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Background: Benralizumab induces rapid and near-complete depletion of eosinophils from blood and lung tissue. We investigated whether benralizumab could attenuate the allergen-induced late asthmatic response (LAR) in participants with allergic asthma., Methods: Participants with allergic asthma who demonstrated increased sputum eosinophils and LAR at screening were randomised to benralizumab 30 mg or matched placebo given every 4 weeks for 8 weeks (3 doses). Allergen challenges were performed at weeks 9 and 12 when blood, sputum, bone marrow and bronchial tissue eosinophils and LAR were assessed., Results: 46 participants (mean age 30.9 years) were randomised to benralizumab (n=23) or placebo (n=23). Eosinophils were significantly reduced in the benralizumab group compared with placebo in blood at 4 weeks and sputum and bone marrow at 9 weeks after treatment initiation. At 7 h after an allergen challenge at week 9, sputum eosinophilia was significantly attenuated in the benralizumab group compared to placebo (least squares mean difference -5.81%, 95% CI -10.69- -0.94%; p=0.021); however, the LAR was not significantly different (least squares mean difference 2.54%, 95% CI 3.05-8.12%; p=0.363). Adverse events were reported for seven (30.4%) and 14 (60.9%) participants in the benralizumab and placebo groups, respectively., Conclusion: Benralizumab administration over 8 weeks resulted in a significant attenuation of blood, bone marrow and sputum eosinophilia in participants with mild allergic asthma; however, there was no change in the LAR, suggesting that eosinophils alone are not a key component of allergen-induced bronchoconstriction., Competing Interests: Conflict of interest: G.M. Gauvreau reports support for the present manuscript from AstraZeneca, grants from AstraZeneca, payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, and receipt of equipment, materials, drugs, medical writing, gifts or other services from AstraZeneca. R. Sehmi reports support for the present study from AstraZeneca. R. Leigh reports support for the present study from AstraZeneca, and payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca. D.W. Cockcroft reports support for the present manuscript from AstraZeneca, and grants from SHRF, Biohaven, AllerGen, University of Saskatchewan College of Medicine and CIHR. I. Mayers reports grants from AstraZeneca Canada and Boehringer Ingelheim, consultancy fees from Sanofi Canada and AstraZeneca, payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, and payment for expert testimony from Alberta Justice. L-P. Boulet reports grants from Amgen, AstraZeneca, GlaxoSmithKline, Merck, Novartis and Sanofi-Regeneron, royalties or licences from UptoDate and Taylor & Francis, consultancy fees from AstraZeneca, Novartis, GlaxoSmithKline, Merck and Sanofi-Regeneron, payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, GlaxoSmithKline, Novartis, Merck and Sanofi, and leadership role as Past-Chair of the Global Initiative for Asthma (GINA) Board of Directors, Past President of the Global Asthma Organisation (Interasma), Past Member of the Canadian Thoracic Society Respiratory Guidelines Committee and Past Laval University Chair on Knowledge Transfer, Prevention and Education in Respiratory and Cardiovascular Health. T. Ho reports grants from Fisher & Paykel, consultancy fees from Valeo and AstraZeneca, and payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca and GlaxoSmithKline. I. Satia reports grants from Merck, GlaxoSmithKline and Bellus, consultancy fees from Merck, Genentech, Respiplus and GlaxoSmithKline/Bellus, and payment or honoraria for lectures, presentations, manuscript writing or educational events from Merck, GlaxoSmithKline, AstraZeneca and Sanofi. P.D. Mitchell reports grants from Teva, consultancy fees from Pfizer and GlaxoSmithKline, and support for attending meetings from AstraZeneca. I.P. Magee reports payment or honoraria for lectures, presentations, manuscript writing or educational events from GlaxoSmithKline. C. Bergeron reports support for the present study from AstraZeneca, grants from AstraZeneca, Sanofi and Regeneron, consultancy fees from ValeoPharma, Sanofi, AstraZeneca and GlaxoSmithKline, and payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, GlaxoSmithKline, ValeoPharma, Sanofi and Grifols. M. Bhutani reports grants from CIHR, GlaxoSmithKline, AstraZeneca