Preclinical side effect prediction through pathway engineering of protein interaction network models.

Modeling tools aim to predict potential drug side effects, although they suffer from imperfect performance. Specifically, protein-protein interaction models predict drug effects from proteins surrounding drug targets, but they tend to overpredict drug phenotypes and require well-defined pathway phenotypes. In this study, we used PathFX, a protein-protein interaction tool, to predict side effects for active ingredient-side effect pairs extracted from drug labels. We observed limited performance and defined new pathway phenotypes using pathway engineering strategies. We defined new pathway phenotypes using a network-based and gene expression-based approach. Overall, we discovered a trade-off between sensitivity and specificity values and demonstrated a way to limit overprediction for side effects with sufficient true positive examples. We compared our predictions to animal models and demonstrated similar performance metrics, suggesting that protein-protein interaction models do not need perfect evaluation metrics to be useful. Pathway engineering, through the inclusion of true positive examples and omics measurements, emerges as a promising approach to enhance the utility of protein interaction network models for drug effect prediction.

Preoperative Workup of Patients With Excessive Central Airway Collapse: Does Stent Evaluation Serve a Role?

BACKGROUND: Tracheobronchoplasty (TBP) is a definitive anatomic intervention for patients with severe symptomatic expiratory central airway collapse. Although stent evaluations have been described for surgical workup, current literature does not address if improvement during stent evaluation is sustained after TBP. We compared health-related quality of life (HRQOL) and functional status responses after airway stenting to those post-TBP. METHODS: A retrospective review was performed in patients with severe expiratory central airway collapse who underwent stent evaluation followed by TBP from January 2004 to December 2019. Baseline, poststent, 3- and 12-month postoperative HRQOL scores, and functional status were analyzed with statistical tests as appropriate. RESULTS: One hundred twenty patients underwent a stent evaluation and TBP. Baseline and stent evaluation measurements were compared with statistically and clinically significant differences in the Cough Quality-of-life Questionnaire (CQLQ) (55 vs. 68, P <0.01), Modified Medical Research Council (mMRC) 0 to 2 (90% vs. 47%, P <0.01), 6-minute walk test (6MWT) (1301 ft vs. 1138 ft, P <0.01). Improvements in the HRQOL and functional status were maintained from stent evaluation to 3 months postoperatively [CQLQ 55 vs. 54, P =0.63; mMRC 0 to 2 (87% vs. 84%), P =0.39; 6MWT 1350 ft vs. 1314 ft, P =0.33], and 12 months postoperatively [CQLQ 54 vs. 54, P =0.91; mMRC 0 to 2 (95% vs. 86%), P =0.74; 6MWT 1409 ft vs. 1328 ft, P =0.13]. The magnitude of change between the data was not significantly different between the stent evaluation, 3-, and 12 months postoperative. Predicted forced expiratory volume in 1-second measurements at baseline, after stent placement, 3 months, and 12 months post-TBP were 74%, 79%, 73%, and 73%, respectively, and not clinically significant. CONCLUSIONS: Improvement after stent evaluation and the magnitude of improvement may be predictive of postoperative outcomes up to 1 year after surgery.

An Integrative Review of Grandparents' Experiences in Childhood Cancer.

Background: While it is generally accepted that childhood cancer has a profound impact on the family unit, there has been little focus on the experiences of grandparents who are affected by the diagnosis. Grandparents play an integral role throughout the child's illness trajectory as they are called upon to provide support physically, spiritually, emotionally, and at times financially. This integrative review examines the current research specific to grandparents' experiences of childhood cancer. Method: CINAHL, PubMed, and Web of Science were searched using the key terms "grandparent*" AND "experience*" AND "child*" AND "cancer." Inclusion criteria used for this review were as follows: electronic full text, peer-reviewed, and published in English between 2012 and 2022. Results: Grandparents of children with cancer experience an emotional whirlwind, a double-whammy effect, the giving and receiving of support, a balancing act, and attempt to find meaning throughout the diagnosis. They feel unacknowledged and unsupported by the health care team. Discussion: It is difficult to deny the emotional and familial impact the child's cancer diagnosis has not only on the child and immediate family but also on grandparents. While the reports of grandparents are consistent across studies, there have been lackluster attempts to mitigate the suffering experienced by this group. Pediatric oncology nurses, with their family-centered care approach, are in a unique position to uncover and meet the specific needs of grandparents of children diagnosed with cancer.

