The intrinsic substrate specificity of the human tyrosine kinome.

Phosphorylation of proteins on tyrosine (Tyr) residues evolved in metazoan organisms as a mechanism of coordinating tissue growth1. Multicellular eukaryotes typically have more than 50 distinct protein Tyr kinases that catalyse the phosphorylation of thousands of Tyr residues throughout the proteome1-3. How a given Tyr kinase can phosphorylate a specific subset of proteins at unique Tyr sites is only partially understood4-7. Here we used combinatorial peptide arrays to profile the substrate sequence specificity of all human Tyr kinases. Globally, the Tyr kinases demonstrate considerable diversity in optimal patterns of residues surrounding the site of phosphorylation, revealing the functional organization of the human Tyr kinome by substrate motif preference. Using this information, Tyr kinases that are most compatible with phosphorylating any Tyr site can be identified. Analysis of mass spectrometry phosphoproteomic datasets using this compendium of kinase specificities accurately identifies specific Tyr kinases that are dysregulated in cells after stimulation with growth factors, treatment with anti-cancer drugs or expression of oncogenic variants. Furthermore, the topology of known Tyr signalling networks naturally emerged from a comparison of the sequence specificities of the Tyr kinases and the SH2 phosphotyrosine (pTyr)-binding domains. Finally we show that the intrinsic substrate specificity of Tyr kinases has remained fundamentally unchanged from worms to humans, suggesting that the fidelity between Tyr kinases and their protein substrate sequences has been maintained across hundreds of millions of years of evolution.

An atlas of substrate specificities for the human serine/threonine kinome.

Protein phosphorylation is one of the most widespread post-translational modifications in biology1,2. With advances in mass-spectrometry-based phosphoproteomics, 90,000 sites of serine and threonine phosphorylation have so far been identified, and several thousand have been associated with human diseases and biological processes3,4. For the vast majority of phosphorylation events, it is not yet known which of the more than 300 protein serine/threonine (Ser/Thr) kinases encoded in the human genome are responsible3. Here we used synthetic peptide libraries to profile the substrate sequence specificity of 303 Ser/Thr kinases, comprising more than 84% of those predicted to be active in humans. Viewed in its entirety, the substrate specificity of the kinome was substantially more diverse than expected and was driven extensively by negative selectivity. We used our kinome-wide dataset to computationally annotate and identify the kinases capable of phosphorylating every reported phosphorylation site in the human Ser/Thr phosphoproteome. For the small minority of phosphosites for which the putative protein kinases involved have been previously reported, our predictions were in excellent agreement. When this approach was applied to examine the signalling response of tissues and cell lines to hormones, growth factors, targeted inhibitors and environmental or genetic perturbations, it revealed unexpected insights into pathway complexity and compensation. Overall, these studies reveal the intrinsic substrate specificity of the human Ser/Thr kinome, illuminate cellular signalling responses and provide a resource to link phosphorylation events to biological pathways.

AGA Clinical Practice Guideline on the Management of Pouchitis and Inflammatory Pouch Disorders.

BACKGROUND & AIMS: Pouchitis is the most common complication after restorative proctocolectomy with ileal pouch-anal anastomosis for ulcerative colitis. This American Gastroenterological Association (AGA) guideline is intended to support practitioners in the management of pouchitis and inflammatory pouch disorders. METHODS: A multidisciplinary panel of content experts and guideline methodologists used the Grading of Recommendations Assessment, Development and Evaluation framework to prioritize clinical questions, identify patient-centered outcomes, conduct an evidence synthesis, and develop recommendations for the prevention and treatment of pouchitis, Crohn's-like disease of the pouch, and cuffitis. RESULTS: The AGA guideline panel made 9 conditional recommendations. In patients with ulcerative colitis who have undergone ileal pouch-anal anastomosis and experience intermittent symptoms of pouchitis, the AGA suggests using antibiotics for the treatment of pouchitis. In patients who experience recurrent episodes of pouchitis that respond to antibiotics, the AGA suggests using probiotics for the prevention of recurrent pouchitis. In patients who experience recurrent pouchitis that responds to antibiotics but relapses shortly after stopping antibiotics (also known as "chronic antibiotic-dependent pouchitis"), the AGA suggests using chronic antibiotic therapy to prevent recurrent pouchitis; however, in patients who are intolerant to antibiotics or who are concerned about the risks of long-term antibiotic therapy, the AGA suggests using advanced immunosuppressive therapies (eg, biologics and/or oral small molecule drugs) approved for treatment of inflammatory bowel disease. In patients who experience recurrent pouchitis with inadequate response to antibiotics (also known as "chronic antibiotic-refractory pouchitis"), the AGA suggests using advanced immunosuppressive therapies; corticosteroids can also be considered in these patients. In patients who develop symptoms due to Crohn's-like disease of the pouch, the AGA suggests using corticosteroids and advanced immunosuppressive therapies. In patients who experience symptoms due to cuffitis, the AGA suggests using therapies that have been approved for the treatment of ulcerative colitis, starting with topical mesalamine or topical corticosteroids. The panel also proposed key implementation considerations for optimal management of pouchitis and Crohn's-like disease of the pouch and identified several knowledge gaps and areas for future research. CONCLUSIONS: This guideline provides a comprehensive, patient-centered approach to the management of patients with pouchitis and other inflammatory conditions of the pouch.

