Metabolic Tissue Swelling and Local Microcirculation in Splanchnic Artery Occlusion Shock: Implications for Critical Illness.

Trauma is a leading cause of death in the United States. Advancements in shock resuscitation have been disappointing because the correct upstream mechanisms of injury are not being targeted. Recently, significant advancements have been shown using new cell-impermeant molecules that work by transferring metabolic water from swollen ischemic cells to the capillary, which restores tissue perfusion by microcirculatory decompression. The rapid normalization of oxygen transfer improves resuscitation outcomes. Since poor resuscitation and perfusion of trauma patients also causes critical illness and sepsis and can be mimicked by ischemia-reperfusion of splanchnic tissues, we hypothesized that inadequate oxygenation of the gut during trauma drives development of later shock and critical illness. We further hypothesized that this is caused by ischemia-induced water shifts causing compression no-reflow. To test this, the superior mesenteric artery of juvenile anesthetized swine was occluded for 30 minutes followed by 8 hours of reperfusion to induce mild splanchnic artery occlusion (SAO) shock. One group received the impermeant polyethylene glycol 20,000 Da (PEG-20k) that prevents metabolic cell swelling, and the other received a lactated Ringer's vehicle. Survival doubled in PEG-20k-treated swine along with improved macrohemodynamics and intestinal mucosal perfusion. Villus morphometry and plasma inflammatory cytokines normalized with impermeants. Plasma endotoxin rose over time after reperfusion, and impermeants abolished the rise. Inert osmotically active cell impermeants like PEG-20k improve intestinal reperfusion injury, SAO shock, and early signs of sepsis, which may be due to early restoration of mucosal perfusion and preservation of the septic barrier by reversal of ischemic compression no-reflow. SIGNIFICANCE STATEMENT: Significant advancements in treating shock and ischemia have been disappointing because the correct upstream causes have not been targeted. This study supports that poor tissue perfusion after intestinal ischemia from shock is caused by capillary compression no-reflow secondary to metabolic cell and tissue swelling since selectively targeting this issue with novel polyethylene glycol 20,000 Da-based cell-impermeant intravenous solutions reduces splanchnic artery occlusion shock, doubles survival time, restores tissue microperfusion, and preserves gut barrier function.

The impact of race/ethnicity on pancreaticoduodenectomy outcomes for pancreatic cancer.

PURPOSE: To investigate the impact of race/ethnicity on surgical outcomes following pancreaticoduodenectomy for pancreatic cancer. METHODS: A retrospective review of patients undergoing pancreaticoduodenectomy for adenocarcinoma in the National Surgical Quality Improvement Program (NSQIP) database from 2014 to 2019. Patient and tumor characteristics and 30-day postoperative outcomes were compared. Multivariable logistic and linear regression models were conducted to investigate the relationship between race/ethnicity and surgical outcomes. RESULTS: Six thousand five hundred and sixty-two patients were included (84.5% White, 7.9% Black, 3% Hispanic, 4.6% Asian). Larger proportions of Blacks had preoperative American Society of Anesthesiologists class 3 or 4. There were no significant differences in tumor characteristics or operative techniques. A smaller proportion of Asians and Hispanics received neoadjuvant chemotherapy and/or radiation than Blacks and Whites. Relative to White, the Black race was independently associated with postoperative sepsis and reoperation. Both Black and Hispanic race/ethnicity were associated with prolonged intubation and delayed gastric emptying, and minorities races/ethnicities were associated with longer length of hospital stay. Relative to White, Hispanic, and Asian race/ethnicity were independently associated with a lower likelihood of neoadjuvant therapy (NAT) receipt. CONCLUSION: In ACS-NSQIP participating hospitals, non-White race/ethnicity was independently associated with adverse outcomes after pancreatic cancer resection. A possible disparity in NAT receipt may exist in Asian and Hispanic patients undergoing surgical resection.

Superior Survival Outcomes of a Polyethylene Glycol-20k Based Resuscitation Solution in a Preclinical Porcine Model of Lethal Hemorrhagic Shock.

