Causes and attributable fraction of death from ARDS in inflammatory phenotypes of sepsis.

BACKGROUND: Hypoinflammatory and hyperinflammatory phenotypes have been identified in both Acute Respiratory Distress Syndrome (ARDS) and sepsis. Attributable mortality of ARDS in each phenotype of sepsis is yet to be determined. We aimed to estimate the population attributable fraction of death from ARDS (PAFARDS) in hypoinflammatory and hyperinflammatory sepsis, and to determine the primary cause of death within each phenotype. METHODS: We studied 1737 patients with sepsis from two prospective cohorts. Patients were previously assigned to the hyperinflammatory or hypoinflammatory phenotype using latent class analysis. The PAFARDS in patients with sepsis was estimated separately in the hypo and hyperinflammatory phenotypes. Organ dysfunction, severe comorbidities, and withdrawal of life support were abstracted from the medical record in a subset of patients from the EARLI cohort who died (n = 130/179). Primary cause of death was defined as the organ system that most directly contributed to death or withdrawal of life support. RESULTS: The PAFARDS was 19% (95%CI 10,28%) in hypoinflammatory sepsis and, 14% (95%CI 6,20%) in hyperinflammatory sepsis. Cause of death differed between the two phenotypes (p < 0.001). Respiratory failure was the most common cause of death in hypoinflammatory sepsis, whereas circulatory shock was the most common cause in hyperinflammatory sepsis. Death with severe underlying comorbidities was more frequent in hypoinflammatory sepsis (81% vs. 67%, p = 0.004). CONCLUSIONS: The PAFARDS is modest in both phenotypes whereas primary cause of death among patients with sepsis differed substantially by phenotype. This study identifies challenges in powering future clinical trials to detect changes in mortality outcomes among patients with sepsis and ARDS.

Distinct patterns of cigarette smoking intensity and other substance use among women who experience housing instability.

BACKGROUND: Recent insights into substance use cessation suggest that outcomes short of long-term abstinence are clinically meaningful and may offer more realistic incremental goals, particularly for highly vulnerable individuals. With the goal of informing tobacco treatment programs, we examined distinct patterns of cigarette smoking and their association with the ongoing use of other substances in women who experience housing instability. METHODS: We recruited participants from a longitudinal study of women experiencing housing instability. Between June 2017 and January 2019, participants completed six monthly survey interviews regarding social conditions and the use of multiple substances. We examined associations between cigarette smoking intensity, including number of cigarettes smoked per day, heavy smoking, and an increase in number of cigarettes smoked from the previous 30-days, and other substance use in the past 7-days. RESULTS: Of the 243 participants, 69 % were current smokers and 58 % were daily smokers. Number of cigarettes smoked per day (Adjusted odds ratio [AOR] 1.02, 95 % CI 1.00-1.03), heavy cigarette smoking, compared to none or light smoking (AOR 2.02, 95 % CI 1.46-2.79), and an increase in number of cigarettes smoked from the previous 30-days (AOR 1.06, 95 % CI 1.01-1.12) were all significantly associated with methamphetamine use in the past 7-days. Associations with other substance use were not as strong. CONCLUSIONS: In a sample of unstably housed women, where almost half used multiple substances, methamphetamine use was associated with higher cigarette smoking intensity. Our findings highlight a potential role for integrating tobacco and methamphetamine use treatment to reduce tobacco use among unstably housed women.

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.

Identification of a hyperinflammatory sepsis phenotype using protein biomarker and clinical data in the ProCESS randomized trial.

Sepsis is a heterogeneous syndrome and phenotypes have been proposed using clinical data. Less is known about the contribution of protein biomarkers to clinical sepsis phenotypes and their importance for treatment effects in randomized trials of resuscitation. The objective is to use both clinical and biomarker data in the Protocol-Based Care for Early Septic Shock (ProCESS) randomized trial to determine sepsis phenotypes and to test for heterogeneity of treatment effect by phenotype comparing usual care to protocolized early, goal-directed therapy(EGDT). In this secondary analysis of a subset of patients with biomarker sampling in the ProCESS trial (n = 543), we identified sepsis phenotypes prior to randomization using latent class analysis of 20 clinical and biomarker variables. Logistic regression was used to test for interaction between phenotype and treatment arm for 60-day inpatient mortality. Among 543 patients with severe sepsis or septic shock in the ProCESS trial, a 2-class model best fit the data (p = 0.01). Phenotype 1 (n = 66, 12%) had increased IL-6, ICAM, and total bilirubin and decreased platelets compared to phenotype 2 (n = 477, 88%, p < 0.01 for all). Phenotype 1 had greater 60-day inpatient mortality compared to Phenotype 2 (41% vs 16%; p < 0.01). Treatment with EGDT was associated with worse 60-day inpatient mortality compared to usual care (58% vs. 23%) in Phenotype 1 only (p-value for interaction = 0.05). The 60-day inpatient mortality was similar comparing EGDT to usual care in Phenotype 2 (16% vs. 17%). We identified 2 sepsis phenotypes using latent class analysis of clinical and protein biomarker data at randomization in the ProCESS trial. Phenotype 1 had increased inflammation, organ dysfunction and worse clinical outcomes compared to phenotype 2. Response to EGDT versus usual care differed by phenotype.

