Making what counts be counted: evaluating the use of preference-based outcome measures in Parkinson’s disease

Parkinson’s is a common neurodegenerative disorder that can have a significant impact on an individual’s health, quality of life (QoL), and wellbeing, causing a substantial economic burden on patients, their caregivers, the health service, and broader social and community services. Whilst Parkinson’s wide range of QoL and financial impacts have been well documented relatively little research has explored to what extent such impacts have been appropriately incorporated into economic evaluations. Economic evaluation is used by the National Institute for Health and Care Excellence (NICE) in the UK to guide health-care resource allocation in the NHS. It uses preference-based outcome measures to measure and value the health outcomes of different interventions. These health utilities are combined with durations to estimate quality-adjusted life-years. The important role of the preference-based outcomes requires them to be accurately capturing the benefit of interventions, otherwise the estimation of cost-effectiveness of interventions will be not be reflecting true preference/choice between interventions. This may lead to mistakes in funding decisions and insufficient allocation of resources. Despite the importance of accurately capturing the benefit of interventions, the existing generic preference-based measures (e.g., the EQ-5D measure as recommended by NICE) are sometimes criticised for their ‘health-related’ nature as insufficient to capture all the QoL aspects that are affected by the disease or the intervention. This raises a question of “is the generic ‘prescribed’ measure appropriate for all disease areas and all interventions?” For diseases that have broad impact on people’s health and wellbeing such as Parkinson’s, a broadly scoped preference-based wellbeing instrument which could measure the impact of intervention beyond health may potentially fill the gap of the limited scope of the ‘health-related’ preference-based measures (if any). Meanwhile, there are concerns relating to their relevance and sensitivity to specific health aspects and their validity in general to be used in the healthcare context. Given this, the aim of this thesis is to examine the performance of the existing preference-based outcomes in people with Parkinson’s, and evaluate the potential of using a generic preference-based capability-wellbeing measure, ICECAP-O, in this population. This thesis conducted a systematic review of the existing preference-based measures to assess their construct validity and responsiveness in people with Parkinson’s. Two empirical studies explored these properties of the ICECAP-O measure in people with Parkinson’s. Construct validity and responsiveness are the two key psychometric properties relevant to preference-based measures for their use in economic evaluations. Data for both empirical analyses were obtained from the PD MED large-scale randomised controlled trial. This thesis has identified evidence of limited responsiveness of the existing preference-based measures in people with Parkinson’s and suggested that the current commonly used preference-based health-related QoL measures may underestimate the value placed on the mental and social wellbeing aspects that Parkinson’s populations are affected by. This limited ability of the utility values to differentiate health states may have an impact on resource allocation decisions. Especially as this relates to the cost-effectiveness of interventions that have the capacity to influence the mental and social wellbeing aspects of people’s lives. This highlights the need for consideration of a broadly scoped measure such as the ICECAP-O to incorporate such aspects in economic evaluations of diseases such as Parkinson’s. This thesis established the construct validity and responsiveness of the ICECAP-O instrument and demonstrated that there are valued capability wellbeing attributes in Parkinson’s beyond those quality of life attributes reflected by the EQ-5D instrument. It contributes to understanding the use of broadly scoped outcome measures for economic evaluations in Parkinson’s by showing that the ICECAP-O capability wellbeing instrument was able to provide a preference-based assessment of these under-represented aspects in the Parkinson’s population, without compromising its sensitivity to the clinical and specific physical QoL dimensions in this patient group. While further exploration of the role of ICECAP-O in economic evaluation and decision making through the work of assessing ‘sufficient capability’ is required, this thesis establishes initial foundations for the use of the ICECAP-O as a preference-based instrument to measure the impact of interventions in Parkinson’s populations

Dendrimer conjugates for light-activated delivery of antisense oligonucleotides

PAMAM dendrimer conjugates are used to co-deliver oligonucleotides and photosensitizers to cancer cells. After photo-irradiation, substantial reporter eGFP expression is produced by functional delivery of a model oligonucleotide

Direct oligonucleotide–photosensitizer conjugates for photochemical delivery of antisense oligonucleotides

Direct conjugation of photosensitizer to oligonucleotides allows spatial and temporal co-localization of the two modalities in the target cells and thus leads to superior photochemical delivery of oligonucleotides

