Molecular Phenotypes of Acute Respiratory Distress Syndrome in the ROSE Trial Have Differential Outcomes and Gene Expression Patterns That Differ at Baseline and Longitudinally over Time.

Rationale: Two molecular phenotypes have been identified in acute respiratory distress syndrome (ARDS). In the ROSE (Reevaluation of Systemic Early Neuromuscular Blockade) trial of cisatracurium in moderate to severe ARDS, we addressed three unanswered questions: 1) Do the same phenotypes emerge in a more severe ARDS cohort with earlier recruitment; 2) Do phenotypes respond differently to neuromuscular blockade? and 3) What biological pathways most differentiate inflammatory phenotypes?Methods: We performed latent class analysis in ROSE using preenrollment clinical and protein biomarkers. In a subset of patients (n = 134), we sequenced whole-blood RNA using enrollment and Day 2 samples and performed differential gene expression and pathway analyses. Informed by the differential gene expression analysis, we measured additional plasma proteins and evaluated their abundance relative to gene expression amounts.Measurements and Main Results: In ROSE, we identified the hypoinflammatory (60.4%) and hyperinflammatory (39.6%) phenotypes with similar biological and clinical characteristics as prior studies, including higher mortality at Day 90 for the hyperinflammatory phenotype (30.3% vs. 61.6%; P < 0.0001). We observed no treatment interaction between the phenotypes and randomized groups for mortality. The hyperinflammatory phenotype was enriched for genes associated with innate immune response, tissue remodeling, and zinc metabolism at Day 0 and collagen synthesis and neutrophil degranulation at Day 2. Longitudinal changes in gene expression patterns differed dependent on survivorship. For most highly expressed genes, we observed correlations with their corresponding plasma proteins' abundance. However, for the class-defining plasma proteins in the latent class analysis, no correlation was observed with their corresponding genes' expression.Conclusions: The hyperinflammatory and hypoinflammatory phenotypes have different clinical, protein, and dynamic transcriptional characteristics. These findings support the clinical and biological potential of molecular phenotypes to advance precision care in ARDS.

Phenotyping COVID-19 respiratory failure in spontaneously breathing patients with AI on lung CT-scan.

BACKGROUND: Automated analysis of lung computed tomography (CT) scans may help characterize subphenotypes of acute respiratory illness. We integrated lung CT features measured via deep learning with clinical and laboratory data in spontaneously breathing subjects to enhance the identification of COVID-19 subphenotypes. METHODS: This is a multicenter observational cohort study in spontaneously breathing patients with COVID-19 respiratory failure exposed to early lung CT within 7 days of admission. We explored lung CT images using deep learning approaches to quantitative and qualitative analyses; latent class analysis (LCA) by using clinical, laboratory and lung CT variables; regional differences between subphenotypes following 3D spatial trajectories. RESULTS: Complete datasets were available in 559 patients. LCA identified two subphenotypes (subphenotype 1 and 2). As compared with subphenotype 2 (n = 403), subphenotype 1 patients (n = 156) were older, had higher inflammatory biomarkers, and were more hypoxemic. Lungs in subphenotype 1 had a higher density gravitational gradient with a greater proportion of consolidated lungs as compared with subphenotype 2. In contrast, subphenotype 2 had a higher density submantellar-hilar gradient with a greater proportion of ground glass opacities as compared with subphenotype 1. Subphenotype 1 showed higher prevalence of comorbidities associated with endothelial dysfunction and higher 90-day mortality than subphenotype 2, even after adjustment for clinically meaningful variables. CONCLUSIONS: Integrating lung-CT data in a LCA allowed us to identify two subphenotypes of COVID-19, with different clinical trajectories. These exploratory findings suggest a role of automated imaging characterization guided by machine learning in subphenotyping patients with respiratory failure. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04395482. Registration date: 19/05/2020.

Rapidly improving ARDS differs clinically and biologically from persistent ARDS.

