Immunomodulators after the discontinuation of anti-tumor necrosis factor-alpha antibody treatment and relapse in ulcerative colitis: A multicenter cohort study.

BACKGROUND AND AIM: Strategies to reduce relapse using immunomodulators (IMs) after discontinuing anti-tumor necrosis factor-alpha (TNF-α) antibody treatment are controversial in patients with ulcerative colitis (UC). In this study, we assessed the association between IMs after discontinuing anti-TNF-α antibody treatment and relapse in patients with UC. METHODS: This retrospective, multicenter cohort study included 257 patients with UC in clinical remission. These patients discontinued anti-TNF-α antibody treatment between June 2010 and March 2019 and were followed up until March 2020. We evaluated the differences in relapse rates between patients with IMs (IM group) and those without IMs (non-IM group) after discontinuing the treatment. Relapse was defined as further undergoing an induction treatment or colectomy. Cox proportional hazards models adjusted for confounders were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for relapse. Exploratory analyses were performed to identify other factors that could predict relapse. RESULTS: During the median follow-up period of 22 months (interquartile range: 10-41), 114 relapses occurred: 42/100 (42.0%) in the IM group and 72/157 (45.9%) in the non-IM group. In the multivariable analysis, IMs were not associated with relapse (HR, 0.95 [95% CI, 0.64-1.41]). In the exploratory analyses, discontinuation due to side effects (HR, 1.83 [95% CI, 1.18-2.82]) and younger age (HR, 0.99 [95% CI, 0.98-1.00]) predicted relapse. CONCLUSION: Immunomodulators were not associated with relapse after discontinuing anti-TNF-α antibody treatment in patients with UC. Careful patient follow-up is needed when discontinuing due to side effects or when the patient is of a younger age at the time of discontinuation.

Fatigue wear test comparing vitamin-E-blended crosslinked polyethylene and conventional polyethylene in a Posterior Dynamic Stabilization System of the spine in the laboratory.

BACKGROUND: Although artificial joints using polyethylene have been developed for various joints, the development of Posterior Dynamic Stabilization system of the spine using polyethylene has proceeded at a much slower pace. There are no studies which compare the abrasion resistance of vitamin-E-blended crosslinked polyethylene (VE) and conventional polyethylene (Virgin) in the spinal region. The purpose of this study was to compare the wear resistance of VE and Virgin in a Posterior Dynamic Stabilization System of the spine. METHODS: Posterior Dynamic Stabilization System of the spine uses a polyethylene ball as a sliding surface. A fatigue wear test was repeated up to 1 million cycles at a speed of ±5°, 1 Hz while the rod was being pulled at a load of 50 N. Balls were compared using VE and Virgin in 6 samples each. Ti-6AL-4 V (Ti 64) and Co-Cr-Mo (CoCr) rods were used. Abrasion loss and shape change of the polyethylene balls were compared. RESULTS: When Ti 64 was used as the rod, the average wear amount was -0.01 mg (0.02 mg, 0.01 mg, -0.06 mg) for VE, and 0.23 mg (0.18 mg, 0.13 mg, 0.38 mg) for Virgin. When CoCr was used as the rod, the average wear amount was 0.42 mg (0.71 mg, -0.06 mg, 0.61 mg) for VE, and 0.73 mg (0.72 mg, 0.70 mg, 0.76 mg) for Virgin. Most polyethylene samples showed indentations of 0.1 m or less at the contact point with the set screw. In the combination of Virgin and CoCr, a white patch was observed on the inner side of the polyethylene samples, with a maximum depression of 0.1 mm. CONCLUSIONS: A fatigue wear test showed VE to be more efficient in abrasion resistance than Virgin in a Posterior Dynamic Stabilization System of the spine in the laboratory.

Extent of disease affects the usefulness of fecal biomarkers in ulcerative colitis.