AGA Clinical Practice Guideline on the Role of Biomarkers for the Management of Ulcerative Colitis.

BACKGROUND & AIMS: Biomarkers are used frequently for noninvasive monitoring and treatment decision making in the management of patients with ulcerative colitis (UC). This American Gastroenterological Association (AGA) guideline is intended to support practitioners in decisions about the use of biomarkers for the management of UC. METHODS: A multidisciplinary panel of content experts and guideline methodologists used the Grading of Recommendations Assessment, Development and Evaluation framework to prioritize clinical questions, identify patient-centered outcomes, and conduct an evidence synthesis on the clinical performance of serum C-reactive protein (CRP), fecal calprotectin, and fecal lactoferrin as biomarkers of disease activity in patients with established UC in symptomatic remission or with active symptoms. The guideline panel used the Evidence-to-Decision framework to develop recommendations for the use of biomarkers for monitoring and management of UC and provided implementation considerations for clinical practice. RESULTS: The guideline panel made 7 conditional recommendations. In patients with UC in symptomatic remission, the panel suggests the use of a biomarker- and symptom-based monitoring strategy over a symptom-based monitoring strategy. For patients in symptomatic remission, the panel suggests using fecal calprotectin <150 µg/g, normal fecal lactoferrin, and/or normal CRP to rule out active inflammation and avoid routine endoscopic assessment of disease. In patients with UC with moderate to severe symptoms, the panel suggests using fecal calprotectin >150 µg/g, elevated fecal lactoferrin, or elevated CRP to inform treatment decisions and avoid routine endoscopic assessment of disease. However, in patients in symptomatic remission but elevated biomarkers, and in patients with moderate to severe symptoms with normal biomarkers, the panel suggests endoscopic assessment of disease to inform treatment decisions. In patients with UC with mild symptoms, the panel suggests endoscopic assessment of disease activity to inform treatment decisions. The panel identified the use of a biomarker-based monitoring strategy over an endoscopy-based monitoring strategy as a knowledge gap. The panel also proposed key implementation considerations for optimal use of biomarkers, and identified areas for future research. CONCLUSIONS: In patients with UC, noninvasive biomarkers, including fecal calprotectin, fecal lactoferrin, and serum CRP can inform disease monitoring and management.

AGA Clinical Practice Guideline on the Role of Biomarkers for the Management of Crohn's Disease.

BACKGROUND & AIMS: Biomarkers are used frequently for evaluation and monitoring of patients with Crohn's disease (CD). This American Gastroenterological Association (AGA) guideline is intended to support practitioners in decisions about the use of biomarkers for the management of CD. METHODS: A multidisciplinary panel of content experts and guideline methodologists used the Grading of Recommendations Assessment, Development and Evaluation framework to formulate patient-centered clinical questions and review evidence on the performance of fecal calprotectin, serum C-reactive protein (CRP), and Endoscopic Healing Index in patients with established CD who were asymptomatic, had symptoms of varying severity, or were in surgically induced remission. Biomarker performance was assessed against the gold standard of endoscopic activity, defined as a Simple Endoscopic Score for Crohn's Disease ≥3. The panel used the Grading of Recommendations Assessment, Development and Evaluation Evidence-to-Decision framework to develop recommendations for use of biomarkers in various settings. Implementation considerations were formulated for each recommendation to inform clinical practice. RESULTS: The guideline panel made 11 conditional recommendations. In patients with CD in symptomatic remission, the panel suggests use of a biomarker- and symptom-based monitoring strategy over symptoms alone. In patients in symptomatic remission, a fecal calprotectin <150 µg/g and normal CRP rules out active inflammation, avoiding endoscopic evaluation for assessment of disease activity. However, elevated biomarkers in this setting merit confirmation with endoscopy before treatment adjustment. In patients with CD with mild symptoms, neither normal nor elevated biomarkers alone are sufficiently accurate to determine endoscopic activity. In patients with CD with moderate to severe symptoms, elevated fecal calprotectin or serum CRP suggests endoscopic activity, precluding routine endoscopic assessment for disease activity. In patients with CD in surgically induced remission in low-risk patients on pharmacologic prophylaxis, a normal fecal calprotectin reliably rules out endoscopic recurrence. In other postoperative settings, the panel suggests endoscopic assessment for establishing postoperative recurrence. CONCLUSIONS: In patients with CD, fecal calprotectin and serum CRP can inform disease management in both asymptomatic and symptomatic disease. Discordance between symptom assessment and biomarker value may merit endoscopic evaluation for confirmation of status of disease activity.

Real-World Surgical and Endoscopic Recurrence Based on Risk Profiles and Prophylaxis Utilization in Postoperative Crohn's Disease.

