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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. [ABSTRACT FROM AUTHOR]

Objective: Tourette's disorder (TD) and autism spectrum disorder (ASD) share clinical features and possibly an overlapping etiology. The aims of this study were to examine ASD symptom rates in participants with TD, and to characterize the relationships between ASD symptom patterns and TD, obsessive-compulsive disorder (OCD), and attention-deficit/hyperactivity disorder (ADHD).Method: Participants with TD (n = 535) and their family members (n =234) recruited for genetic studies reported TD, OCD, and ADHD symptoms and completed the Social Responsiveness Scale Second Edition (SRS), which was used to characterize ASD symptoms.Results: SRS scores in participants with TD were similar to those observed in other clinical samples but lower than in ASD samples (mean SRS total raw score = 51; SD = 32.4). More children with TD met cut-off criteria for ASD (22.8%) than adults with TD (8.7%). The elevated rate in children was primarily due to high scores on the SRS Repetitive and Restricted Behaviors (RRB) subscale. Total SRS scores were correlated with TD (r = 0.27), OCD (r = 0.37), and ADHD (r = 0.44) and were higher among individuals with OCD symptom-based phenotypes than for those with tics alone.Conclusion: Higher observed rates of ASD among children affected by TD may in part be due to difficulty in discriminating complex tics and OCD symptoms from ASD symptoms. Careful examination of ASD-specific symptom patterns (social communication vs. repetitive behaviors) is essential. Independent of ASD, the SRS may be a useful tool for identifying patients with TD with impairments in social communication that potentially place them at risk for bullying and other negative sequelae. [ABSTRACT FROM AUTHOR]

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., (© 2024. The Author(s).)

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) PaO 2 :FiO 2  > 300 or (ii) SpO2: FiO 2  > 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., (© 2024. The Author(s).)

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.