and Sanofi, consultancy fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Sanofi, Covis and Valeo, and payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, GlaxoSmithKline, Sanofi and Covis. V. Werkström was an employee of AstraZeneca at the time of the study and reports stock or stock options in AstraZeneca. T. Durżyński was an employee of AstraZeneca at the time of the study and reports stock or stock options in AstraZeneca. K. Shoemaker was an employee of AstraZeneca at the time of the study and reports stock or stock options in AstraZeneca. R.K. Katial was an employee of AstraZeneca at the time of the study and reports personal fees from AstraZeneca. M. Jison was an employee of AstraZeneca at the time of the study and reports stock or stock options in AstraZeneca. C. McCrae was an employee of AstraZeneca at the time of the study and reports stock or stock options in AstraZeneca. P.M. O'Byrne reports support for the present study from AstraZeneca, grants from AstraZeneca, Merck and Biohaven, consultancy fees from AstraZeneca, GlaxoSmithKline, Sage, Teva and Affibody, and payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, Chiesi, GlaxoSmithKline and Covis. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

There is a growing number of studies investigating discriminatory fear conditioning and conditioned inhibition of fear to assess safety learning, in addition to extinction of cued fear. Despite all of these paradigms resulting in a reduction in fear expression, there are nuanced differences among them, which could be mediated through distinct behavioral and neural mechanisms. These differences could impact how we approach potential treatment options in clinical disorders with dysregulated fear responses. The objective of this review is to give an overview of the conditional discrimination and inhibition findings reported in both animal models and human neuropsychiatric disorders. Both behavioral and neural findings are reviewed among human and rodent studies that include conditional fear discrimination via conditional stimuli with and without reinforcement (CS+ vs. CS-, respectively) and/or conditional inhibition of fear through assessment of the fear response to a compound CS-/CS+ cue versus CS+. There are several parallels across species in behavioral fear expression as well as neural circuits promoting fear reduction in response to a CS- and/or CS-/CS+ compound cue. Continued and increased efforts to compare similar behavioral fear inhibition paradigms across species are needed to make breakthrough advances in our understanding and treatment approaches to individuals with fear disorders. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Cortisol and heart rate variability (HRV) are well-established biomarkers of the human stress response system. While a relationship between cortisol and HRV is assumed, few studies have found evidence of their correlation within single study designs. One complication for isolating such a relationship may lie in individual variability in the cortisol response to stress such that atypical cortisol responding (i.e., elevated or blunted) occurs. To-date, studies on the cortisol response have employed traditional mean-difference-based approaches to examine average magnitude change in cortisol over time. Alternatively, data-driven trajectory modelling, such as latent growth mixture modelling, may be advantageous for quantifying cortisol based on patterns of response over time. Latent growth mixture modelling was used in N = 386 adults to identify subgroups based on trajectories of cortisol responses to stress. The relationship between cortisol and HRV was tested within subgroups. Results revealed a 'prototypical' subgroup characterised by expected rise and fall in cortisol response to stress (n = 309), a 'decline' subgroup (n = 28) that declined in cortisol after stress, and a 'rise' subgroup (n = 49) that increased in cortisol after stress. Within the 'prototypical' subgroup, greater HRV during stress was associated with decline in cortisol after stress from its maximum (r (306) = 0.19, p < 0.001). This relationship failed to emerge in the 'decline' and 'rise' subgroups (p > 0.271). Results document different patterns of cortisol response to stress; among those who exhibit a 'prototypical' response, changes in HRV during stress are related to changes in cortisol after stress., (© 2023 John Wiley & Sons Ltd.)

