Escalated complement activation during hospitalization is associated with higher risk of 60-day mortality in SARS-CoV-2-infected patients.

BACKGROUND: The complement system, an upstream recognition system of innate immunity, is activated upon SARS-CoV-2 infection. To gain a deeper understanding of the extent and duration of this activation, we investigated complement activation profiles during the acute phase of COVID-19, its persistence post-recovery and dynamic changes in relation to disease severity. METHODS: Serial blood samples were obtained from two cohorts of hospitalized COVID-19 patients (n = 457). Systemic complement activation products reflecting classical/lectin (C4d), alternative (C3bBbP), common (C3bc) and terminal pathway (TCC and C5a) were measured during hospitalization (admission, days 3-5 and days 7-10), at 3 months and after 1 year. Levels of activation and temporal profiles during hospitalization were related to disease severity defined as respiratory failure (PO2/FiO2 ratio <26.6 kPa) and/or admission to intensive care unit, 60-day total mortality and pulmonary pathology after 3 months. FINDINGS: During hospitalization, TCC, C4d, C3bc, C3bBbP and C5a were significantly elevated compared to healthy controls. Severely ill patients had significantly higher levels of TCC and C4d (p < 0.001), compared to patients with moderate COVID-19. Escalated levels of TCC and C4d during hospitalization were associated with a higher risk of 60-day mortality (p < 0.001), and C4d levels were additionally associated with chest CT changes at 3 months (p < 0.001). At 3 months and 1 year, we observed consistently elevated levels of most complement activation products compared to controls. CONCLUSION: Hospitalized COVID-19 patients display prominent and long-lasting systemic complement activation. Optimal targeting of the system may be achieved through enhanced risk stratification and closer monitoring of in-hospital changes of complement activation products.

The generalized super-twisting algorithm with adaptive gains.

In this article, a novel adaptive generalized super-twisting algorithm (GSTA) is proposed for a class of systems whose perturbations and uncertain control coefficients may depend on both time and state. The proposed approach uses dynamically adapted control gains, and it is proven that this ensures global finite-time convergence. A nonsmooth strict Lyapunov function is used to obtain the conditions for global finite-time stability. A simulation and experimental case study is performed using an articulated intervention autonomous underwater vehicle (AIAUV). It is also shown that the adaptive GSTA causes the tracking errors of the AIAUV to converge to zero in finite time. In the case study, we use the singularity-robust multiple task-priority method to create a continuous trajectory for the AIAUV to follow. The simulation and experimental results validate and verify that the proposed approach is well suited for controlling an AIAUV. We also perform a comparison with the super-twisting algorithm with adaptive gains and the original GSTA to evaluate whether adding adaptive gains to the GSTA actually improves the tracking capabilities by combining the theoretical advantages afforded by the GSTA with the practical advantages afforded by adaptive gains. Based on this comparison, the adaptive GSTA yields the best tracking results overall without increasing the energy consumption, and the simulations and experiments thus indicate that adding adaptive gains to the GSTA does indeed improve the consequent tracking results and capabilities.

Exposure to Broad-Spectrum Visible Light Causes Major Transcriptomic Changes in Listeria monocytogenes EGDe.

