Comparison of the EQ-HWB and EQ-HWB-S With Other Preference-Based Measures Among United States Informal Caregivers.

OBJECTIVES: Several measures have been used or developed to capture the health and well-being of caregivers, including the EQ Health and Well-being (EQ-HWB) and its short form, EQ-HWB-S. This study aimed to evaluate the psychometric properties and construct validity of the EQ-HWB/EQ-HWB-S in a US caregiver population. METHODS: A cross-sectional survey was conducted involving 504 caregivers. Eligible participants were 18+ years old, provided unpaid care to a relative/friend aged 18+ in the past 6 months, and spent on average of at least 1 hour per week caregiving. Survey included the following measures: EQ-HWB, Adult Social Care Outcomes Toolkit for Carers-Carer, CarerQol, and EQ-5D-5L. Psychometric properties were assessed using response distributions, floor/ceiling effects, Spearman's correlation for convergent validity, and effect sizes (ES) for known-group validity based on caregiving situations and intensity. RESULTS: The average age of caregivers was 49.2 (SD = 15.4), with 57.5% being female. More than half (54.4%) reported high caregiving intensity, and 68.3% lived with the care recipient. The EQ-HWB-S index showed a strong positive correlation with the EQ-5D-5L (rs = 0.72), Adult Social Care Outcomes Toolkit for Carers (rs = 0.54), and CarerQol (rs = 0.54) indices. Notably, the EQ-HWB-S index showed the largest ES among measures in differentiating caregiving scenarios with a large ES for caregiver's general health (d = 1.00) and small ES for caregiving intensity (d = 0.39). CONCLUSIONS: Results support construct validity of EQ-HWB and EQ-HWB-S as measures for assessing health and well-being of adult informal caregivers in comparison with other validated instruments. Differing levels of known-group validity across anchors emphasize the importance of selecting appropriate measures for caregivers, depending on research question and/or intervention aims.

A Head-to-Head Comparison of EQ-HWB and EQ-5D-5L in Patients, Carers, and General Public in China.

OBJECTIVES: This study aimed to understand the psychometric properties of EQ Health and Wellbeing (EQ-HWB) and to examine its relationship with EQ-5D-5L in a sample covering patients, carers, and general public. METHODS: A cross-sectional study was conducted in Guizhou Province, China. The acceptability, convergent validity (using Spearman correlation coefficients), internal structure (using exploratory factor analysis), and known-group validity of EQ-HWB, EQ-HWB-Short (EQ-HWB-S), and EQ-5D-5L were reported and compared. RESULTS: A total of 323 participants completed the survey, including 106 patients, 101 carers, and 116 individuals from the general public. Approximately 7.4% of participants had at least 1 missing response. In the EQ-HWB and EQ-5D-5L items related to activities, there were more level 1 responses. The correlations between EQ-HWB and EQ-5D-5L items ranged from low to high, confirming the convergent validity of similar aspects between the 2 instruments. Notably, EQ-HWB measures 2 additional factors compared with EQ-5D-5L or EQ-HWB-S, both of which share 3 common factors. When the patient group was included, EQ-5D-5L had the largest effect size, but it failed to differentiate between the groups of general public and carers. Both EQ-HWB and EQ-HWB-S demonstrated better known-group validity results when carers were included. CONCLUSIONS: EQ-HWB measures a broader quality of life construct that goes beyond health measured by EQ-5D-5L. By encompassing a broader scope, the impact of healthcare interventions may become diluted, given that other factors can influence well-being outcomes as significantly as health conditions do.

The Measurement Properties of the EQ-HWB and the EQ-HWB-S in Italian Population: A Comparative Study With EQ-5D-5L.

