Effectiveness and Persistency of Ustekinumab Treatment for Ulcerative Colitis: A Phoenix retrospective Cohort Study.

Background: Real-world data regarding ustekinumab (UST) for ulcerative colitis (UC) particularly in biologics-naïve patients is currently limited. This study aimed to elucidate the real-world effectiveness and safety of UST for UC. Methods: Overall, 150 patients with UC treated with UST from March 2020 to January 2023 were enrolled across 7 referral hospitals. To assess the clinical efficacy and persistence of UST, retrospective analyses were conducted from weeks 8 to 56. Predictive factors concerning the response and persistence of UST were examined through univariate and multivariate analyses. Results: Of the 150 patients, 125 received UST for remission induction, including 36% biologics-naïve. The response and remission rates were 72.8% and 56.0% at week 8 and 73.2% and 63.4% at week 56, respectively. Biologics-naïve patients represented higher response and remission rates at week 8 (84.4% and 73.3%) than those with biologics exposure (66.2% and 46.2%). Patients with prior antitumor necrosis factor (anti-TNF) and vedolizumab (VDZ) exposure had relatively lower response and remission rates (34.5% and 24.1%, respectively). The 1-year cumulative persistence rate was 84.0%. Multivariate analysis revealed that the chronic continuous type and prior anti-TNF and VDZ exposure were negative predictive factors for week 8 responsiveness. Clinical response at week 8 was a predictor of 1-year persistence. Adverse event incidence remained notably low at 6.4%. Conclusions: This study highlights the safety and effectiveness of UST as an induction and maintenance therapy for UC. Chronic continuous type and previous anti-TNF and VDZ exposure negatively contributed to short-term effectiveness, whereas short-term effectiveness provided good persistency.

Effectiveness of transabdominal ultrasonography in predicting clinical relapse of Crohn's disease.

BACKGROUND/AIMS: Transabdominal ultrasonography (US) helps evaluate Crohn's disease (CD) activity. We investigated whether the US could predict subsequent adverse outcomes for patients with CD in clinical remission. METHODS: This single-center retrospective study included patients with CD in clinical remission who underwent US between April 2011 and April 2021, focusing on the predictability of subsequent adverse outcomes within 5 years. We used the US-CD, which was calculated using multiple US findings. Predictive variables were assessed using Cox proportional hazards regression analysis, and the predictive value was evaluated using receiver operating characteristic curves. RESULTS: Seventy-three patients were included. During a median follow-up of 1,441 days (range, 41-1,825 days), 16.4% (12/73) experienced clinical relapse, 9.6% (7/73) required endoscopic balloon dilation (EBD), 58.9% (43/73) required enhanced treatment, and 20.5% (15/73) underwent surgery. In the multivariate analysis, US-CD was significantly associated with clinical relapse (P= 0.038) and the need for enhanced treatment (P= 0.005). The area under the receiver operating characteristic curve for predicting clinical relapse and the need for EBD was 0.77 and 0.81, respectively, with US-CD (cutoff value = 11), and that for requiring enhanced treatment was 0.74 with US-CD (cutoff value = 6). Patients with US-CD ≥ 11 demonstrated a significantly higher occurrence of clinical relapse (P= 0.001) and EBD (P= 0.002) within 5 years. Patients with US-CD ≥ 6 experienced a significantly higher likelihood of requiring enhanced treatment (P< 0.001) within 5 years. CONCLUSIONS: High US-CD is associated with subsequent adverse outcomes in patients with CD.

Characteristics and usefulness of transabdominal ultrasonography in immune-mediated colitis.

