Toll-like receptor 4 polymorphisms and bacterial infections in patients with cirrhosis and ascites

Altres ajuts: Cofinanced by Fondos FEDER (Fondo Europeo de Desarrollo Regional), "Una manera de hacer Europa", European Union, and CERCA Programme, Generalitat de Catalunya; Silvia Vidal was supported by Fondode Investigaciones Sanitarias (FIS) and is a participant in the Program for Stabilization of Investigators of the Direcció d'Estrategia i Coordinació del Departament de Salut, Generalitat de Catalunya.To assess the relationship between the presence of toll-like receptor 4 (TLR4) polymorphisms and bacterial infections in cirrhotic patients with ascites. We prospectively included consecutive patients with cirrhosis and ascites hospitalized during a 6-year period. Patients with human immunodeficiency virus (HIV) infection or any other immunodeficiency, patients with advanced hepatocellular carcinoma (beyond Milan's criteria) or any other condition determining poor short-term prognosis, and patients with a permanent urinary catheter were excluded. The presence of D299G and/or T399I TLR4 polymorphisms was determined by sequencing and related to the incidence and probability of bacterial infections, other complications of cirrhosis, hepatocellular carcinoma, and mortality during follow-up. A multivariate analysis to identify predictive variables of mortality in the whole series was performed. We included 258 patients: 28 (10.8%) were carriers of D299G and/or T399I TLR4 polymorphisms (polymorphism group) and 230 patients were not (wild-type group). The probability of developing any bacterial infection at one-year follow-up was 78% in the polymorphism group and 69% in the wild-type group (P = 0.54). The one-year probability of presenting infections caused by gram-negative bacilli (51% vs 44%, P = 0.68), infections caused by gram-positive cocci (49% vs 40%, P = 0.53), and spontaneous bacterial peritonitis (29% vs 34%, respectively, P = 0.99) did not differ between the two groups. The one-year probability of transplant-free survival was 55% in the polymorphism group and 66% in the wild-type group (P = 0.15). Multivariate analysis confirmed that age, Child-Pugh score, active alcohol intake, previous hepatic encephalopathy, hepatocellular carcinoma and serum creatinine were associated with a higher risk of death during follow-up. Genetic polymorphisms D299G and/or T399I of TLR4 do not seem to play a relevant role in the predisposition of cirrhotic patients with ascites to bacterial infections

A framework for the evaluation of human machine interfaces of robot-assisted colonoscopy

The Human Machine Interface (HMI) of intraluminal robots has a crucial impact on the clinician's performance. It increases or decreases the difficulty of the tasks, and is connected to the users' physical and mental stress. Objective: This article presents a framework to compare and evaluate different HMIs for robotic colonoscopy, with the objective of identifying the optimal HMI that minimises the clinician's effort and maximises the clinical outcomes. Methods: The framework comprises a 1) a virtual simulator (clinically validated), 2) wearable sensors measuring the cognitive load, 3) a data collection unit of metrics correlated to the clinical performance, and 4) questionnaires exploring the users' impressions and perceived stress. The framework was tested with 42 clinicians investigating the optimal device for tele-operated control of robotic colonoscopes. Two control devices were selected and compared: a haptic serial-kinematic device and a standard videogame joypad. Results: The haptic device was preferred by the endoscopists, but the joypad enabled better clinical performance and reduced cognitive and physical load. Conclusion: The framework can be used to evaluate different aspects of a HMI, both hardware and software, and determine the optimal HMI that can reduce the burden on clinicians while improving the clinical outcome. Significance: The findings of this study, and of future studies performed with this framework, can inform the design and development of HMIs for intraluminal robots, leading to improved clinical performance, reduced physical and mental stress for clinicians, and ultimately better patient outcomes.Peer ReviewedPostprint (published version

Multicenter study of plastic vs. self-expanding metal stents in endoscopic ultrasound-guided drainage of walled-off pancreatic necrosis - PROMETHEUS: a randomized controlled trial protocol.

