Citations

Purpose While the clinical utility for Point-of-Care Ultrasound (POCUS) is well-established through its use in clinical practice to enhance diagnostic accuracy, expedite care, and improve patient interactions/communication, its impact on patient experience in outpatient consultative settings remains largely underexplored. We sought to evaluate patients’ experience and satisfaction by incorporating POCUS use during outpatient consultations. Methods In this prospective, cross-sectional survey study conducted in a consultative outpatient internal medicine practice, a continuous sample of 100 patients undergoing POCUS during routine medical evaluations participated. We assessed patient perspectives using a survey that was adapted from validated instruments. The following items were evaluated using the anonymized survey: the extent of patient understanding, the integration of POCUS into the consultation, its impact on patient-doctor communication, perceived quality of care, and overall patient experience. Results Most respondents felt better informed about their health (88%), more thoroughly examined (94%), and reported improved confidence in their physician’s assessment (92%) after the POCUS exam. In addition, POCUS was perceived as a natural part of the consultation (95%) and minimally burdensome (93%). Overall, 96% of study respondents agreed that POCUS improved their quality of care, and 98% described their experience as positive or very positive. Open-ended comments emphasized the immediacy of results, enhanced communication, and cost-effectiveness of the POCUS experience. Conclusion Incorporating POCUS in this environment improved patients’ perceptions of their physician, clinic, and overall care. These findings support the broader adoption of POCUS in similar clinical settings and its potential impact on healthcare delivery and patient satisfaction.

Background: Understanding drivers of supply and labor cost variation in orthopaedic surgery is crucial to provide value-based care. Time-driven activity-based costing (TDABC) is a more accurate methodology for capturing costs of care than traditional methods. Anterior cruciate ligament reconstruction (ACLR) is one of the most performed outpatient procedures within orthopaedic surgery. The purpose of this study was to characterize the cost composition of ACLR and identify factors that drive cost variation. Methods: Cost data for supplies and time-based personnel usage were extracted from electronic health records and were used to calculate costs using TDABC. TDABC methodology was applied to calculate the cost of personnel usage by multiplying the duration and associated cost per minute. Descriptive statistics and mixed-effects modeling were used to determine cost drivers. Results: This study included 861 patients who underwent ACLR at 8 hospitals. The mean patient age (and standard deviation) was 31.1 ± 11.6 years. Of the 861 patients, 350 were male and 511 were female; 85.6% of patients were White, 8.1% were Asian, and 3.4% were Black. There was 3.2-fold variation in supply costs ($2,950) and 1.6-fold variation in labor costs ($940) between the 10th and 90th percentiles. Overall, supply costs accounted for 58.2% of total costs, whereas labor costs comprised the remaining 41.8%. The intraoperative phase was the greatest generator of total cost (89.7%). After adjusting for surgeon and hospital variability, variation in total cost was most effectively explained by graft type, primary surgery status, and meniscal repair (conditional R 2 = 0.84; marginal R 2 = 0.27). On subanalysis, patients undergoing allograft ACLR had significantly higher total costs, implant costs, and age compared with those undergoing ACLR with any autograft type (all p < 0.01). Conclusions: The most notable drivers of labor and supply cost variation were graft type, surgeon, surgery center, primary surgery status, and concomitant meniscal repair. Understanding modifiable cost drivers may aid health systems in designing value-based pathways, implant formularies, and surgeon education programs. Future studies may integrate cost with outcome measures for a more holistic view of value. Level of Evidence: Economic and Decision Analysis Level III . See Instructions for Authors for a complete description of levels of evidence.