Beta-2 adrenergic receptor agonism alters astrocyte phagocytic activity and has potential applications to psychiatric disease.

Schizophrenia is a debilitating condition necessitating more efficacious therapies. Previous studies suggested that schizophrenia development is associated with aberrant synaptic pruning by glial cells. We pursued an interdisciplinary approach to understand whether therapeutic reduction in glial cell-specifically astrocytic-phagocytosis might benefit neuropsychiatric patients. We discovered that beta-2 adrenergic receptor (ADRB2) agonists reduced phagocytosis using a high-throughput, phenotypic screen of over 3200 compounds in primary human fetal astrocytes. We used protein interaction pathways analysis to associate ADRB2, to schizophrenia and endocytosis. We demonstrated that patients with a pediatric exposure to salmeterol, an ADRB2 agonist, had reduced in-patient psychiatry visits using a novel observational study in the electronic health record. We used a mouse model of inflammatory neurodegenerative disease and measured changes in proteins associated with endocytosis and vesicle-mediated transport after ADRB2 agonism. These results provide substantial rationale for clinical consideration of ADRB2 agonists as possible therapies for patients with schizophrenia.

An electronic health record cohort of Veterans with amyotrophic lateral sclerosis.

Objective: To assemble and characterize an electronic health record (EHR) dataset for a large cohort of US military Veterans diagnosed with ALS (Amyotrophic Lateral Sclerosis). Methods: An EHR dataset for 19,662 Veterans diagnosed with ALS between January 1, 2000 to December 31, 2020 was compiled from the Veterans Health Administration (VHA) EHR database by a query for ICD9 diagnosis (335.20) or ICD10 diagnosis (G12.21) for Amyotrophic Lateral Sclerosis. Results: The cohort is predominantly male (98.94%) and white (72.37%) with a median age at disease onset of 68 years and median survival from the date of diagnosis of 590 days. With the designation of ALS as a compensable illness in 2009, there was a subsequent increase in the number of Veterans diagnosed per year in the VHA, but no change in median survival. The cohort included a greater-than-expected proportion of individuals whose branch of service at the time of separation was the Army. Conclusions: The composition of the cohort reflects the VHA population who are at greatest risk for ALS. The greater than expected proportion of individuals whose branch of service at the time of separation was the Army suggests the possibility of a branch-specific risk factor for ALS.

Intensity of one-lung ventilation and postoperative respiratory failure: A hospital registry study.

BACKGROUND: Studies linked a high intensity of mechanical ventilation, measured as high mechanical power (MP) to postoperative respiratory failure (PRF) in the setting of two-lung ventilation. We investigated whether a higher MP during one-lung ventilation (OLV) is associated with PRF. METHODS: In this registry-based study, adult patients who underwent general anesthesia with OLV for thoracic surgeries between 2006 and 2020 at a New England tertiary healthcare network were included. The association between MP during OLV and PRF (emergency non-invasive ventilation or reintubation within seven days) was assessed in a cohort weighted through a generalized propensity score conditional on a priori defined preoperative and intraoperative factors. Dominance of components of MP and intensity of OLV versus two-lung ventilation in predicting PRF was investigated. RESULTS: Out of 878 included patients, 106 (12.1%) developed PRF. The median (IQR) MP during OLV was 9.8 J/min (7.5-11.8) and 8.3 J/min (6.6-10.2) in patients with and without PRF respectively. A higher MP during OLV was associated with PRF (ORadj 1.22 per 1 J/min increase; 95%CI 1.13-1.31; p < 0.001) and characterized by a U-shaped dose-response curve, with the lowest probability of PRF (7.5%) at 6.4 J/min. Dominance analysis of PRF predictors showed a stronger contribution of driving pressure over respiratory rate and tidal volume, the dynamic over the static component of MP, and MP during OLV over two-lung ventilation (contribution to Pseudo-R2: 0.017, 0.021, and 0.036, respectively). CONCLUSION: A higher intensity of OLV, mainly driven by driving pressure, is dose-dependently associated with PRF and might constitute a target for mechanical ventilation.