BACKGROUND & AIMS: Preoperative risk stratification may help guide prophylactic biologic utilization for the prevention of postoperative Crohn's disease (CD) recurrence; however, there are limited data exploring and validating proposed clinical risk factors. We aimed to explore the preoperative clinical risk profiles, quantify individual risk factors, and assess the impact of biologic prophylaxis on postoperative recurrence risk in a real-world cohort. METHODS: In this multicenter retrospective analysis, patients with CD who underwent ileocolonic resection (ICR) from 2009 to 2020 were identified. High-risk (active smoking, ≥2 prior surgeries, penetrating disease, and/or perianal disease) and low-risk (nonsmokers and age >50 y) features were used to stratify patients. We assessed the risk of endoscopic (Rutgeert score, ≥i2b) and surgical recurrence by risk strata and biologic prophylaxis (≤90 days postoperatively) with logistic and time-to-event analyses. RESULTS: A total of 1404 adult CD patients who underwent ICR were included. Of the high-risk factors, 2 or more ICRs (odds ratio [OR], 1.71; 95% CI, 1.13-2.57), active smoking (OR, 1.73; 95% CI, 1.17-2.53), penetrating disease (OR, 1.41; 95% CI, 1.02-1.94), and history of perianal disease alone (OR, 1.99; 95% CI, 1.42-2.79) were associated with surgical but not endoscopic recurrence. Surgical recurrence was lower in high-risk patients receiving prophylaxis vs not (10.2% vs 16.7%; P = .02), and endoscopic recurrence was lower in those receiving prophylaxis irrespective of risk strata (high-risk, 28.1% vs 37.4%; P = .03; and low-risk, 21.1% vs 38.3%; P = .002). CONCLUSIONS: Clinical risk factors accurately illustrate patients at risk for surgical recurrence, but have limited utility in predicting endoscopic recurrence. Biologic prophylaxis may be of benefit irrespective of risk stratification and future studies should assess this.

Perianal Fistulizing Crohn's Disease-Associated Anorectal and Fistula Cancers: Systematic Review and Expert Consensus.

BACKGROUND & AIMS: Perianal fistulizing Crohn's disease (PFCD)-associated anorectal and fistula cancers are rare but often devastating diagnoses. However, given the low incidence and consequent lack of data and clinical trials in the field, there is little to no guidance on screening and management of these cancers. To inform clinical practice, we developed consensus guidelines on PFCD-associated anorectal and fistula cancers by multidisciplinary experts from the international TOpClass consortium. METHODS: We conducted a systematic review by standard methodology, using the Newcastle-Ottawa Scale quality assessment tool. We subsequently developed consensus statements using a Delphi consensus approach. RESULTS: Of 561 articles identified, 110 were eligible, and 76 articles were included. The overall quality of evidence was low. The TOpClass consortium reached consensus on 6 structured statements addressing screening, risk assessment, and management of PFCD-associated anorectal and fistula cancers. Patients with long-standing (>10 years) PFCD should be considered at small but increased risk of developing perianal cancer, including squamous cell carcinoma of the anus and anorectal carcinoma. Risk factors for squamous cell carcinoma of the anus, notably human papilloma virus, should be considered. New, refractory, or progressive perianal symptoms should prompt evaluation for fistula cancer. There was no consensus on timing or frequency of screening in patients with asymptomatic perianal fistula. Multiple modalities may be required for diagnosis, including an examination under anesthesia with biopsy. Multidisciplinary team efforts were deemed central to the management of fistula cancers. CONCLUSIONS: Inflammatory bowel disease clinicians should be aware of the risk of PFCD-associated anorectal and fistula cancers in all patients with PFCD. The TOpClass consortium consensus statements outlined herein offer guidance in managing this challenging scenario.

Perianal Fistulizing Crohn's Disease: Utilizing the TOpClass Classification in Clinical Practice to Provide Targeted Individualized Care.

BACKGROUND & AIMS: Perianal fistulation is a challenging phenotype of Crohn's disease, with significant impact on quality of life. Historically, fistulae have been classified anatomically in relation to the sphincter complex, and management guidelines have been generalized, with lack of attention to the clinical heterogenicity seen. The recent 'TOpClass classification system' for perianal fistulizing Crohn's disease (PFCD) addresses this issue, and classifies patients into defined groups, which provide a focus for fistula management that aligns with disease characteristics and patient goals. In this article, we discuss the clinical applicability of the TOpClass model and provide direction on its use in clinical practice. METHODS: An international group of perianal clinicians participated in an expert consensus to define how the TOpClass system can be incorporated into real-life practice. This included gastroenterologists, inflammatory bowel disease surgeons, and radiologists specialized in PFCD. The process was informed by the multi-disciplinary team management of 8 high-volume fistula centres in North America, Europe, and Australia. RESULTS: The process produced position statements to accompany the classification system and guide PFCD management. The statements range from the management of patients with quiescent perianal disease to those with severe PFCD requiring diverting-ostomy and/or proctectomy. The optimization of medical therapies, as well as the use of surgery, in fistula closure and symptom management is explored across each classification group. CONCLUSION: This article provides an overview of the system's use in clinical practice. It aims to enable clinicians to have a pragmatic and patient goal-centered approach to medical and surgical management options for individual patients with PFCD.

Histologic Activity From Neoterminal Ileal Biopsies in Patients With Crohn's Disease in Endoscopic Remission is Associated With Postoperative Recurrence.

