Impact of dissociation on exposure therapy for PTSD outcomes and Adherence among U.S. Military service members.

Emotional engagement is necessary for successful exposure therapy for posttraumatic stress disorder (PTSD), but dissociation is considered a barrier to emotional engagement. Virtual reality exposure therapy (VRE) uses multi-sensory virtual environments to increase emotional engagement during exposure therapy, and average treatment outcomes are comparable to traditional exposure therapy. However, individual factors (e.g., depression) can predict differential responses to VRE. Studies have yet to investigate whether VRE would be more effective in treating patients with dissociation compared to traditional PE. This secondary analysis of a randomized clinical trial explores whether dissociation predicts treatment outcomes to exposure therapy among active-duty soldiers (N = 108) diagnosed with PTSD. We also examine whether individuals reporting dissociative symptoms demonstrated differential treatment responses to VRE and PE. Results indicated a significant two-way interaction between dissociation and time in treatment, such that dissociation blunted the negative relationship between time and PTSD symptoms. Dissociation was not associated with treatment session attendance or drop out. Results also revealed no significant effect of treatment group (PE or VRE) on the relationship between dissociation and PTSD symptoms. Findings contribute to a body of literature supporting the potential clinical and research utility of a dissociative subtype of PTSD.

Perceptions of Palliative and End-Of-Life Care Capacity Among Frontline Staff and Administrators in Long-Term Care Homes During the COVID-19 Pandemic in Ontario, Canada: A Mixed-Methods Evaluation.

OBJECTIVES: The COVID-19 pandemic has greatly affected the morbidity and mortality of residents in long-term care (LTC) homes. However, not much is known about its impact on staff's perception of their capacity to provide palliative and end-of-life (EOL) care for LTC residents over the course of the pandemic. We investigated changes in self-reported confidence among LTC workers and their experience in providing palliative and EOL care to residents before and during the COVID-19 pandemic. DESIGN: Mixed-methods evaluation using a survey (n = 19) and semistructured interviews (n = 28). SETTING AND PARTICIPANTS: Frontline workers from 9 LTC homes who participated in Communication at End-of-Life Program in Ontario, Canada, between August 2019 and March 2020. METHODS: The survey captured LTC staff's confidence level, including attitudes toward death and dying; relationships with residents and families; and participation in palliative and EOL care. The interviews identified facilitators and barriers to providing palliative and EOL care during the pandemic. RESULTS: The COVID-19 pandemic negatively impacted frontline LTC staff's confidence in their role as palliative care providers. Participants also reported notable challenges to providing resident-centered palliative and EOL care. Specifically, visitation restriction has led to increased loneliness and isolation of residents and impeded staff's ability to build supportive relationships with families. Furthermore, staffing shortages due to the single-site work restriction and illness increased workload. Psychological stress caused by a fear of COVID-19 infection and transmission also hindered staff's capacity to provide good palliative and EOL care. CONCLUSIONS AND IMPLICATIONS: Frontline LTC staff-even those who felt competent in their knowledge and skills in providing palliative and EOL care after receiving training-reported notable difficulties in providing resident-centered palliative and EOL care during the COVID-19 pandemic.

Chaotic advection mixer for capturing transient states of diverse biological macromolecular systems with time-resolved small-angle X-ray scattering.

Advances in time-resolved structural techniques, mainly in macromolecular crystallography and small-angle X-ray scattering (SAXS), allow for a detailed view of the dynamics of biological macromolecules and reactions between binding partners. Of particular promise, are mix-and-inject techniques, which offer a wide range of experimental possibility as microfluidic mixers are used to rapidly combine two species just prior to data collection. Most mix-and-inject approaches rely on diffusive mixers, which have been effectively used within crystallography and SAXS for a variety of systems, but their success is dependent on a specific set of conditions to facilitate fast diffusion for mixing. The use of a new chaotic advection mixer designed for microfluidic applications helps to further broaden the types of systems compatible with time-resolved mixing experiments. The chaotic advection mixer can create ultra-thin, alternating layers of liquid, enabling faster diffusion so that even more slowly diffusing molecules, like proteins or nucleic acids, can achieve fast mixing on timescales relevant to biological reactions. This mixer was first used in UV-vis absorbance and SAXS experiments with systems of a variety of molecular weights, and thus diffusion speeds. Careful effort was also dedicated to making a loop-loading sample-delivery system that consumes as little sample as possible, enabling the study of precious, laboratory-purified samples. The combination of the versatile mixer with low sample consumption opens the door to many new applications for mix-and-inject studies.

