Search

Background: Secondhand tobacco smoke exposure impairs the control of pediatric asthma. Evidence of the efficacy of interventions to reduce children's exposure and improve disease outcomes has been inconclusive.Methods: Caregivers of 519 children aged 3 to 12 years with asthma and reported smoke exposure attended two baseline assessment visits, which involved a parent interview, sampling of the children's urine (for cotinine assay), and spirometry (children≥5 years). The caregivers and children (n=352) with significant documented exposure (cotinine≥10 ng/mL) attended a basic asthma education session, provided a third urine sample, and were randomized to the Lowering Environmental Tobacco Smoke: LET'S Manage Asthma (LET'S) intervention (n=178) or usual care (n=174). LET'S included three in-person, stage-of-change-based counseling sessions plus three follow-up phone calls. Cotinine feedback was given at each in-person session. Follow-up visits at 6 and 12 months postrandomization repeated the baseline data collection. Multivariate regression analyses estimated the intervention effect on the natural logarithm of the cotinine to creatinine ratio (lnCCR), use of health-care services, and other outcomes.Results: In the sample overall, the children in the LET'S intervention had lower follow-up lnCCR values compared with the children in usual care, but the group difference was not significant (β coefficient=-0.307, P=.064), and there was no group difference in the odds of having>one asthma-related medical visit (β coefficient=0.035, P=.78). However, children with high-risk asthma had statistically lower follow-up lnCCR values compared with children in usual care (β coefficient=-1.068, P=.006).Conclusions: The LET'S intervention was not associated with a statistically significant reduction in tobacco smoke exposure or use of health-care services in the sample as a whole. However, it appeared effective in reducing exposure in children at high risk for subsequent exacerbations.Trial Registry: ClinicialTrials.gov; No.: NCT00217958; URL: clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Rationale: Poor adherence to asthma controller medications results in poor treatment outcomes.Objectives: To compare controller medication adherence and clinical outcomes in 612 adults with poorly controlled asthma randomized to one of two different treatment decision-making models or to usual care.Methods: In shared decision making (SDM), nonphysician clinicians and patients negotiated a treatment regimen that accommodated patient goals and preferences. In clinician decision making, treatment was prescribed without specifically eliciting patient goals/preferences. The otherwise identical intervention protocols both provided asthma education and involved two in-person and three brief phone encounters.Measurements and Main Results: Refill adherence was measured using continuous medication acquisition (CMA) indices-the total days' supply acquired per year divided by 365 days. Cumulative controller medication dose was measured in beclomethasone canister equivalents. In follow-up Year 1, compared with usual care, SDM resulted in: significantly better controller adherence (CMA, 0.67 vs. 0.46; P < 0.0001) and long-acting beta-agonist adherence (CMA, 0.51 vs. 0.40; P = 0.0225); higher cumulative controller medication dose (canister equivalent, 10.9 vs. 5.2; P < 0.0001); significantly better clinical outcomes (asthma-related quality of life, health care use, rescue medication use, asthma control, and lung function). In Year 2, compared with usual care, SDM resulted in significantly lower rescue medication use, the sole clinical outcome available for that year. Compared with clinician decision making, SDM resulted in: significantly better controller adherence (CMA, 0.67 vs. 0.59; P = 0.03) and long-acting beta-agonist adherence (CMA, 0.51 vs. 0.41; P = 0.0143); higher cumulative controller dose (CMA, 10.9 vs. 9.1; P = 0.005); and quantitatively, but not significantly, better outcomes on all clinical measures.Conclusions: Negotiating patients' treatment decisions significantly improves adherence to asthma pharmacotherapy and clinical outcomes. Clinical trials registered with www.clinicaltrials.gov (NCT00217945 and NCT00149526). [ABSTRACT FROM AUTHOR]

OBJECTIVE: Phase III clinical trials for depression enroll participants with major depressive disorder according to stringent inclusion and exclusion criteria. These patients may not be representative of typical depressed patients seeking treatment. This analysis used data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project--which used broad inclusion and minimal exclusion criteria--to evaluate whether phase III clinical trials recruit representative depressed outpatients. METHOD: Of 2,855 participants, 22.2% met typical entry criteria for phase III clinical trials (efficacy sample) and 77.8% did not (nonefficacy sample). These groups were compared regarding baseline sociodemographic and clinical features and the characteristics and outcomes of acute-phase treatment. RESULTS: The efficacy sample had a shorter average duration of illness and lower rates of family history of substance abuse, prior suicide attempts, and anxious and atypical symptom features. Despite similar medication dosing and time at exit dose, the efficacy participants tolerated citalopram better. They also had higher rates of response (51.6% versus 39.1%) and remission (34.4% versus 24.7%). These differences persisted even after adjustments for baseline differences. CONCLUSIONS: Phase III trials do not recruit representative treatment-seeking depressed patients. Broader phase III inclusion criteria would increase the generalizability of results to practice, potentially reducing placebo response and remission rates (reducing the risk of failed trials) but at the risk of some increase in adverse events. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Treatment of major depressive disorder typically entails implementing treatments in a stepwise fashion until a satisfactory outcome is achieved. This study sought to identify factors that affect patients' willingness to accept different second-step treatment approaches. METHOD: Participants in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial who had unsatisfactory outcomes after initial treatment with citalopram were eligible for a randomized second-step treatment trial. An equipoise-stratified design allowed participants to exclude or include specific treatment strategies. Analyses were conducted to identify factors associated with the acceptability of the following second-step treatments: cognitive therapy versus no cognitive therapy, any switch strategy versus any augmentation strategy (including cognitive therapy), and a medication switch strategy only versus a medication augmentation strategy only. RESULTS: Of the 1,439 participants who entered second-step treatment, 1% accepted all treatment strategies, 3% accepted only cognitive therapy, and 26% accepted cognitive therapy (thus, 71% did not accept cognitive therapy). Those with higher educational levels or a family history of a mood disorder were more likely to accept cognitive therapy. Participants in primary care settings and those who experienced a greater side effect burden or a lower reduction in symptom severity with citalopram were more likely to accept a switch strategy as compared with an augmentation strategy. Those with concurrent drug abuse and recurrent major depressive disorder were less likely to accept a switch strategy. CONCLUSIONS: Few participants accepted all treatments. Acceptance of cognitive therapy was primarily associated with sociodemographic characteristics, while acceptance of a treatment switch was associated with the results of the initial treatment. [ABSTRACT FROM AUTHOR]

Context: Accumulation of iron in excess of physiologic requirements has been implicated in risk of cardiovascular disease because of increased iron-catalyzed free radical-mediated oxidative stress.Objective: To test the hypothesis that reducing body iron stores through phlebotomy will influence clinical outcomes in a cohort of patients with symptomatic peripheral arterial disease (PAD).Design, Setting, and Patients: Multicenter, randomized, controlled, single-blinded clinical trial based on the Iron (Fe) and Atherosclerosis Study (FeAST) (VA Cooperative Study #410) and conducted between May 1, 1999, and April 30, 2005, within the Department of Veterans Affairs Cooperative Studies Program and enrolling 1277 patients with symptomatic but stable PAD. Those with conditions likely to cause acute-phase increase of the ferritin level or with a diagnosis of visceral malignancy within the preceding 5 years were excluded. Analysis was by intent-to-treat.Intervention: Patients were assigned to a control group (n = 641) or to a group undergoing reduction of iron stores by phlebotomy with removal of defined volumes of blood at 6-month intervals (avoiding iron deficiency) (n = 636), stratified by hospital, age, and baseline smoking status, diagnosis of diabetes mellitus, ratio of high-density to low-density lipoprotein cholesterol level, and ferritin level.Main Outcome Measures: The primary end point was all-cause mortality; the secondary end point was death plus nonfatal myocardial infarction and stroke.Results: There were no significant differences between treatment groups for the primary or secondary study end points. All-cause deaths occurred in 148 patients (23%) in the control group and in 125 (20%) in the iron-reduction group (hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.67-1.08; P = .17). Death plus nonfatal myocardial infarction and stroke occurred in 205 patients (32%) in the control group and in 180 (28%) in the iron-reduction group (HR, 0.88; 95% CI, 0.72-1.07; P = .20).Conclusion: Reduction of body iron stores in patients with symptomatic PAD did not significantly decrease all-cause mortality or death plus nonfatal myocardial infarction and stroke.Trial Registration: Clinicaltrials.gov Identifier: NCT00032357. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This report describes the participants and compares the acute and longer-term treatment outcomes associated with each of four successive steps in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. METHOD: A broadly representative adult outpatient sample with nonpsychotic major depressive disorder received one (N=3,671) to four (N=123) successive acute treatment steps. Those not achieving remission with or unable to tolerate a treatment step were encouraged to move to the next step. Those with an acceptable benefit, preferably symptom remission, from any particular step could enter a 12-month naturalistic follow-up phase. A score of /=11 (HRSD(17)>/=14) defined relapse. RESULTS: The QIDS-SR(16) remission rates were 36.8%, 30.6%, 13.7%, and 13.0% for the first, second, third, and fourth acute treatment steps, respectively. The overall cumulative remission rate was 67%. Overall, those who required more treatment steps had higher relapse rates during the naturalistic follow-up phase. In addition, lower relapse rates were found among participants who were in remission at follow-up entry than for those who were not after the first three treatment steps. CONCLUSIONS: When more treatment steps are required, lower acute remission rates (especially in the third and fourth treatment steps) and higher relapse rates during the follow-up phase are to be expected. Studies to identify the best multistep treatment sequences for individual patients and the development of more broadly effective treatments are needed. [ABSTRACT FROM AUTHOR]