Dendritic nanoconjugates of photosensitizer for targeted photodynamic therapy

Abstract Application of photodynamic therapy for treating cancers has been restrained by suboptimal delivery of photosensitizers to cancer cells. Nanoparticle (NP)-based delivery has become an important strategy to improve tumor delivery of photosensitizers; however, the success is still limited. One problem for many NPs is poor penetration into tumors, and thus the photokilling is not complete. We aimed to use chemical conjugation method to engineer small NPs for superior cancer cell uptake and tumor penetration. Thus, Chlorin e6 (Ce6) was covalently conjugated to PAMAM dendrimer (generation 7.0) that was also modified by tumor-targeting RGD peptide. With multiple Ce6 molecules in a single nanoconjugate molecule, the resultant targeted nanoconjugates showed uniform and monodispersed size distribution with a diameter of 28 nm. The singlet oxygen generation efficiency and fluorescence intensity of the nanoconjugates in aqueous media were significantly higher than free Ce6. Targeted nanoconjugates demonstrated approximately 16-fold enhancement in receptor-specific cellular delivery of Ce6 into integrin-expressing A375 cells compared to free Ce6 and thus were able to cause massive cell killing at low nanomolar concentrations under photo-irradiation. In contrast, they did not cause significant toxicity up to 2 μM in dark. Due to their small size, the targeted nanoconjugates could penetrate deeply into tumor spheroids and produced strong photo-toxicity in this 3-D tumor model. As a result of their great cellular delivery, small size, and lack of dark cytotoxicity, the nanoconjugates may provide an effective tool for targeted photodynamic therapy of solid tumors. Graphical abstrac

Within-trial cost and 1-year cost-effectiveness of the DiRECT/Counterweight-Plus weight-management programme to achieve remission of type 2 diabetes

No abstract available

Parent-reported outcomes in young children with disorders/differences of sex development

Background: There is a paucity of tools that can be used in routine clinical practice to assess the psychosocial impact of Disorders/Differences of Sex Development (DSD) on parents and children. Objective: To evaluate the use of short Parent Self-Report and Parent Proxy-Report questionnaires that can be used in the outpatient setting. Methods: Previously validated DSD-specific and generic items were combined to develop a Parent Self-Report questionnaire and a Parent Proxy-Report questionnaire for children under 7 years. Of 111 children approached at one tertiary paediatric hospital, the parents of 95 children (86%) with DSD or other Endocrine conditions completed these questionnaires. Results: Questionnaires took under 10 min to complete and were found to be easy to understand. Compared to reference, fathers of children with DSD reported less stress associated with Clinic Visits (p = 0.02) and managing their child’s Medication (p = 0.04). However, parents of children with either DSD or other Endocrine conditions reported more symptoms of Depression (p = 0.03). Mothers of children with DSD reported greater Future Concerns in relation to their child’s condition (median SDS − 0.28; range − 2.14, 1.73) than mothers of children with other Endocrine conditions (SDS 1.17; − 2.00, 1.73) (p = 0.02). Similarly, fathers of children with DSD expressed greater Future Concerns (median SDS -1.60; − 4.21, 1.00) than fathers of children with other Endocrine conditions (SDS 0.48; − 2.13, 1.52) (p = 0.04). Conclusion: DSD was associated with greater parental concerns over the child’s future than other Endocrine conditions. Brief parent-report tools in DSD can be routinely used in the outpatient setting to assess and monitor parent and patient needs

Feasibility study for interactive reporting of network meta-analysis : experiences from the development of the MetaInsight COVID-19 app for stakeholder exploration, re-analysis and sensitivity analysis from living systematic reviews

