Obstructive sleep apnea severity, circulating biomarkers, and cancer risk.

STUDY OBJECTIVES: To determine if obstructive sleep apnea (OSA) severity and/or biomarkers of inflammation/angiogenesis are associated with incident cancer in this clinical cohort. METHODS: Consenting adult patients at the University of British Columbia Hospital between 2003-2014 completed a questionnaire about their medical history and sleep habits prior to undergoing a polysomnogram (PSG). Blood samples were collected the morning after PSG and processed for biomarkers of inflammation and angiogenesis. The clinical, PSG, and biomarker data were linked to the British Columbia Cancer Registry to ascertain incident cancer diagnoses. Cox proportional hazard regression were used to assess the association between OSA severity and biomarker concentrations with cancer risk. RESULTS: A total of 1,990 patients were included in the analysis with a mean follow-up time of 12.8 years; 181 of them (9.1%) developed cancer after PSG. OSA severity was significantly associated with cancer risk after controlling for relevant covariates (hazard ratio (HR) = 1.08 per 10 events/h apnea-hypopnea index (AHI) increase, CI = 1.02-1.15, p=0.015). In an exploratory analysis, two biomarkers were significantly associated with an increased cancer risk after controlling for relevant covariates (HR per interquartile range (IQR) pg/mL increase of endostatin = 1.45, CI = 1.12-1.87, p=0.01 and HR for IQR pg/mL increase of VCAM-1 = 1.48, CI = 1.04-2.11, p=0.03, respectively). CONCLUSIONS: OSA severity was an independent risk factor for cancer. Furthermore, two circulating markers were significantly associated with cancer risk. If these preliminary findings can be reproduced in other cohorts, biomarkers could potentially be used to prognosticate OSA patients with respect to cancer risk.

All Obstructive Sleep Apnea Events Are Not Created Equal: The Relationship between Event-related Hypoxemia and Physiologic Response.

Rationale: Obstructive sleep apnea (OSA) severity is typically assessed by the apnea-hypopnea index (AHI), a frequency-based metric that allocates equal weight to all respiratory events. However, more severe events may have a greater physiologic impact. Objectives: The purpose of this study was to determine whether the degree of event-related hypoxemia would be associated with the postevent physiologic response. Methods: Patients with OSA (AHI, ⩾5/h) from the multicenter Canadian Sleep and Circadian Network cohort were studied. Using mixed-effect linear regression, we examined associations between event-related hypoxic burden (HBev) assessed by the area under the event-related oxygen saturation recording with heart rate changes (ΔHRev), vasoconstriction (vasoconstriction burden [VCBev] assessed with photoplethysmography), and electroencephalographic responses (power ratio before and after events). Results: Polysomnographic recordings from 658 patients (median [interquartile range] age, 55.00 [45.00, 64.00] yr; AHI, 27.15 [14.90, 64.05] events/h; 42% female) were included in the analyses. HBev was associated with an increase in all physiologic responses after controlling for age, sex, body mass index, sleep stage, total sleep time, and study centers; for example, 1 standard deviation increase in HBev was associated with 0.21 [95% confidence interval, 0.2, 0.22], 0.08 [0.08, 0.09], and 0.22 [0.21, 0.23] standard deviation increases in ΔHRev, VCBev, and ß-power ratio, respectively. Conclusions: Increased event-related hypoxic burden was associated with greater responses across a broad range of physiologic signals. Future metrics that incorporate information about the variability of these physiologic responses may have promise in providing a more nuanced assessment of OSA severity.

Dual-targeting compounds possessing enhanced anticancer activity via microtubule disruption and histone deacetylase inhibition.

Dual-targeting anticancer agents 4-29 are designed by combining the structural features of purine-type microtubule-disrupting compounds and HDAC inhibitors. A library of the conjugate compounds connected by appropriate linkers was synthesized and found to possess HDACs inhibitory activity and render microtubule fragmentation by activating katanin, a microtubule-severing protein. Among various zinc-binding groups, hydroxamic acid shows the highest inhibitory activity of Class I HDACs, which was also reconfirmed by three-dimensional quantitative structure-activity relationship (3D-QSAR) pharmacophore prediction. The purine-hydroxamate conjugates exhibit enhanced cytotoxicity against MDA-MB231 breast cancer cells, H1975 lung cancer cells, and various clinical isolated non-small-cell lung cancer cells with different epidermal growth factor receptor (EGFR) status. Pyridyl substituents could be used to replace the C2 and N9 phenyl moieties in the purine-type scaffold, which can help to improve the solubility under physiological conditions, thus increasing cytotoxicity. In mice treated with the purine-hydroxamate conjugates, the tumor growth rate was significantly reduced without causing toxic effects. Our study demonstrates the potential of the dual-targeting purine-hydroxamate compounds for cancer monotherapy.

