Type 1 interferon auto-antibodies are elevated in patients with decompensated liver cirrhosis.

Patients with decompensated liver cirrhosis, in particular those classified as Childs-Pugh class C, are at increased risk of severe coronavirus disease-2019 (COVID-19) upon infection with severe acute respiratory coronavirus 2 (SARS-CoV-2). The biological mechanisms underlying this are unknown. We aimed to examine the levels of serum intrinsic antiviral proteins as well as alterations in the innate antiviral immune response in patients with decompensated liver cirrhosis. Serum from 53 SARS-CoV-2 unexposed and unvaccinated individuals, with decompensated liver cirrhosis undergoing assessment for liver transplantation, were screened using SARS-CoV-2 pseudoparticle and SARS-CoV-2 virus assays. The ability of serum to inhibit interferon (IFN) signalling was assessed using a cell-based reporter assay. Severity of liver disease was assessed using two clinical scoring systems, the Child-Pugh class and the MELD-Na score. In the presence of serum from SARS-CoV-2 unexposed patients with decompensated liver cirrhosis there was no association between SARS-CoV-2 pseudoparticle infection or live SARS-CoV-2 virus infection and severity of liver disease. Type I IFNs are a key component of the innate antiviral response. Serum from patients with decompensated liver cirrhosis contained elevated levels of auto-antibodies capable of binding IFN-α2b compared to healthy controls. High MELD-Na scores were associated with the ability of these auto-antibodies to neutralize type I IFN signalling by IFN-α2b but not IFN-ß1a. Our results demonstrate that neutralizing auto-antibodies targeting IFN-α2b are increased in patients with high MELD-Na scores. The presence of neutralizing type I IFN-specific auto-antibodies may increase the likelihood of viral infections, including severe COVID-19, in patients with decompensated liver cirrhosis.

Outruling cholangiocarcinoma in patients with primary sclerosing cholangitis wait-listed for liver transplantation: A report on the Irish national experience.

BACKGROUND: The presence of diffuse biliary stricturing in Primary Sclerosing Cholangitis (PSC) makes the diagnosis of early Cholangiocarcinoma (CCA) in this context difficult. A finding of incidental CCA on liver explant is associated with poor oncological outcomes, despite this; there remains no international consensus on how best to outrule CCA in this group ahead of transplantation. The objectives of this study were to report the Irish incidence of incidental CCA in individuals with PSC undergoing liver transplantation, and to critically evaluate the accuracy of diagnostic modalities in outruling CCA in our wait-listed PSC cohort. METHODS: We conducted a retrospective analysis of our prospectively maintained database, which included all PSC patients wait-listed for liver transplant in Ireland. RESULTS: 4.41% of patients (n = 3) were found to have an incidental finding of CCA on liver explant. Despite only being performed in 35.06% of wait-listed PSC patients (n = 27), Endoscopic Retrograde Cholangiopancreatogram (ERCP) with brush cytology was found to be the most effective tool in correctly outruling CCA in this context; associated with a specificity of 96.15%. CONCLUSION: Our findings support a future role for routine surveillance of PSC patients awaiting liver transplantation; however further research is required in order to identify which investigative modalities are of optimal diagnostic utility in this specific context.

Clinical Outcomes After Total Pancreatectomy: A Prospective Multicenter Pan-European Snapshot Study.

