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The Child Health and Development Studies is a > or =40-year follow-up of 20,754 pregnancies occurring between 1959 and 1967 in California. There were 84 cases of undescended testes at birth persisting to at least age 2 years among 7,574 liveborn sons whose mothers were interviewed in early pregnancy. Cases were matched to three controls on birth year and race. Compared with mothers of controls, mothers of cryptorchid boys consumed more caffeine during pregnancy (odds ratio = 1.4, 95% confidence interval: 1.1, 1.9 for an interquartile range equivalent to three cups of coffee per day) but were not more likely to smoke or drink alcohol when all behaviors were considered together. Other maternal and perinatal risk factors were not significantly associated with persistent cryptorchidism and did not confound the association with caffeine. [ABSTRACT FROM AUTHOR]

Background & Aims: Risankizumab is a selective interleukin-23 inhibitor approved for the treatment of Crohn's disease (CD). We report a large long-term real-world experience with risankizumab in CD., Methods: We performed a prospective monitoring of clinical outcomes in patients at a large tertiary center who started treatment with risankizumab. Patients with active luminal disease who had at least 12 weeks of follow-up were included in the effectiveness analysis. Harvey-Bradshaw Index, as well as C-reactive protein and fecal calprotectin, were used to monitor disease activity. Primary outcomes were clinical remission and steroid-free clinical remission rates at weeks 12, 26, and 52. Univariate analysis followed by a multivariate analysis using a logistic regression model was performed to identify predictors of steroid-free clinical remission at 1 year. All patients who started treatment with risankizumab for any indication were included in the safety analysis., Results: A total of 134 patients were included in the effectiveness analysis. Seventy (52%) were ustekinumab-experienced. Clinical remission rates were 69%, 64%, and 54% at weeks 12, 26, and 52, respectively. Steroid-free clinical remission rates at 12, 26, and 52 weeks were 58%, 58%, and 50%, respectively. Remission rates in ustekinumab-experienced patients were not statistically lower compared with naïve patients, and in a multivariate analysis, prior ustekinumab treatment was not associated with lower odds of achieving steroid-free clinical remission at 1 year. Adverse effects were assessed in 243 patients and were consistent with previous literature., Conclusions: This large real-world experience with risankizumab with long-term follow-up demonstrates effectiveness and safety in patients with CD; there was comparable effectiveness in ustekinumab-naïve and ustekinumab-experienced patients., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: The modified pouchitis disease activity index (mPDAI) based on clinical symptoms and endoscopic findings is used to diagnose pouchitis, but validated instruments to monitor pouchitis are still lacking. We recently established an endoscopic classification that described 7 endoscopic phenotypes with different outcomes. We assessed symptoms and compared mPDAIs among phenotypes in inflammatory bowel disease (IBD)., Methods: We retrospectively reviewed pouchoscopies and classified them into 7 main phenotypes: normal ( n  = 25), afferent limb (AL) involvement ( n  = 4), inlet involvement ( n  = 14), diffuse ( n  = 7), focal inflammation of the pouch body ( n  = 25), cuffitis ( n  = 18), and pouch-related fistulas ( n  = 10) with a single phenotype were included. Complete-case analysis was conducted., Results: One hundred and three IBD patients were included. The median mPDAI was 0 (IQR 0-1.0) in patients with a normal pouch. Among inflammatory phenotypes, the highest median mPDAI was 4.0 (IQR 2.25-4.75) in cuffitis, followed by 3.0 (IQR 2.5-4.0) in diffuse inflammation, 2.5 (IQR 1.25-4.0) in inlet involvement, 2.5 (IQR 2.0-3.5) in AL involvement, 2.0 (IQR 1.0-3.0) in focal inflammation, and 1.0 (IQR 0.25-2.0) in the fistula phenotype. Perianal symptoms were frequently observed in pouch-related fistulas (8/10, 80%) and cuffitis (13/15, 87%). Among patients with cuffitis, all had incomplete emptying (6/6, 100%)., Conclusions: We correlated the mPDAI with the endoscopic phenotypes and described the limited utility of symptoms in distinguishing between inflammatory phenotypes. Further studies are warranted to understand which symptoms should be monitored for each phenotype and whether mPDAI can be minimized after pouch normalization., Competing Interests: S.A., J.E.O., N.A.C., V.R., L.R.G., Y.Y., C.T., J.R., K.B.S., R.D.H., K.U., B.D.S., N.H.H., and A.S. have no relevant disclosures. R.D.C. is on the speaker’s bureau from AbbVie and Takeda. He is a consultant/advisor for AbbVie Laboratories, BM/celgene, Eli Lilly, Gilead Sciences, Janssen, Pfizer, Takeda, UCB Pharma. He has received clinical trial support/grants from Abbvie, BMS/Celgene, Boehringer Ingelheim, Crohn’s and Colitis Foundation of America, Genentech, Gilead Sciences, Hollister, Medimmune, Mesoblast Ltd., Osiris Therpeutics, Pfizer, Receptos, RedHill Biopharma, Sanofi-Aventis, Schwarz Pharma, Seres Therapeutics, Takeda Pharma, UCB Pharma. His wife is on the board of directors of Aerpio Therapeutics, Novus Therapeutics, Vital Therapeutics, Inc, and NantKwest. M.A.R. has served as a consultant for Pfizer. S.R.D. has served as a consultant for Pfizer and is on the speaker’s bureau for AbbVie. J.P. has received grant support from AbbVie and Takeda. He has served as a consultant for Veraste,. CVS Caremark and is on the advisory board for Takeda, Janssen and Pfizer. E.B.C. is the founder and chief medical officer of AVnovum Therapeutics. D.T.R. has received grant support from Takeda; and has served as a consultant for Abbvie, Altrubio, Amgen, AvaloTherapeutics, Bristol-Myers Squibb, Buhlmann Diagnostics Corp, Chronicles Health, ClostraBio, Connect BioPharma, Cytoki Pharma, Douglas Pharmaceuticals, EcoR1, Ferring Pharma, Image Analysis Group, Index Pharmaceuticals, Iterative Health, Janssen Pharmaceuticals, Lilly, Odyssey Therapeutics, Pfizer, Prometheus Biosciences, Reistone Biopharma, Samsung Neurologica, Sangamo Therapeutics, Shanghai Pharma Biotherapeutics USA, Takeda, Tissium S.A., and Trellus Health., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn's & Colitis Foundation.)

