Robust and prototypical immune responses toward COVID-19 vaccine in First Nations peoples are impacted by comorbidities.

High-risk groups, including Indigenous people, are at risk of severe COVID-19. Here we found that Australian First Nations peoples elicit effective immune responses to COVID-19 BNT162b2 vaccination, including neutralizing antibodies, receptor-binding domain (RBD) antibodies, SARS-CoV-2 spike-specific B cells, and CD4+ and CD8+ T cells. In First Nations participants, RBD IgG antibody titers were correlated with body mass index and negatively correlated with age. Reduced RBD antibodies, spike-specific B cells and follicular helper T cells were found in vaccinated participants with chronic conditions (diabetes, renal disease) and were strongly associated with altered glycosylation of IgG and increased interleukin-18 levels in the plasma. These immune perturbations were also found in non-Indigenous people with comorbidities, indicating that they were related to comorbidities rather than ethnicity. However, our study is of a great importance to First Nations peoples who have disproportionate rates of chronic comorbidities and provides evidence of robust immune responses after COVID-19 vaccination in Indigenous people.

Australian inflammatory bowel disease consensus statements for preconception, pregnancy and breast feeding.

OBJECTIVE: Because pregnancy outcomes tend to be worse in women with inflammatory bowel disease (IBD) than in those without, we aimed to update consensus statements that guide the clinical management of pregnancy in patients with IBD. DESIGN: A multidisciplinary working group was established to formulate these consensus statements. A modified RAND/UCLA appropriateness method was used, consisting of a literature review, online voting, discussion meeting and a second round of voting. The overall agreement among the delegates and appropriateness of the statement are reported. RESULTS: Agreement was reached for 38/39 statements which provide guidance on management of pregnancy in patients with IBD. Most medications can and should be continued throughout pregnancy, except for methotrexate, allopurinol and new small molecules, such as tofacitinib. Due to limited data, no conclusion was reached on the use of tioguanine during pregnancy. Achieving and maintaining IBD remission before conception and throughout pregnancy is crucial to optimise maternofetal outcomes. This requires a multidisciplinary approach to engage patients, allay anxieties and maximise adherence tomedication. Intestinal ultrasound can be used for disease monitoring during pregnancy, and flexible sigmoidoscopy or MRI where clinically necessary. CONCLUSION: These consensus statements provide up-to-date, comprehensive recommendations for the management of pregnancy in patients with IBD. This will enable a high standard of care for patients with IBD across all clinical settings.

Increased mitochondrial surface area and cristae density in the skeletal muscle of strength athletes.

Mitochondria are the cellular organelles responsible for resynthesising the majority of ATP. In skeletal muscle, there is an increased ATP turnover during resistance exercise to sustain the energetic demands of muscle contraction. Despite this, little is known regarding the mitochondrial characteristics of chronically strength-trained individuals and any potential pathways regulating the strength-specific mitochondrial remodelling. Here, we investigated the mitochondrial structural characteristics in skeletal muscle of strength athletes and age-matched untrained controls. The mitochondrial pool in strength athletes was characterised by increased mitochondrial cristae density, decreased mitochondrial size, and increased surface-to-volume ratio, despite similar mitochondrial volume density. We also provide a fibre-type and compartment-specific assessment of mitochondria morphology in human skeletal muscle, which reveals across groups a compartment-specific influence on mitochondrial morphology that is largely independent of fibre type. Furthermore, we show that resistance exercise leads to signs of mild mitochondrial stress, without an increase in the number of damaged mitochondria. Using publicly available transcriptomic data we show that acute resistance exercise increases the expression of markers of mitochondrial biogenesis, fission and mitochondrial unfolded protein responses (UPRmt ). Further, we observed an enrichment of the UPRmt in the basal transcriptome of strength-trained individuals. Together, these findings show that strength athletes possess a unique mitochondrial remodelling, which minimises the space required for mitochondria. We propose that the concurrent activation of markers of mitochondrial biogenesis and mitochondrial remodelling pathways (fission and UPRmt ) with resistance exercise may be partially responsible for the observed mitochondrial phenotype of strength athletes. KEY POINTS: Untrained individuals and strength athletes possess comparable skeletal muscle mitochondrial volume density. In contrast, strength athletes' mitochondria are characterised by increased cristae density, decreased size and increased surface-to-volume ratio. Type I fibres have an increased number of mitochondrial profiles with minor differences in the mitochondrial morphological characteristics compared with type II fibres. The mitochondrial morphology is distinct across the subcellular compartments in both groups, with subsarcolemmal mitochondria being bigger in size when compared with intermyofibrillar. Acute resistance exercise leads to signs of mild morphological mitochondrial stress accompanied by increased gene expression of markers of mitochondrial biogenesis, fission and mitochondrial unfolded protein response (UPRmt ).

