Safety and Efficacy of Inpatient Infliximab Rescue Therapy for Acute Crohn's Disease Flares.

PURPOSE: Describe the safety, complications, and need for urgent surgery in patients requiring inpatient rescue infliximab for acute Crohn's disease (CD) flare. BACKGROUND: Infliximab is increasingly used for patients hospitalized with acute severe ulcerative colitis as rescue therapy; however, optimal management for patients hospitalized for CD flares remains unclear. METHODS: A single-institution retrospective study of patients aged 18+ admitted from 2008 to 2020 with acute Crohn's flare requiring induction of rescue infliximab therapy. Outcomes included postoperative and medication-related complications and need for urgent surgery. RESULTS: 52 patients were included in analysis; 8% required surgery on index admission, and 19% required surgery within 90 days of infliximab. Postoperative complications included 1 anastomotic leak, 3 superficial wound infections, 3 prolonged ileus, and 1 urinary infection. There were no adverse reactions to infliximab infusion, and medical complication rates were low. Patients with penetrating disease were more likely to undergo surgery within 90 days of infliximab (43% vs 8%; P = .01). Mean LOS was longer for patients undergoing surgery within 90 days of therapy compared to those who did not (13.4 vs 8.3 days, P = .04). CONCLUSION: Inpatient rescue infliximab is safe for treating acute Crohn's disease flare in addition to standard steroid therapy. The majority of patients hospitalized with Crohn's flare requiring rescue infliximab avoided surgery with low postoperative and medication-related complications. More research is needed to clarify the optimal rescue infliximab therapy dosage.

Mental health disorders as a risk factor in young patients with rectal prolapse.

BACKGROUND: Rectal prolapse (RP) typically presents in the elderly, though it can present in younger patients lacking traditional risk factors. The current study compares medical and mental health history, presentation, and outcomes for young and older patients with RP. METHODS: This is a single-center retrospective review of patients who underwent abdominal repair of RP between 2005 and 2019. Individuals were dichotomized into two groups based on age greater or less than 40 years. RESULTS: Of 156 patients, 25 were < 40. Younger patients had higher rates of diagnosed mental health disorders (80% vs 41%, p < 0.001), more likely to take SSRIs (p = .02), SNRIs (p = .021), anxiolytics (p = 0.033), and antipsychotics (p < 0.001). Younger patients had lower preoperative incontinence but higher constipation. Both groups had low rates of recurrence (9.1% vs 11.6%, p = 0.73). CONCLUSIONS: Young patients with RP present with higher concomitant mental health diagnoses and represent unique risk factors characterized by chronic straining compared to pelvic floor laxity.

Outcomes Following Recent and Distant Neoadjuvant Radiation in Rectal Cancer: An Institutional Retrospective Review and Analysis of NSQIP.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) is the standard of care in locally advanced rectal cancer (LARC). However, radiation therapy is thought to increase operative difficulty due to induction of fibrosis. Total neoadjuvant therapy (TNT) protocols increase the time between completion of radiation and surgical resection which may lead to increased operative difficulty and complications. METHODS: A single institution retrospective review of patients ≥18 years with LARC undergoing nCRT from 2015 to 2022. Patients were dichotomized in 2 cohorts: <90 days from radiation to surgery (recent radiation), and ≥90 days from radiation to surgery (distant radiation). Institutional data was compared to National Surgical Quality Improvement Program (NSQIP) rectal cancer data from 2016 to 2020. Outcomes included intraoperative complications, 30-day morbidity, and oncologic outcomes. RESULTS: One hundred forty-six institutional patients included, 120 had recent radiation, 26 had distant radiation. Thirty-day morbidity and intraoperative complications did not differ. There was greater radial margin positivity (7% vs. 24%), fewer lymph nodes harvested (17 ± 5 vs. 15 ± 6), and a lower rate of complete mesorectal dissection (88% vs. 65%,) in distant radiation patients 3059 patients were included in NSQIP analysis, 2029 completed radiation <90 days before surgery and 1030 without radiation 90 days before surgery. Patients without radiation 90 days preoperatively had more radial margin positivity (9.2% vs. 4.6%), organ space infection (8.6% vs. 6.4%), and pneumonia (2.2% vs. 0.9%). CONCLUSION: The present study suggests that increased time between radiation and surgery results in more challenging dissection with less complete mesorectal dissection and increased radial margin positivity without increasing technical complications.