BACKGROUND: Fecal biomarkers are considered to be useful surrogate markers for endoscopic activity. Given the mechanisms of fecal biomarkers, we hypothesized that the extent of ulcerative colitis (UC; pancolitis, left-sided colitis, and proctitis) could affect the usefulness of fecal biomarkers for assessing endoscopic and clinical disease activity; however, few studies have evaluated the utility of fecal biomarkers in the disease extent of UC. METHODS: Fecal calprotectin, a fecal immunochemical test for hemoglobin, and fecal lactoferrin were used as fecal biomarkers. UC patients, who underwent colonoscopy within 30 days of the fecal biomarker test, participated in this observational study. Clinical and endoscopic disease activity was assessed using the Lichtiger Index and Mayo endoscopic subscore (MES), respectively. RESULTS: A total of 162 colonoscopies were performed on 133 UC patients. A correlation analysis between each biomarker and the MES for each disease-extent subgroup showed a decreased correlation in the proctitis compared with the other groups. With the exception of proctitis, it was possible to distinguish between MES 0 and MES ≥ 1 with high area-under-the-curve values for fecal calprotectin and fecal lactoferrin. The fecal immunochemical test for hemoglobin was superior at discriminating MES 0 for proctitis. CONCLUSIONS: For the practical application of fecal biomarkers for UC patients, it is necessary to consider disease extent before use. In particular, patients with proctitis exhibit a low correlation between stool biomarkers and endoscopic findings. The usefulness of these biomarkers for endoscopic remission is reduced, except for the fecal immunochemical test for hemoglobin.

Differential effects of mesalazine formulations on thiopurine metabolism through thiopurine S-methyltransferase inhibition.

BACKGROUND AND AIM: Thiopurines are often used in combination with mesalazine for the treatment of ulcerative colitis (UC). Mesalazine formulations are delivered to the digestive tract by various delivery systems and absorbed as 5-aminosalicylic acid (5-ASA). 5-ASA is known to inhibit thiopurine S-methyltransferase (TPMT) activity and to affect thiopurine metabolism. There have been no studies comparing TPMT inhibition by multimatrix mesalazine (MMX) with other formulations. We investigated the difference in TPMT inhibition by different mesalazine formulations and prospectively confirmed the clinical relevance. METHODS: Plasma concentrations of 5-ASA, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA), and TPMT activities were measured in UC patients receiving various mesalazine formulations (time-dependent or pH-dependent mesalazine or MMX) as monotherapy. Patients already on both time-dependent or pH-dependent mesalazine and thiopurines switched their mesalazine to MMX, examining 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine (6-MMP) 0 and 8 weeks after switching. Clinical relapse after switching was also monitored for 24 weeks. RESULTS: Plasma 5-ASA and N-Ac-5-ASA levels were significantly higher in patients receiving time-dependent mesalazine (n = 12) compared with pH-dependent mesalazine (n = 12) and MMX (n = 15), accompanied by greater TPMT inhibition. Prospective switching from time-dependent mesalazine to MMX decreased 6-TGN levels, increased those of 6-MMP, and increased 6-MMP/6-TGN ratios. Furthermore, this resulted in significantly more relapses than switching from pH-dependent mesalazine to MMX. CONCLUSIONS: Time-dependent mesalazine has higher plasma 5-ASA and N-Ac-5-ASA levels and greater TPMT inhibition than MMX. Therefore, switching from time-dependent mesalazine to MMX may lead to an increase of 6-MMP/6-TGN, which may reduce the clinical effectiveness of thiopurines, warranting close monitoring after switch.

Determining the usefulness of Capsule Scoring of Ulcerative Colitis in predicting relapse of inactive ulcerative colitis.

BACKGROUND AND AIM: The usefulness of second-generation colon capsule endoscopy (CCE2) in ulcerative colitis (UC), especially in clinically inactive patients, has been reported. Capsule Scoring of Ulcerative Colitis (CSUC) was developed as a severity index for UC. We aimed to determine whether CSUC is useful for predicting relapse during clinical remission. METHODS: Forty-one UC patients in clinical remission who underwent CCE2 were prospectively registered from April 2016 to August 2019. Patients' CSUC score was obtained; those with subsequent relapse were followed up retrospectively. The correlation of CSUC with white blood cell count, platelet count, albumin, C-reactive protein, fecal calprotectin and fecal lactoferrin levels, and fecal immunochemical test results was evaluated; their predictive values for future relapse were compared. RESULTS: The correlations of CSUC with white blood cell, platelet, albumin, C-reactive protein, fecal calprotectin, fecal immunochemical test, and fecal lactoferrin values were rs  = 0.13, 0.27, -0.25, 0.15, 0.50, 0.43, and 0.50, respectively. CSUC was higher in 12 patients who relapsed within 1 year than in 29 patients who remained in clinical remission (2.83 ± 1.95 vs 0.72 ± 1.00, P < 0.01). Receiver operator characteristic curve analysis showed that CSUC ≥ 1 was a predictor of relapse (area under the curve of 0.82, sensitivity of 83.3%, specificity of 58.6%) and maybe superior to fecal biomarkers. In the univariate analysis, patients with CSUC of 0 had a lower relapse rate than those with CSUC of ≧ 1 (P = 0.03, log-rank test). After analyzing patients who underwent CCE2 within 6 months after the successful induction treatment, results showed that those with CSUC of ≤ 1 remained in clinical remission for a year. CONCLUSION: CSUC predicts relapse within 1 year in UC patients in clinical remission, especially when used 6 months after induction treatment.

