge this gap. OBJECTIVE: Using the Centre for Evidence-Based Management Critically Appraised Topics framework, to provide systematic evidence of the usefulness of PHSO interventions for HPs. METHODS: A systematic search was conducted in 4 electronic databases: PubMed, Web of Science, CINAHL, and Cochrane (publication dates between January 1980 and November 2020). In total, 2,872 articles were identified. Primary research about PHSO for HPs in high-income countries were included. Data were extracted from eligible studies, summarized, and collated into a narrative account. RESULTS: Twenty-four studies that described and evaluated PHSO interventions for adults experiencing homelessness were selected in the final synthesis. Most studies had a nonrandomized design. PHSO was found to successfully address some barriers to health care access for HPs through flexible appointments in convenient locations, fostering an understanding relationship between doctor and patients, and provision of additional basic necessities and referrals. Outreach was provided for a range of health care concerns, and several solutions to engage more HPs in primary care, improve continuity of care and to decrease the running costs were identified. Outreach also helped to implement preventative measures and reduced emergency service admissions. CONCLUSION: Our review adds to the evidence that PHSO likely improves health care access for HPs. Further studies over longer time periods, involving collaborations with experts with lived experience of homelessness, and utilizing randomized study designs are needed to test outreach efficacy.

The endoplasmic reticulum protein SEC22B interacts with NBEAL2 and is required for megakaryocyte α-granule biogenesis.

Studies of inherited platelet disorders have provided many insights into platelet development and function. Loss of function of neurobeachin-like 2 (NBEAL2) causes gray platelet syndrome (GPS), where the absence of platelet α-granules indicates NBEAL2 is required for their production by precursor megakaryocytes. The endoplasmic reticulum is a dynamic network that interacts with numerous intracellular vesicles and organelles and plays key roles in their development. The megakaryocyte endoplasmic reticulum is extensive, and in this study we investigated its role in the biogenesis of α-granules by focusing on the membrane-resident trafficking protein SEC22B. Coimmunoprecipitation (co-IP) experiments using tagged proteins expressed in human HEK293 and megakaryocytic immortalized megakaryocyte progenitor (imMKCL) cells established binding of NBEAL2 with SEC22B, and demonstrated that NBEAL2 can simultaneously bind SEC22B and P-selectin. NBEAL2-SEC22B binding was also observed for endogenous proteins in human megakaryocytes using co-IP, and immunofluorescence microscopy detected substantial overlap. SEC22B binding was localized to a region of NBEAL2 spanning amino acids 1798 to 1903, where 2 GPS-associated missense variants have been reported: E1833K and R1839C. NBEAL2 containing either variant did not bind SEC22B coexpressed in HEK293 cells. CRISPR/Cas9-mediated knockout of SEC22B in imMKCL cells resulted in decreased NBEAL2, but not vice versa. Loss of either SEC22B or NBEAL2 expression resulted in failure of α-granule production and reduced granule proteins in imMKCL cells. We conclude that SEC22B is required for α-granule biogenesis in megakaryocytes, and that interactions with SEC22B and P-selectin facilitate the essential role of NBEAL2 in granule development and cargo stability.

The contribution of respiratory and hearing protection use to psychological distress in the workplace: a scoping review.

OBJECTIVE: Workers from various industries use personal protective equipment (PPE) including masks, respirators, and hearing protection to reduce their exposures to workplace hazards. Many studies have evaluated the physiological impacts of PPE use, but few have assessed the psychological impacts. The aim of the present study was to carry out a scoping review to compile existing evidence and determine the extent of knowledge on workplace mask, respirator or hearing protection use as a psychosocial hazard (stressor) that could result in a stress response and potentially lead to psychological injury. METHODS: The scoping review followed recognized methods and was conducted using Ovid Emcare, PubMed, Sage Journals, ScienceDirect, Scopus, SpringerLink, Google Scholar and preprint databases (OSF Preprints and medRxiv). Articles on the stressors associated with the use of masks, respirators, and hearing protection were included. The extracted data included author(s) name, year of publication, title of article, study design, population data, stressors assessed, and key findings. RESULTS: We retrieved 650 articles after removal of duplicates, of which 26 were deemed eligible for inclusion for review. Identified factors associated with PPE use that could potentially create a stress response were identified: communication impacts, physical impacts, psychological illness symptoms, cognitive impacts, and perceived PPE-related impacts. Evidence for respirators suggest that there may be psychological injury associated with their use. However, hearing protection appears to have a protective effect in reducing psychological symptoms such as anxiety, depression, and aggression. CONCLUSIONS: Mask or respirator use may lead to an increase in work-related stress. Whereas hearing protection may have protective effects against psychological symptoms and improves speech intelligibility. More research is needed to better understand potential psychosocial impacts of mask, respirator and/or hearing protection use.

