Citations

ABSTRACT Periprosthetic joint infection (PJI) is a devastating complication of total joint arthroplasty that can be challenging to diagnose and treat. Neutrophils are a prominent feature in PJI, with neutrophil extracellular traps (NETs) known to be present; little is known, however, about the physiology of PJI-associated NETs. Here, the proteomes of PJI and non-infectious arthroplasty failure (NIAF), analyzed using liquid chromatography tandem mass-spectrometry (LC-MS/MS) and proximity extension assay (PEA)-based profiling of fluids derived from sonication of arthroplasty components removed from patients who had undergone revision arthroplasty, were compared, with a focus on NET formation. In addition, in vitro effects of synovial fluid components on Staphylococcus aureus- induced NET formation were characterized. LC-MS/MS (PJI n = 85, NIAF n = 26) and PEA (PJI n = 95, NIAF n = 39) showed NET formation and neutrophil degranulation to be associated with PJI, with the complement cascade and platelet activation pathways identified as potential contributors. In vitro studies showed delayed NET formation in artificial synovial fluid compared to standard cell culture media conventionally used to evaluate NETs. Together, these results demonstrate the presence of NETs in PJI, identify potential pathways involved in PJI-associated NETosis, and point to an influence of synovial components on NET formation during PJI. IMPORTANCE Periprosthetic joint infection (PJI) is a major complication of joint replacement, placing a significant burden on patients and the healthcare system. Our research reveals that neutrophils and their antimicrobial “traps” are dominant features of the immune response at the infection joint site. Importantly, we found that the unique environment of the joint delays the formation of these traps, potentially contributing to the pathogenesis of PJI. By establishing a new experimental platform tailored for the infected joint, this work provides a foundational platform for probing these mechanisms and supports the development of improved diagnostic and therapeutic strategies.

PURPOSE Patients with breast cancer requiring postmastectomy radiation therapy (PMRT) often desire breast reconstruction. Reconstructions can be adversely affected by PMRT, and fear of reconstruction complications has discouraged adoption of short-course radiation therapy used after lumpectomy. To fill the evidence gap, we conducted a noninferiority trial of hypofractionated versus conventional PMRT in patients undergoing breast reconstruction. The primary outcome was reconstruction complication rate, a composite of wound healing, readmission, capsular contracture, unplanned reoperation, and reconstruction failure. METHODS Women with unilateral invasive breast cancer with planned immediate or delayed reconstruction and PMRT were randomly assigned (1:1) to 50 Gy (25 fractions/5 weeks) or 42.56 Gy (16 fractions/3 weeks). This study was designed with a noninferiority margin of 10%, assuming a 2-year reconstruction complication rate of 25% with conventional PMRT. Randomization was stratified by immediate versus delayed and autologous versus implant-only reconstruction. RESULTS Between 2018 and 2021, 898 patients enrolled with a median follow-up of 3.9 years; 825 patients were evaluable for the primary end point. The 24-month reconstruction complication rates were 12.3% (52/422) with hypofractionated PMRT and 10.2% (41/403) with conventional PMRT, corresponding to an estimated difference of -2.1% (95% CI, -6.5 to 2.2). The complication rate was higher (regardless of arm) with implant-only versus autologous reconstruction (odds ratio = 1.65). There was no statistically significant difference in 36-month locoregional recurrence rates: 1.5% (95% CI, 0.7 to 3.2) with hypofractionated and 2.2% (95% CI, 1.1 to 4.3) with conventional PMRT. Acute and late toxicity rates were not statistically different. CONCLUSION A 16-fraction course of hypofractionated PMRT is safe and noninferior to conventional PMRT in women undergoing breast reconstruction after mastectomy.

