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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.)

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.)

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.)

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.)

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.)

Background: We evaluated the cost-effectiveness of a hepatitis C (HCV) screening and active linkage to care intervention in US methadone maintenance treatment (MMT) patients using data from a randomized trial conducted in New York City and San Francisco., Methods: We used a decision analytic model to compare 1) no intervention; 2) HCV screening and education (control); and 3) HCV screening, education, and care coordination (active linkage intervention). We also explored an alternative strategy wherein HCV/HIV co-infected participants linked elsewhere. Trial data include population characteristics (67% male, mean age 48, 58% HCV infected) and linkage rates. Data from published sources include treatment efficacy and HCV re-infection risk. We projected quality-adjusted life years (QALYs) and lifetime medical costs using an established model of HCV (HEP-CE). Incremental cost-effectiveness ratios (ICERs) are in 2015 US$/QALY discounted 3% annually., Results: The control strategy resulted in a projected 35% linking to care within 6 months and 31% achieving sustained virologic response (SVR). The intervention resulted in 60% linking and 54% achieving SVR with an ICER of $24,600/QALY compared to no intervention from the healthcare sector perspective and was a more efficient use of resources than the control strategy. The intervention had an ICER of $76,500/QALY compared to the alternative strategy. From a societal perspective, the intervention had a net monetary benefit of $511,000-$975,600., Conclusions: HCV care coordination interventions that include screening, education and active linkage to care in MMT settings are likely cost-effective at a conventional $100,000/QALY threshold for both HCV mono-infected and HIV co-infected patients., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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., (Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Although individual and group cognitive-behavioral therapy (CBT) is the standard treatment approach for hoarding disorder (HD), it requires trained mental health professionals with specialization in HD. There is a need to offer additional options and services due to the limited number of professionals with advanced training, combined with the high prevalence rate of individuals with HD. A structured support group led by trained facilitators or lay professionals using a facilitator's manual and participant workbook (Buried in Treasures or BiT), addresses this need and increases accessibility. Prior studies of BiT groups have shown decreased hoarding symptoms. Only one retrospective study compared BiT and CBT outcomes in a naturalistic setting and showed no difference. Thus, a well-powered randomized controlled trial is needed to directly compare these forms of treatment. This paper presents a non-inferiority controlled trial protocol that compares group CBT to group BiT. Three hundred participants with HD, 18years or older, are being recruited for a 16-week treatment study. Participants are randomly assigned to either the CBT or BiT group. The primary outcome is reduction in hoarding symptom severity. Secondary outcomes include reduction in other indices of hoarding symptomology, including functional impairment, physical clutter, cognition, and changes in neuropsychological functioning., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To compare patterns of cognitive performance in older adults with late-onset depression (LOD; ≥65 years of age) with that of older adults with early-onset depression (EOD; <65 years)., Methods: Participants were 171 adults aged 60 years or older with major depression and executive dysfunction who were participating in a randomized psychotherapy trial. Participants included 72 LOD and 99 EOD individuals. Cognitive performance on measures of verbal learning, memory, and executive functioning were evaluated. Demographic and clinical characteristics, severity of cerebrovascular risk factors, and disability ratings were also compared between groups., Results: The LOD group was older and had fewer previous episodes of depression and lower severity of depression compared with EOD participants. The LOD group demonstrated poorer performance on measures of verbal learning (F(1,161) = 4.28, p = 0.04) and memory (F(1,160) = 4.65, p = 0.03) than the EOD group. Linear regression analysis demonstrated that LOD and fewer years of education were significant predictors of poorer verbal learning (F(7,114) = 6.25, p <0.001) and memory (F(7,113)=7.24, p <0.001). Performance on measures of executive functioning, severity of vascular risk factors, and disability ratings did not differ between the two groups., Conclusion: In older adults with depression and executive dysfunction, LOD was associated with poorer performance on measures of verbal learning and memory. Aging-related brain changes associated with LOD may play a more important role, leading to dysfunction in these cognitive domains than a history of recurrent depressive episodes in older adults with a dysexecutive syndrome., (Published by Elsevier Inc.)

