Fear attenuation collaborations to optimize translation.

Here, we describe the efforts we dedicated to the challenge of modifying entrenched emotionally laden memories. In recent years, through a number of collaborations and using a combination of behavioral, molecular, and computational approaches, we: (a) developed novel approaches to fear attenuation that engage mechanisms that differ from those engaged during extinction (Monfils), (b) examined whether our approaches can generalize to other reinforcers (Lee, Gonzales, Chaudhri, Cofresi, and Monfils), (c) derived principled explanations for the differential outcomes of our approaches (Niv, Gershman, Song, and Monfils), (d) developed better assessment metrics to evaluate outcome success (Shumake and Monfils), (e) identified biomarkers that can explain significant variance in our outcomes of interest (Shumake and Monfils), and (f) developed better basic research assays and translated efforts to the clinic (Smits, Telch, Otto, Shumake, and Monfils). We briefly highlight each of these milestones and conclude with final remarks and extracted principles. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Low-dose ondansetron: A candidate prospective precision medicine to treat alcohol use disorder endophenotypes.

BACKGROUND: Alcohol use disorder (AUD) is among the leading causes of morbidity and mortality worldwide, and over 95 million people live with alcohol dependence globally. The estimated heritability of AUD is 50-60 %, and multiple genes are thought to contribute to various endophenotypes of the disease. Previous clinical trials support a precision medicine approach using ondansetron (AD04, a 5-HT3 antagonist) by segregating AUD populations by the bio-genetic endophenotype of specific serotonergic genotypes and the bio-psychosocial endophenotype of the severity of drinking or both. By targeting the modulation of biogenetic signaling within the biopsychosocial context of AUD, low-dose AD04 holds promise in reducing alcohol consumption among affected individuals while minimizing adverse effects. METHODS: This was a phase III, 6-month, 25-site, randomized, placebo-controlled clinical trial using AD04 to treat DSM-V-categorized AUD individuals who were pre-stratified into the endophenotypes of heavy or very heavy drinking individuals and possessed a pre-defined profile of genetic variants related to the serotonin transporter and serotonin-3AB receptor. Participants (N = 303) presented moderate to severe AUD, >80 % were men, mostly in their fifties, and >95 % were of European descent. Low-dose AD04 (approx. 033 mg twice daily) or a matching placebo was administered twice daily for 6 months. Brief Behavioral Compliance Enhancement Treatment (BBCET [53]) was administered every two weeks to enhance medication compliance and clinic attendance. RESULTS: There was a significant reduction in the monthly percentage of heavy drinking days, PHDD (-46·7 % (2·7 %), 95 %CI: -52·1 % to -41·2 % vs. -38·1 % (2·9 %), 95 %CI: -43·8 % to -32·5 %, respectively; LS mean difference=-8·5 %; p = 0.03) among AD04-treated vs. placebo-receiving heavy drinking individuals at month 6. Heavy drinking individuals were also less likely to be diagnosed with AUD [Month 1: -32·0 % (2·8 %), 95 %CI: -37·5 % to -26·5 % vs. -23·2 % (2·9 %), 95 %CI: -28·9 to -17·5 %; LS mean difference= -8·8 %; p = 0·026)], and improved on the WHO quality of life BREF scale with a significant effect for at least a 1-level downward shift (OR = 3.4; 95 % CI: 1·03-11·45, p = 0·044). Importantly, heavy drinking individuals, as distinct from very heavy drinking individuals, were the bio-psychosocial endophenotype more predictive of therapeutic response to AD04. AD04 had an exceptional safety and tolerability profile, like the placebo's. CONCLUSIONS: In this Phase 3 clinical trial, AD04 was shown to be a promising treatment for currently drinking heavy drinking individuals with AUD who also possess a specific genotypic profile in the serotonin transporter and serotonin-3AB receptor complex. Using AD04 to reduce the harm of AUD in heavy drinking individuals who are currently drinking, without the necessity of abstinence or detoxification from alcohol use, is an important advance in the field of precision medicine. AD04's adverse events profile, which was like placebo, should enhance accessibility and acceptance of modern medical treatment for AUD by lowering the incorrect but commonly perceived stigma of personal failure.

