Citations

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.

Background/Objectives: A 12-week trial demonstrated that phenotype-tailored lifestyle intervention (PLI) was associated with greater weight loss than standard lifestyle intervention (SLI); however, differences in dietary patterns between groups were not examined. Methods: This secondary analysis evaluated caloric and macronutrient intake at 12 weeks in adults with obesity (BMI ≥ 30 kg/m2), classified into four energy-balance phenotypes (abnormal satiation, reduced postprandial satiety, low energy expenditure, emotional eating) (n = 77) who underwent PLI or SLI. Dietary intake was assessed by 24-h recalls and verified by a blinded registered dietitian. Results: Groups were compared at 12 weeks adjusting for baseline values. PLI was associated with lower total energy intake than SLI (1273 ± 182 vs. 1894 ± 176 kcal/day; p = 0.018), due to lower carbohydrate (464 ± 76 vs. 818 ± 73 kcal/day; p = 0.002) and fat intake (479 ± 76 vs. 697 ± 73 kcal/day; p = 0.036); absolute protein intake did not differ. However, protein comprised a greater proportion of energy intake in PLI (26.8 ± 1.6%) than SLI (19.8 ± 1.5%; p = 0.003), and dairy protein contributed more to total energy in PLI (6.8 ± 0.8% vs. 3.7 ± 0.7%; p = 0.004). Conclusions: PLI was associated with lower energy intake, mainly due to reduced carbohydrate and fat intake, and a higher relative contribution of protein, consistent with phenotype-based recommendations rather than macronutrient prescriptions. These findings suggest a potential role for personalized dietary approaches in obesity management. However, the non-randomized design does not allow causal inferences.

Introduction: Frontotemporal lobar degeneration (FTLD) is a devastating disease that commonly results in early onset dementia, yet its rarity and heterogeneity limit large-scale research and clinical trials. Remote monitoring via low-burden digital health tools may overcome these barriers. We evaluated clinical utility of passive smartphone monitoring in FTLD using a multi-domain mobile assessment platform. Methods: Participants were 567 adults (53% clinically normal, 21% prodromal FTLD, 26% symptomatic FTLD) who completed an in-person study visit and downloaded the ALLFTD Mobile App on their personal smartphones. The app delivered unsupervised cognitive tests and passively collected continuous data on battery percentage (proxy for smartphone use) and step count. Longitudinal follow-up included smartphone monitoring and annual in-person study visits. Primary analyses examined associations between passive smartphone features and markers of disease severity at baseline and longitudinally, and tested whether passive features added incremental value beyond app-based cognitive testing. Results: Passive smartphone features were feasible to collect and showed excellent reliability with <2 weeks of monitoring (ICCs>0.9). Features capturing smartphone use and movement demonstrated sensitivity to gold-standard clinical measures of disease severity both at baseline and longitudinally. A classification model combining passive features, the app-based cognitive composite score, and demographics detected longitudinal functional decline (AUC=0.89); passive features alone (AUC=0.84) performed comparably to a cognitive screener (AUC=0.85). Discussion: Passive smartphone monitoring is a valid, zero-burden measure of disease severity and progression in FTLD that adds modest incremental value beyond app-based cognitive testing. Findings support its use as a scalable digital endpoint in longitudinal FTLD research.

