Development of a Health-State Classification System for the Pediatric Quality-of-Life Inventory Version 4.0 Generic Core Scales for Preference-Based Valuation in Australia.

OBJECTIVES: Pediatric Quality-of-Life Inventory Version 4.0 Generic Core Scales (PedsQL GCS), comprising 23 items covering 4 subscales (physical, emotional, social, and school functioning), is a widely applied generic measure of childhood health-related quality of life but does not provide health utilities for cost-effectiveness-based decision making. This study aimed to develop a reduced item version of PedsQL GCS amenable to health utility derivation in Australia. METHODS: Data sources were 2 cohorts of the Longitudinal Study of Australian Children, including proxy responses for all PedsQL GCS versions (Toddlers, Young Children, Children, and Teens), and the CheckPoint sample containing child self-report to the Children version. Three analytic samples were CheckPoint sample (n = 1874); Mallinson sample containing 1 measurement per child from one of the Young Children, Children, or Teens versions (n = 7855); and Toddlers sample (n = 7401). Exploratory and confirmatory factor analyses assessed dimensionality. Psychometric analyses used Rasch and classical criteria on 3 randomly selected subsamples (n = 500) per sample. Item selection prioritized psychometric performance in the CheckPoint sample, also considering performance in other samples and conceptual content. RESULTS: Dimensionality assessments did not generate an alternative empirical structure for the measure, and psychometric analyses were conducted on the original 4 subscales. The selected items were: "Get aches and pains" for physical functioning; "Feel sad/blue" for emotional functioning; "Other kids not friends" for social functioning; and "Keeping up with school work" for school functioning. CONCLUSIONS: The final 4-item set, pending further psychometric validation and valuation, can generate health utilities from the widely used PedsQL GCS to inform cost-effectiveness-based decision making.

Longitudinal associations between socioeconomic position and overall health of children with chronic kidney disease and their carers.

BACKGROUND: Disadvantaged socioeconomic position (SEP) is an important predictor of poor health in children with chronic kidney disease (CKD). The time course over which SEP influences the health of children with CKD and their carers is unknown. METHODS: This prospective longitudinal study included 377 children, aged 6-18 years with CKD (stages I-V, dialysis, and transplant), and their primary carers. Mixed effects ordinal regression was performed to assess the association between SEP and carer-rated child health and carer self-rated health over a 4-year follow-up. RESULTS: Adjusted for CKD stage, higher family household income (adjusted odds ratio (OR) (95% CI) 3.3, 1.8-6.0), employed status of primary carers (1.7, 0.9-3.0), higher carer-perceived financial status (2.6, 1.4-4.8), and carer home ownership (2.2, 1.2-4.0) were associated with better carer-rated child health. Household income also had a differential effect on the carer's self-rated health over time (p = 0.005). The predicted probabilities for carers' overall health being 'very good' among lower income groups at 0, 2, and 4 years were 0.43 (0.28-0.60), 0.34 (0.20-0.51), and 0.25 (0.12-0.44), respectively, and 0.81 (0.69-0.88), 0.84 (0.74-0.91), and 0.88 (0.76-0.94) for carers within the higher income group. CONCLUSIONS: Carers and their children with CKD in higher SEP report better overall child and carer health compared with those in lower SEP. Carers of children with CKD in low-income households had poorer self-rated health compared with carers in higher-income households at baseline, and this worsened over time. These cumulative effects may contribute to health inequities between higher and lower SEP groups over time. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information.

Incorporating frailty to address the key challenges to geriatric economic evaluation.

