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Introduction: Acetaminophen (APAP) toxicity remains a significant cause of adult and pediatric liver failure in North America and Europe. Previous research has evaluated the impaired mitochondrial function associated with APAP toxicity. The primary aim of this study was to evaluate the effects of APAP toxicity on platelet mitochondrial function using platelet oxygen consumption in a murine model in vivo. Our secondary objectives were to determine the effect of 4-MP on platelet mitochondrial function and hepatic toxicity in the setting of APAP overdose, and to correlate platelet mitochondrial function with other markers of APAP toxicity., Methods: Male C57Bl/6 mice were randomized to receive APAP (300 or 500 mg/kg) or vehicle followed 90 minutes later by either 4-MP (50 mg/kg) or vehicle via intraperitoneal injection. Mice were euthanized 0, 12, or 24 hours later and platelets isolated from cardiac blood and counted. Platelet oxygen consumption (POC) was determined using a closed-system respirometer. Liver injury was assessed by measuring alanine transferase (ALT) and histological evaluation., Results: Injection of 500 mg/kg APAP led to increased POC versus pair-matched control (vehicle) (p < 0.001). Administration of 4-MP did not affect POC in control or 300 mg/kg APAP mice. In mice receiving 500 mg/kg APAP and 4-MP, POC decreased significantly compared to mice receiving 500 mg/kg APAP alone (p < 0.01). Serum and histological analysis confirmed APAP-induced hepatic damage in mice receiving 500 mg/kg APAP and these effects blunted by treatment with 4-MP., Conclusions: Platelet oxygen consumption as a measure of mitochondrial function may be useful as a biomarker of hepatic APAP toxicity in the setting of moderate to severe overdose. Treatment with 4-MP decreases hepatic necrosis and may mitigate the harmful effects of APAP on platelet mitochondrial function detected via POC., (© 2023. American College of Medical Toxicology.)

Introduction: Jejunojejunal intussusception (JI) is a serious but rare complication that may occur following Roux-en-Y gastric bypass (RYGB) surgery. Causes of JI and best management strategy are not clearly defined., Methods: Electronic health records were queried for ICD 9/10 codes for intussusception after RYGB surgery (2009-2019), and charts retrospectively reviewed. Patient demographics, operative technique, presentation, radiology, and JI management were analyzed., Results: Of the 2,327 RYGB patients identified at our institute, 34 (1.5%) were treated for JI. The mean age was 45.0 ± 8.6 years, mean BMI (RYGB surgery) was 43.1 ± 8.2 kg/m 2 , mean BMI at JI was 28.3 ± 5.8 kg/m 2 , and 30/34 were female, The mean time between RYGB and JI was 5.5 ± 4.3 years (range 1-17 years). Of the JI patients identified, 9 had operative notes that did not include jejunojejunostomy linear stapler length (JJ-LSL). Of the remaining 25 JI patients, 9 had a 60-mm JJ-LSL and 16 had a 120-mm JJ-LSL. Rate of intussusception was higher in the 120-mm versus 60-mm JJ-LSL group (p < 0.05). Acute abdominal pain was present in all JI patients and 32/34 had radiologic findings (CT scan) that corroborated for JI. The majority of JI patients were managed operatively (26/34) with 22/26 using laparoscopy (2/22 were converted to open). Intraoperative findings included intussusception (15/26), and 9/26 had other pathologies (internal hernia (2/26), cholecystitis (4/26), marginal ulcer (3/26)). Operative management of JI was either reduction and enteropexy (7/15), reduction only (5/15), or JJ revision (3/15). Recurrence of JI occurred in 7/23 patients, of who 4/7 were managed operatively., Conclusions: In our experience, JI appears to be a relatively rare complication after RYGB surgery. However, for patients developing JI, the majority had a JJ length ≥ 120 mm, and most patients required operative management which was associated with a higher rate of conversion to open and risk of JI recurrence. Reduction only technique had the highest risk of JI recurrence and therefore is not recommended.

Background: Bariatric surgery is the most effective modality to treat obesity and obesity-related comorbidities. This study sought to utilize the MBASQIP® Data Registry to analyze the impact of age at time of surgery on outcomes following sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB) procedures., Methods: The MBSAQIP® Data Registry for patients undergoing SG or RYGB procedures between 2015 and 2016 was reviewed. Patients were divided into 4 age groups [18-44; 45-54; 55-64; > 65 years]. Minimal exclusions for revisional and/or emergency surgery were selected and combination variables created to classify complications as major or minor. A comorbidity index was constructed to include diabetes, gastroesophageal reflux disease (GERD), obstructive sleep apnea (OSA), and prior cardiac surgery. Univariate and multivariate logistic regression analyses were performed to compare age stratifications to the young adult (18-45 years) cohort., Results: Of 301,605 cases, 279,419 cases (71.2% SG) remained after applying exclusion criteria (79.2% female, mean BMI 45.5 ± 8.1 kg/m 2 , 8.9% insulin-dependent diabetics). Mean age was 44.7 ± 12.0 years (51.3% 18-44 years; 26.9% 45-54 years; 16.3% 55-64 years; 5.5% > 65 years). A univariate analysis demonstrated preoperative differences of lower BMI with increasing age concomitant with increasing frequency of RYGB and a higher comorbidity index (p < 0.0001 vs. 18-45 years). At age > 45 years, major complications and 30-day mortality increased independent of procedure type (p < 0.0001). A multivariate analysis controlling for comorbidity indices demonstrated increasing age (> 45 years) increased risk for major complications and mortality., Conclusion: Overall, bariatric surgery (SG or RYGB) remains a low mortality risk procedure for all age groups. However, all age group classifications > 45 years had higher incidence of major complications and mortality compared to patients 18-45 years (despite older individuals having lower preoperative BMI) indicating delaying surgery is detrimental.