Characterization of cell-to-cell variation in nuclear transport rates and identification of its sources.

Nuclear transport is an essential part of eukaryotic cell function. Here, we present scFRAP, a model-assisted fluorescent recovery after photobleaching (FRAP)- based method to determine nuclear import and export rates independently in individual live cells. To overcome the inherent noise of single-cell measurements, we performed sequential FRAPs on the same cell. We found large cell-to-cell variation in transport rates within isogenic yeast populations. For passive transport, the variability in NPC number might explain most of the variability. Using this approach, we studied mother-daughter cell asymmetry in the active nuclear shuttling of the transcription factor Ace2, which is specifically concentrated in daughter cell nuclei in early G1. Rather than reduced export in the daughter cell, as previously hypothesized, we found that this asymmetry is mainly due to an increased import in daughters. These results shed light on cell-to-cell variation in cellular dynamics and its sources.

Rationale and design of a multisite randomized clinical trial examining an integrated behavioral treatment for veterans with co-occurring chronic pain and opioid use disorder: The pain and opioids integrated treatment in veterans (POSITIVE) trial.

BACKGROUND: Chronic pain and opioid use disorder (OUD) individually represent a risk to health and well-being. Concerningly, there is evidence that they are frequently co-morbid. While few treatments exist that simultaneously target both conditions, preliminary work has supported the feasibility of an integrated behavioral treatment targeting pain interference and opioid misuse. This treatment combined Acceptance and Commitment Therapy (ACT) and Mindfulness-Based Relapse Prevention (ACT+MBRP). This paper describes the protocol for the adequately powered efficacy study of this integrated treatment. METHODS: A multisite randomized controlled trial will examine the efficacy of ACT+MBRP in comparison to a parallel education control condition, focusing on opioid safety and pain education. Participants include veterans (n = 160; 21-75 years old) recruited from three Veterans Administration (VA) Healthcare Systems with chronic pain who are on a stable dose of buprenorphine. Both conditions include twelve weekly 90 min group sessions delivered via telehealth. Primary outcomes include pain interference (Patient Reported Outcome Measurement Information System - Pain Interference) and hazardous opioid use (Current Opioid Misuse Measure), which will be examined at the end of the active treatment phase and through 12 months post-intervention. Secondary analyses will evaluate outcomes including pain intensity, depression, pain-related fear, and substance use, as well as treatment mechanisms. CONCLUSION: This study will determine the efficacy of an integrated behavioral treatment program for pain interference and hazardous opioid use among veterans with chronic pain and OUD who are prescribed buprenorphine, addressing a critical need for more integrated treatments for chronic pain and OUD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04648228.

Associations Between Repetitive Negative Thinking and Habituation of Defensive Responding Within and Between Sessions.

Repetitive negative thinking (RNT) is a transdiagnostic risk factor for internalizing psychopathology, and theoretical models suggest that RNT may maintain symptoms by interfering with psychophysiological habituation. The present study therefore examined associations between RNT and habituation within and between study sessions. Community members (N=86) completed a habituation task involving exposure to acoustic probes at up to five sessions spaced 7 days apart on average. Eyeblink startle response was measured using the electromyography startle magnitude. Self-reported anxiety was assessed before and after the habituation task at each session. Multilevel growth curve modeling indicated that RNT was associated with a higher "floor" (i.e., asymptote) of startle responding as evidenced by reduced within-session startle habituation at later sessions. Results suggest that RNT may disrupt startle habituation and are consistent with theoretical models proposing that RNT sustains physiological activation to support avoidance of negative emotional contrasts or perceived future threats. Supplementary Information: The online version contains supplementary material available at 10.1007/s42761-022-00121-w.

Observation of substrate diffusion and ligand binding in enzyme crystals using high-repetition-rate mix-and-inject serial crystallography.

