UK Valuation of EQ-5D-5L, a Generic Measure of Health-Related Quality of Life: A Study Protocol.

OBJECTIVES: A high-quality and widely accepted UK EQ-5D-5L value set is urgently required to enable the latest version of EQ-5D scored using recent UK public preferences to inform policy including health technology assessments submitted to the National Institute for Health and Care Excellence. This article outlines the study protocol for the generation of a new EQ-5D-5L UK value set. METHODS: Twelve hundred interviews will be undertaken using the composite time trade-off elicitation technique for 102 health states (86 from the international EQ-5D-5L valuation protocol, plus 16 with best predictive performance in an extended design used in the Native American EQ-5D-5L valuation). The sample will be UK adults (age ≥18 years) proportionately representative across England, Wales, Scotland, and Northern Ireland, representative for age, sex, ethnicity, and socioeconomic group, with inclusion of participants with/without health problems. Participants will choose to be interviewed via videoconference (by Zoom) or in-person in a central venue. Data quality will be rigorously assessed. RESULTS: The value set will be generated using tobit random effects and heteroscedastic tobit models (with censoring at -1) using all data, excluding time trade-off values highlighted by participants as ones they would reconsider and data from interviewers failing protocol compliance. Quality and acceptance will be achieved by public involvement, regular Steering Group meetings, independent assessment of data quality at 4 time points, and final endorsement of data and analyses. CONCLUSION: This study will produce a UK value set for the EQ-5D-5L for use in prospective and retrospective data sets containing EQ-5D-5L data.

High coordination number actinide-noble gas complexes; a computational study.

The geometries, electronic structures and bonding of early actinide-noble gas complexes are studied computationally by density functional and wavefunction theory methods, and by ab initio molecular dynamics. AcHe183+ is confirmed as being an 18-coordinate system, with all of the He atoms accommodated in the primary coordination shell, and this record coordination number is reported for the first time for Th4+ and Th3+. For Pa and U in their group valences of 5 and 6 respectively, the largest number of coordinated He atoms is 17. For AnHe17q+ (An = Ac, q = 3; An = Th, q = 4; An = Pa, q = 5; An = U, q = 6), the average An-He binding energy increases significantly across the series, and correlates linearly with the extent of He → Anq+ charge transfer. The interatomic exchange-correlation term Vxc obtained from the interacting quantum atoms approach correlates linearly with the An-He quantum theory of atoms-in-molecules delocalization index, both indicating that covalency increases from AcHe173+ to UHe176+. The correlation energy in AnHe163+ obtained from MP2 calculations decreases in the order Pa > Th > U > Ac, the same trend found in Vxc. The most stable complexes of Ac3+ with the heavier noble gases Ar-Xe are 12 coordinate, best described as Ng12 cages encapsulating an Ac3+ ion. There is enhanced Ng → Ac3+ charge transfer as the Ng gets heavier, and Ac-Ng covalency increases.

Can the UK 'Netflix' Payment Model Boost the Antibacterial Pipeline?

The silent pandemic of antimicrobial resistance (AMR) is a global issue needing prompt attention. A comprehensive one-health approach across human and animal health, agriculture and the environment is needed to solve this, addressing overuse of antibacterials, and of course, optimising measures for preventing and controlling infection. We also need a robust pipeline of new antibacterials. However, the current pipeline is inadequate and several companies with new antibacterials have gone bankrupt due to low sales, leading to a 'broken market'. To address this, the UK has completed a project using novel approaches to value assessment and reimbursement for two antibacterials. The new funding arrangements for these products commenced on 1st July 2022, delinking reimbursement from volume of sales; a so-called 'pull incentive', with payments based on the added value to the whole-health and social-care system, not just to individual patients. This article describes how the project was devised, developed, and progressed. The learning from this work might help other countries to adopt or adapt the approach to fit with their national systems, and collectively achieve a global incentive to reinvigorate the antibacterial pipeline.

Covalency in AnCl2 (An = Th-No).

