Substance Use after Completion of an Intensive Treatment Program with Concurrent Treatment for Posttraumatic Stress Disorder and Substance Use among Veterans: Examining the Role of PTSD Symptoms.

OBJECTIVE: Substance use disorders (SUDs) and posttraumatic stress disorder (PTSD) are costly and highly co-occurring diagnoses, particularly among veterans, suggesting a need to understand this comorbidity and effectively treat both disorders among this population. METHODS: The current study aimed to examine substance use outcomes among post-9/11 veterans and service members (N = 48) who completed a two-week intensive outpatient program with concurrent treatment for and PTSD using Prolonged Exposure and substance use. Substance use was assessed at two weeks and three months posttreatment. RESULTS: The intensive program had high completion rates and demonstrated decreases in substance use at two weeks and three months posttreatment. Additionally, lower PTSD symptoms at treatment completion were related to less substance use posttreatment. CONCLUSIONS: Concurrent intensive treatment of PTSD and SUDs can lead to symptom improvement in a short period of time. Findings support the self-medication model, such that PTSD symptoms at treatment completion were related to substance use at follow-up.

A Laboratory Test of Alcohol-Related Intimate Partner Aggression: Expectancies Are Not to Blame.

Background: The role of alcohol expectancies and evaluations (i.e., perceived outcomes of drinking and whether these outcomes are desirable) in alcohol-related intimate partner aggression (IPA) has been debated, with some researchers arguing that expectancies fully account for the alcohol-IPA relationship and others suggesting they play a minimal if any role in alcohol-related IPA. In the current study, we examine the impact of expectancies and evaluations on alcohol-related IPA observed in the lab, in order to clarify what impact, if any, alcohol expectancies have on alcohol-related IPA. Consistent with findings from laboratory studies examining general aggression, we expected that individuals who were intoxicated would display greater IPA than individuals who were sober, but that alcohol expectancies and evaluations would be unrelated to in vivo IPA. Method: Participants were 69 dating couples (total N = 138), randomly assigned to consume either an alcohol or placebo beverage. IPA was measured with an in vivo aggression task based on the Taylor Aggression Paradigm. Results: As expected, alcohol intoxication predicted in vivo IPA following provocation (p < .03), whereas alcohol expectancies and evaluations were not related to IPA. Conclusions: These findings provide further support that alcohol expectancies and evaluations play little if any role in alcohol-related IPA. Rather, intoxication likely increases risk for IPA through its physiological effects on perception and thought. Further, treatments targeting alcohol use, rather than beliefs about outcomes of drinking, may have a greater impact on alcohol-related IPA.

Simulation-based Ultrasound Curriculum for Novice Clinicians to Assess Neonatal Endotracheal Tube Position.

Background: To evaluate the efficacy of a simulation-based mastery curriculum to train clinicians with limited-to-no sonography experience how to use ultrasound (US) to assess neonatal endotracheal tube (ETT) positioning. Methods: In a single-centered, prospective, educational study, 29 neonatology clinicians participated in a simulation-based mastery curriculum composed of a didactic lecture, followed by a one-on-one simulation session using a newly designed, three-dimensional (3D) printed US phantom model of the neonatal trachea and aorta. After mastery training, clinicians were evaluated with a performance checklist on their skills obtaining US images and assessing ETT positioning in the US phantom model. They also completed pre- and postcurriculum knowledge assessment tests and self-assessment surveys. The data were analyzed using Wilcoxon signed rank tests and repeated measures analysis of variance. Results: The mean checklist score improved significantly during three attempts (mean difference: 2.6552; 95% confidence interval [CI]: 2.2578-3.0525; P < 0.0001). The mean time to perform US decreased significantly from the first to third attempt (mean difference: -1.8276 min; 95% CI: -3.3391 to - 0.3161; P = 0.0196). In addition, there was a significant improvement in median knowledge assessment scores (50% vs. 80%; P < 0.0001) and survey ratings on knowledge and self-efficacy (P < 0.0001). Conclusion: Clinicians with limited-to-no sonography experience demonstrated improved knowledge and skill acquisition in using US to assess ETT positioning through simulation-based mastery training. The use of 3D modeling enhances simulation experiences and optimizes the quality of training during limited opportunities to achieve procedural competency in a controlled environment before further application into the clinical setting.

