RATIONALE:CFTR modulators (CFTRms) have transformed cystic fibrosis care, yet concern exists regarding their mental health safety profile. OBJECTIVE:To provide further information, we conducted an analysis of CFTRm-related mental health disorders using two spontaneous pharmacovigilance reporting databases in real-world settings. METHODS:We analyzed reports from the French Pharmacovigilance Database (FPD) and VigiBase, the WHO global individual case safety reports database. Reports recorded between 2012 and 2024 involving any CFTRm and psychiatric disorders were included. In VigiBase, we conducted a case-non case, disproportionality analysis using the Reporting Odds Ratio (ROR), overall and stratified by age group (pediatrics vs. adults) and by CFTRm type. This study was conducted in accordance with the STROBE and the READUS-PV guidelines. RESULTS:In the FPD, 116 cases were analyzed. ELX/TEZ/IVA was suspected in 98% of cases and no single case was reported with ivacaftor alone. Sleep (61%), mood (37%), and anxiety disorders (27%) were the most frequently reported, with suicidal behaviors being infrequent, including 6 suicide attempts and no completed suicide. In VigiBase (n = 3,407), sleep disorders predominated in children, whereas mood and suicidality disorders were most frequent in adolescents. The median time to onset was 60 days (Q1-Q3: 12-150 days). Mental health disorders were disproportionately reported with CFTRms, particularly ELX/TEZ/IVA, while they were not with other combination therapies, compared to other drugs in the database. Disproportionality signals were slightly stronger in pediatrics than in adults. CONCLUSIONS:CFTRms, especially ELX/TEZ/IVA, are associated with increased reporting of mental health disorders, predominantly sleep and mood disorders. Pediatrics appear to be particularly affected. Prospective observational studies are warranted to confirm these findings and elucidate underlying pathophysiological mechanisms. REGISTRATION:OSF: mfyx3.
RATIONALE:Mycobacterium avium complex lung disease (MAC-LD) is clinically heterogeneous and carries diverse outcomes. OBJECTIVES:To describe predictors of clinical progression of MAC-LD in a state-wide cohort. METHODS:We enrolled adults with MAC-LD from across Virginia, USA starting in 2021. Every 6 months we performed respiratory quality of life questionnaire, scored CT scans, and recorded respiratory mycobacterial cultures including MAC speciation. Outcomes were classified using NTM-NET consensus definitions, factors predicting clinical progression analyzed by Poisson regression, and hierarchical clustering on principal components derived from Factorial Analysis of Mixed Data. MEASUREMENTS AND MAIN RESULTS:Of 105 participants the median follow-up was 917 days. Mean age was 69.8 years, 79 (75%) were women, and 70 (67%) had nodular bronchiectasis. M. intracellulare was the most common species, present in 48 (46%) participants at enrollment, followed by M. avium (29, 28%), and M. intracellulare subspecies chimaera (11, 10%). Only 2 (9%) of 22 evaluable participants met the NTM-NET definition of cure. In all participants after multivariable adjustment, older baseline age (incidence rate ratio 1.03 [1, 1.06], p = 0.04) and fibrocavitary CT scan pattern (2.57 [1.33, 4.96], p = 0.005), were associated with unfavorable 12-month clinical progression. Species type and species persistence contributed to characteristics of three distinct phenotypes of MAC-LD of varying severity and clinical progression. CONCLUSIONS:The majority of participants were not assessable for MAC-LD treatment outcomes using strict NTM-NET definitions. Species informed phenotypes of MAC lung disease are prognostically useful and can inform routine management and trial design.
