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Abstract Background Progress in clinical trials and drug development for paediatric perianal fistulising CD (pfCD) depends upon accurate, reproducible imaging to assess disease activity and measure treatment response. We evaluated the inter- and intra-rater reliability of existing radiologic disease activity indices and anatomical classification systems previously identified as appropriate for assessment of paediatric pfCD.1 Methods A retrospective cohort (N=50) of magnetic resonance imaging (MRI) exams representing a full spectrum of paediatric (<18 years) perianal CD severity was selected by a single expert paediatric radiologist. Methods described by Zou2 were used to estimate sample size. Three separate radiologists (2 paediatric) blinded to clinical information assessed pfCD in the exams using the Magnetic Resonance Novel Index for Fistula Imaging in CD (MAGNIFI-CD), Van Assche Index (VAI), modified VAI (mVAI), Paediatric MRI based Perianal Crohn’s disease (PEMPAC) index, a visual analogue scale (VAS) of overall pfCD disease severity (range, 0-100 mm), as well as with the Park’s and St. James University Hospital anatomic classification systems. Two radiologists read all exams twice, separated by 2 weeks, and 1 radiologist read the exams once (250 total reads). Intra- and inter-rater reliability was evaluated using intraclass correlation coefficients (ICC; equivalent to weighted kappa). Precision of the ICC estimates was quantified with 95% confidence intervals (CIs) obtained using clustered bootstrapping. Degree of reliability was interpreted with benchmarks proposed by Landis and Koch3. Results Median age of children was 13.5 years (IQR 11.4-16.1), and 64% were male. Median Paediatric Crohn’s Disease Activity Index score at time of imaging was 17.5 (IQR 10-32.5). Substantial (ICC>0.61) inter-rater reliability was observed for MAGNIFI-CD, VAI, and mVAI (Table 1), with the highest ICCs observed for the mVAI (0.72 [0.6 to 0.79]). Moderate (ICC>0.41) inter-rater reliability was observed for PEMPAC, St. James University Hospital classification, and the VAS, and fair (ICC>0.21) inter-rater reliability was observed for Parks classification. Intra-rater reliability was nearly perfect (ICC>0.81) for the VAS, and substantial for all indices except for Parks classification, which had moderate (0.60 [0.44 to 0.75]) intra-rater reliability (Table 1). Conclusion Most existing multi-item MRI-based disease activity indices and the St. James Hospital classification were reliable for the assessment of paediatric pfCD in our cohort. Our preliminary results suggest that the disease activity indices may have utility to measure treatment effect in paediatric pfCD clinical trials. References 1.Crowley E, Ma C, Guizzetti L, Zou G, Lewindon PJ, Gee MS, et al. Recommendations for Standardizing MRI-based Evaluation of Perianal Fistulizing Disease Activity in Pediatric Crohn's Disease Clinical Trials. Inflamm Bowel Dis. 2024;30(3):357-69. 2.Zou GY. Sample size formulas for estimating intraclass correlation coefficients with precision and assurance. Statistics in Medicine. 2012;31(29):3972-398 3.Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics. 1977;33(1):159-74.

Importance Depressive symptoms are associated with cognitive decline in older individuals. Uncertainty about underlying mechanisms hampers diagnostic and therapeutic efforts. This large-scale study aimed to elucidate the association between depressive symptoms and amyloid pathology. Objective To examine the association between depressive symptoms and amyloid pathology and its dependency on age, sex, education, and APOE genotype in older individuals without dementia. Design, Setting, and Participants Cross-sectional analyses were performed using data from the Amyloid Biomarker Study data pooling initiative. Data from 49 research, population-based, and memory clinic studies were pooled and harmonized. The Amyloid Biomarker Study has been collecting data since 2012 and data collection is ongoing. At the time of analysis, 95 centers were included in the Amyloid Biomarker Study. The study included 9746 individuals with normal cognition (NC) and 3023 participants with mild cognitive impairment (MCI) aged between 34 and 100 years for whom data on amyloid biomarkers, presence of depressive symptoms, and age were available. Data were analyzed from December 2022 to February 2024. Main Outcomes and Measures Amyloid-β1-42 levels in cerebrospinal fluid or amyloid positron emission tomography scans were used to determine presence or absence of amyloid pathology. Presence of depressive symptoms was determined on the basis of validated depression rating scale scores, evidence of a current clinical diagnosis of depression, or self-reported depressive symptoms. Results In individuals with NC (mean [SD] age, 68.6 [8.9] years; 5664 [58.2%] female; 3002 [34.0%] APOE ε4 carriers; 937 [9.6%] had depressive symptoms; 2648 [27.2%] had amyloid pathology), the presence of depressive symptoms was not associated with amyloid pathology (odds ratio [OR], 1.13; 95% CI, 0.90-1.40; P = .29). In individuals with MCI (mean [SD] age, 70.2 [8.7] years; 1481 [49.0%] female; 1046 [44.8%] APOE ε4 carriers; 824 [27.3%] had depressive symptoms; 1668 [55.8%] had amyloid pathology), the presence of depressive symptoms was associated with a lower likelihood of amyloid pathology (OR, 0.73; 95% CI 0.61-0.89; P = .001). When considering subgroup effects, in individuals with NC, the presence of depressive symptoms was associated with a higher frequency of amyloid pathology in APOE ε4 noncarriers (mean difference, 5.0%; 95% CI 1.0-9.0; P = .02) but not in APOE ε4 carriers. This was not the case in individuals with MCI. Conclusions and Relevance Depressive symptoms were not consistently associated with a higher frequency of amyloid pathology in participants with NC and were associated with a lower likelihood of amyloid pathology in participants with MCI. These findings were not influenced by age, sex, or education level. Mechanisms other than amyloid accumulation may commonly underlie depressive symptoms in late life.