OBJECTIVE: To compare early outcomes and 24-hour survival after LVR with the novel polyethylene glycol-20k-based crystalloid (PEG-20k), WB, or hextend in a preclinical model of lethal HS. BACKGROUND: Posttraumatic HS is a major cause of preventable death. current resuscitation strategies focus on restoring oxygen-carrying capacity (OCC) and coagulation with blood products. Our lab shows that PEG-20k is an effective non-sanguineous, LVR solution in acute models of HS through mechanisms targeting cell swelling-induced microcirculatory failure. METHODS: Male pigs underwent splenectomy followed by controlled hemorrhage until lactate reached 7.5-8.5 mmol/L. They were randomized to receive LVR with PEG-20k, WB, or Hextend. Surviving animals were recovered 4 hours post-LVR. Outcomes included 24-hour survival rates, mean arterial pressure, lactate, hemoglobin, and estimated intravascular volume changes. RESULTS: Twenty-four-hour survival rates were 100%, 16.7%, and 0% in the PEG-20k, WB, and Hextend groups, respectively (P= 0.001). PEG-20k significantly restored mean arterial press, intravascular volume, and capillary perfusion to baseline, compared to other groups. This caused complete lactate clearance despite decreased OCC. Neurological function was normal after next-day recovery in PEG-20k resuscitated pigs. CONCLUSION: Superior early and 24-hour outcomes were observed with PEG-20k LVR compared to WB and Hextend in a preclinical porcine model of lethal HS, despite decreased OCC from substantial volume-expansion. These findings demonstrate the importance of enhancing microcirculatory perfusion in early resuscitation strategies.

Does Race or Ethnicity Impact Complications After Pulmonary Lobectomy for Patients With Lung Cancer?

BACKGROUND: Racial disparity in surgical access and postoperative outcomes after pulmonary lobectomy continues to be a concern and target for improvement; however, evidence of independent impact of race on complications is lacking. The objective of this study was to investigate the impact of race/ethnicity on surgical outcomes after lobectomy for lung cancer and estimate the distribution of racial/ethnic groups among expected resectable lung cancer cases using a large national database. METHODS: Patients who underwent lobectomy for lung cancer between 2005 and 2016 were identified in the American College of Surgeon National Surgical Quality Improvement Program. Preoperative characteristics and postoperative outcomes were compared between race/ethnicity groups in all patients and in propensity-matched cohorts, controlling for pertinent risk factors. Distribution of each race/ethnicity in the database was calculated relative to estimated numbers of patients with resectable lung cancer in the United States. RESULTS: A total of 10,202 patients (age 67.6 ± 9.7, 46.7% male, 86.4% white) underwent nonemergent lobectomy (46.8% thoracoscopic). Blacks had higher rates of baseline risk factors. In propensity score-matched cohorts of whites, blacks, and Hispanics/Asians (n = 498 each), postoperatively, blacks had higher rates of prolonged intubation and longer hospital stay while whites had a higher rate of pneumonia. Race was independently associated with these adverse outcomes on multivariate analysis. Proportion of blacks and Hispanics in the American College of Surgeon National Surgical Quality Improvement Program was lower than their respective proportion of resectable lung cancer in the United States. CONCLUSIONS: In a large national-level surgical database, there was lower than expected representation of black and Hispanic patients. Black race was independently associated with extended length of stay and prolonged intubation, whereas white was independently associated with postoperative pneumonia.

Changes in Utilization of Bariatric Surgery in the United States From 1993 to 2016.

OBJECTIVE: The aim of this study was to obtain estimates of changes in perioperative outcomes and utilization of bariatric surgery in the United States from 1993 to 2016. BACKGROUND: Bariatric surgery has evolved over the past 2 decades. Nationally representative information on changes of perioperative outcomes and utilization of surgery in the growing eligible population (class III obesity or class II obesity with comorbidities) is lacking. METHODS: Adults with obesity diagnosis who underwent primary bariatric surgery in the United States from 1993 to 2016 were identified in the National Inpatient Sample database. Estimates of the yearly number, types and cost of surgeries, patients' and hospital characteristics, complications and mortality rates were obtained. Prevalence of obesity and comorbidities were obtained from the National Health and Nutrition Examination Survey and changes in utilization of surgery were estimated. RESULTS: An estimated 1,903,273 patients underwent bariatric surgery in the United States between 1993 and 2016. Mean age was 43.9 years (79.9% women, 70.9% white race, 70.7% commercial insurance); these and other characteristics changed over time. Surgeries were exclusively open operations in 1993 (n = 8,631; gastric bypass and vertical banded gastroplasty, 49% each) and 98% laparoscopic (n = 162,969; 69.8% sleeve gastrectomy and 27.8% gastric bypass) in 2016. Complication and mortality rates peaked in 1998 (11.7% and 1%) and progressively decreased to 1.4% and 0.04% in 2016. Utilization increased from 0.07% in 1993 to 0.62% in 2004 and remained low at 0.5% in 2016. CONCLUSIONS: Perioperative safety of bariatric surgery improved over the last quarter-century. Despite growth in number of surgeries, utilization has only marginally increased. Addressing barriers for utilization may allow for greater access to surgical therapy.

Perioperative outcomes and cost of robotic-assisted versus laparoscopic inguinal hernia repair.