RATIONALE:Platelet activation is elevated in chronic obstructive pulmonary disease (COPD) and associated with self-reported respiratory symptoms. Observational studies link the antiplatelet drug aspirin to lower exacerbation rates and fewer symptoms. However, it is unknown if platelet activation predicts incident respiratory exacerbations or mortality. OBJECTIVE:Is systemic platelet activation prospectively associated with respiratory exacerbations and mortality among ever-smokers with or at risk for COPD? METHODS:We measured two systemic platelet activation biomarkers, urinary 11-dehydro-thromboxane B2 (11dTxB2) and plasma soluble CD40 ligand (sCD40L), at baseline in self-reported aspirin non-users in the longitudinal SPIROMICS cohort. Adjusted generalized negative binomial and linear mixed-effects models assessed associations between these biomarkers and prospective rates of total and severe exacerbations, plus cross-sectional and longitudinal respiratory health (St. George's Respiratory Questionnaire, COPD Assessment Test, modified Medical Research Council questionnaire, and six minute walk distance). Cox proportional hazard and competing risk models evaluated associations between platelet activation biomarkers and all-cause and cause-specific mortality. RESULTS:Among 2,711 participants, 1,572 (58.0%) reported aspirin non-use; of these, 1,433 and 1,437 had 11dTxB2 and sCD40L measured, respectively. Over a median 6.6 years, a two-fold higher baseline 11dTxB2 was associated with increased rates of total (8.8%; 95%CI: 0.4-17.8%) and severe (18.1%; 95%CI: 5.1-32.6%) exacerbations. Although there were no significant interactions, there was a trend toward higher severe exacerbation rates among current cigarettes smokers and those with COPD. There were no significant results for sCD40L. Among aspirin non-users, higher 11dTxB2, but not sCD40L, was associated with worse cross-sectional respiratory health and modestly increased all-cause mortality over a median 8.2 years (adjusted hazard ratio 1.11; 95%CI: 1.00-1.24). After covariate adjustment, there were no associations with longitudinal respiratory health or cause-specific mortality. CONCLUSIONS:Systemic platelet activation, measured by urinary 11dTxB2, is a statistically significant but modest predictor of respiratory exacerbations and all-cause mortality in individuals with or at risk for COPD, suggesting its potential utility as a prognostic and predictive biomarker for antiplatelet therapy trials. CLINICAL TRIAL REGISTRATION:NCT01969344.
RATIONALE:For critically ill adults receiving invasive mechanical ventilation, randomized trials have found no significant average treatment effect of a higher (96-100%) versus lower (88-92%) peripheral oxygen saturation (SpO2) target. The effect of SpO2 targets on outcomes, however, may differ for patients with different characteristics. Machine learning methods have been used recently to derive and validate a statistical model capable of predicting which SpO2 target will result in lower mortality for an individual patient, as a personalized SpO2 target. Personalized targets can only improve patient outcomes, however, if the SpO2 target predicted to be best for them differs from the SpO2 values they are already experiencing in care. Whether the SpO2 values experienced in clinical care differ for patients predicted to benefit from a higher vs a lower SpO2 target is unknown. METHODS:Among consecutive patients receiving invasive mechanical ventilation in an intensive care unit, we used the previously validated machine learning model to calculate a personalized SpO2 target (predicted to benefit from a higher SpO2 target (96-100%) vs predicted to benefit from a lower SpO2 target (88-92%)) from baseline characteristics for each patient. We compared the personalized SpO2 target as the primary exposure to the observed SpO2 values experienced in clinical care as the primary outcome using a proportional odds model accounting for within-subject correlation. FiO2 values received in clinical care were analyzed as the secondary outcome. MEASUREMENTS AND MAIN RESULTS:Among 615 patients (median age, 58 years; 41% female), 325 (53%) were predicted by the machine learning model to benefit from a higher SpO2 target and 290 (47%) were predicted to benefit from a lower SpO2 target. Patients predicted to benefit from higher and lower targets experienced similar SpO2 values (mean 96.2% vs 95.6%; median 97% vs 96%; adjusted median difference 0.3%; 95%CI: -0.1% to 0.6%; P = 0.18) and FiO2 values (mean 0.45 vs 0.47; median 0.40 vs 0.40; adjusted median difference -0.02; 95%CI: -0.07 to 0.03; P = 0.38) in clinical care. In subgroups of interest, differences in the SpO2 or FiO2 values between groups were found only among patients with shock. CONCLUSIONS:In current clinical care, patients do not experience SpO2 values consistent with those predicted to result in the best outcomes for them, based on a machine learning model derived and validated in data from prior clinical trials. This lack of difference in care suggests that using evidence-based personalized oxygen saturation targets to guide oxygen administration in clinical care has the potential to improve outcomes.
