Citations

Variants in TMEM106B and GRN , which encode lysosomal proteins, interact through unknown mechanisms to increase the risk of age-related cognitive decline and neurodegeneration. Here, we show that these variants converge on a single molecular intermediate: the cleaved intra-lysosomal fibril core of TMEM106B, a precursor to amyloid fibrils that accumulate in the aging brain. A protein-coding TMEM106B risk variant (p.T185) drives fibril core accumulation by impairing its degradation and GRN risk variants amplify this effect. Mice over-expressing the fibril core develop hallmarks of neurodegeneration, and cryo-electron tomography reveals intra-lysosomal fibrils in cultured neurons, mice, and diseased human brain. In GRN -mutation carriers, in whom fibril burden is greatest, fibrils extrude through ruptured lysosomal membranes. These findings identify intra-lysosomal TMEM106B fibrillization as a convergent neurodegeneration mechanism and potential therapeutic target.

Background: Pyrocarbon metacarpophalangeal (MCP) arthroplasty is associated with high rates of recurrent deformity and reoperation in patients with rheumatoid arthritis (RA). We sought to determine the impact of preoperative hand grip strength (HGS) on implant survivorship in these patients. Methods: We included primary pyrocarbon MCP arthroplasties in patients with RA at our single institution from 2000 to 2022. Cox proportional hazard models with restricted cubic splines were used to model the continuous relationship between HGS and hazard for revision, all-cause reoperation, and development of any complication, accounting for multiple joints per patient and adjusting for sex. Kaplan-Meier estimates were used to report survivorship at 2, 5, and 10 years. Results: We included 75 joints in 27 patients with an average preoperative HGS of 8.6 kg (11.1 years of follow-up). There were 16 (21%) total revisions, most commonly for recurrent deformity, along with 8 nonrevision reoperations, most commonly for tendon/ligamentous repair. There was a significant, J-shaped relationship between HGS and hazard for revision ( P = .001) and all-cause reoperation ( P < .001). Patients with HGS below 5.5 and 5.3 kg had an increased risk for revision (hazard ratio [HR]: 13.5) and all-cause reoperation (HR: 9.8) compared with patients with sufficiently high HGS. The 10-year revision survival was 93% in patients with HGS >5.5 kg and 63% in patients ≤5.5 kg. Hand grip strength did not significantly affect hazard for developing a first complication. Conclusion: Very low preoperative HGS is associated with worsened implant survivorship following pyrocarbon MCP arthroplasty in patients with RA.

Sharing research code in an open access version-controlled repository offers significant benefits for both science as a whole and for individual researchers. In this article, we focus on this practice, which is fully aligned with the NIH’s Gold Standard Science (GSS) program as well as FAIR (findable, accessible, interoperable, reusable) and TRUST (transparency, responsibility, user focus, sustainability, technology) principles. Gold Standard Science supports open science by emphasizing transparency, reproducibility, and the use of best practices that enable others to verify and extend research. Pairing a research article’s cited data snapshot with a versioned, environment-specific code release, deposited in a companion code repository, ensures that, upon submission to a medical journal, readers and reviewers can directly verify results. An executable and updatable companion code repository complements, rather than replaces, established research data repositories. When code underlying medical research results is made openly available, then other scientists can inspect, run, and validate analyses. These activities enhance reproducibility, which is a core aim of GSS. Shared code also facilitates collaborative innovation by allowing researchers to extend the utility of the code to new datasets and applications. For researchers, code sharing can increase visibility, credibility, and citation impact. Demonstrating transparency through shared executable and updatable code builds trust with journal readers, peer reviewers, funders, and peers. Shared code in an open access repository signals adherence to high standards of scientific integrity and attracts opportunities for collaboration. A researcher who shares code receives recognition as a leader in reproducible, trustworthy research consistent with NIH’s GSS principles.

