A model-based cost-utility analysis of an automated notification system for deteriorating patients on general wards.

BACKGROUND: Delayed response to clinical deterioration of hospital inpatients is common. Deployment of an electronic automated advisory vital signs monitoring and notification system to signal clinical deterioration is associated with significant improvements in clinical outcomes but there is no evidence on the cost-effectiveness compared with routine monitoring, in the National Health Service (NHS) in the United Kingdom (UK). METHODS: A decision analytic model was developed to estimate the cost-effectiveness of an electronic automated advisory notification system versus standard care, in adults admitted to a district general hospital. Analyses considered: (1) the cost-effectiveness of the technology based on secondary analysis of patient level data of 3787 inpatients in a before-and-after study; and (2) the cost-utility (cost per quality-adjusted life-year (QALY)) over a lifetime horizon, extrapolated using published data. Analysis was conducted from the perspective of the NHS. Uncertainty in the model was assessed using a range of sensitivity analyses. RESULTS: The study population had a mean age of 68 years, 48% male, with a median inpatient stay of 6 days. Expected life expectancy at discharge was assumed to be 17.74 years. (1) Cost-effectiveness analysis: The automated notification system was more effective (-0.027 reduction in mean events per patient) and provided a cost saving of -£12.17 (-182.07 to 154.80) per patient admission. (2) Cost-utility analysis: Over a lifetime horizon the automated notification system was dominant, demonstrating a positive incremental QALY gain (0.0287 QALYs, equivalent to ~10 days of perfect health) and a cost saving of £55.35. At a threshold of £20,000 per QALY, the probability of automated monitoring being cost-effective in the NHS was 81%. Increased use of cableless sensors may reduce cost-savings, however, the intervention remains cost-effective at 100% usage (ICER: £3,107/QALY). Stratified cost-effectiveness analysis by age, National Early Warning Score (NEWS) on admission, and primary diagnosis indicated the automated notification system was cost-effective for most strategies and that use representative of the patient population studied was the most cost-saving strategy. CONCLUSION: Automated notification system for adult patients admitted to general wards appears to be a cost-effective use in the NHS; adopting this technology could be good use of scarce resources with significance for patient safety.

Laser desorption rapid evaporative ionization mass spectrometry (LD-REIMS) demonstrates a direct impact of hypochlorous acid stress on PQS-mediated quorum sensing in Pseudomonas aeruginosa.

To establish infections in human hosts, Pseudomonas aeruginosa must overcome innate immune-generated oxidative stress, such as the hypochlorous acid (HOCl) produced by neutrophils. We set out to find specific biomarkers of oxidative stress through the development of a protocol for the metabolic profiling of P. aeruginosa cultures grown in the presence of different oxidants using a novel ionization technique for mass spectrometry, laser desorption rapid evaporative ionization mass spectrometry (LD-REIMS). We demonstrated the ability of LD-REIMS to classify samples as untreated or treated with a specific oxidant with 100% accuracy and identified a panel of 54 metabolites with significantly altered concentrations after exposure to one or more of the oxidants. Key metabolic changes were conserved in P. aeruginosa clinical strains isolated from patients with cystic fibrosis lung infections. These data demonstrated that HOCl stress impacted the Pseudomonas quinolone signal (PQS) quorum sensing system. Ten 2-alkyl-4-quinolones (AHQs) associated with the PQS system were significantly lower in concentration in HOCl-stressed P. aeruginosa cultures, including 2-heptyl-3-hydroxy-4(1H)-quinolone (PQS), the most active signal molecule of the PQS system. The PQS system regulates the production of virulence factors, including pyocyanin and elastase, and their levels were markedly affected by HOCl stress. No pyocyanin was detectable and elastase concentrations were reduced by more than 75% in cultures grown with sub-lethal concentrations of HOCl, suggesting that this neutrophil-derived oxidant may disrupt the ability of P. aeruginosa to establish infections through interference with production of PQS-associated virulence factors. IMPORTANCE: This work demonstrates that a high-throughput ambient ionization mass spectrometry method can be used successfully to study a bacterial stress response. Its application to the opportunistic pathogen Pseudomonas aeruginosa led to the identification of specific oxidative stress biomarkers, and demonstrated that hypochlorous acid, an oxidant specifically produced by human neutrophils during infection, affects quorum sensing and reduces production of the virulence factors pyocyanin and elastase. No pyocyanin was detectable and elastase levels were reduced by more than 75% in bacteria grown in the presence of hypochlorous acid. This approach has the potential to be widely applicable to the characterization of the stress responses of bacteria.

