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Background: End-stage ankle arthritis is successfully treated with surgery with either ankle arthrodesis (AA) or total ankle arthroplasty (TAA). Much is described comparing the 2 treatments in tightly selected patient groups. Limited evidence attempts to examine specific elements of technical complexity that increase perioperative risk for the surgical treatment of ankle arthritis. There is suspicion that AA may be preferable in the setting of elevated patient complexity, or that procedures may require staging to diminish complication risk when there is also foot deformity present. The aim of this study is to evaluate the effect of adjunctive procedures on overall postoperative complication (POC) risk, for both TAA and AA. Primary outcome measures were to compare overall complication and reoperation risk for TAA and AA. Secondary outcome measures were to identify patient factors, intraoperative factors, and factors of procedural complexity via number of associated surgeries and the incidence of complications and reoperation. Methods: A retrospective chart review of AAs and TAAs performed at a single academic institution from the years 2008-2024 was performed using Current Procedural Terminology ( CPT ) codes identifying AA and TAA. Patient demographics, operative details, and postoperative data were abstracted to collect relevant information. Statistical analyses, including odds ratios and analysis of variance, were then performed to reveal specific risk factors and correlations. Results: Four hundred ninety-one patients were identified in the initial database query. After exclusions, 246 remained, of which 110 underwent AA and 136 underwent TAA. The mean length of follow-up was 36.4 months for TAA patients and 46.1 months for AA patients in this study. Overall, patients who underwent TAA were older and had an increased number of preoperative comorbidities (5.74 ± 3.07) compared to AA (4.74 ± 2.76) ( P = .008). Additionally, TAA patients experienced a lower overall rate of POCs (20/136, 14.71%) and reoperation (14/136, 10.29%) compared with patients who underwent AA (21/110, 19.09%; 21/110, 19.09%) ( P = .36 and P = .05, respectively). As the number of adjunctive procedures increased, so did the rate of POCs, but not reoperation, in patients who underwent TAA. The number of adjunctive procedures was not significantly associated with complication or reoperation risk in AA patients. There were no specific adjunctive procedures that demonstrated a significant correlation with increased risk of complications or reoperation in both groups. Osteoporosis and coagulopathies were identified as predisposing TAA patients to postoperative complications. Conclusion: In our retrospective cohort study with relatively low statistical power, we found that patients who undergo TAA or AA plus adjunctive procedures did not experience an increased risk of major complications or reoperation compared to patients who did not undergo adjunctive procedures. Several preexisting comorbidities in TAA patients were associated with higher rates of POCs or reoperation, including osteoporosis and coagulopathies; no comorbidities were linked to increased reoperation or POC risk in the AA group. These findings suggest a need to evaluate comorbidities, and lifestyle factors when recommending an ankle reconstruction procedure to minimize the odds of postoperative complications and improve likelihood of patient satisfaction. Level of Evidence: Level III, retrospective cohort study.

Abstract Background We aimed to evaluate the effectiveness and safety of risankizumab (RZB) for Crohn’s disease (CD) in routine clinical practice. Methods We performed a retrospective review of a multicenter consortium of CD patients treated with RZB. Co-primary outcomes were week 12 clinical remission (Harvey Bradshaw Index [HBI] score of ≤4 or physician global assessment in those without HBI or with ileostomy) and 6-month endoscopic remission (Simplified Endoscopic Mucosal Assessment for Crohn’s Disease of 0-1 or absence of ulcers). Secondary outcomes included steroid-free clinical remission, clinical response, radiographic response, cumulative clinical and endoscopic remission rates at 6 and 12 months, and adverse events. Results A total of 309 patients were included (median disease duration 14 years [IQR, 6-24]; median follow-up 7.1 months [IQR, 4.1-10.3]). Most patients (85.8%) were advanced therapy (AT)-exposed, and 169 (54.7%) had prior ustekinumab (UST) exposure. Week 12 clinical remission rates were 49.7% (98/197) overall, and 44.2% (50/113) vs 57.1% (48/84) in UST-exposed vs naïve patients (P = .073). Among those with active disease on baseline endoscopy (n = 122) who had an available follow-up at 6 months, 52.4% (22/42) achieved endoscopic remission. Cumulative rates of clinical and endoscopic remission at 12 months were 65.0% and 49.5%, respectively. Cumulative 12-month endoscopic remission was 33.9% (19/56) in UST-exposed and 68.1% (32/47) in UST-naïve patients (P < .001). Risankizumab was well-tolerated with no new safety signals identified. Conclusions In this large multicenter cohort of patients with CD, RZB was well-tolerated and effective in achieving favorable clinical and endoscopic outcomes in both AT-exposed and naïve populations, including those with exposure to UST.