Information technology can support the implementation of clinical research findings in practice settings. Technology can address the quality gap in health care by providing automated decision support to clinicians that integrates guideline knowledge with electronic patient data to present real-time, patient-specific recommendations. However, technical success in implementing decision support systems may not translate directly into system use by clinicians. Successful technology integration into clinical work settings requires explicit attention to the organizational context. We describe the application of a "sociotechnical" approach to integration of ATHENA DSS, a decision support system for the treatment of hypertension, into geographically dispersed primary care clinics. We applied an iterative technical design in response to organizational input and obtained ongoing endorsements of the project by the organization's administrative and clinical leadership. Conscious attention to organizational context at the time of development, deployment, and maintenance of the system was associated with extensive clinician use of the system. [ABSTRACT FROM AUTHOR]

Individual HIV risk estimates were generated from reported sexual behavior for 1,146 California Latino Couples Study participants (573 couples). These Bernoulli process model-based estimates proved strongly associated with individual sexually transmitted disease history. Mean estimated background risk from sexual contacts other than with their primary partner was substantially lower for the females than the males (1.4 vs. 7.4 per 10,000). After including their chance of infection from each other, mean net estimated risk was higher for the females than the males (9.2 vs. 8.6 per 10,000). Individual background risk was predicted by individual demographic and psychosocial characteristics (females: coefficient of concordance C = 0.84 predicting any (nonzero) risk; adjusted R(2) = 36% predicting level of risk, given any risk; males: C = 0.78; R(2) = 24%). Characteristics of women with higher risk primary partners were also identifiable (C = 0.65; R(2) = 13%). There was no significant negative association between the male partner's background sexual risk and the aggregate infectivity of the woman from him (taking into account the total number of their condom-protected and unprotected acts of different types). [ABSTRACT FROM AUTHOR]

Mechanistically targeted behavioral interventions are a much-needed strategy for improving outcomes in depression, especially for vulnerable populations with comorbidities such as obesity. Such interventions may change behavior and outcome by changing underlying neural circuit function. However, it is unknown how these circuit-level modifications unfold over intervention and how individual differences in early circuit-level modifications may explain the heterogeneity of treatment effects. We addressed this need within a clinical trial of problem-solving therapy for participants with depression symptoms and comorbid obesity, focusing on the cognitive control circuit as a putative neural mechanism of action. Functional magnetic resonance imaging was applied to measure the cognitive control circuit activity at five time points over 24 months. Compared with participants who received usual care, those receiving problem-solving therapy showed that attenuations in cognitive control circuit activity were associated with enhanced problem-solving ability, which suggests that this circuit plays a key role in the mechanisms of problem-solving therapy. Attenuations in circuit activity were also associated with improved depression symptoms. Changes in cognitive control circuit activity at 2 months better predicted changes in problem-solving ability and depression symptoms at 6, 12, and 24 months, with predictive improvements ranging from 17.8 to 104.0%, exceeding baseline demographic and symptom characteristics. Our findings suggest that targeting the circuit mechanism of action could enhance the prediction of treatment outcomes, warranting future model refinement and improvement to pave the way for its clinical application.

Rationale: Randomized evidence for endovascular thrombectomy safety and efficacy in patients with large core strokes is lacking., Aims: To demonstrate endovascular thrombectomy efficacy and safety in patients with large core on non-contrast CT or perfusion imaging (CT/MR) and determine if there is heterogeneity of treatment effect in large cores based on the imaging modality., Design: SELECT2 is a prospective, randomized, multi-center, assessor-blinded controlled trial with adaptive enrichment design, enrolling up to 560 patients., Procedure: Patients who meet the clinical criteria and have anterior circulation large vessel occlusions with large core on either NCCT (ASPECTS 3-5) or perfusion imaging (CTP [rCBF < 30%] and/or MRI [ADC < 620] ≥ 50 cc) will be randomized in a 1:1 ratio to undergo endovascular thrombectomy or medical management (MM) only up to 24 h of last known well., Study Outcomes: The distribution of 90-day mRS scores is the primary outcome. Functional independence (mRS = 0-2) rate is a secondary outcome. Other secondary outcomes include safety (symptomatic ICH, neurological worsening, mortality) and imaging outcomes., Analysis: A normal approximation of the Wilcoxon-Mann-Whitney test (the generalized likelihood ratio test) to assess the primary outcome. Functional independence rates, safety and imaging outcomes will also be compared., Discussion: The SELECT2 trial will evaluate endovascular thrombectomy safety and efficacy in large cores on either CT or perfusion imaging and may provide randomized evidence to extend endovascular thrombectomy eligibility to larger population. Registration: ClinicalTrials.gov-NCT03876457.

Background: Integrated treatments for comorbid depression (often with anxiety) and obesity are lacking; mechanisms are poorly investigated., Methods: In a mechanistic pilot trial, adults with body mass index ≥30 and Patient Health Questionnaire-9 scores ≥10 were randomized to usual care ( n  = 35) or an integrated behavioral intervention ( n  = 71). Changes at 6 months in body mass index and Depression Symptom Checklist-20 scores were co-primary outcomes, and Generalized Anxiety Disorder Scale-7 score was a secondary outcome. Changes at 2 months in the activation and functional connectivity of regions of interest in the negative affect circuit were primary neural targets, and secondary targets were in the cognitive control, default mode, and positive affect circuits., Results: Participants were 47.0 years (SD = 11.9 years), 76% women, 55% Black, and 20% Latino. Depression Symptom Checklist-20 (between-group difference, -0.3 [95% CI: -0.6 to -0.1]) and Generalized Anxiety Disorder Scale-7 (-2.9 [-4.7 to -1.1]) scores, but not body mass index, decreased significantly at 6 months in the intervention versus usual care groups. Only Generalized Anxiety Disorder Scale-7 score changes at 6 months significantly correlated with neural target changes at 2 months in the negative affect (anterior insula, subgenual/pregenual anterior cingulate cortex, amygdala) and cognitive control circuits (dorsal lateral prefrontal cortex, dorsal anterior cingulate cortex). Effects were medium to large (0.41-1.18 SDs). Neural target changes at 2 months in the cognitive control circuit only differed by treatment group. Effects were medium (0.58-0.79 SDs)., Conclusions: Compared with usual care, the study intervention led to significantly improved depression but not weight loss, and the results on neural targets were null for both outcomes. The significant intervention effect on anxiety might be mediated through changes in the cognitive control circuit, but this warrants replication., (© 2022 The Authors.)