Noninvasive Home Mechanical Ventilation for Stable Hypercapnic COPD: A Clinical Respiratory Review from Canadian Perspectives.

Acute short-term noninvasive ventilation (NIV) for hypercapnic respiratory failure in chronic obstructive pulmonary disease (COPD) has well-established benefits; however, the role of long-term home NIV remains controversial. In the past decade, studies utilizing aggressive NIV settings to maximally reduce carbon dioxide levels (PaCO2) have resulted in several positive clinical trials and led to updated guidelines on home NIV for stable hypercapnic COPD patients. This clinical respiratory review discusses the high-intensity NIV approach, summarizes recent key trials and guidelines pertaining to home NIV in COPD, and considers key clinical questions for future research and application in the Canadian context. With recent evidence and Canadian Thoracic Society (CTS) guidelines supporting the use of NIV in carefully selected COPD patients with persistent daytime hypercapnia, we believe it is time to reconsider our approach.

Acceptance of and adherence with long-term positive airway pressure treatment in adults with chronic obstructive pulmonary disease: A systematic review protocol.

BACKGROUND: Long-term noninvasive positive airway pressure (PAP) treatment is effective treatment for sleep-related breathing disorders and chronic hypercarbic respiratory failure secondary to chronic obstructive pulmonary disease (COPD). PAP treatment may be delivered as continuous positive airway pressure or noninvasive ventilation. Success in initiating PAP treatment and barriers to its use in adult patients with COPD are largely unknown. This systematic review aims to identify the acceptance of and adherence to PAP treatment prescribed for long-term use in adult patients with COPD and to summarize variables associated with these measures. METHODS: Seven online electronic databases will be searched by an experienced medical librarian to identify records containing the concepts "obstructive airways disease" and "noninvasive positive airway pressure" and "acceptance" or "adherence". Randomized and non-randomized studies of interventions will be included. Citation lists from relevant articles will be reviewed, and experts will be contacted regarding unpublished studies. Abstracts from key conferences between 2018-2023 and Google Scholar search results will be reviewed for inclusion. Titles, abstracts and full texts will be reviewed independently for inclusion by two reviewers. Data extraction will be completed by one author using a pre-established form and primary outcomes confirmed by a second author. Methodological quality will be evaluated. If sufficient data are available for meta-analysis, a pooled summary statistic for the primary outcome will be calculated using a random-effects generic inverse-variance meta-analysis, weighted proportion or weighted medians-based approach. Subgroup analysis will explore clinically meaningful sources of heterogeneity. Variables that are associated with acceptance and adherence will be described. DISCUSSION: Long-term PAP treatment is a complex intervention prescribed to patients with COPD for several indications. Synthesis of the evidence on success with PAP treatment and variables associated with acceptance or adherence will inform program and policy development for supporting patients with COPD who are prescribed this therapy. TRIAL REGISTRATION: Systematic review registration: This protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on July 13, 2021 (registration number CRD42021259262), with revisions submitted on April 17, 2023.

