Propensity score matched analysis of laparoscopic revisional and conversional sleeve gastrectomy with concurrent hiatal hernia repair.

INTRODUCTION: The primary aim of this study was to evaluate outcomes associated with concurrent hiatal hernia repair (CHHR) when performing a conversional or revisional vertical sleeve gastrectomy (VSG). CHHR is often necessary during VSG due to potential gastroesophageal reflux disease (GERD) development or obstructive symptoms. METHODS: The Metabolic and Bariatric Surgery Accreditation and Quality Improvement (MBSAQIP) participant use file was assessed for the years 2015-2020 for revisional/conversional VSG procedures. The presence of CHHR was used to create two groups. Propensity score matching (PSM) was performed with E-analysis. RESULTS: There were 33,909 patients available, with 5986 undergoing the VSG procedure with CHHR. In the unmatched analysis, there was an increased frequency of patients being female (85.72 vs 83.30%; p < 0.001), having a history of GERD (38.01 vs 31.25%; p < 0.001), and being of older age (49.59 ± 10.97 vs 48.70 ± 10.83; p < 0.001). Patients undergoing VSG with CHHR experienced decreased sleep apnea (25.00 vs 28.84%; p < 0.001) and diabetes (14.27 vs 17.80%; p < 0.001). PSM yielded 5986 patient pairs. Matched patients with CHHR experienced increased operative time (115 min ± 53 vs 103 min ± 51; p < 0.001), increased risk of postoperative pneumonia (0.45 vs 0.15%; p = 0.005) and readmission (4.69 vs 3.58%; p = 0.002) within thirty days. However, patients undergoing CHHR with revisional or conversional VSG did not experience increased risk of death, postoperative bleeding, postoperative leak, or reoperations. CONCLUSION: Despite a small association with increased postoperative pneumonia, the rate of complications in patients undergoing laparoscopic revisional/conversional VSG and CHHR are low. CHHR is a safe option when combined with the laparoscopic revisional/conversional VSG procedure in the early postoperative period.

Hepatocellular RECK as a Critical Regulator of Metabolic Dysfunction-associated Steatohepatitis Development.

BACKGROUND & AIMS: Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is an extracellular matrix regulator with anti-fibrotic effects. However, its expression and role in metabolic dysfunction-associated steatohepatitis (MASH) and hepatic fibrosis are poorly understood. METHODS: We generated a novel transgenic mouse model with RECK overexpression specifically in hepatocytes to investigate its role in Western diet (WD)-induced liver disease. Proteomic analysis and in vitro studies were performed to mechanistically link RECK to hepatic inflammation and fibrosis. RESULTS: Our results show that RECK expression is significantly decreased in liver biopsies from human patients diagnosed with MASH and correlated negatively with severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and fibrosis. Similarly, RECK expression is downregulated in WD-induced MASH in wild-type mice. Hepatocyte-specific RECK overexpression significantly reduced hepatic pathology in WD-induced liver injury. Proteomic analysis highlighted changes in extracellular matrix and cell-signaling proteins. In vitro mechanistic studies linked RECK induction to reduced ADAM10 (a disintegrin and metalloproteinase domain-containing protein 10) and ADAM17 activity, amphiregulin release, epidermal growth factor receptor activation, and stellate cell activation. CONCLUSION: Our in vivo and mechanistic in vitro studies reveal that RECK is a novel upstream regulator of inflammation and fibrosis in the diseased liver, its induction is hepatoprotective, and thus highlights its potential as a novel therapeutic in MASH.

Order of amino acid recruitment into the genetic code resolved by Last Universal Common Ancestor's protein domains.

