The hook effect is a well-described but clinically underappreciated immunoassay interference, where a falsely lowered result is caused by analyte excess. We describe a situation in which ferritin immunoassay results from a 27-year-old female with immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome were more than 1000 times lower at a reference laboratory than those determined in-house after dilution. This case underscores the importance for clinical care providers to be aware of the impact of the hook effect on ferritin measurements, and to promptly communicate with the laboratory when there are discrepancies between clinical symptoms and test results.

Objectives This article describes Pathologists Overseas (PO) experience supporting external quality assessment (EQA) programs in 10 clinical laboratories across 3 countries between 2009 and 2017. Methods Laboratories were enrolled in the condensed chemical pathology EQA program provided by the Royal College of Pathologists of Australasia Quality Assurance Program. Participants were given an initial 2- to 4-day in-person training, followed by 1 year of active feedback on performance via emails or phone calls by a PO volunteer. Results There were 2 performance metrics: percentage of reported results as a measure of compliance and percentage of acceptable reported results as a measure of accuracy. Laboratories demonstrated high compliance with result reporting, with medians of 69.9%, 71.7%, and 81.3% before, during, and after feedback, respectively. Concomitant medians for the percentage of acceptable reported results were 41.2%, 57.3%, and 53.5%, respectively. Six laboratories had low performance in terms of accuracy at baseline (<60%). Active feedback improved the percentage of acceptable reported results for these lower-performing laboratories. Conclusions External quality assessment programs can be successfully adopted long term by laboratories in low-resource settings. Active feedback requires significant time and effort but could be especially beneficial for laboratories with poor baseline performance.

BACKGROUND:Systemic allergic reactions (sARs) following coronavirus disease 2019 (COVID-19) mRNA vaccines were initially reported at a higher rate than after traditional vaccines. OBJECTIVE:We aimed to evaluate the safety of revaccination in these individuals and to interrogate mechanisms underlying these reactions. METHODS:In this randomized, double-blinded, phase 2 trial, participants aged 16 to 69 years who previously reported a convincing sAR to their first dose of COVID-19 mRNA vaccine were randomly assigned to receive a second dose of BNT162b2 (Comirnaty) vaccine and placebo on consecutive days in a blinded, 1:1 crossover fashion at the National Institutes of Health. An open-label BNT162b2 booster was offered 5 months later if the second dose did not result in severe sAR. None of the participants received the mRNA-1273 (Spikevax) vaccine during the study. The primary end point was recurrence of sAR following second dose and booster vaccination; exploratory end points included biomarker measurements. RESULTS:Of 111 screened participants, 18 were randomly assigned to receive study interventions. Eight received BNT162b2 second dose followed by placebo; 8 received placebo followed by BNT162b2 second dose; 2 withdrew before receiving any study intervention. All 16 participants received the booster dose. Following second dose and booster vaccination, sARs recurred in 2 participants (12.5%; 95% CI, 1.6 to 38.3). No sAR occurred after placebo. An anaphylaxis mimic, immunization stress-related response (ISRR), occurred more commonly than sARs following both vaccine and placebo and was associated with higher predose anxiety scores, paresthesias, and distinct vital sign and biomarker changes. CONCLUSIONS:Our findings support revaccination of individuals who report sARs to COVID-19 mRNA vaccines. Distinct clinical and laboratory features may distinguish sARs from ISRRs.

