Validation of the Emergency Department Work Index in a Pediatric Freestanding Community Emergency Department.

OBJECTIVES: The Emergency Department Work Index (EDWIN) is a validated overcrowding score shown to correlate well with staff assessment of adult emergency department (ED) overcrowding and the potential need for diversion. It derives from the number of staffed ED beds, attending physicians on duty, patients within each triage category, and admitted patients. To date, no study has validated EDWIN in a pediatric community ED setting. We aim to determine if EDWIN correlates with established overcrowding measures and provider perception of overcrowding within a freestanding, community-based pediatric ED. METHODS: In this prospective observational study at a freestanding, community-based pediatric ED, EDWIN was calculated hourly over 8 weeks throughout the year. EDWIN was compared with other objective and previously established ED metrics of overcrowding, including rates of patients who left without being seen (LWBS), average time from arrival to ED room, average length of stay (LOS), ED occupancy rates, and number of patients in the waiting room. Furthermore, EDWIN was compared with provider perception of overcrowding by surveying providers 6 times a day during the study period using novel, real-time, longitudinal, electronic health record-based survey distribution methodology. Spearman correlation coefficients were calculated to characterize the associations between EDWIN vs provider perception and EDWIN vs ED metrics. ANOVA and Tukey HSD were used to compare means of ED metrics of overcrowding across EDWIN severity categories. RESULTS: Five hundred eleven provider perception survey responses were collected from July 2022 through January 2023. EDWIN directly correlated with all measures of overcrowding, including provider perception of crowdedness (rho = 0.67), LWBS rates (rho = 0.44), average time from arrival to ED room (rho = 0.74), average LOS (rho = 0.70), ED occupancy rates (rho = 0.68), and number of patients in the waiting room (rho = 0.65). All findings were statistically significant (P < 0.05). CONCLUSIONS: Our findings suggest that EDWIN is an accurate tool to measure overcrowding in a freestanding, community-based pediatric ED.

Sex-Dependent Attentional Impairments in a Subchronic Ketamine Mouse Model for Schizophrenia.

Background: The development of more effective treatments for schizophrenia targeting cognitive and negative symptoms has been limited, partly due to a disconnect between rodent models and human illness. Ketamine administration is widely used to model symptoms of schizophrenia in both humans and rodents. In mice, subchronic ketamine treatment reproduces key dopamine and glutamate dysfunction; however, it is unclear how this translates into behavioral changes reflecting positive, negative, and cognitive symptoms. Methods: In male and female mice treated with either subchronic ketamine or saline, we assessed spontaneous and amphetamine-induced locomotor activity to measure behaviors relevant to positive symptoms, and used a touchscreen-based progressive ratio task of motivation and the rodent continuous performance test of attention to capture specific negative and cognitive symptoms, respectively. To explore neuronal changes underlying the behavioral effects of subchronic ketamine treatment, we quantified expression of the immediate early gene product, c-Fos, in key corticostriatal regions using immunofluorescence. Results: We showed that spontaneous locomotor activity was unchanged in male and female subchronic ketamine-treated animals, and amphetamine-induced locomotor response was reduced. Subchronic ketamine treatment did not alter motivation in either male or female mice. In contrast, we identified a sex-specific effect of subchronic ketamine on attentional processing wherein female mice performed worse than control mice due to increased nonselective responding. Finally, we showed that subchronic ketamine treatment increased c-Fos expression in prefrontal cortical and striatal regions, consistent with a mechanism of widespread disinhibition of neuronal activity. Conclusions: Our results highlight that the subchronic ketamine mouse model reproduces a subset of behavioral symptoms that are relevant for schizophrenia.

Gpr88 Deletion Impacts Motivational Control Without Overt Disruptions to Striatal Dopamine.

