Citations

Abstract Background Anti‐amyloid therapy trials have reported changes in some Alzheimer's disease (AD) blood biomarkers (BBMs) suggesting that these BBMs may be useful minimally invasive measures of amyloid clearance and treatment outcomes. However, a better understanding of how AD BBMs changes at the individual level reflect treatment response in relation to other relevant clinical endpoints is necessary before they can be adopted for treatment monitoring. Here, several AD BBMs were assessed longitudinally in patients undergoing lecanemab therapy. Method Patients undergoing lecanemab therapy at Mayo Clinic, Rochester, MN were recruited to participate in this study. Patients were asked to provide an EDTA‐plasma sample before treatment initiation during the first infusion visit and thereafter at 3‐, 6‐, 12‐, and 18 months post‐treatment. p ‐tau217, p ‐tau181, GFAP, NfL, Aβ42, Aβ40, Aβ42/40, and p ‐tau217/Aβ42 measurements were obtained using Fujirebio Lumipulse assays. Biomarker median differences were assessed between all time points. Patients were grouped into three categories: a decreased biomarker (median decrease of at least 10%), an increased biomarker (median increase of at least 10%), and a stable biomarker (median change < +/−10%.) Biomarker data up to 6 months after treatment is presented. Result Of forty‐one patients enrolled since November 2023, twenty had time points up to 6 months. None of the biomarkers showed a statistically significant median change from baseline at 3 months ( p >0.05). At 6 months, only Aβ42/40 showed a statistically significant median change (decrease) between 0 and 6 months ( n = 20, p = 0.0058). Table 1 shows patients grouped by median biomarker changes from baseline to 6 months. GFAP, p ‐tau217, and Aβ42/40 exhibited the greatest number of patients with decreased biomarker concentrations (80%, 60%, and 60% of patients with median decreases of ‐25%, ‐26%, and ‐18% respectively), followed by p ‐tau181 (50% of patients; median decrease ‐22%), p ‐tau217/Aβ42 (45% of patients; median decrease ‐40%) and Aβ42 (45% of patients; median decrease ‐18%). None of the patients showed a decreased NfL or Aβ40 concentration. Conclusion Preliminarily analysis revealed that GFAP, p ‐tau217, and Aβ42/40 had the most frequent post‐lecanemab biomarker decreases. Additional sample collection is ongoing to assess the association of AD BBM changes with Amyloid PET over time.

Abstract Purpose Iliopsoas tendinitis following total hip arthroplasty (THA) has been described to result from acetabular component overhang as well as prominent femoral collars. Yet, a portion of patients experience iliopsoas tendinitis in the setting of well-positioned components. The purpose of this study was to assess anatomic factors predisposing to iliopsoas tendinitis after THA. Methods Patients with THAs performed at three academic institutions who subsequently underwent arthroscopic iliopsoas release were retrospectively reviewed from 2015 to 2025 and propensity matched in a 1:3 fashion to a control group of THAs without subsequent iliopsoas release. Controls were matched by age, surgery date, laterality, sex, surgical approach, and implanted femoral component. Patients with iliopsoas tendinitis and subsequent release (THA-IP) were evaluated for anterior acetabular component overhang and femoral collar overhang, when a collar was present. We also evaluated the absolute and relative profile of the lesser trochanter on anteroposterior radiographs, understanding that when less of the lesser trochanter is visualized, the trochanter is anatomically displaced posterolaterally, resulting in a more arduous route from the inner pelvic origin of the iliopsoas to its insertion on the femur. Results Forty-five patients (mean age: 57±11; 71% female; 19 direct anterior, 10 anterolateral, 16 posterior approach) undergoing THA-IP were analyzed and matched to 135 controls. Both groups demonstrated a median cup size of 54 mm and head size of 36 mm. Average time to iliopsoas release after THA was 4 years. Anterior cup overhang of &gt;2 mm was present in 49% of THA-IP patients, with 18% having collared femoral components, and 9% demonstrating collar overhang of &gt;2 mm. Overall, 19 THA-IP patients had &lt;2 mm of cup and collar overhang and 26 patients had &gt;2 mm of overhang. THA-IP patients with &lt;2 mm of cup and collar overhang had significantly greater relative posterolateralization of the lesser trochanter compared to those with overhang of &gt;2 mm (p=0.010) and to controls (p=0.037). Conclusion Visualizing “Less of the Lesser” on anteroposterior hip radiographs and associated posterolateralization of the lesser trochanter may be an anatomic risk factor for iliopsoas tendinitis following THA, even in the presence of satisfactorily positioned components.