OBJECTIVES: The EQ Health and Well-being, EQ-HWB (25-item) and the EQ-HWB-S (9-item), are new generic measures of health and well-being. The purpose of this study was to examine the measurement properties of the EQ-HWB and EQ-HWB-S measures in relation to the EQ-5D-5L among the Italian general population. METHODS: A cross-sectional survey was conducted from October 2020 to February 2021, followed by secondary analysis of collected data from Italian adults. This analysis included response pattern distributions, correlation strength, and known-group comparison. Known-group comparison was assessed using effect sizes (ES) across health conditions, caregiver status, and social care usage. The EQ-HWB-S index-based score was based on the UK pilot value set, whereas the Italian value set was used for scoring the EQ-5D-5L index. RESULTS: Out of the 1182 participants, 461 reported having a chronic condition, 185 identified as caregivers, and 42 were social care users. EQ-HWB items (7.5%) showed fewer ceiling effects than EQ-5D-5L items (34.7%). Strong correlations (rs > 0.5) were found between overlapping EQ-HWB and EQ-5D-5L items. EQ-HWB-S and EQ-5D-5L index scores demonstrated similar discrimination based on symptomatic chronic conditions (ES d = 0.68 vs d = 0.71), but EQ-HWB-S had slightly higher ES for social care users (ES d = 0.84 vs d = 0.74). CONCLUSIONS: Initial evidence supports the validity of EQ-HWB/EQ-HWB-S because outcome measures in the Italian population. EQ-HWB-S performed comparably to EQ-5D-5L among patients and was better in differentiating social care users. A slight decrease in discriminative properties for caregivers was observed when transitioning from EQ-HWB to EQ-HWB-S.

Scoring the EQ-HWB-S: can we do it without value sets? A non-parametric item response theory analysis.

BACKGROUND: Only one pilot value set (UK) is currently available for the EQ Health and Wellbeing Instrument short version (EQ-HWB-S). As an alternative to preference-weighted scoring, we examined whether a level summary score (LSS) is appropriate for the EQ-HWB-S using Mokken scaling analyses. METHODS: Data from patients, carers and the general population collected during the developmental phase of the EQ-HWB-S in Australia, US and UK were used, noting 3 of 9 items have since undergone revision. EQ-HWB-S data fit was examined using R package Mokken scaling's monotone homogeneity model, utilizing the automated item selection procedure (AISP) as well as Loevinger's scaling coefficients for items and the scale (HS). Manifest monotonicity was assessed by examining whether the cumulative probability for responses at or above each response level did not decrease across the summary score. RESULTS: EQ-HWB-S data were available for 3340 respondents: US = 903, Australia = 514 and UK = 1923. Mean age was 50 ± 18 and 1841 (55%) were female. AISP placed all 9 items of the EQ-HWB-S on a single scale when the lower bound was set to < 0.448. Strong scalability (HS = 0.561) was found for the EQ-HWB-S as a single scale. Stronger scales were formed by separating the psychosocial items (n = 6, HS = 0.683) and physical sensation items (n = 3, HS = 0.713). No violations of monotonicity were found except for the items mobility and daily activities for the subgroups with long-term conditions and UK subjects, respectively. DISCUSSION: As EQ-HWB-S items formed a strong scale and subscales based on Mokken analysis, LSS is a promising weighting-free approach to scoring.

Valuing the EQ Health and Wellbeing Short Using Time Trade-Off and a Discrete Choice Experiment: A Feasibility Study.

OBJECTIVES: The EQ Health and Wellbeing Short (EQ-HWB-S) is a new generic measure that covers health and wellbeing developed for use in economic evaluation in health and social care. The aim was to test the feasibility of using composite time trade-off (cTTO) and a discrete choice experiment (DCE) based on an international protocol to derive utilities for the EQ-HWB-S and to generate a pilot value set. METHODS: A representative UK general population was recruited. Online videoconference interviews were undertaken where cTTO and DCE tasks were administered using EuroQol Portable Valuation Technology. Quality control (QC) was used to assess interviewers' performance. Data were modeled using Tobit, probit, and hybrid models. Feasibility was assessed based on the distribution of data, participants, and reports of understanding from the interviewer, QC and modeling results. RESULTS: cTTO and DCE data were available for 520 participants. Demographic characteristics were broadly representative of the UK general population. Interviewers met QC requirements. cTTO values ranged between -1 to 1 with increasing disutility associated with more severe states. Participants understood the tasks and the EQ-HWB-S states; and the interviewers reported high levels of understanding and engagement. The hybrid Tobit heteroscedastic model was selected for the pilot value set with values ranging from -0.384 to 1. Pain, mobility, daily activities, and sad/depressed had the largest disutilities, followed by loneliness, anxiety, exhaustion, control, and cognition in the selected model. CONCLUSIONS: EQ-HWB-S can be valued using cTTO and DCE. Further methodological work is recommended to develop a valuation protocol specific to the EQ-HWB-S.