BACKGROUND: Rapidly improving acute respiratory distress syndrome (RIARDS) is an increasingly appreciated subgroup of ARDS in which hypoxemia improves within 24 h after initiation of mechanical ventilation. Detailed clinical and biological features of RIARDS have not been clearly defined, and it is unknown whether RIARDS is associated with the hypoinflammatory or hyperinflammatory phenotype of ARDS. The purpose of this study was to define the clinical and biological features of RIARDS and its association with inflammatory subphenotypes. METHODS: We analyzed data from 215 patients who met Berlin criteria for ARDS (endotracheally intubated) and were enrolled in a prospective observational cohort conducted at two sites, one tertiary care center and one urban safety net hospital. RIARDS was defined according to previous studies as improvement of hypoxemia defined as (i) PaO2:FiO2 > 300 or (ii) SpO2: FiO2 > 315 on the day following diagnosis of ARDS (day 2) or (iii) unassisted breathing by day 2 and for the next 48 h (defined as absence of endotracheal intubation on day 2 through day 4). Plasma biomarkers were measured on samples collected on the day of study enrollment, and ARDS phenotypes were allocated as previously described. RESULTS: RIARDS accounted for 21% of all ARDS participants. Patients with RIARDS had better clinical outcomes compared to those with persistent ARDS, with lower hospital mortality (13% vs. 57%; p value < 0.001) and more ICU-free days (median 24 vs. 0; p value < 0.001). Plasma levels of interleukin-6, interleukin-8, and plasminogen activator inhibitor-1 were significantly lower among patients with RIARDS. The hypoinflammatory phenotype of ARDS was more common among patients with RIARDS (78% vs. 51% in persistent ARDS; p value = 0.001). CONCLUSIONS: This study identifies a high prevalence of RIARDS in a multicenter observational cohort and confirms the more benign clinical course of these patients. We report the novel finding that RIARDS is characterized by lower concentrations of plasma biomarkers of inflammation compared to persistent ARDS, and that hypoinflammatory ARDS is more prevalent among patients with RIARDS. Identification and exclusion of RIARDS could potentially improve prognostic and predictive enrichment in clinical trials.

Latent class analysis-derived subphenotypes are generalisable to observational cohorts of acute respiratory distress syndrome: a prospective study.

RATIONALE: Using latent class analysis (LCA), two subphenotypes of acute respiratory distress syndrome (ARDS) have consistently been identified in five randomised controlled trials (RCTs), with distinct biological characteristics, divergent outcomes and differential treatment responses to randomised interventions. Their existence in unselected populations of ARDS remains unknown. We sought to identify subphenotypes in observational cohorts of ARDS using LCA. METHODS: LCA was independently applied to patients with ARDS from two prospective observational cohorts of patients admitted to the intensive care unit, derived from the Validating Acute Lung Injury markers for Diagnosis (VALID) (n=624) and Early Assessment of Renal and Lung Injury (EARLI) (n=335) studies. Clinical and biological data were used as class-defining variables. To test for concordance with prior ARDS subphenotypes, the performance metrics of parsimonious classifier models (interleukin 8, bicarbonate, protein C and vasopressor-use), previously developed in RCTs, were evaluated in EARLI and VALID with LCA-derived subphenotypes as the gold-standard. RESULTS: A 2-class model best fit the population in VALID (p=0.0010) and in EARLI (p<0.0001). Class 2 comprised 27% and 37% of the populations in VALID and EARLI, respectively. Consistent with the previously described 'hyperinflammatory' subphenotype, Class 2 was characterised by higher proinflammatory biomarkers, acidosis and increased shock and worse clinical outcomes. The similarities between these and prior RCT-derived subphenotypes were further substantiated by the performance of the parsimonious classifier models in both cohorts (area under the curves 0.92-0.94). The hyperinflammatory subphenotype was associated with increased prevalence of chronic liver disease and neutropenia and reduced incidence of chronic obstructive pulmonary disease. Measurement of novel biomarkers showed significantly higher levels of matrix metalloproteinase-8 and markers of endothelial injury in the hyperinflammatory subphenotype, whereas, matrix metalloproteinase-9 was significantly lower. CONCLUSION: Previously described subphenotypes are generalisable to unselected populations of non-trauma ARDS.

The prognostic value of early measures of the ventilatory ratio in the ARDS ROSE trial.