BACKGROUND: Type 2 long-QT syndrome results from KCNH2 -encoded Kv11.1 loss-of-function, but whether secondary inward-current dysfunction amplifies dysfunction remains unclear. METHODS: We characterized sodium ( SCN5A , I Na ) and L-type calcium channel ( CACNA1C , I Ca ) function in KCNH2-G604S and variant-corrected isogenic control induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs). Whole-cell patch-clamp measured action potential duration at 90% repolarization (APD90), and potassium (I Kr ), sodium (I Na ), and calcium (I Ca, L ) currents. Fluo-4 imaging quantified calcium transients. A modified Kernik-Clancy iPSC-CM model incorporated experimentally measured persistent I Na,L and I Ca,L fractions and simulated isolated and combined current defects. RESULTS: KCNH2-G604S caused severe I Kr loss-of-function (72.5% reduction). APD90 was prolonged in G604S-iPSC-CMs (765±58 ms) compared with isogenic controls (368±37 ms; P <0.005), with early afterdepolarizations in 50% of G604S cells. Nifedipine, verapamil, and mexiletine successfully shortened APD90 and abolished early afterdepolarizations. Compared with isogenic control, I Na,L (0.60±0.1% versus 0.26±0.06%; P <0.01), persistent I Ca,L (2.88±0.55% versus 1.26±0.35%; P <0.05), and calcium transient decay times ( P <0.0001) were greater in G604S iPSC-CMs. Increased persistent I Ca,L was phenocopied by E-4031 in isogenic controls and reduced by nifedipine in G604S iPSC-CMs. In silico modeling revealed that the I Kr defect alone prolonged APD90 to only 620 ms. The addition of the observed I Na,L defect had a small additive effect (+20 ms); however, incorporating persistent I Ca,L synergistically extended APD90 to 758 ms, replicating the experimental phenotype. Flux dynamics analysis indicated that this persistent Ca 2+ entry suppresses the forward-mode sodium-calcium exchanger, forcing a compensatory reliance on sarcoplasmic-endoplasmic reticulum Ca-ATPase that primes for calcium instability. CONCLUSIONS: The KCNH2-G604S variant drives a severe multihit phenotype via primary I Kr loss-of-function and secondary state-dependent gain-of-function in persistent I Ca,L . These comprehensive validations demonstrate that the remodeled persistent I Ca,L acts as the essential amplifier driving extreme action potential duration prolongation and Ca 2+ mishandling.

Background: Iliopsoas impingement (IPI) is a known cause of persistent anterior hip pain following total hip arthroplasty (THA). Management of IPI has often relied on an 8-mm anterior acetabular overhang threshold to guide operative treatment, favoring acetabular revision for greater overhang and iliopsoas tenotomy for lesser overhang. These thresholds were initially established on the basis of the outcomes of open tenotomy, and now, with an improved understanding of IPI and the advent of arthroscopic iliopsoas fractional lengthening (IPFL), a review of the 8-mm threshold is warranted. Methods: A retrospective review was performed to identify patients who underwent arthroscopic IPFL following primary THA between 2017 and 2024, with a minimum follow-up of 1 year. Acetabular overhang was measured for all patients using cross-table lateral radiographs, and patients were stratified into <8-mm and ≥8-mm cohorts. Patient-reported outcome measures, reoperations, revisions, and complications were collected and analyzed on the basis of both the classic 8-mm threshold and continuous statistical methods. Results: We evaluated 86 hips undergoing IPFL. There were 83 patients (30 men and 53 women), with a mean age of 63.0 ± 11.2 years; with regard to race, 80 patients were White, 1 patient was Black or African American, and 2 patients listed other race or chose not to disclose. The acetabular overhang was <8 mm for 67 hips and ≥8 mm for 19 hips. The mean follow-up was 2.5 ± 1.6 years (range, 1 to 7.5 years). When comparing patients with <8-mm and ≥8-mm acetabular overhang, we observed no significant differences (p > 0.06) in the preoperative and postoperative visual analog scale (VAS) pain scores, modified Harris hip score, Single Assessment Numeric Evaluation (SANE) score, Tegner activity level, subjective groin pain improvement, subjective hip flexion strength improvement, and overall satisfaction. Reoperation (2.9% compared with 10.5%; p = 0.210) and acetabular revision rates (1.5% compared with 5%; p = 0.387) were not significantly different between the <8-mm and ≥8-mm overhang groups. Conclusions: Arthroscopic IPFL provided satisfactory outcomes for patients with IPI, independent of the magnitude of acetabular overhang. IPFL should be considered for first-line surgical management of IPI refractory to nonoperative management, even in the setting of substantial acetabular overhang, given positive outcomes and low rates of subsequent acetabular revision. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