Generation, Selection, and Face Validation of Items for a New Generic Measure of Quality of Life: The EQ-HWB.

OBJECTIVES: This article aims to describe the generation and selection of items (stage 2) and face validation (stage 3) of a large international (multilingual) project to develop a new generic measure, the EQ-HWB (EQ Health and Wellbeing), for use in economic evaluation across health, social care, and public health to estimate quality-adjusted life-years. METHODS: Items from commonly used generic, carer, social care, and mental health quality of life measures were mapped onto domains or subdomains identified from a literature review. Potential terms and items were reviewed and refined to ensure coverage of the construct of the domains/subdomain (stage 2). Input on the potential item pool, response options, and recall period was sought from 3 key stakeholder groups. The pool of candidate items was tested in qualitative interviews with potential future users in an international face validation study (stage 3). RESULTS: Stage 2 resulted in the generation of 687 items. Predetermined selection criteria were applied by the research team resulting in 598 items being dropped, leaving 89 items that were reviewed by key stakeholder groups. Face validation (stage 3) tested 97 draft items and 4 response scales. A total of 47 items were retained and 14 were modified, whereas 3 were added to the candidate pool of items. This resulted in a 64-item set. CONCLUSIONS: This international multiculture, multilingual study with a common methodology identified many items that performed well across all countries. These were taken to the psychometric testing along with modified and new items for the EQ-HWB.

A Comparison of a Preliminary Version of the EQ-HWB Short and the 5-Level Version EQ-5D.

OBJECTIVES: The EQ Health and Wellbeing Short (EQ-HWB-S) is a new broad generic measure of health and wellbeing for use in economic evaluations of interventions across healthcare, social care, and public health. This measure conceptually overlaps with the 5-level version EQ-5D (EQ-5D-5L), while expanding on the coverage of health and social care related dimensions. This study aims to examine the extent to which the EQ-HWB-S and EQ-5D-5L overlap and are different. METHODS: A sample of US-based respondents (n = 903; n = 400 cancer survivors and n = 503 general population) completed a survey administered via an online panel. The survey included the EQ-HWB item pool (62 items, including 11 items used in this analysis), EQ-5D-5L, and questions about sociodemographic and health characteristics. The analysis included (Spearman's) correlations, the comparison of patterns of response (distributions and ceiling effects), and the ability to discriminate between known groups. RESULTS: Moderate to strong associations were found between conceptually overlapping dimensions of the EQ-5D-5L and the EQ-HWB-S (rs > 0.5, P < .001). Among respondents reporting full health on the EQ-5D-5L (n = 161, 18.23%), the EQ-HWB-S identified ceiling effects, particularly with the item "feeling exhausted." Most EQ-5D-5L and EQ-HWB-S items demonstrated discriminative ability among those with and without physical and mental conditions, yielding medium (> 0.5) to large effect sizes (> 0.8). Nevertheless, only EQ-HWB-S items distinguished between caregivers and noncaregivers and those with low and high caregiver burden, albeit with small effect sizes (0.2-0.5). CONCLUSIONS: Results indicate a convergence between the measures, especially between overlapping dimensions, lending support to the validity of the EQ-HWB-S. The EQ-HWB-S performed similarly or better than the EQ-5D-5L among patient groups and is better able to differentiate among caregivers and respondents closer to full health.

Developing a New Generic Health and Wellbeing Measure: Psychometric Survey Results for the EQ-HWB.

OBJECTIVES: The development of measures such as the EQ-HWB (EQ Health and Wellbeing) requires selection of items. This study explored the psychometric performance of candidate items, testing their validity in patients, social carer users, and carers. METHODS: Article and online surveys that included candidate items (N = 64) were conducted in Argentina, Australia, China, Germany, United Kingdom, and the United States. Psychometric assessment on missing data, response distributions, and known group differences was undertaken. Dimensionality was explored using exploratory and confirmatory factor analysis. Poorly fitting items were identified using information functions, and the function of each response category was assessed using category characteristic curves from item response theory (IRT) models. Differential item functioning was tested across key subgroups. RESULTS: There were 4879 respondents (Argentina = 508, Australia = 514, China = 497, Germany = 502, United Kingdom = 1955, United States = 903). Where missing data were allowed, it was low (UK article survey 2.3%; US survey 0.6%). Most items had responses distributed across all levels. Most items could discriminate between groups with known health conditions with moderate to large effect sizes. Items were less able to discriminate across carers. Factor analysis found positive and negative measurement factors alongside the constructs of interest. For most of the countries apart from China, the confirmatory factor analysis model had good fit with some minor modifications. IRT indicated that most items had well-functioning response categories but there was some evidence of differential item functioning in many items. CONCLUSIONS: Items performed well in classical psychometric testing and IRT. This large 6-country collaboration provided evidence to inform item selection for the EQ-HWB measure.