Background: Depression hinders obesity treatment; elucidating mechanisms may enable treatment enhancements., Objectives: The aim was to investigate whether changes in neural targets in the negative affect circuit following psychotherapy mediate subsequent changes in weight and behaviors., Methods: Adults (n = 108) with obesity and depression were randomly assigned to usual care or an intervention that delivered problem-solving therapy (PST) for depression over 2 mo. fMRI for brain imaging was performed at baseline and 2 mo. BMI, physical activity, and diet were measured at baseline and 12 mo. Mediation analysis assessed between-group differences in neural target changes using t test and correlations between neural target changes and outcome changes (simple and interaction effect) using ordinary least-squares regression., Results: Compared with usual care, PST led to reductions in left amygdala activation (-0.75; 95% CI: -1.49, -0.01) and global scores of the negative affect circuit (-0.43; -0.81, -0.06), engaged by threat stimuli. Increases in amygdala activation and global circuit scores at 2 mo correlated with decreases in physical activity outcomes at 12 mo in the usual-care group; these relations were altered by PST. In relation to change in leisure-time physical activity, standardized β-coefficients were -0.67 in usual care and -0.01 in the intervention (between-group difference: 0.66; 0.02, 1.30) for change in left amygdala activation and -2.02 in usual care and -0.11 in the intervention (difference: 1.92; 0.64, 3.20) for change in global circuit scores. In relation to change in total energy expenditure, standardized β-coefficients were -0.65 in usual care and 0.08 in the intervention (difference: 0.73; 0.29, 1.16) for change in left amygdala activation and -1.65 in usual care and 0.08 in the intervention (difference: 1.74; 0.85, 2.63) for change in global circuit scores. Results were null for BMI and diet., Conclusions: Short-term changes in the negative affect circuit engaged by threat stimuli following PST for depression mediated longer-term changes in physical activity. This trial was registered at www.clinicaltrials.gov as NCT02246413 (https://clinicaltrials.gov/ct2/show/NCT02246413)., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Depression exerts a staggering toll that is worsened with co-occurring chronic conditions such as obesity. It is imperative to develop more effective interventions for depression and to identify objective and biological plausible neural mechanisms to understand intervention outcomes. The current study uses functional neuroimaging to determine whether a behavioural intervention changes the negative affect circuit and whether these changes relate to subsequent improvements in both symptom and problem-solving outcomes in depressed patients with co-occurring obesity., Methods: This study ('ENGAGE') was a pre-planned element of the randomized controlled trial, 'RAINBOW' (ClinicalTrials.gov NCT02246413). 108 depressed patients with obesity were randomized to receive an integrated collaborative care intervention (I-CARE) or usual care. Participants underwent functional neuroimaging using an established facial emotion task at baseline and two months (coinciding with the first two months of intervention focused on problem-solving therapy ('PST')). Amygdala, insula and anterior cingulate cortex activation was extracted using pre-planned definitions and standardized methods. The primary health and behavioural outcomes were depression symptom severity and problem-solving ability respectively, assessed at baseline, the main 6-month outcome point and at 12-month follow up. Mediation analyses used an intent-to-treat approach., Findings: PST, relative to usual care, reduced amygdala activation engaged by threat stimuli at two months. This reduction mediated subsequent improvements in depression severity in an intervention-dependent manner. PST did not change insula activation at two months but did temper the strength of the relationship between insula activation and improvements in problem-solving ability., Interpretation: The negative affect circuit may be an important neural target and potential mediator of PST in patients with comorbid obesity., Funding: US National Institutes of Health/National Heart Lung and Blood Institute R01 HL119453 and UH2/UH3 HL132368., Competing Interests: Declaration of Competing Interest LMW is on the Scientific Advisory Board for One Mind Psyberguide and the External Advisory Board for the Laureate Institute for Brain Research. JM is a paid scientific consultant for Health Mentor, Inc. (San Jose, CA). OA is the co-founder of Keywise AI and the servers on the advisory boards of Blueprint Health and Embodied Labs. TS reports in the last 36 months grants from Merck, grants from National Institute on Drug Abuse, grants from National Institute of Health, grants from Palo Alto Health Sciences, grants from Stanley Medical Research Institute, grants from Pathways Genomics, personal fees from Sunovion Pharmaceuticals, Inc., personal fees from American Society of Clinical Psychopharmacology, personal fees from Impel NeuroPharma Inc., personal fees from Intracellular Therapies, personal fees from Servier (Australia), personal fees from Allergan, Inc., personal fees from Medscape (WebMD), personal fees from CME Institute (Physicians Postgraduate Press, Inc.), personal fees from CMEology, personal fees from American Psychiatric Association Publishing, personal fees from Hogrefe Publishing, personal fees from Jones and Bartlett, personal fees from Wolters Kluwer Health (UpToDate), outside the submitted work., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

The RAINBOW trial demonstrated that an integrated collaborative care intervention was effective for improving weight and depression. This study examined mediation of the treatment effect by a priori specified lifestyle behaviors and cognitive functioning. Participants were randomized to a 12-month integrated intervention (n = 204) or usual care (n = 205). Body mass index (BMI) and 20-item Depression Symptom Check List (SCL-20) were co-primary outcomes (Y). To examine mediation, we assessed (a) the effect of the integrated intervention (X) on lifestyle behaviors (diet and physical activity) and cognitive functioning (problem-solving; M, X→M path a) and (b) the association of these behaviors with BMI and SCL-20 (M→Y path b). Mediation existed if paths a and b were significant or if path a and the product of coefficients test (paths a and b) were significant. Compared with usual care, the intervention led to significant improvements in leisure time physical activity (201.3 MET minutes/week [SD, 1,457.6]) and total calorie intake (337.4 kcal/day [818.3]) at 6 months but not 12 months (path a). These improvements were not significantly associated with improvements in BMI or SCL-20 (path b). However, avoidant problem-solving style score and increased fruit and vegetable intake significantly correlated with improvements in BMI at 6 and 12 months, respectively. Also, increased fruit and vegetable intake, higher dietary quality, and better problem-solving abilities significantly correlated with improvements in SCL-20 at 6 and 12 months. These findings did not support the hypothesized mediation, but suggest lifestyle behaviors and cognitive functioning to target in future intervention optimization., (© Society of Behavioral Medicine 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Despite evidence for effective integrated behavior therapy for treating comorbid obesity and depression, treatment response is highly variable and the underlying neurobiological mechanisms remain unknown. This hampers efforts to identify mechanistic targets in order to optimize treatment precision and potency. Funded within the NIH Science of Behavior Change (SOBC) Research Network, the 2-phased ENGAGE research project applies an experimental precision medicine approach to address this gap. The Phase 1 study focused on demonstrating technical feasibility, target engagement and potential neural mechanisms of responses to an integrated behavior therapy. This therapy combines a video-based behavioral weight loss program and problem-solving therapy for depression, with as-needed intensification of antidepressant medications, and its clinical effectiveness was demonstrated within a parent randomized clinical trial. Here, we describe the ENGAGE Phase 2 (ENGAGE-2) study protocol which builds on Phase 1 in 2 ways: (1) pilot testing of an motivational interviewing-enhanced, integrated behavior therapy in an independent, primarily minority patient sample, and (2) evaluation of a priori defined neural targets, specifically the negative affect (threat and sadness) circuits which demonstrated engagement and malleability in Phase 1, as mediators of therapeutic outcomes. Additionally, the Phase 2 study includes a conceptual and methodological extension to explore the role of microbiome-gut-brain and systemic immunological pathways in integrated behavioral treatment of obesity and depression. This protocol paper documents the conceptualization, design and the transdisciplinary methodologies in ENGAGE-2, which can inform future clinical and translational research in experimental precision medicine for behavior change and chronic disease management. Trial registration: ClinicalTrials.gov #NCT 03,841,682., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: The RAINBOW randomized clinical trial validated the efficacy of an integrated collaborative care intervention for obesity and depression in primary care, although the effect was modest. To inform intervention optimization, this study investigated within-treatment variability in participant engagement and progress., Methods: Data were collected in 2014-2017 and analyzed post hoc in 2018. Cluster analysis evaluated patterns of change in weekly self-monitored weight from week 6 up to week 52 and depression scores on the Patient Health Questionnaire-9 (PHQ-9) from up to 15 individual sessions during the 12-month intervention. Chi-square tests and ANOVA compared weight loss and depression outcomes objectively measured by blinded assessors to validate differences among categories of treatment engagement and progress defined based on cluster analysis results., Results: Among 204 intervention participants (50.9 [SD, 12.2] years, 71% female, 72% non-Hispanic White, BMI 36.7 [6.9], PHQ-9 14.1 [3.2]), 31% (n = 63) had poor engagement, on average completing self-monitored weight in <3 of 46 weeks and <5 of 15 sessions. Among them, 50 (79%) discontinued the intervention by session 6 (week 8). Engaged participants (n = 141; 69%) self-monitored weight for 11-22 weeks, attended almost all 15 sessions, but showed variable treatment progress based on patterns of change in self-monitored weight and PHQ-9 scores over 12 months. Three patterns of weight change (%) represented minimal weight loss (n = 50, linear β1 = -0.06, quadratic β2 = 0.001), moderate weight loss (n = 61, β1 = -0.28, β2 = 0.002), and substantial weight loss (n = 12, β1 = -0.53, β2 = 0.005). Three patterns of change in PHQ-9 scores represented moderate depression without treatment progress (n = 40, intercept β0 = 11.05, β1 = -0.11, β2 = 0.002), moderate depression with treatment progress (n = 20, β0 = 12.90, β1 = -0.42, β2 = 0.006), and milder depression with treatment progress (n = 81, β0 = 7.41, β1 = -0.23, β2 = 0.003). The patterns diverged within 6-8 weeks and persisted throughout the intervention. Objectively measured weight loss and depression outcomes were significantly worse among participants with poor engagement or poor progress on either weight or PHQ-9 than those showing progress on both., Conclusions: Participants demonstrating poor engagement or poor progress could be identified early during the intervention and were more likely to fail treatment at the end of the intervention. This insight could inform individualized and timely optimization to enhance treatment efficacy., Trial Registration: ClinicalTrials.gov# NCT02246413., Competing Interests: The authors declare that no competing interests existed for the research as reported. Dr. Lenard Lesser’s affiliation with 1Life Healthcare/One Medical constituted no competing interests. Dr. Lesser had originally supported on the NIH grant for his role as a study physician on this study while he was an employee at the Palo Alto Medical Foundation Research Institute (PAMFRI) where the study was conducted. Starting from 07/2016 till 10/2017, Dr. Lesser transitioned from PAMFRI to 1Life Healthcare, Inc/One Medical. At that time, his continuous involvement in the study was compensated through a research contract as an independent consultant with PAMFRI specifically for the NIH grant supporting the study. 1Life Healthcare/One Medical provided no support of any form for the study; and had no role in the study design, data collection/analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.”

