A Case of Pedunculated Adenoma of the Bile Duct Proving Adenoma to Cancer Sequence.

Ampullary adenocarcinoma is a rare malignancy that originates in the ampulla of Vater. It typically presents in the seventh decade of life. This condition shares overlapping features with periampullary tumors such as pancreatic cancer, but treatment modalities and prognosis vary. Histology will demonstrate either intestinal or pancreato-biliary epithelial subtype in ampullary adenocarcinoma. Despite its rare occurrence, ampullary adenocarcinoma should be included as a differential in elderly patients presenting with biliary obstruction. This case presentation is unique as it highlights the importance of histopathological findings and their progression. In this case, initial histology results revealed tubulovillous adenomatous polyps, but later biopsies revealed adenocarcinoma cells. These findings suggest that ampullary adenocarcinoma and several gastrointestinal cancers share a similar mechanism of action as it is related to the adenoma-to-carcinoma sequence. This case presentation aims to highlight the rare occurrence of this phenomenon at the ampulla of Vater.

Acute Burn Care.

LEARNING OBJECTIVES: After studying this article and viewing the videos, the participant should be able to: 1. Describe the current epidemiology of burn injuries. 2. Understand burn pathophysiology and perform a wound assessment. 3. Summarize the initial emergency management of a burn patient. 4. Calculate the anticipated fluid resuscitation requirements for a burn injury, and diagnose the complications of overresuscitation. 5. Describe the diagnosis and management of inhalation injury. 6. List the goals of wound care for superficial and deep burns, and describe the closed dressing technique. 7. Perform excision of a burn wound. 8. Compare various wound closure techniques using autografts and skin substitutes. SUMMARY: Plastic surgeons are essential members of the multidisciplinary burn team. Burn injuries remain common, and plastic surgeons have an opportunity to develop and innovate the field of acute burn care in light of workforce shortages. Burn pathophysiology is complex and dynamic, which informs the challenges encountered during the perioperative phase. Accurate burn wound assessment remains difficult, with implications for diagnosis and management. A systematic approach is required when stabilizing a major burn and/or inhalation injury with newly updated fluid resuscitation and triage guidelines. Wound care continues to evolve, with an emphasis on a closed dressing technique. For deeper burns, new surgical techniques are emerging for surgical débridement, along with improvements to traditional methods of tangential excision. Following excision, a number of established and novel techniques are available to close the wound with either autografts or skin substitutes.

TCF4 Mutations Disrupt Synaptic Function Through Dysregulation of RIMBP2 in Patient-Derived Cortical Neurons.

BACKGROUND: Genetic variation in the TCF4 (transcription factor 4) gene is associated with risk for a variety of developmental and psychiatric conditions, which includes a syndromic form of autism spectrum disorder called Pitt-Hopkins syndrome (PTHS). TCF4 encodes an activity-dependent transcription factor that is highly expressed during cortical development and in animal models has been shown to regulate various aspects of neuronal development and function. However, our understanding of how disease-causing mutations in TCF4 confer pathophysiology in a human context is lacking. METHODS: To model PTHS, we differentiated human cortical neurons from human induced pluripotent stem cells that were derived from patients with PTHS and neurotypical individuals. To identify pathophysiology and disease mechanisms, we assayed cortical neurons with whole-cell electrophysiology, Ca2+ imaging, multielectrode arrays, immunocytochemistry, and RNA sequencing. RESULTS: Cortical neurons derived from patients with TCF4 mutations showed deficits in spontaneous synaptic transmission, network excitability, and homeostatic plasticity. Transcriptomic analysis indicated that these phenotypes resulted in part from altered expression of genes involved in presynaptic neurotransmission and identified the presynaptic binding protein RIMBP2 as the most differentially expressed gene in PTHS neurons. Remarkably, TCF4-dependent deficits in spontaneous synaptic transmission and network excitability were rescued by increasing RIMBP2 expression in presynaptic neurons. CONCLUSIONS: Taken together, these results identify TCF4 as a critical transcriptional regulator of human synaptic development and plasticity and specifically identifies dysregulation of presynaptic function as an early pathophysiology in PTHS.

Tyvaso DPI: Drug-device characteristics and patient clinical considerations.