Degradation of neurodegenerative disease-associated TDP-43 aggregates and oligomers via a proteolysis-targeting chimera.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) associated with TAR DNA-binding protein 43 (TDP-43) aggregation has been considered as a lethal and progressive motor neuron disease. Recent studies have shown that both C-terminal TDP-43 (C-TDP-43) aggregates and oligomers were neurotoxic and pathologic agents in ALS and frontotemporal lobar degeneration (FTLD). However, misfolding protein has long been considered as an undruggable target by applying conventional inhibitors, agonists, or antagonists. To provide this unmet medical need, we aim to degrade these misfolding proteins by designing a series of proteolysis targeting chimeras (PROTACs) against C-TDP-43. METHODS: By applying filter trap assay, western blotting, and microscopy imaging, the degradation efficiency of C-TDP-43 aggregates was studied in Neuro-2a cells overexpressing eGFP-C-TDP-43 or mCherry-C-TDP-43. The cell viability was characterized by alarmarBlue assay. The beneficial and disaggregating effects of TDP-43 PROTAC were examined with the YFP-C-TDP-43 transgenic C. elegans by motility assay and confocal microscopy. The impact of TDP-43 PROTAC on C-TDP-43 oligomeric intermediates was monitored by fluorescence lifetime imaging microscopy and size exclusion chromatography in the Neuro-2a cells co-expressing eGFP-C-TDP-43 and mCherry-C-TDP-43. RESULTS: Four PROTACs with different linker lengths were synthesized and characterized. Among these chimeras, PROTAC 2 decreased C-TDP-43 aggregates and relieved C-TDP-43-induced cytotoxicity in Neuro-2a cells without affecting endogenous TDP-43. We showed that PROTAC 2 bound to C-TDP-43 aggregates and E3 ligase to initiate ubiquitination and proteolytic degradation. By applying advanced microscopy, it was further shown that PROTAC 2 decreased the compactness and population of C-TDP-43 oligomers. In addition to cellular model, PROTAC 2 also improved the motility of transgenic C. elegans by reducing the C-TDP-43 aggregates in the nervous system. CONCLUSIONS: Our study demonstrated the dual-targeting capacity of the newly-designed PROTAC 2 against both C-TDP-43 aggregates and oligomers to reduce their neurotoxicity, which shed light on the potential drug development for ALS as well as other neurodegenerative diseases.

The rs579459 ABO gene polymorphism and risk of incident cardiovascular events in obstructive sleep apnea: a pilot study.

PURPOSE: We have previously shown that the TT genotype (rs579459 location of the ABO gene) is significantly associated with circulating levels of e-selectin in patients with suspected obstructive sleep apnea (OSA). We hypothesized that this genotype would be associated with incident cardiovascular disease (CVD). METHODS: Patients with suspected OSA who had a full diagnostic polysomnogram from 2003 to 2011 were recruited; CV events occurring within 8 years of polysomnography were identified by linkage to provincial health databases. Cox proportional hazards models were used to evaluate the incidence of first CV events as a function of the rs579459 genotype. RESULTS: In this targeted study, 408 patients were studied, and 39 incident events were identified. A larger proportion of patients with the TT genotype had an event (31/247; 12.6%) than the CT and CC genotypes (8/161; 5.0%); in univariate analysis, the TT genotype was significantly associated with CV events (HR = 2.53; 95% CI = 1.16-5.51, p = 0.02). After adjustment for age, AHI, sex, smoking, diabetes, statin use, and BMI, the TT genotype remained a significant predictor (HR = 2.35; 95% CI = 1.02-5.42, p = 0.046). No events were found in patients with an absence of both OSA and the TT genotype (N = 30). The effect of the SNP was partially (16.2%) mediated by e-selectin levels. CONCLUSION: This is the first study to examine genetic variants as a risk factor for incident CVD in the context of OSA. Although these results are preliminary and in need of replication, it suggests that genetic markers may become useful in helping to guide precision clinical care.

Association of alternative polysomnographic features with patient outcomes in obstructive sleep apnea: a systematic review.

STUDY OBJECTIVES: Polysomnograms (PSGs) collect a plethora of physiologic signals across the night. However, few of these PSG data are incorporated into standard reports, and hence, ultimately, under-utilized in clinical decision making. Recently, there has been substantial interest regarding novel alternative PSG metrics that may help to predict obstructive sleep apnea (OSA)-related outcomes better than standard PSG metrics such as the apnea-hypopnea index. We systematically review the recent literature for studies that examined the use of alternative PSG metrics in the context of OSA and their association with health outcomes. METHODS: We systematically searched EMBASE, MEDLINE, and the Cochrane Database of Systematic Reviews for studies published between 2000 and 2022 for those that reported alternative metrics derived from PSG in adults and related them to OSA-related outcomes. RESULTS: Of the 186 initial studies identified by the original search, data from 31 studies were ultimately included in the final analysis. Numerous metrics were identified that were significantly related to a broad range of outcomes. We categorized the outcomes into 2 main subgroups: (1) cardiovascular/metabolic outcomes and mortality and (2) cognitive function- and vigilance-related outcomes. Four general categories of alternative metrics were identified based on signals analyzed: autonomic/hemodynamic metrics, electroencephalographic metrics, oximetric metrics, and respiratory event-related metrics. CONCLUSIONS: We have summarized the current landscape of literature for alternative PSG metrics relating to risk prediction in OSA. Although promising, further prospective observational studies are needed to verify findings from other cohorts, and to assess the clinical utility of these metrics. CITATION: Hajipour M, Baumann B, Azarbarzin A, et al. Association of alternative polysomnographic features with patient outcomes in obstructive sleep apnea: a systematic review. J Clin Sleep Med. 2023;19(2):225-242.