ABSTRACT Objective To estimate the pooled prevalence of lymphedema among adults with mucosal head and neck cancer treated with radiation therapy. Data Sources PubMed, Embase, Scopus, and Cochrane Library. Review Methods A comprehensive literature search of PubMed, Embase, Scopus, and Cochrane Library (2000–2025) identified cohort, case series, cross‐sectional, and clinical trial studies reporting lymphedema after radiotherapy for head and neck cancer. Logit‐transformed lymphedema prevalence was pooled using a DerSimonian‐Laird random‐effects model with Hartung‐Knapp‐Sidik‐Jonkman variance correction; statistical heterogeneity was evaluated using I 2 . This review was not prospectively registered. Results A total of 26 studies ( n = 3133 patients) met inclusion criteria. The pooled prevalence of lymphedema was 49% (95% CI, 36%–62%), with considerable heterogeneity (I 2 = 94%). Subgroup analyses yielded a pooled prevalence of 37% (12%–71%) for external and 45% (31%–60%) for internal lymphedema. Among studies reporting severity‐graded data, the pooled prevalence of clinically significant (grade ≥ 2) lymphedema was 32% (14%–59%). Lymphedema definitions and assessment methods varied across the included studies, most commonly employing clinical grading. Methodological quality was mixed, reflecting the predominantly retrospective, single‐arm nature of the available evidence. Overall certainty of evidence was very low. Funnel plot inspection and Egger's test suggested small‐study effects ( p = 0.06). Conclusion Lymphedema affects nearly half of patients following radiation for head and neck cancer. These findings may support routine surveillance, early identification, and timely referral for lymphedema management within survivorship care pathways. Future prospective studies should adopt standardized definitions and outcome measures to refine risk estimates and guide prevention strategies. Level of Evidence N/A.

The bone marrow immune microenvironment (BMME) is a critical factor in multiple myeloma (MM) pathogenesis. Despite higher incidence of MM among self-identified African Americans, the relationship between African genetic similarity and the BMME remains unclear. We present the largest analysis to date assessing the impact of Ancestry on the BMME in myeloma (N=320, including 64 with ≥50% African genetic similarity, AFR-High) leveraging our recently generated Immune Atlas. AFR-High was associated with enrichment of late T-effector cells, driven by rare cytotoxic CD4⁺ T cells, suggesting a distinct adaptive BMME. AFR-High exhibited expansion of late-differentiated adaptive NK cells with high cytotoxic GNLY and GZMH expression. AFR-High depicted reduced CD14⁺ monocytes, increased CD16⁺ non-classical monocytes, and expansion of macrophage-like monocyte populations with enrichment of metabolic adaptation, efferocytosis and phagocytic clearance programs, and immunoregulatory pathways. These findings reveal a shift from an innate inflammatory immune landscape toward adaptive cytotoxic and immunoregulatory remodeling associated with African genetic similarity in MM.