Listeria monocytogenes, the causative agent of the serious foodborne disease listeriosis, can rapidly adapt to a wide range of environmental stresses, including visible light. This study shows that exposure of the L. monocytogenes EGDe strain to low-intensity, broad-spectrum visible light inhibited bacterial growth and caused altered multicellular behavior during growth on semisolid agar compared to when the bacteria were grown in complete darkness. These light-dependent changes were observed regardless of the presence of the blue light receptor (Lmo0799) and the stressosome regulator sigma B (SigB), which have been suggested to be important for the ability of L. monocytogenes to respond to blue light. A genome-wide transcriptional analysis revealed that exposure of L. monocytogenes EGDe to broad-spectrum visible light caused altered expression of 2,409 genes belonging to 18 metabolic pathways compared to bacteria grown in darkness. The light-dependent differentially expressed genes are involved in functions such as glycan metabolism, cell wall synthesis, chemotaxis, flagellar synthesis, and resistance to oxidative stress. Exposure to light conferred reduced bacterial motility in semisolid agar, which correlates well with the light-dependent reduction in transcript levels of flagellar and chemotaxis genes. Similar light-induced reduction in growth and motility was also observed in two different L. monocytogenes food isolates, suggesting that these responses are typical for L. monocytogenes Together, the results show that even relatively small doses of broad-spectrum visible light cause genome-wide transcriptional changes, reduced growth, and motility in L. monocytogenesIMPORTANCE Despite major efforts to control L. monocytogenes, this pathogen remains a major problem for the food industry, where it poses a continuous risk of food contamination. The ability of L. monocytogenes to sense and adapt to different stressors in the environment enables it to persist in many different niches, including food production facilities and in food products. The present study shows that exposure of L. monocytogenes to low-intensity broad-spectrum visible light reduces its growth and motility and alters its multicellular behavior. Light exposure also caused genome-wide changes in transcript levels, affecting multiple metabolic pathways, which are likely to influence the bacterial physiology and lifestyle. In practical terms, the data presented in this study suggest that broad-spectrum visible light is an important environmental variable to consider as a strategy to improve food safety by reducing L. monocytogenes contamination in food production environments.

Survival of Listeria monocytogenes during in vitro gastrointestinal digestion after exposure to 5 and 0.5 % sodium chloride.

The food industry is under pressure to reduce the NaCl content in food, but the consequences on the ability of L. monocytogenes to survive in the human host and cause listeriosis is not known. In this study, a recently developed internationally harmonized static in vitro digestion (IVD) model was used to investigate the survival of L. monocytogenes in the gastric and intestinal phases after exposure to 5 or 0.5% NaCl. Six isolates from three Scandinavian foodborne listeriosis outbreaks, all related to NaCl containing foods, the EGDe reference strain and an EGDe mutant, deleted for the major stress regulator gene, sigB, were included. A ten-fold reduction of NaCl in the cultivation media significantly reduced the survival fraction of the EGDe strain in the IVD model while one of the clinical outbreak isolates showed a significantly increased survival fraction. Finally, the EGDe strain was able to attach and invade cultured HT-29 cells after passage through the IVD model. Altogether, these results suggest that a reduction of the NaCl content from 5 to 0.5% prior to exposure to the IVD model has the potential to cause a change in the relative survival fraction and that the effect is strain dependent.

National outbreak of Yersinia enterocolitica infections in military and civilian populations associated with consumption of mixed salad, Norway, 2014.

In May 2014, a cluster of Yersinia enterocolitica (YE) O9 infections was reported from a military base in northern Norway. Concurrently, an increase in YE infections in civilians was observed in the Norwegian Surveillance System for Communicable Diseases. We investigated to ascertain the extent of the outbreak and identify the source in order to implement control measures. A case was defined as a person with laboratory-confirmed YE O9 infection with the outbreak multilocus variable-number tandem repeat analysis (MLVA)-profile (5-6-9-8-9-9). We conducted a case-control study in the military setting and calculated odds ratios (OR) using logistic regression. Traceback investigations were conducted to identify common suppliers and products in commercial kitchens frequented by cases. By 28 May, we identified 133 cases, of which 117 were linked to four military bases and 16 were civilians from geographically dispersed counties. Among foods consumed by cases, multivariable analysis pointed to mixed salad as a potential source of illness (OR 10.26; 95% confidence interval (CI): 0.85-123.57). The four military bases and cafeterias visited by 14/16 civilian cases received iceberg lettuce or radicchio rosso from the same supplier. Secondary transmission cannot be eliminated as a source of infection in the military camps. The most likely source of the outbreak was salad mix containing imported radicchio rosso, due to its long shelf life. This outbreak is a reminder that fresh produce should not be discounted as a vehicle in prolonged outbreaks and that improvements are still required in the production and processing of fresh salad products.

Transcriptomic and proteomic analysis of the virulence inducing effect of ciprofloxacin on enterohemorrhagic Escherichia coli.

