Citations

Abstract Background Hemiarthroplasty may be indicated for patients with distal radioulnar joint (DRUJ) arthritis. Recently, the use of the pyrocarbon metacarpophalangeal implant has been proposed as a novel means of treating DRUJ arthritis due to the materials improved mechanical properties and wear characteristics. Purpose This study compares midterm outcomes of metallic and pyrocarbon hemiarthroplasties for the treatment of symptomatic DRUJ arthritis. Questions of interest included outcomes and complications. Materials and Methods In total, 32 hemiarthroplasties, 10 metallic and 22 pyrocarbon, were performed between 2010 and 2020 by three surgeons at one tertiary medical center. Patients' retrospective outcomes were extracted from the electronic medical record. Results Postoperatively, the metallic implant group (mean follow-up: 38 months) demonstrated decreased pain but no changes in range of motion. Comparatively, the pyrocarbon group experienced an improved range of motion and postoperative pain (p < 0.05). Radiographic analysis demonstrated 10% of metallic implants and 9% of pyrocarbon implants to have resulted in thinning of the lateral cortex of the radius at the final follow-up. Minor complications in metallic and pyrocarbon implant groups warranting reoperation occurred at rates of 10 and 13.5% while implant failure occurred at a rate of 30 and 18%, respectively. Discussion Within this study, pyrocarbon implants resulted in significant functional improvement with comparable complication and failure rates to the metallic implant. Long-term stability demonstrated efficacy for both techniques in symptomatic DRUJ treatment. Type of Study/Level of Evidence Observational Case Series IV.

Abstract Background Neonatal hemophagocytic lymphohistiocytosis (nHLH), defined as HLH that presents in the first month of life, is clinically devastating. There have been few large descriptive studies of nHLH. Objectives The objective of this study was to perform a meta‐analysis of published cases of nHLH. Methods A comprehensive literature database search was performed. Cases of HLH were eligible for inclusion if clinical analysis was performed at age ≤30 days. Up to 70 variables were extracted from each case. Results A total of 544 studies were assessed for eligibility, and 205 cases of nHLH from 142 articles were included. The median age of symptom onset was day of life 3 (interquartile range [IQR]: 0–11, n = 141). Median age at diagnosis was day of life 15 (IQR: 6–27, n = 87). Causes of HLH included familial HLH (48%, n = 99/205), infection (26%, n = 53/205), unknown (17%, n = 35/205), macrophage activation syndrome/rheumatologic (2.9%, n = 4/205), primary immune deficiency (2.0%, n = 5/205), inborn errors of metabolism (2.4%, n = 5/205), and malignancy (2.0%, n = 4/205). Fever was absent in 19% ( n = 28/147) of all neonates and 39% ( n = 15/38) of preterm neonates. Bicytopenia was absent in 26% ( n = 47/183) of patients. Central nervous system (CNS) manifestations were reported in 63% of cases ( n = 64/102). Liver injury (68%, n = 91/134) and/or liver failure (24%, n = 32/134) were common. Flow cytometry was performed in 22% ( n = 45/205) of cases. Many patients (63%, n = 121/193) died within the period of reporting. Discernable values for HLH diagnostic criteria were reported between 30% and 83% of the time. Conclusions Evaluation of nHLH requires rapid testing for a wide range of differential diagnoses. HLH diagnostic criteria such as fever and bicytopenia may not occur as frequently in the neonatal population as in older pediatric populations. Neurologic and hepatic manifestations frequently occur in the neonatal population. Current reports of nHLH suggest a high mortality rate. Future publications containing data on nHLH should improve reporting quality by reporting all clinically relevant data.

Staphylococcus aureus skin colonization and eosinophil infiltration are associated with many inflammatory skin disorders, including atopic dermatitis, bullous pemphigoid, Netherton’s syndrome, and prurigo nodularis. However, whether there is a relationship between S. aureus and eosinophils and how this interaction influences skin inflammation is largely undefined. We show in a preclinical mouse model that S. aureus epicutaneous exposure induced eosinophil-recruiting chemokines and eosinophil infiltration into the skin. Remarkably, we found that eosinophils had a comparable contribution to the skin inflammation as T cells, in a manner dependent on eosinophil-derived IL-17A and IL-17F production. Importantly, IL-36R signaling induced CCL7-mediated eosinophil recruitment to the inflamed skin. Last, S. aureus proteases induced IL-36α expression in keratinocytes, which promoted infiltration of IL-17-producing eosinophils. Collectively, we uncovered a mechanism for S. aureus proteases to trigger eosinophil-mediated skin inflammation, which has implications in the pathogenesis of inflammatory skin diseases.