Reliability and Responsiveness of Histologic Indices for the Assessment of Crohn's Disease Activity.

BACKGROUND & AIMS: The operating properties of histologic indices for evaluating Crohn's disease (CD) activity are poorly characterized. We assessed the reliability and responsiveness of existing histologic indices/items used in CD and ulcerative colitis (UC), in addition to 3 novel items, and developed exploratory ileal, colonic, and colonic-ileal CD instruments. METHODS: Blinded central readers independently reviewed paired baseline and week 12 image sets from the EXTEND trial. Disease activity was scored using 4 indices (the Global Histologic Activity Score, Geboes Score, Nancy Histological Index, and Robarts Histopathology Index) and 3 items identified by an expert panel (mucin depletion, basal plasmacytosis, and ileal pyloric gland metaplasia). Reliability and responsiveness were quantified using the intraclass correlation coefficient (ICC) and area under the receiver operating curve (AUC), respectively. Exploratory indices were developed using backward stepwise linear regression analysis. Candidate independent variables were items with an inter-rater ICC ≥0.40 and AUC ≥0.56. The dependent variable was histologic disease activity measured by a 100-mm visual analogue scale. RESULTS: Paired image sets were available from 55 patients. Substantial to almost perfect inter-rater reliability (ICC, 0.63-0.87) and some responsiveness (AUC, 0.57-0.94) were observed for all existing indices regardless of whether individual colonic and ileal segments, combined colonic segments, or combined colonic and ileal segments were assessed and the calculation method used. Five items were tested as candidate items, and exploratory colonic, ileal, and colonic-ileal indices were developed. CONCLUSIONS: CD and UC indices were similarly reliable and responsive in measuring histologic CD activity. Exploratory index development did not offer benefit over current histologic instruments.

Prevalence of low protein intake in 80+-year-old community-dwelling adults and association with dietary patterns and modifiable risk factors: a cross-sectional study.

Low protein intake may accelerate age-related loss of lean mass and physical function. We investigated the prevalence of low protein intake (<1·0 g/kg/day) and the associations between dietary patterns, modifiable risk factors and low protein intake in self-reliant community-dwelling adults ≥ 80 years. This cross-sectional study consisted of two home visits. Data collection consisted of physical measurements (e.g. physical function, physical activity) and self-report of nutritional intake (4-d food records), appetite, eating symptoms and medical conditions. Binary analyses were performed to compare participants with low and normal protein intake. Multiple logistic regression analyses were performed to investigate associations between low protein intake, dietary patterns and modifiable risk factors adjusted for age, sex, BMI categories and diseases. One hundred twenty-six were included in the study. Prevalence of low protein intake was 54 %. A greater day-to-day variation in protein intake was associated with low protein intake (adjusted OR 2·5; 95 % CI 1·14, 5·48). Participants with low protein intake had a higher prevalence of nausea, diarrhoea and mouth dryness. Reduced appetite, mouth dryness and pain increased odds of low protein intake (adjusted OR 3·06, 95 % CI 1·23, 7·63; OR 3·41, 95 % CI 1·51, 7·7; OR 1·54, 95 % CI 1·00, 2·36, respectively). There was a high prevalence of low protein intake in community-dwelling adults aged ≥ 80 years. Day-to-day variability, appetite, mouth dryness and pain may be potentially modifiable risk factors. Targeting dietary patterns and risk factors in primary prevention strategies may potentially improve intake of protein and minimise risk of physical frailty.