Background: There is little agreement on clinically useful criteria for identifying real-world responders to biologic treatments for asthma., Objective: To investigate the impact of pre-biologic impairment on meeting domain-specific biologic responder definitions in adults with severe asthma., Methods: This was a longitudinal, cohort study across 22 countries participating in the International Severe Asthma Registry (https://isaregistries.org/) between May 2017 and January 2023. Change in 4 asthma domains (exacerbation rate, asthma control, long-term oral corticosteroid [LTOCS] dose, and lung function) was assessed from biologic initiation to 1 year post-treatment (minimum 24 weeks). Pre- to post-biologic changes for responders and nonresponders were described along a categorical gradient for each domain derived from pre-biologic distributions (exacerbation rate: 0 to 6+/y; asthma control: well controlled to uncontrolled; LTOCS: 0 to >30 mg/d; percent-predicted forced expiratory volume in 1 second [ppFEV 1 ]: <50% to ≥80%)., Results: Percentage of biologic responders (ie, those with a category improvement pre- to post-biologic) varied by domain and increased with greater pre-biologic impairment, increasing from 70.2% to 90.0% for exacerbation rate, 46.3% to 52.3% for asthma control, 31.1% to 58.5% for LTOCS daily dose, and 35.8% to 50.6% for ppFEV 1 . The proportion of patients having improvement post-biologic tended to be greater for anti-IL-5/5R compared with for anti-IgE for exacerbation, asthma control, and ppFEV 1 domains, irrespective of pre-biologic impairment., Conclusion: Our results provide realistic outcome-specific post-biologic expectations for both physicians and patients, will be foundational to inform future work on a multidimensional approach to define and assess biologic responders and response, and may enhance appropriate patient selection for biologic therapies., Trial Registration: The ISAR database has ethical approval from the Anonymous Data Ethics Protocols and Transparency (ADEPT) committee (ADEPT0218) and is registered with the European Union Electronic Register of Post-Authorization studies (ENCEPP/DSPP/23720). The study was designed, implemented, and reported in compliance with the European Network Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) Code of Conduct (EUPAS38288) and with all applicable local and international laws and regulation, and registered with ENCEPP (https://www.encepp.eu/encepp/viewResource.htm?id=38289). Governance was provided by ADEPT (registration number: ADEPT1220)., Competing Interests: Disclosures Dr Perez-de-Llano reports grants, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from GlaxoSmithKline, grants, personal fees and non-financial support from Teva, personal fees and non-financial support from Chiesi, grants, personal fees and non-financial support from Sanofi, personal fees from MSD, personal fees from Techdow Pharma, grants, personal fees and non-financial support from Faes Farma, personal fees from Leo-Pharma, grants and personal fees from Gebro, personal fees from Gilead, outside the submitted work. Dr Scelo is a consultant for Observational and Pragmatic Research Institute (OPRI). OPRI conducted this study in collaboration with Optimum Patient Care and AstraZeneca. Dr Canonica has received research grants and lecture or advisory board fees from Menarini, Alk-Albello, Allergy Therapeutics, Anallergo, AstraZeneca, MedImmune, Boehringer Ingelheim, Chiesi Farmaceutici, Circassia, Danone, Faes, Genentech, Guidotti Malesci, GlaxoSmithKline, Hal Allergy, Merck, Merck Sharp & Dohme, Mundipharma, Novartis, Orion, Sanofi Aventis, Sanofi, Genzyme/Regeneron, Stallergenes, UCB Pharma, Uriach Pharma, Teva, Thermo Fisher, and Valeas. Dr Henley is affiliated with OPRI and reports receiving travel support from Eisai Limited. Dr Larenas-Linnemann reports receiving personal fees from ALK-Abelló, AstraZeneca national and global, Bayer, Chiesi, Grunenthal, Grin, GlaxoSmithKline national and global, Viatris, Menarini, Merck Sharp & Dohme, Novartis, Pfizer, Sanofi, Siegfried, UCB, Carnot, grants from AbbVie, Bayer, Lilly, Sanofi, AstraZeneca, Pfizer, Novartis, Circassia, UCB, and GlaxoSmithKline, outside the submitted work. Dr