IMPORTANCE Posttraumatic stress disorder (PTSD) is a prevalent and serious mental health problem. Although there are effective psychotherapies for PTSD, there is little information about their comparative effectiveness. OBJECTIVE To compare the effectiveness of prolonged exposure (PE) vs cognitive processing therapy (CPT) for treating PTSD in veterans. DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial assessed the comparative effectiveness of PE vs CPT among veterans with military-related PTSD recruited from outpatient mental health clinics at 17 Department of Veterans Affairs medical centers across the US from October 31, 2014, to February 1, 2018, with follow-up through February 1, 2019. The primary outcome was assessed using centralized masking. Tested hypotheses were prespecified before trial initiation. Data were analyzed from October 5, 2020, to May 5, 2021. INTERVENTIONS Participants were randomized to 1 of 2 individual cognitive-behavioral therapies, PE or CPT, delivered according to a flexible protocol of 10 to 14 sessions. MAIN OUTCOMES AND MEASURES The primary outcome was change in PTSD symptom severity on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) from before treatment to the mean after treatment across posttreatment and 3- and 6-month follow-ups. Secondary outcomes included other symptoms, functioning, and quality of life. RESULTS Analyses were based on all 916 randomized participants (730 [79.7%] men and 186 [20.3%] women; mean [range] age 45.2 [21-80] years), with 455 participants randomized to PE (mean CAPS-5 score at baseline, 39.9 [95% CI, 39.1-40.7] points) and 461 participants randomized to CPT (mean CAPS-5 score at baseline, 40.3 [95% CI, 39.5-41.1] points). PTSD severity on the CAPS-5 improved substantially in both PE (standardized mean difference [SMD], 0.99 [95% CI, 0.89-1.08]) and CPT (SMD, 0.71 [95% CI, 0.61-0.80]) groups from before to after treatment. Mean improvement was greater in PE than CPT (least square mean, 2.42 [95% CI, 0.53-4.31]; P = .01), but the difference was not clinically significant (SMD, 0.17). Results for self-reported PTSD symptoms were comparable with CAPS-5 findings. The PE group had higher odds of response (odds ratio [OR], 1.32 [95% CI, 1.00-1.65]; P < .001), loss of diagnosis (OR, 1.43 [95% CI, 112-1.74]; P < .001), and remission (OR, 1.62 [95% Cl, 1.24-2.00]; P < .001) compared with the CPT group. Groups did not differ on other outcomes. Treatment dropout was higher in PE (254 participants [55.8%]) than in CPT (215 participants [46.6%]; P < .01). Three participants in the PE group and 1 participant in the CPT group were withdrawn from treatment, and 3 participants in each treatment dropped out owing to serious adverse events. CONCLUSIONS AND RELEVANCE This randomized clinical trial found that although PE was statistically more effective than CPT, the difference was not clinically significant, and improvements in PTSD were meaningful in both treatment groups. These findings highlight the importance of shared decision-making to help patients understand the evidence and select their preferred treatment.