Objective: This study examined the relationships between treatment fidelity and treatment outcomes in a community-based trial of a 12-Step Facilitation (TSF) intervention., Method: In a prior multi-site randomized clinical trial, 234 participants in 10 outpatient drug treatment clinics were assigned to receive the Stimulant Abuser Groups to Engage in 12-Step (STAGE-12) intervention. A secondary analysis reviewed and coded all STAGE-12 sessions for fidelity to the protocol, using the Twelve Step Facilitation Adherence Competence Empathy Scale (TSF ACES). Linear mixed-effects models tested the relationship between three fidelity measures (adherence, competence, empathy) and six treatment outcomes (number of days of drug use and five Addiction Severity Index (ASI) composite scores) measured at 3 months post-baseline., Results: Adherence, competence and empathy were robustly associated with improved employment status at follow up. Empathy was inversely associated with drug use, as was competence in a non-significant trend (p=.06). Testing individual ASI drug composite score items suggested that greater competence was associated with fewer days of drug use and, at the same time, with an increased sense of being troubled or bothered by drug use., Conclusions: Greater competence and empathy in the delivery of a TSF intervention were associated with better drug use and employment outcomes, while adherence was associated with employment outcomes only. Higher therapist competence was associated with lower self-report drug use, and also associated with greater self-report concern about drug use. The nature of TSF intervention may promote high levels of concern about drug use even when actual use is low., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: This study examined stability of remission in patients who were abstainers and non-problem users at 1-year after entering private, outpatient alcohol and drug treatment. We examined: (a) How does risk of relapse change over time? (b) What was the risk of relapse for non-problem users versus abstainers? (c) What individual, treatment, and extra-treatment characteristics predicted time to relapse, and did these differ by non-problem use versus abstinence?, Methods: The sample consisted of 684 adults in remission (i.e., abstainers or non-problem users) 1 year following treatment intake. Participants were interviewed at intake, and 1, 5, 7, 9, and 11 years after intake. We used discrete-time survival analysis to examine when relapse is most likely to occur and predictors of relapse., Results: Relapse was most likely at 5-year, and least likely at 11-year follow-up. Non-problem users had twice the odds of relapse compared to abstainers. Younger individuals and those with fewer 12-step meetings and shorter index treatment had higher odds of relapse than others. We found no significant interactions between non-problem use and the other covariates suggesting that significant predictors of outcome did not differ for non-problem users., Conclusions: Non-problem use is not an optimal 1-year outcome for those in an abstinence-oriented, heterogeneous substance use treatment program. Future research should examine whether these results are found in harm reduction treatment and self-help models, or in those with less severe problems. Results suggest treatment retention and 12-step participation are prognostic markers of long-term positive outcomes for those achieving remission at 1 year., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: The treatment of alcohol and other drugs is now more commonly framed in terms of a chronic condition which requires ongoing monitoring. A model which includes continuing access to health care may optimize outcomes. Most studies of chronic care models have not included health care and have only examined short term effects., Methods: The sample (n = 783) included consecutive admissions in ten public and private alcohol and other drug (AOD) treatment programs followed over seven years. The outcome was remission which was defined as alcohol and drug abstinence or non-problem use., Results: In the private sample, receiving health care services predicted remission across the seven years; however this did not occur in the public sample. More patients in the public treatment sample received AOD treatment readmissions each year, while more of those in the private sector received psychiatric and general health visits. Except for drug problem severity, there were no other clinical differences between the samples. There were no differences in the proportions of patients in the two sectors who received the full spectrum of chronic care services. In the final models, 12-step participation was markedly significant for both samples., Conclusions: Models of chronic care for substance use need to consider differences between private and public treatment and should take into account that individuals may not always have access, or avail themselves of services that may optimize long-term outcomes., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Addiction treatment programs are increasingly working to address prevalent and comorbid tobacco dependence in their service populations. However at present there are few published measurement tools, with known psychometric properties, that can be used to assess client-level constructs related to tobacco dependence in addiction treatment settings. Following on previous work that developed a staff-level survey instrument, this report describes the development and measurement characteristics of the smoking knowledge, attitudes and services (S-KAS) for use with clients in addiction treatment settings., Method: 250 clients enrolled in residential drug abuse treatment programs were surveyed. Summary statistics were used to characterize both the participants and their responses, and exploratory factor analysis (EFA) was used to examine the underlying factor structure., Results: Examination of the rotated factor pattern indicated that the latent structure was formed by one knowledge factor, one attitude factor, and two "service" factors reflecting program services and clinician services related to tobacco dependence. Standardized Cronbach's alpha coefficients for the four scales were, respectively, .57, .75, .82 and .82., Conclusions: The proposed scales have reasonably good psychometric characteristics, although the knowledge scale leaves room for improvement, and will allow researchers to quantify client knowledge, attitudes and services regarding tobacco dependence treatment. Researchers, program administrators, and clinicians may find the S-KAS useful in changing organizational culture and clinical practices related to tobacco addiction, help in program evaluation studies, and in tracking and improving client motivation., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Objective: This study was conducted to determine the effect of cognitive impairment (CI) on mental healthcare costs for older low-income adults with severe psychiatric illness., Methods: Data were collected from 62 ethnically diverse low-income older adults with severe psychiatric illness who were participating in day programming at a large community mental health center. CI was diagnosed by a neuropsychologist utilizing the Mattis Dementia Rating Scale-Second Edition and structured ratings of functional impairment (Clinical Dementia Rating Scale). Mental healthcare costs for 6, 12, and 24-month intervals before cognitive assessments were obtained for each participant. Substance abuse history was evaluated utilizing a structured questionnaire, depression symptom severity was assessed utilizing the Hamilton Depression Rating Scale, and psychiatric diagnoses were obtained through medical chart abstraction., Results: CI was exhibited by 61% of participants and was associated with significantly increased mental healthcare costs during 6, 12, and 24-month intervals. Results of a regression analysis indicated that ethnicity and CI were both significant predictors of log transformed mental healthcare costs over 24 months with CI accounting for 13% of the variance in cost data., Conclusions: CI is a significant factor associated with increased mental healthcare costs in patients with severe psychiatric illness. Identifying targeted interventions to accommodate CI may lead to improving treatment outcomes and reducing the burden of mental healthcare costs for individuals with severe psychiatric illness.