Impact of neoadjuvant chemotherapy for locally advanced colon cancer on postoperative complications.

PURPOSE: Although not considered standard therapy, neoadjuvant chemotherapy (NAC) is an encouraging alternative for selected patients with locally advanced colon cancer (LAC). The aim of this study was to compare 30-day postoperative outcomes between patients undergoing upfront surgery and those undergoing NAC for LAC. METHODS: Using the ACS-NSQIP data from 2016 to 2020, 11,498 patients with LAC were divided into those who underwent upfront colectomy (96.2%) and those who received NAC (3.8%). The primary outcome was a composite outcome encompassing 30-day major postoperative complications. Propensity score matched (PSM) analysis and multivariable logistic regression were performed. RESULTS: After PSM analysis, there was no statistically significant difference in the development of a major complication. NAC was not significantly associated with the primary outcome. Risk factors for postoperative complications were T4 stage, older age, male sex, black race, smoking, dependent status, severe COPD, hypoalbuminemia, and preoperative transfusion. Laparoscopic and robotic surgery was protective. CONCLUSION: NAC did not increase the odds of developing a major complication.

Early C-reactive protein after colorectal surgery is not predictive of anastomotic leak: a retrospective cohort study.

PURPOSE: Prior studies suggest postoperative C-reactive protein (CRP) trends are sensitive for predicting anastomotic leak (AL) after elective colorectal surgery. However, in the setting of enhanced recovery pathways, multi-day CRP trends may not be feasible. This study aimed to assess the realistic and clinical utility of CRP in prediction of AL. METHODS: A retrospective review of patients who underwent elective colectomy or proctectomy from January 2019 to October 2020 at a single institution was performed. Comorbidities, operative characteristics, and perioperative outcomes were recorded. CRP was checked routinely on POD1 and on a clinical basis subsequently. The association between 10-point change in CRP-POD1 and AL was evaluated using multivariable logistic regression. The relationships between CRP-POD3, CRP-POD1, and AL were assessed using exploratory analyses. RESULTS: Among 332 patients, 23 (6.9%) developed AL, of which 9 cases (39%) were diagnosed upon readmission. AL was not associated with mortality. Median length of stay was 3 days (IQR 2-5). Median days to AL diagnosis was 7 (IQR 4-15). Adjusting for diverting stoma, steroid use, diagnosis, and open surgery, each 10-point increase in CRP was associated with increased odds of AL (OR 1.12, 95% CI 1.03-1.21, p=0.008). CRP-POD1 had poor discriminant utility for detecting AL (AUC 0.62, 95% CI = 0.494-0.746; p=0.061). CONCLUSION: CRP on POD1 is not a reliable method to predict a leak, and trending CRP may not be practical with decreasing lengths of stay in colorectal surgery.

Perioperative use of NSAIDs and the risk of short-term endoscopic recurrence in Crohn's disease patients: A retrospective cohort study.

BACKGROUND: More evidence is needed on the use of NSAID based postoperative pain regimens for Crohn's disease (CD) and its association with recurrence. Our goal is to assess the impact of perioperative use of NSAIDs on endoscopic disease recurrence in patients with CD. METHODS: A retrospective cohort study was conducted. The primary outcome measured was endoscopic disease recurrence within 24 months of surgery, defined as a Rutgeerts score ≥ i2. RESULTS: We identified 107 patients with CD that underwent index ileocolectomy with primary anastomosis between January 2009 and July 2019. Endoscopic disease recurrence was identified in 28 (26.2%) and clinical recurrence in 18 (16.8%) patients. Exposure to NSAIDs did not increase 24-month endoscopic recurrence risk (22.2% vs. 38.5% patients, p = 0.12). CONCLUSION: In patients with CD undergoing elective ileocolic resection and primary ileocolic anastomosis, NSAID use in the perioperative period did not impact endoscopic or clinical disease recurrence rate.