The current "consensus" order in which amino acids were added to the genetic code is based on potentially biased criteria such as absence of sulfur-containing amino acids from the Urey-Miller experiment which lacked sulfur. Even if inferred perfectly, abiotic abundance might not reflect abundance in the organisms in which the genetic code evolved. Here, we instead exploit the fact that proteins that emerged prior to the genetic code's completion are likely enriched in early amino acids and depleted in late amino acids. We identify the most ancient protein-coding sequences born prior to the archaeal-bacterial split. Amino acid usage in protein sequences whose ancestors date back to a single homolog in the Last Universal Common Ancestor (LUCA) largely matches the consensus order. However, our findings indicate that metal-binding (cysteine and histidine) and sulfur-containing (cysteine and methionine) amino acids were added to the genetic code much earlier than previously thought. Surprisingly, even more ancient protein sequences - those that had already diversified into multiple distinct copies in LUCA - show a different pattern to single copy LUCA sequences: significantly less depleted in the late amino acids tryptophan and tyrosine, and enriched rather than depleted in phenylalanine. This is compatible with at least some of these sequences predating the current genetic code. Their distinct enrichment patterns thus provide hints about earlier, alternative genetic codes.

Laparoscopic Conversion of Gastric Bypass to Distal Gastric Bypass for Inadequate Weight Loss.

BACKGROUND: Although uncommon, significant weight recurrence after Roux-en-Y gastric bypass (RYGB) can occur. Options are limited to help patients achieve additional weight loss, and improved techniques for revisional/conversional surgery are needed to achieve optimal outcomes while avoiding significant side effects. Although limited data exist regarding distalization of the Roux limb to achieve a longer biliopancreatic limb leading to some level of malabsorption, we have seen adequate weight loss with minimal significant side effects in patients undergoing this procedure with our approach. An appropriate technical approach to this procedure is important to avoid immediate and long-term complications. METHODS AND RESULTS: We present a video describing our approach to Roux limb distalization for weight gain after gastric bypass, describing our approach for work-up, operative technical pearls, and postoperative monitoring in these patients. A 61 year-old female who initially had good weight loss after RYGB with a body mass index (BMI) nadir of 33, from a preoperative BMI of 53, experienced weight recurrence with her BMI increasing to 48. After preoperative nutritional optimization, dietary counseling, and behavioral counseling, she underwent conversion of RYGB to distalization of Roux limb to create a distal RYGB. She tolerated the procedure well and was discharged on postoperative day 2. At 1-year follow-up, her BMI had decreased to 37 with improvement in dyslipidemia, elevation of liver transaminases, and improvement in hemoglobin A1C. This reflects the impact of this procedure on not only weight loss but also concurrent metabolic diseases associated with obesity. CONCLUSION: We present a case of distalization of a RYGB for weight recurrence, highlighting the technical pearls when performing the procedure. Accurate, intraoperative measurement of the total alimentary limb length is essential to achieve weight loss while minimizing malnutrition and vitamin deficiencies. Assessment of preoperative nutritional levels for evidence of any protein calorie malnutrition is important during surgical decision-making when this conversional metabolic operation is considered. Frequent, postoperative nutritional monitoring is important and occurs with a full bariatric nutritional panel at 3, 6, 9, and 12 months then yearly thereafter. Using our approach, we feel that conversion of RYGB to distalization of Roux limb can lead to improved weight loss without significant side effects.

Neuraminidase-induced externalization of phosphatidylserine activates ADAM17 and impairs insulin signaling in endothelial cells.

Endothelial insulin resistance represents a causal factor in the pathogenesis of type 2 diabetes (T2D) and vascular disease, thus the need to identify molecular mechanisms underlying defects in endothelial insulin signaling. We previously have shown that a disintegrin and metalloproteinase-17 (ADAM17) is increased while insulin receptor α-subunit (IRα) is decreased in the vasculature of patients with T2D, leading to impaired insulin-induced vasodilation. We have also demonstrated that ADAM17 sheddase activity targets IRα; however, the mechanisms driving endothelial ADAM17 activity in T2D are largely unknown. Herein, we report that externalization of phosphatidylserine (PS) to the outer leaflet of the plasma membrane causes ADAM17-mediated shedding of IRα and blunting of insulin signaling in endothelial cells. Furthermore, we demonstrate that endothelial PS externalization is mediated by the phospholipid scramblase anoctamin-6 (ANO6) and that this process can be stimulated by neuraminidase, a soluble enzyme that cleaves sialic acid residues. Of note, we demonstrate that men and women with T2D display increased levels of neuraminidase activity in plasma, relative to age-matched healthy individuals, and this occurs in conjunction with increased ADAM17 activity and impaired leg blood flow responses to endogenous insulin. Collectively, this work reveals the neuraminidase-ANO6-ADAM17 axis as a novel potential target for restoring endothelial insulin sensitivity in T2D.NEW & NOTEWORTHY This work provides the first evidence that neuraminidase, an enzyme increased in the circulation of men and women with type 2 diabetes (T2D), promotes anoctamin-6 (ANO6)-dependent externalization of phosphatidylserine in endothelial cells, which in turn leads to activation of a disintegrin and metalloproteinase-17 (ADAM17) and consequent shedding of the insulin receptor-α from the cell surface. Hence, this work supports that consideration should be given to the neuraminidase-ANO6-ADAM17 axis as a novel potential target for restoring endothelial insulin sensitivity in T2D.