Enterohemorrhagic E. coli (EHEC) is considered to be the most dangerous pathotype of E. coli, as it causes severe conditions such as hemorrhagic colitis (HC) and hemolytic uremic syndrome (HUS). Antibiotic treatment of EHEC infections is generally not recommended since it may promote the production of the Shiga toxin (Stx) and lead to worsened symptoms. This study explores how exposure to the fluoroquinolone ciprofloxacin reorganizes the transcriptome and proteome of EHEC O157:H7 strain EDL933, with special emphasis on virulence-associated factors. As expected, exposure to ciprofloxacin caused an extensive upregulation of SOS-response- and Stx-phage proteins, including Stx. A range of other virulence-associated factors were also upregulated, including many genes encoded by the LEE-pathogenicity island, the enterohemolysin gene (ehxA), as well as several genes and proteins involved in LPS production. However, a large proportion of the genes and proteins (17 and 8%, respectively) whose expression was upregulated upon ciprofloxacin exposure (17 and 8%, respectively) are not functionally assigned. This indicates a knowledge gap in our understanding of mechanisms involved in EHECs response to antibiotic-induced stress. Altogether, the results contribute to better understanding of how exposure to ciprofloxacin influences the virulome of EHEC and generates a knowledge base for further studies on how EHEC responds to antibiotic-induced stress. A deeper understanding on how EHEC responds to antibiotics will facilitate development of novel and safer treatments for EHEC infections.

Femoral nailing associated with bone marrow emboli in pigs induced a specific increase in blood IL-6 and broad inflammatory responses in the heart and lungs.

Introduction: Bone marrow embolization may complicate orthopedic surgery, potentially causing fat embolism syndrome. The inflammatory potential of bone marrow emboli is unclear. We aimed to investigate the inflammatory response to femoral intramedullary nailing, specifically the systemic inflammatory effects in plasma, and local tissue responses. Additionally, the plasma response was compared to that following intravenous injection of autologous bone marrow. Methods: Twelve pigs underwent femoral nailing (previously shown to have fat emboli in lung and heart), four received intravenous bone marrow, and four served as sham controls. Blood samples were collected hourly and tissue samples postmortem. Additionally, we incubated bone marrow and blood, separately and in combination, from six pigs in vitro. Complement activation was detected by C3a and the terminal C5b-9 complement complex (TCC), and the cytokines TNF, IL-1ß, IL-6 and IL-10 as well as the thrombin-antithrombin complexes (TAT) were all measured using enzyme-immunoassays. Results: After nailing, plasma IL-6 rose 21-fold, compared to a 4-fold rise in sham (p=0.0004). No plasma differences in the rest of the inflammatory markers were noted across groups. However, nailing yielded 2-3-times higher C3a, TCC, TNF, IL-1ß and IL-10 in lung tissue compared to sham (p<0.0001-0.03). Similarly, heart tissue exhibited 2-times higher TCC and IL-1ß compared to sham (p<0.0001-0.03). Intravenous bone marrow yielded 8-times higher TAT than sham at 30 minutes (p<0.0001). In vitro, incubation of bone marrow for four hours resulted in 95-times higher IL-6 compared to whole blood (p=0.03). Discussion: A selective increase in plasma IL-6 was observed following femoral nailing, whereas lung and heart tissues revealed a broad local inflammatory response not reflected systemically. In vitro experiments may imply bone marrow to be the primary IL-6 source.

Effect of N-3 Polyunsaturated Fatty Acids on Lipid Composition in Familial Hypercholesterolemia: A Randomized Crossover Trial.

