Tolerant Control Research Articles

Class I HLA Alleles are associated with an increased risk of osimertinib-induced hypersensitivity

BackgroundOsimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), shows superior lung cancer treatment efficacy. However, osimertinib-induced severe hypersensitivity, including Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), is frequently observed in Asian populations and hinders cancer treatment. ObjectiveWe investigated the genetic HLA predisposition and immune pathomechanism of osimertinib-induced hypersensitivity. MethodsWe enrolled 17 patients with osimertinib-induced delayed hypersensitivity (7 with severe SJS/TEN and 10 with mild maculopapular exanthema [MPE]), 98 osimertinib-tolerant subjects, and 2123 general population controls. HLA genotyping, drug-induced lymphocyte activation test (LAT), and surface plasmon resonance (SPR) assay were performed. ResultsHLA-B*51:02 was present in 83.3% of osimertinib-induced SJS/TEN patients but only in 3.3% of the general population controls (P = 2.8×10−7, Pc=6.9×10−6, odds ratio [OR]=146), and 0% of osimertinib-tolerant controls (P = 6.5×10−8, Pc=1.6×10−6, OR=707). The association of HLA-B*51:01 and HLA-A*24:02 with osimertinib-induced MPE patients, rather than with osimertinib-tolerant subjects (P = 0.002, OR=15.7 for HLA-B*51:01; P = 0.003, OR=9.5 for HLA-A*24:02), was identified as a phenotype-specific association. Granulysin—the SJS/TEN-specific cytotoxic protein—was significantly higher in SJS/TEN patients’ plasma (39.8±4.5 ng/ml, P<0.001) and in in vitro LAT (sensitivity=83.3%, P<0.01) compared to the tolerant controls. Patients with osimertinib-induced hypersensitivity appeared to tolerate alternative EGFR-TKIs. SPR results also confirmed that HLA-B*51:02 protein has a higher binding affinity for osimertinib and lower or no affinity for other EGFR-TKIs. ConclusionsHLA-B*51:02 frequently occurs in Asian populations and is strongly associated with osimertinib-induced SJS/TEN. Our findings suggest HLA-B*51:02 screening as a preemptive test to reduce osimertinib-induced severe hypersensitivity.

How do different game genres impact adolescent players’ problematic game use?

This study investigates the influence of video game genres on adolescent behavior, focusing on tolerance, withdrawal symptoms, and impaired control. With the increasing prevalence of gaming among adolescents, understanding the specific impacts of game genres becomes crucial. This research aims to identify how different genres affect adolescent gamers and to provide insights for educators, parents, and policymakers on managing gaming-related behaviors. Using ANOVA and Sidak post-hoc test to analyze responses from a sample size of 60,029 adolescents, the study found significant differences in tolerance, withdrawal symptoms, and impaired control across various game genres. RPG and AOS games were associated with higher levels of tolerance and withdrawal symptoms compared to sports and casual games, suggesting a genre-specific influence on these behaviors. The findings underscore the need for targeted strategies in educational and parental guidance to address game genre-related issues among adolescents. The implications of this research are vital for developing effective interventions and supports that cater to the specific needs of adolescent gamers, aiming to foster healthier gaming habits and mitigate potential negative outcomes.

Design of Neural Network-Based Multi-Fault Tolerant Control System for Unmanned Aerial Vehicles

Actuator failure seriously threatens the flight safety of unmanned helicopters. Considering the problem of multiple faults such as actuator bias and failure in unmanned helicopters, a composite fault-tolerant flight control algorithm is proposed. For actuator bias fault, a nonlinear fault observer is designed to estimate it in real time; for actuator failure fault, a same-dimensional auxiliary system is constructed and processed by neural network technology. The composite fault-tolerant flight controller of the unmanned helicopter is designed by backstepping method, and the Lyapunov stability theory is used to prove that the error signals of the closed-loop system are bounded and convergent. Simulation results show that the proposed control algorithm can improve the fault tolerance of the unmanned helicopter when multiple actuator faults occur, ensuring its safe flight.