Abstract INTRODUCTION β‐synuclein is a promising blood marker to track synaptic degeneration in Alzheimer's disease (AD) but changes in preclinical AD are unclear. METHODS We investigated serum β‐synuclein in 69 cognitively unimpaired mutation non‐carriers, 78 cognitively unimpaired AD mutation carriers (asymptomatic AD), and 31 symptomatic mutation carriers from the Dominantly Inherited Alzheimer Network. RESULTS β‐synuclein levels were already higher in asymptomatic AD mutation carriers compared to non‐carriers and highest in symptomatic carriers. Longitudinal trajectories and correlation analyses indicated that β‐synuclein levels start to rise after amyloid deposition preceding axonal degeneration, brain atrophy and hypometabolism, and cognitive decline. β‐synuclein levels were associated with cognitive impairment and gradually increased with declining cognition. DISCUSSION Our study supports the use of blood β‐synuclein to track synaptic changes in preclinical AD and as a surrogate marker for cognitive impairment which might be used in early diagnosis and to support patient selection and monitoring of treatment effects in clinical trials. Highlights Blood β‐synuclein levels were already higher in asymptomatic Alzheimer's disease (AD) mutation carriers. Blood β‐synuclein levels were highest in symptomatic AD mutation carriers. Blood β‐synuclein levels start to rise 11 years before symptom onset. Rise of β‐synuclein precedes axonal degeneration, brain atrophy, and cognitive decline. β‐synuclein levels gradually increased with declining cognition.

Abstract Hereditary tumor predisposition syndromes pose a challenge for early detection and timely treatment of tumors. In von Hippel–Lindau disease, desirable personalized surveillance programs are lacking due to insufficient data on genotype-specific risk profiles of individual mutations. To describe neoplastic risk profiles for carriers of pathogenic and likely pathogenic VHL germline mutations, our observational study recruited 1,350 participants from 40 centers worldwide. 432 different VHL germline mutations were observed, with p.Asn78Ser, p.Arg161Ter, p.Arg161Gln, p.Arg167Gln, p.Arg167Trp and p.Tyr98His being the six most frequent, occurring in a total of 493 carriers (36.5%) and in ≥30 patients each. Age-related penetrance risks for retinal hemangioblastoma, central nervous system hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumors and pheochromocytoma/paraganglioma in carriers of the most frequent VHL mutations were assessed. In addition, the number of organs affected, the frequency of surgery and the outcome are reported. Pairwise comparisons of the age-dependent tumor penetrance of these six mutations showed that 47 out of 90 pairs were significantly different. The most significant associations were found in p.Tyr98His (n = 19), followed by p.Arg161Ter (n = 10). All pairwise comparisons of mutations affecting different codons showed at least one significant (P < 0.05) difference, except for p.Asn78Ser vs p.Arg161Ter. Thus, tumor risk varied by VHL mutation type and location, but did not differ between the truncating mutation p.Arg161Ter and the missense mutation p.Asn78Ser. Our study demonstrates the importance of mutation-specific phenotype prediction. With appropriate validation, the data have important implications for risk assessment and decision making in tumor prevention for carriers of the respective VHL mutations.

Abstract Background Patient age can impact the safety and efficacy of ulcerative colitis (UC) treatments. Etrasimod is an oral, once daily (QD), selective sphingosine 1-phosphate1,4,5 receptor modulator for the treatment of moderately to severely active UC. Here, we evaluate the impact of age on etrasimod safety and efficacy in patients with UC in the phase 3 ELEVATE UC clinical program. Methods Data were pooled from ELEVATE UC 52 and ELEVATE UC 12 in patients receiving etrasimod 2 mg QD or placebo. Proportions and incidence rates (IRs) per 100 patient-years of treatment-emergent adverse events (AEs) were stratified by age (<40, 40-59, and ≥60 years). With the same age stratifications, efficacy was evaluated in patients with baseline Modified Mayo scores of 5-9 and 4-9 for the primary efficacy endpoint (clinical remission) and secondary efficacy endpoints. Results Overall, 787 patients were enrolled (<40 years, n = 420 [53.4%]; 40-59 years, n = 276 [35.1%]; and ≥60 years, n = 91 [11.6%]). Arthralgia, fatigue, and hypertension IRs were higher in older patients, irrespective of treatment. Serious AEs and AEs leading to treatment discontinuation were low and consistent across age groups. Significantly more patients receiving etrasimod 2 mg QD vs placebo achieved efficacy endpoints, regardless of age. Conclusions The safety profile of etrasimod 2 mg QD in the ELEVATE UC population was consistent across age groups, with no change in the incidence of AEs. Patients receiving etrasimod vs placebo showed significant clinical benefit, regardless of age. ClinicalTrials.gov NCT03945188; NCT03996369.