Tyvaso DPI is a drug-device combination therapy comprised of a small, portable, reusable, breath-powered, dry powder inhaler (DPI) for the delivery of treprostinil. It is approved for the treatment of pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease. Tyvaso DPI utilizes single-use prefilled cartridges to ensure proper dosing. Unlike nebulizer devices, administration of Tyvaso DPI is passive and does not require coordination with the device. The low-flow rate design results in targeted delivery to the peripheral lungs due to minimal drug loss from impaction in the oropharynx. The inert fumaryl diketopiperazine (FDKP) excipient forms microparticles that carry treprostinil into the airways, with a high fraction of the particles in the respirable range. In a clinical study in patients with pulmonary arterial hypertension, Tyvaso DPI had similar exposure and pharmacokinetics, low incidence of adverse events, and high patient satisfaction compared with nebulized treprostinil solution. Tyvaso DPI may be considered as a first prostacyclin agent or for those that do not tolerate other prostacyclin formulations, patients with pulmonary comorbidities, patients with mixed Group 1 and Group 3 pulmonary hypertension, or those that prefer an active lifestyle and need a portable, non-invasive treatment. Tyvaso DPI is a patient-preferred, maintenance-free, safe delivery option that may improve patient compliance and adherence.

Propranolol treatment during repetitive mild traumatic brain injuries induces transcriptomic changes in the bone marrow of mice.

Introduction: There are 1.5 million new mild traumatic brain injuries (mTBI) annually in the US, with many of the injured experiencing long-term consequences lasting months after the injury. Although the post injury mechanisms are not well understood, current knowledge indicates peripheral immune system activation as a causal link between mTBI and long-term side effects. Through a variety of mechanisms, peripheral innate immune cells are recruited to the CNS after TBI to repair and heal the injured tissue; however, the recruitment and activation of these cells leads to further inflammation. Emerging evidence suggests sympathetic nervous system (SNS) activity plays a substantial role in the recruitment of immune cells post injury. Methods: We sought to identify the peripheral innate immune response after repeated TBIs in addition to repurposing the nonselective beta blocker propranolol as a novel mTBI therapy to limit SNS activity and mTBI pathophysiology in the mouse. Mice underwent repetitive mTBI or sham injury followed by i.p. saline or propranolol. Isolated mRNA derived from femur bone marrow of mice was assayed for changes in gene expression at one day, one week, and four weeks using Nanostring nCounter® stem cell characterization panel. Results: Differential gene expression analysis for bone marrow uncovered significant changes in many genes following drug alone, mTBI alone and drug combined with mTBI. Discussion: Our data displays changes in mRNA at various timepoints, most pronounced in the mTBI propranolol group, suggesting a single dose propranolol injection as a viable future mTBI therapy in the acute setting.

Comparing Inertial Measurement Units to Markerless Video Analysis for Movement Symmetry in Quarter Horses.

BACKGROUND: With an increasing number of systems for quantifying lameness-related movement asymmetry, between-system comparisons under non-laboratory conditions are important for multi-centre or referral-level studies. This study compares an artificial intelligence video app to a validated inertial measurement unit (IMU) gait analysis system in a specific group of horses. METHODS: Twenty-two reining Quarter horses were equipped with nine body-mounted IMUs while being videoed with a smartphone app. Both systems quantified head and pelvic movement symmetry during in-hand trot (hard/soft ground) and on the lunge (left/right rein, soft ground). Proportional limits of agreement (pLoA) were established. RESULTS: Widths of pLoA were larger for head movement (29% to 50% in-hand; 22% to 38% on lunge) than for pelvic movement (13% to 24% in-hand; 14% to 24% on lunge). CONCLUSION: The between-system pLoAs exceed current "lameness thresholds" aimed at identifying the affected limb(s) in lame horses. They also exceed published limits of agreement for stride-matched data but are similar to repeatability values and "lameness thresholds" from "non-lame" horses. This is encouraging for multi-centre studies and referral-level veterinary practice. The narrower pLoA values for pelvic movement asymmetry are particularly encouraging, given the difficulty of grading hind limb lameness "by eye".

Altered Knee Loading Following Primary ACL Repair versus ACL Reconstruction.