ABSTRACT Objective To determine the test performance of cutaneous phosphorylated alpha‐synuclein (P‐SYN) in dementia with Lewy bodies (DLB), individuals with reduced Montreal Cognitive Assessment (MoCA) and healthy controls. Methods This is the first subgroup analysis of the Synuclein‐One study, a prospective, blinded study evaluating P‐SYN detection from skin biopsies in 218 subjects with a referral diagnosis of control ( N = 151) and DLB ( N = 67). All subjects completed detailed examinations, questionnaires, and had skin biopsies for detection of P‐SYN. DLB patients were included if meeting the 4th DLB consensus probable criteria. Control subjects, aged 40–99, had no history, examination findings, or symptoms suggestive of a synucleinopathy or neurodegenerative disease. An expert review panel, blinded to pathological data, determined the final diagnosis. Controls with reduced MoCA (MoCA < 26, N = 26) at screening were analyzed separately. Results After expert panel review, only 50/67 patients met consensus criteria for DLB, 26/151 controls had a reduced MoCA, and 120/151 controls had a normal MoCA. The proportions of subjects with cutaneous P‐SYN detected by skin biopsy were 96.0% (48 of 50) of the DLB group, 31% (8 of 26) of the controls with reduced MoCA, and 3.3% (4 of 120) of the controls with normal MoCA. Interpretation In this prospective, blinded, cross‐sectional study, a high proportion of subjects meeting clinical consensus criteria for DLB had P‐SYN detected in skin biopsies. Almost 1/3 of subjects with reduced MoCA testing also had P‐SYN detected. These results support a role for skin biopsy detection of P‐SYN in patients with DLB. Trial Registration NCT04700722

This cohort study evaluates the use of definitive rhinectomy and adjuvant radiotherapy with or without chemotherapy for patients who declined rhinectomy or had unresectable disease.

Abstract Introduction: First-line therapy for mantle cell lymphoma (MCL) represents a critical opportunity for clinical benefit via sustained complete response. Multitargeted combinations, including optimized chemotherapy with novel agents targeted to MCL, may best address the biologic heterogeneity of this disease. Building on prior experience using modified VR-CAP and R-cytarabine, we enhanced this regimen by adding acalabrutinib while reducing cytarabine, aiming for improved efficacy and safety without impeding stem cell collection. To evaluate this regimen, we conducted a phase 2 multicenter trial at four centers in the Academic and Community Cancer Research United (ACCRU) network. Methods: CARiBOU (ACCRU-LY-1804) employs alternating VR-CAP and R-cytarabine with continuous acalabrutinib, in six 21-day cycles, for previously untreated MCL. Eligible patients (pts) were at least 18 years old with adequate organ function, measurable disease, no CNS involvement; and were ASCT-eligible per investigator. VR-CAP (cycles 1, 3, and 5) employed bortezomib 1.3 mg/m² subcutaneously days 1,8, and 15; rituximab 375 mg/m² day 1; cyclophosphamide 750 mg/m² day 1; doxorubicin 50 mg/m2 day 1; and prednisone 100 mg PO days 1-5. Cycles 2,4, and 6 used outpatient rituximab with cytarabine at 3 g/m² x 2 daily doses in the first 5 pts, after which the dose was reduced to 2 gm/m2 x 2 daily doses due to thrombocytopenia. Acalabrutinib 100 mg p.o. twice daily was given continuously but held for grade 4 thrombocytopenia or clinically significant toxicity. Growth factors and prophylactic antimicrobials were required. Responses were assessed after six cycles using FDG PET/CT, bone marrow aspirate/biopsy (BM Bx), and endoscopy when indicated (Lugano 2014). The primary endpoint was complete metabolic response (CMR) rate at end of treatment (EOT). Secondary endpoints included safety, feasibility of stem cell collection, proportion proceeding to ASCT, and progression-free (PFS) and overall survival (OS). Peripheral blood measurable residual disease (MRD) was evaluated using the ClonoSEQ assay (Adaptive Biotechnologies). A Simon two-stage design was used, targeting a CMR rate ≥ 70% versus a null rate of 50%, with a total sample size of 39 evaluable pts. Results: 41 pts were accrued from October 2021 through May 2025, 37 of whom completed all 6 cycles and are evaluable for response; two are still on therapy, and two discontinued therapy early for toxicity. Median age was 63 years (range 41-73), 22% were female, and 85% were White. MIPI risk groups were low (44%), intermediate (39%), and high (17%), and Ki-67 was ≥ 30% in 54% of pts. Three pts (7%) had known TP53 mutations by sequencing. At EOT, the CMR rate was 85.3% among all pts (35/41; 95% CI 67.9%-92.9%), or 94.5% among evaluable pts (35/37). BM Bx was performed in 31 pts at EOT, 30 of which (96.8%) were negative for MCL. Undetectable peripheral blood MRD using a 10^6 threshold (uMRD6) was achieved at EOT in 78.1% (25/32) of tested pts, and 93.8% (30/32) achieved uMRD5. Nine of 41 pts underwent ASCT; no patient failed stem cell collection. Maintenance therapy was not protocol-defined but included rituximab in 91.9% of pts and a BTK inhibitor in 21.6% of pts. With a median follow-up of 16.7 months, PFS and OS rates at 18 months were 76.7% (95% CI: 60.7%-96.9%) and 95.5% (95% CI: 87.1%-100%). Toxicities were primarily hematologic. Grade 3+ toxicities included thrombocytopenia (66.6%), neutropenia (28.2%), and anemia (25.6%). Grade 3+ febrile neutropenia was observed in 10.2% of pts. Peripheral neuropathy was seen in 20.5% of pts and all grade 1-2. Bleeding events included purpura in 2 pts (5.2%) and epistaxis in 1 patient (2.6%). One case of atrial fibrillation was observed. Eighteen pts required temporary dose hold of acalabrutinib for toxicity (mainly thrombocytopenia), and 2 had acalabrutinib dose reductions. Serious adverse events occurred in 6 pts, and no treatment-related deaths occurred. Conclusions: CARiBOU is an efficient, highly effective outpatient regimen for 1st line MCL, employing intermediate dose cytarabine with continuous acalabrutinib. With supportive care and platelet monitoring, this approach safely yielded high rates of CMR and uMRD6, supporting multitargeted induction therapy for appropriate pts with untreated MCL.

