COVID-19 and the Global Impact on Colorectal Practice and Surgery

Background: The novel severe acute respiratory syndrome coronavirus 2 virus that emerged in December 2019 causing coronavirus disease 2019 (COVID-19) has led to the sudden national reorganization of health care systems and changes in the delivery of health care globally. The purpose of our study was to use a survey to assess the global effects of COVID-19 on colorectal practice and surgery. Materials and Methods: A panel of International Society of University Colon and Rectal Surgeons (ISUCRS) selected 22 questions, which were included in the questionnaire. The questionnaire was distributed electronically to ISUCRS fellows and other surgeons included in the ISUCRS database and was advertised on social media sites. The questionnaire remained open from April 16 to 28, 2020. Results: A total of 287 surgeons completed the survey. Of the 287 respondents, 90% were colorectal specialists or general surgeons with an interest in colorectal disease. COVID-19 had affected the practice of 96% of the surgeons, and 52% were now using telemedicine. Also, 66% reported that elective colorectal cancer surgery could proceed but with perioperative precautions. Of the 287 respondents, 19.5% reported that the use of personal protective equipment was the most important perioperative precaution. However, personal protective equipment was only provided by 9.1% of hospitals. In addition, 64% of surgeons were offering minimally invasive surgery. However, 44% reported that enough information was not available regarding the safety of the loss of intra-abdominal carbon dioxide gas during the COVID-19 pandemic. Finally, 61% of the surgeons were prepared to defer elective colorectal cancer surgery, with 29% willing to defer for ≤ 8 weeks. Conclusion: The results from our survey have demonstrated that, globally, COVID-19 has affected the ability of colorectal surgeons to offer care to their patients. We have also discussed suggestions for various practical adaptation strategies for use during the recovery period. We have presented the results of a survey used to assess the global impact of coronavirus disease 2019 (COVID-19) on the delivery of colorectal surgery. Despite accessible guidance information, our results have demonstrated that COVID-19 has significantly affected the ability of colorectal surgeons to offer care to patients. We have also discussed practical adaptation strategies for use during the recovery phase

Abstract TP129: Increased Levels Of Matrix Metalloproteinases-induced BBB Dysfunction May Be Responsible For Increased Post-sich Hematoma Growth In Nicotine-exposed Rats

Byline: Priyanka Khushal, Univ of Miami, Miami, FL; Sunjoo Cho, Miami, FL; Ashish K Rehni, UNIVERSITY OF MIAMI MILLER SCHOOL O, Miami, FL; Ami P Raval, UNIVERSITY OF MIAMI, Miami, FL; Miguel A Perez-Pinzon, UNIVERSITY MIAMI MILLER SCH. OF MED, Miami, FL; Kunjan R Dave, Univ of Miami, Miami, FL Spontaneous intracerebral hemorrhage (sICH) is the deadliest type of stroke, accounting for as high as 28% of all strokes. Tobacco use is one of the major risk factors of sICH, and it also worsens outcomes following sICH. In our earlier study, we observed that nicotine exposure increases TNFð levels in brain vessels, impairs BBB integrity, and increases post-sICH hematoma volume in a TNFð-dependent manner compared to saline-exposed controls. Earlier studies have demonstrated interactions between MMPs and TNFð. Increased levels of matrix metalloproteinases (MMPs) have been found in sICH patients and nicotine-exposed individuals. MMPs are involved in BBB breakdown, edema formation, hematoma expansion, and neuronal loss that follow hematoma development after sICH. In the present study, we tested the hypothesis that nicotine exposure-induced increase in TNFð is responsible for increased post-sICH hematoma volume in a MMP-dependent manner. To test our hypothesis, young male and female rats were exposed to chronic nicotine treatment for 2-3 weeks using osmotic pumps containing either saline or nicotine (4.5 mg/kg/day). Levels of MMPs (2, 3, 9, and 12) and GAPDH were evaluated in brain homogenates using Western blot. Nicotine-treated female rats showed a 37% (100Ø7 vs. 137Ø10, p<0.05), 144% (100Ø18 vs. 244Ø16, p<0.01), 29% (100Ø7 vs. 129Ø9, p<0.05), 22% (100Ø6 vs. 122Ø6, p<0.05), and 24% (100Ø6 vs. 124Ø7, p<0.05) increase in levels of pro and cleaved forms of MMP-3, cleaved form of MMP-9, pro and cleaved forms of MMP-12, respectively, compared to saline-treated female rats. We are in the process of evaluating levels of MMPs in male samples. Considering the role of MMP-9 in BBB integrity, using both TNFð and MMP-9 inhibitors, we are also in the process of evaluating if TNFð increases post-sICH hematoma growth in nicotine-exposed rats via increased levels of MMP-9. The results so far imply that increased TNFð levels in nicotine-exposed rats may be responsible for increased post-sICH hematoma growth in a MMP-dependent manner. Support: James Esther King Biomedical Research Grant 9JK08 and PK is a recipient of the Lois Pope Neuroscience Summer Research Fellowship.Academi

