Augusta University

Peripheral artery diseases (PADs) are a growing public health problem globally and a common, debilitating comorbidity among dialysis patients. However, the impact of social determinants of health on PAD within this population remains underexplored. This study evaluated associations between zip code-level socioeconomic indicators and PAD incidence and prevalence among US dialysis patients. The 2022 Medicare Dialysis Facilities dataset was used to identify US dialysis centers and matched associated zip codes with the Centers for Disease Control and Prevention and Agency for Toxic Substance and Disease Registry Social Vulnerability Index. Variables included community-level indicators of income, housing, employment, insurance, and access to care. Multivariable linear regression models were constructed in SPSS between social determinants of health and PAD burden. PAD incidence and prevalence were highest in the Northeast (M = 9.11, M = 18.66 respectively). Incidence was positively associated with poverty (β = 0.200, P < 0.001) and uninsurance (β = 0.052, P = 0.015), whereas housing burden, unemployment, education, and region showed inverse associations. For PAD prevalence, uninsurance remained positively associated (β = 0.088, P < 0.001); poverty, rurality, and region were negative predictors. Interaction terms (uninsurance × region; uninsurance × rurality) were significant for both outcomes. Model fit was modest (adjusted R2 = 0.018-0.031). Uninsured status and poverty are key SDHs linked to PAD in dialysis patients, although effects vary by incidence and prevalence, reflecting the combined influence of structural, geographical, and facility disparities.

Covalent inhibitors have re-emerged as powerful therapeutic agents, offering the ability to modulate "undruggable" proteins including oncogenic drivers that have eluded traditional drug discovery efforts. Expanding the repertoire of electrophilic moieties remains a critical frontier in covalent drug discovery. Here, we report a Rh(I)-catalyzed cycloisomerization of N-allyl bicyclo[1.1.0]butane amides (BCB amides) to access the 5-methylene-3-azabicyclo[5.1.0]octan-4-one (MABO) scaffold via strain-release reactivity. Both N-allyl BCB amides and MABOs can react with nucleophiles, highlighting their potential as electrophilic moieties for covalent drug design. Kinetic assays against glutathione revealed that selected N-allyl BCB amides and MABOs exhibit half-lives comparable to that of (±)-sotorasib, whose enantiomerically pure form received FDA approval as an anticancer drug. Biological evaluation in human-derived head and neck squamous cell carcinoma (HNSCC) models identified specific BCB amides and MABO compounds capable of modulating cancer cell growth. The toxicity of the compounds was evaluated by flow cytometry in human peripheral blood mononuclear cells (PBMCs) and by monitoring LDH release in the monocytic cell line THP-1, both under basal and activated conditions. Together, these findings suggest that BCB amides and MABOs represent promising classes of electrophilic scaffolds for covalent drug discovery.

Contrast-enhanced echocardiography (CE-echo) is commonly used in adult patients to optimize endocardial border delineation (EBD) but there is limited experience in children. A prospective, open-label, non-randomized, multicenter study was performed to evaluate the efficacy of intravenous Optison for CE-echo in pediatric patients and determine the optimal dose of Optison. Subjects ≥ 9 and < 18years with suboptimal echocardiograms (defined as ≥ 2 contiguous segments that could not be adequately visualized) were enrolled. After a baseline non-contrast echocardiogram (NC-echo), CE-echo was performed with 2 dose levels of Optison based on patient weight. The primary endpoint was visualization of the LV wall segments (LVWS) in apical 2- and 4-chamber views. An EBD score was calculated by assigning a value from 0 (no visualization) to 3 (optimal visualization) for 12 LVWS. 37 subjects across 8 sites completed the study. 30 had complete echocardiograms at both dose levels. 2 patients had usable images at dose 2 only. Mean age was 13.4years (± 2.6) with 23 males (62%). Mean weight was 73.9kg (± 36.8) with wide distribution of weight (interquartile range of 42-102kg). There were 8 patients under 40kg. Most subjects had a prior medical/surgical history (n = 33, 89%). Both dose levels of Optison CE-echo improved the number of LVWS visualized from 3.7 ± 1.1 on NC-echo to 10.0 ± 0.1 with dose 1 (p < 0.001) and 10.5 ± 0.1 with dose 2 (p < 0.001). EBD score also improved at both dose levels from 11.9 ± 2.5 for NC-echo to 28.5 ± 1.7 for dose 1 (p < 0.001) and 30.2 ± 8.4 for dose 2 (p < 0.001). The number of suboptimal echocardiograms improved from 92.3% ± 10.7 in NC-echo to 26.2% ± 9 with dose 1 (p < 0.001) and 30.8% ± 4.5 with dose 2 (p < 0.001). CE-echo with intravenous Optison in pediatric patients improved the number of LVWS visualized, improved EBD score, and reduced the number of suboptimal echocardiograms at both dosages used in this study. Intravenous Optison can improve LV visualization in pediatric patients with suboptimal echocardiograms.

