Dysregulation in CD39/CD73 Axis May Trigger the Upsurge of the Immune Suppressive Agent Adenosine in OSA Patients

Introduction Although higher incidence of cancer represents a major burden for obstructive sleep apnea (OSA) patients, the molecular pathways driving this association are not completely understood. Interestingly, adenosinergic signaling has emerged as a powerful immune checkpoint driving tumor development and progression. Methods Here, we explored the expression of the adenosinergic ecto-enzymes CD39 and CD73 in T-lymphocytes of OSA patients without any evidence of cancer, as well as their soluble forms in plasma (sCD39 and sCD73), along with adenosine. In addition, we explored the role of intermittent hypoxia (IH) in this context by in vitro models. Results Our results showed that CD39 is upregulated while CD73 is downregulated in OSA T-cells’ membrane. Moreover, our findings suggest that IH, through HIF-1, mediates the upregulation of both CD39 and CD73; and that CD73 downregulation could be mediated by a higher release of sCD73 by OSA T-lymphocytes. Importantly, we found that both sCD39 and sCD73 are upregulated in OSA plasma, suggesting T-lymphocytes as a potential source for plasmatic sCD73. Finally, our data propose the alterations in CD39/CD73 axis could underlie the upsurge of adenosine levels in the plasma of OSA patients. Conclusion Our study reveals a hypoxia-mediated alteration of the CD39/CD73 axis in OSA patients, which could trigger ADO upregulation, thus potentially contributing to the immune suppressive environment and ultimately facilitating tumor development and progression. Therefore, our data highlights the need for new longitudinal studies evaluating CD39 and/or CD73 as potential cancer-risk prognostic biomarkers in OSA patients. (AU)

Dysregulation in CD39/CD73 Axis May Trigger the Upsurge of the Immune Suppressive Agent Adenosine in OSA Patients.

INTRODUCTION: Although higher incidence of cancer represents a major burden for obstructive sleep apnea (OSA) patients, the molecular pathways driving this association are not completely understood. Interestingly, adenosinergic signaling has emerged as a powerful immune checkpoint driving tumor development and progression. METHODS: Here, we explored the expression of the adenosinergic ecto-enzymes CD39 and CD73 in T-lymphocytes of OSA patients without any evidence of cancer, as well as their soluble forms in plasma (sCD39 and sCD73), along with adenosine. In addition, we explored the role of intermittent hypoxia (IH) in this context by in vitro models. RESULTS: Our results showed that CD39 is upregulated while CD73 is downregulated in OSA T-cells' membrane. Moreover, our findings suggest that IH, through HIF-1, mediates the upregulation of both CD39 and CD73; and that CD73 downregulation could be mediated by a higher release of sCD73 by OSA T-lymphocytes. Importantly, we found that both sCD39 and sCD73 are upregulated in OSA plasma, suggesting T-lymphocytes as a potential source for plasmatic sCD73. Finally, our data propose the alterations in CD39/CD73 axis could underlie the upsurge of adenosine levels in the plasma of OSA patients. CONCLUSION: Our study reveals a hypoxia-mediated alteration of the CD39/CD73 axis in OSA patients, which could trigger ADO upregulation, thus potentially contributing to the immune suppressive environment and ultimately facilitating tumor development and progression. Therefore, our data highlights the need for new longitudinal studies evaluating CD39 and/or CD73 as potential cancer-risk prognostic biomarkers in OSA patients.

Continuous Positive Airway Pressure Effect on Progression of Retinal Disease in Patients with Sleep Apnea and Nonproliferative Diabetic Retinopathy: A Randomized Clinical Trial.

