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BackgroundThe robotic platform in pancreatic disease has gained popularity in the hepatobiliary community due to significant advantages it technically offers over conventional open and laparoscopic techniques. Despite promising initial studies, there remains scant literature on operative and oncologic outcomes of robotic pancreaticoduodenectomy (RPD) for pancreatic adenocarcinoma.MethodsA retrospective review evaluated all RPD performed for pancreatic adenocarcinoma from 2008 to 2019 in a single tertiary institution. RPD cases were matched to open cases (OPD) by demographic and oncologic characteristics and outcomes compared using Mann–Whitney U test, log rank tests, and Kaplan–Meier methods.ResultsThirty-eight RPD cases were matched to 38 OPD. RPD had significantly higher lymph node (LN) yield (21.5 vs 13.5; p = 0.0036) and no difference in operative time or estimated blood loss (EBL). RPD had significantly lower rate of delayed gastric emptying (DGE) (3% vs 32%; p = 0.0009) but no difference in leaks, infections, hemorrhage, urinary retention ,or ileus. RPD had significantly shorter length of stay (LOS) (7.5 vs. 9; p = 0.0209). There were no differences in 30- or 90-day readmissions or 90-day mortality. There was an equivalent R0 resection rate and LN positivity ratio. There was a trend towards improved median overall survival in RPD (30.4 vs. 23.0 months; p = 0.1105) and longer time to recurrence (402 vs. 284 days; p = 0.7471). OPD had two times the local recurrent rate (16% vs. 8%) but no difference in distant recurrence.ConclusionsWhile the feasibility and safety of RPD has been demonstrated, the impact on oncologic outcomes had yet to be investigated. We demonstrate that RPD not only offers similar if not superior immediate post-operative benefit by decreasing DGE but more importantly may offer improved oncologic outcomes. The significantly higher LN yield and decreased inflammatory response demonstrated in robotic surgery may improve overall survival.

Thoroughbred horses are bred for competitive racing and undergo intense training regimes. The maintenance of physical soundness and desirable behavioural characteristics are critical to the longevity of a racing career. Horses intended for Flat racing generally enter training as yearlings and undergo introductory training prior to exercise conditioning for racing. This period requires rapid adjustment to a novel environment. As a prey animal, a horse’s ‘fight-or-flight’ response is highly adapted, in which a well-understood component of this response, the hypothalamic-pituitary-axis, is activated in response to a stress stimulus, releasing cortisol. In the Thoroughbred, a significant difference in salivary cortisol concentrations between pre- and post-first time ridden (i.e., first backing) by a jockey have previously been identified. Here, to test the hypothesis that salivary cortisol concentrations may be used to objectively detect individual variations in the acute physiological stress response we investigate individual variation in cortisol response to training milestones. Saliva samples were collected from a cohort of n = 96 yearling Flat racehorses, at the same training yard, across three timepoints at rest: before entering the training yard ( n = 66), within three days of entry to the training yard ( n = 67) and following 2–3 weeks in the training yard ( n = 50). Salivary cortisol concentration was measured using an ELISA. There was no significant difference in cortisol concentration (ANOVA, P > 0.05) across the samples collected at timepoints at rest. Samples were also collected before and 30 minutes after exposure to three novel training events: first time long-reined ( n = 6), first time backed by a jockey ( n = 34), and first time ridden on the gallops ( n = 10). Mean salivary cortisol concentration after all three novel training events was significantly higher than prior to the training event (Paired t-test, P <0.005). The ranges of post-event salivary cortisol concentration across all timepoints suggest individual variation in the measured stress response, reflecting individual differences in stress response to the early training environment. This measure may be used as an objective assessment of the stress response of Thoroughbred racehorses during training.