Background: In sepsis and acute respiratory distress syndrome (ARDS), heterogeneity has contributed to difficulty identifying effective pharmacotherapies. In ARDS, two molecular phenotypes (hypoinflammatory and hyperinflammatory) have consistently been identified, with divergent outcomes and treatment responses. In this study, we sought to derive molecular phenotypes in critically ill adults with sepsis, determine their overlap with previous ARDS phenotypes, and evaluate whether they respond differently to treatment in completed sepsis trials., Methods: We used clinical data and plasma biomarkers from two prospective sepsis cohorts, the Validating Acute Lung Injury biomarkers for Diagnosis (VALID) study (N=1140) and the Early Assessment of Renal and Lung Injury (EARLI) study (N=818), in latent class analysis (LCA) to identify the optimal number of classes in each cohort independently. We used validated models trained to classify ARDS phenotypes to evaluate concordance of sepsis and ARDS phenotypes. We applied these models retrospectively to the previously published Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis and Septic Shock (PROWESS-SHOCK) trial and Vasopressin and Septic Shock Trial (VASST) to assign phenotypes and evaluate heterogeneity of treatment effect., Findings: A two-class model best fit both VALID and EARLI (p<0·0001). In VALID, 804 (70·5%) of the 1140 patients were classified as hypoinflammatory and 336 (29·5%) as hyperinflammatory; in EARLI, 530 (64·8%) of 818 were hypoinflammatory and 288 (35·2%) hyperinflammatory. We observed higher plasma pro-inflammatory cytokines, more vasopressor use, more bacteraemia, lower protein C, and higher mortality in the hyperinflammatory than in the hypoinflammatory phenotype (p<0·0001 for all). Classifier models indicated strong concordance between sepsis phenotypes and previously identified ARDS phenotypes (area under the curve 0·87-0·96, depending on the model). Findings were similar excluding participants with both sepsis and ARDS. In PROWESS-SHOCK, 1142 (68·0%) of 1680 patients had the hypoinflammatory phenotype and 538 (32·0%) had the hyperinflammatory phenotype, and response to activated protein C differed by phenotype (p=0·0043). In VASST, phenotype proportions were similar to other cohorts; however, no treatment interaction with the type of vasopressor was observed (p=0·72)., Interpretation: Molecular phenotypes previously identified in ARDS are also identifiable in multiple sepsis cohorts and respond differently to activated protein C. Molecular phenotypes could represent a treatable trait in critical illness beyond the patient's syndromic diagnosis., Funding: US National Institutes of Health., Competing Interests: Declaration of interests PS reports funding from the US National Institutes of Health (NIH) and National Institute of General Medical Sciences; and consulting fees from AstraZeneca. LBW reports funding from NIH, Department of Defense (DoD), Genentech, Boehringer Ingelheim, and CSL Behring; consulting fees from Akebia Therapeutics, Santhera, Global Blood Therapeutics, and Boehringer Ingelheim; and stock options in Virtuoso Surgical. CSC reports funding from NIH; research grants from Roche Genentech and Quantum Leap Healthcare Collaborative; consulting fees from Vasomune Therapeutics, GEn1E Lifesciences, NGM Bio, Cellenkos, and Janssen; and a patent on metagenomic sequencing for sepsis diagnosis (co-recipient). MAM reports funding from Roche Genentech, Quantum Therapeutics, NIH/National Heart, Lung, and Blood Institute/National Institute of Allergy and Infectious Diseases, DoD, and California Institute for Regenerative Medicine; and consulting fees from Johnson & Johnson, Gilead Sciences, and Novartis. MMC reports funding from NIH and DoD; and intellectual property royalties from an issued patent (#11 410 777). JAR reports an investigator-initiated grant from Grifols provided to and administered by the University of British Columbia, Canadian Institutes of Health Research; three grants from the St Paul's Foundation; patents owned by the University of British Columbia related to the use of PCSK9 inhibitor(s) in sepsis and the use of vasopressin in septic shock, and by Ferring Pharmaceuticals for use of selepressin in septic shock; formerly being a founder, Director, and shareholder in Cyon Therapeutics (now closed); being a shareholder in Molecular You; receiving consulting fees in the last 3 years from SIB, Ferring Pharmaceuticals, and Par Pharmaceutical; and having been a funded member of the Data and Safety Monitoring Board of an NIH-sponsored trial of plasma in COVID-19 (PASS-IT-ON). KDL reports grants from NIH: National Institute of Diabetes and Digestive and Kidney Diseases; consulting fees from bioMérieux, UpToDate, SeaStar Medical, AM-Pharma, and Baxter; and stock or stock options in Amgen. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Importance: Reducing the duration of untreated psychosis (DUP) is essential to improving outcomes for people with first-episode psychosis (FEP). Current US approaches are insufficient to reduce DUP to international standards of less than 90 days., Objective: To determine whether population-based electronic screening in addition to standard targeted clinician education increases early detection of psychosis and decreases DUP, compared with clinician education alone., Design, Setting, and Participants: This cluster randomized clinical trial included individuals aged 12 to 30 years presenting for services between March 2015 and September 2017 at participating sites that included community mental health clinics and school support and special education services. Eligible participants were referred to the Early Diagnosis and Preventative Treatment (EDAPT) Clinic. Data analyses were performed in September and October 2019 for the primary and secondary analyses, with the exploratory subgroup analyses completed in May 2021., Interventions: All sites in both groups received targeted education about early psychosis for health care professionals. In the active screening group, clients also completed the Prodromal Questionnaire-Brief using tablets at intake; referrals were based on those scores and clinical judgment. In the group receiving treatment as usual (TAU), referrals were based on clinical judgment alone., Main Outcomes and Measures: Primary outcomes included DUP, defined as the period from full psychosis onset to the date of the EDAPT diagnostic telephone interview, and the number of individuals identified with FEP or a psychosis spectrum disorder. Exploratory analyses examined differences by site type, completion rates between conditions, and days from service entry to telephone interview., Results: Twenty-four sites agreed to participate, and 12 sites were randomized to either the active screening or TAU group. However, only 10 community clinics and 4 school sites were able to fully implement population screening and were included in the final analysis. The total potentially eligible population size within each study group was similar, with 2432 individuals entering at active screening group sites and 2455 at TAU group sites. A total of 303 diagnostic telephone interviews were completed (178 [58.7%] female individuals; mean [SD] age, 17.09 years [4.57]). Active screening sites reported a significantly higher detection rate of psychosis spectrum disorders (136 cases [5.6%], relative to 65 [2.6%]; P < .001) and referred a higher proportion of individuals with FEP and DUP less than 90 days (13 cases, relative to 4; odds ratio, 0.30; 95% CI, 0.10-0.93; P = .03). There was no difference in mean (SD) DUP between groups (active screening group, 239.0 days [207.4]; TAU group 262.3 days [170.2])., Conclusions and Relevance: In this cluster trial, population-based technology-enhanced screening across community settings detected more than twice as many individuals with psychosis spectrum disorders compared with clinical judgment alone but did not reduce DUP. Screening could identify people undetected in US mental health services. Significant DUP reduction may require interventions to reduce time to the first mental health contact., Trial Registration: ClinicalTrials.gov Identifier: NCT02841956.

Background: The ventilatory ratio (VR, [minute ventilation × PaCO 2 ]/[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 PaO 2 /FiO 2 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., (© 2022. The Author(s).)