Background: It seems that lumen-apposing metal stents (LAMS) are displacing plastic stents in the therapy of pancreatic-fluid collection in walled-off necrosis (WON). To date, there is no quality of evidence to recommend LAMS as the standard treatment in the management of WON. The theoretical benefit of LAMS over plastic stents needs to be proven. Methods/design: This is a randomized controlled, multicenter, prospective clinical trial with two parallel groups, without masking. One-hundred and fourteen patients with WON will undergo endoscopic ultrasound (EUS)-guided transmural draining in nine tertiary hospitals in Spain and will be randomized to the LAMS or plastic-stent group. The primary endpoint is the short-term (4 weeks) clinical success determined by the reduction of the collection (to < 50% or < 5 cm in size), along with clinical improvement. Secondary endpoints: long-term (4 months) clinical success (total resolution or 5 cm), procedure duration, level of difficulty, safety, and recurrences. Discussion: The PROMETHEUS trial has been designed to determine whether LAMS are superior to plastic stents in EUS-guided transmural drainage of WON

Clinical validation of risk scoring systems to predict risk of delayed bleeding after EMR of large colorectal lesions

[Background and Aims]: The Endoscopic Resection Group of the Spanish Society of Endoscopy (GSEED-RE) model and the Australian Colonic Endoscopic Resection (ACER) model were proposed to predict delayed bleeding (DB) after EMR of large superficial colorectal lesions, but neither has been validated. We validated and updated these models.[Methods]: A multicenter cohort study was performed in patients with nonpedunculated lesions ≥20 mm removed by EMR. We assessed the discrimination and calibration of the GSEED-RE and ACER models. Difficulty performing EMR was subjectively categorized as low, medium, or high. We created a new model, including factors associated with DB in 3 cohort studies.[Results]: DB occurred in 45 of 1034 EMRs (4.5%); it was associated with proximal location (odds ratio [OR], 2.84; 95% confidence interval [CI], 1.31-6.16), antiplatelet agents (OR, 2.51; 95% CI, .99-6.34) or anticoagulants (OR, 4.54; 95% CI, 2.14-9.63), difficulty of EMR (OR, 3.23; 95% CI, 1.41-7.40), and comorbidity (OR, 2.11; 95% CI, .99-4.47). The GSEED-RE and ACER models did not accurately predict DB. Re-estimation and recalibration yielded acceptable results (GSEED-RE area under the curve [AUC], .64 [95% CI, .54-.74]; ACER AUC, .65 [95% CI, .57-.73]). We used lesion size, proximal location, comorbidity, and antiplatelet or anticoagulant therapy to generate a new model, the GSEED-RE2, which achieved higher AUC values (.69-.73; 95% CI, .59-.80) and exhibited lower susceptibility to changes among datasets.[Conclusions]: The updated GSEED-RE and ACER models achieved acceptable prediction levels of DB. The GSEED-RE2 model may achieve better prediction results and could be used to guide the management of patients after validation by other external groups. (Clinical trial registration number: NCT 03050333.)Research support for this study was received from “La Caixa/Caja Navarra” Foundation (ID 100010434;project PR15/11100006)

Impacte fisiològic de la cirurgia endoscòpica transluminal a través d’orificis naturals (NOTES) utilitzant diferents vies d’accés: estudi comparatiu en un model porcí