Nonmyeloablative total lymphoid irradiation and antithymocyte globulin (TLI-ATG) conditioning is protective against graft-versus-host disease (GVHD), while retaining graft-versus-tumor activity across various hematologic malignancies. We report our comprehensive experience using TLI-ATG conditioning in 612 patients with hematologic malignancies who underwent allogeneic transplantation at Stanford University from 2001 to 2016. All patients received granulocyte colony-stimulating factor-mobilized peripheral blood grafts and cyclosporine and mycophenolate mofetil for GVHD prophylaxis. The median age was 60 years (range, 21-78), with a median follow-up of 6.0 years (range, 1.0-16.4). Common diagnoses included acute myeloid leukemia (AML; n = 193), myelodysplastic syndrome (MDS; n = 94), chronic lymphocytic leukemia (CLL; n = 80), non-Hodgkin lymphoma (NHL; n = 175), and Hodgkin lymphoma (HL; n = 35). Thirty-four percent of patients had a comorbidity index ≥3, 30% had a high to very high disease risk index, and 56% received unrelated donor grafts, including 15% with HLA-mismatched donors. Ninety-eight percent underwent transplant in the outpatient setting, and 57% were never hospitalized from days 0 through 100. The 1-year rates of nonrelapse mortality (NRM), grade II-IV acute GVHD, and extensive chronic GVHD were 9%, 14%, and 22%, respectively. The 4-year estimates for overall and progression-free survival were 42% and 32% for AML, 30% and 21% for MDS, 67% and 43% for CLL, 68% and 45% for NHL, and 78% and 49% for HL. Mixed chimerism correlated with the risk of relapse. TLI-ATG conditioning was well tolerated, with low rates of GVHD and NRM. Durable remissions were observed across hematologic malignancies, with particularly favorable outcomes for heavily pretreated lymphomas. Several efforts are underway to augment donor chimerism and reduce relapse rates while maintaining the favorable safety and tolerability profile of this regimen., (© 2019 by The American Society of Hematology.)

Importance: The DEFUSE 3 randomized clinical trial previously demonstrated benefit of endovascular thrombectomy for acute ischemic stroke in the 6- to 16-hour time window. For treatment recommendations, it is important to know if the treatment benefit was universal., Objective: To determine the outcomes among patients who may have a reduced effect of thrombectomy, including those who are older, have milder symptoms, or present late., Design, Setting, and Participants: DEFUSE 3 was a randomized, open-label, blinded end point trial conducted from May 2016 to May 2017. This multicenter study included 38 sites in the United States. Of 296 patients who were enrolled in DEFUSE 3, 182 patients met all inclusion criteria and were randomized and included in the intention-to-treat analysis, which was conducted in August 2017. These patients had acute ischemic strokes due to an occlusion of the internal carotid artery or middle cerebral artery and evidence of salvageable tissue on perfusion computed tomography or magnetic resonance imaging. The study was stopped early for efficacy., Interventions: Endovascular thrombectomy plus medical management vs medical management alone., Main Outcomes and Measures: Functional outcome at day 90, assessed on the modified Rankin Scale. Multivariate ordinal logistic regression was used to calculate the adjusted proportional association between endovascular treatment and clinical outcome (shift in the distribution of modified Rankin Scale scores expressed as a common odds ratio) among patients of different ages, baseline stroke severities, onset-to-treatment times, locations of the arterial occlusion, and imaging modalities used to document the presence of salvageable tissue (computed tomography vs magnetic resonance imaging)., Results: This study included 182 patients (median [interquartile range] age, 70 [59-80] years; median [interquartile range] National Institutes of Health Stroke Scale score, 16 [11-21], and 92 women [51%]). In the overall cohort, independent predictors of better functional outcome were younger age, lower baseline National Institutes of Health Stroke Scale score, and lower serum glucose level. The common odds ratio for improved functional outcome with endovascular therapy, adjusted for these variables, was 3.1 (95% CI, 1.8-5.4). There was no significant interaction between this treatment effect and age (P = .93), National Institutes of Health Stroke Scale score (P = .87), time to randomization (P = .56), imaging modality (P = .49), or location of the arterial occlusion (P = .54)., Conclusions and Relevance: Endovascular thrombectomy, initiated up to 16 hours after last known well time in patients with salvageable tissue on perfusion imaging, benefits patients with a broad range of clinical features. Owing to the small sample size of this study, a pooled analysis of late time window endovascular stroke trials is needed to confirm these results., Trial Registration: ClinicalTrials.gov identifier: NCT02586415.

Importance: Coexisting obesity and depression exacerbate morbidity and disability, but effective treatments remain elusive., Objective: To test the hypothesis that an integrated collaborative care intervention would significantly improve both obesity and depression at 12 months compared with usual care., Design, Setting, and Participants: The Research Aimed at Improving Both Mood and Weight (RAINBOW) randomized clinical trial enrolled 409 adults with body mass indices (BMIs) of 30 or greater (≥27 for Asian adults) and 9-item Patient Health Questionnaire (PHQ-9) scores of 10 or greater. Primary care patients at a health system in Northern California were recruited from September 30, 2014, to January 12, 2017; the date of final 12-month follow-up was January 17, 2018., Interventions: All participants randomly assigned to the intervention (n = 204) or the usual care control group (n = 205) received medical care from their personal physicians as usual, received information on routine services for obesity and depression at their clinic, and received wireless physical activity trackers. Intervention participants also received a 12-month intervention that integrated a Diabetes Prevention Program-based behavioral weight loss treatment with problem-solving therapy for depression and, if indicated, antidepressant medications., Main Outcomes and Measures: The co-primary outcome measures were BMI and 20-item Depression Symptom Checklist (SCL-20) scores (range, 0 [best] to 4 [worst]) at 12 months., Results: Among 409 participants randomized (mean age of 51.0 years [SD, 12.1 years]; 70% were women; mean BMI of 36.7 [SD, 6.4]; mean PHQ-9 score of 13.8 [SD, 3.1]; and mean SCL-20 score of 1.5 [SD, 0.5]), 344 (84.1%) completed 12-month follow-up. At 12 months, mean BMI declined from 36.7 (SD, 6.9) to 35.9 (SD, 7.1) among intervention participants compared with a change in mean BMI from 36.6 (SD, 5.8) to 36.6 (SD, 6.0) among usual care participants (between-group mean difference, -0.7 [95% CI, -1.1 to -0.2]; P = .01). Mean SCL-20 score declined from 1.5 (SD, 0.5) to 1.1 (SD, 1.0) at 12 months among intervention participants compared with a change in mean SCL-20 score from 1.5 (SD, 0.6) to 1.4 (SD, 1.3) among usual care participants (between-group mean difference, -0.2 [95% CI, -0.4 to 0]; P = .01). There were 47 adverse events or serious adverse events that involved musculoskeletal injuries (27 in the intervention group and 20 in the usual care group)., Conclusions and Relevance: Among adults with obesity and depression, a collaborative care intervention integrating behavioral weight loss treatment, problem-solving therapy, and as-needed antidepressant medications significantly improved weight loss and depressive symptoms at 12 months compared with usual care; however, the effect sizes were modest and of uncertain clinical importance., Trial Registration: ClinicalTrials.gov Identifier: NCT02246413.

