Molecular dissection of the pseudokinase ZED1 expands effector recognition to the tomato immune receptor ZAR1.

The highly conserved angiosperm immune receptor HOPZ-ACTIVATED RESISTANCE 1 (ZAR1) is a bacterial pathogen recognition hub that mediates resistance by guarding host kinases for modification by pathogen effectors. The pseudokinase HOPZ-ETI DEFICIENT 1 (ZED1) is the only known ZAR1-guarded protein that interacts directly with a pathogen effector, HopZ1a, from the bacterial pathogen Pseudomonas syringae, making it a promising system for rational design of effector recognition for plant immunity. Here, we conducted an in-depth molecular analysis of ZED1. We generated a library of 164 random ZED1 mutants and identified 50 mutants that could not recognize the effector HopZ1a when transiently expressed in Nicotiana benthamiana. Based on our random mutants, we generated a library of 27 point mutants and found evidence of minor functional divergence between Arabidopsis (Arabidopsis thaliana) and N. benthamiana ZAR1 orthologs. We leveraged our point mutant library to identify regions in ZED1 critical for ZAR1 and HopZ1a interactions and identified two likely ZED1-HopZ1a binding conformations. We explored ZED1 nucleotide and cation binding activity and showed that ZED1 is a catalytically dead pseudokinase, functioning solely as an allosteric regulator upon effector recognition. We used our library of ZED1 point mutants to identify the ZED1 activation loop regions as the most likely cause of interspecies ZAR1-ZED1 incompatibility. Finally, we identified a mutation that abolished ZAR1-ZED1 interspecies incompatibility while retaining the ability to mediate HopZ1a recognition, which enabled recognition of HopZ1a through tomato (Solanum lycopersicum) ZAR1. This provides an example of expanded effector recognition through a ZAR1 ortholog from a non-model species.

An immunohistochemical atlas of necroptotic pathway expression.

Necroptosis is a lytic form of regulated cell death reported to contribute to inflammatory diseases of the gut, skin and lung, as well as ischemic-reperfusion injuries of the kidney, heart and brain. However, precise identification of the cells and tissues that undergo necroptotic cell death in vivo has proven challenging in the absence of robust protocols for immunohistochemical detection. Here, we provide automated immunohistochemistry protocols to detect core necroptosis regulators - Caspase-8, RIPK1, RIPK3 and MLKL - in formalin-fixed mouse and human tissues. We observed surprising heterogeneity in protein expression within tissues, whereby short-lived immune barrier cells were replete with necroptotic effectors, whereas long-lived cells lacked RIPK3 or MLKL expression. Local changes in the expression of necroptotic effectors occurred in response to insults such as inflammation, dysbiosis or immune challenge, consistent with necroptosis being dysregulated in disease contexts. These methods will facilitate the precise localisation and evaluation of necroptotic signaling in vivo.

Osteo-cutaneous microvascular free-flaps are a viable option for reconstructing the temporomandibular joint.

Background: There are multiple reconstructive options after mandibular resection and disarticulation of the condyle. The purpose of this study was to assess the clinical outcomes and functionality of osteocutaneous free flaps in the reconstruction of mandibular defects that involve the Temporo-Mandibular Joint (TMJ). Methods: Our study is a retrospective cohort study involving subjects who underwent mandibular resection and needed TMJ reconstruction with vascularized bony-free flaps from February 2016 to June 2018. Data gathered included patient demographics, post-operative function, maximum interincisal opening (MIO), occlusion status, deviation on opening, and TMJ symptoms. Data points collected from postoperative CT imaging included the following: position of the flap in relation to the glenoid fossa and articular eminence, and closest point of contact. Results: Eight out of the nine patients who underwent free flap reconstruction of mandibular defects involving the TMJ qualified for the study. The mean age was 39.7 years old. In all 8 cases, virtual surgical planning (VSP) was used. The mean follow-up time was 18.75 months. The flap success rate was 100%. The mean MIO was 37.37 mm. Six patients resumed their premorbid diet, and one patient developed dysphagia and was peg tube dependent. In seven cases the occlusion was intact and reproducible, one case was without sufficient teeth for occlusion. On imaging, the mean distance from the neo-condyle to the glenoid fossa was 14 mm and to the articular eminence 8.68 mm. The point of closest contact in all cases appeared to be the articular eminence. Conclusion: Vascularized Osteocutaneous-flaps such as FFFs and DCIA flaps provide a good option for the reconstruction of mandibular defects that involve the TMJ. Ipsilateral deviation on opening does not negatively affect clinical outcomes or function. Placing patients in Maxillomandibular fixation for 4-6 weeks may help to prevent condylar sag and provide stable post-operative occlusion.