BACKGROUND: The multidimensional and dynamically complex process of ageing presents key challenges to economic evaluation of geriatric interventions, including: (1) accounting for indirect, long-term effects of a geriatric shock such as a fall; (2) incorporating a wide range of societal, non-health outcomes such as informal caregiver burden; and (3) accounting for heterogeneity within the demographic group. Measures of frailty aim to capture the multidimensional and syndromic nature of geriatric health. Using a case study of community-based falls prevention, this article explores how incorporating a multivariate frailty index in a decision model can help address the above key challenges. METHODS: A conceptual structure of the relationship between geriatric shocks and frailty was developed. This included three key associations involving frailty: (A) the shock-frailty feedback loop; (B) the secondary effects of shock via frailty; and (C) association between frailty and intervention access. A case study of economic modelling of community-based falls prevention for older persons aged 60 + was used to show how parameterising these associations contributed to addressing the above three challenges. The English Longitudinal Study of Ageing (ELSA) was the main data source for parameterisation. A new 52-item multivariate frailty index was generated from ELSA. The main statistical methods were multivariate logistic and linear regressions. Estimated regression coefficients were inputted into a discrete individual simulation with annual cycles to calculate the continuous variable value or probability of binary event given individuals' characteristics. RESULTS: All three conceptual associations, in their parameterised forms, contributed to addressing challenge (1). Specifically, by worsening the frailty progression, falls incidence in the model increased the risk of falling in subsequent cycles and indirectly impacted the trajectories and levels of EQ-5D-3 L, mortality risk, and comorbidity care costs. Intervention access was positively associated with frailty such that the greater access to falls prevention by frailer individuals dampened the falls-frailty feedback loop. Association (B) concerning the secondary effects of falls via frailty was central to addressing challenge (2). Using this association, the model was able to estimate how falls prevention generated via its impact on frailty paid and unpaid productivity gains, out-of-pocket care expenditure reduction, and informal caregiving cost reduction. For challenge (3), frailty captured the variations within demographic groups of key model outcomes including EQ-5D-3 L, QALY, and all-cause care costs. Frailty itself was shown to have a social gradient such that it mediated socially inequitable distributions of frailty-associated outcomes. CONCLUSION: The frailty-based conceptual structure and parameterisation methods significantly improved upon the methods previously employed by falls prevention models to address the key challenges for geriatric economic evaluation. The conceptual structure is applicable to other geriatric and non-geriatric intervention areas and should inform the data selection and statistical methods to parameterise structurally valid economic models of geriatric interventions.

Influence of colour background on anti-viral activity against viral haemorrhagic septicaemia virus in zebrafish regulated by circadian rhythm signalling pathway.

The influence of colour background on the regulation of behavioural and physiological responses in zebrafish is widely recognized. However, its specific effect on virus infection in zebrafish remains unclear. This study aimed to explore the susceptibility of zebrafish to viral haemorrhagic septicaemia virus (VHSV) infection in relation to background colour, investigate the underlying mechanisms, and elucidate the involvement of key molecules, using proteomic and gene expression analyses. The results revealed that zebrafish housed in a blue tank exhibited higher survival rates and considerably reduced VHSV replication compared to those housed in a yellow tank. Further, up-regulation of apolipoprotein 1 (APOA1) was identified as a crucial shared mechanism associated with survival in zebrafish exposed to VHSV infection and reared in a blue background. The mRNA expression level of bmal1a, a core gene involved in the circadian rhythm, was consistently downregulated in fish from the blue tank compared to fish from the yellow tank, regardless of infection status. Subsequently, zebrafish in the blue tank were exposed to daylight conditions to stimulate per2 and pgc1a expression, aiming to investigate their potential impact on VHSV infection. The validity of these interconnected events, triggered by background colour, involving APOA1 up-regulation, circadian rhythm modulation, and antiviral responses, was confirmed by treatments with hesperetin and cyclosporine A, an activator and inhibitor of apoa1 respectively. Our findings revealed the influence of background colour on the apoa1 expression level, thus establishing the involvement of a novel network through circadian rhythm signalling.

Longitudinal assessment of the health-related quality of life of children and adolescents with chronic kidney disease.

In this multi-center longitudinal cohort study conducted in Australia and New Zealand, we assessed the trajectories of health-related quality of life (HRQoL) in children with chronic kidney disease (CKD) over time. A total of 377 children (aged 6-18 years) with CKD stages 1-5 (pre-dialysis), dialysis, or transplant, were followed biennially for four years. Multi Attribute Utility (MAU) scores of HRQoL were measured at baseline and at two and four years using the McMaster Health Utilities Index Mark 3 tool, a generic multi-attribute, preference-based system. A multivariable linear mixed model was used to assess the trajectories of HRQoL over time in 199 children with CKD stage 1-5, 43 children receiving dialysis and 135 kidney transplant recipients. An interaction between CKD stage at baseline and follow-up time indicated that the slopes of the HRQoL scores differed between children by CKD stage at inception. Over half of the cohort on dialysis at baseline had received a kidney transplant by the end of year four and the MAU scores of these children increased by a meaningful amount averaging 0.05 (95% confidence interval 0.01 to 0.09) per year in comparison to those who were transplant recipients at baseline. The mean difference between baseline and year two MAU scores was 0.09 (95% confidence interval -0.05, 0.23), (Cohen's d effect size 0.31). Thus, improvement in HRQoL over time of children on dialysis at baseline was likely to have been driven by their transition from dialysis to transplantation. Additionally, children with CKD stage 1-5 and transplant recipients at baseline had no changes in their disease stage or treatment modality and experienced stable HRQoL over time.

