Model Checked Reinforcement Learning For Multi-Agent Planning

Autonomous systems, or agents as they sometimes are called can be anything from drones, self-driving cars, or autonomous construction equipment. The systems are often given tasks of accomplishing missions in a group or more. This may require that they can work within the same area without colliding or disturbing other agents' tasks. There are several tools for planning and designing such systems, one of them being UPPAAL STRATEGO. Multi-agent planning (MAP) is about planning actions in optimal ways such that the agents can accomplish their mission efficiently. A method of doing this named MCRL, utilizes Q learning as the algorithm for  finding an optimal plan. These plans then need to be verified to ensure that they can accomplish what a user intended within the allowed time, something that UPPAAL STRATEGO can do. This is because a Q-learning algorithm does not have a correctness guarantee. Using this method alleviates the state-explosion problem that exists with an increasing number of agents. Using UPPAAL STRATEGO it is also possible to acquire the best and worst-case execution time (BCET and WCET) and their corresponding traces. This thesis aims to obtain the BCET and WCET and their corresponding traces in the model

Model Checked Reinforcement Learning For Multi-Agent Planning

Autonomous systems, or agents as they sometimes are called can be anything from drones, self-driving cars, or autonomous construction equipment. The systems are often given tasks of accomplishing missions in a group or more. This may require that they can work within the same area without colliding or disturbing other agents' tasks. There are several tools for planning and designing such systems, one of them being UPPAAL STRATEGO. Multi-agent planning (MAP) is about planning actions in optimal ways such that the agents can accomplish their mission efficiently. A method of doing this named MCRL, utilizes Q learning as the algorithm for  finding an optimal plan. These plans then need to be verified to ensure that they can accomplish what a user intended within the allowed time, something that UPPAAL STRATEGO can do. This is because a Q-learning algorithm does not have a correctness guarantee. Using this method alleviates the state-explosion problem that exists with an increasing number of agents. Using UPPAAL STRATEGO it is also possible to acquire the best and worst-case execution time (BCET and WCET) and their corresponding traces. This thesis aims to obtain the BCET and WCET and their corresponding traces in the model

CT is unreliable in locoregional staging of early colon cancer : A nationwide registry-based study

BACKGROUND AND OBJECTIVE: The option to treat early colon cancer (CC) with local resection, as well as trials investigating neoadjuvant treatment, has increased the importance of identifying early-stage disease in the workup. Most CC patients are T- and N-staged preoperatively with CT, although its reliability in staging early CC remains elusive. The aim of this study was to investigate CT-staging accuracy in early CC by evaluating pT and pN stages in patients staged as cT1-2, and cT and cN stages in patients with pT1 tumors.METHODS: Retrospective population-based cohort study on data from the nationwide Swedish colorectal cancer registry on all CC patients staged as cT1-2 and all patients with pT1 undergoing surgical resection 2009-2018. CT-acquired T- and N-stages were compared with final histopathology. Factors potentially influencing accuracy were analyzed with uni- and multivariate logistic regression.RESULTS: Computed tomography (CT) staged 4849 patients as cT1-2, whereas 2445 (50%) were pT3 and 453 (9%) pT4. Positive predictive value of the cT1-2 stage was 40%. Of 1401 pT1 patients, 624 (45%) were staged as cT1-2, 139 (10%) as cT3, 15 (1%) as cT4 and 623 (44%) as cTx. In all, 1474 (30%) of the cT1-2 patients were pN+, whereas CT staged 1062 (72%) as cN0. A total of 771 patients were staged as cN+, whereas 403 (52%) were pN0. Overall accuracy in determining N+ was 67%, with 26% sensitivity and 88% specificity. Positive and negative predictive values in determining N+ were 48% and 73%, respectively.CONCLUSIONS: This nationwide population-based study shows that CT-staging carries a substantial risk of understaging locally advanced tumors as cT1-2 and pT1 tumors as cTx, in addition to poor N-staging. Thus, CT obtained T- and N-staging should not be used for deciding treatment strategies in early CC

Histone Deacetylase Regulates Trypsin Activation, Inflammation, and Tissue Damage in Acute Pancreatitis in Mice.