Here, we illustrate what happens inside the catalytic cleft of an enzyme when substrate or ligand binds on single-millisecond timescales. The initial phase of the enzymatic cycle is observed with near-atomic resolution using the most advanced X-ray source currently available: the European XFEL (EuXFEL). The high repetition rate of the EuXFEL combined with our mix-and-inject technology enables the initial phase of ceftriaxone binding to the Mycobacterium tuberculosis ß-lactamase to be followed using time-resolved crystallography in real time. It is shown how a diffusion coefficient in enzyme crystals can be derived directly from the X-ray data, enabling the determination of ligand and enzyme-ligand concentrations at any position in the crystal volume as a function of time. In addition, the structure of the irreversible inhibitor sulbactam bound to the enzyme at a 66 ms time delay after mixing is described. This demonstrates that the EuXFEL can be used as an important tool for biomedically relevant research.

Characterizing Enzyme Reactions in Microcrystals for Effective Mix-and-Inject Experiments using X-ray Free-Electron Lasers.

Mix-and-inject serial crystallography is an emerging technique that utilizes X-ray free-electron lasers (XFELs) and microcrystalline samples to capture atomically detailed snapshots of biomolecules as they function. Early experiments have yielded exciting results; however, there are limited options to characterize reactions in crystallo in advance of the beamtime. Complementary measurements are needed to identify the best conditions and timescales for observing structural intermediates. Here, we describe the interface of XFEL compatible mixing injectors with rapid freeze-quenching and X-band EPR spectroscopy, permitting characterization of reactions in crystals under the same conditions as an XFEL experiment. We demonstrate this technology by tracking the reaction of azide with microcrystalline myoglobin, using only a fraction of the sample required for a mix-and-inject experiment. This spectroscopic method enables optimization of sample and mixer conditions to maximize the populations of intermediate states, eliminating the guesswork of current mix-and-inject experiments.

Pilot trial of a transdiagnostic computerized anxiety sensitivity intervention among VA primary care patients.

People in need of mental health treatment do not access care at high rates or in a timely manner, inclusive of Veterans at Department of Veteran's Affairs (VA) medical centers. Barriers to care have been identified, and one potential solution is the use of technology-based interventions within primary care. This study evaluated the Cognitive Anxiety Sensitivity Treatment (CAST), a previously developed computerized treatment that has shown efficacy in community samples for mental health symptoms including: anxiety, depression, post-traumatic stress, and suicidal ideation. VA primary care patients with elevated anxiety sensitivity (N = 25) were recruited to participate in a mixed-method open pilot to examine acceptability, usability, and preliminary effectiveness in a VA primary care setting. Participants completed an initial visit, that included the intervention, and a one-month follow-up. Veterans found CAST to be generally acceptable, with strong usability ratings. Qualitative analyses identified areas of strength and areas for improvement for use with VA primary care Veterans. Repeated measures ANCOVAs revealed significant effects for symptoms of anxiety, depression, traumatic-stress, and suicidal ideation. CAST could potentially have a large public health impact if deployed across VA medical centers as a first-step intervention for a range of mental health presenting concerns.

Changes in physiological reactivity in response to the trauma memory during prolonged exposure and virtual reality exposure therapy for posttraumatic stress disorder.

OBJECTIVE: A key symptom of posttraumatic stress disorder (PTSD) is hyperreactivity to trauma-relevant stimuli. Though physiological arousal is reliably elevated in PTSD, the question remains whether this arousal responds to treatment. Virtual reality (VR) has been posited to increase emotional engagement during prolonged exposure therapy (PE) for PTSD by augmenting imaginal exposures with trauma-relevant sensory information. However, the comparative effects of VR exposure therapy (VRE) have received limited empirical inquiry. METHOD: Ninety active-duty soldiers with combat-related PTSD participating in a randomized-controlled trial to receive PE, VRE, or a waitlist-control (WL) condition had their physiological reactivity, indexed by galvanic skin response (GSR), to their trauma memories assessed at pre-, mid-, and posttreatment. RESULTS: Although both VRE and PE conditions showed reduced GSR reactivity to trauma memories from pre- to posttreatment, only the VRE group differed significantly from WL. Across the sample, reductions in GSR were significantly correlated with reductions in self-reported PTSD and anxiety symptoms. CONCLUSIONS: This was the first study comparing effects of VRE and PE on psychophysiological variables. Given previous research finding limited differences between VRE and PE in PTSD symptom reduction, these findings lend support to the rationale for including VR in exposure therapy protocols while raising important questions about the potential benefits of VRE. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Innovative Recruitment Strategies to Increase Diversity of Participation in Parkinson's Disease Research: The Fox Insight Cohort Experience.