Rheological dynamics and structural characteristics of supramolecular assemblies of ß-cyclodextrin and sulfonic surfactants.

Cyclodextrins are highly functional compounds with a hydrophobic cavity capable of forming supramolecular inclusion complexes with various classes of molecules including surfactants. The resultant rich nanostructures and their dynamics are an interesting research problem in the area of soft condensed matter and related applications. Herein, we report novel dynamical supramolecular assemblies based on the complexation of ß-cyclodextrin with 3 different sulfonic surfactants, which are sodium hexadecylsulfate, sodium dodecylbenzenesulfonate, and myristyl sulfobetaine. It was observed that a ß-cyclodextrin : surfactant/2 : 1 molar ratio was ideal for inducing axial growth and imparting large viscosities in the suspensions. Such complexation processes were accompanied by intriguing nanostructural phase behaviors and rheological properties that were very sensitive to the molecular architecture of sulfonic surfactants. The presence of an amino group in the head group of the surfactant allowed for large viscosities that reached 2.4 × 104 Pa s which exhibited gel-like behavior. In contrast, smaller viscosity values with a lower consistency index were observed when a bulky aromatic ring was present instead. DIC microscopy was used to visually probe the microstructure of the systems with respect to sulfonate molecular architecture. Additionally, surface tension measurements, and FTIR and NMR spectroscopies were used to gain insights into the nature of interactions that lead to the complexation and nanostructural characteristics. Finally, mechanics correlating the supramolecular morphologies to the rheological properties were proposed.

pH- and temperature-responsive supramolecular assemblies with highly adjustable viscoelasticity: a multi-stimuli binary system.

Stimuli-responsive materials are increasingly needed for the development of smart electronic, mechanical, and biological devices and systems relying on switchable, tunable, and adaptable properties. Herein, we report a novel pH- and temperature-responsive binary supramolecular assembly involving a long-chain hydroxyamino amide (HAA) and an inorganic hydrotrope, boric acid, with highly tunable viscous and viscoelastic properties. The system under investigation demonstrates a high degree of control over its viscosity, with the capacity to achieve over four orders of magnitude of control through the concomitant manipulation of pH and temperature. In addition, the transformation from non-Maxwellian to Maxwellian fluid behavior could also be induced by changing the pH and temperature. Switchable rheological properties were ascribed to the morphological transformation between spherical vesicles, aggregated/fused spherical vesicles, and bicontinuous gyroid structures revealed by cryo-TEM studies. The observed transitions are attributed to the modulation of the head group spacing between HAA molecules under different pH conditions. Specifically, acidic conditions induce electrostatic repulsion between the protonated amino head groups, leading to an increased spacing. Conversely, under basic conditions, the HAA head group spacing is reduced due to the intercalation of tetrahydroxyborate, facilitated by hydrogen bonding.

Economic model of community-based falls prevention: seeking methodological solutions in evaluating the efficiency and equity of UK guideline recommendations.

BACKGROUND: Falls significantly harm geriatric health and impose substantial costs on care systems and wider society. Decision modelling can inform the commissioning of falls prevention but face methodological challenges, including: (1) capturing non-health outcomes and societal intervention costs; (2) considering heterogeneity and dynamic complexity; (3) considering theories of human behaviour and implementation; and (4) considering issues of equity. This study seeks methodological solutions in developing a credible economic model of community-based falls prevention for older persons (aged 60 +) to inform local falls prevention commissioning as recommended by UK guidelines. METHODS: A framework for conceptualising public health economic models was followed. Conceptualisation was conducted in Sheffield as a representative local health economy. Model parameterisation used publicly available data including English Longitudinal Study of Ageing and UK-based falls prevention trials. Key methodological developments in operationalising a discrete individual simulation model included: (1) incorporating societal outcomes including productivity, informal caregiving cost, and private care expenditure; (2) parameterising dynamic falls-frailty feedback loop whereby falls influence long-term outcomes via frailty progression; (3) incorporating three parallel prevention pathways with unique eligibility and implementation conditions; and (4) assessing equity impacts through distributional cost-effectiveness analysis (DCEA) and individual-level lifetime outcomes (e.g., number reaching 'fair innings'). Guideline-recommended strategy (RC) was compared against usual care (UC). Probabilistic sensitivity, subgroup, and scenario analyses were conducted. RESULTS: RC had 93.4% probability of being cost-effective versus UC at cost-effectiveness threshold of £20,000 per QALY gained under 40-year societal cost-utility analysis. It increased productivity and reduced private expenditure and informal caregiving cost, but productivity gain and private expenditure reduction were outstripped by increases in intervention time opportunity costs and co-payments, respectively. RC reduced inequality delineated by socioeconomic status quartile. Gains in individual-level lifetime outcomes were small. Younger geriatric age groups can cross-subsidise their older peers for whom RC is cost-ineffective. Removing the falls-frailty feedback made RC no longer efficient or equitable versus UC. CONCLUSION: Methodological advances addressed several key challenges associated with falls prevention modelling. RC appears cost-effective and equitable versus UC. However, further analyses should confirm whether RC is optimal versus other potential strategies and investigate feasibility issues including capacity implications.

