Citations

Abstract INTRODUCTION Plasma biomarkers of Alzheimer's disease (AD) represent accessible alternatives to positron emission tomography (PET) and cerebrospinal fluid (CSF)‐based biomarkers in well‐characterized cohorts. It remains to be determined whether performance is maintained in outpatient clinics comprised of patients with multiple causes of cognitive impairment. METHODS Plasma phosphorylated tau217 (p‐tau217) and amyloid beta (Aβ) 42/40 were measured in 509 patients evaluated in a tertiary‐care memory clinic. Biomarker performance was compared across diagnoses, referencing established cutpoints for positive and negative biomarkers. RESULTS Plasma p‐tau217 distinguished patients with diagnoses of symptomatic AD with 95% sensitivity and 82% specificity. Integration of Aβ42 measurements (p‐tau217/Aβ42) incrementally improved specificity (86%). Plasma p‐tau217 and p‐tau217/Aβ42 concentrations closely associated with established CSF biomarkers of AD (area under the curve [AUC]: 0.94 and 0.96, respectively). Reduced kidney function associated with elevated plasma p‐tau217 and p‐tau217/Aβ42 concentrations in patients without AD (referencing CSF biomarkers). DISCUSSION Plasma p‐tau217 and p‐tau217/Aβ42 concentrations demonstrated robust diagnostic performance in a heterogeneous clinical cohort; interpretation requires consideration of kidney function. Highlights Plasma phosphorylated tau217 (p‐tau217) reliably identified clinic patients with Alzheimer's disease. A two‐cutpoint strategy yielded definitive results in 86% of patients. Integration of plasma amyloid beta (Aβ; p‐tau217/Aβ42) minimally improved diagnostic performance. Plasma p‐tau217 levels were increased in patients with kidney dysfunction.

BACKGROUND: Small, randomized trials of patients with cervical artery dissection showed conflicting results regarding optimal stroke prevention strategies. We aimed to compare outcomes in patients with cervical artery dissection treated with antiplatelets versus anticoagulation. METHODS: This is a multicenter observational retrospective international study (16 countries, 63 sites) that included patients with cervical artery dissection without major trauma. The exposure was antithrombotic treatment type (anticoagulation versus antiplatelets), and outcomes were subsequent ischemic stroke and major hemorrhage (intracranial or extracranial hemorrhage). We used adjusted Cox regression with inverse probability of treatment weighting to determine associations between anticoagulation and study outcomes within 30 and 180 days. The main analysis used an as-treated crossover approach and only included outcomes occurring with the above treatments. RESULTS: The study included 3636 patients (402 [11.1%] received exclusively anticoagulation and 2453 [67.5%] received exclusively antiplatelets). By day 180, there were 162 new ischemic strokes (4.4%) and 28 major hemorrhages (0.8%); 87.0% of ischemic strokes occurred by day 30. In adjusted Cox regression with inverse probability of treatment weighting, compared with antiplatelet therapy, anticoagulation was associated with a nonsignificantly lower risk of subsequent ischemic stroke by day 30 (adjusted hazard ratio [HR], 0.71 [95% CI, 0.45–1.12]; P =0.145) and by day 180 (adjusted HR, 0.80 [95% CI, 0.28–2.24]; P =0.670). Anticoagulation therapy was not associated with a higher risk of major hemorrhage by day 30 (adjusted HR, 1.39 [95% CI, 0.35–5.45]; P =0.637) but was by day 180 (adjusted HR, 5.56 [95% CI, 1.53–20.13]; P =0.009). In interaction analyses, patients with occlusive dissection had significantly lower ischemic stroke risk with anticoagulation (adjusted HR, 0.40 [95% CI, 0.18–0.88]; P interaction =0.009). CONCLUSIONS: Our study does not rule out the benefit of anticoagulation in reducing ischemic stroke risk, particularly in patients with occlusive dissection. If anticoagulation is chosen, it seems reasonable to switch to antiplatelet therapy before 180 days to lower the risk of major bleeding. Large prospective studies are needed to validate our findings.