ß-Lactoglobulin Is Insulinotropic Compared with Casein and Whey Protein Ingestion during Catabolic Conditions in Men in a Double-Blinded Randomized Crossover Trial.

BACKGROUND: Muscle loss during acute infectious disease is mainly triggered by inflammation, immobilization, and malnutrition. OBJECTIVE: The objective was to compare muscle protein kinetics and metabolism following ingestion of the dairy protein supplements ß-lactoglobulin (BLG), casein (CAS), and whey (WHE) during controlled catabolic conditions. METHODS: We used a randomized crossover design (registered at clinicaltrials.gov as NCT03319550) to investigate 9 healthy male participants [age: 20-40 y; BMI (in kg/m2) 20-30] who were randomly assigned servings of BLG, CAS, or WHE (0.6 g protein/kg, one-third as bolus and two-thirds as sip every 20 min) on 3 separate occasions separated by ∼6-8 wk. The participants received an infusion of lipopolysaccharide (1 ng/kg) combined with 36 h of fasting and bed rest before each study day, mimicking a clinical catabolic condition. The forearm model and isotopic tracer techniques were used to quantify muscle protein kinetics. Muscle biopsy specimens were obtained and intramyocellular signaling investigated using Western blot. RESULTS: BLG, CAS, and WHE improved the net balance of phenylalanine (NBphe) from baseline with ∼75% (P < 0.001) with no difference between interventions (primary outcome, P < 0.05). No difference in rates of appearance and disappearance of phenylalanine or in intramyocellular signaling activation was found between interventions (secondary outcomes). The incremental AUC for serum insulin was 62% higher following BLG compared with CAS (P < 0.001) and 30% higher compared with WHE (P = 0.002), as well as 25% higher in WHE compared with CAS (P = 0.006). Following BLG consumption, plasma concentrations of glucose-dependent insulinotropic peptide (GIP) increased 70% compared with CAS (P = 0.001) and increased 34% compared with WHE (P = 0.06). No significant difference was found between WHE and CAS (P = 0.12). CONCLUSION: BLG, WHE, and CAS have similar effects on muscle in young male participants during catabolic conditions. BLG showed specific, possibly GIP-dependent, insulinotropic properties, which may have future clinical implications.

Evaluation and management of rectal bleeding in pregnancy.

Rectal bleeding occurs in about 40% of pregnant women, and is predominantly attributed to benign perianal pathology (haemorrhoids or anal fissures). More sinister causes of rectal bleeding may be heralded by key red flag clinical and biochemical features. These features should be evaluated in all women with rectal bleeding. Imaging investigations or flexible sigmoidoscopy may be warranted. The latter can be performed safely by experienced operators in pregnant women. Women with evidence of haemodynamic compromise, elevated inflammatory markers, significant anaemia, signs of intestinal obstruction or compromise to the fetus should be evaluated urgently. Providers must be mindful of the changes in normal ranges for common haematological and biochemical parameters in pregnancy compared with the non-pregnant state. Faecal calprotectin is an established tool for identification of intestinal inflammation and is valid in pregnancy. An elevated faecal calprotectin level (≥ 50 µg/g) signifies a need for further diagnostic evaluation. Inflammatory bowel disease may present initially, or with worsening disease activity, in pregnancy. Expedient diagnosis with the use of faecal calprotectin, sigmoidoscopy with or without intestinal ultrasound, exclusion of alternative or compounding infective aetiologies, and institution of appropriate therapy are critical. Medical therapies for management of inflammatory bowel disease can be safely instituted in pregnancy. Colorectal cancer incidence is increasing in younger age groups, but fortunately remains rare. When diagnosed in pregnancy, colorectal cancer can be successfully and safely managed with a collaborative multidisciplinary team approach. Early diagnosis is key to optimising outcomes.