Objective The objective of the study was to determine risk factors for relapse of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) after reinduction of remission with rituximab and discontinuation of maintenance therapy. Methods This is a post hoc analysis of the RITAZAREM clinical trial. Patients aged 15 years or older with AAV and a positive test for anti–proteinase‐3 or anti‐myeloperoxidase‐ANCA who achieved remission after reinduction with rituximab and glucocorticoids were randomized at month 4 to receive continued rituximab or azathioprine for a maintenance period up to 24 months, followed by observation until relapse or up to 48 months. Generalized estimating equations logistic regression identified baseline and time‐varying risk factors for relapse by the next visit for the two study phases: maintenance (months 4–24) and off‐treatment (months 24–48). Results Among 170 patients (median [interquartile range] age 59 [48–68] years, disease duration 5 [2–10] years), 99 relapses occurred (46 during maintenance). During maintenance, musculoskeletal involvement (odds ratio [OR]: 2.8, 95% confidence interval [CI]: 1.1–7.2; P = 0.03) and higher patient global assessment (OR: 1.1, 95% CI: 1.0–1.2; P = 0.04) were associated with relapse. During the off‐treatment phase, presence of CD19 + B cells (OR: 2.5, 95% CI: 1.2–5.1; P = 0.01) and reappearance of ANCA (OR: 3.2, 95% CI: 1.3–7.7; P = 0.01) were each associated with higher relapse risk. Multivariable analysis identified markers of inflammation (changes in platelets, white blood cells, and IgA) associated with relapse. Conclusion Risk factors for relapse in AAV vary by treatment phase. Monitoring markers of inflammation and immune reconstitution may identify patients at risk for relapse, particularly after treatment withdrawal.

ABSTRACT The concentration of cells is a key component of modern blood tests. Given the biomarker potential of extracellular vesicles (EVs) in blood, we aimed to establish reference ranges for blood cell‐derived EVs using flow cytometry. To address the orders‐of‐magnitude variability in reported EV concentrations between different flow cytometers (FCMs), we first validated a calibration methodology to enable reproducible EV concentration measurements. The methodology was evaluated in an interlaboratory comparison study and shows that calibration reduces the median absolute deviation of EV concentrations measured on 25 different FCMs from 67 % to 25 %–31 %. The calibration methodology was then used to determine reference ranges of erythrocyte‐, leukocyte‐, and platelet‐derived EVs in human blood plasma in a cohort of healthy individuals ( n = 224). This study demonstrates that calibration enables comparable concentration measurements of blood cell‐derived EVs, thereby bringing EVs one step closer to clinical applications.

Abstract Background 0.05% Chlorhexidine gluconate (CHG) is now commonly used as an antiseptic irrigation for inflatable penile prosthesis (IPP) surgery. Limited in vitro data suggest compatibility of 0.05% CHG with antibiotic impregnated IPP devices; however, very little clinical research exists to guide use of 0.05% CHG in this population. Aim Assess the relationship of 0.05% CHG and antibiotic impregnated IPP infection in a large multi-institutional cohort. Methods We retrospectively reviewed a multi-institutional cohort of patients who underwent antibiotic impregnated IPP implantation. We identified cases using intraoperative 0.05% CHG and an equal number of consecutive control cases without 0.05% CHG use from each center for comparison. The primary outcome was IPP infection requiring explantation. Patient demographics and surgical variables were analyzed using chi-square tests and multivariable logistic regression to identify variables associated with infection. Outcomes The primary outcome was IPP infection requiring device explanation. Results Among 14 participating institutions, 761 cases using an antibiotic impregnated IPP were analyzed. Of these, 348 (45.7%) had 0.05% CHG used during the case. Median follow-up was 4 months (interquartile range 1-12) for the 0.05% CHG group and 8 months (interquartile range 2-21) for the control group. Intraoperative 0.05% CHG utilization was not associated with antibiotic impregnated IPP infection rate (1.9% vs. 2.0%, P = .9). On multivariable analysis, prior IPP infection (OR 6.32, 95% CI 1.32-30.2, P = .021) and prior priapism (OR 10.01, 95% CI 1.18-89.7, P = .039) were associated with increased infection risk. Clinical implications The use of 0.05% CHG irrigation with antibiotic impregnated IPPs was associated with similar infection rates compared to antibiotic irrigation. Strengths and limitations Limitations include the use of a historical comparator cohort which may introduce unknown confounders, practice variation between multiple sites, shorter follow-up in the 0.05% CHG cohort, and the low incidence of IPP infection which may limit statistical power despite a large sample. The major strengths include the large, multi-institutional cohort, and the use of consecutive patients to minimize selection bias. Conclusion 0.05% CHG utilization was not associated with infection rates in antibiotic impregnated IPPs.