Relationships of State Alcohol Policy Environments with Homicides and Suicides.

INTRODUCTION: Alcohol use is involved in a large proportion of homicides and suicides each year in the United States, but there is limited evidence on how policies targeting alcohol influence violence in the U.S. CONTEXT: Extant studies generally focus on individual policies in isolation of each other. This study examines of the effects of changes in states' alcohol policy restrictions on overall homicide and suicide rates and firearm-related homicide and suicide rates using a holistic measure of states' alcohol policy environments. METHODS: Using a composite measure of state-level alcohol policies (Alcohol Policy Scale) and data from the National Vital Statistics System from 2002 to 2018, this study applied a Bayesian time series model to estimate the effects of alcohol policy changes on overall and firearm-involved homicide and suicide rates. The analysis was performed in 2023 and 2024. RESULTS: A one standard deviation change in the Alcohol Policy Scale was associated with a 6 percent decline in homicide rates both overall (IRR=0.94; 95-percent credibility interval = [0.89, 1.00]) and for firearm homicides specifically (IRR=0.94, 95-percent CI=[0.88, 1.01]). There was no clear association of alcohol policy with suicides. The model predicts that a nationwide increase in alcohol restrictions equivalent to a shift from the 25th to 75th percentile of the scale's distribution would result in almost 1200 fewer homicides annually. CONCLUSIONS: Increases in the restrictiveness of state-level alcohol policies are associated with reductions in homicides. More restrictive alcohol policy environments may offer an opportunity to reduce homicides.

Co-clustering of EphB6 and ephrinB1 in trans restrains cancer cell invasion.

EphB6 is an understudied ephrin receptor tyrosine pseudokinase that is downregulated in multiple types of metastatic cancers. Unlike its kinase-active counterparts which autophosphorylate and transmit signals upon intercellular interaction, little is known about how EphB6 functions in the absence of intrinsic kinase activity. Here, we unveil a molecular mechanism of cell-cell interaction driven by EphB6. We identify ephrinB1 as a cognate ligand of EphB6 and show that in trans interaction of EphB6 with ephrinB1 on neighboring cells leads to the formation of large co-clusters at the plasma membrane. These co-clusters exhibit a decreased propensity towards endocytosis, suggesting a unique characteristic for this type of cell-cell interaction. Using lattice light-sheet microscopy, 3D structured illumination microscopy and cryo-electron tomography techniques, we show that co-clustering of EphB6 and ephrinB1 promotes the formation of double-membrane tubular structures between cells. Importantly, we also demonstrate that these intercellular structures stabilize cell-cell adhesion, leading to a reduction in the invasive behavior of cancer cells. Our findings rationalize a role for EphB6 pseudokinase as a tumor suppressor when interacting with its ligands in trans.

Neural correlates of increased alcohol demand following alcohol cue exposure in adult heavy drinkers.