A potential connection has previously been proposed between the emergence of unexpected covalent behaviour in various transcurium complexes and the increasing stability of the +2 oxidation state in the later members of the actinide series. We recently used computational methods to study AnCl3, finding evidence for energy degeneracy driven covalency in the later actinides, and here present a comparative study of AnCl2. The An-Cl bond lengths of the latter divide into two data sets; Th-Np, Cm, Bk and Pu, Am, Cf-No. On average the An-Cl bond length decreases for both sets but, with significant increases between Np and Pu, and between Bk and Cf, unlike the former group (Pu, Am, Cf-No)Cl2 have significantly larger lengths than the corresponding trichlorides. Using a range of Natural Bond Orbital (NBO), Natural Resonance Theory (NRT) and Quantum Theory of Atoms In Molecules (QTAIM) metrics, the covalency of the dichloride bonds is analysed. We find that the first group of dichlorides are similar to their trichloride counterparts and possess significantly more covalent bonds than (Pu, Am, Cf-No)Cl2. We believe this change in covalent behaviour across the series for the dichlorides is due to a decreased involvement of the 6d orbital in the later elements (as a result of the f-d excitation energy exceeding the d-stabilisation energy of the actinide ions in question). Moreover, we find that unlike the trichlorides, where the QTAIM delocalisation index indicates that covalency plateaus/moderately increases, An-Cl covalency decreases across the second half of the series for AnCl2. We attribute this difference in behaviour to a lack of significant energy degeneracy driven covalency for the dichlorides, with the energy difference between the dichlorides' ß 5f and 3p Natural Atomic Orbitals being larger than for the trichlorides. Hence we find it is not the presence of a stable +2 oxidation state, but instead the extent of energy matching between the actinide 5f orbitals and the ligand 3p, that drives covalency in the transcurium chlorides.

Covalency in AnCl3 (An = Th-No).

The geometric and electronic structures of AnCl3 are studied computationally using scalar relativistic, hybrid density functional theory (PBE0). The An-Cl bond lengths generally decrease across the 5f series, although there is a slight lengthening from Fm-Cl to No-Cl as the metal ions display increasing M(ii) character. Covalency in the An-Cl bond is studied using a wide range of metrics drawn from the Natural Bond Orbital, Natural Resonance Theory and Quantum Theory of Atoms-in-Molecules (QTAIM) methods, including bond order, orbital composition, orbital overlap and electron density topology data. Most metrics agree that the later An-Cl bonds are less ionic than might be anticipated on the basis of trends in the first half of the series, due to energy degeneracy-driven covalency in the ß spin manifold; for example, the An-Cl QTAIM delocalisation index (bond order) for MdCl3 (0.88) is almost exactly the same as for NpCl3 (0.89). By contrast, the ratio of the kinetic to potential energy densities at the An-Cl bond critical points indicates that ionicity increases across the series, suggesting that the delocalisation index measures both orbital overlap and energy degeneracy-based covalency, while the bond critical point metric gauges only the former. Recalculation of all the data using the generalised gradient approximation PBE functional finds larger energy degeneracy-driven covalency in the later actinides than using hybrid DFT. Hence, we find that conclusions concerning the covalency of the An-Cl bond are dependent not only on the metric used to evaluate it, but also on the underlying electronic structure method.

Metal and metallothionein content in bullfrogs: study of a whole watershed impacted by agricultural activities.

Among the various anthropogenic activities potentially affecting amphibian populations, agriculture has often been evoked. Fertilizers used in agriculture are documented sources of metals that may contaminate nearby rivers. Bullfrogs (Rana catesbeiana) were collected within the Yamaska River basin (Quebec, Canada) along a gradient of agricultural land use intensity. Hepatic, renal and intestinal metal content, along with hepatic metallothionein content, were determined. In general, dissolved metal concentrations and accumulated metal concentrations in bullfrogs varied little among sites. Hepatic Cu and Zn concentrations were significantly different among subwatersheds and were in accordance with the gradient in agricultural activities in at least one of the three years studied. Liver metallothionein content did not vary significantly among the subwatersheds, but they were correlated with Cu content within two sites and Cd content at one site. We conclude that R. catesbeiana could be used as a biomonitor for Cu contamination and potentially for other metals.