Diverse pathogenetic roles of SOX genes in acute myeloid leukaemia and their therapeutic implications.

Acute myeloid leukaemia (AML) is a heterogeneous group of diseases with diverse pathogenetic pathways. When treated uniformly with conventional chemotherapy and allogeneic haematopoietic stem cell transplantation (HSCT), it showed variable clinical outcome and prognosis. Members of the SOX [Sry-related high-mobility group (HMG) box] gene family are involved in diverse embryonic and oncogenic processes. The roles of SOX genes in AML are not entirely clear but emerging evidence, including that arising from studies in solid-cancers, showed that SOX genes can function as tumour suppressors or oncogenes and may be involved in key pathogenetic pathways in AML involving C/EBPα mutations, activation of ß-catenin/Wnt and Hedgehog pathways and aberrant TP53 signals. Recent data based on genomics and proteomics have identified key interactions between SOX genes and partnering proteins of pathogenetic significance. The observations illustrated the principles and feasibilities of developing lead molecules of potential therapeutic values. Studying the diverse pathogenetic roles of SOX genes in AML may shed lights to the heterogeneity of AML and generate information that can be translated into novel therapeutic strategies.

Sleep and Pathological Wakefulness at the Time of Liberation from Mechanical Ventilation (SLEEWE). A Prospective Multicenter Physiological Study.

Rationale: Abnormal patterns of sleep and wakefulness exist in mechanically ventilated patients. Objectives: In this study (SLEEWE [Effect of Sleep Disruption on the Outcome of Weaning from Mechanical Ventilation]), we aimed to investigate polysomnographic indexes as well as a continuous index for evaluating sleep depth, the odds ratio product (ORP), to determine whether abnormal sleep or wakefulness is associated with the outcome of spontaneous breathing trials (SBTs). Methods: Mechanically ventilated patients from three sites were enrolled if an SBT was planned the following day. EEG was recorded using a portable sleep diagnostic device 15 hours before the SBT. The ORP was calculated from the power of four EEG frequency bands relative to each other, ranging from full wakefulness (2.5) to deep sleep (0). The correlation between the right and left hemispheres' ORP (R/L ORP) was calculated. Measurements and Main Results: Among 44 patients enrolled, 37 had technically adequate signals: 11 (30%) passed the SBT and were extubated, 8 (21%) passed the SBT but were not deemed to be clinically ready for extubation, and 18 (49%) failed the SBT. Pathological wakefulness or atypical sleep were highly prevalent, but the distribution of classical sleep stages was similar between groups. The mean ORP and the proportion of time in which the ORP was >2.2 were higher in extubated patients compared with the other groups (P < 0.05). R/L ORP was significantly lower in patients who failed the SBT, and the area under the receiver operating characteristic curve of R/L ORP to predict failure was 0.91 (95% confidence interval, 0.75-0.98). Conclusions: Patients who pass an SBT and are extubated reach higher levels of wakefulness as indicated by the ORP, suggesting abnormal wakefulness in others. The hemispheric ORP correlation is much poorer in patients who fail an SBT.

Learning how to learn: can embedded discussion boards help first-year students discover new learning strategies?