Single-Operator Left atrial appendage Occlusion utilizing Conscious sedation TEE, Lack of Outpatient pre-imaging, and Same-day Expedited discharge (SOLO-CLOSE): A comparison with conventional approach.

BACKGROUND: Left atrial appendage occlusion (LAAO) with WATCHMAN currently requires preprocedural imaging, general anesthesia, and inpatient overnight admission. We sought to facilitate simplification of LAAO. AIMS: We describe and compare SOLO-CLOSE (single-operator LAA occlusion utilizing conscious sedation TEE, lack of outpatient pre-imaging, and same-day expedited discharge) with the conventional approach (CA). METHODS: A single-center retrospective analysis of 163 patients undergoing LAAO between January 2017 and April 2022 was conducted. The SOLO-CLOSE protocol was enacted on December 1, 2020. Before this date, we utilized the CA. The primary efficacy endpoint was defined as successful LAAO with ≤5 mm peri-device leak at time of closure. The primary safety endpoint was the composite incidence of all-cause deaths, any cerebrovascular accident (CVA), device embolization, pericardial effusion, or major postprocedure bleeding within 7 days of the index procedure. Procedure times, 7-day readmission rates, and cost analytics were collected as well. RESULTS: Baseline characteristics were similar in both cohorts. Congestive heart failure (37.5% vs. 11.1%) and malignancy (28.8% vs. 12.5%) were higher in SOLO-CLOSE. Median CHA2D2SVASc score was 5 in both cohorts. The primary efficacy endpoint was met 100% in both cohorts. Primary safety endpoint was similar between cohorts (p = 0.078). Mean procedure time was 30 min shorter in SOLO-CLOSE (p < 0.01). Seven-day readmissions for SOLO-CLOSE was zero. After SOLO-CLOSE implementation, there was a 188% increase in positive contribution margin per case. CONCLUSIONS: The SOLO-CLOSE methodology offers similar efficacy and safety when compared to the CA, while improving clinical efficiency, reducing procedural times, and increasing economic benefit.

Isradipine augmentation of virtual reality cue exposure therapy for tobacco craving: a triple-blind randomized controlled trial.

Preclinical research with rodents suggests that the L-type calcium channel blocker isradipine can enhance long-term extinction of conditioned place preference for addictive substances when it is administered in conjunction with extinction training. Although isradipine alone, which is FDA-approved for hypertension, has not shown a direct effect on craving in human drug users, its potential to augment behavioral treatments designed to reduce craving remains unknown. We conducted a triple-blind, randomized placebo-controlled pilot clinical trial of isradipine combined with a novel virtual reality cue exposure therapy (VR-CET) approach with multimodal cues that targeted craving. After 24 hours of abstinence, 78 adults with an ongoing history of daily cigarette use received isradipine (n = 40) or placebo (n = 38) and reported craving levels after each of 10 trials of VR-CET. Consistent with pre-registered hypotheses, the isradipine group had significantly lower mean craving across cue exposure trials at the medication-free 24-hour follow-up (d = -0.42, p = 0.046). There were no serious adverse events; however, side effects such as headache and dizziness occurred more frequently in the isradipine group. The findings of the current study support follow-up clinical trials that specifically test the efficacy of isradipine-augmented VR-CET for reducing smoking relapse rates after an initial quit attempt. clinicaltrials.gov: NCT03083353.

Improving Exposure Therapy: Rationale and Design of an International Consortium.

The Exposure Therapy Consortium (ETC) was established to advance the science and practice of exposure therapy. To encourage participation from researchers and clinicians, this article describes the organizational structure and activities of the ETC. Initial research working group experiences and a proof-of-principle study underscore the potential of team science and larger-scale collaborative research in this area. Clinical working groups have begun to identify opportunities to enhance access to helpful resources for implementing exposure therapy effectively. This article discusses directions for expanding the consortium's activities and its impact on a global scale.

The Role of Functional Health Literacy in terms of Harmful Alcohol Use in Adults with Probable Posttraumatic Stress Disorder and Alcohol Use Disorder.