Purpose To project the future utilization of open and arthroscopic rotator cuff repair (RCR) in the Medicare population through 2050, incorporating post‐COVID recovery data to provide insight into evolving surgical preferences, economic pressures, and implications for health care delivery. Methods We analyzed 2003‐2024 data from the Centers for Medicare and Medicaid Services Medicare Part‐B National Summary, which captures all Medicare beneficiaries undergoing open or arthroscopic RCR as identified by Current Procedural Terminology codes. Projections were based on 2003‐2019 and 2023‐2024 data, reflecting post‐COVID‐19 recovery and avoiding distortions from 2020 to 2022 pandemic‐related disruptions. Statistical models evaluated included log‐linear, Poisson, negative binomial, and autoregressive integrated moving average. Autoregressive integrated moving average was selected based on the lowest normalized root mean square error, reflecting superior predictive accuracy and its ability to capture time‐dependent trends, and was used to forecast RCR volumes through 2050. Results In 2024, there were 23,154 open and 188,700 arthroscopic RCR procedures, which served as the baseline for modeling. Open RCR is projected to decline on average by 5.91% annually, while arthroscopic RCR is projected to grow by 2.88% annually. By 2050, arthroscopic RCR volume is expected to reach 394,434 procedures (95% forecast interval: 363,424‐425,321), whereas open RCR is expected to decline to 4748 procedures (95% forecast interval: 1243‐43,747). Conclusions Autoregressive integrated moving average modeling projects that by 2050 arthroscopic RCR utilization will increase by 2‐fold and open RCR will decline to one‐fifth compared with 2024 baseline volumes. Level of Evidence Level III, retrospective cohort study.

ABSTRACT Polyglucosan body myopathy type 2 (PGBM2; OMIM #616199) is an autosomal recessive myopathy caused by biallelic variants in GYG1 , which encodes glycogenin‐1. It is characterized by progressive muscle weakness and PAS‐positive, diastase‐resistant polyglucosan inclusions on muscle biopsy. We report a 64‐year‐old woman who developed progressive proximal weakness beginning in her early 50s, with polyglucosan bodies identified on muscle histopathology. Genome sequencing (GS) detected a single heterozygous pathogenic splice‐site variant, NM_004130.4( GYG1 ):c.143+3G>C. Given strong histopathologic evidence of PGBM2, GS data were reanalyzed, revealing an additional rare deep intronic variant, NM_004130.4( GYG1 ):c.7+992T>G, predicted to activate a cryptic exon. RNA sequencing (RNA‐seq) confirmed aberrant splicing from both variants, demonstrating exon 2 skipping associated with c.143+3G>C and cryptic exon inclusion caused by c.7+992T>G. Variant phasing posed a diagnostic challenge due to unavailable parental DNA, and long‐range PCR results were inconclusive. Long‐read GS definitively demonstrated that the two variants were in trans , establishing compound heterozygosity and confirming the molecular diagnosis. These findings enabled reclassification of the deep intronic variant as likely pathogenic. This case highlights the diagnostic limitations of conventional phasing approaches in adult‐onset recessive disorders and demonstrates the clinical utility of integrating genome reanalysis, RNA‐seq, and long‐read GS for resolving complex phasing challenges.

Abstract In 2011, a workgroup of the Alzheimer's Association Research Roundtable introduced recommendations for detecting and monitoring amyloid‐related imaging abnormalities (ARIA) in Alzheimer's disease (AD) clinical trials. Since then, anti‐amyloid immunotherapies have received regulatory approval for AD treatment and are beginning to enter clinical practice, underscoring the importance of informing healthcare providers, researchers, and patients about ARIA's implications in real‐world settings. In response, the Alzheimer's Association convened a new workgroup to review current knowledge of ARIA, including underlying mechanisms, clinical presentations, associated risk factors, mitigation strategies, radiologic detection methods, patients’ perspectives in treatment decision‐making, and outstanding challenges. Here, we outline key insights from this workgroup, highlighting that effective ARIA detection and monitoring in clinical practice requires adherence to robust protocols to mitigate risks and enhance patient safety. Limited availability of clinical and pathologic data on predictors of symptomatic and severe ARIA underscores the importance of continued real‐world data collection.

