Effects of intestine-specific deletion of FGF15 on the development of fatty liver disease with vertical sleeve gastrectomy.

BACKGROUND: Vertical sleeve gastrectomy (SGx) is a type of bariatric surgery to treat morbid obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). The molecular mechanisms of SGx to improve MASLD are unclear, but increased bile acids (BAs) and FGF19 (mouse FGF15) were observed. FGF15/19 is expressed in the ileum in response to BAs and is critical in not only suppressing BA synthesis in the liver but also promoting energy expenditure. We hypothesized the reduction of obesity and resolution of MASLD by SGx may be mediated by FGF15/19. METHODS: First, we conducted hepatic gene expression analysis in obese patients undergoing SGx, with the results showing increased expression of FGF19 in obese patients' livers. Next, we used wild-type and intestine-specific Fgf15 knockout mice (Fgf15ile-/-) to determine the effects of FGF15 deficiency on improving the metabolic effects. RESULTS: SGx improved metabolic endpoints in both genotypes, evidenced by decreased obesity, improved glucose tolerance, and reduced MASLD progression. However, Fgf15ile-/- mice showed better improvement compared to wild-type mice after SGx, suggesting that other mediators than FGF15 are also responsible for the beneficial effects of FGF15 deficiency. Further gene expression analysis in brown adipose tissue suggests increased thermogenesis. CONCLUSIONS: FGF15 deficiency, the larger BA pool and higher levels of secondary BAs may increase energy expenditure in extrahepatic tissues, which may be responsible for improved metabolic functions following SGx.

Identification and Functional Characterization of Alternative Transcripts of LncRNA HNF1A-AS1 and Their Impacts on Cell Growth, Differentiation, Liver Diseases, and in Response to Drug Induction.

The long non-coding RNA (lncRNA) hepatocyte nuclear factor-1 alpha (HNF1A) antisense RNA 1 (HNF1A-AS1) is an important lncRNA for liver growth, development, cell differentiation, and drug metabolism. Like many lncRNAs, HNF1A-AS1 has multiple annotated alternative transcripts in the human genome. Several fundamental biological questions are still not solved: (1) How many transcripts really exist in biological samples, such as liver samples and liver cell lines? (2) What are the expression patterns of different alternative HNF1A-AS1 transcripts at different conditions, including during cell growth and development, after exposure to xenobiotics (such as drugs), and in disease conditions, such as metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD) cirrhosis, and obesity? (3) Does the siRNA used in previous studies knock down one or multiple transcripts? (4) Do different transcripts have the same or different functions for gene regulation? The presented data confirm the existence of several annotated HNF1A-AS1 transcripts in liver samples and cell lines, but also identify some new transcripts, which are not annotated in the Ensembl genome database. Expression patterns of the identified HNF1A-AS1 transcripts are highly correlated with the cell differentiation of matured hepatocyte-like cells from human embryonic stem cells (hESC), growth and differentiation of HepaRG cells, in response to rifampicin induction, and in various liver disease conditions. The expression levels of the HNF1A-AS1 transcripts are also highly correlated to the expression of cytochrome P450 enzymes, such as CYP3A4, during HepaRG growth, differentiation, and in response to rifampicin induction.

Feasibility and Efficacy of Magnetic Sphincter Augmentation for the Management of Gastroesophageal Reflux Disease Post-Sleeve Gastrectomy for Obesity.

BACKGROUND: Patients with medically intractable GERD after laparoscopic sleeve gastrectomy (LSG) have limited surgical options. Fundoplication is difficult post-LSG. Roux-en-Y gastric bypass may be used as a conversion procedure but is more invasive with potential for serious complications. Magnetic sphincter augmentation (MSA) is a less invasive GERD treatment alternative. The objective of this study was to assess safety and efficacy outcomes of MSA after LSG. METHODS: The primary outcome of this observational, multicenter, single-arm prospective study was the rate of serious device and/or procedure-related adverse events (AEs). The efficacy of the LINX device was measured comparing baseline to 12-month post-implant reductions in distal acid exposure, GERD-HRQL score, and average daily PPI usage. RESULTS: Thirty subjects who underwent MSA implantation were followed 12 months post-implant. No unanticipated adverse device effects were observed. There were two adverse events deemed serious (dysphagia, pain, 6.7%) which resolved without sequelae. GERD-HRQL scores showed significant improvement (80.8%, P < 0.001), and reduction in daily PPI usage was seen (95.8%, P < 0.001). Forty-four percent of subjects demonstrated normalization or > = 50% reduction of total distal acid exposure time (baseline 16.2%, 12 months 11%; P = 0.038). CONCLUSIONS: Post-LSG, MSA showed an overall improvement of GERD symptoms, and reduction in PPI use with explants within anticipated range along with improvement in distal esophageal acid exposure time.

A validated LC-MS/MS method for the quantitation of cefazolin in human adipose tissue: Application of EMR-Lipid sorbent as an efficient sample clean-up before mass spectrometric analyses.

A novel, simple, rapid, and sensitive high-performance liquid chromatography-tandem mass spectrometry method was developed to determine cefazolin concentrations in human adipose tissue. Sample preparation was performed by protein precipitation followed by using Captiva EMR-Lipid plates. The mobile phase consisted of 5 mM ammonium formate and 0.1% formic acid in water and 0.1% formic acid in ACN, and was pumped through a Synergi Fusion-RP column with a gradient elution program at a flow rate of 0.3 mL/min. The mass spectrometer was operated in a positive ion mode. Cloxacillin was used as an internal standard due to the observed cross-signal contribution between cefazolin and 13C2,15N-cefazolin. The method was validated according to the FDA and EMA guidelines and passed all the acceptance criteria. The calibration range was 0.05-50 µg/mL in adipose tissue homogenate (0.15-150 µg/g in adipose tissue), precision CV < 4.5%, accuracy within 93.1-100.4%. The carry-over was negligible, recovery of the method was high, and no significant matrix effect was present. Rat subcutaneous adipose tissue was demonstrated to be a suitable surrogate matrix for human adipose tissue. The validated method was successfully applied in a pilot pharmacokinetic study and will further be used in a large cohort of non-obese and obese patients dosed prophylactically with cefazolin before surgeries.

