Glued suture-less peritoneum closure in laparoscopic inguinal hernia repair reduces acute postoperative pain.

Inguinal hernia repair is performed more than 20 million times per annum, representing a significant health and economic burden. Over the last three decades, significant technical advances have started to reduce the invasiveness of these surgeries, which translated to better recovery and reduced costs. Here we bring forward an innovative surgical technique using a biodegradable cyanoacrylate glue instead of a traumatic suture to close the peritoneum, which is a highly innervated tissue layer, at the end of endoscopy hernia surgery. To test how this affects the invasiveness of hernia surgery, we conducted a cohort study. A total of 183 patients that underwent minimally invasive hernia repair, and the peritoneum was closed with either a conventional traumatic suture (n = 126, 68.9%) or our innovative approach using glue (n = 57, 31.1%). The proportion of patients experiencing acute pain after surgery was significantly reduced (36.8 vs. 54.0%, p = 0.032) by using glue instead of a suture. In accordance, the mean pain level was higher in the suture group (VAS = 1.5 vs. 1.3, p = 0.029) and more patients were still using painkillers (77.9 vs. 52.4%, p = 0.023). Furthermore, the rate of complications was not increased in the glue group. Using multivariate regressions, we identified that using a traumatic suture was an independent predictor of acute postoperative pain (OR 2.0, 95% CI 1.1-3.9, p = 0.042). In conclusion, suture-less glue closure of the peritoneum is innovative, safe, less painful, and possibly leads to enhanced recovery and decreased health costs.

Kupffer cell-like syncytia replenish resident macrophage function in the fibrotic liver.

Kupffer cells (KCs) are localized in liver sinusoids but extend pseudopods to parenchymal cells to maintain their identity and serve as the body's central bacterial filter. Liver cirrhosis drastically alters vascular architecture, but how KCs adapt is unclear. We used a mouse model of liver fibrosis and human tissue to examine immune adaptation. Fibrosis forced KCs to lose contact with parenchymal cells, down-regulating "KC identity," which rendered them incapable of clearing bacteria. Commensals stimulated the recruitment of monocytes through CD44 to a spatially distinct vascular compartment. There, recruited monocytes formed large aggregates of multinucleated cells (syncytia) that expressed phenotypical KC markers and displayed enhanced bacterial capture ability. Syncytia formed via CD36 and were observed in human cirrhosis as a possible antimicrobial defense that evolved with fibrosis.

Combination of Sterile Injury and Microbial Contamination to Model Post-surgical Peritoneal Adhesions in Mice.

Abdominal surgeries are frequently associated with the development of post-surgical adhesions. These are irreversible fibrotic scar bands that appear between abdominal organs and the abdominal wall. Patients suffering from adhesions are at risk of severe complications, such as small bowel obstruction, chronic pelvic pain, or infertility. To date, no cure exists, and the understanding of underlying molecular mechanisms of adhesion formation is incomplete. The current paradigm largely relies on sterile injury mouse models. However, abdominal surgeries in human patients are rarely completely sterile procedures. Here, we describe a modular surgical procedure for simultaneous or separate induction of sterile injury and microbial contamination. Combined, these insults synergistically lead to adhesion formation in the mouse peritoneal cavity. Surgical trauma is confined to a localized sterile injury of the peritoneum. Microbial contamination of the peritoneal cavity is induced by a limited perforation of the microbe-rich large intestine or by injection of fecal content. The presented protocol extends previous injury-based adhesion models by an additional insult through microbial contamination, which may more adequately model the clinical context of abdominal surgery. Graphical abstract.

Splenic red pulp macrophages provide a niche for CML stem cells and induce therapy resistance.

Disease progression and relapse of chronic myeloid leukemia (CML) are caused by therapy resistant leukemia stem cells (LSCs), and cure relies on their eradication. The microenvironment in the bone marrow (BM) is known to contribute to LSC maintenance and resistance. Although leukemic infiltration of the spleen is a hallmark of CML, it is unknown whether spleen cells form a niche that maintains LSCs. Here, we demonstrate that LSCs preferentially accumulate in the spleen and contribute to disease progression. Spleen LSCs were located in the red pulp close to red pulp macrophages (RPM) in CML patients and in a murine CML model. Pharmacologic and genetic depletion of RPM reduced LSCs and decreased their cell cycling activity in the spleen. Gene expression analysis revealed enriched stemness and decreased myeloid lineage differentiation in spleen leukemic stem and progenitor cells (LSPCs). These results demonstrate that splenic RPM form a niche that maintains CML LSCs in a quiescent state, resulting in disease progression and resistance to therapy.