BACKGROUND/AIMS: The usefulness of ultrasonography (US) in diseases of the gastrointestinal tract has been reported recently. This prospective study aimed to determine the features of US findings in immune-mediated colitis (IMC), an adverse event induced by immune checkpoint inhibitor, and examine the correlation between US findings, colonoscopy (CS) findings, and severity of colitis. METHODS: We studied patients examined using CS and US upon suspicion of IMC in Hokkaido University Hospital between April 2018 and February 2021. Endoscopic findings of IMC were assessed using the Ulcerative Colitis Endoscopic Index of Severity (UCEIS). The severity of US findings in IMC was evaluated using US grade, which is the ultrasonographic grading scale in ulcerative colitis. Bowel wall thickness and the intensity of the color Doppler signal were also analyzed. Severity of colitis was evaluated using Common Terminology Criteria for Adverse Events (CTCAE) grade version 5. RESULTS: Fourteen patients with IMC were enrolled. The US findings were bowel wall thickening, loss of stratification, ulceration and increased blood flow signal. The US grade was moderately correlated with the UCEIS (r=0.687, p=0.009) and CTCAE grade (r=0.628, p=0.035). Bowel wall thickness and UCEIS (r=0.628, p=0.020), as well as color Doppler signal grade and CTCAE grade (r=0.724, p=0.008), were significantly correlated. CONCLUSIONS: US findings in IMC were mainly similar to those of ulcerative colitis, but there were some findings that were characteristic only of IMC. Significant correlation was found between US findings, CS findings, and severity of colitis. Hence, US could be useful for the evaluation of IMC.

Endoscopic balloon dilations for strictures of rectum, ileocecal valve and duodenum in a patient with X-linked inhibitor of apoptosis deficiency: a case report.

X-linked inhibitor of apoptosis (XIAP) deficiency is a rare primary immunodeficiency and gastrointestinal (GI) lesions in XIAP deficiency are similar to Crohn's disease. For patients with Crohn's disease, endoscopic balloon dilation (EBD) is known to be a standard procedure for intestinal strictures including upper GI tract. However, there are no articles which mention the efficacy of EBDs for the strictures in upper GI tract in patients with XIAP deficiency. Herein, we describe an 18-year-old male with XIAP deficiency in whom EBDs for the rectum, ileocecal valve (ICV), and duodenum were performed. Before hematopoietic stem cell transplantation (HSCT), GI endoscopy revealed strictures of the rectum, ICV and duodenum with active ulcers. Although these ulcers healed after HSCT, the strictures progressed. Therefore, we performed EBDs for the strictures of the rectum, ICV, and duodenum. In contrast studies, we did not find any other strictures in the small intestine. Throughout the patient's clinical course, no complications of EBD occurred. He started eating after EBDs, but abdominal symptoms did not relapse without any dietary restrictions. Our case suggests that EBD could be an effective and safe procedure for intestinal strictures including upper GI tract after HSCT in patients with XIAP deficiency.

Effectiveness of administering zinc acetate hydrate to patients with inflammatory bowel disease and zinc deficiency: a retrospective observational two-center study.

BACKGROUND/AIMS: Inflammatory bowel disease (IBD) patients frequently have zinc deficiency. IBD patients with zinc deficiency have higher risks of IBD-related hospitalization, complications, and requiring surgery. This study aimed to examine the effectiveness of zinc acetate hydrate (ZAH; Nobelzin) in IBD patients with zinc deficiency. METHODS: IBD patients with zinc deficiency who received ZAH from March 2017 to April 2020 were registered in this 2-center, retrospective, observational study. Changes in serum zinc levels and disease activity (Crohn's Disease Activity Index [CDAI]) before and after ZAH administration were analyzed. RESULTS: Fifty-one patients with Crohn's disease (CD, n = 40) or ulcerative colitis (UC, n = 11) were registered. Median serum zinc level and median CDAI scores significantly improved (55.5-91.0 µg/dL, P< 0.001; 171.5-129, P< 0.001, respectively) in CD patients 4 weeks after starting ZAH administration. Similarly, median serum zinc levels and CDAI scores significantly improved (57.0-81.0 µg/dL, P< 0.001; 177-148, P= 0.012, respectively) 20 weeks after starting ZAH administration. Similar investigations were conducted in groups where no treatment change, other than ZAH administration, was implemented; significant improvements were observed in both serum zinc level and CDAI scores. Median serum zinc levels in UC patients 4 weeks after starting ZAH administration significantly improved from 63.0 to 94.0 µg/dL (P= 0.002), but no significant changes in disease activity were observed. One patient experienced side effects of abdominal discomfort and nausea. CONCLUSIONS: ZAH administration is effective in improving zinc deficiency and may contribute to improving disease activity in IBD.