Background: Network meta-analysis (NMA) has been increasingly adopted worldwide by Cochrane reviews, guideline developers and decision-making bodies to identify optimal treatment choices. However, NMA results are often produced statically, not allowing stakeholders to ‘dig deeper’ and interrogate with their own judgement. Additionally, amid the COVID-19 pandemic, unnecessary or duplicated reviews have been proposed which analyse from the same pool of evidence. We developed the ‘MetaInsight COVID-19’ app as a prototype for an interactive platform to eliminate such duplicated efforts, by empowering users to freely analyse the data and improve scientific transparency. Methods: MetaInsight COVID-19 (https://crsu.shinyapps.io/metainsightcovid/) was developed to conduct NMA with the evolving evidence on treatments for COVID-19. It was updated weekly between 19th May – 19th Oct 2020, incorporating new evidence identified from a living systematic review. Results: The app includes embedded functions to facilitate study selection based on study characteristics, and displays the synthesised results in real time. It allows both frequentist and Bayesian NMA to be conducted as well as consistency and heterogeneity assessments. A demonstration of the app is provided and experiences of building such a platform are discussed. Conclusions: MetaInsight COVID-19 allows users to take control of the evidence synthesis using the analytic approach they deem appropriate to ascertain how robust findings are to alternative analysis strategies and study inclusion criteria. It is hoped that this app will help avoid many of the duplicated efforts when reviewing and synthesising the COVID-19 evidence, and, in addition, establish the desirability of an open platform format such as this for interactive data interrogation, visualisation, and reporting for any traditional or ‘living’ NMA

Orbital parameters for an ELM white dwarf with a white dwarf companion: LAMOST J033847.06+413424.2

Double white dwarf systems are of great astrophysical importance in the field of gravitational wave and Type Ia supernova. While the binary fraction of CO core white dwarf is about a few percents, the extremely low mass white dwarfs are all thought to be within binary systems. In this work, we report the orbital solution of a double degenerate system: J033847.06+413424.24, an extremely low mass He core white dwarf orbiting a CO core white dwarf. With LAMOST and P200, time domain spectroscopic observations have been made and spectral atmosphere parameters are estimated to be $T_{\rm eff}\sim22500$ K and log $g\sim5.6$ dex. Combining Gaia parallax, 3D extinction, and evolution tracks, we estimate a radius of $\sim0.12$ $R_{\odot}$ and a mass of $\sim0.22$ $M_{\odot}$. With the 37 single exposure spectra, the radial velocities are measured and the orbital parameters are estimated to be $P=0.1253132(1)$ days, $K1=289\pm4$ km/s and $V_{sys}=-41\pm3$ km/s. The radial velocity based system ephemeris is also provided. The light curves from several photometric surveys show no orbital modulation. The orbital solution suggests that the invisible companion has a minimum mass of about 0.60 $M_{\odot}$ and is $\sim0.79$ $M_{\odot}$ for an inclination of $60.0^{\circ}$, indicating most probably a CO core white dwarf. The system is expected to merge in about 1 Gyr. With present period and distance ($\sim596$ pc) it can not irradiate strong enough gravitational wave for LISA. More double degenerate systems are expected to be discovered and parameterized as the LAMOST survey goes on.Comment: 12 pages, 11 figure

Dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter-2 inhibitors for people with cardiovascular disease: a network meta-analysis (Protocol)

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To systematically review the available evidence on the effects (benefits and harms) of DPP‐4 inhibitors, GLP‐1 receptor agonists, and SGLT‐2 inhibitors in people with established CVD, using network meta‐analysis

Development and validation of a short version of the quality of life-DSD questionnaire for parents of young children with conditions affecting sex development

There is a paucity of information on health-related quality of life (HRQoL) outcomes in parents and children with conditions affecting sex development. The objective of this study was to develop short forms of HRQoL questionnaires which consist of a 63-item and 25-item parent self-report (PSR) and parent proxy-report (PPR), respectively, optimising use in routine clinic settings. Short questionnaires were developed following exploratory factor analysis using raw data from 132 parents. Long and short PSRs were completed by 24 parents of children with conditions affecting sex development with median age of 3.6 years (range 0.1, 6.6); 21 (88%) were boys and 11 (46%) had proximal hypospadias. A subset of 19 parents completed long and short PPRs. Item selection based on factor loadings of >0.8 and expert consultation, produced short PSR and PPRs containing 16 and 7 items, respectively. There was no statistically significant difference in 11 out of 12 (92%) scales on the PSR and 4 out of 5 (80%) scales on the PPR when comparing short and long questionnaire scores. Short and long questionnaires took <1 minute and 5 minutes for completion, respectively. Eighteen parents (75%) reported that the time taken to complete short questionnaires was acceptable; 10 (42%) preferred short questionnaires. Ten (42%) versus 6 (25%) stated a preference for completing short versus long questionnaires. Short versions were largely representative of the long questionnaires and are acceptable to evaluate psychosocial distress in young children and their caregivers. Further psychometric validation of short forms is warranted