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Purpose To describe whether subspecialty training, specifically arthroscopic fellowship training, influences intraoperative range‐of‐motion (ROM) gains, postoperative ROM retention, and lysis of adhesions (LOA) complication rates. Methods Between August 1989 and May 2025, all patients who underwent arthroscopic LOA for stiffness after primary total knee arthroplasty (TKA) at a single multisite academic institution with a minimum follow‐up of 3 months were reviewed. Cases were stratified by the surgeon's training: 1 group with arthroscopic fellowship training and another with nonarthroscopic or no fellowship training. Primary outcomes were intraoperative ROM change and postoperative ROM retention compared with intraoperative and pre‐TKA baseline values. Revision and periprosthetic joint infection rates were also collected. Results A total of 94 LOA cases were identified, where 48 (51.1%) were performed by nonarthroscopically trained surgeons. Intraoperative ROM improvements were similar between groups in both knee flexion (35.2° arthroscopic vs 31.1° nonarthroscopic, P = .130) and extension (2.43° vs 3.91°, P = .079). Compared with the intraoperative ROM, procedures performed by arthroscopically trained surgeons showed significantly better long‐term retention of both flexion (loss of 4.85° vs 15.98°, P = .006) and extension (gain of 0.50° vs loss of 1.58°, P = .036) at postoperative follow‐up. When compared with preprimary TKA baseline ROM, flexion at follow‐up was slightly improved in the arthroscopic group but declined significantly in the nonarthroscopic group (gain of 1.66° vs loss of 21.76°, P < .001). Eight revision TKAs (8.51%) occurred after LOA, 6 of which involved nonarthroscopic surgeons, and 1 periprosthetic joint infection case was reported. Conclusions LOA performed by arthroscopic fellowship‐trained surgeons results in significantly better retention of postoperative ROM than nonfellowship‐trained surgeons when used for arthrofibrosis after TKA. Level of Evidence Level III, retrospective comparative study.

ABSTRACT Background Primary Biliary Cholangitis (PBC) is an autoimmune cholangiopathy with polygenic architecture and unknown aetiology. Evidence links Neanderthal‐derived genetic variants to autoimmune conditions; however, their contribution to PBC susceptibility remains unexplored. Objective We investigate whether archaic alleles influence PBC risk. Design Genotype data from four PBC cohorts were analysed: CANUK (4615 cases, 9233 controls), OLD IT (444 cases, 901 controls), NEW IT (255 cases, 579 controls) and MAYO (891 cases, 621 controls). Association testing with 235 592 Neanderthal Informative Markers (NIMs) was performed, adjusting for population stratification. Heritability was estimated using RHE‐mc and temporal haplotype dynamics were assessed using ancient DNA data from Europe and Asia. Results A Neanderthal‐derived variant in TNPO3 (rs12531711), previously reported by Cordell et al. showed strong association in CANUK ( p = 2.04 × 10 −26 ) and replicated across all validation cohorts. This variant functions as an eQTL, upregulating IRF5 and downregulating TNPO3 in blood. It is rare in African populations but common both in Europeans and Asians. Temporal analysis of the haplotype carrying rs12531711 revealed frequency increased substantially during the Bronze Age (5000–3000 BP), rising from 2.0% to 7.7% in Europe and 3.4% to 17.4% in Asia, before stabilizing. Despite this strong single‐variant association, the heritability explained by NIMs was not significantly different from that of non‐NIM variants. Conclusion A Neanderthal‐derived variant contributes to PBC risk and its frequency increased in the Bronze Age, possibly due to pathogen‐driven selection. Archaic introgression overall has limited influence on PBC heritability. Functional studies are needed to elucidate the role of rs12531711.