Are IBD Patients Underscored when Determining Postoperative VTE Risk?

BACKGROUND: Patients with inflammatory bowel disease (IBD) have an increased risk of venous thromboembolism (VTE) following colorectal surgery and there is currently no consensus on post-surgical VTE prevention or specific VTE risk assessment tools. We sought to evaluate VTE risk after colorectal surgery and determine if known risk factors used in risk assessment tools adequate correlate with VTE risk in IBD patients. METHODS: Retrospective cohort study using the National Surgical Quality Improvement Project (NSQIP) Participant User File from 2010 to 2018. RESULTS: A total of 27,679 patients were included; 19,015 (68.7%) had Crohn's disease (CD) and 8664 (31.3%) ulcerative colitis (UC). Of these, 16,749 (60.5%) underwent abdominopelvic procedures, 10,178 (36.8%) complex pelvic procedures, and 752 (2.7%) small bowel operations. The overall VTE rate was 2.3%. The VTE rate in patients with CD and UC was 1.8% and 3.6% (p < 0.001) respectively. Overall median time to VTE was 9 days after surgery. VTE rate was highest in patients who underwent complex pelvic procedures (3.6%; 361/10,178). A risk score was calculated using 16/40 available variables from the Caprini VTE Risk Assessment tool; risk score ranged from 3 to 12 points. Most patients that developed a VTE had a score between 3 and 5 points (75.6%), and only 24.5% had a score of 6 or higher. Patients with higher risk scores did not have a higher VTE incidence. CONCLUSION: Post-surgical VTE rates are high in IBD patients. Over half of the events occurred following discharge and in patients with an apparent low-risk score. Additional studies are warranted to define a recommended postoperative VTE prophylaxis regimen for patients with IBD.

Dose-Intensified Infliximab Rescue Therapy for Severe Ulcerative Colitis Does Not Reduce Short-term Colectomy Rates or Increase Postoperative Complications.