After an overview of the Food and Drugs Administration's 2012 draft guidance on enrichment strategies for clinical trials to support drug/biologic approval, we describe subsequent advances in adaptive enrichment designs in this direction. We also provide a concrete application in the enrichment design of the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution 3 trial comparing a new endovascular treatment with standard of care for ischemic stroke patients., (© 2018 John Wiley & Sons, Ltd.)

Background: Thrombectomy is currently recommended for eligible patients with stroke who are treated within 6 hours after the onset of symptoms., Methods: We conducted a multicenter, randomized, open-label trial, with blinded outcome assessment, of thrombectomy in patients 6 to 16 hours after they were last known to be well and who had remaining ischemic brain tissue that was not yet infarcted. Patients with proximal middle-cerebral-artery or internal-carotid-artery occlusion, an initial infarct size of less than 70 ml, and a ratio of the volume of ischemic tissue on perfusion imaging to infarct volume of 1.8 or more were randomly assigned to endovascular therapy (thrombectomy) plus standard medical therapy (endovascular-therapy group) or standard medical therapy alone (medical-therapy group). The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability) at day 90., Results: The trial was conducted at 38 U.S. centers and terminated early for efficacy after 182 patients had undergone randomization (92 to the endovascular-therapy group and 90 to the medical-therapy group). Endovascular therapy plus medical therapy, as compared with medical therapy alone, was associated with a favorable shift in the distribution of functional outcomes on the modified Rankin scale at 90 days (odds ratio, 2.77; P<0.001) and a higher percentage of patients who were functionally independent, defined as a score on the modified Rankin scale of 0 to 2 (45% vs. 17%, P<0.001). The 90-day mortality rate was 14% in the endovascular-therapy group and 26% in the medical-therapy group (P=0.05), and there was no significant between-group difference in the frequency of symptomatic intracranial hemorrhage (7% and 4%, respectively; P=0.75) or of serious adverse events (43% and 53%, respectively; P=0.18)., Conclusions: Endovascular thrombectomy for ischemic stroke 6 to 16 hours after a patient was last known to be well plus standard medical therapy resulted in better functional outcomes than standard medical therapy alone among patients with proximal middle-cerebral-artery or internal-carotid-artery occlusion and a region of tissue that was ischemic but not yet infarcted. (Funded by the National Institute of Neurological Disorders and Stroke; DEFUSE 3 ClinicalTrials.gov number, NCT02586415 .).

Precision medicine models for personalizing achieving sustained behavior change are largely outside of current clinical practice. Yet, changing self-regulatory behaviors is fundamental to the self-management of complex lifestyle-related chronic conditions such as depression and obesity - two top contributors to the global burden of disease and disability. To optimize treatments and address these burdens, behavior change and self-regulation must be better understood in relation to their neurobiological underpinnings. Here, we present the conceptual framework and protocol for a novel study, "Engaging self-regulation targets to understand the mechanisms of behavior change and improve mood and weight outcomes (ENGAGE)". The ENGAGE study integrates neuroscience with behavioral science to better understand the self-regulation related mechanisms of behavior change for improving mood and weight outcomes among adults with comorbid depression and obesity. We collect assays of three self-regulation targets (emotion, cognition, and self-reflection) in multiple settings: neuroimaging and behavioral lab-based measures, virtual reality, and passive smartphone sampling. By connecting human neuroscience and behavioral science in this manner within the ENGAGE study, we develop a prototype for elucidating the underlying self-regulation mechanisms of behavior change outcomes and their application in optimizing intervention strategies for multiple chronic diseases., (Copyright © 2017. Published by Elsevier Ltd.)

Background and Purpose: Adaptive trial designs that allow enrichment of the study population through subgroup selection can increase the chance of a positive trial when there is a differential treatment effect among patient subgroups. The goal of this study is to illustrate the potential benefit of adaptive subgroup selection in endovascular stroke studies., Methods: We simulated the performance of a trial design with adaptive subgroup selection and compared it with that of a traditional design. Outcome data were based on 90-day modified Rankin Scale scores, observed in IMS III (Interventional Management of Stroke III), among patients with a vessel occlusion on baseline computed tomographic angiography (n=382). Patients were categorized based on 2 methods: (1) according to location of the arterial occlusive lesion and onset-to-randomization time and (2) according to onset-to-randomization time alone. The power to demonstrate a treatment benefit was based on 10 000 trial simulations for each design., Results: The treatment effect was relatively homogeneous across categories when patients were categorized based on arterial occlusive lesion and time. Consequently, the adaptive design had similar power (47%) compared with the fixed trial design (45%). There was a differential treatment effect when patients were categorized based on time alone, resulting in greater power with the adaptive design (82%) than with the fixed design (57%)., Conclusions: These simulations, based on real-world patient data, indicate that adaptive subgroup selection has merit in endovascular stroke trials as it substantially increases power when the treatment effect differs among subgroups in a predicted pattern., Competing Interests: Disclosures/Conflict of Interest All other authors report no conflict of interest., (© 2016 American Heart Association, Inc.)

Rigorous research on the benefit of healthy eating patterns for asthma control is lacking.We randomised 90 adults with objectively confirmed uncontrolled asthma and a low-quality diet (Dietary Approaches to Stop Hypertension (DASH) scores <6 out of 9) to a 6-month DASH behavioural intervention (n=46) or usual-care control (n=44). Intention-to-treat analyses used repeated-measures mixed models.Participants were middle-aged, 67% female and multiethnic. Compared with controls, intervention participants improved on DASH scores (mean change (95% CI) 0.6 (0, 1.1) versus -0.3 (-0.8, 0.2); difference 0.8 (0.2, 1.5)) and the primary outcome, Asthma Control Questionnaire scores (-0.2 (-0.5, 0) versus 0 (-0.3, 0.3); difference -0.2 (-0.5, 0.1)) at 6 months. The mean group differences in changes in Mini Asthma Quality of Life Questionnaire overall and subdomain scores consistently favoured the intervention over the control group: overall 0.4 (95% CI 0, 0.8), symptoms 0.5 (0, 0.9), environment 0.4 (-0.1, 1.0), emotions 0.4 (-0.2, 0.9) and activities 0.3 (0, 0.7). These differences were modest, but potentially clinical significant.The DASH behavioural intervention improved diet quality with promising clinical benefits for better asthma control and functional status among adults with uncontrolled asthma. A full-scale efficacy trial is warranted., Competing Interests: can be found alongside the online version of this article at erj.ersjournals.com, (Copyright ©ERS 2016.)