The Development of a New International Generic Measure (EQ-HWB): Face Validity and Psychometric Stages in Argentina.

OBJECTIVES: This study aimed to present the face validity and psychometric stages performed in Spanish in Argentina, the only Spanish-speaking country of an international collaboration that undertook the construction of a new measure that can be used in economic evaluation across health, social care, and public health, the EQ EQ-HWB (EQ Health and Wellbeing). We also explored the relationship among 3-level version EQ-5D (EQ-5D-3L), 5-level version EQ-5D (EQ-5D-5L), and EQ-HWB. METHODS: Face validity was based on semistructured face to face interviews of a purposive sample to explore translatability of language and concepts of 97 candidate items, translated into Argentina Spanish. The psychometric evaluation using an online panel assessed the psychometric properties of 64 items that were carried forward (floor and ceiling effects, item correlations, known-group differences in relevant prespecified subgroups by the international and local teams, exploratory and confirmatory factor analysis, and item response theory). EQ-5D-3L, EQ-5D-5L, and EQ-HWB correlations were explored. RESULTS: In the face validity stage, 24 interviews with carers, general public, patients, and users of social services were included. Most items showed adequate face validity. In the psychometric assessment, 497 participants were recruited (64% reporting a long-term health condition). Most of the items showed adequate psychometrics in an Argentinian context. EQ-5D-3L and EQ-5D-5L had strong correlations, and EQ-HWB was moderately correlated to EQ visual analog scale. The Argentina team recommended 23 of the final 25 items. CONCLUSIONS: The assessment of Spanish items contributed to the overall development of EQ-HWB and helped inform the design of an internationally relevant 25-item and a short 9-item measure intended to be used in economic evaluations.

Qualitative Review on Domains of Quality of Life Important for Patients, Social Care Users, and Informal Carers to Inform the Development of the EQ-HWB.

OBJECTIVES: To identify the themes to inform the content of a new generic measure, the EQ-HWB (EQ Health and Wellbeing), that can be used in economic evaluation across health, social care, and public health, based on the views of users and beneficiaries of these services including informal carers. METHODS: A qualitative review was undertaken. Systematic and citation searches were undertaken focusing on qualitative evidence of the impact on quality of life from reviews for selected health conditions, informal carers, social care users, and primary qualitative work used in the development of selected measures. A subset of studies was included in the review. Framework analysis and synthesis were undertaken based on a conceptual model. RESULTS: A total of 42 reviews and 24 primary studies were selected for inclusion in the review. Extraction and synthesis resulted in 7 high-level themes (with subthemes): (1) feelings and emotions (sadness, anxiety, hope, frustration, safety, guilt/shame); (2) cognition (concentration, memory, confusion, thinking clearly); (3) self-identity (dignity/respect, self-esteem); (4) "coping, autonomy, and control" relationships; (5) social connections (loneliness, social engagement, stigma, support, friendship, belonging, burden); (6) physical sensations (pain, discomfort, sleep, fatigue); and (7) activity (self-care, meaningful activities, mobility, communication, hearing, vision). Apart from physical sensations, most of the other themes and subthemes were relevant across both health and social care, including for informal carers. CONCLUSIONS: The findings from this broad review identified themes that go beyond health and that are relevant to patients, informal carers, and social care users. The themes and subthemes informed the domains for the EQ-HWB.

The EQ-HWB: Overview of the Development of a Measure of Health and Wellbeing and Key Results.

