Citations

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.

Abstract Background Cryoglobulins are immunoglobulins that precipitate at cold temperatures. They are associated with plasma cell disorders, infectious and autoimmune diseases. Laboratory testing is manual and requires strict temperature control, from keeping the blood sample warm from the moment of draw until processing in the laboratory. Serum samples are transferred to Kolmer glass graduated tubes upon arrival, and kept on ice for visualization of a precipitate for up to 7 days. Because of the temperature variation samples are subjected to, positive sample identification is important. The Kolmer glass tubes are not disposable, and undergo several steps of deidentification and cleaning for reuse. The goal of this project was to improve patient safety and label adherence in cryoglobulin testing by using the Managing for Daily Improvement (MDI) method to monitor and implement changes effectively. Methods During a Plan Do Study Act (PDSA) initiative, it was discovered that labels were not being secured on both ends with tape due to safety concerns when using a box cutter to remove the label prior to cleaning. This practice led to an increase in labels detaching from the glass tubes. To address this issue, we employed the MDI method and established a Key Performance Indicator (KPI) to monitor and evaluate potential changes aimed at improving label adherence. The MDI method facilitates problem-solving through daily visual indicators and discussions by empowering technologists to identify and address issues affecting daily operations. This approach encourages open communication and collaborative problem-solving, allowing the entire team to share insights and solutions in real time. Results A PDSA initiative via MDI uncovered the label adherence challenges. A KPI was developed to monitor interventions to improve the process. First, removable tape was used to secure both sides of the label. Initial results were worse than the original method but slight improvement occurred at about 3 weeks. A Just Do It (JDI) approach was initiated to leave additional space between samples. No improvements were observed and the practice discontinued within < 2 weeks. A second JDI was trialed with a different tool to remove labels post-use. The entire sample identification process was reviewed and the original identification process resumed, by adding scotch tape securing both sides of the labels and using a ceramic box cutter to remove the labels. Significant improvements to labels adherence was observed, from about 60% of labels coming off to zero, while the new tool was also safer for the team. Another PDSA was initiated to investigate if plastic, disposable tubes were a viable option for testing, and a full method validation of the new plastic tubes followed, finally eliminating the challenges with the larger process or reusing glass tubes. Conclusion MDI helped recognize a problem from the front-line and find real time solutions that benefited end-to-end operations. Visual daily indicators clearly showed effectiveness of interventions. Identifying real issues, even if they appear small, can lead to improved patient and staff safety, and empowerment to initiate meaningful change.

Objective: To evaluate the function and safety of the SteadiSet™ infusion set over a continuous 7-day wear period in adults with type 1 diabetes. Research Design and Methods: Participants used a SteadiSet infusion set with a t:slim X2™ insulin pump with Control-IQ™ technology, and either insulin aspart or insulin lispro, for a target of 7 days for 12 consecutive wear periods. Each set removed before 7 days was adjudicated by an independent committee to assess the cause of early removal and to determine whether criteria for primary or key secondary endpoints were met. Results: There were 260 participants who inserted 3028 infusion sets. For the primary endpoint, the Kaplan–Meier 7-day survival estimate was 95% (95% CI 94% to 96%). For the key secondary endpoint, which expanded the reasons for a failed infusion set, the Kaplan–Meier 7-day survival estimate was 84% (95% CI 82% to 86%). For both endpoints, the P value was <0.001 compared with a prespecified survival rate of 75%. Time-in-range 70–180 mg/dL (TIR) increased through day 3 of set wear and then decreased through day 7, with the average TIR being 70.6% over the entire wear period across all infusion sets, including those that failed. An increase in total daily insulin was observed from day 4 through day 7. Conclusions: The 7-day survival of the SteadiSet infusion set was very high for the primary endpoint and at an acceptable level with respect to early removal for any reason related to the device.

Purpose Genitourinary syndrome of menopause (GSM) describes the symptoms and physical changes that result from declining estrogen and androgen concentrations in the genitourinary tract during the menopausal transition. This guideline provides information to clinicians regarding identification, diagnosis, counseling, and treatment for patients with GSM to optimize symptom control and quality of life while minimizing adverse events. Methods The systematic review used in the creation of this guideline is based on research conducted by the Minnesota Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality and funded by the Patient Centered Outcomes Research Institute. The EPC synthesized effectiveness and/or harms outcomes from 68 publications. An additional 66 articles evaluating 46 nonhormonal interventions were described in an evidence map. Results Clinicians diagnose GSM based on symptoms, with or without related physical findings, and after ruling out other etiologies or co-occurring pathologies. There is a large body of evidence examining the use of hormonal and nonhormonal treatment options to manage the symptoms of GSM; however, the local low-dose vaginal estrogen has the most robust evidence base. Conclusion The strategies defined in this document were derived from evidence-based and consensus-based processes. Given that there is insufficient information to recommend one hormonal therapy over another, this guideline is not meant to support a stepwise progression through different hormonal approaches. The clinician should make treatment decisions in the context of shared decision-making, considering patient goals and preferences, using the evidence of efficacy and adverse events of each possible intervention as a guide.