8273 ACTH-Dependent Cushing's Syndrome Due To Metastatic Cervical Cancer: A Case Report

Abstract Disclosure: T.D. Bertolacini da Silva: None. V.D. Kamura: None. P.D. Buchalla: None. A.G. Simoes: None. S. Glina: None. Z.M. Campos: None. I.S. Rosa: None. P.X. Santi: None. Background: The association of dependent Cushing's ACTH Syndrome with certain types of cancer is well known, such as small cell lung cancer, enteropancreatic tumors, thymoma, thyroid cancer, however, in association with cervical cancer there are almost no cases described. Clinical Case: A 39-year women, showed about 2.5 years ago with abnormal uterine bleeding, being submitted to colposcopy with the presence of exophytic, friable and hardened lesion in the anterior region of the cervix. Biopsies revealed adenocarcinoma, endometrioid type and immunohistochemistry (IHC) positive for: Ki-67 80%, vimentin and CEA. Patient underwent initial treatment with chemotherapy and radiotherapy, losing follow-up with Oncology. After 1 year, the patient was admitted to a hospital with behavioral alteration, including suicidal ideation, muscle weakness, breast enlargement and hair growth on the face. On physical examination, there was the presence of hypertension, hyperglycemia, centripetal obesity, legs edema and hirsutism. Due to the typical symptoms, the hypothesis of Cushing's Syndrome was made and laboratory and imaging tests were requested. Initial tests: K 1.9 mmol/L (3.5-5.6 mmol/L), Na 146 mmol/L (137-145 mmol/L), TSH 0.25 uIU/mL (0.49-5.58 uIU/mL/mL), free T4 0.78 ng/dL (0.89-1.53 ng/dL), pH 7.57 (7.36-7.41), HCO3 43.1 mmol/L (23-27 mmol/L), LH 0.15 mIU/mL (1.9-12.5 mIU/mL), FSH 1.02 mIU/mL (2.5-10 mIU/mL), estradiol 84.1 pg/mL (&amp;lt; 32.2 pg/mL), ACTH 365.0 pg/mL and 98.6 pg/mL (&amp;lt; 46 pg/mL), cortisol &amp;gt; 75 ug/dL (5.27-22.5 ug/dL), urinary cortisol 3790 ug/24h (4-60 ug/24h), testosterone 333 ng/dL (12 - 59 ng/dL), free testosterone 10.12 ng/dL (0.08-1.1 ng/dL), dehydrotestosterone 1,620 pg/mL (&amp;lt; 596 pg/mL), androstenedione &amp;gt; 10 ng/mL (0.3-3.3 ng/mL). The dosages of ACTH and cortisol were performed after the dexamethasone suppression test and a pituitary MRI was normal. The MRI of the abdomen and pelvis showed multiple solid nodular lesions in liver with varying sizes compatible with metastatic disease, in addition, showed the increase in the bilateral volume of the adrenals. Liver biopsy was performed exhibiting carcinoma infiltration with IHC compatible with neuroendocrine tumor, positive for: CDX-2, SATB2, chromogranin A and synaptophysin (waiting for ACTH). Other primary sites were ruled out. The patient was initially treated with Etomidate in a continuous infusion, without tolerance and little control of hypercortisolism, after initiating Ketoconazole which was suspended due to hepatotoxicity, and then underwent bilateral adrenalectomy. Unfortunately, she died 4 days after surgery due to septic shock. Conclusion: This case report brings a very rare association of Cushing's syndrome by ectopic ACTH due to cervical cancer, with less than 10 cases reported, in which we highlight the diagnostic difficulty, the complexity of treatment and the high risk of morbidity and mortality. Presentation: 6/1/2024