Profiles of vulnerability for suicide and self-harm in UK prisoners: Neurodisability, mood disturbance, substance use, and bullying.

Screening for vulnerability factors associated with historic suicidality and self-harm on entry to prison is critical to help prisons understand how to allocate extremely limited mental health resources. It has been established that having previous suicide attempts increases odds of future suicidality and self-harm in prison. We utilised administrative screening data from 665 adult male prisoners on entry to a category B prison in Wales, UK, collected using the Do-IT Profiler. This sample represents 16% of all prisoners who entered that prison during a 26-month period. 12% of prisoners reported a history of attempted suicide, 11% reported historic self-harm, and 8% reported a history of both. Historic traumatic brain injury and substance use problems were associated with a 3.3- and 1.9- times increased odds of a historic suicide attempt, respectively, but no significant increased risk of historic self-harm (95% CI: 1.51-6.60 and 1.02-3.50). However, those who were bullied at school had 2.7 times increased odds of reporting a history of self-harm (95% CI: 1.63-6.09). The most salient risk factors associated with both historic suicide and self-harm were higher levels of functional neurodisability (odds ratio 0.6 for a 1 standard deviation change in score, 95% CI: 0.35-0.75), and mood disturbance (odds ratio 2.1 for a 1 standard deviation change in score, 95% CI: 1.26-3.56). Therefore, it could be beneficial for prisons to screen for broader profiles of needs, to better understand how to provide appropriate services to prisoners vulnerable to suicide and self-harm. Multidisciplinary care pathways for prisoner mental health interventions are important, to account for complex multimorbidity. Adaptations may be needed for mental health interventions to be appropriate for, for example, a prisoner with a brain injury. Understanding this broad profile of vulnerability could also contribute to more compassionate responses to suicide and self-harm from prison staff.

Inline dynamometry provides reliable measurements of quadriceps strength in healthy and ACL-reconstructed individuals and is a valid substitute for isometric electromechanical dynamometry following ACL reconstruction.

BACKGROUND: Quadriceps strength testing is recommended to guide rehabilitation and mitigate the risk of second injury following anterior cruciate ligament (ACL) reconstruction. Hand-held dynamometry is a practical alternative to electromechanical dynamometry but demonstrates insufficient reliability and criterion validity in healthy and ACL-reconstructed participants respectively. The purpose of this study is to investigate the reliability and concurrent validity of inline dynamometry for measuring quadriceps strength. The hypotheses are that intra-class correlation coefficient (ICC) values will be >0.90 for reliability and concurrent validity. METHODS: This was a cross sectional study using a within-participant, repeated measures design. Isometric quadriceps testing was performed at 60° knee flexion in 50 healthy and 52 ACL-reconstructed participants. Interrater reliability, intrarater reliability, and concurrent validity of inline dynamometry was investigated through calculation of ICCs, Bland-Altman analysis, linear regression, standard error of measurement (SEM) and minimal detectable change (MDC). RESULTS: The lower bounds of the 95% confidence intervals were >0.90 for all reliability and validity ICCs in healthy and ACL-reconstructed participants, except for intrarater reliability in healthy participants using absolute scores (ICC = 0.936 [95% CI 0.890-0.963]). In ACL-reconstructed participants, Bland-Altman bias was 0.01 Nm/kg for absolute and average scores, limits of agreement were -11.74% to 12.59% for absolute scores, the SEM was 0.13Nm/kg (95% CI 0.10-0.17) and the MDC was 0.36Nm/kg (95% CI 0.28 - 0.47). CONCLUSION: Inline dynamometry is a reliable and economical alternative to electromechanical dynamometry for the assessment of quadriceps strength following ACL-reconstruction. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT05109871).

Undergraduate perceptions on the educational value of a novel ENT e-Learning platform.

ENT is a consistently under-represented specialty in medical school curricula. With social distancing measures limiting face-to-face (FtF) teaching and clinical opportunities, we created an e-Learning platform to consolidate and improve knowledge on common ENT emergencies. Following invitation to medical students undergoing their rotation in ENT at University Hospital Wales (UHW) Cardiff, five focus groups were shown an e-Learning module and interviewed between June and July 2021. 13 medical students participated in total (9 female, 4 male, median age 22 years). These structured interviews were recorded and transcribed. Transcripts were analysed using the qualitative data analysis software NVivo (QSR International, UK). The modules were found to be concise, clinically relevant and beneficial to student confidence in recognising and managing ENT emergencies. While e-Learning will likely never replace face-to-face learning, it was perceived to be a beneficial resource both academically and practically- especially in the context of limited clinical opportunities.