SAXS-guided unbiased coarse-grained Monte Carlo simulation for identification of self-assembly nanostructures and dimensions.

Recent studies have shown that solvated amphiphiles can form nanostructured self-assemblies called dynamic binary complexes (DBCs) in the presence of ions. Since the nanostructures of DBCs are directly related to their viscoelastic properties, it is important to understand how the nanostructures change under different solution conditions. However, it is challenging to obtain a three-dimensional molecular description of these nanostructures by utilizing conventional experimental characterization techniques or thermodynamic models. To this end, we combined the structural data from small angle X-ray scattering (SAXS) experiments and thermodynamic knowledge from coarse-grained Monte Carlo (CGMC) simulations to identify the detailed three-dimensional nanostructure of DBCs. Specifically, unbiased CGMC simulations are performed with SAXS-guided initial conditions, which aids us to sample accurate nanostructures in a computationally efficient fashion. As a result, an elliptical bilayer nanostructure is obtained as the most probable nanostructure of DBCs whose dimensions are validated by scanning electron microscope (SEM) images. Then, utilizing the obtained molecular model of DBCs, we could also explain the pH tunability of the system. Overall, our results from SAXS-guided unbiased CGMC simulations highlight that using potential energy combined with SAXS data, we can distinguish otherwise degenerate nanostructures resulting from the inherent ambiguity of SAXS patterns.

Identification of rearing temperature-dependent host defense signaling against viral hemorrhagic septicemia virus infection.

Viral hemorrhagic septicemia virus (VHSV) infection is associated with fatal outcomes in the aquaculture production of olive flounder (Paralichthys olivaceus). Olive flounders at low and high temperatures are known to be highly susceptible and resistant to VHSV infection, respectively. To study temperature-dependent innate immune activity, 4-aminobenzoic hydrazide (4-AH), a myeloperoxidase (MPO) inhibitor, was used to treat VHSV-infected olive flounders reared at a high temperature of 20 °C (20VI). Mortality, the MPO transcription, and the proteomic expression pattern of the 20VI group were then compared with those of groups of VHSV-infected flounders reared at 15 °C (15V) and 20 °C (20V). The cumulative mortality rate of the 20VI group was increased by 35% compared with that of the untreated 20V group. The MPO transcription was decreased 5.8-fold in 20VI than in 20V group. Its expression decreased further at a lower temperature and after exposure to VHSV. Histopathological analysis revealed necrosis of splenic tissue in 20VI and 15V, but not in 20V group. Based on clustering analysis, proteins with increased expression in 15V and 20VI groups were associated with viral mRNA translation and reproduction compared with those of 20V group. Increased expression of DHX58, MX1, and UBB was detected in 15V and 20VI groups, suggesting a role in triggering innate immune response. Unfortunately, these genes failed to induce the translocation of GLUT4 to the surface membrane from the intracellular location due to decreased expression of 14-3-3 proteins (YWHAB and YWHAZ) and microtubules (TUBA1A and TUBB4B). Suppression of glucose supply led to inactivation of MPO and suppression of MHC-I and MHC-II-linked immune activity, resulting in high viral infection and spread. In conclusion, this study highlights that defective GLUT4 translocation-dependent glucose uptake increases the mortality of VHSV-infected olive flounders by inhibiting MPO activity.

Systematic review and critical methodological appraisal of community-based falls prevention economic models.

