The multistep sequence leading to leukocyte migration is thought to be locally regulated at the inflammatory site. Here, we show that broad systemic programs involving long-range signals from the ...sympathetic nervous system (SNS) delivered by adrenergic nerves regulate rhythmic recruitment of leukocytes in tissues. Constitutive leukocyte adhesion and migration in murine bone marrow (BM) and skeletal-muscle microvasculature fluctuated with circadian peak values at night. Migratory oscillations, altered by experimental jet lag, were implemented by perivascular SNS fibers acting on β-adrenoreceptors expressed on nonhematopoietic cells and leading to tissue-specific, differential circadian oscillations in the expression of endothelial cell adhesion molecules and chemokines. We showed that these rhythms have physiological consequences through alteration of hematopoietic cell recruitment and overall survival in models of septic shock, sickle cell vaso-occlusion, and BM transplantation. These data provide unique insights in the leukocyte adhesion cascade and the potential for time-based therapeutics for transplantation and inflammatory diseases.
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► Leukocyte recruitment in tissues exhibits a circadian rhythm peaking at night ► Absence of local innervation abolishes oscillations ► Diurnal expression of adhesion molecules mediates circadian leukocyte recruitment ► Circadian time influences leukocyte recruitment in inflammation
Background
Surgical phase recognition using computer vision presents an essential requirement for artificial intelligence-assisted analysis of surgical workflow. Its performance is heavily dependent ...on large amounts of annotated video data, which remain a limited resource, especially concerning highly specialized procedures. Knowledge transfer from common to more complex procedures can promote data efficiency. Phase recognition models trained on large, readily available datasets may be extrapolated and transferred to smaller datasets of different procedures to improve generalizability. The conditions under which transfer learning is appropriate and feasible remain to be established.
Methods
We defined ten operative phases for the laparoscopic part of Ivor-Lewis Esophagectomy through expert consensus. A dataset of 40 videos was annotated accordingly. The knowledge transfer capability of an established model architecture for phase recognition (CNN + LSTM) was adapted to generate a “Transferal Esophagectomy Network” (TEsoNet) for co-training and transfer learning from laparoscopic Sleeve Gastrectomy to the laparoscopic part of Ivor-Lewis Esophagectomy, exploring different training set compositions and training weights.
Results
The explored model architecture is capable of accurate phase detection in complex procedures, such as Esophagectomy, even with low quantities of training data. Knowledge transfer between two upper gastrointestinal procedures is feasible and achieves reasonable accuracy with respect to operative phases with high procedural overlap.
Conclusion
Robust phase recognition models can achieve reasonable yet phase-specific accuracy through transfer learning and co-training between two related procedures, even when exposed to small amounts of training data of the target procedure. Further exploration is required to determine appropriate data amounts, key characteristics of the training procedure and temporal annotation methods required for successful transferal phase recognition. Transfer learning across different procedures addressing small datasets may increase data efficiency. Finally, to enable the surgical application of AI for intraoperative risk mitigation, coverage of rare, specialized procedures needs to be explored.
Graphical abstract
Background
Increased uptake of robotic surgery has led to interest in learning curves for robot‐assisted procedures. Learning curves, however, are often poorly defined. This systematic review was ...conducted to identify the available evidence investigating surgeon learning curves in robot‐assisted surgery.
Methods
MEDLINE, Embase and the Cochrane Library were searched in February 2018, in accordance with PRISMA guidelines, alongside hand searches of key congresses and existing reviews. Eligible articles were those assessing learning curves associated with robot‐assisted surgery in patients.
Results
Searches identified 2316 records, of which 68 met the eligibility criteria, reporting on 68 unique studies. Of these, 49 assessed learning curves based on patient data across ten surgical specialties. All 49 were observational, largely single‐arm (35 of 49, 71 per cent) and included few surgeons. Learning curves exhibited substantial heterogeneity, varying between procedures, studies and metrics. Standards of reporting were generally poor, with only 17 of 49 (35 per cent) quantifying previous experience. Methods used to assess the learning curve were heterogeneous, often lacking statistical validation and using ambiguous terminology.