Background: Two acute respiratory distress syndrome (ARDS) subphenotypes (hyperinflammatory and hypoinflammatory) with distinct clinical and biological features and differential treatment responses have been identified using latent class analysis (LCA) in seven individual cohorts. To facilitate bedside identification of subphenotypes, clinical classifier models using readily available clinical variables have been described in four randomised controlled trials. We aimed to assess the performance of these models in observational cohorts of ARDS., Methods: In this observational, multicohort, retrospective study, we validated two machine-learning clinical classifier models for assigning ARDS subphenotypes in two observational cohorts of patients with ARDS: Early Assessment of Renal and Lung Injury (EARLI; n=335) and Validating Acute Lung Injury Markers for Diagnosis (VALID; n=452), with LCA-derived subphenotypes as the gold standard. The primary model comprised only vital signs and laboratory variables, and the secondary model comprised all predictors in the primary model, with the addition of ventilatory variables and demographics. Model performance was assessed by calculating the area under the receiver operating characteristic curve (AUC) and calibration plots, and assigning subphenotypes using a probability cutoff value of 0·5 to determine sensitivity, specificity, and accuracy of the assignments. We also assessed the performance of the primary model in EARLI using data automatically extracted from an electronic health record (EHR; EHR-derived EARLI cohort). In Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE; n=2813), a multinational, observational ARDS cohort, we applied a custom classifier model (with fewer variables than the primary model) to determine the prognostic value of the subphenotypes and tested their interaction with the positive end-expiratory pressure (PEEP) strategy, with 90-day mortality as the dependent variable., Findings: The primary clinical classifier model had an area under receiver operating characteristic curve (AUC) of 0·92 (95% CI 0·90-0·95) in EARLI and 0·88 (0·84-0·91) in VALID. Performance of the primary model was similar when using exclusively EHR-derived predictors compared with manually curated predictors (AUC=0·88 [95% CI 0·81-0·94] vs 0·92 [0·88-0·97]). In LUNG SAFE, 90-day mortality was higher in patients assigned the hyperinflammatory subphenotype than in those with the hypoinflammatory phenotype (414 [57%] of 725 vs 694 [33%] of 2088; p<0·0001). There was a significant treatment interaction with PEEP strategy and ARDS subphenotype (p=0·041), with lower 90-day mortality in the high PEEP group of patients with the hyperinflammatory subphenotype (hyperinflammatory subphenotype: 169 [54%] of 313 patients in the high PEEP group vs 127 [62%] of 205 patients in the low PEEP group; hypoinflammatory subphenotype: 231 [34%] of 675 patients in the high PEEP group vs 233 [32%] of 734 patients in the low PEEP group)., Interpretation: Classifier models using clinical variables alone can accurately assign ARDS subphenotypes in observational cohorts. Application of these models can provide valuable prognostic information and could inform management strategies for personalised treatment, including application of PEEP, once prospectively validated., Funding: US National Institutes of Health and European Society of Intensive Care Medicine., Competing Interests: Declaration of interests MC has a patent (ARCD P0535US.P2) pending to the University of Chicago (IL, USA) related to clinical deterioration risk prediction algorithms for patients admitted to hospital. MAM reports grants from Roche/Genentech, and personal fees from Johnson and Johnson, Novartis Pharmaceuticals, Gilead Pharmaceuticals, and Pliant Therapeutics, outside the submitted work. LBW reports grants and personal fees from Boehringer Ingelheim, outside the submitted work; grants from Genentech and CSL Behring, outside the submitted work; and personal fees from Merck, Citius, Quark, and Foresee, outside the submitted work. JGL reports personal fees from GlaxoSmithKline and Baxter, outside of the submitted work. GB reports grants and personal fees from Draeger Medical, and personal fees from Ge Healthcare, Hamilton Medical, and Flowmeter SPA, outside the submitted work. CSC reports grants and personal fees from Roche/Genentech and Bayer, outside the submitted work; personal fees from Quark Pharmaceuticals, Gen1e Life Sciences, and Vasomune, outside the submitted work; and grants from Quantum Leap Healthcare Collaborative, outside the submitted work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Previous latent class analysis of adults with acute respiratory distress syndrome (ARDS) identified two phenotypes, distinguished by the degree of inflammation. We aimed to identify phenotypes in children with ARDS in whom developmental differences might be important, using a latent class analysis approach similar to that used in adults., Methods: This study was a secondary analysis of data aggregated from the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) clinical trial and the Genetic Variation and Biomarkers in Children with Acute Lung Injury (BALI) ancillary study. We used latent class analysis, which included demographic, clinical, and plasma biomarker variables, to identify paediatric ARDS (PARDS) phenotypes within a cohort of children included in the RESTORE and BALI studies. The association of phenotypes with clinically relevant outcomes and the performance of paediatric data in adult ARDS classification algorithms were also assessed., Findings: 304 children with PARDS were included in this secondary analysis. Using latent class analysis, a two-class model was a better fit for the cohort than a one-class model (p<0·001). Latent class analysis identified two classes: class 1 (181 [60%] of 304 patients with PARDS) and class 2 (123 [40%] of 304 patients with PARDS), referred to as phenotype 1 and 2 hereafter. Phenotype 2 was characterised by higher concentrations of inflammatory biomarkers, a higher incidence of vasopressor use, and more frequent diagnosis of sepsis, consistent with the adult hyperinflammatory phenotype. All levels of severity of PARDS were observed across both phenotypes. Children with the hyperinflammatory phenotype (phenotype 2) had worse clinical outcomes than those with the hypoinflammatory phenotype (phenotype 1), with a longer duration of mechanical ventilation (median 10·0 days [IQR 6·3-21·0] for phenotype 2 vs 6·6 days [4·1-10·8] for phenotype 1, p<0·0001), and higher incidence of mortality (17 [13·8%] of 123 patients vs four [2·2%] of 181 patients, p=0·0001). When using adult phenotype classification algorithms in children, the soluble tumour necrosis factor receptor-1 (sTNFr1), vasopressor use, and interleukin (IL)-6 variables gave an area under the curve (AUC) of 0·956, and the sTNFr1, vasopressor use, and IL-8 variables gave an AUC of 0·954, compared with the gold standard of latent class analysis., Interpretation: Latent class analysis identified two phenotypes in children with ARDS with characteristics similar to those in adults, including worse outcomes among patients with the hyperinflammatory phenotype. PARDS phenotypes should be considered in design and analysis of future clinical trials in children., Funding: US National Institutes of Health., Competing Interests: Declaration of interests MKD, MZ, MAQC, AS, KLD, and HF report grants from the US National Institutes of Health. CSC reports grants from the US National Institutes of Health, Roche/Genentech, Bayer, and Quantum Leap Healthcare Collaborative; and consultancy fees from Quark Pharmaceuticals, Prometic, Gen1e Life Sciences, and Vasomune. MWQ reports consultancy fees from Mitchell Leeds, Tanoury, Nauts, and McKinney and Barbarino. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Conflict of interest: J. Dutra Silva has nothing to disclose. Conflict of interest: Y. Su has nothing to disclose. Conflict of interest: C.S. Calfee reports grants from NIH, during the conduct of the study; grants and personal fees for consultancy from Roche/Genentech and Bayer, personal fees for advisory board work from Quark Pharmaceuticals and Prometic, personal fees for consultancy from Gen1e Life Sciences and Vasomune, outside the submitted work. Conflict of interest: K.L. Delucchi has nothing to disclose. Conflict of interest: D. Weiss has nothing to disclose. Conflict of interest: D.F. McAuley reports personal fees from consultancy for GlaxoSmithKline, Boehringer Ingelheim and Bayer, outside the submitted work; his institution has received grants from the UK NIHR, Wellcome Trust and others; has a patent issued to his institution for a treatment for ARDS; and is a Director of Research for the Intensive Care Society and NIHR EME Programme Director. Conflict of interest: C. O'Kane reports grants from Wellcome Trust, MRC and NI HSC R& D, outside the submitted work, and that her spouse has received consultancy fees from GlaxoSmithKline, Boehringer Ingelheim and Bayer. Conflict of interest: A.D. Krasnodembskaya reports grants from Medical Research Council, UK, during the conduct of the study., (Copyright ©ERS 2021.)

