Mediating Effects of Neural Targets on Depression, Weight, and Anxiety Outcomes of an Integrated Collaborative Care Intervention: The ENGAGE-2 Mechanistic Pilot Randomized Clinical Trial.

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.

Problem-solving therapy-induced amygdala engagement mediates lifestyle behavior change in obesity with comorbid depression: a randomized proof-of-mechanism trial.

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 ß-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 ß-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).

Development of immunosuppressive myeloid cells to induce tolerance in solid organ and hematopoietic cell transplant recipients.

Replacement of failed organs followed by safe withdrawal of immunosuppressive drugs has long been the goal of organ transplantation. We studied changes in the balance of T cells and myeloid cells in the blood of HLA-matched and -mismatched patients given living donor kidney transplants followed by total lymphoid irradiation, anti-thymocyte globulin conditioning, and donor hematopoietic cell transplant to induce mixed chimerism and immune tolerance. The clinical trials were based on a conditioning regimen used to establish mixed chimerism and tolerance in mice. In preclinical murine studies, there was a profound depletion of T cells and an increase in immunosuppressive polymorphonuclear (pmn) myeloid-derived suppressor cells (MDSCs) in the spleen and blood following transplant. Selective depletion of pmn MDSCs in mice abrogated mixed chimerism and tolerance. In our clinical trials, patients given an analogous tolerance conditioning regimen developed similar changes, including profound depletion of T cells and a marked increase in MDSCs in blood posttransplant. Posttransplant pmn MDSCs transiently increased expression of lectin-type oxidized LDL receptor-1, a marker of immunosuppression, and production of the T-cell inhibitor arginase-1. These posttransplant pmn MDSCs suppressed the activation, proliferation, and inflammatory cytokine secretion of autologous T-cell receptor microbead-stimulated pretransplant T cells when cocultured in vitro. In conclusion, we elucidated changes in receptors and function of immunosuppressive myeloid cells in patients enrolled in the tolerance protocol that were nearly identical to those of MDSCs required for tolerance in mice. These trials were registered at www.clinicaltrials.gov as #NCT00319657 and #NCT01165762.

Early changes in neural circuit function engaged by negative emotion and modified by behavioural intervention are associated with depression and problem-solving outcomes: A report from the ENGAGE randomized controlled trial.

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.

Correction: Variability in engagement and progress in efficacious integrated collaborative care for primary care patients with obesity and depression: Within-treatment analysis in the RAINBOW trial.

[This corrects the article DOI: 10.1371/journal.pone.0231743.].

The ENGAGE-2 study: Engaging self-regulation targets to understand the mechanisms of behavior change and improve mood and weight outcomes in a randomized controlled trial (Phase 2).

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.

Variability in engagement and progress in efficacious integrated collaborative care for primary care patients with obesity and depression: Within-treatment analysis in the RAINBOW trial.

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 ß1 = -0.06, quadratic ß2 = 0.001), moderate weight loss (n = 61, ß1 = -0.28, ß2 = 0.002), and substantial weight loss (n = 12, ß1 = -0.53, ß2 = 0.005). Three patterns of change in PHQ-9 scores represented moderate depression without treatment progress (n = 40, intercept ß0 = 11.05, ß1 = -0.11, ß2 = 0.002), moderate depression with treatment progress (n = 20, ß0 = 12.90, ß1 = -0.42, ß2 = 0.006), and milder depression with treatment progress (n = 81, ß0 = 7.41, ß1 = -0.23, ß2 = 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.

Mixed chimerism and acceptance of kidney transplants after immunosuppressive drug withdrawal.

Preclinical studies have shown that persistent mixed chimerism is linked to acceptance of organ allografts without immunosuppressive (IS) drugs. Mixed chimerism refers to continued mixing of donor and recipient hematopoietic cells in recipient tissues after transplantation of donor cells. To determine whether persistent mixed chimerism and tolerance can be established in patients undergoing living donor kidney transplantation, we infused allograft recipients with donor T cells and hematopoietic progenitors after posttransplant lymphoid irradiation. In 24 of 29 fully human leukocyte antigen (HLA)-matched patients who had persistent mixed chimerism for at least 6 months, complete IS drug withdrawal was achieved without subsequent evidence of rejection for at least 2 years. In 10 of 22 HLA haplotype-matched patients with persistent mixed chimerism for at least 12 months, reduction of IS drugs to tacrolimus monotherapy was achieved. Withdrawal of tacrolimus during the second year resulted in loss of detectable chimerism and subsequent rejection episodes, unless tacrolimus therapy was reinstituted. Posttransplant immune reconstitution of naïve B cells and B cell precursors was more rapid than the reconstitution of naïve T cells and thymic T cell precursors. Robust chimerism was observed only among naïve T and B cells but not among memory T cells. No evidence of rejection was observed in all surveillance graft biopsies obtained from mixed chimeric patients withdrawn from IS drugs, and none developed graft-versus-host disease. In conclusion, persistent mixed chimerism established in fully HLA- or haplotype-matched patients allowed for complete or partial IS drug withdrawal without rejection.