Policy and Practice Changes Associated with a Tobacco-Free Initiative in Residential Substance Use Disorder Treatment.

A California-sponsored, 18-month, tobacco-free intervention in residential substance use disorder (SUD) programs was associated with increases in tobacco-free grounds and tobacco-related client services. The current study examined whether positive results would be replicated in 11 programs participating subsequently. Program directors (N = 11) completed surveys of tobacco-related policies pre- and post-intervention. Pre- (n = 163) and post-intervention (n = 128) cross-sectional staff surveys examined tobacco-related training, beliefs, practices, smoking policy, and smoking status. Directors reported increases in tobacco-free grounds (from 3 to 8 programs), tobacco-related staff training (1 to 10 programs), tobacco cessation staff services (1 to 9 programs) and nicotine replacement therapy (NRT) provision (6 to 10 programs). At post-intervention, staff were more likely to report smoke-free workplaces (p = 0.008), positive beliefs about treating tobacco use (p = 0.017) and less likely to report current smoking (p = 0.003). Clinical staff were more likely to report tobacco-related training receipt (p = 0.001), program-level NRT provision (p = 0.009) and conducting tobacco-related client services (p < 0.0001) post-intervention. Findings of increases in tobacco-free grounds and tobacco cessation client services corroborated prior results. These and the additional finding of decreases in staff smoking strengthen evidence that initiatives supporting tobacco-free policies can be successfully implemented in SUD treatment.

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.

Novel subtypes of severe COVID-19 respiratory failure based on biological heterogeneity: a secondary analysis of a randomized controlled trial.

BACKGROUND: Despite evidence associating inflammatory biomarkers with worse outcomes in hospitalized adults with COVID-19, trials of immunomodulatory therapies have met with mixed results, likely due in part to biological heterogeneity of participants. Latent class analysis (LCA) of clinical and protein biomarker data has identified two subtypes of non-COVID acute respiratory distress syndrome (ARDS) with different clinical outcomes and treatment responses. We studied biological heterogeneity and clinical outcomes in a multi-institutional platform randomized controlled trial of adults with severe COVID-19 hypoxemic respiratory failure (I-SPY COVID). METHODS: Clinical and plasma protein biomarker data were analyzed from 400 trial participants enrolled from September 2020 until October 2021 with severe COVID-19 requiring ≥ 6 L/min supplemental oxygen. Seventeen hypothesis-directed protein biomarkers were measured at enrollment using multiplex Luminex panels or single analyte enzyme linked immunoassay methods (ELISA). Biomarkers and clinical variables were used to test for latent subtypes and longitudinal biomarker changes by subtype were explored. A validated parsimonious model using interleukin-8, bicarbonate, and protein C was used for comparison with non-COVID hyper- and hypo-inflammatory ARDS subtypes. RESULTS: Average participant age was 60 ± 14 years; 67% were male, and 28-day mortality was 25%. At trial enrollment, 85% of participants required high flow oxygen or non-invasive ventilation, and 97% were receiving dexamethasone. Several biomarkers of inflammation (IL-6, IL-8, IL-10, sTNFR-1, TREM-1), epithelial injury (sRAGE), and endothelial injury (Ang-1, thrombomodulin) were associated with 28- and 60-day mortality. Two latent subtypes were identified. Subtype 2 (27% of participants) was characterized by persistent derangements in biomarkers of inflammation, endothelial and epithelial injury, and disordered coagulation and had twice the mortality rate compared with Subtype 1. Only one person was classified as hyper-inflammatory using the previously validated non-COVID ARDS model. CONCLUSIONS: We discovered evidence of two novel biological subtypes of severe COVID-19 with significantly different clinical outcomes. These subtypes differed from previously established hyper- and hypo-inflammatory non-COVID subtypes of ARDS. Biological heterogeneity may explain inconsistent findings from trials of hospitalized patients with COVID-19 and guide treatment approaches.