BACKGROUND: Utilization of robotic-assisted inguinal hernia repair (IHR) has increased in recent years, but randomized or prospective studies comparing outcomes and cost of laparoscopic and Robotic-IHR are still lacking. With conflicting results from only five retrospective series available in the literature comparing the two approaches, the question remains whether current robotic technology provides any added benefits to treat inguinal hernias. We aimed to compare perioperative outcomes and costs of Robotic-IHR versus laparoscopic totally extraperitoneal IHR (Laparoscopic-IHR). METHODS: Retrospective analysis of consecutive patients who underwent Robotic-IHR or Laparoscopic-IHR at a dedicated MIS unit in the USA from February 2015 to June 2017. Demographics, anthropometrics, the proportion of bilateral and recurrent hernias, operative details, cost, length of stay, 30-day readmissions and reoperations, and rates and severity of complications were compared. RESULTS: 183 patients had surgery: 45 (24.6%) Robotic-IHR and 138 (75.4%) Laparoscopic-IHR. There were no differences between groups in age, gender, BMI, ASA class, the proportion of bilateral hernias and recurrent hernias, and length of stay. Operative time (Robotic-IHR: 116 ± 36 min, vs. Laparoscopic-IHR: 95±44 min, p < 0.01), reoperations (Robotic-IHR: 6.7%, vs. Laparoscopic-IHR: 0%, p = 0.01), and readmissions rates were greater for Robotic-IHR. While the overall perioperative complication rate was similar in between groups (Robotic-IHR: 28.9% vs. Laparoscopic-IHR: 18.1%, p = 0.14), Robotic-IHR was associated with a significantly greater proportion of grades III and IV complications (Robotic-IHR: 6.7% vs. Laparoscopic-IHR: 0%, p = 0.01). Total hospital cost was significantly higher for the Robotic-IHRs ($9993 vs. $5994, p < 0.01). The added cost associated with the robotic device itself was $3106 per case and the total cost of disposable supplies was comparable between the 2 groups. CONCLUSIONS: In the setting in which it was studied, the outcomes of Laparoscopic-IHR were significantly superior to the Robotic-IHR, at lower hospital costs. Laparoscopic-IHR remains the preferred minimally invasive surgical approach to treat inguinal hernias.

Emergent Esophagectomy in Patients with Esophageal Malignancy Is Associated with Higher Rates of Perioperative Complications but No Independent Impact on Short-Term Mortality.

Background: Data on perioperative outcomes of emergent versus elective resection in esophageal cancer patients requiring esophagectomy are lacking. We investigated whether emergent resection was associated with increased risks of morbidity and mortality. Methods: Data on patients with esophageal malignancy who underwent esophagectomy from 2005 to 2020 were retrospectively analyzed from the American College of Surgeons National Surgical Quality Improvement Program database. Thirty-day complication and mortality rates were compared between emergent esophagectomy (EE) and non-emergent esophagectomy. Logistic regression assessed factors associated with complications and mortality. Results: Of 10,067 patients with malignancy who underwent esophagectomy, 181 (1.8%) had EE, 64% had preoperative systemic inflammatory response syndrome, sepsis, or septic shock, and 44% had bleeding requiring transfusion. The EE group had higher American Society of Anesthesiologists (ASA) class and functional dependency. More transhiatal esophagectomies and diversions were performed in the EE group. After EE, the rates of 30-day mortality (6.1% vs. 2.8%), overall complications (65.2% vs. 44.2%), bleeding, pneumonia, prolonged intubation, and positive margin (17.7% vs. 7.4%) were higher, while that of anastomotic leak was similar. On adjusted logistic regression, older age, lower albumin, higher ASA class, and fragility were associated with increased complications and mortality. McKeown esophagectomy and esophageal diversion were associated with a higher risk of postoperative complications. EE was associated with 30-day postoperative complications (odds ratio, 2.39; 95% confidence interval, 1.66-3.43; p<0.0001). Conclusion: EE was associated with a more than 2-fold increase in complications compared to elective procedures, but no independent increase in short-term mortality. These findings may help guide data-driven critical decision-making for surgery in select cases of complicated esophageal malignancy.

Restoring microcirculatory perfusion in a preclinical model of severe hemorrhagic shock: The role of microcirculatory function.

