¤ ¤Purpose: To determine the effect of curvature on the magnitude and direction of displacement forces acting on aortic endografts in 3-dimensional (3D) computational models.Method: A 3D computer model was constructed based on magnetic resonance angiography data from a patient with an infrarenal aortic aneurysm. Computational fluid dynamics tools were used to simulate realistic flow and pressure conditions of the patient. An aortic endograft was deployed in the model, and the displacement forces acting on the endograft were calculated and expressed in Newtons (N). Additional models were created to determine the effects of reducing endograft curvature, neck angulation, and iliac angulation on displacement forces. Results: The aortic endograft had a curved configuration as a result of the patient's anatomy, with curvature in the anterolateral direction. Total displacement force acting on the endograft was 5.0 N, with 28% of the force in a downward (caudal) direction and 72% of the force in a sideways (anterolateral) direction. Elimination of endograft curvature (planar graft configuration) reduced total displacement force to 0.8 N, with the largest component of force (70%) acting in the sideways direction. Straightening the aortic neck in the curved endograft configuration reduced the total force acting on the endograft to 4.2 N, with a reduction of the sideways component to 55% of the total force. Straightening the iliac limbs of the endograft reduced the total force acting on the endograft to 2.1 N but increased the sideways component to 91% of the total force. Conclusion: The largest component of the force acting on the aortic endograft is in the sideways direction, with respect to the blood flow, rather than in the downward (caudal) direction as is commonly assumed. Increased curvature of the aortic endograft increases the magnitude of the sideways displacement force. The degree of angulation of the proximal and distal ends of the endograft influence the magnitude and direction of displacement force. These factors may have a significant influence on the propensity of endografts to migrate in vivo.

The orientation of the DF varies depending on curvature and location of the endograft, but in all instances, it is in the cranial rather than caudal direction on axial imaging. This is counter to the intuitive notion that displacement forces act in the downward direction of blood flow. Therefore, we postulate that migration of thoracic endografts may be different from abdominal endografts since it may involve upward rather than downward movement of the graft. Computational methods can enhance the understanding of the magnitude and orientation of the loads experienced in vivo by thoracic aortic endografts and therefore improve their design and performance.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, life-threatening bullous genodermatosis (1, 2). Genetic mutations in the COL7A1 gene lead to lack of functional type VII collagen (C7), a large triple-helical protein found beneath the lamina densa (2-4). C7 contains 2 noncollagenous domains (NC1 and NC2) and a central collagenous domain, forming anchoring fibrils (AFs) that are critical to dermal-epidermal basement cohesion (2, 4). Mutations in COL7A1 lead to disruptions in keratinocyte adhesion, reducing mucocu-BACKGROUND. Recessive dystrophic epidermolysis bullosa (RDEB) patients have mutations in the COL7A1 gene and thus lack functional type VII collagen (C7) protein; they have marked skin fragility and blistering. This single-center phase 1/2a open-label study evaluated the long-term efficacy, safety, and patient-reported outcomes in RDEB patients treated with gene-corrected autologous cell therapy. METHODS. Autologous keratinocytes were isolated from participant skin biopsies. Epidermal sheets were prepared from cells transduced with a retrovirus carrying the full-length human COL7A1 gene. These gene-corrected autologous epidermal sheets measured 5 × 7 cm (35 cm 2) and were transplanted onto 6 wound sites in each of 7 adult participants (n = 42 sites total) from 2013 to 2017. Participants were followed for 2 to 5 years. RESULTS. No participants experienced any serious related adverse events. Wound healing of 50% or greater by Investigator Global Assessment was present in 95% (36 of 38) of treated wounds versus 0% (0 of 6) of untreated control wounds at 6 months (P < 0.0001). At year 1, 68% (26 of 38) of treated wounds had 50% or greater healing compared with 17% (1 of 6) of control wounds (P = 0.025). At year 2, 71% (27 of 38) of treated wounds had 50% or greater healing compared with 17% (1 of 6) of control wounds (P = 0.019). CONCLUSION. C7 expression persisted up to 2 years after treatment in 2 participants. Treated wounds with 50% or greater healing demonstrated improvement in patient-reported pain, itch, and wound durability. This study provides additional data to support the clinically meaningful benefit of treating chronic RDEB wounds with ex vivo, C7 gene-corrected autologous cell therapy. This approach was safe and promoted wound healing that was associated with improved patientreported outcomes. TRIAL REGISTRATION. Clinicaltrials.gov identifier: NCT01263379.