Analysis of applying a patient safety taxonomy to patient and clinician-reported incident reports during the COVID-19 pandemic: a mixed methods study.

BACKGROUND: The COVID-19 pandemic resulted in major disruption to healthcare delivery worldwide causing medical services to adapt their standard practices. Learning how these adaptations result in unintended patient harm is essential to mitigate against future incidents. Incident reporting and learning system data can be used to identify areas to improve patient safety. A classification system is required to make sense of such data to identify learning and priorities for further in-depth investigation. The Patient Safety (PISA) classification system was created for this purpose, but it is not known if classification systems are sufficient to capture novel safety concepts arising from crises like the pandemic. We aimed to review the application of the PISA classification system during the COVID-19 pandemic to appraise whether modifications were required to maintain its meaningful use for the pandemic context. METHODS: We conducted a mixed-methods study integrating two phases in an exploratory, sequential design. This included a comparative secondary analysis of patient safety incident reports from two studies conducted during the first wave of the pandemic, where we coded patient-reported incidents from the UK and clinician-reported incidents from France. The findings were presented to a focus group of experts in classification systems and patient safety, and a thematic analysis was conducted on the resultant transcript. RESULTS: We identified five key themes derived from the data analysis and expert group discussion. These included capitalising on the unique perspective of safety concerns from different groups, that existing frameworks do identify priority areas to investigate further, the objectives of a study shape the data interpretation, the pandemic spotlighted long-standing patient concerns, and the time period in which data are collected offers valuable context to aid explanation. The group consensus was that no COVID-19-specific codes were warranted, and the PISA classification system was fit for purpose. CONCLUSIONS: We have scrutinised the meaningful use of the PISA classification system's application during a period of systemic healthcare constraint, the COVID-19 pandemic. Despite these constraints, we found the framework can be successfully applied to incident reports to enable deductive analysis, identify areas for further enquiry and thus support organisational learning. No new or amended codes were warranted. Organisations and investigators can use our findings when reviewing their own classification systems.

Design, Synthesis, and Application of Fluorescent Ligands Targeting the Intracellular Allosteric Binding Site of the CXC Chemokine Receptor 2.

The inhibition of CXC chemokine receptor 2 (CXCR2), a key inflammatory mediator, is a potential strategy in the treatment of several pulmonary diseases and cancers. The complexity of endogenous chemokine interaction with the orthosteric binding site has led to the development of CXCR2 negative allosteric modulators (NAMs) targeting an intracellular pocket near the G protein binding site. Our understanding of NAM binding and mode of action has been limited by the availability of suitable tracer ligands for competition studies, allowing direct ligand binding measurements. Here, we report the rational design, synthesis, and pharmacological evaluation of a series of fluorescent NAMs, based on navarixin (2), which display high affinity and preferential binding for CXCR2 over CXCR1. We demonstrate their application in fluorescence imaging and NanoBRET binding assays, in whole cells or membranes, capable of kinetic and equilibrium analysis of NAM binding, providing a platform to screen for alternative chemophores targeting these receptors.

Discovery of new imidazotetrazinones with potential to overcome tumor resistance.

We describe the design, organic synthesis, and characterization, including X-ray crystallography, of a series of novel analogues of the clinically used antitumor agent temozolomide, together with their in vitro biological evaluation. The work has resulted in the discovery of a new series of anticancer imidazotetrazines that offer the potential to overcome the resistance mounted by tumors against temozolomide. The rationally designed compounds that incorporate a propargyl alkylating moiety and a thiazole ring as isosteric replacement for a carboxamide, are readily synthesized (gram-scale), exhibit defined solid-state structures, and enhanced growth-inhibitory activity against human tumor cell lines, including MGMT-expressing and MMR-deficient lines, molecular features that confer tumor resistance. The cell proliferation data were confirmed by clonogenic cell survival assays, and DNA flow cytometry analysis was undertaken to determine the effects of new analogues on cell cycle progression. Detailed 1H NMR spectroscopic studies showed that the new agents are stable in solution, and confirmed their mechanism of action. The propargyl and thiazole substituents significantly improve potency and physicochemical, drug metabolism and permeability properties, suggesting that the thiazole 13 should be prioritized for further preclinical evaluation.

