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Background/Objectives: The role of iron in Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) has been debated. However, the effects of iron on protein burden in these diseases remain poorly elucidated. We hypothesized that there is an association between iron deposition and tau and beta-amyloid deposition in deep grey matter (GM) regions in FTLD. Methods: Neuropathological samples were collected from two control subjects and 10 disease subjects. This included 12 subjects, with several pathological subgroups represented by only one or two cases. Of the 10 disease subjects, one had low-level AD neuropathology (L-AD), and one had high-level AD neuropathology (H-AD), whereas the remaining eight subjects had FTLD-tau pathology, including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), globular glial tauopathy (GGT), and Pick’s disease (PiD). Neuropathological samples were stained for iron with Prussian blue (PB) and ferritin, tau, and beta-amyloid in the basal ganglia (BG). All 12 subjects had also undergone diffusion MRI, amyloid-PET (PiB-PET), and Tau-PET (flortaucipir) before death. Diffusion tensor imaging mean diffusivity (MD) from BG was examined in each subject. Spearman’s rank correlations between imaging and histology were calculated. Results: Increased BG iron was observed in PSP subjects. Prussian blue and ferritin measures were associated with higher tau- and β-amyloid pathological burden. Tau-PET uptake correlated with iron in the BG. Conclusions: The results of this exploratory study suggest associations between iron burden and tau- and β-amyloid-related measures within basal ganglia regions that may help to explain increased PET signals in AD and FTLD-Tau. Our findings should be considered to be hypothesis-generating and require validation. These preliminary findings require validation in larger cohorts.

Imaging biomarkers complement traditional risk assessment by enabling direct patient-specific detection and characterization of subclinical atherosclerotic cardiovascular disease, which supports earlier diagnosis, improved risk stratification, and more personalized cardiovascular prevention.

Abstract We are interested in DNA stiffness in vitro and in vivo . Classical approaches for measuring this parameter in vitro involve tedious T4 DNA ligase-mediated cyclization kinetics experiments performed for one DNA fragment length at a time to establish effective local end-end concentrations ( J -factors). Protein-mediated DNA looping is a more relevant biological reaction. An efficient approach to determine length-dependent protein-mediated DNA J - loop values in vitro has been lacking. We describe LOOP-TAG, a massively-parallel method. We leverage intramolecular DNA looping and tagmentation catalyzed by Tn5 transposase (Tnp) tethered to the terminus of a ∼1,000-bp bead-bound duplex DNA. We detected loops terminating with Tnp. Counts of the resulting DNA looping-dependent bead-bound tagmentation products from deep sequencing determine DNA loop length probabilities at single-base pair resolution for all bead-bound fragments. When normalized to DNA fragment length probabilities from tagmentation using known concentrations of free Tnp, length-dependent J - loop values are directly determined. We demonstrate LOOP-TAG for Tnp tethered in two ways and in the presence of DNA-kinking architectural DNA binding protein Nhp6A. Intermediate length J-loop values are consistent with expectations of wormlike chain theory after accounting for strong sequence-dependence of Tnp. DNA loops are shifted to smaller sizes in the presence of Nhp6A, as predicted. (200/200 words)

Abstract Varlilumab is a monoclonal antibody with agonistic activity on CD27. The efficacy of single-agent PD-1 inhibitors on aggressive B-cell non-Hodkin lymphoma is limited. Preclinical and phase 1 data suggest that Varlilumab is safe and may have synergistic activity with PD-1 inhibitors. In the DIAL study, we explored whether dual immunomodulatory therapy with Varlilumab and Nivolumab in patients with relapsed/refractory aggressive B-NHL was safe and effective. We conducted a randomized phase II clinical trial on adult patients with relapsed/refractory aggressive B-NHL. Patients were randomized to receive Nivolumab monotherapy in the control group and Varlilumab combined with Nivolumab in the experimental group. Crossover to the experimental group was allowed upon progression in the control group. The primary endpoint was the overall response rate based on the Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC). 54 patients underwent randomization, and 51 received assigned intervention and were included in the intention-to-treat analysis. Objective response was observed in 6 out of 51 patients (ORR 12%). There were 4 responders (ORR 16%) in the Nivolumab group and 2 responders (ORR 7.6%) in the Nivolumab and Varlilumab combination group (p = 0.3). None of the 7 patients that crossed over to the experimental group responded to the addition of Varlilumab. The ORR of patients who were previously exposed to CAR-T cell therapy was 13% (5 out of 39) compared to 8.3% (1 out of 12) in the unexposed patients (p > 0.99). The rate of treatment emergent adverse events was similar between groups, and there was no fatal TEAE in the study. The addition of Varlilumab to Nivolumb did not improve outcomes in patients with aggressive B-NHL. Even though this trial was not designed to evaluate immunotherapy as a rescue therapy after CAR-T failure, most patients (76%) had previously received CAR-T therapy, and their outcomes were equally poor.

