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Abstract Background Lyme arthritis is a manifestation of disseminated infection with Borrelia spp., typically presenting as knee monoarthritis weeks to months after infection. Most patients respond to antibiotics, but some develop antibiotic-refractory Lyme arthritis (ARLA), characterized by proliferative or autoimmune synovitis despite clearance of active infection, with proposed risk factors including treatment delay, host genetics, and intra-articular steroid use prior to antibiotics. Table 1 Characteristics of cohort. IQR = interquartile range, ESR = erythrocyte sedimentation rate, CRP = C-reactive protein, WBC = white blood cell. Table 2 Comparison of characteristics and outcomes between ARLA and non-ARLA patients Methods We performed a retrospective chart review of adult patients with Lyme PCR-positive synovial fluid at our center between 01/2004 and 02/2025. ARLA was defined as persistent inflammatory arthritis despite ≥8 weeks of antibiotics and/or negative repeat PCR after antibiotics. Statistical analysis was done on R and STATA. Figure 1 Type of antibiotics administered during the first course (A) and the second course (B) Figure 2 Box plot comparing the median time from symptom onset and treatment initiation in patients who had complete symptomatic resolution with any duration of antibiotic therapy, and those that did not have symptomatic resolution with antibiotic therapy. Results Table 1 summarizes the characteristics of the study cohort. Definitive Lyme arthritis was diagnosed in 67 patients. Of these, 35 patients (52%) achieved complete symptom resolution after one course of antibiotics, and 45 patients (67%) achieved resolution after up to two courses. Doxycycline was used as first-line therapy in 97% of cases (Figure 1). Antibiotic-refractory Lyme arthritis (ARLA) developed in 20 patients (30%); of these, 7 required disease-modifying antirheumatic drugs (DMARDs), and 3 underwent synovectomy. ARLA was associated with incomplete response to a single antibiotic course and persistent joint effusion on post-treatment radiography (Table 2). Intra-articular steroid use prior to antibiotic therapy was associated with a threefold increased odds of ARLA, although this did not reach statistical significance. Patients who responded to antibiotics had a shorter median time to treatment (19 days) compared to non-responders (42 days) (Figure 2). Conclusion In this cohort, 30% of patients were ultimately diagnosed with antibiotic-refractory Lyme arthritis (ARLA), a rate notably higher than the previously reported 10%. Despite advancements in Lyme disease diagnostics, we observed significant delays in diagnosis and initiation of appropriate antibiotic therapy, as well as the use of intra-articular steroids prior to antibiotics. These factors may contribute to the development of ARLA. Disclosures All Authors: No reported disclosures

Abstract Background Cytomegalovirus (CMV) infection remains one of the most prevalent and important infections following solid organ transplant (SOT). Treatment is often challenging, especially when dealing with refractory and resistant CMV infections.Table 1:Univariable logistic regression analyses of associations with early refractory CMV infectionTable 2:Univariable logistic regression analyses of associations with resistant CMV infection Methods We performed a retrospective cohort study of SOT recipients with clinically significant CMV infection (csCMVi) at a tertiary transplant center in the US during 2010-2016. The primary outcome was early refractory CMV infection and secondary outcomes were drug resistance, CMV recurrence, and mortality. Kaplan-Meier estimation, univariable logistic regression analysis, and multivariable Cox regression were used for outcome analysis.Table 3:Multivariable Cox regression analysis of associations with recurrent CMV infection after primary treatment endedNote: Refractory CMV was not included in the model for recurrent CMV as no patients with refractory infection had recurrence. Results A total of 145 SOT recipients with csCMVi were included. Most patients were recipients of liver (49%), followed by kidney (22.1%), heart (6.9%), lung (5.5%), and pancreas (4.1%). Multiple organ transplants accounted for 12.4% of the cohort. Most common induction was an anti-IL-2 antibody (43.9%) followed by ATG (29.5%). 82 (56.5%) had CMV D+/R- mismatch. In total, 34 (23.4%) had CMV syndrome, 38 (26.2%) had tissue-invasive CMV disease, while the rest (50.3%) were asymptomatic. After the initial 3 weeks of antiviral therapy, 13 (8.9%) patients had probable refractory csCMVi; most of them (10 [76.9%]) were CMV D+/R- mismatch. Longer time after transplant had lower risk (OR 0.68; CI 0.48-0.95, p=0.029) while lower absolute lymphocyte count (ALC) was higher risk of early refractory csCMVi (OR 1.54; CI 1.01-2.44, p=0.048) (Table 1). Drug-resistant CMV occurred in 7 patients (4.8%); a high initial CMV DNA level was associated with resistant csCMVi (OR 2; CI 1.08-3.93, p=0.031) (Table 2). Of 144 patients with post-treatment follow-up, 25 (17.2%) experienced recurrent csCMVi within 6 months. Table 3 shows the associations with recurrence of csCMVi after initial treatment. 30 patients (20.7%) died during a median follow-up of 4 years, but refractory, resistant or recurrent CMV were not associated with mortality. Conclusion Refractory csCMVi is associated with low ALC and an earlier onset post-transplant. Resistant csCMVi is associated with high levels of initial CMV DNA. Recurrence of csCMVi is common and possibly associated with low ALC at the end of antiviral treatment. Disclosures All Authors: No reported disclosures

