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Tailored tobacco cessation interventions focusing on minoritized communities are proliferating, but the extent to which these interventions address the needs of individuals with multiple minoritized social identities is unclear. We developed Empowered, Queer, Quitting, and Living (EQQUAL), an avatar-led digital smoking cessation intervention tailored for lesbian, gay, bisexual, transgender, queer or questioning, intersex, asexual, and more (LGBTQIA+) young adults based on acceptance and commitment therapy (ACT), via a multistage user-centered design process. The purpose was to evaluate feedback from EQQUAL development activities using an intersectional lens. Intersectionality is a paradigm created by Kimberlé Crenshaw illustrating the multiple social identities each person possesses along with the marginalization of these different social identities. We conducted a rapid deductive content analysis focused on intersectional design gaps using interviewer notes from user testing ( n = 7), a diary study ( n = 8), and treatment satisfaction responses from a single-arm trial of the EQQUAL intervention ( n = 22). Feedback related to intersectional design fell under three broad themes: (a) inadequate representativeness of the avatar, (2) inadequate representativeness within the program broadly, and (3) non-inclusive ACT intervention content. Feedback on inclusiveness included reference to socioeconomic status, race/ethnicity, religious/cultural affiliation, and ability/disability. Although we previously found that EQQUAL was highly acceptable and showed promise in terms of efficacy in a single-arm pilot trial, we identified several gaps in intersectional design as the iterative intervention development proceeded. Because intersectional design is a critical part of developing interventions with a health equity focus, applying standardized procedures for intersectional design and analysis could improve intervention design and better address tobacco cessation treatment needs of individuals who may experience multiple forms of marginalization.

BackgroundChronic pain and problematic substance use are commonly co-occurring and highly detrimental issues that are especially prevalent in U.S. veteran populations. Although COVID-19 made clinical management of these conditions potentially difficult, some research suggests that certain veterans with these conditions did not experience this period as negatively as others. It is thus important to consider whether resilience factors, such as the increasingly-studied process of psychological flexibility, might have led to better outcomes for veterans managing pain and problematic substance use during this time of global crisis.MethodsThis planned sub-analysis of a larger cross-sectional, anonymous, and nationally-distributed survey (N = 409) was collected during the first year of the COVID-19 pandemic. Veteran participants completed a short screener and battery of online surveys assessing pain severity and interference, substance use, psychological flexibility, mental health functioning, and pandemic-related quality of life.ResultsFor veterans with chronic pain and problematic substance use, the pandemic resulted in a significant lowering of their quality of life related to meeting basic needs, emotional health, and physical health compared to veterans with problematic substance use but no chronic pain diagnosis. However, moderation analyses revealed that veterans with these comorbid conditions experienced less negative impacts from the pandemic on quality of life and mental health when they reported greater psychological flexibility. For veterans with problematic substance use only, psychological flexibility was also related to better mental health functioning, but did not significantly correlate with their quality of life.ConclusionResults highlight how COVID-19 differentially impacted veterans with both problematic substance use and chronic pain, such that this group reported particularly negative impacts of the pandemic on multiple areas of quality of life. However, our findings further emphasize that psychological flexibility, a modifiable resiliency process, also buffered against some of the negative impacts of the pandemic on mental health and quality of life. Given this, future research into the impact of natural crises and healthcare management should investigate how psychological flexibility can be targeted to help increase resiliency for veterans with chronic pain and problematic substance use.

Bullied adolescents experience myriad poor outcomes, yet certain responses can have significant mitigatory effects. However, research has yet to examine how the racial context of these interactions affects adolescents' evaluations of and beliefs about responding to social-exclusionary bullying (SEB). The sample comprised 219 ninth-grade Black (

BACKGROUND In the veteran community, chronic pain is particularly prevalent and often debilitating. Until recently, veterans with chronic pain were offered primarily pharmacological intervention options, which rarely suffice and can also have negative health consequences. To better address chronic pain in veterans, the Veterans Health Administration has invested in novel, nonpharmacological behavior interventions that target both pain management and chronic pain–related functional issues. One approach, acceptance and commitment therapy (ACT) for chronic pain, is supported by decades of efficacy evidence for improving pain outcomes; however, ACT can be difficult to obtain owing to issues such as a lack of trained therapists or veterans having difficulty committing to the time and resources needed for the full clinician-led ACT protocol. Given the strong ACT evidence base combined with access limitations, we set out to develop and evaluate Veteran ACT for Chronic Pain (VACT-CP), an online program guided by an embodied conversational agent to improve pain management and functioning. OBJECTIVE The aims of this study are to develop, iteratively refine, and then conduct a pilot feasibility randomized controlled trial (RCT) of a VACT-CP group (n=20) versus a waitlist and treatment-as-usual control group (n=20). METHODS This research project includes 3 phases. In phase 1, our research team consulted with pain and virtual care experts, developed the preliminary VACT-CP online program, and conducted interviews with providers to obtain their feedback on the intervention. In phase 2, we incorporated feedback from phase 1 into the VACT-CP program and completed initial usability testing with veterans with chronic pain. In phase 3, we are conducting a small pilot feasibility RCT, with the primary outcome being assessment of usability of the VACT-CP system. RESULTS This study is currently in phase 3; recruitment for the RCT began in April 2022 and is expected to continue through April 2023. Data collection is expected to be completed by October 2023, with full data analysis completed by late 2023. CONCLUSIONS The findings from this research project will provide information on the usability of the VACT-CP intervention, as well as secondary outcomes related to treatment satisfaction, pain outcomes (pain-related daily functioning and pain severity), ACT processes (pain acceptance, behavioral avoidance, and valued living), and mental and physical functioning. CLINICALTRIAL ClinicalTrials.gov NCT03655132; https://clinicaltrials.gov/ct2/show/NCT03655132 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/45887