OBJECTIVE The objective was to synthesize denominator-based evidence on indications, techniques, and postoperative outcomes of cervicomedullary decompression (CMD), spinal canal stenosis surgery, and cerebrospinal fluid (CSF) diversion for hydrocephalus in achondroplasia. METHODS This systematic review followed PRISMA 2020 and was prospectively registered (PROSPERO CRD42025626915). MEDLINE (via PubMed), Embase, Scopus, Web of Science, and the Cochrane Library were searched from inception through November 2025. The authors included observational studies of patients with achondroplasia who underwent CMD, spinal canal stenosis surgery, or CSF diversion for hydrocephalus with extractable outcomes and definable denominators. Two reviewers independently screened studies and extracted data. Risk of bias was assessed using ROBINS-I. Random-effects single-arm meta-analyses were performed for prespecified endpoints (any improvement, complete resolution, and mortality) only in cohorts with fully categorizable symptom status. RESULTS The authors included 38 observational studies (1442 patients): 18 CMD studies with 600 patients, 18 spinal stenosis studies with 686 patients, and 4 hydrocephalus studies with 156 patients. No study was at low risk of bias. For CMD (mean age 3.5 years; mean follow-up 27.8 months), any improvement was observed in 93% (95% CI 84%–97%) of patients and complete resolution in 44% (95% CI 16%–77%), and pooled mortality was 0% (95% CI 0%–5%). For spinal stenosis (mean age 36.6 years; mean follow-up 53.1 months), any improvement was observed in 92% (95% CI 78%–97%) and complete resolution in 30% (95% CI 16%–51%), and pooled mortality was 1% (95% CI 0%–2%). Hydrocephalus management was predominantly ventriculoperitoneal shunting (74.4%), with endoscopic third ventriculostomy in 23.1%, but symptom outcomes were rarely classifiable (9.6%), precluding strategy-level inference. CONCLUSIONS CMD and spinal stenosis surgery were frequently followed by symptom improvement in published series, whereas complete resolution was variably defined and inconsistently reported. Hydrocephalus studies described practice patterns but lacked outcome reporting adequate for comparing diversion strategies. Validated patient-reported outcomes were rarely reported, limiting inference on health-related quality of life.

Abstract Pancreatic ductal adenocarcinoma (PDAC), the most common subtype of pancreatic cancer, is a deadly disease with a complex tumor microenvironment (TME). Cytotoxic combination chemotherapy treatments are the mainstay of PDAC therapy, but patients rapidly develop chemoresistance, highlighting the need to elucidate how chemotherapy alters the TME and whether these changes drive chemoresistance. Here, we examined matched pre- and post-treatment tissue specimens using single-cell RNA-sequencing and found near-universal enrichment after treatment of axonal guidance genes in cancer-associated fibroblasts (CAFs). These neural CAFs were enriched near sites of perineural invasion, coinciding with regions of increased tumor cell proliferation, and were enriched in tumor areas distant from nerves after chemotherapy. Metastatic recurrent lesions had the highest prevalence of neural CAFs versus primary tumors and untreated metastases. Neural CAFs showed elevated non-canonical WNT mediators and axonal guidance genes, which complemented matching cognate binding partners in tumor epithelial cells, suggesting a role in tumor-stroma crosstalk. Additionally, in vitro studies revealed enrichment of axonal guidance genes in patient-derived CAF lines upon exposure to chemotherapy or tumor cells. Altogether, these findings implicate fibroblast-derived axonal-guidance genes in promoting PDAC invasion and point to a promising therapeutic target for this disease.