Aim: To evaluate potential mediators of an extended cognitive behavioral smoking cessation intervention., Design: Analysis of data from a randomized clinical trial of smoking cessation., Setting: The Habit Abatement Clinic, University of California, San Francisco., Participants: Participants were older cigarette smokers (>/=50 years old). Those receiving Standard Treatment (N=100) were compared to those receiving extended cognitive behavioral treatment (N=99)., Measurements: Negative affect was measured with the Profile of Mood States (POMS), the Medical Outcome Studies 36-item Short-Form Health Survey (SF-36), and the Perceived Stress Scale (PSS). Abstinence-specific social support was measured with the Partner Interaction Questionnaire (PIQ). Motivation to quit and abstinence self-efficacy were measured on 1-10 scales with the Thoughts about Abstinence Questionnaire. All were measured at the beginning of treatment and week 52., Results: Analyses revealed that extended CBT increased abstinence self-efficacy over the first 52 weeks postcessation. This effect, in turn, was positively associated with 7-day point prevalence abstinence at week 64 while controlling for treatment condition, and eliminated the independent effect of treatment condition on abstinence. The test of mediation indicated a significant effect, and abstinence self-efficacy accounted for 61% to 83% of the total effect of treatment condition on smoking abstinence. Results failed to support a mediational role of negative affect, abstinence-specific social support, or motivation to quit., Conclusions: The results of the present study are consistent with theories of relapse and studies of more time-limited interventions, and underscore the importance of abstinence self-efficacy in achieving long-term abstinence from cigarettes., (Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Residential therapeutic communities (TCs) have demonstrated effectiveness, yet for the most part they adhere to a drug-free ideology that is incompatible with the use of methadone. This study used equivalency testing to explore the consequences of admitting opioid-dependent clients currently on methadone maintenance treatment (MMT) into a TC., Methods: The study compared 24-month outcomes between 125 MMT patients and 106 opioid-dependent drug-free clients with similar psychiatric history, criminal justice pressure and expected length of stay who were all enrolled in a TC. Statistical equivalence was expected between groups on retention in the TC and illicit opioid use. Secondary hypotheses posited statistical equivalence in the use of stimulants, benzodiazepines, and alcohol, as well as in HIV risk behaviors., Results: Mean number of days in treatment was statistically equivalent for the two groups (166.5 for the MMT group and 180.2 for the comparison group). At each assessment, the proportion of the MMT group testing positive for illicit opioids was indistinguishable from the proportion in the comparison group. The equivalence found for illicit opioid use was also found for stimulant and alcohol use. The groups were statistically equivalent for benzodiazepine use at all assessments except at 24 months where 7% of the MMT group and none in the comparison group tested positive. Regarding injection- and sex-risk behaviors the groups were equivalent at all observation points., Conclusions: Methadone patients fared as well as other opioid users in TC treatment. These findings provide additional evidence that TCs can be successfully modified to accommodate MMT patients.