BACKGROUND: Dose-intensified rescue therapy with infliximab for hospitalized patients with ulcerative colitis has become increasingly popular in recent years. However, there is ongoing debate about both the efficacy of these regimens to reduce the rate of colectomy and the associated risks of increased infliximab exposure. OBJECTIVE: The purpose of this study was to compare the colectomy and postoperative complication rates in hospitalized patients with severe ulcerative colitis receiving standard infliximab induction therapy (3 doses of 5 mg/kg at weeks 0, 2, and 6) and dose-intensified regimens including a higher weight-based dosing or more rapid interval. DESIGN: This was a retrospective cohort study. SETTINGS: This study was conducted at an academic tertiary care hospital. PATIENTS: A total of 145 adult patients received inpatient rescue infliximab therapy for the treatment of ulcerative colitis between 2008 and 2020. MAIN OUTCOME MEASURES: The primary outcome was colectomy rate within 3 months of rescue therapy. Secondary outcomes include mid-term colectomy rates, as well as perioperative complications in patients receiving colectomy within 3 months of rescue infliximab initiation. RESULTS: The proportion of dose-intensified regimens increased over time. Unadjusted 3-month colectomy rates were 14% in patients who received standard rescue infliximab dosing, 16% in patients given a single dose-escalated dose, and 24% in patients given multiple inpatient dose-escalated doses. These rates were not statistically significantly different. Of the patients requiring colectomy within 3 months of infliximab rescue, those who received multiple inpatient doses of dose-escalated therapy had a higher percentage of colectomy during the initial hospitalization but a lower rate of perioperative complications. LIMITATIONS: This study was limited by the use of retrospective data and the limited power to account for the heterogeneity of disease. CONCLUSIONS: No significant difference was found in colectomy rates between patients receiving standard or dose-intensified regimens. However, dose-intensified regimens, including multiple inpatient doses given to patients with more severe disease, were not associated with a greater risk of perioperative complications. See Video Abstract at http://links.lww.com/DCR/B864 . LA TERAPIA DE RESCATE CON DOSIS INTENSIFICADA DE INFLIXIMAB EN COLITIS ULCEROSA GRAVE NO REDUCE LAS TASAS DE COLECTOMA A CORTO PLAZO NI AUMENTA LAS COMPLICACIONES POSOPERATORIAS: ANTECEDENTES:La terapia de rescate de dosis intensificada con infliximab para pacientes hospitalizados con colitis ulcerosa se ha vuelto cada vez más popular en los últimos años. Sin embargo, existe un debate en curso sobre la eficacia de estos regímenes para reducir la tasa de colectomía y los riesgos asociados a una mayor exposición al infliximab.OBJETIVO:El propósito de este estudio fue comparar las tasas de colectomía y complicaciones posoperatorias en pacientes hospitalizados con colitis ulcerosa grave que recibieron terapia estándar de inducción de infliximab (3 dosis de 5 mg/kg en las semanas 0, 2, 6) y regímenes de dosis intensificada que incluyen una dosificación más alta basada en el peso o intervalo más rápido.DISEÑO:Fue un estudio de cohorte retrospectivo.ENTORNO CLÍNICO:Este estudio se realizó en un hospital académico de tercer nivel.PACIENTES:Un total de 145 pacientes adultos que recibieron terapia de rescate con infliximab para el tratamiento de la colitis ulcerosa entre 2008 y 2020.PRINCIPALES MEDIDAS DE VALORACIÓN:El resultado principal fue la tasa de colectomía dentro de los 3 meses posteriores a la terapia de rescate. Los resultados secundarios incluyen tasas de colectomía a mediano plazo, así como las complicaciones perioperatorias en pacientes que reciben colectomía dentro de los 3 meses posteriores al inicio de infliximab de rescate.RESULTADOS:La proporción de regímenes de dosis intensificada aumentó con el tiempo. Las tasas de colectomía de 3 meses no ajustadas fueron del 14% en los pacientes que recibieron dosis estándar de infliximab de rescate, del 16% en los pacientes que recibieron una dosis única escalonada y del 24% en los pacientes que recibieron múltiples dosis hospitalarias escalonadas. Estas tasas no fueron estadísticamente significativas. De los pacientes que requirieron colectomía dentro de los 3 meses posteriores al rescate de infliximab, aquellos que recibieron terapia de múltiples dosis hospitalarias escalonadas tuvieron un mayor porcentaje de colectomía durante la hospitalización inicial pero una menor tasa de complicaciones perioperatorias.LIMITACIONES:Datos retrospectivos y poder limitado para explicar la heterogeneidad de la enfermedad.CONCLUSIONES:No se encontraron diferencias significativas en las tasas de colectomía entre los pacientes que recibieron regímenes estándar o de dosis intensificada. Sin embargo, los regímenes de dosis intensificadas, incluidas múltiples dosis hospitalarias administradas a pacientes con enfermedad más grave, no se asociaron con un mayor riesgo de complicaciones perioperatorias. Consulte Video Resumen en http://links.lww.com/DCR/B864 . (Traducción-Dr. Ingrid Melo ).

Disparities in industry funding among Colorectal Surgeons: a cross-sectional study.