Alcohol use disorder is associated with overvaluation of alcohol relative to other rewards, in part due to dynamic increases in value in response to alcohol-related cues. In a neuroeconomic framework, alcohol cues increase behavioral economic demand for alcohol, but the neural correlates these cue effects are unknown. This functional magnetic resonance imaging study combined a neuroeconomic alcohol purchase task with an alcohol cue exposure in 72 heavy drinkers with established sensitivity to alcohol cues (51 % female; mean age=33.74). Participants reported how many drinks they would consume from $0-$80/drink following exposure to neutral and alcohol images in a fixed order. Participants purchased significantly more drinks in the alcohol compared to the neutral condition, which was also evident for demand indices (i.e., intensity, breakpoint, Omax, elasticity; ps<0.001; ds=0.46-0.92). Alcohol purchase decisions were associated with activation in rostral middle and medial frontal gyri, anterior insula, posterior parietal cortex, and dorsal striatum, among other regions. Activation was lower across regions in the alcohol relative to neutral cue condition, potentially due to greater automaticity of choices in the presence of alcohol cues or attenuation of responses due to fixed cue order. These results contribute to growing literature using neuroeconomics to understand alcohol misuse and provide a foundation for future research investigating decision-making effects of environmental alcohol triggers.

Sleep, Alcohol and Cannabis Use in College Students With and Without Attention-Deficit/Hyperactivity Disorder.

Background: Relations among attention-deficit/hyperactivity disorder (ADHD), sleep, and substance-related negative consequences are largely unknown. In this cross-sectional study, we examined associations among ADHD diagnosis, sleep, and alcohol-related consequences. We also evaluated the independent and interactive effects of sleep and ADHD on alcohol-related negative consequences, above and beyond levels of alcohol use. Methods: College students who drink alcohol with (n = 51) and without (n = 50) ADHD completed an assessment that included a diagnostic interview assessing ADHD, and questionnaire measures of sleep quality, substance use, and associated consequences. Analyses utilized a series of hierarchical linear regression models and explored these aims for cannabis use in a subset of participants (n = 52 participants that used cannabis). Results: College students who drink alcohol with ADHD reported significantly worse sleep quality and more alcohol-related consequences, relative to those without ADHD. When ADHD and sleep quality were included in the model, ADHD-but not sleep quality-was independently associated with alcohol consequences, but not cannabis consequences. There were no moderating effects of ADHD on the associations between sleep and substance-related consequences. Conclusions: Students who drank alcohol with ADHD may be particularly vulnerable to experiencing poor sleep and consequences from their substance use, compared to their heavy drinking peers without ADHD. Future, larger scale studies should consider longitudinal effects as well as underlying mechanisms of risk.

Gasdermin and MLKL necrotic cell death effectors: Signaling and diseases.

Diverse inflammatory conditions, from infections to autoimmune disease, are often associated with cellular damage and death. Apoptotic cell death has evolved to minimize its inflammatory potential. By contrast, necrotic cell death via necroptosis and pyroptosis-driven by membrane-damaging MLKL and gasdermins, respectively-can both initiate and propagate inflammatory responses. In this review, we provide insights into the function and regulation of MLKL and gasdermin necrotic effector proteins and drivers of plasma membrane rupture. We evaluate genetic evidence that MLKL- and gasdermin-driven necrosis may either provide protection against, or contribute to, disease states in a context-dependent manner. These cumulative insights using gene-targeted mice underscore the necessity for future research examining pyroptotic and necroptotic cell death in human tissue, as a basis for developing specific necrotic inhibitors with the potential to benefit a spectrum of pathological conditions.

Behavioral economic and wellness-based approaches for reducing alcohol use and consequences among diverse non-student emerging adults: study protocol for Project BLUE, a randomized controlled trial.