BACKGROUND: The ventilatory ratio (VR, [minute ventilation × PaCO2]/[predicted body weight × 100 × 37.5]) is associated with mortality in ARDS. The aims of this study were to test whether baseline disease severity or neuromuscular blockade (NMB) modified the relationship between VR and mortality. METHODS: This was a post hoc analysis of the PETAL-ROSE trial, which randomized moderate-to-severe ARDS patients to NMB or control. Survival among patients with different VR trajectories or VR cutoff above and below the median was assessed by Kaplan-Meier analysis. The relationships between single-day or 48-h VR trajectories with 28- or 90-day mortality were tested by logistic regression. Randomization allocation to NMB and markers of disease severity were tested as confounders by multivariable regression and interaction term analyses. RESULTS: Patients with worsening VR trajectories had significantly lower survival compared to those with improving VR (n = 602, p < 0.05). Patients with VR > 2 (median) at day 1 had a significantly lower 90-day survival compared to patients with VR ≤ 2 (HR 1.36, 95% CI 1.10-1.69). VR at day 1 was significantly associated with 28-day mortality (OR = 1.40, 95% CI 1.15-1.72). There was no interaction between NMB and VR for 28-day mortality. APACHE-III had a significant interaction with VR at baseline for the outcome of 28-day mortality, such that the relationship between VR and mortality was stronger among patients with lower APACHE-III. There was a significant association between rising VR trajectory and mortality that was independent of NMB, baseline PaO2/FiO2 ratio and generalized markers of disease severity (Adjusted OR 1.81, 95% CI 1.28-2.84 for 28-day and OR 2.07 95% CI 1.41-3.10 for 90-day mortality). APACHE-III and NMB were not effect modifiers in the relationship between VR trajectory and mortality. CONCLUSIONS: Elevated baseline and day 1 VR were associated with higher 28-day mortality. The relationship between baseline VR and mortality was stronger among patients with lower APACHE-III. APACHE-III was not an effect modifier for the relationship between VR trajectory and mortality, so that the VR trajectory may be optimally suited for prognostication and predictive enrichment. VR was not different between patients randomized to NMB or control, indicating that VR can be utilized without correcting for NMB.

Enhanced Stress Resilience Training in Surgeons: Iterative Adaptation and Biopsychosocial Effects in 2 Small Randomized Trials.

OBJECTIVE: To determine the effects of ESRT (an iteratively adapted and tailored MBI) on perceived stress, executive cognitive function, psychosocial well-being (ie, burnout, mindfulness), and pro-inflammatory gene expression in surgical (ESRT-1) and mixed specialty (ESRT-2) PGY-1 volunteers. SUMMARY OF BACKGROUND AND DATA: Tailored MBIs have proven beneficial in multiple high-stress and high-performance populations. In surgeons, tailored MBIs have been shown to be feasible and potentially beneficial, but whether mindfulness-based cognitive training can improve perceived stress, executive function, well-being or physiological distress in surgical and nonsurgical trainees is unknown. METHODS: In 2 small single-institution randomized clinical trials, ESRT, a tailored mindfulness-based cognitive training program, was administered and iteratively adapted for first-year surgical (ESRT-1, 8 weekly, 2-hour classes, n = 44) and mixed specialty (ESRT-2, 6 weekly, 90-minute classes, n = 45) resident trainees. Primary and secondary outcomes were, respectively, perceived stress and executive function. Other prespecified outcomes were burnout (assessed via Maslach Burnout Inventory), mindfulness (assessed via Cognitive Affective Mindfulness Scale - Revised), and pro-inflammatory gene expression (assessed through the leukocyte transcriptome profile "conserved transcriptional response to adversity"). RESULTS: Neither version of ESRT appeared to affect perceived stress. Higher executive function and mindfulness scores were seen in ESRT-1, and lower emotional exhaustion and depersonalization scores in ESRT-2, at pre-/postintervention and/or 50-week follow-up (ESRT-1) or at 32-week follow-up (ESRT-2), compared to controls. Pooled analysis of both trials found ESRT-treated participants had reduced pro-inflammatory RNA expression compared to controls. CONCLUSIONS: This pilot work suggests ESRT can variably benefit executive function, burnout, and physiologic distress in PGY-1 trainees, with potential for tailoring to optimize effects.

