Theratyping cystic fibrosis patients to guide elexacaftor/tezacaftor/ivacaftor out-of-label prescription.

BACKGROUND: Around 20% of people with cystic fibrosis (pwCF) do not have access to the triple combination elexacaftor/tezacaftor/ivacaftor (ETI) in Europe because they do not carry the F508del allele on the CF transmembrane conductance regulator (CFTR) gene. Considering that pwCF carrying rare variants may benefit from ETI, including variants already validated by the US Food and Drug Administration (FDA), a compassionate use programme was launched in France. PwCF were invited to undergo a nasal brushing to investigate whether the pharmacological rescue of CFTR activity by ETI in human nasal epithelial cell (HNEC) cultures was predictive of the clinical response. METHODS: CFTR activity correction was studied by short-circuit current in HNEC cultures at basal state (dimethyl sulfoxide (DMSO)) and after ETI incubation and expressed as percentage of normal (wild-type (WT)) CFTR activity after sequential addition of forskolin and Inh-172 (ΔI ETI/DMSO%WT). RESULTS: 11 pwCF carried variants eligible for ETI according to the FDA label and 28 carried variants not listed by the FDA. ETI significantly increased CFTR activity of FDA-approved CFTR variants (I601F, G85E, S492F, M1101K, R347P, R74W;V201M;D1270N and H1085R). We point out ETI correction of non-FDA-approved variants, including N1303K, R334W, R1066C, Q552P and terminal splicing variants (4374+1G>A and 4096-3C>G). ΔI ETI/DMSO%WT was significantly correlated to change in percentage predicted forced expiratory volume in 1 s and sweat chloride concentration (p<0.0001 for both). G85E, R74W;V201M;D1270N, Q552P and M1101K were rescued more efficiently by other CFTR modulator combinations than ETI. CONCLUSIONS: Primary nasal epithelial cells hold promise for expanding the prescription of CFTR modulators in pwCF carrying rare mutants. Additional variants should be discussed for ETI indication.

A Case of Pulmonary Adenocarcinoma Presenting with Diffuse Cystic Lesions.

The main causes of diffuse cystic lung diseases include lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, Birt-Hogg-Dubé syndrome, lymphoid interstitial pneumonia, light chain deposition disease, Pneumocystis jirovecii pneumonia, hypersensitivity pneumonitis, and desquamative interstitial pneumonia. Diffuse cystic lung diseases are rarely caused by a malignant process, which are secondary to metastases from sarcomas and gastrointestinal and gynecologic adenocarcinomas. Here, we present a rare case of invasive pulmonary adenocarcinoma associated with progressive diffusion of cystic lesions, revealed by chronic cough and progressive shortness of breath. It is important for clinicians to be aware of this unusual imaging manifestation of lung cancer, to avoid misdiagnoses.

Different phenotypes in dermatomyositis associated with anti-MDA5 antibody: Study of 121 cases.

OBJECTIVES: The predominance of extramuscular manifestations (e.g., skin rash, arthralgia, interstitial lung disease [ILD]) as well as the low frequency of muscle signs in anti-melanoma differentiation-associated gene 5 antibody-positive (anti-MDA5+) dermatomyositis caused us to question the term myositis-specific antibody for the anti-MDA5 antibody, as well as the homogeneity of the disease. METHODS: To characterize the anti-MDA5+ phenotype, an unsupervised analysis was performed on anti-MDA5+ patients (n = 83/121) and compared to a group of patients with myositis without anti-MDA5 antibody (anti-MDA5-; n = 190/201) based on selected variables, collected retrospectively, without any missing data. RESULTS: Within anti-MDA5+ patients (n = 83), 3 subgroups were identified. One group (18.1%) corresponded to patients with a rapidly progressive ILD (93.3%; p < 0.0001 across all) and a very high mortality rate. The second subgroup (55.4%) corresponded to patients with pure dermato-rheumatologic symptoms (arthralgia; 82.6%; p < 0.01) and a good prognosis. The third corresponded to patients, mainly male (72.7%; p < 0.0001), with severe skin vasculopathy, frequent signs of myositis (proximal weakness: 68.2%; p < 0.0001), and an intermediate prognosis. Raynaud phenomenon, arthralgia/arthritis, and sex permit the cluster appurtenance (83.3% correct estimation). Nevertheless, an unsupervised analysis confirmed that anti-MDA5 antibody delineates an independent group of patients (e.g., dermatomyositis skin rash, skin ulcers, calcinosis, mechanic's hands, ILD, arthralgia/arthritis, and high mortality rate) distinct from anti-MDA5- patients with myositis. CONCLUSION: Anti-MDA5+ patients have a systemic syndrome distinct from other patients with myositis. Three subgroups with different prognosis exist.