Safety and usability of an endo staple line reinforcement device for pulmonary resections.

Background: Pulmonary resection can present technical challenges for surgeons due to the dissection and closure of tissues, which vary in thickness and elastic properties, occasionally leading to prolonged air leaks. Staple line reinforcements (SLRs) are widely utilized tools for fortifying the stability and integrity of closures in thoracic surgery, however, materials available and ease of use for both surgeon and scrub nurse have been suboptimal. A novel "click-and-go" device pre-loaded with bioabsorbable buttress material was recently developed, the Echelon Endopath SLR (ESLR, Ethicon, Inc., Cincinnati, OH, USA). This prospective study examines the safety and efficacy of this novel device in lung resections. Methods: Adult surgical candidates undergoing primary pulmonary resection (both open and thoracoscopic) where the ESLR would be used were enrolled. Exclusion included reoperation/revision in same anatomical location, hypersensitivity to polyglactin or related products, and body mass index (BMI) ≥46.0 kg/m2. The primary endpoint assessed the incidence of specific device-related adverse events (AEs): prolonged air leak and empyema. Additional endpoints included number of devices replaced during surgery due to slippage or bunching, and surgeon-reported usability responses. Data was summarized for AEs deemed device-related and usability questionnaire responses. Results: A total of 131 subjects were included in the primary endpoint analysis data set with 120 subjects completing the study (91.6%). The mean age at consent was 62.8±12.0 years and 55.7% were female. The most common primary indication for the procedure was malignancy 61.1%, and primary non-malignant lung disease (non-chronic obstructive pulmonary disease) 12.2%. Common procedures performed were wedge resection (58.0%) and lobectomy (34.4%). There were zero reported device-specific/-related AEs which counted toward the primary endpoint. Responses from a usability questionnaire found all surgeons (100.0%) reported the ease of setup was superior to previous devices utilized. Surgeons expressed greater confidence in the buttress material of the ESLR than that of previous SLR devices (strongly agree 88.9%; slightly agree 11.1%). Most also felt that there was less wastage with the click-and-go ESLR (strongly agree 77.8%, slightly agree 11.1%, neutral 11.1%). Conclusions: The ESLR device demonstrates safe and effective performance in this post-market study of specific thoracic procedures. Furthermore, surgeons found this was easier to use.

Duodenal Diverticulitis Following Biliopancreatic Diversion: A Case Report.

Duodenal diverticulitis is a relatively uncommon finding in patients. Treatment of complications of duodenal diverticulitis may be challenging in patients with altered intestinal anatomy such as those with altered anatomy from weight loss procedures involving intestinal bypass. We present a case report describing the management of duodenal diverticulitis following a biliopancreatic diversion, our decision-making process, and our final treatment strategy.