Background: Important questions remain regarding the necessary duration and intensity for methadone treatment to be effective., Methods: As part of a clinical trial of tuberculosis chemoprophylaxis [Batki, S.L., Gruber, V.A., Bradley, J.M., Bradley, M., Delucchi, K., 2002. A controlled trial of methadone treatment combined with directly observed isoniazid for tuberculosis prevention in injection drug users. Drug Alcohol Depend. 66 283-293. doi:10.1016/S0376-8716(01)00208-3], patients with opioid dependence were recruited from an outpatient 21-day methadone detoxification program and were randomly assigned to one of three treatment conditions: (1) continuation in 21-day methadone detoxification; (2) transfer to 6-month methadone maintenance with only minimal counseling; or (3) transfer to 6-month methadone maintenance with standard twice monthly counseling and as-needed social work and psychiatric services. Both the 6-month maintenance treatments were followed by 1.5 months of detoxification. Urine drug tests and self-report measures were collected at baseline, months 1-6, and month 8.5., Results: Compared to 21-day methadone detoxification, 6-month methadone maintenance with either minimal or standard counseling resulted in fewer opiate positive urine tests and days of self-reported heroin and alcohol use. There was no change in cocaine use or other outcome measures. The increased counseling available in the standard counseling condition did not appear to reduce heroin use further than the minimal counseling condition, in contrast to the effect found for more structured counseling in long-term methadone maintenance (McLellan et al., 1993)., Conclusions: Six months of methadone maintenance, even with minimal counseling, reduces heroin and alcohol use more than 21-day methadone detoxification.

This clinical trial evaluated a contingency management intervention designed to improve medication adherence among HIV-positive methadone maintenance patients. After a 4-week baseline observation phase, eligible participants (N=66) were randomly assigned to: (a) medication coaching sessions every other week to assist with adherence strategies (comparison group) or (b) medication coaching plus voucher reinforcement for opening electronic medication caps on time (voucher group). Baseline adherence (percent doses taken/percent total possible doses) was 51% using electronic measurement, 75% using self-report and 75% using pill count. The intervention was provided for 12 weeks, with a 4-week follow-up. The primary outcome results of the clinical trial indicated effectiveness during the intervention, with significant mean adherence differences between voucher and comparison groups using electronic measurement (78% versus 56%), pill count (86% versus 75%), and self-report (87% versus 69%). Differences between groups faded after vouchers were discontinued. Contingency management shows promise as a strategy to promote antiretroviral medication adherence in this population.