OBJECTIVES: Existing measures for estimating quality-adjusted life-years are mostly limited to health-related quality of life. This article presents an overview of the development the EQ-HWB (EQ Health and Wellbeing), which is a measure that encompasses health and wellbeing. METHODS: Stages: (1) Establishing domains through reviews of the qualitative literature informed by a conceptual framework. (2) Generation and selection of items to cover the domains. (3) Face validation of these items through qualitative interviews with 168 patients, social care users, general population, and carers across 6 countries (Argentina, Australia, China, Germany, United Kingdom, United States). (4) Extensive psychometric testing of candidate items (using classical, factor analysis, and item response theory methods) on > 4000 respondents in the 6 countries. Stakeholders were consulted throughout. RESULTS: A total of 32 subdomains grouped into 7 high-level domains were identified from the qualitative literature and 97 items generated to cover them. Face validation eliminated 36 items, modified 14, and added 3. Psychometric testing of 64 items found little difference in missing data or problems with response distribution, the conceptual model was confirmed except in China, and most items performed well in the item response theory in all countries. Evidence was presented to stakeholders in 2 rounds of consultation to inform the final selection of items for the EQ-HWB (25-item) and the short version of EQ-HWB (9-items). CONCLUSIONS: EQ-HWB measures have been developed internationally for evaluating interventions in health, public health, and social care including the impact on patients, social care users, and carers.

Discovery of novel BTK inhibitors with carboxylic acids.

We report the design and synthesis of a series of novel Bruton's Tyrosine Kinase (BTK) inhibitors with a carboxylic acid moiety in the ribose pocket. This series of compounds has demonstrated much improved off-target selectivities including adenosine uptake (AdU) inhibition compared to the piperidine amide series. Optimization of the initial lead compound 4 based on BTK enzyme inhibition, and human peripheral blood mononuclear cell (hPBMC) and human whole blood (hWB) activity led to the discovery of compound 40, with potent BTK inhibition, reduced off target activities, as well as favorable pharmacokinetic profile in both rat and dog.

Discovery of potent aryl-substituted 3-[(3-methylpyridine-2-carbonyl) amino]-2,4-dimethyl-benzoic acid EP4 antagonists with improved pharmacokinetic profile.

Two new series of EP4 antagonists containing a 3-methylaryl-2-carbonyl core have been identified. One series has a 3-substituted-phenyl core, while the other one incorporates a 3-substituted pyridine. Both series led to compounds with potent activity in functional and human whole blood (hWB) assays. In the pyridine series, compound 7a was found to be a highly potent and selective EP4 antagonist, with suitable rat and dog pharmacokinetic profiles.

Enhancing the pharmacodynamic profile of a class of selective COX-2 inhibiting nitric oxide donors.

We report herein the development, synthesis, physicochemical and pharmacological characterization of a novel class of pharmacodynamic hybrids that selectively inhibit cyclooxygenase-2 (COX-2) isoform and present suitable nitric oxide releasing properties. The replacement of the ester moiety with the amide group gave access to in vivo more stable and active derivatives that highlighted outstanding pharmacological properties. In particular, the glycine derivative proved to be extremely active in suppressing hyperalgesia and edema.

The performance of the EQ-HWB-S as a measure of quality-of-life of caregivers in families that have experienced adverse events.

PURPOSE: The recently developed EQ Health and Wellbeing Instrument (EQ-HWB) is a broad, generic measure of quality-of-life designed to be suitable for caregivers. The aim of this study was to investigate performance and validity of the 9-item version (EQ-HWB-S) for caregivers where families had experienced adverse-life-events. METHODS: Using survey data from caregivers of children aged 0-8 years attending a community-health centre in 2021-2022, the general performance, feasibility, convergent and known-group validity, responsiveness-to-change, and test-retest reliability of the EQ-HWB-S was assessed. Twelve semi-structured interviews were conducted with survey respondents to assess acceptability and content validity. RESULTS: The sample included  234 caregivers at baseline (81% female, mean age 36-years, 38% Australian-born) and 190 at 6-months follow-up. Most EQ-HWB-S item responses were evenly spread, except for 'Mobility'. The instrument showed good convergent validity with psychological distress (Kessler 6 (K6)) and personal-wellbeing (PWI-A) scales. EQ-HWB-S level sum-scores and preference-weighted scores were significantly different in all known-group analyses, in expected directions, and the instrument was responsive to change. For test-retest reliability, Intraclass Correlation Coefficients were excellent and individual item Kappa scores were moderate. The instrument was well received by interviewees who found the questions clear and relevant. The items were appropriate for parents experiencing adversity and carers of children with additional needs. CONCLUSION: The EQ-HWB-S appeared valid, responsive to change, feasible, and well accepted by caregivers. By demonstrating the validity of the EQ-HWB-S in this hard-to-reach population of caregivers in families experiencing adverse events, this study adds to existing international evidence supporting its use.