Rationale: Obstructive sleep apnea (OSA) is associated with impaired glycemic control and a higher risk of vascular complications, such as diabetic retinopathy. However, the effect of apnea-hypopnea suppression on retinal disease progression is unclear. Objectives: To evaluate the efficacy and safety of continuous positive airway pressure (CPAP) for the reduction of retinal lesions in patients with non-proliferative diabetic retinopathy (NPDR) and OSA. Methods: This open-label, parallel-group, randomized controlled trial was conducted between October 2016 and February 2020 at a university hospital in Spain. The date of final follow-up was March 2, 2021. Eighty-three patients with OSA and mild to moderate NPDR receiving stable treatment were randomized to receive CPAP and usual care (43 patients with 79 available eyes) or usual care alone (40 patients with 67 available eyes) for 52 weeks. The primary outcomes were the change in the percentage of eyes with retinal exudates and the number of retinal microhemorrhages from baseline to week 52. We also assessed the effects of both interventions on retinal thickness by means of optical coherence tomography, serum concentrations of glycated hemoglobin, blood pressure, lipid concentrations, sleepiness, and quality of life. Results: Fifty-two weeks of CPAP treatment was associated with reductions from baseline in the percentage of eyes with hard exudates (overall difference, -21.7%; P = 0.035) and in optical coherence tomography indices of retinal edema, including central subfield thickness and cube volume. However, in patients who met prespecified criteria for CPAP adherence, treatment was also associated with a higher number of retinal microhemorrhages at 52 weeks (intergroup adjusted difference, 6.0 [95% confidence interval, 0.6-11.5]; P = 0.029), which was directly related to prescribed pressure levels. CPAP treatment also improved glycemic control, sleepiness, and general health-related quality of life. Conclusions: In patients with OSA and NPDR, long-term CPAP treatment in addition to usual care may result in slower progression of retinal disease, although it could also induce an increase in retinal microhemorrhages. Clinical trial registered with www.clinicaltrials.gov (NCT02874313).

Changes in sleep-disordered breathing from the acute to the stable phase of pulmonary embolism: The ESAET study.

BACKGROUND: /Objective: Sleep-disordered breathing (SDB) may change from the acute to stable phase of some cardiovascular disorders, but little is known whether these dynamic changes also exist in pulmonary embolism (PE). This study aimed to analyze the changes in the apnea-hypopnea index (AHI) from the acute to stable phase of PE as well as the factors associated. PATIENTS/METHODS: We conducted a prospective, longitudinal and multicenter study of consecutive adults requiring hospitalization for non-hypotensive acute PE, with a protocol including clinical, imaging (transthoracic echocardiography [TTE] and computed tomography), blood tests and a sleep study within 48 h of diagnosis of PE. After 3 months of follow-up, the sleep study was repeated. Right ventricular (RV) dysfunction was defined according to TTE criteria. RESULTS: One hundred and eleven patients (mean age [SD]: 63 [15] years; body mass index: 28.4 [4.7] kg/m2) were included. The initial AHI was 24.4 (21.8) events/h (AHI≥5: 82.8 %; AHI≥30: 33.3 %). Seventy-seven patients (69.4 %) had RV dysfunction. In the overall cohort, the AHI decreased by 8.7 events/h from the acute to stable phase (24.4/h vs. 15.7/h; p=0.013). Patients with RV dysfunction showed a greater decrease in AHI (mean decrease 12.3/h vs. 0.43/h). In the multivariable analysis a drop of an AHI≥5 events/hour was independently associated with the presence of initial RV dysfunction (hazard ratio 3.9; 95%CI 1.3 to 12.1). CONCLUSIONS: In hemodynamically stable patients with acute PE, there is a transient but clinically significant decrease in the AHI from the acute to stable phase, particularly when initially presenting with RV dysfunction.

PSGL-1: a novel immune checkpoint driving T-cell dysfunction in obstructive sleep apnea.

Introduction: Although higher incidence of cancer represents a major burden for obstructive sleep apnea (OSA) patients, the molecular pathways driving this association are not completely understood. Recently, the adhesion receptor P-selectin glycoprotein-1 (PSGL 1) has been identified as a novel immune checkpoint, which are recognized major hallmarks in several types of cancer and have revolutionized cancer therapy. Methods: The expression of PSGL-1 and its ligands VISTA and SIGLEC-5 was assessed in the leucocytes of OSA patients and control subjects exploring the role of intermittent hypoxia (IH) using in vitro models. In addition, PSGL-1 impact on T-cells function was evaluated by ex vivo models. Results: Data showed PSGL-1 expression is upregulated in the T-lymphocytes from patients with severe OSA, indicating a relevant role of hypoxemia mediated by intermittent hypoxia. Besides, results suggest an inhibitory role of PSGL-1 on T-cell proliferation capacity. Finally, the expression of SIGLEC-5 but not VISTA was increased in monocytes from OSA patients, suggesting a regulatory role of intermittent hypoxia. Discussion: In conclusion, PSGL-1 might constitute an additional immune checkpoint leading to T-cell dysfunction in OSA patients, contributing to the disruption of immune surveillance, which might provide biological plausibility to the higher incidence and aggressiveness of several tumors in these patients.