[cat] L’aparició de la cirurgia mínimament invasiva ha revolucionat el camp de la cirurgia abdominal. El cirurgians intenten minimitzar el dany produït per les grans incisions de la cirurgia oberta mitjançant la tecnologia endoscòpica. D’altra banda, els endoscopistes tenen la possibilitat de realitzar teràpies cada cop més agressives i que substitueixen, en molts casos, la necessitat de cirurgia El paradigma de la cirurgia combinada amb l’endoscòpia és la cirurgia endoscòpica transluminal a través d’orificis naturals (NOTES, de l’anglès Natural Orifice Transluminal Endoscopic Surgery). Aquest procediment híbrid utilitza la tecnologia de l’endoscòpia flexible per realitzar cirurgia aprofitant els orificis naturals del cos i, per tant, sense necessitat d’incisions externes. Tot i això, abans de la seva implementació en humans, aquesta nova tècnica ha de demostrar que és segura i que ofereix avantatges reals pels pacients. Un dels potencials beneficis de la NOTES és la possibilitat de reduir l’estrès fisiològic que té qualsevol cirurgia. Tot i això, no es tracta en realitat d’una cirurgia sense incisions, sinó que es canvien les incisions de la pell per incisions a les vísceres. Això podria tenir unes conseqüències més perjudicials que les esperades a causa del pas mantingut de fluids intestinals, àcid gàstric, bilis o patògens entèrics a través de les viscerotomies, que podria tenir un elevat impacte inflamatori i, fins i tot, associar-se a més risc d’infeccions. Per aquests motius vam dur a terme un estudi que avalués l’impacte de la NOTES a través de les diferents vies d’accés a la cavitat peritoneal, és a dir, estómac, recte i vagina, i que el compares amb la laparoscòpia convencional. Quaranta animals d’un model porcí es van randomitzar en quatre grups, realitzant una peritoneoscòpia de 30 minuts, bé per laparoscòpia o bé per un dels diferents accessos NOTES (10 animals per grup). El principal objectiu del projecte va ser avaluar l’impacte fisiològic de cada tècnica amb les mostres de sang recollides durant el procediment i durant les dues setmanes posteriors. Una manera de quantificar aquest impacte és a través de la determinació de citocines o d’interleucines. Es va produir un augment dels nivells de TNFα a les 2 hores post-cirurgia en tots els grups respecte del basal. Els nivells basals i post-quirúrgics de TNFα no van ser diferents entre els quatre grups d’estudi. A l’avaluar els nivells de TNFα en sang com a diferència respecte els valors basals, els nivells en el grup NOTES transvaginal van ser els més baixos de tots els grups i inferiors de forma estadísticament significativa a les 2 i 8 hores respecte al grup NOTES transrectal. De tot això es pot concloure que l’impacte fisiològic de la peritoneoscòpia realitzada per NOTES en qualsevol dels accessos estudiats, avaluat mitjançant la resposta de TNFα, és comparable al de la laparoscòpia. Tot i això, l’accés transvaginal podria tenir un impacte fisiològic inferior, com a mínim respecte a l’accés transrectal. Com a segon objectiu vam avaluar l’aparició d’infeccions mitjançant cultius i seguiment clínic en el post-operatori. No es van observar diferencies rellevants entre els grups, pel que es pot concloure que els diferents accessos NOTES semblen comparables a la laparoscòpia en termes d’episodis infecciosos amb repercussió clínica. A més vam avaluar dos sistemes de sutura endoscòpic en desenvolupament: el Brace Bar pel tancament transgàstric i el Padlock-G pel transcolònic. Per últim, els resultats tècnics dels procediments van mostrar un temps quirúrgic superior en tots els grups de NOTES, principalment a causa del temps d’incisió i/o de sutura. D’altra banda, la pressió mitjana del pneumoperitoni va ser inferior en tots els grups NOTES. No es van observar diferències en l’aparició de complicacions quirúrgiques intraoperatòries ni postoperatòries.[eng] "Physiological impact of natural orifice transluminal endoscopic surgery (NOTES) thorough different access sites: comparative study in a survival porcine model" Minimally invasive surgery has revolutionized abdominal surgery in many fields and has slowly taken over a vast majority of surgical procedures. Natural orifice transluminal endoscopic surgery (NOTES) uses flexible endoscopy technology to perform laparoscopic surgery without the need of skin incisions. However, the physiologic impact of NOTES is unknown. This is because NOTES is not incisionless, it exchanges skin incisions for internal viscerotomies. Thus, contamination of the peritoneal cavity by enteric contents may render NOTES more physiologically invasive than previously thought. The aim of our studies was to compare the inflammatory effects of NOTES different accesses and laparoscopy. Forty female pigs were assigned to transgastric, transrectal, and transvaginal NOTES and laparoscopic peritoneoscopy groups. Pre- and postoperative blood samples and peritoneal fluid collected at surgery were analyzed. Animals were followed daily for 14 days. There were no statistical differences in serum levels of TNFα among the groups. When serum TNFα values were expressed as the difference from the baseline, in the transvaginal group they were significantly lower than in the transrectal at 2 h and at 8 h. We therefore concluded that inflammatory parameters are similar after NOTES and laparoscopic peritoneoscopy despite longer surgery time in the NOTES group. The vaginal route seems to reduce the inflammatory stress. We also evaluated the frequency of infection during. In these small series of animals and with the careful lavage and preparation used, NOTES appeared to be comparable to laparoscopy in terms of peritoneal contamination and clinical infection. Finally, we tested to suture systems: the Brace Bar for transgastric incision and the Padlock-G for the transcolonic

Effect of long-term acid gastric inhibition on bacterial translocation in cirrhotic rats

