New therapeutic agents such as proteins, peptides, and nucleic acid-based agents are being developed every year, making it vital to find a non-invasive route such as nasal or pulmonary for their ...administration. However, a major concern for some of these newly developed therapeutic agents is their poor absorption. Therefore, absorption enhancers have been investigated to address this major administration problem. This paper describes the basic concepts of transmucosal administration of drugs, and in particular the use of the pulmonary or nasal routes for administration of drugs with poor absorption. Strategies for the exploitation of absorption enhancers for the improvement of pulmonary or nasal administration are discussed, including use of surfactants, cyclodextrins, protease inhibitors, and tight junction modulators, as well as application of carriers such as liposomes and nanoparticles.
Arboviruses: A Family on the Move Young, Paul R
Advances in experimental medicine and biology,
01/2018, Letnik:
1062
Journal Article
Recenzirano
Arboviruses are a diverse group of vector-borne viruses, many of whose members are the cause of significant human morbidity and mortality. Over the last 30 years, the emergence and/or resurgence of ...arboviruses have posed a considerable global health threat. The ongoing geographical expansion of the dengue viruses (DENV), along with the explosive outbreaks of West Nile virus (WNV), Chikungunya virus (CHIKV) and more recently, Zika virus (ZIKV) have all served as reminders that new epidemics may emerge at any time from this diversity. A clearer understanding of what mechanisms drive these dramatic changes in vector-host transmission cycles that result in the human population becoming significantly more exposed, will help to prepare us for the next emerging epidemic/pandemic. This Chapter seeks to provide a brief overview of the arboviruses, their mode of transmission and some of the known factors that drive their expansion.
•We review the vast array of activities reported for the enigmatic NS1 protein.•NS1 is a major player in diagnosis, viral replication, protection and pathogenesis.•NS1 is found in cell-associated ...membrane forms as well as a secreted lipoparticle.•NS1 engages with a range of complement factors to subvert the immune response.
The flavivirus nonstructural glycoprotein NS1 is an enigmatic protein whose structure and mechanistic function have remained somewhat elusive ever since it was first reported in 1970 as a viral antigen circulating in the sera of dengue-infected patients. All flavivirus NS1 genes share a high degree of homology, encoding a 352-amino-acid polypeptide that has a molecular weight of 46–55kDa, depending on its glycosylation status. NS1 exists in multiple oligomeric forms and is found in different cellular locations: a cell membrane-bound form in association with virus-induced intracellular vesicular compartments, on the cell surface and as a soluble secreted hexameric lipoparticle. Intracellular NS1 co-localizes with dsRNA and other components of the viral replication complex and plays an essential cofactor role in replication. Although this makes NS1 an ideal target for inhibitor design, the precise nature of its cofactor function has yet to be elucidated. A plethora of potential interacting partners have been identified, particularly for the secreted form of NS1, with many being implicated in immune evasion strategies. Secreted and cell-surface-associated NS1 are highly immunogenic and both the proteins themselves and the antibodies they elicit have been implicated in the seemingly contradictory roles of protection and pathogenesis in the infected host. Finally, NS1 is also an important biomarker for early diagnosis of disease. In this article, we provide an overview of these somewhat disparate areas of research, drawing together the wealth of data generated over more than 40years of study of this fascinating protein.
A connected autonomous vehicle (CAV) network can be defined as a set of connected vehicles including CAVs that operate on a specific spatial scope that may be a road network, corridor, or segment. ...The spatial scope constitutes an environment where traffic information is shared and instructions are issued for controlling the CAVs movements. Within such a spatial scope, high‐level cooperation among CAVs fostered by joint planning and control of their movements can greatly enhance the safety and mobility performance of their operations. Unfortunately, the highly combinatory and volatile nature of CAV networks due to the dynamic number of agents (vehicles) and the fast‐growing joint action space associated with multi‐agent driving tasks pose difficultly in achieving cooperative control. The problem is NP‐hard and cannot be efficiently resolved using rule‐based control techniques. Also, there is a great deal of information in the literature regarding sensing technologies and control logic in CAV operations but relatively little information on the integration of information from collaborative sensing and connectivity sources. Therefore, we present a novel deep reinforcement learning‐based algorithm that combines graphic convolution neural network with deep Q‐network to form an innovative graphic convolution Q network that serves as the information fusion module and decision processor. In this study, the spatial scope we consider for the CAV network is a multi‐lane road corridor. We demonstrate the proposed control algorithm using the application context of freeway lane‐changing at the approaches to an exit ramp. For purposes of comparison, the proposed model is evaluated vis‐à‐vis traditional rule‐based and long short‐term memory‐based fusion models. The results suggest that the proposed model is capable of aggregating information received from sensing and connectivity sources and prescribing efficient operative lane‐change decisions for multiple CAVs, in a manner that enhances safety and mobility. That way, the operational intentions of individual CAVs can be fulfilled even in partially observed and highly dynamic mixed traffic streams. The paper presents experimental evidence to demonstrate that the proposed algorithm can significantly enhance CAV operations. The proposed algorithm can be deployed at roadside units or cloud platforms or other centralized control facilities.