Nocturnal hypoxemia and prognosis in patients with acute symptomatic pulmonary embolism.

BACKGROUND: Nocturnal hypoxemia has been associated with cardiovascular and non-cardiovascular morbidity and mortality. This study aimed to investigate the prognostic value of nocturnal hypoxemia among patients with hemodynamically stable acute symptomatic pulmonary embolism (PE). METHODS: We performed an ad hoc secondary analysis of clinical data from a prospective cohort study. Nocturnal hypoxemia was measured by the percent sleep registry with oxygen saturation <90% [TSat90]). Outcomes assessed over the 30-days after the diagnosis of PE included PE-related death, other cardiovascular deaths, clinical deterioration requiring an escalation of treatment, recurrent venous thromboembolism (VTE), acute myocardial infarction [AMI], or stroke. RESULTS: Of the 221 hemodynamically stable patients with acute PE from which the TSat90 could be calculated and did not receive supplemental oxygen, the primary outcome occurred in 11 (5.0%; 95% confidence interval [CI], 2.5% to 8.7%) within 30-days after the diagnosis of PE. When categorized by quartiles, TSat90 was not significantly associated with the occurrence of the primary outcome in unadjusted Cox regression analysis (hazard ratio, 0.96; 95% CI, 0.57 to 1.63; P = 0.88), or after adjustment for body mass index (adjusted hazard ratio, 0.97; 95% CI, 0.57 to 1.65; P = 0.92). When examined as a completely continuous variable (between 0 and 100), TSat90 was not associated with a significant increase in the adjusted hazard of 30-day primary outcome rates (hazard ratio, 0.97; 95% CI, 0.86 to 1.10; P = 0.66). CONCLUSIONS: In this study, nocturnal hypoxemia did not identify stable patients with acute symptomatic PE at increased risk for adverse cardiovascular events.

SMAD4 Expression in Monocytes as a Potential Biomarker for Atherosclerosis Risk in Patients with Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) patients are at special risk of suffering atherosclerosis, leading to major cardiovascular diseases. Notably, the transforming growth factor (TGF-ß) plays a crucial role in the development and progression of atherosclerosis. In this context, the central regulator of TGF-ß pathway, SMAD4 (small mother against decapentaplegic homolog 4), has been previously reported to be augmented in OSA patients, which levels were even higher in patients with concomitant cardiometabolic diseases. Here, we analyzed soluble and intracellular SMAD4 levels in plasma and monocytes from OSA patients and non-apneic subjects, with or without early subclinical atherosclerosis (eSA). In addition, we used in vitro and ex vivo models to explore the mechanisms underlying SMAD4 upregulation and release. Our study confirmed elevated sSMAD4 levels in OSA patients and identified that its levels were even higher in those OSA patients with eSA. Moreover, we demonstrated that SMAD4 is overexpressed in OSA monocytes and that intermittent hypoxia contributes to SMAD4 upregulation and release in a process mediated by NLRP3. In conclusion, this study highlights the potential role of sSMAD4 as a biomarker for atherosclerosis risk in OSA patients and provides new insights into the mechanisms underlying its upregulation and release to the extracellular space.

Continuous Positive Airway Pressure Effect on Albuminuria Progression in Patients with Obstructive Sleep Apnea and Diabetic Kidney Disease: A Randomized Clinical Trial.

Rationale: Obstructive sleep apnea (OSA) is associated with impaired glycemic control and a higher risk of vascular complications, such as diabetic kidney disease (DKD). However, the effect of apnea-hypopnea suppression on DKD progression is unclear. Objectives: To assess the effect of continuous positive airway pressure (CPAP) on the urinary albumin-to-creatinine ratio (UACR) in patients with DKD and OSA. Methods: In a 52-week, multicentric, open-label, parallel, and randomized clinical trial, 185 patients with OSA and DKD were randomized to CPAP and usual care (n = 93) or usual care alone (n = 92). Measurements and Main Results: UACR, estimated glomerular filtration rate, serum concentrations of creatinine and glycated hemoglobin, insulin resistance, lipid concentrations, sleepiness, and quality of life. A 52-week change in UACR from baseline did not differ significantly between the CPAP group and the usual-care group. However, in per-protocol analyses that included 125 participants who met prespecified criteria for adherence, CPAP treatment was associated with a great reduction in UACR (mean difference, -10.56% [95% confidence interval, -19.06 to -2.06]; P = 0.015). CPAP effect on UACR was higher in nonsleepy patients with more severe OSA, worse renal function, and a more recent diagnosis of DKD. CPAP treatment also improved glycemic control and insulin resistance, as well as sleepiness and health-related quality of life. Conclusions: In patients with OSA and DKD, the prescription of CPAP did not result in a statistically significant reduction in albuminuria. However, good adherence to CPAP treatment in addition to usual care may result in long-term albuminuria reduction compared with usual care alone. Clinical trial registered with www.clinicaltrials.gov (NCT02816762).