Outcomes of shared institutional review board compared with multiple individual site institutional review board models in a multisite clinical trial.

BACKGROUND: Institutional review boards play a crucial role in initiating clinical trials. Although many multicenter clinical trials use an individual institutional review board model, where each institution uses their local institutional review board, it is unknown if a shared (single institutional review board) model would reduce the time required to approve a standard institutional review board protocol. OBJECTIVE: This study aimed to compare processing times and other processing characteristics between sites using a single institutional review board model and those using their individual site institutional review board model in a multicenter clinical trial. STUDY DESIGN: This was a retrospective study of sites in an open-label, multicenter randomized control trial from 2014 to 2021. Participating sites in the multicenter Chronic Hypertension and Pregnancy trial were asked to complete a survey collecting data describing their institutional review board approval process. RESULTS: A total of 45 sites participated in the survey (7 used a shared institutional review board model and 38 used their individual institutional review board model). Most sites (86%) using the shared institutional review board model did not require a full-board institutional review board meeting before protocol approval, compared with 1 site (3%) using the individual institutional review board model (P<.001). Median total approval times (41 vs 56 days; P=.42), numbers of submission rounds (1 vs 2; P=.09), and numbers of institutional review board stipulations (1 vs 4; P=.12) were lower for the group using the shared institutional review board model than those using the individual site institutional review board model; however, these differences were not statistically significant. CONCLUSION: The findings supported the hypothesis that the shared institutional review board model for multicenter studies may be more efficient in terms of cumulative time and effort required to obtain approval of an institutional review board protocol than the individual institutional review board model. Given that these data have important implications for multicenter clinical trials, future research should evaluate these findings using larger or multiple multicenter trials.

Concept Analysis of Family-Centered Care in Childhood Cancer: An Evolutionary Approach.

The purpose of this article is to further develop the concept of family-centered care (FCC) in childhood cancer using Rodgers' evolutionary method of concept analysis. A search of the existing literature related to the overarching concept of FCC revealed several concept analyses specific to hospitalized children and children with chronic illness; however, none of these were specific to children with cancer. Five defining attributes of FCC in childhood cancer were identified through this concept analysis: ripple effect, customized care, family functioning, collaboration, and communication. A definition of FCC in childhood cancer is offered based on identified characteristics of the concept. Findings of this concept analysis provide a starting point for on-going development of the concept of FCC in childhood cancer and may facilitate more rigorous nursing studies involving FCC in childhood cancer.

Robotic Surgery for Tracheobronchomalacia.

Robotic tracheobronchoplasty (TBP) is a new surgical approach to treat tracheobronchomalacia (TBM), and is based on open TBP, which has undergone various technical iterations since the 1950s. The robotic approach to TBM may allow for more patients to undergo TBP, and in retrospective series has demonstrated equivalent outcomes compared to open TBP if not superior in terms of postoperative complications. Long-term data are eagerly awaited, and we describe our approach in this article.

Tracheobronchoplasty yields long-term anatomy, function, and quality of life improvement for patients with severe excessive central airway collapse.