Learning anatomy and physiology at university can be challenging, as students need to understand both the language of the discipline and complex topics, such as system integration. Yet learning strategies are rarely taught at university, making it difficult for students to adopt new strategies, if their approach to learning has not been effective or efficient. This study evaluated the use of small-group peer discussion boards as an avenue for sharing learning strategies between students in a first-year anatomy and physiology course. The majority of students (91%) identified strategies from the discussion board worth trying before they completed the midsemester exam. The most frequently reported type of strategy was transforming records. By the end of semester, 76% of students had adopted at least one new strategy; however, these students performed significantly worse on the exam compared with students who did not adopt new strategies. The students who adopted new strategies learned about them from peers (33%), the discussion board (32%), or through self-discovery (32%). The majority of students (83%) found the discussion boards to be useful as a source of new learning strategies and for insight into how others learn. Although the discussion boards provided an avenue for students to learn about new strategies from each other, further guidance from instructors may be required to help students evaluate the effectiveness of these learning strategies.

NBEAL2 (Neurobeachin-Like 2) Is Required for Retention of Cargo Proteins by α-Granules During Their Production by Megakaryocytes.

Objective- Human and mouse megakaryocytes lacking NBEAL2 (neurobeachin-like 2) produce platelets where α-granules lack protein cargo. This cargo is mostly megakaryocyte-synthesized, but some proteins, including FGN (fibrinogen), are endocytosed. In this study, we examined the trafficking of both types of cargo within primary megakaryocytes cultured from normal and NBEAL2-null mice, to determine the role of NBEAL2 in α-granule maturation. We also examined the interaction of NBEAL2 with the granule-associated protein P-selectin in human megakaryocytes and platelets. Approach and Results- Fluorescence microscopy was used to compare uptake of labeled FGN by normal and NBEAL2-null mouse megakaryocytes, which was similar in both. NBEAL2-null cells, however, showed decreased FGN retention, and studies with biotinylated protein showed rapid loss rather than increased degradation. Intracellular tracking via fluorescence microscopy revealed that in normal megakaryocytes, endocytosed FGN sequentially associated with compartments expressing RAB5 (Ras-related protein in brain 5), RAB7 (Ras-related protein in brain 7), and P-selectin, where it was retained. A similar initial pattern was observed in NBEAL2-null megakaryocytes, but then FGN passed from the P-selectin compartment to RAB11 (Ras-related protein in brain 11)-associated endosomes before release. Megakaryocyte-synthesized VWF (Von Willebrand factor) was observed to follow the same route out of NBEAL2-null cells. Immunofluorescence microscopy revealed intracellular colocalization of NBEAL2 with P-selectin in human megakaryocytes, proplatelets, and platelets. Native NBEAL2 and P-selectin were coimmunoprecipitated from platelets and megakaryocytes. Conclusions- NBEAL2 is not required for FGN uptake by megakaryocytes. NBEAL2 is required for the retention of both endocytosed and megakaryocyte-synthesized proteins by maturing α-granules, and possibly by platelet-borne granules. This function may involve interaction of NBEAL2 with P-selectin.

Obstructive sleep apnoea is not a risk factor for incident hospitalised depression: a historical cohort study.

We evaluated whether obstructive sleep apnoea (OSA) was related to the incidence of hospitalisation for depression, a robust end-point that is unlikely to result from misdiagnosis.All adults referred with suspected OSA who underwent a diagnostic sleep study at a large urban academic hospital between 1994 and 2010 and were linked to provincial health administrative data between 1991 and 2015 were included. Cox regression analysis was used to investigate the association between OSA symptoms and severity and incident hospitalised depression, the primary outcome.Over a median follow-up of 9.7 years, 136 (1.3%) out of 10 149 participants were hospitalised for depression. A significant crude effect of OSA symptoms (waking unrefreshed and impact on memory and concentration) on hospitalised depression became nonsignificant after controlling for confounders. Apnoea-hypopnoea index was not significantly associated with the outcome: adjusted hazard ratio (33 versus 6 events·h-1) 1.13 (95% CI 0.91-1.40). Factors associated with hospitalised depression were female sex, younger age, use of hypnotics, alcoholism and unemployment.In a large clinical cohort with suspected OSA, controlling for confounders, OSA symptoms and severity were not related to the risk of hospitalisation for depression, suggesting that previously reported links between OSA and depression may be due to overlapping diagnostic criteria. However, our findings cannot exclude a potential link between OSA and milder depression.