Intraperitoneal microbial contamination drives post-surgical peritoneal adhesions by mesothelial EGFR-signaling.

Abdominal surgeries are lifesaving procedures but can be complicated by the formation of peritoneal adhesions, intra-abdominal scars that cause intestinal obstruction, pain, infertility, and significant health costs. Despite this burden, the mechanisms underlying adhesion formation remain unclear and no cure exists. Here, we show that contamination of gut microbes increases post-surgical adhesion formation. Using genetic lineage tracing we show that adhesion myofibroblasts arise from the mesothelium. This transformation is driven by epidermal growth factor receptor (EGFR) signaling. The EGFR ligands amphiregulin and heparin-binding epidermal growth factor, are sufficient to induce these changes. Correspondingly, EGFR inhibition leads to a significant reduction of adhesion formation in mice. Adhesions isolated from human patients are enriched in EGFR positive cells of mesothelial origin and human mesothelium shows an increase of mesothelial EGFR expression during bacterial peritonitis. In conclusion, bacterial contamination drives adhesion formation through mesothelial EGFR signaling. This mechanism may represent a therapeutic target for the prevention of adhesions after intra-abdominal surgery.

Sterile Injury Repair and Adhesion Formation at Serosal Surfaces.

Most multicellular organisms have a major body cavity containing vital organs. This cavity is lined by a mucosa-like serosal surface and filled with serous fluid which suspends many immune cells. Injuries affecting the major body cavity are potentially life-threatening. Here we summarize evidence that unique damage detection and repair mechanisms have evolved to ensure immediate and swift repair of injuries at serosal surfaces. Furthermore, thousands of patients undergo surgery within the abdominal and thoracic cavities each day. While these surgeries are potentially lifesaving, some patients will suffer complications due to inappropriate scar formation when wound healing at serosal surfaces defects. These scars called adhesions cause profound challenges for health care systems and patients. Therefore, reviewing the mechanisms of wound repair at serosal surfaces is of clinical importance. Serosal surfaces will be introduced with a short embryological and microanatomical perspective followed by a discussion of the mechanisms of damage recognition and initiation of sterile inflammation at serosal surfaces. Distinct immune cells populations are free floating within the coelomic (peritoneal) cavity and contribute towards damage recognition and initiation of wound repair. We will highlight the emerging role of resident cavity GATA6+ macrophages in repairing serosal injuries and compare serosal (mesothelial) injuries with injuries to the blood vessel walls. This allows to draw some parallels such as the critical role of the mesothelium in regulating fibrin deposition and how peritoneal macrophages can aggregate in a platelet-like fashion in response to sterile injury. Then, we discuss how serosal wound healing can go wrong, causing adhesions. The current pathogenetic understanding of and potential future therapeutic avenues against adhesions are discussed.

Automation of surgical skill assessment using a three-stage machine learning algorithm.

Surgical skills are associated with clinical outcomes. To improve surgical skills and thereby reduce adverse outcomes, continuous surgical training and feedback is required. Currently, assessment of surgical skills is a manual and time-consuming process which is prone to subjective interpretation. This study aims to automate surgical skill assessment in laparoscopic cholecystectomy videos using machine learning algorithms. To address this, a three-stage machine learning method is proposed: first, a Convolutional Neural Network was trained to identify and localize surgical instruments. Second, motion features were extracted from the detected instrument localizations throughout time. Third, a linear regression model was trained based on the extracted motion features to predict surgical skills. This three-stage modeling approach achieved an accuracy of 87 ± 0.2% in distinguishing good versus poor surgical skill. While the technique cannot reliably quantify the degree of surgical skill yet it represents an important advance towards automation of surgical skill assessment.

