Optimal initial diet in mild acute pancreatitis: A comprehensive meta-analysis of randomized control trials.

OBJECTIVE: We performed a comprehensive systematic review and meta-analysis comparing initiation of full solid diet (FSD) versus stepwise diet to better define the management of patients with mild acute pancreatitis (AP). METHODS: Electronic databases were searched through August 2, 2021 for trials comparing initial FSD versus stepwise advancement in patients with mild AP on length of hospital stay (LOHS). We stratified by whether diet was initiated early (within 24 h or immediately upon presence of bowel sounds). RESULTS: We identified seven RCTs that compared LOHS in AP patients who received initial oral intake with solid diet versus stepwise diet. Across the studies a total of 305 patients were randomized to immediate FSD and 308 patients to sequential advancement. Patients who were initiated on a FSD had a significant reduction in total LOHS (Standardized Mean Difference (SMD) -0.52 [95% CI -0.69, -0.36]). There was no difference in post refeeding abdominal pain, tolerance of diet, or necessity to cease diet between the two groups. Sub-analysis of three studies that initiated FSD early reduced total LOHS (OR -0.95 [95% CI -1.26, -0.65]) compared to those who received graded diet advancement as well as higher likelihood of tolerating the assigned diet (OR 6.8 [95% CI 1.2, 39.2]). CONCLUSIONS: Our meta-analysis shows that initiation of FSD reduces total LOHS in patients with mild AP and does not increase post refeeding abdominal pain. Though additional high-quality studies are needed, these findings support initial solid diet for AP and consideration of feeding within the first 24 h.

G protein-coupled receptors activate p38 MAPK via a non-canonical TAB1-TAB2- and TAB1-TAB3-dependent pathway in endothelial cells.

Endothelial dysfunction is induced by inflammatory mediators including multiple G protein-coupled receptor (GPCR) agonists. However, the GPCR signaling pathways that promote endothelial dysfunction are incompletely understood. We previously showed that thrombin promotes endothelial barrier disruption through autophosphorylation and activation of p38 mitogen-activated protein kinase (MAPK) via a non-canonical transforming growth factor-ß-activated protein kinase-1-binding protein-1 (TAB1) and TAB2-dependent pathway rather than the canonical three-tiered kinase cascade. Here, we sought to determine whether other GPCR agonists stimulate p38 MAPK activation via this non-canonical pathway in human endothelial cells derived from different vascular beds. Using primary human umbilical vein endothelial cells (HUVECs), HUVEC-derived EA.hy926 cells, and human dermal microvascular endothelial cells (HDMECs), we found that both non-canonical and canonical p38 activation pathways components are expressed in these various endothelial cell types, including TAB3, a structurally-related TAB2 homolog. Moreover, multiple GPCRs agonists, including thrombin, histamine, prostaglandin E2, and ADP, stimulated robust p38 autophosphorylation, whereas phosphorylation of the upstream MAPKs MAP kinase kinase 3 (MKK3) and MKK6, was virtually undetectable, indicating that non-canonical p38 activation may exist for other GPCRs. Indeed, in EA.hy926 cells, thrombin- and histamine-stimulated p38 activation depended on TAB1-TAB2, whereas in primary HUVECs, both TAB1-TAB2 and TAB1-TAB3 were required for p38 activation. In HDMECs, thrombin-induced p38 activation depended on TAB1-TAB3, but histamine-induced p38 activation required TAB1-TAB2. Moreover, thrombin- and histamine-stimulated interleukin-6 production required both TAB1-TAB2 and TAB1-TAB3 in HUVEC. We conclude that multiple GPCR agonists utilize non-canonical TAB1-TAB2 and TAB1-TAB3-dependent p38 activation to promote endothelial inflammatory responses.

Underwater versus conventional endoscopic mucosal resection for colorectal lesions: An updated meta-analysis of randomized controlled trials.

Background and study aims Colorectal malignancy is a leading cause of death. Conventional endoscopic mucosal resection (CEMR) is a strategy used to resect precancerous lesions that involves injecting fluid beneath a polyp to create a gap for resection. Underwater endoscopic mucosal resection (UEMR) is a newer method that forgoes injection, instead filling the intestinal cavity with water to facilitate polyp resection. Our aim was to compare the safety and efficacy of these approaches by synthesizing the most contemporary evidence. Methods PubMed, Embase, and Cochrane libraries were searched from inception through November 11, 2022 for randomized controlled trials (RCTs) comparing UEMR and CEMR for resection of colorectal lesions. The primary outcome was the rate of en bloc resection and secondary outcomes included recurrence, procedure time, and adverse events (AEs). Results A total of 2539 studies were identified through our systematic literature search. After screening, seven RCTs with a total of 1581 polyps were included. UEMR was associated with significantly increased rates of en bloc resection (RR 1.18 [1.03, 1.35]; I 2 = 76.6%) versus conventional approaches. No significant differences were found in procedure time, recurrence, or AEs. Conclusions UEMR is a promising effective technique for removal of colorectal lesions. The most contemporary literature indicates that it improves en bloc resection rate without increasing procedure time, recurrence, or AEs (PROSPERO ID CRD42022374935).

A Tyrosine Switch on NEDD4-2 E3 Ligase Transmits GPCR Inflammatory Signaling.

Ubiquitination is essential for protein degradation and signaling and pivotal to many physiological processes. Ubiquitination of a subset of G-protein-coupled receptors (GPCRs) by the E3 ligase NEDD4-2 is required for p38 activation, but how GPCRs activate NEDD4-2 to promote ubiquitin-mediated signaling is not known. Here, we report that the GPCR protease-activated receptor-1 (PAR1) stimulates c-Src-mediated tyrosine phosphorylation and activation of NEDD4-2 to promote p38 signaling and endothelial barrier disruption. Using mass spectrometry, we identified a unique phosphorylated tyrosine (Y)-485 within the 2,3-linker peptide between WW domain 2 and 3 of NEDD4-2 in agonist-stimulated cells. Mutation of NEDD4-2 Y485 impaired E3 ligase activity and failed to rescue PAR1-stimulated p38 activation and endothelial barrier permeability. The purinergic P2Y1 receptor also required c-Src and NEDD4-2 tyrosine phosphorylation for p38 activation. These studies reveal a novel role for c-Src in GPCR-induced NEDD4-2 activation, which is critical for driving ubiquitin-mediated p38 inflammatory signaling.