FlnA binding to PACSIN2 F-BAR domain regulates membrane tubulation in megakaryocytes and platelets.

Bin-Amphiphysin-Rvs (BAR) and Fes-CIP4 homology BAR (F-BAR) proteins generate tubular membrane invaginations reminiscent of the megakaryocyte (MK) demarcation membrane system (DMS), which provides membranes necessary for future platelets. The F-BAR protein PACSIN2 is one of the most abundant BAR/F-BAR proteins in platelets and the only one reported to interact with the cytoskeletal and scaffold protein filamin A (FlnA), an essential regulator of platelet formation and function. The FlnA-PACSIN2 interaction was therefore investigated in MKs and platelets. PACSIN2 associated with FlnA in human platelets. The interaction required FlnA immunoglobulin-like repeat 20 and the tip of PACSIN2 F-BAR domain and enhanced PACSIN2 F-BAR domain membrane tubulation in vitro. Most human and wild-type mouse platelets had 1 to 2 distinct PACSIN2 foci associated with cell membrane GPIbα, whereas Flna-null platelets had 0 to 4 or more foci. Endogenous PACSIN2 and transfected enhanced green fluorescent protein-PACSIN2 were concentrated in midstage wild-type mouse MKs in a well-defined invagination of the plasma membrane reminiscent of the initiating DMS and dispersed in the absence of FlnA binding. The DMS appeared less well defined, and platelet territories were not readily visualized in Flna-null MKs. We conclude that the FlnA-PACSIN2 interaction regulates membrane tubulation in MKs and platelets and likely contributes to DMS formation.

Obstructive sleep apnea and incident diabetes. A historical cohort study.

RATIONALE: Despite emerging evidence that obstructive sleep apnea (OSA) may cause metabolic disturbances independently of other known risk factors, it remains unclear whether OSA is associated with incident diabetes. OBJECTIVES: To evaluate whether risk of incident diabetes was related to the severity and physiologic consequences of OSA. METHODS: A historical cohort study was conducted using clinical and provincial health administrative data. All adults without previous diabetes referred with suspected OSA who underwent a diagnostic sleep study at St. Michael's Hospital (Toronto, Canada) between 1994 and 2010 were followed through health administrative data until May 2011 to examine the occurrence of diabetes. All OSA-related variables collected from the sleep study were examined as predictors in Cox regression models, controlling for sex, age, body mass index, smoking status, comorbidities, and income. MEASUREMENTS AND MAIN RESULTS: Over a median follow-up of 67 months, 1,017 (11.7%) of 8,678 patients developed diabetes, giving a cumulative incidence at 5 years of 9.1% (95% confidence interval, 8.4-9.8%). In fully adjusted models, patients with apnea-hypopnea index (AHI) greater than 30 had a 30% higher hazard of developing diabetes than those with AHI less than 5. Among other OSA-related variables, AHI in rapid eye movement sleep and time spent with oxygen saturation less than 90% were associated with incident diabetes, as were heart rate, neck circumference, and sleep time. CONCLUSIONS: Among people with OSA, and controlling for multiple confounders, initial OSA severity and its physiologic consequences predicted subsequent risk for incident diabetes.

Obstructive sleep apnea and risk of cardiovascular events and all-cause mortality: a decade-long historical cohort study.