Abstract Background Tau phosphorylation and aggregation are hallmark features of Alzheimer's disease pathology(AD). Previous studies have shown that plasma phosphorylated tau( p ‐tau) at threonine 217 can detect AD‐related tau tangle pathology. However, the head‐to‐head association between p ‐tau217 and different tau PET tracers remains unexplored. Here, we conducted a head‐to‐head comparison of the association between plasma p ‐tau217 and four distinct tau PET tracers[MK6240, Flortaucipir(FTP), PI2620, RO948]. Method We studied 338 individuals across the AD continuum from the HEAD study[190 cognitively unimpaired elderly(CU), 109 with mild cognitive impairment(MCI), and 39 with dementia] with available FTP, MK6240, and plasma p ‐tau217 measured by ALZpath assay. A subset of 64 individuals(28 CU, 25 MCI, and 11 dementia) also had PI2620 and RO948, and p ‐tau217 measured by Lumipulse. The strength of the association was determined using t‐value maps from regression models testing the association between each tau PET tracer and plasma p ‐tau217, and the extent was measured by the percentage of significant voxels(t‐value>3.2). R‐square metric was used to determine how much of the variance in tau PET tracer estimates was explained by plasma p ‐tau217 concentrations. Associations between p ‐tau217 with tau PET were evaluated using the Spearman test. Result We found that in CU, both the extent and magnitude of the association with plasma p ‐tau217 were higher for MK6240 compared to FTP (Figure 1A‐D). Plasma p ‐tau217 explained a greater proportion of the variance in MK6240 than in FTP (Figure 1E‐F). In CI, the extent and magnitude of the association were similar for MK6240 and FTP. Additionally, plasma p ‐tau217 explained a similar proportion of the variance in MK6240 and FTP. Using the subset of individuals who had all tau tracers, MK6240 showed a slightly higher extent of association with p ‐tau217, followed by FTP, PI2620, and RO948 (Figure 2A‐B). The magnitude of association was stronger for MK6240, followed by PI2620, RO948, and FTP (Figure 2C‐D). Plasma p ‐tau217 explained a greater proportion of the variance in MK6240, followed by FTP, RO948, and PI2620 (Figure 2E‐F). We compared the associations between different p ‐tau217 assays, and both assays presented similar associations with all tau PET tracers (Figure 3). Conclusion In summary, our results indicate that the four tau PET tracers exhibit robust associations with plasma p ‐tau217 in similar topographical regions.