Host and Microbe Blood Metagenomics Reveals Key Pathways Characterizing Critical Illness Phenotypes.

Rationale: Two molecular phenotypes of sepsis and acute respiratory distress syndrome, termed hyperinflammatory and hypoinflammatory, have been consistently identified by latent class analysis in numerous cohorts, with widely divergent clinical outcomes and differential responses to some treatments; however, the key biological differences between these phenotypes remain poorly understood.Objectives: We used host and microbe metagenomic sequencing data from blood to deepen our understanding of biological differences between latent class analysis-derived phenotypes and to assess concordance between the latent class analysis-derived phenotypes and phenotypes reported by other investigative groups (e.g., Sepsis Response Signature [SRS1-2], molecular diagnosis and risk stratification of sepsis [MARS1-4], reactive and uninflamed).Methods: We analyzed data from 113 patients with hypoinflammatory sepsis and 76 patients with hyperinflammatory sepsis enrolled in a two-hospital prospective cohort study. Molecular phenotypes had been previously assigned using latent class analysis.Measurements and Main Results: The hyperinflammatory and hypoinflammatory phenotypes of sepsis had distinct gene expression signatures, with 5,755 genes (31%) differentially expressed. The hyperinflammatory phenotype was associated with elevated expression of innate immune response genes, whereas the hypoinflammatory phenotype was associated with elevated expression of adaptive immune response genes and, notably, T cell response genes. Plasma metagenomic analysis identified differences in prevalence of bacteremia, bacterial DNA abundance, and composition between the phenotypes, with an increased presence and abundance of Enterobacteriaceae in the hyperinflammatory phenotype. Significant overlap was observed between these phenotypes and previously identified transcriptional subtypes of acute respiratory distress syndrome (reactive and uninflamed) and sepsis (SRS1-2). Analysis of data from the VANISH trial indicated that corticosteroids might have a detrimental effect in patients with the hypoinflammatory phenotype.Conclusions: The hyperinflammatory and hypoinflammatory phenotypes have distinct transcriptional and metagenomic features that could be leveraged for precision treatment strategies.

Identifying molecular phenotypes in sepsis: an analysis of two prospective observational cohorts and secondary analysis of two randomised controlled trials.

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.

Gambling, tobacco use, and health among individuals in substance use disorder treatment.

BACKGROUND AND OBJECTIVES: Gambling is highly comorbid with disordered use of tobacco and other drugs, and may increase relapse risk among substance use disorder (SUD) patients. We investigated associations between gambling and tobacco use behaviors among SUD patients to inform clinical care. METHODS: Patients (N = 651, 170 female) from 25 residential SUD treatment programs in California completed surveys about tobacco use, health, and gambling. Using multivariate regression, we examined associations between gambling, tobacco use behaviors, and mental and physical health. RESULTS: Past-year gamblers were more likely than non-gamblers to be current smokers (adjusted odds ratio [AOR] = 1.44, 95% confidence interval [CI] = 1.03, 2.01). Smokers who gambled had higher mean Heaviness of Smoking Index (HSI) scores (mean difference = +0.32, 95% CI = 0.04, 0.60), and more often reported smokeless tobacco use (AOR = 1.73, 95% CI = 1.16, 2.58), compared to non-gambling smokers. Past-year problem gamblers were more likely than all others (non-gamblers and non-problem gamblers) to be current smokers (AOR = 1.44, 95% CI = 1.08, 1.90) and to report high psychosocial stress (AOR = 1.87, 95% CI = 1.34, 2.61). Smokers with problem gambling also had higher HSI scores (mean difference = +0.54, 95% CI = 0.14, 0.95) compared to smokers without problem gambling. DISCUSSION AND CONCLUSIONS: Gambling and problem gambling were associated with tobacco use and heavier smoking. SUD patients with gambling comorbidity may be heavier smokers and may need concurrent treatment for tobacco use and problem gambling. SCIENTIFIC SIGNIFICANCE: This study provides novel data regarding gambling and tobacco use behaviors among SUD patients.

A cluster-randomized trial of a brief multi-component intervention to improve tobacco outcomes in substance use treatment.