L23 is a recognized cytokine involved in the pathogenesis of inflammatory bowel diseases (IBDs). 1 The first IL23-targeting agent that became available for clinical use in IBD was Ustekinumab, a monoclonal antibody that targets p40, a shared subunit of both IL23 and IL12. 2,3 Risankizumab (Skyrizi; Abbvie) is a humanized IgG1 monoclonal antibody which binds to the p19 subunit and therefore selectively inhibits IL23. 4 In June 2022, it was approved by the United States Food and Drug Administration for the treatment of moderately to severely active Crohn's disease (CD). Here, we describe the effectiveness and safety of risankizumab throughout the induction period in a real-world setting of a large tertiary center., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) have an increased risk of developing colorectal neoplasia (CRN) in the proximal colon., Objectives: To evaluate whether duration and severity of inflammation are linked to the development of CRN in this population., Design: Retrospective, case-control chart review of patients with PSC and IBD at a tertiary care center., Methods: Disease activity was scored per colonic segment at each colonoscopy prior to the first instance of observed CRN using a modified Mayo endoscopic sub-score and histologic assessment. Patients in the CRN-positive group were compared to controls that did not., Results: In all, 72 PSC-IBD patients with no history of CRN were identified, 13 of whom developed CRN after at least one colonoscopy at our institution. Patients in the CRN-positive group had significantly more endoscopic ( p  < 0.01) and histologic ( p  < 0.01) inflammation in the right compared to the control group prior to the development of dysplasia. There was significantly greater endoscopic inflammation in the segment of the colon with a dysplastic lesion than other segments of the colon ( p  = 0.018). Patients with moderate/severe lifetime endoscopic ( p  = 0.02) or histologic inflammation ( p  = 0.04) score had a lower probability of remaining free of dysplasia during follow-up. Nearly half of the patients with dysplasia had invisible lesions found on random biopsy., Conclusions: Endoscopic and histologic inflammation in the proximal colon are risk factors for CRN in patients with PSC-IBD. PSC-IBD patients frequently have subclinical inflammation, and these findings support the practice of regular assessment of disease activity and random biopsy of inflamed and uninflamed areas in patients with PSC with the goal of reducing inflammation to prevent the development of CRN., Competing Interests: OKJ, DS, ZD, ND, NF, SK, NK, AS, CRW, SD, BJ, and JP report no relevant conflicts of interest. RDC reports consulting for Abbvie Laboratories, BMS/Celgene, Eli Lilly, Genentech, Gilead Sciences, Hoffmann La-Roche, Janssen, Pfizer, Takeda, and UCB Pharma; and engaging in clinical trials/receiving grant support from, Abbvie, BMS/Celgene, Boehringer Ingelheim, Crohn’s & Colitis Foundation of America, Genentech, Gilead Sciences, Hollister, Medimmune, Mesoblast Ltd., Osiris Therapeutics, Pfizer, Receptos, RedHill Biopharma, Sanofi-Aventis, Schwarz Pharma, Seres Therapeutics, Takeda Pharma, UCB Pharma; DTR reports consulting for Abbvie, Altrubio, Allergan, Inc., Arena Pharmaceuticals, Aslan Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim Ltd., Bristol-Myers Squibb, Celgene Corp/Syneos, Connect BioPharma, GalenPharma/Atlantica, Genentech/Roche, Glycominds, InDex Pharmaceuticals, Ironwood Pharmaceuticals, Iterative Scopes, Janssen Pharmaceuticals, Lilly, Materia Prima, Pfizer, Prometheus Biosciences, Reistone, Takeda and Techlab, Inc.; and receiving grant support from Takeda., (© The Author(s), 2023.)