ABSTRACT Introduction Desmoplastic small round cell tumor (DSRCT) is a rare malignant mesenchymal neoplasm of polyphenotypic differentiation, characterized by EWSR1‐WT1 gene fusion. Despite multimodality therapy, the tumor carries poor prognosis. We report cytomorphological, immunohistochemical (IHC) and molecular features of seven cases of DSRCT from four patients. Materials and Methods A retrospective review of cytology smears, biopsies and molecular features of cases diagnosed as DSRCT at Department of Pathology, Henry Ford Health System, and Indiana University, USA between 2016 and 2022 were performed. A total of seven cases of DSRCT from four patients were included in this study. The cytological findings were correlated with concurrent or subsequent biopsy findings. Results All patients were male, with age ranging from 21 to 29 years. Two patients had primary tumor in the abdomen, one in the retroperitoneum, and one in the inguinal region. The tumors measured from 7.5 to 17 cm in size. Six out of seven cases showed typical hypercellular smears of small round cells with inconspicuous nucleoli, scant cytoplasm, and rare nuclear molding. The cytomorphology in Case no. 1 was unusual, showing discohesive pleomorphic tumor cells with large irregular nuclei, prominent nucleoli, occasional binucleation, and frequent mitotic activity. A subset of tumor cells demonstrated rhabdoid features. The tumor cells were positive for keratins (dot‐like), desmin, WT‐1, and CD15. In Case no. 4, the immunohistochemistry for desmin and WT‐1 was unusually negative reflecting the variability of the staining pattern. Three cases were positive for EWSR1 rearrangement by fluorescence in situ hybridization (FISH) and one positive for EWSR1‐WTI gene fusion by reverse transcriptase‐polymerase chain reaction (RT‐PCR). All seven cases had concurrent/subsequent surgical pathology diagnosis consistent with DSRCT. Conclusion Cytologic diagnosis for DSRCT is challenging but can be achieved with appropriate cytomorphology, IHC profiles, molecular studies, and demographic information. Rare rhabdoid differentiation can occur in DSRCT and can be present in effusion cytology.

Abstract Background The tau PET imaging with 18F‐flortacipir (18F‐FTP) has focused interest in accurately tracking longitudinal tau changes in Alzheimer's disease [1]. Thus, minimizing variability is critical. Off‐target signal has the potential to complicate interpretation of tau‐PET imaging due to potential spillover or bleed‐in effects, with increased effects seen in later stages of Alzheimer's due to cerebral atrophy and proximity of off‐target areas to relevant cortical areas[2]. Previously, we demonstrated the effect of uptake period activity on 18F‐FTP signal. With increasing recent interest in demographic factors that may affect off‐target binding, we investigated the effect of age in extra‐cerebral off‐target signal in 18F‐FTP PET imaging. Method Standard 18F‐FTP PET protocol was performed in 330 participants. Two independent readers measured tau uptake in predetermined off‐target regions, including extraocular muscle, meninges, and occipital bone among others. Linear regression models assessed the relationship between participants’ age, sex, and tau uptake values (SUV and SUVr) (SUV = (Tissue radioactivity concentration / Injected dose) / Body weight & SUVr = SUV of target region/ SUV of reference region.) Result Sex had a significant effect on off‐target signal in most brain regions, with variable positive or negative correlation based on area. Notably, SUV in the eyeball‐retina, occipital bone, upper skull meninges all showed significant positive correlation with sex, with ‘male’ status generally associated with lower SUV. The greatest effect of sex was observed in superior skull meninges, occipital bone, and internal carotid artery ( p <0.001). Age showed minimally affected SUV and SUVr in off‐target regions. SUVr values show a significant correlation with SUV values of upper skull meninges in sex. Cognitive status did not significantly affect off‐target SUV. Conclusion We observed that sex significantly affected extra‐brain off‐target signal in 18F‐FTP PET imaging, while age has minimal effect, adding to previous evidence of off‐target binding within brain regions. Further evaluation is necessary to understand the age‐related effects on off‐target regions. As a result, the variability introduced by sex may pose challenges to studying tau accumulation.

Background: One in five Americans turn to TikTok before calling their own physician. Objective: With social media on the rise as a source of health-related information, we aimed to investigate and evaluate popular content about mast cell activation syndrome (MCAS) on TikTok. Methods: Between June 14 and 16, 2024, four different MCAS-relevant phrases were searched on TikTok, and the top 50 most watched videos were analyzed independently by three subinvestigators. The global quality score (GQS) (range from 1 to 5) was applied to assess the value of the educational videos. The profession of the content creator, use of MCAS Vienna diagnostic criteria, association with postural orthostatic syndrome (POTS)/Ehlers Danlos syndrome (EDS), and information trends were also analyzed. Results: The 50 most watched MCAS-related videos collectively had > 6.5 million views, and the average number of views per video was 131,500. Most videos were created by health-care professionals (58%), including physicians (26%) and other health-care professionals (32%), whereas the minority were created by non‐health-care professionals (42%). Only one video included the MCAS Vienna criteria (2%), and 12 videos associated MCAS with POTS and/or EDS (24%). The average GQS was 1.94 (SD 0.34). Common MCAS misinformation trends included the following: inaccuracy of symptoms, diagnostic criteria, triggers, and treatment options. Conclusion: Most MCAS videos on TikTok contained misinformation, did not include key diagnostic criteria, and had poor GQS. The most viewed videos were primarily created by health-care professionals. Patients and health-care providers need to be aware of the quality of health-care information on social media.

