•Development of a seamless two-speed transmission applied in a BEV.•Proposing a power-on gearshift control strategy.•Improving the gearshift quality by the optimal coordinating gearshift ...controllers.•Developing observers for estimating the unmeasured torque information to achieve the feedback control.
With the sustained technology advancement in the power battery, battery electric vehicles (BEVs) are considered as the most advisable alternatives of their internal combustion engine (ICE) counterparts. Research reveals that the implementation of multispeed transmissions for BEVs can reduce the vehicle energy consumption, improve the vehicle dynamic performance and downsize the battery package and the driving motor volume. Considering the potential advantages of multispeed transmissions equipped BEVs, this paper presents an investigation into the optimal coordinating gearshift control of a seamless two-speed transmission for BEVs. Firstly, to achieve the gearshift transient behaviour, the mathematical model of the powertrain system is established. Next, model-based gearshift tactics are proposed for the torque phase and the inertia phase respectively. Subsequently, the proposed control tactics based optimal controllers are developed to achieve high-quality gearshift in the whole gear shifting process. To be more specific, in the torque phase, the controller aims at optimising dual objectives together, namely the vehicle jerk and friction work, and the control objective of the inertia phase only focuses on decreasing the friction work due to the coordinating gear shifting tactic. Finally, based on available sensor signals, sliding mode observers are employed to estimate unmeasurable torque as feedback information for the optimal controllers in different gear states. Simulation results demonstrate that the devised control approaches can promote gear change performance comprehensively.
Early identification of toxicity associated with new chemical entities (NCEs) is critical in preventing late-stage drug development attrition. Liver injury remains a leading cause of drug failures in ...clinical trials and post-approval withdrawals reflecting the poor translation between traditional preclinical animal models and human clinical outcomes. For this reason, preclinical strategies have evolved over recent years to incorporate more sophisticated human in vitro cell-based models with multi-parametric endpoints. This review aims to highlight the evolution of the strategies adopted to improve human hepatotoxicity prediction in drug discovery and compares/contrasts these with recent activities in our lab. The key role of human exposure and hepatic drug uptake transporters (e.g. OATPs, OAT2) is also elaborated.
Early detection of chronic obstructive pulmonary disease (COPD) exacerbations using telemonitoring of physiological variables might reduce the frequency of hospitalization.
To evaluate the efficacy ...of home monitoring of lung mechanics by the forced oscillation technique and cardiac parameters in older patients with COPD and comorbidities.
This multicenter, randomized clinical trial recruited 312 patients with Global Initiative for Chronic Obstructive Lung Disease grades II to IV COPD (median age, 71 yr interquartile range, 66-76 yr; 49.6% grade II, 50.4% grades III-IV), with a history of exacerbation in the previous year and at least one nonpulmonary comorbidity. Patients were randomized to usual care (n = 158) or telemonitoring (n = 154) and followed for 9 months. All telemonitoring patients self-assessed lung mechanics daily, and in a subgroup with congestive heart failure (n = 37) cardiac parameters were also monitored. An algorithm identified deterioration, triggering a telephone contact to determine appropriate interventions.
Primary outcomes were time to first hospitalization (TTFH) and change in the EuroQoL EQ-5D utility index score. Secondary outcomes included: rate of antibiotic/corticosteroid prescription; hospitalization; the COPD Assessment Tool, Patient Health Questionnaire-9, and Minnesota Living with Heart Failure questionnaire scores; quality-adjusted life years; and healthcare costs. Telemonitoring did not affect TTFH, EQ-5D utility index score, antibiotic prescriptions, hospitalization rate, or questionnaire scores. In an exploratory analysis, telemedicine was associated with fewer repeat hospitalizations (-54%; P = 0.017).
In older patients with COPD and comorbidities, remote monitoring of lung function by forced oscillation technique and cardiac parameters did not change TTFH and EQ-5D. Clinical trial registered with www.clinicaltrials.gov (NCT 01960907).