Individuals with familial hypercholesterolemia (FH) have an increased risk of cardiovascular disease. Treatment is mainly low-density lipoprotein cholesterol (LDL-C) reduction. How omega-3 polyunsaturated fatty acids (n-3 PUFAs) supplements affect lipoproteins in FH subjects is unknown. We hypothesized that a high-dose n-3 PUFA supplement would reduce atherogenic lipoproteins and influence the high-density lipoprotein cholesterol (HDL-C) function. We performed a randomized, double-blinded crossover study with 34 genetically verified FH individuals (18−75 years, clinically stable, statin treatment > 12 months). Treatment was 4 g n-3 PUFAs (1840 mg eicosapentaenoic acid and 1520 mg docosahexaenoic acid daily) or four capsules of olive oil for three months in a crossover design with a washout period of three months. The defined outcomes were changes in triglycerides, lipoproteins, lipoprotein subfractions, apolipoproteins, and HDL-C function. After treatment with n-3 PUFAs, total cholesterol, LDL-C, and triglycerides were reduced compared to placebo (p ≤ 0.01 for all). Total HDL-C levels were unchanged, but the subfraction of large HDL-C was higher (p ≤ 0.0001) after n-3 PUFAs than after placebo, and intermediate HDL-C and small HDL-C were reduced after n-3 PUFAs compared to placebo (p = 0.02 and p ≤ 0.001, respectively). No changes were found in apolipoproteins and HDL-C function. N-3 PUFAs supplements reduced atherogenic lipoproteins in FH subjects, leaving HDL-C function unaffected.

Venous Air Embolism Activates Complement C3 Without Corresponding C5 Activation and Trigger Thromboinflammation in Pigs.

Introduction: Air embolism may complicate invasive medical procedures. Bubbles trigger complement C3-mediated cytokine release, coagulation, and platelet activation in vitro in human whole blood. Since these findings have not been verified in vivo, we aimed to examine the effects of air embolism in pigs on thromboinflammation. Methods: Forty-five landrace pigs, average 17 kg (range 8.5-30), underwent intravenous air infusion for 300 or 360 minutes (n=29) or served as sham (n=14). Fourteen pigs were excluded due to e.g. infections or persistent foramen ovale. Blood was analyzed for white blood cells (WBC), complement activation (C3a and terminal C5b-9 complement complex [TCC]), cytokines, and hemostatic parameters including thrombin-antithrombin (TAT) using immunoassays and rotational thromboelastometry (ROTEM). Lung tissue was analyzed for complement and cytokines using qPCR and immunoassays. Results are presented as medians with interquartile range. Results: In 24 pigs receiving air infusion, WBC increased from 17×109/L (10-24) to 28 (16-42) (p<0.001). C3a increased from 21 ng/mL (15-46) to 67 (39-84) (p<0.001), whereas TCC increased only modestly (p=0.02). TAT increased from 35 µg/mL (28-42) to 51 (38-89) (p=0.002). ROTEM changed during first 120 minutes: Clotting time decreased from 613 seconds (531-677) to 538 (399-620) (p=0.006), clot formation time decreased from 161 seconds (122-195) to 124 (83-162) (p=0.02) and α-angle increased from 62 degrees (57-68) to 68 (62-74) (p=0.02). In lungs from pigs receiving air compared to sham animals, C3a was 34 ng/mL (14-50) versus 4.1 (2.4-5.7) (p<0.001), whereas TCC was 0.3 CAU/mL (0.2-0.3) versus 0.2 (0.1-0.2) (p=0.02). Lung cytokines in pigs receiving air compared to sham animals were: IL-1ß 302 pg/mL (190-437) versus 107 (66-120), IL-6 644 pg/mL (358-1094) versus 25 (23-30), IL-8 203 pg/mL (81-377) versus 21 (20-35), and TNF 113 pg/mL (96-147) versus 16 (13-22) (all p<0.001). Cytokine mRNA in lung tissue from pigs receiving air compared to sham animals increased 12-fold for IL-1ß, 121-fold for IL-6, and 17-fold for IL-8 (all p<0.001). Conclusion: Venous air embolism in pigs activated C3 without a corresponding C5 activation and triggered thromboinflammation, consistent with a C3-dependent mechanism. C3-inhibition might represent a therapeutic approach to attenuate this response.

A Novel Porcine Model of Ischemia-Reperfusion Injury After Cross-Clamping the Thoracic Aorta Revealed Substantial Cardiopulmonary, Thromboinflammatory and Biochemical Changes Without Effect of C1-Inhibitor Treatment.