Ursodeoxycholic Acid Triggers Primary Enterolith Growth in a Crohn's Disease Patient with Jejunal Stenosis.

Primary enteroliths associated with Crohn's disease have been considered to be rare and are most likely caused by severe ileal stenosis. Herein, we report the case of a primary enterolith possibly caused by mild jejunal stenosis in a Crohn's disease patient who received oral administration of ursodeoxycholic acid (UDCA). A 62-year-old woman with a 6-year history of Crohn's disease, currently in clinical remission, was on UDCA prescription for liver dysfunction. Magnetic resonance imaging and double-balloon endoscopy, which were performed to examine epigastric pain, revealed mild jejunal stenosis and an enterolith on the oral side. Since it was difficult to remove or crush the enterolith endoscopically, we decided to remove it surgically with the stenotic jejunum. Component analysis revealed that more than 98% of the enterolith was composed of UDCA; subsequently, oral administration of UDCA was discontinued. This case demonstrated that primary enterolith might develop in Crohn's disease patients with mild intestinal stenosis, and oral administration of UDCA can trigger an enterolith in such patients. Therefore, routine follow-up imaging is necessary for early detection. Oral UDCA should be administered with caution for Crohn's disease patients with stenosis of the proximal small intestine.

Freshwater alga Raphidocelis subcapitata undergoes metabolomic changes in response to electrostatic adhesion by micrometer-sized nylon 6 particles.

Nylon powders are a type of microplastic (MP) used in personal care products such as cosmetics and sunscreens. To determine the effects of nylon polymers on freshwater microalgae, we investigated the effects of two types of micrometer-sized nylon polymers, i.e., powdered nylon 6 (Ny6-P) and nylon 12 (Ny12), and four other micrometer-sized MPs, i.e., low-density polyethylene, polyethylene terephthalate, polystyrene, and ultra-high-molecular-weight polyethylene, on the microalga Raphidocelis subcapitata. The results showed that Ny6-P inhibited R. subcapitata growth more than the other MPs; R. subcapitata growth was inhibited by 54.2% with 6.25 mg/L Ny6-P compared with the control. Ny6-P in the culture media adhered to R. subcapitata cells electrostatically, which may have disrupted growth and photosynthetic activity. Metabolomic analysis revealed that many metabolites related to the amino acid catabolic pathway and γ-glutamyl cycle were induced, which might trigger responses to avoid starvation and oxidative stress. Our study provides important information on the effects of Ny6-P on algae in freshwater environments.

Crohn's Disease Activity Evaluation by Transabdominal Ultrasonography: Correlation with Double-Balloon Endoscopy.

OBJECTIVES: Transabdominal ultrasonography (US) has been reported as a useful tool for evaluating Crohn's disease (CD) activity. Endoscopic findings and Crohn's disease activity index (CDAI) are currently considered the gold standard for assessing CD activity. We assessed the correlation between US and double-balloon endoscopy (DBE), and CDAI for evaluating CD activity. METHODS: We analyzed patients with CD undergoing US and DBE within 10 days between the procedures. The intestine was divided into four segments and analyzed by the US scoring system (US-CD) and the simple endoscopic score for Crohn's disease (SES-CD). CDAI was compared with US-CD and SES-CD. Spearman's rank correlation coefficient was used for statistical analysis. RESULTS: Twenty-five patients with CD (11 women, 14 men; mean age 35.4 ± 14.9 years, range 16-65 years) were enrolled. Twenty-four patients received antitumor necrosis factor inhibitor therapy. CDAI was 128.1 (range 36-227). A significant moderate correlation was found between the US-CD and SES-CD in all segments (ρ = .64, P < .01). The US-CD showed a strong correlation with CDAI (ρ = .78, P < .01), whereas the SES-CD showed a moderate correlation (ρ = .55, P < .05). CONCLUSIONS: US-CD and SES-CD showed a moderate correlation for assessing CD activity. US-CD showed a stronger correlation with CDAI than SES-CD, suggesting that US could more accurately evaluate the disease activity.