BACKGROUND: No reflow in capillaries (no reflow) is the lack of tissue perfusion that occurs once central hemodynamics are restored. This prevents oxygen transfer and debt repayment to vital tissues after shock resuscitation. Since metabolic swelling of cells and tissues can cause no reflow, it is a target for study in shock. We hypothesize no reflow secondary to metabolic cell swelling causes the problem not addressed by current strategies that increase central hemodynamics alone. METHODS: Anesthetized swine were bled until plasma lactate reached 7.5 mM to 9 mM. Intravenous low volume resuscitation solutions were administered (6.8 mL/kg over 5 minutes) consisting of; (1) lactated Ringer (LR), (2) autologous whole blood, (3) high-dose vitamin C (200 mg/kg), or (4) 10% PEG-20k, a polymer-based cell impermeant that corrects metabolic cell swelling. Outcomes were macrohemodynamics (MAP), plasma lactate, capillary flow in the gut and tongue mucosa using orthogonal polarization spectral imaging (OPSI), and survival to 4 hours. RESULTS: All PEG-20k resuscitated swine survived 240 minutes with MAP above 60 mm Hg compared with 50% and 0% of the whole blood and LR groups, respectively. The vitamin C group died at just over 2 hours with MAPs below 40 and high lactate. The LR swine only survived 30 minutes and died with low MAP and high lactate. Capillary flow positively correlated ( p < 0.05) with survival and MAP. Sublingual OPSI correlated with intestinal OPSI and OPSI was validated with a histological technique. DISCUSSION: Targeting micro-hemodynamics in resuscitation may be more important than macrohemodynamics. Fixing both is optimal. Sublingual OPSI is clinically achievable to assess micro-hemodynamic status. Targeting tissue cell swelling that occurs during ATP depletion in shock using optimized osmotically active cell impermeants in crystalloid low volume resuscitation solutions improves perfusion in shocked tissues, which leverages a primary mechanism of injury.

Multiphase preclinical assessment of a novel device to locate unintentionally retained surgical sharps: a proof-of-concept study.

BACKGROUND: Retained surgical sharps (RSS) is a "never event" that is preventable but may still occur despite of correct count and negative X-ray. This study assesses the feasibility of a novel device ("Melzi Sharps Finder®" or MSF) in effective detection of RSS. METHODS: The first study consisted of determination of the presence of RSS or identification of RSS in an ex-vivo model (a container with hay in a laparoscopic trainer box). The second study consisted of determining presence of RSS in an in-vivo model (laparoscopy in live adult Yorkshire pigs) with 3 groups: C-arm, C-arm with MSF and MSF. The third study used similar apparatus though with laparotomy and included 2 groups: manual search and MSF. RESULTS: In the first study, the MSF group had a higher rate of identification of a needle and decreased time to locate a needle versus control (98.1% vs. 22.0%, p < 0.001; 1.64 min ± 1.12vs. 3.34 min ± 1.28, p < 0.001). It also had increased accuracy of determining the presence of a needle and decreased time to reach this decision (100% vs. 58.8%, p < 0.001; 1.69 min ± 1.43 vs. 4.89 min ± 0.63, p < 0.001). In-the second study, the accuracy of determining the presence of a needle and time to reach this decision were comparable in each group (88.9% vs. 100% vs. 84.5%, p < 0.49; 2.2 min ± 2.2 vs. 2.7 min ± 2.1vs. 2.8 min ± 1.7, p = 0.68). In the third study, MSF group had higher accuracy in determining the presence of a needle and decreased time to reach this decision than the control (97.0% vs. 46.7%, p < 0.001; 2.0 min ± 1.5 vs. 3.9 min ± 1.4; p < 0.001). Multivariable analysis showed that MSF use was independently associated with an accurate determination of the presence of a needle (OR 12.1, p < 0.001). CONCLUSIONS: The use of MSF in this study's RSS models facilitated the determination of presence and localization of RSS as shown by the increased rate of identification of a needle, decreased time to identification and higher accuracy in determining the presence of a needle. This device may be used in conjunction with radiography as it gives live visual and auditory feedback for users during the search for RSS.

Perioperative outcomes of inpatient laparoscopic Heller myotomy and per-oral endoscopic myotomy in the United States.