Effect of mandibular advancement therapy on inflammatory and metabolic biomarkers in patients with severe obstructive sleep apnoea: a randomised controlled trial.

Systemic inflammation and metabolic disorders are among the mechanisms linking obstructive sleep apnoea (OSA) and cardiovascular disease (CVD). In 109 patients with severe OSA and no overt CVD, biomarkers of inflammation (C reactive protein, interleukin-6, tumour necrosis factor-α and its receptors, adiponectin, leptin and P-selectin), glucose and lipid metabolism, and N-terminal pro-brain natriuretic peptide, were measured before and after 2 months of treatment with a mandibular advancement device (MAD) (n=55) or a sham device (n=54). MAD reduced the Apnoea-Hypopnoea Index (p<0.001) but had no effect on circulating biomarkers compared with the sham device, despite high treatment adherence (6.6 hour/night). TRIAL REGISTRATION NUMBER: NCT01426607.

Polyphenols Have No Impact on Endothelial Function in Patients with Obstructive Sleep Apnea: A Randomized Controlled Trial.

Background: Endothelial dysfunction, a pathophysiologic determinant of atherogenesis, has been found to occur in obstructive sleep apnea syndrome (OSA) and is improved by continuous positive airway pressure (CPAP). However, the efficacy of CPAP therapy is limited by variable adherence. Alternative treatment strategies are needed. The impact of polyphenols on endothelial function has never been evaluated in OSA. Objective: We evaluated the impact of 1-mo supplementation with grape juice polyphenols (GJPs) on the reactive hyperemia index (RHI), a validated measure of endothelial function in patients with severe OSA. Methods: Forty participants [75% men, median (IQR) age: 61 y (34, 64 y), BMI (in kg/m2): 30.6 (20.9, 33.7)] with severe OSA [median apnea-hypopnea index 43/h (33/h, 56/h)] were randomly assigned to receive GJPs (300 mg/d; n = 20) or placebo (n = 20) for 1 mo. The primary outcome was the change in RHI between baseline and after 1 mo of GJPs or placebo. Secondary outcome measures included changes in blood pressure (BP), heart rate (HR), and polysomnographic indexes. Results: No significant differences in RHI and BP outcomes were observed between the GJPs and placebo groups. A significant between-group difference was observed for HR changes [-1 bpm (-5, +5 bpm) in the GJPs group compared with +6 bpm (+3, +10 bpm) in the placebo group; P = 0.001]. A significant decrease in total sleep time was observed in the GJPs group compared with the placebo group [-10 min (-33, 6 min) compared with +15 min (-12, 40 min), respectively; P = 0.02], with no between-group differences in the distribution of sleep stages. Conclusions: In participants with severe OSA and no overt cardiovascular disease, 1-mo GJP supplementation had no effect on endothelial function. This trial was registered at clinicaltrials.gov as NCT01977924.

Cumulative association of obstructive sleep apnea severity and short sleep duration with the risk for hypertension.

Obstructive sleep apnea (OSA) and short sleep duration are individually associated with an increased risk for hypertension (HTN). The aim of this multicenter cross-sectional study was to test the hypothesis of a cumulative association of OSA severity and short sleep duration with the risk for prevalent HTN. Among 1,499 patients undergoing polysomnography for suspected OSA, 410 (27.3%) previously diagnosed as hypertensive and taking antihypertensive medication were considered as having HTN. Patients with total sleep time (TST) <6 h were considered to be short sleepers. Logistic regression procedures were performed to determine the independent association of HTN with OSA and sleep duration. Considering normal sleepers (TST ≥6 h) without OSA as the reference group, the odds ratio (OR) (95% confidence intervals) for having HTN was 2.51 (1.35-4.68) in normal sleepers with OSA and 4.37 (2.18-8.78) in short sleepers with OSA after adjustment for age, gender, obesity, diabetes, depression, current smoking, use of thyroid hormones, daytime sleepiness, poor sleep complaint, time in bed, sleep architecture and fragmentation, and study site. The risk for HTN appeared to present a cumulative association with OSA severity and short sleep duration (p<0.0001 for linear trend). The higher risk for HTN was observed in short sleepers with severe OSA (AHI ≥30) (OR, 4.29 [2.03-9.07]). In patients investigated for suspected OSA, sleep-disordered breathing severity and short sleep duration have a cumulative association with the risk for prevalent HTN. Further studies are required to determine whether interventions to optimize sleep may contribute to lower BP in patients with OSA.

