Post-translational S-palmitoylation directs the trafficking and membrane localization of hundreds of cellular proteins, often involving a coordinated palmitoylation cycle that requires both protein acyl transferases (PATs) and acyl protein thioesterases (APTs) to actively re-distribute S-palmitoylated proteins towards different cellular membrane compartments. This process is necessary for the trafficking and oncogenic signaling of S-palmitoylated Ras isoforms, and potentially many peripheral membrane proteins. The de-palmitoylating enzymes APT1 and APT2 are separately conserved in all vertebrates, suggesting unique functional roles for each enzyme. The recent discovery of the APT isoform-selective inhibitors ML348 and ML349 has opened new possibilities to probe the function of each enzyme, yet it remains unclear how each inhibitor achieves orthogonal inhibition. Herein we report the high-resolution structure of human APT2 in complex with ML349 (1.64 Å), as well as the complementary structure of human APT1 bound to ML348 (1.55 Å). Although the overall peptide backbone structures are nearly identical, each inhibitor adopts a distinct conformation within each active site. In APT1, ML348 is positioned above the catalytic triad, but in APT2, the sulfonyl group of ML349 forms hydrogen bonds with active site resident waters to indirectly engage the catalytic triad and oxyanion hole. Reciprocal mutagenesis and activity profiling revealed several differing residues surrounding the active site that serve as critical gatekeepers for isoform accessibility and dynamics. Structural and biochemical analysis suggests the inhibitors occupy a putative acyl-binding region, establishing the mechanism for isoform-specific inhibition, hydrolysis of acyl substrates, and structural orthogonality important for future probe development.

Periprosthetic osteolysis is a common occurrence after total ankle arthroplasty (TAA) and poses many challenges for the foot and ankle surgeon. Osteolysis may be asymptomatic and remain benign, or it may lead to component instability and require revision or arthrodesis. In this article, we present a current and comprehensive review of osteolysis in TAA with illustrative cases. We examine the basic science principles behind the etiology of osteolysis, discuss the workup of a patient with suspected osteolysis, and present a review of the evidence of various management strategies, including grafting of cysts, revision TAA, and arthrodesis. Level of Evidence: Level V, expert opinion.

Purpose of Review Ankle sprains are a common injury that can lead to chronic lateral ankle instability resulting in pain, poor function, and decreased quality of life. The purpose of this review is to present information regarding injury mechanisms to the lateral ligaments of the ankle and the necessary steps to appropriately diagnose lateral ligament instability. Recent Findings The literature demonstrates that history and physical examination is often a reliable method for diagnosis of lateral ankle instability. In addition, imaging modalities are often used as adjuncts for diagnosis, especially when physical exam findings are equivocal. Summary In summary, chronic lateral ligament instability of the ankle occurs secondary to failure of the lateral ligamentous complex. A focused physical examination to evaluate the anterior talofibular ligament, calcaneofibular ligament, and posterior talofibular ligament is necessary for diagnosis. Imaging modalities including plain radiographs, stress radiographs, and MRI are helpful for definitive diagnosis and to rule out other pathology.

Background: In the United States, the COVID-19 pandemic led to a nationwide quarantine that forced individuals to adjust their daily activities, potentially impacting the burden of foot and ankle disease. The purpose of this study was to compare diagnoses made in an orthopaedic foot and ankle clinic during the shelter-in-place period of the COVID-19 pandemic to diagnoses made during the same months of the previous year. Methods: A retrospective review of new patients presenting to the clinics of 4 fellowship-trained orthopaedic foot and ankle surgeons in a major United States city was performed. Patients in the COVID-19 group presented between March 22 and July 1, 2020, during the peak of the quarantine for this city. Patients in the control group presented during the same period of 2019. Final diagnosis, chronicity of symptoms (acute: ≤1 month), and mechanism of disease were compared between groups. Results: A total of 1409 new patient visits were reviewed with 449 visits in the COVID-19 group and 960 visits in the control group. The COVID-19 group had a significantly higher proportion of ankle fractures (8.7% vs 5.4%, P = .020) and stress fractures (4.2% vs 2.2%, P = .031), but a smaller proportion of Achilles tendon ruptures (0.7% vs 2.5%, P = .019). The COVID-19 group had a higher proportion of acute injuries (35.4% vs 23.5%, P < .001). Conclusion: There was a shift in prevalence of pathology seen in the foot and ankle clinic during the COVID-19 pandemic, which may reflect the adoption of different activities during the quarantine period and reluctance to present for evaluation of non-urgent injuries. Level of Evidence: Level III, retrospective cohort study.

Background:Unicompartmental knee arthroplasty (UKA) is a common procedure for unicompartmental knee arthritis, often resulting in pain relief and improved function. The demand for total knee arthroplasty in the U.S. is projected to grow 85% between 2014 and 2030, and the volume of UKA procedures is growing 3 to 6 times faster than that of total knee arthroplasty. The purpose of the present study was to examine the safety of outpatient and inpatient UKA and to investigate changes over time as outpatient procedures were performed more frequently.Methods:Patients who underwent UKA from 2005 to 2018 as part of the National Surgical Quality Improvement Program were identified. Patients were divided into an early cohort (5,555 patients from 2005 to 2015) and late cohort (5,627 patients from 2016 to 2018). Outpatient status was defined as discharge on the day of surgery. Adverse events within 30 days postoperatively were compared, with adjustment for baseline characteristics with use of standard multivariate regression and propensity-score-matching techniques.Results:Among the 5,555 cases in the early cohort, the rate of surgical-site infection was lower for inpatient (0.84%) compared with outpatient UKA (1.69%; adjusted relative risk [RR] for inpatient, 0.5; 95% confidence interval [CI], 0.2 to 1.0; p = 0.045); no other significant differences were identified. Among the 5,627 cases in the late cohort, inpatient UKA had higher rates of any complication (2.53% compared with 0.95% for outpatient UKA; adjusted RR for inpatient, 2.5; 95% CI, 1.4 to 4.3; p = 0.001) and readmission (1.81% compared with 0.88% for outpatient UKA; adjusted RR for inpatient, 2.0; 95% CI, 1.1 to 3.5; p = 0.023). In the propensity-score-matched comparison for the late cohort, inpatient UKA had a higher rate of any complication (RR for inpatient, 2.0; 95% CI, 1.0 to 4.0; p = 0.049) and return to the operating room (RR for inpatient, 4.3; 95% CI, 1.4 to 12.6; p = 0.009). Although the rate of readmission was almost twice as high among inpatients (1.67% compared with 0.84% for outpatients; RR for inpatient, 2.0; 95% CI, 1.0 to 4.1; p = 0.059), this difference did not reach significance with the sample size studied. There was a significant reduction in the overall rate of complications over time (3.44% in the early cohort compared with 2.11% in the late cohort; adjusted RR for late cohort, 0.7; 95% CI, 0.5 to 0.8; p = 0.001), with a more than fourfold reduction among outpatients (3.95% in the early cohort compared with 0.95% in the late cohort; adjusted RR for late cohort, 0.3; 95% CI, 0.1 to 0.5; p < 0.001).Conclusions:Outpatient UKA was associated with a lower risk of complications compared with inpatient UKA when contemporary data are examined. We identified a dramatic reduction in complications across the early and late cohorts, suggesting an improvement in quality over time, with the largest improvements seen among outpatients. This shift may represent changes in patient selection or improvements in perioperative protocols.Level of Evidence:Therapeu...