Multiscale Simulation of an Influenza A M2 Channel Mutant Reveals Key Features of Its Markedly Different Proton Transport Behavior.

The influenza A M2 channel, a prototype for viroporins, is an acid-activated viroporin that conducts protons across the viral membrane, a critical step in the viral life cycle. Four central His37 residues control channel activation by binding subsequent protons from the viral exterior, which opens the Trp41 gate and allows proton flux to the interior. Asp44 is essential for maintaining the Trp41 gate in a closed state at high pH, resulting in asymmetric conduction. The prevalent D44N mutant disrupts this gate and opens the C-terminal end of the channel, resulting in increased conduction and a loss of this asymmetric conduction. Here, we use extensive Multiscale Reactive Molecular Dynamics (MS-RMD) and quantum mechanics/molecular mechanics (QM/MM) molecular dynamics simulations with an explicit, reactive excess proton to calculate the free energy of proton transport in this M2 mutant and to study the dynamic molecular-level behavior of D44N M2. We find that this mutation significantly lowers the barrier of His37 deprotonation in the activated state and shifts the barrier for entry to the Val27 tetrad. These free energy changes are reflected in structural shifts. Additionally, we show that the increased hydration around the His37 tetrad diminishes the effect of the His37 charge on the channel's water structure, facilitating proton transport and enabling activation from the viral interior. Altogether, this work provides key insight into the fundamental characteristics of PT in WT M2 and how the D44N mutation alters this PT mechanism, and it expands understanding of the role of emergent mutations in viroporins.

The relations between C-reactive protein and trauma exposure, PTSD and depression symptoms, and PTSD psychotherapy treatment response in treatment seeking veterans and service members.

While inflammatory markers have been implicated in the link between PTSD and poor health outcomes, there is a paucity of research investigating C-reactive protein (CRP) and psychotherapy treatment response for posttraumatic stress disorder (PTSD). The present study utilized a large, well-characterized sample of veterans and service members (N = 493) engaged in intensive psychotherapy to investigate the associations between CRP, trauma exposure, related variables, and PTSD and depression, as well as investigating if CRP was associated with PTSD psychotherapy treatment response. Bivariate correlation results indicate that CRP was significantly associated with BMI (r = 0.48) and severity of experiences of childhood physical and sexual abuse (r = 0.14 and 0.15, respectively) and was not significantly associated with baseline PTSD total symptom severity, PTSD symptom clusters, or depression symptom severity (rs ranging from -0.03 to 0.04). In multivariate regression models investigating if CRP and related variables were associated with PTSD baseline symptom severity, CRP was not a significant predictor (ß = -0.03). Hierarchical linear modeling did not identify CRP as a significant predictor of PTSD psychotherapy outcome. Given that findings indicate that CRP was broadly elevated in this treatment seeking sample but not associated with PTSD and depression symptom severity, results suggest CRP may not be a specific biomarker for PTSD or depression but may be elevated in psychiatric disease more generally.

The Utility of Point-of-Care Ultrasound in the Pediatric Intensive Care Unit.

Objectives: Point of care ultrasound (POCUS) in adult critical care environments has become the standard of care in many hospitals. A robust literature shows its benefits for both diagnosis and delivery of care. The utility of POCUS in the pediatric intensive care unit (PICU), however, is understudied. This study describes in a series of PICU patients the clinical indications, protocols, findings and impact of pediatric POCUS on clinical management. Design: Retrospective analysis of 200 consecutive POCUS scans performed by a PICU physician. Patients: Pediatric critical care patients who required POCUS scans over a 15-month period. Setting: The pediatric and cardiac ICUs at a tertiary pediatric care center. Interventions: Performance of a POCUS scan by a pediatric critical care attending with advanced training in ultrasonography. Measurement and Main Results: A total of 200 POCUS scans comprised of one or more protocols (lung and pleura, cardiac, abdominal, or vascular diagnostic protocols) were performed on 155 patients over a 15-month period. The protocols used for each scan reflected the clinical question to be answered. These 200 scans included 133 thoracic protocols, 110 cardiac protocols, 77 abdominal protocols, and 4 vascular protocols. In this series, 42% of scans identified pathology that required a change in therapy, 26% confirmed pathology consistent with the ongoing plans for new therapy, and 32% identified pathology that did not result in initiation of a new therapy. Conclusions: POCUS performed by a trained pediatric intensivist provided useful clinical information to guide patient management.