Background: ACL repair (ACL-r) has recently gained renewed clinical interest for treatment of ACL tears. ACL-r has several potential benefits over ACL reconstruction (ACL-R) including maintaining the native ACL innervation and blood supply, no graft site morbidity, and possible improved knee biomechanics and decrease in osteoarthritis. The purpose of this study was to assess for differences in metrics of knee joint loading during a single limb squat task between individuals following a primary ACL-r versus those who underwent a standard ACL-R with a patella bone-tendon-bone autograft. Study type: Case Control Study. Methods: The ACL-r group [n: 15, age(yrs): 38.8±13.9] sustained a proximal ACL disruption that was amenable to repair, while the ACL-R group [n: 15, age(yrs): 25.60±1.7] underwent primary reconstruction with patella bone-tendon-bone autograft. At 12-weeks post-operation, both groups completed the IKDC questionnaire and biomechanical testing during performance of the single limb squat. Bilateral peak knee extension moment and total knee joint power as a measure of eccentric loading (contraction) during the descent phase of the squat were calculated on the surgical and non-surgical limb and averaged across the middle three of five trials. Participants also completed quadriceps strength testing on both limbs three months after surgery on an isokinetic dynamometer at 60°/sec. LSI (Limb Strength Index) was calculated for all variables. Separate ANCOVAs were performed on each biomechanical variable to examine differences between groups. Results: The ACL-r had a significantly greater peak knee extension moment LSI (ACL-r: 78.46±5.79%; ACL-R: 56.86±5.79%; p=0.019, ηp2=.186) and total knee joint power LSI (ACL-r: 72.47±7.39%; ACL-R: 39.70±7.39%, p=0.006, ηp2=.245) than the ACL-R group. The ACL-r also had a significantly greater quadriceps LSI than the ACL-R group (ACL-r: 66.318±4.61%, ACL-R: 48.03±4.61%, p=0.013, ηp2=.206). Conclusions: Individuals following ACL-r demonstrate increased knee joint loading symmetry during a single leg squat task and greater quadriceps strength symmetry at 12 weeks post-surgery compared to those who underwent ACL-R. Level of Evidence: 3.

Repeated mild traumatic brain injury in mice elicits long term innate immune cell alterations in blood, spleen, and brain.

Mild traumatic brain injury is an insidious event whereby the initial injury leads to ongoing secondary neuro- and systemic inflammation through various cellular pathways lasting days to months after injury. Here, we investigated the impact of repeated mild traumatic brain injury (rmTBI) and the resultant systemic immune response in male C57B6 mice using flow cytometric methodology on white blood cells (WBCs) derived from the blood and spleen. Isolated mRNA derived from spleens and brains of rmTBI mice was assayed for changes in gene expression at one day, one week, and one month following the injury paradigm. We observed increases in Ly6C+, Ly6C-, and total monocyte percentages in both blood and spleen at one month after rmTBI. Differential gene expression analysis for the brain and spleen tissues uncovered significant changes in many genes, including csf1r, itgam, cd99, jak1,cd3ε, tnfaip6, and nfil3. Additional analysis revealed alterations in several immune signaling pathways over the course of one month in the brain and spleen of rmTBI mice. Together, these results indicate that rmTBI produces pronounced gene expression changes in the brain and spleen. Furthermore, our data suggest that monocyte populations may reprogram towards the proinflammatory phenotype over extended periods of time after rmTBI.

Reduction in Rumen Tetracycline-Insensitive Bacteria during a Grain Challenge Using the Isoflavone Biochanin A.

The isoflavone biochanin A was previously shown to promote weight gain in growing steers by selectively inhibiting rumen bacteria-like growth-promoting feed antibiotics. The hypothesis that biochanin A inhibited the action of drug efflux pumps was tested by enumerating tetracycline-insensitive bacteria from steers in a subacute rumen acidosis (SARA) challenge. Steers (n = 3/group) treatment groups were forage only, SARA control, SARA with monensin (0.2 g d-1), and SARA with biochanin A (6.0 g d-1). As the steers were stepped up from the forage-only basal diet to 70% cracked corn, the number of rumen bacteria enumerated on two tetracycline-containing media types (nutrient glucose agar and tetracycline, and bile esculin azide and tetracycline) increased (p < 0.05) from as little as 1.7(105) to as great as 6.7(106) cfu mL-1 on the nutrient glucose agar in the SARA and monensin control groups. The biochanin A group maintained the same number of tetracycline-insensitive bacteria as the forage-only controls (p > 0.05). The effects were similar to the more selective media type, but the differences were smaller. These results support the hypothesis that biochanin A inhibits the activity of drug efflux pumps in vivo.