Background: Disrupted motivational control is a common-but poorly treated-feature of psychiatric disorders, arising via aberrant mesolimbic dopaminergic signaling. GPR88 is an orphan G protein-coupled receptor that is highly expressed in the striatum and therefore well placed to modulate disrupted signaling. While the phenotype of Gpr88 knockout mice suggests a role in motivational pathways, it is unclear whether GPR88 is involved in reward valuation and/or effort-based decision making in a sex-dependent manner and whether this involves altered dopamine function. Methods: In male and female Gpr88 knockout mice, we used touchscreen-based progressive ratio, with and without reward devaluation, and effort-related choice tasks to assess motivation and cost/benefit decision making, respectively. To explore whether these motivational behaviors were related to alterations in the striatal dopamine system, we quantified expression of dopamine-related genes and/or proteins and used [18F]DOPA positron emission tomography and GTPγ[35S] binding to assess presynaptic and postsynaptic dopamine function, respectively. Results: We showed that male and female Gpr88 knockout mice displayed greater motivational drive than wild-type mice, which was maintained following reward devaluation. Furthermore, we showed that cost/benefit decision making was impaired in male, but not female, Gpr88 knockout mice. Surprisingly, we found that Gpr88 deletion had no effect on striatal dopamine by any of the measures assessed. Conclusions: Our results highlight that GPR88 regulates motivational control but that disruption of such behaviors following Gpr88 deletion occurs independently of gross perturbations to striatal dopamine at a gene, protein, or functional level. This work provides further insights into GPR88 as a drug target for motivational disorders.

Molecular and structural insights into the 5-HT2C receptor as a therapeutic target for substance use disorders.

Substance use disorder (SUD) is a chronic condition, with maintained abuse of a substance leading to physiological and psychological alterations and often changes in cognitive and social behaviours. Current therapies include psychotherapy coupled with medication; however, high relapse rates reveal the shortcomings of these therapies. The signalling, expression profile, and neurological function of the serotonin 2C receptor (5-HT2C receptor) make it a candidate of interest for the treatment of SUD. Recently, psychedelics, which broadly act at 5-HT2 receptors, have indicated potential for the treatment of SUD, implicating the 5-HT2C receptor. The modern psychedelic movement has rekindled interest in the 5-HT2C receptor, resulting in many new studies, especially structural analyses. This review explores the structural, molecular and cellular mechanisms governing 5-HT2C receptor function in the context of SUD. This provides the basis of the preclinical and clinical evidence for their role in SUD and highlights the potential for future exploration.

Frontline perspectives on adoption and non-adoption of care management tools for high-risk patients in primary care.

BACKGROUND: Population health management tools (PHMTs) embedded within electronic health records (EHR) could improve management of high-risk patients and reduce costs associated with potentially avoidable emergency department visits or hospitalizations. Adoption of PHMTs across the Veterans Health Administration (VA) has been variable and previous research suggests that understaffed primary care (PC) teams might not be using the tools. METHODS: We conducted a retrospective content analysis of open-text responses (n = 1804) from the VA's 2018 national primary care personnel survey to, 1) identify system-level and individual-level factors associated with why clinicians are not using the tools, and 2) to document clinicians' recommendations to improve tool adoption. RESULTS: We found three themes pertaining to low adoption and/or tool use: 1) IT burden and administrative tasks (e.g., manually mailing letters to patients), 2) staffing shortages (e.g., nurses covering multiple teams), and 3) no training or difficulty using the tools (e.g., not knowing how to access the tools or use the data). Frontline clinician recommendations included automating some tasks, reconfiguring team roles to shift administrative work away from providers and nurses, consolidating PHMTs into a centralized, easily accessible repository, and providing training. CONCLUSIONS: Healthcare system-level factors (staffing) and individual-level factors (lack of training) can limit adoption of PHMTs that could be useful for reducing costs and improving patient outcomes. Future research, including qualitative interviews with clinicians who use/don't use the tools, could help develop interventions to address barriers to adoption. IMPLICATIONS: Shifting more administrative tasks to clerical staff would free up clinician time for population health management but may not be possible for understaffed PC teams. Additionally, healthcare systems may be able to increase PHMT use by making them more easily accessible through the electronic health record and providing training in their use.

Molecular insights into orphan G protein-coupled receptors relevant to schizophrenia.

Schizophrenia remains a sizable socio-economic burden that continues to be treated with therapeutics based on 70-year old science. All currently approved therapeutics primarily target the dopamine D2 receptor to achieve their efficacy. Whilst dopaminergic dysregulation is a key feature in this disorder, the targeting of dopaminergic machinery has yielded limited efficacy and an appreciable side effect burden. Over the recent decades, numerous drugs that engage non-dopaminergic G protein-coupled receptors (GPCRs) have yielded a promise of efficacy without the deleterious side effect profile, yet none have successfully completed clinical studies and progressed to the market. More recently, there has been increased attention around non-dopaminergic GPCR-targeting drugs, which demonstrated efficacy in some schizophrenia symptom domains. This provides renewed hope that effective schizophrenia treatment may lie outside of the dopaminergic space. Despite the potential for muscarinic receptor- (and other well-characterised GPCR families) targeting drugs to treat schizophrenia, they are often plagued with complications such as lack of receptor subtype selectivity and peripheral on-target side effects. Orphan GPCR studies have opened a new avenue of exploration with many demonstrating schizophrenia-relevant mechanisms and a favourable expression profile, thus offering potential for novel drug development. This review discusses centrally expressed orphan GPCRs: GPR3, GPR6, GPR12, GPR52, GPR85, GPR88 and GPR139 and their relationship to schizophrenia. We review their expression, signalling mechanisms and cellular function, in conjunction with small molecule development and structural insights. We seek to provide a snapshot of the growing evidence and development potential of new classes of schizophrenia therapeutics.