Abstract Clinical syndromes of frontotemporal dementia present both distinct and overlapping neuroimaging abnormalities and, consequently, domains of impairment. The aim of this study was to determine how well covariance patterns from multiple neuroimaging modalities discriminate across clinical frontotemporal dementia syndromes. Four-hundred participants with a clinical frontotemporal dementia diagnosis, including behavioral variant of frontotemporal dementia, semantic variant of primary progressive aphasia, right temporal variant of frontotemporal dementia, primary progressive aphasia, apraxia of speech with agrammatic aphasia, primary progressive apraxia of speech, progressive supranuclear palsy and corticobasal syndrome, and 109 cognitively unimpaired participants underwent extensive neurological and neuropsychological assessments, structural MRI, flortaucipir-PET for tau and [18F] fluorodeoxyglucose-PET. Multimodal imaging covariance was investigated at the voxel-level using principal component analysis after adjusting for age and sex effects. Linear regression models were fit to investigate the relationship between principal components and clinical scores. Multinomial logistic regression models investigated the ability of imaging principal components to discriminate across syndromes. The first principal component, which describes the largest source of variability in the data, was a pattern of widespread cortical atrophy (21% variability explained) and of frontoparietal and temporal hypometabolism (21%): scores were lowest in behavioral variant of frontotemporal dementia and correlated with general cognitive impairment. On tau-PET, the first principal component (43% variability) was not significantly different among syndromes and captured a widespread cortical tau uptake, with a focus on the temporal lobe. In all three modalities, the second principal component captured temporal lobe imaging abnormalities, contrasting the motor and semantic clinical syndromes. Subsequent components described smaller variability. On cross-validation, the classifiers based on principal components from MRI (multiclass area under the receiver operating characteristic: 0.76) and [18F]fluorodeoxyglucose-PET (0.79) outperformed tau-PET (0.71), while combining all three modalities did not significantly improve the classifier performance. On cross-validation, the sensitivity of the image-based classifiers was heterogeneous across syndromes and modalities, with highest values for progressive supranuclear palsy and semantic variant of primary progressive aphasia and lowest for primary progressive aphasia and corticobasal syndrome. Our study found that the covariance components of structural and molecular neuroimaging underlying frontotemporal dementia clinical syndromes exist both as a continuum and with syndrome-specific patterns. More than one imaging model was able to correctly classify several frontotemporal dementia clinical syndromes with good specificity and sensitivity, highlighting the value of imaging in aiding patient diagnosis.

Abstract Glioblastoma (GBM) remains the most lethal primary brain cancer due to its remarkable metabolic plasticity and therapeutic resistance. Here, we identify cholesterol dependency as a therapeutically exploitable vulnerability in GBM using two FDA-approved drugs: the H1 histamine antagonist clemastine and the retinoid X receptor agonist bexarotene. Combined treatment induces potent synergistic anti-tumor activity across patient-derived glioma models, suppressing proliferation, stemness, and survival at sub-IC50 concentrations. Mechanistically, this therapy disrupts cholesterol biosynthesis, transport, and homeostasis, triggering endoplasmic reticulum stress and activation of the unfolded protein response, ultimately leading to autophagy and apoptotic cell death. Orthotopic patient-derived glioma models recapitulate these mechanisms in vivo, where local intracranial administration significantly reduces tumor progression and prolongs survival using fourfold lower doses than systemic intraperitoneal delivery. Single-cell RNA sequencing revealed activation of regeneration and plasticity programs, accompanied by immune microenvironment remodeling and enhanced inflammatory signaling. Importantly, syngeneic models preserved immune cell composition, supporting future integration with immunotherapeutic strategies. Together, these findings establish cholesterol dysregulation–induced metabolic collapse as a promising therapeutic approach for GBM.

The total number of total hip arthroplasties performed each year is expected to increase significantly over the coming decades. As a result, an increasing number of young patients are undergoing total hip arthroplasty while similarly, a growing subset of active elderly patients desire to return to sports or high-impact activity after surgery. Patients are typically provided restrictions and activities to avoid following surgery. For these patients, there is no clear consensus or guidelines regarding whether they should limit their activity level postoperatively and in particular, if returning to high-impact exercise increases their risk of complications and subsequent revision surgery. This article will discuss the most common complications after total hip arthroplasty and whether patients who return to sports or a high-impact activity after surgery may be more predisposed to these complications in comparison to their more sedentary peers.