Ulcerative colitis (UC) is a chronic inflammatory condition affecting the colon and rectum. Long-term therapy is generally required to achieve and maintain disease control. 1 In May 2021 the US Food and Drug Administration approved the use of ozanimod in patients with moderate to severe UC. We describe the first report of the use of ozanimod in real-world clinical practice., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Upadacitinib is a novel selective Janus kinase 1 inhibitor that has shown efficacy in the treatment of moderate to severe ulcerative colitis (UC) and Crohn's disease (CD), and has received Food and Drug Administration approval for UC. We report a large real-world experience with upadacitinib in UC and CD., Methods: We performed a prospective analysis of clinical outcomes on upadacitinib in patients with UC and CD using predetermined intervals at weeks 0, 2, 4, and 8 as part of a formalized treatment protocol at our institution. We used the Simple Clinical Colitis Activity Index and the Harvey-Bradshaw index, as well as C-reactive protein and fecal calprotectin to assess efficacy, and also recorded treatment-related adverse events and serious adverse events., Results: A total of 105 patients were followed up for 8 weeks on upadacitinib, 84 of whom (44 UC patients, 40 CD patients) were initiated because of active luminal or perianal disease and included in the analysis. One hundred percent previously received anti-tumor necrosis factor therapy, and 89.3% had received 2 or more advanced therapies. At 4 and 8 weeks of treatment for UC, 19 of 25 (76.0%) and 23 of 27 (85.2%) achieved clinical response and 18 of 26 (69.2%) and 22 of 27 (81.5%) achieved clinical remission, respectively. Of those who previously were tofacitinib-exposed, 7 of 9 (77.8%) achieved clinical remission by 8 weeks. In CD, 13 of 17 (76.5.%) achieved clinical response and 12 of 17 (70.6%) achieved clinical remission by 8 weeks. Of those with increased fecal calprotectin and C-reactive protein levels, 62% and 64% normalized by week 8, respectively. Results were seen as early as week 2 in both UC and CD, with clinical remission rates of 36% and 56.3.%, respectively. Acne was the most commonly reported adverse event, occurring in 24 of 105 patients (22.9%)., Conclusions: In this large real-world experience in medically resistant patients with UC or CD, we report that upadacitinib is rapidly effective and safe, including in those who had prior tofacitinib exposure. This study was approved by the Institutional Review Board at the University of Chicago (IRB20-1979)., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Primary sclerosing cholangitis (PSC) is an immune-mediated disease of the bile ducts that co-occurs with inflammatory bowel disease (IBD) in almost 90% of cases. Colorectal cancer is a major complication of patients with PSC and IBD, and these patients are at a much greater risk compared to patients with IBD without concomitant PSC. Combining flow cytometry, bulk and single-cell transcriptomics, and T and B cell receptor repertoire analysis of right colon tissue from 65 patients with PSC, 108 patients with IBD and 48 healthy individuals we identified a unique adaptive inflammatory transcriptional signature associated with greater risk and shorter time to dysplasia in patients with PSC. This inflammatory signature is characterized by antigen-driven interleukin-17A (IL-17A) + forkhead box P3 (FOXP3) + CD4 T cells that express a pathogenic IL-17 signature, as well as an expansion of IgG-secreting plasma cells. These results suggest that the mechanisms that drive the emergence of dysplasia in PSC and IBD are distinct and provide molecular insights that could guide prevention of colorectal cancer in individuals with PSC., (© 2023. The Author(s).)

HMBC is an essential NMR experiment for determining multiple bond heteronuclear correlations in small to medium-sized organic molecules, including natural products, yet its major limitation is the inability to differentiate two-bond from longer-range correlations. There have been several attempts to address this issue, but all reported approaches suffer various drawbacks, such as restricted utility and poor sensitivity. Here we present a sensitive and universal methodology to identify two-bond HMBC correlations using isotope shifts, referred to as i-HMBC (isotope shift detection HMBC). Experimental utility was demonstrated at the sub-milligram / nanomole scale with only a few hours of acquisition time required for structure elucidation of several complex proton-deficient natural products, which could not be fully elucidated by conventional 2D NMR experiments. Because i-HMBC overcomes the key limitation of HMBC without significant reduction in sensitivity or performance, i-HMBC can be used as a complement to HMBC when unambiguous identifications of two-bond correlations are needed., (© 2023. The Author(s).)

Density functional theory (DFT) benchmark studies of 1 H and 13 C NMR chemical shifts often yield differing conclusions, likely due to non-optimal test molecules and non-standardized data acquisition. To address this issue, we carefully selected and measured 1 H and 13 C NMR chemical shifts for 50 structurally diverse small organic molecules containing atoms from only the first two rows of the periodic table. Our NMR dataset, DELTA50, was used to calculate linear scaling factors and to evaluate the accuracy of 73 density functionals, 40 basis sets, 3 solvent models, and 3 gauge-referencing schemes. The best performing DFT methodologies for 1 H and 13 C NMR chemical shift predictions were WP04/6-311++G(2d,p) and ωB97X-D/def2-SVP, respectively, when combined with the polarizable continuum solvent model (PCM) and gauge-independent atomic orbital (GIAO) method. Geometries should be optimized at the B3LYP-D3/6-311G(d,p) level including the PCM solvent model for the best accuracy. Predictions of 20 organic compounds and natural products from a separate probe set had root-mean-square deviations (RMSD) of 0.07 to 0.19 for 1 H and 0.5 to 2.9 for 13 C. Maximum deviations were less than 0.5 and 6.5 ppm for 1 H and 13 C, respectively.

Background: Determining the relative cost-effectiveness between advanced therapeutic options for ulcerative colitis (UC) may optimize resource utilization. We evaluated total cost per response, cost per remission, and cost of safety events for patients with moderately-to-severely active UC after 52 weeks of treatment with advanced therapies at standard dosing., Methods: An analytic model was developed to estimate costs from the US healthcare system perspective associated with achieving efficacy outcomes and managing safety outcomes for advanced therapies approved for the treatment of UC. Numbers needed to treat (NNT) for response and remission, and numbers needed to harm (NNH) for serious adverse events (SAEs) and serious infections (SIs) were derived from a network meta-analysis of pivotal trials. NNT for induction and maintenance were combined with drug regimen costs to calculate cost per clinical remission. Cost of managing AEs was calculated using NNH for safety outcomes and published costs of treating respective AEs., Results: Costs per remission were $205,240, $249,417, $267,463, $365,050, $579,622, $750,200, and $787,998 for tofacitinib 10 mg, tofacitinib 5 mg, infliximab, vedolizumab, golimumab, adalimumab, and ustekinumab, respectively. Incremental costs of SAEs and SIs collectively were $136,390, $90,333, $31,888, $31,061, $20,049, $12,059, and $0 for tofacitinib 5 mg, golimumab, adalimumab, tofacitinib 10 mg, infliximab, ustekinumab, and vedolizumab (reference), respectively., Conclusions: Tofacitinib was associated with the lowest cost per response and cost per remission, while vedolizumab had the lowest costs related to SAEs and SIs. Balancing efficacy versus safety is important when evaluating the costs associated with treatment of moderate-to-severe UC., (© 2022. The Author(s).)

