Inflammatory mechanisms in acute pancreatitis

Acute pancreatitis is an inflammatory condition. It is associated with a systemic inflammatory response, the degree of which appears to correlate with the severity of the illness. The role of circulating leucocytes and their production of cytokines in the development of severe acute pancreatitis is unknown. Monocytes are believed to be a major source of pro-inflammatory cytokines, but lymphocytes and endothelial cells also produce such cytokines. These cell types, in particular lymphocytes, also produce a variety of down-regulatory signals so that monocytes, lymphocytes and endothelial cells interact to produce a net systemic inflammatory signal, influenced further by the varying degree of lymphocyte sub-populations to undergo blastogenesis in response to inflammation. The focus of this thesis is on pro-inflammatory cytokines and their release in vitro from peripheral blood mononuclear cells (PBMCs) isolated from patients with acute pancreatitis.On admission to hospital, patients with acute pancreatitis demonstrated increased interleukin-6 and interleukin-8 release but not tumour necrosis factor-a release from isolated PBMCs compared with healthy volunteers. The severity of the disease was not related to the level of cytokine release from a standard cell number. However, when allowance was made for the variation in PBMC numbers in the blood, the estimated IL-6 and IL-8 release per unit of blood was greater in those patients with severe disease compared with those with mild disease. Severe disease is also characterised by a more prolonged duration of increased pro-inflammatory cytokine release compared with patients with mild disease. Products of the cyclooxygenase pathway play a down-regulatory role in PBMCs in patients with acute pancreatitis as indomethacin (a cyclo-oxygenase inhibitor) had no significant effect on pro-inflammatory cytokine release by PBMCs isolated from healthy volunteers, but increased IL-6 and IL-8 release by PBMCs isolated from patients with both mild and severe disease. PBMC pro-inflammatory cytokine release remains sensitive to the down-regulatory action of the T-cell regulatory cytokines, interleukin-4 and interleukin-10. Lymphocyte proliferation (as measured by thymidine incorporation) is impaired in acute pancreatitis and correlates with the severity of the disease. Following the successful isolation and culture of human umbilical vein endothelial cells, IL-4 and IL-10 (in contrast to their inhibitory action on PBMCs), produce a dose dependent increase in endothelial cell IL-6 and IL-8 release. TNFa is often undetectable in patients with acute pancreatitis on admission, even in severe disease. However, elevation in the serum concentration of soluble TNFa receptors would suggest significant TNFa-induced inflammation early in the course of the disease. Glutamine is a conditionally essential amino acid in patients with severe acute pancreatitis and is important for immune function. A double blind, randomised controlled trial of glutamine supplemented versus conventional total parenteral nutrition in patients with severe acute pancreatitis demonstrated a trend towards improved lymphocyte proliferation in the glutamine supplemented group. Furthermore, PBMC IL-8 release but not TNFa and IL-6 release was significantly reduced over the study period.Severe acute pancreatitis is associated with prolonged PBMC pro¬ inflammatory cytokine release and impaired lymphocyte proliferation. However, these cells remain sensitive to the down-regulatory action of T-cell cytokines in vitro, but the exogenous administration of these cytokines may have an unpredictable clinical effect because of their different actions on various cell types. More general methods of immuno-modulation, such as the exogenous administration of glutamine may have therapeutic benefit in patients with severe acute pancreatitis

Certified Fellowship in Abdominal Wall Surgery—A Collaboration Between the UEMS and the European Hernia Society