Introduction: The use of modular components provides several advantages in total knee arthroplasty (TKA), including exchange of the polyethylene insert while retaining the stable components in the revision TKA. Compared to full, non-modular component revision TKA, isolated polyethylene exchange (IPE) has the advantage of decreased morbidity, faster rehabilitation, and acceptable outcomes. Methods: A review of published literature on revision TKA was conducted, with a specific focus on studies evaluating the use of IPE for managing complications such as stiffness, instability, and periprosthetic joint infection (PJI). Results: IPE with downsizing may be considered for patients with mild stiffness and stable, well-positioned implants that have increased polyethylene thickness, though expectations for motion gain should be cautious. There is no clear consensus on IPE for instability. Some studies report high re-revision rates, while others show clinical and functional improvement when the TKA is well-aligned, well-fixed, and intraoperative gap balance is achieved. Additionally, irrigation and debridement with polyethylene exchange (IDPE) may be effective for acute TKA PJI management, particularly within the first two weeks of symptom onset. Conclusions: Based on current literature, IPE in aseptic TKA revisions may be effective for stiffness or instability when implants are well-fixed and well-aligned—particularly if polyethylene constraint can be adjusted for instability or downsized for stiffness. The role of IDPE in acute TKA PJI is better defined in the literature, with strong emphasis on its time-sensitive effectiveness—most notably within the first two weeks of symptom onset.

Abstract Invariant Natural Killer T (iNKT) cells recognize glycolipid antigens presented on CD1d and rapidily respond to direct immune responses. iNKT cells develop in the thymus and migrate to peripheral tissues in what has been presumed to be differentiated/committed states. Accordingly, colonic iNKT cells are established in early life, considered to remain ‘fixed’ post-weaning, and determine life-long colitis susceptibility. Using single cell RNA sequencing (scRNA-seq), we demonstrate that humans and mice contain colonic iNKT populations transcriptionally resembling immature and intermediate thymic iNKT precursors. Contrary to prevailing paradigms, we demonstrate colonic iNKT cell populations expand in adult mice when CD1d expressing colonic goblet cells form goblet cell-associated antigen passages. Expansion preferentially affected intermediate iNKT cells, was durable, and protective in a colitis model. These studies reveal that the adult colon harbors iNKT cells with retained plasticity and uncover a novel role for goblet cells as unconventional antigen presenting cells regulating this axis.

Abstract PARP inhibitors (PARPis) are now a standard of care for high-grade serous ovarian cancer (HGSOC), but resistance to these drugs poses a significant concern, necessitating the exploration of novel treatment strategies. Here we investigated the mechanism underlying enhanced PARPi activity in HGSOC cells following treatment with brigatinib—a second-generation anaplastic lymphoma kinase (ALK) inhibitor approved for treating lung cancer. Our previous work has shown that brigatinib is a dual inhibitor of tyrosine kinases FAK and EPHA2 with subsequent additive reduction in downstream PI3K/AKT and MAPK/ERK cell survival signaling. Suppression of these pathways conferred PARPi sensitivity to HGSOC cell lines and patient-derived xenograft (PDX) models, particularly in those with high FAK and EPHA2. To dissect the mechanism linking the FAK/EPHA2 – AKT/ERK pathway to PARPi synergy, we focused on proteomics approaches which revealed that FRA1—an Activator Protein 1 (AP-1) transcription factor known to be downstream of AKT/ERK—and its targets were decreased by brigatinib treatment. In subsequent phosphoproteomics approaches and cell-based confirmatory studies, a phosphorylation crucial for FRA1 stability was found to be disrupted, leading to reduction in total FRA1 protein levels and synergy with PARPis. To explore how FRA1 mediates response to PARPis, immunoblotting analysis revealed that PARPis increased the abundance of FRA1 in HGSOC cells at early timepoints, indicating potential involvement in an adaptive survival response. Follow-up pharmacologic and gene silencing techniques demonstrated that brigatinib still reduces FRA1 in PARPi-treated cells, and FRA1 depletion induces apoptosis when combined with PARPi to levels comparable to brigatinib treatment. Overall, our studies unveil a beneficial ALK-independent effect of brigatinib that may offer new avenues for considering its repurposing as a HGSOC therapy through disruption of a PARPi-induced adaptive survival mechanism. Citation Format: Julie R. Duffield, Xiaonan Hou, Benjamin W. Wilson, Anjali Prasad, Iman K. McKeon-Makki, Amelia M. Huehls, Xinyan Wu, Cristina Correia, Melissa C. Larson, Fergus J. Couch, Ann L. Oberg, Scott H. Kaufmann, Larry M. Karnitz, Arun Kanakkanthara. A PARP-inhibitor-induced early adaptive survival response is tackled through depletion of FRA1 by brigatinib in high-grade serous ovarian carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A024.