Background Thymic epithelial tumors (TETs) are associated with defects of the immune system which can increase the risk of infections and compromise the efficacy of vaccines.1 2 Limited data are available on the effectiveness of SARS-CoV-2 vaccines in patients with TETs.3–5 To further characterize the immunogenicity of SARS-CoV-2 mRNA vaccines in patients with TETs, we measured antibody and T-cell-specific immune responses and compared these results with a fully vaccinated population of individuals employed in a healthcare setting. Methods Twenty-two individuals with TETs enrolled in an NIH IRB-approved clinical trial (NCT02146170) and a control cohort of 57 healthcare personnel presenting for vaccination were included in this study. All participants had received two doses of a SARS-CoV-2 mRNA vaccine (BNT162b2 or mRNA-1273) and 8 individuals with TET had received a booster dose. Individuals with paraneoplastic autoimmunity and patients receiving anticancer therapy or immunosuppressive medicines were included. A known history of prior COVID-19 infection was an exclusion factor. Plasma samples were analyzed for SARS-CoV-2 anti-spike (S) antibody (ab), anti-nucleocapsid (N) ab, and neutralizing abs using the Roche anti-SARS-CoV-2-S/anti-SARS-CoV-2-N immunoassays, and the Imanis IMMUNO-COV SARS-CoV-2 Neutralizing Antibody Test, respectively. Peripheral blood mononuclear cells collected after booster vaccination were analyzed for T-cell-specific immune responses. Continuous variables were analyzed using Wilcoxon rank sum tests and Spearman correlations, and Fisher's exact test was used for comparison of categorical features. Results Baseline characteristics are presented in table 1. Anti-N abs were absent in all individuals tested (TET = 12, Controls = 57), confirming absence of prior SARS-CoV-2 infection. Ab responses to vaccination are presented in table 2. There was no statistical difference in log(anti-S) ab titers between the TET and control groups (p=0.40). Neutralizing abs were detected in all evaluable participants with thymic carcinoma (6/6) versus 70% with thymoma (7/10). Clinical correlates of response in the TET cohort included vaccine type (BNT162b2 or mRNA-1273; p=0.0052), paraneoplastic autoimmunity (p=0.0085), and immunosuppressant use (p=0.031). CD3 and CD19 counts had strong, positive correlations with log(anti-S) ab titers (ρ = 0.70 and ρ = 0.81, respectively). Six of 8 participants with TETs had an increase in anti-S ab titers in response to booster vaccination. T-cell responses to vaccination are under analysis and will be reported. Conclusions A majority of patients with TETs have a demonstrable response to COVID-19 mRNA vaccines, which is influenced by clinical and biological factors including vaccine type, paraneoplastic autoimmunity, immunosuppressant use, and lymphocyte subsets (CD3 and CD19). Acknowledgements This research was supported in part by the intramural research program of the Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health. References Multani A, Gomez CA, Montoya JG. Prevention of infectious disease in patients with Good syndrome. Curr Opin Infect Dis. 2018;31(4):266–277. Martinez B, Browne, SK. Good syndrome, bad problem. Front Oncol. 2014;4:307. Delmonte OM, Bergerson JRE, Burbelo PD, et al. Antibody responses to the SARS-CoV-2 vaccine in individuals with various inborn errors of immunity. J Allergy Clin Immunol. 2021;148(5):1192–1197. Koller A, Szebeni J. Covid-19 vaccines elicit effective IgG responses in an elderly thymus cancer patient with chemotherapy. Hum Vaccin Immunother. 2023;19(1):2188035. Pietroluongo E, De Placido P, Morra, R, et al. Impaired seroconversion after SARS-CoV-2 mRNA vaccine in patients with thymic epithelial tumors. J Clin Oncol. 2022;40(16_suppl):8588–8588. Ethics Approval All patients with TETs included in this study provided written informed consent for participation in a clinical trial that was approved by the National Institutes of Health Institutional Review Board (NIH IRB) (ClinicalTrials ID: NCT02146170; NCI Clinical Trial ID: 14-C-0105). Use of samples from individuals in the control group was deemed exempt by the NIH IRB.

For thirty years Pathologists Overseas (PO) has worked in low- and middle-income countries (LMICs) to provide affordable, sustainable, and high-quality pathology and laboratory medicine (PALM) services through strategic partnerships and the efforts of our large volunteer network. We address low quality diagnostic services by targeting the 3 pillars of PALM quality: human resources, systems, and quality and accreditation. To improve human resource capacity, PO and our partnering organizations provide virtual continuing education to pathologists and laboratory professionals in these countries. To improve systems, we provide laboratory information system installation and implementation support. Lastly, to improve quality and help laboratories progress toward accreditation, we support an external quality assurance program for laboratories in LMICs. As a relatively small organization, PO demonstrates that a network of dedicated volunteers, in partnership with corporations and professional organizations, can initiate sustainable change in the quality of PALM services in LMICs by focusing efforts on the core components of laboratory quality.