INTRODUCTION: Following ileocolic resection (ICR), the clinical importance and prognostic implications of histologic activity on biopsies in Crohn's disease (CD) patients with endoscopic remission are not well defined. The aim of this study was to determine if histologic activity in patients with endoscopic remission is associated with future risk of endoscopic and/or radiologic postoperative recurrence (POR). METHODS: In this multicenter retrospective cohort study, adult patients with CD who underwent ICR between 2009 and 2020 with endoscopic biopsies of ileal mucosa from Rutgeerts i0 on index colonoscopy were included. The composite rate of endoscopic (Rutgeerts score ≥i2b) and radiologic (active inflammation on imaging) recurrence was compared in patients with and without histologic activity using a Kaplan-Meier survival analysis. A multivariable Cox proportional hazard regression model including clinically relevant risk factors of POR, postoperative biologic prophylaxis, and histology activity was designed. RESULTS: A total of 113 patients with i0 disease on index colonoscopy after ICR were included. Of these, 42% had histologic activity. Time to POR was significantly earlier in the histologically active versus normal group ( P = 0.04). After adjusting for clinical risk factors of POR, histologic activity (HR 2.37, 95% CI 1.17-4.79; P = 0.02) and active smoking (HR 2.54, 95% CI 1.02-6.33; P = 0.05) were independently associated with subsequent composite POR risk. DISCUSSION: In patients with postoperative CD, histologic activity despite complete endoscopic remission is associated with composite, endoscopic, and radiographic recurrence. Further understanding of the role of histologic activity in patients with Rutgeerts i0 disease may provide a novel target to reduce disease recurrence in this population.

A Propensity Score-Matched Analysis of Single-Port Vs Multiport Laparoscopic Total Abdominal Colectomy With End Ileostomy for Medically Refractory Ulcerative Colitis.

BACKGROUND: Medically refractory ulcerative colitis necessitates surgical intervention, with total abdominal colectomy with end ileostomy being a definitive treatment. The comparison between single-port and multiport laparoscopic surgery outcomes remains underexplored. OBJECTIVE: To compare the surgical outcomes of single-port versus multiport laparoscopic surgery in patients undergoing total abdominal colectomy with end ileostomy for medically refractory ulcerative colitis. DESIGN: A retrospective analysis comparing single-port to multiport surgery in patients with ulcerative colitis from 2010 to 2020. Patients were propensity score-matched 3:1 (multiport to single-port) on baseline characteristics. SETTINGS: Single-center academic hospital. PATIENTS: A total of 756 patients with medically refractory ulcerative colitis who underwent multiport vs single-port total abdominal colectomy with end ileostomy from 2010 to 2020 were included. MAIN OUTCOME MEASURES: Binary outcomes were compared using a multivariable logistic regression model, and a subset analysis was conducted for postoperative stump leak based on stump implantation during surgery. These metrics were compared between the single-port and multiport groups to assess the differences in surgical outcomes. RESULTS: The multiport and single-port groups included 642 and 114 patients, respectively. The matched cohort included 342 multiports and 114 single ports. We observed a statistically significant difference in mean operation time, with the single-port procedure taking 43 minutes less than the multiport laparoscopy. There were no significant differences between the 2 groups in postoperative stump leaks, postoperative ileus, stoma site complications, postoperative readmission within 30 days, postoperative reoperation within 30 days, and subsequent IPAA surgery. In the subset analysis, stump implantation was associated with a higher risk of stump leak in the multiport group. The single-port group had a shorter hospital stay. LIMITATIONS: Retrospective nature and being conducted at a single center. CONCLUSION: Single-incision laparoscopic total abdominal colectomy in the treatment of mucosal ulcerative colitis is a safe, effective, and efficient approach. In our cohort, single-incision laparoscopy has had shorter operation times and better overall length of stay compared with the multiport approach. Taking into account a less invasive approach, decreased abdominal trauma, and faster recovery, single-port surgery is a viable alternative to multiport surgery. See Video Abstract . UN ANLISIS EMPAREJADO POR PUNTUACIN DE PROPENSIN DE LA COLECTOMA ABDOMINAL TOTAL LAPAROSCPICA CON PUERTO NICO VERSUS PUERTO MLTIPLE CON ILEOSTOMA TERMINAL PARA LA COLITIS ULCEROSA MDICAMENTE REFRACTARIA: ANTECEDENTES:La colitis ulcerosa (CU) médicamente refractaria requiere una intervención quirúrgica, siendo la colectomía abdominal total con ileostomía terminal un tratamiento definitivo. La comparación entre los resultados de la cirugía laparoscópica con puerto único y con puerto múltiple aún no se ha explorado lo suficiente.OBJETIVO:Comparar los resultados quirúrgicos de la cirugía laparoscópica con puerto único versus con puerto múltiple en pacientes sometidos a colectomía abdominal total con ileostomía terminal para CU médicamente refractaria.DISEÑO:Un análisis retrospectivo que comparó la cirugía de puerto único con la de puerto múltiple en pacientes con CU de 2010 a 2020. Los pacientes fueron emparejados por puntuación de propensión 3:1 (puerto múltiple a puerto único) según las características iniciales.AJUSTES:Hospital académico unicentrico.PRINCIPALES MEDIDAS DE RESULTADO:Los resultados binarios se compararon utilizando un modelo de regresión logística multivariable y se realizó un análisis de subconjunto para la fuga postoperatoria del muñón basado en la implantación del muñón durante la cirugía. Estas métricas se compararon entre los grupos de puerto único y de puerto múltiple para evaluar las diferencias en los resultados quirúrgicos.RESULTADOS:Los grupos de puerto único y multipuerto incluyeron 642 y 114 pacientes, respectivamente. La cohorte emparejada incluyó 342 puertos múltiples y 114 puertos únicos. Observamos una diferencia estadísticamente significativa en el tiempo medio de operación, ya que el procedimiento de puerto único duró 43 minutos menos que la laparoscopia de puerto múltiple. No hubo diferencias significativas entre los dos grupos en las fugas del muñón posoperatorio, el íleo posoperatorio, las complicaciones del sitio del estoma, el reingreso posoperatorio dentro de los 30 días, la reoperación posoperatoria dentro de los 30 días y la cirugía IPAA posterior. En el análisis de subconjunto, la implantación del muñón se asoció con un mayor riesgo de fuga del muñón en el grupo multipuerto. El grupo de puerto único tuvo una estancia hospitalaria más corta.LIMITACIONES:Carácter retrospectivo, realizándose en un único centro.CONCLUSIÓN:La colectomía abdominal total laparoscópica de incisión única en el tratamiento de la colitis ulcerosa mucosa es un enfoque seguro, eficaz y eficiente. En nuestra cohorte, en comparación con el abordaje multipuerto, la laparoscopia de incisión única ha mostrado tiempos de operación más cortos y una mejor duración total de la estancia hospitalaria. Teniendo en cuenta un enfoque menos invasivo, un menor traumatismo abdominal y una recuperación más rápida, la cirugía con puerto único es una alternativa viable a la cirugía con puertos múltiples. (Traducción-Dr. Mauricio Santamaria ).

