922017 research outputs found
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Development and external validation of prediction models for adverse health outcomes in rheumatoid arthritis: a multinational real-world cohort analysis
No full textBackgroundIdentification of rheumatoid arthritis (RA) patients at high risk of adverse health outcomes remains a major challenge. We aimed to develop and validate prediction models for a variety of adverse health outcomes in RA patients initiating first-line methotrexate (MTX) monotherapy. MethodsData from 15 claims and electronic health record databases across 9 countries were used. Models were developed and internally validated on Optum® De-identified Clinformatics® Data Mart Database using L1-regularized logistic regression to estimate the risk of adverse health outcomes within 3 months (leukopenia, pancytopenia, infection), 2 years (myocardial infarction (MI) and stroke), and 5 years (cancers [colorectal, breast, uterine]) after treatment initiation. Candidate predictors included demographic variables and past medical history. Models were externally validated on all other databases. Performance was assessed using the area under the receiver operator characteristic curve (AUC) and calibration plots. FindingsModels were developed and internally validated on 21,547 RA patients and externally validated on 131,928 RA patients. Models for serious infection (AUC: internal 0.74, external ranging from 0.62 to 0.83), MI (AUC: internal 0.76, external ranging from 0.56 to 0.82), and stroke (AUC: internal 0.77, external ranging from 0.63 to 0.95), showed good discrimination and adequate calibration. Models for the other outcomes showed modest internal discrimination (AUC < 0.65) and were not externally validated.InterpretationWe developed and validated prediction models for a variety of adverse health outcomes in RA patients initiating first-line MTX monotherapy. Final models for serious infection, MI, and stroke demonstrated good performance across multiple databases and can be studied for clinical use.<br/
Formation-containment tracking and scaling for multiple quadcopters with an application to choke-point navigation
No full textThis paper investigates the cooperative control problem of choke-point navigation for multiple quadcopters when only their subgroup is equipped with obstacle detecting sensors. We define a quadcopter as a leader if it is equipped with an obstacle detecting sensor; otherwise, it is a follower. In addition, we introduce a virtual leader agent to create the group motion. First, we apply the leader-follower approach and propose a formation-containment tracking controller for multiple quadcopters to track the time-varying velocity of the virtual leader agent. At the same time, the leader quadcopters form the prescribed formation while the follower quadcopters converge inside a safe region, which is the convex hull spanned by those leaders. Then, we introduce a scaling vector into the displacement-based formation constraints. When the leader quadcopters identify the choke-point via their obstacle detecting sensors, they update the scaling variable to adjust the size of the formation (i.e. the safe region) and guide all quadcopters to safely pass through the choke-point. The proposed cooperative controllers are distributed because each quadcopter’s control command only relies on the information states from its neighbours. Finally, two autonomous flight experiments, including formation-containment tracking and choke-point navigation, are provided to validate the effectiveness of the proposed cooperative control laws
Position Paper: Towards a Hybrid Approach to Protect Against Memory Safety Vulnerabilities
No full textMemory corruption bugs continue to plague lowlevel systems software, generally written in unsafe programming languages. In order to detect and protect against such exploits, many pre- and post-deployment techniques exist. In this position paper, we propose and motivate the need for a hybrid approach for the protection against memory safety vulnerabilities, combining techniques that can identify the presence (and absence) of vulnerabilities pre-deployment with those that can detect and mitigate such vulnerabilities post-deployment. Our proposed hybrid approach involves three layers: hardware runtime protection provided by capability hardware, software runtime protection provided by compiler instrumentation, and static analysis provided by bounded model checking and symbolic execution. The key aspect of the proposed hybrid approach is that the protection offered is greater than the sum of its parts – the expense of postdeployment runtime checks is potentially reduced via information obtained during pre-deployment analysis. During pre-deployment analysis, static checking can be guided by runtime information
Educational psychologists’ use of cognitive behavioural therapy in professional practice