Understanding the Molecular Conformation and Viscoelasticity of Low Sol-Gel Transition Temperature Gelatin Methacryloyl Suspensions.

For biomedical applications, gelatin is usually modified with methacryloyl groups to obtain gelatin methacryloyl (GelMA), which can be crosslinked by a radical reaction induced by low wavelength light to form mechanically stable hydrogels. The potential of GelMA hydrogels for tissue engineering has been well established, however, one of the main disadvantages of mammalian-origin gelatins is that their sol-gel transitions are close to room temperature, resulting in significant variations in viscosity that can be a problem for biofabrication applications. For these applications, cold-water fish-derived gelatins, such as salmon gelatin, are a good alternative due to their lower viscosity, viscoelastic and mechanical properties, as well as lower sol-gel transition temperatures, when compared with mammalian gelatins. However, information regarding GelMA (with special focus on salmon GelMA as a model for cold-water species) molecular conformation and the effect of pH prior to crosslinking, which is key for fabrication purposes since it will determine final hydrogel's structure, remains scarce. The aim of this work is to characterize salmon gelatin (SGel) and salmon methacryloyl gelatin (SGelMA) molecular configuration at two different acidic pHs (3.6 and 4.8) and to compare them to commercial porcine gelatin (PGel) and methacryloyl porcine gelatin (PGelMA), usually used for biomedical applications. Specifically, we evaluated gelatin and GelMA samples' molecular weight, isoelectric point (IEP), their molecular configuration by circular dichroism (CD), and determined their rheological and thermophysical properties. Results showed that functionalization affected gelatin molecular weight and IEP. Additionally, functionalization and pH affected gelatin molecular structure and rheological and thermal properties. Interestingly, the SGel and SGelMA molecular structure was more sensitive to pH changes, showing differences in gelation temperatures and triple helix formation than PGelMA. This work suggests that SGelMA presents high tunability as a biomaterial for biofabrication, highlighting the importance of a proper GelMA molecular configuration characterization prior to hydrogel fabrication.

Effect of sweeteners and carbonation on aroma partitioning and release in beverage systems.

The effect of monosaccharides (glucose, fructose and galactose) and disaccharides (sucrose and lactose) at 10, 20 and 30 % w/v on the in-vitro aroma partitioning of C4 - C10 aldehydes and ethyl esters, as well as limonene (concentration of aroma compounds at 1 µg mL-1), was studied using atmospheric pressure chemical ionisation-mass spectrometry. An increase in sugar concentration from 0 to 30 % w/v resulted in a significant increase in partitioning under static headspace conditions for the majority of the compounds (p < 0.05), an effect generally not observed when 10 % w/v sucrose was substituted with low-calorie sweeteners (p > 0.05). The complexity of the system was increased to model a soft drink design - comprising water, sucrose (10, 20 and 30 % w/v), acid (0.15 % w/v), carbonation (∼7.2 g/L CO2) and aroma compounds representative of an apple style flavouring, namely ethyl butanoate and hexanal (10 µg mL-1 each). Although the addition of sucrose had no significant in-vivo effect, carbonation significantly decreased breath-by-breath (in-vivo) aroma delivery (p < 0.05). To understand the physical mechanisms behind aroma release from the beverage matrix, the effect of sucrose on the kinetics of the matrix components was explored. An increase in sucrose concentration from 0 to 30 % w/v resulted in a significant decrease in water activity (p < 0.05), which accounted for the significantly slower rate of self-diffusion of aroma compounds (p < 0.05), measured using diffusion-ordered spectroscopy-nuclear magnetic resonance spectroscopy. No significant effect of sucrose on carbon dioxide volume flux was found (p > 0.05).

Relative Abundance of Lipid Metabolites in Spermatozoa across Three Compartments.