A case of immune checkpoint inhibitor-associated gastroenteritis detected by ultrasonography.

While immune checkpoint inhibitors (ICIs) have antitumor effects, they also have characteristic side effects, including colitis. However, gastritis has rarely been reported. We report a case of a patient with lung adenocarcinoma who presented with epigastric pain and diarrhea following pembrolizumab administration. Sonography of the abdomen demonstrated diffuse, although mild, gastric wall thickening (mainly in the submucosa), as well as a slight decrease in echogenicity throughout the gastric wall. While the mucosal surface was relatively smooth, color Doppler examination showed increased vascularity. Esophagogastroduodenoscopy and pathological examination confirmed the diagnosis of ICI-related gastroenteritis.

Chronic Diarrhea as the Presenting Feature of Amyloidosis with Multiple Myeloma: A Case Report Diagnosed by a Myocardial Biopsy.

A 73-year-old woman with a history of diarrhea for one year and other various symptoms was admitted to our hospital. Gastrointestinal endoscopy that included enteroscopy with multiple biopsies was performed. However, no significant findings were observed. Electrocardiography showed low voltage in all limb leads, and an echocardiogram showed thickened cardiac walls with granular sparkling pattern. A myocardial biopsy revealed amyloidosis, and a bone marrow biopsy showed multiple myeloma. This case suggests that we should suspect the possibility of amyloidosis in a patient with diarrhea and various symptoms involving multiple organ systems. Additionally, electrocardiograms and echocardiograms should be performed even when gastrointestinal biopsies reveal negative results.

Immune checkpoint inhibitor-induced enteritis assessed using capsule endoscopy.

We performed capsule endoscopy for a patient with immune checkpoint inhibitor-induced enteritis and found multiple erosions or small ulcers in the small intestine. No reports demonstrated the effectiveness of capsule endoscopy for immune checkpoint inhibitor-induced gastrointestinal adverse events, and our case suggests that capsule endoscopy may be useful to evaluate immune checkpoint inhibitor-induced enteritis.

Removal characteristics and fluctuation of norovirus in a pilot-plant by an ultrafiltration membrane for the reclamation of treated sewage.

When ultrafiltration (UF) membrane processes that are able to effectively reduce viruses are installed in a waste water reclamation system, the security of sanitation safety for water-borne diseases is essential. It is important to understand the behaviour of enteric viruses such as Adenovirus, Rotavirus and Norovirus (NV), the detection rate of which is relatively high in sewage. This study focused on the UF membrane process for the reclaimed water treatment process, and investigated the removal performance in NV type GI and GII in the UF membrane process by performing coagulation and sedimentation as the pre-treatment process in a pilot-plant by considering the concentration fluctuation of the influent. The removal ratio of GI and GII by the UF membrane process alone was 3.3 ± 0.7 Log in GI and 3.6 ± 1.0 Log in GII, and no clear difference in the removal ratio by NV species type was observed. The removal ratio of NV GII was increased by about 0.6 Log on average (4.2 ± 1.1 Log) compared with the UF membrane process only when the coagulation and sedimentation process were conducted as pre-treatment. However, there was no significant difference in the removal of NV GI by conducting the coagulation and sedimentation process.

Anaerobic Codigestion of Grass and Sewage Sludge: Laboratory Experiments and Feasibility Analysis.

