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

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

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

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

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

Necessary and unnecessary treatment options for hemorrhoids

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.Das Hämorrhoidalleiden ist eine häufige Krankheit an der bis zu einem Drittel der Bevölkerung leidet. Handelt es sich nicht um eine Notfallsituation mit akutem Hämorrhoidalprolaps oder Thrombose, so sollte wegen der minimalen Morbidität primär konservativ behandelt werden. Eine Stuhlregulation mit faserreicher Ernährung und/oder Quellmitteln ist dabei der erste Behandlungspfeiler, wird aber auch perioperativ empfohlen und dient der Langzeitprophylaxe. Gegebenenfalls kann zusätzlich vorübergehend mit Salben oder Suppositorien und/oder Flavonoiden behandelt werden. Die meisten Patienten werden dadurch beschwerdefrei, so dass von einem interventionellen oder invasiven Eingriff abgesehen werden kann. Erst bei persistierenden Symptomen kommen, bei Grad I–II Hämorrhoiden zunächst interventionelle, und bei höhergradigen bzw. therapierefraktären Hämorrhoiden, operative Therapien zum Einsatz. Interventionell konnte sich die Gummibandligatur als Therapie der Wahl etablieren. Ein vergleichbarer Effekt der Sklerosierungs- und Infrarottherapie wurde bisher nicht gezeigt. Wir können die Methoden daher nicht empfehlen. Die Selbstbehandlung mit analer Bougierung zeigt insbesondere bei Vorliegen eines erhöhten Sphinkterdruckes Erfolge und kann, relativ risikolos versucht werden. Gewisse chirurgische Verfahren wie die anale Dilatation, die Sphinkterotomie, die Kryochirurgie, die bipolare Diathermie, die galvanische Elektrotherapie und die Hitzebehandlung können aufgrund schlechter Resultate oder fehlender Daten nicht mehr empfohlen und müssen als obsolet betrachtet werden. Lange Zeit galt die klassische Hämorrhoidektomie bei der Behandlung des höhergradigen Hämorrhoidalleidens als operativer Goldstandard. Dabei ist die geschlossene Variante nach Ferguson bezüglich postoperativen Schmerzen und Wundheilung der offenen Variante nach Milligan-Morgan eher überlegen. Die in jüngerer Zeit vorgeschlagene, alternative Technik der Stapler-Hemorrhoidopexie nach Longo hat sich, insbesondere bei zirkulären Befunden, durchsetzen können. Die Longo-Operation ist der klassischen Methode in punkto postoperativer Schmerzen, Wiedererlangen der Arbeitsfähigkeit, Hospitalisationsdauer und Operationszeit überlegen, zeigt aber mehr Rezidive. Daten zur Hämorrhoiden-Arterien-Ligatur (HAL), allenfalls in Kombination mit rekto-analem-repair (HAL/RAR) zeigen einen ähnlichen Trend: bessere Verträglichkeit, mehr Rezidive. Diese „neueren“ Verfahren eignen sich auch für die Behandlung von höhergradigen Hämorrhoiden (Grad III und IV nach Parks) und können im Falle der Stapler-Hämorrhoidopexie auch bei Notfallsituationen wie dem akuten Hämorrhoidalprolaps erfolgreich zur Anwendung kommen. Unter bestimmten Bedingungen können gewisse Methoden äquivalent eingesetzt werden, während für andere Situationen klare Spezifitäten bezüglich Anwendung der einzelnen Behandlungen bestehen. Diese Vor- und Nachteile sollen dem Patienten dargelegt werden, so dass ein auf seine Bedürfnisse zugeschnittener Behandlungsplan entwickelt werden kann

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

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

Chronische Schmerzen nach Inguinalhernienchirurgie.

Chronic postoperative pain after inguinal hernia repair is common. Current evidence reveals a reduction of chronic postoperative pain after endoscopic mesh repair. This review describes diagnostic and therapeutic options for patients with chronic pain post hernia surgery