Background/aims: We assessed the effectiveness of anti-TNF agents and its associated factors to prevent endoscopic and clinical postoperative recurrence (POR) in Crohn's disease (CD)., Methods: From a prospectively-maintained database, we retrieved 316 CD patients who underwent intestinal resection (2011-2017). Endoscopic (Rutgeerts index ≥ i2 at 6 months) and clinical (recurrence of symptoms leading to hospitalization or therapeutic escalation) POR were assessed., Results: In 117 anti-TNF-naïve patients, anti-TNF therapy was more effective than immunosuppressive agents (odds ratio [OR], 8.8; 95% confidence interval [CI], 1.8-43.9; P= 0.008) and no medication/5-aminosalicylates (OR, 5.2; 95% CI, 1.0-27.9; P= 0.05) to prevent endoscopic POR. In 199 patients exposed to anti-TNF prior to the surgery, combination with anti-TNF and immunosuppressive agents was more effective than anti-TNF monotherapy (OR, 2.32; 95% CI, 1.02-5.31; P= 0.046) to prevent endoscopic POR. Primary failure to anti-TNF agent prior to surgery was predictive of anti-TNF failure to prevent endoscopic POR (OR, 2.41; 95% CI, 1.10-5.32; P= 0.03). When endoscopic POR despite anti-TNF prophylactic medication (n = 55), optimizing anti-TNF and adding an immunosuppressive drug was the most effective option to prevent clinical POR (hazard ratio, 7.38; 95% CI, 1.54-35.30; P= 0.012). Anti-TNF therapy was the best option to prevent clinical POR (hazard ratio, 3.10; 95% CI, 1.09-8.83; P= 0.034) in patients with endoscopic POR who did not receive any biologic to prevent endoscopic POR (n = 55)., Conclusions: Anti-TNF was the most effective medication to prevent endoscopic and clinical POR. Combination with anti-TNF and immunosuppressive agents should be considered in patients previously exposed to anti-TNF.

Background & Aims: Whether preoperative treatment of inflammatory bowel disease (IBD) with tumor necrosis factor inhibitors (TNFis) increases the risk of postoperative infectious complications remains controversial. The primary aim of this study was to determine whether preoperative exposure to TNFis is an independent risk factor for postoperative infectious complications within 30 days of surgery., Methods: We conducted a multicenter prospective observational study of patients with IBD undergoing intra-abdominal surgery across 17 sites from the Crohn's & Colitis Foundation Clinical Research Alliance. Infectious complications were categorized as surgical site infections (SSIs) or non-SSIs. Current TNFi exposure was defined as use within 12 weeks of surgery, and serum was collected for drug-level analyses. Multivariable models for occurrence of the primary outcome, any infection, or SSI were adjusted by predefined covariates (age, sex, preoperative steroid use, and disease type), baseline variables significantly associated (P < .05) with any infection or SSI separately, and TNFi exposure status. Exploratory models used TNFi exposure based on serum drug concentration., Results: A total of 947 patients were enrolled from September 2014 through June 2017. Current TNFi exposure was reported by 382 patients. Any infection (18.1% vs 20.2%, P = .469) and SSI (12.0% vs 12.6%, P = .889) rates were similar in patients currently exposed to TNFis and those unexposed. In multivariable analysis, current TNFi exposure was not associated with any infection (odds ratio, 1.050; 95% confidence interval, 0.716-1.535) or SSI (odds ratio, 1.249; 95% confidence interval, 0.793-1.960). Detectable TNFi drug concentration was not associated with any infection or SSI., Conclusions: Preoperative TNFi exposure was not associated with postoperative infectious complications in a large prospective multicenter cohort., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background/aims: Perianal fistulas are a debilitating manifestation of Crohn's disease (CD). Despite the advent of anti-tumor necrosis factor (anti-TNF) therapy, the medical management of fistulizing CD continues to be challenged by unmet needs. We conducted a systematic review and meta-analysis of the effectiveness of vedolizumab for the management of perianal fistulizing CD., Methods: A search of PubMed, EMBASE and the Cochrane Library was performed from inception to June 2020 for studies reporting rates of perianal fistula healing in CD patients treated with vedolizumab. The primary outcome of interest was complete healing of perianal fistulas and the secondary outcome was partial healing. The pooled fistula healing rates with 95% confidence intervals (CI) were calculated utilizing a random effects model., Results: A total of 74 studies were initially identified, 4 of which met the inclusion criteria. A total of 198 patients with active perianal fistulas were included, 87% of whom had failed previous anti-TNF therapy. The pooled complete healing rate was 27.6% (95% CI, 18.9%-37.3%) with moderate heterogeneity (I2=49.4%) and the pooled partial healing rate was 34.9% (95% CI, 23.2%-47.7%) with high heterogeneity (I2=67.1%)., Conclusions: In a meta-analysis of 4 studies that included 198 patients with perianal fistulizing CD, the majority of whom had failed previous anti-TNF therapy, vedolizumab treatment led to healing of perianal fistulas in nearly one-third of the patients. The lack of high-quality data and significant study heterogeneity underscores the need for future prospective studies of fistula healing in patients receiving anti-integrin therapy.