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.

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., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Health behavior theorists and prevention researchers use a variety of measures of adolescent and young adult (AYA) risk and benefit perceptions to predict tobacco-use and marijuana-use behaviors. However, studies have not examined whether and how perception measures that ask about likelihood of more general outcomes such as "harm" versus ask about specific risk or benefit outcomes compare or whether they differentially predict AYA willingness to use if one of your best friends were to offer it and intentions to use in the next year; and if these measures have differential ability to predict actual use of tobacco and marijuana. We used data from a prospective cohort of California AYAs to create and test new scales to measure perceptions of specific health and social outcomes related to risks (e.g., smell bad) and benefits (e.g., look cool) related to tobacco and marijuana, and then addressed three questions: (1) Whether and how measures of perceptions of specific social and health risks and benefits (for our purposes "specific measures") and measures of perceived general harm are differentially associated with measures of willingness, social norms, and intentions to use? (2) Are specific versus general measures differentially associated with and predictive of tobacco and cannabis use behavior? (3) Are specific perceptions measures differentially predictive of behavior compared to measures of willingness, social norms, and behavioral intentions? Our results demonstrate that to better predict AYA tobacco and marijuana use, measures that address general outcomes, such as harmfulness, as well as willingness and behavioral intention should be used. We also found that measures of specific perceived risks (short-term, long-term, social) and benefits were unrelated and correlated differently with different products. For example, adolescents perceived both risks and benefits from using products like e-cigarettes, and perceived greater risk from smokeless tobacco compared to combustible cigarettes. These findings indicate that measures of specific perceived social and health outcomes can be useful to discern nuanced differences in motivation for using different substances. Study implications are important for survey dimension-reduction and assessing relationships among perceptions, motivations, and use of tobacco and marijuana products., Competing Interests: Competing interests The authors declare no competing interests.