Abstract Background Long-term use of corticosteroids (CS) is a concern for patients with Crohn’s disease (CD), as prolonged use is associated with increased mortality and adverse outcomes. Upadacitinib (UPA), an oral, selective, reversible Janus kinase inhibitor, is approved for the treatment of moderate-to-severe CD and demonstrated CS-sparing efficacy, with a consistent safety profile through maintenance week (wk) 52.1-4 Here, we evaluated the long-term efficacy of UPA in achieving CS-free clinical and endoscopic outcomes in patients enrolled in the ongoing U-ENDURE long-term extension (LTE) study. Methods Patients who completed the U-ENDURE 52-wk maintenance study were eligible for the subsequent LTE study wherein they continued their previously assigned treatment (once daily UPA 15 mg [UPA15] or UPA 30 mg [UPA30]). Efficacy was assessed from LTE wk 0-wk48, among patients with 2 year (yr) (100 wk) of total maintenance therapy, within the overall population and in patients with baseline CS use (induction wk 0). CS-free endpoints (without CS use for ≥90 days before evaluation), included clinical remission (per stool frequency/abdominal pain score [SF/APS] and CD Activity Index [CDAI]), endoscopic response, and endoscopic remission, were evaluated using both as-observed and nonresponder imputation (NRI) methods, with NRI analysis presented in text. Safety was not evaluated here but was reported previously.3 Results Among patients with 2 yr of total maintenance therapy, 35.7% (87/244) received CS at baseline, with 13.1% (32/244) receiving CS at any time during the LTE study regardless of baseline CS use. Among patients taking baseline CS and those who received CS at any time during the LTE study (n=20), the median (range) time of CS use was 127.5 (2-1589) days. CS-free clinical remission was achieved at LTE wk 0 and wk 48 per SF/APS (overall population: UPA15, 71.7%, 58.9%; UPA30, 81.8%, 57.7%; patients with baseline CS use: UPA15, 71.8%, 53.8%; UPA30, 79.2%, 54.2%, NRI, Fig.1A-B) and CDAI criteria (overall population: UPA15, 74.8%, 60.7%; UPA30, 83.9%, 65.0%; patients with baseline CS use: UPA15, 74.4%, 56.4%; UPA30, 81.3%, 58.3%, NRI, Fig.1C-D). At LTE wk 48, a high fraction of UPA-treated patients achieved CS-free endoscopic response (overall population: UPA15, 48.6%; UPA30, 55.5%; patients with baseline CS use: UPA15, 38.5%; UPA30, 60.4%, NRI) and CS-free endoscopic remission (overall population: UPA15, 33.6%; UPA30, 46.0%; patients with baseline CS use: UPA15, 28.2%; UPA30, 54.2%, NRI, Fig.2). Conclusion Patients with moderate-to-severe CD who received long-term UPA maintenance treatment sustained high rates of CS-free clinical and endoscopic outcomes, suggesting that UPA may serve as an effective long-term CS-sparing therapy. References 1.RINVOQ [package insert], extended-release tablets, FDA Prescribing Information. AbbVie Inc; 2022. Accessed 1 June 2022.2. 2.RINVOQ [package insert], prolonged-release tablets. EMA Summary of Product Characteristics. AbbVie; 2022. Accessed 1 June 2022. 3.Loftus EV and Panes J et al. N Engl J Med 2023;388:1966-1980. J 4.M C Dubinsky, et al. JCC, 17; (Supp_1); 2023: i104–i106.