ABSTRACT Biofilms hinder wound infection healing, making wound infections a healthcare challenge for which innovative treatments are needed. A 1.77 cm 2 electrochemical bandage (e-bandage), which generates the biocide hypochlorous acid (HOCl), has shown promising anti-biofilm activity in vitro , ex vivo , and in vivo . The e-bandage is a three-electrode system operationalized by a hydrogel. In addition to providing a conductive electrolyte for the electrodes, the hydrogel provides a protective barrier for the wound. How different hydrogels impact e-bandage functionality is not completely defined. Here, the in vitro activity of seven clinically available hydrogels (xanthan gum, 3M, Duoderm, Prontosan, Purilon, Skintegrity, and Solosite) was evaluated with 1.77 cm 2 HOCl-generating e-bandages using a potentiostat with a multiplexer in a membrane biofilm model against methicillin-resistant Staphylococcus aureus IDRL-6169 and Acinetobacter baumannii ATCC-17978. When applied with polarized HOCl-producing e-bandages, all evaluated hydrogels except Solosite yielded ≥5.5 log 10 CFU/cm 2 reductions in bacterial quantities after 6 h of treatment, with most being below the detection limit at that time point. Prontosan exhibited antibacterial activity independent of e-bandage. Results of this study inform the selection of clinically available hydrogels that may be suitable for use with a 1.77 cm 2 HOCl-producing e-bandage. IMPORTANCE In this study, it was shown that some clinically available hydrogels, combined with a 1.77 cm 2 HOCl-generating electrochemical bandage, deliver time-dependent antimicrobial activity against methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii biofilms, offering a potential approach to treat wound infections, including those caused by antimicrobial-resistant bacteria.

ImportanceStudies suggest that everolimus may reduce the risk of rejection, cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD), and cytomegalovirus (CMV) after heart transplant. Everolimus use is controversial because of data demonstrating higher infection deaths when everolimus is introduced de novo after transplant. It is unclear whether everolimus is safe and effective when initiated at 6 months posttransplant in children, a population in which median graft survival is limited to 15 years and randomized clinical trials are lacking.ObjectiveTo evaluate the safety and efficacy of everolimus combined with low-dose tacrolimus to prevent major adverse transplant events (MATEs) in children after heart transplant.Design, Setting, and ParticipantsMulticenter, randomized, open-label, clinical trial enrolling 211 patients who were alive 6 months after pediatric heart transplant at 25 US sites from February 2018 to August 2020. The last date of follow-up was April 17, 2023.InterventionsParticipants were randomized to receive everolimus and low-dose tacrolimus (n = 107) or standard-dose tacrolimus and mycophenolate mofetil (n = 104) for 30 months.Main Outcomes and MeasuresThe primary efficacy end point was the MATE-3 score at 30 months, a validated composite ordinal end point including acute cellular rejection, CAV, and CKD. The primary safety end point was the MATE-6 score, encompassing the MATE-3 score plus antibody-mediated rejection, infection, and posttransplant lymphoproliferative disorder.ResultsAmong 211 children randomized, the mean age was 8.2 (SD, 6.3) years, 97 (46%) underwent transplant for congenital heart disease, and 49 (23%) were treated for rejection before 6 months. At 30 months, the mean MATE-3 score did not differ between the 2 treatment groups (mean difference, −0.32; 95% CI, −0.90 to 0.20; P = .16). The mean MATE-6 score was no higher in the everolimus group than in the mycophenolate group (baseline-adjusted mean difference, −0.40; 95% CI, −1.81 to 0.93), meeting the success criterion for safety (noninferiority margin &amp;lt;3). There were no differences in graft survival, MATE-free survival, or freedom from any individual MATE. Everolimus was associated with greater improvement in estimated glomerular filtration rate at 12 months (mean difference, 10.5 mL/min/1.73 m2; 95% CI, 1.09-19.91 mL/min/1.73 m2) and a lower incidence of CMV infection (hazard ratio, 0.50; 95% CI, 0.26-0.93).Conclusions and RelevanceAmong 6-month pediatric heart transplant survivors, everolimus and low-dose tacrolimus did not differ from tacrolimus and mycophenolate in preventing the composite of cellular rejection, CAV, and CKD at 30 months. However, everolimus and low-dose tacrolimus appear to be safe based on the total burden of 6 MATEs and may be associated with improved kidney function and less CMV infection.Trial RegistrationClinicalTrials.gov Identifier: NCT03386539

This study evaluated the efficacy of the multiple sclerosis disease-modifying therapies, intramuscular interferon beta-1a (Avonex) and subcutaneous peginterferon beta-1a (Plegridy), using data from the United States Network of Pediatric Multiple Sclerosis Centers. In this retrospective analysis, 154 patients with multiple sclerosis were included who were treated with Avonex (n = 130), Plegridy (n = 23), or both treatments (n = 1) before the age of 18 years. After 3 months’ sustained use acclimation (“wash-in”), the probability of being relapse-free during the first year was 68.3% for Avonex-treated patients and 69.9% for Plegridy-treated patients; annualized relapse rates were 0.50 and 0.59, respectively. Both disease-modifying therapies demonstrated efficacy similar to that reported in adult populations. Despite the lack of formal approval for pediatric multiple sclerosis, these outcomes indicate that patients may benefit from treatment with Avonex or Plegridy. Understanding efficacy of specific disease-modifying therapies in pediatric multiple sclerosis is essential to making informed treatment decisions.