Importance Cerebral hemodynamic impairment in patients with asymptomatic internal carotid artery (ICA) stenosis is associated with reduced cognition. It is uncertain whether revascularization might be an effective treatment for cognitive impairment in these patients. Objective To test whether any cognitive benefit from revascularization of high-grade, asymptomatic ICA stenosis varies based on the degree of baseline cerebral hemodynamic impairment. Design, Setting, and Participants This substudy was conducted within a multicenter phase 3 randomized clinical trial. Adults (aged 35-86 years) without dementia with eighth-grade education or higher and unilateral asymptomatic ICA stenosis greater than or equal to 70% were enrolled from January 2018 to July 2024 at 61 sites in North America (last follow-up in July 2025). Of 607 participants screened from 2485 in CREST-2, 392 were enrolled. Magnetic resonance or computed tomographic perfusion imaging tested for baseline hemodynamic impairment defined by delayed time-to-peak (TTP) arrival of intravenous contrast in the hemisphere ipsilateral minus contralateral to the stenotic artery. Intervention Carotid revascularization (endarterectomy or stenting) plus intensive medical management (IMM) vs IMM alone. Main Outcomes and Measures The primary outcome was the difference in composite cognitive z score over 1 year based on 5 cognitive tests. The primary analysis tested for an interaction between treatment group (revascularization vs IMM alone) and degree of baseline hemodynamic impairment among those with reduced baseline cognition (cognitive z score ≤−1.0 SD). Results Of 392 participants enrolled (mean age, 71 years; 125 [32%] females), 61 were excluded for missing baseline imaging and 40 for missing cognitive examinations or other covariates, leaving 291 with complete data. Fifty-one had reduced cognition at baseline (25 in the revascularization group and 26 in the IMM alone group). TTP ranged from no interhemispheric TTP delay to a more-than-2-second delay. Mean (SD) cognitive z scores were −1.36 (0.51) at baseline and −1.17 (0.47) at 1 year in the revascularization group and −1.34 (0.83) at baseline and −1.01 (0.97) at 1 year in the IMM alone group. The primary analysis showed no difference in cognition by treatment group over 1 year, adjusting for treatment group × hemodynamic status interaction and other covariates (adjusted difference in cognitive z score, −0.15 SD [95% CI, −0.54 to 0.24]). The interaction was not significant (β estimate = 0.018 [95% CI, −0.025 to 0.061]; P = .40). Conclusions and Relevance In this substudy of a randomized clinical trial, there was no differential effect of revascularization vs IMM alone on cognition over 1 year by cerebral hemodynamic status among those with baseline reduced cognition, suggesting that revascularization does not improve cognitive dysfunction by restoring flow to the brain in chronic asymptomatic carotid stenosis. Trial Registration ClinicalTrials.gov Identifier: NCT03121209

ABSTRACT The prognostic relevance of multiple myeloma (MM)‐defined high‐risk (HR) cytogenetic abnormalities in AL amyloidosis is incompletely defined. We retrospectively evaluated 517 newly diagnosed AL amyloidosis patients seen at Mayo Clinic between 2012 and 2021 who had baseline plasma cell FISH. HR cytogenetics were defined as t (4;14), t (14;16), t (14;20), del(17p), or 1q gain/amplification (+1q). HR abnormalities were identified in 151 patients (29%); +1q accounted for most HR cases (122/151, 81%). Compared with standard‐risk (SR), patients harboring +1q demonstrated a greater clonal disease burden, including higher dFLC and bone marrow plasma cells, greater intact immunoglobulin secretion, higher plasma cell proliferative index, and enrichment for modified SLiM‐CRAB features. Hematologic and organ response patterns of +1q patients were generally comparable to SR patients, whereas non‐1q HR patients had a higher proportion of early hematologic responses. Patients harboring +1q demonstrated significantly inferior overall survival (OS) compared with both non‐1q HR patients and SR patients (median OS 57 months vs. not reached vs. 120 months, p = 0.02). In multivariable piecewise Cox analysis, the adverse prognostic impact of +1q was most evident beyond 24 months from diagnosis (HR 2.89, 95% CI 1.64–5.09, p < 0.001), whereas non‐1q HR lesions were not independently prognostic. These findings suggest that +1q identifies a biologically distinct AL amyloidosis subset characterized by plasma cell–dominant features and inferior long‐term disease control. In contrast, other MM‐defined HR cytogenetic abnormalities appear to have limited prognostic relevance in AL amyloidosis.