OBJECTIVES: This study examines the long-term anatomic and clinical effects of tracheobronchoplasty in severe excessive central airway collapse. METHODS: Included patients underwent tracheobronchoplasty for excessive central airway collapse (2002-2016). The cross-sectional area of main airways on dynamic airway computed tomography was measured before and after tracheobronchoplasty. Expiratory collapse was calculated as the difference between inspiratory and expiratory cross-sectional area divided by inspiratory cross-sectional area ×100. The primary outcome was improvement in the percentage of expiratory collapse in years 1, 2, and 5 post-tracheobronchoplasty. Secondary outcomes included mean response profile for the 6-minute walk test, Cough-Specific Quality of Life Questionnaire, Karnofsky Performance Status score, and St George Respiratory Questionnaire. Repeated-measures analysis of variance was used for statistical analyses. RESULTS: The cohort included 61 patients with complete radiological follow-up at years 1, 2, and 5 post-tracheobronchoplasty. A significant linear decrease in the percentage of expiratory collapsibility of the central airways after tracheobronchoplasty was present. Anatomic repair durability was preserved 5 years after tracheobronchoplasty, with decrease in percentage of expiratory airway collapse up to 40% and 30% at years 1 and 2, respectively. The St George Respiratory Questionnaire (74.7 vs 41.8%, P < .001) and Cough-Specific Quality of Life Questionnaire (78 vs 47, P < .001) demonstrated significant improvement at year 5 compared with baseline. Similar results were observed in the 6-minute walk test (1079 vs 1268 ft, P < .001) and Karnofsky score (57 vs 82, P < .001). CONCLUSIONS: Tracheobronchoplasty has durable effects on airway anatomy, functional status, and quality of life in carefully selected patients with severe excessive central airway collapse.

Stent Evaluation for Expiratory Central Airway Collapse: Does the Type of Stent Really Matter?

BACKGROUND: Careful selection of patients with expiratory central airway collapse (ECAC) that may benefit from tracheobronchoplasty (TBP) can be aided by a short-term airway stent evaluation. This can be performed with either silicone Y-stents (SYSs) or uncovered self-expanding metallic airway-stents (USEMAS). No direct comparison has been made between these 2 stent types. METHODS: This was a small retrospective review of consecutive patients that underwent a stent evaluation. A propensity score was used to match patients in the USEMAS and SYS groups. Outcomes included complications, changes in the health-related quality-of-life (HR-QoL), and changes in exercise capacity. Baseline measurements were compared with those obtained during stent evaluation and after TBP. RESULTS: Forty-two patients with severe ECAC underwent USEMAS placement, while 18 patients had an SYS placed. Propensity score matching resulted in 13 matched SYS and USEMAS pairs. The SYS group had an increased rate of mucus plugging (38.5% vs. 0%, P <0.047). Although not statically significant, a clinical improvement was observed in HR-QoL and exercise capacity in the USEMAS group during stent placement. In patients who underwent TBP, both USEMAS and SYS groups had a statistically significant change in the Modified Medical Research Council Dyspnea Scale during stent evaluation and after TBP. CONCLUSION: In patients with severe ECAC, short-term evaluation with airway stents appears to be safe and improves respiratory symptoms, HR-QoL, and exercise capacity. The use of USEMAS led to a lower complication rate, a greater improvement in HR-QoL and exercise capacity, and appeared to better predict how the patients would respond to TBP.

Video- and Robotic-Assisted Thoracoscopic Truncal Vagotomy.

A subset of patients with marginal ulcers after Roux-en-Y gastric bypass (RNYGB) is refractory to medical management. Here we report a retrospective review of a single institution cohort (N = 10) of video- or robotic-assisted thoracoscopic (VATS or RATS) truncal vagotomies performed between 2013 and 2018. All patients had recurrent marginal ulcers following RNYGB complicated by bleeding or perforation, refractory to medical management for a median of 3.5 months prior to undergoing truncal vagotomy. With a median of 23 months' follow-up, only three patients had continued symptoms (70% symptom resolution) post-operatively. Only one patient who had repeat endoscopy after the procedure had documented endoscopic evidence of recurrent marginal ulcer (83% endoscopic resolution). VATS or RATS truncal vagotomy is a safe and effective method to treat complicated marginal ulceration after RNYGB. After an average duration of unsuccessful medical treatment lasting three months, vagotomy led to successful resolution in 70-83% of patients.

