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BACKGROUND: Lung- and diaphragm-protective (LDP) ventilation may prevent diaphragm atrophy and patient self-inflicted lung injury in acute respiratory failure, but feasibility is uncertain. The objectives of this study were to estimate the proportion of patients achieving LDP targets in different modes of ventilation, and to identify predictors of need for extracorporeal carbon dioxide removal (ECCO2R) to achieve LDP targets. METHODS: An in silico clinical trial was conducted using a previously published mathematical model of patient-ventilator interaction in a simulated patient population (n = 5000) with clinically relevant physiological characteristics. Ventilation and sedation were titrated according to a pre-defined algorithm in pressure support ventilation (PSV) and proportional assist ventilation (PAV+) modes, with or without adjunctive ECCO2R, and using ECCO2R alone (without ventilation or sedation). Random forest modelling was employed to identify patient-level factors associated with achieving targets. RESULTS: After titration, the proportion of patients achieving targets was lower in PAV+ vs. PSV (37% vs. 43%, odds ratio 0.78, 95% CI 0.73-0.85). Adjunctive ECCO2R substantially increased the probability of achieving targets in both PSV and PAV+ (85% vs. 84%). ECCO2R alone without ventilation or sedation achieved LDP targets in 9%. The main determinants of success without ECCO2R were lung compliance, ventilatory ratio, and strong ion difference. In silico trial results corresponded closely with the results obtained in a clinical trial of the LDP titration algorithm (n = 30). CONCLUSIONS: In this in silico trial, many patients required ECCO2R in combination with mechanical ventilation and sedation to achieve LDP targets. ECCO2R increased the probability of achieving LDP targets in patients with intermediate degrees of derangement in elastance and ventilatory ratio.

BACKGROUND: Insufficient or excessive respiratory effort during acute hypoxemic respiratory failure (AHRF) increases the risk of lung and diaphragm injury. We sought to establish whether respiratory effort can be optimized to achieve lung- and diaphragm-protective (LDP) targets (esophageal pressure swing - 3 to - 8 cm H2O; dynamic transpulmonary driving pressure ≤ 15 cm H2O) during AHRF. METHODS: In patients with early AHRF, spontaneous breathing was initiated as soon as passive ventilation was not deemed mandatory. Inspiratory pressure, sedation, positive end-expiratory pressure (PEEP), and sweep gas flow (in patients receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO)) were systematically titrated to achieve LDP targets. Additionally, partial neuromuscular blockade (pNMBA) was administered in patients with refractory excessive respiratory effort. RESULTS: Of 30 patients enrolled, most had severe AHRF; 16 required VV-ECMO. Respiratory effort was absent in all at enrolment. After initiating spontaneous breathing, most exhibited high respiratory effort and only 6/30 met LDP targets. After titrating ventilation, sedation, and sweep gas flow, LDP targets were achieved in 20/30. LDP targets were more likely to be achieved in patients on VV-ECMO (median OR 10, 95% CrI 2, 81) and at the PEEP level associated with improved dynamic compliance (median OR 33, 95% CrI 5, 898). Administration of pNMBA to patients with refractory excessive effort was well-tolerated and effectively achieved LDP targets. CONCLUSION: Respiratory effort is frequently absent  under deep sedation but becomes excessive when spontaneous breathing is permitted in patients with moderate or severe AHRF. Systematically titrating ventilation and sedation can optimize respiratory effort for lung and diaphragm protection in most patients. VV-ECMO can greatly facilitate the delivery of a LDP strategy. TRIAL REGISTRATION: This trial was registered in Clinicaltrials.gov in August 2018 (NCT03612583).

Mechanical ventilation is used to sustain respiratory function in patients with acute respiratory failure. To aid clinicians in consistently selecting lung- and diaphragm-protective ventilation settings, a physiology-based decision support system is needed. To form the foundation of such a system, a comprehensive physiological model which captures the dynamics of ventilation has been developed. The Lung and Diaphragm Protective Ventilation (LDPV) model centers around respiratory drive and incorporates respiratory system mechanics, ventilator mechanics, and blood acid-base balance. The model uses patient-specific parameters as inputs and outputs predictions of a patients transpulmonary and esophageal driving pressures (outputs most clinically relevant to lung and diaphragm safety), as well as their blood pH, under various ventilator and sedation conditions. Model simulations and global optimization techniques were used to evaluate and characterize the model. The LDPV model is demonstrated to describe a CO2 respiratory response that is comparable to what is found in literature. Sensitivity analysis of the model indicate that the ventilator and sedation settings incorporated in the model have a significant impact on the target output parameters. Finally, the model is seen to be able to provide robust predictions of esophageal pressure, transpulmonary pressure and blood pH for patient parameters with realistic variability. The LDPV model is a robust physiological model which produces outputs which directly target and reflect the risk of ventilator-induced lung and diaphragm injury. Ventilation and sedation parameters are seen to modulate the model outputs in accordance with what is currently known in literature.