Conclusion
Learning curve estimates were subject to considerable uncertainty. Robust evidence was lacking, owing to limitations in study design, frequent reporting gaps and substantial heterogeneity in the methods used to assess learning curves. The opportunity remains for the establishment of optimal quantitative methods for the assessment of learning curves, to inform surgical training programmes and improve patient outcomes.
Antecedentes
La aceptación creciente de la cirugía robótica ha generado interés en las curvas de aprendizaje para los procedimientos asistidos por robot. Sin embargo, las curvas de aprendizaje a menudo están mal definidas. Esta revisión sistemática se realizó para identificar la evidencia disponible en relación a las curvas de aprendizaje del cirujano en la cirugía asistida por robot.
Métodos
En Febrero de 2018, se realizaron búsquedas en MEDLINE, Embase y Cochrane Library, de acuerdo con las recomendaciones PRISMA, junto con búsquedas manuales de congresos clave y de revisiones ya existentes. Los artículos elegibles fueron aquellos que evaluaron las curvas de aprendizaje asociadas con la cirugía asistida por robot efectuada en pacientes.
Resultados
Las búsquedas bibliográficas identificaron 2.316 registros de los cuales 68 cumplían los criterios de elegibilidad y correspondían a 68 estudios primarios. De estos 68 estudios, 49 evaluaron las curvas de aprendizaje basadas en datos de pacientes de 10 especialidades quirúrgicas. Los 49 estudios eran todos estudios observacionales, en su mayoría de un solo brazo (35/49 (71%)) e incluían pocos cirujanos. Las curvas de aprendizaje mostraban una notable heterogeneidad, variando entre procedimientos, estudios y parámetros analizados. Los estándares de presentación de informes fueron generalmente deficientes, con solo 17/49 (35%) cuantificando la experiencia previa. Los métodos utilizados para evaluar la curva de aprendizaje fueron heterogéneos, a menudo carecían de validación estadística y usaban terminología ambigua.
Conclusión
Las estimaciones de la curva de aprendizaje estaban sujetas a una considerable incertidumbre, careciendo de evidencia robusta por las limitaciones en el diseño del estudio, lagunas de información en los artículos y heterogeneidad sustancial en los métodos utilizados para evaluar las curvas de aprendizaje. Queda pendiente establecer métodos cuantitativos óptimos para evaluar las curvas de aprendizaje, informar de los programas de formación quirúrgica y mejorar los resultados del paciente.
A broad systematic literature review was performed to characterize the current evidence base and appraise the methods used to measure and define learning curves for surgeons performing robot‐assisted surgery, taking a holistic, panspecialty view. The learning curve estimates identified are subject to considerable uncertainty, and robust evidence was often lacking due to limitations in study design and frequent reporting gaps. Thus, the opportunity remains for the establishment of optimal quantitative methods for the assessment of learning curves, which may inform surgical training programmes and improve patient outcomes.