Trauma-focused psychotherapies, such as prolonged exposure and cognitive processing therapy, are the most effective forms of treatment for posttraumatic stress disorder. These treatments are commonly delivered in the Veterans Health Administration; however, dropout means that some veterans fail to benefit. Ending treatment prematurely is a common problem across psychotherapies, with on average, 20% to 25% of patients dropping out. The purpose of this study was to examine veterans' self-reported reasons for dropping out of prolonged exposure or cognitive processing therapy. Veterans who dropped out from prolonged exposure or cognitive processing therapy (N = 28) completed qualitative interviews about their experiences. Interviews were coded by 2 coders using grounded theory. Therapy-related barriers were the largest category reported, and included lack of buy-in to the rationale or specific therapy tasks, believing that treatment was not working, alliance issues, or switching to a different treatment. Practical barriers and finding treatment "too stressful" were also common reasons for dropout. This research provides information that can shape how PTSD treatments are delivered in health care settings. Therapy-related barriers were the largest group, suggesting that providers may need to find more effective ways to communicate the rationale for these therapies or to tailor them to individual patients' needs. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Veterans with posttraumatic stress disorder (PTSD) report more aggression than civilians with PTSD. Because emotion regulation difficulties mediated the relationship between PTSD symptoms and impulsive aggression in veterans, we developed an intervention to increase emotion regulation skills. This pilot study tested the feasibility and acceptability of a three-session treatment, Manage Emotions to Reduce Aggression (MERA), and examined its effectiveness at reducing aggression and emotion dysregulation. Male combat veterans with PTSD and impulsive aggression completed assessments before and 4 weeks after MERA. Overt Aggression Scale measured frequency of aggression; Difficulties in Emotion Regulation Scale assessed emotion dysregulation. Most veterans (95%) who completed MERA and the posttreatment assessment (n = 20) reported MERA was helpful. Veterans in the intent-to-treat sample demonstrated a significant decrease in their frequency of aggression (Cohen's d = -0.55) and emotion dysregulation (Cohen's d = -0.55). MERA may be an innovative treatment that helps veterans reduce aggression.

Background: The Veterans Health Administration (VHA) has pioneered the implementation of video to home (VTH) technology to increase access to mental health treatments for Veterans facing barriers to receiving in-person care, particularly for posttraumatic stress disorder (PTSD). Randomized controlled trials have established the noninferiority of evidence-based psychotherapies (EBPs) for PTSD delivered through VTH, compared to in-person delivery. Less is known about the use of VTH to deliver EBPs for PTSD in routine clinical practice.Objective: We examined the provision of EBPs for PTSD delivered via VTH at a large Southwestern VHA PTSD outpatient clinic.Methods: Data were obtained from chart review of the electronic medical records of Veterans receiving at least one session of Cognitive Processing Therapy or Prolonged Exposure via VTH in the VHA PTSD clinic during the study time frame.Results: Fourteen providers (including six psychology trainees) delivered EBPs for PTSD via VTH between 2016 and 2018. Providers treated 74 Veterans (33.8% women) from diverse sociocultural backgrounds who ranged in age from 25 to 79. Each provider treated about 3.08 (± 2.18) Veterans using VTH, not including one provider who saw more than 30. A hybrid approach, in which VTH-delivery was coupled with in-person delivery, was used with 70.3% of Veterans across treatment (including sessions completed before initiation and after termination of the EBP). This demonstrates the versatility of VTH for meeting individual patient needs. Most EBP sessions (85.4%) were conducted over VTH. Despite Veterans attending an average of 6.85 (± 4.88) EBP sessions, 50% terminated before session 7. This dropout rate is consistent with national and local EBP completion averages within the VHA. Veterans receiving Cognitive Processing Therapy via VTH were more likely to complete treatment than those receiving Prolonged Exposure. No other patient factors predicted attrition.Conclusions: This study highlights the use of VTH as “tool in the toolbox” that expands the scope of practice for providers and increases opportunities for Veterans to receive EBPs for PTSD. We describe other potential advantages of using VTH to deliver EBPs for PTSD.

The growth factor-like lipid mediator, lysophosphatidic acid (LPA), is a potent signaling molecule that influences numerous physiologic and pathologic processes. Manipulation of LPA signaling is of growing pharmacotherapeutic interest, especially because LPA resembles compounds with drug-like features. The action of LPA is mediated through activation of multiple types of molecular targets, including six G protein-coupled receptors that are clear targets for drug development. However, the LPA signaling has been linked to pathological responses that include promotion of fibrosis, atherogenesis, tumorigenesis, and metastasis. Thus, a question arises: Can we harness, in an LPA-like drug, the many beneficial activities of this lipid without eliciting its dreadful actions? We developed octadecyl thiophosphate (OTP; subsequently licensed as Rx100), an LPA mimic with higher stability in vivo than LPA. This article highlights progress made toward developing analogs like OTP and exploring prosurvival and regenerative LPA signaling. We determined that LPA prevents cell death triggered by various cellular stresses, including genotoxic stressors, and rescues cells condemned to apoptosis. LPA2 agonists provide a new treatment option for secretory diarrhea and reduce gastric erosion caused by nonsteroidal anti-inflammatory drugs. The potential uses of LPA2 agonists like OTP and sulfamoyl benzoic acid-based radioprotectins must be further explored for therapeutic uses.