Abstract Background Tumor necrosis factor-like ligand 1A (TL1A) is upregulated in inflammatory bowel disease and believed to promote inflammation and intestinal fibrosis. RO7790121, an anti-TL1A antibody, showed promising results in the phase IIa TUSCANY trial.1 Here we report post-hoc analyses of patient-reported outcomes from the TUSCANY-2 trial. Methods This phase IIb, multicenter, randomized, double-blind, treat-through, dose-ranging study evaluated RO7790121 in patients (pts) aged 18–75 years with moderately to severely active ulcerative colitis (UC) (total Mayo score [MS] ≥6, endoscopic subscore ≥2). Pts were randomized to receive subcutaneous (SC) RO7790121 50mg, 150mg, 450mg or matched placebo (PBO) monthly during the 12-week induction period, and SC RO7790121 50mg, 150mg or 450mg monthly during the 40-week treat-through maintenance period. To assess efficacy of RO7790121 in supporting pts achieving early symptomatic improvement, rectal bleeding (RB), stool frequency (SF) and partial modified MS (RB+SF) were evaluated at baseline and Weeks 2, 4, 8, 12 and 14. The exploratory endpoint of symptomatic remission, defined as a RB subscore of 0 and a SF subscore of 0 or 1, was assessed throughout induction. Safety was assessed throughout the study. Results Overall, 245 pts received ≥1 dose of RO7790121 or PBO. At Week 2, pts receiving RO7790121 were more likely to report a RB subscore of 0 (34% RO7790121; 20% PBO) and less likely to report a RB subscore of 2 or 3 (25% RO7790121; 40% PBO) (Figure). Improvements in SF increased from Week 2 and throughout induction, with ~60% of pts receiving RO7790121 reporting a SF subscore of 0 or 1 at Weeks 12 and 14, vs ~40% for PBO. Greater rates of symptomatic remission were observed in pts receiving RO7790121 vs PBO throughout induction and from Week 2 (17.5% RO7790121; 8.9% PBO) (Table). Treatment-emergent adverse events (TEAEs) were reported during induction in 117/245 pts, the most common (reported in ≥5% of pts in any treatment group) were nausea, urinary tract infection and UC (highest in the 50mg arm), anemia (highest in the placebo arm) and fatigue, headache and pyrexia (highest in the 450mg arm). Serious TEAEs were reported in ten pts during induction (PBO=4; 50mg=3; 450mg=3); two were treatment related (PBO=1; 450mg=1). There were six treatment discontinuations due to TEAEs and a generally similar safety profile was observed during the maintenance period. Conclusion Greater and earlier improvements in RB and SF were observed in pts receiving RO7790121 vs PBO. These results indicate early symptom relief and a favorable safety profile for pts treated with RO7790121, supporting its further clinical development. RO7790121 is currently being evaluated in phase III studies (NCT06589986 and NCT06588855). References 1.Danese S, Klopocka M, Scherl EJ, et al. Anti-TL1A antibody PF-06480605 safety and efficacy for ulcerative colitis: A phase 2a single-arm study. Clin GastroenterolHepatol. 2021;19(11):2324-2332.e6. http://doi.org/10.1016/j.cgh.2021.06.011

Abstract Background The SEQUENCE trial, in bio-exposed Crohn's disease (CD) patients, demonstrated non-inferiority for clinical remission at 24 weeks and superiority for endoscopic remission at week 48 for risankizumab (RZB) compared to ustekinumab (UST). However, this comparison has not been adequately explored in bio-naive CD patients. Our study aimed to compare the clinical effectiveness among bio-naive CD patients treated with RZB vs. UST in a real-world setting, using data from a US-based multicenter cohort. Methods This retrospective cohort study utilized data from the TriNetX US Collaborative Network, comprising sixty-eight tertiary institutions, to examine adult (≥18 years) bio-naive CD patients initiated on RZB or UST from June 17th, 2022 (FDA approval date) to October 31st, 2024. Patients with prior advanced therapy usage and those with approved rheumatologic disease indications for RZB/UST were excluded. A 1:1 propensity score matching (PSM) analysis was conducted to balance cohorts on demographics, baseline comorbidities, and indicators of CD severity, including CD phenotype, extraintestinal manifestations, concurrent corticosteroid use, hemoglobin, and body weight. Cox proportional hazards models estimated hazard ratios (HRs) in matched cohorts for one-year post-treatment composite outcomes (need for corticosteroids, hospitalizations, emergency room visits, surgeries) with a priori significance threshold of p < 0.05. Results The study sample included 1,630 bio-naive CD patients treated with RZB and 3,105 with UST. Among patients on UST, 658 (21%) were dosed every four to six weeks, after the first dose. Baseline characteristics of the PSM RZB and UST cohorts are shown in Table 1 with 1,568 patients in each cohort. After PSM (Figure 1), there were no significant differences in composite outcome (HR 1.077, p = 0.170), corticosteroid use (HR 1.099, p = 0.110), CD-related surgery (HR 1.231, p = 0.284), hospitalization (HR 0.947, p = 0.615) or ER visits (HR 1.041, p = 0.687). Additionally, no significant differences were observed in opioid use (HR 1.062, p = 0.366), switch to different advanced therapy (HR 1.097, p = 0.468) or elevated disease biomarkers, including CRP (>10mg/l, HR 1.186 p = 0.101) or fecal calprotectin (>150 µg/g; HR 1.109, p = 0.407) at 1-year follow-up. Conclusion In this real-world experience allowing for drug optimization, no difference was observed in bio naïve patients between UST and RZB as far as clinical remission and progression of CD.