Predictors of VA Primary Care Clerical Staff Burnout Using the Job Demands-Resources Model.

Primary care clerical staff may experience burnout if not adequately prepared and supported for patient-facing customer service tasks. Guided by the Job Demands-Resources (JD-R) model, we use national survey data from 707 primary care clerks at 349 VA clinics (2018; response rate: 12%) to evaluate associations between clerks' perceptions of tasks, work environment, training, and burnout. We found challenges with customer-facing tasks contribute to higher burnout, and supportive work environment was associated with lower burnout. Although perceptions of training were not associated with burnout, our results combined with the JD-R model suggest that customer service training may protect against burnout.

Targeting appetite and satiety in diabetes and obesity, via G protein-coupled receptors.

Type 2 diabetes and obesity have reached pandemic proportions throughout the world, so much so that the World Health Organisation coined the term "Globesity" to help encapsulate the magnitude of the problem. G protein-coupled receptors (GPCRs) are highly tractable drug targets due to their wide involvement in all aspects of physiology and pathophysiology, indeed, GPCRs are the targets of approximately 30% of the currently approved drugs. GPCRs are also broadly involved in key physiologies that underlie type 2 diabetes and obesity including feeding reward, appetite and satiety, regulation of blood glucose levels, energy homeostasis and adipose function. Despite this, only two GPCRs are the target of approved pharmaceuticals for treatment of type 2 diabetes and obesity. In this review we discuss the role of these, and select other candidate GPCRs, involved in various facets of type 2 diabetic or obese pathophysiology, how they might be targeted and the potential reasons why pharmaceuticals against these targets have not progressed to clinical use. Finally, we provide a perspective on the current development pipeline of anti-obesity drugs that target GPCRs.

Large bowel obstruction secondary to a cecal bascule with internal herniation through the foramen of Winslow: A case report.

INTRODUCTION: Internal hernias are a rare phenomenon, and even rarer is a herniation through the foramen of Winslow. The clinical presentation of patients with an internal hernia is often vague and difficult to diagnose clinically. If internal hernias go undiagnosed and untreated, patients can develop bowel compromise leading to a high morbidity and potential mortality. Radiologic imaging is helpful in bringing the diagnosis to the forefront of the clinicians mind, but the diagnosis is often made intra-operatively. PRESENTATION OF CASE: An eighty-one year old female presenting with a few months of vague abdominal symptoms who was found to have a cecal bascule internally herniating through the foramen of Winslow was treated successfully with surgical intervention. DISCUSSION: Internal hernias occur when there is a protrusion of a viscera through the peritoneum or mesentery and confined within the abdominal cavity. Internal hernias are classified according to location and vary from paraduodenal, transmesenteric, and pelvic to name a few. Hernias through the foramen of Winslow are a rare subset, and were the internal hernia found in our patient intra-operatively. Our patient's clinical presentation was vague with generic abdominal complaints and radiologic imaging was inconclusive for a definitive diagnosis. However, prompt surgical intervention resulted in a good outcome for our patient. CONCLUSION: Internal hernias, to be diagnosed and treated promptly, require a high index of suspicion from a clinician based on clinical presentation and radiologic imaging. These patients belong in the operating room, and interventions are directed based on the anatomical findings intra-operatively.

Factors Associated With Patient-Centered Medical Home Teams' Use of Resources for Identifying and Approaches for Managing Patients With Complex Needs.

Using data from a Veterans Health Administration national primary care survey, this study identified the most highly rated tools and care approaches for patients with complex needs and how preferences varied by professional role, staffing, and training. Nurses were significantly more likely to rate most tools as very important as compared with primary care providers. Having a fully staffed team was also significantly associated with a very important rating on all tools. Nurses and fully staffed teams reported a greater likeliness to use most care approaches, and those with perceived need for training reporting a lower likeliness to use.