BackgroundBrepocitinib is a first-in-class, oral, selective TYK2–JAK1 inhibitor that blocks cytokine signaling, which has been implicated in dermatomyositis.MethodsIn this phase 3, double-blind, randomized, placebo-controlled trial, adults with dermatomyositis were assigned in a 1:1:1 ratio to receive once-daily oral brepocitinib at a dose of 30 mg, brepocitinib at a dose of 15 mg, or placebo for 52 weeks. Standard therapies were continued, and glucocorticoids were tapered. The primary end point was the Total Improvement Score, a validated composite myositis index (with scores ranging from 0 to 100 and higher scores indicating greater improvement) at week 52. Key secondary end points, including skin disease activity, glucocorticoid tapering, and physical function, were tested in a multiplicity-controlled sequence.ResultsA total of 241 patients underwent randomization: 81 to receive brepocitinib 30 mg, 81 to receive brepocitinib 15 mg, and 79 to receive placebo. At week 52, the mean Total Improvement Score was 46.5, 37.5, and 31.2, respectively (difference with brepocitinib 30 mg vs. placebo, 15.3; 95% confidence interval [CI], 6.7 to 24.0; P<0.001; difference with brepocitinib 15 mg vs. placebo, 6.3; 95% CI, −2.4 to 14.9). Brepocitinib 30 mg was superior to placebo across all nine key secondary end points, including skin disease activity, systemic glucocorticoid tapering, and functional disability, with improvements observed as early as week 4. Serious infections were more frequent in the brepocitinib 30-mg group than in the placebo group (10% vs. 1%). No deaths occurred during the trial.ConclusionsIn adults with dermatomyositis that was resistant to previous therapy, the use of brepocitinib at a dose of 30 mg (but not at a dose of 15 mg) resulted in significant benefits with respect to a composite myositis index, skin disease severity, glucocorticoid tapering, and functional disability. (Funded by Priovant Therapeutics; ClinicalTrials.gov number, NCT05437263.)

High-throughput transcriptomic technologies have advanced rapidly, enabling genome-wide gene expression profiling. Microarrays, introduced in 1995, laid the foundation for large-scale analysis but were later surpassed in 2008 by RNA sequencing (RNA-seq), which offers single-nucleotide resolution, detects low-abundance transcripts, and does not require prior sequence knowledge. Bulk RNA-seq provides robust insights into global transcriptomic changes but lacks single-cell resolution. Single-cell RNA-seq (scRNA-seq), introduced in 2009, addressed this limitation by revealing cellular heterogeneity and dynamic gene expression. However, its application in bone research is constrained due to difficulties in releasing bone cells called osteocytes from the mineralized matrix, often resulting in low yield and dissociation-induced artifacts. In order to address these challenges, single-nucleus RNA-seq (snRNA-seq), first introduced in 2016 to enable transcriptomic profiling from isolated nuclei, was used in this study. We developed a protocol for snRNA-seq on bone tissue, achieving high-yield recovery of osteocyte nuclei from snap-frozen, marrow-flushed long bones. This approach minimized dissociation bias and enhanced osteocyte representation. We applied this robust method to long bones from young adult male and female mice, generating a high-resolution map of osteocyte gene expression under physiological conditions. Compared to scRNA-seq datasets, where osteocytes represent only 0.18%-6.64% of cells, our snRNA-seq approach increased osteocyte capture and transcriptomic fidelity to 18.5%. We identified an osteocyte transcriptomic signature highlighting the top 30 genes, including Sost, which is typically undetected or lowly-expressed in scRNA-seq. Notably, 23 of these genes have not been well-characterized in osteocytes, including Tg, Kcnq5, Rapgef4os1, Cacna1a, Egr3, Dok5, and Lgr6, which may represent novel regulators of osteocyte biology. This study represents the first application of snRNA-seq specifically for osteocyte analysis in bone tissue, providing a valuable resource for investigating osteocyte biology and skeletal disorders.

Standard catheter-directed thrombolysis (CDT) (S-CDT) is widely accepted as a safer alternative to open surgery for acute limb ischemia (ALI), but data on ultrasound-enhanced CDT (UE-CDT) for limb salvage are limited. This study compares outcomes of UE-CDT versus S-CDT. A 10-year single institution retrospective review identified 68 adult patients who underwent 93 CDT events for ALI, including 62 with UE-CDT and 22 with S-CDT. Following intervention, inpatient, 30 day, and 90 day outcomes were compared; one outcome for comparison was major adverse limb events (MALEs) defined as amputation of any type. No significant differences were observed between UE-CDT and S-CDT in hospital stay (5.6 vs. 7.1 days, P = 0.31), intensive care unit stay (2.5 vs. 2.9 days, P = 0.26), or duration of thrombolysis (24.2 vs. 29.6 hours, P = 0.39). Technical success was achieved in 92% of UE-CDT cases and 95% of S-CDT cases. At 30 days, UE-CDT patients had significantly fewer MALEs compared to S-CDT (6.5% vs. 31.8%; P = 0.01). However, when amputation type was stratified between digit amputation versus above/below knee amputation, there was only a significant difference between digit amputations in the S-CDT compared to UE-CDT at 30 days (P = 0.004). Otherwise, there was no significant difference between the groups at 30 and 90 days when comparing rates of above ankle amputations. UE-CDT and S-CDT for ALI show similar hospital and procedural outcomes. However, UE-CDT is associated with lower 30-day MALE, driven by reduced digit amputations, and becomes nonsignificant when stratifying by above ankle amputations.