No full textAim: There is increasing recognition of the centrality schools have in supporting children and young people’s mental health and wellbeing, and the role of educational psychologists (EPs) in supporting this. Cognitive behavioural therapy (CBT) is a frequently-used, evidence-based approach for supporting a range of outcomes. The purpose of this study is to explore how EPs are operationalising CBT in their practice, and which therapeutic competencies are demonstrated. Method: Semi-structured interviews were completed with a self-selecting sample of eight EPs reporting to be knowledgeable about CBT and to regularly use it in their practice. Transcribed data were analysed using inductive and deductive thematic analysis. Findings: Key themes related to CBT in applied practice, the EP role, drawing on other psychological approaches, ethical practice, external influences and having a holistic view of the child. EPs were using CBT across a continuum of formality in therapeutic work and multi-faceted casework. A range of CBT competencies was demonstrated in practice with children and young people, and adults. Limitations: As an exploratory research study the sample size was very small. The self-selecting sample does not claim to be representative of the wider EP population. The extent to which findings enable an understanding of the effectiveness of CBT within wider EP practice is extremely limited. Conclusions: The flexibility of CBT as a therapeutic modality gives insight into its potential wider contribution across EP practice. Potential implications for EP professional training and practice are considered
Assessing Immunogenicity of Biologic Drugs in Inflammatory Joint Diseases: Progress Towards Personalized Medicine
No full textBiologic drugs have greatly improved treatment outcomes of inflammatory joint diseases (IJDs), but a substantial proportion of patients either do not respond to treatment or lose response over time. Drug immunogenicity, manifested as formation of anti-drug antibodies (ADAb), constitute a significant clinical problem. ADAb influence the pharmacokinetics of the drug, are associated with reduced clinical efficacy, and increased risk of adverse events such as infusion reactions. The prevalence of ADAb differ among drugs and diseases, and detection of ADAb also depends on assay format. Most data exist for the tumor necrosis factor alpha inhibitors infliximab and adalimumab, with a frequency of ADAb ranging from 10-60% across studies. Measurement of ADAb and serum drug levels, therapeutic drug monitoring (TDM), has been suggested as a strategy to optimize therapy with biologic drugs. Although the recent randomized clinical Norwegian Drug Monitoring (NOR-DRUM) trials show promise towards a personalized medicine prescribing approach by TDM, several challenges remain. A plethora of assay formats, with widely differing properties, is currently used for measuring ADAb. Comparing results between different assays and laboratories is difficult, which complicates development of cut-offs necessary for guidelines and implementation of ADAb measurements in clinical practice. With the possible exception of infliximab, limited data on clinical relevance and cost-effectiveness exist to support TDM as a routine clinical strategy to monitor biologic drugs in IJDs. The aim of this review is to provide an overview of the characteristics and prevalence of ADAb, predisposing factors to ADAb formation, commonly used assessment methods, clinical consequences of ADAb, and the potential implications of ADAb assessments for everyday treatment of IJDs
Mechanism of melatonin metabolism by CYP1A1. What determines the bifurcation pathways of hydroxylation versus deformylation?
No full textMelatonin, a widely consumed cosmetic active ingredient, has a variety of uses as skin protector through antioxidant and anti-inflammatory functions as well as giving the body UV-induced defenses and immune system support. In the body, melatonin is synthesized from a tryptophan amino acid in a cascade of reactions, but as melatonin is toxic at high concentrations it is metabolized in the human skin by the cytochrome P450 enzymes. The P450s are diverse heme based monooxygenases that catalyze oxygen atom transfer processes that trigger metabolism and detoxification in the body. In the cata-lytic cycle of the P450s, a short-lived high-valent iron(IV)-oxo heme cation radical is formed that has been proposed to be the active oxidant. How and why it activates melatonin in the human body and what the origin of the product distributions is, are unknown. This encouraged us to do a detailed computational study on a typical human P450 isozyme, namely CYP1A1. We initially did a series of molecular dynamics simulations with substrate docked into several orientations. These simulations reveal several stable substrate-bound orientations in the active site, which may lead to differences in substrate activation channels. Using tunneling analysis on the full protein structures, we show that two of the four binding conformations lead to open substrate binding pockets. As a result, in these open pockets the substrate is not tightly bound and can escape back into the solution. In the closed conformations, by contrast, the substrate is mainly oriented with the methoxy group pointing toward the heme, although under a different angle. We then created large quantum cluster models of the