IntroductionThe COVID-19 pandemic generated concerns about rising stress and alcohol use, especially in U.S. veterans who experience high rates of anxiety disorders (ADs), alcohol use disorder (AUD), and dual AD+AUD diagnoses. This study investigated differences among these diagnostic groups in a veteran population related to their concern about COVID-19, impacts of COVID-19 on quality of life, and self-reported changes to urge to drink and drinking frequency.MethodsA nationally administered online survey was given to a sample of U.S. veterans reporting substance use issues during the pandemic. Differences in the level of concern about COVID-19, impacts of COVID-19 on quality of life, and drinking behaviors were examined in those self-reporting AD (n = 98), AUD (n = 46), or AD+AUD (n = 67). Consensual qualitative research was used to analyze an open-ended question about COVID-19’s impact on substance use, health, and quality of life.ResultsVeterans with AD+AUD experienced significant increases in urge to drink and alcohol consumption compared to veterans with AD only. Greater urge and frequency of drinking were associated with greater negative impacts of COVID-19 on quality of life. There were no differences among groups in global negative impact on quality of life or level of COVID-19 concern. However, respondents described specific COVID-19 worries, with qualitative findings revealing that those with AD+AUD reported a disproportionate psychosocial burden due to the pandemic.DiscussionSpecial attention in screening and treatment should be given to those with a dual AD+AUD diagnosis who may be experiencing both an increase in alcohol use and psychosocial burden as stress increases due to the pandemic.

BACKGROUND Despite the declining prevalence of cigarette smoking in the United States, socioeconomically disadvantaged veterans receiving care from the Veterans Health Administration have a high prevalence of smoking. Currently, available treatment options for these veterans focus on tobacco users who are ready to quit and have limited reach. Consequently, there is a great need for accessible, effective smoking cessation interventions for veterans at all levels of readiness to quit smoking. OBJECTIVE To address these needs, we developed Vet Flexiquit, a web-based Acceptance and Commitment Therapy program for veterans, and evaluated its acceptability (primary aim), efficacy, and impact on theory-based change processes relative to the National Cancer Institute’s SmokefreeVET program in a pilot randomized controlled trial. METHODS Participants (N=49) were randomized 1:1 to receive either the Vet Flexiquit (n=25) or SmokefreeVET (n=24) web program. Both groups received SMS text messages as part of the intervention for 6 weeks. Both interventions are fully automated and self-guided. Primary outcome data were collected at 3 months after the randomization. Self-reported smoking abstinence was biochemically verified using saliva cotinine. Multivariable logistic regression, negative binomial regression, and linear regression models were used to evaluate the association between the treatment arm and outcomes of interest. RESULTS Acceptability, as measured by overall treatment satisfaction, was high and similar across treatment arms: 100% (17/17) for Vet Flexiquit and 95% (18/19) for SmokefreeVET. Acceptability, as measured by utilization, was more modest (log-ins: M=3.7 for Vet Flexiquit and M=3.2 for SmokefreeVET). There were no statistically significant differences between treatment arms for any acceptability measures. Similarly, there were no statistically significant differences between treatment arms in the secondary outcomes of smoking cessation or change in Acceptance and Commitment Therapy’s theory-based processes. In open-ended survey responses, some veterans in both treatment arms expressed interest in having support from a professional or peer to enhance their experience, as well as an expanded SMS text messaging program. CONCLUSIONS Both programs had high ratings of acceptability, limited utilization, and a similar impact on cessation and cessation processes. Taken together with the qualitative data suggesting that additional support may enhance participants’ experience of both programs, these preliminary findings suggest that the programs may have similar outcomes among veterans who are looking for a digital cessation treatment option and that integrating provider or peer support and enhancing the SMS text messaging program holds promise as a means of boosting engagement and outcomes for both programs. CLINICALTRIAL ClinicalTrials.gov NCT04502524; https://clinicaltrials.gov/ct2/show/NCT04502524

Proteostasis, the balance of protein synthesis, folding and degradation, is essential to maintain cellular function and viability, and the many known intracellular chaperones are recognized as playing key roles in sustaining life. In contrast, the identity of constitutively secreted extracellular chaperones (ECs) and their physiological roles in extracellular proteostasis is less completely understood. We designed and implemented a novel strategy, based on the well‐known propensity of chaperones to bind to regions of hydrophobicity exposed on misfolding proteins, to discover new ECs present in human blood. We used a destabilized protein that misfolds at 37°C as “bait” to bind to potential ECs in human serum and captured the complexes formed on magnetic beads. Proteins eluted from the beads were identified by mass spectrometry and a group of seven abundant serum proteins was selected for in vitro analysis of chaperone activity. Five of these proteins were shown to specifically inhibit protein aggregation. Vitronectin and plasminogen activator‐3 inhibited both the in vitro aggregation of the Alzheimer's β peptide (Aβ(1–42)) to form fibrillar amyloid, and the aggregation of citrate synthase (CS) to form unstructured (amorphous) aggregates. In contrast, prothrombin, C1r, and C1s inhibited the aggregation of Aβ(1–42) but did not inhibit CS aggregation. This study thus identified five novel and abundant putative ECs which may play important roles in the maintenance of extracellular proteostasis, and which apparently have differing abilities to inhibit the amorphous and amyloid‐forming protein aggregation pathways.

BACKGROUND: No studies have examined vocational identity among individuals with co-occurring mental health and substance use disorders. OBJECTIVE: Influenced by Blustein’s relational theory of working (2011), this study examined the relationships between several social-environmental variables (external/relational conflicts, employment barriers, substance abuse stigma) and vocational identity. METHODS: Eighty-four veterans receiving treatment from the Veterans Health Administration (VHA) for co-occurring mental health and substance use disorders participated in this survey study. RESULTS: Education, employment, clinical, disability, and substance abuse factors were not associated with vocational identity, but external/relational conflicts, employment barriers, and substance abuse stigma were. Multiple regression analysis found that these variables accounted for 34%of the variance in vocational identity and that external/relational conflicts was the only significant predictor. CONCLUSIONS: Findings suggest that more conflictual messages about work from external/relational sources is related to less clarity around one’s vocational interests, goals, and talents.

