Citations

Abstract We have investigated the genetic and molecular basis of immune responsiveness to short ragweed (SRW) (Ambrosia artemisiifolia) extract, and group 5 allergens from short and giant (Ambrosia trifida) ragweed using transgenic mice expressing DQ6 (HLA-DQA1*0103, HLA-DQB1*0601) and DQ8 (HLA-DQA1*0301, HLA-DQB1*0302) genes in class II knockout (Aβ0) mice. Panels of overlapping peptides spanning the Amb a 5 and Amb t 5 Ags were synthesized. Mice were immunized with whole SRW extract or individual peptides s.c. and lymph node cells (LNC) were challenged in vitro. Strong T cell responses to SRW extract were measured in both HLA-DQ transgenic mice, while control, HLA-DQ6−/DQ8−/H-2Aβ0, mice were unresponsive. IL-5 and IL-10 were the primary cytokines produced by in vitro challenged LNC of SRW-primed transgenic mice. HLA-DQ6-restricted T cell responses were detected to all three peptides of Amb t 5 and two determinants (residues 1–20 and 11–30) on Amb a 5. In contrast, LNC of HLA-DQ8 mice did not recognize peptide 11–30 of Amb t 5 Ag, but recognized several Amb a 5 determinants. The immune response in transgenic mice was dependent upon CD4+ T cells and was HLA-DQ restricted. Primed with purified Amb t 5, both transgenics recognized peptide 21–40, and an additional DQ6-restricted epitope was found within residue 1–20. SRW-immunized HLA-DQ6 mice respond to peptide 11–30 of Amb a 5, while HLA-DQ8 mice strongly recognize peptide 1–20. These results demonstrate the specificity of HLA class II polymorphism in allergen sensitivity and pave the way for developing antagonistic peptides for desensitization.

Abstract We have introduced HLA-DQ8 (HLADQB*0302 and HLA-DQA*0301) genes into A β 0 knockout mice. Transgenic animals were immunized with a whole body extract of Dermatophagoides pteronyssinus (Der p), one of the causative agents of house dust mite allergy. Transgenic mice expressing HLA-DQ8 genes elicited HLA-DQ8-restricted responses driven by CD4+ T cells. Synthetic-overlapping peptides representing a major allergen of house dust mite (Der p 2) were synthesized and used as immunogens. HLA-DQ8+ mice responded to three peptides: 8 (residues 61-80), 11 (residues 91-110), and 13 (residues 111-129). The mice produced IL-2, IL-4, and IL-6 response to Der p challenge, suggesting a mixed Th1/Th2 response. These mice represent a new model for studies of the immune basis of allergy.

Background: Congenital clasped thumb is associated with deficient thumb extensor tendons. Reconstruction includes tendon transfer. Here, we describe a variant of the abductor pollicis longus (APL) tendon, not previously reported, contributing to the flexion deformity. The purpose of this study is to report examples of and offer surgical repair techniques for APL variants identified in patients with clasped thumb. Methods: We reviewed records of 11 consecutive patients undergoing reconstruction for clasped thumb. Surgical anatomy of the APL tendon was evaluated in all patients, followed by release of aberrant APL attachments. Participants were invited to return for an in-person assessment with a certified hand therapist. Data were collected regarding intraoperative findings, surgical techniques for reconstruction, postoperative thumb motion, and patient and caregiver satisfaction. Results: Eleven children (12 thumbs) underwent aberrant APL release and rerouting between 2019 and 2021. Preoperatively, all thumbs were passively correctible to 0° of extension. In all patients, the APL was found to terminate palmar to the metacarpophalangeal (MCP) joint, creating an MCP flexion moment when tensioned. The average age at surgery was 7 years (range: 1-15 years), and the average follow-up was 14.2 months (range: 1-21 months). The mean postoperative thumb radial abduction was 55° (range: 20°-75°). Conclusions: When reconstructing clasped thumbs, surgeons should explore the presence of APL abnormalities. Release and centralization of the APL can improve thumb position and function. This technique may avoid the need for extra-anatomical tendon transfer in patients with clasped thumb.