Background: Incidental thyroid nodules (ITNs) detected on nonthyroid imaging contribute to thyroid cancer overdiagnosis, largely through downstream evaluation initiated by thyroid ultrasound (TUS). However, TUS follow-up rates for ITNs and their drivers in routine practice remain unclear. We quantified TUS utilization after ITN detection and identified patient, imaging, nodule, and reporting factors associated with this first step in the diagnostic cascade. Methods: We conducted a retrospective cohort study of adults without prior thyroid disease who underwent imaging that incidentally captured the thyroid at Mayo Clinic sites (2017–2023). A validated natural language processing pipeline identified ITNs and extracted nodule characteristics from radiology reports across multiple imaging modalities. The main outcome was the rate of TUS within 180 days after ITN detection. Clinical outcomes, including thyroid biopsy, thyroidectomy, and thyroid cancer diagnosis, were compared between patients who underwent TUS and those who did not. Factors associated with TUS utilization were assessed using multivariable logistic regression with penalized variable selection. Results: Among 115,683 patients who underwent thyroid-capturing imaging, 8426 (7.3%) had an ITN. These patients were predominantly female (64.6%) and White (89.7%), with a mean age of 61.7 years (standard deviation 15.2). Most nodules were detected on computed tomography (80.8%), most commonly from chest imaging (52.3%). Overall, 1677 patients with ITNs (19.9%) underwent TUS. In multivariable analysis, TUS use was independently associated with higher body mass index (odds ratio [OR], 1.20 per 10-unit increase; confidence interval [CI] [1.08–1.33]), nodule size ≥1.5 cm (OR, 1.79; CI [1.52–2.10]), and a radiologist recommendation (OR, 2.51; CI [2.12–2.98]), whereas older age was associated with lower odds of TUS (OR, 0.89 per 10-year increase; CI [0.84–0.93]). Patients undergoing TUS had higher rates of thyroid biopsy, partial thyroidectomy, and total thyroidectomy compared with those without it. All detected thyroid cancers (103 cases) occurred in the TUS group, representing 6.1% of that cohort. Conclusions: One in five patients with ITNs underwent TUS, representing a critical gateway to downstream diagnostic procedures and thyroid cancer detection. Factors associated with TUS utilization highlight opportunities to better define appropriateness of ultrasound after incidental nodule detection and to reduce unnecessary testing and treatment.

Objective To evaluate the efficacy of cytokine‐directed therapies in VEXAS (vacuoles, E1 enzyme, X‐linked, autoinflammatory somatic) syndrome using previously proposed treatment response criteria. Methods All patients with genetically confirmed VEXAS syndrome who received targeted therapies with JAK inhibitors (JAKi), tumor necrosis factor α inhibitors (TNFαi), or interleukin‐1 (IL‐1) or IL‐6 inhibitors were identified. Clinical and biochemical data were recorded for patients at time of targeted therapy initiation, and at 3‐, 6‐, and 12‐month follow‐up time points. Treatment response was labeled as complete response (CR; normalization of C‐reactive protein [CRP], prednisone <10 mg/day, and resolution of disease activity), partial response (PR; >50% improvement in CRP, >50% prednisone dose reduction, improvement or resolution of disease features), treatment failure (TF; worsening CRP, increasing prednisone, worsening of disease features), or no response (not meeting criteria for CR, PR, or TF). Results Overall, 52 patients received an IL‐1i, IL‐6i, or JAKi therapy. At six‐month follow‐up, 3 of 19 IL‐6i patients experienced CR, 4 of 19 experienced PR, and 7 of 19 experienced TF. 2 of 17 patients receiving JAKi experienced CR, 3 of 17 experienced PR, and 6 of 17 experienced TF. No patients receiving IL‐1i or TNFαi experienced CR, and only 1 of 5 IL‐1i patients experienced PR. Among those still receiving biologic therapy at 12 months, only 1 of 11 receiving IL‐6i and 0 of 7 receiving JAKi experienced CR. Conclusion IL‐6i and JAKi therapies demonstrated limited, unsustained efficacy for management of VEXAS syndrome. IL‐1i and TNFαi therapies were not efficacious. Useful application of previously reported treatment response criteria was demonstrated, but future incorporation of hematologic parameters may be beneficial.