Age-related decrements in the central nervous system (CNS) are thought to result from: (1) increased susceptibility to and accumulating effects of free radicals and inflammation; and (2) dysregulation in Ca2+ homeostasis, which affects numerous signaling pathways. Certain bioactive phytochemicals exhibit potent anti-inflammatory activities which may mitigate these age-related CNS decrements. This study investigated the individual and combination effects of green tea catechin (epigallocatechin gallate, EGCG), curcumin from turmeric, and broccoli sprouts which contain the isothiocyanate sulforaphane on inflammation and dysregulation in Ca2+ homeostasis to determine if the individual compounds were working synergistically and/or through independent mechanisms. Rat hippocampal neurons or highly aggressive proliferating immortalized (HAPI) microglial cells were pre-treated for a week with either the individual components or all in combination before inducing Ca2+ buffering deficits with dopamine (DA, 0.1 µM for 2 h) or inflammation using lipopolysaccharide (LPS, 100 ng/mL for 18 h), respectively. The EGCG (3 µM) and combination protected against DA-induced deficits in Ca2+ buffering (both % of cells that recovered and recovery time, p < 0.05). Additionally, the EGCG and combination reduced stress-mediated inflammation in HAPI rat microglial cells by attenuating LPS-induced nitrite release, inducible nitrous oxide synthase (iNOS) expression, and tumor necrosis factor-alpha (TNF-α) release (p < 0.05), but not cyclooxygenase-2 (COX-2) expression. Overall, broccoli sprouts (2 µM) and curcumin (1 µM) were not as effective as the EGCG or combination. Further research is needed to determine if dietary intervention with a variety of foods containing compounds such as those found in green tea, turmeric, or broccoli sprouts can play a role in reducing age-related CNS inflammation, microglial activation, and downstream signaling pathways that can lead to neuronal dysfunction.

Endogenous RNA interference (RNAi) pathways regulate a wide range of cellular processes in diverse eukaryotes, yet in the ciliated eukaryote, Tetrahymena thermophila, the cellular purpose of RNAi pathways that generate ∼23-24 nucleotide (nt) small (s)RNAs has remained unknown. Here, we investigated the phenotypic and gene expression impacts on vegetatively growing cells when genes involved in ∼23-24 nt sRNA biogenesis are disrupted. We observed slower proliferation and increased expression of genes involved in DNA metabolism and chromosome organization and maintenance in sRNA biogenesis mutants RSP1Δ, RDN2Δ, and RDF2Δ. In addition, RSP1Δ and RDN2Δ cells frequently exhibited enlarged chromatin extrusion bodies, which are nonnuclear, DNA-containing structures that may be akin to mammalian micronuclei. Expression of homologous recombination factor Rad51 was specifically elevated in RSP1Δ and RDN2Δ strains, with Rad51 and double-stranded DNA break marker γ-H2A.X localized to discrete macronuclear foci. In addition, an increase in Rad51 and γ-H2A.X foci was also found in knockouts of TWI8, a macronucleus-localized PIWI protein. Together, our findings suggest that an evolutionarily conserved role for RNAi pathways in maintaining genome integrity may be extended even to the early branching eukaryotic lineage that gave rise to Tetrahymena thermophila.

Background People with serious mental illness are disproportionately affected by smoking and face barriers to accessing smoking cessation treatments in mental health treatment settings. Text-based interventions are cost-effective and represent a widely accessible approach to providing smoking cessation support. Objective We aimed to identify key factors for adapting text-based cessation interventions for people with serious mental illness who smoke. Methods We recruited 24 adults from mental health programs who had a serious mental illness and currently smoked cigarettes or had quit smoking within the past 5 years. We then conducted virtual qualitative interviews between November 2020 and August 2021. Data were analyzed using the rapid thematic analytic approach. Results We identified the following 3 major themes: (1) interplay between smoking and having a serious mental illness, (2) social contextual factors of smoking in adults with serious mental illness, and (3) smoking and quitting behaviors similar to the general population. Participants reported barriers and facilitators to quitting across the 3 themes. Within the “interplay between smoking and having a serious mental illness” theme, barriers included smoking to manage stress and mental health symptoms, and facilitators to quitting included the awareness of the harm of smoking on mental health and patient-provider discussions on smoking and mental health. In the “social contextual factors of smoking in adults with serious mental illness” theme, barriers included high social acceptability of smoking among peers. Positive support and the combined social stigma of smoking and having a mental health condition outside of peer groups motivated individuals to quit. Some participants indicated that low exposure to other smokers during the COVID-19 pandemic helped them to engage in cessation efforts. In the “smoking and quitting behaviors similar to the general population” theme, barriers included smoking after eating, having coffee, drinking alcohol, and experiencing negative social support, and facilitators included health concerns, improvement in the general quality of life, and use of evidence-based tobacco treatments when available. Conclusions People with serious mental illness often smoke to cope with intense emotional states, manage mental health symptoms, or maintain social bonds. Text message content emphasizing equally effective and less harmful ways for stress reduction and mental health symptom management may improve quit rates in individuals with serious mental illness.

Veterans with PTSD often have substantial interpersonal difficulties and low levels of social support, which puts them at increased risk of mortality, but few treatments address global social impairment for veterans with PTSD. This study is a pilot randomized trial of Acceptance and Commitment Therapy to Improve Social Support for Veterans with PTSD (ACT-SS), a psychotherapy that targets social avoidance and eroded social relationships, compared to Person-Centered Therapy (PCT), a non-directive psychotherapy. Participants were randomized to twelve sessions of either ACT-SS (n = 21) or PCT (n = 19). The results showed that veterans with PTSD had high ratings of satisfaction for both treatments. Contrary to the PCT group, participants in the ACT-SS group showed a significant improvement in the quality of social relationships, engagement in social and leisure activities, and PTSD symptoms from the baseline assessment to the end of treatment and a three-month follow-up. Veterans in the ACT-SS group, but not the PCT group, also showed significant improvements in mindfulness and valued living and a reduction in experiential avoidance from baseline to the end of treatment, with sustained improvements in valued living at the three-month follow-up. Overall, the present study demonstrated the feasibility, acceptability, and positive preliminary outcomes of ACT-SS for veterans with PTSD.

This article reports on original research investigating the pivotal role that teachers play in student engagement, using a tri-dimensional framework. This framework identifies how teachers’ pedagogical choices impact student engagement in ways that influence students’ external behaviours, internal emotions and internal cognitions. A questionnaire was developed to explore secondary teachers’ (n = 223) perceptions of pedagogies that support students’ behavioural, emotional and cognitive engagement in the classroom. Findings revealed that female participants placed higher importance on pedagogies that support students’ cognitive and behavioural engagement, and participants with leadership roles placed higher importance on pedagogies that support students’ cognitive and emotional engagement. Also emerging from the research was a negative correlation between the importance teachers placed on pedagogies that support cognitive and behavioural engagement and their school’s ICSEA value (the measure of socio-educational advantage in Australian schools). Overall, results support the tri-dimensional framework of student engagement utilised in this study and provide a robust framework for future research to further explore teachers’ pedagogical choices and how these choices impact student engagement.