OBJECTIVES Despite extensive research on procalcitonin (PCT)-guided therapy in lower respiratory tract infections, the association between PCT and bacterial pneumonia remains unclear. METHODS We evaluated retrospectively the performance of PCT in patients presenting with lower respiratory tract infection symptoms and grouped by seven diagnoses. All patients had microbial testing, chest imaging, and CBC counts within 1 day of PCT testing. RESULTS Median PCT level in patients diagnosed with bacterial pneumonia was significantly higher than in patients diagnosed with other sources of infections or those not diagnosed with infections. Median PCT levels were not different among patients grouped by type or quantity of pathogen detected. They were significantly higher in patients with higher pathogenicity scores for isolated bacteria, those with abnormal WBC count, and those with chest imaging consistent with bacterial pneumonia. A diagnostic workup that included imaging, WBC count, and Gram stain had an area under the receiver operating characteristic curve of 0.748, and the addition of PCT increased it to 0.778. CONCLUSIONS PCT was higher in patients diagnosed with bacterial pneumonia. Less clear is its diagnostic ability to detect bacterial pneumonia over and above imaging and laboratory data routinely available to clinicians.

OBJECTIVESWe developed and participated in a 1-week laboratory medicine training presented from June 3, 2019, to June 7, 2019.METHODSThe training was a combination of daily morning lectures and case presentations as well as afternoon practical sessions in the clinical laboratory. The content was selected over months by local organizers and the visiting faculty and further modified on site to reflect local needs.RESULTSParticipants identified practice changes that could be realized in the short term but most faced significant barriers to implementation in the absence of structured and long-term follow-up.CONCLUSIONSIn this report, we review insights learned from our experience and reflect on strategies for realistic, meaningful, and relevant contributions in the setting of laboratory medicine-oriented short-term programs.

Objectives: Thyroid dysfunction in pregnancy is associated with increased risk of adverse outcomes to mother and child. Trimester-specific reference intervals for thyroid function tests are not routinely provided by clinical laboratories. In this study, we present first- and second-trimester-specific reference intervals in a US population for thyroid-stimulating hormone (TSH), free thyroxine (FT4), total thyroxine (T4), and total triiodothyronine (T3) measured on Roche analyzers. Methods: We used patient samples from first- and second-trimester prenatal screening. Samples were limited to singleton pregnancies and negative screening results for thyroid peroxidase and thyroglobulin antibodies. Analytes (TSH, FT4, T4, and T3) were measured on a Roche Modular e170 then verified on a Roche cobas e801. Results: The reference intervals established on the e170 and verified on the e801 for the first trimester were 0.16 to 2.82 mIU/L for TSH, 12.0 to 18.5 pmol/L for FT4, 62.8 to 177.9 nmol/L for T4, and 1.5 to 3.4 nmol/L for T3. The reference intervals for the second trimester were 0.40 to 3.62 mIU/L for TSH, 10.2 to 16.6 pmol/L for FT4, 66.6 to 176.0 nmol/L for T4, and 1.56 to 3.6 nmol/L for T3. Conclusions: This is the first report of trimester-specific reference intervals for thyroid function tests on Roche analyzers in the United States, and it is consistent with worldwide reports.