BACKGROUND: Per-oral endoscopic myotomy is an alternative to pneumatic dilation and laparoscopic Heller myotomy to treat lower esophageal sphincter diseases. Laparoscopic Heller myotomy and per-oral endoscopic myotomy perioperative outcomes data come from relatively small retrospective series and 1 randomized trial. We aimed to estimate the number of inpatient procedures performed in the United States and compare perioperative outcomes and costs of laparoscopic Heller myotomy and per-oral endoscopic myotomy using a nationally representative database. METHODS: Cross-sectional retrospective analysis of hospital admissions for laparoscopic Heller myotomy or per-oral endoscopic myotomy from October 2015 through December 2018 in the National Inpatient Sample. Patient and hospital characteristics, concurrent antireflux procedures, perioperative adverse events (any adverse event and those associated with extended length of stay ≥3 days), mortality, length of stay, and costs were compared. Logistic regression evaluated factors independently associated with adverse events. RESULTS: An estimated 11,270 patients had laparoscopic Heller myotomy (n = 9,555) or per-oral endoscopic myotomy (n = 1,715) without significant differences in demographics and comorbidities. A concurrent anti-reflux procedure was more frequent with laparoscopic Heller myotomy (72.8% vs 15.5%, P < .001). Overall adverse event rate was higher with per-oral endoscopic myotomy (13.3% vs 24.8%, P < .001), and mortality was similar. Per-oral endoscopic myotomy had higher rates of adverse events associated with extended length of stay (9.3% vs 16.6%, P < .001), infectious adverse events (3.5% vs 8.2%, P < .001), gastrointestinal bleeding (3.4% vs 5.8%, P = .04), accidental injuries (3% vs 5.5%, P = .03), and thoracic adverse events (4.5% vs 9%, P < .01). Rates of adverse events of both procedures remained similar during the years of the study. Per-oral endoscopic myotomy was independently associated with adverse events. Length of stay (laparoscopic Heller myotomy: 3.2 ± 0.1 vs per-oral endoscopic myotomy: 3.7 ± 0.3 days, P = .17) and costs (laparoscopic Heller myotomy: $15,471 ± 406 vs per-oral endoscopic myotomy: $15,146 ± 1,308, P = .82) were similar. CONCLUSION: In this national database review, laparoscopic Heller myotomy had a lower rate of perioperative adverse events at similar length of stay and costs than per-oral endoscopic myotomy. Laparoscopic Heller myotomy remains a safer procedure than per-oral endoscopic myotomy for a myotomy of the distal esophagus and lower esophageal sphincter in the United States.

Early video-assisted thoracoscopic surgery (VATS) for non-emergent thoracic trauma remains underutilized in trauma accredited centers despite evidence of improved patient outcomes.

PURPOSE: Thoracic injury is a major contributor to morbidity in trauma patients. There is limited data regarding practice patterns of video-assisted thoracoscopic surgery (VATS) across trauma-accredited hospitals in the United States. We hypothesized that early VATS remains underutilized affecting patient outcomes. METHOD: We evaluated a cohort of patients who underwent non-urgent thoracic surgical intervention for trauma from the ACS-TQIP database in 2017 excluding patients who were discharged within 48-h or died within 72-h. We selected patients who underwent partial lung resection and decortication to assess the effect of early (day 2-5) versus late VATS. Univariate followed by multivariate regression analyses were utilized to evaluate the independent impact of timing. RESULTS: Over 12 months, 997,970 patients were admitted to 850 trauma-accredited centers. Thoracic injury occurred in 23.5% of patients, 1% of whom had non-urgent thoracic procedures. A total of 406 patients underwent VATS for pulmonary decortication with/out partial resection, 39% were Early VATS (N = 159) compared to 61% late VATS (N = 247). Both groups had comparable demographics and comorbidities with exception of a higher ISS score in the late surgical group (17.9 ± 9.8 vs 14.9 ± 7.6, p < 0.01). The late VATS patients' group had higher rates of superficial site infection, unplanned intubation, and pneumonia. Early VATS was associated with shorter ICU stay and HLOS. Multivariate analysis confirmed the independent effect of surgical timing on postoperative complications and LOS. The conversion rate from VATS to thoracotomy was 1.9% in early group compared to 6.5%, p = 0.03. There was no difference in surgical pattern among participating facilities. CONCLUSION: Despite established practice guidelines supporting early VATS for thoracic trauma management, there is underutilization with less than half of patients undergoing early VATS. Early VATS is associated with improved patient outcomes.

Trends of utilization and perioperative outcomes of robotic and video-assisted thoracoscopic surgery in patients with lung cancer undergoing minimally invasive resection in the United States.

Objective: The objective of this study was to evaluate utilization and perioperative outcomes of video-assisted thoracoscopic surgery (VATS) or robotic-assisted thoracoscopic surgery (RATS) for lung cancer in the United States using a nationally representative database. Methods: Hospital admissions for lobectomy or sublobar resection (segmentectomy or wedge resection) using VATS or RATS in patients with nonmetastatic lung cancer from October 2015 through December 2018 in the National Inpatient Sample were studied. Patient and hospital characteristics, perioperative complications and mortality, length of stay (LOS), and total hospital cost were compared. Logistic regression was used to assess whether the surgical approach was independently associated with adverse outcomes. Results: There were 83,105 patients who had VATS (n = 65,375) or RATS (n = 17,710) for lobectomy (72.7% VATS) or sublobar resection (84.2% VATS). Utilization of RATS for lobectomy and sublobar resection increased from 19.2% to 34% and 7.3% to 22%, respectively. Mortality, LOS, and conversion rates were comparable. The cost was higher for RATS (P <.01). Multivariate analyses showed comparable RATS and VATS complications with no independent association between the minimally invasive surgery approach used and adverse surgical outcomes, except for a decreased risk of pneumonia with RATS, relative to VATS sublobar resection (P <.01). Thoracic complication rates and LOS decreased after RATS lobectomy in 2018, compared with previous years (P <.005). Conclusions: The utilization of robotic-assisted lung resection for cancer has increased in the United States between 2015 and 2018 for sublobar resection and lobectomy. In adjusted regression analysis, compared with VATS, patients who underwent RATS had similar complication rates and LOS. The robotic approach was associated with increased total hospital cost. LOS and thoracic complication rates trended down after RATS lobectomy.