BACKGROUND Addiction treatment evolved quickly during the first year of the COVID-19 pandemic in the United States, with changes likely increasing access to some forms of care (eg, medications for opioid use disorder) and reducing access to others (eg, inpatient treatments). Efforts to continue providing quality addiction treatment to veterans may have benefitted from the Veteran’s Healthcare Administration’s existing telehealth infrastructure. Veterans’ experiences of care during this time are key to evaluating these efforts. OBJECTIVE This study aimed to examine veterans’ experiences of mental health and addiction treatment during the first year of the COVID-19 pandemic. METHODS Cross-sectional self-report data were collected over 3 months starting in April 2021, using Qualtrics panels. Participants were 401 veterans who (1) endorsed one or more substance use–related problems and (2) reported attending one or more mental health or addiction treatment appointments since April 1, 2020. The survey included standardized assessments of the risk severity of substance use and treatment satisfaction, as well as study-specific questions assessing care in the past year, including the proportion of care received in person versus telehealth appointments and perceptions of treatment quality and access relative to before the pandemic. RESULTS Overall, 22% of the participants were women and 67% were White and non-Hispanic, with an average age of 41.7 (SD 9.4) years. The majority were combat veterans (85%), and the army was the most commonly represented branch (61%). Most of them (98%) endorsed items consistent with a moderate to severe risk for one or more substance use disorders, with alcohol being the most common one (91%), and most (74%) met the risk criteria for 2 or more substances. One-fifth of participants (20%) reported that their past year appointments were evenly split between in-person and telehealth consultations, while 43% of them received care primarily via telehealth, and 37% of them attended mostly in person. The average satisfaction with mental health and addiction treatment was comparable with that reported in previous addiction treatment studies (mean 25.4, SD 4.1) and did not differ as a function of the proportion of care received via telehealth (F2,398=2.77; P=.06). Most participants rated treatment as much better (27%), slightly better (38%), or the same (26%), and overall health care access as better (51%) or the same (30%) relative to before the pandemic. The distribution of satisfaction, quality, and access did not differ as a function of treatment modalities accessed in the past year (eg, medications and inpatient care). CONCLUSIONS Veterans rated their treatment satisfaction, perceived quality of care, and overall health care access as largely better or the same relative to prepandemic care. These data should be interpreted in the context of web-based administration of care and the cross-sectional study design. Nevertheless, our findings align with those of recent work suggesting that veterans with substance use disorders are particularly open to telehealth treatment options. These results also suggest that health care providers’ efforts to continue providing care during the first year of the COVID-19 pandemic were well received.

Background Despite the declining prevalence of cigarette smoking in the United States, socioeconomically disadvantaged veterans receiving care from the Veterans Health Administration have a high prevalence of smoking. Currently, available treatment options for these veterans focus on tobacco users who are ready to quit and have limited reach. Consequently, there is a great need for accessible, effective smoking cessation interventions for veterans at all levels of readiness to quit smoking. Objective To address these needs, we developed Vet Flexiquit, a web-based Acceptance and Commitment Therapy program for veterans, and evaluated its acceptability (primary aim), efficacy, and impact on theory-based change processes relative to the National Cancer Institute’s SmokefreeVET program in a pilot randomized controlled trial. Methods Participants (N=49) were randomized 1:1 to receive either the Vet Flexiquit (n=25) or SmokefreeVET (n=24) web program. Both groups received SMS text messages as part of the intervention for 6 weeks. Both interventions are fully automated and self-guided. Primary outcome data were collected at 3 months after the randomization. Self-reported smoking abstinence was biochemically verified using saliva cotinine. Multivariable logistic regression, negative binomial regression, and linear regression models were used to evaluate the association between the treatment arm and outcomes of interest. Results Acceptability, as measured by overall treatment satisfaction, was high and similar across treatment arms: 100% (17/17) for Vet Flexiquit and 95% (18/19) for SmokefreeVET. Acceptability, as measured by utilization, was more modest (log-ins: M=3.7 for Vet Flexiquit and M=3.2 for SmokefreeVET). There were no statistically significant differences between treatment arms for any acceptability measures. Similarly, there were no statistically significant differences between treatment arms in the secondary outcomes of smoking cessation or change in Acceptance and Commitment Therapy’s theory-based processes. In open-ended survey responses, some veterans in both treatment arms expressed interest in having support from a professional or peer to enhance their experience, as well as an expanded SMS text messaging program. Conclusions Both programs had high ratings of acceptability, limited utilization, and a similar impact on cessation and cessation processes. Taken together with the qualitative data suggesting that additional support may enhance participants’ experience of both programs, these preliminary findings suggest that the programs may have similar outcomes among veterans who are looking for a digital cessation treatment option and that integrating provider or peer support and enhancing the SMS text messaging program holds promise as a means of boosting engagement and outcomes for both programs. Trial Registration ClinicalTrials.gov NCT04502524; https://clinicaltrials.gov/ct2/show/NCT04502524