Linked color imaging versus white light imaging colonoscopy for colorectal adenoma detection: A randomized controlled trial.

BACKGROUND AND AIM: The adenoma detection rate is an important indicator of colonoscopy quality and colorectal cancer incidence. We compared the adenoma detection rates between white light imaging (WLI) and linked color imaging (LCI) colonoscopy. METHODS: Patients undergoing colonoscopy for positive fecal immunochemical tests, follow-up of colon polyps, and abdominal symptoms at three institutions were randomly assigned to the LCI or WLI groups. Mean adenoma number per patient (including based on endoscopists' experience), adenoma detection rate, cecal intubation time, withdrawal time, mean adenoma number per location, and adenoma size were compared. RESULTS: The LCI and WLI groups comprised 494 and 501 patients, respectively. No significant differences in the cecal intubation rate (LCI vs WLI: 99.5% vs 99.4%), cecal intubation time, and withdrawal time were noted between groups. The mean adenoma number per patient was significantly higher in the LCI group than in the WLI group (1.07 vs 0.88, P = 0.04), particularly in the descending [0.12 (58/494) vs 0.07 (35/501), P = 0.01] and sigmoid colon [0.41 (201/494) vs 0.30 (149/501), P ≤ 0.001]. However, the adenoma detection rate was 47.1% in the LCI group and 46.9% in the WLI group, with no significant difference (P = 0.93). The total number of sessile-type adenomas was significantly higher in the LCI group than in the WLI group (346/494 vs 278/501, P = 0.04). As for polyp size, small polyps (≤ 5 mm) were detected at a significantly higher rate in the LCI group (271/494 vs 336/501, P = 0.04). CONCLUSION: Linked color imaging is significantly superior to WLI in terms of mean adenoma number per patient.

MEFV Gene-Related Enterocolitis Account for Some Cases Diagnosed as Inflammatory Bowel Disease Unclassified.

BACKGROUND AND AIMS: Familial mediterranean fever (FMF), an autoinflammatory disease, is characterized by periodic fever and serositis. An MEFV gene mutation has been identified as the cause of FMF. Recently, patients with MEFV gene mutations and chronic gastrointestinal mucosal inflammation mimicking inflammatory bowel disease (IBD) have been reported. In this retrospective study, we analyzed the clinical characteristics of patients with IBD unclassified (IBDU) with MEFV gene mutations. METHODS: MEFV gene analysis was performed on 8 patients with IBDU among 710 patients with IBD who had been treated at Kyorin University Hospital from April 2016 to December 2018. Clinical manifestations, endoscopic findings, and serological markers were also analyzed. RESULTS: The average of the 8 patients with IBDU (3 men, 5 women) was 32.7 ± 6.4 years (range 26-76 years). Their symptoms comprised diarrhea (n = 8, 100%), hematochezia (n = 3, 37.5%), abdominal pain (n = 3, 37.5%), high fever (n = 2, 16.5%), and other periodic symptoms (n = 2, 16.5%). MEFV gene mutation was confirmed in 4/8 of these patients. Colonoscopy showed various mucosal lesions, rectal sparing, right side dominant colitis, pseudopolyposis, and granular protrusions. Colchicine was administered to 5 of the 8 patients (4 with and 1 without MEFV mutation) who were resistant to conventional treatment for ulcerative colitis. Clinical and endoscopic improvement was observed in all of 5 patients treated with colchicine. CONCLUSIONS: Some patients diagnosed as having IBDU have enterocolitis related to MEFV gene mutation and respond to colchicine therapy.