Profiling of cool-season forage arabinoxylans via a validated HPAEC-PAD method.

Cool-season pasture grasses contain arabinoxylans (AX) as their major cell wall hemicellulosic polysaccharide. AX structural differences may influence enzymatic degradability, but this relationship has not been fully explored in the AX from the vegetative tissues of cool-season forages, primarily because only limited AX structural characterization has been performed in pasture grasses. Structural profiling of forage AX is a necessary foundation for future work assessing enzymatic degradability and may also be useful for assessing forage quality and suitability for ruminant feed. The main objective of this study was to optimize and validate a high-performance anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD) method for the simultaneous quantification of 10 endoxylanase-released xylooligosaccharides (XOS) and arabinoxylan oligosaccharides (AXOS) in cool-season forage cell wall material. The following analytical parameters were determined or optimized: chromatographic separation and retention time (RT), internal standard suitability, working concentration range (CR), limit of detection (LOD), limit of quantification (LOQ), relative response factor (RRF), and quadratic calibration curves. The developed method was used to profile the AX structure of four cool-season grasses commonly grown in pastures (timothy, Phleum pratense L.; perennial ryegrass, Lolium perenne L.; tall fescue, Schedonorus arundinaceus (Schreb.) Dumort.; and Kentucky bluegrass, Poa pratensis L.). In addition, the cell wall monosaccharide and ester-linked hydroxycinnamic acid contents were determined for each grass. The developed method revealed unique structural aspects of the AX structure of these forage grass samples that complemented the results of the cell wall monosaccharide analysis. For example, xylotriose, representing an unsubstituted portion of the AX polysaccharide backbone, was the most abundantly-released oligosaccharide in all the species. Perennial rye samples tended to have greater amounts of released oligosaccharides compared to the other species. This method is ideally suited to monitor structural changes of AX in forages as a result of plant breeding, pasture management, and fermentation of plant material.

Study design and methods for the pilot study of muscadine grape extract supplement to improve fatigue among older adult cancer survivors (FOCUS) trial.

INTRODUCTION: Fatigue is a prevalent symptom among both cancer survivors and older adults. Negative consequences of fatigue include increased sedentary behavior, decreased physical activity and function, and lower quality of life. Few pharmacologic interventions improve fatigue. Our preclinical and clinical data show promising effects of a muscadine grape extract supplement (MGES) on oxidative stress, mitochondrial bioenergetics, the microbiome, and the symptom of fatigue. This pilot study seeks to translate these observations to cancer survivorship by testing the preliminary effect of MGE supplementation on older adult cancer survivors with self-reported fatigue. MATERIALS AND METHODS: We designed a double-blinded placebo-controlled pilot study to evaluate preliminary efficacy of MGE supplementation versus placebo on fatigue among older adult cancer survivors (aged ≥65 years) who report baseline fatigue. Sixty-four participants will be enrolled and randomized 1:1 to twice daily MGES (four tablets twice daily) versus placebo for 12 weeks. The primary outcome is change in Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue score from baseline to 12 weeks. Secondary outcomes are change in self-reported physical function, physical fitness (6-min walk test), self-reported physical activity, global quality of life (QOL), and the Fried frailty index. Correlative biomarker assays will assess changes in 8-hydroxy-2 deoxyguanosine, peripheral blood mitochondrial function, inflammatory markers, and the gut microbiome. DISCUSSION: This pilot study builds on preclinical and clinical observations to estimate effects of MGE supplementation on fatigue, physical function, QOL, and biologic correlates in older adult cancer survivors. Trial registration #: CT.govNCT04495751; IND 152908.

Red clover supplementation modifies rumen fermentation and promotes feed efficiency in ram lambs.