AbstractBackgroundMayo Test Drive (MTD): Test Development through Rapid Iteration, Validation and Expansion, is a web‐based platform optimized for remote self‐administered assessment that includes a computer adaptive word list memory test (Stricker Learning Span; SLS) and a measure of processing speed (Symbols Test). Study aims were to determine 1) convergent validity of MTD through correlations with in‐person neuropsychological measures and 2) criterion validity of MTD by qualitatively comparing the ability of Mayo Test Drive and in‐person administered neuropsychological measures to differentiate biomarker‐defined groups, independent of clinical diagnosis.MethodsMayo Clinic Study of Aging participants (N = 282) completed a brief remote cognitive assessment (mean age = 74, SD = 12; 262 CU and 20 MCI per consensus conference diagnosis; see Table 1). A subset of participants had brain amyloid and/or brain tau PET scans available within 3 years; overlapping groups were formed for 1) those on the Alzheimer’s disease (AD) continuum (A+, n = 31) or not (A‐, n = 57) and for 2) those with biological AD (A+T+, n = 19) or without any AD biomarkers (A‐T‐, n = 47). Primary outcome variables were SLS sum of trials, AVLT sum of trials, SYM Correct Trials response time, Digit Symbol Coding, MTD composite and Mayo‐PACC (AVLT sum of trials, Trails B, animals). Bivariate correlations were performed across all participants. Linear model ANOVAs were used to investigate biomarker subgroup differences; Hedge’s g effect sizes are reported.ResultsConvergent validity was supported through significant correlation (p’s < .001) of SLS and AVLT (r = .63), SYM and Coding (r = ‐.64), and MTD composite with Mayo‐PACC (r = .67); see Table 2. MTD subtests showed expected relationships with age and education (p’s < .05; Table 3). All MTD performances were significantly lower for A+ and A+T+ participants relative to A‐ or A‐T‐ (p’s<.001; Table 4). All MTD outcome measures showed a similar or greater group difference effect size relative to traditional in‐person administered neuropsychological measures for separating A+ vs. A‐ and A+T+ vs. A‐T‐ groups. See Figure 1 and Table 4.ConclusionsMTD subtests show evidence of convergent validity through strong correlations with traditional in‐person cognitive measures. Preliminary analyses suggest MTD has promise for differentiating PET biomarker groups.

AbstractBackgroundRemote assessment tools offer significant promise for aiding early detection of cognitive impairment. Mayo Test Drive (MTD): Test Development through Rapid Iteration, Validation and Expansion, is a web‐based platform for remote self‐administered assessment that includes a computer adaptive word list memory test (Stricker Learning Span; SLS) and a measure of processing speed (Symbols Test). We examined the diagnostic accuracy of the SLS and a MTD composite (SLS max span, SLS trials 1–5 total correct, SLS delay correct, [Symbols correct item response time*‐1]) for amnestic mild cognitive impairment (aMCI). We also explored diagnostic accuracy for a broader group that included individuals with possible MCI (pMCI; see Figure 1).MethodsParticipants were recruited from the Mayo Clinic Study of Aging for this ancillary remote study. 226 were cognitively unimpaired (CU; concordant CU diagnosis by 3 independent raters). Fifty‐six participants had possible MCI (at least 1 of 3 raters indicated MCI) and 16 had a consensus diagnosis of aMCI. Primary outcome variables were SLS sum of trials, AVLT sum of trials, Symbols correct items response time, and MTD composite. Mean difference analyses used linear model ANOVAs (alpha = .05). Receiver operating characteristic (ROC) curves were applied; we derived optimal cutoff scores based on the Youden index method.ResultsBoth aMCI and possible MCI groups showed significantly lower performance than the CU group on SLS (Hedge’s g aMCI = ‐1.72, pMCI = ‐1.04), Symbols (Hedge’s g aMCI = 1.38, pMCI = 0.64), and MTD composite (Hedge’s g aMCI = ‐1.89, pMCI = ‐1.09); see Tables 1 and 2 (all p‘s<.01 even when additionally covarying age, education, sex). Total area under the curve was high for differentiating of CU vs. aMCI (MTD Composite = 0.91, SLS = 0.91) and acceptable for CU vs. pMCI (MTD Composite = 0.77, SLS = 0.77); see Table 2. Consistent with our flexible platform, a variety of device types were used to complete remote testing (32% smartphone, 12% tablet, 56% PC).ConclusionsMTD and the SLS show high diagnostic accuracy for aMCI. MTD is a flexible, brief, and easy‐to‐use remote cognitive assessment tool with great potential for scalable use in future studies seeking to maximize inclusion of individuals with aMCI in clinical trials or for cognitive screening in clinical settings.