BACKGROUND: Health Industry and physician collaboration generates innovation. Colorectal Surgeon (CRS) selection to collaborate might not be random. We aim to identify CRS personal and professional characteristics that facilitate collaboration with the Industry. METHOD: Cross-sectional study of Industry payments to CRS (2014-2018) using Open Payments Database from Centers for Medicare & Medicaid Services. Multivariable regression compared variables predicting payment amount including gender, years in practice, leadership positions, H-index, Twitter presence and geographic location. RESULTS: Surgeons who were male received 3.1 times the amount in Industry payments as compared to females (p = 0.014). Chairs and Division Chiefs received 2.7 times the amount in payments as compared to those without these leadership positions (p = 0.003). Surgeons with an H-index ≥ 8 received 2.2 times the amount in payments as compared to those with H-index < 8 (p = 0.001). Surgeons in practice for 12-19 and 20-30 years received 3 times and 4.4 times the amount in payments as compared to surgeons in practice for 1-11 years (p = 0.036 and p = 0.017, respectively). Surgeons in the South received 3.2 times and 2 times the amount in payments as compared to surgeons in the Northeast (p < 0.0005) and in the Midwest (p = 0.006). Surgeons with Twitter accounts received 1.7 times the amount in payments as compared to surgeons without Twitter (p = 0.036). Among Twitter users, those with 321-17,200 followers received 4.7 times and 9.5 times the amount in payments as compared to those with 0-15 and 16-79 followers, respectively (p = 0.008 and p = 0.009). CONCLUSION: Industry payments are more commonly addressed to male, senior surgeons in leadership tracks with strong social media outreach. With the increasing gender and racial variety in the CRS field, it is expected that collaborations between industry and surgeons will become more diverse and inclusive.

"How to" Course for Resident Reviewers: from the Resident and Fellow Education Committee of the Society for Surgery of the Alimentary Tract (SSAT).

The Resident and Fellow Education Committee of the Society for Surgery of the Alimentary Tract (SSAT) hosted a "How to" course for resident reviewers at the 2021 Annual Meeting at Digestive Disease Week. This panel drew from their extensive experience to help neophyte reviewers perform high quality, comprehensive peer reviews. Dr. Snyder kicked off the session with "Why Should I be a Resident Reviewer?" Dr. Talamini followed by "Defining the Review Process," while Dr. Keller presented "OK, You Are Ready to Review, Where to Start?" Dr. Pawlik ended the session with "How to Be an Excellent Reviewer." Residents are encouraged to apply the content from these sessions to volunteer as reviewers and develop critical skills to help further their academic surgery career.

Alcohol Acutely Antagonizes Refeeding-Induced Alterations in the Rag GTPase-Ragulator Complex in Skeletal Muscle.

The Ragulator protein complex is critical for directing the Rag GTPase proteins and mTORC1 to the lysosome membrane mediating amino acid-stimulated protein synthesis. As there is a lack of evidence on alcohol's effect on the Rag-Ragulator complex as a possible mechanism for the development of alcoholic skeletal muscle wasting, the aim of our study was to examine alterations in various protein-protein complexes in the Rag-Ragulator pathway produced acutely by feeding and how these are altered by alcohol under in vivo conditions. Mice (C57Bl/6; adult males) were fasted, and then provided rodent chow for 30 min ("refed") or remained food-deprived ("fasted"). Mice subsequently received ethanol (3 g/kg ethanol) or saline intraperitoneally, and hindlimb muscles were collected 1 h thereafter for analysis. Refeeding-induced increases in myofibrillar and sarcoplasmic protein synthesis, and mTOR and S6K1 phosphorylation, were prevented by alcohol. This inhibition was not associated with a differential rise in the intracellular leucine concentration or plasma leucine or insulin levels. Alcohol increased the amount of the Sestrin1•GATOR2 complex in the fasted state and prevented the refeeding-induced decrease in Sestrin1•GATOR2 seen in control mice. Alcohol antagonized the increase in the RagA/C•Raptor complex formation seen in the refed state. Alcohol antagonized the increase in Raptor with immunoprecipitated LAMPTOR1 (part of the Ragulator complex) after refeeding and decreased the association of RagC with LAMPTOR1. Finally, alcohol increased the association of the V1 domain of v-ATPase with LAMPTOR1 and prevented the refeeding-induced decrease in v-ATPase V1 with LAMPTOR1. Overall, these data demonstrate that acute alcohol intake disrupts multiple protein-protein complexes within the Rag-Ragulator complex, which are associated with and consistent with the concomitant decline in nutrient-stimulated muscle protein synthesis under in vivo conditions.

Contractility and Myofibrillar Content in Skeletal Muscle are Decreased During Post-Sepsis Recovery, But Not During the Acute Phase of Sepsis.