Background In the veteran community, chronic pain is particularly prevalent and often debilitating. Until recently, veterans with chronic pain were offered primarily pharmacological intervention options, which rarely suffice and can also have negative health consequences. To better address chronic pain in veterans, the Veterans Health Administration has invested in novel, nonpharmacological behavior interventions that target both pain management and chronic pain–related functional issues. One approach, acceptance and commitment therapy (ACT) for chronic pain, is supported by decades of efficacy evidence for improving pain outcomes; however, ACT can be difficult to obtain owing to issues such as a lack of trained therapists or veterans having difficulty committing to the time and resources needed for the full clinician-led ACT protocol. Given the strong ACT evidence base combined with access limitations, we set out to develop and evaluate Veteran ACT for Chronic Pain (VACT-CP), an online program guided by an embodied conversational agent to improve pain management and functioning. Objective The aims of this study are to develop, iteratively refine, and then conduct a pilot feasibility randomized controlled trial (RCT) of a VACT-CP group (n=20) versus a waitlist and treatment-as-usual control group (n=20). Methods This research project includes 3 phases. In phase 1, our research team consulted with pain and virtual care experts, developed the preliminary VACT-CP online program, and conducted interviews with providers to obtain their feedback on the intervention. In phase 2, we incorporated feedback from phase 1 into the VACT-CP program and completed initial usability testing with veterans with chronic pain. In phase 3, we are conducting a small pilot feasibility RCT, with the primary outcome being assessment of usability of the VACT-CP system. Results This study is currently in phase 3; recruitment for the RCT began in April 2022 and is expected to continue through April 2023. Data collection is expected to be completed by October 2023, with full data analysis completed by late 2023. Conclusions The findings from this research project will provide information on the usability of the VACT-CP intervention, as well as secondary outcomes related to treatment satisfaction, pain outcomes (pain-related daily functioning and pain severity), ACT processes (pain acceptance, behavioral avoidance, and valued living), and mental and physical functioning. Trial Registration ClinicalTrials.gov NCT03655132; https://clinicaltrials.gov/ct2/show/NCT03655132 International Registered Report Identifier (IRRID) DERR1-10.2196/45887

Severe Post-Traumatic Stress Disorder (PTSD) has been identified as a significant impediment to employment. However, little is known about correlates of employment recovery after a period of not working among veterans with severe PTSD treated in specialized intensive treatment programs. This study examines rates and correlates of transitioning from not being employed at admission to working four months after discharge using national Veterans Health Administration (VHA) program evaluation data on veterans engaged in specialized intensive PTSD treatment (N = 27,339). Results suggest that only 5.68% of the sample made the transition to employment while 10.6% lost employment, 8.9% worked both at admission and following discharge, and 74.9%, did not work either at admission or following discharge. Multinomial regression analysis found that compared to other groups, veterans who became employed were younger, less likely to receive service-connected disability payments, and experienced a significantly greater reduction in PTSD symptoms. Findings from this study highlight that this distinct population has very poor employment outcomes and deserves more attention, and that reducing PTSD symptoms can lead to improved employment outcomes. Efforts to integrate evidence-based vocational rehabilitation practice into residential PTSD treatment targeting PTSD symptoms is encouraged.

Active pharmaceutical ingredients (APIs) constitute a significant and growing global market. In the past few decades, labor costs, concerns regarding chemical waste, and more stringent regulations in developed countries have shifted the production of APIs to emerging economies, notably India and China. Nowadays, Europe and North America rely on imports for the majority of pharmaceuticals. The recent COVID pandemic as well as logistical challenges have called this model into question and have raised the interest in rebalancing distributed global API supply chains and possibly reshoring some API production to Europe and North America. API production often suffers from unfavorable Green Chemistry metrics, owing to complex routes, outdated chemistry for established entities, or lack of maturity of routes for newer entities. The environmental footprint of API synthesis routes benefits from renewables as starting materials. One such abundant renewable material is lignin, which can be converted to phenol and catechol. In addition, waste could be reduced by co-producing APIs in an integrated plant and the use of advanced catalysts. This Perspective demonstrates green production routes from phenol or catechol in four large scale examples: paracetamol (Tylenol®), acetyl salicylic acid (Aspirin®), amoxicillin (as sole API or as combination with potassium clavulanate (Augmentin®), and epinephrine (adrenaline, also as trademark Adrenaline®). We compare conventional routes with more modern routes with respect to Green Chemistry metrics. Overall, API production from renewable materials stands to combine low environmental footprint with high quality and economical manufacture of pharmaceuticals.

Identifying small molecules that selectively bind an RNA target while discriminating against all other cellular RNAs is an important challenge in RNA-targeted drug discovery. Much effort has been directed toward identifying drug-like small molecules that minimize electrostatic and stacking interactions that lead to nonspecific binding of aminoglycosides and intercalators to many stem–loop RNAs. Many such compounds have been reported to bind RNAs and inhibit their cellular activities. However, target engagement and cellular selectivity assays are not routinely performed, and it is often unclear whether functional activity directly results from specific binding to the target RNA. Here, we examined the propensities of three drug-like compounds, previously shown to bind and inhibit the cellular activities of distinct stem–loop RNAs, to bind and inhibit the cellular activities of two unrelated HIV-1 stem–loop RNAs: the transactivation response element (TAR) and the rev response element stem IIB (RREIIB). All compounds bound TAR and RREIIB in vitro, and two inhibited TAR-dependent transactivation and RRE-dependent viral export in cell-based assays while also exhibiting off-target interactions consistent with nonspecific activity. A survey of X-ray and NMR structures of RNA-small molecule complexes revealed that aminoglycosides and drug-like molecules form hydrogen bonds with functional groups commonly accessible in canonical stem–loop RNA motifs, in contrast to ligands that specifically bind riboswitches. Our results demonstrate that drug-like molecules can nonspecifically bind stem–loop RNAs most likely through hydrogen bonding and electrostatic interactions and reinforce the importance of assaying for off-target interactions and RNA selectivity in vitro and in cells when assessing novel RNA-binders.

Posttraumatic stress disorder (PTSD) often negatively impacts social functioning, which can lead to increased risk of morbidity and mortality. Although current evidence-based and exposure-specific treatments can improve PTSD symptoms, they rarely target the interpersonal difficulties that impact quality of life. This case study describes the use of a manualized treatment for a veteran who continues to experience poor social functioning even after previous exposure-based treatment for PTSD. This treatment, ACT to Improve Social Support for Veterans with PTSD (ACT-SS), explicitly targeted the veteran’s maladaptive patterns of interpersonal difficulties, feelings of detachment from others, irritability, and avoidance of social situations. Following treatment, the veteran reported significant improvements in social relationships, quality of life, and depressive symptoms, even though he still met the clinical threshold for PTSD. This case study provides preliminary evidence for the efficacy of a psychosocial intervention that directly targets social functioning issues for veterans with PTSD, and the importance of incorporating social goals and exercises into treatment.