Background & Aims: Pouchitis is a common complication of ileal pouch-anal anastomosis (IPAA) in patients with ulcerative colitis who have undergone colectomy. Pouchitis has been considered a single entity despite a broad array of clinical and endoscopic patterns. We developed a novel classification system based on the pattern of inflammation observed in pouches and evaluated the contributing factors and prognosis of each phenotype., Methods: We identified 426 patients (384 with ulcerative colitis) treated with proctocolectomy and IPAA who subsequently underwent pouchoscopies at the University of Chicago between June 1997 and December 2019. We retrospectively reviewed 1359 pouchoscopies and classified them into 7 main pouch phenotypes: (1) normal, (2) afferent limb involvement, (3) inlet involvement, (4) diffuse, (5) focal inflammation of the pouch body, (6) cuffitis, and (7) pouch with fistulas noted 6 months after ileostomy takedown. Logistic regression analysis was used to assess factors contributing to each phenotype. Pouch survival was estimated by the log-rank test and the Cox proportional hazards model., Results: Significant contributing factors for afferent limb involvement were a body mass index of 25 or higher and hand-sewn anastomosis, for inlet involvement the significant contributing factor was male sex; for diffuse inflammation the significant contributing factors were extensive colitis and preoperative use of anti-tumor necrosis factor drugs, for cuffitis the significant contributing factors were stapled anastomosis and preoperative Clostridioides difficile infection. Inlet stenosis, diffuse inflammation, and cuffitis significantly increased the risk of pouch excision. Diffuse inflammation was associated independently with pouch excision (hazard ratio, 2.69; 95% CI, 1.34-5.41; P = .005)., Conclusions: We describe 7 unique IPAA phenotypes with different contributing factors and outcomes, and propose a new classification system for pouch management and future interventional studies., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Models to predict colectomy in ulcerative colitis (UC) are valuable for identification, clinical management, and follow-up of high-risk patients. Our aim was to develop a clinical predictive model based on admission data for one-year colectomy in adults hospitalized for severe UC., Methods: We performed a retrospective analysis of patients hospitalized at a tertiary academic center for management of severe UC from 1/2013 to 4/2018. Multivariate regression was performed to identify individual predictors of one-year colectomy. Outcome probabilities of colectomy based on the prognostic score were estimated using a bootstrapping technique., Results: Two hundred twenty-nine individuals were included in the final analytic cohort. Four independent variables were associated with one-year colectomy which were incorporated into a point scoring system: (+) 1 for single class biologic exposure prior to admission; (+) 2 for multiple classes of biologic exposure; (+) 1 for inpatient salvage therapy with cyclosporine or a TNF-alpha inhibitor; (+) 1 for age <40. The risk probabilities of colectomy within one year in patients assigned scores 1, 2, 3, and 4 were 9.4% (95% CI, 1.7-17.2), 33.7% (95% CI, 23.9-43.5), 58.5% (95% CI, 42.9-74.1), 75.0% (95% CI, 50.5-99.5). An assigned score of zero was a perfect predictor of no colectomy., Conclusion: Risk factors most associated with one-year colectomy for severe UC included: prior biologic exposure, need for inpatient salvage therapy, and younger age. We developed a simple scoring system using these variables to identify and stratify patients during their index hospitalization., (© The Author(s) 2021. Published by Oxford University Press on behalf of Crohn's & Colitis Foundation.)

Data regarding the management and outcomes of acute severe ulcerative colitis (ASUC) in pregnant patients is sparse, consisting mainly of case reports. 1-3 We report on the largest cohort of pregnant patients hospitalized with ASUC and performed a systematic review of the medical literature., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Herein the discovery of potent IDO1 inhibitors with low predicted human dose is discussed. Metabolite identification (MetID) and structural data were used to strategically incorporate cyclopropane rings into this tetrahydronaphthyridine series of IDO1 inhibitors to improve their metabolic stability and potency. Enabling synthetic chemistry was developed to construct these unique fused cyclopropyl compounds, leading to inhibitors with improved pharmacokinetics and human whole blood potency and a predicted human oral dose as low as 9 mg once daily (QD)., Competing Interests: The authors declare no competing financial interest., (© 2021 American Chemical Society.)

Background & Aims: Pregnant women with inflammatory bowel disease (IBD) may require biologic or thiopurine therapy to control disease activity. Lack of safety data has led to therapy discontinuation during pregnancy, with health repercussions to mother and child., Methods: Between 2007 and 2019, pregnant women with IBD were enrolled in a prospective, observational, multicenter study across the United States. The primary analysis was a comparison of 5 outcomes (congenital malformations, spontaneous abortions, preterm birth, low birth weight, and infant infections) among pregnancies exposed vs unexposed in utero to biologics, thiopurines, or a combination. Bivariate analyses followed by logistic regression models adjusted for relevant confounders were used to determine the independent effects of specific drug classes on outcomes of interest., Results: Among 1490 completed pregnancies, there were 1431 live births. One-year infant outcomes were available in 1010. Exposure was to thiopurines (n = 242), biologics (n = 642), or both (n = 227) vs unexposed (n = 379). Drug exposure did not increase the rate of congenital malformations, spontaneous abortions, preterm birth, low birth weight, and infections during the first year of life. Higher disease activity was associated with risk of spontaneous abortion (hazard ratio, 3.41; 95% confidence interval, 1.51-7.69) and preterm birth with increased infant infection (odds ratio, 1.73; 95% confidence interval, 1.19-2.51)., Conclusions: Biologic, thiopurine, or combination therapy exposure during pregnancy was not associated with increased adverse maternal or fetal outcomes at birth or in the first year of life. Therapy with these agents can be continued throughout pregnancy in women with IBD to maintain disease control and reduce pregnancy-related adverse events. ClinicalTrials.gov, Number: NCT00904878., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as an attractive target for cancer immunotherapy. An automated ligand identification system screen afforded the tetrahydroquinoline class of novel IDO1 inhibitors. Potency and pharmacokinetic (PK) were key issues with this class of compounds. Structure-based drug design and strategic incorporation of polarity enabled the rapid improvement on potency, solubility, and oxidative metabolic stability. Metabolite identification studies revealed that amide hydrolysis in the D-pocket was the key clearance mechanism for this class. Strategic survey of amide isosteres revealed that carbamates and N -pyrimidines, which maintained exquisite potencies, mitigated the amide hydrolysis issue and led to an improved rat PK profile. The lead compound 28 is a potent IDO1 inhibitor, with clean off-target profiles and the potential for quaque die dosing in humans., Competing Interests: The authors declare no competing financial interest., (© 2021 American Chemical Society.)