Purpose: The current study examined functional health literacy (FHL) in regard to hazardous drinking among a sample with probable posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD). Methods: Participants were 565 adults with probable PTSD and hazardous alcohol use (52.2% female, 68.8% Non-Hispanic White, average age = 39.2 years ± 10.9 years). Results: FHL literacy maintained statistically significant role in terms of hazardous drinking (p < .001) even in the context of posttraumatic stress. Conclusion: FHL may be important to better understand hazardous drinking among persons with comorbid PTSD and AUD.

[Current diagnostics and treatment of ankle sprains in German]. / Aktuelle Diagnostik und Behandlung der Sprunggelenks-Distorsion in Deutschland.

BACKGROUND: Ankle sprains are one of the most frequent injuries of the musculoskeletal system. The injury pattern determines the treatment and are crucial for the outcome. Nonoperative treatment is commonly recommended for isolated injuries of the lateral ligaments but no standard strategy exists in combined ankle ligament injuries. The goal of this national survey was to achieve an overview about the current diagnostic strategies and common treatment concepts in Germany. MATERIAL AND METHODS: All members of the German Society for Orthopaedics and Trauma Surgery (DGOU) were invited to participate in an anonymous survey about the diagnostic and therapeutic approach in cases of ankle sprains. The online survey consisted of 20 questions. Besides questions about the speciality and scope of activities the participants were ask to depict their diagnostic and therapeutic strategy. RESULTS: A total of 806 participants completed the survey. Most of them were orthopedic trauma surgeons and worked in a hospital. During the first presentation the anterior drawer test (89.5%) and the inversion/eversion test (81.6%) were most commonly used, 88.1% always make an X­ray examination and 26.5% an ultrasonography examination. Isolated injuries of the anterior fibulotalar ligament (LFTA) were treated nonoperatively by 99.7% of the participants, 78.8% recommend full weight bearing in an orthesis, 78.8% treat the complete rupture of the lateral ligaments without operation whereas 30.1% stated that they would treat a combined lateral ligaments rupture with an injury of the syndesmosis nonoperatively. DISCUSSION: Due to the heterogeneity of injury patterns after ankle sprain no consistent recommendations for diagnostics and treatment exist. The Ottawa ankle rules and ultrasonography were not often utilized despite of the good evidence. The isolated rupture of the LFTA is diagnosed and treated according to the national guidelines by most of the participants. In cases of combined injuries of the lateral and medial ankle ligaments the majority choose a nonoperative treatment strategy which is justified by the guidelines with a low level of evidence. Combined injuries of the syndesmosis and the lateral ankle ligaments were treated operatively, which also correlates with the recommendations in the literature. The standard care of ankle sprain in Germany is in accordance with the recommendations from the current literature.

Carbon Dioxide Reactivity Differentially Predicts Fear Expression After Extinction and Retrieval-Extinction in Rats.

Background: Cues present during a traumatic event may result in persistent fear responses. These responses can be attenuated through extinction learning, a core component of exposure therapy. Exposure/extinction is effective for some people, but not all. We recently demonstrated that carbon dioxide (CO2) reactivity predicts fear extinction memory and orexin activation and that orexin activation predicts fear extinction memory, which suggests that a CO2 challenge may enable identification of whether an individual is a good candidate for an extinction-based approach. Another method to attenuate conditioned responses, retrieval-extinction, renders the original associative memory labile via distinct neural mechanisms. The purpose of the current study was to examine whether we could replicate previous findings that retrieval-extinction is more effective than extinction at preventing the return of fear and that CO2 reactivity predicts fear memory after extinction. We also examined whether CO2 reactivity predicts fear memory after retrieval-extinction. Methods: Male rats first underwent a CO2 challenge and fear conditioning and were assigned to receive either standard extinction (n = 28) or retrieval-extinction (n = 28). Then, they underwent a long-term memory (LTM) test and a reinstatement test. Results: We found that retrieval-extinction resulted in lower freezing during extinction, LTM, and reinstatement than standard extinction. Using the best subset approach to linear regression, we found that CO2 reactivity predicted LTM after extinction and also predicted LTM after retrieval-extinction, although to a lesser degree. Conclusions: CO2 reactivity could be used as a screening tool to determine whether an individual may be a good candidate for an extinction-based therapeutic approach.

