Temporal trends in ileoanal pouch surgery for paediatric onset ulcerative colitis in England from 1997 to 2015 using hospital episode statistics.

INTRODUCTION: Ileal pouch-anal anastomosis (IPAA) following colectomy for ulcerative colitis (UC) achieves restoration of intestinal continuity with potential return of continence. It is undertaken relatively infrequently in children. We aimed to investigate the national frequency of IPAA in paediatric UC and report outcomes useful for surgeon/centre benchmarking. METHODS: Hospital Episode Statistics data were obtained for all admissions in England (1997-2015) in children (< 18 years) who underwent IPAA for UC using OPCS-4 procedural codes. Surgeon specialty, readmission, and reoperation rates were identified. Data are median (interquartile range). RESULTS: UC was diagnosed in 7604 children in whom 346 (4.6%) underwent IPAA at age 15 [13-17] years. Laparoscopy was used in 55 (15.9%) cases and in the most recent 10 years more commonly by specialist paediatric surgeons (SPS) than general surgeons (GS) (34.3%vs14.7%, p = 0.001). National frequency of IPAA ranged from 12 to 34 annually. Where specialty was available, 95/342 (57%) cases were undertaken by GS and 147/342 (43%) cases by SPS. The proportion of cases undertaken by SPS increased significantly compared to GS over the study period, p = 0.0003. Post-operative length of stay was 8 [6-11] days. During the index admission, unplanned return to theatre was required in 25/346 (7.2%). Following discharge 58 (16.8%) were readmitted within 30 days. Overall return to theatre rate within 30 days of pouch surgery was 11.0% (38/346). CONCLUSION: IPAA for UC within childhood is undertaken infrequently in England, with a shift towards SPS undertaking surgery. These data can be used by surgeons to benchmark outcomes. LEVEL OF EVIDENCE: IV.

Rational design of potent and selective VLA-4 inhibitors and their utility in the treatment of asthma.

Asthma, a chronic inflammatory disease of the airways, is a significant burden on our healthcare system. There is high unmet need for treatments directed towards the underlying causes of the disease. The cell surface integrin VLA-4 (very late antigen-4; alpha4beta1; CD49d/CD29) plays an important role in the trafficking of white blood cells to sites of inflammation and represents an exciting target for the development of novel anti-inflammatory drugs for the treatment of asthma. Here, we review our efforts to use rational design to identify potent, selective inhibitors of VLA-4. We describe the discovery of a series of potent VLA-4 inhibitors through the addition of a novel N-terminal organic cap to a tetrapeptide VLA-4 binding motif 4-((N'-2-methylphenyl)uriedo)phenylacetyl-Leu-Asp-Val-Pro ; Kd = 70 pM), and rationalize their structure-activity relationships using 3D-QSAR. Also, we show our rational peptidomimetic design strategy using "template hopping" from the gpIIb/IIIa integrin antagonist field, and also a novel virtual screening strategy. Two series have been developed, one that has high selectivity for the activated over the non-activated state of the receptor, and the other which is non-selective inhibiting both activated and non-activated VLA-4. Both series are highly selective for VLA-4 versus against other integrin family members. These inhibitors show promise in the treatment of asthma, based upon efficacy in a sheep model of asthma, where they inhibit both the early and late-phase responses to asthma and also block hypersensitivity.