Quality of care in adult patients with inflammatory bowel disease transferring between healthcare providers: multicentre audit

Background: Inflammatory bowel disease (IBD) predominantly affects young adults at critical socioeconomic periods of their lives. There are no studies examining the process of transfer of care for adult patients with IBD changing healthcare providers. Our aims were to assess the quality of referral information provided when patients with an established IBD diagnosis transfer care between heathcare providers and to assess the impact of referral quality on patient outcome. / Methods: Retrospective data pertaining to IBD transfer of care referrals were collected from 16 hospitals across London over a 2-month period. Data were collected on patient demographics, source and content of referral and cross-referenced with an established transfer of care checklist. Patient outcome within the 6 months following transfer was also documented. / Results: 154 cases were identified, over half of which transferred due to patient relocation. Details included in transfer letters were in many cases incomplete. In over 70% of cases, the letter came from primary care, including when a tertiary opinion was sought. Although referrals from primary care contained fewer patient data points, there was no association with poor patient outcomes at 6 months. / Conclusion: This is the first study examining the quality of transfer of care in adult patients with IBD. We highlighted a significant and underreported issue and found that the majority of referrals were led by primary care. Though the inclusion in the referral of fewer data points was not associated with poor outcomes, we highlighted an area where gastroenterologists might take more responsibility to provide smooth and robust transfer of care

Epigenetic and metabolic reprogramming of fibroblasts in Crohn's disease strictures reveals histone deacetylases as therapeutic targets.

BACKGROUND & AIMS: No effective therapeutic intervention exists for intestinal fibrosis in Crohn's disease [CD]. We characterised fibroblast subtypes, epigenetic and metabolic changes, and signalling pathways in CD fibrosis to inform future therapeutic strategies. METHODS: We undertook immunohistochemistry, metabolic, signalling pathway and Epigenetic [Transposase-Accessible Chromatin using sequencing] analyses associated with collagen production in CCD-18Co intestinal fibroblasts and primary fibroblasts isolated from stricturing [SCD] and non-stricturing [NSCD] CD small intestine. SCD/ NSCD fibroblasts were cultured with TGFβ and valproic acid [VPA]. RESULTS: Stricturing CD was characterised by distinct histone deacetylase [HDAC] expression profiles, particularly HDAC1, HDAC2, and HDAC7. As a proxy for HDAC activity, reduced numbers of H3K27ac+ cells were found in SCD compared to NSCD sections. Primary fibroblasts had increased extracellular lactate [increased glycolytic activity] and intracellular hydroxyproline [increased collagen production] in SCD compared to NSCD cultures. The metabolic effect of TGFβ-stimulation was reversed by the HDAC inhibitor VPA. SCD fibroblasts appear "metabolically primed" and responded more strongly to both TGFβ and VPA. Treatment with VPA revealed TGFβ-dependent and independent Collagen-I production in CCD-18Co cells and primary fibroblasts. VPA altered the epigenetic landscape with reduced chromatin accessibility at the COL1A1 and COL1A2 promoters. CONCLUSIONS: Increased HDAC expression profiles, H3K27ac hypoacetylation, a significant glycolytic phenotype, and metabolic priming, characterise SCD-derived as compared to NSCD fibroblasts. Our results reveal a novel epigenetic component to Collagen-I regulation and TGFβ-mediated CD fibrosis. HDAC inhibitor therapy may 'reset' the epigenetic changes associated with fibrosis

Small-molecule Wnt inhibitors are a potential novel therapy for intestinal fibrosis in Crohns disease

Intestinal fibrosis and stricture formation is an aggressive complication of Crohns disease (CD), linked to increased morbidity and costs. The present study investigates the contribution of Wingless-Int-1 (Wnt) signalling to intestinal fibrogenesis, considers potential cross-talk between Wnt and transforming growth factor β1 (TGFβ) signalling pathways, and assesses the therapeutic potential of small-molecule Wnt inhibitors. β-catenin expression was explored by immunohistochemistry (IHC) in formalin-fixed paraffin embedded (FFPE) tissue from patient-matched nonstrictured (NSCD) and strictured (SCD) intestine (n=6 pairs). Functional interactions between Wnt activation, TGFβ signalling, and type I collagen (Collagen-I) expression were explored in CCD-18Co cells and primary CD myofibroblast cultures established from surgical resection specimens (n=16) using small-molecule Wnt inhibitors and molecular techniques, including siRNA-mediated gene knockdown, immunofluorescence (IF), Wnt gene expression arrays, and western blotting. Fibrotic SCD tissue was marked by an increase in β-catenin-positive cells. In vitro, activation of Wnt-β-catenin signalling increased Collagen-I expression in CCD-18Co cells. Conversely, ICG-001, an inhibitor of β-catenin signalling, reduced Collagen-I expression in cell lines and primary CD myofibroblasts. TGFβ increased β-catenin protein levels but did not activate canonical Wnt signalling. Rather, TGFβ up-regulated WNT5B, a noncanonical Wnt ligand, and the Wnt receptor FZD8, which contributed directly to the up-regulation of Collagen-I through a β-catenin-independent mechanism. Treatment of CCD-18Co fibroblasts and patient-derived myofibroblasts with the FZD8 inhibitor 3235-0367 reduced extracellular matrix (ECM) expression. Our data highlight small-molecule Wnt inhibitors of both canonical and noncanonical Wnt signalling, as potential antifibrotic drugs to treat SCD intestinal fibrosis. They also highlight the importance of the cross-talk between Wnt and TGFβ signalling pathways in CD intestinal fibrosis

Chronic relapsing ascending myelopathy: a treatable progressive neurological syndrome following traumatic spinal cord injury.

BACKGROUND: We describe a novel progressive neurological syndrome complicating traumatic spinal cord injury (TSCI). Based on clinical and radiological features, we propose the term 'Chronic Relapsing Ascending Myelopathy' (CRAM). We distinguish between the previously described sub-acute progressive ascending myelopathy (SPAM) and post-traumatic syringomyelia (PTS), which may lie on a spectrum with CRAM. CASE REPORT: A 60-year-old man sustained a T4 ASIA-A complete TSCI. Four months post-injury, he developed a rapidly progressive ascending sensory level to C4. Clinical and radiological evaluation revealed ascending myelopathy with progressive T2 hyper-intense cord signal change. He underwent cord detethering and expansion duroplasty. Following an initial dramatic resolution of symptoms, the patient sustained two relapses, each 1-month post-discharge characterised by recurrence of disabling ascending sensory changes, each correlating with the radiological recurrence of cord signal change. Symptoms and radiological signal change permanently resolved with more extensive detethering and expansion duroplasty. There is radiological and clinical resolution at 1-year follow-up. CONCLUSION: Acute neurological deterioration post-TSCI may be due to SPAM or may occur after years due to PTS. We propose CRAM as a previously unrecognised phenomenon. The radiological characteristics overlap with SPAM. However, CRAM presents later and, clinically, behaves like PTS, but without cord cystic change. Cord detethering with expansion duroplasty are an effective treatment