To the Editor.—Three coronavirus disease 2019 (COVID-19) vaccines targeting the viral spike protein (S)1 have received US Food and Drug Administration (FDA) Emergency Use Authorization (EUA).2 We measured levels of anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in adults after they received Moderna, Pfizer-BioNTech (Pfizer), or Janssen/Johnson & Johnson (J&J) vaccines.Between March and May 2021, we collected blood from 60 adults who had received at least 1 of 2 doses of Moderna (n = 48) or Pfizer (n = 6) vaccines or 1 dose of the J&J (n = 6) vaccine. Use of the samples was deemed exempt by the National Institutes of Health Institutional Review Board.Plasma was analyzed for antibodies using Roche anti–SARS-CoV-2-S and anti–SARS-CoV-2-nucleocapsid (N) immunoassays on a cobas-6000 analyzer. Both assays have FDA EUAs and measure immunoglobulin (Ig) G, IgA, and IgM against their target proteins. Twelve J&J specimens were additionally analyzed for anti-S using a luciferase immunoprecipitation system assay.3Participants had a median age of 46.2 years (range, 18–64 years) and 36 of the 60 participants (60%) were women. All Moderna (n = 48) vaccine recipients and all but 1 Pfizer vaccine recipients (n = 5) were positive for anti-S (Figure, A). This included 5 Moderna participants and 1 Pfizer participant who had received only 1 dose. All anti-N results were negative, except for 4 participants with history of SARS-CoV-2 infection (Figure, A).Moderna and Pfizer vaccines induced positive anti-S as early as 7 and 19 days, respectively, post–first shot. A Pfizer participant with sequential samples was negative at day 27 and positive at day 84 (Figure, B). In J&J vaccine recipients (Figure, C), 2 participants (participant [P] 1 and P2) negative at days 16 (P1) and 19 (P2) became positive by days 20 and 30, respectively. P3 and P4 were positive when first tested at days 19 and 20 postvaccine. All 4 participants showed increases in anti-S levels, reaching 250 U/mL or more and 227.6 U/mL or more in P2 and P3, respectively, on day 69. Two participants, P5 (positive) and P6 (negative), were only tested once, at day 26. The 12 J&J specimens analyzed with a different assay showed even fewer specimens positive for anti-S (n = 6) than the Roche assay (n = 9) (Figure, D).We found that nearly all vaccinated Moderna participants had anti-S levels that exceeded the upper limit of the Roche assay. By contrast, J&J vaccine recipients had anti-S levels that were negative or low 2 weeks after vaccination and gradually increased over time. Our results suggest that if J&J vaccine recipients were tested 2 weeks after vaccination, many may erroneously have been considered vaccine failures. It is possible that the commercial assay is insensitive, but there were even fewer positives with the immunoprecipitation assay. Alternatively, the J&J vaccine may induce an effective amnestic response, and/or another antibody or T-cell response may correlate with efficacy. Of note, the highly effective varicella vaccine induces antibody responses that are often not detected using commercial assays, and thus it is recommended that vaccinated patients not get tested.4 Our study is limited by the number of participants, particularly those who had received the Pfizer vaccine, which does not allow for strong conclusions regarding the similarities with or differences from Moderna or J&J in antibody temporal responses. Despite this limitation, the repeated testing of J&J participants indicates that measuring antibody levels within the first weeks of vaccination may give negative results and lead to unwarranted additional doses of vaccine.

Importance Low-density lipoprotein cholesterol (LDL-C), a key cardiovascular disease marker, is often estimated by the Friedewald or Martin equation, but calculating LDL-C is less accurate in patients with a low LDL-C level or hypertriglyceridemia (triglyceride [TG] levels >= 400 mg/dL). Objective To design a more accurate LDL-C equation for patients with a low LDL-C level and/or hypertriglyceridemia. Design, Setting, and Participants Data on LDL-C levels and other lipid measures from 8656 patients seen at the National Institutes of Health Clinical Center between January 1, 1976, and June 2, 1999, were analyzed by the beta-quantification reference method (18 715 LDL-C test results) and were randomly divided into equally sized training and validation data sets. Using TG and non-high-density lipoprotein cholesterol as independent variables, multiple least squares regression was used to develop an equation for very low-density lipoprotein cholesterol, which was then used in a second equation for LDL-C. Equations were tested against the internal validation data set and multiple external data sets of either beta-quantification LDL-C results (n = 28 891) or direct LDL-C test results (n = 252 888). Statistical analysis was performed from August 7, 2018, to July 18, 2019. Main Outcomes and Measures Concordance between calculated and measured LDL-C levels by beta-quantification, as assessed by various measures of test accuracy (correlation coefficient [R-2], root mean square error [RMSE], mean absolute difference [MAD]), and percentage of patients misclassified at LDL-C treatment thresholds of 70, 100, and 190 mg/dL. Results Compared with beta-quantification, the new equation was more accurate than other LDL-C equations (slope, 0.964; RMSE = 15.2 mg/dL; R-2 = 0.9648; vs Friedewald equation: slope, 1.056; RMSE = 32 mg/dL; R-2 = 0.8808; vs Martin equation: slope, 0.945; RMSE = 25.7 mg/dL; R-2 = 0.9022), particularly for patients with hypertriglyceridemia (MAD = 24.9 mg/dL; vs Friedewald equation: MAD = 56.4 mg/dL; vs Martin equation: MAD = 44.8 mg/dL). The new equation calculates the LDL-C level in patients with TG levels up to 800 mg/dL as accurately as the Friedewald equation does for TG levels less than 400 mg/dL and was associated with 35% fewer misclassifications when patients with hypertriglyceridemia (TG levels, 400-800 mg/dL) were categorized into different LDL-C treatment groups. Conclusions and Relevance The new equation can be readily implemented by clinical laboratories with no additional costs compared with the standard lipid panel. It will allow for more accurate calculation of LDL-C level in patients with low LDL-C levels and/or hypertriglyceridemia (TG levels, <= 800 mg/dL) and thus should improve the use of LDL-C level in cardiovascular disease risk management.