Male fertility, as manifest by the quantity and progressive motility of spermatozoa, is negatively impacted by obesity, dyslipidaemia and metabolic disease. However, the relative distribution of lipids in spermatozoa and the two compartments which supply lipids for spermatogenesis (seminal fluid and blood serum) has not been studied. We hypothesised that altered availability of lipids in blood serum and seminal fluid may affect the lipid composition and progressive motility of sperm. 60 men of age 35 years (median (range 20-45) and BMI 30.4 kg/m2 (24-36.5) under preliminary investigation for subfertility were recruited at an NHS clinic. Men provided samples of serum and semen, subject to strict acceptance criteria, for analysis of spermatozoa count and motility. Blood serum (n = 60), spermatozoa (n = 26) and seminal fluid (n = 60) were frozen for batch lipidomics analysis. Spermatozoa and seminal fluid had comparable lipid composition but showed marked differences with the serum lipidome. Spermatozoa demonstrated high abundance of ceramides, very-long-chain fatty acids (C20-22), and certain phospholipids (sphingomyelins, plasmalogens, phosphatidylethanolamines) with low abundance of phosphatidylcholines, cholesterol and triglycerides. Men with spermatozoa of low progressive motility had evidence of fewer concentration gradients for many lipid species between blood serum and spermatozoa compartments. Spermatozoa are abundant in multiple lipid species which are likely to contribute to key cellular functions. Lipid metabolism shows reduced regulation between compartments in men with spermatozoa with reduced progressive motility.

Paternal nutritional programming of lipid metabolism is propagated through sperm and seminal plasma.

BACKGROUND: The paternal diet affects lipid metabolism in offspring for at least two generations through nutritional programming. However, we do not know how this is propagated to the offspring. OBJECTIVES: We tested the hypothesis that the changes in lipid metabolism that are driven by paternal diet are propagated through spermatozoa and not seminal plasma. METHODS: We applied an updated, purpose-built computational network analysis tool to characterise control of lipid metabolism systemically (Lipid Traffic Analysis v2.3) on a known mouse model of paternal nutritional programming. RESULTS: The analysis showed that the two possible routes for programming effects, the sperm (genes) and seminal plasma (influence on the uterine environment), both have a distinct effect on the offspring's lipid metabolism. Further, the programming effects in offspring suggest that changes in lipid distribution are more important than alterations in lipid biosynthesis. CONCLUSIONS: These results show how the uterine environment and genes both affect lipid metabolism in offspring, enhancing our understanding of the link between parental diet and metabolism in offspring.

Which human factors design issues are influencing system performance in out-of-hours community palliative care? Integration of realist approaches with an established systems analysis framework to develop mid-range programme theory.

OBJECTIVE: To develop mid-range programme theory from perceptions and experiences of out-of-hours community palliative care, accounting for human factors design issues that might be influencing system performance for achieving desirable outcomes through quality improvement. SETTING: Community providers and users of out-of-hours palliative care. PARTICIPANTS: 17 stakeholders participated in a workshop event. DESIGN: In the UK, around 30% of people receiving palliative care have contact with out-of-hours services. Interactions between emotions, cognition, tasks, technology and behaviours must be considered to improve safety. After sharing experiences, participants were presented with analyses of 1072 National Reporting and Learning System incident reports. Discussion was orientated to consider priorities for change. Discussions were audio-recorded and transcribed verbatim by the study team. Event artefacts, for example, sticky notes, flip chart lists and participant notes, were retained for analysis. Two researchers independently identified context-mechanism-outcome configurations using realist approaches before studying the inter-relation of configurations to build a mid-range theory. This was critically appraised using an established human factors framework called Systems Engineering Initiative for Patient Safety (SEIPS). RESULTS: Complex interacting configurations explain relational human-mediated outcomes where cycles of thought and behaviour are refined and replicated according to prior experiences. Five such configurations were identified: (1) prioritisation; (2) emotional labour; (3) complicated/complex systems; (4a) system inadequacies and (4b) differential attention and weighing of risks by organisations; (5) learning. Underpinning all these configurations was a sixth: (6a) trust and access to expertise; and (6b) isolation at night. By developing a mid-range programme theory, we have created a framework with international relevance for guiding quality improvement work in similar modern health systems. CONCLUSIONS: Meta-cognition, emotional intelligence, and informal learning will either overcome system limitations or overwhelm system safeguards. Integration of human-centred co-design principles and informal learning theory into quality improvement may improve results.

Site-Selective Installation of Nϵ -Modified Sidechains into Peptide and Protein Scaffolds via Visible-Light-Mediated Desulfurative C-C Bond Formation.