Background: In acute respiratory distress syndrome (ARDS) unrelated to COVID-19, two phenotypes, based on the severity of systemic inflammation (hyperinflammatory and hypoinflammatory), have been described. The hyperinflammatory phenotype is known to be associated with increased multiorgan failure and mortality. In this study, we aimed to identify these phenotypes in COVID-19-related ARDS., Methods: In this prospective observational study done at two UK intensive care units, we recruited patients with ARDS due to COVID-19. Demographic, clinical, and laboratory data were collected at baseline. Plasma samples were analysed for interleukin-6 (IL-6) and soluble tumour necrosis factor receptor superfamily member 1A (TNFR1) using a novel point-of-care assay. A parsimonious regression classifier model was used to calculate the probability for the hyperinflammatory phenotype in COVID-19 using IL-6, soluble TNFR1, and bicarbonate levels. Data from this cohort was compared with patients with ARDS due to causes other than COVID-19 recruited to a previous UK multicentre, randomised controlled trial of simvastatin (HARP-2)., Findings: Between March 17 and April 25, 2020, 39 patients were recruited to the study. Median ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air (PaO 2 /FiO 2 ) was 18 kpa (IQR 15-21) and acute physiology and chronic health evaluation II score was 12 (10-16). 17 (44%) of 39 patients had died by day 28 of the study. Compared with survivors, patients who died were older and had lower PaO 2 /FiO 2 . The median probability for the hyperinflammatory phenotype was 0·03 (IQR 0·01-0·2). Depending on the probability cutoff used to assign class, the prevalence of the hyperinflammatory phenotype was between four (10%) and eight (21%) of 39, which is lower than the proportion of patients with the hyperinflammatory phenotype in HARP-2 (186 [35%] of 539). Using the Youden index cutoff (0·274) to classify phenotype, five (63%) of eight patients with the hyperinflammatory phenotype and 12 (39%) of 31 with the hypoinflammatory phenotype died. Compared with matched patients recruited to HARP-2, levels of IL-6 were similar in our cohort, whereas soluble TNFR1 was significantly lower in patients with COVID-19-associated ARDS., Interpretation: In this exploratory analysis of 39 patients, ARDS due to COVID-19 was not associated with higher systemic inflammation and was associated with a lower prevalence of the hyperinflammatory phenotype than that observed in historical ARDS data. This finding suggests that the excess mortality observed in COVID-19-related ARDS is unlikely to be due to the upregulation of inflammatory pathways described by the parsimonious model., Funding: US National Institutes of Health, Innovate UK, and Randox., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Using latent class analysis (LCA) in five randomised controlled trial (RCT) cohorts, two distinct phenotypes of acute respiratory distress syndrome (ARDS) have been identified: hypoinflammatory and hyperinflammatory. The phenotypes are associated with differential outcomes and treatment response. The objective of this study was to develop parsimonious models for phenotype identification that could be accurate and feasible to use in the clinical setting., Methods: In this retrospective study, three RCT cohorts from the National Lung, Heart, and Blood Institute ARDS Network (ARMA, ALVEOLI, and FACTT) were used as the derivation dataset (n=2022), from which the machine learning and logistic regression classifer models were derived, and a fourth (SAILS; n=715) from the same network was used as the validation test set. LCA-derived phenotypes in all of these cohorts served as the reference standard. Machine-learning algorithms (random forest, bootstrapped aggregating, and least absolute shrinkage and selection operator) were used to select a maximum of six important classifier variables, which were then used to develop nested logistic regression models. Only cases with complete biomarker data in the derivation dataset were used for variable selection. The best logistic regression models based on parsimony and predictive accuracy were then evaluated in the validation test set. Finally, the models' prognostic validity was tested in two external ARDS clinical trial datasets (START and HARP-2) by assessing mortality at days 28, 60, and 90 and ventilator-free days to day 28., Findings: The six most important classifier variables were interleukin (IL)-8, IL-6, protein C, soluble tumour necrosis factor receptor 1, bicarbonate, and vasopressor use. From the nested models, three-variable (IL-8, bicarbonate, and protein C) and four-variable (3-variable plus vasopressor use) models were adjudicated to be the best performing. In the validation test set, both models showed good accuracy (AUC 0·94 [95% CI 0·92-0·95] for the three-variable model and 0·95 [95% CI 0·93-0·96] for the four-variable model) against LCA classifications. As with LCA-derived phenotypes, the hyperinflammatory phenotype as identified by the classifier model was associated with higher mortality at day 90 (87 [39%] of 223 patients vs 112 [23%] of 492 patients; p<0·0001) and fewer ventilator-free days (median 14 days [IQR 0-22] vs 22 days [0-25]; p<0·0001). In the external validation datasets, three-variable models developed in the derivation dataset identified two phenotypes with distinct clinical features and outcomes consistent with previous findings, including differential survival with simvastatin versus placebo in HARP-2 (p=0·023 for survival at 28 days)., Interpretation: ARDS phenotypes can be accurately identified with parsimonious classifier models using three or four variables. Pending the development of real-time testing for key biomarkers and prospective validation, these models could facilitate identification of ARDS phenotypes to enable their application in clinical trials and practice., Funding: National Institutes of Health., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: Specialty addiction programs treat people who are addicted to alcohol, opioids, stimulants, and other drugs. This study identified the proportion of addiction program clients who received tobacco-related services and factors associated with receipt of such services., Methods: In 2015 and 2016, clients (N=2,119) in 24 programs were surveyed for receipt of services aligning with three of the five As of tobacco cessation: ask, advise, assist. Multivariate analyses examined factors associated with receipt of each service., Results: Most clients (76%) were asked about smoking. Among smokers (N=1,630), 53% were advised to quit, 41% received counseling, 26% received cessation medication, and 17% received counseling and medication. Clients were more likely to receive tobacco-related services if they wanted help quitting smoking or were enrolled in programs with tobacco-free grounds., Conclusions: These correlational findings suggest that increasing client motivation to quit and implementing tobacco-free policies on the grounds of treatment centers may increase tobacco-related services in addiction treatment.