Introduction: It is estimated that 70% of patients with posttraumatic stress disorder (PTSD) have chronic insomnia. A recent meta-analysis examined cognitive-behavioural therapy for insomnia (CBT-I) in veterans with and without PTSD, and suggested that most studies had questionable methodology, but generally supported its effectiveness in this population. Further, while CBT-I via telehealth (i.e. using telecommunication and information technology to deliver health services) has shown effectiveness for primary insomnia, it has not been applied to PTSD-related insomnia. Methods: Veterans with insomnia who were diagnosed with PTSD (n = 12) or having significant subthreshold PTSD symptoms (n = 6) on the Clinician Administered PTSD Scale were randomly assigned to receive CBT-I in-person (n = 7) or by telephone (n = 11), to pilot test the potential effectiveness, acceptability, and feasibility of administering CBT-I in rural veterans. A six-week CBT-I protocol was delivered, and the veteran's insomnia was assessed at post-treatment and follow-up. Results: Given the small sample size, Cohen's d was used to detect group differences, finding large effect sizes favouring the in-person delivery, until three-months post-treatment when this difference diminished. Most veterans found the treatment acceptable, regardless of mode of delivery. Based on the results, a larger project is feasible. Feasibility for a larger project is favourable. Discussion: In summary, our findings uphold and extend previous research. Specifically, current pilot data suggest that telephone-delivered CBT-I may be able to reduce trauma-related insomnia symptoms. Future trials are needed to assess the effectiveness of CBT-I delivered to rural veterans with posttraumatic insomnia.

Diarrheal disease is a severe global health problem. It is estimated that secretory diarrhea causes 2.5 million deaths annually among children under the age of five in the developing world. A critical barrier in treating diarrheal disease is lack of easy-to-use effective treatments. While antibiotics may shorten the length and severity of diarrhea, oral rehydration remains the primary approach in managing secretory diarrhea. Existing treatments mostly depend on reconstituting medicines with water that is often contaminated which can be an unresolved problem in the developing world. Standard treatments for secretory diarrhea also include drugs that decrease intestinal motility. This approach is less than ideal because in cases where infection is the cause, this can increase the incidence of bacterial translocation and the potential for sepsis. Our goal is to develop a safe, effective, easy-to-use, and inexpensive treatment to reduce fluid loss in secretory diarrhea. We have developed Rx100, which is a metabolically stable analog of lysophosphatidic acid. We tested the hypothesis that Rx100, similarly to lysophosphatidic acid, inhibits the activation of the cystic fibrosis transmembrane regulator Cl− channel and also reduces barrier permeability resulting in the decrease of fluid loss in multiple etiologies of secretory diarrhea. Here we have established the bioavailability and efficacy of Rx100 in cholera toxin-induced secretory diarrhea models. We have demonstrated the feasibility of Rx100 as an effective treatment for Citrobacter rodentium infection-induced secretory diarrhea. Using both the open- and closed-loop mouse models, we have optimized the dosing regimen and time line of delivery for Rx100 via oral and parenteral delivery. Impact statement A critical barrier in treating diarrheal disease is easy-to-use effective treatments. Rx100 is a first in class, novel small molecule that has shown efficacy after both subcutaneous and oral administration in a mouse cholera-toxin- and Citrobacter rodentium infection-induced diarrhea models. Our findings indicate that Rx100 a metabolically stable analog of the lipid mediator lysophosphatidic acid blocks activation of CFTR-mediated secretion responsible for fluid discharge in secretory diarrhea. Rx100 represents a new treatment modality which does not directly block CFTR but attenuates its activation by bacterial toxins. Our results provide proof-of-principle that Rx100 can be developed for use as an effective oral or injectable easy-to-use drug for secretory diarrhea which could significantly improve care by eliminating the need for severely ill patients to regularly consume large quantities of oral rehydration therapies and offering options for pediatric patients.