A network paradigm predicts drug synergistic effects using downstream protein-protein interactions.

In some cases, drug combinations affect adverse outcome phenotypes by binding the same protein; however, drug-binding proteins are associated through protein-protein interaction (PPI) networks within the cell, suggesting that drug phenotypes may result from long-range network effects. We first used PPI network analysis to classify drugs based on proteins downstream of their targets and next predicted drug combination effects where drugs shared network proteins but had distinct binding proteins (e.g., targets, enzymes, or transporters). By classifying drugs using their downstream proteins, we had an 80.7% sensitivity for predicting rare drug combination effects documented in gold-standard datasets. We further measured the effect of predicted drug combinations on adverse outcome phenotypes using novel observational studies in the electronic health record. We tested predictions for 60 network-drug classes on seven adverse outcomes and measured changes in clinical outcomes for predicted combinations. These results demonstrate a novel paradigm for anticipating drug synergistic effects using proteins downstream of drug targets.

Complete pathologic response to short-course neoadjuvant alectinib in mediastinal node positive (N2) ALK rearranged lung cancer.

OBJECTIVES: Neoadjuvant therapy prior to surgical resection for locally advanced lung cancer has evolved to incorporate systemic cytotoxic chemotherapy +/- immunotherapy +/- radiotherapy. The role of neoadjuvant precision therapies remains understudied. MATERIALS AND METHODS: We report cases with major and complete pathologic responses to off-label neoadjuvant alectinib. RESULTS: A case with stage IIIA (cT1b cN2 cM0) EML4-ALK variant 3a/b lung adenocarcinoma received 6 weeks of alectinib followed by R0 left upper lobectomy with complete pathological response (ypT0 ypN0). Another case with stage IIIA (cT3 cN2 cM0) EML4-ALK variant 2 received 12 weeks of alectinib followed by R0 right middle lobectomy with a major pathologic response (ypT1a ypN0) but systemic recurrence 12 months post-operatively. CONCLUSION: Ongoing clinical trials are evaluating the role of both neoadjuvant and adjuvant ALK-directed therapy. Our cases support the completion of ongoing trials (ALINA: NCT03456076 and ALNEO: NCT05015010), and highlight the ability of second generation ALK inhibitors to induce major and complete pathologic responses in the neoadjuvant setting plus the likely role of long-term adjuvant kinase inhibitor therapy to prevent radiographic/clinical recurrence.

Controlling astrocyte-mediated synaptic pruning signals for schizophrenia drug repurposing with deep graph networks.

Schizophrenia is a debilitating psychiatric disorder, leading to both physical and social morbidity. Worldwide 1% of the population is struggling with the disease, with 100,000 new cases annually only in the United States. Despite its importance, the goal of finding effective treatments for schizophrenia remains a challenging task, and previous work conducted expensive large-scale phenotypic screens. This work investigates the benefits of Machine Learning for graphs to optimize drug phenotypic screens and predict compounds that mitigate abnormal brain reduction induced by excessive glial phagocytic activity in schizophrenia subjects. Given a compound and its concentration as input, we propose a method that predicts a score associated with three possible compound effects, i.e., reduce, increase, or not influence phagocytosis. We leverage a high-throughput screening to prove experimentally that our method achieves good generalization capabilities. The screening involves 2218 compounds at five different concentrations. Then, we analyze the usability of our approach in a practical setting, i.e., prioritizing the selection of compounds in the SWEETLEAD library. We provide a list of 64 compounds from the library that have the most potential clinical utility for glial phagocytosis mitigation. Lastly, we propose a novel approach to computationally validate their utility as possible therapies for schizophrenia.