OBJECTIVE: To assess outcomes among patients undergoing total pancreatectomy (TP) including predictors for complications and in-hospital mortality. BACKGROUND: Current studies on TP mostly originate from high-volume centers and span long time periods and therefore may not reflect daily practice. METHODS: This prospective pan-European snapshot study included patients who underwent elective (primary or completion) TP in 43 centers in 16 European countries (June 2018-June 2019). Subgroup analysis included cutoff values for annual volume of pancreatoduodenectomies (<60 vs ≥60).Predictors for major complications and in-hospital mortality were assessed in multivariable logistic regression. RESULTS: In total, 277 patients underwent TP, mostly for malignant disease (73%). Major postoperative complications occurred in 70 patients (25%). Median hospital stay was 12 days (IQR 9-18) and 40 patients were readmitted (15%). In-hospital mortality was 5% and 90-day mortality 8%. In the subgroup analysis, in-hospital mortality was lower in patients operated in centers with ≥60 pancreatoduodenectomies compared <60 (4% vs 10%, P = 0.046). In multivariable analysis, annual volume <60 pancreatoduodenectomies (OR 3.78, 95% CI 1.18-12.16, P = 0.026), age (OR 1.07, 95% CI 1.01-1.14, P = 0.046), and estimated blood loss ≥2L (OR 11.89, 95% CI 2.64-53.61, P = 0.001) were associated with in-hospital mortality. ASA ≥3 (OR 2.87, 95% CI 1.56-5.26, P = 0.001) and estimated blood loss ≥2L (OR 3.52, 95% CI 1.25-9.90, P = 0.017) were associated with major complications. CONCLUSION: This pan-European prospective snapshot study found a 5% inhospital mortality after TP. The identified predictors for mortality, including low-volume centers, age, and increased blood loss, may be used to improve outcomes.

Risk of pancreatic ductal adenocarcinoma associated with carriage of BRCA1 and/or BRCA2 mutation: A systematic review and meta-analysis.

Germline BRCA1/2 mutations lead to malfunction of DNA damage repair pathways and predispose to pancreatic ductal adenocarcinoma (PDAC). The aim of this study is to synthesise the available research on this topic. Four studies reporting risk ratio (RR) were included in the final meta-analysis to minimise misrepresenting our results by combining separate risk estimates. Our meta-analysis revealed a statistically significant increased risk of PDAC in BRCA carriers overall (RR: 2.65, 95% confidence interval: 1.43-4.91, p = 0.002).

The role of bariatric surgery in liver transplantation: timing and type.

INTRODUCTION: The rise in obesity worldwide has shifted the indications for liver transplantation (LT), with non-alcoholic steatohepatitis (NASH) being the second most common indication for transplantation. There remains an underestimation of cirrhosis being attributed to NASH. Bariatric surgery (BS) is a reliable solution to overcome obesity and its associated comorbidities. The role of BS in LT has been investigated by different studies; however, the type of BS and timing of LT need further investigation. METHODS: A systemic review examining the role of BS in LT patients was performed. After selection of the studies based on inclusion and exclusion criteria, data extraction was performed by two independent reviewers. Primary outcomes included patient and graft survival. RESULTS: From a total of 2374 articles, five met the prefined criteria. One hundred sixty-two patients had both BS + LT and 1426 underwent LT alone. The percentage of female patients in the BS + LT and LT cohorts was 75% and 35% respectively. The average age in BS + LT and LT cohorts was 43.05 vs. 56.22 years respectively. Patients undergoing BS had comparable outcomes in terms of overall patient survival, graft survival and post-operative morbidity compared to LT alone. When comparing BMI change in patients with prior versus simultaneous BS + LT, no significant difference was found. CONCLUSION: BS and LT patients achieve comparable outcomes to general LT populations. Further studies examining simultaneous BS + LT are needed to answer questions concerning patient selection and timing of surgery.

Incidence and risk factors of delirium in patients post pancreaticoduodenectomy.

BACKGROUND: Post-operative delirium is an important and common complication of major abdominal surgery characterized by acute confusion with fluctuating consciousness. The aim of this study was to establish the incidence of post-operative delirium in patients undergoing a pancreaticoduodenectomy and to determine the risk factors for its development. METHODS: From a prospectively maintained database, a retrospective cohort analysis was performed of 50 consecutive patients who underwent a pancreaticoduodenectomy at the National Surgical Centre for Pancreatic Cancer in St. Vincent's University Hospital, Dublin and whose entire post-operative stay was in this institution, between July 2011 and December 2012. Two independent medical practitioners assessed all data and delirium was diagnosed according to criteria of the Diagnostic and Statistical Manual Disorder (DSM), fourth edition. Univariate and multivariate analyses were performed. RESULTS: Seven patients (14%) developed post-operative delirium. The median onset was on the second post-operative day. Older age was predictive of an increased risk of delirium post-operatively. Those who developed delirium had a significantly increased length of stay (LOS) as well as a significantly increased risk of developing at least a grade 3 complication (Clavien-Dindo classification). CONCLUSION: This study demonstrates that post-operative delirium is associated with a more complicated recovery after a pancreaticoduodenectomy and that older age is independently predictive of its development. Focused screening may allow targeted preventative strategies to be used in the peri-operative period to reduce complications and costs associated with delirium.