Background & Aims: A subset of patients with Crohn's disease (CD) do not respond to ustekinumab at the standard dose of 90 mg every 8 weeks. Little is known about the efficacy of shortening the interval between doses., Methods: We performed a retrospective study to determine the effectiveness of ustekinumab dose interval shortening, collecting data from 506 patients with CD who received subcutaneous ustekinumab 90 mg every 8 weeks at a single center. We obtained data from 110 patients who initially received subcutaneous ustekinumab 90 mg every 8 weeks and then had their interval shortened to every 4 weeks. Harvey Bradshaw Index (HBI) scores before and after the dose interval shortening was available for 78 patients in the cohort (71%), levels of C-reactive protein (CRP) for 60 patients (55%), and levels of fecal calprotectin for 8 patients (7%)., Results: Following dose interval shortening, the patients' median HBI decreased from 4.5 to 3 (P = .002), the median level of CRP decreased from 8 mg/L to 3 mg/L (P = .031), and median level of fecal calprotectin decreased from 378 μg/g to 157 μg/g (P = .57). Among patients who had an HBI >4, a level of CRP ≥5mg/dL, a level of fecal calprotectin >250ug/g, or endoscopic evidence for disease activity before dose interval shortening, after the dose interval was shortened, 28% achieved clinical remission (an HBI score ≤4), 22% had a normal level of CRP (<5 mg/dL), 50% had reduced levels of fecal calprotectin, and 36% achieved endoscopic remission., Conclusions: Shortening the ustekinumab 90 mg dose interval to 4 weeks for patients with CD who did not respond to doses every 8 weeks improved clinical and biological indices of disease activity. Patients who lose response to the standard dose of ustekinumab might benefit from dose interval shortening, which was effective and safe., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: This study aims to evaluate sarcopenia defined by skeletal muscle index (SMI) with cutoffs adjusted for sex and body mass index as a predictive marker for postoperative outcomes among individuals with inflammatory bowel disease., Methods: The SMI was measured using the cross-sectional computed tomography images at the lumbar spine. Multivariate logistic regression was performed to identify independent risk factors of postoperative complications., Results: Ninety-one patients were included in the study. In multivariate analysis, sarcopenia (odds ratio = 5.37; confidence interval: 1.04-27.6) was predictive of infectious postoperative complications., Conclusions: Sarcopenia as defined by the SMI is a predictor for 30-day postoperative infection complications in inflammatory bowel disease surgeries., (© The Author(s) 2020. Published by Oxford University Press on behalf of Crohn's & Colitis Foundation.)

The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update was to rapidly review the emerging evidence and provide timely expert recommendations regarding the management of patients with inflammatory bowel disease during the coronavirus disease 2019 pandemic. This expert commentary was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely perspective on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the Clinical Practice Updates Committee and external peer review through standard procedures of Gastroenterology., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Insufficient data exist for peristomal pyoderma gangrenosum (PPG), which primarily affects patients with inflammatory bowel disease (IBD)., Aims: To evaluate the risk factors and treatment response of PPG in IBD patients in a real-life cohort., Methods: Cases of PPG were identified retrospectively using ICD-9/10 codes in patients with IBD who had an ostomy at a tertiary care centre. Disease-specific characteristics were compared between groups with and without PPG, and response to therapy was evaluated in patients with PPG., Results: The cohort included 41 IBD patients with PPG and 123 IBD controls with an ostomy who never developed PPG. Patients with PPG were more likely to be female (76% vs 51%, P = 0.006), had higher BMIs (29.78 ± 0.89 vs 23.53 ± 0.51, P < 0.0001) and had increased usage of pouch belts (97% vs 71%, P = 0.0008) compared to controls. There were no differences in age at surgery (41.76 ± 2.60 vs 43.49 ± 1.50, P = 0.57) or IBD diagnosis (63% vs 54% Crohn's disease, P = 0.28) between PPG and controls. 85% of PPG patients achieved complete resolution with different treatments, including surgery. Complete resolution with topical corticosteroids and calcineurin inhibitors alone were low (14% and 13% respectively). Higher rates of complete resolution were reported with anti-tumour necrosis factor (TNF) agents (63%) and surgical interventions (80%)., Conclusions: Female gender, higher BMI and pouch belts were associated with increased risk of developing PPG. Most PPG cases resolved after treatment with the highest rates of complete resolution seen with anti-TNF agents and surgical intervention., (© 2020 John Wiley & Sons Ltd.)