BACKGROUND: Emerging adults (EAs) who are not 4-year college students nor graduates are at elevated risk for lifetime alcohol use disorder, comorbid drug use, and mental health symptoms, compared to college graduates. There is a need for tailored brief alcohol intervention (BAI) approaches to reduce alcohol risk and to facilitate healthy development in this high-risk population. Most BAIs include a single session focused on discussing risks associated with drinking and correcting normative beliefs about drinking rates. EAs may benefit from additional elements that enhance general wellness. The substance-free activity session (SFAS) aims to clarify life goals and values and increase goal-directed activities that provide alternatives to alcohol use, and the relaxation training (RT) session teaches relaxation and stress reduction skills. METHODS: The present study is a randomized 3-group (BAI + SFAS vs. RT + SFAS vs. education control) trial with 525 EAs (175 per group; estimated 50% women and 50% African American) who report recent risky drinking and who are not students or graduates of 4-year colleges. Participants will have the option of completing the intervention sessions in person or via a secure video teleconference. Levels of drinking and alcohol-related problems will be evaluated at baseline and 1, 3, 6, and 12 months post-intervention. The primary hypothesis is that both BAI + SFAS and RT + SFAS participants will report significantly greater reductions in alcohol use and problems relative to education control participants, with no differences in outcomes between the two active treatment conditions. DISCUSSION: The results of this study will inform alcohol prevention efforts for high-risk community dwelling emerging adults. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04776278.

Longitudinal examination of alcohol demand and alcohol-related reinforcement as predictors of heavy drinking and adverse alcohol consequences in emerging adults.

BACKGROUND AND AIMS: Behavioral economic theory predicts that high alcohol demand and high proportionate alcohol-related reinforcement are important determinants of risky alcohol use in emerging adults, but the majority of research to date has been cross-sectional in nature. The present study investigated prospective and dynamic relationships between alcohol demand and proportionate alcohol-related reinforcement in relation to heavy drinking days and alcohol problems. DESIGN: Longitudinal cohort with assessments every 4 months for 20 months. SETTING: Ontario, Canada. PARTICIPANTS: Emerging adults reporting regular heavy episodic drinking (n = 636, Mage = 21.44; 55.8% female). MEASUREMENTS: Heavy drinking days (HDD; Daily Drinking Questionnaire), alcohol problems (Brief Young Adult Alcohol Consequences Questionnaire), alcohol demand (Alcohol Purchase Task) and proportionate alcohol-related reinforcement (Activity Level Questionnaire). FINDINGS: Linear mixed effects models revealed that behavioral economic indicators and alcohol-related outcomes significantly decreased over the study, consistent with 'aging out' of risky alcohol use. Random intercept cross-lagged panel models revealed significant between-person relationships, such that higher alcohol demand and alcohol-related reinforcement were positively associated with HDD and alcohol problems (random intercepts = 0.187-0.534, Ps < 0.01). Moreover, alcohol demand indicators (particularly the rate of change in elasticity of the demand curve, as measured by α, and the maximum expenditure, Omax) and proportionate alcohol-related reinforcement significantly forecasted changes in HDD at all time points (|ßs| = 0.063-0.103, Ps < 0.05) in cross-lagged relationships, with bidirectional associations noted for the rate of change in elasticity (ßs = -0.085 to -0.104, Ps < 0.01). Proportionate alcohol-related reinforcement also significantly forecasted changes in alcohol problems at all time points (ßs = 0.072-0.112, Ps < 0.01). CONCLUSIONS: Multiple behavioral economic indicators (demand elasticity, maximum expenditure and reinforcement ratio) forecast changes in heavy episodic drinking and alcohol problems over the course of emerging adulthood. These results further implicate alcohol demand and proportionate alcohol-related reinforcement as etiologically and developmentally important mechanisms in alcohol use trajectories.

Prostate Cancer Screening Uptake in Transgender Women.