BACKGROUND:The anion gap is primarily used in the diagnosis of acid-base disorders. We conducted a study to determine the anion gap reference interval in our patient population, investigated the workup of abnormal vs normal anion gaps, and examined the anion gap variation upon repeated testing.METHODS:A retrospective review was performed on 17137 adult and pediatric patients who presented to Yale-New Haven Hospital outpatient clinics, emergency department, or intensive care units between 2012 and 2017.RESULTS:We derived a new reference interval of 7 to 18 mmol/L with a median of 13 mmol/L in healthy adults with no significant differences owing to partitioning by sex or age. Based on the new reference interval, 5%, 23%, and 18% of healthy, emergency department, and intensive care unit adult patients, respectively, were misclassified as having high values with the previous interval of 6 to 16 mmol/L. However, there were no significant differences in the number of tests ordered in patients with anion gaps above and below the upper limit of the previous reference interval. The majority of increased anion gaps that were repeated normalized by 12 h. In a subgroup of healthy adult patients with annual testing, the median percent change in each patient's anion gap from 2015 to 2016 was approximately 13%.CONCLUSIONS:The anion gap should be used with an appropriate reference interval to avoid misclassification. There may be a moderate degree of individuality that argues for comparing the anion gap with its baseline value in the same patient pending further studies that formally derive its biological variation.

OBJECTIVES:To apply a simple method to validate testing for albumin, glucose, lactate dehydrogenase (LDH) and total protein (TP) in peritoneal, pleural, and cerebrospinal fluids (CSF) at a hospital in Liberia.METHODS:Serum and body fluid specimens were mixed to create 100% serum and 25%, 50%, 75%, and 100% fluid tubes, which were tested on a Biotecnica BT3500. Differences less than 10% between calculated and measured concentrations were considered acceptable.RESULTS:The means (confidence intervals) of the percent differences were: albumin/peritoneal 12.8 (6.0-19.7), albumin/pleural 2.8 (1.3-4.2), albumin/CSF 4.8 (2.2-7.5), glucose/peritoneal 4.0 (1.9-6.0), glucose/pleural 4.4 (3.1-5.7), glucose/CSF 2.9 (1.8-4.0), LDH/peritoneal 9.5 (6.3-12.7), LDH/pleural 9.5 (5.4-13.6), LDH/CSF 9.2 (5.2-13.3), TP/peritoneal 7.6 (3.8-11.4), TP/pleural 3.8 (1.5-6.2), and TP/CSF 4.5 (1.0-8.1).CONCLUSIONS:All mean differences except for one were less than 10%, allowing for the adoption of clinical testing. The mixing study is a low-cost method for quality-assured testing that can be performed by resource-limited laboratories.

Abstract Background Procalcitonin (PCT) rises early upon bacterial infection and has a long-half life, making it useful in the diagnosis of infections and antibiotic stewardship. We sought to determine the utility of PCT in diagnosing pneumonia (PNU) in the patient population presenting to our hospital during real-world clinical practice. Methods PCT results from patients in 2015 were reviewed retrospectively. Patients were eligible for inclusion if all of following criteria were met: PCT in 2015 and a lower respiratory tract culture, respiratory virus testing, chest x-ray, and white blood cell (WBC) count within 1 day of the PCT. Patients who opted out of research and those with mycobacterial infections and culture-positive infections of body sites other than urine and lower respiratory tract were excluded from further analysis. Results A total of 400 patients remained with 413 eligible PCT results across the ED (109), ICU (134), and inpatient (167) and outpatient (3) areas with a mean (SD) age of 66.2 (18.1). PCT was higher in patients with multiple pathogens reported on their respiratory cultures, direct fluorescence antibody (DFA), or PCR-based tests (mean ± SD = 2.43 ± 0.74 ng/mL; N = 32), than those with no pathogens reported (3.25 ± 1.13 ng/mL; N = 224; P < .05). Patients were grouped for the presence or absence of clinically defined PNU, according to a modification of the Centers for Disease Control (CDC) PNU1 criteria incorporating (1) chest x-ray results, (2) altered WBC number/altered mental status/fever, and (3) respiratory/breathing signs. PCT was higher in patients with clinically defined PNU, and the high PCTs were consistent with positive chest x-rays (criterion 1), and positive criterion 2 but not criterion 3. Incorporation of an elevated PCT >0.1 ng/mL into the PNU score slightly improved the area under the ROC curve (AUC) for the algorithm’s detection of PNU against the final clinical diagnosis (0.73 without PCT vs 0.76 with PCT). Furthermore, higher PCT was associated with higher 30-day and 1-year mortality. Conclusion PCT results were largely consistent with other markers of PNU such as imaging and CDC criterion 2, which suggests that PCT can be useful in evaluating for the presence of PNU. However, the PCT may not add additional information to assist in decision making above the already commonly ordered tests.