Background: Previous research has demonstrated that moderate-intensity inspiratory muscle training (IMT) improves inspiratory strength and exercise performance in athletes, but the impact of high-intensity IMT on inspiratory strength in healthy adults is unclear. The purpose of this study was to compare the effects of high-intensity versus moderate-intensity IMT on inspiratory strength and VO 2 peak in healthy adults. Methods: Twenty-six adults enrolled in this double-blinded randomized controlled trial. Participants completed an inspiratory strength assessment through S-Index and VO 2 peak testing before randomization into a moderate-intensity or high-intensity group. Participants in both groups performed IMT to 40 repetitions or task failure once per day, 5 times per week for 8 weeks. IMT intensity was 50% and 80% of pretraining S-Index for the moderate-intensity and high-intensity groups, respectively. S-Index and VO 2 peak testing were repeated at the end of the trial. Repeated measures ANOVA were used to assess differences of pretraining and post-training S-Index and VO 2 peak between groups. Results: A significant increase in mean (SD) S-Index from pretraining to post-training was present for both moderate-intensity (7.6% (8.9), P = .001) and high-intensity (10.8% (11.7), P < .001) groups. No significant group ( P = .88) or interaction ( P = .44) effects existed for S-Index. There were no significant main effects for group, time, or interaction for VO 2 peak ( P > .05 for all). Conclusions: Both moderate-intensity and high-intensity IMT to task failure in healthy adults led to significant improvements in inspiratory strength. No effects were observed in either group on changes in VO 2 peak. Given that moderate-intensity and high-intensity IMT to task failure were both effective at improving inspiratory strength in healthy adults, training intensity at less intense, moderate levels can be used to achieve similar strength gains.

Importance The 2007 US Food and Drug Administration (FDA) Amendments Act (FDAAA) expanded its safety-related regulatory authorities, including enhanced postmarketing safety surveillance and new clinical study requirements. However, whether FDAAA has been associated with differences in the frequency and timing of postmarket safety-related actions remains poorly understood. Objectives To assess whether FDAAA was associated with differences in time to first FDA postmarket drug safety−related action, and to assess whether therapeutic and regulatory characteristics were associated with differences in time to these actions post-FDAAA implementation. Design and Setting This was a cross-sectional study of all novel therapeutics approved by FDA between January 1, 2001, and December 31, 2019, and followed up through December 31, 2024. Approvals were categorized as pre- or post-FDAAA (before or after March 25, 2008). Post-FDAAA therapeutic and regulatory characteristics included drug class, therapeutic area, orphan status, special regulatory pathway, and presence of a boxed warning or FDAAA-mandated postmarket study requirement at approval. Main Outcomes and Measures Time to first FDA postmarket drug safety−related action, a composite of withdrawals due to safety concerns, incremental boxed warnings, and safety-related communications. Results Of the 560 novel therapeutics approved, FDA took postmarket safety-related actions for 130 (23.2%) during a median (IQR) follow-up of 12.1 (7.8-18.2) years. These comprised actions within 5 years of approval for 34 of 164 therapeutics (20.7%) approved pre-FDAAA, and 57 of 396 (14.4%) approved post-FDAAA (rate ratio, 0.69; 95% CI, 0.47-1.02; P = .06). Compared to pre-FDAAA approvals, after accounting for therapeutic and regulatory characteristics, there was no statistically significant difference in time to first postmarket safety-related action for post-FDAAA approvals (time ratio, 0.40; 95% CI, 0.15-1.07; P = .07). However, among therapeutics with postmarket safety-related actions within 5 years of approval, median time to first action was shorter post-FDAAA (median [IQR], 3.1 (2.0-4.2) years for pre-FDAAA vs 1.8 [1.3-2.5] years post-FDAAA; P = .004). Among 260 novel therapeutics approved post-FDAAA, after the October 2013 enactment of breakthrough therapy designation, the following therapeutic and regulatory characteristics were associated with time to first postmarket safety-related action: small molecule type (time ratio, 0.24; 95% CI, 0.07-0.81; P = .02), orphan designation (time ratio, 8.29; 95% CI, 2.43-28.27; P &amp;lt; .001), fast track (time ratio, 0.22; 95% CI, 0.08-0.64; P = .005), breakthrough therapy designation (time ratio, 0.10; 95% CI, 0.03-0.32; P &amp;lt; .001), prolonged regulatory review time (&amp;gt;400 days; time ratio, 0.16; 95% CI, 0.03-0.73; P = .02), and FDAAA-mandated postmarket study requirements at approval (time ratio, 0.35; 95% CI, 0.15-0.80; P = .01). Conclusions and Relevance This cross-sectional analysis found that the enhanced safety-related regulatory authorities of FDAAA were not associated with differences in time to first postmarket safety-related action. However, among therapeutics with postmarket safety-related actions within 5 years of approval, median time to first action was shorter post-FDAAA implementation.