Untreated obstructive sleep apnea and cardiovascular outcomes in patients with acute symptomatic pulmonary embolism.

There is a paucity of data examining the prognostic significance of untreated obstructive sleep apnea (OSA) in hemodynamically stable patients with acute pulmonary embolism (PE). This prospective cohort study enrolled consecutive non-hypotensive patients with acute PE who underwent an overnight sleep study within 48 h after diagnosis. The patients were divided into 2 groups based on apnea-hypopnea index (AHI): OSA (AHI ≥15) and non-OSA (AHI <15) groups. The study used a composite of fatal or nonfatal cardiovascular events, including PE-related death, other cardiovascular deaths, clinical deterioration requiring an escalation of treatment, recurrent venous thromboembolism, acute myocardial infarction, or stroke within 30-days after the diagnosis of PE as the primary outcome. Between January 1, 2018, and December 31, 2020, 283 eligible patients were prospectively enrolled in 2 academic hospitals, of whom 268 patients completed a sleep study within 7 days of PE diagnosis. OSA was found in 47% (95% confidence interval [CI], 41 to 54%) of patients. The primary outcome occurred in 13 (4.9%) patients within 30-days after the diagnosis of PE. The crude incidence of the composite was not significantly different in the OSA than the non-OSA group (30-day estimate, 6.3% versus 3.5%; P = 0.30). OSA did not significantly predict the incidence of the primary outcome after adjustment for age, sex, body mass index, systolic blood pressure, heart rate, and oxygen saturation (adjusted hazard ratio, 2.15; 95% confidence interval, 0.67-6.87). In this study, untreated OSA was not a significant multivariable predictor of adverse cardiovascular events in patients with acute PE.

Moderate obstructive sleep apnea and cardiovascular outcomes in older adults: a propensity score-matched multicenter study (CPAGE-MODE study).

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) has been associated with cardiovascular events (CVEs), although recent randomized controlled trials have not demonstrated that long-term continuous positive airway pressure (CPAP) prevents CVEs. Our objective was to determine the effect of CPAP on older adults with moderate OSA regarding CVE reduction. METHODS: An observational and multicenter study of a cohort of older adults (> 70 years of age) diagnosed with moderate OSA (apnea-hypopnea index 15.0-29.9 events/h) was conducted. Two groups were formed: (1) CPAP treatment and (2) standard of care. The primary endpoint was CVE occurrence after OSA diagnosis. Association with CPAP treatment was assessed by propensity score matching and inverse weighting probability. Secondary endpoints were incidence of CVE separately and time to first CVE. RESULTS: A total of 614 patients were included. After matching, 236 older adults (111 men, mean age 75.9 ± 4.7 years) with a follow-up of 47 months (interquartile range: 29.6-64.0 months) were considered for primary and secondary endpoint evaluations. Forty-one patients presented at least 1 CVE (17.4%): 20 were in the standard-of-care group (16.9%) and 21 were in the CPAP group (17.8%), with a relative risk of 1.05 (95% confidence interval [CI], 0.60-1.83; P = .43) for CPAP treatment. Inverse probability weighting of the initial 614 patients determined an adjusted relative risk of 1.24 (95% CI, 0.79-1.96; P = .35) for CPAP treatment. No statistical differences were found in secondary endpoint analyses. CONCLUSIONS: CPAP should not be prescribed to reduce CVE probability in older adults with moderate OSA. CITATION: López-Padilla D, Terán-Tinedo J, Cerezo-Lajas A, et al. Moderate obstructive sleep apnea and cardiovascular outcomes in older adults: a propensity score-matched multicenter study (CPAGE-MODE study). J Clin Sleep Med. 2022;18(2):553-561.

Sleep apnea and eye diseases: evidence of association and potential pathogenic mechanisms.