BACKGROUND: Obstructive sleep apnea (OSA) has been reported to be a risk factor for cardiovascular (CV) disease. Although the apnea-hypopnea index (AHI) is the most commonly used measure of OSA, other less well studied OSA-related variables may be more pathophysiologically relevant and offer better prediction. The objective of this study was to evaluate the relationship between OSA-related variables and risk of CV events. METHODS AND FINDINGS: A historical cohort study was conducted using clinical database and health administrative data. Adults referred for suspected OSA who underwent diagnostic polysomnography at the sleep laboratory at St Michael's Hospital (Toronto, Canada) between 1994 and 2010 were followed through provincial health administrative data (Ontario, Canada) until May 2011 to examine the occurrence of a composite outcome (myocardial infarction, stroke, congestive heart failure, revascularization procedures, or death from any cause). Cox regression models were used to investigate the association between baseline OSA-related variables and composite outcome controlling for traditional risk factors. The results were expressed as hazard ratios (HRs) and 95% CIs; for continuous variables, HRs compare the 75th and 25th percentiles. Over a median follow-up of 68 months, 1,172 (11.5%) of 10,149 participants experienced our composite outcome. In a fully adjusted model, other than AHI OSA-related variables were significant independent predictors: time spent with oxygen saturation <90% (9 minutes versus 0; HR = 1.50, 95% CI 1.25-1.79), sleep time (4.9 versus 6.4 hours; HR = 1.20, 95% CI 1.12-1.27), awakenings (35 versus 18; HR = 1.06, 95% CI 1.02-1.10), periodic leg movements (13 versus 0/hour; HR = 1.05, 95% CI 1.03-1.07), heart rate (70 versus 56 beats per minute [bpm]; HR = 1.28, 95% CI 1.19-1.37), and daytime sleepiness (HR = 1.13, 95% CI 1.01-1.28).The main study limitation was lack of information about continuous positive airway pressure (CPAP) adherence. CONCLUSION: OSA-related factors other than AHI were shown as important predictors of composite CV outcome and should be considered in future studies and clinical practice.

Obstructive sleep apnea and the prevalence and incidence of cancer.

BACKGROUND: A link between obstructive sleep apnea and cancer development or progression has been suggested, possibly through chronic hypoxemia, but supporting evidence is limited. We examined the association between the severity of obstructive sleep apnea and prevalent and incident cancer, controlling for known risk factors for cancer development. METHODS: We included all adults referred with possible obstructive sleep apnea who underwent a first diagnostic sleep study at a single large academic hospital between 1994 and 2010. We linked patient data with data from Ontario health administrative databases from 1991 to 2013. Cancer diagnosis was derived from the Ontario Cancer Registry. We assessed the cross-sectional association between obstructive sleep apnea and prevalent cancer at the time of the sleep study (baseline) using logistic regression analysis. Cox regression models were used to investigate the association between obstructive sleep apnea and incident cancer among patients free of cancer at baseline. RESULTS: Of 10 149 patients who underwent a sleep study, 520 (5.1%) had a cancer diagnosis at baseline. Over a median follow-up of 7.8 years, 627 (6.5%) of the 9629 patients who were free of cancer at baseline had incident cancer. In multivariable regression models, the severity of sleep apnea was not significantly associated with either prevalent or incident cancer after adjustment for age, sex, body mass index and smoking status at baseline (apnea-hypopnea index > 30 v. < 5: adjusted odds ratio [OR] 0.96, 95% confidence interval [CI] 0.71-1.30, for prevalent cancer, and adjusted hazard ratio [HR] 1.02, 95% CI 0.80-1.31, for incident cancer; sleep time spent with oxygen saturation < 90%, per 10-minute increase: adjusted OR 1.01, 95% CI 1.00-1.03, for prevalent cancer, and adjusted HR 1.00, 95% CI 0.99-1.02, for incident cancer). INTERPRETATION: In a large cohort, the severity of obstructive sleep apnea was not independently associated with either prevalent or incident cancer. Additional studies are needed to elucidate whether there is an independent association with specific types of cancer.

Murine cell line model of proneural glioma for evaluation of anti-tumor therapies.