Isotope Labeling and Biochemical Assessment of Liver-Triacylglycerol in Patients with Different Levels of Histologically-Graded Liver Disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) prevalence is rapidly growing, and fatty liver has been found in a quarter of the US population. Increased liver lipids, particularly those derived from the pathway of de novo lipogenesis (DNL), have been identified as a hallmark feature in individuals with high liver fat. This has led to much activity in basic science and drug development in this area. No studies to date have investigated the contribution of DNL across a spectrum of disease, although it is clear that inhibition of DNL has been shown to reduce liver fat. OBJECTIVES: The purpose of this study was to determine whether liver lipid synthesis increases across the continuum of liver injury. METHODS: Individuals (n = 49) consumed deuterated water for 10 d before their scheduled bariatric surgeries to label DNL; blood and liver tissue samples were obtained on the day of the surgery. Liver lipid concentrations were quantitated, and levels of protein and gene expression assessed. RESULTS: Increased liver DNL, measured isotopically, was significantly associated with liver fatty acid synthase protein content (R = 0.470, P = 0.003), total steatosis assessed by histology (R = 0.526, P = 0.0008), and the fraction of DNL fatty acids in plasma very low-density lipoprotein-triacylglycerol (R = 0.747, P < 0.001). Regression analysis revealed a parabolic relationship between fractional liver DNL (percent) and NAFLD activity score (R = 0.538, P = 0.0004). CONCLUSION: These data demonstrate that higher DNL is associated with early to mid stages of liver disease, and this pathway may be an effective target for the treatment of NAFLD and nonalcoholic steatohepatitis. This study was registered at clinicaltrials.gov as NCT03683589.

Concurrent paraesophageal hernia repair in revisional/conversional laparoscopic Roux-en-Y gastric bypass: propensity score-matched analysis of the MBSAQIP database.

BACKGROUND: Patients requiring concurrent paraesophageal hernia repair (CPHR) have been shown to have favorable outcomes in primary bariatric surgery. However, patients requiring revisional or conversional surgery represent a group of patients with higher perioperative risk. Currently, few reports on concurrent paraesophageal hernia repair utilizing the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) database are available. The primary aim of this study was to determine perioperative complications associated with CPHR and the Roux-en-Y gastric bypass (RYGB) as a revisional/conversional operation. METHODS: In this study, patients undergoing revisional/conversional RYGB between 2015 and 2020 were accessed via the MBSAQIP database. Patients were categorized based on the presence of a paraesophageal hernia as a concurrent procedure. Patients who underwent revisional/conversional surgery without additional procedures were utilized for controls. A propensity score-matched cohort was generated and E-analysis utilized to assess unmeasured confounding. RESULTS: After exclusions, 35,698 patients were available. Patients receiving CPHR were more likely to be female (90.79% vs 87.37%; p < 0.001) and have increased frequency of gastroesophageal reflux disease (69.20% vs 51.69%; p < 0.001). However, these patients had lower frequencies of sleep apnea (24.12% vs 30.13%; p < 0.001), hypertension requiring medication (38.51% vs 42.59%; p < 0.001), and decreased frequency of hyperlipidemia (19.44% vs 21.60%;p < 0.001). After matching, 6,231 patient pairs were developed and showed that patients undergoing CPHR were at increased risk of readmission (9.44% vs 7.58%; p < 0.001), intervention (3.56% vs 2.79%; p = 0.018), increased requirement for outpatient dehydration treatment (5.87% vs 4.67%;p = 0.004), and overall increased operation time (169.3 min ± 76.0 vs 153.5 ± 73.3; p < 0.001). However, there were no significant increases in the rates of reoperation, death, postoperative leak complications, or bleeding complications after CPHR. CONCLUSION: Patients undergoing revisional/conversional RYGB with CPHR may be at higher risk for a small number of rare postoperative complications. CPHR is a safe procedure in patients undergoing revisional/conversional RYGB in the short-term postoperative period.

Laparoscopic Conversion of Single-Anastomosis Duodenal Switch (SADI-S) to Roux-en-Y Gastric Bypass With Concurrent Paraesophageal Hernia Repair for Refractory Biliary Reflux and Paraesophageal Hernia.

Single-anastomosis duodenal switch (SADI-S) is effective for weight loss with low reported rates of complications. Bile reflux into the stomach or esophagus is an uncommonly reported complication but can lead to significant symptoms for patients suffering from this complication. Concurrent paraesophageal hernia can exacerbate the symptoms of biliary reflux gastritis. We present a case report describing the management of biliary reflux gastritis with concurrent paraesophageal hernia, our decision-making process, and technical pearls and possible pitfalls.