Peri-Operative Optimization of Patients with Crohn's Disease.

PURPOSE OF REVIEW: The management of patients with Crohn's disease (CD) undergoing surgery is complex and optimization of modifiable factors perioperatively can improve outcomes. This review focuses on the perioperative management of CD patients undergoing surgery, emphasizing the need for a multi-disciplinary approach. RECENT FINDINGS: Research highlights the benefits of a comprehensive strategy, involving nutritional optimization, psychological assessment, and addressing septic complications before surgery. Despite many CD patients being on immune-suppressing medications, studies indicate that most of these medications are safe to use and should not delay surgery. However, a personalized approach for each case is needed. This review underscores the importance of multi-disciplinary team led peri-operative management of CD patients. We suggest that this can be done at a dedicated perioperative clinic for prehabilitation, with the potential to enhance outcomes for CD patients undergoing surgery.

Sodium-Glucose Cotransporter 2 Inhibitors Should Be Avoided for the Inpatient Management of Hyperglycemia.

OBJECTIVE: Hyperglycemia in patients with type 2 diabetes mellitus is frequently encountered in the hospital setting. The recent guidelines for the management of inpatient hyperglycemia have included the use of dipeptidyl peptidase 4 inhibitors as an alternative to standard insulin therapy in select patients. This raises the question of the inpatient use of sodium-glucose cotransporter 2 inhibitors (SGLT2i), which have gained increasing popularity in the outpatient setting because of beneficial cardiovascular and renal outcomes. This article describes the risks associated with the use of SGLT2i for the management of inpatient hyperglycemia. METHODS: A literature review was performed using PubMed and Google Scholar for studies assessing the inpatient use of SGLT2i. Search terms included "SGLT2 inhibitors," "euglycemic DKA," "inpatient hyperglycemia," "DPP4 inhibitors," "hypovolemia," and "urinary tract infections." Studies not written in English were excluded. Forty-eight articles were included. RESULTS: Review of the literature showed significant safety concerns with the use of SGLT2i for the inpatient management of hyperglycemia. Hospitalized patients treated with SGLT2i were at increased risk of diabetic ketoacidosis, euglycemic diabetic ketoacidosis, hypovolemia, and urinary tract infections. When compared head-to-head, SGLT2i were not more effective for inpatient glycemic control than dipeptidyl peptidase 4 inhibitors and did not reduce insulin requirements when used in combination with insulin. Although SGLT2i can be considered for the treatment of congestive heart failure, they should be started close to or at the time of discharge. CONCLUSION: Although SGLT2i are a preferred pharmacotherapy class for the outpatient management of type 2 diabetes mellitus, there are considerable safety concerns when using them in a hospital setting, and avoidance is recommended.

Redo IPAA for long rectal cuff syndrome after ileoanal pouch for inflammatory bowel disease.

ABTRACT: BACKGROUND: When constructing an ileal pouch-anal anastomosis (IPAA), the rectal cuff should ideally be 1-2 cm long to avoid subsequent complications. METHODS: We identified patients from our IBD center who underwent redo IPAA for a long rectal cuff. Long rectal cuff syndrome (LRCS) was defined as a symptomatic rectal cuff ≥ 4 cm. RESULTS: Forty patients met the inclusion criteria: 42.5% female, median age at redo surgery 42.5 years. The presentation was ulcerative proctitis in 77.5% of the cases and outlet obstruction in 22.5%. The index pouch was laparoscopically performed in 18 patients (45%). The median rectal cuff length was 6 cm. The pouch was repaired in 16 (40%) cases, whereas 24 (60%) required the creation of a neo-pouch. At the final pathology, the rectal cuff showed chronic active colitis in 38 (90%) cases. After a median follow-up of 34.5 (IQR 12-109) months, pouch failure occurred in 9 (22.5%) cases. The pouch survival rate was 78% at 3 years. Data on the quality of life were available for 11 (27.5%) patients at a median of 75 months after redo surgery. The median QoL score (0-1) was 0.7 (0.4-0.9). CONCLUSION: LRCS, a potentially avoidable complication, presents uniformly with symptoms of ulcerative proctitis or stricture. Redo IPAA was restorative for the majority.