Nonmyeloablative TLI-ATG conditioning for allogeneic transplantation: mature follow-up from a large single-center cohort.

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.

Effect of Integrated Behavioral Weight Loss Treatment and Problem-Solving Therapy on Body Mass Index and Depressive Symptoms Among Patients With Obesity and Depression: The RAINBOW Randomized Clinical Trial.

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.

Association of Thrombectomy With Stroke Outcomes Among Patient Subgroups: Secondary Analyses of the DEFUSE 3 Randomized Clinical Trial.

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.

Adaptive enrichment designs for confirmatory trials.

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.

Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging.

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 .).

The ENGAGE study: Integrating neuroimaging, virtual reality and smartphone sensing to understand self-regulation for managing depression and obesity in a precision medicine model.

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.

Methodologic Considerations in the Application of Next-Generation Sequencing of Human TRB Repertoires for Clinical Use.

Next-generation sequencing (NGS) of immune receptors has become a standard tool to assess minimal residual disease (MRD) in patients treated for lymphoid malignancy, and it is being used to study the T-cell repertoire in many clinical settings. To better understanding the potential clinical utility and limitations of this application outside of MRD, we developed a BIOMED-2 primer-based NGS method and characterized its performance in controls and patients with graft-versus-host disease (GVHD) after allogeneic hematopoietic transplant. For controls and patients with GVHD, replicate sequencing of the same T-cell receptor ß (TRB) libraries was highly reproducible. Higher variability was observed in sequencing of different TRB libraries made from the same DNA stock. Variability was increased in patients with GVHD compared with controls; patients with GVHD also had lower diversity than controls. In the T-cell repertoire of a healthy person, approximately 99.6% of the CDR3 clones were in low abundance, with frequency <10-3. A single library could identify >93% of the clones with frequency ≥10-3 in the repertoire. Sequencing in duplicate increased the average detection rate to >97%. This work demonstrates that NGS reliably and robustly characterizes TRB populations in healthy individuals and patients with GVHD with frequency ≥10-3 and provides a methodologic framework for applying NGS immune repertoire methods to clinical testing applications beyond MRD.

Power of an Adaptive Trial Design for Endovascular Stroke Studies: Simulations Using IMS (Interventional Management of Stroke) III Data.

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.

The VA Point-of-Care Precision Oncology Program: Balancing Access with Rapid Learning in Molecular Cancer Medicine.

The Department of Veterans Affairs (VA) recognized the need to balance patient-centered care with responsible creation of generalizable knowledge on the effectiveness of molecular medicine tools. Embracing the principles of the rapid learning health-care system, a new clinical program called the Precision Oncology Program (POP) was created in New England. The POP integrates generalized knowledge about molecular medicine in cancer with a database of observations from previously treated veterans. The program assures access to modern genomic oncology practice in the veterans affairs (VA), removes disparities of access across the VA network of clinical centers, disseminates the products of learning that are generalizable to non-VA settings, and systematically presents opportunities for patients to participate in clinical trials of targeted therapeutics.

Women in Academic Medicine: Measuring Stereotype Threat Among Junior Faculty.

BACKGROUND: Gender stereotypes in science impede supportive environments for women. Research suggests that women's perceptions of these environments are influenced by stereotype threat (ST): anxiety faced in situations where one may be evaluated using negative stereotypes. This study developed and tested ST metrics for first time use with junior faculty in academic medicine. METHODS: Under a 2012 National Institutes of Health Pathfinder Award, Stanford School of Medicine's Office of Diversity and Leadership, working with experienced clinicians, social scientists, and epidemiologists, developed and administered ST measures to a representative group of junior faculty. RESULTS: 174 School of Medicine junior faculty were recruited (62% women, 38% men; 75% assistant professors, 25% instructors; 50% white, 40% Asian, 10% underrepresented minority). Women reported greater susceptibility to ST than did men across all items including ST vulnerability (p < 0.001); rejection sensitivity (p = 0.001); gender identification (p < 0.001); perceptions of relative potential (p = 0.048); and, sense of belonging (p = 0.049). Results of career-related consequences of ST were more nuanced. Compared with men, women reported lower beliefs in advancement (p = 0.021); however, they had similar career interest and identification, felt just as connected to colleagues, and were equally likely to pursue careers outside academia (all p > 0.42). CONCLUSIONS: Innovative ST metrics can provide a more complete picture of academic medical center environments. While junior women faculty are susceptible to ST, they may not yet experience all of its consequences in their early careers. As such, ST metrics offer a tool for evaluating institutional initiatives to increase supportive environments for women in academic medicine.

Implementation of a Precision Oncology Program as an Exemplar of a Learning Health Care System in the VA.

The program determines and disseminates precision oncology best practices; enhances patient and provider engagement; and fosters collaboration among the VA, National Cancer Institute, academia, other health care systems, and industry to provide cancer patients with access to clinical trial participation.