BACKGROUND: Clinical research in Parkinson's disease (PD) faces practical and ethical challenges due to two interrelated problems: participant under-recruitment and lack of diversity. Fox Insight (FI) is a web-based longitudinal study collecting patient-reported outcomes and genetic data worldwide to inform therapeutic studies. FI's online platform provides an opportunity to evaluate online strategies for recruiting large, diverse research cohorts. OBJECTIVE: This project aimed to determine 1) whether FI's digital marketing was associated with increased enrollment overall and from under-represented patient groups, compared to traditional recruitment methods; 2) the clinical and demographic characteristics of samples recruited online, and 3) the cost of this online recruitment. METHOD: FI recruitment during a 6-week baseline period without digital promotion was compared to recruitment during several periods of digital outreach. Separate online recruiting intervals included general online study promotion and unique Facebook and Google ad campaigns targeting under-represented subgroups: early PD, late/advanced PD, and residents of underrepresented/rural geographic areas. RESULTS: Early PD, late PD, and geotargeting campaigns enrolled more individuals in their respective cohorts compared to baseline. All online campaigns also yielded greater total FI enrollment, attracting more participants who were non-White, Hispanic, older, female, and had lower educational attainment and income, and more medical comorbidities. Cost per new participant ranged from $21 (Facebook) to $108 (Google). CONCLUSION: Digital marketing may allow researchers to increase, accelerate, and diversify recruitment for PD clinical studies, by tailoring digital ads to target PD cohort characteristics.

The Impact of Exposure Therapy on Resting Heart Rate and Heart Rate Reactivity Among Active-Duty Soldiers With Posttraumatic Stress Disorder.

OBJECTIVE: Posttraumatic stress disorder (PTSD) is linked to poor health, including cardiovascular disease. These effects may be a result of increased tonic cardiovascular function and cardiovascular reactivity. Despite PTSD's negative health burden, relatively little is known about whether frontline treatments for PTSD may alleviate cardiovascular risk. METHODS: The current study was a secondary analysis of a larger intervention study of active-duty soldiers with PTSD (n = 104; mean [SD] age = 30.6 [6.7] years; 6% women) randomized to an exposure therapy-either prolonged exposure (PE) or virtual reality exposure (VRE)-or a waitlist control condition. We examined change in participants' resting heart rate (HR) and HR reactivity from baseline (before randomization) to midtreatment and posttreatment using residualized change regression models. RESULTS: The results of the study demonstrated decreased resting HR (B = -5.06, p = .024) and HR reactivity (B = -2.46, p = .005) from baseline to posttreatment of PE and VRE relative to waitlist. Exploratory analyses found that changes in resting HR and HR reactivity were not significantly correlated with either self-reported or clinician-rated PTSD symptom change. CONCLUSIONS: These results suggest that PE and VRE for PTSD may alleviate some cardiovascular health risk associated with PTSD, improving cardiovascular functioning.RCT Registration: ClinicalTrials.gov (identifier: NCT01193725).

Microfluidic Mixing Injector Holder Enables Routine Structural Enzymology Measurements with Mix-and-Inject Serial Crystallography Using X-ray Free Electron Lasers.

The emerging technique of Mix-and-Inject Serial Crystallography (MISC) at X-ray free electron laser sources provides atomically detailed structural information about biomolecules as they function. Despite early successes, MISC is currently limited by the efficiency and robustness of the mixing injectors used to initiate the reaction and propel the sample into the X-ray beam for measurement. Here, we present a new method for fabricating the injector system that leads to simpler, faster, and more effective experiments. A mixing injector can now be produced from raw components in 100 min, only 5 min of which must be spent during the experiment, saving valuable time. The system is modular, enabling parts to be quickly exchanged in the event of unanticipated experimental difficulties, such as clogging. The injector holder is designed to be flexible, allowing each device to be optimized to maximize the number of diffraction patterns measured during each experiment. This holder has been used successfully during four beamtimes at two different X-ray free electron laser sources. Its robustness and ease of use is an important step toward making the MISC technique accessible and routine.

