The CORE syndrome: an overlap of severe asthma, obstructive sleep apnea, rhinosinusitis, and esophageal reflux.

PURPOSE: Asthma, obstructive sleep apnea (OSA), rhinosinusitis, and esophageal reflux are conditions that may overlap, forming a syndrome known as CORE. Whenever clinical remission of severe asthma (SA) is not achieved, it is essential to investigate the presence of comorbidities, in particular the presence of OSA that may lead to the diagnosis of CORE syndrome. METHODS: The study was conducted on naive patients with SA and concomitant rhinosinusitis and esophageal reflux, referred to our institute since 2018. Patients who did not experience clinical remission were investigated for OSA through a home sleep apnea test. Subsequently, for those diagnosed with OSA, continuous positive airway pressure (CPAP) was proposed and was re-evaluated after 12 months. RESULTS: Six patients with CORE syndrome were enrolled. The mean apnea-hypopnea index (AHI) was 33.25 ± 20.13 events/h, oxygen desaturation index (ODI) was 28.95 ± 19.95 events/h, and time in bed with SaO2 < 90% (T90) was 26.40 ± 27.22% for which continuous positive airway pressure (CPAP) treatment was proposed but only 3 out of 6 patients accepted. After 12 months, all CPAP-treated patients manifested a significant reduction in daytime sleepiness (ESS score was 6.33 ± 3.8), an improvement in ACT score (+ 8 (+ 32%), + 9 (+ 36%), and + 14 (+ 56%) points), a discontinuation of oral corticosteroids (OCS), an absence of exacerbations, and an improvement of lung function leading to clinical remission of asthma. CONCLUSION: Whenever facing SA patients, non-responders to therapy, it is important to suspect the presence of CORE syndrome; in particular, the detection and subsequent treatment of OSA would seem to improve the outcome of such patients.

Assessment of BoAHV-1 Seronegative Latent Carrier by the Administration of Two Infectious Bovine Rhinotracheitis Live Marker Vaccines in Calves.

Seronegative latent carriers (SNLCs) are animals that carry the virus without detectable antibodies and pose a risk for disease transmission and diagnostic challenges, suggesting the importance of consideration of marker vaccines in managing them. Therefore, in this study, we evaluated two modified live infectious bovine rhinotracheitis (IBR) marker vaccines (single and double deletions) for their ability to generate SNLC calves. These vaccines were administered to four groups (n = 3 in each group) of three-month-old calves in the presence or absence of passive immunity. Three hundred days after the first vaccination and after confirming the IBR seronegativity of all animals, dexamethasone was administered intravenously for five consecutive days. Only animals immunized with the modified live IBR marker vaccine (single deletion) in the absence of passive immunity exhibited a more enduring immune response than those vaccinated in the presence of passive immunity. Moreover, the administration of a modified live IBR marker vaccine (double deletion) to calves with passive immunity generated SNLC. These findings underscore the potential of live IBR marker vaccine (double-deletions) to aid serological diagnostic tools and develop vaccination protocols in achieving the desired immune response, particularly in the context of latent carrier status, offering valuable insights into optimizing vaccination strategies for effective IBR control.

Mortality in obstructive sleep apnea syndrome (OSAS) and overlap syndrome (OS): The role of nocturnal hypoxemia and CPAP compliance.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) and chronic obstructive pulmonary disease (COPD) are two chronic diseases that afflict many individuals worldwide with negative effects on health that may overlap in Overlap Syndrome (OS). The aim of our study was to investigate the differences in mortality between OSAS alone and OS and the risk factors involved. METHODS: The study was conducted on patients with OSAS or OS diagnosis that completed 15-year follow-up between 2005 and 2023. Of these, the clinical, functional, sleep and survival data were registered and analysed. Risk factors were found by regression analysis. RESULTS: 501 patients (428 OSAS and 73 OS) were enrolled. Patients with OS had higher mortality than OSAS (p < 0,001). The morality risk factors for the overall population found were age >65 years (odds ratio (OR) = 10.69 (95%CI 3,85-29,69), p < 0,001) and low forced-expiratory volume in 1-s (FEV1) (OR = 10.18 (95%CI 2,32-44,68), p = 0,002). In patients with OSAS, age and nocturnal hypoxemia (NH) (OR = 2.41 (95%CI 1,07-5,41), p = 0,03) were risk factors, while adherence to nighttime positive airway pressure (PAP) reduced mortality (OR = 0,36 (95%CI 0,15-0,83), p = 0,017). Multivariate analysis confirmed age and FEV1 as risk factors in OS. Conversely, the risk factors for the overall population under 65 years were NH, which is confirmed in patients with OSAS alone (OR = 4,72 (95%CI 1,07-20,77), p = 0,04) in whom, on the other hand, PAP compliance reduced the mortality risk. CONCLUSIONS: The study suggests that NH is a risk factor for all-cause mortality in sleep disorders by excluding the age; conversely, nighttime PAP improves the survival.