Molecular subtypes of glioblastoma (GBM) with distinct alterations have been identified. There is need for reproducible, versatile preclinical models that resemble specific GBM phenotypes to facilitate preclinical testing of novel therapies. We present a cell line-based murine proneural GBM model and characterize its response to radiation therapy. Proneural gliomas were generated by injecting PDGF-IRES-Cre retrovirus into the subcortical white matter of adult mice that harbor floxed tumor suppressors (Pten and p53) and stop-floxed reporters. Primary cell cultures were generated from the retrovirus induced tumors and maintained in vitro for multiple passages. RNA sequencing-based expression profiling of the resulting cell lines was performed. The tumorigenic potential of the cells was assessed by intracranial injection into adult naïve mice from different strains. Tumor growth was assessed by bioluminescence imaging (BLI). BLI for tumor cells and brain slices were obtained and compared to in vivo BLI. Response to whole-brain radiation was assessed in glioma-bearing animals. Intracranial injection of Pdgf(+)Pten(-/-)p53(-/-)luciferase(+) glioma cells led to formation of GBM-like tumors with 100 % efficiency (n = 48) and tumorigenesis was retained for more than 3 generations. The cell lines specifically resembled proneural GBM based on expression profiling by RNA-Seq. Pdgf(+)Pten(-/-)p53(-/-)luciferase(+) cell number correlated with BLI signal. Serial BLI measured tumor growth and correlated with size and location by ex vivo imaging. Moreover, BLI predicted tumor-related mortality with a 93 % risk of death within 5 days following a BLI signal between 1 × 10(8) and 5 × 10(8) photons/s cm(2). BLI signal had transient but significant response following radiotherapy, which corresponded to a modest survival benefit for radiated mice (p < 0.05). Intracranial injection of Pdgf(+)Pten(-/-)p53(-/-)luciferase(+) cells constitutes a novel and highly reproducible model, recapitulating key features of human proneural GBM, and can be used to evaluate tumor-growth and response to therapy.

Polysomnographic Assessment of Sleep Disturbances in Cancer Development: A Historical Multicenter Clinical Cohort Study.

BACKGROUND: Many cellular processes are controlled by sleep. Therefore, alterations in sleep might be expected to stress biological systems that could influence malignancy risk. RESEARCH QUESTION: What 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 METHODS: We 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. RESULTS: Among 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. INTERPRETATION: In 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 REGISTRY: ClinicalTrials.gov; Nos.: NCT03383354 and NCT03834792; URL: www. CLINICALTRIALS: gov.

Mechanisms of sleep-disordered breathing: causes and consequences.

Obstructive sleep apnea (OSA) is very common in the general population and is characterized by ineffective inspiratory efforts against a collapsed upper airway during sleep. Collapse occurs mainly at the level of the velopharynx and oropharynx due to a combination of predisposing anatomy and the withdrawal of pharyngeal dilator activity during sleep. Central sleep apnea (CSA) is a manifestation of chemoreflex control instability, leading to periods of inadequate respiratory drive sufficient to trigger breathing, usually alternating with periods of hyperventilation. While both forms of apnea are the result of differing pathophysiology, it has become increasingly clear that OSA and CSA often coexist in the same patient, the existence of one can predispose to the other, and that the two are not as distinct as previously thought. Both OSA and CSA exert a number of acute deleterious effects including intermittent hypoxia, arousals from sleep, and swings in negative intrathoracic pressure, which in turn lead to chronic physiologic consequences such as autonomic dysregulation, endothelial dysfunction, and cardiac remodeling. These underlying pathophysiological mechanisms provide a framework for understanding why OSA and CSA may predispose to cardiovascular diseases like ischemic heart disease and stroke.

Polysomnographic Markers of Obstructive Sleep Apnea Severity and Cancer-related Mortality: A Large Retrospective Multicenter Clinical Cohort Study.

Rationale: The evidence for an association between cancer survival and obstructive sleep apnea (OSA) remains underexplored. Objectives: To evaluate an association between markers of OSA severity (respiratory disturbances, hypoxemia, and sleep fragmentation) and cancer-related mortality in individuals with previously diagnosed cancer. Methods: We conducted a multicenter retrospective cohort study using linked clinical and provincial health administrative data on consecutive adults who underwent a diagnostic sleep study between 1994 and 2017 in four Canadian academic hospitals and were previously diagnosed with cancer through the Ontario Cancer Registry. Multivariable cause-specific Cox regressions were used to address the research objective. Results: We included 2,222 subjects. Over a median follow-up time of 5.6 years (interquartile range [IQR], 2.7-9.1 years), 261/2,222 (11.7%) individuals with prevalent cancer died from cancer-related causes, which accounted for 44.2% (261/590) of all-cause death. Controlling for age, sex, alcohol use disorder, prior heart failure, chronic obstructive pulmonary disease, hypertension, diabetes, treatment for OSA, clinic site, year of the sleep study, and time since the cancer diagnosis, measures of hypoxemia and sleep fragmentation, but not apnea-hypopnea index, were significantly associated with the cancer-specific mortality: percentage of time spent with arterial oxygen saturation (SaO2) < 90% (hazard ratio [HR] per 5% increase, 1.05; 95% confidence interval, 1.01-1.09); mean SaO2 (HR per 3% increase, 0.79; 0.68-0.92); and percentage of stage 1 sleep (HR per 16% increase, 1.27; 1.07-1.51). Conclusions: In a large clinical cohort of adults with suspected OSA and previously diagnosed cancer, measures of nocturnal hypoxemia and sleep fragmentation as markers of OSA severity were significantly associated with cancer-related mortality, suggesting the need for more targeted risk awareness.