6810 Successful Insulin Allergy Desensitization To Humalog During The Second Trimester Of Pregnancy

Abstract Disclosure: J. Noreña: None. S. Seav: None. S. Jiang: None. S. McGhee: None. M. Tan: None. M. Basina: None. Background: Insulin allergy is rare, occurring in only 0.1 to 3% of people with insulin-treated diabetes. During pregnancy, this incidence is even lower due to a relative immunosuppressive state. Currently, there are no standardized insulin allergy desensitization protocols for this specific patient population. Clinical Case: A 39-year-old female (G4P3003) with T2DM and multiple prior medication allergies presented to the antepartum unit in her 17th week of pregnancy due to hyperglycemia and reported insulin allergy to NPH insulin.Patient was initially diagnosed with gestational diabetes during her third pregnancy, requiring NPH insulin which she seemed to tolerate well at the time. She remained medication-free for two years post-delivery but later developed T2DM with an A1c of 6.8%. Metformin and Jardiance, previously prescribed, were discontinued upon confirmation of her current pregnancy. She opted to manage her diabetes through diet and exercise alone, but her A1c rose to 7.0%, prompting the initiation of NPH.Following the first dose of NPH at home, she experienced a localized burning sensation at the injection site associated with facial flushing, followed by a diffuse, pruritic, erythematous rash on her face, chest, abdomen, and bilateral arms. Due to her history of anaphylaxis to other drugs (mainly antibiotics), she was admitted to the hospital for monitoring. Inpatient attempts with lower doses of NPH and then a trial of glargine triggered new rash episodes. Work-up revealed negative insulin antibodies, low IgG, and a normal CBC. She was started on Humalog to cover basal dose administered every 6 hours and additional prandial injections, which she tolerated prior to discharge. One week later, she developed a new local erythematous reaction at the Humalog injection site followed by a generalized rash which led to her readmission.Allergy was consulted and facilitated a successful desensitization protocol to Humalog. The protocol included escalating doses of insulin administered every 30 minutes (0.1u, 0.2u, 0.4u, 0.8u, 1u, 2u, 3u, 3u) to achieve a pre-determined cumulative dose of 10.5 units. Patient tolerated the protocol well and was discharged with q6h Humalog for basal coverage in addition to prandial doses with plan to transition to insulin pump therapy with Humalog soon. Conclusion: This unique case demonstrates how insulin desensitization can be a safe and successful strategy to help achieve insulin tolerance and glycemic control during pregnancy. Election of an insulin, such as Humalog, that can achieve the one-hour post-prandial glucose target during pregnancy and also provide effective basal coverage should be considered as desensitization can only be done with one insulin type at a time. Presentation: 6/2/2024

MPC based fault tolerance control of AC–DC power converters for offshore wind turbines

MPC based fault tolerance control of AC–DC power converters for offshore wind turbines

Finite-time output-feedback fault tolerant adaptive fuzzy control framework for a class of MIMO saturated nonlinear systems

This paper presents a finite-time fault-tolerant fuzzy adaptive controller for uncertain interconnected nonlinear systems in strict-feedback form. The controller addresses input saturation, state-dependent actuator faults, external disturbances, and unavailable states for measurement. To avoid any unexpected alteration due to failures, the proposed control scheme design addresses all types of actuator faults that are bias, drift, and loss of accuracy as additive faults, as well as a multiplicative fault that results in loss of effectiveness with nonaffine state-dependency. Restrictions on control gains and unmatched interconnections are eliminated, and the explosion complexity caused by recursive back-stepping designs is avoided. Fuzzy Systems approximate the unknown ideal control laws along side the acutator faults and disturbances. The stability analysis guarantees that tracking errors converge to a small compact set around the origin in finite time. Simulation results on a quad-rotor UAV and a mathematical system confirm the effectiveness of the proposed approach.

TR3-56 and Treg Regulatory T Cell Subsets as Potential Indicators of Graft Tolerance Control in Kidney Transplant Recipients.

Identification of early signatures of immune rejection represents a key challenge in the clinical management of kidney transplant. To address such an issue, we enrolled 53 kidney transplant recipients without signs of graft rejection, no infectious episodes and no change in the immunosuppressive regimen in the last 6 months. An extensive immune profile revealed increased activation of the T cells, a decreased amount and growth ability of the Treg and a higher level of the TR3-56 regulatory T cell subset, described by us as involved in the preferential control of cytotoxic T lymphocytes. In renal transplant recipients, the high level of the TR3-56 cells associates with a reduction in both the amount and the growth ability of the Treg. Moreover, when the transplanted subjects were categorised according to their stable or unstable disease status, as defined by changes in serum creatinine ≥0.2 mg/dL in two consecutive detections, a higher TR3-56 level and defective Treg growth ability were observed to characterise patients with unstable graft control. Further studies are required to substantiate the hypothesis that immune profiling, including TR3-56 evaluation, might represent a valuable diagnostic tool to identify patients at risk of developing significant anti-donor allo-immune responses.