Tacrolimus Impairs Kupffer Cell Capacity to Control Bacteremia: Why Transplant Recipients Are Susceptible to Infection.

BACKGROUND AND AIMS: Kupffer cells (KCs) are the resident intravascular phagocyte population of the liver and critical to the capture and killing of bacteria. Calcineurin/nuclear factor of activated T cells (NFAT) inhibitors (CNIs) such as tacrolimus are used to prevent rejection in solid organ transplant recipients. Although their effect on lymphocytes has been studied extensively, there are limited experimental data about if and how CNIs shape innate immunity, and whether this contributes to the higher rates of infection observed in patients taking CNIs. APPROACH AND RESULTS: Here, we investigated the impact of tacrolimus treatment on innate immunity and, more specifically, on the capability of Kupffer cells (KCs) to fight infections. Retrospective analysis of data of >2,700 liver transplant recipients showed that taking calcineurin inhibitors such as tacrolimus significantly increased the likelihood of Staphylococcus aureus infection. Using a mouse model of acute methicillin-resistant S. aureus (MRSA) bacteremia, most bacteria were sequestered in the liver and we found that bacteria were more likely to disseminate and kill the host in tacrolimus-treated mice. Using imaging, we unveiled the mechanism underlying this observation: the reduced capability of KCs to capture, phagocytose, and destroy bacteria in tacrolimus-treated animals. Furthermore, in a gene expression analysis of infected KCs, the triggering receptor expressed on myeloid cells 1 (TREM1) pathway was the one with the most significant down-regulation after tacrolimus treatment. TREM1 inhibition likewise inhibited KC bacteria capture. TREM1 levels on neutrophils as well as the overall neutrophil response after infection were unaffected by tacrolimus treatment. CONCLUSIONS: Our results indicate that tacrolimus treatment has a significant impact directly on KCs and on TREM1, thereby compromising their capacity to fend off infections.

Macrophage galactose lectin is critical for Kupffer cells to clear aged platelets.

Every day, megakaryocytes produce billions of platelets that circulate for several days and eventually are cleared by the liver. The exact removal mechanism, however, remains unclear. Loss of sialic acid residues is thought to feature in the aging and clearance of platelets. Using state-of-the-art spinning disk intravital microscopy to delineate the different compartments and cells of the mouse liver, we observed rapid accumulation of desialylated platelets predominantly on Kupffer cells, with only a few on endothelial cells and none on hepatocytes. Kupffer cell depletion prevented the removal of aged platelets from circulation. Ashwell-Morell receptor (AMR) deficiency alone had little effect on platelet uptake. Macrophage galactose lectin (MGL) together with AMR mediated clearance of desialylated or cold-stored platelets by Kupffer cells. Effective clearance is critical, as mice with an aged platelet population displayed a bleeding phenotype. Our data provide evidence that the MGL of Kupffer cells plays a significant role in the removal of desialylated platelets through a collaboration with the AMR, thereby maintaining a healthy and functional platelet compartment.

DAMPs, PAMPs, and LAMPs in Immunity and Sterile Inflammation.

Recognizing the importance of leukocyte trafficking in inflammation led to some therapeutic breakthroughs. However, many inflammatory pathologies remain without specific therapy. This review discusses leukocytes in the context of sterile inflammation, a process caused by sterile (non-microbial) molecules, comprising damage-associated molecular patterns (DAMPs). DAMPs bind specific receptors to activate inflammation and start a highly optimized sequence of immune cell recruitment of neutrophils and monocytes to initiate effective tissue repair. When DAMPs are cleared, the recruited leukocytes change from a proinflammatory to a reparative program, a switch that is locally supervised by invariant natural killer T cells. In addition, neutrophils exit the inflammatory site and reverse transmigrate back to the bloodstream. Inflammation persists when the program switch or reverse transmigration fails, or when the coordinated leukocyte effort cannot clear the immunostimulatory molecules. The latter causes inappropriate leukocyte activation, a driver of many pathologies associated with poor lifestyle choices. We discuss lifestyle-associated inflammatory diseases and their corresponding immunostimulatory lifestyle-associated molecular patterns (LAMPs) and distinguish them from DAMPs.

