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Review objective: Based on the observation that rehabilitation practices for tibial plateau fractures are inconsistent and lack uniformity in the published literature, this scoping review will seek to identify all relevant studies that have reported on rehabilitation for tibial plateau fractures in order to comprehensively map the characteristics of the practices. This scoping review will then be used to identify commonalities across the included studies in order to identify potential focus questions for subsequent systematic reviews. Refereed/Peer-reviewed

The chemopreventive activity of non-steroidal anti-inflammatory drugs (NSAIDs), particularly aspirin, has been well demonstrated in preclinical and clinical studies. However, the primary side effect from this class of drug is gastrointestinal (GI) bleeding, which has limited the widespread use of NSAIDs for the prevention of cancer. The development of GI-safer NSAIDs, which are associated with phosphatidylcholine (PC) may provide a solution to this therapeutic problem. In the present study, the efficacy of two NSAIDs, aspirin and indomethacin, were compared using murine colon cancer cell line MC-26. Each NSAID was assessed alone and in combination with PC, using in vitro and in vivo systems. The results reveal that the PC-associated NSAIDs had a significantly higher degree of protection against cancer cell growth compared with the unmodified NSAIDs. It was also observed that Aspirin-PC and Indomethacin-PC prevented the metastatic spread of cancer cells in a syngeneic mouse model. These results support the potential use of PC-NSAIDs for the chemoprevention of colorectal cancer.

Objective: To identify and describe the characteristics of existing practices for postoperative weight bearing and management of tibial plateau fractures (TPFs), identify gaps in the literature, and inform the design of future research. Methods: Seven electronic databases and clinical trial registers were searched from inception until November 17th 2016. Studies were included if they reported on the surgical management of TPFs, had a mean follow-up time of ≥1. year and provided data on postoperative management protocols. Data were extracted and synthesized according to study demographics, patient characteristics and postoperative management (weight bearing regimes, immobilisation devices, exercises and complications). Results: 124 studies were included involving 5156 patients with TPFs. The mean age across studies was 45.1 years (range 20.8-72; 60% male), with a mean follow-up of 34.9 months (range 12-264). The most frequent fracture types were AO/OTA classification 41-B3 (29.5%) and C3 (25%). The most commonly reported non-weight bearing time after surgery was 4-6 weeks (39% of studies), with a further 4-6 weeks of partial weight bearing (51% of studies), resulting in 9-12 weeks before full weight bearing status was recommended (55% of studies). Loading recommendations for initial weight bearing were most commonly toe-touch/ < 10. kg (28%), 10. kg-20. kg (33%) and progressive (39%). Time to full weight bearing was positively correlated with the proportion of fractures of AO/OTA type C (r = 0.465, p = 0.029) and Schatzker type IV-VI (r = 0.614, p. < . 0.001). Similar rates of rigid (47%) and hinged braces were reported (58%), most frequently for 3-6 weeks (43% of studies). Complication rates averaged 2% of patients (range 0-26%) for abnormal varus/valgus and 1% (range 0-22%) for non-union or delayed union. Conclusions: Postoperative rehabilitation for TPFs most commonly involves significant non-weight bearing time before full weight bearing is recommended at 9-12 weeks. Partial weight bearing protocols and brace use were varied. Type of rehabilitation may be an important factor influencing recovery, with future high quality prospective studies required to determine the impact of different protocols on clinical and radiological outcomes. Refereed/Peer-reviewed

The mechanism by which aspirin consumption is linked to significant reductions in the incidence of multiple forms of cancer and metastatic spread to distant tissues, resulting in increased cancer patient survival is not well understood. In this study, using colon cancer as an example, we provide both in vitro (cell culture) and in vivo (chemically induced mouse model of colon cancer) evidence that this profound antineoplastic action may be associated with aspirin's ability to irreversibly inhibit COX-1–mediated platelet activation, thereby blocking platelet–cancer cell interactions, which promote cancer cell number and invasive potential. This process may be driven by platelet-induced epithelial–mesenchymal transition (EMT), as assessed using confocal microscopy, based upon changes in cell morphology, growth characteristics and fibronectin expression, and biochemical/molecular analysis by measuring changes in the expression of the EMT markers; vimentin, β-catenin, and SNAIL. We also provide evidence that a novel, gastrointestinal-safe phosphatidylcholine (PC)-associated aspirin, PL2200 Aspirin, possesses the same or more pronounced actions versus unmodified aspirin with regard to antiplatelet effects (in vitro: reducing platelet activation as determined by measuring the release of thromboxane and VEGF in culture medium; in vivo: inhibiting platelet number/activation and extravasation into tumor tissue) and chemoprevention (in vitro: inhibiting colonic cell growth and invasive activity; in vivo: inhibiting colonic dysplasia, inflammation, and tumor mass). These results suggest that aspirin's chemopreventive effects may be due, in part, to the drug blocking the proneoplastic action of platelets, and the potential use of Aspirin-PC/PL2200 as an effective and safer chemopreventive agent for colorectal cancer and possibly other cancers. Cancer Prev Res; 10(2); 142–52. ©2016 AACR.