Ischemic injury worsens upon return of blood and innate immunity including the complement system play a central role in ischemia-reperfusion injury (IRI) as in thoracic aortic surgery. Complement component1 inhibitor (C1-INH) has been shown to reduce IRI and is a broad-acting plasma cascade inhibitor. We established a new porcine model of IRI by cross-clamping the thoracic aorta and evaluated the global changes occurring in organ function, systemic inflammatory response and organ damage with or without treatment with C1-INH-concentrate. Twenty-four piglets (8.8-11.1 kg) underwent 45 minutes clamping of the thoracic aorta at the Th8 level. Upfront 12 piglets received human saline and 12 received C1-INH (250 IU/kg) intravenously. Three sham animals received thoracic opening without clamping. Reperfusion lasted 5 hours. We studied ten cardiorespiratory markers, three hematologic markers, eleven inflammatory markers, and twelve organ damage markers over the whole experimental period. Postmortem tissue homogenates from seven organs were examined for inflammatory markers and analysed by two-way repeated-measures ANOVA, area under the curve or unpaired t-tests. By excluding sham and combining treated and untreated animals, the markers reflected a uniform, broad and severe organ dysfunction. The mean and range fold change from before cross-clamp onset to maximum change for the different groups of markers were: cardiorespiratory 1.4 (0.2-3.7), hematologic 1.9 (1.2-2.7), plasma inflammatory 19.5 (1.4-176) and plasma organ damage 2.9 (1.1-8.6). Treatment with C1-INH had only a marginal effect on the IRI-induced changes, reaching statistical significance only for the plasma complement activation product TCC (p=0.0083) and IL-4 (p=0.022) and INF-α (p=0.016) in the colon tissue. In conclusion, the present novel model of porcine global IRI is forceful with regards to central markers and could generally be applicable for pathophysiological studies. C1-INH treatment had no significant effect, but the model allows for future testing of other drugs attenuating IRI globally.

Simultaneous C5 and CD14 inhibition limits inflammation and organ dysfunction in pig polytrauma.

Dysfunctional complement activation and Toll-like receptor signaling immediately after trauma are associated with development of trauma-induced coagulopathy and multiple organ dysfunction syndrome. We assessed the efficacy of the combined inhibition therapy of complement factor C5 and the TLR co-receptor CD14 on thrombo-inflammation and organ damage in an exploratory 72-h polytrauma porcine model, conducted under standard surgical and intensive care management procedures. Twelve male pigs were subjected to polytrauma, followed by resuscitation (ATLS® guidelines) and operation of the femur fracture (intramedullary nailing technique). The pigs were allocated to combined C5 and CD14 inhibition therapy group (n=4) and control group (n=8). The therapy group received intravenously C5 inhibitor (RA101295) and anti-CD14 antibody (rMil2) 30 min post-trauma. Controls received saline. Combined C5 and CD14 inhibition reduced the blood levels of the terminal complement complex (TCC) by 70% (p=0.004), CRP by 28% (p=0.004), and IL-6 by 52% (p=0.048). The inhibition therapy prevented the platelet consumption by 18% and TAT formation by 77% (p=0.008). Moreover, the norepinephrine requirements in the treated group were reduced by 88%. The inhibition therapy limited the organ damage, thereby reducing the blood lipase values by 50% (p=0.028), LDH by 30% (p=0.004), AST by 33%, and NGAL by 30%. Immunofluorescent analysis of the lung tissue revealed C5b-9 deposition on blood vessels in five from the untreated, and in none of the treated animals. In kidney and liver, the C5b-9 deposition was similarly detected mainly the untreated as compared to the treated animals. Combined C5 and CD14 inhibition limited the inflammatory response, the organ damage, and reduced the catecholamine requirements after experimental polytrauma and might be a promising therapeutic approach.

Quantification of Porcine Complement Activation Fragment C3a by a Neoepitope-Based Enzyme-Linked Immunosorbent Assay.

Enzyme-linked immunosorbent assay (ELISA) enables fast and simple quantification of analytes in the pico- to nanogram range in complex samples. Here, we describe an ELISA for the detection of porcine C3a as a marker for complement activation. Antibody specificity is critical for a robust assay. This assay is based on a pair of antibodies specific for the porcine C3a molecule and thus does not react with native C3.

Experimental Verification of a Coordinated Path-Following Strategy for Underactuated Marine Vehicles.