Robotic and laparoscopic Roux-en-Y gastric bypass after learning curve: 30-day and 12-month outcomes.

This study compares laparoscopic RYGB (L-RYGB) and robotic RYGB (R-RYGB) performed by the same team after the learning curve in both approaches. A retrospective cohort study was done, and the surgical outcome was analyzed in 30 days and 12 months for patients with similar characteristics and an equal number of cases in each group (233 cases). Four hundred and sixty-six patients were included in this study. Mean age was 46.8 ± 8.3 years and 2/3 were women. R-RYGB presented a longer operative time (150.7 versus 135.4 min; p < 0.001) with no differences in the length of hospital stay. The main 30-day complications were G-J stricture, leakage, and intraluminal bleeding. The reoperation rate was 1.6% by leakage (G-J anastomosis) and was higher in R-RYGB (2.1 versus 0.4; p = 0.108). The multivariate analysis identified that L-RYGB was the factor independently associated with a LOS longer than 2 days (odds ratio: 4.7, 95% CI: 2.6-8.2, p value < 0.001). At the FU time (12 months), no differences between the groups were found. The outcomes between the groups after the learning curve did not present differences in terms of 30 days and 12 months of FU when same preoperative characteristics and an equal number of cases in each group are considered. L-RYGB was the unique independent factor associated with long LOS.

Roux-en-Y Gastric Bypass Downregulates Angiotensin-Converting Enzyme 2 (ACE2) Gene Expression in Subcutaneous White Adipose Tissue: A Putative Protective Mechanism Against Severe COVID-19.

The angiotensin-converting enzyme 2 (ACE2) is the receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is highly expressed in adipose tissue, possibly associated with progression to severe coronavirus disease 2019 (COVID-19) in obese subjects. We searched the Gene Expression Omnibus (GEO) and reanalyzed the GSE59034 containing microarray data from subcutaneous white adipose tissue (sWAT) biopsies from 16 women before and 2 years after RYGB, and 16 controls matched by sex, age, and BMI. After RYGB, there was a significant decrease in sWAT ACE2 gene expression (logFC=-0.4175, P=0.0015). Interestingly, after RYGB the sWAT ACE2 gene expression was significantly lower than in non-obese matched controls (LogFC=-0.32875, P=0.0014). Our data adds to the well-known benefits of RYGB, a potential protective mechanism against COVID-19.

Cholangiocyte Epithelial to Mesenchymal Transition (EMT) is a potential molecular mechanism driving ischemic cholangiopathy in liver transplantation.

Donation after circulatory death (DCD) has expanded the donor pool for liver transplantation. However, ischemic cholangiopathy (IC) after DCD liver transplantation causes inferior outcomes. The molecular mechanisms of IC are currently unknown but may depend on ischemia-induced genetic reprograming of the biliary epithelium to mesenchymal-like cells. The main objective of this study was to determine if cholangiocytes undergo epithelial to mesenchymal transition (EMT) after exposure to DCD conditions and if this causally contributes to the phenotype of IC. Human cholangiocyte cultures were exposed to periods of warm and cold ischemia to mimic DCD liver donation. EMT was tested by assays of cell migration, cell morphology, and differential gene expression. Transplantation of syngeneic rat livers recovered under DCD conditions were evaluated for EMT changes by immunohistochemistry. Human cholangiocytes exposed to DCD conditions displayed migratory behavior and gene expression patterns consistent with EMT. E-cadherin and CK-7 expressions fell while N-cadherin, vimentin, TGFß, and SNAIL rose, starting 24 hours and peaking 1-3 weeks after exposure. Cholangiocyte morphology changed from cuboidal (epithelial) before to spindle shaped (mesenchymal) a week after ischemia. These changes were blocked by pretreating cells with the Transforming Growth Factor beta (TGFß) receptor antagonist Galunisertib (1 µM). Finally, rats with liver isografts cold stored for 20 hours in UW solution and exposed to warm ischemia (30 minutes) at recovery had elevated plasma bilirubin 1 week after transplantation and the liver tissue showed immunohistochemical evidence of early cholangiocyte EMT. Our findings show EMT occurs after exposure of human cholangiocytes to DCD conditions, which may be initiated by upstream signaling from autocrine derived TGFß to cause mesenchymal specific morphological and migratory changes.