The role of blood cholesterol quality in patients with advanced cancer receiving immune checkpoint inhibitors.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) became the standard of care for several solid tumors. A limited fraction of patients (pts) achieves a long-term benefit. Plasmatic and intracellular cholesterol levels have emerged as promising biomarkers. The aim of the present study was to determine whether cholesterol efflux capacity (CEC), mediated by serum transporters (ABCA1 and ABCG1) and passive diffusion (PD), impacts on clinical outcome of advanced non-small cell lung cancer (NSCLC) and metastatic renal cell carcinoma (mRCC) pts treated with ICIs. MATERIAL AND METHODS: We retrospectively enrolled advanced NSCLC and mRCC pts consecutively treated with ICIs between October 2013 and October 2018. CEC and cholesterol loading capacity (CLC) were assessed by well-established specific cell models. As primary endpoint, CEC, PD and CLC were correlated with overall survival (OS) while the effects of these parameters on progression-free survival (PFS) and clinical benefit (CB), defined as complete/partial response or stable disease, represented secondary endpoints. RESULTS: NSCLC accounted for 94.2% of 70 enrolled cases, and serum sample suitable for CEC and PD determination was available in 68. Blood cholesterol and serum ABCA1, ABCG1, PD and CLC were associated with outcomes (OS, PFS and CB) at univariate analysis. At the multivariate analysis, only PD confirmed its positive prognostic value in terms of OS, PFS and CB. CONCLUSION: The favorable impact of cholesterol PD on clinical outcome might reflect its main conformation in mature HDL particles which potentially shape an inflamed context, ultimately promoting ICI efficacy. Further prospective studies are needed to support our findings and uncover targetable pathways.

Obstructive sleep apnoea-hypopnoea syndrome: state of the art.

Obstructive sleep apnoea-hypopnoea syndrome (OSAHS) is an extremely common sleep-related breathing disorder (SRBD) characterised by complete or partial collapse of the upper airways. These nocturnal phenomena cause high-frequency hypoxemic desaturations (or intermittent hypoxia, IH) during sleep and alterations in gas exchange. The result of IH is the development or worsening of cerebro-cardio-vascular, metabolic and other diseases, which cause a high risk of death. Hence, OSAHS is a multifactorial disease affecting several organs and systems and presenting with various clinical manifestations involving different medical branches. Although it has been estimated that about one billion individuals worldwide are affected by OSAHS, this SRBD remains underestimated also due to misinformation regarding both patients and physicians. Therefore, this review aims to provide information on the main symptoms and risk factors for the detection of individuals at risk of OSAHS, as well as to present the diagnostic investigations to be performed and the different therapeutic approaches. The scientific evidence reported suggest that OSAHS is an extremely common and complex disorder that has a large impact on the health and quality of life of individuals, as well as on healthcare expenditure. Moreover, given its multifactorial nature, the design and implementation of diagnostic and therapeutic programmes through a multidisciplinary approach are necessary for a tailor-made therapy for each patient.

A consumer wearable device for tracking sleep respiratory events.

