Missed Visits Predict Recurrence in Idiopathic Clubfoot.

BACKGROUND: Congenital talipes equinovarus, also known as "clubfoot," is a common congenital deformity. While reported relapse rates vary widely, relapse continues to be a common problem faced in the treatment of this condition. The objective of this study is to assess relationships between demographic/socioeconomic factors, follow-up, and rates of relapse in our population of clubfoot patients. METHODS: Retrospective chart review was conducted for patients undergoing treatment for idiopathic clubfoot from February 2012 to December 2022 at a tertiary children's hospital. Records were analyzed for follow-up adherence and recurrence in the Ponseti method, in addition to patient demographic and socioeconomic factors. Statistical analysis was performed to evaluate associations between recurrence, missed clinical visits, and demographic/socioeconomic factors of interest. RESULTS: Ninety-five patients were included in the study [74.7% male (N=71) and 25.2% female (N=24)]. A total of 64.2% (N=61) of patients developed recurrence during their treatment. Recurrence rates differed significantly by reported bracing noncompliance >1 month (35/46 vs. 26/49, P=0.019), having missed 1 or more clinical visits (38/61 vs. 8/34, P < 0.001), Medicaid or equivalent insurance type (41/56 vs. 20/39, P=0.028), non-white race (47/66 vs. 14/29, P=0.032, higher Social Deprivation Index score (56.13 vs. 41.06, P=0.019). Significant variables were analyzed using a multivariate logistic regression analysis (MVLR). After MVLR, having 1 or more missed clinical visits (OR 4.462, 95% CI: 1.549-12.856) remained significantly associated with increased rates of recurrence. Primary language preference and distance to the hospital were not associated with recurrence. CONCLUSIONS: Higher SDI scores, non-white race, Medicaid insurance, and missed clinical follow-up visits were all associated with increased rates of recurrence for clubfoot patients. Using an MVLR model, missed clinical follow-up visits remained independently associated with increased recurrence rates. LEVEL OF EVIDENCE: Level 2-retrospective, prognostic study.

Ferroptosis Inhibitors Suppress Prostaglandin Synthesis in Lipopolysaccharide-Stimulated Macrophages.

Necrostatin-1 blocks ferroptosis via an unknown mechanism and necroptosis through inhibition of receptor-interacting protein kinase-1 (RIP1). We report that necrostatin-1 suppresses cyclooxygenase-2-dependent prostaglandin biosynthesis in lipopolysaccharide-treated RAW264.7 macrophages (IC50 ∼ 100 µM). This activity is shared by necrostatin-1i (IC50 ∼ 50 µM), which lacks RIP1 inhibitory activity, but not the RIP1 inhibitors necrostatin-1s or deschloronecrostatin-1s. Furthermore, we show that the potent ferroptosis inhibitors and related compounds ferrostatin-1, phenoxazine, phenothiazine, and 10-methylphenothiazine strongly inhibit cellular prostaglandin biosynthesis with IC50's in the range of 30 nM to 3.5 µM. None of the compounds inhibit lipopolysaccharide-mediated cyclooxygenase-2 protein induction. In the presence of activating hydroperoxides, the necrostatins and ferroptosis inhibitors range from low potency inhibition to stimulation of in vitro cyclooxygenase-2 activity; however, inhibitory potency is increased under conditions of low peroxide tone. The ferroptosis inhibitors are highly effective reducing substrates for cyclooxygenase-2's peroxidase activity, suggesting that they act by suppressing hydroperoxide-mediated activation of the cyclooxygenase active site. In contrast, for the necrostatins, cellular prostaglandin synthesis inhibition does not correlate with peroxidase-reducing activity but rather with the presence of a thiohydantoin substituent, which conveys the ability to reduce the endoperoxide intermediate prostaglandin H2 to prostaglandin F2α in vitro. This finding suggests that necrostatin-1 blocks cellular prostaglandin synthesis and ferroptosis via a redox mechanism distinct from action as a one-electron donor. The results indicate that a wide range of compounds derived from redox-active chemical scaffolds can block cellular prostaglandin biosynthesis.

Molecular Imaging of Inflammation in Osteoarthritis Using a Water-Soluble Fluorocoxib.

Clinical imaging approaches to detect inflammatory biomarkers, such as cyclooxygenase-2 (COX-2), may facilitate the diagnosis and therapy of inflammatory diseases. To this end, we report the discovery of N-[(rhodamin-X-yl)but-4-yl]-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide chloride salt (fluorocoxib D), a hydrophilic analog of fluorocoxib A. Fluorocoxib D inhibits COX-2 selectively in purified enzyme preparations and cells. It exhibits adequate photophysical properties to enable detection of COX-2 in intact cells, in a mouse model of carrageenan-induced acute footpad inflammation and inflammation in a mouse model of osteoarthritis. COX-2-selectivity was verified either by blocking the enzyme's active site with celecoxib or by molecular imaging with nontargeted 5-carboxy-X-rhodamine dye. These data indicate that fluorocoxib D is an ideal candidate for early detection of inflammatory or neoplastic lesions expressing elevated levels of COX-2.