This work presents the results of an experimental verification of a coordinated path following strategy for underactuated marine vehicles. The coordinated path following strategy is presented, and is then experimentally verified using three autonomous underwater vehicles. The vehicles are required to coordinate their motion along spatially separated straight-line paths to obtain a desired formation. The vehicles are steered to the paths using an integral line-of-sight guidance approach that allows the vehicles to reject constant ocean currents. Simultaneously, the coordination is achieved by adjusting the velocity based on the along-path distance. First, simulation results are presented, which serve as benchmarks for the experimental results. Furthermore, the simulations are used to show the effect of changing different parameters. The simulation results are performed using high-fidelity hardware simulation models. The results obtained from experiments in the harbor of Porto are then presented and compared with the results of the simulation.

Path Following, Obstacle Detection and Obstacle Avoidance for Thrusted Underwater Snake Robots.

The use of unmanned underwater vehicles is steadily increasing for a variety of applications such as mapping, monitoring, inspection and intervention within several research fields and industries, e.g., oceanography, marine biology, military, and oil and gas. Particularly interesting types of unmanned underwater vehicles are bio-inspired robots such as underwater snake robots (USRs). Due to their flexible and slender body, these versatile robots are highly maneuverable and have better access capabilities than more conventional remotely operated vehicles (ROVs). Moreover, the long and slender body allows for energy-efficient transit over long distances similar to torpedo-shaped autonomous underwater vehicles (AUVs). In addition, USRs are capable of performing light intervention tasks, thereby providing intervention capabilities which exceed those of AUVs and inspection class ROVs. USRs may also propel themselves using energy-efficient motion patterns inspired by their biological counterparts. They can thereby increase the propulsion efficiency during transit and maneuvering, which is among the great challenges for autonomous underwater vehicles. In this paper, a control system for path following, and algorithms for obstacle detection and avoidance, are presented for a USR with thrusters attached at the tail module. The position of the obstacles is detected using a single camera in the head module of the USR and a developed computer vision algorithm. For the proposed control concept the robot joints are used for directional control while the thrusters are used for forward propulsion. The USR circumvents obstacles by following a circular path around them before converging back to the main straight line path when this is safe. Experimental results that validate the proposed methods are also presented.

Addition of marine omega-3 fatty acids to statins in familial hypercholesterolemia does not affect in vivo or in vitro endothelial function.

BACKGROUND: Prestatin trials reported positive effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) in cardiovascular disease, whereas recent studies and meta-analyses have not reproduced these results. The effect of n-3 PUFA in patients with familial hypercholesterolemia (FH), a group with particularly high risk of cardiovascular disease, is not well established. OBJECTIVE: We investigated the effect of n-3 PUFA in the early stage of atherosclerosis in FH patients by evaluating in vivo (peripheral arterial tonometry [PAT]) and in vitro (plasma asymmetric dimethylarginine and E-selectin) endothelial function. METHODS: This was a double-blind, placebo-controlled cross-over study with 34 FH patients on statin treatment (mean age 46.6 years). In random order, all individuals were treated for 3 months with high-dose n-3 PUFA (2 g, ×2) and 3 months placebo (olive oil, 2 g ×2), separated by a 3-month washout period. Anthropometric data, blood samples, and PAT were collected at 4 time points. RESULTS: There were no significant changes in reactive hyperemia index measured by PAT after n-3 PUFA compared with placebo, median reactive hyperemia index after n-3 PUFA was 1.98 and after placebo 1.96 (P = .51). No significant changes were detected in the soluble endothelial marker asymmetric dimethylarginine (in 2 different assays) when comparing n-3 PUFA and placebo (P = .92 and .14, respectively). Finally, the level of E-selectin did not change significantly during the trial (P = .26). CONCLUSION: Addition of n-3 PUFA to standard lipid-lowering treatment in genetically verified FH patients did not affect the in vivo endothelial function or soluble endothelial markers.

Complement activation assessed by the plasma terminal complement complex and future risk of venous thromboembolism.