[Pulmonary tuberculosis following anti-tumor necrosis factor-α therapy in Crohn's disease:a case report].

Anti-tumor necrosis factor-α (TNF-α) is a principal treatment for Crohn's disease (CD). However, it increases the susceptibility to tuberculosis (TB) infection, and therefore, screening examination prior to treatment initiation is crucial. Here, we report the case of a patient with CD who developed pulmonary TB following anti-TNF-α therapy, despite negative screening. A 19-year-old female who had no history of TB or had traveled to TB-endemic regions was diagnosed with CD. After negative TB screening with chest X-ray and interferon-gamma release assay, the patient was initiated on oral prednisolone and pH-dependent mesalazine. The treatment was changed to infliximab (IFX) because of the inadequate response observed to prednisolone;however, she developed pulmonary TB only 10 weeks after the initiation of IFX. The standard short-course anti-TB regimen was initiated to treat pulmonary TB, whereas IFX was discontinued and replaced with budesonide. Our case suggests that the risk of developing TB should not be excluded, despite the initial negative TB screening, particularly when a patient develops respiratory symptoms during anti-TNF-α therapy.

White Blood Cell Counts and Future Relapse in Ulcerative Colitis under Low-Dose Thiopurine Treatment in Real-World Practice: A 3-Year Japanese Multi-Center Retrospective Cohort Study.

Introduction: Whether white blood cell (WBC) counts are predictors for the effectiveness of thiopurine treatment in ulcerative colitis (UC) has been inconclusive in previous studies with small sample sizes. We investigated the association between WBC counts and future relapses in UC patients in a large-scale multi-center study. Methods: This retrospective cohort study enrolled a total of 723 UC patients in remission from 33 hospitals and followed up for 3 years. Relapse was defined as a need for treatment intensification. The risk of relapse was compared among patients with the baseline WBC counts <3,000/µL (N = 31), 3,000-4,000/µL (N = 167), 4,000-5,000/µL (N = 241), and ≥5,000/µL (N = 284) using a Cox regression model analysis. Moreover, exploratory analyses were conducted to identify other factors predicting relapse. Results: During a median follow-up period of 1,095 (interquartile range, 1,032-1,119) days, relapse occurred in 17.2% (125/723). In a crude analysis, WBC counts were not associated with relapse; hazard ratios (HRs) (95% confidence interval [CI]) were 1.50 (0.74-3.06), 1.02 (0.66-1.59), and 0.67 (0.43-1.05) in WBC <3,000/µL, 3,000-4,000/µL, and 4,000-5,000/µL groups, respectively (WBC ≥5,000/µL group, as reference). Multivariable-adjusted analyses showed similar results; HRs (95% CI) were 1.21 (0.59-2.49), 1.08 (0.69-1.69), and 0.69 (0.44-1.07), in <3,000/µL, 3,000-4,000/µL, and 4,000-5,000/µL groups, respectively. In the exploratory analyses, thiopurine use <1 year and a mean corpuscular volume <90 fL were predictors for relapse. Discussion/Conclusion: WBC counts were not predictors for future relapses in patients with UC treated with thiopurine as a maintenance therapy.

Endoscopic Treatment of Colo-Colonic Intussusception in a Patient with Peutz-Jeghers Syndrome.

A 19-year-old man with a history of Peutz-Jeghers syndrome (PJS) and two previous partial small bowel resections because of intussusception presented with lower abdominal pain. Computed tomography (CT) showed concentric multilayer and cord-like structures in the transverse colon. Colo-colonic intussusception was suspected and he was hospitalized. After two therapeutic enemas were unsuccessful, a colonoscopy was performed. The intussusception was reduced and a 40-mm transverse colon polyp with a thick stalk was resected. After the procedure, his abdominal pain was relieved and he was discharged on the sixth hospital day. This case and several previous reports suggest that PJS polyps with tumor diameter exceeding 30 mm and location in the transverse or sigmoid colon can cause intussusception. Endoscopic treatment should be considered for these lesions.