The past decade witnessed major developments in innovative designs of confirmatory clinical trials, and adaptive designs represent the most active area of these developments. We give an overview of the developments and associated statistical methods in several classes of adaptive designs of confirmatory trials. We also discuss their statistical difficulties and implementation challenges, and show how these problems are connected to other branches of mainstream Statistics, which we then apply to resolve the difficulties and bypass the bottlenecks in the development of adaptive designs for the next decade., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to compare Common Terminology Criteria for Adverse Events (CTCAE), Brock and Chang hearing loss grading in patients with head and neck cancer receiving cis-diamminedichloroplatinum (CDDP). Endpoints were baseline distribution of hearing loss, interobserver consistency, and sensitivity to hearing loss after CDDP treatment., Methods: Four hundred sixty single ear audiograms in 110 patients with head and neck cancer were graded. Hearing loss at baseline, interobserver agreement rates, and changes in hearing loss after CDDP were evaluated., Results: The Chang and Brock tools' baseline hearing loss distribution was concentrated at grade 0 (57% and 41%, respectively), whereas 47%, per the CTCAE, had grade 3 baseline hearing loss. Interobserver agreement was highest for the Brock scale (≥90%) followed by the Chang (≥89%) and CTCAE (≥75%) scales. Detection of change after CDDP was highest for Chang (48%) followed by Brock (45%) and the CTCAE (32%)., Conclusion: The Brock and Chang tools may be superior to the CTCAE in patients with head and neck cancer receiving CDDP using baseline hearing loss distribution, interobserver agreement, and detection of hearing loss grade change as performance indicators., (© 2014 Wiley Periodicals, Inc.)

Nonadherence to assigned treatment jeopardizes the power and interpretability of intent-to-treat comparisons from clinical trial data and continues to be an issue for effectiveness studies, despite their pragmatic emphasis. We posit that new approaches to design need to complement developments in methods for causal inference to address nonadherence, in both experimental and practice settings. This paper considers the conventional study design for psychiatric research and other medical contexts, in which subjects are randomized to treatments that are fixed throughout the trial and presents an alternative that converts the fixed treatments into an adaptive intervention that reflects best practice. The key element is the introduction of an adaptive decision point midway into the study to address a patient's reluctance to remain on treatment before completing a full-length trial of medication. The clinical uncertainty about the appropriate adaptation prompts a second randomization at the new decision point to evaluate relevant options. Additionally, the standard 'all-or-none' principal stratification (PS) framework is applied to the first stage of the design to address treatment discontinuation that occurs too early for a midtrial adaptation. Drawing upon the adaptive intervention features, we develop assumptions to identify the PS causal estimand and to introduce restrictions on outcome distributions to simplify expectation-maximization calculations. We evaluate the performance of the PS setup, with particular attention to the role played by a binary covariate. The results emphasize the importance of collecting covariate data for use in design and analysis. We consider the generality of our approach beyond the setting of psychiatric research., (Copyright © 2015 John Wiley & Sons, Ltd.)

Rationale: The effect of weight loss on asthma in obese adults warrants rigorous investigation., Objectives: To examine an evidence-based, practical, and comprehensive lifestyle intervention targeting modest weight loss and increased physical activity for asthma control., Methods: The trial randomized 330 obese adults with uncontrolled asthma to receive usual care enhanced with a pedometer, a weight scale, information about existing weight management services at the participating clinics, and an asthma education DVD, or with these tools plus the 12-month intervention., Measurements and Main Results: The primary outcome was change in Asthma Control Questionnaire (ACQ) scores from baseline to 12 months. Participants (mean [SD] age, 47.6 [12.4] yr) were 70.6% women, 20.0% non-Hispanic black, 20.3% Hispanic/Latino, and 8.2% Asian/Pacific Islander. At baseline, they were obese (mean [SD] body mass index, 37.5 [5.9] kg/m(2)) and had uncontrolled asthma (Asthma Control Test score, 15.1 [3.8]). Compared with control subjects, intervention participants achieved significantly greater mean weight loss (±SE) (intervention, -4.0 ± 0.8 kg vs. control, -2.1 ± 0.8 kg; P = 0.01) and increased leisure-time activity (intervention, 418.2 ± 110.6 metabolic equivalent task-min/wk vs. control, 178.8 ± 109.1 metabolic equivalent task-min/wk; P = 0.05) at 12 months. But between-treatment mean (±SE) differences were not significant for ACQ changes (intervention, -0.3 ± 0.1 vs. control, -0.2 ± 0.1; P = 0.92) from baseline (mean [SD], 1.4 [0.8]), nor for any other clinical asthma outcomes (e.g., spirometric results and asthma exacerbations). Among all participants regardless of treatment assignment, weight loss of 10% or greater was associated with a Cohen d effect of 0.76 and with 3.78 (95% confidence interval, 1.72-8.31) times the odds of achieving clinically significant reductions (i.e., ≥0.5) on ACQ as stable weight (<3% loss or gain from baseline). The effects of other weight change categories were small., Conclusions: Moderately and severely obese adults with uncontrolled asthma can safely participate in evidence-based lifestyle intervention for weight loss and active living. The modest average weight and activity improvements are comparable to those shown to reduce cardiometabolic risk factors in studies of similar interventions in other populations but are not associated with significant net benefits for asthma control or other clinical asthma outcomes in the current population. Instead, weight loss of 10% or greater may be required to produce clinically meaningful improvement in asthma. Clinical trial registered with www.clinicaltrials.gov (NCT00901095).

This paper is motivated by a randomized controlled trial to compare an endovascular procedure with conventional medical treatment for stroke patients, in which the endovascular procedure may be effective only in a subgroup of patients. Since the subgroup is not known at the design stage but can be learned statistically from the data collected during the course of the trial, we develop a novel group sequential design that incorporates adaptive choice of the patient subgroup among several possibilities which include the entire patient population as a choice. We define the type I and type II errors of a test in this design and show how a prescribed type I error can be maintained by using the closed testing principle in multiple testing. We also show how asymptotically optimal tests can be constructed by using generalized likelihood ratio statistics for parametric problems and analogous standardized or Studentized statistics for nonparametric tests such as Wilcoxon's rank sum test commonly used for treatment comparison in stroke patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: In June 2013, a 1-day workshop on Dynamic Treatment Strategies (DTSs) and Sequential Multiple Assignment Randomized Trials (SMARTs) was held at the University of Pennsylvania in Philadelphia, Pennsylvania. These two linked topics have generated a great deal of interest as researchers have recognized the importance of comparing entire strategies for managing chronic disease. A number of articles emerged from that workshop., Purpose: The purpose of this survey of the DTS/SMART methodology (which is taken from the introductory talk in the workshop) is to provide the reader the collected articles presented in this volume with sufficient background to appreciate the more detailed discussions in the articles., Methods: The way that the DTS arises naturally in clinical practice is described, along with its connection to the well-known difficulties of interpreting the analysis by intention-to-treat. The SMART methodology for comparing DTS is described, and the basics of estimation and inference presented., Results: The DTS/SMART methodology can be a flexible and practical way to optimize ongoing clinical decision making, providing evidence (based on randomization) for comparative effectiveness., Limitations: The DTS/SMART methodology is not a solution for unstandardized study protocols., Conclusions: The DTS/SMART methodology has growing relevance to comparative effectiveness research and the needs of the learning healthcare system., (© The Author(s), 2014.)