Anticoagulant activity of enoxaparin and unfractionated heparin for venous thromboembolism prophylaxis in obese patients undergoing sleeve gastrectomy.

BACKGROUND: One risk of bariatric surgery is venous thromboembolism and the optimal strategy to reduce risk requires further clarification. OBJECTIVES: The objectives of this study were to identify antiXa goal attainment with the institutional standard chemoprophylaxis, analyze discordance between antiXa and thrombin generation assay (TGA) in terms of adequacy of anticoagulation, and to identify correlations between patient characteristics or covariates and markers of coagulation status. SETTING: Large academic medical center in Northeastern United States. METHODS: A total of 60 sleeve gastrectomy patients were enrolled in this institutional review board-approved, prospective cohort study. Patients received the institutional standard prophylactic therapy (subcutaneous enoxaparin 40 mg twice daily or unfractionated heparin [UFH]). The UFH dose was weight based, 5000 units (<120 kg) or 7500 units (≥120 kg) every 8 hours. Various measures of coagulation status were measured at or near steady state. RESULTS: Patients receiving enoxaparin achieved goal antiXa more frequently compared with the UFH group, and statistical significance was demonstrated (93.8 % versus 4.5%, respectively; P < .0001). Target endogenous thrombin potential reduction from baseline was more frequently obtained in the enoxaparin group versus UFH (50% versus 27.7%, respectively; P = .12). AntiXa was below the limit of detection for the majority of UFH patients; while TGA suggested patients did experience anticoagulation at some level of effectiveness. Endogenous thrombin potential change in the enoxaparin group was correlated to several measures of body composition. CONCLUSIONS: Patients receiving enoxaparin achieved goal antiXa more often versus UFH. There was discordance between antiXa and TGA-based assessment of coagulation status. TGA may provide a more robust assessment of the adequacy of chemoprophylaxis.

Case report of EUS-guided endoscopic transduodenal necrosectomy in a patient with sleeve gastrectomy.

BACKGROUND: After an acute attack of pancreatitis, walled-off pancreatic fluid collections (PFC) occur in approximately 10 % of cases. Drainage of the cavity is recommended when specific indications are met. Endoscopic drainage has been adopted as the main intervention for symptomatic walled-off PFC. Altered gastric anatomy in these patients poses an interesting challenge. We present the first case of a patient with sleeve gastrectomy who underwent successful endoscopic transduodenal necrosectomy (TDN). CASE PRESENTATION: Forty year old woman with history of morbid obesity status post sleeve gastrectomy in 2009 was found to have symptomatic gallstone disease complicated by severe necrotizing gallstone pancreatitis and further complicated by symptomatic walled off pancreatic necrosis (WOPN). Imaging significant for 10.8 × 7.6 cm fluid collection with necrotic debris in the body and tail of the pancreas and endoscopic necrosectomy was attempted. EGD showed tubular gastric body and antrum, with extrinsic compression in the antrum and duodenal bulb from the pancreatic cyst. Duodenal bulb was selected as the preferred fistula site due to sleeve gastrectomy. Patient underwent successful TDN in two sessions. Patient had symptomatic improvement at follow-up with resolution of WOPN. CONCLUSION: To our knowledge, this is the first reported case of EUS-guided endoscopic necrosectomy in a patient with sleeve gastrectomy. The duodenal approach was used in our patient due to history of sleeve gastrectomy.

Use of aerosolized aminoglycosides in the treatment of Gram-negative ventilator-associated pneumonia.

BACKGROUND AND PURPOSE: Ventilator-associated pneumonia (VAP) in the surgical intensive care unit (ICU) is associated with substantial morbidity and mortality. Affected patients are at higher risk for infection with multi-drug-resistant (MDR) pathogens, often necessitating therapeutic regimens of two parenteral antibiotics. Aerosolized antibiotics achieve high alveolar concentrations and have been reported anecdotally to have value in the treatment of VAP. This study examined the role of aerosolized aminoglycosides in the treatment of VAP in surgical ICU patients. METHODS: We reviewed retrospectively the medical records of 22 patients who received aerosolized aminoglycosides in conjunction with parenteral antibiotics for VAP in the surgical ICU. Sixteen patients received inhaled tobramycin, and six received inhaled amikacin. Demographic information and data on the length of stay (LOS), mortality rate, days of antibiotic therapy, days of mechanical ventilation, and recurrence of VAP were collected. Results of bronchoscopic and sputum cultures were reviewed to identify bacterial pathogens and antimicrobial susceptibilities. RESULTS: The average duration of mechanical ventilation was 31 +/- 12 days, the mean ICU LOS was 41 +/- 13 days, and the mean hospital LOS was 71 +/- 25 days. There were three deaths. The average duration of mechanical ventilation after initiation of aerosolized antibiotics was 4.3 days. Seven patients (40%) developed recurrent pneumonia with the same pathogen, but only one had a change in antibiotic susceptibility pattern. There were no renal or pulmonary complications of aminoglycoside treatment. CONCLUSIONS: Ventilator-associated pneumonia in critically ill patients is associated with substantial morbidity, longer ICU stays, and prolonged mechanical ventilation. Along with systemic therapy, aerosolized aminoglycosides are valuable adjuncts in select patients with minimal risk of antibiotic resistance.