Sorghum is considered a challenging species for transformation due to the limited choice in genotypes that can be transformed and the reliance on callus derived from immature embryos that need to be teased out of developing seeds. We have developed a more practical tissue culture procedure to generate embryogenic callus from leaf whorl explants obtained from 4 week-old seedlings. This procedure offers greater ease of obtaining explants, enables a more rapid turnover of growth chamber or greenhouse plants that can be used for explant collection, and eliminates the dependency on obtaining flowering plants with adequate numbers of seeds. Callus derived from these somatic embryos was amenable to biolistic transformation with DNA-coated gold particles and transformants were shown to express the Cas9 transgene. A comparison between genotypes RTx430 and P898012 indicated that the former was more suitable to tissue culture from leaf whorls based on greater callus induction and regeneration. Callus from both genotypes secreted colored compounds into the medium that we determined to be phenolic in nature, likely 3-deoxyanthocyanidins, based on UV–Vis absorbance profiles and thin layer chromatography. In order to reduce negative impacts of these compounds on regeneration, the addition of activated charcoal (AC) or polyvinylpyrrolidone (PVP) to the culture medium was examined. The addition of 0.5 g L−1 of AC after 4 weeks on callus induction medium accelerated callus regeneration, whereas culturing leaf whorl explants on medium containing 1 g L−1 PVP reduced the production of colored compounds and enhanced callus growth. The use of leaf whorl explants from developing sorghum plants serves as a practical alternative to immature embryos as a source of embryogenic callus and doesn’t require plants to flower.

We often rely on external devices to store to-be-remembered information in our everyday lives (e.g., writing grocery lists, setting reminders), yet there is limited research about how certain information (i.e., valuable information) may be differentially encoded when we rely on our internal memory versus an external store. Across three preregistered experiments, we examined the effect of relying on an external store on the recall of high-value and low-value information. In Experiments 1a and 1b, we presented participants with words associated with point values and examined mean recall performance during two critical trials in which the external store was not available: (1) a trial in which participants were told that they would have access to an external memory store at test (told-external-store) and (2) a trial in which participants were told that they would not have access to their external store at test (told-no-external-store). In Experiment 2, we explored participants' metacognitive predictions of performance on the recall test. Critically, across all of the experiments, we found that the value effect (i.e., better recall for valuable information) was significantly reduced when individuals were told that they could rely on an external store. The same pattern was present in participant's metacognitive judgements. Together, these results suggest that when relying on external stores, individuals forgo (to some extent, at least) selective encoding by value and that individuals might be aware of this change in strategy.

Introduction Smokers with bipolar disorder (BD) are less successful at quitting than the general population. In this study, we evaluated in a pilot randomized controlled trial a novel, targeted, web-based intervention for smokers with BD based on acceptance and commitment therapy (ACT) and designed for reach and disseminability. Aims and Methods Daily smokers (n = 51) with bipolar I or II disorder were recruited from four US sites and randomly assigned to one of two web-based smoking cessation interventions—ACT-based WebQuit Plus (n = 25) or Smokefree.gov (n = 26) over a 10-week treatment period. All participants received nicotine patch for 8 weeks. Key outcomes were trial design feasibility, intervention acceptability, and cessation at end of treatment and 1-month follow-up. Results We screened 119 to enroll 51 participants (target sample size = 60) over 24 months. The most common reason for ineligibility was the inability to attend study appointments. Retention was 73% at end of treatment and 80% at follow-up, with no differences by arm. The mean number of logins was twice as high for WebQuit Plus (10.3 vs. 5.3). The usefulness of program skills was rated higher for WebQuit Plus (75% vs. 29%). Biochemically confirmed, 7-day abstinence at end of treatment was 12% in WebQuit Plus versus 8% in Smokefree.gov (odds ratio = 1.46, 95% confidence interval = 0.21 to 9.97). At follow-up, abstinence rates were 8% in both arms. Conclusions Trial design produced favorable retention rates, although alternative recruitment methods will be needed for a larger trial. At end of treatment, acceptability and estimated effect size of WebQuit Plus relative to Smokefree.gov were promising and support continued program refinement and evaluation. Implications In this first randomized controlled trial of a targeted intervention for smokers with BD, we found that the ACT-based WebQuit Plus intervention, delivered in combination with the nicotine patch, had promising acceptability and cessation outcomes relative to Smokefree.gov. The observed signals for acceptability and cessation suggest that the WebQuit Plus program should be refined based on participant feedback and evaluated in a larger trial. Feasibility findings from this study also provide direction for refining trial procedures to enhance the recruitment of smokers with BD.

Individuals with body dysmorphic disorder (BDD) experience elevated social avoidance, both as a consequence and independent of BDD concerns. To explore how social avoidance relates to the long-term course of functioning for people with BDD, this prospective longitudinal study evaluated the hypothesis that initial social avoidance would predict changes in psychosocial functioning over 3 years, such that greater initial social avoidance would predict worsening functioning. At intake, individuals with BDD (N = 200) completed measures of social avoidance independent of BDD, social avoidance due to BDD or any other source, overall psychosocial functioning, and psychosocial functioning in specific domains. Overall and specific functioning was prospectively evaluated at three subsequent yearly follow-up assessments. Mixed model analyses evaluated the relation between baseline social avoidance and changes in functioning. Results provided mixed support for hypotheses, indicating that higher baseline social avoidance independent of BDD predicted worsening functioning in two of the four overall functioning indices and in both specific domains—interpersonal relationship quality and work/academic/household functioning. Higher global social avoidance (due to BDD or any other source) predicted poorer overall functioning for two of the four global functioning indices but did not predict functioning in either specific domain. Social avoidance, both related and unrelated to body image, might play an important role in the trajectory of psychosocial functioning for people with BDD.