Ulcerative colitis complicated with linear immunoglobulin A bullous dermatosis.

Linear immunoglobulin A (IgA) bullous dermatosis (LABD) is a rare disorder involving subepidermal blistering characterised by IgA deposition along the basement membrane. The clinical features of LABD are variable but can include bullae, vesicles and erythematous lesions. Histopathology reveals formation of subepidermal bullae and linearly deposition of IgA in the basement membrane of the epidermis. LABD has been reported as a rare complication of ulcerative colitis (UC). We report the case of a young woman with UC complicated by LABD. The latter manifested as vesicles with erythema on almost the entire body. A biopsy of the skin lesions revealed linear IgA deposits in the basement membrane according to a direct immunofluorescence assay. Prednisolone administration resulted in clinical remission of UC but poor improvement of skin lesions. Oral administration of diaminodiphenyl sulfone led to improvement of blisters. Thereafter, abdominal and skin symptoms did not recur and she was discharged from hospital.

Ratio of submucosal thickness to total bowel wall thickness as a new sonographic parameter to estimate endoscopic remission of ulcerative colitis.

BACKGROUND: The development of feasible, reliable parameters and criteria for intestinal ultrasound (IUS) to estimate endoscopic remission of ulcerative colitis (UC) is a crucial clinical challenge. Such parameters must be simple, objective, and reproducible so that IUS can be widely used in daily practice. We developed a new parameter called the submucosa index (SMI), defined as a percentage of the submucosal thickness (SMT) in the total bowel wall thickness (BWT), and investigated its clinical potential. METHODS: The inclusion criteria were performance of both IUS and endoscopy (sigmoidoscopy or colonoscopy) for UC and a ≤ 15-day time interval between IUS and endoscopy. Loss of stratification was defined as inability to identify the submucosa even with a BWT of > 3 mm. The vascularity of the colon was assessed by the modified Limberg score (mLS) and evaluated as bowel wall flow (BWF) ( -) or ( +) using color Doppler mode. A Mayo endoscopic subscore (MES) of 0 or 1 was defined as endoscopic remission. RESULTS: Seventy-four colonic segments were analyzed. The SMI, mLS, and BWF could distinguish an MES of 1 versus 2 (p < 0.05, p < 0.01, and adjusted p < 0.001, respectively). The criteria using the BWT and SMI and using the BWT and BWF had the same estimating ability for endoscopic remission (sensitivity, 70.0%; specificity, 97.7%; positive predictive value, 95.5%; and negative predictive value, 82.7%). CONCLUSION: The SMI is a practical, quantitative parameter based on the bowel wall structure and may be used to estimate endoscopic remission of UC.

Molecular and Mechanistic Characterization of PddB, the First PLP-Independent 2,4-Diaminobutyric Acid Racemase Discovered in an Actinobacterial D-Amino Acid Homopolymer Biosynthesis.

We recently disclosed that the biosynthesis of antiviral γ-poly-D-2,4-diaminobutyric acid (poly-D-Dab) in Streptoalloteichus hindustanus involves an unprecedented cofactor independent stereoinversion of Dab catalyzed by PddB, which shows weak homology to diaminopimelate epimerase (DapF). Enzymological properties and mechanistic details of this enzyme, however, had remained to be elucidated. Here, through a series of biochemical characterizations, structural modeling, and site-directed mutageneses, we fully illustrate the first Dab-specific PLP-independent racemase PddB and further provide an insight into its evolution. The activity of the recombinant PddB was shown to be optimal around pH 8.5, and its other fundamental properties resembled those of typical PLP-independent racemases/epimerases. The enzyme catalyzed Dab specific stereoinversion with a calculated equilibrium constant of nearly unity, demonstrating that the reaction catalyzed by PddB is indeed racemization. Its activity was inhibited upon incubation with sulfhydryl reagents, and the site-directed substitution of two putative catalytic Cys residues led to the abolishment of the activity. These observations provided critical evidence that PddB employs the thiolate-thiol pair to catalyze interconversion of Dab isomers. Despite the low levels of sequence similarity, a phylogenetic analysis of PddB indicated its particular relevance to DapF among PLP-independent racemases/epimerases. Secondary structure prediction and 3D structural modeling of PddB revealed its remarkable conformational analogy to DapF, which in turn allowed us to predict amino acid residues potentially responsible for the discrimination of structural difference between diaminopimelate and its specific substrate, Dab. Further, PddB homologs which seemed to be narrowly distributed only in actinobacterial kingdom were constantly encoded adjacent to the putative poly-D-Dab synthetase gene. These observations strongly suggested that PddB could have evolved from the primary metabolic DapF in order to organize the biosynthesis pathway for the particular secondary metabolite, poly-D-Dab. The present study is on the first molecular characterization of PLP-independent Dab racemase and provides insights that could contribute to further discovery of unprecedented PLP-independent racemases.