Post-translational modifications (PTMs) enhance the repertoire of protein function and mediate or influence the activity of many cellular processes. The preparation of site-specifically and homogeneously modified proteins, to apply as tools to understand the biological role of PTMs, is a challenging task. Herein, we describe a visible-light-mediated desulfurative C(sp3 )-C(sp3 ) bond forming reaction that enables the site-selective installation of Nϵ -modified sidechains into peptides and proteins of interest. Rapid, operationally simple, and tolerant to ambient atmosphere, we demonstrate the installation of a range of lysine (Lys) PTMs into model peptide systems and showcase the potential of this technology by site-selectively installing an Nϵ Ac sidechain into recombinantly expressed ubiquitin (Ub).

An ALS-associated variant of the autophagy receptor SQSTM1/p62 reprograms binding selectivity toward the autophagy-related hATG8 proteins.

Recognition of human autophagy-related 8 (hATG8) proteins by autophagy receptors represents a critical step within this cellular quality control system. Autophagy impairment is known to be a pathogenic mechanism in the motor neuron disorder amyotrophic lateral sclerosis (ALS). Overlapping but specific roles of hATG8 proteins belonging to the LC3 and GABARAP subfamilies are incompletely understood, and binding selectivity is typically overlooked. We previously showed that an ALS-associated variant of the SQSTM1/p62 (p62) autophagy receptor bearing an L341V mutation within its ATG8-interacting motif (AIM) impairs recognition of LC3B in vitro, yielding an autophagy-deficient phenotype. Improvements in understanding of hATG8 recognition by AIMs now distinguish LC3-interaction and GABARAP-interaction motifs and predict the effects of L341V substitution may extend beyond loss of function to biasing AIM binding preference. Through biophysical analyses, we confirm impaired binding of the L341V-AIM mutant to LC3A, LC3B, GABARAP, and GABARAPL1. In contrast, p62 AIM interactions with LC3C and GABARAPL2 are unaffected by this mutation. Isothermal titration calorimetry and NMR investigations provided insights into the entropy-driven GABARAPL2/p62 interaction and how the L341V mutation may be tolerated. Competition binding demonstrated reduced association of the L341V-AIM with one hATG8 manifests as a relative increase in association with alternate hATG8s, indicating effective reprogramming of hATG8 selectivity. These data highlight how a single AIM peptide might compete for binding with different hATG8s and suggest that the L341V-AIM mutation may be neomorphic, representative of a disease mechanism that likely extends into other human disorders.

A pipeline for making 31P NMR accessible for small- and large-scale lipidomics studies.

Detailed molecular analysis is of increasing importance in research into the regulation of biochemical pathways, organismal growth and disease. Lipidomics in particular is increasingly sought after as it provides insight into molecular species involved in energy storage, signalling and fundamental cellular structures. This has led to the use of a range of tools and techniques to acquire lipidomics data. 31P NMR for lipidomics offers well-resolved head group/lipid class analysis, structural data that can be used to inform and strengthen interpretation of mass spectrometry data and part of a priori structural determination. In the present study, we codify the use of 31P NMR for lipidomics studies to make the technique more accessible to new users and more useful for a wider range of questions. The technique can be used in isolation (phospholipidomics) or as a part of determining lipid composition (lipidomics). We describe the process from sample extraction to data processing and analysis. This pipeline is important because it allows greater thoroughness in lipidomics studies and increases scope for answering scientific questions about lipid-containing systems.

Knowledge Implementation and Transfer With an Adaptive Learning Network for Real-Time Power Management of the Plug-in Hybrid Vehicle.

Essential decision-making tasks such as power management in future vehicles will benefit from the development of artificial intelligence technology for safe and energy-efficient operations. To develop the technique of using neural network and deep learning in energy management of the plug-in hybrid vehicle and evaluate its advantage, this article proposes a new adaptive learning network that incorporates a deep deterministic policy gradient (DDPG) network with an adaptive neuro-fuzzy inference system (ANFIS) network. First, the ANFIS network is built using a new global K-fold fuzzy learning (GKFL) method for real-time implementation of the offline dynamic programming result. Then, the DDPG network is developed to regulate the input of the ANFIS network with the real-world reinforcement signal. The ANFIS and DDPG networks are integrated to maximize the control utility (CU), which is a function of the vehicle's energy efficiency and the battery state-of-charge. Experimental studies are conducted to testify the performance and robustness of the DDPG-ANFIS network. It has shown that the studied vehicle with the DDPG-ANFIS network achieves 8% higher CU than using the MATLAB ANFIS toolbox on the studied vehicle. In five simulated real-world driving conditions, the DDPG-ANFIS network increased the maximum mean CU value by 138% over the ANFIS-only network and 5% over the DDPG-only network.