NSAID use is limited due to the drugs’ toxicity to the gastrointestinal mucosa, an action incompletely understood. Lower gut injury induced by NSAIDs is dependent on bile secretion and is reported to increase the growth of a number of bacterial species, including an enterococcal species, Enterococcus faecalis. This study examined the relationships between indomethacin (INDO)‐induced intestinal injury/bleeding, small bowel overgrowth (SBO) and dissemination of enterococci, and the contribution of bile secretion to these pathological responses. Rats received either a sham operation (SO) or bile duct ligation (BDL) prior to administration of two daily subcutaneous doses of saline or INDO, and 24 h later, biopsies of ileum and liver were collected for plating on selective bacterial media. Fecal hemoglobin (Hb) and blood hematocrit (Hct) were measured to assess intestinal bleeding. Of the four treatment groups, only SO/INDO rats experienced a significant 10‐ to 30‐fold increase in fecal Hb and reduction in Hct, indicating that BDL attenuated INDO‐induced intestinal injury/bleeding. Ileal enterococcal colony‐forming units were significantly increased (500‐ to 1000‐fold) in SO/INDO rats. Of all groups, only the SO/INDO rats demonstrated gut injury, and this was associated with enterococcal overgrowth of the gut and dissemination to the liver. We also demonstrated that INDO‐induced intestinal injury and E. faecalis overgrowth was independent of the route of administration of the drug, as similar findings were observed in rats orally dosed with the NSAID. Bile secretion plays an important role in INDO‐induced gut injury and appears to support enterococcal overgrowth of the intestine. NSAID‐induced enterococcal SBO may be involved either as a compensatory response to gut injury or with the pathogenic process itself and the subsequent development of sepsis.

Objectives: Breast feeding protects infants from many diseases, including necrotizing enterocolitis, peptic ulceration and infectious diarrhea. Conversely, maternal separation stress and Non-Steroidal Anti-Inflammatory Drugs (NSAID’s) can induce intestinal injury and bleeding. This study aimed to evaluate in suckling rats if maternal separation/formula feeding leads to increased intestinal sensitivity to indomethacin (indo)-induced intestinal injury and to look at potential mechanisms involved. Methods: Nine-day-old rats were dam-fed or separated/trained to formula-feed for 6 days prior to indo administration (5 mg/kg/day) or saline (control) for 3 days. Intestinal bleeding and injury were assessed by measuring luminal and Fecal Hemoglobin (Hob) and jejunal histology. Maturation of the intestine was assessed by measuring luminal bile acids, jejunal sucrase, serum corticosterone, and mRNA expression of ileal Apical Sodium-Dependent Bile Acid Transporter (ASBT). Results: At 17 days, formula-fed indo-treated pups had a 2-fold increase in luminal Hb compared to formula-fed control pups and had evidence of morphological injury to the small intestinal mucosa as observed at the light microscopic level, whereas indo had no effect on dam-fed littermates. In addition, formula-fed rats had significant increases in luminal bile acid, sucrase specific activity, serum corticosterone, and expression of ASBT mRNA compared to dam-fed rats. Conclusion: Maternal separation stress may cause early intestinal maturational changes induced by corticosteroid release, including increased epithelial exposure to bile acids. These maturational changes may have a sensitizing rather than protective effect against indo-induced injury in the new-born.