Connexin-43-dependent ATP release mediates macrophage activation during sepsis.

Bacterial spillage into a sterile environment following intestinal hollow-organ perforation leads to peritonitis and fulminant sepsis. Outcome of sepsis critically depends on macrophage activation by extracellular ATP-release and associated autocrine signalling via purinergic receptors. ATP-release mechanisms, however, are poorly understood. Here, we show that TLR-2 and -4 agonists trigger ATP-release via Connexin-43 hemichannels in macrophages leading to poor sepsis survival. In humans, Connexin-43 was upregulated on macrophages isolated from the peritoneal cavity in patients with peritonitis but not in healthy controls. Using a murine peritonitis/sepsis model, we identified increased Connexin-43 expression in peritoneal and hepatic macrophages. Conditional Lyz2cre/creGja1flox/flox mice were developed to specifically assess Connexin-43 impact in macrophages. Both macrophage-specific Connexin-43 deletion and pharmacological Connexin-43 blockade were associated with reduced cytokine secretion by macrophages in response to LPS and CLP, ultimately resulting in increased survival. In conclusion, inhibition of autocrine Connexin-43-dependent ATP signalling on macrophages improves sepsis outcome.

Antibodies Set Boundaries Limiting Microbial Metabolite Penetration and the Resultant Mammalian Host Response.

Although the mammalian microbiota is well contained within the intestine, it profoundly shapes development and metabolism of almost every host organ. We questioned the range and depth of microbial metabolite penetration into the host, and how this is modulated by intestinal immunity. Chemically identical microbial and host metabolites were distinguished by stable isotope tracing from 13C-labeled live non-replicating Escherichia coli, differentiating 12C host isotopes with high-resolution mass spectrometry. Hundreds of endogenous microbial compounds penetrated 23 host tissues and fluids after intestinal exposure: subsequent 12C host metabolome signatures included lipidemia, reduced glycolysis, and inflammation. Penetrant bacterial metabolites from the small intestine were rapidly cleared into the urine, whereas induced antibodies curtailed microbial metabolite exposure by accelerating intestinal bacterial transit into the colon where metabolite transport mechanisms are limiting. Pervasive penetration of microbial molecules can cause extensive host tissue responses: these are limited by immune and non-immune intestinal mucosal adaptations to the microbiota.

Prophylactic, Synthetic Intraperitoneal Mesh Versus No Mesh Implantation in Patients with Fascial Dehiscence.

BACKGROUND: Primary closure of post-operative facial dehiscence (FD) is associated with a high incidence of recurrence, revisional surgery, and incisional hernia. This retrospective study compares outcomes of implantation of non-absorbable intra-abdominal meshes with primary closure of FD. The outcomes of different mesh materials were assessed in subgroup analysis. METHODS: A total of 119 consecutive patients with FD were operated (70 mesh group and 49 no mesh group) between 2001 and 2015. Primary outcome parameter was hernia-free survival. Secondary outcome parameters include re-operations of the abdominal wall, intestinal fistula, surgical site infections (SSI), and mortality. Kaplan-Meier analysis for hernia-free survival, adjusted Poisson regression analysis for re-operations and adjusted regression analysis for chronic SSI was performed. RESULTS: Hernia-free survival was significantly higher in the mesh group compared to the no mesh group (P = 0.005). Fewer re-operations were necessary in the mesh group compared to the no mesh group (adjusted incidence risk ratio 0.44, 95% confidence interval [CI] 0.20-0.93, P = 0.032). No difference in SSI, intestinal fistula, and mortality was observed between groups. Chronic SSI was observed in 7 (10%) patients in the mesh group (n = 3 [6.7%] with polypropylene mesh and 4 [28.6%] with polyester mesh). The risk for chronic SSI was significantly higher if a polyester mesh was used when compared to a polypropylene mesh (adjusted odds ratio 8.69, 95% CI 1.30-58.05, P = 0.026). CONCLUSION: Implantation of a polypropylene but not polyester-based mesh in patients with FD decreases incisional hernia with a low rate of mesh-related morbidity.