PURPOSE: The diagnosis of obstructive sleep apnea (OSA) is instrument, operator, and time-dependent and therefore requires long waiting times. In recent decades, technological development has produced useful devices to monitor the health status of the population, including sleep. Therefore, the aim of this study was to evaluate a wearable device (WD) in a group of individuals at high risk of OSA. METHODS: The study was conducted on consecutive subjects with high risk of OSA assessed by sleep questionnaires and clinical evaluation. All subjects performed cardio-respiratory monitoring (CRM) and WD simultaneously on a single night, after which the parameters of the two sleep investigations were compared. RESULTS: Of 20 individuals enrolled, 60% were men and mean age was 57.3 ± 10.7 years. The apnea-hypopnea index (AHI) for the CRM was 23.1 ± 19.6 events·h-1 while it was 10.3 ± 8.3 events·h-1 for the WD. Correlation analysis between the results of the two investigations showed r = 0.19 (p = 0.40) for AHI and r = 0.4076 (p = 0.07) for sO2%. The accuracy for different stages of OSA severity was 70% in OSA cases and 60% in moderate to severe cases with sensitivity and specificity varying a great deal. CONCLUSION: Small and low-cost devices may prove to be a valuable resource to reduce costs and waiting times for a sleep investigation in suspected OSA. However, diagnosis of sleep apnea requires valid and reliable instruments, so validation tests are necessary before a device can be commercialized.

Clinical Evaluation and Management of Overlap Syndrome (OS) and Obesity Hypoventilation Syndrome (OHS).

Background and Aim: Sleep-disordered breathing (SDB) is an extremely common disorder with a high impact on morbidity and mortality. The purpose of this study was to compare overlap syndrome (OS) and obesity hypoventilation syndrome (OHS) and to highlight and understand the differences between them. Material and Methods: The study was conducted retrospectively on 132 subjects selected by consecutive sampling from those attending our unit for suspected SDB. After clinical evaluation as well as functional and sleep investigations, the population was divided according to diagnosis in OS and OHS; then, the clinical parameters of two groups were compared with different statistical analysis. Results: The subjects with OHS were younger and reported higher rated daytime sleepiness (p = 0.005). In addition, they presented more nocturnal respiratory events (apnea-hypopnea index (AHI) 63.61 ± 22.79 events·h−1 vs. AHIOS 42.21 ± 22.91 events·h−1, p < 0.0001) at the sleep investigation as worse gas exchange during sleep leading to a higher percentage of nocturnal hypoxemia (p < 0.0001). In contrast, subjects with OS had more an impaired respiratory function. With regard to night-time ventilatory therapy, more subjects with OS were effectively treated with continuous positive airway pressure (CPAP) (p = 0.011), while more OHS were treated with auto-adjusting PAP (APAP) (14% vs. 1%, p = 0.008). Conclusions: The present study tried to establish a framework for OS and OHS because proper management of the two disorders would reduce their burden on healthcare.

The Burden of Respiratory Alterations during Sleep on Comorbidities in Obstructive Sleep Apnoea (OSA).

BACKGROUND: Obstructive sleep apnoea (OSA) has an important impact on the risk of morbidity and mortality, so we have designed the present study to understand which factor is most involved in the risk of developing a comorbidity between OSA severity and nocturnal hypoxemia. METHODS: A retrospective study was conducted on 617 adult subjects who were referred to our unit for a suspicion of OSA between January 2018 and January 2020. RESULTS: Sleep investigations performed by participants (72% male and obese in 70% of cases) reported an overall mean apnoea-hypopnoea index (AHI) of 44.0 ± 24.8 events·h-1. Overall, 66% were classified as severe OSA and 76% experienced nocturnal hypoxemia. By analysing the burden of OSA severity and nocturnal hypoxemia on the comorbidities risk, multivariate analysis highlighted the predominant role of age and obesity. Accordingly, after the exclusion of the older and obese participants from the analyses, we noticed that severe OSA was related to the risk of hypertension (odds ratio (OR) = 3.0 [95% confidence interval [CI] 1.4-6.2], p = 0.004) as well as nocturnal hypoxemia (OR = 2.6 [95% CI 1.2-5.4], p = 0.01). CONCLUSIONS: The study seems to suggest that in young, non-obese subjects, OSA is a predisposing factor for the risk of developing hypertension.

Assessment of Different Infectious Bovine Rhinotracheitis Marker Vaccines in Calves.