Importance Although adding immune checkpoint inhibitors to neoadjuvant chemotherapy improves outcomes in high-risk early-stage breast cancer, opportunities remain to further enhance response. Dual checkpoint blockade offers a potential strategy to further enhance efficacy. Objective To evaluate the combination of anti−programmed cell death 1 protein (PD-1) cemiplimab and anti−lymphocyte activation gene 3 (LAG-3) added to neoadjuvant therapy in ERBB2 -negative early-stage, high-risk breast cancer. Design, Setting, and Participants The I-SPY2 (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2) is an ongoing randomized clinical platform trial being conducted at multiple US clinical sites including patients with early-stage (II or III) ERBB2 -negative, high-risk breast cancer. Participants, continuously enrolled since 2010, were adaptively randomized from February 2, 2020, to December 9, 2021, to one of several experimental neoadjuvant therapies or control groups based on receptor subtypes defined by hormone receptor (HR), ERBB2 status, and MammaPrint (Agendia Inc) molecular risk, categorized as high (MP1) or ultrahigh (MP2). Data were analyzed from January 1, 2022, to August 5, 2025. Interventions Both groups received weekly paclitaxel for 12 weeks, then doxorubicin and cyclophosphamide followed by surgery; concomitant with paclitaxel, the intervention group also received 4 doses of cemiplimab and fianlimab (PCF) every 3 weeks. Main Outcomes and Measures Pathologic complete response (pCR). Treatments graduated when they achieved 85% bayesian probability of success in a subtype-specific phase 3 trial. Pathway-specific biomarkers were assessed for response prediction. Results A total of 78 participants (mean [SD] age, 47 [39-54] years) were randomized to the intervention group, with 350 participants (mean [SD] age, 48 [39-57] years) randomized to the historical control population. PCF graduated in all clinical signatures, with pCR rates vs control of 44% (95% CI, 34%-53%) vs 21% (95% CI, 17%-25%) in all ERBB2 , 53% (95% CI, 39%-67%) vs 29% (95% CI, 22%-36%) in triple-negative, and 36% (95% CI, 23%-49%) vs 14% (95% CI, 9%-19%) in HR-positive and ERBB2 -negative disease. Among the total participants, 16 (21%) experienced adrenal insufficiency, including hypophysitis (11% grade 3 or 4), mostly occurring after immunotherapy completion. PCF was found to be highly effective in the subset of patients with immune signature positive status (ImPrint positive). Conclusions and Relevance In this randomized clinical trial, the combination of PD-1 and anti−LAG-3 inhibition with standard NAC was effective in early-stage ERBB2 -negative breast cancer, particularly in patients displaying a positive ImPrint immune signature. These results warrant further definitive trials. Trial Registration ClinicalTrials.gov Identifier: NCT01042379

Abstract Concerns about declining gray fox (Urocyon cinereoargenteus) populations in the Midwest, United States, prompted a petition to list the prairie gray fox subspecies (Urocyon cinereoargenteus ocythous) under the US Endangered Species Act. Although previous studies identified a deep phylogenetic break between eastern and western lineages of the gray fox at the Great Plains Suture Zone, population structure within the Midwest remains poorly understood, complicating subspecies classification. To address this, we genotyped 339 individuals from the eastern lineage of the gray fox using single nucleotide polymorphisms (SNPs) generated from 2bRAD genomic sequencing to assess genetic diversity and structure. Bayesian clustering and principal component analysis supported three genetic clusters (K = 3), revealing a cryptic break within Missouri that subdivides the morphologically defined range of U. c. ocythous and a secondary break coinciding with the Mississippi River and the currently accepted subspecies boundary. However, low pairwise FST values and admixture indicate weak overall genetic differentiation with ongoing gene flow, whereas declining genetic diversity at northern latitudes is reflective of founder effects from post-glacial population expansion. Consistent with prior mitochondrial DNA (mtDNA) results, nuclear SNP data suggest that U. c. ocythous and Urocyon cinereoargenteus cinereoargenteus are unlikely to represent distinct evolutionary units. However, because 2bRAD detects primarily neutral variation, whole-genome sequencing will be needed to test for adaptive divergence that might persist despite gene flow. Our findings provide an important step toward a comprehensive understanding of population structure and refining subspecies boundaries within the eastern lineage of the gray fox.

ABSTRACT Objectives Alar reconstruction is common, yet high‐quality outcomes data are limited. This review synthesizes the available literature to guide evidence‐informed reconstructive choices. Methods A systematic review identified 35 eligible studies reporting defect characteristics, techniques, and aesthetic, functional, and graft/flap outcomes. Single‐patient case reports, purely technical papers, and studies without outcome data were excluded. Results Full‐thickness skin grafts (FTSG), FTSG with cartilage, and composite grafts have been used with acceptable aesthetic outcomes for small defects. Local flaps are most common for small to intermediate defects, while regional flaps, particularly melolabial (MLF) and paramedian forehead flaps (PMFF), are the primary options for larger defects. PMFFs have higher reported cosmetic satisfaction but may require more secondary procedures. Conclusions Standard data and evidence reporting for alar subunit reconstruction is very limited, with a predominance of retrospective and technique‐driven studies and gestalt‐based outcomes. Standardized reporting of defect size, functional outcomes, and validated patient‐reported measures is needed. Until higher‐quality data is available, reconstructive decisions should be individualized.