Eye diseases are an important group of increasingly prevalent disorders that contribute very significantly to disability and represent a considerable health burden. Some data suggest that several of these diseases may be associated with sleep-disordered breathing, mainly obstructive sleep apnea (OSA), due to intermediate mechanisms, such as intermittent hypoxia or sleep fragmentation. The aims of this systematic review were to identify and critically evaluate the current evidence supporting the existence of a possible relationship between OSA and the more relevant eye diseases as well as to evaluate the potential pathogenic mechanisms. There is a body of largely low-level evidence for the association of OSA with glaucoma, nonarteritic ischemic optic neuropathy, central serous chorioretinopathy, and diabetic retinopathy. Meta-analysis of available case-control studies shows that OSA increases the risk of glaucoma (pooled odds ratio: 1.50; 95% confidence interval: 1.25 to 1.80; P < .001), nonarteritic ischemic optic neuropathy (3.62; 1.94 to 6.76; P < .001), and diabetic retinopathy (1.57; 1.09 to 2.27; P = .02). Moreover, several pathogenic pathways have been identified, mainly related to hypoxic damage, mechanical stress, systemic inflammation, oxidative stress, sympathetic tone, and endothelial dysfunction. In contrast, information about the effect of apnea-hypopnea suppression on the development and progression of eye damage is either nonexistent or of a very low level of evidence. In conclusion, OSA has emerged as an additional potential risk factor for many eye diseases, although their link is weak and contradictory, so further examination is required. CITATION: García-Sánchez A, Villalaín I, Asencio M, García J, García-Rio F. Sleep apnea and eye diseases: evidence of association and potential pathogenic mechanisms. J Clin Sleep Med. 2022;18(1):265-278.

Contribution of sleep characteristics to the association between obstructive sleep apnea and dyslipidemia.

OBJECTIVES/BACKGROUND: Little information is available about the association of obstructive sleep apnea (OSA) with atherogenic dyslipidemia and the contribution of sleep characteristics to lipid alterations. We compare dyslipidemia prevalence among non-apneic subjects and mild-severe OSA patients to identify the sleep characteristics that are independently associated with dyslipidemia and serum lipid levels in OSA patients. PATIENTS/METHODS: We recruited 809 consecutive patients who had been referred for polysomnography study by OSA suspicion. Anthropometric characteristics, body composition and comorbidities were recorded. Spirometry and 24-h ambulatory blood pressure monitoring were performed the same day of the sleep study. The day after attended polysomnography, fasting blood samples were drawn to measure the lipid profile. RESULTS: Dyslipidemia prevalence increased with the presence of OSA, from non-OSA subjects to mild, moderate and severe OSA patients (31%, 33%, 42% and 51%, respectively; p < 0.001). After adjusting for sex, age, body mass index and smoking habit, only severe OSA had an independent association with dyslipidemia when compared to non-OSA subjects (adjusted odds ratio 1.71, 95%CI 1.09 to 2.69, p = 0.019). In OSA patients, multivariate logistic regression identified active smoking, apnea-hypopnea index (AHI) and mean nocturnal saturation as variables independently associated with dyslipidemia. However, in these patients, arousal index, slow wave sleep duration and REM latency were also independently associated with cholesterol and low-density lipoprotein levels. CONCLUSIONS: The association between dyslipidemia and OSA is limited to severe patients, with high AHI and nocturnal hypoxemia. However, sleep fragmentation and increased sympathetic activity could also contribute to OSA-related lipid dysregulation.

Obstructive sleep apnea is associated with impaired renal function in patients with diabetic kidney disease.

Obstructive sleep apnea (OSA) is a recognized risk factor for the development of diabetic kidney disease (DKD). Our objectives were to compare the urinary albumin-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) of patients with DKD according to OSA severity, and to evaluate the contribution of sleep parameters to their renal function. In a multicenter, observational, cross-sectional study, 214 patients with DKD were recruited. After a sleep study, UACR and eGFR were measured, as well as serum creatinine, fasting glucose, glycated hemoglobin, insulin resistance, lipid profile and C-reactive protein. UACR was higher in severe OSA patients (920 ± 1053 mg/g) than in moderate (195 ± 232 mg/g, p < 0.001) or mild OSA/non-OSA subjects (119 ± 186 mg/g, p < 0.001). At the same time, eGFR showed an OSA severity-dependent reduction (48 ± 23 vs. 59 ± 21 vs. 73 ± 19 ml/min per 1.73 m2, respectively; p < 0.001). Apnea-hypopnea index (AHI and desaturation index (ODI) were identified as independent predictors for UACR and eGFR, respectively. Therefore, in patients with DKD under optimized treatment, severe OSA is associated with a higher UACR and a lower eGFR, reflecting an additional contribution to the impairment of their renal function, although no causality can be inferred.

