Liu, Danting

Abstract Peanut allergy is a leading cause of food-induced allergy (prevalence of ∼1%). The diagnosis relies on evaluating clinical symptoms consistent with peanut exposure, supported by the detection of total peanut specific IgE (sIgE) and peanut component IgE antibodies (Ara h1, Ara h2, Ara h3, Ara h6, Ara h8, Ara h9 and Bet v2) through serum or skin testing. However, sensitization patterns across different ages and regions in the United States remain largely unknown. In this study, we investigated regional and demographic patterns of peanut component sensitization in a large U.S. population tested for suspected peanut allergy. Retrospective data were collected from 13,702 individuals tested at Mayo Clinic Laboratories. sIgEs were measured using the ImmunoCAP system (Thermo Fisher Scientific). Samples with detectable total peanut sIgE (≥0.1 kU/L) were reflexed to testing for seven peanut component IgEs. Statistical analyses including linear regression and correlation matrix analysis were conducted using R Studio. Regional differences were assessed using care provider zip code information. Among the study population, 92.0% (12,604 of 13,702) had detectable total peanut sIgE, with the Western U.S. region exhibiting the highest detectable rate (95.6%), and the Southeast the lowest (85.6%) (p < 0.001). On average, 3.38 different component IgEs were detectable per person with a detectable total peanut sIgE; 7.1% (892) had no detectable component IgEs, possibly due to antibodies against other peanut components. Correlation analysis revealed strong associations between Ara h2 and Ara h6 (r = 0.94), with moderate correlations observed between Ara h2, Ara h3, and Ara h6 to Ara h1 (r ranging from 0.72 to 0.77). Age-stratified analysis indicated higher total peanut sIgE detectable rates in children and adolescents (95.2%, ≤18 years) compared to adults (76.5%, >18 years). Interestingly, adults were more likely than children to have negative results for all component IgEs. Sensitization rates to different peanut components varied, with Ara h2 (77.5%) and Ara h6 (73.2%) being the most frequently detected, followed by Ara h1 (56%), and Ara h3 (47.3%). Lower detectable rates were observed for Ara h8, Ara h9, and Bet v2 (34.8%, 26.1% and 22.7%, respectively). Regional analysis showed consistently high detectable rates for Ara h2 and Ara h6 (>70%) across most areas (p < 0.001) with slightly lower rates in the Southwest (<63%). Bet v2, despite its overall low prevalence (<24%), had a relatively higher detectable rate in the Southwest (29%). This study provides valuable insights into potential demographic and geographic factors influencing peanut allergy sensitization. Our study demonstrates that peanut sensitization patterns vary by age and geographic location. Children and adolescents exhibit higher detectable rates for total peanut sIgE and component IgEs compared to adults, with Ara h2 and Ara h6 as the most frequently detected and highly correlated components.

Abstract Background Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers, including the Aß42/40 and p-tau181/Aß42 ratios, are used in clinical practice to detect the presence of amyloid pathology for the diagnosis of AD. However, in some instances, discrepancies between Aß42/40 and p-tau181/Aß42 are observed. Such discrepancies may introduce uncertainties in the clinical management of patients presenting with cognitive decline. Identifying the underlying causes of these discrepancies and determining which biomarker abnormalities better predict disease progression is crucial to enhancing confidence in the use of these CSF biomarkers for the diagnosis of AD. This study aims to investigate the discordance between the Aß42/40 and p-tau181/Aß42 ratios, evaluate the frequency of these discrepancies, and identify potential causes. Methods Data from 958 individuals who had both CSF Aß42/40 and p-tau181/Aß42 tested at Mayo Clinic Laboratories between 2022 and 2024 and where the tests were ordered in CSF collected during the same lumbar puncture procedure were included. Cases with an inadequate sample collection, which could cause a false decrease in Aß42 concentrations, were excluded from the analysis. Aß42/40 was measured using the Fujirebio LUMIPULSE assays and reported as negative, likely positive, or positive. For this analysis, likely positive and positive results were combined and considered as positive (<0.072). P-tau181/Aß42 was measured using the Roche Elecsys assays and above 0.028 was considered positive. Statistical analyses were conducted using R Studio. Results Aß42/40 was positive in 69.1% of cases (n=661), while p-tau181/Aß42 was positive in 62.1% (n=594). There were 8.0% discordant cases (n=77). Most frequently, the discordant cases had an abnormal Aß42/40 with a normal p-tau181/Aß42 (Aß42/40+/p-tau181/Aß42-; n=72, 94%). Compared to the concordant Aß42/40+/p-tau181/Aß42+ group, the discordant Aß42/40+/p-tau181/Aß42- group showed significantly higher Aß42 concentrations (p <0.001, median [pg/mL]: 878.5 vs 587.0, respectively); whereas p-tau181 concentrations were significantly lower (p <0.001, median [pg/mL]: 19.3 vs 32.1, respectively). Among the Aß42/40+/p-tau181/Aß42- group, 30 cases exhibited abnormally low Aß42 and normal p-tau181, possibly reflecting early-stage AD. There were 41 cases with a normal Aß42 concentration despite an abnormal Aß42/40, possibly reflecting an overall higher production of Aß peptides resulting in an increased Aß40 peptide (median [pg/mL]: 12627 compared to 9487 in the low Aß42 and normal p-tau181 cases (n=30); p <0.001). Of these 41, 19 showed normal Aß42 but elevated p-tau181 concentrations where the use of Aß42/40 compensated for the overall higher production of Aß peptides, resulting in an abnormal ratio. In contrast, the p-tau181/Aß42 ratio was not able to normalize for these differences, leading to a normal ratio. Conclusion While overall concordance was 92.0%, our findings suggest that discrepancies between CSF Aß42/40 and p-Tau181/Aß42 are more often due to the presence of an abnormal Aß42/40 and a normal p-Tau181/Aß42. Two potential explanations for these discrepancies are early-stage AD or higher production of Aß peptides in some individuals. In the latter, differences in amyloid production would be normalized by ratios of the same biomarker (i.e. Aß42/40) but not by ratios of different biomarkers (i.e. p-Tau181/Aß42).