Violence can lead to posttraumatic stress disorder (PTSD), which in turn is related to perpetration of aggression. Importantly, not all aggression is motivated by the same mechanisms, and understanding the driving force behind the aggression is imperative in order to select treatments that will assist the individual in decreasing the behavior. PTSD is specifically related to impulsive aggression, or aggression that is emotionally charged and uncontrolled, rather than premeditated aggression, which is planned, unemotional, and goal-directed. Emotion regulation, or the ability to recognize emotions, accept them, and control emotion-related behaviors, is related to both PTSD and impulsive aggression. This conceptual paper uses the Catalyst Model to review the literature on PTSD, impulsive aggression, and emotion regulation. Because of their high rates of PTSD, veterans are presented as a demonstration of the relationship between emotion regulation and impulsive aggression. The integrative model can be viewed as an alternative to the traditional model that proposes anger is the primary underlying mechanism of impulsive aggression in adults. Treatment recommendations, such as helping clients develop emotion regulation skills, are offered for providers who are working with individuals who have experienced trauma and who are now perpetrating impulsive aggression.

Traumatic brain injury (TBI) and mental health (MH) disorders are prevalent in combat veterans returning from Afghanistan and/or Iraq (hereafter referred to as returning veterans). Accurate estimates of service utilization for veterans with and without TBI exposure (referred to as TBI history) are imperative in order to provide high quality healthcare to returning veterans. We examined associations between TBI history and MH service utilization in a subsample of returning veterans who were newly diagnosed with posttraumatic stress disorder (PTSD), depression, and/or anxiety in the 2010 fiscal year (N = 55,458). Data were extracted from the Veterans Health Administration (VHA) National Patient Care Database. Veterans with MH diagnoses and TBI histories attended significantly more psychotherapy visits, (M = 8.32 visits, SD = 17.15) and were more likely to attend at least 8 psychotherapy visits, (15.7%) than veterans with MH diagnoses but no TBI history (M = 6.48 visits, SD = 12.12; 10.1% attended at least 8 sessions). PTSD and TBI history, but not depression or anxiety, were associated with a greater number of psychotherapy visits when controlling for demographic and clinical variables. PTSD, anxiety, depression, and TBI history were associated with number of psychotropic medication-management visits. TBI history was related to greater MH service utilization, independent of MH diagnoses. Future research should examine what MH services are being utilized and if these services are helping veterans recover from their disorders.

Prior single-site and regional studies have documented difficulties in implementing prolonged exposure (PE) and cognitive processing therapy (CPT) for posttraumatic stress disorder (PTSD) into practice in Veterans Affairs (VA) Medical Centers, estimating that between 6% and 13% of VA patients with PTSD receive PE or CPT (Lu, Plagge, Marsiglio, & Dobscha, 2016; Mott et al., 2014; Shiner et al., 2013). However, these studies examined data from fiscal years 2008-2012, and therefore may not reflect more recent utilization patterns. Beginning in 2007, the VA invested heavily in increasing implementation of PE and CPT, including nationwide training rollouts and consultation. Given the length of time required for successful implementation of new practices, it is important to evaluate use of PE and CPT over time. We examined current use of PE and CPT at 1 VA medical center PTSD specialty clinic and compared this to prior rates for the same clinic. Chart reviews for all patients receiving a PTSD clinic initial evaluation between January 1, 2015, and May 31, 2015, indicated that 52% of patients began a course of PE or CPT within the 1-year follow-up period, representing a 5-fold increase from 2008 to 2012. We discuss changes in clinic structure, processes, training, and clinician support that might account for the successful implementation of PE and CPT in this clinic. We also present data on alternative referrals provided to patients not engaging in PE and CPT, and predictors of engagement in PE and CPT. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