Little consistency between studies
Intraductal papillary mucinous neoplasm (IPMN), the most common pancreatic cystic neoplasm, is known to progress to invasive ductal adenocarcinoma. IPMNs commonly harbor activating somatic mutations ...in GNAS and KRAS, primarily GNAS(R201H) and KRAS(G12D). GNAS encodes the stimulatory G-protein α subunit (Gsα) that mediates a stimulatory signal to adenylyl cyclase to produce cyclic adenosine monophosphate (cAMP), subsequently activating cAMP-dependent protein kinase A. The GNAS(R201H) mutation results in constitutive activation of Gsα. To study the potential role of GNAS in pancreatic tumorigenesis in vivo, we generated lines of transgenic mice in which the transgene consisted of Lox-STOP-Lox (LSL)-GNAS(R201H) under the control of the CAG promoter (Tg(CAG-LSL-GNAS)). These mice were crossed with pancreatic transcription factor 1a (Ptf1a)-Cre mice (Ptf1a(Cre/+)), generating Tg(CAG-LSL-GNAS);Ptf1a(Cre/+) mice. This mouse line showed elevated cAMP levels, small dilated tubular complex formation, loss of acinar cells and fibrosis in the pancreas; however, no macroscopic tumorigenesis was apparent by 2 months of age. We then crossed Tg(CAG-LSL-GNAS);Ptf1a(Cre/+) mice with LSL-Kras(G12D) mice, generating Tg(CAG-LSL-GNAS);LSL-Kras(G12D);Ptf1a(Cre/+) mice. We used these mice to investigate a possible cooperative effect of GNAS(R201H) and Kras(G12D) in pancreatic tumorigenesis. Within 5 weeks, Tg(CAG-LSL-GNAS);LSL-Kras(G12D);Ptf1a(Cre/+) mice developed a cystic tumor consisting of marked dilated ducts lined with papillary dysplastic epithelia in the pancreas, which closely mimicked the human IPMN. Our data strongly suggest that activating mutations in GNAS and Kras cooperatively promote murine pancreatic tumorigenesis, which recapitulates IPMN. Our mouse model may serve as a unique in vivo platform to find biomarkers and effective drugs for diseases associated with GNAS mutations.
The inactivation of the Hippo pathway lead to TAZ (PDZ-binding motif)/YAP (yes-associated protein) overexpression, and is associated with worse prognostic outcomes in various cancers including ...hepatocellular carcinoma (HCC). Although there are several reports of microRNA (miR) targeting for YAP, miR targeting for TAZ remains unclear. The aim of this study is to identify the miR targeting TAZ expression in HCC.
MicroRNA expression was analysed using the Human miFinder 384HC miScript miR PCR array, and was compared between low and high TAZ expression cell lines. Then, we extracted miR-9-3p as a tumour-suppressor miR targeting TAZ. We examined the functional role of miR-9-3p using miR-9-3p mimic and inhibitor in HCC cell lines).
In HCC cell lines and HCC clinical samples, there was the inverse correlation between miR-9-3p and TAZ expressions. TAZ expression was induced by treatment of miR-9-3p inhibitor and was downregulated by treatment of miR-9-3p mimic. Treatment of miR-9-3p mimic inhibited cell proliferative ability with downregulated phosphorylations of Erk1/2, AKT, and β-catenin in HLF. Inversely, treatment of miR-9-3p inhibitor accelerated cell growth compared with control in HuH1.
MicroRNA-9-3p was identified as the tumour-suppressor miR targetting TAZ expression in HCC cells.
Circulating tumour cells (CTCs) have an important role in metastatic processes, but details of their basic characteristics remain elusive. We hypothesised that CD44-expressing CTCs show a mesenchymal ...phenotype and high potential for survival in hepatocellular carcinoma (HCC).
Circulating CD44(+)CD90(+) cells, previously shown to be tumour-initiating cells, were sorted from human blood and their genetic characteristics were compared with those of tumour cells from primary tissues. The mechanism underlying the high survival potential of CD44-expressing cells in the circulatory system was investigated in vitro.
CD44(+)CD90(+) cells in the blood acquired epithelial-mesenchymal transition, and CD44 expression remarkably increased from the tissue to the blood. In Li7 and HLE cells, the CD44(high) population showed higher anoikis resistance and sphere-forming ability than did the CD44(low) population. This difference was found to be attributed to the upregulation of Twist1 and Akt signal in the CD44(high) population. Twist1 knockdown showed remarkable reduction in anoikis resistance, sphere formation, and Akt signal in HLE cells. In addition, mesenchymal markers and CD44s expression were downregulated in the Twist1 knockdown.
CD44s symbolises the acquisition of a mesenchymal phenotype regulating anchorage-independent capacity. CD44s-expressing tumour cells in peripheral blood are clinically important therapeutic targets in HCC.
Background
Total pancreatectomy is required to completely clear tumours that are locally advanced or located in the centre of the pancreas. However, reports describing clinical outcomes after total ...pancreatectomy are rare. The aim of this retrospective observational study was to assess clinical outcomes following total pancreatectomy using a nationwide registry and to create a risk model for severe postoperative complications.