Red clover produces isoflavones, including biochanin A, which have been shown to have microbiological effects on the rumen while also promoting growth in beef cattle. The objective was to determine if supplementation of biochanin A via red clover hay would produce similar effects on the rumen microbiota and improve growth performance of lambs. Twenty-four individually-housed Polypay ram lambs (initial age: 114 ± 1 d; initial weight: 38.1 ± 0.59 kg) were randomly assigned to one of three experimental diets (85:15 concentrate:roughage ratio; N = 8 rams/treatment): CON-control diet in which the roughage component (15.0%, w/w, of the total diet) consisted of orchardgrass hay; 7.5-RC-red clover hay substituted for half (7.5%, w/w, of the total diet) of the roughage component; and 15-RC-the entire roughage component (15.0%, w/w, of the total diet) consisted of red clover hay. Feed intake and weight gain were measured at 14-d intervals for the duration of the 56-d trial, and rumen microbiological measures were assessed on days 0, 28, and 56. Red clover supplementation impacted growth performance of ram lambs. Average daily gains (ADG) were greater in ram lambs supplemented with red clover hay (7.5-RC and 15-RC) than for those fed the CON diet (P < 0.05). Conversely, dry matter intake (DMI) was lower in 7.5-RC and 15-RC than for CON lambs (P = 0.03). Differences in ADG and DMI resulted in greater feed efficiency in ram lambs supplemented with red clover hay (both 7.5-RC and 15-RC) compared to CON (P < 0.01). Rumen microbiota were also altered by red clover supplementation. The total viable number of hyper-ammonia-producing bacteria in 7.5-RC and 15-RC decreased over the course of the experiment and were lower than CON by day 28 (P ≤ 0.04). Amylolytic bacteria were also lower in 15-RC than in CON (P = 0.03), with a trend for lower amylolytic bacteria in 7.5-RC (P = 0.08). In contrast, there was tendency for greater cellulolytic bacteria in red clover supplemented lambs than in CON (P = 0.06). Red clover supplementation also increased fiber utilization, with greater ex vivo dry matter digestibility of hay for both 7.5-RC and 15-RC compared to CON by day 28 (P < 0.03). Results of this study indicate that low levels of red clover hay can elicit production benefits in high-concentrate lamb finishing systems through alteration of the rumen microbiota.

Red clover is rich in the bioactive isoflavone, biochanin A. The goal was to evaluate the impacts of biochanin A supplementation via red clover hay on growth performance of ram lambs as well as the rumen microbiota and fermentation. Low levels of red clover hay inclusion (7.5% and 15.0%, w/w, of the total diet) in high-concentrate finishing diets improved feed efficiency of ram lambs, promoting weight gain while decreasing feed intake. Red clover hay supplementation suppressed ruminal protein-wasting, peptide- and amino-acid degrading and starch-utilizing bacteria compared to control diets without isoflavones. Red clover hay also promoted fiber degrading bacteria and fiber utilization. Lamb growth and microbiological effects of red clover were consistent regardless of supplementation level in the diet. Results of this study indicate that low levels of red clover hay can produce production benefits in lamb finishing systems and demonstrated the efficacy of red clover as a functional feed, or feed with biological activities, in the context of its traditional use as a forage feedstuff.

TCF4 mutations disrupt synaptic function through dysregulation of RIMBP2 in patient-derived cortical neurons.

Genetic variation in the transcription factor 4 ( TCF4) gene is associated with risk for a variety of developmental and psychiatric conditions, which includes a syndromic form of ASD called Pitt Hopkins Syndrome (PTHS). TCF4 encodes an activity-dependent transcription factor that is highly expressed during cortical development and in animal models is shown to regulate various aspects of neuronal development and function. However, our understanding of how disease-causing mutations in TCF4 confer pathophysiology in a human context is lacking. Here we show that cortical neurons derived from patients with TCF4 mutations have deficits in spontaneous synaptic transmission, network excitability and homeostatic plasticity. Transcriptomic analysis indicates these phenotypes result from altered expression of genes involved in presynaptic neurotransmission and identifies the presynaptic binding protein, RIMBP2 as the most differentially expressed gene in PTHS neurons. Remarkably, TCF4-dependent deficits in spontaneous synaptic transmission and network excitability were rescued by increasing RIMBP2 expression in presynaptic neurons. Together, these results identify TCF4 as a critical transcriptional regulator of human synaptic development and plasticity and specifically identifies dysregulation of presynaptic function as an early pathophysiology in PTHS.

CaPTure: Calcium PeakToolbox for analysis of in vitro calcium imaging data.