Extinction learning underlies exposure therapy, a treatment for anxiety disorders. However, not everyone benefits from exposure therapy, highlighting the need in developing approaches that may help predict which individuals will respond. We tested whether extinction or an alternative treatment called retrieval-extinction would be more effective at reducing conditioned fear responses in rats and whether the response to a carbon dioxide (CO₂) challenge would predict treatment response. We found that retrieval-extinction was more effective at reducing fear, and CO₂ reactivity was better at predicting the response to extinction. These findings could help improve treatment strategies for anxiety disorders.

Efficacy and implementation of exercise-based smoking cessation treatment for adults with high anxiety sensitivity (STEP): Study protocol for a randomized controlled trial.

Anxiety sensitivity (AS), reflecting the fear of bodily sensations, is a transdiagnostic vulnerability factor that underpins both affective psychopathology and smoking. Phase II research supports the efficacy of a 15-week community-based intervention (STEP) that combines high-intensity exercise offered by the YMCA with standard smoking cessation treatment (tobacco quitline and nicotine replacement therapy) for sedentary smokers with elevated AS. This Phase III study aims to enroll 360 adults to evaluate whether STEP efficacy for achieving smoking abstinence generalizes to Black and Hispanic smokers with elevated AS.

Safety and compliance of long-term low-dose ondansetron in alcohol use disorder treatment.

BACKGROUND: The increasing prevalence of alcohol use disorder (AUD) and the parallel surge in alcohol-associated liver disease (ALD) emphasize the urgent need for comprehensive alcohol management strategies. Low-dose ondansetron (AD04, a 5-HT3 antagonist) was shown recently to be a promising treatment for AUD with a specific genotypic profile (5-marker). The liver safety of AD04 has never been evaluated in subjects with AUD. The aim of the present study was to assess the liver safety profile of AD04 compared with placebo in subjects with AUD. METHODS: Liver biochemical parameters were assessed in subjects with AUD with a 5-marker genetic profile who participated in a Phase 3 randomized controlled trial and received either twice-daily, low-dose AD04 (ondansetron 0.33 mg twice daily) or matching placebo, combined with brief psychosocial counseling. ALT, AST, GGT, Serum Bilirubin, MCV, and Prothrombin were evaluated at weeks 0, 12, and 24. Adverse cardiac events, general well-being, and study completion were also assessed. RESULTS: Low-dose AD04 did not significantly change biochemical markers of liver injury, such as ALT, AST, and Serum Bilirubin. While patients with AUD displayed elevated GGT levels, typically associated with increased alcohol consumption, this parameter remained unaffected by low-dose AD04. Notably, no significant adverse effects were observed due to oral low-dose AD04 treatment. CONCLUSIONS: Low-dose AD04 has the potential to be a safe treatment option for subjects with AUD and ALD, indicating the need for an RCT for this specific cohort. Such a trial would pave the way for the design of a precision treatment for combined AUD with ALD.

Staphylococcus aureus colonisation and strategies for decolonisation.

Staphylococcus aureus is a leading cause of death by infectious diseases worldwide. Treatment of S aureus infections is difficult due to widespread antibiotic resistance, necessitating alternative approaches and measures for prevention of infection. Because S aureus infections commonly arise from asymptomatic colonisation, decolonisation is considered a key approach for their prevention. Current decolonisation procedures include antibiotic-based and antiseptic-based eradication of S aureus from the nose and skin. However, despite the widespread implementation and partial success of such measures, S aureus infection rates remain worrisome, and resistance to decolonisation agents is on the rise. In this Review we outline the epidemiology and mechanisms of S aureus colonisation, describe how colonisation underlies infection, and discuss current and novel approaches for S aureus decolonisation, with a focus on the latest findings on probiotic strategies and the intestinal S aureus colonisation site.

Methicillin Resistance Elements in the Canine Pathogen Staphylococcus pseudintermedius and Their Association with the Peptide Toxin PSM-mec.