Mesenchymal stromal cell extracellular vesicles rescue mitochondrial dysfunction and improve barrier integrity in clinically relevant models of ARDS.

Alveolar epithelial-capillary barrier disruption is a hallmark of acute respiratory distress syndrome (ARDS). Contribution of mitochondrial dysfunction to the compromised alveolar-capillary barrier in ARDS remains unclear. Mesenchymal stromal cells-derived extracellular vesicles (MSC-EVs) are considered as a cell-free therapy for ARDS. Mitochondrial transfer was shown to be important for the therapeutic effects of MSCs and MSC-EVs. Here we investigated the contribution of mitochondrial dysfunction to the injury of alveolar epithelial and endothelial barriers in ARDS and the ability of MSC-EVs to modulate alveolar-capillary barrier integrity through mitochondrial transfer.Primary human small airway epithelial and pulmonary microvascular endothelial cells and human precision cut lung slices (PCLSs) were stimulated with endotoxin or plasma samples from patients with ARDS and treated with MSC-EVs, barrier properties and mitochondrial functions were evaluated. Lipopolysaccharide (LPS)-injured mice were treated with MSC-EVs and degree of lung injury and mitochondrial respiration of the lung tissue were assessed.Inflammatory stimulation resulted in increased permeability coupled with pronounced mitochondrial dysfunction in both types of primary cells and PCLSs. Extracellular vesicles derived from normal MSCs restored barrier integrity and normal levels of oxidative phosphorylation while an extracellular vesicles preparation which did not contain mitochondria was not effective. In vivo, presence of mitochondria was critical for extracellular vesicles ability to reduce lung injury and restore mitochondrial respiration in the lung tissue.In the ARDS environment, MSC-EVs improve alveolar-capillary barrier properties through restoration of mitochondrial functions at least partially via mitochondrial transfer.

Practitioner's Guide to Latent Class Analysis: Methodological Considerations and Common Pitfalls.

Latent class analysis is a probabilistic modeling algorithm that allows clustering of data and statistical inference. There has been a recent upsurge in the application of latent class analysis in the fields of critical care, respiratory medicine, and beyond. In this review, we present a brief overview of the principles behind latent class analysis. Furthermore, in a stepwise manner, we outline the key processes necessary to perform latent class analysis including some of the challenges and pitfalls faced at each of these steps. The review provides a one-stop shop for investigators seeking to apply latent class analysis to their data.

The long shadow of childhood trauma for depression in midlife: examining daily psychological stress processes as a persistent risk pathway.

BACKGROUND: Childhood trauma (CT) increases the risk of adult depression. Buffering effects require an understanding of the underlying persistent risk pathways. This study examined whether daily psychological stress processes - how an individual interprets and affectively responds to minor everyday events - mediate the effect of CT on adult depressive symptoms. METHODS: Middle-aged women (N = 183) reported CT at baseline and completed daily diaries of threat appraisals and negative evening affect for 7 days at baseline, 9, and 18 months. Depressive symptoms were measured across the 1.5-year period. Mediation was examined using multilevel structural equation modeling. RESULTS: Reported CT predicted greater depressive symptoms over the 1.5-year time period (estimate = 0.27, s.e. = 0.07, 95% CI 0.15-0.38, p < 0.001). Daily threat appraisals and negative affect mediated the effect of reported CT on depressive symptoms (estimate = 0.34, s.e. = 0.08, 95% CI 0.22-0.46, p < 0.001). Daily threat appraisals explained more than half of this effect (estimate = 0.19, s.e. = 0.07, 95% CI 0.08-0.30, p = 0.004). Post hoc analyses in individuals who reported at least moderate severity of CT showed that lower threat appraisals buffered depressive symptoms. A similar pattern was found in individuals who reported no/low severity of CT. CONCLUSIONS: A reported history of CT acts as a latent vulnerability, exaggerating threat appraisals of everyday events, which trigger greater negative evening affect - processes that have important mental health consequences and may provide malleable intervention targets.

Effects of e-cigarette use on cigarette smoking among U.S. youth, 2004-2018.