BACKGROUND: Calcium imaging is a powerful technique for recording cellular activity across large populations of neurons. However, analysis methods capable of single-cell resolution in cultured neurons, especially for cultures derived from human induced pluripotent stem cells (hiPSCs), are lacking. Existing methods lack scalability to accommodate high-throughput comparisons between multiple lines, across developmental timepoints, or across pharmacological manipulations. RESULTS: To address this need we developed CaPTure, a scalable, automated Ca2+ imaging analysis pipeline ( https://github.com/LieberInstitute/CaPTure ). CaPTuredetects neurons, classifies and quantifies spontaneous activity, quantifies synchrony metrics, and generates cell- and network-specific metrics that facilitate phenotypic discovery. The method is compatible with parallel processing on computing clusters without requiring significant user input or parameter modification. CONCLUSION: CaPTure allows for rapid assessment of neuronal activity in cultured cells at cellular resolution, rendering it amenable to high-throughput screening and phenotypic discovery. The platform can be applied to both human- and rodent-derived neurons and is compatible with many imaging systems.

NRSF/REST lies at the intersection between epigenetic regulation, miRNA-mediated gene control and neurodevelopmental pathways associated with Intellectual disability (ID) and Schizophrenia.

Genetic evidence indicates disrupted epigenetic regulation as a major risk factor for psychiatric disorders, but the molecular mechanisms that drive this association remain to be determined. EHMT1 is an epigenetic repressor that is causal for Kleefstra Syndrome (KS), a genetic disorder linked with neurodevelopmental disorders and associated with schizophrenia. Here, we show that reduced EHMT1 activity decreases NRSF/REST protein leading to abnormal neuronal gene expression and progression of neurodevelopment in human iPSC. We further show that EHMT1 regulates NRSF/REST indirectly via repression of miRNA and leads to aberrant neuronal gene regulation and neurodevelopment timing. Expression of a NRSF/REST mRNA that lacks the miRNA-binding sites restores neuronal gene regulation to EHMT1 deficient cells. Significantly, the EHMT1-regulated miRNA gene set not only controls NRSF/REST but is enriched for association for Intellectual Disability (ID) and schizophrenia. This reveals a broad molecular interaction between H3K9 demethylation, NSRF/REST regulation and risk for ID and Schizophrenia.

Key considerations for child and adolescent MRI data collection.

Cognitive neuroimaging researchers' ability to infer accurate statistical conclusions from neuroimaging depends greatly on the quality of the data analyzed. This need for quality control is never more evident than when conducting neuroimaging studies with children and adolescents. Developmental neuroimaging requires patience, flexibility, adaptability, extra time, and effort. It also provides us a unique, non-invasive way to understand the development of cognitive processes, individual differences, and the changing relations between brain and behavior over the lifespan. In this discussion, we focus on collecting magnetic resonance imaging (MRI) data, as it is one of the more complex protocols used with children and youth. Through our extensive experience collecting MRI datasets with children and families, as well as a review of current best practices, we will cover three main topics to help neuroimaging researchers collect high-quality datasets. First, we review key recruitment and retention techniques, and note the importance for consistency and inclusion across groups. Second, we discuss ways to reduce scan anxiety for families and ways to increase scan success by describing the pre-screening process, use of a scanner simulator, and the need to focus on participant and family comfort. Finally, we outline several important design considerations in developmental neuroimaging such as asking a developmentally appropriate question, minimizing data loss, and the applicability of public datasets. Altogether, we hope this article serves as a useful tool for those wishing to enter or learn more about developmental cognitive neuroscience.

A clinical trial comparing trauma-informed guilt reduction therapy (TrIGR), a brief intervention for trauma-related guilt, to supportive care therapy.

INTRODUCTION: Trauma-related guilt is common, associated with posttraumatic mental health problems, and can persist after posttraumatic stress disorder (PTSD) treatment. We compared the efficacy of two six-session psychotherapies, Trauma-Informed Guilt Reduction (TrIGR) and Supportive Care Therapy (SCT), for reducing trauma-related guilt. TrIGR helps patients accurately appraise their role in the trauma and re-engage in values. In SCT, patients guide session content. METHODS: A total of 184 veterans seeking VA mental health services were enrolled across two sites; 145 veterans (mean age: 39.2 [8.1]; 92.4% male; 84.8% with PTSD) who endorsed guilt related to a traumatic event that occurred during a post 9/11 Iraq or Afghanistan deployment were randomized and assessed at baseline, posttreatment, 3- and 6-month follow-up. RESULTS: Linear mixed models using intent-to-treat analyses showed guilt decreased in both conditions with a greater decrease for TrIGR (treatment × time, -0.22; F 1, 455.2 = 18.49, p = .001; d = 0.92) than supportive therapy. PTSD and depressive symptoms showed the same pattern. TrIGR had significantly higher likelihood of PTSD treatment response (67% vs. 40%), loss of PTSD diagnosis (50% vs. 14%), and meaningful change in depression (54% vs. 27%) than supportive therapy. Psychological distress and trait shame improved in both conditions. Quality of life did not change. CONCLUSIONS: Targeting guilt appears to be an effective means for reducing posttraumatic symptoms and distress.