Abstract Introduction: Epoxy fatty acid (EpFA) mechanisms of hormone therapy resistance (HTR) in ER+HER2- breast cancer (BC) are poorly understood. EETs are EpFAs that contribute to BC progression and HTR by promoting oxidative phosphorylation (OXPHOS). However, it remains unclear how EETs contribute to HTR. In this study, two fulvestrant resistant (FR) subclones of the letrozole resistant (LR) MCF-7AC1 line were isolated (termed LR/FR) and were incidentally resistant to the CDKi palbociclib (PR) (termed MCF-7AC1 LR/FR/PR or multiply resistant - MCF-7AC1 MR). These HTR cell lines exhibited CYP3A4 upregulation (2.3- to 4.3-fold) and increased cellular (±)14,15-EET levels, which were suppressed by biguanide treatment (P&lt;0.05). Structure activity studies led to the design of hexyl cuban-1-yl biguanide (HCB) and fluorinated HCB derivatives C5F2-HCB and C6F3-HCB, which inhibited CYP3A4-mediated EET biosynthesis and growth of the HTR lines. HCB fluorination improved pharmacokinetics (PK) and toxicity. Methods: HCB and fluorinated HCBs were tested for impact on EET biosynthesis, OXPHOS, PK, and growth inhibition and reversal of hypoxia in the MCF-7AC1 MR tumor model. Results: Fulvestrant selection for MCF-7AC1 MR cell lines resulted in undetectable cyclin D1 and estrogen receptor (ERα) expression, while cyclin E1, CDK4, CDK6, CYP3A4, and c-MYC were upregulated (P&lt;0.001). MCF-7 MR cells demonstrated 1.8, 1.4, and 1.2- fold higher levels of (±)8,9, (±)11,12, and (±)14,15-EET compared to parental MCF-7 cells (P&lt;0.05). The most potent fluorinated HCB, C6F3-HCB, suppressed cellular levels of (±)8,9-EET, (±)11,12-EET, and (±)14,15-EET by 53-60% (P&lt;0.029). The MCF-7AC1 MR cells were more potently inhibited by HCBs and fluorinated derivatives compared to the MCF-7 cell line. Comparing an MCF-7 MR line vs. MCF-7, HCB exhibited IC50 values of 4.1 vs. 7.0 uM, C5F2-HCB 10 vs. 25 uM, and C6F3-HCB 5.4 vs. 12 uM (P values all &lt;0.05). C5F2-HCB exhibited the best PK and treatment of the MCF-7AC1 MR xenograft model showed reversal of hypoxia (P&lt;0.05) and transient inhibition by C5F2-HCB (P=0.025 at 20 days). P/F also transiently inhibited this model (P=0.006 at 20 days). C5F2-HCB and P/F showed synergy in vitro (CI=0.46) leading to testing of C5F2-HCB/P/F in vivo enabled by acceptable toxicity of the triplet in mice. This combination showed synergy in vivo vs. standard of care palbociclib/fulvestrant by nonparametric statistical tests (Mann Whitney; P=0.0389; Kolmogorov-Smirnov; P=0.0473), providing a pathway for possible clinical development of the combination. Conclusions: MR BC cell lines exhibit upregulation of CYP3A4 and biosynthesis of EETs, indicating a role for EETs in HTR. The C5F2-HCB/P/F exhibits activity against the highly resistant MCF-7 MR xenograft with acceptable toxicity indicating an avenue for clinical development. Citation Format: Zhijun Guo, Jianxun Lei, Christian T. Wells, Allison M. Makovec, Andrew C. Yates, Swaathi Jayaraman, John R. Hawse, Joshua A. McCarra, Qing Cao, Michael J. Pryzbilla, Brenda L. Koniar, Beverly J. Norris, Craig M. Florey, Robert J. Schumacher, Michael A. Farrar, Kaylee L. Schwertfeger, Elizabeth A. Ambrose, Henry Wong, Gunda I. Georg, Antonino D'Assoro, Matthew P. Goetz, David A. Potter. Fluorinated cuban-1-yl biguanides overcome hormone therapy resistance to standard of care fulvestrant, and palbociclib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB196.