Grass is drawing attention for its high potential for biogas production. Anaerobic digesters in wastewater treatment plants can be used for producing biogas by processing grass without having to invest in the construction of new treatment facilities. Batch and continuous digestion experiments were conducted to assess the feasibility of codigestion of sewage sludge and grass. The focus was on a thermophilic condition, starting-up from existing mesophilic anaerobic digestion of sewage sludge only. The batch and continuous experiments used two different sewage sludges. Results demonstrated a methane generation of approximately 0.2 normal liter-methane/g volatile solids-grass. The addition of grass did not affect the ammonia concentration and improved the dewaterability of the digested sludge. The start-up performance from mesophilic digested sewage sludge to thermophilic codigestion with grass was confirmed. A feasibility analysis demonstrated that codigestion is applicable in terms of energy recovery and greenhouse gas emission, depending on the transport distance of grass.

Anaerobic co-digestion of steam-treated Quercus serrata chips and sewage sludge under mesophilic and thermophilic conditions.

The biodegradation of Quercus serrata chips was evaluated by anaerobic digestion under various steam explosion conditions. In continuous experiments, untreated chips (W0) and chips steam-treated at less than 1.0 MPa (W1) and 2.0 MPa (W4) were co-digested with sewage sludge (S1 and S2) taken from two different wastewater treatment plants. The apparent methane yield of W1 and W4 co-digested with S1 (thermophilic) was 261 dm(3)/kgVS (volatile solids) and 248 dm(3)/kgVS, respectively. The apparent methane yield of W4 co-digested with S2 was 258 dm(3)/kgVS (mesophilic) and 271 dm(3)/kgVS (thermophilic). Methane production was inhibited by W0 due to components released during hydrolysis. The methane conversion ratio of pretreated chips obtained in batch experiments varied from 40.5% to 53.8% (mesophilic) and from 49.0% to 63.7% (thermophilic). The methane conversion ratio increased with decreasing acid-soluble lignin content in the chips.

Morphology and release kinetics of protein-loaded porous poly(l-lactic Acid) spheres prepared by freeze-drying technique.

Freeze-drying a biodegradable polymer, poly(L-lactic acid) (PLLA), from 1,4-dioxane solutions provided very porous spherical particles of ca. 3 mm in radius with specific surface area of 8-13 m(2) g(-1). The surface of the particle was found to be less porous compared with its interior. To apply the freeze-dried PLLA (FDPLLA) to drug delivery system, its morphology and drug releasing kinetics were investigated, bovine serum albumin (BSA) being used as a model drug compound. Immersion of FDPLLA into a BSA aqueous solution gave BSA-loaded FDPLLA, where mass fraction of the adsorbed BSA reached up to 79%. Time-dependent release profile of BSA in water suggested a two-step mechanism: (1) very rapid release of BSA deposited on and near the particle surface, which results in an initial burst, and (2) leaching of BSA from the interior of the particle by the diffusion process. It was suggested that the latter process is largely governed by the surface porosity. The porosity of both the interior and surface was found to decrease remarkably as the concentration of the original PLLA/1,4-dioxane solution increases, C(0). Thus, C(0) is a key parameter that controls the loading and releasing of BSA.

Interactions between spiropyrans and room-temperature ionic liquids: photochromism and solvatochromism.

A series of imidazolium-based room-temperature ionic liquids (RTILs) containing anions from organic carboxylic acids were prepared. A set of dye probes, including Reichardt's dye (30), 4-nitrioaniline, and N, N-diethyl-4-nitroaniline, were used to determine the ET(30) scales and the Kamlet-Taft parameters (pi*, alpha, and beta) of the RTILs. On the basis of the polarity properties, these RTILs were categorized into three groups: group A with beta >0.9, alpha <0.9; group B with beta <0.9, alpha <0.9; and group C with beta <0.9, alpha >0.9. Interactions of these RTILs with four photochromic spiropyran derivatives (SP-I, SP-II, SP-III, and SP-IV) were investigated. It was found that the spiropyrans could present photochromism (positive or negative) or not, depending mainly on the polarity properties of the RTILs and also on the structure itself. A new spectroscopic method based on the molecular transition energy of the spiropyran probes (ESP) was proposed to determine the polarity of those protic or fluorine-containing RTILs, which were failed with the Reichardt's dye (30) probe.