Peters declares receiving personal fees and nonfinancial support from AstraZeneca, GlaxoSmithKline, and Sanofi. Dr Pfeffer has attended advisory boards for AstraZeneca, GlaxoSmithKline, and Sanofi; has given lectures at meetings supported by AstraZeneca and GlaxoSmithKline; has taken part in clinical trials sponsored by AstraZeneca, GlaxoSmithKline, Novartis, and Sanofi, for which his institution received remuneration; and has a current research grant funded by GlaxoSmithKline. Dr Tran is an employee of AstraZeneca and may own stock or stock options in AstraZeneca. Dr Suppli Ulrik reports receiving personal fees for talks and having participation in advisory boards and others from AstraZeneca, GlaxoSmithKline, TEVA, Boehringer Ingelheim, Orion Pharma, Sanofi Genzyme, TFF Pharmaceuticals, Covis Pharma, Berlin-Chemie, Takeda, Chiesi, and Pfizer, outside the submitted work. Dr Popov declares relevant research support from Novartis and Chiesi Pharma. Dr Sadatsafavi has received honoraria from AstraZeneca, Boehringer Ingelheim, TEVA, and GlaxoSmithKline for purposes unrelated to the content of this manuscript and has received research funding from AstraZeneca and Boehringer Ingelheim directly into his research account from AstraZeneca for unrelated projects. Dr Hew declares receiving grants and other advisory board fees (made to his institutional employer) from AstraZeneca, GlaxoSmithKline, Novartis, Sanofi, Teva, and Seqirus, for unrelated projects. Dr Maspero reports receiving speaker fees and grants or serving on the advisory boards for AstraZeneca, Sanofi, GlaxoSmithKline, Novartis, Inmunotek, Menarini, and Noucor. Dr Gibson has received speaker fees and grants to his institution from AstraZeneca, GlaxoSmithKline, and Novartis. Dr FitzGerald previously declared receiving grants from AstraZeneca, GlaxoSmithKline, Sanofi Regeneron, and Novartis paid directly to UBC and receiving personal fees for lectures and attending advisory boards for AstraZeneca, GlaxoSmithKline, Sanofi Regeneron, and TEVA. Dr Torres-Duque has received fees as advisory board participant and/or speaker from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Sanofi-Aventis; has taken part in clinical trials from AstraZeneca, Novartis, and Sanofi-Aventis; and has received unrestricted grants for investigator-initiated studies at Fundacion Neumologica Colombiana from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Grifols, and Novartis. Dr Porsbjerg has attended advisory boards for AstraZeneca, Novartis, TEVA, and Sanofi-Genzyme; has given lectures at meetings supported by AstraZeneca, Novartis, TEVA, Sanofi-Genzyme, and GlaxoSmithKline; has taken part in clinical trials sponsored by AstraZeneca, Novartis, Merck Sharp & Dohme, Sanofi-Genzyme, GlaxoSmithKline, and Novartis; and has received educational and research grants from AstraZeneca, Novartis, TEVA, GlaxoSmithKline, ALK, and Sanofi-Genzyme. Dr Papadopoulos has been a speaker and/or advisory board member for Abbott, AbbVie, ALK, Asit Biotech, AstraZeneca, Biomay, Boehringer Ingelheim, GlaxoSmithKline, HAL, Faes Farma, Medscape, Menarini, Merck Sharp & Dohme, Novartis, Nutricia, OM Pharma, Regeneron, Sanofi, Takeda, and Viatris. Dr Papaioannou has received fees and honoraria from Menarini, GlaxoSmithKline, Novartis, Elpen, Boehringer Ingelheim, AstraZeneca, and Chiesi. Dr Heffler declares receiving personal fees from Sanofi, Regeneron, GlaxoSmithKline, Novartis, AstraZeneca, Stallergenes, and Circassia. Dr Iwanaga received lecture fees from Kyorin, GlaxoSmithKline, Novartis, Boehringer Ingelheim, and AstraZeneca. Dr Al-Ahmad has received advisory board and speaker fees from AstraZeneca, Sanofi, Novartis, and GlaxoSmithKline and received a grant from Kuwait Foundation for the Advancement of Sciences. Dr Kuna reports receiving personal fees from Adamed, AstraZeneca, Berlin Chemie Menarini, FAES, Glenmark, Novartis, Polpharma, Boehringer Ingelheim, Teva, and Zentiva, outside the submitted work. Dr Fonseca reports receiving grants from research agreements with AstraZeneca, Mundipharma, Sanofi Regeneron, and Novartis and personal fees for lectures and attending advisory boards for AstraZeneca, GlaxoSmithKline, Mundipharma, Novartis, Sanofi Regeneron, and TEVA. Dr