Background Neoadjuvant therapy may improve survival of patients with pancreatic adenocarcinoma; however, determining response to therapy is difficult. Artificial intelligence allows for novel analysis of images. We hypothesized that a deep learning model can predict tumor response to NAC. Methods Patients with pancreatic cancer receiving neoadjuvant therapy prior to pancreatoduodenectomy were identified between November 2009 and January 2018. The College of American Pathologists Tumor Regression Grades 0-2 were defined as pathologic response (PR) and grade 3 as no response (NR). Axial images from preoperative computed tomography scans were used to create a 5-layer convolutional neural network and LeNet deep learning model to predict PRs. The hybrid model incorporated decrease in carbohydrate antigen 19-9 (CA19-9) of 10%. Accuracy was determined by area under the curve. Results A total of 81 patients were included in the study. Patients were divided between PR (333 images) and NR (443 images). The pure model had an area under the curve (AUC) of .738 (P < .001), whereas the hybrid model had an AUC of .785 (P < .001). CA19-9 decrease alone was a poor predictor of response with an AUC of .564 (P = .096). Conclusions A deep learning model can predict pathologic tumor response to neoadjuvant therapy for patients with pancreatic adenocarcinoma and the model is improved with the incorporation of decreases in serum CA19-9. Further model development is needed before clinical application.

Several cytokines and chemokines are now known to play normal physiological roles in the brain where they act as key regulators of communication between neurons, glia, and microglia. In particular, cytokines and chemokines can affect cardinal cellular and molecular processes of hippocampal-dependent long-term memory consolidation including synaptic plasticity, synaptic scaling and neurogenesis. The chemokine, CX3CL1 (fractalkine), has been shown to modulate synaptic transmission and long-term potentiation (LTP) in the CA1 pyramidal cell layer of the hippocampus. Here, we confirm widespread expression of CX3CL1 on mature neurons in the adult rat hippocampus. We report an up-regulation in CX3CL1 protein expression in the CA1, CA3 and dentate gyrus (DG) of the rat hippocampus 2 h after spatial learning in the water maze task. Moreover, the same temporal increase in CX3CL1 was evident following LTP-inducing theta-burst stimulation in the DG. At physiologically relevant concentrations, CX3CL1 inhibited LTP maintenance in the DG. This attenuation in dentate LTP was lost in the presence of GABAA receptor/chloride channel antagonism. CX3CL1 also had opposing actions on glutamate-mediated rise in intracellular calcium in hippocampal organotypic slice cultures in the presence and absence of GABAA receptor/chloride channel blockade. Using primary dissociated hippocampal cultures, we established that CX3CL1 reduces glutamate-mediated intracellular calcium rises in both neurons and glia in a dose dependent manner. In conclusion, CX3CL1 is up-regulated in the hippocampus during a brief temporal window following spatial learning the purpose of which may be to regulate glutamate-mediated neurotransmission tone. Our data supports a possible role for this chemokine in the protective plasticity process of synaptic scaling.

Prenatal exposure to cocaine causes abnormalities in foetal brain development, which are linked to later development of anxiety, depression and cognitive dysfunction. Previous studies in rodent models have indicated that prenatal cocaine exposure affects proliferation, differentiation and connectivity of neural cell types. Here, using cerebral organoids derived from the human iPSC cell line HPSI1213i-babk_2, we investigated cocaine-induced changes of the gene expression regulatory landscape at an early developmental time point, leveraging recent advances in single cell RNA-seq and single cell ATAC-seq. iPSC-cerebral organoids replicated well-established cocaine responses observed in vivo and provided additional information about the cell-type specific regulation of gene expression following cocaine exposure. Cocaine altered gene expression patterns, in part through epigenetic landscape remodelling, and revealed disordered neural plasticity mechanisms in the cerebral organoids. Perturbed neurodevelopmental cellular signalling and an inflammatory-like activation of astrocyte populations were also evident following cocaine exposure. The combination of altered neuroplasticity, neurodevelopment and neuroinflammatory signalling suggests cocaine exposure can mediate substantial disruption of normal development and maturation of the brain. These findings offer new insights into the cellular mechanism underlying the adverse effects of cocaine exposure on neurodevelopment and point to the possible pathomechanisms of later neuropsychiatric disturbances.

Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pathophysiologic states. Discrete cohorts of genes can be either up- or down-regulated in response to hypoxia. While the Hypoxia-Inducible Factor (HIF) is the primary driver of hypoxia-induced adaptive gene expression, less is known about the signalling mechanisms regulating hypoxia-dependent gene repression. Using RNA-seq, we demonstrate that equivalent numbers of genes are induced and repressed in human embryonic kidney (HEK293) cells. We demonstrate that nuclear localization of the Repressor Element 1-Silencing Transcription factor (REST) is induced in hypoxia and that REST is responsible for regulating approximately 20% of the hypoxia-repressed genes. Using chromatin immunoprecipitation assays we demonstrate that REST-dependent gene repression is at least in part mediated by direct binding to the promoters of target genes. Based on these data, we propose that REST is a key mediator of gene repression in hypoxia.

Background Feasibility and safety of robotic surgery for pancreatic disease has been well demonstrated; however, there is scarce literature on long-term oncologic outcomes. We compared perioperative and oncologic outcomes between robotic left pancreatectomy (RLP) and laparoscopic left pancreatectomy (LLP) for pancreatic adenocarcinoma. Methods A retrospective review evaluated left pancreatectomies performed for pancreatic adenocarcinoma from 2009 to 2019 in a tertiary institution. Baseline characteristics, operative and oncologic outcomes were compared between RLP and LLP. Results There were 75 minimally invasive left pancreatectomy cases for pancreatic adenocarcinoma identified of which 33 cases were done robotically and 42 laparoscopically. Baseline characteristics demonstrated no difference in gender, age, BMI, T stage, N stage, neoadjuvant, or adjuvant chemotherapy. An analysis of operative variables demonstrated no difference in blood loss, increased duration, and higher lymph node yield with RLP (20 vs 12; P = .0029). Postoperatively, both cohorts had 30% pancreatic fistulas and no difference in complications. There were no differences in length of stay (LOS), 30- or 90-day readmission rates, or 90-day mortality. The analysis of oncologic outcomes demonstrated similar R0 resections (RLP: 72% vs OLP: 67%), recurrence rates (RLP: 36% vs OLP: 41%), and time to recurrence (RLP: 324 vs OLP 218 days). There was increased survival in the RLP cohort that was not significant (32 vs 19 months). Conclusion This analysis demonstrates RLP is at least equivalent to LLP in perioperative and oncologic outcomes. The significantly higher lymph node yield and trend toward an improved survival suggests oncologic advantage. Randomized controlled studies are needed to clarify benefit.

Over four decades ago, it was discovered that high-frequency stimulation of the dentate gyrus induces long-term potentiation (LTP) of synaptic transmission. LTP is believed to underlie how we process and code external stimuli before converting it to salient information that we store as 'memories'. It has been shown that rats performing spatial learning tasks display theta-frequency (3-12 Hz) hippocampal neural activity. Moreover, administering theta-burst stimulation (TBS) to hippocampal slices can induce LTP. TBS triggers a sustained rise in intracellular calcium [Ca2+]i in neurons leading to new protein synthesis important for LTP maintenance. In this study, we measured TBS-induced [Ca2+]i oscillations in thousands of cells at increasing distances from the source of stimulation. Following TBS, a calcium wave propagates radially with an average speed of 5.2 µm/s and triggers multiple and regular [Ca2+]i oscillations in the hippocampus. Interestingly, the number and frequency of [Ca2+]i fluctuations post-TBS increased with respect to distance from the electrode. During the post-tetanic phase, 18% of cells exhibited 3 peaks in [Ca2+]i with a frequency of 17 mHz, whereas 2.3% of cells distributed further from the electrode displayed 8 [Ca2+]i oscillations at 33 mHz. We suggest that these observed [Ca2+]i oscillations could lead to activation of transcription factors involved in synaptic plasticity. In particular, the transcription factor, NF-κB, has been implicated in memory formation and is up-regulated after LTP induction. We measured increased activation of NF-κB 30 min post-TBS in CA1 pyramidal cells and also observed similar temporal up-regulation of NF-κB levels in CA1 neurons following water maze training in rats. Therefore, TBS of hippocampal slice cultures in vitro can mimic the cell type-specific up-regulations in activated NF-κB following spatial learning in vivo. This indicates that TBS may induce similar transcriptional changes to spatial learning and that TBS-triggered [Ca2+]i oscillations could activate memory-associated gene expression.