OBJECTIVE Dural arteriovenous fistulas (dAVFs) are rare cerebrovascular anomalies. Tentorial dAVFs (TDAVFs) have more aggressive features, making them prone to symptomatic presentations and hemorrhage. TDAVFs are heterogenous and require tailored surgical approaches. Presented is a multicenter analysis of TDAVF surgical outcomes. METHODS The Consortium for Dural Arteriovenous Fistula Outcomes Research (CONDOR) consortium compiled data on dAVFs from 16 international centers from 1990 to 2021 retrospectively. Microsurgical treatment success was defined as angiographically confirmed complete obliteration of the fistula or discontinuation of cortical venous drainage (CVD) in high-grade TDAVFs. TDAVF subtypes and tailored surgical approaches were reviewed. RESULTS Of 1360 patients in CONDOR, 161 had TDAVFs and 27% (44/161) of these patients underwent surgical management, with the majority (52% [23/44]) receiving surgery as a salvage treatment following failed embolization. The mean age (SD) of this cohort was 56 (15) years, and 68% (30/44) were male. In total, 91% (40/44) of surgically treated patients presented with aggressive symptoms: 64% (28/44) presented with hemorrhage and 27% (12/44) with nonhemorrhagic neurological deficit (NHND). The median (IQR) duration from symptom onset to diagnosis was 1 (1–4) day. The median time (IQR) between diagnosis and surgery was 15 (3–80) days. Surgical approaches varied across the cohort, with the retrosigmoid being the most common (44% [18/41]), followed by the midline suboccipital (24% [10/41]) and occipital (15% [6/41]) approaches. Perioperative complications occurred in 11% (5/44) of cases, as well as permanent neurological deficits in 2% (1/44). Surgical success was achieved in 90% of patients (38/42). During the mean 3-year follow-up, 2 patients experienced a recurrence of their fistula including representation of CVD (2/38 [5%]) and 1 patient had a new NHND (1/43 [2%]). Shorter symptom duration was significantly associated with success (15.6 vs 181.5 days, p = 0.001). Primary versus salvage microsurgery showed no difference in outcomes. Both patients with recurrent fistula were effectively treated with Gamma Knife radiosurgery. CONCLUSIONS Resection is safe and durable for the treatment of TDAVF not otherwise amenable to embolization. It can achieve a high degree of success with a low rate of perioperative complications and permanent neurological deficits, benefits far exceeding the risks associated with TDAVF natural history or management with less effective modalities.

Morel-Lavallee lesions (MLLs) are traumatic closed degloving injuries with operative intervention (OI), especially excisional debridement, remaining the mainstay of treatment. However, high-quality evidence describing operative techniques and outcomes remains limited. This study aimed to characterize current OI practices and associated outcomes, especially among patients undergoing excisional debridement, hypothesizing an increased risk of wound complications with this approach for MLLs. Methods This prospective (2021-2024), multicenter, observational study was conducted across 15 trauma centers and included patients diagnosed with MLL who underwent OI. The association between operative technique (eg, excisional debridement) and the primary outcome of wound complications was evaluated. Wound complications were defined as cellulitis, deep wound infection, skin necrosis, necrotizing soft tissue infection (NSTI), and/or organized hematoma. Results Of 88 MLL patients undergoing OI, 36 (40.9%) had excisional debridement, with 4 (11.1%) limited excision to skin, 20 (55.6%) extended to subcutaneous tissue, and 12 (33.3%) down to muscle. Excisional debridement had higher rates of skin necrosis (22.2% vs. 1.9%, P = .002). Although overall rates of wound complications were statistically similar between cohorts (33.3% vs. 17.3%, P = .098), univariate analysis demonstrated excisional debridement had increased risk of wound complications (OR 2.52, CI 1.07-5.97, P = .035). Conclusion This prospective multicenter study over three years demonstrated that a fifth of MLLs undergoing excisional debridement developed postoperative skin necrosis. Excisional debridement also had a more than two-fold increased risk of wound complications compared to other OIs. These findings underscore the importance of investigating alternative operative techniques, such as incision and drainage or minimally invasive debridement methods.

Abstract Scientific foundation models learn high-dimensional representations from diverse data modalities, yet what they encode and how to extract that knowledge remain open questions. Here we show that probing the internal representations of Evo 2, a 7-billion-parameter genomic foundation model, enables accurate and interpretable genetic variant effect prediction. We introduce a covariance-based probe that captures second-order structure from Evo 2 sequence embeddings to predict variant pathogenicity across variant types and functional consequences, matching or exceeding specialized predictors within their domains. To ground these predictions in known biological mechanisms, we train a complementary panel of probes on existing annotations to detect which genomic properties are disrupted by a variant. This categorized evidence is then integrated with each variant’s genomic context through a language model to generate variant-specific mechanistic hypotheses. Our pathogenicity predictions correlate with experimental measures of variant function, clinical penetrance, and biobank disease associations while the mechanistic hypotheses are consistent with expert reviews, known mechanism classes, and downstream molecular readouts. We release pathogenicity scores, disruption profiles, and contextualized interpretations for 4.2 million variants from the ClinVar database as an open resource through the Evo Variant Effect Explorer (EVEE). More broadly, this structured probing approach offers a general framework for interrogating foundation models across scientific disciplines and grounding their outputs in existing domain concepts.