ABSTRACT: Convalescence in humans after severe sepsis occurs over weeks to months and is associated with prolonged functional disabilities and impaired quality-adjusted survival. While much is known regarding the acute early phase of sepsis, there is a knowledge gap pertaining to restoration of muscle mass and function after elimination of the septic nidus. We used a sepsis-recovery model-where cecal-ligation-puncture (CLP) was performed in adult male mice followed 24 h later by removal of the cecum and antibiotic treatment-to assess changes in the abundance of muscle contractile proteins and function during the acute phase of sepsis (24 h post-CLP) and during the recovery phase (day 10 post-CLP). Although body weight and food consumption decreased acutely with sepsis, both had normalized by day 10; however, extensor digitorum longus mass remained decreased 10%. During acute sepsis, there were few contractile defects or significant changes in contractile proteins. In contrast, during sepsis recovery, specific maximum isometric twitch and specific maximum tetanic force were decreased ≈50%, compared with time-matched pair-fed controls, and defects were independent of the concomitant reduction in muscle mass. Force generation in sepsis-recovery mice was decreased 30% with increasing stimulus frequency. Contractile defects during sepsis-recovery were associated with 50% to 90% reductions in thin filament (troponin T, troponin I, tropomyosin, α-sarcomeric actin), thick filament (myosin heavy and myosin light chains), Z-disc (α-actinin 3), and M-band (myomesin-2) proteins, but no change in the intermediate filaments desmin and vimentin. During sepsis recovery, myofibrillar protein synthesis did not differ from control, but synthesis of sarcoplasmic proteins was increased 60%. These data suggest intrinsic defects in muscle contractile function exist during the recovery phase of sepsis and may negatively impact convalescence.

Temporally Distinct Regulation of Pathways Contributing to Cardiac Proteostasis During the Acute and Recovery Phases of Sepsis.

BACKGROUND: Cardiac dysfunction is a common manifestation of sepsis and is associated with early increases in inflammation and decreases in myocardial protein synthesis. However, little is known regarding the molecular mechanisms regulating protein homeostasis during the recovery phase after the removal of the septic nidus. Therefore, the purpose of this study was to investigate diverse signal transduction pathways that regulate myocardial protein synthesis and degradation. METHODS: Adult male C57BL/6 mice were used to identify potential mechanisms mediating the acute (24 h) effect of cecal ligation and puncture as well as long-term changes that manifest during the chronic (10 days) recovery phase. RESULTS: Sepsis acutely decreased cardiac protein synthesis that was associated with reduced phosphorylation of S6K1/S6 but not 4E-BP1. Sepsis also decreased proteasome activity, although with no change in MuRF1 and atrogin-1 mRNA expression. Sepsis acutely increased apoptosis (increased caspase-3 and PARP cleavage), autophagosome formation (increased LC3B-II), and canonical inflammasome activity (increased NLRP3, TMS1, cleaved caspase-1). In contrast, during the recovery phase, independent of a difference in food consumption, global protein synthesis was increased, the early repression in proteasome activity was restored to basal levels, whereas stimulation of apoptosis, autophagosome formation, and the canonical inflammasome pathway had abated. However, during recovery there was a selective stimulation of the noncanonical inflammasome pathway as evidenced by activation of caspase-11 with cleavage of Gasdermin D. CONCLUSIONS: These data demonstrate a temporally distinct homeostatic shift in the cardiac proteostatic response to acute infection and recovery.

Postoperative Outcomes in Ustekinumab-Treated Patients Undergoing Abdominal Operations for Crohn's Disease.