Importance: There is no consensus in prostate-specific antigen (PSA) screening guidelines regarding transgender women despite their known prostate cancer risk. Objective: To identify factors associated with recent (within the last 2 years) PSA screening in transgender women compared with cisgender men. Design, Setting, and Participants: This case-control study used data from the 2018 and 2020 Behavioral Risk Factor Surveillance System (BRFSS) surveys to characterize rates of PSA screening for prostate cancer within the past 2 years and multivariable logistic regressions to characterize factors associated with recent screening among transgender women. The BRFSS program of the Centers for Disease Control and Prevention annually surveys over 400 000 US adults on behavioral risk factors, chronic illnesses, and use of preventive services. Respondents to the BRFSS who were cisgender men or transgender women 40 years or older and who had complete PSA testing responses and no prostate cancer history were included; 313 transgender women and 138 937 cisgender men met inclusion criteria. Matching was performed by age, race and ethnicity, educational level, employment, annual income, survey year, and cost barriers to care. Data were collected on November 2, 2022, and analyzed from November 2, 2022, to December 3, 2023. Main Outcomes and Measures: Rates of and factors associated with recent PSA screening in transgender women. Results: Among the 1275 participants included in the matched cohort (255 transgender women and 1020 cisgender men; 570 [44.7%] aged 55-69 years), recent PSA screening rates among transgender women and cisgender men aged 55 to 69 were 22.2% (n = 26) and 36.3% (n = 165), respectively; among those 70 years and older, these rates were 41.8% (n = 26) and 40.2% (n = 98), respectively. In the matched cohort, transgender women had lower univariable odds of recent screening than cisgender men (odds ratio [OR], 0.65 [95% CI, 0.46-0.92]; P = .02). In a hierarchical regression analysis adding time since the last primary care visit, effect size and significance were unchanged (OR, 0.61 [95% CI, 0.42-0.87]; P = .007). After adding whether a clinician recommended a PSA test, there was no statistically significant difference in odds of screening between transgender women and cisgender men (OR, 0.83 [95% CI, 0.45-1.27]; P = .21). The results were further attenuated when clinician-led discussions of PSA screening advantages and disadvantages were added (OR, 0.87 [95% CI, 0.47-1.31]; P = .32). In a multivariable logistic regression among transgender women, having a recommendation for PSA testing was the factor with the strongest association with recent screening (OR, 12.40 [95% CI, 4.47-37.80]; P < .001). Conclusions and Relevance: In this case-control study of one of the largest cohorts of transgender women studied regarding PSA screening, the findings suggest that access to care or sociodemographic factors were not principal drivers of the screening differences between transgender women and cisgender men; rather, these data underscore the clinician's role in influencing PSA screening among transgender women.

Association of platinum-based chemotherapy with live birth and infertility in female survivors of adolescent and young adult cancer.

OBJECTIVE: To estimate the effect of platinum-based chemotherapy on live birth (LB) and infertility after cancer, in order to address a lack of treatment-specific fertility risks for female survivors of adolescent and young adult cancer, which limits counseling on fertility preservation decisions. DESIGN: Retrospective cohort study. SETTING: US administrative database. PATIENTS: We identified incident breast, colorectal, and ovarian cancer cases in females aged 15-39 years who received platinum-based chemotherapy or no chemotherapy and matched them to females without cancer. INTERVENTION: Platinum-based chemotherapy. MAIN OUTCOME MEASURES: We estimated the effect of chemotherapy on the incidence of LB and infertility after cancer, overall, and after accounting for competing events (recurrence, death, and sterilizing surgeries). RESULTS: There were 1,287 survivors in the chemotherapy group, 3,192 in the no chemotherapy group, and 34,147 women in the no cancer group, with a mean age of 33 years. Accounting for competing events, the overall 5-year LB incidence was lower in the chemotherapy group (3.9%) vs. the no chemotherapy group (6.4%). Adjusted relative risks vs. no chemotherapy and no cancer groups were 0.61 (95% confidence interval [CI] 0.42-0.82) and 0.70 (95% CI 0.51-0.93), respectively. The overall 5-year infertility incidence was similar in the chemotherapy group (21.8%) compared with the no chemotherapy group (20.7%). The adjusted relative risks vs. no chemotherapy and no cancer groups were 1.05 (95% CI 0.97-1.15) and 1.42 (95% CI 1.31-1.53), respectively. CONCLUSIONS: Cancer survivors treated with platinum-based chemotherapy experienced modestly increased adverse fertility outcomes. The estimated effects of platinum-based chemotherapy were affected by competing events, suggesting the importance of this analytic approach for interpretations that ultimately inform clinical fertility preservation decisions.