Biguanides and glucagon like peptide 1 receptor agonists in the amelioration of post liver transplant weight gain; a scoping review of the mechanism of action, safety and efficacy.

Weight gain post-liver transplant can lead to adverse patient outcomes in the post-transplant period. Pharmacotherapy and other measures can be utilised to reduce the burden and occurrence of weight gain in this population. We explored the mechanism of action, safety, and efficacy of these medications, specifically GLP-1 receptor agonists and metformin, focusing on liver transplant patients. This scoping review was conducted in line with the scoping review structure as outlined by the PRISMA guidelines. Metformin and GLP-1 receptor agonists have been observed to be safe and effective in liver transplant patients. Experimental models have found liver-centric weight loss mechanisms in this drug cohort. There is a paucity of evidence about the use of antihyperglycemics in a post-transplant population for weight loss purposes. However, some small studies have shown strong safety and efficacy data. The evidence in relation to using these medications in patients with metabolic syndrome for weight loss warrants further study in a transplant population.

The role of neo-adjuvant therapy in cholangiocarcinoma: A systematic review.

Introduction: Cholangiocarcinoma (CCA) is the most common malignancy affecting the biliary tree. The only curative treatment is surgical resection, aiming for negative margins (R0). For those who have locally advanced disease, which is borderline resectable, neoadjuvant chemoradiation presents an opportunity to reduce tumour size and allow for surgical resection. The aim of this review is to establish the role of neoadjuvant therapy in each subtype of CCA and establish its impact on survival. Methods: Search terms such as 'neoadjuvant therapy' and 'cholangiocarcinoma' were searched on multiple databases, including Pubmed, Ovid and Embase. They were then reviewed separately by two reviewers for inclusion criteria. 978 studies were initially identified from the search strategy, with 21 being included in this review. Results: 5,009 patients were included across 21 studies. 1,173 underwent neoadjuvant therapy, 3,818 had surgical resection alone. 359 patients received Gemcitabine based regimes, making it the most commonly utilised regimen for patients CCA and Biliary Tract Cancer (BTC). Data on tolerability of regimes was limited. All included papers were found to have low risk of bias when assessed using The Newcastle Ottawa Scale. Patients who underwent neoadjuvant therapy had a similar median overall survival compared to those who underwent upfront surgery (38.4 versus 35.1 months respectively). Pre-operative CA19-9, microvascular invasion, perineurial invasion and positive lymph nodes were of prognostic significance across BTC and CCA subtypes. Conclusion: Neoadjuvant therapy and surgical resection is associated with improved patient outcomes and longer median overall survival compared to therapy and upfront surgery, however heterogeneity between research papers limited the ability to further analyse the significance of these results. Although initial studies are promising, further research is required in order to define suitable treatment protocols and tolerability of neoadjuvant regimes. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42020164781.

Human Hepatic CD56bright NK Cells Display a Tissue-Resident Transcriptional Profile and Enhanced Ability to Kill Allogenic CD8+ T Cells.