The natural history of ulcerative colitis (UC) follows a relapsing and remitting course of inflammation and is accompanied by associated mucosal injury and historically, microscopic features of chronicity that were the sine qua non for the diagnosis. 1 As goals for the management of UC have evolved to include objectively measured endoscopic improvement of the mucosa, there also has been a move to include histological endpoints in assessment of disease activity. 2,3 However, there remain a number of unanswered questions about histology in UC and this is not yet a specific treatment goal. 4 ., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Following induction therapy with a calcineurin inhibitor (CNI) in severe ulcerative colitis, transitioning to vedolizumab as maintenance therapy could be an option., Aim: To report on the largest cohort of patients successfully induced with CNIs who were transitioned to vedolizumab maintenance therapy., Methods: This is a retrospective observational study of adult patients with severe steroid-refractory ulcerative colitis. Patients were included if they were induced with a CNI followed by maintenance therapy with vedolizumab between January 2014 and December 2018. The primary endpoint was colectomy-free survival. Secondary endpoints included survival without vedolizumab discontinuation as well as clinical, steroid-free and biochemical remission at week 14., Results: A total of 71 patients (59% male) were treated with vedolizumab after induction therapy with CNIs for severe steroid-refractory colitis. Patients were followed for a median time of 25 months (IQR 16-36). Colectomy-free survival rates from vedolizumab initiation were 93% at 3 months, 67% at 1 year and 55% at 2 years. At the end of induction with vedolizumab at week 14, 50% of patients were in clinical remission, and 62% of patients had a normal CRP. At 1 and 2 years following vedolizumab initiation, 43% and 28% of patients were still on vedolizumab respectively. Vedolizumab was dose escalated to infusions every 4 weeks in 44% of patients. The median time to dose escalation was 5.6 months (IQR 4.1-8.2). No serious adverse events were recorded in our patient cohort., Conclusions: Transitioning to vedolizumab following induction of remission with CNIs is effective and safe., (© 2019 John Wiley & Sons Ltd.)

Patients with ulcerative colitis (UC) limited to distal segments of the colon and rectum are often poorly represented in large clinical therapeutic trials, yet they constitute up to two-thirds of all UC patients. The propensity of UC to be most severe distally has also resulted in many oral or systemic therapies with lower levels of therapeutic success and mucosal healing in the distal regions of the colon. Topically administered mesalamine and corticosteroid agents have been utilized for decades in patients with distal UC but are often poorly accepted by patients and their prescribing physicians due to difficulties in administration and embarrassment. Formulation advances in the mesalamine preparations have led to the addition of topical 5-aminosalicylic acid (5-ASA) foams and gels to the existing options of liquid enemas and suppositories. Comparable advances in the use of topical corticosteroids have also taken advantage of the development of topical budesonide and similar safer corticosteroid preparations that promise clinical efficacy while delivering fewer systemic corticosteroid side effects. Combination therapy with oral and topical 5-ASA agents, or with topical 5-ASA and topical corticosteroid compounds, has further expanded the armamentarium for prescribers. Novel topical applications of currently existing therapies such as tacrolimus and cyclosporine show varying degrees of promise; the growing area of biologic and novel small molecules raises the possibility of a new wave of topically applied therapies for patients with distal UC and ulcerative proctitis., Competing Interests: Dr Cohen serves on the speakers bureau for AbbVie and Takeda; serves as a consultant for AbbVie, Celgene, Janssen, Pfizer, and Takeda; and has conducted clinical trials for AbbVie, Boehringer Ingelheim, Celgene Corp, Crohn’s & Colitis Foundation of America, Genentech, Gilead, Hollister, Medimmune, Pfizer, Receptos, Schwarz Pharma, Seres Therapeutics, and Takeda. His spouse serves on the Board of Directors for Aerpio Therapeutics, Novus Therapeutics, and Vital Therapies, Inc. Dr Weisshof serves on the speakers bureau for AbbVie, Takeda, and Janssen., (Copyright © 2019, Gastro-Hep Communications, Inc.)

Selective modification of proteins enables synthesis of antibody-drug conjugates, cellular drug delivery and construction of new materials. Many groups have developed methods for selective N-terminal modification without affecting the side chain of lysine by judicious pH control. This is due to lower basicity of the N-terminus relative to lysine side chains. But none of the methods are capable of selective modification of secondary amines or N-terminal proline, which has similar basicity as lysine. Here, we report a secondary amine selective Petasis (SASP) reaction for selective bioconjugation at N-terminal proline. We exploited the ability of secondary amines to form highly electrophilic iminium ions with aldehydes, which rapidly reacted with nucleophilic organoboronates, resulting in robust labeling of N-terminal proline under biocompatible conditions. This is the first time the Petasis reaction has been utilized for selective modification of secondary amines on completely unprotected peptides and proteins under physiological conditions. Peptide screening results showed that the reaction is highly selective for N-terminal proline. There are no other chemical methods reported in literature that are selective for N-terminal proline in both peptides and proteins. This is a multicomponent reaction leading to the synthesis of doubly functionalized bioconjugates in one step that can be difficult to achieve using other methods. The key advantage of the SASP reaction includes its high chemoselective and stereoselective (>99% de) nature, and it affords dual labeled proteins in one pot. The broad utility of this bioconjugation is highlighted for a variety of peptides and proteins, including aldolase and creatine kinase., (This journal is © The Royal Society of Chemistry 2020.)

An asymmetric synthesis of HCV NS5B nucleoside polymerase inhibitor (1) is described. This novel route features several remarkably diastereoselective and high-yielding transformations, including construction of the all-carbon quaternary stereogenic center at C-2 via a thermodynamic aldol reaction. A subsequent glycosylation reaction with activated uracil via C-1 phosphate and installation of the cyclic phosphate group using an achiral phosphorus(III) reagent followed by oxidation provides 1.