Structural compositions and biological activities of cell wall polysaccharides in the rhizome, stem, and leaf of Polygonatum odoratum (Mill.) Druce.

Polygonatum odoratum is a perennial rhizomatous medicinal plant and different plant parts have been used in the treatment of various ailments. Herein, we have investigated the structural compositions of rhizome, leaf, and stem cell walls. We found 30-44% of polysaccharides in these wall preparations were cyclohexanediaminetetraacetic acid (CDTA) extractable, the proportion of heteromannans (HMs) in the rhizome is nearly three-fold compared to that of the leave and stem. The pectic polysaccharides of the rhizome are also structurally more diverse, with arabinans and type I and type II arabinogalactans being richest as shown by linkage study of the sodium carbonate (Na2CO3) extract. In addition, the 2-linked Araf was rhizome-specific, suggesting the cell walls in the rhizome had adapted to a more complex structure compared to that of the leaf and stem. Water-soluble polysaccharide fractions were also investigated, high proportion of Man as in 4-linked Manp indicated high proportion of HMs. The 21.4 kDa pectic polysaccharides and HMs derived from rhizome cell walls induced specific immune response in mice macrophage cells producing IL-1α and hematopoietic growth factors GM-CSF and G-CSF in vitro.

Design and Synthesis of 1-O- and 6'-C-Modified Heparan Sulfate Trisaccharides as Human Endo-6-O-Sulfatase 1 Inhibitors.

The extracellular human endo-6-O-sulfatases (Sulf-1 and Sulf-2) are responsible for the endolytic cleavage of the 6-sulfate groups from the internal D-glucosamine residues in the highly sulfated subdomains of heparan sulfate proteoglycans. A trisaccharide sulfate, IdoA2OS-GlcNS6S-IdoA2OS, was identified as the minimal size of substrate for Sulf-1. In order to study the complex structure with Sulf-1 for developing potential drugs, two trisaccharide analogs, IdoA2OS-GlcNS6OSO2NH2-IdoA2OS-OMe and IdoA2OS-GlcNS6NS-IdoA2OS-OMe, were rationally designed and synthesized as the Sulf-1 inhibitors with IC50 values at 0.27 and 4.6 µM, respectively.

Sleep Deficiency: Epidemiology and Effects.

Adequate sleep is an important pillar of physical and mental health. Sleep deficiency, resulting from short sleep or suboptimal sleep quality, is highly prevalent in modern society. Occupation, social demands, psychiatric disorders, physical disorders, and sleep disorders are some of the contributing factors to sleep deficiency. Some populations are at increased risk of sleep deficiency based on ethnicity, age, marital status, sex, and hospitalization. Sleep deficiency influences cognition, alertness, mood, behavior, diabetes, cardiovascular health, renal function, immune system, and respiratory physiology. This review summarizes the epidemiology and effects of sleep deficiency.

Photoaffinity labeling of benzophenone-containing salicylanilide compounds to give an insight into the mechanism in disrupting peptidoglycan formation.

A series of salicylanilide compounds was previously identified as antibacterial agents that inhibit the peptidoglycan formation. To find the exact binding mode, we synthesized a benzophenone-containing salicylanilide compound (1) and used it as a photoaffinity probe to label Acinetobacter baumannii penicillin-binding protein (PBP1b). After incubation and photo-irradiation, the labeled protein was subjected to trypsin digestion, dialysis enrichment, LC-ESI-MS/MS analysis, and Mascot search to reveal an octadecapeptide sequence 364RQLRTEYQESDLTNQGLR381 that was labeled at E372. Our molecular docking experiments suggest a hydrophobic pocket surrounded by R367 and E372 is the binding site of salicylanilide 1. The pocket lies in between the transglycosylase and transpeptidase domains, thus binding of salicylanilide 1 can block the propagation pathway to disrupt the growth of peptidoglycan chain.