Effect of folic acid supplementation on genomic DNA methylation in patients with colorectal adenoma

Background and aims: A low dietary folate intake can cause genomic DNA hypomethylation and may increase the risk of colorectal neoplasia. The hypothesis that folic acid supplementation increases DNA methylation in leucocytes and colorectal mucosa was tested in 31 patients with histologically confirmed colorectal adenoma using a randomised, double blind, placebo controlled, parallel design. Methods: Subjects were randomised to receive either 400 μg/day folic acid supplement (n = 15) or placebo (n = 16) for 10 weeks. Genomic DNA methylation, serum and erythrocyte folate, and plasma homocysteine concentrations were measured at baseline and post intervention. Results: Folic acid supplementation increased serum and erythrocyte folate concentrations by 81% (95% confidence interval (CI) 57–104%; p<0.001 v placebo) and 57% (95% CI 40–74%; p<0.001 v placebo), respectively, and decreased plasma homocysteine concentration by 12% (95% CI 4–20%; p = 0.01 v placebo). Folic acid supplementation resulted in increases in DNA methylation of 31% (95% CI 16–47%; p = 0.05 v placebo) in leucocytes and 25% (95% CI 11–39%; p = 0.09 v placebo) in colonic mucosa. Conclusions: These results suggest that DNA hypomethylation can be reversed by physiological intakes of folic acid

Bioactivity-Guided Synthesis: In Silico and In Vitro Studies of <i>β</i>-Glucosidase Inhibitors to Cope with Hepatic Cytotoxicity

The major cause of hyperglycemia can generally be attributed to β-glucosidase as per its involvement in non-alcoholic fatty liver disease. This clinical condition leads to liver carcinoma (HepG2 cancer). The phthalimides and phthalamic acid classes possess inhibitory potential against glucosidase, forming the basis for designing new phthalimide and phthalamic acid analogs to test their ability as potent inhibitors of β-glucosidase. The study also covers in silico (molecular docking and MD simulations) and in vitro (β-glucosidase and HepG2 cancer cell line assays) analyses. The phthalimide and phthalamic acid derivatives were synthesized, followed by spectroscopic characterization. The mechanistic complexities associated with β-glucosidase inhibition were identified via the docking of the synthesized compounds inside the active site of the protein, and the results were analyzed in terms of the best binding energy and appropriate docking pose. The top-ranked compounds were subjected to extensive MD simulation studies to understand the mode of interaction of the synthesized compounds and binding energies, as well as the contribution of individual residues towards binding affinities. Lower RMSD/RMSF values were observed for 2c and 3c, respectively, in the active site, confirming more stabilized, ligand-bound complexes when compared to the free state. An anisotropic network model was used to unravel the role of loop fluctuation in the context of ligand binding and the dynamics that are distinct to the bound and free states, supported by a 3D surface plot. An in vitro study revealed that 1c (IC50 = 1.26 µM) is far better than standard acarbose (2.15 µM), confirming the potential of this compound against the target protein. Given the appreciable potential of the candidate compounds against β-glucosidase, the synthesized compounds were further tested for their cytotoxic activity against hepatic carcinoma on HepG2 cancer cell lines. The cytotoxicity profile of the synthesized compounds was performed against HepG2 cancer cell lines. The resultant IC50 value (0.048 µM) for 3c is better than the standard (thalidomide: IC50 0.053 µM). The results promise the hypothesis that the synthesized compounds might become potential drug candidates, given the fact that the β-glucosidase inhibition of 1c is 40% better than the standard, whereas compound 3c holds more anti-tumor activity (greater than 9%) against the HepG2 cell line than the known drug

Red Cell Microparticles Suppress Hematoma Growth Following Intracerebral Hemorrhage in Chronic Nicotine-Exposed Rats

Spontaneous intracerebral hemorrhage (sICH) is a disabling stroke sub-type, and tobacco use is a prominent risk factor for sICH. We showed that chronic nicotine exposure enhances bleeding post-sICH. Reduction of hematoma growth is a promising effective therapy for sICH in smoking subjects. Red-blood-cell-derived microparticles (RMPs) are hemostatic agents that limit hematoma expansion following sICH in naïve rats. Considering the importance of testing the efficacy of experimental drugs in animal models with a risk factor for a disease, we tested RMP efficacy and the therapeutic time window in limiting hematoma growth post-sICH in rats exposed to nicotine. Young rats were chronically treated with nicotine using osmotic pumps. sICH was induced in rats using an injection of collagenase in the right striatum. Vehicle/RMPs were administered intravenously. Hematoma volume and neurological impairment were quantified ≈24 h after sICH. Hematoma volumes in male and female nicotine-exposed rats that were treated with RMPs at 2 h post-sICH were significantly lower by 26 and 31% when compared to their respective control groups. RMP therapy was able to limit hematoma volume when administered up to 4.5 h post-sICH in animals of both sexes. Therefore, RMPs may limit hematoma growth in sICH patients exposed to tobacco use