Electronic Voting to Improve Morbidity and Mortality Conferences.

BACKGROUND: It is of major importance in clinical surgery to identify potential patterns and specific causes of complications. Therefore, morbidity and mortality meetings (M&M) are widely used to discuss and evaluate deviations from expected outcomes in order to improve surgical practice. Moreover, M&M represent an important tool for continuous medical education. In this study, we introduced an electronic voting system to assess whether anonymity during M&M could limit potential biases due to hierarchical structures or opinion leaders. METHODS: This study was conducted in the surgical department of a European tertiary care center. During the study period, electronic voting was applied in 412 M&M cases and compared with a baseline of 330 conventional M&M entries. In this interrupted time series, the educational quality and participant satisfaction of the M&M were assessed using surveys before and after the introduction of electronic voting. The surveys were refined using principle component analysis. In addition, the classification of the cause of the complication was recorded. RESULTS: The introduction of electronic voting led to a significant increase in perceived educational quality from 2.63 to 3.36 (p < 0.01), and the overall participant satisfaction increased from 2.6 ± 0.9 to 3.7 ± 1.2 (p < 0.01) on a five-point Likert scale. The frequency of voting shifted from "patient's disease" (before 42.9, after 27.6%, p = 0.04) to "misadventure" (before 1.1, after 16.0%, p < 0.01). The voting frequencies for the causes attributed to "management" and "technical" remained constant. CONCLUSIONS: An electronic voting system in M&M meetings increases perceived educational quality and participant satisfaction.

A sustaining rod increases necrosis of loop ileostomies: a randomized controlled trial.

PURPOSE: Defunctioning loop ileostomies (LI) are commonly used in colorectal surgery to reduce the potentially detrimental consequences of anastomotic leakages. However, stoma-related morbidity is high with up to 75% of patients having local complications. The aim of this study was to investigate the effect of a sustaining rod on the local complication rate. METHODS: In this prospective, multi-center, randomized controlled trial, subjects were allocated to either a rod or a rod-less protocol (NCT00959738). The primary outcome was local morbidity as measured by a stoma specific morbidity score (SSMS) during the first 3 months postoperatively. RESULTS: Between August 2008 and July 2014, a total of 122 patients were enrolled in the study, of which 78 (63.8%) completed the study [44 (56.4%) rod, 34 (43.6%) rod-less]. There was no significant difference in the SSMS between the two groups. The incidence of necrosis or partial necrosis, however, was significantly increased in the rod group: 13 (29.5%) vs. 1 (2.9%) in the rod-less group (p < 0.01). The retraction rate did not differ significantly between the groups: two (4.5%) in the rod vs. five (14.7%) in the rod-less group (p = 0.13). High body mass index (BMI > 26) was associated with an odds ratio of 5 (p < 0.01) for severe stoma complications. CONCLUSIONS: A rod-less technique for loop ileostomies reduces the risk of stomal necrosis, with a high BMI being an independent risk factor for stomal complications.

Granulocyte Colony-stimulating Factor Producing Anaplastic Carcinoma of the Pancreas: Case Report and Review of the Literature.

We report on the case of a 67-year-old man with granulocyte colony-stimulating factor (G-CSF) producing anaplastic carcinoma of the pancreas. Preoperative routine tests revealed an elevated white blood cell (WBC) count of 25.2 G/l, consisting almost exclusively of neutrophilic granulocytes (23.31 G/l) with a predominance of segmented neutrophils (78% of all neutrophilic granulocytes), and elevated levels of C-reactive protein at 87 mg/l. Upon surgery, local tumour infiltration was more extensive than expected from preoperative imaging. However, no peritoneal dissemination was found and curative resection was attempted. Only seven days after the operation, signs of relapse were seen upon computed tomograpy. Histology revealed an undifferentiated anaplastic carcinoma, on the basis of a poorly differentiated ductal adenocarcinoma. Immunohistochemistry demonstrated G-CSF and G-CSF-Receptor expression in some CD68-positive syncytial macrophages. Granulocyte colony-stimulating factor (G-CSF) in serum was elevated at 5.6 pg/ml, which further raised to 43 pg/ml one week after FOLFIRINOX chemotherapy (oxaliplatin, irinotecan, 5-fluorouracil), while WBC decreased from 103.3 G/l to 59.3 G/l. Granulocyte macrophage-colony stimulating factor (GM-CSF) in serum was normal (<0.5 pg/ml). The patient died on postoperative day 34.