Liver-resident CD56brightCD16- natural killer (NK) cells are enriched in the human liver and are phenotypically distinct from their blood counterparts. Although these cells are capable of rapid cytotoxic effector activity, their functional role remains unclear. We hypothesise that they may contribute to immune tolerance in the liver during transplantation. RNA sequencing was carried out on FACS sorted NK cell subpopulations from liver perfusates (n=5) and healthy blood controls (n=5). Liver-resident CD56brightCD16+/- NK cells upregulate genes associated with tissue residency. They also upregulate expression of CD160 and LY9, both of which encode immune receptors capable of activating NK cells. Co-expression of CD160 and Ly9 on liver-resident NK cells was validated using flow cytometry. Hepatic NK cell cytotoxicity against allogenic T cells was tested using an in vitro co-culture system of liver perfusate-derived NK cells and blood T cells (n=10-13). In co-culture experiments, hepatic NK cells but not blood NK cells induced significant allogenic T cell death (p=0.0306). Allogenic CD8+ T cells were more susceptible to hepatic NK cytotoxicity than CD4+ T cells (p<0.0001). Stimulation of hepatic CD56bright NK cells with an anti-CD160 agonist mAb enhanced this cytotoxic response (p=0.0382). Our results highlight a role for donor liver NK cells in regulating allogenic CD8+ T cell activation, which may be important in controlling recipient CD8+ T cell-mediated rejection post liver-transplant.

Pancreatic Ductal Adenocarcinoma: Relating Biomechanics and Prognosis.

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and carries a dismal prognosis. Resectable patients are treated predominantly with surgery while borderline resectable patients may receive neoadjuvant treatment (NAT) to downstage their disease prior to possible resection. PDAC tissue is stiffer than healthy pancreas, and tissue stiffness is associated with cancer progression. Another feature of PDAC is increased tissue heterogeneity. We postulate that tumour stiffness and heterogeneity may be used alongside currently employed diagnostics to better predict prognosis and response to treatment. In this review we summarise the biomechanical changes observed in PDAC, explore the factors behind these changes and describe the clinical consequences. We identify methods available for assessing PDAC biomechanics ex vivo and in vivo, outlining the relative merits of each. Finally, we discuss the potential use of radiological imaging for prognostic use.

Incidence and Risk Factors of Intracranial Hemorrhage in Liver Transplant Recipients.

BACKGROUND: Intracranial hemorrhage after liver transplantation is an infrequently reported complication but one which can have devastating consequences. METHODS: We performed a retrospective cross-sectional analysis of all liver transplants performed between January 2010 and June 2015 at a single high-volume institution using a prospectively maintained electronic database and query of the electronic medical record. Cases of intracranial hemorrhage were adjudicated as either spontaneous intraparenchymal hemorrhage(IPH) or extra-axial hemorrhage (EAH). Patients with confirmed intracranial hemorrhage were compared with all other liver transplant recipients. Risk factors were identified by univariate analysis and logistic regression models for IPH and EAH. RESULTS: Thirty-one (5.2%) of 595 liver transplant recipients developed an intracranial hemorrhage within 12 months of transplantation, 15 IPH and 16 EAH. The majority of intracranial hemorrhages were diagnosed within 1 month of transplantation. Eight (26%) intracranial hemorrhage patients died during hospitalization. Fourteen (45%) intracranial hemorrhage patients died within 1 year of transplantation and 1-year mortality was greater than in patients without intracranial hemorrhage (11.2%, P < 0.01). Female sex (adjusted odds ratio [OR], 3.291; 95% confidence interval [CI], 1.092-9.924; P = 0.034), higher pretransplant bilirubin (adjusted OR, 1.037; 95% CI, 1.006-1.070; P = 0.020), and greater increase in pretransplant to posttransplant systolic blood pressure (adjusted OR, 1.029; 95% CI, 1.006-1.052; P = 0.012) were associated with posttransplant IPH. Lower pretransplant serum fibrinogen level (adjusted OR, 0.988; 95% CI, 0.979-0.998; P = 0.017) was associated with posttransplant EAH. CONCLUSIONS: Postoperative blood pressure control and pretransplant fibrinogen levels may be modifiable risk factors for preventing posttransplant intracranial hemorrhage.

Techniques and outcomes of combined inferior vena cava and visceral resection for benign and malignant disease.