Abstract Background: Thrombocytopenia commonly occurs in critically ill patients with acute kidney injury (AKI) receiving continuous renal replacement therapy (CRRT) and is associated with poor outcomes. While previous studies have examined static platelet counts and relative declines, the prognostic significance of platelet trajectory patterns before and after CRRT initiation remains unclear. This study investigates the association between platelet count trajectories and in-hospital mortality in critically ill adult patients with AKI receiving CRRT. Methods: This study is a single-center retrospective cohort study utilizing electronic health record (EHR) data from critically ill adults (≥18 years) with AKI who received CRRT at the University of Alabama at Birmingham between January 2012 and December 2023. Platelet trajectories were assessed using mixed-effects models incorporating all platelet measurements within seven days before and after CRRT initiation. The slopes of platelet count change were categorized as descending (≤ -10 × 10³/μL/day), stable (-10 to 10), or ascending (≥ 10), creating a total of nine trajectory patterns by combining the three pre-CRRT and three during-CRRT categories. The primary outcome was in-hospital mortality, which was analyzed in relation to these trajectory patterns using logistic regression models adjusted for demographics, comorbidities, Sequential Organ Failure Assessment (SOFA) score, medications, and use of other organ support devices as covariates. Results: The study included 2,226 critically ill adults with AKI on CRRT, encompassing 8,569 patient-days before and 11,699 patient-days after CRRT initiation for platelet slope calculation. The median age was 59 years (IQR 48–69) and the median SOFA score at CRRT initiation was 12 (9–14). The in-hospital mortality rate was 57.8%. Before CRRT initiation, the most common trajectory was descending (46.2%), while after CRRT initiation, the stable pattern was most prevalent (58.3%). All patterns with a descending platelet trajectory during-CRRT were significantly associated with higher in-hospital mortality (aOR 1.92 [95% CI: 1.16–3.21] for ascending-descending; 1.49 [1.07–2.08] for stable-descending; 1.52 [1.04–2.23] for descending-descending). In contrast, all patterns with stable or increasing platelet counts during-CRRT tended to have lower mortality. Conclusions: A descending platelet trajectory after CRRT initiation was independently associated with increased in-hospital mortality.

Background: There has been minimal literature evaluating how a prior myocardial infraction (MI) influences outcomes after total knee arthroplasty (TKA). Thus, the purpose of this study was to evaluate how the timing, type, and treatment of MI prior to TKA affect postoperative cardiac complications, general medical complications, and surgical complications. Methods: A retrospective comparative study was conducted using a large insurance database. Patients undergoing primary TKA for osteoarthritis were included. Patients who had experienced MI within 2 years before TKA were identified and were matched 1:4 with patients who had not had such an MI on the basis of demographic variables and comorbidities. Patients who had a prior MI were stratified into 4 groups based on the timing of the MI: 0 to <6 months, 6 to <12 months, 12 to <18 months, and 18 to 24 months before TKA. The rates of postoperative cardiac, general medical, and surgical complications were compared between groups. Subanalyses on the prior MI type, treatment, and location were performed. Results: Prior MI was associated with increased risks of postoperative MI (odds ratio [OR], 3.97 [95% confidence interval (CI), 3.20 to 4.93]), heart failure (OR, 1.45 [95% CI, 1.24 to 1.75]), and 90-day mortality (OR, 2.15 [95% CI, 1.41 to 3.28]). The risk of postoperative MI was highest for those with MI within 6 months before TKA (OR, 6.86 [95% CI, 5.34 to 8.82]). Type-1 MI, ST-elevation MI (STEMI), non-ST-elevation MI (NSTEMI), and anterior and inferior MIs were linked to elevated postoperative MI and/or mortality risks, with timing closer to surgery further amplifying the risk. Percutaneous coronary intervention within 6 months before TKA also increased postoperative risks. Type-2 MI within 6 months before TKA was associated with an increased risk of periprosthetic joint infection compared with controls (OR, 4.23 [95% CI, 1.67 to 10.67]). Conclusions: Patients who had a prior MI, particularly within 6 months before TKA, had significantly elevated risks of postoperative MI, heart failure, and mortality. Outcomes varied by MI type, treatment, and location, with type-1 MIs and STEMIs increasing the postoperative mortality risk. Level of Evidence: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