Central control of opioid-induced mechanical hypersensitivity and tolerance in mice.

Repetitive use of morphine (MF) and other opioids can trigger two major pain-related side effects: opioid-induced hypersensitivity (OIH) and analgesic tolerance, which can be subclassified as mechanical and thermal. The central mechanisms underlying mechanical OIH/tolerance remain unresolved. Here, we report that a brain-to-spinal opioid pathway, starting from μ-opioid receptor (MOR)-expressing neuron in the lateralparabrachial nucleus (lPBNMOR+) via dynorphin (Dyn) neuron in the paraventricular hypothalamic nucleus (PVHDyn+) to κ-opioid receptor (KOR)-expressing GABAergic neuron in the spinal dorsal horn (SDHKOR-GABA), controls repeated systemic administration of MF-induced mechanical OIH and tolerance in mice. The above effect is likely mediated by disruption of dorsal horn gate control for MF-resistant mechanical pain via silencing of the Dyn-positive GABAergic neurons in the SDH (lPBNMOR+ → PVHDyn+ → SDHKOR-GABA → SDHDyn-GABA). Repetitive binding of MF to MORs during repeated MF administration disrupted the above circuits. Targeting the above brain-to-spinal opioid pathways rescued repetitive MF-induced mechanical OIH and tolerance.

Adaptive fault tolerant control of unmanned underwater glider with predefined-time stability

Actuator faults of the underwater gliders (UGs) not only jeopardize the motion control performance but may also threaten the sailing safety. This paper proposes an adaptive sliding mode fault-tolerant controller with predefined-time stability for the UGs, considering the modeling uncertainties and the unknown disturbances. Three types of actuator faults are developed and incorporated in the fault model of the UGs, which are utilized for the fault tolerant controller design. Then, the adaptive terms are utilized to estimate the modeling uncertainties and the unknown disturbances. An adaptive sliding mode fault tolerant controller is thus designed with the theoretical proof that the global stability can be achieved within a predefined time. The hardware-in-the-loop simulations are conducted to verify the effectiveness of the proposed fault tolerant controller. The simulation results show that the UG can achieve the stability of the pitching attitude under three kinds of actuator fault conditions.

Event-triggered adaptive fault-tolerant control with pre-specified performance for AUVs trajectory tracking

This paper investigates the problem of fault-tolerant control of the preset performance of autonomous underwater vehicles (AUVs) in case of external disturbances and actuator failures. To begin with, a specific new nonlinear auxiliary function with dual performance constraints is designed to establish the foundation for achieving prescribed performance in the closed-loop system. Subsequently, an event-triggered fault tolerant controller employing Nussbaum gain technique is introduced to accomplish the precision trajectory tracking control of the AUVs by predetermining control index. It is shown that the effect by resulting in actuator faults is on-line compensated by an adaptive estimator. Theoretical analyses demonstrate the boundedness of the signals of the designed closed-loop control system, and the Zeno phenomenon can be effectively avoided. Finally, simulation experiments are conducted to verify the effectiveness of the proposed methods.

The activation of autophagy by molecular hydrogen is functionally associated with osmotic tolerance in Arabidopsis

The role of molecular hydrogen (H2) in autophagy during inflammatory response is controversial in mammalian cells. Although the stimulation of H2 production in response to osmotic stress was observed in plants, its synthetic pathway and the interrelationship between its induction and plant autophagy remain unclear. Here, the induction of autophagy was observed in Arabidopsis upon osmotic stress, assessing by the autophagosome formation and autophagy-related genes expression. Above responses were intensified by H2 fumigation. Meanwhile, the reduction in seedling growth and roots vigor was obviously abolished, accompanied by reestablishing redox balance. These H2 responses were markedly impaired in T-DNA knockout lines atg2, atg5, and atg18. Further evidence showed that the increased endogenous H2 synthesis by genetic manipulation, not only stimulated autophagosome formation, but also triggered various plant responses toward osmotic stress. By contrast, these responses were obviously abolished by the disruption of endogenous H2 synthesis with the addition of 2,6-dichloroindophenol sodium salt. Together, the integrated genetic and molecular evidence clearly illustrated the requirement of autophagy activation in H2 control of plant osmotic tolerance.