Three commercially available infectious bovine rhinotracheitis (IBR) live marker vaccines were evaluated for their ability to provide clinical protection to vaccinated calves against wild-type (wt) Bovine alphaherpesvirus-1 (BoHV-1) challenge and their possible effect on wt BoHV-1 latency reactivation following the challenge. On 35 post-vaccination days (PVDs), all animals were challenged with wt BoHV-1. Only the calves in the control group developed severe forms of IBR. The reactivation of latent BoHV-1 was induced by dexamethasone (DMS) treatment on 28 post-challenge days (PCDs). All animals showed IBR clinical signs on three post-DMS treatment days (PDTDs). On PVD 14, all vaccinated animals developed neutralizing antibodies (NAs), whereas in control animals, the NAs appeared post-challenge. The positivity for glycoprotein-B (gB) was detected using real-time polymerase chain reactions in all animals from PCDs 1 to 7. In contrast, the gB-positivity was observed in the immunized calves from PDTDs 3 to 10. Positive expression of gD and gE was observed in nasal swabs of all calves on PDTD 7. These findings suggested that the IBR marker vaccines evaluated in this study protected against wt BoHV-1-induced disease but not against wt BoHV-1-induced latency reactivation, indicating the necessity of developing new products to protect animals from wt BoHV-1-induced latency.

Effect of Hypoxia-Induced Micro-RNAs Expression on Oncogenesis.

MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. An aberrant regulation of gene expression by miRNAs is associated with numerous diseases, including cancer. MiRNAs expression can be influenced by various stimuli, among which hypoxia; however, the effects of different types of continuous hypoxia (moderate or marked) on miRNAs are still poorly studied. Lately, some hypoxia-inducible miRNAs (HRMs, hypoxia-regulated miRNAs) have been identified. These HRMs are often activated in different types of cancers, suggesting their role in tumorigenesis. The aim of this study was to evaluate changes in miRNAs expression both in moderate continuous hypoxia and marked continuous hypoxia to better understand the possible relationship between hypoxia, miRNAs, and colorectal cancer. We used RT-PCR to detect the miRNAs expression in colorectal cancer cell lines in conditions of moderate and marked continuous hypoxia. The expression of miRNAs was analyzed using a two-way ANOVA test to compare the differential expression of miRNAs among groups. The levels of almost all analyzed miRNAs (miR-21, miR-23b, miR-26a, miR-27b, and miR-145) were greater in moderate hypoxia versus marked hypoxia, except for miR-23b and miR-21. This study identified a series of miRNAs involved in the response to different types of continuous hypoxia (moderate and marked), highlighting that they play a role in the development of cancer. To date, there are no other studies that demonstrate how these two types of continuous hypoxia could be able to activate different molecular pathways that lead to a different expression of specific miRNAs involved in tumorigenesis.

Machine learning-based prediction of adherence to continuous positive airway pressure (CPAP) in obstructive sleep apnea (OSA).

Continuous positive airway pressure (CPAP) is the "gold-standard" therapy for obstructive sleep apnea (OSA), but the main problem is the poor adherence. Therefore, we have searched for the causes of poor adherence to CPAP therapy by applying predictive machine learning (ML) methods. The study was conducted on OSAs in nighttime therapy with CPAP. An outpatient follow-up was planned at 3, 6, 12 months. We collected several parameters at the baseline visit and after dividing all patients into two groups (Adherent and Non-adherent) according to therapy adherence, we compared them. Statistical differences between the two groups were not found according to baseline characteristics, except gender (P< .01). Therefore, we applied ML to predict CPAP adherence, and these predictive models showed an accuracy and sensitivity of 68.6% and an AUC (area under the curve) of 72.9% through the SVM (support vector machine) classification method. The identification of factors predictive of long-term CPAP adherence is complex, but our proof of concept seems to demonstrate the utility of ML to identify subjects poorly adherent to therapy. Therefore, application of these models to larger samples could aid in the careful identification of these subjects and result in important savings in healthcare spending.

Obstructive Sleep Apnea: A Look towards Micro-RNAs as Biomarkers of the Future.