Circulating microparticles from obstructive sleep apnea syndrome patients induce endothelin-mediated angiogenesis.

Microparticles are deemed true biomarkers and vectors of biological information between cells. Depending on their origin, the composition of microparticles varies and the subsequent message transported by them, such as proteins, mRNA, or miRNA, can differ. In obstructive sleep apnea syndrome (OSAS), circulating microparticles are associated with endothelial dysfunction by reducing endothelial-derived nitric oxide production. Here, we have analyzed the potential role of circulating microparticles from OSAS patients on the regulation of angiogenesis and the involved pathway. VEGF content carried by circulating microparticles from OSAS patients was increased when compared with microparticles from non-OSAS patients. Circulating microparticles from OSAS patients induced an increase of angiogenesis that was abolished in the presence of the antagonist of endothelin-1 receptor type B. In addition, endothelin-1 secretion was increased in human endothelial cells treated by OSAS microparticles. We highlight that circulating microparticles from OSAS patients can modify the secretome of endothelial cells leading to angiogenesis.

Independent association between obstructive sleep apnea severity and glycated hemoglobin in adults without diabetes.

OBJECTIVE: We tested the hypothesis of an independent cross-sectional association between obstructive sleep apnea (OSA) severity and glycated hemoglobin (HbA(1c)) in adults without known diabetes. RESEARCH DESIGN AND METHODS: HbA(1c) was measured in whole-blood samples from 2,139 patients undergoing nocturnal recording for suspected OSA. Participants with self-reported diabetes, use of diabetes medication, or HbA(1c) value ≥6.5% were excluded from this study. Our final sample size comprised 1,599 patients. RESULTS: A dose-response relationship was observed between apnea-hypopnea index (AHI) and the percentage of patients with HbA(1c) >6.0%, ranging from 10.8% for AHI <5 to 34.2% for AHI ≥50. After adjustment for age, sex, smoking habits, BMI, waist circumference, cardiovascular morbidity, daytime sleepiness, depression, insomnia, sleep duration, and study site, odds ratios (95% CIs) for HbA(1c) >6.0% were 1 (reference), 1.40 (0.84-2.32), 1.80 (1.19-2.72), 2.02 (1.31-3.14), and 2.96 (1.58-5.54) for AHI values <5, 5 to <15, 15 to <30, 30 to <50, and ≥50, respectively. Increasing hypoxemia during sleep was also independently associated with the odds of HbA(1c) >6.0%. CONCLUSIONS: Among adults without known diabetes, increasing OSA severity is independently associated with impaired glucose metabolism, as assessed by higher HbA(1c) values, which may expose them to higher risks of diabetes and cardiovascular disease.

Endothelial dysfunction and circulating microparticles from patients with obstructive sleep apnea.

Endothelial dysfunction is involved in vascular complications of obstructive sleep apnea (OSA). In this study, circulating microparticles (MPs) from patients with OSA-induced nocturnal desaturations were characterized and their effects on endothelial function were evaluated. Two age-matched groups of patients undergoing polysomnography for OSA were compared: 35 desaturators with a 3% oxyhemoglobin desaturation index (ODI) > or = 10 events per hour of sleep and 27 nondesaturators with ODI <10 events per hour. MPs were characterized by flow cytometry and then either used to treat in vitro human endothelial cells or to study endothelial function in mice. Circulating MPs did not differ between groups, but MPs from granulocytes and activated leukocytes (CD62L(+)) were found at higher levels in desaturators. In vitro, MPs from desaturators reduced endothelial nitric oxide (NO) production by enhancing phosphorylation of endothelial NO synthase at the site of inhibition and expression of caveolin-1. CD62L(+) MPs positively correlated with ODI. Endothelial NO production negatively correlated with both CD62L(+) MPs and ODI. MPs from desaturators increased expression of endothelial adhesion molecules including E-selectin, ICAM-1 and ITGA5, and cyclooxygenase 2. Moreover, injection of MPs from desaturators into mice impaired endothelium-dependent relaxation in aorta and flow-induced dilation in small mesenteric arteries. This study demonstrates an association between endothelial dysfunction and increased circulating levels of CD62L(+) MPs. This may initiate atherogenic processes in patients with OSA and severe nighttime hypoxia.