Two-dimensional reinforcement learning model-free fault-tolerant control for batch processes against multi- faults

Aiming at the characteristics of batch process changing along with time and batch directions, the existence of unmodeled dynamics, and the partial failure of actuators or/and sensors, we propose a novel 2D reinforcement learning (RL) fault tolerant control strategy without considering model parameters. Firstly, a two-Dimensional (2D) augmented state space model and 2D Q function-based fault tolerant control (FTC) framework is established. The 2D Bellman equation can be acquired by analyzing the relationship between the 2D value function and the 2D Q function. Based on the extended model and Q-learning concept of RL, a data-driven FTTC independent of model parameters is designed, and a 2D data-driven Q-learning algorithm is proposed. Finally, taking the pressure holding phase in the injection process as the experimental object, the control effect is compared with that of the traditional model-based FTC, and better tracking performance and unbiasedness to the probing noise can be proved.

Distributed-observer-based adaptive fault tolerant formation maneuver for autonomous surface vehicles under stochastic cyber-attack

This paper investigates the distributed adaptive fault-tolerant formation maneuver control strategy for multiple autonomous surface vehicles (ASVs) systems subject to stochastic cyber-attack and actuator failures. Existing works have provided solutions against continuous attacks on communication channels while ignoring the increasingly prevalent intermittent attacks. Compared to the former, the latter are more challenging to detect, having been insufficiently described and addressed. Motivated by this observation, this article is concerned with the stochastic intermittent injection attacks, which are modeled as stochastic impulsive sequences, characterized by stochastic injection instant and intensity, leading to unpredictable changes in the state information transmitted by the neighbors. Taking this dilemma into consideration, a novel distributed observer is proposed, capable of effectively observing the target formation even in the presence of stochastic intermittent injection attacks. Meanwhile, a large feedback gain is incorporated into the observer to reduce the impact of attacks on system stability. A linear sliding manifold, together with the adaptive algorithm, is utilized to construct a fault tolerant control architecture for each follower ASV without employing model parameters which can confront the embarrassing scenario of actuator failures. Eventually, theoretical deduction and numerical simulations are conducted to confirm the feasibility of the proposed collaborative control scheme.

Fault tolerant control of uncertain hydraulic system against actuator fault based on redesign Lyapunov approach

The design of stabilizing controller for uncertain nonlinear systems with control constraints is a challenging problem. This paper proposes the design of fault tolerant control for a class of uncertain nonlinear systems with actuator faults based on Lyapunov redesign principle. First, an assumption is introduced to design the control of the nominal system. Then, a new control law has been introduced to handle the difficulty caused by actuator failures. It is shown that the actuator faults can be completely compensated by the proposed nonlinear controller. Finally, the method will be applied to a hydraulic system to show its effectiveness.

Model predictive control based integrated fault tolerant controller for autonomous vehicles with four-wheel independent steering, driving and braking systems

This paper presents a fault-tolerant control algorithm for path and velocity tracking of an autonomous vehicle based on four-wheel independent steering, driving, and braking systems. The proposed algorithm is designed to distribute the control effort to normal actuators in the occurrence of faults. The proposed algorithm consists of three modules. The reference velocity and yaw rate to track the reference path are determined by the reference state decision module. The model predictive control (MPC)-based fault-tolerant controller determines the optimal inputs to compensate for the effect of the faulty actuator and maintain the tracking performance. A faulty-factor estimator is proposed based on a recursive covariance estimator to evaluate the performance degradation due to the failure of each actuator. The estimated faulty factors are applied to the objective function of the MPC such that the control input is distributed based on the level of the fault. The performance of the proposed algorithm was verified via performing simulations using MATLAB/Simulink and CarSim. The simulations proved that the proposed controller maintained the control performance of the normal case even in multiple actuator failures.

Immunodeficiency: Overview of primary immune regulatory disorders (PIRDs).