•A novel synchronizer named Harpoon-Shift for electric vehicles.•Harpoon-Shift uses torque springs rather than friction clutch for speed synchronization.•Only a small thrust load is required for ...engagement of Harpoon-Shift.•It simplifies control strategy of gear shifting and the actuation process is simpler.•Rotating inertia, speed difference, and spring stiffness affect the Harpoon-shift dynamic performance.
This paper proposes a novel synchronizer ‘Harpoon-Shift’ aiming at improving the comfort and efficiency of gearbox, meanwhile, simplifying the shifting control strategy for multi-speed electric vehicles. It will overcome one of the biggest shortcomings of traditional synchronizer system with frictional cone clutch.
Experiment is established to investigate the torque and speed responses during the engagement of gears pairs. Then, based on previous testing results, the relationship of the peak torque and minimum speed difference to implement gear shifting with various spring coefficients is investigated. In addition, a mathematical model of the Harpoon-Shift system is developed to simulate the engagement process. The simulation results of system transient responses are validated against the data measured on testing rig. The model is then improved to study the impact of the rotating inertia, speed and speed difference on the torsional vibration and required time of engagement. Both of the simulation and experimental results show the significant improvement of proposed synchronizer to conventional cone clutch synchronizer.
SUMMARY OF KEY POINTS
International respiratory organizations now recommend using lower limit of normal and standardized residuals to diagnose airflow obstruction and COPD though using a fixed ratio ...<0.7 is simpler and robustly predicts important clinical outcomes.
The most common COPD comorbidities are coronary artery calcification, emphysema and bronchiectasis. COPD patients with psychological (high anxiety and depression) and cachectic (underweight and osteoporotic) comorbidity have higher mortality and exacerbate more.
Serum eosinophil count remains an important COPD biomarker and we have greater clarity about normal eosinophil levels in COPD and the wider population.
Criteria for entry into COPD clinical trials continue to exclude many patients, in particular those at greater risk of exacerbation and death.
The effect of hyperinflation on cardiac function impacts COPD mortality and is an important target for successful lung volume reduction procedures.
Summary
National material stock (MS) accounts have been a neglected field of analysis in industrial ecology, possibly because of the difficulty in establishing such accounts. In this research, we ...propose a novel method to model national MS based on historical material flow data. This enables us to avoid the laborious data work involved with bottom‐up accounts for stocks and to arrive at plausible levels of stock accumulation for nations. We apply the method for the United States and Japan to establish a proof of concept for two very different cases of industrial development. Looking at a period of 75 years (1930–2005), we find that per capita MS has been much higher in the United States for the entire period, but that Japan has experienced much higher growth rates throughout, in line with Japan's late industrial development. By 2005, however, both Japan and the United States arrive at a very similar level of national MS of 310 to 375 tonnes per capita, respectively. This research provides new insight into the relationship between MS and flows in national economies and enables us to extend the debate about material efficiency from a narrow perspective of throughput to a broader perspective of stocks.
Abstract
Background
Peptide vaccines offer the opportunity to elicit glioma-specific T cells with tumor killing ability. Using antigens eluted from the surface of glioblastoma samples, we designed a ...phase I/II study to test safety and immunogenicity of the IMA950 multipeptide vaccine adjuvanted with poly-ICLC (polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose) in human leukocyte antigen A2+ glioma patients.
Methods
Adult patients with newly diagnosed glioblastoma (n = 16) and grade III astrocytoma (n = 3) were treated with radiochemotherapy followed by IMA950/poly-ICLC vaccination. The first 6 patients received IMA950 (9 major histocompatibility complex MHC class I and 2 MHC class II peptides) intradermally and poly-ICLC intramuscularly (i.m.). After protocol amendment, IMA950 and poly-ICLC were mixed and injected subcutaneously (n = 7) or i.m. (n = 6). Primary endpoints were safety and immunogenicity. Secondary endpoints were overall survival, progression-free survival at 6 and 9 months, and vaccine-specific peripheral cluster of differentiation (CD)4 and CD8 T-cell responses.