The effect of prednisolone on endometrial uterine NK cell concentrations and pregnancy outcome in women with reproductive failure. A retrospective cohort study.

This retrospective study of prospectively collected data examines the effect of prednisolone therapy on raised uterine Natural Killer cell (uNK) concentrations and pregnancy outcomes in women with recurrent miscarriage (RM) and recurrent implantation failure (RIF) after IVF/ICSI treatment. 136 women diagnosed with RRF who had a timed midluteal endometrial biopsy taken for uNK cell analysis were included. Women with high uNK cell concentrations (n = 45) were treated with prednisolone (10 mg/day) for one month, after which a second biopsy was taken for repeat uNK cell analysis. Women for whom prednisolone caused a decrease in uNK cell concentrations continued on prednisolone until 12 weeks of pregnancy. Pregnancy outcomes (live birth, miscarriage and implantation rates) and pregnancy complications were compared for women who received prednisolone and those who did not. Results showed that the prevalence of high uNK cells was 33.1%. Prednisolone significantly decreased the uNK cell concentration (P < 0.001), however reduction to normal limits was achieved in only 48.3% of patients. There was no difference in any of the pregnancy outcomes or complications between women who had received prednisolone and those who had not. In conclusion, this study showed a relatively high prevalence of raised uNK cells in women with recurrent reproductive failure and confirmed the effect of prednisolone on reducing uNK cell concentrations. We found however no evidence for a significant beneficial effect for prednisolone therapy on pregnancy outcomes. Until the results of an adequately powered RCT become available however, these findings should be considered preliminary.

Subcellular partitioning of metals and metalloids (As, Cd, Cu, Se and Zn) in liver and gonads of wild white suckers (Catostomus commersonii) collected downstream from a mining operation.

In the present study, we examined the subcellular distribution of metals and metalloids (As, Cd, Cu, Se and Zn) in the liver and gonads of wild white suckers (Catostomus commersonii) collected downstream from a metal mining operation (exposure area) and in a reference area. Metal partitioning among potentially metal-sensitive fractions (heat-denatured proteins (HDP), mitochondria and microsomes) and potentially biologically detoxified fractions (heat-stable proteins (HSP) and metal-rich granules) within cells was determined after differential centrifugation, NaOH digestion and heat-denaturation steps. Metal-handling strategies between liver and gonads, and between sexes, were examined. Hepatic metal concentrations were significantly higher in exposed compared to reference fish, especially for Se (14x), Cd (5x) and Cu (3x), and did not vary between sexes. In contrast, gonadal Cd, Cu, Se and Zn concentrations were consistently lower in testes than in ovaries; marked differences in Cd and Se concentrations between exposed and reference fish were observed for both sexes. Overall, metal-handling strategies were similar in both liver (male and female pooled) and female gonads, but differed from those in male gonads, likely due to the different functions assigned to ovaries and testes. Subcellular partitioning of As, Cd and Cu showed that the HSP fraction was most responsive to increased metal exposure, presumably reflecting Cu regulation, and possibly Cd and As detoxification. Zinc concentrations were tightly controlled and mainly found in the HDP fraction. Interestingly, changes in Cd-handling strategy in female gonads were particularly evident, with Cd shifting dramatically from the metal-sensitive HDP fraction in reference fish to the metal-detoxified HSP fraction in exposed fish. It seems that Cd detoxification in female gonads was not fully induced in the less contaminated fish, but became more effective above a threshold Cd concentration of 0.05 nmol/g dry weight. Partitioning of Se was different, with the largest contributor to the total liver and gonad Se burdens being the putative metal-sensitive HDP fraction, suggesting that excess Se in this fraction in exposed fish may lead to Se-related stress. The present subcellular partitioning results demonstrate that metal handling strategies vary among metals, between organs and (in some cases) as a function of metal exposure. They also show promise in identifying metals of potential concern in a risk assessment context.