Background: Treatment with bone-marrow-derived mesenchymal stromal cells (MSCs) has shown benefits in preclinical models of acute respiratory distress syndrome (ARDS). Safety has not been established for administration of MSCs in critically ill patients with ARDS. We did a phase 2a trial to assess safety after administration of MSCs to patients with moderate to severe ARDS., Methods: We did a prospective, double-blind, multicentre, randomised trial to assess treatment with one intravenous dose of MSCs compared with placebo. We recruited ventilated patients with moderate to severe ARDS (ratio of partial pressure of oxygen to fractional inspired oxygen <27 kPa and positive end-expiratory pressure [PEEP] ≥8 cm H 2 O) in five university medical centres in the USA. Patients were randomly assigned 2:1 to receive either 10 × 10 6 /kg predicted bodyweight MSCs or placebo, according to a computer-generated schedule with a variable block design and stratified by site. We excluded patients younger than 18 years, those with trauma or moderate to severe liver disease, and those who had received cancer treatment in the previous 2 years. The primary endpoint was safety and all analyses were done by intention to treat. We also measured biomarkers in plasma. MSC viability was tested in a post-hoc analysis. This trial is registered with ClinicalTrials.gov, number NCT02097641., Findings: From March 24, 2014, to Feb 9, 2017 we screened 1038 patients, of whom 60 were eligible for and received treatment. No patient experienced any of the predefined MSC-related haemodynamic or respiratory adverse events. One patient in the MSC group died within 24 h of MSC infusion, but death was judged to be probably unrelated. 28-day mortality did not differ between the groups (30% in the MSC group vs 15% in the placebo group, odds ratio 2·4, 95% CI 0·5-15·1). At baseline, the MSC group had numerically higher mean scores than the placebo group for Acute Physiology and Chronic Health Evaluation III (APACHE III; 104 [SD 31] vs 89 [33]), minute ventilation (11·1 [3·2] vs 9·6 [2·4] L/min), and PEEP (12·4 [3·7] vs 10·8 [2·6] cm H 2 O). After adjustment for APACHE III score, the hazard ratio for mortality at 28 days was 1·43 (95% CI 0·40-5·12, p=0·58). Viability of MSCs ranged from 36% to 85%., Interpretation: One dose of intravenous MSCs was safe in patients with moderate to severe ARDS. Larger trials are needed to assess efficacy, and the viability of MSCs must be improved., Funding: National Heart, Lung, and Blood Institute., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: Sexual and gender minority (SGM) individuals are more likely to smoke than are non-SGM individuals. It is unclear whether smoking cessation interventions for young adults are effective in the SGM population. The purpose of this study was to compare smoking cessation, other health risk behaviors, and intervention usability between SGM and non-SGM young adult smokers participating in a digital smoking cessation intervention trial., Methods: Young adult smokers ( N = 500; 135 SGM) were assigned to a 90-day Facebook smoking cessation intervention (treatment) or referred to Smokefree.gov (control). Intervention participants were assigned to private Facebook groups tailored to their readiness to quit smoking. Participants reported their smoking status and other health risk behaviors at baseline, 3, 6, and 12 months. Usability of the intervention (i.e., perceptions of the intervention and treatment engagement) was assessed in the intervention group at 3 months., Results: Smoking cessation and intervention usability did not significantly differ between SGM participants and non-SGM participants. A greater proportion of SGM participants were at high risk for physical inactivity over the 12-month follow-up period (odds ratio [OR] = 1.55, p = .005)., Conclusion: SGM and non-SGM young adult smokers did not differ in their smoking cessation rates, perceptions of, or engagement in a digital intervention. Health risk behavior patterns were mostly similar; however, the disparity in physical activity between SGM and non-SGM smokers widened over time. Tailored interventions for SGM young adult smokers could increase focus on SGM experiences that can underlie multiple health risk behaviors, such as discrimination and the normativity of smoking. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Purpose: Alcohol use during pregnancy is a significant public health concern. Nearly all U.S. states have enacted policies targeting alcohol use during pregnancy, but there has been little research examining their impact, particularly across racial/ethnic groups. Methods: Using data from the Behavioral Risk Factor Surveillance System and about eight state-level, pregnancy-specific alcohol policies from 1985 to 2016, the aim of this study was to examine the differential effects of these policies on drinking among pregnant women by race/ethnicity. Results: We found evidence of differential effects for priority treatment, prohibitions on criminal prosecution, and civil commitment policies. In relation to priority treatment policies, effects benefited versus harmed different racial/ethnic groups depending on whether the priority treatment policies were for pregnant women only or if they gave priority to both pregnant women and pregnant women with children. Conclusions: Findings from this study suggest that benefits and harms from these policies do not appear to be equitably distributed across different racial/ethnic groups. Research considering the impact of alcohol/pregnancy policies should consider differential effects by race/ethnicity., Competing Interests: No competing financial interests exist.