enzyme and focused on the chemical reaction mechanisms for melatonin activation leading to competitive O-demethylation and C6-aromatic hydroxylation pathways. The calculations show that active site positioning determines the product distributions, but the bond that is activated is not necessarily closest to the heme in the enzyme-substrate complex. As such, the docking and molecular dynamics positioning of substrate versus oxidant gives misleading predictions on product distributions. In particular, in QM cluster model I we observe that through a tight hydrogen bonding network a preferential 6-hydroxylation of melatonin is obtained. However, O-demethylation becomes possible in alternative substrate-binding orientations that have the C6-aro-matic ring position shielded. Finally, we investigated enzymatic and non-enzymatic O-demethylation processes and show that the hydrogen bonding network in the substrate binding pocket can assist and perform this step prior to product release from the enzyme
Translating CPS with Shared-Variable Concurrency in SpaceEx
No full textCyber-physical systems (CPS), combining continuous physical behavior and discrete control behavior, have been widely utilized in recent years. However, the traditional modeling languages used to specify discrete systems are no longer applicable to CPS, since CPS subsume the combination of the cyber and the physical. To address this, a modeling language for CPS based on shared variables is proposed. In this paper, we present an implementation of this language in SpaceEx. Thus, a bridge between our language and hybrid automata is established.<br/
Educational psychologists’ use of cognitive behavioural therapy in professional practice
No full textAim: There is increasing recognition of the centrality schools have in supporting children and young people’s mental health and wellbeing, and the role of educational psychologists (EPs) in supporting this. Cognitive behavioural therapy (CBT) is a frequently-used, evidence-based approach for supporting a range of outcomes. The purpose of this study is to explore how EPs are operationalising CBT in their practice, and which therapeutic competencies are demonstrated. Method: Semi-structured interviews were completed with a self-selecting sample of eight EPs reporting to be knowledgeable about CBT and to regularly use it in their practice. Transcribed data were analysed using inductive and deductive thematic analysis. Findings: Key themes related to CBT in applied practice, the EP role, drawing on other psychological approaches, ethical practice, external influences and having a holistic view of the child. EPs were using CBT across a continuum of formality in therapeutic work and multi-faceted casework. A range of CBT competencies was demonstrated in practice with children and young people, and adults. Limitations: As an exploratory research study the sample size was very small. The self-selecting sample does not claim to be representative of the wider EP population. The extent to which findings enable an understanding of the effectiveness of CBT within wider EP practice is extremely limited. Conclusions: The flexibility of CBT as a therapeutic modality gives insight into its potential wider contribution across EP practice. Potential implications for EP professional training and practice are considered
Virtual wards: A rapid evidence synthesis and implications for the care of older people
No full textBackgroundVirtual wards are being rapidly developed within the National Health Service in the UK, and frailty is one of the first clinical pathways. Virtual wards for older people and existing hospital at home services are closely related.MethodsIn March 2022 we searched Medline, CINAHL, the Cochrane Database of Systematic Reviews and medRxiv for evidence syntheses which addressed clinical-effectiveness, cost-effectiveness, barriers and facilitators, or staff, patient or carer experience for virtual wards, hospital at home or remote monitoring alternatives to inpatient care.ResultsWe included 28 evidence syntheses mostly relating to hospital at home. There is low to moderate certainty evidence that clinical outcomes including mortality (example pooled RR 0.77, 95% CI 0.60 to 0.99) were probably equivalent or better for hospital at home. Subsequent residential care admissions are probably reduced (example pooled RR 0.35, 95% CI 0.22 to 0.57). Cost-effectiveness evidence demonstrated methodological issues which mean the results are uncertain. Evidence is lacking on cost implications for patients and carers. Barriers and facilitators operate at multiple levels (organisational, clinical and patient). Patient satisfaction may be improved by hospital at home relative to inpatient care. Evidence for carer experience is limited.ConclusionsThere is substantial evidence for the clinical effectiveness of hospital at home but less evidence for virtual wards. Guidance for virtual wards is lacking on key aspects including team characteristics, outcome selection and data protection. We recommend that research and evaluation is integrated into development of virtual ward models. The issue of carer strain is particularly relevant