OBJECTIVE: To determine if the declining trend in U.S. youth cigarette smoking changed after e-cigarettes were introduced, and if youth e-cigarette users would have been likely to smoke cigarettes based on psychosocial and demographic predictors of smoking. METHODS: An interrupted time series analysis was used for cross-sectional data from the 2004 to 2018 National Youth Tobacco Surveys (NYTS) to assess changes in cigarette and e-cigarette use over time. A multivariable logistic regression model used 2004-2009 NYTS data on psychosocial risk factors to predict individual-level cigarette smoking risk from 2011 to 2018. Model-predicted and actual cigarette smoking behavior were compared. RESULTS: The decline in current cigarette smoking slowed in 2014 (-0.75 [95% CI: -0.81, -0.68] to -0.26 [95% CI: -0.40, -0.12] percentage points per year). The decline in ever cigarette smoking accelerated after 2012 (-1.45 [95% CI: -1.59, -1.31] to -1.71 [95% CI: -1.75, -1.66]). Ever and current combined cigarette and/or e-cigarette use declined during 2011-2013 and increased during 2013-2014 with no significant change during 2014-2018 for either variable. The psychosocial model estimated that 69.0% of current cigarette smokers and 9.3% of current e-cigarette users (who did not smoke cigarettes) would smoke cigarettes in 2018. CONCLUSIONS: The introduction of e-cigarettes was followed by a slowing decline in current cigarette smoking, a stall in combined cigarette and e-cigarette use, and an accelerated decline in ever cigarette smoking. Traditional psychosocial risk factors for cigarette smoking suggest that e-cigarette users do not fit the traditional risk profile of cigarette smokers.

Effects of Social Media on Adolescents' Willingness and Intention to Use E-Cigarettes: An Experimental Investigation.

INTRODUCTION: This study examined the effects of experimentally manipulated social media exposure on adolescents' willingness and intention to use e-cigarettes. AIMS AND METHODS: Participants were 135 adolescents of age 13-18 (52.6% female, mean age = 15.3) in California. Participants viewed six social media posts online in a 2 (post source: peer or advertisement) × 2 (e-cigarette content exposure: heavy or light) between-subjects design. Analyses were weighted to population benchmarks. We examined adolescents' beliefs, willingness, and intention to use e-cigarettes in association with social media use intensity in daily life and with experimentally manipulated exposure to social media posts that varied by source (peer or advertisement) and content (e-cigarette heavy or light). RESULTS: Greater social media use in daily life was associated with greater willingness and intention to use e-cigarettes and more positive attitudes, greater perceived norms, and lower perceived danger of e-cigarette use (all p-values <.01). In tests of the experimental exposures, heavy (vs. light) e-cigarette content resulted in greater intention (p = .049) to use e-cigarettes and more positive attitudes (p = .019). Viewing advertisements (vs. peer-generated posts) resulted in greater willingness and intention (p-values <.01) to use e-cigarettes, more positive attitudes (p = .003), and greater norm perceptions (p = .009). The interaction effect of post source by post content was not significant for any of the outcomes (all p-values >.529). CONCLUSIONS: Greater social media use and heavier exposure to advertisements and e-cigarette content in social media posts are associated with a greater risk for e-cigarette use among adolescents. Regulatory action is needed to prohibit sponsored e-cigarette content on social media platforms used by youth. IMPLICATIONS: Adolescents who use social media intensely may be at higher risk for e-cigarette use. Even brief exposure to e-cigarette content on social media was associated with greater intention to use and more positive attitudes toward e-cigarettes. Regulatory action should be taken to prohibit sponsored e-cigarette content on social media used by young people, including posts by influencers who appeal to young people.

Menthol cigarette use in substance use disorder treatment before and after implementation of a county-wide flavoured tobacco ban.