Staphylococcus pseudintermedius is a frequent cause of infections in dogs. Infectious isolates of this coagulase-positive staphylococcal species are often methicillin- and multidrug-resistant, which complicates therapy. In staphylococci, methicillin resistance is encoded by determinants found on mobile genetic elements called Staphylococcal Chromosome Cassette mec (SCCmec), which, in addition to methicillin resistance factors, sometimes encode additional genes, such as further resistance factors and, rarely, virulence determinants. In this study, we analyzed SCCmec in a collection of infectious methicillin-resistant S. pseudintermedius (MRSP) isolates from predominant lineages in the United States. We found that several lineages characteristically have specific types of SCCmec elements and Agr types and harbor additional factors in their SCCmec elements that may promote virulence or affect DNA uptake. All isolates had SCCmec-encoded restriction-modification (R-M) systems of types I or II, and sequence types (STs) ST84 and ST64 had one type II and one type I R-M system, although the latter lacked a complete methylation enzyme gene. ST68 isolates also had an SCCmec-encoded CRISPR system. ST71 isolates had a psm-mec gene, which, in all but apparently Agr-dysfunctional isolates, produced a PSM-mec peptide toxin, albeit at relatively small amounts. This study gives detailed insight into the composition of SCCmec elements in infectious isolates of S. pseudintermedius and lays the genetic foundation for further efforts directed at elucidating the contribution of identified accessory SCCmec factors in impacting SCCmec-encoded and thus methicillin resistance-associated virulence and resistance to DNA uptake in this leading canine pathogen.

Negative emotional reactivity to minority stress: measure development and testing.

The purpose of the present investigation was to develop and test a measure of negative emotional reactivity to racial/ethnic minoritized stress. In Study 1, we developed item content for a measure of negative emotional reactivity to racial/ethnic minoritized stress. We then evaluated item performance and produced a refined 15-item scale among a large sample of racial/ethnic minority adults (N = 1,343). Results supported a unidimensional construct and high levels of internal consistency. The factor structure and internal consistency were replicated and extended to a sample of Latinx persons who smoke (N = 338) in Study 2. There was evidence of convergent validity of the Emotional Reactivity to Minoritized Stress (ERMS) total score in terms of theoretically consistent and statistically significant relations with indices of mental health problems, social determinants of health, and substance use processes. There was also evidence that the ERMS demonstrated divergent validity in that it was negatively associated with psychological well-being, health literacy, subjective social status in Study 1, and positive abstinence expectancies in Study 2. Overall, the present study establishes the reliability and validity of measuring individual differences in negative emotional reactivity to racial/ethnic minority stress with the ERMS and that such responsivity is associated with behavioral health problems.

Caveat emptor: Mental health specialty certifications and the public's preferences for clinical care.

Appropriate training and continuing education for mental health professionals are designed to ensure that clinicians provide effective and ethical care. Mental health consumers may depend upon these credentials to judge the level of a professional's competence, but whether these activities and credentials provide a valid indicator of knowledge and skills is subject to debate. The present study was designed to examine preferences for mental health clinicians among potential consumers and factors that may inform these preferences, specifically comparing preferences for doctoral-level mental health clinicians and masters-level clinicians with and without specialty certification for treating anxiety symptoms. Cross-sectional assessment with self-report surveys (clinician preferences, prior mental health diagnosis and treatment, demographic characteristics, generalized anxiety symptoms, mental health literacy, and mental health stigma) was administered in two samples: a college student sample (N = 224; 71.9% female; Mage = 19.1, SD = 1.5) and a sample of adults with chronic pain (N = 116; 74.1% female; Mage = 43.8, SD = 13.8). The present study found that across both samples, therapists with a specialty certification were preferred over those without such credentials within each profession, and that certification status trumped professional standing such that certified masters-level clinicians were rated more highly than noncertified PhD-level clinicians. These findings are indicative of a schism between how the field of clinical psychology conceptualizes itself and how it is seen by its consumers. Implications of our findings for mental health consumers, clinicians, and professional organizations are discussed. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

On the importance of identifying mechanisms and active ingredients of psychological treatments.

This commentary addresses the thought-provoking article by Lorenzo-Luaces (in press). We review areas of both agreement and disagreement with the author's points, noting that readers should not infer that research into active ingredients and mechanisms is pointless. We conclude with a call for more research into the mechanisms of therapeutic change and the active ingredients of therapeutic interventions, with the aim of disseminating treatments that are both effective and efficient.

What good are positive emotions for treatment? A replication test of whether trait positive emotionality predicts response to exposure therapy for social anxiety disorder.