AimsCeramic-on-ceramic (CoC) articulations in total hip arthroplasty (THA) have the advantage of low wear but the unique risk of fracture. After revision for CoC-bearing fracture, third-body ceramic particles can lead to massive wear of cobalt-chrome (CoCr) bearings, causing extremely elevated blood cobalt. We present a multicentre series of five cases where patients sustained fractures of ceramic liners, were revised using a CoCr articulation, and rapidly developed severe cobalt toxicity.MethodsWe identified five cases of cobalt toxicity after fractured CoC THA treated with revision to CoCr on polyethylene bearings. Mean follow-up was three years (5 to 72 months) after re-revision to remove the CoCr bearing.ResultsSymptoms of cobalt toxicity occurred at a mean ten months (6 to 12) after revision for ceramic fracture. All patients developed vision and hearing loss, balance difficulties, and peripheral neuropathy. Several had cardiomyopathy, endocrine abnormalities, and local skin discolouration. Only two reported hip pain. Repeat revision for recognized cobalt toxicity occurred at a mean 22 months after revision for ceramic fracture. Mean serum cobalt level at re-revision was 991 ng/ml (normal value < 1 ng/ml; 734 to 1,302). All CoCr femoral heads exhibited massive wear, and deep tissues showed prominent metal staining. Treatment consisted of debridement and revision to a ceramic femoral head with highly cross-linked polyethylene (HXLPE) liner. Serum cobalt improved to a mean 25 μg/l (1 to 76) at final follow-up. All patients reported partial improvement in vision and hearing, however their peripheral neuropathy and balance difficulties did not recover.ConclusionSystemic cobalt toxicity is a devastating complication of ceramic-bearing fracture in THA treated with CoCr bearings, which may not present with hip symptoms. The diagnosis of this syndrome of systemic cobalt toxicity was significantly delayed following systemic symptoms in this series. Debridement and re-revision to a ceramic-on-HXLPE bearing leads to improvement, but not full resolution, of cobalt toxicity complications.Cite this article: Bone Joint J 2025;107-B(6 Supple B):92–100.

PURPOSE Tumor treating fields (TTFields) use alternating electric fields to disrupt cancer cell proliferation. Feasibility of TTFields therapy with gemcitabine/nab-paclitaxel was previously demonstrated in patients with advanced pancreatic adenocarcinoma. PANOVA-3 was designed to confirm safety and efficacy of TTFields in patients with unresectable locally advanced pancreatic adenocarcinoma (LA-PAC). METHODS In this global phase III trial, 571 patients with newly diagnosed LA-PAC were randomly assigned to receive gemcitabine 1,000 mg/m 2 and nab-paclitaxel 125 mg/m 2 by intravenous infusion once a day on days 1, 8, and 15 of a 28-day cycle with or without TTFields. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), local PFS, pain-free survival, and overall response rate (ORR). Distant PFS was analyzed post hoc. RESULTS OS was significantly prolonged using TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel (median, 16.2 months [95% CI, 15.0 to 18.0] v 14.2 months [95% CI, 12.8 to 15.4]; hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.99]; P = .039). PFS, local PFS, and ORR were not improved. Pain-free survival was significantly prolonged with TTFields with gemcitabine/nab-paclitaxel (median, 15.2 months [95% CI, 10.3 to 22.8] v 9.1 months [95% CI, 7.4 to 12.7]; HR, 0.74 [95% CI, 0.56 to 0.97]; P = .027), as was distant PFS (median, 13.9 months [95% CI, 12.2 to 16.8] v 11.5 months [95% CI, 10.4 to 12.9]; HR, 0.74 [95% CI, 0.57 to 0.96]; P = .022). Device-related skin adverse events (AEs) were experienced by 76.3% of patients. Most device-related skin AEs were mild to moderate, with 7.7% of patients reporting a grade 3 AE. CONCLUSION This study demonstrated significant OS, pain-free survival, and distant PFS benefits for TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in patients with unresectable LA-PAC, with no additive systemic toxicity.