Beyond antipsychotics: a twenty-first century update for preclinical development of schizophrenia therapeutics.

Despite 50+ years of drug discovery, current antipsychotics have limited efficacy against negative and cognitive symptoms of schizophrenia, and are ineffective-with the exception of clozapine-against any symptom domain for patients who are treatment resistant. Novel therapeutics with diverse non-dopamine D2 receptor targets have been explored extensively in clinical trials, yet often fail due to a lack of efficacy despite showing promise in preclinical development. This lack of translation between preclinical and clinical efficacy suggests a systematic failure in current methods that determine efficacy in preclinical rodent models. In this review, we critically evaluate rodent models and behavioural tests used to determine preclinical efficacy, and look to clinical research to provide a roadmap for developing improved translational measures. We highlight the dependence of preclinical models and tests on dopamine-centric theories of dysfunction and how this has contributed towards a self-reinforcing loop away from clinically meaningful predictions of efficacy. We review recent clinical findings of distinct dopamine-mediated dysfunction of corticostriatal circuits in patients with treatment-resistant vs. non-treatment-resistant schizophrenia and suggest criteria for establishing rodent models to reflect such differences, with a focus on objective, translational measures. Finally, we review current schizophrenia drug discovery and propose a framework where preclinical models are validated against objective, clinically informed measures and preclinical tests of efficacy map onto those used clinically.

Psychosocial determinants of anxiety about the COVID-19 pandemic.

Pandemic health threats can cause considerable anxiety, but not all individuals react similarly. To understand the sources of this variability, we applied a theoretical model developed during the H1N1 pandemic of 2009 to quantify relationships among intolerance of uncertainty, stress appraisals, and coping style that predict anxiety about the COVID-19 pandemic. We surveyed 1579 U.S. Amazon Mechanical Turk workers in April 2020. Using structural equation modeling, we found that individuals who were more intolerant of uncertainty reported higher appraisals of threat, stress, and other-control, which predicted higher anxiety when emotion-focused coping was engaged, and lower anxiety when problem-focused coping was engaged. Political affiliation moderated these effects, such that conservatives relied more on self-control and other-control appraisals to mitigate anxiety than independents or liberals. These results show that how people appraise and cope with their stress interacts with political ideology to shape anxiety in the face of a global health threat.

The Primary Care Analytics Team: Integrating research and clinical care within the Veterans Health Administration Office of Primary Care.

By designing and evaluating health system improvements and providing evidence to clinical decision-makers, embedded researchers are a critical part of a Learning Health System (LHS). In this article, we describe the evolution and mission of the Primary Care Analytics Team (PCAT), an integrated research team within the Veterans Health Administration Office of Primary Care. We discuss challenges and strategies for success in working with clinical operations partners and provide recommendations for other Learning Health Systems units embedded in large integrated health care organizations.

CRISPR/Cas9 mediated deletion of the adenosine A2A receptor enhances CAR T cell efficacy.

Adenosine is an immunosuppressive factor that limits anti-tumor immunity through the suppression of multiple immune subsets including T cells via activation of the adenosine A2A receptor (A2AR). Using both murine and human chimeric antigen receptor (CAR) T cells, here we show that targeting A2AR with a clinically relevant CRISPR/Cas9 strategy significantly enhances their in vivo efficacy, leading to improved survival of mice. Effects evoked by CRISPR/Cas9 mediated gene deletion of A2AR are superior to shRNA mediated knockdown or pharmacological blockade of A2AR. Mechanistically, human A2AR-edited CAR T cells are significantly resistant to adenosine-mediated transcriptional changes, resulting in enhanced production of cytokines including IFNγ and TNF, and increased expression of JAK-STAT signaling pathway associated genes. A2AR deficient CAR T cells are well tolerated and do not induce overt pathologies in mice, supporting the use of CRISPR/Cas9 to target A2AR for the improvement of CAR T cell function in the clinic.

Non-Surgical Interventions for Lumbar Spinal Stenosis Leading To Neurogenic Claudication: A Clinical Practice Guideline.