From random to predictive: a context-specific interaction framework improves selection of drug protein-protein interactions for unknown drug pathways.

With high drug attrition, protein-protein interaction (PPI) network models are attractive as efficient methods for predicting drug outcomes by analyzing proteins downstream of drug targets. Unfortunately, these methods tend to overpredict associations and they have low precision and prediction performance; performance is often no better than random (AUROC ~0.5). Typically, PPI models identify ranked phenotypes associated with downstream proteins, yet methods differ in prioritization of downstream proteins. Most methods apply global approaches for assessing all phenotypes. We hypothesized that a per-phenotype analysis could improve prediction performance. We compared two global approaches-statistical and distance-based-and our novel per-phenotype approach, 'context-specific interaction' (CSI) analysis, on severe side effect prediction. We used a novel dataset of adverse events (or designated medical events, DMEs) and discovered that CSI had a 50% improvement over global approaches (AUROC 0.77 compared to 0.51), and a 76-95% improvement in average precision (0.499 compared to 0.284, 0.256). Our results provide a quantitative rationale for considering downstream proteins on a per-phenotype basis when using PPI network methods to predict drug phenotypes.

Obese Patients Undergoing Tracheobronchoplasty Have Excellent Outcomes.

BACKGROUND: Tracheobronchoplasty (TBP) is the gold-standard treatment for severe symptomatic excessive central airway collapse; however outcomes among obese patients are unknown. METHODS: A retrospective, single-center analysis was conducted on consecutive patients undergoing TBP for severe symptomatic excessive central airway collapse from 2003 to 2020. Demographics, comorbidities, functional status, and perioperative complications were collected. Functional status was assessed with a 6-minute walk test (6MWT). Health-related quality of life (HRQOL) was assessed with the St George's Respiratory Questionnaire (SGRQ), Cough-specific Quality of Life Questionnaire, and modified Medical Research Council dyspnea scale (mMRC) at baseline and postoperatively. Wilcoxon rank-sum and χ2 tests were used to compare outcomes between groups. A mixed-effects regression model compared 6MWT and HRQOL over time. RESULTS: One hundred three patients underwent TBP with complete follow-up data. Thirty-four patients (33%) were obese (body mass index ≥ 35 kg/m2). Baseline demographics were similar between obese and nonobese groups, but obese patients had worse preoperative SGRQ and mMRC scores. Overall complication rates were similar (52.9% vs 43.5%, P = .36). At 3 months there was no significant difference in SGRQ, Cough-specific Quality of Life Questionnaire, or 6MWT scores; however mMRC scores were higher in obese patients (P = .04). At 12 months there was no significant difference in SGRQ, Cough-specific Quality of Life Questionnaire, mMRC, or 6MWT scores. Correcting for age, sex, and Charlson Comorbidity Index a mixed-effects regression model demonstrated obesity was not an independent predictor for lower 6MWT scores or HRQOL. CONCLUSIONS: Obese patients achieve similar improvement in HRQOL and functional capacity with comparable morbidity after TBP as nonobese patients. Obesity should not preclude patients with severe symptomatic excessive central airway collapse from TBP.

The impact of pathology grossing protocol measures to improve pathologic nodal staging in lung cancer.