BACKGROUND: Smoking prevalence is high among people in substance use disorder (SUD) treatment, and program interventions to address smoking are often complex and lengthy. This cluster-randomized trial tested whether a brief multi-component intervention impacted tobacco outcomes among staff and clients. METHODS: Seven SUD treatment programs were randomly assigned to the multi-component intervention or to waitlist control. The 6-month intervention included a leadership motivation assessment, program incentives, 4 staff training sessions and a leadership learning community session. Survey data were collected from staff and clients at pre- and post-intervention. Outcomes were first compared across condition (intervention vs waitlist control), and then examined pre- to post-intervention with condition collapsed. RESULTS: Staff in the intervention (n = 48) and control conditions (n = 26) did not differ at post-intervention on smoking prevalence, self-efficacy to help clients quit, or practices used to help clients quit smoking. Intervention clients (n = 113) did not differ from controls (n = 61) in smoking prevalence or receipt of tobacco services. Pre-post comparisons collapsed across condition showed a decrease in client and staff smoking prevalence, which could not be attributed to the intervention, and a decrease in client receipt of cessation medication. CONCLUSION: The brief multi-component intervention did not support changes in smoking prevalence or in tobacco-related services received by clients. Other intervention features are needed to reduce smoking among SUD clients. TRIAL REGISTRATION: Randomization occurred at the program level and outcomes measured are program-level measures. Accordingly, the trial is not registered.

Early plasma angiopoietin-2 is prognostic for ARDS and mortality among critically ill patients with sepsis.

Angiopoietin-2 (Ang-2) is associated with vascular endothelial injury and permeability in the acute respiratory distress syndrome (ARDS) and sepsis. Elevated circulating Ang-2 levels may identify critically ill patients with distinct pathobiology amenable to targeted therapy. We hypothesized that plasma Ang-2 measured shortly after hospitalization among patients with sepsis would be associated with the development of ARDS and poor clinical outcomes. To test this hypothesis, we measured plasma Ang-2 in a cohort of 757 patients with sepsis, including 267 with ARDS, enrolled in the emergency department or early in their ICU course before the COVID-19 pandemic. Multivariable models were used to test the association of Ang-2 with the development of ARDS and 30-day morality. We found that early plasma Ang-2 in sepsis was associated with higher baseline severity of illness, the development of ARDS, and mortality risk. The association between Ang-2 and mortality was strongest among patients with ARDS and sepsis as compared to those with sepsis alone (OR 1.81 vs. 1.52 per log Ang-2 increase). These findings might inform models testing patient risk prediction and strengthen the evidence for Ang-2 as an appealing biomarker for patient selection for novel therapeutic agents to target vascular injury in sepsis and ARDS.

Corrigendum: Comparing client and staff reports on tobacco-related knowledge, attitudes, beliefs and services provided in substance use treatment.

[This corrects the article DOI: 10.18332/tid/160974.].

Subphenotypes of frailty in lung transplant candidates.

Heterogeneous frailty pathobiology might explain the inconsistent associations observed between frailty and lung transplant outcomes. A Subphenotype analysis could refine frailty measurement. In a 3-center pilot cohort study, we measured frailty by the Short Physical Performance Battery, body composition, and serum biomarkers reflecting causes of frailty. We applied latent class modeling for these baseline data. Next, we tested class construct validity with disability, waitlist delisting/death, and early postoperative complications. Among 422 lung transplant candidates, 2 class model fit the best (P = .01). Compared with Subphenotype 1 (n = 333), Subphenotype 2 (n = 89) was characterized by systemic and innate inflammation (higher IL-6, CRP, PTX3, TNF-R1, and IL-1RA); mitochondrial stress (higher GDF-15 and FGF-21); sarcopenia; malnutrition; and lower hemoglobin and walk distance. Subphenotype 2 had a worse disability and higher risk of waitlist delisting or death (hazards ratio: 4.0; 95% confidence interval: 1.8-9.1). Of the total cohort, 257 underwent transplant (Subphenotype 1: 196; Subphenotype 2: 61). Subphenotype 2 had a higher need for take back to the operating room (48% vs 28%; P = .005) and longer posttransplant hospital length of stay (21 days [interquartile range: 14-33] vs 18 days [14-28]; P = .04). Subphenotype 2 trended toward fewer ventilator-free days, needing more postoperative extracorporeal membrane oxygenation and dialysis, and higher need for discharge to rehabilitation facilities (P ≤ .20). In this early phase study, we identified biological frailty Subphenotypes in lung transplant candidates. A hyperinflammatory, sarcopenic Subphenotype seems to be associated with worse clinical outcomes.