Influenza A M2 Inhibitor Binding Understood through Mechanisms of Excess Proton Stabilization and Channel Dynamics.

Prevalent resistance to inhibitors that target the influenza A M2 proton channel has necessitated a continued drug design effort, supported by a sustained study of the mechanism of channel function and inhibition. Recent high-resolution X-ray crystal structures present the first opportunity to see how the adamantyl amine class of inhibitors bind to M2 and disrupt and interact with the channel's water network, providing insight into the critical properties that enable their effective inhibition in wild-type M2. In this work, we examine the hypothesis that these drugs act primarily as mechanism-based inhibitors by comparing hydrated excess proton stabilization during proton transport in M2 with the interactions revealed in the crystal structures, using the Multiscale Reactive Molecular Dynamics (MS-RMD) methodology. MS-RMD, unlike classical molecular dynamics, models the hydrated proton (hydronium-like cation) as a dynamic excess charge defect and allows bonds to break and form, capturing the intricate interactions between the hydrated excess proton, protein atoms, and water. Through this, we show that the ammonium group of the inhibitors is effectively positioned to take advantage of the channel's natural ability to stabilize an excess protonic charge and act as a hydronium mimic. Additionally, we show that the channel is especially stable in the drug binding region, highlighting the importance of this property for binding the adamantane group. Finally, we characterize an additional hinge point near Val27, which dynamically responds to charge and inhibitor binding. Altogether, this work further illuminates a dynamic understanding of the mechanism of drug inhibition in M2, grounded in the fundamental properties that enable the channel to transport and stabilize excess protons, with critical implications for future drug design efforts.

Proton-Induced Conformational and Hydration Dynamics in the Influenza A M2 Channel.

The influenza A M2 protein is an acid-activated proton channel responsible for acidification of the inside of the virus, a critical step in the viral life cycle. This channel has four central histidine residues that form an acid-activated gate, binding protons from the outside until an activated state allows proton transport to the inside. While previous work has focused on proton transport through the channel, the structural and dynamic changes that accompany proton flux and enable activation have yet to be resolved. In this study, extensive Multiscale Reactive Molecular Dynamics simulations with explicit Grotthuss-shuttling hydrated excess protons are used to explore detailed molecular-level interactions that accompany proton transport in the +0, + 1, and +2 histidine charge states. The results demonstrate how the hydrated excess proton strongly influences both the protein and water hydrogen-bonding network throughout the channel, providing further insight into the channel's acid-activation mechanism and rectification behavior. We find that the excess proton dynamically, as a function of location, shifts the protein structure away from its equilibrium distributions uniquely for different pH conditions consistent with acid-activation. The proton distribution in the xy-plane is also shown to be asymmetric about the channel's main axis, which has potentially important implications for the mechanism of proton conduction and future drug design efforts.

The superiority of point of care ultrasound in localizing central venous line tip position over time.