Methods
Patients who underwent total pancreatectomy from 2013 to 2017, and who were recorded in the Japan Society of Gastroenterological Surgery and Japanese Society of Hepato‐Biliary‐Pancreatic Surgery database, were included. Severe complications at 30 days were defined as those with a Clavien–Dindo grade III needing reoperation, or grade IV–V. Occurrence of severe complications was modelled using data from patients treated from 2013 to 2016, and the accuracy of the model tested among patients from 2017 using c‐statistics and a calibration plot.
Results
A total of 2167 patients undergoing total pancreatectomy were included. Postoperative 30‐day and in‐hospital mortality rates were 1·0 per cent (22 of 2167 patients) and 2·7 per cent (58 of 167) respectively, and severe complications developed in 6·0 per cent (131 of 2167). Factors showing a strong positive association with outcome in this risk model were the ASA performance status grade and combined arterial resection. In the test cohort, the c‐statistic of the model was 0·70 (95 per cent c.i. 0·59 to 0·81).
Conclusion
The risk model may be used to predict severe complications after total pancreatectomy.
Antecedentes
La pancreatectomía total está indicada cuando se requiere la resección completa de tumores localmente avanzados o ubicados en el centro del páncreas. Sin embargo, existen pocos artículos que describan los resultados clínicos después de una pancreatectomía total. El objetivo de este estudio observacional retrospectivo fue evaluar los resultados clínicos después de una pancreatectomía total utilizando un registro nacional y crear un modelo de riesgo de complicaciones postoperatorias graves.
Métodos
Se incluyeron aquellos pacientes que se sometieron a una pancreatectomía total entre 2013 y 2017 y que fueron registrados en la base de datos de la Sociedad Japonesa de Cirugía Gastrointestinal y de la Sociedad Japonesa de Cirugía Hepato‐Bilio‐Pancreática. Las complicaciones graves a los 30 días se definieron como Clavien‐Dindo grado III con reintervención o grado IV/V. Se analizó la aparición de complicaciones graves de los pacientes desde 2013 a 2016 y se evaluó la precisión del modelo entre los pacientes operados desde 2017 usando estadísticos c y un gráfico de calibración.
Resultados
Se incluyeron 2.167 pacientes sometidos a una pancreatectomía total. La mortalidad postoperatoria a los 30 días y la mortalidad hospitalaria fueron del 1,0% (22/2167) y del 2,7% (58/2167), respectivamente, y las complicaciones graves ocurrieron en el 6,0% (131/2167) de los pacientes. Los factores que mostraron una fuerte asociación positiva con los resultados en este modelo de riesgo fueron el estado funcional según la Sociedad Americana de Anestesiología y la resección arterial combinada. En la cohorte de prueba, el estadístico c del modelo fue de 0,70 (i.c. del 95% 0,59‐0,81).
Conclusión
El modelo de riesgo puede usarse para predecir las complicaciones graves después de una pancreatectomía total.
This study assessed the clinical outcomes of total pancreatectomy using a nationwide registry in Japan, and proposed a risk model for severe postoperative complications. Rates of mortality and severe complication after total pancreatectomy were lower in this study than in previous reports. The risk model showed good calibration.
Tool for preoperative risk estimation
The mononuclear phagocyte system (MPS) comprises monocytes, macrophages and dendritic cells (DCs). Over the past few decades, classification of the cells of the MPS has generated considerable ...controversy. Recent studies into the origin, developmental requirements and function of MPS cells are beginning to solve this problem in an objective manner. Using high‐resolution genetic analyses and fate‐mapping studies, three main mononuclear phagocyte lineages have been defined, namely, macrophage populations established during embryogenesis, monocyte‐derived cells that develop during adult life and DCs. These subsets and their diverse subsets have specialized functions that are largely conserved between species, justifying the introduction of a new, universal scheme of nomenclature and providing the framework for therapeutic manipulation of immune responses in the clinic. In this review, we have commented on the implications of this novel MPS classification in solid organ transplantation.