AbstractBackgroundMayo Test Drive (MTD): Test Development through Rapid Iteration, Validation and Expansion, is a web‐based platform for self‐administered assessment for novel (Stricker Learning Span) and open access (Symbols Test) cognitive measures with previously demonstrated validity and reliability. Our study aim was to examine the usability of MTD, defined as the extent to which MTD was used to achieve the desired study goal of completing a testing session among participants willing to engage in an all‐remote study.Methods248 Mayo Clinic Study of Aging and Mayo Alzheimer’s Disease Research Center participants were invited to participate in this ancillary, uncompensated remote pilot study via email. To examine 1) willingness to participate in a remote cognitive assessment study and 2) usability of MTD, the initiation and completion rates of MTD were examined by cognitively unimpaired (CU; n = 142) and cognitively impaired (CI; n = 106) groups (see Figure 1). These rates and other factors associated with MTD feasibility were further explored across age in CU (i.e., 50–69, 70–79, and 80+ years) and specific diagnostic groups in CI (i.e., individuals with dementia, mild cognitive impairment (MCI), and possible MCI).ResultsSession completion rate (usability) was 98% across all participants who chose to participate, and, surprisingly, completion rates did not vary by age or diagnostic groups (p = .69; see Table 1). As expected, more individuals chose to participate in the CU (77%) versus CI (52%) group (p < .001). In terms of feasibility, individuals over 80 and with CI were more likely to have some contact with the study coordinator. Use of smartphones decreased with age, with most CU individuals over 70 using a personal computer (69‐73%; Table 2).ConclusionsThough the CI group was less likely to choose to participate than the CU group, out of those that did choose to participate the rate of completion was 98%. This demonstrates high usability of MTD. Study coordinator support and a flexible testing platform is critical for facilitating participation in remote testing across the aging population, and more supports and incentives may be needed for individuals with cognitive impairment to improve participation rates.

AbstractBackgroundMayo Test Drive (MTD): Test Development through Rapid Iteration, Validation and Expansion, is a web‐based platform for self‐administered assessment for novel (Stricker Learning Span) and open access (Symbols Test) cognitive measures with previously demonstrated validity and reliability. Our study aim was to examine the usability of MTD, defined as the extent to which MTD was used to achieve the desired study goal of completing a testing session among participants willing to engage in an all‐remote study.Methods248 Mayo Clinic Study of Aging and Mayo Alzheimer’s Disease Research Center participants were invited to participate in this ancillary, uncompensated remote pilot study via email. To examine 1) willingness to participate in a remote cognitive assessment study and 2) usability of MTD, the initiation and completion rates of MTD were examined by cognitively unimpaired (CU; n = 142) and cognitively impaired (CI; n = 106) groups (see Figure 1). These rates and other factors associated with MTD feasibility were further explored across age in CU (i.e., 50‐69, 70‐79, and 80+ years) and specific diagnostic groups in CI (i.e., individuals with dementia, mild cognitive impairment (MCI), and possible MCI).ResultsSession completion rate (usability) was 98% across all participants who chose to participate, and, surprisingly, completion rates did not vary by age or diagnostic groups (p =.69; see Table 1). As expected, more individuals chose to participate in the CU (77%) versus CI (52%) group (p < .001). In terms of feasibility, individuals over 80 and with CI were more likely to have some contact with the study coordinator. Use of smartphones decreased with age, with most CU individuals over 70 using a personal computer (69‐73%; Table 2).ConclusionsThough the CI group was less likely to choose to participate than the CU group, out of those that did choose to participate the rate of completion was 98%. This demonstrates high usability of MTD. Study coordinator support and a flexible testing platform is critical for facilitating participation in remote testing across the aging population, and more supports and incentives may be needed for individuals with cognitive impairment to improve participation rates.