We have evaluated the stress–strain behavior of calcite precipitated and mechanically twinned in small-offset strike-slip, normal and thrust faults of a variety of ages and from a variety of tectonic settings (n = 3001 twin measurements, 63 strain analyses from 18 field sites). Five strike-slip faults with syn-faulting, horizontally striated calcite (rake = 0°) were studied and we report the orientations of the contemporaneous stress–strain field associated with each fault: intrusion of the Marathon Large Igneous Province mafic dikes (~ 2.1 Ga in Archean crust, Minnesota, USA); post-Keweenaw rift (1.1 Ga) faulting (Island Lake fault, central Ontario, Canada); subduction associated with metamorphic core complex formation (Cretaceous, China); subduction (Cretaceous to Miocene, Italy), and continental extension (recently active Furnace Creek fault, Death Valley, California, USA). Seven normal faults with synfaulting, dip-slip striated calcite were studied and are from the following tectonic settings: a normal fault slip surface in an Ordovician Piedmont fold, Appalachian’s; paleo-subduction associated with Cretaceous metamorphic core complex formation (China, 3 sites); the paleo-extensional Atlantic margin (~ 55 Ma, Ireland, 1 site with a U–Pb calcite age); continental extension (1 active site, Mojave desert); a transcurrent margin (Jamaica, 1 active fault site), and subduction [2 active faults along the Eur-African margin in Italy (with calcite U–Th disequilibria ages) and Crete, respectively]. Six thrust fault examples are all from convergent orogenic settings: the basal thrust of the Penokean (1850 Ma) fold-and-thrust belt; the Penokean orogen foreland in Mesabi Range banded iron formation folds; an offset breccia body in the Permian Gondwanide belt, Ellsworth Mountains, Antarctica; the frontal thrust of the Gondwanide Cape belt, South Africa; the Paleocene frontal Prospect thrust, Sevier belt, Wyoming, and an Alpine foreland back-thrust, Lulworth Cove, U.K. For each strike-slip fault system the twinning shortening strain is horizontal and at an angle of 0°–60° to the respective fault plane (dextral or sinistral) although in the majority of cases the shortening axis is parallel to fault strike (13 of 23 results). In each normal fault example, dip-slip kinematic striations dominate the faulted surface yet the orientation of the maximum principal compressive stress (σ1) and shortening strain axis (e1) are not 45° to the fault plane as predicted but are sub-horizontal and either strike-parallel (25 of 35 results) or strike-normal (10 of 35 results). Thrust faults preserve shortening strain axes parallel to the dip-slip kinematic direction, within the fault plane (plane strain) and not at 45° to the principal plane (5 of 5 results). None of the fault stress–strain field results reported here support the Andersonian or Mohr–Coulomb criteria for stress–strain relations predicted along faults.

Plants have evolved the ability to derive the benzenoid moiety of the respiratory cofactor and antioxidant, ubiquinone (coenzyme Q), either from the β-oxidative metabolism of p-coumarate or from the peroxidative cleavage of kaempferol. Here, isotopic feeding assays, gene co-expression analysis and reverse genetics identified Arabidopsis 4-COUMARATE-COA LIGASE 8 (4-CL8; At5g38120) as a contributor to the β-oxidation of p-coumarate for ubiquinone biosynthesis. The enzyme is part of the same clade (V) of acyl-activating enzymes than At4g19010, a p-coumarate CoA ligase known to play a central role in the conversion of p-coumarate into 4-hydroxybenzoate. A 4-cl8 T-DNA knockout displayed a 20% decrease in ubiquinone content compared with wild-type plants, while 4-CL8 overexpression boosted ubiquinone content up to 150% of the control level. Similarly, the isotopic enrichment of ubiquinone's ring was decreased by 28% in the 4-cl8 knockout as compared with wild-type controls when Phe-[Ring-13C6] was fed to the plants. This metabolic blockage could be bypassed via the exogenous supply of 4-hydroxybenzoate, the product of p-coumarate β-oxidation. Arabidopsis 4-CL8 displays a canonical peroxisomal targeting sequence type 1, and confocal microscopy experiments using fused fluorescent reporters demonstrated that this enzyme is imported into peroxisomes. Time course feeding assays using Phe-[Ring-13C6] in a series of Arabidopsis single and double knockouts blocked in the β-oxidative metabolism of p-coumarate (4-cl8; at4g19010; at4g19010 × 4-cl8), flavonol biosynthesis (flavanone-3-hydroxylase), or both (at4g19010 × flavanone-3-hydroxylase) indicated that continuous high light treatments (500 µE m−2 s−1; 24 h) markedly stimulated the de novo biosynthesis of ubiquinone independently of kaempferol catabolism.

Drug use disorders (DUDs) are highly prevalent in body dysmorphic disorder (BDD), but motives for illicit drug use in BDD have not yet been explored. This study examined motives for drug use and clinical correlates of drug use motives in a sample of individuals with BDD and lifetime drug use, using the Drug Use Motives Questionnaire and 3 additional body image-specific drug use motives. As predicted, the Drug Use Motives Questionnaire coping motive was positively associated with attempted suicide and a lifetime DUD. All 3 body image-specific motives for drug use were also significantly associated with a lifetime DUD. In addition, they were the only variables that were significantly associated with greater severity of BDD. These results build on previous evidence suggesting that coping motives are related to problematic substance use and suicide attempts in BDD.

During the COVID-19 pandemic, social isolation was a common experience as people were trying to keep themselves and others safe from infection. Veterans with problematic substance use are at particular risk of the consequences of social isolation. This study evaluated the nature of social interactions during the COVID-19 pandemic and the effects of loneliness and psychological flexibility on self-reported substance use and physical and mental health functioning among U.S. veterans who reported problematic substance use. Data from 409 veterans with self-reported substance use concerns were obtained via a cross-sectional online survey. Results showed that many veterans who engaged in problematic substance use during the COVID-19 pandemic reported a number of social supports during this period and frequent communication with others, but still felt lonelier during the pandemic. In regression analyses, higher levels of loneliness were associated with more negative impacts of the pandemic, greater substance use, and poorer physical and mental health functioning. Psychological flexibility demonstrated significant unique variance in explaining mental health functioning during the pandemic after accounting for loneliness, but not for substance use or physical functioning. For veterans with high levels of loneliness, high levels of psychological flexibility were associated with a lower negative impact on quality of life due to the pandemic, but for veterans with low levels of loneliness, differing levels of psychological flexibility were not significantly associated with the negative impact of COVID-19. Overall, loneliness and psychological flexibility appear to be highly associated with the negative impact of COVID-19 on veterans with problematic substance use.