BACKGROUND: Involvement of the inferior vena cava (IVC) by neoplasm has traditionally been considered a contra-indication to curative surgery because of high surgical risks and poor long-term prognosis. Advances in surgical and anaesthetic techniques however have made this feasible. The aim of this study is to evaluate the outcome of combined IVC and visceral resection in a single institution. METHODS: A retrospective review of a prospectively maintained database was performed. Pre-operative clinicopathological data, operative details and post-operative outcomes including overall and disease-free survival were analysed. Clinicopathological data of patients over a seven-year period undergoing combined IVC and visceral resection was reviewed, including overall and disease-free survival. RESULTS: Between 2006 and 2012, 14 patients underwent IVC resection was accompanied by major hepatectomy (8), nephrectomy (6) and multivisceral resection (3). Post resection, the IVC was reconstructed primarily (3); with PTFE tube graft (9) or using a Gore-tex patch graft (2). All patients underwent a R0 resection. There were two postoperative deaths within 30 days. 6 patients had postoperative complications. There was 1 early and one late (after 6 months) IVC thrombosis. With a median follow up of 20 months (range 5-84 months), two patients died of tumour recurrence and ten are alive with (n = 5) or without (n = 5) disease. CONCLUSION: Combined IVC and visceral resection can be safely performed in selected patients. Surgery provides the possibility of negative margins, acceptable perioperative morbidity/mortality and prolonged survival. These factors combined with lack of alternative treatments justify this approach. However, specialist teams should perform the surgery preferably in centres with expertise in liver transplantation.

Does aptitude influence the rate at which proficiency is achieved for laparoscopic appendectomy?

BACKGROUND: The attainment of technical competence for surgical procedures is fundamental to a proficiency-based surgical training program. We hypothesized that aptitude may directly affect one's ability to successfully complete the learning curve for minimally invasive procedures. The aim was to assess whether aptitude has an impact on ability to achieve proficiency in completing a simulated minimally invasive surgical procedure. The index procedure chosen was a laparoscopic appendectomy. STUDY DESIGN: Two groups of medical students with disparate aptitude were selected. Aptitude (visual-spatial, depth perception, and psychomotor ability) was measured by previously validated tests. Indicators of technical proficiency for laparoscopic appendectomy were established by trained surgeons with an individual case volume of more than 150. All subjects were tested consecutively on the ProMIS III (Haptica) until they reached predefined proficiency in this procedure. Simulator metrics, critical error scores, and Objective Structured Assessment of Technical Skills (OSATS) scores were recorded. RESULTS: The mean numbers of attempts to achieve proficiency in performing a laparoscopic appendectomy for group A (high aptitude) and B (low aptitude) were 6 (range 4 to 7) and 14 (range 10 to 18), respectively (p < 0.0001). Significant differences were found between the 2 groups for path length (p = 0.014), error score (p = 0.021), and OSATS score (p < 0.0001) at the initial attempt. CONCLUSIONS: High aptitude is directly related to a rapid attainment of proficiency. These findings suggest that resource allocation for proficiency-based technical training in surgery may need to be tailored according to a trainee's natural ability.

Tools used to assess medical students competence in procedural skills at the end of a primary medical degree: a systematic review.

The objective was to systematically review the literature to identify and grade tools used for the end point assessment of procedural skills (e.g., phlebotomy, IV cannulation, suturing) competence in medical students prior to certification. The authors searched eight bibliographic databases electronically - ERIC, Medline, CINAHL, EMBASE, Psychinfo, PsychLIT, EBM Reviews and the Cochrane databases. Two reviewers independently reviewed the literature to identify procedural assessment tools used specifically for assessing medical students within the PRISMA framework, the inclusion/exclusion criteria and search period. Papers on OSATS and DOPS were excluded as they focused on post-registration assessment and clinical rather than simulated competence. Of 659 abstracted articles 56 identified procedural assessment tools. Only 11 specifically assessed medical students. The final 11 studies consisted of 1 randomised controlled trial, 4 comparative and 6 descriptive studies yielding 12 heterogeneous procedural assessment tools for analysis. Seven tools addressed four discrete pre-certification skills, basic suture (3), airway management (2), nasogastric tube insertion (1) and intravenous cannulation (1). One tool used a generic assessment of procedural skills. Two tools focused on postgraduate laparoscopic skills and one on osteopathic students and thus were not included in this review. The levels of evidence are low with regard to reliability - κ = 0.65-0.71 and minimum validity is achieved - face and content. In conclusion, there are no tools designed specifically to assess competence of procedural skills in a final certification examination. There is a need to develop standardised tools with proven reliability and validity for assessment of procedural skills competence at the end of medical training. Medicine graduates must have comparable levels of procedural skills acquisition entering the clinical workforce irrespective of the country of training.