Sleep-disordered breathing (SDB) includes a broad spectrum of diseases, of which obstructive sleep apnea syndrome (OSA) is the most clinically significant manifestation. OSA is a respiratory disorder characterized by episodes of complete or partial obstruction of the upper airways that disturb ventilation and sleep architecture. In recent years, interest in the clinical implications of OSA seems to have increased, probably due to the numerous studies that have shown the existence of an important correlation between OSA and cardiovascular, dysmetabolic, and neoplastic changes. The guidelines currently available highlight the importance of diagnosis and effective treatment for OSA, underlining the need for new biomarkers that are useful in clinical practice, feasible, and reproducible to guide medical decision making. In this review, we intend to provide an overview of the potential role of microRNAs as new indicators for OSA management. MicroRNAs (miRNAs) are small non-coding RNA molecules that play an important role in RNA silencing and regulation of gene expression at the post-transcriptional level. These can bind specifically to their target genes by forming silencing complexes, thus inducing degradation or altered gene expression. A wide range of miRNAs have been extensively studied in a variety of diseases including cancer, and recently, miRNAs have been shown to have enormous potential to function as diagnostic and clinical biomarkers of disease. This review includes recent studies that establish the inevitable role of miRNAs in the pathogenesis of OSA.

The Prognostic Role of High Blood Cholesterol in Advanced Cancer Patients Treated With Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICI) have improved survival in numerous types of cancer. However, a great number of unselected patients still do not respond to ICI. Moreover, there is a need to identify biomarkers that could predict the prognosis of immunotherapy-treated patients. The aim of our study is to evaluate the prognostic value of baseline plasmatic cholesterol levels in metastatic cancer patients treated with immunotherapy. We retrospectively enrolled advanced cancer patients consecutively treated with ICI at our center between October 2013 and October 2018 to correlate the blood cholesterol level before treatment with overall survival (OS, primary endpoint). The secondary endpoints were the correlation between baseline cholesterol and progression-free survival (PFS), objective response rate, and toxicity (immune-related adverse events). Among 187 patients with availability of baseline plasmatic cholesterol, 58 had cholesterol levels >200 mg/dL. The median age was 70 years. Primary tumors were as follows: non-small cell lung cancer (70.0%), melanoma (15.0%), renal cell carcinoma (9.1%), urothelial cancer (4.6%), head-neck carcinoma (0.9%), and others (0.4%). The median follow-up was 21.3 months. Both OS and PFS were better in patients with high plasmatic cholesterol levels: the median OS was 19.4 versus 5.5 months (P=0.001) and the median PFS was 6.1 versus 2.4 months (P=0.002). The multivariate analysis confirmed the prognostic role of hypercholesterolemia in terms of OS, but not PFS. Hypercholesterolemia was associated with better outcomes in ICI-treated cancer patients and, as an expression of low-grade inflammation state, it could identify tumors more likely to be responsive to immunotherapy.

Omalizumab as add-on therapy in a patient with severe asthma and OSA.

Obstructive sleep apnoea (OSA) syndrome, the most frequent sleep-disordered breathing, is a comorbidity of asthma, whose prevalence covers about 49.5% of asthmatic adult patients. A 61-year-old female patient, affected by severe allergic asthma and obesity, started treatment with omalizumab and underwent polysomnography showing a severe OSA pattern (apnoea/hypopnoea index (AHI): 72.7). After six months, she showed functional improvement and good asthma symptoms control and underwent a new polygraphy for the persistence of the night symptoms which showed an ameliorated, despite still severe, OSA pattern (AHI: 31.9). The patient obtained complete polygraphic normalization after adequate positive airway pressure (PAP) titration. While bronchodilator efficacy in chronic obstructive pulmonary disease (COPD)/OSA overlap syndrome has been proven in raising nocturnal oxygen saturation, there is no such evidence about biological therapy in patients affected by severe asthma and OSA. This is the first documented case report that demonstrates a possible role of omalizumab in improving the OSA pattern in a patient affected by severe asthma and OSA.

MicroRNA expression profile during different conditions of hypoxia.