BACKGROUND: Falls impose significant health and economic burdens on community-dwelling older persons. Decision modelling can inform commissioning of alternative falls prevention strategies. Several methodological challenges arise when modelling public health interventions including community-based falls prevention. This study aims to conduct a systematic review (SR) to: systematically identify community-based falls prevention economic models; synthesise and critically appraise how the models handled key methodological challenges associated with public health modelling; and suggest areas for further methodological research. METHODS: The SR followed the 2021 PRISMA reporting guideline and covered the period 2003-2020 and 12 academic databases and grey literature. The extracted methodological features of included models were synthesised by their relevance to the following challenges: (1) capturing non-health outcomes and societal intervention costs; (2) considering heterogeneity and dynamic complexity; (3) considering theories of human behaviour and implementation; and (4) considering equity issues. The critical appraisal assessed the prevalence of each feature across models, then appraised the methods used to incorporate the feature. The methodological strengths and limitations stated by the modellers were used as indicators of desirable modelling practice and scope for improvement, respectively. The methods were also compared against those suggested in the broader empirical and methodological literature. Areas of further methodological research were suggested based on appraisal results. RESULTS: 46 models were identified. Comprehensive incorporation of non-health outcomes and societal intervention costs was infrequent. The assessments of heterogeneity and dynamic complexity were limited; subgroup delineation was confined primarily to demographics and binary disease/physical status. Few models incorporated heterogeneity in intervention implementation level, efficacy and cost. Few dynamic variables other than age and falls history were incorporated to characterise the trajectories of falls risk and general health/frailty. Intervention sustainability was frequently based on assumptions; few models estimated the economic/health returns from improved implementation. Seven models incorporated ethnicity- and severity-based subgroups but did not estimate the equity-efficiency trade-offs. Sixteen methodological research suggestions were made. CONCLUSION: Existing community-based falls prevention models contain methodological limitations spanning four challenge areas relevant for public health modelling. There is scope for further methodological research to inform the development of falls prevention and other public health models.

Economic evaluation of community-based falls prevention interventions for older populations: a systematic methodological overview of systematic reviews.

BACKGROUND: Falls impose significant health and economic burdens on older people. The volume of falls prevention economic evaluations has increased, the findings from which have been synthesised by systematic reviews (SRs). Such SRs can inform commissioning and design of future evaluations; however, their findings can be misleading and incomplete, dependent on their pre-specified criteria. This study aims to conduct a systematic overview (SO) to: (1) systematically identify SRs of community-based falls prevention economic evaluations; (2) describe the methodology and findings of SRs; (3) critically appraise the methodology of SRs; and (4) suggest commissioning recommendations based on SO findings. METHODS: The SO followed the PRISMA guideline and the Cochrane guideline on SO, covering 12 databases and grey literature for the period 2003-2020. Eligible studies were SRs with 50% or more included studies that were economic evaluations of community-based falls prevention (against any comparator) for older persons (aged 60 +) or high-risk individuals aged 50-59. Identified SRs' aims, search strategies and results, extracted data fields, quality assessment methods/results, and commissioning and research recommendations were synthesised. The comprehensiveness of previous SRs' data synthesis was judged against criteria drawn from literature on falls prevention/public health economic evaluation. Outcomes of general population, lifetime decision models were re-analysed to inform commissioning recommendations. The SO protocol is registered in the Prospective Register of Systematic Reviews (CRD42021234379). RESULTS: Seven SRs were identified, which extracted 8 to 33 data fields from 44 economic evaluations. Four economic evaluation methodological/reporting quality checklists were used; three SRs narratively synthesised methodological features to varying extent and focus. SRs generally did not appraise decision modelling features, including methods for characterising dynamic complexity of falls risk and intervention need. Their commissioning recommendations were based mainly on cost-per-unit ratios (e.g., incremental cost-effectiveness ratios) and neglected aggregate impact. There is model-based evidence of multifactorial and environmental interventions, home assessment and modification and Tai Chi being cost-effective but also the risk that they exacerbate social inequities of health. CONCLUSIONS: Current SRs of falls prevention economic evaluations do not holistically inform commissioning and evaluation. Accounting for broader decisional factors and methodological nuances of economic evaluations, particularly decision models, is needed.

Economic models of community-based falls prevention: a systematic review with subsequent commissioning and methodological recommendations.