[Background] Bacterial translocation (BT) related to intestinal bacterial overgrowth (IBO) plays an important role in the pathogenesis of bacterial infections in cirrhosis. Inhibition of acid gastric secretion promotes IBO and might favor BT. We evaluated the effect of long-term inhibition of acid gastric secretion on BT in cirrhotic rats. [Methods] Cirrhotic rats with and without ascites induced by oral CCl4 and controls were randomized to treatment with a daily subcutaneous injection of placebo, ranitidine (50 mg/kg), or pantoprazole (8 mg/kg) during 2 weeks. Continuous pH-metry was performed for 2 h before and at the end of treatment; thereafter, a laparotomy to obtain samples of blood, mesenteric lymph nodes, ascites, spleen, liver, and cecal stools was performed. [Results] Ranitidine and pantoprazole increased gastric pH as compared with placebo (P<0.001). However, antisecretory drugs increased the incidence of BT only in ascitic rats treated with ranitidine (P<0.05) or pantoprazole (P=0.07) when compared with placebo-treated ascitic rats or cirrhotic rats without ascites treated with the same drug. Cirrhotic ascitic rats treated with pantoprazole showed a trend toward an increased incidence of IBO (P=0.08), a higher ileal malondialdehyde level (P<0.01), and an increased production of tumor necrosis factor-α (P<0.05). [Conclusion] Although inhibition of acid gastric secretion increased gastric pH in all animals, the incidence of BT increased only in ascitic rats, and it was associated with a trend toward an increase in IBO incidence, a higher ileal malondialdehyde level, and an increased production of serum tumor necrosis factor-α. Therefore, antisecretory drugs should be carefully administered to cirrhotic ascitic patients.Peer Reviewe

IL-6, IL-10 and TNFα do not improve early detection of post-endoscopic retrograde cholangiopancreatography acute pancreatitis : a prospective cohort study

The most reliable indicators for post-ERCP acute pancreatitis are elevated amylase levels and abdominal pain 24 hours after ERCP. As ERCP is often performed on an outpatient basis, earlier diagnosis is important. We aimed to identify early predictors of post-ERCP pancreatitis. We prospectively analyzed IL-6, IL-10, TNFα, CRP, amylase and lipase before and 4 hours after ERCP, and studied their association with abdominal pain. We included 510 patients. Post-ERCP pancreatitis occurred in 36 patients (7.1%). IL-6, IL-10, TNFα and CRP were not associated with post-ERCP pancreatitis. Levels of amylase and lipase were higher in patients with pancreatitis (522 U/L and 1808 U/L vs. 78 U/L and 61 U/L, respectively; p 3 ULN. Amylase and lipase were the only markers of post-ERCP pancreatitis 4 hours after the procedure

A preliminary study of the upper bowel microbiota in patients with SIBO

Trabajo presentado en el IX Workshop de la Sociedad Española de Probióticos y Prebióticos (SEPyP), celebrado en Zaragoza (España) el 15 y 16 de febrero de 2018Small intestinal bacterial overgrowth (SIBO) is a heterogeneous syndrome characterized by an increased number of bacteria in the small bowel. SIBO is diagnosed when bacterial cultures of upper intestine aspirates are ¿105 CFU/ml. Although investigation of these aspirates is considered the gold standard, non-invasive hydrogen breath test are commonly used for SIBO diagnosis. This syndrome has been related with a decrease of small bowel motility, an increase of intestinal permeability and bacterial translocation, being associated with serious diseases such as liver cirrhosis. To investigate the alterations in the bacterial communities of the small bowel from SIBO patients and the potential link with microbiota from other sites (saliva and feces). Duodenal aspirates from patients diagnosed with SIBO, control subjects and cirrhotic patients, with and without SIBO, were used to determine bacterial load (by quantitative PCR) and composition (by Illumina sequencing of 16S rDNA amplicons). Saliva and feces from cirrhotic patients were also included for comparative purposes. Bacterial quantification by qPCR revealed counts higher than 5 x 106 genome equivalents/ml of duodenal aspirates in SIBO patients whereas in the control subjects were below 106. Bacterial composition was represented by members of the Lactobacillales order, diverse families of protebacteria and genera belonging to Prevotellaceae, Veillonellaceae and Micrococcaceae families. No statistical differences were seen between the taxons presented in SIBO and non-SIBO cirrhotic patients. A further investigation with a broad number of patients is needed to confirm whether: i) the usual methods employed for SIBO diagnosis are reliable, and ii) the microbiota of duodenal aspirates in cirrhosis is more closely related to that of the oral cavity than the distal gut.Peer reviewe