ABSTRACT Musculoskeletal infection (MSKI) remains a major problem after trauma and elective orthopedic surgery. Chronic MSKI is related to the formation of biofilm, which impairs diagnosis and effective treatments. Therefore, to understand and communicate global standards and best practices, the 2025 International Consensus Meeting (ICM) on MSKI created a Biofilm Section to address crucial aspects of biofilm biology pertaining to its mechanisms of drug resistance and immune evasion, and potential approaches to overcome them. This featured a 2‐year process, with final voting and discussion on May 8–10, 2025, in Istanbul, Turkey. This Consensus Article is the effort of the Biofilm Basic Mechanisms Workgroup, which interpreted the results on ICM questions related to (1) the infectious microenvironment; (2) appropriate inocula in preclinical research; (3) biofilm behavior in infected tissues; and (4) synergy within biofilms and with other comorbidities. Collectively, we find that this field has the necessary research tools to discover the pathophysiology of orthopedic implant‐associated biofilm development and maturation, perform clinically relevant studies in animal models, and elucidate mechanisms that allow opportunistic infections in compromised tissues and patients with other health issues.

Abstract Background Ten years after the original publication, the Centiloid framework is now broadly used to harmonize amyloid‐PET quantification, facilitate data sharing and comparison across cohorts, and even assist visual interpretation in clinical settings. We evaluated the global implementation of Centiloids by comparing their distribution and corresponding positivity thresholds across cohorts. Methods We gathered data from publicly available cohorts and reached out to investigators across the world to collect cross‐sectional Centiloids, demographic and clinical information, and visual read data. Gaussian mixture models (GMM, k=2) were fitted to Centiloid values for each cohort and cutoffs were calculated as mean + 2SD of the lower Gaussian. When visual reads were available, we determined Centiloid cutoffs that maximized correspondence with visual reads (Cohen's kappa). Data was combined across cohorts using random effects meta‐analyses. Results As of January 2025, we included 37 cohorts ( n = 41,678 participants) with heterogeneous pipelines, radiotracers, and clinical and demographic characteristics (Table‐1). The low Gaussian peaks ranged from ‐9 to 10CL; the meta‐analysis identified a common peak at 1CL. The second peaks were more heterogeneous (range=38‐102CL; meta‐analysis outcome=64CL). Across cohorts, the proportion of cognitively unimpaired versus impaired participants impacted the position of both peaks, with better separation in cohorts enriched in impaired individuals (Figure 1C). The meta‐analysis indicated a GMM‐based cutoff of 19CL (95%CI: 16‐21CL, Figure 1B); subgroup analyses showed no evidence of significant effect between single versus multicenter settings (17 versus 20CL, p = 0.30), MRI‐based or PET‐only processing (18 versus 19CL, p = 0.88), and no evidence of difference across radiotracers (Flutemetamol: 16CL; PIB: 17CL, Flutafuranol: 18CL, Florbetaben: 19CL, Florbetapir: 20CL, p = 0.78). In a subset of 29,496 participants with visual reads available, binary visual reads corresponded well to Centiloids (common kappa=0.86, Figure 2A). The visual read‐based cutoff of 24CL (95%CI: 21‐27CL, Figure 2B) maximized correspondence between visual read and quantification and was slightly higher than the GMM‐based cutoff. All meta‐analysis models showed high non‐random heterogeneity (I 2 >80%) across studies, suggesting non‐random differences in peaks and cutoffs. Conclusions Meta‐analysis‐based cutoffs align well with thresholds from the existing literature. High heterogeneity among studies underscores the need to investigate contributing factors, raising concerns about applying common cutoffs.

