Single-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis.

Ulcerative colitis (UC) is driven by immune and stromal subsets, culminating in epithelial injury. Vedolizumab (VDZ) is an anti-integrin antibody that is effective for treating UC. VDZ is known to inhibit lymphocyte trafficking to the intestine, but its broader effects on other cell subsets are less defined. To identify the inflammatory cells that contribute to colitis and are affected by VDZ, we perform single-cell transcriptomic and proteomic analyses of peripheral blood and colonic biopsies in healthy controls and patients with UC on VDZ or other therapies. Here we show that VDZ treatment is associated with alterations in circulating and tissue mononuclear phagocyte (MNP) subsets, along with modest shifts in lymphocytes. Spatial multi-omics of formalin-fixed biopsies demonstrates trends towards increased abundance and proximity of MNP and fibroblast subsets in active colitis. Spatial transcriptomics of archived specimens pre-treatment identifies epithelial-, MNP-, and fibroblast-enriched genes related to VDZ responsiveness, highlighting important roles for these subsets in UC.

Single-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis.

Ulcerative colitis (UC) is driven by immune and stromal subsets, culminating in epithelial injury. Vedolizumab (VDZ) is an anti-integrin antibody that is effective for treating UC. VDZ is known to inhibit lymphocyte trafficking to the intestine, but its broader effects on other cell subsets are less defined. To identify the inflammatory cells that contribute to colitis and are affected by VDZ, we performed single-cell transcriptomic and proteomic analyses of peripheral blood and colonic biopsies in healthy controls and patients with UC on VDZ or other therapies. Here we show that VDZ treatment is associated with alterations in circulating and tissue mononuclear phagocyte (MNP) subsets, along with modest shifts in lymphocytes. Spatial multi-omics of formalin-fixed biopsies demonstrates trends towards increased abundance and proximity of MNP and fibroblast subsets in active colitis. Spatial transcriptomics of archived specimens pre-treatment identifies epithelial-, MNP-, and fibroblast-enriched genes related to VDZ responsiveness, highlighting important roles for these subsets in UC.

Fecal Microbiota Transplantation in Pouchitis: Clinical, Endoscopic, Histologic, and Microbiota Results from a Pilot Study.

AIMS: This pilot study assessed the efficacy, safety, and microbiome dynamics of fecal microbiota transplantation (FMT) for patients with chronic pouchitis. METHODS: A prospective open-label pilot study was performed at an academic center among pouchitis patients undergoing FMT. Patients received a minimum of a single FMT by pouchoscopy from healthy, screened donors. The primary outcome was clinical improvement in pouchitis assessed by patient survey at week 4. Secondary outcomes included decrease in total Pouchitis Disease Activity Index (PDAI) Score ≥ 3 at week 4, bowel movement frequency, ESR, CRP, fecal calprotectin, abdominal pain, and PDAI subscores including endoscopic and histologic changes. Stool samples were collected at baseline and 4 weeks post-FMT to assess bacterial microbiota using V4 16S rRNA sequencing. RESULTS: Nineteen patients were enrolled; however, 1 patient was lost to follow-up. No patients had a major adverse event or escalation of therapy related to FMT. Total PDAI scores, endoscopic scores, and histologic scores did not decrease significantly post-FMT. However, there was a statistically significant improvement in bowel movement (BM) frequency (9.25-7.25 BM/day, p = 0.03) and trend for improvement in abdominal pain to improve post-FMT (p = 0.05). Bacterial microbiota profiling revealed no distinct community-level changes post-FMT, though a small number of specific bacterial taxa significantly differed in relative abundance. CONCLUSIONS: A single FMT has a tolerable short-term safety profile and may be associated with a decrease in bowel movements in patients with chronic pouchitis; however, no robust endoscopic or histologic changes were observed.

Gastroenterologist and primary care perspectives on a post-endoscopy discharge policy: impact on clinic wait times, provider satisfaction and provider workload.

BACKGROUND: To reduce unnecessary ambulatory gastroenterology (GI) visits and increase access to GI care, San Francisco Health Network gastroenterologists and primary care providers implemented guidelines in 2013 that discharged certain patients back to primary care after endoscopy with formal written recommendations. This study assesses the longer-term impact of this policy on GI clinic access, workflow, and provider satisfaction. METHODS: An email-based survey assessed gastroenterologist and primary care provider (PCP) opinions about the discharge process. Administrative data and chart review were used to assess clinic access, intervention fidelity, and re-referral rates. RESULTS: 102/299 (34%) of PCPs and 5/7 (71%) of gastroenterologists responded to the survey. 74% of PCPs and 100% of gastroenterologists were satisfied or very satisfied with the discharge process. 80% of gastroenterologists believed the discharge process decreased their workload, while 53.5% of primary care providers believed it increased their workload. 6.7% of patients discharged to primary care in 2013 had re-referrals to GI. Wait time for the third-next-available new outpatient GI clinic appointment had previously decreased from 158 days (2012, pre-intervention) to 74 days (2013, post-intervention). In 2015, wait time was 19 days (p < 0.001 for 2012 vs. 2015). CONCLUSIONS: Primary care providers and gastroenterologists are satisfied with an intervention to discharge patients from gastroenterology to primary care after certain endoscopic procedures, although this conclusion is limited by a relatively low PCP survey response rate. Discharging appropriate patients using consensus criteria from the gastroenterology clinic was instrumental in sustainably reducing clinic wait times with low re-referral rates.

Correlating students' educational background, study habits, and resource usage with learning success in medical histology.

Histology is a traditional core basic science component of most medical and dental education programs and presents a didactic challenge for many students. Identifying students that are likely to struggle with histology would allow for early intervention to support and encourage their learning success. To identify student characteristics that are associated with learning success in histology, three first-year medical school classes at the University of Michigan (>440 students) were surveyed about their educational background, attitudes toward learning histology, and their use of histology learning strategies and resources. These characteristics were linked with the students' quiz and examination results in histology. Students who reported previous experience in histology or pathology and hold science or biomedical science college degrees usually did well in histology. Learning success in histology was also positively associated with students' perception that histology is important for their professional career. Other positive indicators were in-person participation in teacher-guided learning experiences, specifically lecture and laboratory sessions. In contrast, students who relied on watching histology lectures by video rather than going to lectures in-person performed significantly worse. These characteristics and learning strategies of students who did well in this very visual and challenging study subject should be of help for identifying and advising students early, who might be at risk of failing a histology course or component.

The Fanconi anemia gene network is conserved from zebrafish to human.

Fanconi anemia (FA) is a complex disease involving nine identified and two unidentified loci that define a network essential for maintaining genomic stability. To test the hypothesis that the FA network is conserved in vertebrate genomes, we cloned and sequenced zebrafish (Danio rerio) cDNAs and/or genomic BAC clones orthologous to all nine cloned FA genes (FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, and FANCL), and identified orthologs in the genome database for the pufferfish Tetraodon nigroviridis. Genomic organization of exons and introns was nearly identical between zebrafish and human for all genes examined. Hydrophobicity plots revealed conservation of FA protein structure. Evolutionarily conserved regions identified functionally important domains, since many amino acid residues mutated in human disease alleles or shown to be critical in targeted mutagenesis studies are identical in zebrafish and human. Comparative genomic analysis demonstrated conserved syntenies for all FA genes. We conclude that the FA gene network has remained intact since the last common ancestor of zebrafish and human lineages. The application of powerful genetic, cellular, and embryological methodologies make zebrafish a useful model for discovering FA gene functions, identifying new genes in the network, and identifying therapeutic compounds.