Background: Male patients undergoing bariatric surgery have (historically) been considered higher risk than females. The aim of this study was to examine the disparity between genders undergoing laparoscopic sleeve gastrectomy (SG) and laparoscopic Roux-en-Y gastric bypass (RYGB) procedures and assess gender as an independent risk factor., Methods: The MBSAQIP® Data Registry Participant User Files for 2015-2017 was reviewed for patients having primary SG and RYGB. Patients were divided into groups based on gender and procedure. Variables for major complications were grouped together, including but not limited to PE, stroke, and MI. Univariate and propensity matching analyses were performed., Results: Of 429,664 cases, 20.58% were male. Univariate analysis demonstrated males were older (46.48 ± 11.96 vs. 43.71 ± 11.89 years, p < 0.0001), had higher BMI (46.58 ± 8.46 vs. 45.05 ± 7.75 kg/m 2 , p < 0.0001), and had higher incidence of comorbidities. Males had higher rates of major complications (1.72 vs. 1.05%; p < 0.0001) and 30-day mortality (0.18 vs. 0.07%, p < 0.0001). Significance was maintained after subgroup analysis of SG and RYGB. Propensity matched analysis demonstrated male gender was an independent risk factor for RYGB and SG, major complications [2.21 vs. 1.7%, p < 0.0001 (RYGB), 1.12 vs. 0.89%, p < 0.0001 (SG)], and mortality [0.23 vs. 0.12%, p < 0.0001 (RYGB), 0.10 vs. 0.05%; p < 0.0001 (SG)]., Conclusion: Males continue to represent a disproportionately small percentage of bariatric surgery patients despite having no difference in obesity rates compared to females. Male gender is an independent risk factor for major post-operative complications and 30-day mortality, even after controlling for comorbidities.

Background: Hepatocellular carcinoma (HCC) is a major global health burden. Although chronic, heavy alcohol abuse is an established risk factor for HCC, obesity is emerging as an increasingly important factor in HCC development. Given that other risk factors for HCC act synergistically to promote tumorigenesis, we investigated the effects of diet-induced obesity and chronic ethanol consumption on tumor progression., Methods: A diethylnitrosamine (DEN) mouse model of HCC was established and mice randomized to control (CD; 10 % kcal% fat) or high fat (HFD; 60 % kcal% fat diet) at 5 weeks of age. At 35 weeks, mice were randomized to 10/20 % ethanol (EtOH) in drinking water (alternate days), or drinking water (H2O) alone. Tumor incidence/size were measured and confirmed. Liver tissue was analyzed for oxidative stress and EtOH-metabolizing enzymes and serum analyzed for liver function and nutritional status., Results: DEN treatment induced HCC formation in 60 % CD-H2O mice (6 of 10), an effect exacerbated by HFD (89 %). Tumors in HFD animals occupied significantly more of the liver than mice on CD. EtOH-feeding did not impact HCC incidence or tumor size. HFD resulted in increased liver injury and liver:body weight ratio regardless of EtOH consumption. Increased tumor incidence was associated with elevated hepatic oxidative stress in the absence of changes in intrinsic antioxidant (glutathione) levels., Conclusions: Obesity independently promoted HCC formation in the absence or presence of a known hepatocarcinogen (DEN), and enhanced both number and size of hepatic tumors independent of chronic EtOH consumption in mice.