Managing COVID-19 in patients with inflammatory bowel disease: navigating unprecedented challenges.

The COVID-19 pandemic has demanded a rapid adaptation in healthcare provision, including patients with inflammatory bowel disease (IBD). This viewpoint discusses some of the unique challenges in managing comorbid IBD and COVID-10 experienced by our team at The Royal Melbourne Hospital, which was at the epicentre of the COVID-19 'second-wave' surge in Melbourne.

Altered bowel habit and rectal bleeding in pregnancy: the importance of recognising undiagnosed inflammatory bowel disease.

Worsening of disease activity during pregnancy in patients with known inflammatory bowel disease, especially ulcerative colitis (UC), is well recognised, but the diagnosis of new-onset or previously undiagnosed UC in pregnancy has been inadequately studied to date. Recognition of gastrointestinal symptoms in pregnancy as potentially indicating UC is of paramount importance, as this allows appropriate investigation and instigation of therapies to optimise maternal and foetal outcomes. Here, we report three cases of women with gastrointestinal symptoms in pregnancy with disparate outcomes.

Histologic Healing Is More Strongly Associated with Clinical Outcomes in Ileal Crohn's Disease than Endoscopic Healing.

BACKGROUND & AIMS: Deep remission, based on clinical remission and evidence of healing during endoscopic evaluation, are goals of medical treatments for Crohn's disease (CD). We investigated whether histologic healing is associated with outcomes of patients with CD ileitis. METHODS: We performed a retrospective study of 101 patients with CD (52% male) isolated to the terminal ileum who had a colonoscopy between September 2005 and June 2015. Our analysis included patients in clinical remission at colonoscopy who had biopsies collected from colon and ileum. The ileum was evaluated for endoscopic healing (no ulceration) and histologic evidence of healing (no active inflammation, erosions, ulceration, or neutrophil infiltration). We compared times of clinical relapse-free survival, medication escalation, corticosteroid use, or hospitalization secondary to disease activity between patients with and without histological and endoscopic healing, followed for a median 21 months. We identified factors associated with survival using Kaplan Meier analysis and Cox proportional hazard model. RESULTS: At ileo-colonoscopy, 63% of patients had endoscopic healing and 55% had histologic evidence of healing. The level of agreement between endoscopic and histologic activity was fair (62%, K = 0.2250, P = .0064). Forty-two patients had clinical relapse, 45 had medication escalation, 30 required corticosteroids, and 17 were hospitalized (3 required surgery). On multivariate analysis, only histologic healing was associated with decreased risk of clinical relapse (hazard ratio [HR], 2.05; 95% CI, 1.07-3.94; P = .031), medication escalation (HR, 2.17; 95% CI, 1.2-3.96; P = .011), and corticosteroid use (HR, 2.44; 95% CI, 1.17-5.09; P = .018). No factors were associated with hospitalization. CONCLUSIONS: In patients with ileal CD in clinical remission, histologic healing but not endoscopic healing is associated with decreased risk of clinical relapse, medication escalation, or corticosteroid use.

Follow-Up of Patients With Ulcerative Colitis and Histological Normalization.

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.

Practical management of inflammatory bowel disease patients during the COVID-19 pandemic: expert commentary from the Gastroenterological Society of Australia Inflammatory Bowel Disease faculty.

The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has emerged as a public health emergency and challenged healthcare systems globally. In a minority of patients, SARS-CoV-2 manifests with a severe acute respiratory illness and currently there is insufficient data regarding the virulence of COVID-19 in inflammatory bowel disease patients taking immunosuppressive therapy. This review aims to summarise the current literature and provide guidance on the management of inflammatory bowel disease patients in the context of the COVID-19 pandemic in the Australasian setting.

Safety and Efficacy of Combination Treatment With Calcineurin Inhibitors and Vedolizumab in Patients With Refractory Inflammatory Bowel Disease.