Behavioral Economic and Wellness-based Approaches for Reducing Alcohol Use and Consequences Among Diverse Non-Student Emerging Adults: Study Protocol for Project BLUE, a Randomized Controlled Trial.

Background: Emerging adults (EAs) who are not 4-year college students nor graduates are at elevated risk for lifetime alcohol use disorder, comorbid drug use, and mental health symptoms, compared to college graduates. There is a need for tailored brief alcohol intervention (BAI) approaches to reduce alcohol risk and to facilitate healthy development in this high-risk population. Most BAIs include a single session focused on discussing risks associated with drinking and correcting normative beliefs about drinking rates. EAs may benefit from additional elements that enhance general wellness. The Substance-Free Activity Session (SFAS) aims to clarify life goals and values and increase goal-directed activities that provide alternatives to alcohol use, and the Relaxation Training (RT) session teaches relaxation and stress reduction skills. Methods: The present study is a randomized 3-group (BAI+SFAS vs. RT+SFAS vs. education control) trial with 525 EAs (175 per group; estimated 50% women & 50% African American) who report recent risky drinking and who are not students or graduates of 4-year colleges. Participants will have the option of completing the intervention sessions in person or via a secure video teleconference. Levels of drinking and alcohol-related problems will be evaluated at baseline and 1, 3, 6, and 12-months post-intervention. The primary hypothesis is that both BAI+SFAS and RT+SFAS participants will report significantly greater reductions in alcohol use and problems relative to education control participants, with no differences in outcomes between the two active treatment conditions. Discussion: The results of this study will inform alcohol prevention efforts for high-risk community dwelling emerging adults. ClinicalTrialsgov Identifier: NCT04776278.

A mouse model of Zhu-Tokita-Takenouchi-Kim syndrome reveals indispensable SON functions in organ development and hematopoiesis.

Rare diseases are underrepresented in biomedical research, leading to insufficient awareness. Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a rare disease caused by genetic alterations that result in heterozygous loss of function of SON. While patients with ZTTK syndrome live with numerous symptoms, the lack of model organisms hampers our understanding of SON and this complex syndrome. Here, we developed Son haploinsufficiency (Son+/-) mice as a model of ZTTK syndrome and identified the indispensable roles of Son in organ development and hematopoiesis. Son+/- mice recapitulated clinical symptoms of ZTTK syndrome, including growth retardation, cognitive impairment, skeletal abnormalities, and kidney agenesis. Furthermore, we identified hematopoietic abnormalities in Son+/- mice, including leukopenia and immunoglobulin deficiency, similar to those observed in human patients. Surface marker analyses and single-cell transcriptome profiling of hematopoietic stem and progenitor cells revealed that Son haploinsufficiency shifted cell fate more toward the myeloid lineage but compromised lymphoid lineage development by reducing genes required for lymphoid and B cell lineage specification. Additionally, Son haploinsufficiency caused inappropriate activation of erythroid genes and impaired erythropoiesis. These findings highlight the importance of the full gene expression of Son in multiple organs. Our model serves as an invaluable research tool for this rare disease and related disorders associated with SON dysfunction.

An experimental investigation into the effect of negative affect on the behavioral economic demand for alcohol.

OBJECTIVE: It is hypothesized that alcohol use is reinforcing when used as a strategy to cope with negative affect. Although the evidence for this hypothesis in observational data is weak, some experimental evidence suggests that the behavioral economic demand for alcohol increases immediately following a negative emotional event. We hypothesized that people show a higher demand for alcohol following negative (vs. neutral) mood inductions and that this effect is stronger in people who report heavier drinking compared to people who report lighter drinking as well as stronger on days characterized by higher coping motives and negative urgency. METHOD: 309 college students who reported recent alcohol consumption (MAUDIT = 6.86) completed the alcohol purchase task after being subjected to 12 mood inductions (six negative, six neutral, order randomized) on 12 separate days. RESULTS: In our preregistered analyses, we found no evidence that the behavioral economic demand for alcohol was elevated following negative mood inductions. The mood inductions in our study were not as strong as has been reported in previous research, weakening the preregistered inferences. In exploratory analyses performed on a subset of the data in which the mood inductions worked as intended, demand was higher following negative mood inductions. CONCLUSIONS: The results of this study are not conclusive. In light of previous research, we consider these data to slightly increase our confidence that demand for alcohol is increased immediately following a negative emotional event. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A pilot trial of a brief intervention for cannabis use supplemented with a substance-free activity session or relaxation training.