BACKGROUND: Falls impose significant health and economic burdens among older populations, making their prevention a priority. Health economic models can inform whether the falls prevention intervention represents a cost-effective use of resources and/or meet additional objectives such as reducing social inequities of health. This study aims to conduct a systematic review (SR) of community-based falls prevention economic models to: (i) systematically identify such models; (ii) synthesise and critically appraise modelling methods/results; and (iii) formulate methodological and commissioning recommendations. METHODS: The SR followed PRISMA 2021 guideline, covering the period 2003-2020, 12 academic databases and grey literature. A study was included if it: targeted community-dwelling persons aged 60 and over and/or aged 50-59 at high falls risk; evaluated intervention(s) designed to reduce falls or fall-related injuries; against any comparator(s); reported outcomes of economic evaluation; used decision modelling; and had English full text. Extracted data fields were grouped by: (A) model and evaluation overview; (B) falls epidemiology features; (C) falls prevention intervention features; and (D) evaluation methods and outcomes. A checklist for falls prevention economic evaluations was used to assess reporting/methodological quality. Extracted fields were narratively synthesised and critically appraised to inform methodological and commissioning recommendations. The SR protocol is registered in the Prospective Register of Systematic Reviews (CRD42021232147). RESULTS: Forty-six models were identified. The most prevalent issue according to the checklist was non-incorporation of all-cause care costs. Based on general population, lifetime models conducting cost-utility analyses, seven interventions produced favourable ICERs relative to no intervention under the cost-effectiveness threshold of US$41,900 (£30,000) per QALY gained; of these, results for (1) combined multifactorial and environmental intervention, (2) physical activity promotion for women, and (3) targeted vitamin D supplementation were from validated models. Decision-makers should explore the transferability and reaches of interventions in their local settings. There was some evidence that exercise and home modification exacerbate existing social inequities of health. Sixteen methodological recommendations were formulated. CONCLUSION: There is significant methodological heterogeneity across falls prevention models. This SR's appraisals of modelling methods should facilitate the conceptualisation of future falls prevention models. Its synthesis of evaluation outcomes, though limited to published evidence, could inform commissioning.

Development of a hybrid model for a partially known intracellular signaling pathway through correction term estimation and neural network modeling.

Developing an accurate first-principle model is an important step in employing systems biology approaches to analyze an intracellular signaling pathway. However, an accurate first-principle model is difficult to be developed since it requires in-depth mechanistic understandings of the signaling pathway. Since underlying mechanisms such as the reaction network structure are not fully understood, significant discrepancy exists between predicted and actual signaling dynamics. Motivated by these considerations, this work proposes a hybrid modeling approach that combines a first-principle model and an artificial neural network (ANN) model so that predictions of the hybrid model surpass those of the original model. First, the proposed approach determines an optimal subset of model states whose dynamics should be corrected by the ANN by examining the correlation between each state and outputs through relative order. Second, an L2-regularized least-squares problem is solved to infer values of the correction terms that are necessary to minimize the discrepancy between the model predictions and available measurements. Third, an ANN is developed to generalize relationships between the values of the correction terms and the system dynamics. Lastly, the original first-principle model is coupled with the developed ANN to finalize the hybrid model development so that the model will possess generalized prediction capabilities while retaining the model interpretability. We have successfully validated the proposed methodology with two case studies, simplified apoptosis and lipopolysaccharide-induced NFκB signaling pathways, to develop hybrid models with in silico and in vitro measurements, respectively.

Qualitative research to inform economic modelling: a case study in older people's views on implementing the NICE falls prevention guideline.

BACKGROUND: High prevalence of falls among older persons makes falls prevention a public health priority. Yet community-based falls prevention face complexity in implementation and any commissioning strategy should be subject to economic evaluation to ensure cost-effective use of healthcare resources. The study aims to capture the views of older people on implementing the National Institute for Health and Care Excellence (NICE) guideline on community-based falls prevention and explore how the qualitative data can be used to inform commissioning strategies and conceptual modelling of falls prevention economic evaluation in the local area of Sheffield. METHODS: Focus group and interview participants (n = 27) were recruited from Sheffield, England, and comprised falls prevention service users and eligible non-users of varying falls risks. Topics concerned key components of the NICE-recommended falls prevention pathway, including falls risk screening, multifactorial risk assessment and treatment uptake and adherence. Views on other topics concerning falls prevention were also invited. Framework analysis was applied for data analysis, involving data familiarisation, identifying themes, indexing, charting and mapping and interpretation. The qualitative data were mapped to three frameworks: (1) facilitators and barriers to implementing the NICE-recommended pathway and contextual factors; (2) intervention-related causal mechanisms for formulating commissioning strategies spanning context, priority setting, need, supply and demand; and (3) methodological and evaluative challenges for public health economic modelling. RESULTS: Two cross-component factors were identified: health motives of older persons; and professional competence. Participants highlighted the need for intersectoral approaches and prioritising the vulnerable groups. The local commissioning strategy should consider the socioeconomic, linguistic, geographical, legal and cultural contexts, priority setting challenges, supply-side mechanisms spanning provider, organisation, funding and policy (including intersectoral) and health and non-health demand motives. Methodological and evaluative challenges identified included: incorporating non-health outcomes and societal intervention costs; considering dynamic complexity; considering social determinants of health; and conducting equity analyses. CONCLUSIONS: Holistic qualitative research can inform how commissioned falls prevention pathways can be feasible and effective. Qualitative data can inform commissioning strategies and conceptual modelling for economic evaluations of falls prevention and other geriatric interventions. This would improve the structural validity of quantitative models used to inform geriatric public health policies.