Abstract Background and aims This post hoc analysis evaluated the corticosteroid-sparing effects of risankizumab (RZB) therapy in patients with moderate-to-severe ulcerative colitis in the phase 3 induction and maintenance studies, INSPIRE and COMMAND. Methods Patients were randomized (2:1) to 12 weeks of intravenous RZB or placebo (PBO) induction therapy; responders to intravenous RZB were randomized (1:1:1) to receive subcutaneous RZB 180 mg, 360 mg, or PBO (RZB withdrawal) maintenance therapy. Baseline corticosteroid doses were maintained during induction, with a mandatory taper beginning at maintenance week 0. Efficacy outcomes were evaluated by baseline corticosteroid use at induction week 12, while corticosteroid-free clinical and endoscopic outcomes were assessed at maintenance week 52 among the overall population and among patients on corticosteroids at baseline. Safety was also assessed. Results At baseline, 35.7% (348/975) of patients were taking corticosteroids. At induction week 12, greater rates were observed for clinical, endoscopic, and patient-reported outcomes in RZB 1200 mg-treated patients compared with PBO, regardless of baseline corticosteroid use. RZB 180 mg and 360 mg treatment resulted in higher corticosteroid discontinuation rates (RZB 180 mg 64.9% [48/74]; RZB 360 mg 54.2% [32/59]; PBO [withdrawal] 36.8% [25/68], P ≤ .01) and corticosteroid-free clinical, endoscopic, and patient-reported outcomes at week 52, compared with PBO (withdrawal). The rates of treatment-emergent adverse events were similar regardless of baseline corticosteroid use during induction and maintenance. Conclusions The efficacy of RZB induction therapy was independent of corticosteroid use, with high rates of corticosteroid-free outcomes observed in the overall population and among patients with baseline corticosteroid use, reaffirming the potential of RZB to serve as a corticosteroid-sparing therapy for patients with ulcerative colitis. Clinicaltrial.gov numbers NCT03398148 and NCT03398135

Background Flow-diverter stents (FDS) have become the standard of care for a wide range of intracranial aneurysms, but their efficacy/safety in the context of recurrent/recanalized aneurysms following stent-assisted coiling (SAC) is not well established. We evaluate the outcomes of FDS retreatment in a large multicenter cohort. Methods We retrospectively analyzed data from 118 patients across 22 institutions who underwent FDS retreatment for recurrent/persistent aneurysms after SAC (2008–22). The primary outcome was angiographic occlusion status at last follow-up, categorized as complete (100%), near-complete (90–99%), or incomplete (<90%) occlusion. Secondary outcomes included procedural complications and clinical outcomes measured by the modified Rankin Scale (mRS). Results A total of 118 patients (median age 57, 74.6% female) with median follow-up of 15.3 months were identified. Complete occlusion was achieved in 62.5% and near-complete occlusion in 25%. FDS deployment within the pre-existing stent was successful in 98.3% of cases. Major complications occurred in 3.4% of cases, including postoperative aneurysmal rupture with resultant mortality (1.6%) and thromboembolic events with long-term disability (1.6%). Favorable clinical outcomes (mRS 0–2) were observed in 95.1% of patients. Wider aneurysm neck diameter was a significant predictor of incomplete occlusion (adjusted OR (aOR) 1.23 per mm, P=0.044), with male sex trending towards association with non-occlusion (aOR 3.2, P=0.07), while baseline hypertension was associated with complete occlusion (aOR 0.32, P=0.048). Conclusions FDS treatment for recurrent/residual aneurysms after SAC represents a viable treatment option for these challenging cases with acceptable safety and reasonable occlusion rates, although lower than de novo FDS occlusion rates.