Gastric Bypass Increases Circulating Bile Acids and Activates Hepatic Farnesoid X Receptor (FXR) but Requires Intact Peroxisome Proliferator Activator Receptor Alpha (PPARα) Signaling to Significantly Reduce Liver Fat Content.

BACKGROUND: We interrogate effects of gastric bypass (RYGB), compared with a low-calorie diet, on bile acid (BA), liver fat, and FXR, PPARα, and targets in rats with obesity and non-alcoholic fatty liver disease (NAFLD). METHODS: Male Wistar rats received a high-fat diet (obese/NAFLD, n=24) or standard chow (lean, n=8) for 12 weeks. Obese/NAFLD rats had RYGB (n=11), sham operation pair-fed to RYGB (pair-fed sham, n=8), or sham operation (sham, n=5). Lean rats had sham operation (lean sham, n=8). Post-operatively, five RYGB rats received PPARα antagonist GW6417. Sacrifice occurred at 7 weeks. We measured weight changes, fasting total plasma BA, and liver % steatosis, triglycerides, and mRNA expression of the nuclear receptors FXR, PPARα, and their targets SHP and CPT-I. RESULTS: At sacrifice, obese sham was heavier (p<0.01) than all other groups that had lost similar weight loss. Obese sham had lower BA levels and lower hepatic FXR, SHP, and CPT-I mRNA expression than lean sham (P<0.05, for all comparisons). RYGB had increased BA levels compared with obese and pair-fed sham (P<0.05, for both), while pair-fed sham had BA levels, similar to obese sham. Compared with pair-fed sham, RYGB animals had increased liver FXR and PPARα expression and signaling (P<0.05). Percentage of steatosis was lower in RYGB and lean sham, relative to obese and pair-fed sham (P<0.05, for all comparisons). PPARα inhibition after RYGB resulted in similar weight loss but higher liver triglyceride content (P=0.01) compared with RYGB alone. CONCLUSIONS: RYGB led to greater liver fat loss than low-calorie diet, an effect associated to increased fasting BA levels and increased expression of modulators of liver fat oxidation, FXR, and PPARα. However, intact PPARα signaling was necessary for resolution of NAFLD after RYGB.

Population Diversity Challenge the External Validity of the European Randomized Controlled Trials Comparing Laparoscopic Gastric Bypass and Sleeve Gastrectomy.

INTRODUCTION: Two randomized controlled trials (RCTs) from Europe recently showed similar weight loss and rates of type 2 diabetes (T2D) remission following laparoscopic gastric bypass (LRYGB) and laparoscopic sleeve gastrectomy (LSG). However, results from observational studies in the United States (US) have discordant results. We compared 1-year weight loss and T2D remission between LRYGB and LSG in a heterogeneous patient cohort from the US, albeit with similar inclusion and exclusion criteria to the European RCTs. METHODS: Logistic regression was used to propensity match LSG and LRYGB patients according to age, gender, race, preoperative BMI, and T2D. Inclusion and exclusion criteria were adopted from the two European RCTs. Demographic, anthropometric, weight outcomes, and comorbidities prevalence were compared at baseline and 1-year follow-up. RESULTS: We included 278 patients (139 LSG and 139 RYGB; median age 42 years, 89% female, 57% black race, 22% with public health insurance, and 25% with T2D). One year after surgery, mean %EWL was 77.3 ± 19.5% with LRYGB and 63.1 ± 21% with LSG (P < 0.001). Mean %TWL was 34.2 ± 7.3% after LRYGB and 28.1 ± 8.2% after LSG, (P < 0.001). The proportion of patients who achieved T2D remission was comparable between surgeries (LRGYB: 68.6% vs. LSG: 66.7%, P = 0.89). LSG, older age, black race, and higher preoperative BMI were independently associated with lower %EWL. Independent correlates of weight loss were different for LRYGB and LSG. CONCLUSIONS: Weight loss, but not the likelihood of T2D remission, was greater with LRYGB than LSG in a diverse patient cohort in the US. Further research efforts connecting population diversity to discordant results across studies is needed to better counsel patients with regards to expected postoperative outcomes.

Factors Mediating Type 2 Diabetes Remission and Relapse after Gastric Bypass Surgery.