An estimated 3 billion people lack access to dermatological care globally. Artificial intelligence (AI) may aid in triaging skin diseases and identifying malignancies. However, most AI models have not been assessed on images of diverse skin tones or uncommon diseases. Thus, we created the Diverse Dermatology Images (DDI) dataset—the first publicly available, expertly curated, and pathologically confirmed image dataset with diverse skin tones. We show that state-of-the-art dermatology AI models exhibit substantial limitations on the DDI dataset, particularly on dark skin tones and uncommon diseases. We find that dermatologists, who often label AI datasets, also perform worse on images of dark skin tones and uncommon diseases. Fine-tuning AI models on the DDI images closes the performance gap between light and dark skin tones. These findings identify important weaknesses and biases in dermatology AI that should be addressed for reliable application to diverse patients and diseases.

IMPORTANCEPrimary results from the Measure Up 1 and Measure Up 2 studies demonstrated upadacitinib efficacy and safety through 16 weeks in patients with atopic dermatitis. Longer-term outcomes remain unknown.OBJECTIVE To evaluate long-term (52 weeks) efficacy and safety of upadacitinib treatment in patients with atopic dermatitis. DESIGN, SETTING, AND PARTICIPANTSMeasure Up 1 and Measure Up 2 are ongoing double-blind, placebo-controlled, replicate phase 3 randomized clinical trials that include adults and adolescents with moderate to severe atopic dermatitis at 151 and 154 centers, respectively. Cutoffs for this analysis were December 21, 2020 (Measure Up 1), and January 15, 2021 (Measure Up 2).INTERVENTIONS Patients were randomized 1:1:1 to receive once-daily oral upadacitinib 15 mg, 30 mg, or placebo. At week 16, patients randomized at baseline to receive upadacitinib 15 mg (273 and 260 patients in Measure Up 1 and Measure Up 2, respectively) and 30 mg (270 and 268 patients) continued assigned treatment; placebo-treated patients were rerandomized 1:1 to receive upadacitinib 15 mg (121 and 120 patients in Measure Up 1 and Measure Up 2, respectively) or 30 mg (123 and 121 patients) in a double-blinded manner. MAIN OUTCOMES AND MEASURESSafety and efficacy, including 75% improvement in the Eczema Area and Severity Index and Validated Investigator Global Assessment for Atopic Dermatitis score of clear (0) or almost clear (1) with 2 or greater grades of improvement, were assessed. RESULTS Measure Up 1 and Measure Up 2 included a total of 1609 patients (mean [SD] age, 33.8 [15.6] years; 727 women [45.2%]; 882 men [54.8%]). Efficacy at week 16 was maintained through week 52. At week 52, 75% improvement in the Eczema Area and Severity Index was achieved by 82.0% (95% CI, 77.0%-86.9%) and 79.1% (95% CI, 73.9%-84.4%) of patients continuing the 15-mg dose and 84.9% (95% CI, 80.3%-89.5%) and 84.3% (95% CI, 79.6%-89.0%) of patients continuing the 30-mg dose (for Measure Up 1 and Measure Up 2, respectively); Validated Investigator Global Assessment for Atopic Dermatitis score of clear (0) or almost clear (1) with 2 or greater grades of improvement was achieved by 59.2% (95% CI, 52.9%-65.5%) and 52.6% (95% CI, 46.2%-59.1%) and 62.5% (95% CI, 56.3%-68.7%) and 65.1% (95% CI, 58.9%-71.2%) of patients in the Measure Up 1 and Measure Up 2 studies, respectively. Treatment discontinuation due to adverse events was low overall but was slightly higher for the upadacitinib 30-mg dose. Both upadacitinib doses were well tolerated with no new safety signals. CONCLUSIONS AND RELEVANCEIn this analysis of follow-up data from 2 randomized clinical trials, longer-term treatment of adolescents and adults with moderate to severe atopic dermatitis with upadacitinib demonstrated a favorable benefit-risk profile, with sustained efficacy responses through 52 weeks.TRIAL REGISTRATION ClinicalTrials.gov Identifiers: NCT03569293 (Measure Up 1) and NCT03607422 (Measure Up 2)