Lumbar spinal stenosis (LSS) causing neurogenic claudication (NC) is increasingly common with an aging population and can be associated with significant symptoms and functional limitations. We developed this guideline to present the evidence and provide clinical recommendations on nonsurgical management of patients with LSS causing NC. Using the GRADE approach, a multidisciplinary guidelines panel based recommendations on evidence from a systematic review of randomized controlled trials and systematic reviews published through June 2019, or expert consensus. The literature monitored up to October 2020. Clinical outcomes evaluated included pain, disability, quality of life, and walking capacity. The target audience for this guideline includes all clinicians, and the target patient population includes adults with LSS (congenital and/or acquired, lateral recess or central canal, with or without low back pain, with or without spondylolisthesis) causing NC. The guidelines panel developed 6 recommendations based on randomized controlled trials and 5 others based on professional consensus, summarized in 3 overarching recommendations: (Grade: statements are all conditional/weak recommendations) Recommendation 1. For patients with LSS causing NC, clinicians and patients may initially select multimodal care nonpharmacological therapies with education, advice and lifestyle changes, behavioral change techniques in conjunction with home exercise, manual therapy, and/or rehabilitation (moderate-quality evidence), traditional acupuncture on a trial basis (very low-quality evidence), and postoperative rehabilitation (supervised program of exercises and/or educational materials encouraging activity) with cognitive-behavioral therapy 12 weeks postsurgery (low-quality evidence). Recommendation 2. In patients LSS causing NC, clinicians and patients may consider a trial of serotonin-norepinephrine reuptake inhibitors or tricyclic antidepressants. (very low-quality evidence). Recommendation 3. For patients LSS causing NC, we recommend against the use of the following pharmacological therapies: nonsteroidal anti-inflammatory drugs, methylcobalamin, calcitonin, paracetamol, opioids, muscle relaxants, pregabalin (consensus-based), gabapentin (very low-quality), and epidural steroidal injections (high-quality evidence). PERSPECTIVE: This guideline, on the basis of a systematic review of the evidence on the nonsurgical management of lumbar spine stenosis, provides recommendations developed by a multidisciplinary expert panel. Safe and effective non-surgical management of lumbar spine stenosis should be on the basis of a plan of care tailored to the individual and the type of treatment involved, and multimodal care is recommended in most situations.

Baseline, retest, and post-injury profiles of auditory neural function in collegiate football players.

OBJECTIVES: Recent retrospective studies report differences in auditory neurophysiology between concussed athletes and uninjured controls using the frequency-following response (FFR). Adopting a prospective design in college football players, we compared FFRs before and after a concussion and evaluated test-retest reliability in non-concussed teammates. DESIGN: Testing took place in a locker room. We analysed the FFR to the fundamental frequency (F0) (FFR-F0) of a speech stimulus, previously identified as a potential concussion biomarker. Baseline FFRs were obtained during the football pre-season. In athletes diagnosed with concussions during the season, FFRs were measured days after injury and compared to pre-season baseline. In uninjured controls, comparisons were made between pre- and post-season. STUDY SAMPLE: Participants were Tulane University football athletes (n = 65). RESULTS: In concussed athletes, there was a significant group-level decrease in FFR-F0 from baseline (26% decrease on average). By contrast, the control group's change from baseline was not statistically significant, and comparisons of pre- and post-season had good repeatability (intraclass correlation coefficient = 0.75). CONCLUSIONS: Results converge with previous work to evince suppressed neural function to the FFR-F0 following concussion. This preliminary study paves the way for larger-scale clinical evaluation of the specificity and reliability of the FFR as a concussion diagnostic.HighlightsThis prospective study reveals suppressed neural responses to sound in concussed athletes compared to baseline.Neural responses to sound show good repeatability in uninjured athletes tested in a locker-room setting.Results support the feasibility of recording frequency-following responses in non-laboratory conditions.

Translation-Focused Approaches to GPCR Drug Discovery for Cognitive Impairments Associated with Schizophrenia.

There are no effective therapeutics for cognitive impairments associated with schizophrenia (CIAS), which includes deficits in executive functions (working memory and cognitive flexibility) and episodic memory. Compounds that have entered clinical trials are inadequate in terms of efficacy and/or tolerability, highlighting a clear translational bottleneck and a need for a cohesive preclinical drug development strategy. In this review we propose hippocampal-prefrontal-cortical (HPC-PFC) circuitry underlying CIAS-relevant cognitive processes across mammalian species as a target source to guide the translation-focused discovery and development of novel, procognitive agents. We highlight several G protein-coupled receptors (GPCRs) enriched within HPC-PFC circuitry as therapeutic targets of interest, including noncanonical approaches (biased agonism and allosteric modulation) to conventional clinical targets, such as dopamine and muscarinic acetylcholine receptors, along with prospective novel targets, including the orphan receptors GPR52 and GPR139. We also describe the translational limitations of popular preclinical cognition tests and suggest touchscreen-based assays that probe cognitive functions reliant on HPC-PFC circuitry and reflect tests used in the clinic, as tests of greater translational relevance. Combining pharmacological and behavioral testing strategies based in HPC-PFC circuit function creates a cohesive, translation-focused approach to preclinical drug development that may improve the translational bottleneck currently hindering the development of treatments for CIAS.