Biochar efficacy for reducing heavy metals uptake by Cilantro (Coriandrum sativum) and spinach (Spinaccia oleracea) to minimize human health risk.

Environmentally friendly and cost-effective techniques are required to reclaim land degraded during mining activities. Bioaccumulation of heavy metals (HMs) in vegetables grown on contaminated soils can increase human health risks. The potential effects of hardwood biochar (HWB) was assessed for chromium (Cr), zinc (Zn), copper (Cu), manganese (Mn) and lead (Pb) bioavailability in mine-contaminated soils and their subsequently bioaccumulation in crops and associated health risk. HWB was applied to chromium-manganese mine contaminated soils at the rate of 3% to investigate the efficiency of HWB for the second crop in crop rotation technique. Cilantro (Coriandrum sativum) and spinach (Spinaccia oleracea) were grown as second crop in the same pots which were already used for rice cultivation as first crop (without adding further amendments). Application of HWB decreased the concentrations of Cr, Zn, Cu, Mn, and Pb in cilantro by 25.5%, 37.1%, 42.5%, 34.3%, and 36.2%, respectively as compared to control. In spinach, the reduction in concentrations of Cr was 75.0%, Zn 24.1%, Cu 70.1%, Mn 78.0%, and Pb 50.5% as compared to control. HWB significantly (P < 0.01) reduced the HMs uptake in spinach cultivated in the amended soils as compared to the spinach in control. Bioaccumulation factor results also indicate that HWB decreased the bioaccumulation of selected HMs in cilantro and spinach, thus reducing health risks. Results of the study clearly demonstrate that the use of HWB can significantly reduce HMs in vegetables, associated health risk and improve food quality, therefore can be used as soil amendment for reclamation of mine-degraded soils.

Screening Vaccine Formulations in Fresh Human Whole Blood.

Monitoring the immunological functionality of vaccine formulations is critical for vaccine development. While the traditional approach using established animal models has been relatively effective, the use of animals is costly and cumbersome, and animal models are not always reflective of a human response. The development of a human-based approach would be a major step forward in understanding how vaccine formulations might behave in humans. Here, we describe a platform methodology using fresh human whole blood (hWB) to monitor adjuvant-modulated, antigen-specific responses to vaccine formulations, which is amenable to analysis by standard immunoassays as well as a variety of other analytical techniques.

A high ratio of IC31(®) adjuvant to antigen is necessary for H4 TB vaccine immunomodulation.

A tuberculosis (TB) vaccine consisting of a recombinant fusion protein (H4) and a novel TLR9 adjuvant (IC31) is in clinical development. To better understand the H4-IC31 ratio, we measured the binding capacity of IC31 for H4 protein and immunized mice with formulations that contained limiting to excess ratios of IC31 to H4. An immunomodulated H4-specific IFNγ response was only observed when IC31 was present in excess of H4. Since TLR expression is species-specific and the vaccine is intended to boost BCG-primed immunity, we questioned whether data in mice would translate to humans. To address this question, we used the fresh human Whole Blood (hWB) recovered from BCG-vaccinated subjects to screen H4-IC31 formulations. We found IC31 modulation in hWB to be quite distinct from the TLR4-Adjuvant. Unlike TLR4-Adjuvant, IC31 formulations did not induce the pro-inflammatory cytokine TNFα, but modulated a robust H4-specific IFNγ response after 12 d of culture. We then re-stimulated the fresh hWB of 5 BCG-primed subjects with formulations that had excess or limiting IC31 binding for H4 protein and again found that an immunomodulated H4-specific IFNγ response needed an excess of IC31. Finally, we monitored the zeta (ζ) potential of H4-IC31 formulations and found that the overall charge of H4-IC31 particles changes from negative to positive once IC31 is in greater than 9-fold excess. Using two diverse yet mutually supportive approaches, we confirm the need for an excess of IC31 adjuvant in H4 TB vaccine formulations and suggest surface potential may be an important factor.