Symptom subtypes and risk of incident cardiovascular and cerebrovascular disease in a clinic-based obstructive sleep apnea cohort.

STUDY OBJECTIVES: Patients with obstructive sleep apnea (OSA) are at increased risk of cardiovascular and cerebrovascular disease, but predicting those at greatest risk is challenging. Using latent class analysis, patients with OSA can be placed into discrete symptom subtypes. The aim of this study was to determine whether symptom subtypes are associated with future cerebrovascular disease in patients with OSA in a clinic-based cohort. METHODS: Patients with suspected OSA referred for a polysomnogram at an academic sleep center completed a comprehensive symptom survey. Patients with OSA (apnea-hypopnea index ≥ 5 events/h) were then placed into symptom subtypes based on responses to survey questions using latent class analysis. Cardiovascular events (stroke, myocardial infarction, unstable angina, bypass grafting, percutaneous coronary intervention, cardiac resynchronization therapy, defibrillation) occurring within 8 years of polysomnogram were identified by linkage to provincial health databases. RESULTS: 1,607 patients were studied, of whom 1,292 had OSA. One hundred forty first events occurred within 8 years of polysomnogram. Patients in the excessively sleepy with disturbed sleep subtype had a significantly increased rate of events compared to the minimally symptomatic subtype (hazard ratio = 2.25, 95% confidence interval: 1.02-4.94; P = .04). Two symptoms (restless legs and dozing off or sleeping while talking to someone) were significantly associated with future risk of cerebrovascular disease (hazard ratio = 1.68, 1.12-2.49 and 4.23, 1.61-11.16, respectively). CONCLUSIONS: Patients with OSA in the clinic who are in the excessively sleepy with disturbed sleep subtype are significantly more likely to have a future cardiovascular event. This underscores the importance of understanding clinical heterogeneity and incorporating symptom subtype definitions into routine clinical care. CITATION: Allen AJH, Jen R, Mazzotti DR, et al. Symptom subtypes and risk of incident cardiovascular and cerebrovascular disease in a clinic-based obstructive sleep apnea cohort. J Clin Sleep Med. 2022;18(9):2093-2102.

Vaccination with SARS-CoV-2 spike protein lacking glycan shields elicits enhanced protective responses in animal models.

A major challenge to end the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is to develop a broadly protective vaccine that elicits long-term immunity. As the key immunogen, the viral surface spike (S) protein is frequently mutated, and conserved epitopes are shielded by glycans. Here, we revealed that S protein glycosylation has site-differential effects on viral infectivity. We found that S protein generated by lung epithelial cells has glycoforms associated with increased infectivity. Compared to the fully glycosylated S protein, immunization of S protein with N-glycans trimmed to the mono-GlcNAc-decorated state (SMG) elicited stronger immune responses and better protection for human angiotensin-converting enzyme 2 (hACE2) transgenic mice against variants of concern (VOCs). In addition, a broadly neutralizing monoclonal antibody was identified from SMG-immunized mice that could neutralize wild-type SARS-CoV-2 and VOCs with subpicomolar potency. Together, these results demonstrate that removal of glycan shields to better expose the conserved sequences has the potential to be an effective and simple approach for developing a broadly protective SARS-CoV-2 vaccine.

Circulating markers of oxidative stress and risk of incident cardiovascular events in obstructive sleep apnea.

The identification of which patients with obstructive sleep apnea (OSA) are more likely to develop cardiovascular disease (CVD) remains a challenge. OSA causes oxidative stress (OS) which may contribute to CVD pathogenesis. Therefore, OS markers could be useful in risk-stratifying cardiovascular (CV) risk in OSA patients. The purpose of this pilot study was to assess whether three OS marker levels could be associated with incident CVD in suspected OSA patients. Morning plasma levels of 8-isoprostane, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and superoxide dismutase (SOD) were measured in patients with suspected OSA referred for a polysomnogram (PSG). A composite outcome of CV events was defined by linkage with provincial administrative health databases. Cox proportional hazards models were used to assess the relationship between the levels of OS markers and events. 352 patients were included (mean age of 51.4 years, 68% male, median apnea hypopnea index of 16/h). Thirty-one first CV events occurred over an 8-year follow-up. In univariate or fully adjusted models, none of the OS markers were significantly associated with incident CV events (hazard ratio in adjusted models of: 1.25 (95% CI 0.56-2.80, p = 0.59), 1.15 (0.52-2.57, p = 0.73), 0.77 (0.37-1.61, p = 0.48), for 8-OHdG, 8-isoprostane and SOD; however, confidence intervals were wide. In this small preliminary study, oxidative stress markers were not significantly associated with risk of CV events. However, moderate associations between these markers and risk of CV events are possible and should be the focus of future larger studies. Supplementary Information: The online version contains supplementary material available at 10.1007/s41105-022-00399-0.