Dehydrated human amnion/chorion membrane to treat venous leg ulcers: a cost-effectiveness analysis.

OBJECTIVE: To evaluate the cost-effectiveness of dehydrated human amnion/chorion membrane (DHACM) in Medicare enrolees who developed a venous leg ulcer (VLU). METHOD: This economic evaluation used a four-state Markov model to simulate the disease progression of VLUs for patients receiving advanced treatment (AT) with DHACM or no advanced treatment (NAT) over a three-year time horizon from a US Medicare perspective. DHACM treatments were assessed when following parameters for use (FPFU), whereby applications were initiated 30-45 days after the initial VLU diagnosis claim, and reapplications occurred on a weekly to biweekly basis until completion of the treatment episode. The cohort was modelled on the claims of 530,220 Medicare enrolees who developed a VLU between 2015-2019. Direct medical costs, quality-adjusted life years (QALYs), and the net monetary benefit (NMB) at a willingness-to-pay threshold of $100,000/QALY were applied. Univariate and probabilistic sensitivity analyses (PSA) were performed to test the uncertainty of model results. RESULTS: DHACM applied FPFU dominated NAT, yielding a lower per-patient cost of $170 and an increase of 0.010 QALYs over three years. The resulting NMB was $1178 per patient in favour of DHACM FPFU over the same time horizon. The rate of VLU recurrence had a notable impact on model uncertainty. In the PSA, DHACM FPFU was cost-effective in 63.01% of simulations at the $100,000/QALY threshold. CONCLUSION: In this analysis, DHACM FPFU was the dominant strategy compared to NAT, as it was cost-saving and generated a greater number of QALYs over three years from the US Medicare perspective. A companion VLU Medicare outcomes analysis revealed that patients who received AT with a cellular, acellular and matrix-like product (CAMP) compared to patients who received NAT had the best outcomes. Given the added clinical benefits to patients at lower cost, providers should recommend DHACM FPFU to patients with VLU who qualify. Decision-makers for public insurers (e.g., Medicare and Medicaid) and commercial payers should establish preferential formulary placement for reimbursement of DHACM to reduce budget impact and improve the long-term health of their patient populations dealing with these chronic wounds. DECLARATION OF INTEREST: Support for this analysis was provided by MiMedx Group, Inc., US. JLD, and RAF are employees of MiMedx Group, Inc. WHT, BH, PS, BGC and WVP were consultants to MiMedx Group, Inc. VD, AO, MRK, JAN, NW and GAM served on the MiMedx Group, Inc. Advisory Board. MRK and JAN served on a speaker's bureau. WVP declares personal fees and equity holdings from Stage Analytics, US.

Prospective Cohort Study to Investigate the Safety of Preoperative Tumor Necrosis Factor Inhibitor Exposure in Patients With Inflammatory Bowel Disease Undergoing Intra-abdominal Surgery.

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.

CORE-IBD: A Multidisciplinary International Consensus Initiative to Develop a Core Outcome Set for Randomized Controlled Trials in Inflammatory Bowel Disease.

BACKGROUND & AIMS: End points to determine the efficacy and safety of medical therapies for Crohn's disease (CD) and ulcerative colitis (UC) are evolving. Given the heterogeneity in current outcome measures, harmonizing end points in a core outcome set for randomized controlled trials is a priority for drug development in inflammatory bowel disease. METHODS: Candidate outcome domains and outcome measures were generated from systematic literature reviews and patient engagement surveys and interviews. An iterative Delphi process was conducted to establish consensus: panelists anonymously voted on items using a 9-point Likert scale, and feedback was incorporated between rounds to refine statements. Consensus meetings were held to ratify the outcome domains and core outcome measures. Stakeholders were recruited internationally, and included gastroenterologists, colorectal surgeons, methodologists, and clinical trialists. RESULTS: A total of 235 patients and 53 experts participated. Patient-reported outcomes, quality of life, endoscopy, biomarkers, and safety were considered core domains; histopathology was an additional domain for UC. In CD, there was consensus to use the 2-item patient-reported outcome (ie, abdominal pain and stool frequency), Crohn's Disease Activity Index, Simple Endoscopic Score for Crohn's Disease, C-reactive protein, fecal calprotectin, and co-primary end points of symptomatic remission and endoscopic response. In UC, there was consensus to use the 9-point Mayo Clinic Score, fecal urgency, Robarts Histopathology Index or Geboes Score, fecal calprotectin, and a composite primary end point including both symptomatic and endoscopic remission. Safety outcomes should be reported using the Medical Dictionary for Regulatory Activities. CONCLUSIONS: This multidisciplinary collaboration involving patients and clinical experts has produced the first core outcome set that can be applied to randomized controlled trials of CD and UC.