OBJECTIVE: Cannabis use is increasing among college students and commonly co-occurs with anxiety symptoms in this age group. Interventions that reduce anxiety may also reduce cannabis use. Behavioral economic theory suggests that substance use reductions are most likely when there is an increase in substance-free reinforcement. This randomized pilot trial evaluated the efficacy of a brief motivational intervention (BMI) for cannabis supplemented by either a substance-free activity session (SFAS) or a relaxation training (RT) session for reducing cannabis use, problems, craving, and anxiety symptoms. METHOD: One hundred thirty-two college students (Mage = 19.9; 54% female; 67% White, 31% Black) who reported five or more past-month cannabis use days were randomized to: (a) assessment-only (AO); (b) BMI plus SFAS; or (c) BMI plus RT. Participants in the BMI conditions received two individual counselor-administered sessions plus a brief phone booster session. Outcomes were evaluated 1- and 6-months postintervention. RESULTS: Relative to assessment, both BMI + SFAS and BMI + RT were associated with significant reductions in cannabis problems and craving at 1-month follow-up, and significant reductions in anxiety at 6-month follow-up. Relative to AO, BMI + RT was associated with significant reductions in cannabis use at 1-month follow-up. There were no differences between BMI conditions. CONCLUSIONS: This pilot trial was not adequately powered to conclusively evaluate relative efficacy but provides preliminary support for the short-term efficacy of both two-session interventions for reducing anxiety and cannabis-related risk among nontreatment seeking emerging adults. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Attention-deficit/hyperactivity disorder is associated with more alcohol problems and less substance-free reinforcement: A behavioral economics daily diary study of college student drinkers.

OBJECTIVE: Behavioral economic theory suggests that alcohol risk is related to elevated alcohol reinforcing efficacy (demand) combined with diminished availability of reinforcing substance-free activities, but little research has examined these reward-related processes at the daily level in association with comorbid conditions that might influence behavioral patterns and reward. Young people with attention-deficit/hyperactivity disorder (ADHD) report high levels of risky drinking, and this risk may be due in part to elevated demand for alcohol and diminished engagement in enjoyable and valued substance-free activities. METHOD: College student drinkers (N = 101; 48.5% female; 68.3% White; 18-22 years old) with (n = 51) and without (n = 50) ADHD completed 14 consecutive daily diaries (diary entry n = 1,414). We conducted a series of multilevel path models to examine (a) the associations among ADHD and average daily alcohol demand, substance-free enjoyment, and response contingent positive reinforcement (RCPR) for goal-directed behaviors; (b) the associations among concurrent daily alcohol demand, substance-free reinforcement, and RCPR for goal-directed behaviors and daily alcohol use and alcohol-related negative consequences; and (c) the moderating effect of ADHD on these within-day associations. RESULTS: ADHD was significantly associated with more daily alcohol-related negative consequences and less daily substance-free enjoyment and RCPR. Regardless of ADHD status, there were significant associations among behavioral economic risk factors and alcohol use and negative consequences, though effects differed within and between persons. There were no moderating effects of ADHD on within-person associations. CONCLUSIONS: Results expose areas of impairment specific to drinkers with ADHD and advance theory on ADHD and hazardous drinking. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Necroptosis does not drive disease pathogenesis in a mouse infective model of SARS-CoV-2 in vivo.