Effect of Technology-Enhanced Screening in Addition to Standard Targeted Clinician Education on the Duration of Untreated Psychosis: A Cluster Randomized Clinical Trial.

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.

Smoking Behavior and Wellness among Individuals in Substance Use Disorder Treatment.

Tobacco-related morbidity and mortality disproportionately affect people with substance use disorders (SUD). Encouraging overall wellness may support tobacco use cessation. We investigated relationships between wellness (health status, physical activity, sugar-sweetened beverage (SSB) consumption), cigarette smoking, and smoking cessation among SUD treatment patients to inform clinical care. Cross-sectional surveys were conducted with 395 patients in 20 California residential SUD programs. Using multivariate regression, we examined associations between smoking status and wellness. Among smokers, we examined associations between lifetime smoking exposure, cessation behaviors and attitudes, and wellness. Compared to nonsmokers (n = 121), smokers (n = 274) reported more SSB consumption, poorer physical health, and more respiratory symptoms. Among smokers, SSB consumption and respiratory symptoms increased per ten pack-years of smoking. Smokers with respiratory symptoms reported higher motivation to quit and more use of nicotine replacement therapy (NRT). Smokers with more days of poor mental health reported lower motivation to quit. Overall, cigarette smoking was associated with other health-risk behaviors among SUD treatment patients. Respiratory symptoms may increase, and poor mental health may decrease, SUD patients' intent to quit smoking. To reduce chronic disease risk among SUD patients, treatment programs should consider promoting overall wellness concurrently with smoking cessation.

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.

The Two-Factor Structure of the Parent Cognitive Error Questionnaire: A Measure of Parental Cognitive Errors in Relation to Child Problems.

This study evaluated the factor structure of the scores from a parent rating scale, the Parent Cognitive Error Questionnaire (PCEQ), which measures parents' attributions of child misbehavior and problems. The factor structure of the scores of the PCEQ was examined among 199 children (ages 7-11; mean age: 8.64 years, 58.30% boys, 53.80% White) with Attention-Deficit/Hyperactivity Disorder (ADHD), Predominantly Inattentive Presentation. Reliability and validity of the factors were assessed. Two factors emerged from this sample: (1) parent-specific cognitive errors (self-blame for child problems), and (2) child-specific cognitive errors (child-blame for child problems). Both were related to parent-rated parental depression, parenting satisfaction, parenting self-efficacy, and child ADHD and Oppositional Defiant Disorder (ODD) symptoms. After adjusting for child-specific cognitive errors, parent-specific errors were related to parent-rated parent depressive symptoms, and after adjustment for parent-specific cognitive errors, child-specific cognitive errors were related to parent-rated child ADHD and ODD symptoms. A two-factor structure for the PCEQ scores from this sample was found with evidence of reliability and validity of factors, showing promise for measuring sources of parental attributions regarding child problems.

Adolescents' and young adults' perceptions of risks and benefits differ by type of cannabis products.

INTRODUCTION: Cannabis use patterns among adolescents and young adults (AYAs) have changed recently, with increasing use of non-combustible cannabis products. Little is known about perceived risks or benefits related to non-combustible products (e.g., vaporized and edible cannabis). We examined whether AYAs' perceived risks and benefits differ across four cannabis products, and by use status. METHODS: We conducted a survey of 433 California AYAs (Mage = 18.9 years old, 66.5% females) during 2017-2018. We compared a variety of perceived risks and benefits corresponding to short-term and long-term use of each product (combustible, blunt, vaporized, and edible cannabis), and between ever and never users. RESULTS: Participants perceived combustible cannabis and blunts conferred the greatest risk for short-term (bad cough, trouble catching breath) and long-term (lung disease, oral and lung cancer, and heart attack) health outcomes and short-term social risks (friends upset, getting into trouble). These products were also perceived to have greater short-term and long-term benefits (i.e., reducing mental health problems) than vaporized and edible cannabis. The most common perceived risks were "get into trouble" and "become addicted." The most common benefits were "feel high or buzzed" and "feel less anxious." Ever cannabis users perceived less risks and greater benefits related to cannabis use than never users. CONCLUSIONS: AYAs differentially perceived risks and benefits related to use of four cannabis products. Public health and education efforts should address both perceived and real risks and benefits of specific cannabis products to prevent cannabis use among AYAs.