Infection with any of the 4 dengue virus serotypes results in a diverse range of symptoms, from mild undifferentiated fever to life-threatening hemorrhagic fever and shock. Given that dengue virus ...infection elicits such a broad range of clinical symptoms, early and accurate laboratory diagnosis is essential for appropriate patient management. Virus detection and serological conversion have been the main targets of diagnostic assessment for many years, however cross-reactivity of antibody responses among the flaviviruses has been a confounding issue in providing a differential diagnosis. Furthermore, there is no single, definitive diagnostic biomarker that is present across the entire period of patient presentation, particularly in those experiencing a secondary dengue infection. Nevertheless, the development and commercialization of point-of-care combination tests capable of detecting markers of infection present during different stages of infection (viral nonstructural protein 1 and immunoglobulin M) has greatly simplified laboratory-based dengue diagnosis. Despite these advances, significant challenges remain in the clinical management of dengue-infected patients, especially in the absence of reliable biomarkers that provide an effective prognostic indicator of severe disease progression. This review briefly summarizes some of the complexities and issues surrounding clinical dengue diagnosis and the laboratory diagnostic options currently available.
This paper presents a study of different fuzzy neural network (FNN) learning control methods for brushless dc (BLDC) motor drives. The FNN combines fuzzy logic (FL) with the learning capabilities of ...an artificial neural network. The study designs an FNN structure and defines four different training algorithms for the FNN, namely, backpropagation (BP), extended Kalman filter (EKF), genetic (GEN), and particle swarm optimization (PSO). These algorithms are examined in the simple application of pattern matching an input set to an output set and determine the strengths and weaknesses of each algorithm. Tests of each learning algorithm by a pattern matching benchmark are achieved via dSPACE DSP MATLAB/Simulink environment and allows for the capability for adaptive self-tuning of the weights and memberships of the input parameters. Thus, this adds a self-learning capability to the initial fuzzy design for operational adaptively and implements the solution on real hardware using a BLDC motor drive system. The success of the adaptive FNN-controlled BLDC motor drive system is verified by experimental results. Testing results show that the EKF method is the superior method of the four for this specific application. The BP method was also somewhat successful, nearly matching the pattern but not to the accuracy of the EKF. The GEN and PSO methods did not demonstrate success. Demonstrating the proposed self-learning FNN control on real hardware realizes the solution.
To describe the proportion of children screened by the Modified Checklist for Autism in Toddlers (M-CHAT), identify characteristics associated with screen completion, and examine associations between ...autism spectrum disorder (ASD) screening and later ASD diagnosis.
We examined data from children attending 18- and 24-month visits between 2013 and 2016 from 20 clinics within a health care system for evidence of screening with the M-CHAT and subsequent coding of ASD diagnosis at age >4.75 years. We interviewed providers for information about usual methods of M-CHAT scoring and ASD referral.
Of 36 233 toddlers, 73% were screened and 1.4% were later diagnosed with ASD. Hispanic children were less likely to be screened (adjusted prevalence ratio APR: 0.95, 95% confidence interval CI: 0.92-0.98), and family physicians were less likely to screen (APR: 0.12, 95% CI: 0.09-0.15). Compared with unscreened children, screen-positive children were more likely to be diagnosed with ASD (APR: 10.3, 95% CI: 7.6-14.1) and were diagnosed younger (38.5 vs 48.5 months,
< .001). The M-CHAT's sensitivity for ASD diagnosis was 33.1%, and the positive predictive value was 17.8%. Providers routinely omitted the M-CHAT follow-up interview and had uneven referral patterns.
A majority of children were screened for ASD, but disparities exist among those screened. Benefits for screen-positive children are improved detection and younger age of diagnosis. Performance of the M-CHAT can be improved in real-world health care settings by administering screens with fidelity and facilitating timely ASD evaluations for screen-positive children. Providers should continue to monitor for signs of ASD in screen-negative children.
Dangers of hyperoxia Singer, Mervyn; Young, Paul J; Laffey, John G ...
Critical care (London, England),
12/2021, Letnik:
25, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Oxygen (O
) toxicity remains a concern, particularly to the lung. This is mainly related to excessive production of reactive oxygen species (ROS). Supplemental O
, i.e. inspiratory O
concentrations ...(F
O
) > 0.21 may cause hyperoxaemia (i.e. arterial (a) PO
> 100 mmHg) and, subsequently, hyperoxia (increased tissue O
concentration), thereby enhancing ROS formation. Here, we review the pathophysiology of O
toxicity and the potential harms of supplemental O
in various ICU conditions. The current evidence base suggests that PaO
> 300 mmHg (40 kPa) should be avoided, but it remains uncertain whether there is an "optimal level" which may vary for given clinical conditions. Since even moderately supra-physiological PaO
may be associated with deleterious side effects, it seems advisable at present to titrate O
to maintain PaO
within the normal range, avoiding both hypoxaemia and excess hyperoxaemia.
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