This pilot study aims to provide effect size confidence intervals, clinical trial and intervention feasibility data, and procedural materials for a full-scale randomized controlled trial that will determine the efficacy of Dietary Approaches to Stop Hypertension (DASH) as adjunct therapy to standard care for adults with uncontrolled asthma. The DASH diet encompasses foods (e.g., fresh fruit, vegetables, and nuts) and antioxidant nutrients (e.g., vitamins A, C, E, and zinc) with potential benefits for persons with asthma, but it is unknown whether the whole diet is beneficial. Participants (n = 90) will be randomized to receive usual care alone or combined with a DASH intervention consisting of 8 group and 3 individual sessions during the first 3 months, followed by at least monthly phone consultations for another 3 months. Follow-up assessments will occur at 3 and 6 months. The primary outcome measure is the 7-item Juniper Asthma Control Questionnaire, a validated composite measure of daytime and nocturnal symptoms, activity limitations, rescue medication use, and percentage predicted forced expiratory volume in 1 second. We will explore changes in inflammatory markers important to asthma pathophysiology (e.g., fractional exhaled nitric oxide) and their potential to mediate the intervention effect on disease control. We will also conduct pre-specified subgroup analyses by genotype (e.g., polymorphisms on the glutathione S transferase gene) and phenotype (e.g., atopy, obesity). By evaluating a dietary pattern approach to improving asthma control, this study could advance the evidence base for refining clinical guidelines and public health recommendations regarding the role of dietary modifications in asthma management., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: To investigate whether the effects on weight loss and cardiometabolic risk factor reduction of two technology-mediated lifestyle interventions for 15 months in a primary care-based translation trial sustained at 24 months (that is, 9 months after the end of intervention)., Design: This study analyzed data from an extended follow-up of participants in the original 'E-LITE' (Evaluation of Lifestyle Interventions to Treat Elevated Cardiometabolic Risk in Primary Care)-randomized controlled trial, which demonstrated the effectiveness of two adapted Diabetes Prevention Program (DPP) lifestyle interventions compared with usual primary care., Subjects: E-LITE randomized 241 overweight or obese participants with pre-diabetes and/or metabolic syndrome to receive usual care alone (n=81) or usual care plus a coach-led (n=79) or self-directed intervention (n=81). The interventions provided coach-led group behavioral weight-loss treatment or a take-home, self-directed DVD using the same 12-week curriculum, followed by 12 additional months of technology-mediated coach contact and self-monitoring support. Participants received no further intervention after month 15. A blinded assessor conducted 24-month visits by following the measurement protocols of the original trial. Measurements include weight and cardiometabolic risk factors (waist circumference, fasting plasma glucose, resting blood pressure, triglycerides, high- and low-density lipoprotein cholesterol, total cholesterol and triglyceride to high-density lipoprotein cholesterol ratio)., Results: At month 24, mean±s.e. changes in body mass index (trial primary outcome) and weight (kg) from baseline were -1.9±0.3 (P=0.001) and -5.4±0.9 (P<0.001) in the coach-led intervention, and -1.6±0.3 (P=0.03) and -4.5±0.9 (P=0.001) in the self-directed intervention, compared with -0.9±0.3 and 2.4±0.9 in the usual care group. In addition, both interventions led to a greater percentage of participants maintaining 7% weight loss and sustained improvements in waist circumference and fasting plasma glucose levels than usual care., Conclusion: This study shows sustained benefits of the two primary care-based, technology-mediated DPP lifestyle interventions. The findings warrant replication in long-term studies involving diverse populations.

Background: The Diabetes Prevention Program (DPP) lifestyle intervention reduced the incidence of type 2 diabetes mellitus (DM) among high-risk adults by 58%, with weight loss as the dominant predictor. However, it has not been adequately translated into primary care., Methods: We evaluated 2 adapted DPP lifestyle interventions among overweight or obese adults who were recruited from 1 primary care clinic and had pre-DM and/or metabolic syndrome. Participants were randomized to (1) a coach-led group intervention (n = 79), (2) a self-directed DVD intervention (n = 81), or (3) usual care (n = 81). During a 3-month intensive intervention phase, the DPP-based behavioral weight-loss curriculum was delivered by lifestyle coach-led small groups or home-based DVD. During the maintenance phase, participants in both interventions received lifestyle change coaching and support remotely-through secure email within an electronic health record system and the American Heart Association Heart360 website for weight and physical activity goal setting and self-monitoring. The primary outcome was change in body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) from baseline to 15 months., Results: At baseline, participants had a mean (SD) age of 52.9 (10.6) years and a mean BMI of 32.0 (5.4); 47% were female; 78%, non-Hispanic white; and 17%, Asian/Pacific Islander. At month 15, the mean ± SE change in BMI from baseline was -2.2 ± 0.3 in the coach-led group vs -0.9 ± 0.3 in the usual care group (P < .001) and -1.6 ± 0.3 in the self-directed group vs usual care (P = .02). The percentages of participants who achieved the 7% DPP-based weight-loss goal were 37.0% (P = .003) and 35.9% (P = .004) in the coach-led and self-directed groups, respectively, vs 14.4% in the usual care group. Both interventions also achieved greater net improvements in waist circumference and fasting plasma glucose level., Conclusion: Proven effective in a primary care setting, the 2 DPP-based lifestyle interventions are readily scalable and exportable with potential for substantial clinical and public health impact., Trial Registration: clinicaltrials.gov Identifier: NCT00842426.

Although traditional phase II cancer trials are usually single arm, with tumor response as endpoint, and phase III trials are randomized and incorporate interim analyses with progression-free survival or other failure time as endpoint, this paper proposes a new approach that seamlessly expands a randomized phase II study of response rate into a randomized phase III study of time to failure. This approach is based on advances in group sequential designs and joint modeling of the response rate and time to event. The joint modeling is reflected in the primary and secondary objectives of the trial, and the sequential design allows the trial to adapt to increase in information on response and survival patterns during the course of the trial and to stop early either for conclusive evidence on efficacy of the experimental treatment or for the futility in continuing the trial to demonstrate it, on the basis of the data collected so far., (Copyright © 2012 John Wiley & Sons, Ltd.)

Background: Advances in molecular therapeutics in the past decade have opened up new possibilities for treating cancer patients with personalized therapies, using biomarkers to determine which treatments are most likely to benefit them, but there are difficulties and unresolved issues in the development and validation of biomarker-based personalized therapies. We develop a new clinical trial design to address some of these issues. The goal is to capture the strengths of the frequentist and Bayesian approaches to address this problem in the recent literature and to circumvent their limitations., Methods: We use generalized likelihood ratio tests of the intersection null and enriched strategy null hypotheses to derive a novel clinical trial design for the problem of advancing promising biomarker-guided strategies toward eventual validation. We also investigate the usefulness of adaptive randomization (AR) and futility stopping proposed in the recent literature., Results: Simulation studies demonstrate the advantages of testing both the narrowly focused enriched strategy null hypothesis related to validating a proposed strategy and the intersection null hypothesis that can accommodate to a potentially successful strategy. AR and early termination of ineffective treatments offer increased probability of receiving the preferred treatment and better response rates for patients in the trial, at the expense of more complicated inference under small-to-moderate total sample sizes and some reduction in power., Limitations: The binary response used in the development phase may not be a reliable indicator of treatment benefit on long-term clinical outcomes. In the proposed design, the biomarker-guided strategy (BGS) is not compared to 'standard of care', such as physician's choice that may be informed by patient characteristics. Therefore, a positive result does not imply superiority of the BGS to 'standard of care'. The proposed design and tests are valid asymptotically. Simulations are used to examine small-to-moderate sample properties., Conclusion: Innovative clinical trial designs are needed to address the difficulties and issues in the development and validation of biomarker-based personalized therapies. The article shows the advantages of using likelihood inference and interim analysis to meet the challenges in the sample size needed and in the constantly evolving biomarker landscape and genomic and proteomic technologies.

Clinical demand for individualized "adaptive" treatment policies in diverse fields has spawned development of clinical trial methodology for their experimental evaluation via multistage designs, building upon methods intended for the analysis of naturalistically observed strategies. Because often there is no need to parametrically smooth multistage trial data (in contrast to observational data for adaptive strategies), it is possible to establish direct connections among different methodological approaches. We show by algebraic proof that the maximum likelihood (ML) and optimal semiparametric (SP) estimators of the population mean of the outcome of a treatment policy and its standard error are equal under certain experimental conditions. This result is used to develop a unified and efficient approach to design and inference for multistage trials of policies that adapt treatment according to discrete responses. We derive a sample size formula expressed in terms of a parametric version of the optimal SP population variance. Nonparametric (sample-based) ML estimation performed well in simulation studies, in terms of achieved power, for scenarios most likely to occur in real studies, even though sample sizes were based on the parametric formula. ML outperformed the SP estimator; differences in achieved power predominately reflected differences in their estimates of the population mean (rather than estimated standard errors). Neither methodology could mitigate the potential for overestimated sample sizes when strong nonlinearity was purposely simulated for certain discrete outcomes; however, such departures from linearity may not be an issue for many clinical contexts that make evaluation of competitive treatment policies meaningful.

We review adaptive designs for clinical trials, giving special attention to the control of the Type I error in late-phase confirmatory trials, when the trial planner wishes to adjust the final sample size of the study in response to an unblinded analysis of interim estimates of treatment effects. We point out that there is considerable inefficiency in using the adaptive designs that employ conditional power calculations to reestimate the sample size and that maintain the Type I error by using certain weighted test statistics. Although these adaptive designs have little advantage over familiar group-sequential designs, our review also describes recent developments in adaptive designs that are both flexible and efficient. We also discuss the use of Bayesian designs, when the context of use demands control over operating characteristics (Type I and II errors) and correction of the bias of estimated treatment effects.