Influence of a step-change in metal exposure (Cd, Cu, Zn) on metal accumulation and subcellular partitioning in a freshwater bivalve, Pyganodon grandis: a long-term transplantation experiment between lakes with contrasting ambient metal levels.

The objective of the present field experiment was to identify detoxification responses in the gills and digestive gland of a freshwater unionid bivalve, Pyganodon grandis, subjected to a step-change in metal exposure. Adult bivalves were transferred from a reference site (Lake Opasatica) and a metal-contaminated lake (Lake Héva) to a second contaminated lake (Lake Vaudray) in northwestern Quebec, Canada. Changes in organ metal concentrations, in the subcellular distribution of metals and in metallothionein concentrations were followed over time (t=0, 132, (400) and 860 days). At each collection time and for each bivalve, the gills and digestive gland were excised and gently homogenized; six sub-cellular fractions were separated by differential centrifugation and analyzed for their Cd, Cu and Zn content, and metallothionein was quantified independently. Metal detoxification strategies were shown to differ between target organs: in the gills, incoming metals were sequestered largely in the granules, whereas in the digestive gland the same metals primarily accumulated in the cytosol, in the metallothionein-like protein fraction. These metal-handling strategies, as employed by the metal-naïve bivalves originating in the reference lake, closely resemble those identified in free-living P. grandis chronically exposed in the metal-contaminated lake, suggesting that the ability to handle incoming metals (Cd in particular) is inherent in P. grandis and is not a trait acquired after long-term adaptation of the bivalve to metal-contaminated environments. The bivalves transplanted from both Lakes Opasatica and Héva were able to tolerate their new surroundings during the first 400 days of the transplant experiment, as indicated by the absence of mortality and the presence of gravid animals. Over the final 460 days, mortality remained low for the bivalves transplanted from the reference lake (20%) but reached 100% in the transplanted group from the contaminated lake. It would seem that the Lake Héva bivalves were compromised by their initial exposure to metals in their home lake and that the added stress of being transplanted to and caged in a lake with comparable or slightly higher concentrations of metals was sufficient to cause mortality.

Subcellular partitioning of cadmium in the freshwater bivalve, Pyganodon grandis, after separate short-term exposures to waterborne or diet-borne metal.

The dynamics of cadmium uptake and subcellular partitioning were studied in laboratory experiments conducted on Pyganodon grandis, a freshwater unionid bivalve that shows promise as a biomonitor for metal pollution. Bivalves were collected from an uncontaminated lake, allowed to acclimate to laboratory conditions (≥25 days), and then either exposed to a low, environmentally relevant, concentration of dissolved Cd (5nM; 6, 12 and 24h), or fed Cd-contaminated algae (∼70nmol Cdg⁻¹ dry weight; 4×4h). In this latter case, the bivalves were allowed to depurate for up to 8 days after the end of the feeding phase. As anticipated, the gills were the main target organ during the aqueous Cd exposure whereas the intestine was the initial site of Cd accumulation during the dietary exposure; during the subsequent depuration period, the dietary Cd accumulated in both the digestive gland and in the gills. For the gills, the distribution of Cd among the subcellular fractions (i.e., granules>heat-denatured proteins (HDP)∼heat-stable proteins (HSP)>mitochondria∼lysosomes+microsomes) was insensitive to the exposure route; both waterborne and diet-borne Cd ended up largely bound to the granule fraction. The subcellular distribution of Cd in the digestive gland differed markedly from that in the gills (HDP>HSP∼granules∼mitochondria>lysosomes+microsomes), but as in the case of the gills, this distribution was relatively insensitive to the exposure route. For both the gills and the digestive gland, the subcellular distributions of Cd differed from those observed in native bivalves that are chronically exposed to Cd in the field - in the short-term experimental exposures of P. grandis, metal detoxification was less effective than in chronically exposed native bivalves.