The primary objective was to study agreement between X-rays and point of care ultrasound (POC-US) in determining central venous line (CVL) tip position. The secondary objective was to examine malposition rates over time using POC-US. Fifty-six neonates were enrolled who had a CVL placed. Initial X-rays and POC-US were obtained. POC-US was performed daily thereafter for the total of 6 days. US video clips were acquired in four standard echocardiographic views: subcostal, four-chamber, and short- and long-axis parasternal views. Gwet's agreement coefficient (AC1) for agreement measured inter-rater reliability of X-rays and POC-US (correct position/malposition). A generalized linear mixed model for binary clustered data estimated malposition rate over time. All analyses were conducted using SAS version 9.4 and Agree Stat. The study included 108 "pairs" of X-rays and POC-US images. Agreement coefficient (AC1), with respect to correct position/malposition of CVL tip, was high AC1 = 0.872 (UVC-AC1 = 0.814, PICC-AC1 = 0.94). Among birth weight (BW) < 1000 g, 1000-1499 g, and BW > 1500 g, AC1 values were 0.922, 0.774, and 0.873, respectively. CVL tip malposition rate decreased over time.Conclusions: Agreement between POC-US and X-rays for CVL tip position was high, with the highest in BW < 1000 g. The data suggest that POC-US can be used for initial confirmation and follow up of CVL tip position. What is Known • X-ray is currently the gold standard for localizing central venous line (CVL) tip position. • Malposition of CVL tip can lead to life-threatening complications. What is New • POC-US is superior to X-ray as it can follow CVL tip position over time, detecting malpositioned lines, adjusting them in a timely manner thus preventing complications. • Standardizing CVL placement, X-ray acquisition, POC-US acquisition with four views with video clips and ultrasound operator training increases accuracy and thus agreement between X-ray and POC-US. • UVC tip is more likely to be malpositoned than PICC tip. Malposition of UVC tip using POC-US decreased over time due to shrinking of the umbilical cord in the first 48 of life.

Feasibility and preliminary efficacy of dialectical behaviour therapy skills groups for Veterans with suicidal ideation: pilot.

BACKGROUND: Veterans are at high risk for suicide; emotion dysregulation may confer additional risk. Dialectical behaviour therapy (DBT) is a well-supported intervention for suicide attempt reduction in individuals with emotion dysregulation, but is complex and multi-component. The skills group component of DBT (DBT-SG) has been associated with reduced suicidal ideation and emotion dysregulation. DBT-SG for Veterans at risk for suicide has not been studied. AIMS: This study sought to evaluate the feasibility and acceptability of DBT-SG in Veterans and to gather preliminary evidence for its efficacy in reducing suicidal ideation and emotion dysregulation and increasing coping skills. METHOD: Veterans with suicidal ideation and emotion dysregulation (N = 17) enrolled in an uncontrolled pilot study of a 26-week DBT-SG as an adjunct to mental health care-as-usual. RESULTS: Veterans attended an average 66% of DBT-SG sessions. Both Veterans and their primary mental health providers believed DBT-SG promoted Veterans' use of coping skills to reduce suicide risk, and they were satisfied with the treatment. Paired sample t-tests comparing baseline scores with later scores indicated suicidal ideation and emotion dysregulation decreased at post-treatment (d = 1.88, 2.75, respectively) and stayed reduced at 3-month follow-up (d = 2.08, 2.59, respectively). Likewise, skillful coping increased at post-treatment (d = 0.85) and was maintained at follow-up (d = 0.91). CONCLUSIONS: An uncontrolled pilot study indicated DBT-SG was feasible, acceptable, and demonstrated potential efficacy in reducing suicidal ideation and emotion dysregulation among Veterans. A randomized controlled study of DBT-SG with Veterans at risk for suicide is warranted.

Clinically Significant Change in Posttraumatic Stress Disorder Symptoms Is Associated With Lower Levels of Aggression After Residential Treatment Discharge.

Although the link between posttraumatic stress disorder (PTSD) and aggression has been repeatedly demonstrated, to our knowledge no research has examined whether PTSD symptom reductions are linked to less aggression after treatment. The current study aimed to address this gap in the literature by examining the association between reductions in PTSD symptoms and posttreatment aggression among 2,275 veterans in residential treatment for PTSD across 35 Veterans Health Administration sites. We estimated a multilevel model that examined the effect of clinically significant PTSD symptom change on aggression at 4-month posttreatment follow-up, and found significant within-site and between-site contextual effects of clinically significant changes in PTSD symptoms on follow-up aggression. Findings revealed that veterans who reported clinically significant changes in their PTSD symptoms had lower levels of aggression at follow-up than veterans at the same treatment site who did not report clinically significant PTSD change. After we controlled for individual clinically significant PTSD change, participants in treatment sites where the rates of clinically significant PTSD change were higher overall had lower levels of aggression at follow-up. The model explained over one-fourth of the variability in aggression, R2 = .26. Findings from the current study extend previous research that has shown associations between PTSD and aggression, by revealing that clinically significant change in PTSD during residential treatment is associated with less aggression at follow-up. These findings suggest that interventions that effectively reduce PTSD symptoms may also help reduce risk for aggression.