Background: Hepatocellular carcinoma (HCC) is a rapidly increasing cancer whose known risk factors are chronic ethanol abuse, viral hepatitis infection, and aflatoxin exposure. Obesity, an emerging HCC risk factor, is reaching epidemic proportions in developed nations. This study investigated the effects of diet-induced obesity (DIO) and chronic ethanol consumption on HCC progression in mice in vivo., Methods: In this study, C57BL/6 DIO mice and lean litter mates were maintained on a 60% (high-fat diet [HFD]) diet or a 10% (control diet [CD]) kcal% fat diet for 7 weeks before they were weaned to 10/20% ([v/v], alternating days) ethanol in drinking water (EtOH) or maintenance on drinking water (H(2)O) alone. Hepatic tumor formation was initiated by intrahepatic Hepa1-6 cell (6 × 10(6) cells) inoculation 6 weeks later via the mesenteric vein., Results: The animals receiving the HFD showed decreased tumor incidence and area of hepatic foci versus the CD animals maintained on H(2)O alone. The action of EtOH suppressed tumor incidence further in both the CD and the HFD mice. Serologic analysis showed no significant differences in liver enzymes among the groups. Protein analysis demonstrated increased P450 2E1 (CYP2E1) in the groups maintained on EtOH, an effect exacerbated by HFD. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis demonstrated increased tumor necrosis factor-alpha (TNF-α) expression in HFD HCC mice (H(2)O and EtOH) concomitant with decreased transforming growth factor-beta (TGF-β) expression., Conclusions: Although obesity and EtOH consumption are known risk factors for HCC initiation and development, the data in this study suggest that these factors impair progression of established tumors within the liver.

Choline dihydrogen phosphate (CDHP) is an ionic liquid reported to increase thermal stability of model proteins. The current work investigated CDHP effect on structural integrity and biological activity of recombinant human interleukin-2 (rhIL-2), a therapeutic protein used for treating advanced melanoma. In vitro CDHP biocompatibility was also evaluated using primary cell cultures, or B16-F10 cell line, chronically exposed to the ionic liquid. Formulation of rhIL-2 in an aqueous 680mM CDHP pH 7.4 solution resulted in a 12.5°C increase in the T m of rhIL-2 compared to a basic buffer formulation, and provided conformational rhIL-2 stabilization when the solution was heated to 23.3°C above the T m . CDHP solutions (≤80mM), exhibited no cytotoxic activity toward primary splenocytes or B16-F10 cells in culture. However, a 10-fold loss in biological activity was observed when rhIL-2 was used in a 30mM CDHP aqueous solution with NaHCO 3 (pH≥7.2) compared to controls without CDHP. While increased T m is associated with a diminished rhIL-2 biological activity, the therapeutic protein remains structurally intact and functional.

Purpose: Laparoscopic ventral hernia repair is commonly performed with mesh prostheses; however, there is no standard for fixation devices used to secure mesh to the abdominal wall. This study is a functional comparison of novel, screw-type absorbable and permanent fixation devices with a traditional titanium fixation device., Methods: Fifteen pigs each underwent the laparoscopic placement of two 11 × 14-cm mesh prostheses and were randomized for mesh fixation with either titanium spiral tacks (TS), absorbable screw-type fasteners (SF), or permanent screw-type fasteners (PF) (n = 10 mesh prostheses for each fixation group). Adhesions were assessed laparoscopically at 4 weeks. The fixation devices were also embedded in porcine abdominal rectus muscle for ex vivo mechanical testing along with partial thickness polypropylene suture (PR) as a control group (n = 40 for each group). Maximum pull-off forces were measured. All statistical tests were two-tailed, and a P-value < 0.05 was considered to be significant., Results: The mean tenacity adhesion scores were 1.40 ± 0.52 (PF), 1.7 ± 0.82 (SF), and 2.6 ± 1.07 (TS). Adhesions in the PF group were significantly less tenacious compared with the TS group (P = 0.01). Quantitative adhesion scores were not significantly different among groups. The maximum pull-off forces, measured in Newtons, were 28.61 N ± 4.89 N (TS), 22.71 N ± 7.86 N (SF), 16.98 N ± 7.59 N (PF), and 20.83 N ± 6.25 N (PR). The pull-off force in the TS group was higher than all of the other groups (P < 0.001). The SF group also had a higher pull-off force compared with the PF group (P < 0.001)., Conclusions: The screw-type absorbable and permanent fixation devices provided adequate fixation and were associated with decreased adhesions in this porcine model.

Background: Bipolar electrosurgical devices are used to generate rapid and efficient hemostasis in a wide range of surgical procedures. Of the factors that influence seal integrity, vessel (artery) diameter has been considered the most important variable. In this study we hypothesized that the relative ratio of the components that form the seal (collagen and elastin) determine the degree of vessel distensibility and play an equally important role in defining seal strength., Methods: Porcine carotid, renal, iliac, and femoral arteries were sealed using a bipolar electrosurgical device in vivo. Following removal, arterial diameter was measured and vessels' seals tested for arterial burst pressure (ABPr). Samples were then analyzed histologically and biochemically for collagen and elastin content., Results: Arteries with the highest collagen-elastin ratio (C/E) (renal) consistently demonstrated significantly higher burst pressures than those arteries with lower C/E ratios (iliac and femoral) independent of artery diameter., Conclusion: Using arteries of distinct anatomical origin and physiological function, we demonstrate that total collagen content, and more specifically C/E ratio, in porcine arteries is a more accurate predictor of ABPr than vessel size alone.