Intrathecal catheter implantation decreases cerebrospinal fluid dynamics in cynomolgus monkeys.

A detailed understanding of the CSF dynamics is needed for design and optimization of intrathecal drug delivery devices, drugs, and protocols. Preclinical research using large-animal models is important to help define drug pharmacokinetics-pharmacodynamics and safety. In this study, we investigated the impact of catheter implantation in the sub-dural space on CSF flow dynamics in Cynomolgus monkeys. Magnetic resonance imaging (MRI) was performed before and after catheter implantation to quantify the differences based on catheter placement location in the cervical compared to the lumbar spine. Several geometric and hydrodynamic parameters were calculated based on the 3D segmentation and flow analysis. Hagen-Poiseuille equation was used to investigate the impact of catheter implantation on flow reduction and hydraulic resistance. A linear mixed-effects model was used in this study to investigate if there was a statistically significant difference between cervical and lumbar implantation, or between two MRI time points. Results showed that geometric parameters did not change statistically across MRI measurement time points and did not depend on catheter location. However, catheter insertion did have a significant impact on the hydrodynamic parameters and the effect was greater with cervical implantation compared to lumbar implantation. CSF flow rate decreased up to 55% with the catheter located in the cervical region. The maximum flow rate reduction in the lumbar implantation group was 21%. Overall, lumbar catheter implantation disrupted CSF dynamics to a lesser degree than cervical catheter implantation and this effect remained up to two weeks post-catheter implantation in Cynomolgus monkeys.

Differential GLP-1R Binding and Activation by Peptide and Non-peptide Agonists.

Peptide drugs targeting class B1 G-protein-coupled receptors (GPCRs) can treat multiple diseases; however, there remains substantial interest in the development of orally delivered non-peptide drugs. Here, we reveal unexpected overlap between signaling and regulation of the glucagon-like peptide-1 (GLP-1) receptor by the non-peptide agonist PF 06882961 and GLP-1 that was not observed for another compound, CHU-128. Compounds from these patent series, including PF 06882961, are currently in clinical trials for treatment of type 2 diabetes. High-resolution cryoelectron microscopy (cryo-EM) structures reveal that the binding sites for PF 06882961 and GLP-1 substantially overlap, whereas CHU-128 adopts a unique binding mode with a more open receptor conformation at the extracellular face. Structural differences involving extensive water-mediated hydrogen bond networks could be correlated to functional data to understand how PF 06882961, but not CHU-128, can closely mimic the pharmacological properties of GLP-1. These findings will facilitate rational structure-based discovery of non-peptide agonists targeting class B GPCRs.

Proximal threats promote enhanced acquisition and persistence of reactive fear-learning circuits.

Physical proximity to a traumatic event increases the severity of accompanying stress symptoms, an effect that is reminiscent of evolutionarily configured fear responses based on threat imminence. Despite being widely adopted as a model system for stress and anxiety disorders, fear-conditioning research has not yet characterized how threat proximity impacts the mechanisms of fear acquisition and extinction in the human brain. We used three-dimensional (3D) virtual reality technology to manipulate the egocentric distance of conspecific threats while healthy adult participants navigated virtual worlds during functional magnetic resonance imaging (fMRI). Consistent with theoretical predictions, proximal threats enhanced fear acquisition by shifting conditioned learning from cognitive to reactive fear circuits in the brain and reducing amygdala-cortical connectivity during both fear acquisition and extinction. With an analysis of representational pattern similarity between the acquisition and extinction phases, we further demonstrate that proximal threats impaired extinction efficacy via persistent multivariate representations of conditioned learning in the cerebellum, which predicted susceptibility to later fear reinstatement. These results show that conditioned threats encountered in close proximity are more resistant to extinction learning and suggest that the canonical neural circuitry typically associated with fear learning requires additional consideration of a more reactive neural fear system to fully account for this effect.