Clinical response of vedolizumab at week 6 predicted endoscopic remission at week 24 in ulcerative colitis.

BACKGROUND AND AIM: Vedolizumab is a humanized monoclonal antibody that selectively inhibits the migration of gut-homing memory T cells into the intestinal submucosa by antagonizing the interaction of α4ß7 integrin with MAdCAM-1. Vedolizumab is employed for ulcerative colitis with moderate to severe activity; however, predictors of its clinical efficacy have not been established in real-world clinical practice. We investigated the clinical characteristics predicting vedolizumab efficacy. METHODS: This was a single-center, retrospective, observational study that enrolled patients with ulcerative colitis at Kyorin University Hospital. Fifty-two consecutive patients who started vedolizumab induction therapy and were tracked for minimum 14 weeks between August 2018 and February 2021 were included. Clinical and endoscopic disease activities were scored at baseline and at weeks 2, 6, and 14 with the Lichtiger index and at baseline and week 24 with the Mayo endoscopic subscore, respectively. Clinical remission, clinical response, and endoscopic remission were defined as Lichtiger index of ≤3, Lichtiger index of ≤10 with a reduction of minimum 3 points from baseline, and Mayo endoscopic subscore of ≤1, respectively. RESULTS: In these cases, clinical response/remission rates at weeks 2, 6, and 14 were 26.9%/15.3%, 50.0%/46.3%, and 57.6%/50.0%, respectively. The endoscopic remission rate at week 24 was 60%. The clinical response at week 6 was significantly associated with endoscopic remission at week 24 after starting vedolizumab. CONCLUSIONS: In vedolizumab treatment for ulcerative colitis, the clinical response at week 6 can be a predictor for endoscopic remission at week 24.

Increased DNA-incorporated thiopurine metabolite as a possible mechanism for leukocytopenia through cell apoptosis in inflammatory bowel disease patients with NUDT15 mutation.

BACKGROUND AND AIMS: Polymorphisms in the nucleotide diphosphate-linked moiety X-type motif 15 (NUDT15) gene are associated with thiopurine-induced leukopenia in patients with inflammatory bowel disease (IBD). NUDT15-associated subcellular thiopurine metabolism has not been investigated in primary lymphocytes. We hypothesized that NUDT15 mutation increases DNA-incorporated deoxythioguanosine (dTG) and induces apoptosis in lymphocytes. METHODS: DNA-incorporated dTG in peripheral blood mononuclear cells (PBMCs) and 6-thioguanine nucleotides (6-TGN) in red blood cells were measured in patients with IBD undergoing thiopurine treatment. The association of a single nucleotide polymorphism for NUDT15 (rs116855232) with dTGPBMC was examined. The pro-apoptotic effect of DNA-incorporated dTG was examined ex vivo in association with NUDT15 genotypes by co-culturing patient-derived peripheral CD4+ T lymphocytes with 6-thioguanine (6-TG). RESULTS: dTGPBMC was significantly higher in NUDT15 variants than in non-variants. dTGPBMC, but not 6-TGNRBC, negatively correlated with peripheral lymphocyte counts (r = - 0.31 and - 0.12, p = 0.012 and 0.173, respectively). DNA-incorporated dTG significantly accumulated to a greater extent in lymphocytes from NUDT15 variants when co-cultured with 6-TG ex vivo than in those from non-variants and was associated with decreased proliferation and increased apoptosis. CONCLUSION: Increased DNA-incorporated dTG may be responsible for thiopurine-induced leukocytopenia through cell apoptosis in IBD patients with NUDT15 mutation.