Abstract Background Precise cross‐tracer harmonization of tau PET imaging is essential for comparing tau burden across different tracers and studies. Here, we evaluated the performance of the universal tau PET scale (Uniτ) in harmonizing Flortaucipir, MK6240, PI2620, and RO948 tau PET images into a universal scale. Method We assessed 485 individuals across aging and AD spectrum scanned head‐to‐head with Flortaucipir and MK6240, and a subset of 90 individuals with additional PI2620 and RO948. We generated tau PET SUVRs using the inferior cerebellar gray matter as reference with a common 8mm FWHM. We estimated Uniτ parameters on a training set ( n = 200) by fitting a smoothed hyperbolic tangent equation to the Meta‐Temporal ROI anchored in the mean SUVR of young participants and the 90th percentile from cognitively impaired individuals. We compared tau positivity on the Uniτ scale with classifications from SUVRs (mean + 3 SD from Youngs). We applied the same equation to all brain voxels to generate Uniτ 3D images. Then, we extracted mean Uniτ values for key ROIs and correlated them with ROI‐based Uniτ values to evaluate voxel‐wise estimates. Result Using tracer‐specific parameters, Uniτ harmonized Flortaucipir, MK6240, PI2620, and RO948 to the same scale, aligning values near the identity line and confirming its applicability across tau PET tracers (Figure 1). For Flortaucipir, Uniτ tau positivity matched original SUVR classifications (ground truth), with only one mismatch for MK6240 (Figure 1). Applying the Uniτ transformation to all brain voxels effectively harmonized 3D images to a common scale, reducing visual variabilities (Figure 2). Furthermore, ROI‐based estimates and those extracted from the 3D Uniτ images were identical (Figure 3). Conclusion Our results indicate that tau PET tracers can be harmonized to a common scale using a large head‐to‐head dataset. The Uniτ scale can harmonize entire 3D tau PET images, suggesting that there is no need to use pre‐established ROIs, which would constrain the analysis to a few brain regions. Uniτ is freely accessible across platforms ( www.unitau.app ) for ROI and 3D tau PET harmonization.

Abstract Background Sex, education and race/ethnicity are all associated with risk of Alzheimer's disease dementia. Here, we assess the effects of self‐reported sex, educational attainment and race/ethnicity on amyloid‐positivity, and tau‐PET‐positivity in 12,048 (7,394 cognitively unimpaired [CU], 2,177 MCI, and 2,477 dementia) individuals from 42 cohorts worldwide. Method Logistic generalized estimating equations were used to estimate frequency of amyloid‐positivity (using cohort‐specific thresholds for amyloid‐PET [84%] or CSF) and tau‐PET‐positivity (cohort‐specific thresholds of 2SD above mean temporal uptake in amyloid‐negative controls). We assessed: i) sex and APOEε4 ( N = 10,098) associations, to complement earlier findings of a higher frequency of tau‐positivity in females, ii) effects of lower/higher education ( N = 10,970; cohort‐specific median‐split), and iii) effects of race/ethnicity (non‐Hispanic White [hereafter: White], N = 4880; Asian, N = 116; Black or African‐American [hereafter: Black], N = 353; Hispanic, N = 356, only from Northern‐American cohorts). Outcomes were frequency of amyloid‐positivity in CU individuals only, and tau‐PET‐positivity in both amyloid‐positive (AB+) CU and cognitively impaired (CI, i.e. MCI and dementia) individuals. Interaction effects on the relationship between age and amyloid/tau‐positivity were assessed and only retained in the models when significant. Result Female sex was associated with an APOEε4 ‐independent increased frequency of amyloid‐positivity (β=0.51[0.22], p = 0.02) in CU and increase of tau‐positivity in both AB+CU (β=0.27[0.08]) and AB+CI (β=0.37[0.08], both p <0.01). Remarkably, tau‐positivity frequencies of female APOEε4 non‐carriers were equivalent to male APOEε4 carriers in AB+CI (Figure 1). No significant sex* APOE interactions were observed. In CU, higher education was associated with lower amyloid‐positivity frequency (β=‐0.12[0.05], p = 0.02). In contrast, among AB+CU, there was an age*education interaction effect that indicated more pronounced age effects on tau‐positivity in individuals with higher education (age*education:β interaction =0.03[0.01], p <0.01). There were no education effects in AB+CI (Figure 2). In CU, an age*race/ethnicity interaction effect was observed across all non‐White groups compared to White (Hispanic:β interaction =‐0.05[0.01], p <0.01; Black:‐0.04[0.01], p <0.01; Asian:‐0.02[0.01], p = 0.04). This suggests that the impact of age on amyloid‐positivity was less pronounced in non‐White groups. Furthermore, in AB+CI, Hispanic ethnicity was related to higher tau‐positivity frequency than White (β=0.51[0.22], p = 0.02; Figure 3). Conclusion In this multi‐center initiative comprised of clinical and community‐based cohorts, we observed that self‐reported sex, educational attainment and race/ethnicity were related to positivity‐frequencies of Alzheimer's disease pathology.