[Necessary and unnecessary treatment options for hemorrhoids]. / Nötige und unnötige Behandlungen beim Hämorrhoidalleiden: Der Patient bestimmt mit.

Up to one third of the general population suffers from symptoms caused by hemorrhoids. Conservative treatment comes first unless the patient presents with an acute hemorrhoidal prolapse or a thrombosis. A fiber enriched diet is the primary treatment option, recommended in the perioperative period as well as a long-term prophylaxis. A timely limited application of topical ointments or suppositories and/or flavonoids are further treatment options. When symptoms persist interventional procedures for grade I-II hemorrhoids, and surgery for grade III-IV hemorrhoids should be considered. Rubber band ligation is the interventional treatment of choice. A comparable efficacy using sclerosing or infrared therapy has not yet been demonstrated. We therefore do not recommend these treatment options for the cure of hemorrhoids. Self-treatment by anal insertion of bougies is of lowrisk and may be successful, particularly in the setting of an elevated sphincter pressure. Anal dilation, sphincterotomy, cryosurgery, bipolar diathermy, galvanic electrotherapy, and heat therapy should be regarded as obsolete given the poor or missing data reported for these methods. For a long time, the classic excisional hemorrhoidectomy was considered to be the gold standard as far as surgical procedures are concerned. Primary closure (Ferguson) seems to be superior compared to the "open" version (Milligan Morgan) with respect to postoperative pain and wound healing. The more recently proposed stapled hemorrhoidopexy (Longo) is particularly advisable for circular hemorrhoids. Compared to excisional hemorrhoidectomy the Longo-operation is associated with reduced postoperative pain, shorter operation time and hospital stay as well as a faster recovery, with the disadvantage though of a higher recurrence rate. Data from Hemorrhoidal Artery Ligation (HAL)-, if appropriate in combination with a Recto-Anal Repair (HAL/RAR)-, demonstrates a similar trend towards a better tolerance of the procedure at the expense of a higher recurrence rate. These relatively "new" procedures equally qualify for the treatment of grade III and IV hemorrhoids, and, in the case of stapled hemorrhoidopexy, may even be employed in the emergency situation of an acute anal prolapse. While under certain circumstances different treatment options are equivalent, there is a clear specificity with respect to the application of those procedures in other situations. The respective pros and cons need to be discussed separately with every patient. According to their own requirements a treatment strategy has to be defined according to their individual requirements.

Predicting future risk of asthma exacerbations using individual conditional probabilities.

BACKGROUND: Determination of future risk of exacerbations is a key issue in the management of asthma. We previously developed a method to calculate conditional probabilities (π) of future decreases in lung function by using the daily fluctuations in peak expiratory flow (PEF). OBJECTIVE: We aimed to extend calculation of π values to individual patients, validated by using electronically recorded data from 2 past clinical trials. METHODS: Twice-daily PEF data were analyzed from 78 patients with severe (study A) and 61 patients with poorly controlled (study B) asthma. For each patient, the π value was calculated from 5000 PEF data points simulated based on the correlation and distribution properties of observed PEF. Given an initial PEF, the π value was defined as the probability of a decrease in PEF to less than 80% of predicted value on 2 consecutive days within a month. These probabilities were then compared with actual occurrences of such events and clinically defined exacerbations within the following month. RESULTS: π Values were related to actual occurrences of decreases in PEF (adjusted R(2) > 0.800 for both studies). Every increase of 10% in π value was associated with an odds ratio of having a future exacerbation of 1.24 (95% CI, 1.07-1.43) for study A and 1.13 (95% CI, 1.02-1.26) for study B, with better sensitivity and specificity than clinic-measured FEV(1). CONCLUSION: These results from 2 independent datasets with differing asthmatic populations and differing exacerbation criteria provide support that clinically relevant quantification of individual future risk of exacerbations is possible.