ABSTRACT Although animal studies have linked cellular senescence to the pathogenesis and complications of type 2 diabetes mellitus (T2DM), there is a paucity of corroborating data in humans. Thus, we measured a previously validated marker for senescent cell burden in humans, T‐cell expression of p16 mRNA, along with additional biomarkers, to compare the senescence phenotypes of postmenopausal control (lean, N = 37) and T2DM ( N = 27) participants. To control for effects of obesity alone, we included a third group of obese but non‐diabetic women ( N = 29) who were matched for body mass index to the T2DM participants. In addition, given the increase in fracture risk in T2DM despite preserved or even increased bone mineral density, we related these senescence biomarkers in the T2DM participants to skeletal microarchitectural parameters. Relative to the lean participants, T‐cell p16 and p21 Cip1 expression was increased in the T2DM, but not the obese, non‐diabetic participants. Expression of p16 and p21 Cip1 was positively associated with HbA1c and an index of skin advanced glycation end‐products. T2DM was also associated with an increase in a number of SASP factors. Among participants with T2DM, women in the highest tertile for T‐cell expression of p16 had significantly reduced tibial cortical area and thickness as compared to those in the lower two tertiles. Overall, our studies link cellular senescence to metabolic and skeletal alterations in T2DM and point to the need for further studies evaluating the role of cellular senescence in mediating skeletal fragility, as well as potentially other complications in T2DM.

AbstractBackgroundStimulation‐induced dyskinesias (SID) from deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) are uncommon; however, they are increasingly recognized. Once considered transient and indicative of effective neuromodulation, SID are now seen as potential therapy‐limiting side effects, akin to internal capsule activation. The mechanism and anatomical basis for SID remain poorly understood.MethodsWe conducted a retrospective study of individuals with Parkinson's disease with STN or GPi DBS who experienced SID in the dopaminergic medication OFF state during the monopolar review 1‐month post‐implantation.ResultsWe analyzed 137 monopolar stimulation observations (105 GPi, 32 STN). In the GPi cohort, discriminative fiber tract analysis showed a strong association between SID and the modulation of subthalamo‐pallidal fibers. This correlation was confirmed using leave‐one‐out and five‐fold cross‐validation. We further validated this model by predicting SID in independent STN and GPi cohorts, with the GPi‐based model accounting for significant variance in SID occurrence in both cohorts.ConclusionsSID from STN or GPi DBS likely shares a common pathway via subthalamo‐pallidal connectivity. DBS modulation of these fibers correlates with SID, as confirmed by multiple cross‐validation methods. These findings suggest that the fibers are part of a more extensive and yet‐to‐be‐fully‐characterized dyskinesia network. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