The onset of acute pancreatitis (AP) is characterized by early protease activation followed by inflammation and organ damage, but the mechanisms are poorly understood

Inhibition of geranylgeranyltransferase attenuates neutrophil accumulation and tissue injury in severe acute pancreatitis.

Leukocyte infiltration and acinar cell necrosis are hallmarks of severe AP, but the signaling pathways regulating inflammation and organ injury in the pancreas remain elusive. In the present study, we investigated the role of geranylgeranyltransferase in AP. Male C57BL/6 mice were treated with a geranylgeranyltransferase inhibitor GGTI-2133 (20 mg/kg) prior to induction of pancreatitis by infusion of taurocholate into the pancreatic duct. Pretreatment with GGTI-2133 reduced plasma amylase levels, pancreatic neutrophil recruitment, hemorrhage, and edema formation in taurocholate-evoked pancreatitis. Moreover, administration of GGTI-2133 decreased the taurocholate-induced increase of MPO activity in the pancreas and lung. Treatment with GGTI-2133 markedly reduced levels of CXCL2 in the pancreas and IL-6 in the plasma in response to taurocholate challenge. Notably, geranylgeranyltransferase inhibition abolished neutrophil expression of Mac-1 in mice with pancreatitis. Finally, inhibition of geranylgeranyltransferase had no direct effect on secretagogue-induced activation of trypsinogen in pancreatic acinar cells in vitro. A significant role of geranylgeranyltransferase was confirmed in an alternate model of AP induced by L-arginine challenge. Our findings show that geranylgeranyltransferase regulates neutrophil accumulation and tissue damage via expression of Mac-1 on neutrophils and CXCL2 formation in AP. Thus, these results reveal new signaling mechanisms in pancreatitis and indicate that targeting geranylgeranyltransferase might be an effective way to ameliorate severe AP

Platelet-derived CXCL4 regulates neutrophil infiltration and tissue damage in severe acute pancreatitis

Platelets are known to play an important role in acute pancreatitis (AP) via promotion of neutrophil accumulation, although mechanisms behind platelet-dependent accumulation of neutrophils in the pancreas remain elusive. Platelets contain a wide spectrum of different pro-inflammatory compounds, such as chemokines. CXCL4 (platelet factor 4) is one of the most abundant chemokine in platelets, and we hypothesized that CXCL4 might be involved in platelet-dependent accumulation of neutrophils in the inflamed pancreas. The aim of this study was to examine the role of CXCL4 in severe AP. Pancreatitis was provoked by infusion of taurocholate into the pancreatic duct or by intraperitoneal administration of L-arginine in C57BL/6 mice. Animals were treated with an antibody against platelets or CXCL4 before induction of pancreatitis. Plasma and lung levels of CXCL2, CXCL4, and interleukin (IL)-6 were determined by use of enzyme-linked immunosorbent assay. Flow cytometry was used to examine surface expression of macrophage-1 (Mac-1) on neutrophils. Plasma was obtained from healthy individuals (controls) and patients with AP. Challenge with taurocholate increased plasma levels of CXCL4, and depletion of platelets markedly reduced plasma levels of CXCL4 indicating that circulating levels of CXCL4 are mainly derived from platelets in AP. Inhibition of CXCL4 reduced taurocholate-induced neutrophil recruitment, IL-6 secretion, edema formation, amylase release, and tissue damage in the pancreas. However, immunoneutralization of CXCL4 had no effect on CXCL2-evoked neutrophil expression of Mac-1 or chemotaxis in vitro, suggesting an indirect effect of CXCL4 on neutrophil recruitment in AP. Targeting CXCL4 significantly attenuated plasma and lung levels of CXCL2, which is a potent neutrophil chemoattractant, and inhibition of the CXCL2 receptor attenuated neutrophil infiltration and tissue damage in the inflamed pancreas. A significant role of CXCL4 was confirmed in an alternate model of AP induced by L-arginine challenge. Moreover, patients with AP had significantly increased plasma levels of CXCL4 compared with healthy controls. These findings’ results suggest that platelet-derived CXCL4 is a potent stimulator of neutrophil accumulation in AP and that this is mediated via generation of CXCL2 in the inflamed pancreas. We conclude that CXCL4 plays an important role in pancreatic inflammation and that targeting CXCL4 might be a useful way to ameliorate tissue damage in AP