Behavior of pathogenic microbes in a treated wastewater reuse system and examination of new standards for the reuse of treated wastewater.

We researched the behavior of pathogenic microbes in a treated wastewater reuse system to acquire knowledge for establishing new standards for the reuse of treated wastewater. Based on the results that showed occasional growth of total coliforms but barely any growth of Escherichia coli in the supply tank, we found that the total coliform, which includes bacteria that also breed in the soil, etc., is not necessarily suitable as the index bacteria for indicating pollution by excrement. We also clarified that it is possible to decrease the heterotrophic plate count to a specified level in cases where combined residual chlorine is more than 0.3 mg/l, and that the standard value for residual chlorine should be set at 0.3 mg/l or more. At the same time, we found that applying sand filtration treatment to water used for toilet flushing, sprinkling and landscaping, and sand filtration treatment plus coagulation treatment to water for recreational use lowers the annual risk of infection by Cryptosporidium to less than 10(-4). The standard for viruses must be examined in the future because Noroviruses were sometimes detected even in the reclaimed water, although we could not establish the standard at this time due to problems with the virus detection method.

Secretory proprotein convertases PACE4 and PC6A are heparin-binding proteins which are localized in the extracellular matrix. Potential role of PACE4 in the activation of proproteins in the extracellular matrix.

PACE4, PC6 and furin are potent subtilisin-like proprotein convertases (SPCs) which are responsible for the activation of transforming growth factor-beta (TGFbeta)-related factors such as bone morphogenetic proteins. Heparan sulfate proteoglycan within the extracellular matrix (ECM) is known to regulate the biological activity of various differentiation factors including TGFbeta-related molecules. PACE4 binds tightly to heparin and its heparin-binding region was found to be a cationic stretch of amino acids between residues 743 and 760. Furthermore, PACE4 was detected in the extracellular material fraction of the HEK293 cells, defined as the material remaining on the culture plate following the removal of the cells from the plate. PACE4 bound to the extracellular fraction was selectively dislodged by heparin into the culture medium. Heparin has no inhibitory activity against PACE4. Similarly, PC6A is also able to bind to heparin, whereas soluble furin does not. In human placenta, PACE4 is mainly present in syncytiotrophoblasts and can be released by heparin. These results suggest that PACE4 and PC6 are unique SPC family proteases that anchor heparan sulfate proteoglycans at the ECM. The interaction between PACE4 and heparan sulfate proteoglycans might play an important role in the delicate spatiotemporal regulation of TGFbeta-related factors' biological activity.

A critical role for the carboxy terminal region of the proprotein convertase, PACE4A, in the regulation of its autocatalytic activation coupled with secretion.

PACE4A is a member of the mammalian subtilisin-like proprotein convertase family which is responsible for the proteolytic activation of precursors into their biologically active forms. Previously we reported that the maturation of proPACE4A occurs via a intramolecular autoactivation and cleavage of the propeptide is a rate-limiting step for the secretion of PACE4A (Nagahama et al., FEBS Lett. (1998) 434, 155-159). Although PACE4A is a putative secretory enzyme, it matures and is secreted much slower than general secretory proteins. In this study, we investigated the molecular mechanism underlying this slow maturation. The deletion of 25 amino acids at the carboxy terminus is sufficient for a marked acceleration in both the maturation and secretion of PACE4A. The carboxyl-truncated proPACE4A existed only as a monomer-sized form in the endoplasmic reticulum, whereas the wild type of proPACE4A existed in larger forms. Further, the fusion construct of yellow fluorescent protein and the carboxy-terminal sequence of PACE4A associated with the proPACE4A moiety and inhibited maturation. Thus the carboxy terminus of PACE4A functions as a potent autoinhibitor of its activation, resulting in the retention of proPACE4A in the endoplasmic reticulum. These findings indicate that PACE4A activity is highly controlled by a unique system at post-translational level.