BACKGROUND: Ustekinumab, a monoclonal antibody targeting interleukins-12 and -23 is used to treat adults with Crohn's disease [CD]. We determined the 30-day postoperative infectious complication rate among CD patients who received ustekinumab within the 12 weeks prior to an abdominal operation as compared with patients who received anti-tumor necrosis factor [TNF] agents. METHODS: A retrospective chart review of adults with CD who underwent an abdominal operation between January 1, 2015 and May 1, 2017 was performed across six sites. Surgical site infection [SSI] was defined as superficial skin and soft tissue infection, intra-abdominal abscess, anastomotic leak, and mucocutaneous separation of the stoma. RESULTS: Forty-four patients received ustekinumab and 169 patients received anti-TNF therapy within the 12 weeks prior to surgery. The two groups were similar, except anti-TNF patients were more likely to have received combination therapy with an immunomodulator [P = 0.006]. There were no significant differences in postoperative SSI [13% in ustekinumab versus 20% in anti TNF-treated patients, p = 0.61] or hospital readmission rates [18% versus 10%, respectively, p = 0.14], but ustekinumab-treated patients had a higher rate of return to the operating room [16% versus 5%; P = 0.01]. There were no significant predictors identified on multivariable analysis. CONCLUSIONS: Of the 44 patients with CD who received ustekinumab within the 12 weeks prior to a major abdominal operation, 13% experienced a 30-day postoperative SSI, not statistically different from the 20% found in the anti-TNF cohort. Ustekinumab treatment within 12 weeks of surgery does not appear to increase the risk of postoperative SSI above that of CD patients treated with anti-TNF medications.

Immune and metabolic responses in early and late sepsis during mild dietary zinc restriction.

BACKGROUND: Mild dietary zinc (Zn) deficiency is widespread in human populations, but its influence on recovery after acute illness is poorly understood. In a mouse model of abdominal sepsis (cecal ligation puncture), systemic immune responses and liver metabolism were monitored in early (24 h) and late (5 d) phases, under control conditions and during mild dietary Zn restriction. METHODS: Mice were fed diets adequate or marginally deficient (ZM) in Zn (30 versus 10 mg zinc/kg diet) for 4 wk, before undergoing laparotomy alone (nonseptic control) or cecal ligation puncture (septic). RESULTS: Among nonseptic mice, the ZM state was not associated with differences in inflammation or metabolic responses. Among septic mice, mortality did not differ between the zinc adequate and ZM groups. In the early phase, the ZM state amplified increases in plasma interleukin (IL) 6, tumor necrosis factor alpha, and IL-10, while dampening the interferon gamma response. In the late phase, subtle but significant ZM-associated increases were observed in plasma IL-5 and interferon gamma levels and hepatic protein synthesis, the latter of which appeared to be mammalian target of rapamycin independent and was associated with increased hepatic tumor necrosis factor alpha messenger RNA content. CONCLUSIONS: Without increasing mortality, the ZM state is associated with a more disordered acute systemic inflammatory response and persistence or enhancement of acute phase responses within the liver parenchyma.

Force Comparison of Commercially Available Transfascial Suture Passers.

BACKGROUND: Transfascial suture passers (TSPs) are a commonly used surgical tool available in a wide array of tip configurations. We assessed the insertion force of various TSPs in an ex vivo porcine model. METHODS: Uniform sections of porcine abdominal wall were secured to a 3D-printed platform. Nine TSPs were passed through the abdominal wall both without and with prolene suture under the following scenarios: abdominal wall only and abdominal wall plus underlay ePTFE or composite ePTFE/polypropylene mesh. Insertion forces were recorded in Newton (N). RESULTS: When passed without suture through the abdominal wall, smaller diameter TSPs required less insertional force (1.50 ± 0.17 N vs 9.68 ± 1.50 N [ P = 0.00072]). Through composite mesh, the solid tipped TSPs required less force than hollow tipped ones (3.87 ± 0.25 N vs 7.88 ± 0.20 N [ P = 0.00026]). Overall, smaller diameter TSPs required less force than the larger TSPs when passed through ePTFE empty (Gore 2.95 ± 0.83 N vs Carter-Thomason 16.07 ± 2.10 N [ P = .0005]) or with suture (Gore 8.37 ± 2.59 N vs Carter-Thomason 19.12 ± 1.10 N [ P = .003]). CONCLUSIONS: Diameter plays the greatest role in the force required for TSP penetration. However, when passed through underlay mesh or while holding suture, distal tip shape, the mechanism of suture holding, and shaft diameter all contribute to the forces necessary for penetration. These factors should be considered when choosing a TSP for intraoperative use.