OBJECTIVE:The Department of Veterans Affairs (VA) has promoted large-scale dissemination efforts of evidence-based psychotherapies (EBPs) for posttraumatic stress disorder (PTSD). In spite of efforts to make gold-standard treatments available to veterans, few veterans with PTSD receive a full course of psychotherapy. It is unclear if type of trauma experienced is related to treatment initiation and completion. This study aimed to identify patient factors, including experiencing childhood trauma that related to treatment preferences and dropout in a real-world VA PTSD clinic.METHOD:A chart review was conducted for veterans who were referred for individual EBPs for PTSD (N = 199). Extracted variables included demographics, PTSD symptoms, treatment preferences, and treatment completion/dropout.RESULTS:Veterans choose to engage in individual EBP (48%), group treatment (11%), nontrauma focused psychotherapy (15%), or no psychotherapy (26%). Slightly over half of the veterans who began individual EBP completed it, with no statistical differences in completion rates for prolonged exposure and cognitive processing therapy. Childhood trauma was the second-most common type of trauma experienced, next to combat exposure. Those who completed EBP had higher rates of combat trauma (88%) than noncompleters (70%), and noncompleters (50%) had higher rates of childhood trauma than completers (29%). Regardless of trauma experienced, those who completed an EBP experienced substantial reductions in PTSD symptoms.CONCLUSIONS:Assessing veterans for childhood trauma and emotion regulation difficulties may be beneficial even in VA clinics where treatment is most often focused on combat trauma. (PsycINFO Database Record

Posttraumatic stress disorder (PTSD) is common among returning veterans, and aggression frequently co-occurs with PTSD. Veterans with PTSD most commonly engage in impulsive aggression, or aggression that is emotionally charged, unplanned, and uncontrolled, rather than premeditated aggression, which is planned and controlled. Previous research demonstrated a variety of emotions can result in aggression, rather than the traditional conceptualization that only anger leads to aggression. In a veteran sample, deficiencies in the ability to regulate emotions (emotion dysregulation) mediated the relationship between PTSD and impulsive aggression. These results suggest that teaching veterans with PTSD and impulsive aggression how to regulate emotions may decrease aggression. The cases presented illustrate the use of an innovative, single-session emotion regulation treatment for combat veterans with PTSD. Two cases are presented to generate hypotheses on who might benefit from this treatment in the future. The two male veterans treated with this protocol differed in how frequently they used the emotion regulation skills after the treatment and in their treatment outcomes. Teaching veterans how to regulate their emotions in a condensed time frame may be beneficial for certain veterans, and further research on this brief treatment is warranted. (PsycINFO Database Record

Radiomitigators attenuate radiation injury when administered after irradiation. Lysophosphatidic acid (LPA) a lipid mediator rescues apoptotically condemned cells. LPA protects IEC‐6 intestinal epithelial cells in vitro and intestinal crypts in vivo from radiation‐induced apoptosis. Using KO mice and cells we established that the LPA2 receptor is required for radiomitigation. Through its C‐terminal PDZ and LIM‐binding motifs LPA2 forms agonist‐dependent macromolecular signaling complexes. LPA2 interacts with the proapoptotic protein Siva‐1 and targets it for proteasomal degradation. Full activation of the NFkB and ERK1/2 prosurvival pathway requires formation of an LPA2, NHERF2, and TRIP‐6 ternary macromolecular complex. These signals inhibit the mitochondrial apoptosis pathway. Reconstitution of the LPA2 receptor into MEFs derived from LPA1/2 KO mice restores radioprotection. Conditioned medium from irradiated U937 cells induces bystander apoptosis in non‐irradiated IEC‐6 cultures and LPA2‐transfected MEFs. Using in silico drug discovery we found a novel LPA2‐selective agonist GRI977143 that protects cells from radiation‐ and chemotherapy‐induced apoptosis. GRI977143 also increases the survival of mice exposed to lethal levels of radiation. Supported by AI08405.