Abstract Background Celiac disease (CeD) is a chronic autoimmune disorder that can affect people of any age. Both ingestion of gluten and the presence of human leukocyte antigens (HLA)-DQ2 or DQ8 are required for disease development. In adults, correlation between HLA-DQ2/DQ8 allele combinations and tissue transglutaminase (tTG) antibody positivity has been well described. In comparison, this association in pediatric patients is less defined. In this study, we evaluated the roles of HLA-DQ2 and HLA-DQ8 as predictors of tTG-IgA positivity in a pediatric cohort, aiming to enhance understanding of CeD risk assessment in this diagnostic group. Methods Retrospective data were collected from individuals who underwent CeD diagnostic testing at Mayo Clinic Laboratories between 2011 and 2024; all patients were tested for total IgA, HLA-DQ typing, and tTG-IgA. Total IgA was measured using quantitative nephelometry on the BN™ II System (Siemens); HLA-DQ typing was performed using reverse sequence-specific oligonucleotide (SSO) DNA typing (LABType SSO kits, One Lambda, Thermo). tTG-IgA was tested using an enzyme-linked immunosorbent assay (QUANTA Lite® h-tTG IgA, Werfen Diagnostics). Those with total IgA below the age-specific reference interval were excluded from this analysis. Logistic regression was used to evaluate the association between HLA-DQ haplotypes and tTG-IgA positivity to assess the risk gradient across different HLA-DQ genotypes in children. Results The cohort identified in this study consisted of 115,499 individuals for whom total IgA, HLA-DQ typing and tTG-IgA testing was performed. Within this cohort, 20,676 (17.9%) were pediatric patients (age<=18 at the time of testing). Pediatric patients tested for CeD exhibited a slightly higher prevalence of at least one copy of HLA-DQ2 or DQ8 compared to adults (57.6% vs 55.4%, p<0.001). Additionally, these patients showed significantly higher rates of tTG-IgA positive across all genotypes, particularly those carrying HLA-DQ2.5 or DQ8, with positivity rates 1.2 to 2.3 times higher than in adults (p<=0.01). However, in non-permissive genotypes, the positivity rates were 0.3% (p=0.95), for both populations, indicating comparable specificity. Individuals with homozygous HLA-DQ2.5/DQ2.5 and HLA-DQ2.5/DQ2.2 showed the highest risks for tTG-IgA positivity with ORs of 85.7 (95% CI: 55.1-137.7) and 78.5 (95% CI: 51.3-124.3), respectively. Moderate risk was observed for HLA-DQ2.5/DQ8 with an OR of 49.0 (95% CI: 32.1-77.3), followed by single copy HLA-DQ2.5 (OR=35.0, 95% CI: 24.0-53.4) and homozygous HLA-DQ8/DQ8 (OR=21.7, 95% CI: 11.7-39.4). Although single copies of HLA-DQ2.2 and HLA-DQ8 showed lower risks with ORs of 5.4 and 8.9 (95% CI: 3.2-9.2 and 5.7–13.9), their combination increased the OR to 22.6 (95% CI: 13.0-39.2), similar to homozygous HLA-DQ8. Conclusion This large cohort study demonstrates the predictive value of HLA-DQ genotypes for pediatric CeD seropositivity. Notably, pediatric patients showed slightly higher prevalence and positivity rates compared to adults, particularly among those with homozygous HLA-DQ2.5/DQ2.5 and HLA-DQ2.5/DQ2.2 genotypes, which exhibited the highest risks for tTG-IgA positivity. The findings confirm that HLA-DQ2.5 is the main driver of serology positivity and suggest that HLA-DQ8 also influences serological positivity in pediatric patients, which can enhance targeted screening and potentially inform decisions regarding the necessity of duodenal biopsy.