Negative urgency and emotion regulation strategy use: Associations with displaced aggression.

The numerous public health consequences of interpersonal aggression highlight the necessity of a comprehensive understanding of factors influencing its perpetration. This study examined direct and interactive associations between negative urgency and emotion regulation strategy use in predicting displaced aggression under conditions of negative mood. Participants were 197 male and female undergraduate students who were randomly assigned to employ either cognitive reappraisal or expressive suppression in response to a negative mood induction. Immediately afterwards, participants engaged in an analog displaced aggression task. Results revealed direct, positive associations between negative urgency and aggression. In addition, the use of suppression was associated with greater aggression than was the use of reappraisal alone. Counter to the hypothesis, there were no interactive effects between negative urgency and emotion regulation strategy use in predicting aggression. Findings suggest reducing negative urgency and use of suppression as potential intervention targets for individuals who engage in aggressive behavior.

Hazardous alcohol use and intimate partner aggression among dating couples: the role of impulse control difficulties.

To date, research identifying moderators of the alcohol-intimate partner aggression (IPA) relationship has focused almost exclusively on male-perpetrated aggression, without accounting for the dyadic processes of IPA. The current study examined hazardous alcohol use and impulse control difficulties as predictors of IPA among a sample of 73 heterosexual dating couples. Both actor and partner effects of these risk factors on physical and psychological aggression were examined. Results indicated that impulse control difficulties were an important actor and partner predictor of both physical and psychological aggression. Findings supported the multiple threshold model such that the interaction between impulse control difficulties and hazardous alcohol use significantly predicted physical aggression severity. These results suggest the importance of targeting impulse control difficulties and hazardous alcohol use in IPA treatment, as well as the advantages of examining risk factors of IPA within a dyadic rather than individual framework.

Comorbid treatment of traumatic brain injury and mental health disorders.

BACKGROUND: The Emory Healthcare Veterans Program (EHVP) is a multidisciplinary intensive outpatient treatment program for post-9/11 veterans and service members with invisible wounds, including posttraumatic stress disorder (PTSD), traumatic brain injury (TBI), substance use disorders (SUD), and other anxiety- and depression-related disorders. OBJECTIVE: This article reviews the EHVP. METHODS: The different treatment tracks that provide integrated and comprehensive treatment are highlighted along with a review of the standard, adjunctive, and auxiliary services that complement individualized treatment plans. RESULTS: This review particularly emphasizes the adjunctive neurorehabilitation service offered to veterans and service members with a TBI history and the EVHP data that indicate large reductions in PTSD and depression symptoms across treatment tracks that are maintained across 12 months follow up. Finally, there is a discussion of possible suboptimal treatment response and the pilot programs related to different treatment augmentation strategies being deploying to ensure optimal treatment response for all. CONCLUSION: Published data indicate that the two-week intensive outpatient program is an effective treatment program for a variety of complex presentations of PTSD, TBI, SUD, and other anxiety- and depression-related disorders in veterans and active duty service members.

Abdominal biofidelity assessment of 5th percentile female ATD responses relative to recently developed belt and bar loading corridors.