INTRODUCTION: This study examined the impact of a San Francisco City and County ban on all flavoured tobacco products, including menthol cigarettes, among clients in residential substance use disorder (SUD) treatment. METHODS: We conducted cross-sectional surveys of clients at two residential SUD programmes before the County began enforcing the ban (n=160) and twice after enforcement began (n=102, n=120). The samples were compared on demographic characteristics, smoking status, smoking behaviours and the proportion reporting menthol as their usual cigarette. Menthol smokers were asked whether they smoked only menthol cigarettes, mostly menthol, both menthol and non-menthol or mostly non-menthol. Post-ban samples were asked about awareness of the ban and access to menthol cigarettes. RESULTS: In multivariate analyses, we found no evidence that the ban was associated with decreased number of cigarettes per day or increased readiness to quit among current smokers. However, odds were lower post-ban for reporting menthol as the usual cigarette (OR=0.80, 95% CI 0.72 to 0.90), and for smoking only menthol cigarettes (OR=0.19, 95% CI 0.18 to 0.19). Perhaps most importantly, and with the ability to influence all other findings, 50% of self-identified menthol smokers reported purchasing menthol cigarettes in San Francisco nearly 1 year after the ban was implemented. CONCLUSION: In subgroups where smoking has remained elevated, like those receiving SUD treatment, local menthol bans may have only modest impacts on smoking behaviour. Broader regional, state or national bans, that effectively restrict access to menthol products, may be needed to show stronger effects on smoking behaviour.

The Put It Out Project (POP) Facebook Intervention for Young Sexual and Gender Minority Smokers: Outcomes of a Pilot, Randomized, Controlled Trial.

INTRODUCTION: This trial investigated whether a Facebook smoking cessation intervention culturally tailored to young sexual and gender minority (SGM) smokers (versus non-tailored) would increase smoking abstinence. METHODS: Participants were 165 SGM young adult US smokers (age 18-25) recruited from Facebook in April 2018 and randomized to an SGM-tailored (POP; N = 84) or non-tailored (TSP-SGM; N = 81) intervention. Interventions delivered weekly live counseling sessions and 90 daily Facebook posts to participants in Facebook groups. Primary analyses compared POP and TSP-SGM on biochemically verified smoking abstinence (yes/no; primary outcome), self-reported 7-day point prevalence abstinence (yes/no), reduction in cigarettes per week by 50+% from baseline (yes/no), making a quit attempt during treatment (yes/no), and stage of change (precontemplation/contemplation vs. preparation/action). Supplemental analyses compared POP to two historical control groups. RESULTS: POP participants were more likely than TSP-SGM participants to report smoking abstinence at 3 (23.8% vs. 12.3%; OR = 2.50; p = .03) and 6 months (34.5% vs. 12.3%; OR = 4.06; p < .001) and reduction in smoking at 3 months (52.4% vs. 39.5%; OR = 2.11; p = .03). Biochemically verified smoking abstinence did not significantly differ between POP and TSP-SGM at 3 (OR = 2.00; p = .33) or 6 months (OR = 3.12; p = .08), potentially due to challenges with remote biochemical verification. In supplemental analyses, POP participants were more likely to report abstinence at 3 (OR = 6.82, p = .01) and 6 (OR = 2.75, p = .03) months and reduced smoking at 3 months (OR = 2.72, p = .01) than participants who received a referral to Smokefree.gov. CONCLUSIONS: This pilot study provides preliminary support for the effectiveness of a Facebook smoking cessation intervention tailored to SGM young adults. IMPLICATIONS: SGM individuals have disproportionately high smoking prevalence. It is unclear whether smoking cessation interventions culturally tailored to the SGM community are more effective than non-tailored interventions. This pilot trial found preliminary evidence that an SGM-tailored Facebook smoking cessation intervention increased reported abstinence from smoking, compared to a non-tailored intervention. TRIAL REGISTRATION: NCT03259360.

Early Plasma Matrix Metalloproteinase Profiles. A Novel Pathway in Pediatric Acute Respiratory Distress Syndrome.