Incidence of VTE and Bleeding Among Hospitalized Patients With Coronavirus Disease 2019: A Systematic Review and Meta-analysis.

BACKGROUND: Individual studies have reported widely variable rates for VTE and bleeding among hospitalized patients with coronavirus disease 2019 (COVID-19). RESEARCH QUESTION: What is the incidence of VTE and bleeding among hospitalized patients with COVID-19? METHODS: In this systematic review and meta-analysis, 15 standard sources and COVID-19-specific sources were searched between January 1, 2020, and July 31, 2020, with no restriction according to language. Incidence estimates were pooled by using random effects meta-analyses. Heterogeneity was evaluated by using the I2 statistic, and publication bias was assessed by using the Begg and Egger tests. RESULTS: The pooled incidence was 17.0% (95% CI, 13.4-20.9) for VTE, 12.1% (95% CI, 8.4-16.4) for DVT, 7.1% (95% CI, 5.3-9.1) for pulmonary embolism (PE), 7.8% (95% CI, 2.6-15.3) for bleeding, and 3.9% (95% CI, 1.2-7.9) for major bleeding. In subgroup meta-analyses, the incidence of VTE was higher when assessed according to screening (33.1% vs 9.8% by clinical diagnosis), among patients in the ICU (27.9% vs 7.1% in the ward), in prospective studies (25.5% vs 12.4% in retrospective studies), and with the inclusion of catheter-associated thrombosis/isolated distal DVTs and isolated subsegmental PEs. The highest pooled incidence estimate of bleeding was reported for patients receiving intermediate- or full-dose anticoagulation (21.4%) and the lowest in the only prospective study that assessed bleeding events (2.7%). INTERPRETATION: Among hospitalized patients with COVID-19, the overall estimated pooled incidence of VTE was 17.0%, with higher rates with routine screening, inclusion of distal DVT, and subsegmental PE, in critically ill patients and in prospective studies. Bleeding events were observed in 7.8% of patients and were sensitive to use of escalated doses of anticoagulants and nature of data collection. Additional studies are required to ascertain the significance of various thrombotic events and to identify strategies to improve patient outcomes. TRIAL REGISTRY: PROSPERO; No.: CRD42020198864; URL: https://www.crd.york.ac.uk/prospero/.

Prognostic significance of computed tomography-assessed right ventricular enlargement in low-risk patients with pulmonary embolism: Systematic review and meta-analysis.

BACKGROUND: For patients with acute low-risk pulmonary embolism (PE), determined by a validated clinical prognostic score, the additive prognostic significance of computed tomography (CT)-assessed right ventricular (RV) enlargement is uncertain. METHODS: We performed a systematic review and meta-analysis of studies that enrolled patients with acute low-risk PE to assess the prognostic value of concomitant CT-assessed RV enlargement for 30-day all-cause mortality and PE-related death. We conducted unrestricted searches of PubMed and Embase through December 2019. We used a random-effects model to pool study results; Begg rank correlation method to evaluate for publication bias; and I2 testing to assess for heterogeneity. RESULTS: Of the 7 cohorts with 2197 participants who had low-risk PE and provided results on the primary outcome, 743 (34%; 95% confidence interval [CI], 32-36%) patients had concomitant RV enlargement. Six of 743 (0.8%; 95% CI, 0.3-1.8%) patients with concomitant RV enlargement died 30-days after the diagnosis of PE compared with 3 of 1454 (0.2%, 95% CI, 0-0.6%) without RV enlargement. CT-assessed RV enlargement did not have a significant association with 30-day all-cause mortality (odds ratio [OR], 2.6; 95% CI, 0.7-9.4; I2 = 0%; P = 0.15) or PE-related mortality (OR, 2.8; 95% CI, 0.7-12.1; I2 = 0%; P = 0.16). CONCLUSIONS: CT-assessed RV enlargement occurs in a third of PE patients identified as low-risk by clinical scores. Mortality rate in these patients is low, and CT-assessed RV enlargement was not associated with a significantly increased risk of death within 30 days of PE diagnosis.

The optimisation of noninvasive ventilation in amyotrophic lateral sclerosis: a systematic review.