Activation of PI3K, Akt, and ERK during early rotavirus infection leads to V-ATPase-dependent endosomal acidification required for uncoating.

The cellular PI3K/Akt and/or MEK/ERK signaling pathways mediate the entry process or endosomal acidification during infection of many viruses. However, their roles in the early infection events of group A rotaviruses (RVAs) have remained elusive. Here, we show that late-penetration (L-P) human DS-1 and bovine NCDV RVA strains stimulate these signaling pathways very early in the infection. Inhibition of both signaling pathways significantly reduced production of viral progeny due to blockage of virus particles in the late endosome, indicating that neither of the two signaling pathways is involved in virus trafficking. However, immunoprecipitation assays using antibodies specific for pPI3K, pAkt, pERK and the subunit E of the V-ATPase co-immunoprecipitated the V-ATPase in complex with pPI3K, pAkt, and pERK. Moreover, Duolink proximity ligation assay revealed direct association of the subunit E of the V-ATPase with the molecules pPI3K, pAkt, and pERK, indicating that both signaling pathways are involved in V-ATPase-dependent endosomal acidification. Acidic replenishment of the medium restored uncoating of the RVA strains in cells pretreated with inhibitors specific for both signaling pathways, confirming the above results. Isolated components of the outer capsid proteins, expressed as VP4-VP8* and VP4-VP5* domains, and VP7, activated the PI3K/Akt and MEK/ERK pathways. Furthermore, psoralen-UV-inactivated RVA and CsCl-purified RVA triple-layered particles triggered activation of the PI3K/Akt and MEK/ERK pathways, confirming the above results. Our data demonstrate that multistep binding of outer capsid proteins of L-P RVA strains with cell surface receptors phosphorylates PI3K, Akt, and ERK, which in turn directly interact with the subunit E of the V-ATPase to acidify the late endosome for uncoating of RVAs. This study provides a better understanding of the RVA-host interaction during viral uncoating, which is of importance for the development of strategies aiming at controlling or preventing RVA infections.

The influence of heteromultivalency on lectin-glycan binding behavior.

We recently discovered that the nature of lectin multivalency and glycolipid diffusion on cell membranes could lead to the heteromultivalent binding (i.e., a single lectin simultaneously binding to different types of glycolipid ligands). This heteromultivalent binding may even govern the lectin-glycan recognition process. To investigate this, we developed a kinetic Monte Carlo simulation, which only considers the fundamental physics/chemistry principles, to model the process of lectin binding to glycans on cell surfaces. We found that the high-affinity glycan ligands could facilitate lectin binding to other low-affinity glycan ligands, even though these low-affinity ligands are barely detectable in microarrays with immobilized glycan ligands. Such heteromultivalent binding processes significantly change lectin binding behaviors. We hypothesize that living organisms probably utilize this mechanism to regulate the downstream lectin functions. Our finding not only offers a mechanism to describe the concept that lectins are pattern recognition molecules, but also suggests that the two overlooked parameters, surface diffusion of glycan ligand and lectin binding kinetics, can play important roles in glycobiology processes. In this paper, we identified the critical parameters that influence the heteromultivalent binding process. We also discussed how our discovery can impact the current lectin-glycan analysis.

Elucidation of mechanism for host response to VHSV infection at varying temperatures in vitro and in vivo through proteomic analysis.

Seasonal temperature has a major influence on the infectivity of pathogens and the host immune system. Viral hemorrhagic septicemia virus (VHSV) is one such pathogen that only causes the mortality of fish at low temperatures. This study aims to discover the host defense mechanism and pathway for resistance to VHSV at higher temperatures. We first observed the VHSV infection patterns at low and higher temperatures in fathead minnow (FHM) cells (20 °C and 28 °C) and zebrafish (15 °C and 25 °C). In comparison to the 20 °C infection, FHM cells infected at 28 °C showed decreased apoptosis, increased cell viability, and reduced VHSV N gene expression. In zebrafish, infection at 25 °C caused no mortality and significantly reduced the N gene copy number in comparison to infection at 15 °C. To explore the antiviral infection mechanisms induced by high temperature in vitro and in vivo, the changes in the proteomic profile were measured through UPLC-MSE analysis. ACADL, PTPN6, TLR1, F7, A2M, and GLI2 were selected as high temperature-specific biomarkers in the FHM cell proteome; and MYH9, HPX, ANTXR1, APOA1, HBZ, and MYH7 were selected in zebrafish. Increased immune response, anticoagulation effects, and the formation of lymphocytes from hematopoietic stem cells were analyzed as functions that were commonly induced by high temperature in vitro and in vivo. Among these biomarkers, GLI2 was predicted as an upstream regulator. When treated with GANT58, a GLI-specific inhibitor, cell viability was further reduced due to GLI2 inhibition during VHSV infection at varying temperatures in FHM cells, and the mortality in zebrafish was induced earlier at the low temperature. Overall, this study discovered a new mechanism for VHSV infection in vitro and in vivo that is regulated by GLI2 protein.