Necroptosis, a type of lytic cell death executed by the pseudokinase Mixed Lineage Kinase Domain-Like (MLKL) has been implicated in the detrimental inflammation caused by SARS-CoV-2 infection. We minimally and extensively passaged a single clinical SARS-CoV-2 isolate to create models of mild and severe disease in mice allowing us to dissect the role of necroptosis in SARS-CoV-2 disease pathogenesis. We infected wild-type and MLKL-deficient mice and found no significant differences in viral loads or lung pathology. In our model of severe COVID-19, MLKL-deficiency did not alter the host response, ameliorate weight loss, diminish systemic pro-inflammatory cytokines levels, or prevent lethality in aged animals. Our in vivo models indicate that necroptosis is dispensable in the pathogenesis of mild and severe COVID-19.

Posttraumatic stress and delay discounting: a meta-analytic review.

Delay discounting-the extent to which individuals show a preference for smaller immediate rewards over larger delayed rewards-has been proposed as a transdiagnostic neurocognitive process across mental health conditions, but its examination in relation to posttraumatic stress disorder (PTSD) is comparatively recent. To assess the aggregated evidence for elevated delay discounting in relation to posttraumatic stress, we conducted a meta-analysis on existing empirical literature. Bibliographic searches identified 209 candidate articles, of which 13 articles with 14 independent effect sizes were eligible for meta-analysis, reflecting a combined sample size of N = 6897. Individual study designs included case-control (e.g. examination of differences in delay discounting between individuals with and without PTSD) and continuous association studies (e.g. relationship between posttraumatic stress symptom severity and delay discounting). In a combined analysis of all studies, the overall relationship was a small but statistically significant positive association between posttraumatic stress and delay discounting (r = .135, p < .0001). The same relationship was statistically significant for continuous association studies (r = .092, p = .027) and case-control designs (r = .179, p < .001). Evidence of publication bias was minimal. The included studies were limited in that many did not concurrently incorporate other psychiatric conditions in the analyses, leaving the specificity of the relationship to posttraumatic stress less clear. Nonetheless, these findings are broadly consistent with previous meta-analyses of delayed reward discounting in relation to other mental health conditions and provide further evidence for the transdiagnostic utility of this construct.

Principal component analysis of a swine injury model identifies multiple phenotypes in trauma.

BACKGROUND: Trauma is the third leading cause of death in the United States and the primary cause of death for people between the ages of 1 year and 44 years. In addition to tissue damage, trauma may also activate an inflammatory state known as trauma-induced coagulopathy (TIC) that is associated with clotting malfunctions, acidemia, and end-organ dysfunction. Prior work has also demonstrated benefit to acknowledging the type and severity of endothelial injury, coagulation derangements, and systemic inflammation in the management of trauma patients. This study builds upon prior work by combining laboratory, metabolic, and clinical metrics into an analysis of trauma phenotypes, evolution of phenotypes over time after trauma, and significance of trauma phenotype on mortality. METHODS: Seventy 3-month-old female Yorkshire crossbred swine were randomized to injury and resuscitation groups. Principal component analysis (PCA) of longitudinal swine TEG data (Reaction time, Alpha-Angle, Maximum Amplitude, and Clot Lysis at 30 minutes), pH, lactate, and MAP was completed in R at baseline, 1 hour postinjury, 3 hours postinjury, 6 hours postinjury, and 12 hours postinjury. Subjects were compared by principal component factor scores to assess differences in survival, injury severity, and treatment group. RESULTS: Among injured animals, three phenotypes were observed at each time point. Five phenotypes were associated with differences in survival, and of these, four were associated with differences in injury severity. Phenotype alignment was not significantly different by treatment group. CONCLUSION: This application of PCA to a set of coagulation, hemodynamic, and organ perfusion variables has identified multiple evolving phenotypes after trauma. Some of these phenotypes may correlate with injury severity and may have implications for survival. Next steps include validating these findings over greater numbers of subjects and exploring other machine-learning techniques for phenotype identification. LEVEL OF EVIDENCE: Level IV, Therapeutic/Care Management.