In order to study the influence of the space linkage system on the stability of the straddle-type monorail vehicle with single-axle bogies, the sensitivity analysis of the space linkage system is identified based on the Pearson coefficient method to determine the importance of each component of the single-axle bogies. The dynamics model of straddle-type monorail vehicle with single-axle bogies is established by the multi-rigid body dynamics. The Pearson analysis method is used to identify the key parameters of the space linkage system. Based on that, dynamic response optimization model of space bar system is developed to carry out a multi-objective suspension design optimization process. The results show that the maximum sensitivity parameter for the RMS value of yaw acceleration and pitch angle acceleration is the length of the longitudinal tow bar; there is a correlation of approximately 0.088 between the stiffness K and the damping coefficient C of the hydraulic shock absorber. After optimization the root mean square of lateral acceleration of the optimized single-axle bogie vehicle is reduced by 6.0%. [ABSTRACT FROM AUTHOR]

Ni-rich LiNixCoyMn1−x−yO2 (x ≥ 0.6) layered oxide cathodes are among the most promising cathode materials for lithium-ion batteries (LIBs) owing to their superior capacity, prominent energy density and low cost. However, the large volume change caused by phase transition and poor diffusion kinetics limits their application. Herein, a nanorod-like Ni-rich layered LiNi0.6Co0.2Mn0.2O2 cathode is synthesized via a facile surfactant-free co-precipitation route. Due to the unique nanorod morphology, more {010} electrochemically active planes are exposed. As a result, structural stability and diffusion kinetics are greatly improved. In terms of performance, it exhibits outstanding structural stability (the volume change is as small as 2.12% in the processes of charging and discharging) and rate performance (achieving a high discharge capacity of 152.2 mA h g−1 at 5C). Such rationally designed cathode could meet the high high-energy requirements of next generation LIBs. [ABSTRACT FROM AUTHOR]

Background: Bariatric surgery orientation sessions are often the first point of contact and a recommended component of pre-bariatric surgery assessment. Self-removal rates after bariatric program orientation are as high as 25 % despite the proven efficacy of this procedure. The objective of this study was to identify factors contributing to patient self-removal after orientation using a mixed method approach. Methods: Patients who attended the Toronto Western Hospital Bariatric Surgery Program orientation between 2012 and 2013 and then self-removed from the program ( N = 216) were included in the study. Subjects were interviewed via telephone using a semi-structured interview guide, generating both quantitative and qualitative data. Factors leading to discontinuation were rated on a five-point Likert scale. Qualitative data was analyzed using constant comparative methodology. Results: The response rate was 59 % with a 40.7 % completion rate ( N = 88). Concerns about potential surgical risks and complications and the ability to adapt to changes in eating and drinking post-operatively were identified as the top two factors for patients' self-removal from the program. Thematic analysis uncovered 11 major themes related to patient self-removal. Unexpected themes include perceived personal suitability for the surgery, family impact of surgery, miscommunication with the family physician, and fears related to the orientation information. Conclusions: This is one of the first studies examining barriers to bariatric surgery in the pre-operative setting and offers new insights into the reasons patients self-remove from bariatric surgery programs. This study may inform bariatric orientation program changes resulting in improved access to this effective surgical intervention. [ABSTRACT FROM AUTHOR]

Kisspeptin receptor (KISS1R), belonging to the class A peptide-GPCR family, plays a key role in the regulation of reproductive physiology after stimulation by kisspeptin and is regarded as an attractive drug target for reproductive diseases. Here, we demonstrated that KISS1R can couple to the G i/o pathway besides the well-known G q/11 pathway. We further resolved the cryo-electron microscopy (cryo-EM) structure of KISS1R-G q and KISS1R-G i complexes bound to the synthetic agonist TAK448 and structure of KISS1R-G q complex bound to the endogenous agonist KP54. The high-resolution structures provided clear insights into mechanism of KISS1R recognition by its ligand and can facilitate the design of targeted drugs with high affinity to improve treatment effects. Moreover, the structural and functional analyses indicated that conformational differences in the extracellular loops (ECLs), intracellular loops (ICLs) of the receptor, and the "wavy hook" of the Gα subunit may account for the specificity of G protein coupling for KISS1R signaling.