OBJECTIVE: The objective of this study was the quantitative evaluation and comparison of the responses of the Hybrid III 5th percentile female (HIII-05F) and the 5th percentile female Test Device for Human Occupant Restraint (THOR-05F) anthropomorphic test devices (ATDs) subjected to abdominal loading conditions. METHOD: The HIII-05F and THOR-05F were subjected to 3 different abdominal loading conditions: fixed-back belt pull (low compression), fixed-back belt pull (high compression), and free-back rigid bar impact at 6 m/s. The stroke of the impact was controlled to represent injurious and noninjurious loading conditions as observed in the experiments with postmortem human subjects (PMHS). Quantitative comparisons were made between the ATD abdominal force and compression responses and biofidelity corridors obtained from matched-pair PMHS tests under identical loading conditions, using the most recent version of the NHTSA Biofidelity Ranking System (BRS). RESULTS: The overall THOR-05F BRS scores across all tests (BRS score = 1.84) indicated good biofidelity. For the belt loading test conditions, the average BRS scores for both THOR-05F (BRS scores = 1.45 and 1.34) and HIII-05F (BRS scores = 1.42 and 1.01) showed good biofidelity. For the rigid bar loading condition, the THOR-05F (BRS score = 2.74) showed better biofidelity compared to HIII-05F (BRS score = 10.63), with the HIII-05F exhibiting poor performance in this condition. The average pressures recorded by the abdomen pressure twin sensors (APTS) in the current study ranged from 45 to 130 kPa, increasing proportionally with higher stroke and loading rate. CONCLUSIONS: Overall, the THOR-05F BRS scores were better than the HIII-05F BRS scores, which suggests improved biofidelity of the THOR-05F abdomen. The abdominal insert in the HIII-05F did not provide enough room for compression, leading to higher stiffness and occupant motion as observed in the rigid bar tests. Because of practical challenges in measuring abdomen deflection in a soft ATD abdomen component, use of APTS in THOR-05F provides the ability to measure the restraint loading to the abdomen and assess the risk of abdominal injury. With good BRS scores observed in this study for THOR-05F, pressure and other measurements included in the THOR-05F may be used to develop abdominal injury risk functions in the future.

Transient water wires mediate selective proton transport in designed channel proteins.

Selective proton transport through proteins is essential for forming and using proton gradients in cells. Protons are conducted along hydrogen-bonded 'wires' of water molecules and polar side chains, which, somewhat surprisingly, are often interrupted by dry apolar stretches in the conduction pathways, inferred from static protein structures. Here we hypothesize that protons are conducted through such dry spots by forming transient water wires, often highly correlated with the presence of the excess protons in the water wire. To test this hypothesis, we performed molecular dynamics simulations to design transmembrane channels with stable water pockets interspersed by apolar segments capable of forming flickering water wires. The minimalist designed channels conduct protons at rates similar to viral proton channels, and they are at least 106-fold more selective for H+ over Na+. These studies inform the mechanisms of biological proton conduction and the principles for engineering proton-conductive materials.

An NZW-derived interval on chromosome 7 moderates sialadenitis, but not insulitis in congenic nonobese diabetic mice.

Autoimmune lymphocytic infiltration of the salivary glands, termed sialadenitis, is a pathologic feature of Sjögren's syndrome (SjS) that is also prominent in nonobese diabetic (NOD) mice. Genetic factors regulate sialadenitis, and a previous (NOD x NZW)F2 study detected linkage to murine chromosome (Chr) 7. The locus, subsequently annotated as Ssial3, maps to the distal end of Chr7 and overlaps a region associated with type 1 diabetes susceptibility in NOD mice. To examine whether Ssial3 could contribute to both diseases, or was specific for SjS, we generated a congenic mouse strain that harbored an NZW-derived Chr7 interval on the NOD genetic background. This congenic strain exhibited reduced sialadenitis compared with NOD mice and confirmed Ssial3. This reduction, however, did not ameliorate saliva abnormalities associated with SjS-like disease in NOD mice, nor were congenic mice protected against insulitis (lymphocytic infiltration of the pancreatic islets) or diabetes onset. Thus, the Ssial3 locus appears to have a tissue-specific effect for which the NZW allele is unable to prevent other autoimmune traits in the NOD mouse. Anomalous increases for antinuclear Ab production and frequency of marginal-zone B cells were also identified in congenic mice, indicating that the NZW-derived Chr7 interval has a complex effect on the NOD immune system.