Whereas the 20th-century health care system sometimes seemed to be inhospitable to and unmoved by experimental research, its inefficiency and unaffordability have led to reforms that foreshadow a new health care system. We point out certain opportunities and transformational needs for innovations in study design offered by the 21st-century health care system, and describe some innovative clinical trial designs and novel design methods to address these needs and challenges.

Background: Clinical trials are widely considered the gold standard in comparative effectiveness research (CER) but the high cost and complexity of traditional trials and concerns about generalizability to broad patient populations and general clinical practice limit their appeal. Unsuccessful implementation of CER results limits the value of even the highest quality trials. Planning for a trial comparing two standard strategies of insulin administration for hospitalized patients led us to develop a new method for a clinical trial designed to be embedded directly into the clinical care setting thereby lowering the cost, increasing the pragmatic nature of the overall trial, strengthening implementation, and creating an integrated environment of research-based care., Purpose: We describe a novel randomized clinical trial that uses the informatics and statistics infrastructure of the Veterans Affairs Healthcare System (VA) to illustrate one key component (called the point-of-care clinical trial - POC-CT) of a 'learning healthcare system,' and settles a clinical question of interest to the VA., Methods: This study is an open-label, randomized trial comparing sliding scale regular insulin to a weight-based regimen for control of hyperglycemia, using the primary outcome length of stay, in non-ICU inpatients within the northeast region of the VA. All non-ICU patients who require in-hospital insulin therapy are eligible for the trial, and the VA's automated systems will be used to assess eligibility and present the possibility of randomization to the clinician at the point of care. Clinicians will indicate their approval for informed consent to be obtained by study staff. Adaptive randomization will assign up to 3000 patients, preferentially to the currently 'winning' strategy, and all care will proceed according to usual practices. Based on a Bayesian stopping rule, the study has acceptable frequentist operating characteristics (Type I error 6%, power 86%) against a 12% reduction of median length of stay from 5 to 4.4 days. The adaptive stopping rule promotes implementation of a successful treatment strategy., Limitations: Despite clinical equipoise, individual healthcare providers may have strong treatment preferences that jeopardize the success and implementation of the trial design, leading to low rates of randomization. Unblinded treatment assignment may bias results. In addition, generalization of clinical results to other healthcare systems may be limited by differences in patient population. Generalizability of the POC-CT method depends on the level of informatics and statistics infrastructure available to a healthcare system., Conclusions: The methods proposed will demonstrate outcome-based evaluation of control of hyperglycemia in hospitalized veterans. By institutionalizing a process of statistically sound and efficient learning, and by integrating that learning with automatic implementation of best practice, the participating VA Healthcare Systems will accelerate improvements in the effectiveness of care.

Background: Minimizing the imbalance of key baseline covariates between treatments is known to be very important to the precision of the estimate of treatment effect in clinical research. Dynamic randomization allocation techniques have been used to achieve balance across multiple baseline characteristics. However, empirical data are limited on how these techniques compare in terms of balance and efficiency. We are motivated by a newly funded randomized controlled trial, in which we have the option of choosing between two methods of randomization at the subject level: (1) randomizing individual subjects consecutively as they are enrolled, using Pocock and Simon's minimization method, and (2) simultaneously randomizing blocks of subjects once all subjects in a block have been enrolled, using a balance algorithm originally developed for cluster randomized trials., Purpose: To compare dynamic block randomization and minimization in terms of balance on baseline covariates and statistical efficiency. Simple randomization was included as a reference., Methods: A simulation study using data from a previous randomized controlled trial was conducted to compare balance statistics and the accuracy and power of hypothesis testing among the randomization methods., Results: Dynamic block randomization consistently produced the best balance and highest power for various sample and treatment effect sizes, even after post-adjustment of the pre-specified baseline covariates in all three methods. Consistent with previous reports, minimization performed better in balance and power than simple randomization; however, the differences were noticeably smaller compared to those between dynamic block randomization and simple randomization., Limitations: In this simulation study, we considered three sample sizes and two block sizes for a two-arm randomized trial. We assumed no interactions among the multiple baseline covariates. It is necessary to evaluate how the results may vary when the simulation conditions are changed before drawing broader conclusions regarding comparisons between the randomization methods., Conclusions: This study demonstrates that dynamic block randomization outperforms minimization with regard to achieving balance and maximizing efficiency. Nevertheless, the differences across the three randomization strategies are modest. The statistical advantages associated with dynamic block randomization need to be considered in relation to the planned sample size and the practical issues for its implementation in deciding the preferred method of randomization for a given trial (e.g., the time required to accrue blocks of subjects of adequate size as balanced against the need to commence intervention/treatment immediately in those randomized to that experimental condition).

Purpose: The prostate cancer risk calculator from the Prostate Cancer Prevention Trial estimates the risk of positive biopsy and 1 containing high grade disease (Gleason score 7 or greater) based on prostate specific antigen, digital rectal examination, family history, race and prior negative biopsy. Since data used to create the calculator came from an unreferred population that underwent mainly sextant biopsy, to our knowledge its usefulness in the contemporary urology practice is unknown., Materials and Methods: We performed the same multivariate logistic regression used to derive the prostate cancer risk calculator in a cohort of men from the Stanford Prostate Needle Biopsy Database who underwent initial prostate needle biopsy using an extended 12-core scheme., Results: Our predictions of overall prostate cancer risk did not differ significantly from those of the calculator. Prostate specific antigen, abnormal digital rectal examination and family history were independent risk factors. However, our model predicted a much greater risk of high grade disease than the prostate cancer risk calculator. Prostate specific antigen, abnormal digital rectal examination and age were independent risk factors for high grade disease., Conclusions: The difference between our estimated risk of high grade prostate cancer and that of the prostate cancer risk calculator can be potentially explained by 1) differences between the cohorts (referred vs unreferred) or 2) the difference in grading, ie grading accuracy due to the difference in biopsy schemes or to temporally related grade shifts. Caution should be used when applying the prostate cancer risk calculator to counsel patients referred for suspicion of prostate cancer since it underestimates the risk of high grade disease., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Context: Most smokers with mental illness do not receive tobacco cessation treatment., Objective: To determine whether integrating smoking cessation treatment into mental health care for veterans with posttraumatic stress disorder (PTSD) improves long-term smoking abstinence rates., Design, Setting, and Patients: A randomized controlled trial of 943 smokers with military-related PTSD who were recruited from outpatient PTSD clinics at 10 Veterans Affairs medical centers and followed up for 18 to 48 months between November 2004 and July 2009., Intervention: Smoking cessation treatment integrated within mental health care for PTSD delivered by mental health clinicians (integrated care [IC]) vs referral to Veterans Affairs smoking cessation clinics (SCC). Patients received smoking cessation treatment within 3 months of study enrollment., Main Outcome Measures: Smoking outcomes included 12-month bioverified prolonged abstinence (primary outcome) and 7- and 30-day point prevalence abstinence assessed at 3-month intervals. Amount of smoking cessation medications and counseling sessions delivered were tested as mediators of outcome. Posttraumatic stress disorder and depression were repeatedly assessed using the PTSD Checklist and Patient Health Questionnaire 9, respectively, to determine if IC participation or quitting smoking worsened psychiatric status., Results: Integrated care was better than SCC on prolonged abstinence (8.9% vs 4.5%; adjusted odds ratio, 2.26; 95% confidence interval [CI], 1.30-3.91; P = .004). Differences between IC vs SCC were largest at 6 months for 7-day point prevalence abstinence (78/472 [16.5%] vs 34/471 [7.2%], P < .001) and remained significant at 18 months (86/472 [18.2%] vs 51/471 [10.8%], P < .001). Number of counseling sessions received and days of cessation medication used explained 39.1% of the treatment effect. Between baseline and 18 months, psychiatric status did not differ between treatment conditions. Posttraumatic stress disorder symptoms for quitters and nonquitters improved. Nonquitters worsened slightly on the Patient Health Questionnaire 9 relative to quitters (differences ranged between 0.4 and 2.1, P = .03), whose scores did not change over time., Conclusion: Among smokers with military-related PTSD, integrating smoking cessation treatment into mental health care compared with referral to specialized cessation treatment resulted in greater prolonged abstinence., Trial Registration: clinicaltrials.gov Identifier: NCT00118534.