Primary immune regulatory disorders (PIRD) comprise a heterogeneous group of monogenic disorders that impact homeostatic control of inflammation and immune tolerance. Patients with a PIRD typically present to medical care with symptoms of autoimmunity or hyperinflammation as the dominant clinical feature, symptoms that include fever, rash, lymphadenopathy, organomegaly, arthritis, and colitis are commonplace. Notably, PIRDs are a distinct entity from primary immune deficiency disorders (PIDD), which are primarily defined by a qualitative or quantitative defect in immunity, which manifests as a susceptibility to recurrent infections. PIDDs and PIRDs can be challenging to differentiate because the clinical presentations can be similar. Red flags for PIRDs include multiple autoimmune diagnoses in the same patient, chronic lymphadenopathy, hepatomegaly, and/or splenomegaly, chronic colitis, hemophagocytic lymphohistiocytosis (HLH), Epstein Barr virus (EBV) susceptibility, recurrent or persistent fever, vasculitis, and sterile inflammation. For simplicity in this brief review, we limit our discussion of PIRDs to the following categories multiple autoimmune diseases, immune dysregulation with colitis, disorders with HLH and/or EBV susceptibility, autoinflammatory syndromes, type 1 interferonopathies, and disorders of sterile inflammation. Diagnosing a PIRD requires a broad immune evaluation for both immune system deficiencies and inflammation, along with genetic testing. Given the complex nature of these diseases, treatment often requires a team of subspecialists. Treatment, depending on the specific diagnosis, may be somewhat empiric with nonspecific immune modulators, symptom-directed therapies, and, in severe cases, hematopoietic stem cell transplantation; however, with the increasing number of biologics available, we are often able to use targeted immune therapy or even gene therapy.

Adaptive critic design for safety-optimal FTC of unknown nonlinear systems with asymmetric constrained-input

Safe fault tolerant control is one of the key technologies to improve the reliability of dynamic complex nonlinear systems with limited inputs, which is hard to solve and definitely a great challenge to tackle. Thus the paper presents a novel safety-optimal FTC (Fault Tolerant Control) approach for a category of completely unknown nonlinear systems incorporating actuator fault and asymmetric constrained-input, which can guarantee the system’s operation within a safe range while showcasing optimal performance. Firstly, a CBF (Control Barrier Function) is incorporated into the cost function to penalize unsafe behaviors, and then we translate the intractable safety-optimal FTC problem into a differential ZSG (Zero-Sum Game) problem by defining the control input and the actuator fault as two opposing sides. Secondly, a neural-network-based identifier is employed to reconstruct system dynamics using system data, and the resolution of handling asymmetric constrained-input with the introduced non-quadratic cost function is achieved through the design of an adaptive critic scheme, aiming to reduce computational expenses accordingly. Finally, through the theoretical stability analysis, it is demonstrated that all signals in the closed-loop system are consistently UUB (Uniformly Ultimately Bounded). Furthermore, the proposed method’s effectiveness is also verified in the simulation experiments conducted on a model of a single-link robotic arm system with actuator failure. The result shows that the algorithm can fulfill the safety-optimal demand of fault tolerant control in fault system with asymmetric constrained-input.

Topologically Correct Intersection Curves of Two Trimmed Quadrics with Tolerance Control

Topologically Correct Intersection Curves of Two Trimmed Quadrics with Tolerance Control

Adaptive dynamic programming-based multi-fault tolerant control of reconfigurable manipulator with input constraint

In this paper, a multi-fault tolerant controller considering actuator saturation is proposed. Based on the adaptive dynamic programming(ADP) algorithm, the fault tolerant control of the reconfigurable manipulator with sensor and actuator faults are carried out. Firstly, combined with the state space expression, the nonlinear transformation of sensor fault is performed by adopting the differential homeomorphism principle. An improved cost function is constructed based on the fault estimation function obtained by the fault observer, and combined with hyperbolic tangent function to deal with input constraint problem. Then, an evaluation neural network (NN) is established and the Hamilton–Jacobi–Bellman (HJB) equation is solved by online strategy iterative algorithm. Furthermore, based on Lyapunov theorem, the stability of reconfigurable manipulator systems with multi-fault are proved. Lastly, the simulation studies are used to certify the effectiveness of the presented fault tolerant control (FTC) scheme.