BACKGROUND: Noninvasive ventilation (NIV) prolongs survival and quality of life in amyotrophic lateral sclerosis (ALS); however, its benefits depend upon the optimisation of both ventilation and adherence. We aimed to identify factors associated with effective initiation and ongoing use of NIV in ALS to develop evidence-based guidance and identify areas for further research. METHODS: We searched 11 electronic databases (January 1998 to May 2018) for all types of quantitative and qualitative studies. Supplementary grey literature searches were conducted. Records were screened against eligibility criteria, data were extracted from included studies and risk of bias was assessed. We present findings using a narrative synthesis. RESULTS: We screened 2430 unique records and included 52 quantitative and six qualitative papers. Factors reported to be associated with NIV optimisation included coordinated multidisciplinary care, place of initiation, selection of interfaces, ventilator modes and settings appropriate for the individual patient, and adequate secretion management. The literature indicated that patients with significant bulbar dysfunction can still derive considerable benefit from NIV if their needs are met. Research emphasises that obstructive airway events, mask leak and uncontrolled secretions should be addressed by adjustments to the interface and machine settings, and the concomitant use of cough augmentation. CONCLUSION: This review highlights that NIV optimisation requires an individualised approach to respiratory management tailored to the differing needs of each patient. Ultimately, this should lead to improved survival and quality of life. This review expands on recommendations in current international guidelines for NIV use in ALS and identifies areas for future research.

Age-dependent hypoxia-induced PD-L1 upregulation in patients with obstructive sleep apnoea.

BACKGROUND AND OBJECTIVE: In obstructive sleep apnoea (OSA), intermittent hypoxia (IH) compromises immune surveillance through the upregulation of the programmed cell death-1 (PD-1) receptor and its ligand (PD-L1). Because the risk of OSA-related cancer depends on age, we assessed PD-L1/PD-1 expression in middle-aged and older patients with OSA as well as in a murine model. METHODS: PD-L1 expression was studied in 41 patients with severe OSA and 40 healthy volunteers (HV), divided into two groups (≤55 and >55 years of age). We used flow cytometry, quantitative PCR (qPCR) and ELISA to determine PD-L1 expression on monocytes and plasma PD-L1 protein levels. Moreover, we analysed PD-L1 expression on an in vivo IH model with old and young mice. RESULTS: In subjects up to 55 years of age, severe OSA increased PD-L1 surface protein and mRNA level expression on monocytes and soluble-PD-L1 protein concentration in plasma compared to HV. PD-L1 and hypoxia-induced factor (HIF)-1α expression correlated with age in HV, whereas in patients with OSA there was a negative relationship. In the mice exposed to IH, PD-L1 expression on F4/80+ splenocytes was also only increased in young animals. HIF-1α expression was significantly higher in patients with OSA than in HV in subjects up to 55 years of age, while PD-L1 expression in monocytes was related to HIF-1α expression in young patients with OSA. CONCLUSION: PD-L1 upregulation in patients with OSA as a consequence of HIF-1α activation occurs mainly in young patients. In older patients with OSA, upregulation was not detected, possibly due to impaired oxygen sensitivity.

Obstructive sleep apnoea and venous thromboembolism: pathophysiological links and clinical implications.

Obstructive sleep apnoea (OSA) and pulmonary embolism (PE) remain major health issues worldwide. Data from pathophysiological studies suggest that both intermittent hypoxia and sleep fragmentation are associated with increased blood coagulability, endothelial dysfunction and venous stasis. There is growing evidence that OSA is potentially prevalent in and a risk factor for PE. Conversely, patients with acute PE have two to four times greater risk of moderate-to-severe OSA. The role of continuous positive airway pressure (CPAP) treatment in improving clinically meaningful outcomes in PE patients remains unclear, although some authors have suggested that CPAP could improve the hypercoagulability state and normalise circadian alterations in some of the coagulation molecules, as observed in patients with OSA. Emerging research highlights the complex interdependent relationships between OSA and PE, emphasising the need for rigorous, well-powered trials that address the impact of OSA and its treatment on the prevention and management of PE. Undoubtedly, these will require closer collaboration between the sleep medicine and clinical/venous thromboembolism communities.

Amiloidosis como causa de enfermedad pulmonar quística asociada a nódulos pulmonares / Amyloidosis as a Cause of Cystic Pulmonary Fibrosis Associated With Pulmonary Nodules

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