TPS587 Background: Biliary tract cancer (BTC) is characterized by generally poor prognoses with limited treatment options. Systemic chemotherapy usually begins with gemcitabine, platinum agents, and a checkpoint inhibitor followed by 5-FU and oxaliplatin, irinotecan or a taxane. Presently, there is no consensus second-line therapy for patients with BTC. The DLL/Notch signaling pathway has been described to be a major driver of cholangiocarcinogenesis and VEGF-A overexpression has been reported in BTC tumors, correlating with stage, metastasis, and prognosis of the disease. CTX-009 is a recombinant bispecific antibody that binds both delta-like ligand-4 (DLL4) and vascular endothelial growth factor A (VEGF-A). The antibody simultaneously inhibits the DLL4-Notch 1 and VEGF A-VEGF receptor signaling pathways. Methods: COMPANION-002 (CTX-009 -002) is an open-label, randomized, controlled study in patients in second line advanced or metastatic BTC. To be eligible, patients must have radiologically documented progression after a prior gemcitabine and platinum containing chemotherapy regimen as first line therapy for locally advanced unresectable or metastatic disease. 150 patients will be randomized in a 2:1 ratio to receive either CTX-009 plus paclitaxel or paclitaxel alone. The stratification factors to be used at randomization include stage (locally advanced vs. metastatic), anatomic subsite of primary tumor (intrahepatic cholangiocarcinoma vs. other, i.e. extrahepatic cholangiocarcinoma, gallbladder, or ampullary), and Eastern Cooperative Oncology Group (ECOG) Performance status (0 vs. 1). Patients will be treated in 28-day cycles, with CTX-009 administered at 10 mg/kg IV on Day 1 and 15, and paclitaxel administered at 80 mg/m2 on days 1, 8, and 15. The patients randomized to paclitaxel arm can crossover after disease progression if selection criteria continue to be met. The primary objective of the study is to assess the efficacy of CTX-009 in combination with paclitaxel vs. paclitaxel alone, as measured by Overall Response Rate (ORR) assessed by an Independent Central Radiology (ICR) review. Key secondary objectives include overall survival, progression-free survival, and duration of response. Clinical trial information: 251040.

Functional loss of TDP-43, an RNA binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to the inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote the degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43–depleted human iPSC–derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD. Using coordinated transcriptomic and proteomic studies of TDP-43–depleted human iPSC–derived neurons, we identified 65 peptides that mapped to 12 cryptic exons. Cryptic exons identified in TDP-43–depleted human iPSC–derived neurons were predictive of cryptic exons expressed in postmortem brain tissue from patients with TDP-43 proteinopathy. These cryptic exons produced transcript variants that generated de novo proteins. We found that the inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Last, we showed that 18 de novo peptides across 13 genes were present in CSF samples from patients with ALS/FTD spectrum disorders. The demonstration of cryptic exon translation suggests new mechanisms for ALS/FTD pathophysiology downstream of TDP-43 dysfunction and may provide a potential strategy to assay TDP-43 function in patient CSF.