RATIONALE: MMPs (Matrix metalloproteinases) and their endogenous tissue inhibitors may contribute to lung injury through extracellular matrix degradation and modulation of inflammation and fibrosis. OBJECTIVES: To test for an association between MMP pathway proteins and inflammation, endothelial dysfunction, and clinical outcomes. METHODS: We measured MMPs in plasma collected on acute respiratory distress syndrome (ARDS) Day 1 from 235 children at five hospitals between 2008 and 2017. We used latent class analysis to identify patients with distinct MMP profiles and then associated those profiles with markers of inflammation (IL-1RA, -6, -8, -10, and -18; macrophage inflammatory protein-1α and -1ß; tumor necrosis factor-α and -R2), endothelial injury (angiopoietin-2, von Willebrand factor, soluble thrombomodulin), impaired oxygenation (PaO2/FiO2 [P/F] ratio, oxygenation index), morbidity, and mortality. MEASUREMENTS AND MAIN RESULTS: In geographically distinct derivation and validation cohorts, approximately one-third of patients demonstrated an MMP profile characterized by elevated MMP-1, -2, -3, -7, and -8 and tissue inhibitor of metalloproteinase-1 and -2; and depressed active and total MMP-9. This MMP profile was associated with multiple markers of inflammation, endothelial injury, and impaired oxygenation on Day 1 of ARDS, and conferred fourfold increased odds of mortality or severe morbidity independent of the P/F ratio and other confounders (95% confidence interval, 2.1-7.6; P < 0.001). Logistic regression using both the P/F ratio and MMP profiles was superior to the P/F ratio alone in prognosticating mortality or severe morbidity (area under the receiver operating characteristic curve, 0.75; 95% confidence interval, 0.68-0.82 vs. area under the receiver operating characteristic curve, 0.66; 95% confidence interval, 0.58-0.73; P = 0.009). CONCLUSIONS: Pediatric patients with ARDS have specific plasma MMP profiles associated with inflammation, endothelial injury, morbidity, and mortality. MMPs may play a role in the pathobiology of children with ARDS.

Cigarette Smoking Cessation Intervention for Buprenorphine Treatment Patients.

Introduction: Patients receiving medication assisted therapy (MAT) for opioid use disorder have high cigarette smoking rates. Cigarette smoking interventions have had limited success. We evaluated an intervention to increase cigarette abstinence rates in patients receiving buprenorphine-assisted therapy. Methods: Cigarette smokers (N = 175; 78% male; 69% Caucasian; 20% Hispanic), recruited from a buprenorphine clinic were randomly assigned to either an extended innovative system intervention (E-ISI) or to Standard Treatment Control (STC). The E-ISI combined motivational intervention with extended treatment (long-term nicotine replacement therapy , varenicline, and extended cognitive behavioral therapy). STC received written information about quit-lines, medication, and resources. Assessments were held at baseline and 3, 6, 12, and 18 months. Seven-day biochemically verified point-prevalence cigarette abstinence was the primary outcome measure. Results: Fifty-four percent of E-ISI participants entered the extended treatment intervention; E-ISI and STC differed at 3 months on abstinence status but not at months 6, 12, and 18. E-ISI participants were more likely to attempt to quit, to have a goal of complete abstinence, and to be in a more advanced stage of change than STC participants. A higher number of cigarettes smoked and the use of cannabis in the previous 30 days predicted continued smoking. Conclusions: The E-ISI was successful in increasing motivation to quit smoking but did not result in long-term abstinence. The failure of treatments that have been efficacious in the general population to produce abstinence in patients receiving MAT of opioid use disorder suggests that harm reduction and other innovative interventions should be explored. Implications: This study demonstrates that an intervention combining motivational interviewing with an extended treatment protocol can increase cigarette quit attempts, enhance cigarette abstinence goals, and further movement through stages of change about quitting smoking in patients receiving MAT for opioid use disorder who smoke cigarettes. The intervention did not increase abstinence rates over those observed in a standard treatment control, however. The latter finding supports those of earlier investigators who also failed to find efficacy for smoking cessation in this population and who also used interventions effective in the general population. This pattern of findings suggests that patients with opioid use disorder can be motivated to change smoking behavior, but alternative and innovative approaches to cigarette smoking treatment should be studied.

Do cigarette graphic warnings encourage smokers to attend a smoking cessation programme: a quasi-experimental study.