Immunogenicity Evaluation of N-Glycans Recognized by HIV Broadly Neutralizing Antibodies.

While the improved treatment of human immunodeficiency virus type 1 (HIV-1) infection is available, the development of an effective and safe prophylactic vaccine against HIV-1 is still an unrealized goal. Encouragingly, the discovery of broadly neutralizing antibodies (bNAbs) from HIV-1 positive patients that are capable of neutralizing a broad spectrum of HIV-1 isolates of various clades has accelerated the progress of vaccine development in the past few years. Some of these bNAbs recognize the N-glycans on the viral surface gp120 glycoprotein. We have been interested in using the glycan epitopes recognized by bNAbs for the development of vaccines to elicit bNAb-like antibodies with broadly neutralizing activities. Toward this goal, we have identified novel hybrid-type structures with subnanomolar avidity toward several bNAbs including PG16, PGT121, PGT128-3C, 2G12, VRC13, VRC-PG05, VRC26.25, VRC26.09, PGDM1400, 35O22, and 10-1074. Here, we report the immunogenicity evaluation of a novel hybrid glycan conjugated to carrier DTCRM197, a nontoxic mutant of the diphtheria toxin, for immunization in mice. Our results indicated that the IgG response was mainly against the chitobiose motif with nonspecific binding to a panel of N-glycans with reducing end GlcNAc-GlcNAc (chitobiose) printed on the glass slides. However, the IgM response was mainly toward the reducing end GlcNAc moiety. We further used the glycoconjugates of Man3GlcNAc2, Man5GlcNAc2, and Man9GlcNAc2 glycans for immunization, and a similar specificity pattern was observed. These findings suggest that the immunogenicity of chitobiose may interfere with the outcome of N-glycan-based vaccines, and modification may be necessary to increase the immunogenicity of the entire N-glycan epitope.

A Pilot Randomized Controlled Trial of Effect of Genioglossus Muscle Strengthening on Obstructive Sleep Apnea Outcomes.

The genioglossus is a major upper airway dilator muscle. Our goal was to assess the efficacy of upper airway muscle training on Obstructive Sleep Apnea (OSA) as an adjunct treatment. Sixty-eight participants with OSA (AHI > 10/h) were recruited from our clinic. They fall into the following categories: (a) Treated with Automatic Positive Airway Pressure (APAP), (n = 21), (b) Previously failed APAP therapy (Untreated), (n = 25), (c) Treated with Mandibular Advancement Splint (MAS), (n = 22). All subjects were given a custom-made tongue strengthening device. We conducted a prospective, randomized, controlled study examining the effect of upper airway muscle training. In each subgroup, subjects were randomized to muscle training (volitional protrusion against resistance) or sham group (negligible resistance), with a 1:1 ratio over 3 months of treatment. In the baseline and the final visit, subjects completed home sleep apnea testing, Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), SF-36 (36-Item Short Form Survey), and Psychomotor Vigilance Test (PVT). Intervention (muscle training) did not affect the AHI (Apnea-Hypopnea Index), (p-values > 0.05). Based on PSQI, ESS, SF-36 scores, and PVT parameters, the changes between the intervention and sham groups were not significant, and the changes were not associated with the type of treatment (p-value > 0.05). The effectiveness of upper airway muscle training exercise as an adjunct treatment requires further study.

A non-neutralizing antibody broadly protects against influenza virus infection by engaging effector cells.