Examining attendance patterns across integrated therapies for posttraumatic stress disorder and alcohol use disorder.

A substantial body of evidence supports the use of integrated treatments for posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD). Integrated trauma-focused exposure therapies reduce PTSD symptoms more than comparison treatments, including integrated coping skills therapies, but demonstrate lower attendance, raising questions regarding the relationships between attendance, outcomes, and treatment type. We aimed to examine these relationships in a RCT comparing integrated prolonged exposure (Concurrent Treatment for PTSD and Substance Use Disorders Using Prolonged Exposure, COPE; n = 58), to integrated coping skills therapy (Seeking Safety, SS; n = 52) offered in 12 sessions, with an option to extend up to four additional sessions. Participants were categorized based on number of sessions attended (0-4; 5-8; 9-12; 13-16). Multilevel modeling revealed that only when examining therapy attendance segments individually, clinical outcomes were comparable across treatments except in the 9-12 group, with COPE resulting in greater reductions in PTSD symptoms (p < 0.001), but not in alcohol use. Extending past 12 sessions was not associated with additional clinically meaningful symptom improvement for either treatment. These results suggest that attending a complete or near complete course of exposure therapy may enhance PTSD outcomes relative to non-trauma-focused therapies.

Substance use predictors of attendance among veterans in integrated PTSD and alcohol use disorder treatment.

Comorbid post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) is common, defined by greater severity and impairment than either disorder alone, and associated with poor treatment attendance. Exposure therapies are effective in treating PTSD+AUD, yet substance use is still cited as a potential contraindication for exposure. This study examined substance use-related predictors of session attendance among veterans (N = 119) randomized to receive integrated exposure therapy (Concurrent Treatment of PTSD and Substance Use Disorders using Prolonged Exposure [COPE]; Back et al., 2015) or integrated coping skills therapy (Seeking Safety [SS]; Najavits, 2002) in a clinical trial for comorbid PTSD+AUD (Norman et al., 2019). At baseline, greater percentage of heavy drinking days (ß = -0.23, p = .011) and greater AUD severity per structured clinical interview for DSM-IV-TR (ß = -0.21, p = .019) predicted fewer sessions across both treatments. Treatment type did not moderate the relationship between predictors and attendance, except for a trend for craving (p = .057), where greater craving predicted fewer sessions in SS (ß = -0.31, p = .02) but not COPE (ß = 0.14, p = .28). Percentage of abstinence days, AUD duration, and living in a controlled environment (e.g., recovery home) at the start of therapy were not associated with attendance in either treatment condition. Only a subset of substance use characteristics predicted attendance. Findings did not support the notion that alcohol use leads to lower attendance in exposure therapy compared to nonexposure therapy.

Trauma-related guilt and posttraumatic stress disorder symptoms in military veterans: The role of psychological inflexibility.

A growing body of evidence has shown consistent support for the association between trauma-related guilt and posttraumatic stress disorder (PTSD). However, factors that account for this association are not well understood. The present study examined psychological inflexibility as a potential mediator between trauma-related guilt and PTSD symptoms in a sample of U.S. military veterans. Secondary data analyses from a larger randomized control trial were conducted. Specifically, three separate mediation models were used to test if psychological inflexibility mediated the association between trauma-related guilt (guilt cognitions, guilt distress, overall guilt) and PTSD symptoms in 85 treatment-seeking veterans diagnosed with PTSD and alcohol use disorder. All three components of trauma-related guilt were positively associated with both psychological inflexibility and PTSD symptoms; psychological inflexibility was also positively associated with PTSD symptoms. Furthermore, psychological inflexibility partially mediated the association between all facets of trauma-related guilt and PTSD severity. These findings provide further support for the association between trauma-related guilt and PTSD and also provide insight into one mechanism linking trauma-related guilt to PTSD symptoms. Thus, psychological inflexibility may serve as an important intervention target for veterans with comorbid PTSD and alcohol use disorder struggling with trauma-related guilt.