Al-Lehebi has given lectures at meetings supported by AstraZeneca, Boehringer Ingelheim, Novartis, GlaxoSmithKline, and Sanofi and participated in advisory board fees from GlaxoSmithKline, AstraZeneca, Novartis, and Abbott. Dr Rhee received consulting/lecture fees from Merck Sharp & Dohme, AstraZeneca, GlaxoSmithKline, Novartis, Takeda, Mundipharma, Boehringer Ingelheim, Teva, Sanofi, and Bayer. Dr Koh reports receiving grant support from AstraZeneca and honoraria for lectures and advisory board meetings paid to her hospital (Singapore General Hospital) from GlaxoSmithKline, AstraZeneca, Novartis, Sanofi, and Boehringer Ingelheim, outside the submitted work. Dr Cosio declares receiving grants from Chiesi and GlaxoSmithKline; personal fees for advisory board activities from Chiesi, GlaxoSmithKline, Novartis, Sanofi, Teva, and AstraZeneca; and payment for lectures/speaking engagements from Chiesi, Novartis, GlaxoSmithKline, Menarini, and AstraZeneca, outside the submitted work. Dr Perng (Steve) has received sponsorship to attend or speak at international meetings, honoraria for lecturing or attending advisory boards, and research grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Daiichi Sankyo, Shionogi, and Orient Pharma. Dr Menzies-Gow is an employee of AstraZeneca and may own stock or stock options in AstraZeneca. Dr Jackson has received speaker fees and consultancy fees from AstraZeneca, GlaxoSmithKline, Sanofi Regeneron, and Boehringer Ingelheim and research funding from AstraZeneca. Dr Busby has received research grants from AstraZeneca and personnel fees from NuvoAir, outside the submitted work. Dr Heaney has received grant funding, participated in advisory boards, and given lectures at meetings supported by Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Hoffmann-La Roche, GlaxoSmithKline, Novartis, Theravance, Evelo Biosciences, Sanofi, and Teva; has received grants from MedImmune, Novartis United Kingdom, Roche/Genentech Inc, GlaxoSmithKline, Amgen, Genentech/Hoffman-La Roche, AstraZeneca, MedImmune, Aerocrine, and Vitalograph; has received sponsorship for attending international scientific meetings from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Napp Pharmaceuticals; has taken part in asthma clinical trials sponsored by AstraZeneca, Boehringer Ingelheim, Hoffmann-La Roche, and GlaxoSmithKline for which his institution received remuneration; and is the Academic Lead for the Medical Research Council Stratified Medicine United Kingdom Consortium in Severe Asthma which involves industrial partnerships with a number of pharmaceutical companies including Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffmann-La Roche, and Janssen. Dr Patel has received advisory board and speaker fees from AstraZeneca, GlaxoSmithKline, Novartis, and Sanofi/Regeneron. Dr Wang has received honoraria from AstraZeneca, GlaxoSmithKline, and Genentech; has been an investigator on studies sponsored by AstraZeneca, GlaxoSmithKline, Genentech, Sanofi, Novartis, and Teva, for which her institution has received funding. Dr Wechsler reports receiving grants and/or personal fees from Novartis, Sanofi, Regeneron, Genentech, Sentien, Restorbio, Equillium, Genzyme, Cohero Health, Teva, Boehringer Ingelheim, AstraZeneca, Amgen, GlaxoSmithKline, Cytoreason, Cerecor, Sound Biologics, Incyte, and Kinaset. Dr Altraja has received lecture fees from AstraZeneca, Boehringer Ingelheim, Berlin-Chemie Menarini, GlaxoSmithKline, Merck Sharp & Dohme, Norameda, Novartis, Orion, Sanofi, and Zentiva; has sponsorships from AstraZeneca, Boehringer Ingelheim, Berlin-Chemie Menarini, GlaxoSmithKline, Merck Sharp & Dohme, Norameda, Novartis, and Sanofi; and has participated in advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi, and Teva. Dr Lehtimäki has received personal fees from ALK, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Menarini, Novartis, Orion Pharma, and Sanofi. Dr Bourdin has received industry-sponsored grants from AstraZeneca/MedImmune, Boehringer Ingelheim, Cephalon/Teva, GlaxoSmithKline, Novartis, and Sanofi-Regeneron and conducted consultancies with AstraZeneca/MedImmune, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Regeneron-Sanofi, Med-in-Cell, Actelion, Merck, Roche, and