BACKGROUND: It remains uncertain whether activation of the complement system, assessed by the soluble terminal C5b-9 complement complex (plasma TCC), is associated with future risk of incident venous thromboembolism (VTE). OBJECTIVES: To investigate the association between plasma levels of TCC and future risk of incident VTE in a nested case-control study, and to explore genetic variants associated with TCC using protein quantitative trait loci analysis of exome sequencing data. METHODS: We sampled 415 VTE cases and 848 age- and sex-matched controls from a population-based cohort, the Tromsø study. Logistic regression models were used to calculate odds ratios with 95% confidence intervals for VTE across quartiles of plasma levels of TCC. Whole exome sequencing was conducted using the Agilent SureSelect 50 Mb capture kit. RESULTS: The risk of VTE increased across increasing quartiles of plasma TCC, particularly for unprovoked VTE. Participants with TCC in the highest quartile (>1.40 complement arbitrary units/mL) had an odds ratio for unprovoked VTE of 1.74 (95% confidence interval: 1.10-2.78) compared with those with TCC in the lowest quartile (≤0.80 complement arbitrary units/mL) in analyses adjusted for age, sex, and body mass index. A substantially higher risk for VTE was observed in samples taken shortly before VTE event. We found no association between genome-wide or complement-related gene variants and plasma levels of TCC. CONCLUSIONS: We found that high levels of plasma TCC were associated with VTE risk, and unprovoked events in particular. There was no genome-wide association between gene variants and plasma levels of TCC.

Planar maneuvering control of underwater snake robots using virtual holonomic constraints.

This paper investigates the problem of planar maneuvering control for bio-inspired underwater snake robots that are exposed to unknown ocean currents. The control objective is to make a neutrally buoyant snake robot which is subject to hydrodynamic forces and ocean currents converge to a desired planar path and traverse the path with a desired velocity. The proposed feedback control strategy enforces virtual constraints which encode biologically inspired gaits on the snake robot configuration. The virtual constraints, parametrized by states of dynamic compensators, are used to regulate the orientation and forward speed of the snake robot. A two-state ocean current observer based on relative velocity sensors is proposed. It enables the robot to follow the path in the presence of unknown constant ocean currents. The efficacy of the proposed control algorithm for several biologically inspired gaits is verified both in simulations for different path geometries and in experiments.

Experimental investigation of efficient locomotion of underwater snake robots for lateral undulation and eel-like motion patterns.

Underwater snake robots offer many interesting capabilities for underwater operations. The long and slender structure of such robots provide superior capabilities for access through narrow openings and within confined areas. This is interesting for inspection and monitoring operations, for instance within the subsea oil and gas industry and within marine archeology. In addition, underwater snake robots can provide both inspection and intervention capabilities and are thus interesting candidates for the next generation inspection and intervention AUVs. Furthermore, bioinspired locomotion through oscillatory gaits, like lateral undulation and eel-like motion, is interesting from an energy efficiency point of view. Increasing the motion efficiency in terms of the achieved forward speed by improving the method of propulsion is a key issue for underwater robots. Moreover, energy efficiency is one of the main challenges for long-term autonomy of these systems. In this study, we will consider both these two aspects of efficiency. This paper considers the energy efficiency of swimming snake robots by presenting and experimentally investigating fundamental properties of the velocity and the power consumption of an underwater snake robot for both lateral undulation and eel-like motion patterns. In particular, we investigate the relationship between the parameters of the gait patterns, the forward velocity and the energy consumption for different motion patterns. The simulation and experimental results are seen to support the theoretical findings.

Path following control of planar snake robots using virtual holonomic constraints: theory and experiments.

This paper considers path following control of planar snake robots using virtual holonomic constraints. In order to present a model-based path following control design for the snake robot, we first derive the Euler-Lagrange equations of motion of the system. Subsequently, we define geometric relations among the generalized coordinates of the system, using the method of virtual holonomic constraints. These appropriately defined constraints shape the geometry of a constraint manifold for the system, which is a submanifold of the configuration space of the robot. Furthermore, we show that the constraint manifold can be made invariant by a suitable choice of feedback. In particular, we analytically design a smooth feedback control law to exponentially stabilize the constraint manifold. We show that enforcing the appropriately defined virtual holonomic constraints for the configuration variables implies that the robot converges to and follows a desired geometric path. Numerical simulations and experimental results are presented to validate the theoretical approach.