Inability to replete white adipose tissue during recovery phase of sepsis is associated with increased autophagy, apoptosis, and proteasome activity.

Adipose tissue is an important energy depot and endocrine organ, and the degree of adiposity impacts the host response to infection. However, little is known regarding the mechanisms by which white adipose tissue (WAT) is lost acutely and then restored after the resolution of sepsis. Therefore, the signaling pathways governing protein synthesis, autophagy, apoptosis, and the ubiquitin-proteasome were investigated to identify potential mechanisms mediating the acute (24 h) loss of WAT after cecal ligation and puncture as well as the failure to replenish WAT during recovery (day 10). While whole body fat mass was decreased equally in pair-fed control and septic mice at 5 days after cecal ligation and puncture, fat mass remained 35% lower in septic mice at day 10 During sepsis-recovery, protein synthesis in epididymal WAT was increased compared with control values, and this increase was associated with an elevation in eukaryotic translation initiation factor (eIF)2Bε but no change in mammalian target of rapamycin complex 1 activity (eIF4E-binding protein-1 or S6 kinase 1 phosphorylation). Protein breakdown was increased during sepsis-recovery, as evidenced by the elevation in ubiquitin-proteasome activity. Moreover, indexes of autophagy (light chain 3B-II, autophagy-related protein 5/12, and beclin) were increased during sepsis-recovery and associated with increased AMP-activated kinase-dependent Ser555-phosphorylated Unc-51-like autophagy activating kinase-1. Apoptosis was increased, as suggested by the increased cleavage of caspase-3 and poly(ADP-ribose) polymerase. These changes were associated with increased inflammasome activity (increased NLR family, pyrin domain containing 3; TMS1; and caspase-1 cleavage) and the endoplasmic reticulum stress response (increased eIF2α and activating transcription factor-4) and browning (uncoupling protein-1) in epididymal WAT. Our data suggest that WAT stores remain depleted during recovery from sepsis due to sustained inflammation and elevations in protein and cellular degradation, despite the increase in protein synthesis.

Restorative Mechanisms Regulating Protein Balance in Skeletal Muscle During Recovery From Sepsis.

Muscle deconditioning is commonly observed in patients surviving sepsis. Little is known regarding the molecular mechanisms regulating muscle protein homeostasis during the recovery or convalescence phase. We adapted a sepsis-recovery mouse model that uses cecal ligation and puncture (CLP), followed 24 h later by cecal resection and antibiotic treatment, to identify putative cellular pathways regulating protein synthesis and breakdown in skeletal muscle. Ten days after CLP, body weight and food consumption did not differ between control and sepsis-recovery mice, but gastrocnemius weight was reduced. During sepsis-recovery, muscle protein synthesis was increased 2-fold and associated with enhanced mTOR kinase activity (4E-BP1 and S6K1 phosphorylation). The sepsis-induced increase in 4E-BP1 was associated with enhanced formation of the eIF4E-eIF4G active cap-dependent complex, while the increased S6K1 was associated with increased phosphorylation of downstream targets S6 and eIF4B. Proximal to mTOR, sepsis-recovery increased Akt and TSC2 phosphorylation, did not alter AMPK phosphorylation, and decreased REDD1 protein content. Despite the decreased mRNA content for the E3 ubiquitin ligases atrogin-1 and muscle RING-finger 1, proteasomal activity was increased 50%. In contrast, sepsis-recovery was associated with an apparent decrease in autophagy (e.g., increased ULK-1 phosphorylation, decreased LCB3-II, and increased p62). The mRNA content for IL-1ß, IL-18, TNFα, and IL-6 in muscle was elevated in sepsis-recovery. During recovery after sepsis skeletal muscle responds with an increase in Akt-TSC2-mTOR-dependent protein synthesis and decreased autophagy, but full restoration of muscle protein content may be slowed by the continued stimulation of ubiquitin-proteasome activity.