Does virtual reality increase emotional engagement during exposure for PTSD? Subjective distress during prolonged and virtual reality exposure therapy.

Prolonged exposure (PE) is a treatment for posttraumatic stress disorder (PTSD) based on emotional processing theory. According to this theory, emotional engagement during imaginal exposure is critical to clinical outcome. One rationale for virtual reality exposure therapy (VRE) is the ability of trauma-relevant, multi-sensory stimuli to increase emotional engagement. This study compared the subjective distress of active duty soldiers (N = 108) during exposure via PE or VRE. Soldiers with higher mean or peak distress during the first imaginal exposure had higher baseline PTSD symptom severity. There was no difference between groups on average or peak distress during imaginal exposure at the first or final exposure session. There were no significant differences in between-session habituation observed between VRE and PE groups. However, each ten-point decrease in SUDS scores, either mean or peak, from the initiation of imaginal exposure to the end of treatment, was associated with a greater decrease in CAPS-W scores for both groups. There were no group differences in these trajectories or the magnitude of the association between distress/habituation, and PTSD symptoms. Future research on VRE should measure patient ratings of engagement during exposure to better understand which patients are aided by this innovative approach to treatment.

Reductions in reported persecutory ideation and psychotic-like experiences during exposure therapy for posttraumatic stress disorder.

While psychotic-like experiences (PLEs), including persecutory ideation and auditory or visual hallucinations, are common in PTSD, questions remain about their relationships to core PTSD symptoms and responsiveness to treatment. This study examined data from a waitlist (WL) controlled clinical study of the effect of virtual reality (VR) and prolonged exposure (PE) in a sample of active-duty service members with deployment-related trauma (n = 161). PLEs were assessed and examined with regard to their responsiveness to trauma focused treatment (combining conditions) relative to the WL, as well as their relationships to PTSD symptoms. Persecutory ideation symptoms, which were most closely related to PTSD Cluster C (avoidance and numbing) symptoms, were reduced post-treatment in the trauma-focused condition relative to WL. Auditory and visual hallucinations-which were most closely associated with PTSD re-experiencing-decreased from baseline to post-treatment assessments for WL and exposure therapy participants. The presence of PLEs at baseline did not predict a reduced PTSD symptom response to treatment. Trauma-focused treatments appear effective in addressing psychotic-like experiences that can emerge in individuals with PTSD.

Divalent ions tune the kinetics of a bacterial GTPase center rRNA folding transition from secondary to tertiary structure.

Folding of an RNA from secondary to tertiary structure often depends on divalent ions for efficient electrostatic charge screening (nonspecific association) or binding (specific association). To measure how different divalent cations modify folding kinetics of the 60 nucleotide Ecoli rRNA GTPase center, we combined stopped-flow fluorescence in the presence of Mg2+, Ca2+, or Sr2+ together with time-resolved small angle X-ray scattering (SAXS) in the presence of Mg2+ to observe the folding process. Immediately upon addition of each divalent ion, the RNA undergoes a transition from an extended state with secondary structure to a more compact structure. Subsequently, specific divalent ions modulate populations of intermediates in conformational ensembles along the folding pathway with transition times longer than 10 msec. Rate constants for the five folding transitions act on timescales from submillisecond to tens of seconds. The sensitivity of RNA tertiary structure to divalent cation identity affects all but the fastest events in RNA folding, and allowed us to identify those states that prefer Mg2+ The GTPase center RNA appears to have optimized its folding trajectory to specifically utilize this most abundant intracellular divalent ion.

Enzyme intermediates captured "on the fly" by mix-and-inject serial crystallography.