Western diet contributes to the pathogenesis of non-alcoholic steatohepatitis in male mice via remodeling gut microbiota and increasing production of 2-oleoylglycerol.

The interplay between western diet and gut microbiota drives the development of non-alcoholic fatty liver disease and its progression to non-alcoholic steatohepatitis. However, the specific microbial and metabolic mediators contributing to non-alcoholic steatohepatitis remain to be identified. Here, a choline-low high-fat and high-sugar diet, representing a typical western diet, named CL-HFS, successfully induces male mouse non-alcoholic steatohepatitis with some features of the human disease, such as hepatic inflammation, steatosis, and fibrosis. Metataxonomic and metabolomic studies identify Blautia producta and 2-oleoylglycerol as clinically relevant bacterial and metabolic mediators contributing to CL-HFS-induced non-alcoholic steatohepatitis. In vivo studies validate that both Blautia producta and 2-oleoylglycerol promote liver inflammation and hepatic fibrosis in normal diet- or CL-HFS-fed mice. Cellular and molecular studies reveal that the GPR119/TAK1/NF-κB/TGF-ß1 signaling pathway mediates 2-oleoylglycerol-induced macrophage priming and subsequent hepatic stellate cell activation. These findings advance our understanding of non-alcoholic steatohepatitis pathogenesis and provide targets for developing microbiome/metabolite-based therapeutic strategies against non-alcoholic steatohepatitis.

Hypoalbuminemia as a risk factor for complications in revisional/conversional bariatric surgery: an MBSAQIP analysis.

BACKGROUND: Hypoalbuminemia (HA) is a risk factor for serious complications after elective bariatric surgery. Patients undergoing revisional/conversional bariatric surgery may represent a higher-risk group who often have underlying co-morbid medical illnesses and more complex surgery. OBJECTIVES: This study investigated the postoperative complications in patients with HA undergoing revisional/conversional bariatric surgery. SETTING: Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP), years 2015-2019. METHODS: The MBSAQIP database was used to evaluate patients undergoing non-banding revisional/conversional bariatric surgery between 2015 and 2019. Patients were categorized by serum albumin (≤3.5 g/dL). Variables were assessed via bivariate analysis and multivariable regression. Propensity score matching was conducted to compare gastric bypass (RYGB) to sleeve gastrectomy (VSG). RESULTS: One hundred forty-seven thousand four hundred thirty patients underwent revisional/conversional procedures. After applied exclusions, 58,777 patients were available for analysis. The HA group had a significantly (P < .05) higher prevalence of being black (22.95% versus 17.76%), renal insufficiency (1.08% versus .36%), smoking history (9.47% versus 6.91%), chronic obstructive pulmonary disease (COPD) (2.54% versus 1.33%), and history of deep vein thrombosis (DVT) (4.03% versus 2.3%). Postoperative complications associated with HA included perioperative blood transfusion (3.1% versus 1.27%; P < .001), 30day readmission (10.87 versus 6.77%; P < .001), 30day reoperation (4.9% versus 3.18%; P < .001), and 30day mortality (.40% versus .14%; P < .0001). HA was a significant predictor of 30day readmission in the RYGB versus VSG matched cohort (odds ratio [OR], 1.30; 95% confidence interval [CI], [1.14, 1.48]; P < .001). CONCLUSIONS: HA is a risk factor requiring attention for patients undergoing revisional/conversional bariatric surgery and optimization of nutritional status or medical comorbidities associated with HA prior to bariatric surgery may help avoid postoperative complications.

Frailty, Comorbidity, and Associations With In-Hospital Mortality in Older COVID-19 Patients: Exploratory Study of Administrative Data.