BACKGROUND: Defining factors associated with remission and relapse of type 2 diabetes (T2D) after Roux-en-Y gastric bypass (RYGB) can allow targeting modifiable factors. We investigated factors associated with T2D remission and relapse after RYGB. STUDY DESIGN: We conducted a retrospective review of consecutive patients with T2D who underwent RYGB between 1993 and 2017. T2D remission was defined as medication discontinuation and/or hemoglobin A1c <6.5%. Relapse was defined as recurrence medication use and/or hemoglobin A1c ≥6.5%. Independent correlates of T2D remission and relapse were identified using logistic regression. RESULTS: Six hundred and twenty-one patients (aged 46.7 ± 10.6 years; 30% on insulin; BMI 49.8 ± 8.3 kg/m2) had at least 1-year follow-up. Median follow-up was 4.9 years (range 1 to 23.6 years). Prevalence of T2D remission was 74% at 1 year, 73% from 1 to 3 years, 63% between 3 and 10 years, and 47% beyond 10 years. Ninety-three percent of remissions occurred within 3 years of RYGB, 25% relapsed. Median time to relapse was 5.3 years (interquartile range 3 to 7.8 years) after remission. Higher 1-year percentage total body weight loss, lack of preoperative insulin use, and younger age at operation were independently associated with T2D remission. Preoperative insulin use, lower percentage total body weight loss at 1 year, and greater percentage total body weight regain after 1 year were independently associated with T2D relapse. CONCLUSIONS: This longitudinal retrospective analysis shows that preoperative insulin use and age, 1-year weight loss, and regain after that influence T2D remission and relapse after RYGB. Referring patients at a younger age, before insulin is needed, and optimizing weight loss and preventing weight regain after RYGB can improve the rates and durability of T2D remission.

Changes in Bile Acid Metabolism, Transport, and Signaling as Central Drivers for Metabolic Improvements After Bariatric Surgery.

PURPOSE OF REVIEW: We review current evidence regarding changes in bile acid (BA) metabolism, transport, and signaling after bariatric surgery and how these might bolster fat mass loss and energy expenditure to promote improvements in type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD). RECENT FINDINGS: The two most common bariatric techniques, Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), increase the size and alter the composition of the circulating BA pool that may then impact energy metabolism through altered activities of BA targets in the many tissues perfused by systemic blood. Recent reports in human patients indicate that gene expression of the major BA target, the farnesoid X receptor (FXR), is increased in the liver but decreased in the small intestine after RYGB. In contrast, intestinal expression of the transmembrane G protein-coupled BA receptor (TGR5) is upregulated after surgery. Despite these apparent conflicting changes in receptor transcription, changes in BAs after both RYGB and VSG are associated with elevated postprandial systemic levels of fibroblast growth factor 19 (from FXR activation) and glucagon-like peptide 1 (from TGR5 activation). These signaling activities are presumed to support fat mass loss and related metabolic benefits of bariatric surgery, and this supposition is in agreement with findings from rodent models of RYGB and VSG. However, inter-species differences in BA physiology limit direct translation and mechanistic understanding of how changes in individual BA species contribute to post-operative improvements of T2D and NAFLD in humans. Thus, details of all these changes and their influences on BAs' biological actions are still under scrutiny. Changes in BA physiology and receptor activities after RYGB and VSG likely support weight loss and promote sustained metabolic improvements.

Factors Associated to Abnormal Distal Esophageal Exposure to Acid and Esophagitis in Individuals Seeking Bariatric Surgery.

BACKGROUND: Gastroesophageal reflux disease (GERD) impacts choice and outcomes of bariatric surgery. However, GERD diagnosis based solely on symptoms yields inaccurate results. OBJECTIVE: To determine the factors associated with a positive 24h pH-monitoring (pH-test) or esophagitis in patients with severe obesity seeking bariatric surgery. SETTING: Private practice. METHODS: 93 patients with severe obesity underwent prospective evaluation for GERD symptoms, body composition, upper gastrointestinal endoscopy, esophageal manometry and pH-test. Correlation analyses were performed. RESULTS: 50 patients (53.8%) had GERD symptoms, 49 (52.7%) had esophagitis and 33 (35.5%) had a positive pH-test. Among patients with GERD symptoms, 18% had normal pH-test and no esophagitis, while 34.9% of patients without GERD symptoms had positive pH-test, esophagitis or both. Factors independently associated with positive pH-test were esophagitis (PR:3.08, 95%CI: 1.4-6.9, P = 0.006) and defective lower esophageal sphincter (PR:1.88, 95%CI: 1.09-3.21, P = 0.02). Factors independently associated with esophagitis were hiatal hernia (PR: 2.46; 95%CI: 1.6-3.7, P<0.001), GERD symptoms (PR:2.09; 95%CI: 1.3-3.4, P = 0.003) and positive pH-test (PR:1.82; 95%CI: 1.2-2.7, P = 0.003). The combined presence of GERD symptoms and esophagitis had a low positive predictive value for a positive pH-test (57%). On the other hand, the absence of both GERD symptoms and esophagitis had a 90% predictive value for a negative pH-test. CONCLUSIONS: Investigation for GERD before bariatric surgery should consist of routine upper endoscopy and GERD symptom evaluation in all patients. Patients with GERD symptoms and no esophagitis may need a pH-test for GERD diagnosis. Prospective studies are needed to understand significance of GERD diagnosis prior to bariatric surgery.