Abstract Background The primary objective of the VIVID-1 trial (NCT03926130) was to demonstrate efficacy and safety of mirikizumab (miri), a p19-directed anti-IL-23 antibody, compared to placebo (PBO) in patients (pts) with moderate-to-severe Crohn’s disease. Miri demonstrated statistically significant improvements in co-primary and all key secondary endpoints versus (vs) PBO1. Here we present the results of secondary endpoints on the comparisons of miri to ustekinumab (uste), a p40 directed anti-IL-12/IL-23 inhibitor from the Phase 3, randomised, double-blind, double-dummy, active- and PBO-controlled, treat-through (TT) study, VIVID-1 (NCT03926130). Methods Adult pts (N=1065) were randomised 6:3:2 to miri (N=579) 900mg intravenously (IV) every 4 weeks (Q4W) to W12, then 300mg subcutaneously (SC) Q4W to W52, uste (N=287) one ~6 mg/kg IV dose, then 90mg SC Q8W to W52 or PBO (N=199). At W12 PBO responders continued PBO to W52; PBO non-responders received the same blinded miri regimen as described above (IV then SC). Efficacy of miri vs uste was assessed by the proportion of pts achieving endoscopic response and by the proportion of pts achieving clinical remission by Crohn’s Disease Activity Index (CDAI) at W52 (both gated). Additional non-multiplicity-adjusted endpoints included endoscopic remission, corticosteroid-free clinical remission by CDAI, and the composite of CDAI clinical remission and endoscopic response at W52. (Figure 1 for definitions). Results Baseline characteristics were overall balanced across the three treatment groups (table 1). Pts treated with miri achieved all key major secondary endpoints (p&lt;.000001) compared to PBO (Figure 1). Miri achieved non-inferiority to uste for clinical remission by CDAI (p=0.113117) (Figure 1C). Although superiority to uste in endoscopic response was not achieved (p=0.51) (Figure 1A), in biologic failed pts miri demonstrated a numerical trend towards greater response rates compared to uste for endoscopic response and clinical remission by CDAI (Figure 1 B & D). The overall safety profile was consistent with the known safety profile of miri. The proportion of treatment emergent adverse events (TEAE) were similar for miri (78.6%) and uste (77.3%); most common TEAEs were COVID-19, anaemia, arthralgia, headache, upper respiratory tract infection, nasopharyngitis and injection site reaction. Instances of serious adverse events were comparable for miri (10.3%) and uste (10.7%). Conclusion In this phase 3 TT design study, miri achieved non-inferiority to uste for clinical remission by CDAI. In biologic failed pts miri had a numerical trend towards greater response compared to uste in clinical and endoscopic endpoints, with an acceptable safety profile. 1Ferrante et al., submitted to ECCO 2024

Abstract Objective The aim of this study is to determine if supervised machine learning algorithms can accurately predict cancelled and self-intercepted computerized physician order entry in oral and maxillofacial surgery inpatients. Methods Data from Electronic Medical Record included patient demographics, comorbidities, procedures, vital signs, laboratory values, and medication orders were retrospectively collected. Predictor variables included patient demographics, comorbidities, procedures, vital signs, and laboratory values. Outcome of interest is if a medication order was voided or not. Data was cleaned and pro1cessed using Microsoft Excel and Python v3.12. Gradient Boosted Decision Trees, Random Forest, K-Nearest Neighbor, and Naïve Bayes were trained, validated, and tested for accuracy of the prediction of voided medication orders. Results 37,546 medication orders from 1,204 patient admissions over 5 years were used for this study included 3,892 (10.4%) medication orders that were voided. Gradient Boosted Decision Trees, Random Forest, K-Nearest Neighbor, and Naïve Bayes had an Area Under the Receiver Operating Curve of 0.802 802 with 95% CI [0.787, 0.825], 0.746 with 95% CI [0.722, 0.765], 0.685 with 95% CI [0.667, 0.699], and 0.505 with 95% CI [0.489, 0.539], respectively. Area Under the Precision Recall Curve was 0.684 with 95% CI [0.679, 0.702], 0.647 with 95% CI [0.638, 0.664], 0.429 with 95% CI [0.417, 0.434], and 0.551 with 95% CI [0.551, 0.552], respectively. Conclusion Gradient Boosted Decision Trees is the best model of the supervised machine learning algorithms with satisfactory performance in validation cohort for predicting voided Computerized Physician Order Entry in Oral and Maxillofacial Surgery inpatients.

Abstract Biceps tenodesis has been proven to be an effective treatment for biceps tendon and superior labral pathology. Many techniques including both open and arthroscopic approaches have been reported. Open techniques afford management of the entire proximal biceps tendon but are limited by wound healing issues, increased bleeding, and increased surgical time. Arthroscopic tenodesis offers benefits in terms of surgical efficiency, cosmesis, and bleeding risk. However, standard arthroscopic tenodesis only addresses intra‐articular biceps pathology. In this report we describe an all‐arthroscopic biceps tenodesis technique at the suprapectoral region of the humerus using knotless suture anchor fixation. Technique Video video See video under supplementary data.