Study Design Retrospective cohort study using a nationally representative inpatient database. Objective To determine the incidence, timing, and predictors of new-onset psychiatric disorders following lumbar fusion surgery, and to propose a data-driven risk stratification model for early identification and intervention. Methods We queried the Nationwide Readmissions Database (2016-2019) to identify adults undergoing elective inpatient lumbar fusion. Patients with preexisting psychiatric diagnoses were excluded. Outcomes included new-onset depression, anxiety, suicidal ideation, and homicidal ideation within 12 months postoperatively. Predictors were assessed using odds ratios. Timing of onset was evaluated with density plots. Results Among 839,576 patients, 12,011 developed depression, 11,828 anxiety, 916 suicidal ideation, and 63 homicidal ideation. Most diagnoses occurred within 90 days postoperatively, with peak incidence around 3 weeks. Opioid use during the index admission significantly increased odds of suicidal ideation (OR 2.13, P = 0.001), anxiety (OR 1.26, P = 0.002), and showed a trend toward depression (OR 1.14, P = 0.087). Medicaid insurance was the strongest predictor of suicidal (OR 3.69) and homicidal ideation (OR 6.41). Female sex and younger age were associated with anxiety and depression; older age was protective against ideation. Conclusions New-onset psychiatric disorders are a frequent and early complication following lumbar fusion. Several modifiable and demographic factors - including perioperative opioid use and socioeconomic status - significantly predict risk. These findings underscore the need for structured mental health screening within the first 3 months post-surgery. Implementing a predictive risk stratification tool could enable earlier psychiatric referral, reduce long-term morbidity, and improve both recovery trajectories and overall quality of life.

ABSTRACT Objectives To characterize practice patterns and outcomes in the management of low‐ and intermediate‐grade salivary gland carcinoma prior to the existence of treatment guidelines. Methods Analysis of a registry of patients who underwent parotid and submandibular gland resections for low‐and intermediate‐grade carcinomas between 2010 and 2019. Results Of all 786 patients included in the study, 726 (92%) had preoperative imaging and 653 (83%) had preoperative biopsy. Of the 729 patients with parotid gland cancer, the majority underwent superficial ( n = 384, 53%) or total ( n = 254, 35%) parotidectomy. In patients with facial nerve preservation, total parotidectomy was associated with a significant increase in transient facial weakness (72/177 (41%) vs. 82/311 (26%), RR 0.65, 95% CI 0.50–0.84, p < 0.05) and permanent facial nerve weakness (23/176 (13%) vs. 16/301 (5%), RR 0.41, 95% CI 0.22–0.75, p < 0.05) compared to superficial parotidectomy. Adjuvant radiation therapy ( RT ) was delivered to 285 (36%) patients. The proportion of patients receiving adjuvant RT declined significantly over the time period from 2015 to 2019 compared to 2010 to 2014 at 162/504 (32%) and 123/282 (44%), respectively ( RR 0.74, 95% CI 0.61–0.89, p < 0.05). When comparing the time periods from 2015 to 2019 and 2010 to 2014, there was no significant difference in local control rates ( RR 0.52, 95% CI 0.26–1.04, p = 0.06) or regional control rates ( RR 0.75, 95% CI 0.26–2.13, p = 0.58). Conclusions Management of low‐ and intermediate‐grade salivary cancer from 2010 to 2019 was variable, which is expected given the rarity and heterogeneity of the disease and the lack of treatment guidelines prior to 2021. Most patients with parotid malignancies underwent superficial or total parotidectomy. The extent of parotidectomy had an impact on facial nerve function outcomes. Delivery of adjuvant radiation trended down with time. The data presented here will support dissemination of the guidelines and provide data that could inform future trials. Level of Evidence 2b.