The authors review the implications of a novel mononuclear phagocyte system nomenclature in solid organ transplantation and provide the phenotypic characterization to distinguish its multiple subsets.
Background
A strategy for accelerating liver regeneration after hepatectomy would offer great benefits in preventing postoperative liver failure and improving surgical outcomes. Transforming growth ...factor (TGF) β is a potent inhibitor of hepatocyte proliferation. Recently, thrombospondin (TSP) 1 has been identified as a negative regulator of liver regeneration by activation of local TGF‐β signals. This study aimed to clarify whether the LSKL (leucine–serine–lysine–leucine) peptide, which inhibits TSP‐1‐mediated TGF‐β activation, promotes liver regeneration after hepatectomy in mice.
Methods
Mice were operated on with a 70 per cent hepatectomy or sham procedure. Operated mice received either LSKL peptide or normal saline intraperitoneally at abdominal closure and 6 h after hepatectomy. Perioperative plasma TSP‐1 levels were measured by enzyme‐linked immunosorbent assay in patients undergoing hepatectomy.
Results
Administration of LSKL peptide attenuated Smad2 phosphorylation at 6 h. S‐phase entry of hepatocytes was accelerated at 24 and 48 h by LSKL peptide, which resulted in faster recovery of the residual liver and bodyweight. Haematoxylin and eosin tissue staining and blood biochemical examinations revealed no significant adverse effects following the two LSKL peptide administrations. In the clinical setting, plasma TSP‐1 levels were lowest on the first day after hepatectomy. However, plasma TSP‐1 levels at this stage were significantly higher in patients with subsequent liver dysfunction compared with levels in those without liver dysfunction following hepatectomy.
Conclusion
Only two doses of LSKL peptide during the early period after hepatectomy can promote liver regeneration. The transient inhibition of TSP‐1/TGF‐β signal activation using LSKL peptide soon after hepatectomy may be a promising strategy to promote subsequent liver regeneration.
Surgical relevance
Although the mechanisms of liver regeneration after hepatectomy have been explored intensively in vivo, no therapeutic tools are thus far available to accelerate liver regeneration after hepatectomy in the clinical setting. Recently, the matricellular protein thrombospondin (TSP) 1, a major activator of latent transforming growth factor (TGF) β1, has been identified as a negative regulator of liver regeneration after hepatectomy.
In this study, the inhibition of TSP‐1‐mediated TGF‐β signal activation by LSKL (leucine–serine–lysine–leucine) peptide in the early period after hepatectomy accelerated liver regeneration without any adverse effects. In addition, continuous high plasma TSP‐1 levels after hepatectomy were associated with liver damage in humans.
The transient inhibition of TSP‐1/TGF‐β signal activation using LSKL peptide in the early period after hepatectomy could be a novel therapeutic strategy to accelerate liver regeneration after hepatectomy.
A promising treatment target
Background
Intestinal microbial ecology is actively regulated by Paneth cell‐derived antimicrobial peptides, α‐defensins. Graft‐versus‐host disease (GVHD) is a major complication of allogeneic ...hematopoietic stem cell transplantation (SCT). We previously demonstrated that Paneth cells are targeted by GVHD, and their expression of antimicrobial peptide α‐defensins is impaired, leading to a loss of physiological diversity among the microflora and development of bloodstream infection. Herein, we evaluated whether fecal levels of α‐defensins could be surrogate marker of intestinal dysbiosis.
Methods
We directly measured α‐defensin cryptdin‐1 (Crp1) in fecal pellets of mice with GVHD by using a novel enzyme‐linked immunosorbent assay.
Results
Fecal levels of Crp1 were significantly decreased in mice with GVHD but unchanged in mice without GVHD after SCT. These were correlated with intestinal flora diversity.
Conclusion
We demonstrate a link between reduced secretion of Paneth cell α‐defensins and dysbiosis of intestinal flora in GVHD. Fecal levels of α‐defensins could be surrogate markers for intestinal microbial homeostasis.
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