OBJECTIVE: Accurate assessment of lymph node (LN) status is essential for proper staging of resected lung cancer specimens. Here, we assessed pathology-centric interventions to increase the number of peribronchial LNs identified and evaluated in anatomic lung cancer resection specimens as part of a quality improvement initiative. MATERIALS AND METHODS: All non-small cell lung cancer (NSCLC) anatomic resection specimens from 2017 to 2020 were evaluated, comprising two years pre-intervention and one year post-intervention. We instituted 3 measures to increase peribronchial LN yield: 1) educational grossing sessions for pathology assistants and residents, 2) directions to submit additional peribronchial tissue if no LNs were identified grossly, and 3) a hard-stop prior to sign-out by the attending pathologist if no peribronchial LNs were identified. RESULTS: Of the total 227 resection specimens for NSCLC, 107/151 (70.9%) of specimens prior to the intervention had peribronchial LNs identified, whereas after the intervention significantly more (66/76, 86.8%, p < 0.01) specimens had peribronchial LNs identified. In addition, the mean number of peribronchial LNs identified significantly increased from 2.7 ± 3.3 pre-intervention to 4.3 ± 4.0 post-intervention (p < 0.001). Further analysis revealed a strong correlation between peribronchial LN metastases with both overall tumor size and invasive component size (for adenocarcinomas), correlation coefficient 0.974, p < 0.0001. CONCLUSION: Establishing focused grossing measures by pathology led to a significant increase in the number of peribronchial LNs identified and assessed during histopathologic evaluation of anatomic lung cancer resection specimens. Larger tumors are more likely to have occult peribronchial LN metastases, which may warrant more aggressive peribronchial LN assessment for larger tumors.

PhenClust, a standalone tool for identifying trends within sets of biological phenotypes using semantic similarity and the Unified Medical Language System metathesaurus.

OBJECTIVES: We sought to cluster biological phenotypes using semantic similarity and create an easy-to-install, stable, and reproducible tool. MATERIALS AND METHODS: We generated Phenotype Clustering (PhenClust)-a novel application of semantic similarity for interpreting biological phenotype associations-using the Unified Medical Language System (UMLS) metathesaurus, demonstrated the tool's application, and developed Docker containers with stable installations of two UMLS versions. RESULTS: PhenClust identified disease clusters for drug network-associated phenotypes and a meta-analysis of drug target candidates. The Dockerized containers eliminated the requirement that the user install the UMLS metathesaurus. DISCUSSION: Clustering phenotypes summarized all phenotypes associated with a drug network and two drug candidates. Docker containers can support dissemination and reproducibility of tools that are otherwise limited due to insufficient software support. CONCLUSION: PhenClust can improve interpretation of high-throughput biological analyses where many phenotypes are associated with a query and the Dockerized PhenClust achieved our objective of decreasing installation complexity.

Quetiapine augmentation of prolonged exposure therapy in veterans with PTSD and a history of mild traumatic brain injury: design and methodology of a pilot study.

BACKGROUND: Selective serotonergic reuptake inhibitors (SSRIs) are first-line pharmacologic treatments for patients with posttraumatic stress disorder (PTSD), but must be given over extended period of time before the onset of action. The use of SSRIs in PTSD patients with mild traumatic brain injury (mTBI) is problematic since SSRIs could exacerbate post-concussion syndrome (PCS) symptoms. VA/DOD guidelines identify trauma-focused psychotherapy as the best evidence-based treatment for PTSD, but overall effectiveness is limited by reduced levels of patient engagement and retention. A previous study from this research group suggested that quetiapine monotherapy, but not risperidone or valproate, could increase engagement in trauma-focused psychotherapy. METHODS: We report the study protocol of a pilot study funded under the South-Central Mental Illness Research, Education, and Clinical Center pilot study program from the U.S. Department of Veterans Affairs. This randomized, open-label study was designed to evaluate the feasibility of completing a randomized trial of quetiapine vs. treatment as usual to promote patient engagement in PTSD patients with a history of mTBI. DISCUSSION: We expect that the success of this ongoing study should provide us with the preliminary data necessary to design a full-scale randomized trial. Positive efficacy results in a full- scale trial should inform new VA guidelines for clinical practice by showing that quetiapine-related improvements in patient engagement and retention may be the most effective approach to assure that VA resources achieve the best possible outcome for veterans. TRIAL REGISTRATION: NCT04280965 .