Two cases in which tofacitinib effectively treated both ulcerative colitis and alopecia areata.

A 40-year-old woman (case 1) visited the hospital complaining of diarrhea and was diagnosed with ulcerative colitis (UC). She was administered 5-aminosalicylic acid (5-ASA), but developed intolerance. Prednisolone (PSL) was administered, and her symptoms improved. However, alopecia areata developed as the PSL was tapered, and her UC relapsed. Adalimumab, Infliximab (IFX), and golimumab were used, but all showed insufficient efficacy. Therefore, we started tofacitinib (TOF). Her bloody stools and diarrhea improved 3 days after TOF administration, and clinical remission occurred on day 14. Her alopecia areata improved 14 days after starting TOF and improved completely during TOF maintenance therapy. A 19-year-old man (case 2) had developed alopecia areata at 10 years old and was diagnosed with UC at 17 years old. He achieved sustained remission with IFX, but then stopped IFX to receive a live vaccination. His UC relapsed 4 months later, immediately after the live vaccine was administered. Vedolizumab was administered, but was ineffective, as was re-administration of IFX. TOF was administered, and his clinical symptoms improved 7 days later. He achieved clinical remission on day 20. In addition, his hair began to regrow 14 days after starting TOF.

A nationwide, multi-center, retrospective study of symptomatic small bowel stricture in patients with Crohn's disease.

BACKGROUND: Small bowel stricture is one of the most common complications in patients with Crohn's disease (CD). Endoscopic balloon dilatation (EBD) is a minimally invasive treatment intended to avoid surgery; however, whether EBD prevents subsequent surgery remains unclear. We aimed to reveal the factors contributing to surgery in patients with small bowel stricture and the factors associated with subsequent surgery after initial EBD. METHODS: Data were retrospectively collected from surgically untreated CD patients who developed symptomatic small bowel stricture after 2008 when the use of balloon-assisted enteroscopy and maintenance therapy with anti-tumor necrosis factor (TNF) became available. RESULTS: A total of 305 cases from 32 tertiary referral centers were enrolled. Cumulative surgery-free survival was 74.0% at 1 year, 54.4% at 5 years, and 44.3% at 10 years. The factors associated with avoiding surgery were non-stricturing, non-penetrating disease at onset, mild severity of symptoms, successful EBD, stricture length < 2 cm, and immunomodulator or anti-TNF added after onset of obstructive symptoms. In 95 cases with successful initial EBD, longer EBD interval was associated with lower risk of surgery. Receiver operating characteristic analysis revealed that an EBD interval of ≤ 446 days predicted subsequent surgery, and the proportion of smokers was significantly high in patients who required frequent dilatation. CONCLUSIONS: In CD patients with symptomatic small bowel stricture, addition of immunomodulator or anti-TNF and smoking cessation may improve the outcome of symptomatic small bowel stricture, by avoiding frequent EBD and subsequent surgery after initial EBD.

Unsupervised Phoneme and Word Discovery From Multiple Speakers Using Double Articulation Analyzer and Neural Network With Parametric Bias.

This paper describes a new unsupervised machine-learning method for simultaneous phoneme and word discovery from multiple speakers. Phoneme and word discovery from multiple speakers is a more challenging problem than that from one speaker, because the speech signals from different speakers exhibit different acoustic features. The existing method, a nonparametric Bayesian double articulation analyzer (NPB-DAA) with deep sparse autoencoder (DSAE) only performed phoneme and word discovery from a single speaker. Extending NPB-DAA with DSAE to a multi-speaker scenario is, therefore, the research problem of this paper.This paper proposes the employment of a DSAE with parametric bias in the hidden layer (DSAE-PBHL) as a feature extractor for unsupervised phoneme and word discovery. DSAE-PBHL is designed to subtract speaker-dependent acoustic features and speaker-independent features by introducing parametric bias input to the DSAE hidden layer. An experiment demonstrated that DSAE-PBHL could subtract distributed representations of acoustic signals, enabling extraction based on the types of phonemes rather than the speakers. Another experiment demonstrated that a combination of NPB-DAA and DSAE-PBHL outperformed other available methods accomplishing phoneme and word discovery tasks involving speech signals with Japanese vowel sequences from multiple speakers.