Background: Abdominal wall surgery (AWS) is characterised by the increasing caseload and the complexity of the surgical procedures. The introduction of a tailored approach to AWS utilising laparoendoscopic, robotic and/or open techniques requires the surgeon to master several surgical techniques. All of which have an associated learning curve, and the necessary knowledge/experience to know which operation is the right one for the individual patient. However, the reality in general surgery training shows that training in just a limited number of procedures is not enough. By the end of general surgery training, many chief residents do not feel they are yet ready to carry out surgery independently. Therefore, hernia surgery experts and societies have called for the introduction of a Fellowship in Abdominal Wall Surgery. Methods: The UEMS (Union Européenne des Médecins Spécialistes, European Union of Medical Specialists) in collaboration with the European Hernia Society (EHS) introduced a fellowship by examination in 2019. As a prerequisite, candidates must complete further training of at least 2 years with a special focus on abdominal wall surgery after having completed their training in general surgery. To be eligible for the examination, candidates must provide evidence of having performed 300 hernia procedures. In addition, candidates must have accrued sufficient “knowledge points” by attending abdominal wall surgery congresses, courses and clinical visitations, and engaged in scientific activities. On meeting the requirements, a candidate may be admitted to the written and oral examination. Results: To date, three examinations have been held on the occasion of the Annual Congress of the European Hernia Society in Copenhagen (2021), Manchester (2022) and Barcelona (2023). Having met the requirements, 48 surgeons passed the written and oral examination and were awarded the Fellow European Board of Surgery—Abdominal Wall Surgery certificate. During this time period, a further 25 surgeons applied to sit the examination but did not fulfil all the criteria to be eligible for the examination. Fifty experienced abdominal wall surgeons applied to become an Honorary Fellow European Board of Surgery—Abdominal Wall Surgery. Fourty eight were successful in their application. Conclusion: The Fellowship of the European Board of Surgery - Abdominal Wall Surgery by examination has been successfully introduced at European level by the joint work of the UEMS and the EHS. The examination is also open to surgeons who work outside the European area, if they can fulfil the eligibility criteria

Predicting Inadequate Weight Loss After Bariatric Surgery:Derivation and Validation of a Four Factor Model

Introduction: Weight loss following bariatric surgery is variable and predicting inadequate weight loss is required to help select patients for bariatric surgery. The aim of the present study was to determine variables associated with inadequate weight loss and to derive and validate a predictive model. Methods: All patients who underwent laparoscopic sleeve gastrectomy and Roux-en-Y gastrectomy (2008–2022) in a tertiary referral centre were followed up prospectively. Inadequate weight loss was defined as excess weight loss (EWL) &lt; 50% by 24 months. A top-down approach was performed using multivariate logistic regression and then internally validated using bootstrapping. Patients were categorised into risk groups. Results: A total of 280 patients (median age, 49 years; M:F, 69:211) were included (146 LSG; 134 LRYGB). At 24 months, the median total weight loss was 30.9% and 80.0% achieved EWL ≥ 50% by 24 months. Variables associated with inadequate weight loss were T2DM (OR 2.42; p = 0.042), age 51–60 (OR 1.93, p = 0.006), age &gt; 60 (OR 4.93, p &lt; 0.001), starting BMI &gt; 50 kg/m² (OR 1.93, p = 0.037) and pre-operative weight loss (OR 3.51; p = 0.036). The validation C-index was 0.75 (slope = 0.89). Low, medium and high-risk groups had a 4.9%, 16.7% and 44.6% risk of inadequate weight loss, respectively. Conclusions: Inadequate weight loss can be predicted using a four factor model which could help patients and clinicians in decision-making for bariatric surgery. Graphical Abstract: (Figure presented.)</p

Update of the international HerniaSurge guidelines for groin hernia management

Background: Groin hernia repair is one of the most common operations performed globally, with more than 20 million procedures per year. The last guidelines on groin hernia management were published in 2018 by the HerniaSurge Group. The aim of this project was to assess new evidence and update the guidelines. The guideline is intended for general and abdominal wall surgeons treating adult patients with groin hernias. Method: A working group of 30 international groin hernia experts and all involved stakeholders was formed and examined all new literature on groin hernia management, available until April 2022. Articles were screened for eligibility and assessed according to GRADE methodologies. New evidence was included, and chapters were rewritten. Statements and recommendations were updated or newly formulated as necessary. Results: Ten chapters of the original HerniaSurge inguinal hernia guidelines were updated. In total, 39 new statements and 32 recommendations were formulated (16 strong recommendations). A modified Delphi method was used to reach consensus on all statements and recommendations among the groin hernia experts and at the European Hernia Society meeting in Manchester on October 21, 2022. Conclusion: The HerniaSurge Collaboration has updated the international guidelines for groin hernia management. The updated guidelines provide an overview of the best available evidence on groin hernia management and include evidence-based statements and recommendations for daily practice. Future guideline development will change according to emerging guideline methodology

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707