OBJECTIVE: This study assessed whether exposure to cigarette graphic warning labels (GWLs) increased attendance to a smoking cessation programme. METHOD: From 2014 to 2016, alternating cohorts of smokers in 3 residential drug treatment programmes received either GWLs (experimental) or transparent (control) labels placed on their cigarette packs for 30 days. The primary outcome was the proportion of participants who chose to attend a smoking cessation group after the labelling period. RESULTS: The sample (N=601) was 72.6% male, with a mean age of 41.9 (SD=11.16) and included African-American (37%), White (29.4%) and Hispanic (19.6%) participants. While similar on most measures, controls were more likely to be married, had been in the treatment programme longer and registered higher on expired carbon monoxide (CO). After labelling, the proportion attending at least one cessation group was 26% in the experimental condition and 18.8% among controls. In an intent-to-treat analysis adjusting for group differences at baseline, and for 2 levels of nesting, those who received GWLs were more likely than controls to attend the smoking cessation group (OR=1.58, 95% CI 1.02 to 2.44). CONCLUSIONS: Smokers who received GWLs on their cigarette packs were more likely to attend a cessation programme. Thus, this study is one of the first to document a change in a directly observed behavioural outcome as a function of month-long exposure to cigarette pack GWLs.

The Association Between Psychiatric Disorders and Telomere Length: A Meta-Analysis Involving 14,827 Persons.

OBJECTIVE: This study examined the relationship between leukocyte telomere length (LTL), a marker of cell aging, and psychiatric disorders in adults compared with controls using meta-analytic methods. METHODS: Data were abstracted from studies examining the relationship between LTL and adult psychiatric disorders. In addition to an overall estimate of effect size, subgroup analyses and meta-regression were performed to examine whether covariates (including psychiatric diagnoses) moderated the estimate. RESULTS: A significant overall effect size showing LTL shortening was found across all psychiatric disorders (Hedge g = -0.50, p < .001). Subgroup analyses did not demonstrate significant differences in effect size based on individual covariates (psychiatric disorder, sex, age, or assay method). The meta-regression indicated that although type of disorder and, likely, age moderate the overall effect size, the heterogeneity between studies could not be explained by a model that included these variables as well as sex and assay method. Although not significantly different, posttraumatic stress disorder, anxiety disorders, and depressive disorders had comparatively larger effect sizes (-1.27, -0.53, and -0.55), and psychotic and bipolar disorders had comparatively smaller ones (-0.23 and -0.26). CONCLUSIONS: We observed a robust effect size of LTL shortening for psychiatric disorders as a whole compared with controls. The results were less straightforward regarding relative differences in the strength of this association by specific disorder. Future studies should focus on mechanisms explaining accelerated cell aging with psychiatric illness, defining directions (if any) of causality and elucidating possible differences in this association between disorders.

A Randomized Controlled Trial of Mindfulness-Based Cognitive Therapy for Treatment-Resistant Depression.

BACKGROUND: Due to the clinical challenges of treatment-resistant depression (TRD), we evaluated the efficacy of mindfulness-based cognitive therapy (MBCT) relative to a structurally equivalent active comparison condition as adjuncts to treatment-as-usual (TAU) pharmacotherapy in TRD. METHODS: This single-site, randomized controlled trial compared 8-week courses of MBCT and the Health Enhancement Program (HEP), comprising physical fitness, music therapy and nutritional education, as adjuncts to TAU pharmacotherapy for outpatient adults with TRD. The primary outcome was change in depression severity, measured by percent reduction in the total score on the 17-item Hamilton Depression Rating Scale (HAM-D17), with secondary depression indicators of treatment response and remission. RESULTS: We enrolled 173 adults; mean length of a current depressive episode was 6.8 years (SD = 8.9). At the end of 8 weeks of treatment, a multivariate analysis showed that relative to the HEP condition, the MBCT condition was associated with a significantly greater mean percent reduction in the HAM-D17 (36.6 vs. 25.3%; p = 0.01) and a significantly higher rate of treatment responders (30.3 vs. 15.3%; p = 0.03). Although numerically superior for MBCT than for HEP, the rates of remission did not significantly differ between treatments (22.4 vs. 13.9%; p = 0.15). In these models, state anxiety, perceived stress and the presence of personality disorder had adverse effects on outcomes. CONCLUSIONS: MBCT significantly decreased depression severity and improved treatment response rates at 8 weeks but not remission rates. MBCT appears to be a viable adjunct in the management of TRD.