Chiesi. Dr Bjermer has (in the last 3 years) received lecture or advisory board fees from Alk-Abello, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mundipharma, Novartis, Sanofi, Genzyme/Regeneron, and Teva. Ms Bulathsinhala is an employee of the OPRI. OPRI conducted this study in collaboration with Optimum Patient Care and AstraZeneca. Ms Carter is an employee of Optimum Patient Care, which is a co-funder of the International Severe Asthma Registry. Dr Murray is a consultant for OPRI. OPRI conducted this study in collaboration with Optimum Patient Care and AstraZeneca. Mr Beastall is an employee of the Optimum Patient Care Global, a co-funder of the International Severe Asthma Registry. Dr Denton declares receiving grants to her institution from AstraZeneca, GlaxoSmithKline, Novartis, Sanofi, Teva, and Seqirus, for unrelated projects and speaker fees from Sanofi. Dr Price has advisory board membership with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Viatris, and Teva Pharmaceuticals; consultancy agreements with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Viatris, and Teva Pharmaceuticals; grants and unrestricted funding for investigator-initiated studies (conducted through OPRI Pte Ltd) from AstraZeneca, Chiesi, Viatris, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, and United Kingdom National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Commune Digital, GlaxoSmithKline, Medscape, Viatris, Novartis, Regeneron Pharmaceuticals and Sanofi Genzyme, and Teva Pharmaceuticals; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Novartis, Medscape, and Teva Pharmaceuticals; stock/stock options from AKL Research and Development Ltd which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and United Kingdom) and 92.61% of OPRI Pte Ltd (Singapore); 5% shareholding in Timestamp which develops adherence monitoring technology; is peer reviewer for grant committees of the United Kingdom Efficacy and Mechanism Evaluation Programme and Health Technology Assessment; and was an expert witness for GlaxoSmithKline. The remaining authors have no conflicts of interest to report., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Childhood abuse (physical, emotional, and sexual) is associated with aberrant connectivity of the amygdala, a key threat-processing region. Heightened amygdala activity also predicts adult anxiety and posttraumatic stress disorder (PTSD) symptoms, as do experiences of childhood abuse. The current study explored whether amygdala resting-state functional connectivity may explain the relationship between childhood abuse and anxiety and PTSD symptoms following trauma exposure in adults., Methods: Two weeks posttrauma, adult trauma survivors ( n  = 152, mean age [SD] = 32.61 [10.35] years; women = 57.2%) completed the Childhood Trauma Questionnaire and underwent resting-state functional magnetic resonance imaging. PTSD and anxiety symptoms were assessed 6 months posttrauma. Seed-to-voxel analyses evaluated the association between childhood abuse and amygdala resting-state functional connectivity. A mediation model evaluated the potential mediating role of amygdala connectivity in the relationship between childhood abuse and posttrauma anxiety and PTSD., Results: Childhood abuse was associated with increased amygdala connectivity with the precuneus while covarying for age, gender, childhood neglect, and baseline PTSD symptoms. Amygdala-precuneus resting-state functional connectivity was a significant mediator of the effect of childhood abuse on anxiety symptoms 6 months posttrauma ( B  = 0.065; 95% CI, 0.013-0.130; SE = 0.030), but not PTSD. A secondary mediation analysis investigating depression as an outcome was not significant., Conclusions: Amygdala-precuneus connectivity may be an underlying neural mechanism by which childhood abuse increases risk for anxiety following adult trauma. Specifically, this heightened connectivity may reflect attentional vigilance for threat or a tendency toward negative self-referential thoughts. Findings suggest that childhood abuse may contribute to longstanding upregulation of attentional vigilance circuits, which makes one vulnerable to anxiety-related symptoms in adulthood., (© 2024 The Authors.)

Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume, as well as reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), vermis (VI, VIII), flocculonodular lobe (lobule X), and corpus medullare (all p -FDR  < 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status. These findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in higher-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Rationale: Previous studies investigating the impact of comorbidities on the effectiveness of biologic agents have been relatively small and of short duration and have not compared classes of biologic agents. Objectives: To determine the association between type 2-related comorbidities and biologic agent effectiveness in adults with severe asthma (SA). Methods: This cohort study used International Severe Asthma Registry data from 21 countries (2017-2022) to quantify changes in four outcomes before and after biologic therapy-annual asthma exacerbation rate, FEV 1 % predicted, asthma control, and long-term oral corticosteroid daily dose-in patients with or without allergic rhinitis, chronic rhinosinusitis (CRS) with or without nasal polyps (NPs), NPs, or eczema/atopic dermatitis. Measurements and Main Results: Of 1,765 patients, 1,257, 421, and 87 initiated anti-IL-5/5 receptor, anti-IgE, and anti-IL-4/13 therapies, respectively. In general, pre- versus post-biologic therapy improvements were noted in all four asthma outcomes assessed, irrespective of comorbidity status. However, patients with comorbid CRS with or without NPs experienced 23% fewer exacerbations per year (95% CI, 10-35%; P  < 0.001) and had 59% higher odds of better post-biologic therapy asthma control (95% CI, 26-102%; P  < 0.001) than those without CRS with or without NPs. Similar estimates were noted for those with comorbid NPs: 22% fewer exacerbations and 56% higher odds of better post-biologic therapy control. Patients with SA and CRS with or without NPs had an additional FEV 1 % predicted improvement of 3.2% (95% CI, 1.0-5.3; P  = 0.004), a trend that was also noted in those with comorbid NPs. The presence of allergic rhinitis or atopic dermatitis was not associated with post-biologic therapy effect for any outcome assessed. Conclusions: These findings highlight the importance of systematic comorbidity evaluation. The presence of CRS with or without NPs or NPs alone may be considered a predictor of the effectiveness of biologic agents in patients with SA.

Background: Childhood maltreatment is associated with reduced activation of the nucleus accumbens, a central region in the reward network, and overactivity in the amygdala, a key region in threat processing. However, the long-lasting impact of these associations in the context of later-life stress is not well understood. The current study explored the association between childhood threat and deprivation and functional connectivity of threat and reward regions in an adult trauma sample., Methods: Trauma survivors (N = 169; mean age [SD] = 32.2 [10.3] years; female = 55.6%) were recruited from a level I trauma center. Two weeks after injury, participants completed the Childhood Trauma Questionnaire (measuring experiences of threat and deprivation) and underwent resting-state functional magnetic resonance imaging. Seed-to-voxel analyses evaluated the effect of childhood threat and deprivation on amygdala and nucleus accumbens resting-state connectivity., Results: Higher levels of threat were associated with increased connectivity between the right nucleus accumbens with temporal fusiform gyrus/parahippocampal gyrus and the left amygdala and the precuneus (false discovery rate-corrected p < .05). After controlling for posttraumatic symptoms 2 weeks posttrauma and lifetime trauma exposure, only the nucleus accumbens findings survived. There were no significant relationships between experiences of childhood deprivation and amygdala or nucleus accumbens connectivity., Conclusions: Experiences of threat are associated with increased nucleus accumbens and amygdala connectivity, which may reflect a preparedness to detect salient and visual stimuli. This may also reflect a propensity toward dysregulated reward processing. Overall, these results suggest that childhood threat may be contributing to aberrant neural baseline reward and threat sensitivity later in life in an adult trauma sample., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)