Internet delivered cognitive behavior therapy for antenatal depression : A randomised controlled trial

Major depression occurs in 5-10% of pregnancies and is associated with many negative effects for mother and child, yet treatment options are scarce. To our knowledge, this is the first published randomised controlled trial on Internet delivered Cognitive Behavior Therapy (ICBT) for this group. Objective: To test the efficacy of a pregnancy adapted version of an existing 10-week ICBT-program for depression as well as assessing acceptability and adherence. Design: Randomised controlled trial. Setting: Online and telephone. Population or sample: Self-referred pregnant women (gestational week 10-28 at intake) currently suffering from major depressive disorder. Methods: 42 pregnant women (gestational week 12-28) with major depression were randomised to either treatment as usual (TAU) provided at their antenatal clinic or to ICBT as an add-on to usual care. Main outcome measures: The primary outcome was depressive symptoms measured with the Montgomery-Asberg depression rating scale-self report (MADRS-S). The Edinburgh Postnatal Depression Scale and measures of anxiety and sleep were used. Credibility, satisfaction, adherence and utilization were also assessed. Results: The ICBT group had significantly lower levels of depressive symptoms post treatment (p < 0.001, Hedges g = 1.21) and were more likely to be responders (i.e. achieve a statistically reliable improvement) (RR = 0.36; p = 0.004). Measures of treatment credibility, satisfaction, utilization, and adherence were comparable to implemented ICBT for depression. Limitations: Small sample size and no long-term evaluation. Conclusion: Pregnancy adapted ICBT for antenatal depression is feasible, acceptable and efficacious. These results need to be replicated in larger trials to validate these promising findings

Inhibition of geranylgeranyltransferase attenuates neutrophil accumulation and tissue injury in severe acute pancreatitis

Leukocyte infiltration and acinar cell necrosis are hallmarks of severe AP, but the signaling pathways regulating inflammation and organ injury in the pancreas remain elusive. In the present study, we investigated the role of geranylgeranyltransferase in AP. Male C57BL/6 mice were treated with a geranylgeranyltransferase inhibitor GGTI-2133 (20 mg/kg) prior to induction of pancreatitis by infusion of taurocholate into the pancreatic duct. Pretreatment with GGTI-2133 reduced plasma amylase levels, pancreatic neutrophil recruitment, hemorrhage, and edema formation in taurocholate-evoked pancreatitis. Moreover, administration of GGTI-2133 decreased the taurocholate-induced increase of MPO activity in the pancreas and lung. Treatment with GGTI-2133 markedly reduced levels of CXCL2 in the pancreas and IL-6 in the plasma in response to taurocholate challenge. Notably, geranylgeranyltransferase inhibition abolished neutrophil expression of Mac-1 in mice with pancreatitis. Finally, inhibition of geranylgeranyltransferase had no direct effect on secretagogue-induced activation of trypsinogen in pancreatic acinar cells in vitro. A significant role of geranylgeranyltransferase was confirmed in an alternate model of AP induced by L-arginine challenge. Our findings show that geranylgeranyltransferase regulates neutrophil accumulation and tissue damage via expression of Mac-1 on neutrophils and CXCL2 formation in AP. Thus, these results reveal new signaling mechanisms in pancreatitis and indicate that targeting geranylgeranyltransferase might be an effective way to ameliorate severe AP