Lipid Traffic Analysis reveals the impact of high paternal carbohydrate intake on offsprings' lipid metabolism.

In this paper we present an investigation of parental-diet-driven metabolic programming in offspring using a novel computational network analysis tool. The impact of high paternal carbohydrate intake on offsprings' phospholipid and triglyceride metabolism in F1 and F2 generations is described. Detailed lipid profiles were acquired from F1 neonate (3 weeks), F1 adult (16 weeks) and F2 neonate offspring in serum, liver, brain, heart and abdominal adipose tissues by MS and NMR. Using a purpose-built computational tool for analysing both phospholipid and fat metabolism as a network, we characterised the number, type and abundance of lipid variables in and between tissues (Lipid Traffic Analysis), finding a variety of reprogrammings associated with paternal diet. These results are important because they describe the long-term metabolic result of dietary intake by fathers. This analytical approach is important because it offers unparalleled insight into possible mechanisms for alterations in lipid metabolism throughout organisms.

Psychophysiological Responses to a Brief Self-Compassion Exercise in Armed Forces Veterans.

Armed Forces personnel are exposed to traumatic experiences during their work; therefore, they are at risk of developing emotional difficulties such as post-traumatic stress disorder (PTSD), following traumatic experiences. Despite evidence to suggest that self-compassion is effective in reducing the symptoms of PTSD, and greater levels of self-compassion are associated with enhanced resilience, self-compassion in armed forces personnel and armed forces veterans remains under-researched. As a result, it is not known if therapeutic approaches that use self-compassion interventions are an acceptable and effective treatment for this population. Having previously shown that a one-off self-compassion exercise has temporary beneficial psychophysiological effects in non-clinical participants, we conducted this proof-of concept study to investigate whether this exercise is equally beneficial in veterans who had experienced deployment to a combat zone. Additionally, we examined if brief a self-compassion exercise can temporarily reduce hyperarousal symptoms and increase feelings of social connectedness. The current study also investigated the association between PTSD symptom severity, emotion regulation, and self-compassion in 56 veterans. All participants listened to a loving-kindness meditation for self-compassion (LKM-S) and psychophysiological recordings were taken throughout. Psychophysiological effects were observed including heart-rate (HR), skin conductance (SCL), and heart-rate variability (HRV) to determine associations with PTSD and changes in response associated with the self-compassion induction. PTSD symptom severity, dispositional emotion regulation, and self-compassion were measured, and participants also completed state measures of hyperarousal and social connectedness before and after the LKM-S. The findings partially demonstrated that self-compassion can be elicited in a veteran population but there were considerable individual differences in psychophysiological responses. The findings are discussed in light of existing theories of PTSD and self-compassion and the implications of using self-compassion based psychological approaches with veterans.

A systematic review of economic evaluations of advanced therapy medicinal products.

AIMS: Advanced therapy medicinal products (ATMPs) represent a new category of medicinal products with a potential for transformative improvements in health outcomes but at exceptionally high prices. Routine adoption of ATMPs requires robust evidence of their cost-effectiveness. METHODS: A systematic literature review of economic evaluations of ATMPs, including gene therapies, somatic cell therapies and tissue-engineered products, was conducted. Literature was searched using MedLine, Embase, PubMed, Cochrane Register, the NHS Economic Evaluation Database and the grey literature of health technology assessment organisations with search terms relating to ATMPs and economic evaluations. Titles were screened independently by 2 reviewers. Articles deemed to meet the inclusion criteria were screened independently on abstract, and full texts reviewed. Study findings were appraised critically. RESULTS: 4514 articles were identified, of which 23 met the inclusion criteria. There was some evidence supporting the cost-effectiveness of: chimeric antigen receptor T-cell therapy axicabtagene-ciloleucel (Yescarta), embryonic neural stem cells, tumour infiltrating lymphocytes, in vitro expanded myoblast, autologous chondrocyte implantation, ex vivo gene therapy (Strimvelis) and voretigene neparvovec (Luxturna). However, estimates of cost-effectiveness were associated with significant uncertainty and high likelihood of bias, resulting from largely unknown long-term outcomes, a paucity of evidence on health state utilities and extensive modelling assumptions. CONCLUSION: There are critical limitations to the economic evidence for ATMPs, most notably in relation to evidence on the durability of treatment effect, and the reliability of opinion-based assumptions necessary when evidence is absent.