The objective of this study was to quantify incidence and determine predictors of Gram-negative bacilli (GNB) in people who inject drugs (PWID) with injection-drug use (IDU)-related infections. The investigation was a retrospective cohort of hospitalized PWID from January 2017 to December 2019. Inclusion criteria were age of ≥18 years, active IDU, treated IDU-attributable infection, and organism growth from microbiology cultures. Infection types included infective endocarditis (IE), acute bacterial skin/skin structure infection (ABSSSI), osteoarticular infection (OAI), and other bloodstream infections (BSI). Primary outcome was GNB identification from microbiologic culture; descriptive statistics were used to describe the cohort. Multivariable regression was used to identify variables associated with GNB infection. A total of 230 PWID were included, 65 (28%) with GNB infections and 165 (72%) with Gram-positive infections. The median (interquartile range [IQR]) population age was 38 (31 to 45) years. Most patients were women (56%); 37% had no insurance. Infection types were as follows: IE, 41%; ABSSSI, 37%; OAI, 20%; and other BSI, 2%. A total of 278 organisms were isolated from 230 patients. The most common organisms were methicillin-resistant Staphylococcus aureus (43%), Streptococcus spp. (19%), methicillin-susceptible S. aureus (17%), and Serratia marcescens (8%); 10% of infections were mixed GNB and Gram-positive infections. A total of 80% of patients received empirical Pseudomonas aeruginosa coverage; only 7% had P. aeruginosa infections. In multivariable regression, age of >50 years (adjusted odds ratio [adjOR], 2.9; 95% confidence interval [CI], 1.2 to 7.2), prior hospitalization within 90 days (adjOR, 2.2; 95% CI, 1.2 to 4.3), and OAI (adjOR, 3.2; 95% CI, 1.5 to 6.6) were associated with GNB infection. GNB in PWID with IDU-attributable infections were more frequently observed in recently hospitalized, older patients with OAI. The majority of patients received empirical antipseudomonal antibiotic coverage, but P. aeruginosa was infrequent. PWID are a potential population to target improved empirical antibiotic use.

As the COVID-19 pandemic sweeps the globe, many veterans with substance use issues have faced the closure of treatment facilities, mandates to shelter in place, and social distancing measures. To better understand their pandemic experiences, substance use changes, and functioning, a survey was nationally administered to a sample of United States veterans reporting substance use issues during the pandemic. The purpose of this cross-sectional online survey for veterans (N = 409) was to report on COVID-19 experiences, safety behaviors, and infection experiences while also investigating the relationship among addictive behaviors, mental and physical health, and COVID-19 impact. Measures also assessed specific substance use concerns, pandemic-related loneliness, and functioning. Though few veterans reported personally receiving a confirmed COVID-19 medical diagnosis (10.5%), the impact of pandemic stressors was evident, with a majority reporting anxiety related to contracting COVID-19 (61.4%) or fear of a family member or close friend contracting COVID-19 (58.7%). Participants reported increased use of alcohol (45.3%), sedatives (36.6%), inhalants (35.7%), tobacco (35.0%), and cannabis (34.9%), attributed specifically to the pandemic. Regression analyses revealed that even when controlling for the contribution of problematic substance use issues, negative pandemic impacts and self-reported COVID-19 related loneliness were related to more impaired physical and mental health functioning during the pandemic. Findings from this sample of veterans with addiction issues add to the growing literature suggesting unique and adverse effects of COVID-19 stressors on functioning while also revealing specific pandemic impacts for this group.

Previous work demonstrates that individuals often recall less information if, at study, there is expectation that an external memory store will be available at test. One explanation for this effect is that when individuals can expect access to an external memory store, they forgo intentional, controlled efforts at encoding. The present work offers a novel test of this account by examining study effort, indexed by study time and self-reported strategy use, as a function of instructed external store availability. In two preregistered experiments, participants studied lists of to-be-remembered items for a free recall test and were either instructed that they could use their study list to support them at test or that they could not. Critically, participants controlled their own study time, and no participant had their study list at test, regardless of instruction. Consistent with the effort at encoding account, external store availability influenced both study time and strategy use, and there was evidence that these effects mediated the influence of external store availability on recall performance. Interestingly, much of the memory cost remained when controlling for study effort, thus, suggesting that the cost is potentially multiply determined.

Body dysmorphic disorder (BDD), characterized by a distressing or impairing preoccupation with nonexistent or slight defects in appearance, is associated with markedly poor quality of life and high rates of suicidality. Onset of BDD is usually in childhood or adolescence and, unless appropriately treated, tends to be chronic. The first-line pharmacologic approach for both delusional and non-delusional BDD is serotonin reuptake inhibitors (SRIs), often at high doses. SRI augmentation and switching strategies can be effective. The first-line psychotherapy is cognitive-behavioral therapy (CBT) tailored to BDD's unique clinical features. Cosmetic treatment (such as surgery or dermatologic treatment), although received by a majority of patients with BDD, is not recommended. BDD has many similarities to obsessive-compulsive disorder (OCD) and appears closely related to OCD but also has some important differences. This article, which updates a 2015 article on BDD that we published in this journal, provides a clinically focused overview of BDD and its relationship to OCD.

Relying on external memory aids is a common memory strategy that has long allowed us to "remember" vast amounts of information more reliably than with our internal memory alone. However, recent work has provided evidence consistent with the idea that offloading memory demands encourages a reduced engagement in intentional or top-down memory strategies/efforts, leading to lower memory performance in general. Evidence for this view comes from results demonstrating a reduced primacy effect but intact recency and isolation effects when individuals could offload memory demands (but had to unexpectedly rely on their internal memory at test). In the present investigation, we attempt a replication of these critical results, given some inconsistencies in the findings between studies. In addition, we extend the examination of offloading's impact on memory via examining individual differences in reliance on the external store (when available) and different strategies for the use of that store. Results of the replication are generally consistent with previous research. An individual differences analysis yielded results consistent with the notion that increased reliance on an external store can compromise internal/biological memory in the absence of that store. Finally, a verbal model of offloading memory demands within a framework of effort and study time allocation is presented. Together, the results both reinforce extant research and extend it in new directions.

Previous research has demonstrated the effectiveness of both extended-release injectable naltrexone (XR-NTX) and buprenorphine/naloxone (BUP-NX) in the treatment of opioid use disorder (OUD). However, studies using real-world samples with multiple medical and psychiatric comorbidities are lacking. The study's primary aims were to: (1) compare clinical presentations in an inclusive sample of OUD-diagnosed US military veterans receiving XR-NTX and BUP-NX, and (2) investigate differences in 90-day treatment outcomes between these two groups.