Establishing plausibility of cardiovascular adverse effects of immunotherapies using Mendelian randomisation.

Immune checkpoint inhibitors (ICIs) and Janus kinase inhibitors (JAKis) have raised concerns over serious unexpected cardiovascular adverse events. The widespread pleiotropy in genome-wide association studies offers an opportunity to identify cardiovascular risks from in-development drugs to help inform appropriate trial design and pharmacovigilance strategies. This study uses the Mendelian randomization (MR) approach to study the causal effects of 9 cardiovascular risk factors on ischemic stroke risk both independently and by mediation, followed by an interrogation of the implicated expression quantitative trait loci (eQTLs) to determine if the enriched pathways can explain the adverse stroke events observed with ICI or JAKi treatment. Genetic predisposition to higher systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), waist-to-hip ratio (WHR), low-density lipoprotein cholesterol (LDL), triglycerides (TG), type 2 diabetes (T2DM), and smoking index were associated with higher ischemic stroke risk. The associations of genetically predicted BMI, WHR, and TG on the outcome were attenuated after adjusting for genetically predicted T2DM [BMI: 53.15% mediated, 95% CI 17.21%-89.10%; WHR: 42.92% (4.17%-81.67%); TG: 72.05% (10.63%-133.46%)]. JAKis, programmed cell death protein 1 and programmed death ligand 1 inhibitors were implicated in the pathways enriched by the genes related to the instruments for each of SBP, DBP, WHR, T2DM, and LDL. Overall, MR mediation analyses support the role of T2DM in mediating the effects of BMI, WHR, and TG on ischemic stroke risk and follow-up pathway enrichment analysis highlights the utility of this approach in the early identification of potential harm from drugs.

Novel gain-tuning for sliding mode control of second-order mechanical systems: theory and experiments.

The sliding mode control is well-known as a useful control technique that can be applied in several real-world applications. However, a straightforward and efficient process of selecting the sliding mode control gains remains a challenging but interesting topic. This paper investigates a novel gain tuning method for the sliding mode control of second-order mechanical systems. Firstly, we obtain relations between the gains and the natural and damping ratio of the closed-loop system. Secondly, the time constant of the system's actuators and the system response performance criteria, including settling time and delay time, are taken into consideration to determine appropriate ranges of the gains. These gain ranges allow control designers to select the controller gains in a time-saving manner and ensure that the desired system performance is met and the actuators work properly. Finally, the proposed method is applied to the gain tuning process of a sliding mode altitude controller for an actual quadcopter unmanned aerial vehicle. Simulation and experimental results demonstrate the applicability and effectiveness of this method.

A genomic deep field view of hypertension.

Blood pressure is regulated by a complex neurohumoral system including the renin-angiotensin-aldosterone system, natriuretic peptides, endothelial pathways, the sympathetic nervous system, and the immune system. This review charts the evolution of our understanding of the genomic basis of hypertension at increasing resolution over the last 5 decades from monogenic causes to polygenic associations, spanning ∼30 monogenic rare variants and >1500 single nucleotide variants. Unexpected early wins from blood pressure genomics include deepening of our understanding of the complex causation of hypertension; refinement of causal estimates bidirectionally between blood pressure, risk factors, and outcomes through Mendelian randomization; risk stratification using polygenic risk scores; and opportunities for precision medicine and drug repurposing.

Unravelling the Distinct Effects of Systolic and Diastolic Blood Pressure Using Mendelian Randomisation.

A true discrepancy between the effect of systolic blood pressure (SBP) and diastolic blood pressure (DBP) on cardiovascular (CV) outcomes remains unclear. This study performed two-sample Mendelian randomization (MR) using genetic instruments that exclusively predict SBP, DBP or both to dissect the independent effect of SBP and DBP on a range of CV outcomes. Genetic predisposition to higher SBP and DBP was associated with increased risk of coronary artery disease (CAD), myocardial infarction (MI), stroke, heart failure (HF), atrial fibrillation (AF), chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). Genetically proxied SBP exclusively was associated with CAD (OR 1.18, 95% CI: 1.03-1.36, per 10 mmHg), stroke (1.44[1.28-1.62]), ischemic stroke (1.49[1.30-1.69]), HF (1.41[1.20-1.65]), AF (1.28[1.15-1.43]), and T2DM (1.2[1.13-1.46]). Genetically proxied DBP exclusively was associated with stroke (1.21[1.06-1.37], per 5 mmHg), ischemic stroke (1.24[1.09-1.41]), stroke small-vessel (1.35[1.10-1.65]) and CAD (1.19[1.00-1.41]). Multivariable MR using exclusive SBP and DBP instruments showed the predominant effect of SBP on CAD (1.23[1.05-1.44], per 10 mmHg), stroke (1.39[1.20-1.60]), ischemic stroke (1.44[1.25-1.67]), HF (1.42[1.18-1.71]), AF (1.26[1.10-1.43]) and T2DM (1.31[1.14-1.52]). The discrepancy between effects of SBP and DBP on outcomes warrants further studies on underpinning mechanisms which may be amenable to therapeutic targeting.

Quadcopter UAVs Extended States/Disturbance Observer-Based Nonlinear Robust Backstepping Control.

A trajectory tracking control for quadcopter unmanned aerial vehicle (UAV) based on a nonlinear robust backstepping algorithm and extended state/disturbance observer (ESDO) is presented in this paper. To obtain robust attitude stabilization and superior performance of three-dimension position tracking control, the construction of the proposed algorithm can be separated into three parts. First, a mathematical model of UAV negatively influenced by exogenous disturbances is established. Following, an extended state/disturbance observer using a general second-order model is designed to approximate undesirable influences of perturbations on the UAVs dynamics. Finally, a nonlinear robust controller is constructed by an integration of the nominal backstepping technique with ESDO to enhance the performance of attitude and position control mode. Robust stability of the closed-loop disturbed system is obtained and guaranteed through the Lyapunov theorem without precise knowledge of the upper bound condition of perturbations. Lastly, a numerical simulation is carried out and compared with other previous controllers to demonstrate the great advantage and effectiveness of the proposed control method.

Robust Position Control of an Over-actuated Underwater Vehicle under Model Uncertainties and Ocean Current Effects Using Dynamic Sliding Mode Surface and Optimal Allocation Control.

Underwater vehicles (UVs) are subjected to various environmental disturbances due to ocean currents, propulsion systems, and un-modeled disturbances. In practice, it is very challenging to design a control system to maintain UVs stayed at the desired static position permanently under these conditions. Therefore, in this study, a nonlinear dynamics and robust positioning control of the over-actuated autonomous underwater vehicle (AUV) under the effects of ocean current and model uncertainties are presented. First, a motion equation of the over-actuated AUV under the effects of ocean current disturbances is established, and a trajectory generation of the over-actuated AUV heading angle is constructed based on the line of sight (LOS) algorithm. Second, a dynamic positioning (DP) control system based on motion control and an allocation control is proposed. For this, motion control of the over-actuated AUV based on the dynamic sliding mode control (DSMC) theory is adopted to improve the system robustness under the effects of the ocean current and model uncertainties. In addition, the stability of the system is proved based on Lyapunov criteria. Then, using the generalized forces generated from the motion control module, two different methods for optimal allocation control module: the least square (LS) method and quadratic programming (QP) method are developed to distribute a proper thrust to each thruster of the over-actuated AUV. Simulation studies are conducted to examine the effectiveness and robustness of the proposed DP controller. The results show that the proposed DP controller using the QP algorithm provides higher stability with smaller steady-state error and stronger robustness.