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.

Protein supplementation combined with low-intensity resistance training in geriatric medical patients during and after hospitalisation: a randomised, double-blind, multicentre trial.

Sarcopenia (loss of muscle mass/strength) burdens many older adults - hospitalised older adults being particularly vulnerable. Treating the condition, protein supplementation (PrS) and resistance training (RT) may act synergistically. Therefore, this block-randomised, double-blind, multicentre intervention study, recruiting geriatric patients > 70 years from three medical departments, investigated the effect of PrS combined with RT during hospitalisation and 12 weeks after discharge. Participants were randomly allocated (1:1) to receive PrS (totally 27·5 g whey protein/d, about 2000 kJ/d) or isoenergetic placebo-products (< 1·5 g protein/d) divided into two servings per d to supplement the habitual diet. Both groups were engaged in a standardised, progressive low-intensity RT programme for the lower extremities (hospital: supervised daily/after discharge: self-training 4×/week). From April 2016 to September 2017, 2351 patients were screened, 462 were eligible, and 165 included. Fourteen were excluded and ten dropped out, leaving 141 participants in the intention-to-treat analysis. The average total protein intake during hospitalisation/after discharge was 1·0 (interquartile range (IQR) 0·8, 1·3)/1·1 (IQR 0·9, 1·3) g/kg per d (protein-group) and 0·6 (IQR 0·5, 0·8)/0·9 (IQR 0·6, 1·0) g/kg per d (placebo group). Both groups improved significantly for the primary and secondary endpoints of muscle mass/strength, functional measurements and quality of life, but no additional effect of PrS was seen for the primary endpoint (30-s chair stand test, repetitions, median changes from baseline: (standard test: 0 (IQR 0, 5) (protein group) v. 2 (IQR 0, 6) (placebo group) and modified test: 2 (IQR 0, 5) (protein group) v. 2 (IQR -1, 5) (placebo group)) or any secondary endpoints (Mann-Whitney U tests, P > 0·05). In conclusion, PrS increasing the total protein intake by 0·4 and 0·2 g/kg per d during hospitalisation and after discharge, respectively, does not seem to increase the adaptive response to low-intensity RT in geriatric medical patients.

Higher Thioguanine Nucleotide Metabolite Levels are Associated With Better Long-term Outcomes in Patients With Inflammatory Bowel Diseases.

GOALS: The aim of this study was to assess whether sustained 6-thioguaninenucleotide (6-TGN) levels were associated with improved long-term outcomes in patients with inflammatory bowel diseases (IBD). BACKGROUND: Cross-sectional data have shown that thiopurine metabolites are correlated with clinical efficacy in patient receiving thiopurines for IBD but the role for serial measurements through treatment course is unclear. STUDY: We conducted a retrospective cohort study including patients with IBD on thiopurine monotherapy and had serial 6-TGN levels measured. Predictive variables included demographics, disease phenotype, 6-TGN levels (nadir, median, and peak levels). The primary outcome was the development of a disease relapse. The secondary outcome was the need for IBD surgery. RESULTS: Two hundred eighteen 6-TGN samples from 87 patients were analyzed. Nadir and median 6-TGN levels were significantly higher in patients who did not relapse [185 and 233 pmol per 8×10 red blood cells (RBCs)] as compared with levels in patients who did relapse (150 and 167 pmol per 8×10 RBCs, P=0.025) but there was no significant difference in peak 6-TGN level. When adjusted for confounding factors, a nadir 6-TGN level ≥161 and a median 6-TGN level ≥264 were associated with a significant decrease in the rate of disease exacerbation (hazard ratio: 0.5; 95% confidence interval, 0.26-0.87; P=0.016 and hazard ratio: 0.4; 95% confidence interval, 0.2-0.82; P=0.14). CONCLUSIONS: Serial thiopurine metabolite level assessments and dose adjustment aiming to maintain higher 6-TGN levels may be helpful to improve long-term outcomes in patients with IBD.