Anastomotic Configuration and Temporary Diverting Ileostomy Do Not Increase Risk of Anastomotic Stricture in Postoperative Crohn's Disease.

INTRODUCTION: Surgical management of Crohn's disease (CD) is common. Postoperative complications include anastomotic stricturing (AS). The natural history and risk factors for AS have not been elucidated. METHODS: A retrospective cohort study of patients with CD who underwent ileocolonic resection (ICR) with ≥1 postoperative ileocolonoscopy between 2009 and 2020. Postoperative ileocolonoscopies with corresponding cross-sectional imaging were evaluated for evidence of AS without neoterminal ileal extension. Severity of AS and endoscopic intervention at time of detection were collected. Primary outcome was development of AS. Secondary outcome was time to AS detection. RESULTS: A total of 602 adult patients with CD underwent ICR with postoperative ileocolonoscopy. Of these, 426 had primary anastomosis, and 136 had temporary diversion at time of ICR. Anastomotic configuration consisted of 308 side-to-side, 148 end-to-side, and 136 end-to-end. One hundred ten (18.3%) patients developed AS with median time of 3.2 years to AS detection. AS severity at time of detection was associated with need for repeat surgical resection for AS. On multivariable Cox proportional hazard regression, anastomotic configuration and temporary diversion were not associated with risk of or time to AS. Preoperative stricturing disease was associated with decreased time to AS (adjusted hazard ratio 1.8; P = 0.049). Endoscopic ileal recurrence before AS was not associated with subsequent AS detection. DISCUSSION: AS is a relatively common postoperative CD complication. Patients with previous stricturing disease behavior are at increased risk of AS. Anastomotic configuration, temporary diversion, and ileal CD recurrence do not increase risk of AS. Early detection and intervention for AS may help prevent progression to repeat ICR.

Venous Thromboembolism in Patients Admitted for IBD: An Enterprise-Wide Experience of 86,000 Hospital Encounters.

BACKGROUND: Recommendations regarding venous thromboembolism prophylaxis in patients admitted to the hospital for IBD continue to evolve. OBJECTIVE: This study aimed to determine the 90-day rate and risk factors of deep venous thromboembolism and pulmonary embolism in cohorts of patients with IBD admitted to medical and surgical services. DESIGN: This was a retrospective review. SETTING: The study was conducted at a quaternary IBD referral center. PATIENTS: The study included adult patients ( > 18 y of age) with a known diagnosis of either ulcerative colitis or Crohn's disease who had an inpatient hospital admission for IBD between January 1, 2002, and January 1, 2020. MAIN OUTCOME MEASURES: The primary outcome measures were 90-day rate of deep venous thromboembolism and pulmonary embolism among admitted patients. RESULTS: A total of 86,276 hospital admissions from 16,551 patients with IBD occurred between January 1, 2002, and January 1, 2020. A total of 35,992 patients (41.7%) were given subcutaneous heparin for venous thromboembolism prophylaxis, and 8188 patients (9.49%) were given enoxaparin for venous thromboembolism prophylaxis during the inpatient hospital admission. From the date of hospital admission, the 90-day rate of deep venous thromboembolism was 4.3% (n = 3664); of these, 1731 patients (47%) were diagnosed during the admission and 1933 patients (53%) were diagnosed after discharge. From the date of hospital admission, the 90-day rate of pulmonary embolism was 2.4% (n = 2040); of these, 960 patients (47%) were diagnosed during admission and 1080 patients (53%) were diagnosed after discharge. LIMITATIONS: The study was limited by its retrospective nature and unmeasured severity of the disease. CONCLUSIONS: Patients admitted for IBD had a 90-day deep venous thromboembolism event rate of 4.3% and pulmonary embolism event rate of 2.4%. More than half of the events occurred after discharge, and venous thromboembolism events were higher among patients with IBD admitted to a medical service than those admitted to a surgical service. See Video Abstract at http://links.lww.com/DCR/B947 . TROMBOEMBOLIA VENOSA EN PACIENTES INGRESADOS CON ENFERMEDAD INFLAMATORIA INTESTINAL UNA EXPERIENCIA EN TODA LA EMPRESA DE ENCUENTROS HOSPITALARIOS: ANTECEDENTES:Recomendaciones sobre la profilaxis de tromboembolia venosa en pacientes ingresados con enfermedad inflamatoria intestinal (EII) continúa evolucionando.OBJETIVO:Determinar la tasa a 90 días y los factores de riesgo de tromboembolia venosa profunda y embolia pulmonar en cohortes de pacientes ingresados con EII médico y quirúrgico.DISEÑO:Esta fue una revisión retrospectiva.AJUSTE:El estudio se llevó a cabo en un centro cuaternario de derivación de EII.PACIENTES:Se incluyeron pacientes adultos (> 18 años) con diagnóstico conocido de colitis ulcerosa o enfermedad de Crohn que fueron hospitalizados por EII entre el 1 de Enero de 2002 y el 1 de Enero de 2020.PRINCIPALES MEDIDAS DE RESULTADOS:Las medidas principales fueron la tasa de tromboembolia venosa profunda a 90 días y la embolia pulmonar entre los pacientes ingresados.RESULTADOS:Un total de 86.276 ingresos hospitalarios de 16.551 pacientes con EII ocurrieron entre el 1 de Enero de 2002 y el 1 de Enero de 2020. A un total de 35.992 (41,7%) se les administró heparina subcutánea para profilaxis de tromboembolia venosa y a 8.188 (9,49%) se les administró enoxaparina para profilaxis de tromboembolia venosa durante el ingreso hospitalario. A partir de la fecha de ingreso hospitalario, la tasa de tromboembolia venosa profunda a 90 días fue del 4,3% (n = 3.664); de estos 1.731 (47%) se diagnosticaron durante el ingreso y 1.933 (53%) se diagnosticaron después del alta. Desde la fecha de ingreso hospitalario, la tasa de embolia pulmonar a los 90 días fue de 2,4% (n = 2.040); De estos, 960 (47%) fueron diagnosticados durante el ingreso y 1.080 (53%) fueron diagnosticados después del alta.LIMITACIONES:El estudio fue retrospectivo y no se midió la gravedad de la enfermedad.CONCLUSIÓNES:Los pacientes ingresados por EII tuvieron una tasa de tromboembolia venosa profunda y de eventos de embolia pulmonar de 4,3% y 2,4%, respectivamente, a 90 días. Más de la mitad de los eventos ocurrieron después del alta y los eventos de TEV fueron más altos entre los pacientes de EII médicos que quirúrgicos. Consulte Video Resumen en http://links.lww.com/DCR/B947 . (Traducción- Dr. Yesenia Rojas-Khalil ).