Day-case laparoscopic Nissen fundoplication: a default pathway or is selection the key?

BACKGROUND: In recent years, day-case laparoscopic Nissen fundoplication (LNF) has became popular. Our study aims to evaluate the effect of patient factors and severity of gastroesophageal reflux disease measured by DeMeester score on the success of day-case LNF. SUBJECTS AND METHODS: We conducted a retrospective case series review of patient demographics (age, gender, body mass index [BMI], and smoking status) and DeMeester score over a 5-year period. Between 2005 and 2010, 112 patients had day-case LNF. Same-day discharge was achieved in 80.3%. Twenty-two patients (19.7%) required postoperative admission ("failed day-case surgery"), with a resultant mean length of stay of 1.41 days. Univariate analysis showed that female gender had a significantly higher incidence of postsurgical admission (30.76% females versus 13.69% males, P=.03 by Mann-Whitney U test). Compared with the same-day discharge group, the failed day-case group has a higher mean DeMeester score (50.89 versus 36.03, P=.021 by t test) and BMI (28.71±0.778 kg/m(2) versus 26.79±0.3737 kg/m(2), P=.023). Age and smoking status were not significant determining factors in postoperative admission rates. Using multivariable analysis and logistical regression, we derived a model based on gender, BMI, and DeMeester score to predict the probability of admission following day-case LNF. CONCLUSIONS: We conclude that day-case LNF is a safe, feasible procedure in the appropriately selected patient population. Our novel finding of higher admission rates in females, high DeMeester score, and high BMI should be used in planning perioperative hospitalization in this cohort.

Constitutive basal and stimulated human small bowel contractility is enhanced in obesity.

Small bowel contractility may be more prominent in obese subjects, such that there is enhanced nutrient absorption and hunger stimulation. However, there is little evidence to support this. This study examined in vitro small bowel contractility in obese patients versus non-obese patients. Samples of histologically normal small bowel were obtained at laparoscopic Roux-en-Y gastric bypass from obese patients. Control specimens were taken from non-obese patients undergoing small bowel resection for benign disease or formation of an ileal pouch-anal anastomosis. Samples were transported in a pre-oxygenated Krebs solution. Microdissected circular smooth muscle strips were suspended under 1 g of tension in organ baths containing Krebs solution oxygenated with 95% O2/5% CO2 at 37 degrees C. Contractile activity was recorded using isometric transducers at baseline and in response to receptor-mediated contractility using prostaglandin F2a, a nitric oxide donor and substance P under both equivocal and non-adrenergic, non-cholinergic conditions (guanethidine and atropine). Following equilibration, the initial response to the cholinergic agonist carbachol (0.1 mmol/L) was significantly increased in the obese group (n = 63) versus the lean group (n = 61) with a mean maximum response: weight ratio of 4.58 +/- 0.89 vs 3.53 +/- 0.74; (p = 0.032). Following washout and re-calibration, cumulative application of substance P and prostaglandin F2a produced concentration-dependent contractions of human small bowel smooth muscle strips. Contractile responses of obese small bowel under equivocal conditions were significantly increased compared with non-obese small bowel (p < 0.05 for all agonists). However, no significant differences were shown between the groups when the experiments were performed under NANC conditions. There were no significant differences found between the groups when challenged with nitric oxide, under either equivocal or NANC conditions. Stimulated human small bowel contractility is increased in obese patients suggesting faster enteric emptying and more rapid intestinal transit. This may translate into enhanced appetite and reduced satiety.

Gastric applications of electrical field stimulation.

Advances in clinical applications of electricity have been vast since the launch of Hayman's first cardiac pacemaker more than 70 years ago. Gastric electrical stimulation devices have been recently licensed for treatment of gastroparesis and preliminary studies examining their potential for use in refractory obesity yield promising results.