TPS3650 Background: A total neoadjuvant therapy (TNT) approach improves compliance with chemotherapy and increases rates of tumor response compared to neoadjuvant chemoradiation (CRT) alone in those with locally advanced rectal cancer. Recent data indicate that optimal sequencing of TNT involves consolidation (rather than induction) chemotherapy to improve complete response rates. The use of FOLFIRINOX has shown to improve response and outcomes compared to CRT and surgery alone. Data have also shown that patients with clinical complete response (cCR) after TNT may be managed with a watch and wait approach (WW) instead of preemptive total mesorectal resection (TME). However, the optimal consolidation chemotherapy regimen to improve cCR rates has not been established, and a randomized clinical trial has not robustly evaluated cCR as a primary endpoint. We designed this NCI-sponsored study of chemotherapy intensification to address this and to increase cCR rates, provide opportunity for organ preservation, and survival outcomes. Methods: In this multigroup randomized, seamless phase II/III trial (1:1), up to 760 patients with LARC, T4N0, any T with node positive disease (any T, N+) or T3N0 requiring abdominoperineal resection or coloanal anastomosis and distal margin within 12 cm of anal verge will be enrolled. Stratification factors include tumor stage (T4 vs T1-3), nodal stage (N+ vs N0) and distance from anal verge (0–4; 4–8; 8–12 cm). Patients will be randomized to receive neoadjuvant long-course chemoradiation (LCRT) followed by consolidation doublet (mFOLFOX6 or CAPOX (control arm)) or triplet chemotherapy (FOLFIRINOX (experimental arm)) for 3–4 months. LCRT in both arms involve 4500 cGy in 25 fractions over 5 weeks +900 cGy boost in 5 fractions with a fluoropyrimidine. Patients will undergo assessment 8–12 (±4) weeks post-TNT completion. The primary endpoint for the phase II portion will compare cCR between treatment arms. A total number of 312 patients (156 per arm) will provide statistical power of 90.5% to detect a 17% increase in cCR rate, at a one-sided alpha = 0.048. The primary endpoint for the phase III portion will compare disease-free survival (DFS) between arms. A total of 285 DFS events will provide 85% power to detect an effect size of hazard ratio 0.70 at a one-sided alpha of 0.025, requiring enrollment of 760 patients (380 per arm). Secondary objectives include overall survival, organ preservation time, time to distant metastasis, and adverse event rates. This study has accrued 587 patients as of January 2025, and is investigating exploratory correlatives (e.g., ctDNA). Support: U10CA180821, U10CA180882, U24 CA196171. https://acknowledgments.alliancefound.org. Clinicaltrials.gov ID: NCT05610163. Clinical trial information: NCT05610163 .

Abstract Infection is increasingly recognized as a significant cause of morbidity and mortality in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) receiving CD19 chimeric antigen receptor (CAR) T-cell therapy. The current study analyzed the natural history, risk factors, and outcomes of infection in 3350 patients with R/R LBCL receiving commercial CD19 CAR T-cell therapy (n = 2804 axicabtagene ciloleucel [axi-cel], n = 546 tisagenlecleucel) from December 2017 to June 2022. Infection developed in 834 patients (24.9%) within 100 days after infusion, resulting in an infection density of 0.43 per 100 patient days and a 100-day cumulative incidence of 22%. Bacterial, viral, and fungal infections were recorded in 527 (15.7%), 374 (11.2%), and 108 patients (3.2%), respectively, with corresponding infection densities of 0.23, 0.15, and 0.04 per 100 patient days. After a 24-month median follow-up, 1482 patients (44%) had died, with infection as the primary cause in 173 cases (12%). The 100-day infection-related mortality (IRM) was 1.6% (95% confidence interval, 1.2-2.0). Patients with a Karnofsky performance score of ≤80, infection history before CAR T-cell therapy, axi-cel therapy, severe cytokine release syndrome (grade ≥3), and severe immune effector cell–associated neurotoxicity syndrome (grade ≥3) had increased infection risk. Infections within 100 days were an independent risk factor for inferior overall survival beyond day 100 after CD19 CAR T-cell therapy. In conclusion, study results show a significant incidence of infection and IRM in patients with R/R LBCL treated with CD19 CAR T-cell therapy. Furthermore, results identify patients at a heightened risk of infection, offering insights to guide potential interventions aimed at mitigating infection and improving patient outcomes after CAR T-cell therapy.