Alzheimer Disease Occurs More Frequently In Patients With Inflammatory Bowel Disease: Insight From a Nationwide Study.

Alzheimer disease (AD) affects 5 million Americans and early recognition improves cognitive function. Chronic inflammation and gut microbiome alteration are linked to cognitive decline which are common in inflammatory bowel disease (IBD). We investigated the association of IBD with development of AD. A commercial database (Explorys Inc., Cleveland, OH), an aggregate of electronic health records from 26 major US health care systems, was surveyed. Cohorts of patients with Systematized Nomenclature of Medicine-Clinical Terms (SNOMED-CT) diagnoses of Crohn's disease (CD), ulcerative colitis (UC), and AD were identified. IBD patients with new diagnosis of AD were characterized based on demographic and traditional AD risk factors and IBD-related features. Among 342,740 IBD patients in the database, AD developed in 5750 IBD patients (1.55%). After adjusting for traditional AD risk factors, IBD was identified as an independent risk factor for development of AD [odds ratio (OR)=2.30, 95% confidence interval (CI)=2.10-2.51]. IBD patients with AD were younger in comparison to AD patients without IBD. On sub-group analysis, patients with CD had higher odds of developing AD (adjusted OR=3.34, 95% CI=3.25-3.42) than UC (adjusted OR=1.09, 95% CI=1.06-1.14). Use of tumor necrosis factor (TNF-α) inhibitors in IBD was associated with significantly lower odds of developing AD in both CD and UC. In this population based study, IBD was independently associated with development of AD. Among IBD; the association was stronger in patients with CD in comparison with UC. Use of TNF-α inhibitors was associated with lower odds of developing AD.

Change in Biologic Class Promotes Endoscopic Remission Following Endoscopic Postoperative Crohn's Disease Recurrence.

GOALS: Assess the outcomes of various therapeutic regimens to treat initial endoscopic postoperative recurrence despite biologic prophylaxis. BACKGROUND: Postoperative biologic prophylaxis reduces postoperative Crohn's disease (CD) recurrence rates. Optimal treatment strategies for endoscopic recurrence have not been elucidated. STUDY: Retrospective cohort study of adult CD patients who underwent ileocolonic resection between 2009 and 2020. Patients with endoscopic postoperative recurrence despite prophylactic biologic therapy and ≥1 subsequent colonoscopy were included. Treatment changes after recurrence were categorized as (1) therapy optimization or continuation or (2) new biologic class. The primary outcome was composite endoscopic or surgical recurrence at the time of or prior to subsequent follow-up colonoscopy. RESULTS: Eighty-one CD patients with endoscopic recurrence (54.3% i2b, 22.2% i3, and 23.5% i4) despite biologic prophylaxis (86.4% anti-tumor necrosis factor, 8.6% vedolizumab, 4.9% ustekinumab) were included. Most patients received therapy optimization or continuation (76.3%, n=61) following recurrence compared to being started on a new biologic class. Sixty patients (N=48 therapy optimization; N=12 new biologic class) experienced composite recurrence (78.3% endoscopic, 21.7% surgical). On multivariable modeling, initiation of a new biologic class was associated with reduced risk for composite recurrence compared to therapy optimization or continuation (aOR: 0.26; P=0.04). Additionally, initiation of a new biologic class was associated with endoscopic improvement when adjusting for endoscopic severity at the time of recurrence (aOR: 3.4; P=0.05). On sensitivity analysis, a new biologic class was associated or trended with improved rates of endoscopic healing and composite recurrence when directly compared to therapy optimization or continuation. CONCLUSION: In patients with CD who experience endoscopic recurrence despite biologic prophylaxis, changing the mechanism of biologic action may promote endoscopic improvement.