Abstract Background Risankizumab (RZB), a high-affinity humanised IgG1 monoclonal antibody targeting interleukin-23 p19, has shown sustained efficacy and an acceptable safety profile for patients (pts) with ulcerative colitis (UC).1 This interim analysis reports efficacy data at week (wk) 0 and wk 96, as well as safety data of the COMMAND (NCT03398135) open-label extension (OLE). Methods The COMMAND OLE enrolled pts who completed 52-wks maintenance dosing in the COMMAND substudies or entered directly from the induction study.1 All pts received RZB180 subcutaneous (SC) starting at OLE wk 0, except pts who had prior rescue therapy (single RZB 1200 mg intravenous [IV] dose then RZB360 Q8w) who continued RZB360 in the OLE. The OLE was not designed to compare RZB180 and RZB360 groups. The data cut-off date for this interim analysis was as of June 30, 2024. Efficacy endpoints assessed were clinical remission (CR) per AMS, clinical response per AMS, endoscopic improvement, endoscopic remission, and corticosteroid-free CR per Partial AMS up to wk 96. Data are reported as observed prior to RZB rescue therapy during OLE. The safety analysis also includes pts who directly entered the OLE from induction; presented as events/100 pt years (E/100 PY). Results Of the pts who entered the OLE (RZB180, N = 701; RZB360, N = 302), approximately 40% of pts had the opportunity to reach OLE wk 96 as of the cut-off date. At OLE wk 0 and 96, a similar proportion of patients in the RZB180 group achieved clinical and endoscopic outcomes (Figure 1A). In the RZB360 group, the percent of pts achieving clinical and endoscopic endpoints increased from OLE wk 0 through OLE wk 96 (Figure 1B). Similar rates of serious AEs, severe AEs, and AEs leading to discontinuation of study drug were reported in the RZB180 group and the RZB360 group with no new safety risks identified (Table 1). Conclusion In this interim analysis of the OLE, a sustained benefit was observed with long-term RZB treatment up to 96 wks. The long-term safety profile for RZB remains consistent and supports the long-term use. References 1. Louis E et al. JAMA 2024;332(11):881-897

Abstract Background Histologic inflammation persists in up to 1/4 of patients with Crohn’s disease (CD) despite endoscopic mucosal healing. Histologic and combined endoscopic-histologic endpoints are evolving measures of treatment efficacy in CD; however, the impact of histologic healing on long-term outcomes and disease progression is unknown. Week (W) 52 data comparing mirikizumab (Miri) vs placebo (PBO) in the randomized, double-blind, placebo- and active-controlled, treat-through Phase 3 VIVID-1 trial in patients with moderately-to-severely active CD (NCT03926130) were reported previously.1 Methods The main objective was to evaluate the association of W12 histologic response and W12 histologic remission with W52 clinical and endoscopic outcomes in VIVID-1. Two biopsy specimens from each of 5 intestinal segments (1 ileal and 4 colonic) were obtained from the edge of the ulcers, or the most inflamed mucosa from randomized patients at screening, W12, and W52. All analyses were post hoc and among patients with active histologic disease (defined as a Robarts Histopathology Index >0 and a Global Histologic Disease Activity Score >0) at baseline. Results At W12, treatment with Miri resulted in statistically significantly higher rates of achieving histologic response and histologic remission vs. PBO (Figure). At W12, 62.1% of patients had agreement (k=0.27 [fair]) between histologic response and endoscopic response, with a greater percentage achieving histologic over endoscopic response (59.0% vs. 38.8%)*. Significantly greater proportions of patients who achieved histologic response at W12 also achieved histologic response, histologic remission, endoscopic response, endoscopic remission, combined CDAI (Crohn’s Disease Activity Index) remission and endoscopic response, and normalisation of faecal calprotectin levels ≤250 µg/g and ≤150 µg/g at W52 (Table). Similar associations were observed between W12 histologic remission and W52 outcomes. Conclusion Histologic response seems to be an early objective sign of anti-inflammatory response and was significantly associated with one-year endoscopic and histologic outcomes, as well as biomarker normalisation. *Observed data References 1.Jairath V, et al. Presented at: UEGW 2024. OP131.