BACKGROUND: Ever since the first atomic structure of an enzyme was solved, the discovery of the mechanism and dynamics of reactions catalyzed by biomolecules has been the key goal for the understanding of the molecular processes that drive life on earth. Despite a large number of successful methods for trapping reaction intermediates, the direct observation of an ongoing reaction has been possible only in rare and exceptional cases. RESULTS: Here, we demonstrate a general method for capturing enzyme catalysis "in action" by mix-and-inject serial crystallography (MISC). Specifically, we follow the catalytic reaction of the Mycobacterium tuberculosis ß-lactamase with the third-generation antibiotic ceftriaxone by time-resolved serial femtosecond crystallography. The results reveal, in near atomic detail, antibiotic cleavage and inactivation from 30 ms to 2 s. CONCLUSIONS: MISC is a versatile and generally applicable method to investigate reactions of biological macromolecules, some of which are of immense biological significance and might be, in addition, important targets for structure-based drug design. With megahertz X-ray pulse rates expected at the Linac Coherent Light Source II and the European X-ray free-electron laser, multiple, finely spaced time delays can be collected rapidly, allowing a comprehensive description of biomolecular reactions in terms of structure and kinetics from the same set of X-ray data.

Revealing the distinct folding phases of an RNA three-helix junction.

Remarkable new insight has emerged into the biological role of RNA in cells. RNA folding and dynamics enable many of these newly discovered functions, calling for an understanding of RNA self-assembly and conformational dynamics. Because RNAs pass through multiple structures as they fold, an ensemble perspective is required to visualize the flow through fleetingly populated sets of states. Here, we combine microfluidic mixing technology and small angle X-ray scattering (SAXS) to measure the Mg-induced folding of a small RNA domain, the tP5abc three helix junction. Our measurements are interpreted using ensemble optimization to select atomically detailed structures that recapitulate each experimental curve. Structural ensembles, derived at key stages in both time-resolved studies and equilibrium titrations, reproduce the features of known intermediates, and more importantly, offer a powerful new structural perspective on the time-progression of folding. Distinct collapse phases along the pathway appear to be orchestrated by specific interactions with Mg ions. These key interactions subsequently direct motions of the backbone that position the partners of tertiary contacts for later bonding, and demonstrate a remarkable synergy between Mg and RNA across numerous time-scales.

Virtual reality exposure versus prolonged exposure for PTSD: Which treatment for whom?

BACKGROUND: The majority of studies comparing active psychological treatments for posttraumatic stress disorder (PTSD) do not find significant differences at posttreatment. This was the case in a recent trial examining prolonged exposure (PE) and virtual reality exposure (VRE) among active-duty soldiers with combat-related PTSD. Matching individual patients to specific treatments provides a potential avenue to improve significantly the public health impact of effective treatments for PTSD. A composite moderator approach was used to identify profiles of patients who would see superior PTSD symptom reduction in VRE or PE to inform future treatment matching. METHODS: Active duty U.S. army soldiers (N = 108) were enrolled in a randomized clinical trial comparing VRE and PE in the treatment of PTSD stemming from deployments to Iraq or Afghanistan. Eighteen baseline variables were examined to identify treatment response heterogeneity in two patient groups: those with a superior response to PE and those with a superior response to VRE. The final composite moderator comprised four of 18 baseline variables. RESULTS: Results revealed that patients who were predicted to see greater PTSD symptom reduction in VRE were likely to be younger, not taking antidepressant medication, had greater PTSD hyperarousal symptoms, and were more likely to have greater than minimal suicide risk. CONCLUSIONS: Results suggest that treatment matching based on patient profiles could meaningfully improve treatment efficacy for combat-related PTSD. Future research can build on these results to improve our understanding of how to improve treatment matching for PTSD.

A Family Study of the DSM-5 Section III Personality Pathology Model Using the Personality Inventory for the DSM-5 (PID-5).

In Section III of the DSM-5, the American Psychiatric Association (APA) proposes a pathological personality trait model of personality disorders. The recommended assessment instrument is the Personality Inventory for the DSM-5 (PID-5), an empirically derived scale that assesses personality pathology along five domains and 25 facets. Although the PID-5 demonstrates strong convergent validity with other personality measures, no study has examined whether it identifies traits that run in families, another important step toward validating the DSM-5's dimensional model. Using a family study method, we investigated familial associations of PID-5 domain and facet scores in 195 families, examining associations between parents and offspring and across siblings. The Psychoticism, Antagonism, and Detachment domains showed significant familial aggregation, as did facets of Negative Affect and Disinhibition. Results are discussed in the context of personality pathology and family study methodology. The results also help validate the PID-5, given the familial nature of personality traits.