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: This study examined whether phoneme-level posterior probabilities generated by an articulatory-informed deep learning model (Phonet) can serve as interpretable and sensitive markers of articulatory impairment in motor speech disorders (MSDs). The goal was to determine whether these features distinguish individuals with and without MSDs and reflect varying severity levels of articulatory impairment. Method: A total of 676 participants (199 with MSDs, 477 without MSDs) completed a remotely captured word repetition task. Speech recordings were phonetically aligned, and posterior probabilities were extracted using a retrained version of the Phonet model, which estimates frame-level probabilities for 23 phonological classes. Segment-level posterior values were computed and compared across groups and severity levels using linear mixed-effects regression models. Results: Posterior probabilities were significantly reduced in the MSD group across all phoneme types. Within the MSD group, posterior probabilities decreased progressively with greater clinical severity, as measured by both perceptual sound distortion ratings and a cumulative articulation error score. Segment-specific analyses revealed systematic differences across phoneme classes, indicating that posterior probabilities capture distinct patterns of articulatory degradation associated with motor speech impairment. Conclusions: Phoneme-level posterior probabilities serve as interpretable, segment-specific indicators of articulatory impairment in MSDs. These features differentiate clinical status and reflect gradations of severity, making them promising tools for augmenting traditional perceptual speech assessments. Their linguistic transparency and scalability support future clinical applications in diagnosis, monitoring, and targeted intervention.

ABSTRACT Background and Objectives Among patient with early‐stage breast cancer, breast conservation surgery (BCS) is the most performed surgery, utilized in approximately two‐thirds of patients. While 5‐year overall‐survival rates are strong—typically above 90%—additional re‐excisions can occur in up to 25% of patients who undergo index BCS and some patients will require subsequent surgery for new breast cancer or recurrences. As such, these additional procedures can complicate patients’ pathway to survivorship, negatively impact quality of life, and lead to excess healthcare costs. Methods This retrospective cohort study used linked claims and an electronic healthcare record database to (1) characterize patients at higher risk for additional breast oncologic surgery (aBOS) following BCS, and (2) quantify the long‐term financial impact of aBOS after BCS. In total, 87,190 patients with breast cancer, who had an index BCS between January 1, 2012, to March 31, 2023, were followed for up to 5‐years post‐operatively. Patients with and without aBOS were analyzed, comparing demographics, tumor characteristics, healthcare utilization, and per‐person‐per‐month (PPPM) costs. Results Twenty‐three percent ( n = 20,212) of patients underwent aBOS. These patients were younger, had higher tumor grades and larger tumor sizes, and incurred greater healthcare costs compared to patients who did not undergo a secondary surgery. Conclusion This study highlights significant factors influencing BCS outcomes and healthcare utilization, underscoring the need for tailored therapeutic strategies for patients with breast cancer.

Purpose This study aimed to develop and validate a tool to predict the primary tumor site in patients with metastatic cancer of unknown primary using demographic and clinical variables, including imaging-derived sites of metastasis, without pathology or laboratory data. Methods In this population-based study, data were extracted from the SEER database. Patients diagnosed between 2010 and 2020 with a known primary cancer site, metastatic staging, and metastasis in the bone, liver, brain, and lungs were included. Patients were randomly split into training (70%) and/or testing (30%) sets. A total of 27 primary tumor sites were included. A gradient boosting model was trained to predict the primary tumor site, with random forest and classification tree models evaluated as comparators. Random guess and frequency-weighted guessing models were used for baseline comparison. Results A total of 689,715 patients were included from 9,208,295 queried. The most common primary cancer sites were non–small cell lung cancer (NSCLC) (n = 211,338), intestines (n = 64,187), and pancreas (n = 60,310). The baseline models achieved Top-5 accuracies of 0.179 for a random guess and 0.476 for a frequency-weighted guess. The gradient boosting model achieved Top-1, Top-3, and Top-5 accuracies of 0.40 ± 0.001, 0.680 ± 0.001, and 0.790 ± 0.001, respectively, across 100 Monte-Carlo replicates. Top-5 accuracy was highest for primary NSCLC (0.990 ± 0.001) and intestinal cancer (0.900 ± 0.003). Our model was most influenced by sex (gain = 0.27) and metastasis to bone (gain = 0.20). A web app was constructed: primarycancerpredictor.netlify.app. Conclusion This study developed and evaluated a gradient boosting machine learning model and a user-friendly web tool to aid in the diagnosis of cancer of unknown primary.