BACKGROUND: Older adults have worse outcomes following hospitalization with COVID-19, but within this group there is substantial variation. Although frailty and comorbidity are key determinants of mortality, it is less clear which specific manifestations of frailty and comorbidity are associated with the worst outcomes. OBJECTIVE: We aimed to identify the key comorbidities and domains of frailty that were associated with in-hospital mortality in older patients with COVID-19 using models developed for machine learning algorithms. METHODS: This was a retrospective study that used the Hospital Episode Statistics administrative data set from March 1, 2020, to February 28, 2021, for hospitalized patients in England aged 65 years or older. The data set was split into separate training (70%), test (15%), and validation (15%) data sets during model development. Global frailty was assessed using the Hospital Frailty Risk Score (HFRS) and specific domains of frailty were identified using the Global Frailty Scale (GFS). Comorbidity was assessed using the Charlson Comorbidity Index (CCI). Additional features employed in the random forest algorithms included age, sex, deprivation, ethnicity, discharge month and year, geographical region, hospital trust, disease severity, and International Statistical Classification of Disease, 10th Edition codes recorded during the admission. Features were selected, preprocessed, and input into a series of random forest classification algorithms developed to identify factors strongly associated with in-hospital mortality. Two models were developed; the first model included the demographic, hospital-related, and disease-related items described above, as well as individual GFS domains and CCI items. The second model was similar to the first but replaced the GFS domains and CCI items with the HFRS as a global measure of frailty. Model performance was assessed using the area under the receiver operating characteristic (AUROC) curve and measures of model accuracy. RESULTS: In total, 215,831 patients were included. The model using the individual GFS domains and CCI items had an AUROC curve for in-hospital mortality of 90% and a predictive accuracy of 83%. The model using the HFRS had similar performance (AUROC curve 90%, predictive accuracy 82%). The most important frailty items in the GFS were dementia/delirium, falls/fractures, and pressure ulcers/weight loss. The most important comorbidity items in the CCI were cancer, heart failure, and renal disease. CONCLUSIONS: The physical manifestations of frailty and comorbidity, particularly a history of cognitive impairment and falls, may be useful in identification of patients who need additional support during hospitalization with COVID-19.

ADAM17 cleaves the insulin receptor ectodomain on endothelial cells and causes vascular insulin resistance.

Inflammation and vascular insulin resistance are hallmarks of type 2 diabetes (T2D). However, several potential mechanisms causing abnormal endothelial insulin signaling in T2D need further investigation. Evidence indicates that the activity of ADAM17 (a disintegrin and metalloproteinase-17) and the presence of insulin receptor (IR) in plasma are increased in subjects with T2D. Accordingly, we hypothesized that in T2D, increased ADAM17 activity sheds the IR ectodomain from endothelial cells and impairs insulin-induced vasodilation. We used small visceral arteries isolated from a cross-sectional study of subjects with and without T2D undergoing bariatric surgery, human cultured endothelial cells, and recombinant proteins to test our hypothesis. Here, we demonstrate that arteries from subjects with T2D had increased ADAM17 expression, reduced presence of tissue inhibitor of metalloproteinase-3 (TIMP3), decreased extracellular IRα, and impaired insulin-induced vasodilation versus those from subjects without T2D. In vitro, active ADAM17 cleaved the ectodomain of the IRß subunit. Endothelial cells with ADAM17 overexpression or exposed to the protein kinase-C activator, PMA, had increased ADAM17 activity, decreased IRα presence on the cell surface, and increased IR shedding. Moreover, pharmacological inhibition of ADAM17 with TAPI-0 rescued PMA-induced IR shedding and insulin-signaling impairments in endothelial cells and insulin-stimulated vasodilation in human arteries. In aggregate, our findings suggest that ADAM17-mediated shedding of IR from the endothelial surface impairs insulin-mediated vasodilation. Thus, we propose that inhibition of ADAM17 sheddase activity should be considered a strategy to restore vascular insulin sensitivity in T2D.NEW & NOTEWORTHY To our knowledge, this is the first study to investigate the involvement of ADAM17 in causing impaired insulin-induced vasodilation in T2D. We provide evidence that ADAM17 activity is increased in the vasculature of patients with T2D and support the notion that ADAM17-mediated shedding of endothelial IRα ectodomains is a novel mechanism causing vascular insulin resistance. Our results highlight that targeting ADAM17 activity may be a potential therapeutic strategy to correct vascular insulin resistance in T2D.