BACKGROUND:Waste persists in healthcare and negatively impacts patients. Clinicians have direct control over test ordering and ongoing international efforts to improve test utilisation have identified multifaceted approaches as critical to the success of interventions. Prior to 2015, Yale New Haven Health lacked a coherent strategy for laboratory test utilisation management.METHODS:In 2015, a system-wide laboratory formulary committee was formed at Yale New Haven Health to manage multiple interventions designed to improve test utilisation. We report here on specific interventions conducted between 2015 and 2017 including reduction of (1) obsolete or misused testing, (2) duplicate orders, and (3) daily routine lab testing. These interventions were driven by a combination of modifications to computerised physician order entry, test utilisation dashboards and physician education. Measurements included test order volume, blood savings and cost savings.RESULTS:Testing for a number of obsolete/misused analytes was eliminated or significantly decreased depending on alert rule at order entry. Hard stops significantly decreased duplicate testing and educational sessions significantly decreased daily orders of routine labs and increased blood savings but the impact waned over time for select groups. In total, we realised approximately $100 000 of cost savings during the study period.CONCLUSION:Through a multifaceted approach to utilisation management, we show significant reductions in low-value clinical testing that have led to modest but significant savings in both costs and patients' blood.

Loss of glutamine synthetase (GS) in hippocampal astrocytes has been implicated in the causation of human mesial temporal lobe epilepsy (MTLE). However, the mechanism by which the deficiency in GS leads to epilepsy is incompletely understood. Here we ask how hippocampal GS inhibition affects seizure phenotype and neuronal activation during epilepsy development (epileptogenesis). Epileptogenesis was induced by infusing the irreversible GS blocker methionine sulfoximine (MSO) unilaterally into the hippocampal formation of rats. We then used continuous video-intracranial electroencephalogram (EEG) monitoring and c-Fos immunohistochemistry to determine the type of seizures and spatial distribution of neuronal activation early (1-5days postinfusion) and late (16-43days postinfusion) in epileptogenesis. Early in epileptogenesis, seizures were preferentially mild (stage 1-2), activating neurons in the entorhinal-hippocampal area, the basolateral amygdala, the piriform cortex, the midline thalamus, and the anterior olfactory area. Late in epileptogenesis, the seizures were generally more severe (stages 4-5) with neuronal activation extending to the neocortex, the bed nucleus of the stria terminalis, the mediodorsal thalamu\s, and the central nucleus of the amygdala. Our findings demonstrate that inhibition of GS focally in the hippocampal formation triggers a process of epileptogenesis characterized by gradual worsening of seizure severity and involvement of progressively larger neuronal populations over a period of several weeks. Knowledge about the underlying mechanism of epileptogenesis is important because such knowledge may result in more specific and efficacious treatments of MTLE by moving away from large and poorly specific surgical resections to highly targeted surgical or pharmacological interventions of the epileptogenic process.

Fear is a well-characterized biological response to threatening or stressful situations in humans and other social animals. Importantly, fearful stimuli in the natural environment are likely to be encountered concurrently by a group of animals. The modulation of fear acquisition and fear memory by a group as opposed to an individual experience, however, remains largely unknown. Here, we demonstrate a robust reduction in fear memory to an aversive event undertaken in a group despite similar fear learning between individually- and group-conditioned rats. This reduction persists outside the group confines, appears to be a direct outcome of group cognizance and is counteracted by loss of olfactory signaling among the group members. These results show that a group experience of fear can be protective and suggest that distinct neural pathways from those classically studied in individuals modulate collective fear memories.