Background Society consensus guidelines are commonly used to guide management of pancreatic cystic neoplasms (PCNs). However, downsides of these guidelines include unnecessary surgery and missed malignancy. The aim of this study was to use computed tomography (CT)-guided deep learning techniques to predict malignancy of PCNs. Materials and Methods Patients with PCNs who underwent resection were retrospectively reviewed. Axial images of the mucinous cystic neoplasms were collected and based on final pathology were assigned a binary outcome of advanced neoplasia or benign. Advanced neoplasia was defined as adenocarcinoma or intraductal papillary mucinous neoplasm with high-grade dysplasia. A convolutional neural network (CNN) deep learning model was trained on 66% of images, and this trained model was used to test 33% of images. Predictions from the deep learning model were compared to Fukuoka guidelines. Results Twenty-seven patients met the inclusion criteria, with 18 used for training and 9 for model testing. The trained deep learning model correctly predicted 3 of 3 malignant lesions and 5 of 6 benign lesions. Fukuoka guidelines correctly classified 2 of 3 malignant lesions as high risk and 4 of 6 benign lesions as worrisome. Following deep learning model predictions would have avoided 1 missed malignancy and 1 unnecessary operation. Discussion In this pilot study, a deep learning model correctly classified 8 of 9 PCNs and performed better than consensus guidelines. Deep learning can be used to predict malignancy of PCNs; however, further model improvements are necessary before clinical use.

BackgroundThrombocytopenia is a common finding in patients with chronic liver disease. It is associated with poor clinical outcomes due to increased risk of bleeding after even minor procedures. We sought to determine an algorithm for pre-operative platelet transfusion in patients with cirrhosis and hepatocellular carcinoma (HCC) undergoing laparoscopic microwave ablation (MIS-MWA).MethodsA retrospective review identified all patients with cirrhosis and HCC who underwent MIS-MWA at a single tertiary institution between 2007 and 2019. Demographics, pre-operative and post-operative laboratory values, transfusion requirements, and bleeding events were collected. The analyzed outcome of bleeding risk included any transfusion received intra-operatively or a transfusion or surgical intervention post-operatively. Logistic regression models were created to predict bleeding risk and identify patients who would benefit from pre-operative transfusion.ResultsThere were 433 patients with cirrhosis and HCC who underwent MIS-MWA identified; of these, 353 patients had complete laboratory values and were included. Bleeding risk was evaluated through bivariate analysis of statistically and clinically significant variables. The accuracy of both models was substantiated through bootstrap validation for 500 iterations (model 1: ROC 0.8684, Brier score 0.0238; model 2: ROC 0.8363, Brier score 0.0252). The first model captured patients with both thrombocytopenia and anemia: platelet count < 60 × 109 / L (OR 7.75, p 0.012, CI 1.58–38.06) and hemoglobin < 10 gm/dL (OR 5.76, p 0.032, CI 1.16–28.63). The second model captured patients with thrombocytopenia without anemia: platelet count < 30 × 109/L (OR 8.41, p 0.05, CI 0.96–73.50) and hemoglobin > 10 gm/dL (OR 0.16, p 0.026, CI 0.031–0.80).ConclusionThe prediction of patients with cirrhosis and HCC requiring pre-operative platelet transfusions may help to avoid bleeding complications after invasive procedures. This study needs to be prospectively validated and ultimately may be beneficial in assessment of novel therapies for platelet-based clinical treatment in liver disease.