The Utility and Diagnostic Accuracy of Transient Elastography in Adults with Morbid Obesity: A Prospective Study.

Patients with morbid obesity are at high risk for nonalcoholic fatty liver disease (NAFLD) complicated by liver fibrosis. The clinical utility of transient elastography (TE) by Fibroscan in patients with morbid obesity (body mass index (BMI) ≥ 40 kg/m2) is not well-defined. We examined the diagnostic accuracy of Fibroscan in predicting significant liver fibrosis (fibrosis stage ≥2) in morbidly obese patients (BMI ≥ 40 kg/m2). Patients scheduled for bariatric surgery were prospectively enrolled. Intraoperative liver biopsy, liver-stiffness measurement (LSM) by Fibroscan (XL probe), and biochemical evaluation were all performed on the same day. The endpoint was significant liver fibrosis defined as fibrosis stage ≥2 based on the Nonalcoholic Steatohepatitis Clinical Research Network. The optimal LSM cutoff value for detecting significant fibrosis was determined by using the Youden Index method. Routine clinical, laboratory, and elastography data were analyzed by stepwise logistic regression analysis to identify predictors of significant liver fibrosis and build a predictive model. An optimal cutoff point of the new model's regression formula for predicting significant fibrosis was determined by using the Youden index method. One hundred sixty-seven patients (mean age, 46.4 years) were included, of whom 83.2% were female. Histological assessment revealed the prevalence of steatohepatitis and significant fibrosis of 40.7% and 11.4%, respectively. The median LSM was found to be significantly higher in the significant fibrosis group compared to those in the no or non-significant fibrosis group (18.2 vs. 7.7 kPa, respectively; p = 0.0004). The optimal LSM cutoff for predicting significant fibrosis was 12.8 kPa, with an accuracy of 71.3%, sensitivity of 73.7%, specificity of 70.9%, positive predictive value of 24.6%, negative predictive value of 95.5%, and ROC area of 0.723 (95% CI: 0.62-0.83). Logistic regression analysis identified three independent predictors of significant fibrosis: LSM, hemoglobin A1c, and alkaline phosphatase. A risk score was developed by using these three variables. At an optimal cutoff value of the regression formula, the risk score had an accuracy of 79.6% for predicting significant fibrosis, sensitivity of 89.5%, specificity of 78.4%, positive predictive value of 34.7%, negative predictive value of 98.3%, and ROC area of 0.855 (95% CI: 0.76-0.95). Fibroscan utility in predicting significant liver fibrosis in morbidly obese subjects is limited with accuracy of 71.3%. A model incorporating hemoglobin A1c and alkaline phosphatase with LSM improves accuracy in detecting significant fibrosis in this patient population.

Compromised hepatic mitochondrial fatty acid oxidation and reduced markers of mitochondrial turnover in human NAFLD.

BACKGROUND AND AIMS: NAFLD and its more-advanced form, steatohepatitis (NASH), is associated with obesity and is an independent risk factor for cardiovascular, liver-related, and all-cause mortality. Available human data examining hepatic mitochondrial fatty acid oxidation (FAO) and hepatic mitochondrial turnover in NAFLD and NASH are scant. APPROACH AND RESULTS: To investigate this relationship, liver biopsies were obtained from patients with obesity undergoing bariatric surgery and data clustered into four groups based on hepatic histopathological classification: Control (CTRL; no disease); NAFL (steatosis only); Borderline-NASH (steatosis with lobular inflammation or hepatocellular ballooning); and Definite-NASH (D-NASH; steatosis, lobular inflammation, and hepatocellular ballooning). Hepatic mitochondrial complete FAO to CO2 and the rate-limiting enzyme in ß-oxidation (ß-hydroxyacyl-CoA dehydrogenase activity) were reduced by ~40%-50% with D-NASH compared with CTRL. This corresponded with increased hepatic mitochondrial reactive oxygen species production, as well as dramatic reductions in markers of mitochondrial biogenesis, autophagy, mitophagy, fission, and fusion in NAFL and NASH. CONCLUSIONS: These findings suggest that compromised hepatic FAO and mitochondrial turnover are intimately linked to increasing NAFLD severity in patients with obesity.