Background & Aims: Little is known about the efficacy and safety of induction therapy with calcineurin inhibitors in combination with vedolizumab for patients with Crohn's disease (CD) or ulcerative colitis (UC). We analyzed the outcomes of patients receiving vedolizumab along with calcineurin inhibitors., Methods: We collected data on patients with CD (n = 9) or UC (n = 11) who began treatment with vedolizumab from May 20, 2014, through March 30, 2015, and received calcineurin inhibitors (tacrolimus or cyclosporin) during the first 12 months of vedolizumab therapy. Clinical activity scores and inflammatory markers were measured at baseline and at weeks 14, 30, and 52 of vedolizumab treatment. Clinical remission was defined as a Harvey-Bradshaw index score ≤4 or short clinical colitis activity index score ≤2; steroid-free clinical remission was defined as clinical remission without corticosteroids., Results: By week 14 of treatment, 44% of the patients with CD and 55% of the patients with UC achieved steroid-free clinical remission; after 52 weeks of treatment, 33% of the patients with CD and 45% of the patients with UC were in steroid-free clinical remission. Seven patients received salvage therapy with a calcineurin inhibitor after primary nonresponse to vedolizumab-1 of the 2 patients with UC and 2 of 5 patients with CD stopped taking the calcineurin inhibitors and achieved steroid-free remission at week 52. In total, 16 patients (59%) received 52 weeks of treatment with vedolizumab. Three serious adverse events were associated with calcineurin inhibitors., Conclusions: Combination therapy of vedolizumab with either cyclosporin or tacrolimus is effective and safe at inducing and maintaining clinical remission in patients with CD and UC with up to 52 weeks of follow-up evaluation. Larger studies of the ability of calcineurin inhibitors to induce remission in patients on vedolizumab are warranted., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Immune checkpoint inhibitors (ICPIs) are increasingly being used in the treatment of a variety of malignancies. The original studies that demonstrated the efficacy of ICPIs excluded patients actively being treated for autoimmune conditions, and there is only limited evidence that these treatments are safe and effective in this population of patients., Case Presentation: We present a case of a man with Crohn's disease actively requiring immunosuppressive therapy who subsequently received pembrolizumab for metastatic melanoma. He had no further progression of metastatic disease and had resolution of his pulmonary nodule while he experienced no Crohn's disease flares or immune related adverse events. We surveyed the existing literature for studies examining the use of ICPIs in patients with autoimmune disorders and reviewed the unique mechanism of action of the α4β7 inhibitor, vedolizumab., Conclusion: Patients with autoimmune conditions should be considered candidates for immune checkpoint inhibition even in the setting of active immunosuppressive therapy. The mechanism of action of immunosuppressive therapy should be considered with the most targeted form of treatment being used when possible. Further prospective studies investigating immunotherapy in patients with autoimmune conditions are warranted.

The historical approach to neoplasia in the setting of chronic colitis was to perform a total proctocolectomy. Recent consensus and society guidelines 1-3 suggest that when dysplastic lesions can be removed endoscopically, continued surveillance is appropriate. This is based on improvements in optical technologies and the low risk of metachronous colorectal carcinoma in these patients. 4-6 We hypothesized that if a lesion was completely removed surgically and followed up endoscopically, metachronous colorectal carcinoma would be a rare occurrence. Thus, segmental resection may be offered as a definitive surgery in patients with chronic colitis and localized colorectal neoplasia in whom endoscopic resection is not feasible. Retention of the distal colon/rectum is expected to result in an overall improved quality of life compared with permanent ileostomy or an ileoanal J-pouch. Here, we report our experience and follow-up evaluation of segmental resections for preoperative neoplasia in patients with Crohn's disease (CD) or ulcerative colitis (UC)., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Many patients with Crohn's disease will develop complications that require surgery. Recurrence after surgery is common., Aim: To assess racial differences in postoperative recurrence between African-Americans and Caucasians., Methods: Medical records of Crohn's disease patients who underwent surgery (ileal, colonic, or ileocolonic resection) between June 2014 and June 2016 were reviewed. The primary endpoints were clinical and endoscopic remission at 6-12 months after a Crohn's disease surgery. Secondary outcomes included biological and histologic remission. Risks of recurrence were assessed by univariate, multivariate, and propensity score-matched analysis., Results: Thirty-six African-American and 167 Caucasian patients with Crohn's disease were included for analysis. There was no difference in disease location, disease behaviour, type of surgery performed, and pre- or postoperative medication use between the two groups. The rate of endoscopic remission did not differ between African-American and Caucasian patients (50% vs 42%, P = 0.76), and race did not influence the risk of endoscopic recurrence on univariate, multivariate, or propensity score-matched analysis. The rate of clinical remission was significantly lower in African-American patients compared to Caucasian patients (36% vs. 63%, P = 0.008). African-American race was significantly associated with clinical recurrence on univariate (odds ratio (OR) 6.76, 95% CI 1.50-30.40; P = 0.01), multivariate (OR 5.02, 95% CI 1.60-15.80; P = 0.006), and propensity-matched analysis (68% vs. 32% in Caucasians, P = 0.005). Rates of biologic and histologic remission were similar between the two groups on all analyses., Conclusions: We found that African-American patients with Crohn's disease have a similar degree of objective measures of mucosal inflammation after surgery including endoscopic recurrence as compared to Caucasian patients. However, African-American race was significantly associated with clinical recurrence, suggesting the presence of ethnic variation in postoperative presentation in Crohn's disease., (© 2018 John Wiley & Sons Ltd.)