The relationship between opioid use and obstructive sleep apnea: A systematic review and meta-analysis.

We conducted a systematic review to address limited evidence suggesting that opioids may induce or aggravate obstructive sleep apnea (OSA). All clinical trials or observational studies on adults from 1946 to 2018 found through MEDLINE, EMBASE, CINAHL, PsycINFO, Cochrane Databases were eligible. We assessed the quality of the studies using published guidelines. Fifteen studies (six clinical trials and nine observational) with only two of good quality were included. Fourteen studies investigated the impact of opioids on the presence or severity of OSA, four addressed the effects of treatment for OSA  in opioid users, and none explored the consequences of opioid use in individuals with OSA. Eight of 14 studies found no significant relationship between opioid use or dose and apnea-hypopnea index (AHI) or degree of nocturnal desaturation. A random-effects meta-analysis (n = 10) determined the pooled mean change in AHI associated with opioid use of 1.47/h (-2.63-5.57; I2 = 65%). Three of the four studies found that continuous positive airway pressure (CPAP) therapy reduced AHI by 17-30/h in opioid users with OSA. Bilevel therapy with a back-up rate and adaptive servo-ventilation (ASV) without mandatory pressure support successfully normalized AHI (≤5) in opioid users. Limited by a paucity of good-quality studies, our review did not show a significant relationship between opioid use and the severity of OSA. There was some evidence that CPAP, Bilevel therapy, and ASV alleviate OSA for opioid users, with higher failure rates observed in patients on CPAP in opioid users.

Obstructive Sleep Apnea and Incident Cancer: A Large Retrospective Multicenter Clinical Cohort Study.

BACKGROUND: To examine the association between the severity of obstructive sleep apnea (OSA) and nocturnal hypoxemia with incident cancer. METHODS: This was a multicenter retrospective clinical cohort study using linked clinical and provincial health administrative data on consecutive adults who underwent a diagnostic sleep study between 1994 and 2017 in four academic hospitals (Canada) who were free of cancer at baseline. Cancer status was derived from the Ontario Cancer Registry. Cox cause-specific regressions were utilized to address the objective and to calculate the 10-year absolute risk difference (ARD) in the marginal probability of incident cancer and the number needed to harm (NNH). RESULTS: Of 33,997 individuals considered, 33,711 with no missing OSA severity were included: median age, 50 years; 58% male; and 23% with severe OSA (apnea-hypopnea index >30). Of the 18,458 individuals with information on sleep time spent with oxygen saturation (SaO2) <90%, 5% spent >30% of sleep with SaO2 <90% (severe nocturnal hypoxemia). Over a median of 7 years, 2,498 of 33,711 (7%) individuals developed cancer, with an incidence rate of 10.3 (10.0-10.8) per 1,000 person-years. Controlling for confounders, severe OSA was associated with a 15% increased hazard of developing cancer compared with no OSA (HR = 1.15, 1.02-1.30; ARD = 1.28%, 0.20-2.37; and NNH = 78). Severe hypoxemia was associated with about 30% increased hazard (HR = 1.32, 1.08-1.61; ARD = 2.38%, 0.47-4.31; and NNH = 42). CONCLUSIONS: In a large cohort of individuals with suspected OSA free of cancer at baseline, the severity of OSA and nocturnal hypoxemia was independently associated with incident cancer. IMPACT: These findings suggest the need for more targeted cancer risk awareness in individuals with OSA.