Hemagglutinin (HA) is the immunodominant protein of the influenza virus. We previously showed that mice injected with a monoglycosylated influenza A HA (HAmg) produced cross-strain-reactive antibodies and were better protected than mice injected with a fully glycosylated HA (HAfg) during lethal dose challenge. We employed a single B-cell screening platform to isolate the cross-protective monoclonal antibody (mAb) 651 from mice immunized with the HAmg of A/Brisbane/59/2007 (H1N1) influenza virus (Bris/07). The mAb 651 recognized the head domain of a broad spectrum of HAs from groups 1 and 2 influenza A viruses and offered prophylactic and therapeutic efficacy against A/California/07/2009 (H1N1) (Cal/09) and Bris/07 infections in mice. The antibody did not possess neutralizing activity; however, antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis mediated by natural killer cells and alveolar macrophages were important in the protective efficacy of mAb 651. Together, this study highlighted the significance of effector functions for non-neutralizing antibodies to exhibit protection against influenza virus infection.

Revisiting level II sleep studies in the era of COVID-19: a theoretical economic decision model in patients with suspected obstructive sleep apnea.

BACKGROUND: The recent pandemic has made it more challenging to assess patients with suspected obstructive sleep apnea (OSA) with in laboratory polysomnography (PSG) due to concerns of patient and staff safety. The purpose of this study was to assess how Level II sleep studies (LII, full PSG in the home) might be utilized in diagnostic algorithms of suspected OSA using a theoretical decision model. METHODS: We examined four diagnostic algorithms for suspected OSA: an initial PSG approach, an initial LII approach, an initial Level III approach (LIII, limited channel home sleep study) followed by PSG if needed, and an initial LIII approach followed by LII if needed. Costs per patient assessed was calculated as a function of pretest OSA probability and a variety of other variables (e.g. costs of tests, failure rate of LIII/LII, sensitivity/specificity of LIII). The situation in British Columbia was used as a case study. RESULTS: The variation in cost per test was calculated for each algorithm as a function of the above variables. For British Columbia, initial LII was the least costly across a broad range of pretest OSA probabilities (< 0.80) while initial LIII followed by LII as needed was least costly at very high pretest probability (> 0.8). In patients with a pretest OSA probability of 0.5, costs per patient for initial PSG, initial LII, initial LIII followed by PSG, and initial LIII followed by LII were: $588, $417, $607, and $481 respectively. CONCLUSIONS: Using a theoretical decision model, we developed a preliminary cost framework to assess the potential role of LII studies in OSA assessment. Across a broad range of patient pretest probabilities, initial LII studies may provide substantial cost advantages. LII studies might be especially useful during pandemics as they combine the extensive physiologic information characteristic of PSG with the ability to avoid in-laboratory stays. More empiric studies need to be done to test these different algorithms. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s41606-021-00063-5.

Circulating levels of cell adhesion molecules and risk of cardiovascular events in obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) patients are at increased risk of cardiovascular disease (CVD). Cell adhesion molecules (CAM) are increased in OSA and CAM are also implicated in the development of CVD. RESEARCH QUESTION: Do CAM (ICAM-1, VCAM-1 and E-selectin) have prognostic value in identifying risk of cardiovascular events in OSA? STUDY DESIGN AND METHODS: Patients with suspected OSA referred for a polysomnogram provided a fasting blood sample. Plasma levels of ICAM-1, VCAM-1 and E-selectin were determined by multiplex Luminex Assay (Milliporesigma ON, Canada). Cardiovascular events were determined by deterministic linkage to provincial health databases. RESULTS: 418 patients were included in the analysis. Mostly male (68.2%), mean age of 50.7 yrs, median AHI 16.5 events/hour, and mean BMI of 31.7 kg/m2. 36 cardiovascular events occurred in 8-yrs of follow up. Higher levels of ICAM-1 were associated with developing CVD (HR = 3.65 95% CI 1.40-9.53, 2nd and 3rd tertiles vs. 1st tertile), including in patients with OSA (HR = 3.1 95% CI 1.16-8.25). E-selectin was significantly associated with cardiovascular events in patients with moderate to severe OSA (HR = 3.31 95% CI 0.94-11.72, 2nd and 3rd tertiles vs. 1st tertile) but not in patients without moderate to severe OSA (HR = 0.67 95% CI 0.19-2.38), p-value for interaction = 0.07. INTERPRETATION: In a suspected OSA cohort, patients with higher levels of ICAM-1 (>816 ng/ml) were significantly more likely to experience a cardiovascular event within 8 years after PSG. In moderate to severe OSA patients, a higher E-selectin (>36.4 ng/ml) was significantly associated with cardiovascular events.