Abstract Background Large cohort studies from the Veteran’s Administration support the negative predictive value of the methicillin resistant Staphylococcus aureus (MRSA) nasal polymerase chain reaction (PCR) swabs for skin and soft tissue infection (SSTI). We investigated the use of the nasal MRSA PCR swab to reduce the inappropriate empiric use of vancomycin and piperacillin-tazobactam for SSTI at our institution. Methods Between July and August 2021, we educated Hospital Internal Medicine (HIM) and Internal Medicine Residents (IMR) on the basics of SSTI management and the utility of a negative nasal MRSA PCR swab. Data on empiric use of vancomycin and piperacillin-tazobactam for SSTIs were collected 3/1/2021 to 7/1/2021 (pre-intervention) and 8/30/2021 to 12/29/2021 (post-intervention). We excluded patients who didn’t have an SSTI, weren’t managed by IMR or HIM, and whose empiric antibiotics were for another indication. To account for antibiotics started in the emergency department (ED), a patient was regarded as having received appropriate empiric antibiotics if they were de-escalated in the first 24 hours of being admitted to IMR or HIM. Example of education material. These fliers were distributed to resident rooms following a series of noon conferences Results Pre-intervention there were 106 patient encounters. In 56 of these (52.8%), patients were placed on inappropriate empiric antibiotics. Post-intervention, there were 72 patient encounters. In 23of these (31.9%), patients were placed on inappropriate empiric antibiotic for an absolute risk reduction (ARR) of 20.9% with a statistically significant 95% CI (6.522 - 35.249) and a number needed to treat (NNT) of 4.78. Nasal MRSA PCR testing increased from 40.6% to 56.9%. The ARR among the HIM teams was 21.3% and was statistically significant with a 95% CI (4.24 - 38.394). Their proportion of MRSA testing increased from 41.5% to 50%. The IMR teams had an ARR of 14.8%, which was not statistically significant (95% CI, -11.339 to 40.884). Their MRSA nasal PCR testing increased from 37.5% to 72%. Conclusion Education on SSTI treatment coupled with use of the MRSA nares PCR appeared to improve empiric antibiotic choices. Residents stated that the nasal MRSA PCR facilitated empiric antibiotic choice. Positive ARR was seen in whole and sub-group analyses of physician teams. We theorize that the lack of statistical significance in the IMR group was related to a small sample size. Disclosures All Authors: No reported disclosures.

ImportanceLate-onset meningitis (LOM) has been associated with adverse neurodevelopmental outcomes in children born extremely preterm.ObjectiveTo report the incidence of LOM during birth hospitalization and neurodevelopmental outcomes at 18 to 26 months’ corrected age.Design, Setting, and ParticipantsThis cohort study is a secondary analysis of a multicenter prospective cohort of children born at 22 to 26 weeks’ gestation between 2003 and 2017 with follow-up from 2004 to 2021. The study was conducted at 25 Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers.ExposuresCulture-confirmed LOM.Main Outcomes and MeasuresIncidence and microbiology of LOM (2003-2017); lumbar puncture (LP) performance in late-onset sepsis (LOS) evaluations (2011-2017); composite outcome of death or neurodevelopmental impairment (NDI; 2004-2021).ResultsAmong 13 372 infants (median [IQR] gestational age, 25.4 [24.4-26.1] weeks; 6864 [51%] boys), LOM was diagnosed in 167 (1%); LOS without LOM in 4564 (34%); and neither LOS nor LOM in 8641 (65%). The observed incidence of LOM decreased from 2% (95% CI, 1%-3%) in 2003 to 0.4% (95% CI, 0.7%-1.0%) in 2017 (P &amp;lt; .001). LP performance in LOS evaluations decreased from 36% (95% CI, 33%-40%) in 2011 to 24% (95% CI, 21%-27%) in 2017 (P &amp;lt; .001). Among infants with culture-confirmed LOS, LP performance decreased from 58% (95% CI, 51%-65%) to 45% (95% CI, 38%-51%; P = .008). LP performance varied by center among all LOS evaluations (10%-59%, P &amp;lt; .001) and among those with culture-confirmed LOS (23%-79%, P &amp;lt; .001). LOM occurred in the absence of concurrent LOS in 27 of 167 cases (16%). The most common LOM isolates were coagulase-negative Staphylococcus (98 [59%]), Candida albicans (38 [23%]), and Escherichia coli (27 [16%]). Death or NDI occurred in 22 of 46 children (48%) with LOM due to coagulase-negative Staphylococcus, 43 of 67 (64%) due to all other bacterial pathogens, and 26 of 33 (79%) due to fungal pathogens. The adjusted relative risk of death or NDI was increased among children with LOM (aOR, 1.53; 95% CI, 1.04-2.25) and among those with LOS without LOM (aOR, 1.41; 95% CI, 1.29-1.54) compared with children with neither infection.Conclusions and RelevanceIn this cohort study, LP was performed with decreasing frequency, and the observed incidence of LOM also decreased. Both LOM and LOS were associated with increased risk of death or NDI; risk varied by LOM pathogen. The full association of LOM with outcomes of children born extremely preterm may be underestimated by current diagnostic practices.