Results
The IMA950/poly-ICLC vaccine was safe and well tolerated. Four patients presented cerebral edema with rapid recovery. For the first 6 patients, vaccine-induced CD8 T-cell responses were restricted to a single peptide and CD4 responses were absent. After optimization of vaccine formulation, we observed multipeptide CD8 and sustained T helper 1 CD4 T-cell responses. For the entire cohort, CD8 T-cell responses to a single or multiple peptides were observed in 63.2% and 36.8% of patients, respectively. Median overall survival was 19 months for glioblastoma patients.
Conclusion
We provide, in a clinical trial, using cell surface-presented antigens, insights into optimization of vaccines generating effector T cells for glioma patients.
Trial registration
Clinicaltrials.gov NCT01920191.
Australian surveillance data document for the first time a significant decline in the incidence of juvenile-onset recurrent respiratory papillomatosis after a national quadrivalent HPV vaccination ...program.
Abstract
Background
Recurrent respiratory papillomatosis is a rare but morbid disease caused by human papillomavirus (HPV) types 6 and 11. Infection is preventable through HPV vaccination. Following an extensive quadrivalent HPV vaccination program (females 12–26 years in 2007–2009) in Australia, we established a method to monitor incidence and demographics of juvenile-onset recurrent respiratory papillomatosis (JORRP) cases.
Methods
The Australian Paediatric Surveillance Unit undertakes surveillance of rare pediatric diseases by contacting practitioners monthly. We enrolled pediatric otorhinolaryngologists and offered HPV typing. We report findings for 5 years to end 2016.
Results
The average annual incidence rate was 0.07 per 100000. The largest number of cases was reported in the first year, with decreasing annual frequency thereafter. Rates declined from 0.16 per 100000 in 2012 to 0.02 per 100000 in 2016 (P = .034). Among the 15 incident cases (60% male), no mothers were vaccinated prepregnancy, 20% had maternal history of genital warts, and 60% were first born; 13/15 were born vaginally. Genotyped cases were HPV-6 (n = 4) or HPV-11 (n = 3).
Conclusion
To our knowledge, this is the first report internationally documenting decline in JORRP incidence in children following a quadrivalent HPV vaccination program.
Immune checkpoint blockade (ICB) is currently evaluated in patients with glioblastoma (GBM), based on encouraging clinical data in other cancers, and results from studies with the ...methylcholanthrene-induced GL261 mouse glioma. In this paper, we describe a novel model faithfully recapitulating some key human GBM characteristics, including low mutational load, a factor reported as a prognostic indicator of ICB response. Consistent with this observation, SB28 is completely resistant to ICB, contrasting with treatment sensitivity of the more highly mutated GL261. Moreover, SB28 shows features of a poorly immunogenic tumor, with low MHC-I expression and modest CD8
T-cell infiltration, suggesting that it may present similar challenges for immunotherapy as human GBM. Based on these key features for immune reactivity, SB28 may represent a treatment-resistant malignancy likely to mirror responses of many human tumors. We therefore propose that SB28 is a particularly suitable model for optimization of GBM immunotherapy.
Marked heterogeneity exists among patients with sepsis, both in terms of distribution of organ dysfunction and its severity. Such heterogeneity could be explained by the presence of multiple subtypes ...of sepsis that may have important implications for treatment.
Narrative review of published literature involving endotoxin from 1970 to 2022.
In humans, endotoxemia is most consistently associated with a specific pattern of organ failure including shock, endothelial dysfunction, acute kidney injury, and hepatic dysfunction. This pattern is consistent with complement activation and uncontrolled inflammation, two features of endotoxemia. Unbiased discovery using artificial intelligence also identifies a subtype of sepsis which features these same organ failures.
Endotoxin appears to represent an important molecular phenotype of sepsis with unique clinical features and high mortality.
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