INTRODUCTION: MicroRNAs (miRNAs) are small non coding RNAs which play a role in several cellular processes. MiRNA expression is influenced by oxidative stress, inflammatory cascade and hypoxia. Effects of different types of hypoxia (intermittent and chronic) have been poorly investigated. The aim of this study was to evaluate how intermittent and chronic hypoxia influence the expression of a pool of miRNAs. RESULTS: Subjects with HI presented higher levels of miR-21, miR-23b, miR-145 and miR-210 compared to the other groups, while higher levels of miR-26 was observed in the HC group. Subjects with HCHI had lower levels of all selected miRNAs. A strong correlation was found between miR-23b and miR-210 and both correlated with PaO2, age and FEV1. MiR-145 is correlated with miR-21 but no correlations were found with other parameters. The level of miR-26a seems to be correlated only with BMI. MATERIALS AND METHODS: We used RT-PCR to detect the miRNAs expression in three different models of hypoxemia: intermittent (HI), chronic (HC) and both of them (HCHI). Expression of miRNAs was analyzed using ANOVA and post hoc analysis, moreover, Spearman correlation and Cluster analysis were applied to study the relationship between miRNAs and main clinical parameters. CONCLUSIONS: Intermittent hypoxia induces the expression of some miRNAs more than chronic hypoxia. These miRNAs may play an important role in the development of different diseases usually associated with OSA such as cardiovascular disease. In addition, mechanisms involved in cancer progression may be induced in the presence of chronic and more often intermittent hypoxia.

Prevalence of comorbidities in patients with obstructive sleep apnea syndrome, overlap syndrome and obesity hypoventilation syndrome.

INTRODUCTION: Sleep-disordered breathing causes a burden to the sufferer, the health care system and the society. Most studies have focused on obstructive sleep apnea (OSA); however, the prevalence of comorbidities in patients affected by overlap syndrome (OS) and obesity hypoventilation syndrome (OHS) has not been carefully evaluated. STUDY OBJECTIVES: The principal aim of this study was to identify the presence of comorbidities in patients suffering from OSA, OS, OHS and the differences in three groups of patients. Another purpose was to verify if sleepiness is associated with a greater prevalence of comorbidities. METHODS: A retrospective analysis in 989 adults referred for sleep diagnostic testing to our sleep center was performed. Patients were classified in OSA (721), OS (123) and OHS (145). RESULTS: The prevalence of comorbidities was higher in patients affected by OS and was the highest in the OHS group, while the prevalence of arterial hypertension is the highest in patients affected by OS. The probability of having more than two comorbidities follows the same trend. Excessive daytime sleepiness was associated with an increased rate of arterial hypertension, diabetes mellitus and the presence of multimorbidity in each group of patients. CONCLUSIONS: The presence and the association of comorbidities seem to be higher in patients suffering from OSA, OS and OHS. Subjects suffering of OHS present a high prevalence of main diseases despite their younger age compared with others patients with SDB. Sleepiness may have a role, at least in a subset of these patients, into the development of comorbidities.

New non invasive ventilator strategy applied to COPD patients in acute ventilator failure.

INTRODUCTION: There is no evidence in the literature regarding the combined use of positive ventilation with negative ventilation. A recent study reported that the two techniques can be combined in patients with ARDS, who undergo ventilatory support for severe acute respiratory failure (ARF). There is experience of non-invasive ventilation in patients with chronic respiratory diseases and ARF. The aim of this study was to test the efficacy of a non-invasive ventilatory strategy based on the combined use of negative (N) and positive ventilation (P) in bi-level mode (PN). METHODS: We enrolled 8 patients with severe COPD exacerbations and exacerbated chronic respiratory failure admitted in a monitored setting of an intermediate-intensive respiratory Unit. RESULTS: Patients underwent combined positive/negative ventilation and at different times, in place of the two singular ventilation modes (P and N). After each cycle, in the combined P/N ventilatory mode, gas exchanges were significantly increased compared to the two singular P/N mode: pH (7.42 vs 7.40 and 7.40); PCO2 (85.01 vs 72.05 and 66.81 mmHg); FiO2/PO2 (488.75 vs 352.62 and 327.87). All patients well tolerated the application of the double ventilation mode. CONCLUSIONS: In conclusion, the use of dual mode ventilation appears well tolerated and superior to the individual modes in patients with COPD exacerbations and ARF.