Abstract Objective To evaluate whether systemic hormone replacement therapy (HRT) influences recurrence outcomes in postmenopausal patients with idiopathic subglottic stenosis (iSGS). Study Design Retrospective cohort study. Setting Tertiary academic medical center. Methods Postmenopausal women (≥50 years) with iSGS who underwent laser‐wedge excision between 2002 and 2024 were included. Patients were categorized by systemic HRT exposure (oral estrogen, progesterone, combined estrogen‐progesterone, or transdermal estrogen) at or before their first surgery. Overdispersion was assessed for all Poisson models; given significant overdispersion, negative binomial regression with a log‐offset for follow‐up time was used as the primary model. Surgery‐free intervals were analyzed using linear mixed models, and time to first recurrence using Cox regression. Models were adjusted for age, body mass index (BMI), parity, oophorectomy, follow‐up length, surgery type, and serial intralesional steroid injections (SILSI) use. Results Among 125 patients, 96 had never used HRT (Never HRT) and 29 used HRT, including 19 actively using HRT at presentation (Current HRT), 5 past users, and 5 subsequent users. The HRT versus Never‐HRT recurrence rate comparison was not significant (adjusted incidence rate ratio [IRR] = 0.81, 95% CI: 0.48‐1.37, P = .422). However, Current HRT use was associated with a 53% lower adjusted recurrence rate versus Never‐HRT use (adjusted IRR = 0.47, 95% CI: 0.25, 0.89, P = .0203). Surgery‐free intervals and time to first recurrence trended longer in Current HRT users but were not statistically significant. Conclusion Current HRT use at presentation was associated with significantly fewer recurrences in postmenopausal iSGS patients. These findings may inform individualized, shared decision‐making regarding HRT use in this population. Level of Evidence 3.

Purpose To compare short‐term outcomes of intratunnel anchor fixation versus transtibial pull‐through repair for meniscus root tears with a minimum of 12‐month follow‐up. Methods Patients who underwent primary meniscus root repair between 2011 and 2024 at a single institution were retrospectively reviewed. Inclusion criteria consisted of primary medial or lateral meniscus root repair using either intratunnel anchor fixation or transtibial pull‐through repair, availability of preoperative radiographs, and completion of postoperative patient‐reported outcome measures with a minimum of 12‐month follow‐up. The groups were propensity‐matched by age, sex, body mass index, operative side, root laterality, and concomitant procedures. Baseline radiographic characteristics (hip‐knee‐ankle angle and posterior tibial slope) were measured. Outcomes included Lysholm score, International Knee Documentation Committee score, Tegner activity score (preoperative and postoperative), Visual Analog Scale for pain at rest and with activity, satisfaction, subjective surgical outcome, and reoperations. Results Fifty patients who underwent intratunnel anchor fixation (mean age, 44 years) were propensity‐matched to 100 patients who underwent transtibial pull‐through repair (mean age, 41 years). Mean follow‐up was 1.5 years (range, 1.0‐2.3) in the intratunnel anchor group and 6.1 years (range, 2.7‐13.7) in the transtibial pull‐through group. Reoperation rates were 8% and 14%, respectively ( P = .43), with repair failure occurring in 4% and 6% ( P > .99). Preoperative and postoperative Tegner scores were similar between groups. Tegner minimal clinical important difference was 0.8, and 26.5% of intratunnel anchor patients achieved this compared with 0% of transtibial pull‐through patients. Patients in the intratunnel anchor cohort reported slightly lower Visual Analog Scale pain with activity (1.8 vs 2.5, P = .02). Postoperative Lysholm (87 vs 83, P = .05) and International Knee Documentation Committee scores (79 vs 76, P = .09) were comparable between groups. A greater proportion of intratunnel anchor patients achieved Patient Acceptable Symptomatic State compared with transtibial pull‐through patients for Visual Analog Scale with activity (74% vs 56%, P = .03) and Lysholm (66% vs 47%, P = .01). Most patients in both cohorts rated their outcome as “much better” or “slightly better” ( P = .49), and satisfaction scores were high. Conclusions At short‐term follow‐up, both the intratunnel anchor and transtibial pull‐through techniques showed high patient satisfaction and comparable overall clinical outcomes. There were no differences in reoperation rates between techniques. Level of Evidence Level III, retrospective comparative case series.