Abstract Deep brain stimulation (DBS) is a targeted manipulation of brain circuitry to treat neurological and neuropsychiatric conditions. Optimal DBS lead placement is essential for treatment efficacy. Current targeting practice is based on preoperative and intraoperative brain imaging, intraoperative electrophysiology, and stimulation mapping. Electrophysiological mapping using extracellular microelectrode recordings aids in identifying functional subdomains, anatomical boundaries, and disease-correlated physiology. The shape of single-unit action potentials may differ due to different biophysical properties between cell-types and brain regions. Here, we describe a technique to parameterize the structure and duration of sorted spike units using a novel algorithmic approach based on canonical response parameterization, and illustrate how it may be used on DBS microelectrode recordings. Isolated spike shapes are parameterized then compared using a spike similarity metric and grouped by hierarchical clustering. When spike morphology is associated with anatomy, we find regional clustering in the human globus pallidus. This method is widely applicable for spike removal and single-unit characterization and could be integrated into intraoperative array-based technologies to enhance targeting and clinical outcomes in DBS lead placement. Author summary We developed a new algorithmic approach to capture the structure of single neuron electrophysiology from microelectrode recordings during deep brain stimulation surgery. This method has broad applications for spike characterization, clustering, removal from the background field potential, and comparison across recording sites. Using this technique, we illustrate regional clustering of spike morphologies in the human globus pallidus.

ABSTRACT The Burkholderia cepacia complex (BCC) is a group of Gram-negative bacteria that cause opportunistic infections, most notably in people with cystic fibrosis (CF), and have been associated with outbreaks caused by contaminated medical products. Antimicrobial susceptibility testing (AST) is often used to guide treatment for BCC infections, perhaps most importantly in people with CF who are being considered for lung transplant. However, recent studies have highlighted problems with AST methods. Here, we address limitations from previous studies to further evaluate BCC AST methods. We assessed the performance of reference broth microdilution (BMD), disk diffusion (DD) using Mueller-Hinton agar (MHA) from three manufacturers, agar dilution (AD), and gradient diffusion (ETEST) for ceftazidime (CAZ), levofloxacin (LVX), meropenem (MEM), minocycline (MIN), and trimethoprim-sulfamethoxazole (TMP-SMX) on a set of 205 BCC isolates. The isolate set included 100 isolates from people with CF and 105 isolates from people without CF from a variety of sources, which enabled us to systematically evaluate whether specimen source impacts AST performance. For all BCC isolates, BMD reproducibility was 93%, 98%, 99%, 98%, and 96% for CAZ, LVX, MEM, MIN, and TMP-SMX, respectively. Using BMD as the comparator method, we show that DD, AD, and ETEST perform poorly, with neither MHA manufacturer nor specimen source significantly impacting method performance. Based on our data, we recommend that routine AST should not be performed for BCC isolates. If a provider requests AST, clinical microbiology laboratories should perform Clinical and Laboratory Standards Institute reference methodology for BMD (stored frozen) and report MIC only. IMPORTANCE Antimicrobial susceptibility testing for the Burkholderia cepacia complex (BCC) is often used to determine eligibility for lung transplant in people with cystic fibrosis. However, problems with method performance have been reported. Here, we systematically evaluate the performance of reference broth microdilution, disk diffusion, agar dilution, and gradient diffusion (ETEST) for BCC organisms isolated from people with and without cystic fibrosis. We show that broth microdilution reproducibility is acceptable for levofloxacin, meropenem, minocycline, and trimethoprim-sulfamethoxazole, while ceftazidime was just below the acceptability cut-off. Regardless of specimen source, the results from disk diffusion, agar dilution, and ETEST do not correlate with broth microdilution. Based on these findings, we recommend that antimicrobial susceptibility testing should not be routinely performed for BCC, and if requested by the provider, only broth microdilution following Clinical and Laboratory Standards Institute guidelines should be used. Providers should be aware of the significant limitations of antimicrobial susceptibility testing methods for BCC.