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Background: Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Using a novel electronic reporting tool, we aimed to prospectively describe the onset of tofacitinib efficacy during induction therapy in a real-world study., Methods: Patient-reported outcome data (PROs) including the simple clinical colitis activity index (SCCAI), PRO Measurement Identification Systems (PROMIS) measures, and adverse events were collected daily for the first 14 days and at day 28 and 56. Paired t tests and P for trend were utilized to compare changes in SCCAI over time. Bivariate analyses and logistic regression models were performed to describe response (SCCAI <5) and remission (SCCAI ≤2) by clinical factors., Results: Of all included patients (n = 96), 67% had failed ≥2 biologics, and 61.5% were on concomitant steroids. Starting at day 3, PROs showed significant and persistent decline of the mean SCCAI (-1.1, P < 000.1) including significantly lower SCCAI subscores for stool frequency (-0.3; P < .003), bleeding (-0.3; P < .0002) and urgency (-0.2; P < .001). Steroid-free remission at day 14, 28, and 56 was achieved in 25%, 30.2%, and 29.2% of patients, respectively. Neither prior biologics nor endoscopic severity were independently predictive of response or remission in multivariate models. Numeric improvements in all PROMIS measures (anxiety, depression, social satisfaction) were seen through day 56. Rates of discontinuation due to adverse events were low., Conclusions: In this prospective real-world study, tofacitinib resulted in a rapid and persistent improvement in UC disease activity PROs. The safety findings were consistent with the established safety profile of tofacitinib., (© 2022 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Background: Current biomarkers in ulcerative colitis (UC) are limited by their performance, cost, and limited availability in daily practice. This study examined alterations in the leukocyte profiles as biomarkers of UC activity, including the effects of age, gender, and medications., Methods: Case-control study that included 110 UC subjects, 75 subjects with Clostridium difficile infection, and 75 non-inflammatory bowel disease (IBD) subjects, randomly selected from a single-institution IBD database. Mean values of neutrophils (N), lymphocytes (L), monocytes (M) and their ratios were compared between groups. Receiver operator curve analyses assessed the performance of each biomarker in discriminating disease states. Subgroup analyses examined leukocytes profiles with endoscopic activity., Results: Elevated monocyte counts and decreased L/M values significantly differed between subjects with active UC and UC in remission and performed better than the other leukocyte profiles. A monocyte count of 483 and L/M ratio of 3.1 were 60% sensitive and had a specificity of 61% and 53%, respectively for active UC. Monocyte count >860 and L/M value <1.6 had a 75% positive predictive value for UC activity. Those markers also correlated with endoscopically active disease. L/M and N/L values performed best at differentiating active UC from non-IBD controls, whereas N/L and N values performed best at differentiating from C. difficile controls., Conclusions: Monocytosis and a low L/M ratio might be effective, readily available, and low-cost biomarkers to identify disease activity in UC patients. N/L values were more effective in distinguishing active UC patients from patients without IBD and those with C. difficile infection., Competing Interests: None to declare for all authors.

Background: The role of combined localized positron emission tomography (lPET) and computed tomography enterography (CTe) in Crohn's disease is unclear. We examined if this imaging modality using fluorine-18 labeled-fluoro-2-deoxy-D-glucose (FDG) could more effectively identify disease activity., Methods: 52 lPET-CTe scans were analyzed in this retrospective study. CTe scores and FDG uptake were quantified. Correlations of CTe scores and standard uptake value (SUV) with C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), short Inflammatory Bowel Disease Questionnaire (sIBDq), and Harvey-Bradshaw index (HBI) were estimated using Pearson analysis. Imaging scores were compared to medical outcome by logistics regression model., Results: CTe scores correlated with SUV, but additional abnormal segments of small bowel were not identified. In all, 38 (79%) abnormal CTe segments demonstrated increased FDG uptake with mean SUVmax 4.77; 10 (21%) abnormal CTe segments lacked FDG accumulation, with mean SUVmax 1.27. There was no correlation between SUVmax and CRP, ESR, sIBDq, or HBI. There were no significant differences in clinical indices, biochemical parameters, and presence of multiple abnormal segments between medical responders and uptake were associated with failed medical therapy (P = 0.001)., Conclusions: PET scanning added to CTe did not identify additional abnormal segments when compared to CTe alone. Abnormal segments with mucosal enhancement on CTe that did not accumulate FDG were significantly associated with failure of medical therapy. A larger trial is warranted to confirm if combined lPET-CTe has an important role in the clinical management of stricturing Crohn's disease.

The hepatitis C virus (HCV) envelope glycoprotein-2 inhibits the interferon (IFN)-induced, double-stranded RNA-activated protein kinase (PKR) via the PKR eukaryotic initiation factor-2alpha phosphorylation homology domain (PePHD). The present study examined the genetic variability of the PePHD in patients receiving IFN therapy. The PePHD from 12 HCV genotype 1 (HCV-1)-infected patients receiving daily IFN therapy was amplified by reverse-transcriptase polymerase chain reaction and analyzed by direct and clonal sequencing. The PePHD was highly conserved in 38 HCV GenBank isolates. There was no difference in pretreatment PePHD sequences isolated from IFN responders versus nonresponders. The major PePHD quasi-species variant did not change after 6 weeks of daily IFN therapy, and in 1 patient the major quasi-species variant did not change during 9 months of observation. Sequencing of 25 pretreatment PePHD clones from 3 patients confirmed that there was extremely low sequence variability surrounding the PePHD. The PePHD is highly conserved in HCV-1-infected IFN responders and nonresponders and does not appear to evolve in response to IFN therapy.

To improve site-specific cleavage of a methionyl porcine growth hormone [[Met1]-pGH(1-46)-IGF-II] fusion protein by the enzyme H64A subtilisin, a series of flexible, unstructured spacer peptides were introduced N-terminal to the cleavage site. When enzymatic digestion preceded refolding of the fusion proteins, IGF-II could only be liberated from substrates which contained spacer peptides. Compared with the parent construct, the yield of IGF-II from refolded fusion proteins containing spacers was improved up to two-fold. Furthermore, this cleavage rate was improved by removing a competing protease recognition motif from the fusion partner. These data show that fusion partners can influence site-specific proteolysis of fusion proteins. Introduction of flexible spacers between the moieties can alleviate these interactions.

Hepatitis C virus (HCV) quasispecies heterogeneity was assessed in pretreatment sera of 22 patients treated with interferon (IFN). Quasispecies heterogeneity was quantitated by analysis of 490 hypervariable region 1 (HVR1) clones using gel shift analysis (GSA), which allowed determination of two components of HCV quasispecies heterogeneity: genetic complexity (number of variants) and genetic diversity (mean genetic distance between variants). HCV genotype and pretreatment RNA titer were similar between responders (n = 12) and nonresponders (n = 10). GSA correlated well with nucleotide sequencing for estimating HCV genetic diversity (R = .952; P < .001). A positive correlation of .666 (P < .001) was observed between genetic diversity and complexity, suggesting that these components of quasispecies heterogeneity were related. However, while there were no significant differences in pretreatment complexity or genetic diversity among response groups, higher pretreatment genetic diversity was predictive of response failure (P = .041). Assessment of HVR1 heterogeneity by GSA revealed important relationships between quasispecies genetic diversity, complexity, and response to IFN therapy and suggested a need for analysis of other HCV genes.