Patterns, trends and methodological associations in the measurement and valuation of childhood health utilities.

PURPOSE: To systematically assess patterns and temporal changes in the measurement and valuation of childhood health utilities and associations between methodological factors. METHODS: Studies reporting childhood health utilities using direct or indirect valuation methods, published by June 2017, were identified through PubMed, Embase, Web of Science, PsycINFO, EconLit, CINAHL, Cochrane Library and PEDE. The following were explored: patterns in tariff application; linear trends in numbers of studies/samples and paediatric cost-utility analyses (CUAs) and associations between them; changes in proportions of studies/samples within characteristic-based categories over pre-specified periods; impact of National Institute for Health and Care Excellence (NICE) guidance on primary UK research and associations between valuation method, age and methodological factors. RESULTS: 335 studies with 3974 samples covering all ICD-10 chapters, 23 valuation methods, 12 respondent types and 42 countries were identified by systematic review. 34.0% of samples using indirect methods compatible with childhood applied childhood-derived tariffs. There was no association between numbers of studies/samples and numbers of CUAs. Compared to 1990-2008, 2009-June 2017 saw a significant fall in the proportion of studies using case series; significant compositional changes across ICD-10 chapters and significantly higher sample proportions using childhood-specific and adult-specific indirect valuation methods, and based on pre-adolescents, self-assessment, self-administration and experienced health states. NICE guidance was weakly effective in promoting reference methods. Associations between valuation method, age and methodological factors were significant. CONCLUSION: 1990-2017 witnessed significant changes in primary research on childhood health utilities. Health technology assessment agencies should note the equivocal effect of methodological guidance on primary research.

Activation of COX-2/PGE2 Promotes Sapovirus Replication via the Inhibition of Nitric Oxide Production.

Enteric caliciviruses in the genera Norovirus and Sapovirus are important pathogens that cause severe acute gastroenteritis in both humans and animals. Cyclooxygenases (COXs) and their final product, prostaglandin E2 (PGE2), are known to play important roles in the modulation of both the host response to infection and the replicative cycles of several viruses. However, the precise mechanism(s) by which the COX/PGE2 pathway regulates sapovirus replication remains largely unknown. In this study, infection with porcine sapovirus (PSaV) strain Cowden, the only cultivable virus within the genus Sapovirus, markedly increased COX-2 mRNA and protein levels at 24 and 36 h postinfection (hpi), with only a transient increase in COX-1 levels seen at 24 hpi. The treatment of cells with pharmacological inhibitors, such as nonsteroidal anti-inflammatory drugs or small interfering RNAs (siRNAs) against COX-1 and COX-2, significantly reduced PGE2 production, as well as PSaV replication. Expression of the viral proteins VPg and ProPol was associated with activation of the COX/PGE2 pathway. We observed that pharmacological inhibition of COX-2 dramatically increased NO production, causing a reduction in PSaV replication that could be restored by inhibition of nitric oxide synthase via the inhibitor N-nitro-l-methyl-arginine ester. This study identified a pivotal role for the COX/PGE2 pathway in the regulation of NO production during the sapovirus life cycle, providing new insights into the life cycle of this poorly characterized family of viruses. Our findings also reveal potential new targets for treatment of sapovirus infection. IMPORTANCE: Sapoviruses are among the major etiological agents of acute gastroenteritis in both humans and animals, but little is known about sapovirus host factor requirements. Here, using only cultivable porcine sapovirus (PSaV) strain Cowden, we demonstrate that PSaV induced the vitalization of the cyclooxygenase (COX) and prostaglandin E2 (PGE2) pathway. Targeting of COX-1/2 using nonsteroidal anti-inflammatory drugs (NSAIDs) such as the COX-1/2 inhibitor indomethacin and the COX-2-specific inhibitors NS-398 and celecoxib or siRNAs targeting COXs, inhibited PSaV replication. Expression of the viral proteins VPg and ProPol was associated with activation of the COX/PGE2 pathway. We further demonstrate that the production of PGE2 provides a protective effect against the antiviral effector mechanism of nitric oxide. Our findings uncover a new mechanism by which PSaV manipulates the host cell to provide an environment suitable for efficient viral growth, which in turn can be a new target for treatment of sapovirus infection.