RATIONALE:The Medicare Competitive Bidding Program (CBP), a policy that reduces durable medical equipment reimbursement rates through a bidding process, was expanded nationwide in 2016. Lower bid-derived prices may affect supplemental oxygen access, but little is known about the 2016 policy impact. OBJECTIVE:Evaluate the association between the 2016 implementation of CBP and supplemental oxygen use among patients with chronic obstructive pulmonary disease (COPD). METHODS:We used fee-for-service Medicare data of beneficiaries with COPD enrolled between July 1, 2009 and June 30, 2017, to conduct a single-group interrupted time series analysis of the 2016 expansion of CBP. MEASUREMENTS:Primary outcomes were measured at the ZIP-month, including the proportion of COPD beneficiaries with a new oxygen claim, and the proportion of COPD beneficiaries on supplemental oxygen that had oxygen claims discontinued. MAIN RESULTS:CBP expansion was not associated with a change in the monthly proportion of new oxygen claims at policy implementation [-0.0084 percentage points (ppt); 95% confidence interval (CI) -0.024, 0.0077], but was associated with a small decrease in monthly trend afterwards (-0.0054 ppt; 95%CI -0.0078, -0.0032). For discontinuation of oxygen claims, CBP expansion was associated with a small increase in the monthly proportion of discontinuations at policy implementation (0.24 ppt; 95%CI 0.14, 0.35), but no change in the post-policy trend (0.010 ppt; 95%CI -0.0051, 0.026). CONCLUSIONS:Medicare CBP nationwide expansion in 2016 was not associated with a clinically meaningful change in oxygen use among beneficiaries with COPD and do not support removal of supplemental oxygen from the CBP.
RATIONALE:Neighborhood socioeconomic disadvantage is associated with adverse cardiovascular outcomes, but its relationship with obstructive sleep apnea (OSA) severity and sleep-related hypoxemia is not well defined. OBJECTIVE:To assess the association of Area Deprivation Index (ADI) with OSA and major adverse cardiovascular events (MACE). METHODS:We conducted an observational cohort study of adults in a large institutional sleep registry who underwent polysomnography (PSG) or type III sleep testing. Neighborhood disadvantage was quantified using Area Deprivation Index (ADI) quintiles (ADI-Q1 least disadvantaged; ADI-Q5 most disadvantaged). Associations between ADI, OSA severity (apnea-hypopnea index [AHI]), sleep hypoxemia (percentage of sleep time with oxygen saturation<90%, T90), and incident MACE (heart failure, stroke, atrial fibrillation, coronary artery disease, or death) were assessed using multivariable models adjusted for demographics, comorbidities, smoking, and cardiovascular medications. MEASUREMENTS AND MAIN RESULTS:Among 72,443 adults (52,874 PSG;19,569 type III testing), greater neighborhood deprivation was associated with more severe sleep-related hypoxia (higher T90 and lower oxygen saturation nadir; p < 0.0001) but not with AHI. Over median follow-up of 5.6 years (PSG) and 2.8 years (type III), residence in the most disadvantaged neighborhoods was associated with increased risk of MACE or death (PSG ADI-Q5 vs Q1:HR1.22,95%CI1.13-1.33; type III ADI-Q4 vs Q1:HR1.41,95%CI1.12-1.78). In the type III cohort, hypoxia modified the association between ADI and outcomes (interaction p = 0.025). CONCLUSIONS:Neighborhood disadvantage is associated with greater sleep-related hypoxia and worse cardiovascular outcomes among patients evaluated for OSA, independent of apnea frequency. Incorporating measures of sleep-related hypoxia and neighborhood disadvantage into cardiovascular risk stratification may play a role in the identification of high-risk populations.