Background/Aims: Proton pump inhibitors (PPIs) are widely used to prevent nonsteroidal anti-inflammatory drug (NSAID)-induced peptic ulcers. NSAIDs produce small intestinal injury and some PPIs have been reported to protect against NSAID-induced small bowel injury in rats. The aim of this study was to compare PPIs, revaprazan, and phosphatidylcholine-associated indomethacin (Indo-PC) for protection against indomethacin (Indo)-induced small bowel injury. Methods: Rat intestinal epithelial cells (IEC-6) were pretreated with omeprazole, lansoprazole, or revaprazan prior to exposure to Indo or Indo-PC. Cell viability was assessed by methyl thiazolyl tetrazolium assay. Omeprazole, lansoprazole, or revaprazan was administered orally to rats prior to the vehicle or Indo. Indo-PC was administered alone. After 24 h, small intestinal erosions were counted; intestinal bleeding was assessed as the hemoglobin concentration of small intestinal fluid. Results: Omeprazole, lansoprazole, and revaprazan did not protect against Indo-induced IEC-6 cell injury. Indo-PC was less damaging in vitro than Indo alone. In vivo, neither omeprazole nor lansoprazole protected against Indo-induced small bowel injury; however, revaprazan pretreatment and Indo-PC resulted in significantly fewer erosions (>50% reduction) or bleeding (>80% reduction). Conclusion: PPIs showed no small bowel protective effect in vitro or in vivo. Revaprazan showed a small bowel protective effect in vivo, whereas Indo-PC was protective both in vitro and in vivo.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat a number of conditions, and proton pump inhibitors (PPIs) are often used to prevent NSAID-induced gastric mucosal damage; however, the effects of NSAIDs on intestinal motility are poorly understood. The purpose of the present study is to determine the effects of a prototypical NSAID, indomethacin, either alone or in conjunction with the PPI omeprazole, on intestinal motility. Rats were randomly divided into four groups treated with vehicle, omeprazole, indomethacin, or a combination of indomethacin and omeprazole. Intestinal motility and transit were measured along with inflammatory mediators in the intestinal smooth muscle, markers of mucosal damage, and bacterial counts in the intestinal wall. Indomethacin, but not omeprazole, caused mucosal injury indicated by lower gut bleeding; however, both omeprazole and indomethacin suppressed contractile activity and frequency in the distal part of the small intestine. Cotreatment with omeprazole did not reduce indomethacin-induced intestinal bleeding. Furthermore, although indomethacin caused increased inflammation as indicated by increased edema development and inflammatory mediators, cotreatment with omeprazole did not reduce inflammation in the intestinal smooth muscle or prevent the increased bacterial count in the intestinal wall induced by indomethacin. We conclude that both NSAID and PPI treatment suppressed contractile activity in the distal regions of the small intestine. The suppression of intestinal contractility was associated with increased inflammation in both cases; however, indomethacin and omeprazole appear to affect intestinal motility by different mechanisms.

Background: The chronic use of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, is associated with a reduction in risk for colorectal and other cancers. However, when used chronically, these drugs carry a significant side effect to induce GI bleeding. Our laboratory has developed a class of NSAIDs that are complexed with phosphatidylcholine (PC-NSAIDs) which have been shown in preclinical and clinical trials to reduce NSAID GI toxicity. To date these drugs have been shown to possess equal or better efficacy compared to traditional NSAIDs in regard to anti-inflammatory, analgesic and anti-pyretic activities. To evaluate the chemopreventive activity of PC-NSAIDs, an animal model of carcinogeninduced colonic aberrant crypts was tested. Methods: Rats were treated at two weekly intervals with azoxymethane (AOM, 15mg/kg), followed two weeks later by daily oral dosing with control or test drugs for 4weeks (indomethacin, 2mg/kg; indomethacin-PC, 2mgNSAID/ kg; ibuprofen, 20mg/kg; ibuprofen-PC, 20mg NSAID/kg; or aspirin-PC, 20mg NSAID/kg). Assessments were made of GI toxicity/bleeding by measurement of the hematocrit and of hemoglobin in the feces, and of chemopreventive efficacy by the number of aberrant crypts in the distal colon. Results: At the doses used, no GI toxicity was detected from any of the test agents. The number of colonic aberrant crypts were significantly reduced by treatment with indomethacin-PC, but not by indomethacin (AOM control=40±11; indomethacin= 46±9; indomethacin-PC=10±2). In a separate study colonic aberrant crypts were significantly reduced by treatment with ibuprofen-PC and aspirin-PC, but not by ibuprofen (AOM control=133±18; ibuprofen=189±32; ibuprofen-PC=76±8; aspirin-PC=86±24). Conclusions: At equivalent doses, a novel class of PC-NSAIDs exhibit enhanced chemopreventive activity over traditional NSAIDs in a rodent model of colon carcinogenesis. (Supported by NIH grants R41CA171408 and R03CA171613).