Dissecting Differential Complex Behavioral Responses to Simulated Space Radiation Exposures.

This study has established the impact that space radiation exposure has on the capability of rats to successfully negotiate behavioral tasks of increasing complexity. Rats previously exposed to a low dose (10 cGy) of either 4He ions or a cocktail of 6 ions that simulates the galactic cosmic ray spectrum (GCRSim) were screened initially on an attentional set shifting (ATSET) task that provides a measure of executive function. Rats that exhibited superior ATSET performance were then selected for follow up behavioral assessments designed to evaluate how the cohort of "good performers" would fare when presented with a novel behavioral paradigm termed the Associative Recognition Memory and Interference Touchscreen (ARMIT) task. Central to this approach was to discriminate if/how adaptive problem solving would be impacted by changing the options of associative cues presented over several learning sessions to obtain a reward under time constraints using this newly designed touch screen-based task. Data from these studies indicated that when faced with an increased cognitive load, possibly due to interference from prior associative recognition memories, rats exhibited impairments in their capability to negotiate task dynamics and efficiently engage abstract reasoning. Interestingly, while exposure to the GCRSim adversely impacted problem-solving capabilities, single ion exposure did not, pointing to the nuances of space radiation exposure on CNS functionality. Since the selected behavioral paradigms exhibit strong cross-species correlates, data suggest that rodents succumb to increased task rigor as observed in humans, and make similar mistakes when challenged with the interference of overlapping associative memories. Furthermore, data clearly points to the limitations of over-reliance on a single cognitive endpoint that may underestimate global neurocognitive risk due to space radiation exposure.

A Model Incorporating Serum Alkaline Phosphatase for Prediction of Liver Fibrosis in Adults with Obesity and Nonalcoholic Fatty Liver Disease.

We assessed the relationship between serum alkaline phosphatase (ALP) and liver fibrosis by histology, in addition to other noninvasive parameters, in obese patients undergoing metabolic surgery. Patients scheduled for elective bariatric surgery were prospectively recruited from a bariatric clinic. An intraoperative liver biopsy was performed, and liver histology was evaluated by a pathologist blinded to the patients' data. The endpoint was significant fibrosis defined as fibrosis stage ≥ 2. Independent predictors of fibrosis were identified by logistic regression. Two hundred ten patients were recruited. Liver histology revealed steatosis in 87.1%, steatohepatitis in 21.9%, and significant fibrosis in 10%. Independent predictors of significant fibrosis were ALP (Odds Ratio (OR) 1.03; 95% Confidence interval (CI), 1.01-1.05), alanine aminotransferase (OR 1.02; 95% CI, 1.01-1.03), HbA1c (OR 1.58; 95% CI, 1.20-2.09), and body mass index (OR 1.06; 95% CI, 1.00-1.13). A tree-based model was developed to predict significant fibrosis, with a receiver operating characteristic (ROC) area of 0.845, sensitivity of 0.857, specificity of 0.836, and accuracy of 0.931. The applicability of serum ALP as an independent biomarker of liver fibrosis should be considered in obesity surgery patients, and in the broader context of obese patients with nonalcoholic fatty liver disease.

Type IV Hiatal Hernia Containing the Gastric Pouch and Proximal Roux Limb: A Rare Cause of Bowel Obstruction Following Roux-en-Y Bypass Surgery.

Roux-en-Y gastric bypass (RYGB) is considered the gold standard for weight loss surgery and is an effective, safe treatment for morbid obesity and associated metabolic derangements. Complications such as small bowel obstruction are rare with a reported incidence of 5%. Obstruction caused by hiatal herniation of the gastric pouch and alimentary limb occurs even less frequently. Prompt recognition and treatment are imperative as delayed intervention may result in significant morbidity. At the time of this manuscript there have only been four reported cases in the literature highlighting a paucity of clinical guidance for the recognition and management of this complication. Here we present a case of acute small bowel obstruction secondary to hiatal herniation of the gastric pouch and proximal Roux limb. Furthermore, we review the literature and discuss the key aspects for the management of this complication.