Lipid droplet size and location in human skeletal muscle fibers are associated with insulin sensitivity.

In skeletal muscle, an accumulation of lipid droplets (LDs) in the subsarcolemmal space is associated with insulin resistance, but the underlying mechanism is not clear. We aimed to investigate how the size, number, and location of LDs are associated with insulin sensitivity and muscle fiber types and are regulated by aerobic training and treatment with an erythropoiesis-stimulating agent (ESA) in healthy young untrained men. LD analyses were performed by quantitative transmission electron microscopy, and insulin sensitivity was assessed by a hyperinsulinemic-euglycemic clamp. At baseline, we found that only the diameter (and not the number) of individual subsarcolemmal LDs was negatively associated with insulin sensitivity (R2 = 0.20, P = 0.03, n = 29). Despite 34% (P = 0.004) fewer LDs, the diameter of individual subsarcolemmal LDs was 20% (P = 0.0004) larger in type 2 fibers than in type 1 fibers. Furthermore, aerobic training decreased the size of subsarcolemmal LDs in the type 2 fibers, and ESA treatment lowered the number of both intermyofibrillar and subsarcolemmal LDs in the type 1 fibers. In conclusion, the size of individual subsarcolemmal LDs may be involved in the mechanism by which LDs are associated with insulin resistance in skeletal muscle.

Histologic Normalization Occurs in Ulcerative Colitis and Is Associated With Improved Clinical Outcomes.

BACKGROUND & AIMS: Mucosal healing, determined by histologic analysis, is a potential therapeutic target for patients with ulcerative colitis (UC). However, the histologic features of tissue normalization, as an outcome of treatment, have not been well described. We examined the prevalence and predictive values of normalization of the colonic mucosa, based on histologic analysis (histologic normalization) in patients with UC, and determined its association with risk of clinical relapse, compared with histologic disease quiescence and endoscopic mucosal healing. METHODS: We performed a retrospective study of 646 patients with confirmed UC who underwent colonoscopy at a tertiary medical center from August 2005 through October 2013. We reviewed reports from pathology analyses of random mucosal biopsies from each colon segment, and categorized them into 3 groups based on histology findings: (1) normalization (completely normal mucosa with no features of chronicity present), (2) quiescence (crypt atrophy or branching without signs of active inflammation including erosions, abscesses, or focal neutrophil infiltration), or (3) active disease (epithelial infiltration by neutrophils, crypt abscesses, erosions, or ulceration). Histology findings were compared with clinical and endoscopic findings. We assessed variables associated with histology findings and, in patients in clinical remission (Simple Clinical Colitis Activity Index score ≤2 and subscore of ≤1 for stool frequency or rectal bleeding), predictive values for clinical relapse at follow-up evaluations 6 months later or more were calculated. RESULTS: Of the 646 patients included in the study, 60% had endoscopic mucosal healing, 40% had histologic quiescence, and 10% had histologic normalization. The level of agreement between mucosal and histologic activity was moderate (agreement for 68% of samples; κ = 0.50; P < .001). On multivariate analysis, only proctitis associated with histologic normalization (P = .002). Of 310 patients in clinical remission at initial review, 25% had a clinical relapse, after a median time of 16 months (interquartile range, 10-23 months). Histologic normalization was independently associated with increased odds of relapse-free survival compared with histologic quiescence (hazard ratio, 4.31; 95% confidence interval, 1.48-12.46; P = .007) and histologic activity (hazard ratio, 6.69; 95% confidence interval, 2.16-20.62; P = .001); mucosal healing was not associated with increased odds of relapse-free survival compared with no mucosal healing (hazard ratio, 1.02; 95% confidence interval, 0.56-1.85; P = .954). CONCLUSIONS: Histologic normalization of colonic mucosa can be used as a clinical endpoint for patients with UC. We associated histologic normalization with increased odds of relapse-free survival compared with endoscopic healing or histologic quiescence. Further studies are needed to determine whether histologic normalization should be a goal of treatment for patients with UC.