Understanding the long-term course of problematic drinking is a fundamental concern for health services research in the alcohol field. The stability of, or change in, the course of drinking--especially heavy drinking--has both theoretical and applied relevance to alcohol research. We explore the application of latent class growth modeling to 5 years of survey data collected from dependent and problem drinkers--some not in treatment at baseline--in an attempt to uncover prototypical longitudinal drinking patterns. Results indicated that five profiles of drinkers can be used to represent their longitudinal course of alcohol consumption: early quitters (N = 88), light/non-drinkers (N = 76), gradual improvers (N = 129), moderate drinkers (N = 229), and heavy drinkers (N = 572). Significant baseline factors included ASI drug severity, dependence symptoms, and marital status. Attendance at AA meetings, the size of one's heavy drinking and drug using social network, past treatment, receiving suggestions about one's drinking, and contacts with the medical system were significant influences. The size of heavy drinking and drug using social networks was noticeably larger for the heavy drinkers. Findings also support the usefulness of a semi-parametric latent group-based approach as a tool for analyzing alcohol-related behaviors.

Background: A close link between smoking and depression has been documented by research primarily based on U.S. white populations. This study examined the association between depressive symptoms and smoking behaviors in Chinese American smokers., Methods: Analyses were based on baseline data collected from a convenience sample of 199 Chinese smokers who resided in northern California. The sample included 20.6% women, 97% immigrants, with mean age of 40.8 years and mean cigarettes/day of 8.9., Results: Compared with population-based studies of Chinese Americans, the Chinese smokers in the current study reported higher depressive symptoms assessed by the Center for Epidemiologic Studies-Depression Scale [M, 20.4; 95% confidence interval (CI), 18.8-22.2], higher lifetime prevalence rates of major depressive disorders (30.3%; 95% CI, 24.0-37.2%) and dysthymia (11.6%; 95% CI, 7.5-16.9%). Multiple regression analysis suggested female gender, unemployment, major depression or dysthymia within the past year, previous experience with nicotine withdrawal syndrome, and high temptation to smoke under negative affect situations are associated with a higher level of depressive symptoms., Conclusions: The level of depressive symptoms among Chinese American smokers is comparable with that observed in other US populations reported. In the current sample, elevated depressive symptoms were more prominent among women or those who were unemployed, smokers who reported significant nicotine withdrawal at previous quit attempts, and high temptation to smoke when experiencing negative emotions. Findings support further examination of the role of depression in smoking among Chinese Americans and underscore the importance of addressing depressive symptoms when treating tobacco use in Chinese smokers.

We examined the prevalence of drug use related infectious complications among opioid using or dependent individuals and service charges associated with medical care received over a 2-year period at a public hospital. A computerized medical record review was used to identify 3147 individuals with diagnoses related to opioid use or dependence. Forty-nine percent of these patients were treated for bacterial infections and 30% presented for treatment of medical problems arising from the effects of the drugs themselves (e.g. drug withdrawal, overdoses, and drug-induced psychiatric symptoms). Mean charges were $13393 for these patients, nearly 2.5 times the average per patient charges for non-opioid using patients during the study period. Patients with diagnoses related to opioid use or dependence comprised 2% of the total patient population for this period, yet accounted for 5% of total charges. Homeless patients were less likely to have used ambulatory services and were more likely than non-homeless patients to have used emergency and inpatient services. Early detection of patients with opioid use or dependence problems, coupled with effective strategies to engage them in ambulatory preventive services, could allow interventions to reduce morbidity and associated charges in this patient population. The findings suggest that health care providers and policy makers consider policies that promote ambulatory care use among opioid users seeking medical care through the public health care system.