BACKGROUND: Positive valence emotions serve functions that may facilitate response to exposure therapy - they encourage approach behavior, diminish perceived threat reactivity, and enhance assimilation of new information in memory. Few studies have examined whether positive emotions predict exposure therapy success and extant findings are mixed. METHODS: We conducted a secondary analysis of an exposure therapy trial for social anxiety disorder to test the hypothesis that patients endorsing higher trait positive emotions at baseline would display the greatest treatment response. N = 152 participants enrolled in a randomized controlled trial of d-cycloserine augmentation completed five sessions of group exposure therapy. Pre-treatment positive emotionality was assessed using the NEO Five-Factor Inventory. Social anxiety symptoms were assessed throughout treatment by blinded evaluators using the Liebowitz Social Anxiety Scale. RESULTS: Accounting for baseline symptom severity, multilevel growth curve models revealed that patients with higher pre-treatment positive emotionality displayed faster social anxiety symptom reductions and lower scores at 3-month follow-up. This predictive effect remained significant after controlling for baseline depression and extraversion (without the positive emotionality facet). CONCLUSIONS: These findings add to emerging evidence suggesting that explicitly targeting and enhancing positive emotions during exposure to perceived threat may improve treatment outcomes for anxiety and fear-based disorders. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02066792https://clinicaltrials.gov/ct2/show/NCT02066792.

Staphylococcus aureus delta toxin modulates both extracellular membrane vesicle biogenesis and amyloid formation.

IMPORTANCE: Extracellular membrane vesicles (MVs) produced by Staphylococcus aureus in planktonic cultures encapsulate a diverse cargo of bacterial proteins, nucleic acids, and glycopolymers that are protected from destruction by external factors. δ-toxin, a member of the phenol soluble modulin family, was shown to be critical for MV biogenesis. Amyloid fibrils co-purified with MVs generated by virulent, community-acquired S. aureus strains, and fibril formation was dependent on expression of the S. aureus δ-toxin gene (hld). Mass spectrometry data confirmed that the amyloid fibrils were comprised of δ-toxin. Although S. aureus MVs were produced in vivo in a localized murine infection model, amyloid fibrils were not observed in the in vivo setting. Our findings provide critical insights into staphylococcal factors involved in MV biogenesis and amyloid formation.

Severe aortic insufficiency-induced cardiogenic shock treated with left atrial VA-ECMO and emergent valve-in-valve TAVR.

Conventional venoarterial extracorporeal membrane oxygenation (VA-ECMO) places a functional afterload burden on the left ventricle. In the setting of acute severe aortic insufficiency-induced cardiogenic shock, the utility of VA-ECMO in combination with a failing valve may result in catastrophic haemodynamic consequences. This challenge is compounded when the culprit is a failing surgical bioprosthetic valve. We present a case of severe rapid-onset bioprosthetic aortic insufficiency-induced cardiogenic shock successfully resuscitated with left atrial VA-ECMO promptly followed by emergent percutaneous valve-in-valve transaortic valve replacement. We discuss the logistics, implications, and associated haemodynamic manifestations in utilizing this strategy for such disease processes.

Virulence Mechanisms of Staphylococcal Animal Pathogens.

Staphylococci are major causes of infections in mammals. Mammals are colonized by diverse staphylococcal species, often with moderate to strong host specificity, and colonization is a common source of infection. Staphylococcal infections of animals not only are of major importance for animal well-being but have considerable economic consequences, such as in the case of staphylococcal mastitis, which costs billions of dollars annually. Furthermore, pet animals can be temporary carriers of strains infectious to humans. Moreover, antimicrobial resistance is a great concern in livestock infections, as there is considerable antibiotic overuse, and resistant strains can be transferred to humans. With the number of working antibiotics continuously becoming smaller due to the concomitant spread of resistant strains, alternative approaches, such as anti-virulence, are increasingly being investigated to treat staphylococcal infections. For this, understanding the virulence mechanisms of animal staphylococcal pathogens is crucial. While many virulence factors have similar functions in humans as animals, there are increasingly frequent reports of host-specific virulence factors and mechanisms. Furthermore, we are only beginning to understand virulence mechanisms in animal-specific staphylococcal pathogens. This review gives an overview of animal infections caused by staphylococci and our knowledge about the virulence mechanisms involved.