This study compares the effectiveness of approaches used to recruit a diverse sample for a randomized clinical trial for Hoarding Disorder (HD) in the San Francisco Bay Area. Of the 632 individuals who inquired about the study, 313 were randomized and 231 completed treatment. Most participants heard about the study via flyering (N = 161), followed by advocacy groups (N = 113), word of mouth (N = 84), health care professionals (N = 78), online (N = 68), and media (N = 11). However, those that heard about the study via advertising methods, such as flyers, were less likely to complete the study, p = .01, while those recruited via advocacy groups were most likely to be randomized, p = .03. No source proved more effective in recruiting underrepresented groups such as men, p = .60; non-whites, p = .49; or Hispanics, p = .97. Advertising recruited the youngest individuals, p < 0.001, and word of mouth was most likely to recruit unemployed, disabled, or retired individuals, p = .01. Thus, results suggest an ongoing multimodal approach is likely to be most effective in both soliciting and retaining a diverse sample. Future studies should compare recruitment methods across greater geographical regions too, as well as in terms of financial and human costs.

Purpose: Using latent class analysis (LCA), we have consistently identified two distinct subphenotypes in four randomized controlled trial cohorts of ARDS. One subphenotype has hyper-inflammatory characteristics and is associated with worse clinical outcomes. Further, within three negative clinical trials, we observed differential treatment response by subphenotype to randomly assigned interventions. The main purpose of this study was to identify ARDS subphenotypes in a contemporary NHLBI Network trial of infection-associated ARDS (SAILS) using LCA and to test for differential treatment response to rosuvastatin therapy in the subphenotypes., Methods: LCA models were constructed using a combination of biomarker and clinical data at baseline in the SAILS study (n = 745). LCA modeling was then repeated using an expanded set of clinical class-defining variables. Subphenotypes were tested for differential treatment response to rosuvastatin., Results: The two-class LCA model best fit the population. Forty percent of the patients were classified as the "hyper-inflammatory" subphenotype. Including additional clinical variables in the LCA models did not identify new classes. Mortality at day 60 and day 90 was higher in the hyper-inflammatory subphenotype. No differences in outcome were observed between hyper-inflammatory patients randomized to rosuvastatin therapy versus placebo., Conclusions: LCA using a two-subphenotype model best described the SAILS population. The subphenotypes have features consistent with those previously reported in four other cohorts. Addition of new class-defining variables in the LCA model did not yield additional subphenotypes. No treatment effect was observed with rosuvastatin. These findings further validate the presence of two subphenotypes and demonstrate their utility for patient stratification in ARDS.