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 Bioprosthetic aortic valve replacement, specifically surgical (SAVR) and transcatheter (TAVR), is among the most frequently performed cardiac interventions globally, yet anticoagulation strategies after implantation remain incompletely defined. Atrial fibrillation, notably prevalent pre- and post-operatively in these patients, substantially amplifies thromboembolic risk and complicates decision-making in an already elderly, frail, and comorbid population. Objectives To critically evaluate current anticoagulation strategies after bioprosthetic aortic valve replacement across sinus rhythm and atrial fibrillation in both SAVR and TAVR, and to identify evidence gaps and guideline inconsistencies. Methods We conducted a narrative review of major international guidelines (ESC/EACTS 2025, ACC/AHA 2020, and NICE 2021) and key clinical trials on antithrombotic therapy in valve replacement populations. Focus was placed on bioprosthetic aortic valve replacement, with mechanical and non-aortic valves excluded. Results Aspirin monotherapy is the most consistently supported strategy after bioprosthetic TAVR in sinus rhythm, though guidelines diverge on duration and recommendation strength. In atrial fibrillation, all three guidelines apply uniform CHA 2 DS 2 -VASc-based frameworks irrespective of AF phenotype, procedural context, or detection modality, reflecting lacking evidence rather than deliberate clinical judgement. No trial has enrolled patients specifically with new-onset post-procedural AF or stratified by AF subtype, and subclinical AF after bioprosthetic AVR remains entirely uncharacterised. Conclusions Guideline divergence reflects a structurally inadequate evidence base rather than genuine clinical equipoise. Individualised decisions informed by procedure type, AF phenotype, frailty, and bleeding risk are required to guide clinical practice, alongside an adequately powered stratified randomised trial incorporating mandatory continuous rhythm monitoring.

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: Left atrial (LA) stiffening augments the LA V wave, pressurizing the pulmonary artery (PA) out of proportion to left ventricular end-diastolic pressure. We characterized the pathophysiologic, diagnostic, and clinical implications of LA stiffening, as defined by prominent V waves, in heart failure with preserved ejection fraction. METHODS: In this retrospective cohort study, patients with heart failure with preserved ejection fraction and less than moderate mitral regurgitation at rest underwent invasive hemodynamic exercise testing. Patients with heightened operant LA stiffening were defined by the PA wedge pressure (PAWP) V wave exceeding mean PAWP by ≥10 mm Hg. A previously used formula for V wave–corrected PAWP was validated against the PAWP waveform pressure-time-area to explore impact of the V wave on transpulmonary pressure gradients. Clinical, echocardiographic, hemodynamic, and outcome data were compared for patients with and without prominent V waves. RESULTS: Compared with patients without prominent V waves (n=844, 79%), those with prominent V waves (n=225, 21%) were older and more likely to be women, with more severe LA myopathy, evidenced by greater LA volume index (42.2±15.0 versus 32.5±13.0 mL/m 2 , P <0.001), lower LA reservoir strain (16.4±7.5% versus 23.2±8.3%, P <0.001), more atrial fibrillation (61.3% versus 22.9%, P <0.001), and increased operant LA reservoir stiffness (0.59±0.25 versus 0.23±0.24 mm Hg/mL, P <0.001). Patients with prominent V waves had markedly higher PA systolic pressure than those without (54±16 versus 38±12 mm Hg, P <0.001) despite no difference in end-diastolic PAWP-PA pressure gradient (3±5 versus 3±4 mm Hg, P =0.950). Incorporating the V wave into PAWP improved correlation between directly measured PAWP pressure-time integral compared with mid–A wave PAWP (R 2 =0.96 versus R 2 =0.86, P <0.001 for comparison). In patients with prominent V waves, the prevalence of combined pre- and postcapillary pulmonary hypertension decreased from 60.2% to 29.3% after V wave correction for the transpulmonary pressure gradients. Despite similar corrected pulmonary vascular resistances in patients with and without prominent V waves, apparent PA compliance was much lower in patients with prominent V waves (3.03±1.56 versus 4.90±2.27 mL/mm Hg, P <0.001), augmenting right ventricular afterload, and these changes were coupled with more severe right ventricular dysfunction, tricuspid regurgitation, blunted cardiopulmonary exercise reserve, and increased risk of hospitalization for heart failure or death in patients with versus without prominent V waves (adjusted hazard ratio, 2.09 [95% CI, 1.53–2.86]; P <0.001). CONCLUSIONS: More than 1 in 5 patients with heart failure with preserved ejection fraction display prominent V waves in excess of end-diastolic PAWP. This augments right ventricular afterload due to backward transmission of the V wave, contributing to right heart failure that is independent of the pulmonary vasculature. Failure to account for the V wave during hemodynamic assessment overestimates the severity of pulmonary vascular disease present.