Background: Precision medicine approaches that target patients on the basis of disease subtype have transformed treatment approaches to cancer, asthma, and other heterogeneous syndromes. Two distinct subphenotypes of acute respiratory distress syndrome (ARDS) have been identified in three US-based clinical trials, and these subphenotypes respond differently to positive end-expiratory pressure and fluid management. We aimed to investigate whether these subphenotypes exist in non-US patient populations and respond differently to pharmacotherapies., Methods: HARP-2 was a multicentre, randomised controlled trial of simvastatin (80 mg) versus placebo done in general intensive care units (ICUs) at 40 hospitals in the UK and Ireland within 48 h of onset of ARDS. The primary outcome was ventilator-free days, and secondary outcomes included non-pulmonary organ failure-free days and mortality. In a secondary analysis of HARP-2, we applied latent class analysis to baseline data without consideration of outcomes to identify subphenotypes, and we compared clinical outcomes across subphenotypes and treatment groups., Findings: 540 patients were recruited to HARP-2. One patient withdrew consent for the use of their data, so data from 539 patients were analysed. In our secondary analysis, a two-class (two subphenotype) model was an improvement over a one-class model (p<0·0001), with 353 (65%) patients in the hypoinflammatory subphenotype group and 186 (35%) in the hyperinflammatory subphenotype group. Additional classes did not improve model fit. Clinical and biological characteristics of the two subphenotypes were similar to previous studies. Patients with the hyperinflammatory subphenotype had fewer ventilator-free days (median 2 days [IQR 0-17] vs 18 [IQR 0-23]; p<0·0001), fewer non-pulmonary organ failure-free days (15 [0-25] vs 27 [21-28]; p<0·0001), and higher 28-day mortality (73 [39%] vs 59 [17%]; p<0·0001) than did those with the hypoinflammatory subphenotype. Although HARP-2 found no difference in 28-day survival between placebo and simvastatin, significantly different survival was identified across patients stratified by treatment and subphenotype (p<0·0001). Specifically, within the hyperinflammatory subphenotype, patients treated with simvastatin had significantly higher 28-day survival than did those given placebo (p=0·008). A similar pattern was observed for 90-day survival., Interpretation: Two subphenotypes of ARDS were identified in the HARP-2 cohort, with distinct clinical and biological features and disparate clinical outcomes. The hyperinflammatory subphenotype had improved survival with simvastatin compared with placebo. These findings support further pursuit of predictive enrichment strategies in critical care clinical trials., Funding: UK Efficacy and Mechanism Evaluation Programme and National Institutes of Health., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

The combined use of opioid and benzodiazepine medications increases the risk of hazardous effects, such as respiratory depression. Although recent increases in outpatient use of opioid prescriptions have been documented, there are limited data regarding rates and correlates of combined opioid and benzodiazepines among adults in outpatient settings. Our objective was to examine annual trends in outpatient visits including opioids, benzodiazepines, and their combination among adults as well as clinical and demographic correlates. We used data from the 1993-2014 National Ambulatory Medical Care Survey (NAMCS) among non-elderly (i.e., ages 18-64 years) adults to examine the probability of a visit including an opioid, benzodiazepine, or their combination, in addition to clinical and demographic correlates. From 1993 to 2014, benzodiazepines-with-opioids visits increased from 9.8 to 62.5 (OR = 9.23, 95% CI = 5.45-15.65) per 10,000 visits. Highest-represented groups among benzodiazepines-with-opioids visits were older (50-64 years) (49.1%), white (88.8%), commercially insured (58.0%) patients during their first visit (87.6%) to a primary-care physician (41.9%). We identified a significant increase in the outpatient co-prescription of opioids and benzodiazepines, notably among adults aged 50-64 years during primary-care visits. Educational and policy changes to provide alternatives to benzodiazepine-with-opioid co-prescription and limiting opioid prescription to pain specialists may reduce rates of this potentially hazardous combination.

This investigation is a secondary analysis of demographic, smoking, and depression information in a global sample of Spanish- and English-speaking smokers who participated in a series of randomized controlled smoking cessation trials conducted via the Internet. The final sample consisted of 17,579 smokers from 157 countries. Smoking profiles were similar across languages and world regions and consistent with characteristics of participants in traditional smoking cessation studies. Participants were predominantly Spanish-speakers, evenly divided between men and women and relatively few indicated using traditional smoking cessation methods (e.g., groups or medication). This study demonstrates that substantial numbers of smokers from numerous countries seek Web-based smoking cessation resources and adds to the growing support for Web-assisted tobacco interventions as an additional tool to address the need for global smoking cessation efforts.