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Value-adaptive clinical trial designs for efficient delivery of publicly funded trials - a discussion of methods, case studies, opportunities and challenges
Get PDFBackground
Value-adaptive designs for clinical trials are a novel set of emerging methods for delivering greater value for clinical research. There is increasing interest in using them within publicly funded health systems. A value-adaptive design permits ‘in progress’ changes to be made to the trial according to criteria which reflect its overall value to the healthcare system, including the cost-effectiveness of the technologies under investigation, the cost of running the trial and the total health benefit delivered to patients. These trial designs offer the potential to explicitly balance the costs and benefits of adaptive clinical trials with the health economic benefits expected for populations that are affected by any subsequent health technology adoption decisions. They may also improve the expected value of learning from the budget that is spent within a trial.
Main body
This paper introduces value-adaptive designs for publicly funded clinical trials. It discusses the idea of delivering ‘value for money’ in health technology assessment, what is meant by being ‘value-adaptive’ and the key features that characterise these designs. The methodology behind one kind of value-adaptive design – the value-based sequential model of a two-armed clinical trial proposed by Chick et al. (2017) – is described and illustrated using three retrospective case studies from the United Kingdom. The paper concludes by reviewing a range of perspectives provided by stakeholders, together with our own thoughts, on the practical opportunities and changes required for implementing a value-adaptive approach.
Conclusions
Value-adaptive clinical trial designs offer the potential to align health research funding allocations with population health economic goals. Many of the systems required to deploy value-adaptive designs within a publicly funded health system already exist and, with increased application, experience, and refinement they have the potential to deliver improved value for money
Novel hybrid rare‐earth and ferrite magnet asymmetric V‐shape and U‐shape IPMSMs accounting for demagnetisation withstand capability
Get PDFThis paper presents two novel hybrid rare-earth and ferrite permanent magnet (HPM) asymmetric V-shape and U-shape interior PM synchronous machines (IPMSMs) with high ferrite PM (FEPM) torque contribution accounting for the enhanced demagnetisation withstand capability of FEPM at both open circuit and overload conditions. The proposed topologies are designed and compared with a rare-earth PM (REPM)-based symmetrical V-shape baseline in terms of electromagnetic performances, mechanical strength, demagnetisation withstand capability, and PMs cost. All machines are optimised for the same torque with the minimum volume of high-cost REPM at the same specification and size as a commercialised electric vehicle (EV) IPMSM. It is shown that the synergies of magnetic field shifting effect and HPM utilisation have improved the torque per REPM usage in both proposed machines. However, the magnetic field shifting of the proposed HPM asymmetric U-shape IPMSM is twice of that in the V-shape IPMSM counterpart along with a slightly better FEPM demagnetisation withstand capability. Meanwhile, the results show that the proposed HPM asymmetric V-shape IPMSM would be cheaper than the U-shape counterpart as the former and latter topologies require ∼31% and ∼23.5% less REPM volume than the baseline, respectively. Finally, two small laboratory size prototypes are made and tested to verify the finite element analyses
Parents' experiences of the financial and employment impacts of their child receiving end-of-life care:a national qualitative study
Get PDFBACKGROUND: Bereaved parents are at higher risk of poor mental and physical health outcomes than people bereaved under other circumstances. These challenges are exacerbated by the continued effects on parents' working lives and the financial strain of a child receiving end-of-life care. There has been very little recent research of parents' experiences of these impacts. Analysis of data from the second workstream of a national research programme on end-of-life care for infants, children and young people (ENHANCE) aimed to understand parents' experiences of the impact on their finances and working lives while their child received end-of-life care. METHODS: A multi-site qualitative study using in-depth interviews with bereaved parents, analysed using thematic analysis. Recruited through NHS sites, children's hospices and via the social media of third sector organisations. RESULTS: Forty-two interviews with 55 parents were conducted (Fathers = 16, Mothers = 39), representing 44 children. Four themes were developed: (1) The added cost burden; (2) Pressures of juggling work; (3) Accessing support; and (4) Financial impacts continue after a child dies. CONCLUSIONS: Financial hardship is a known consequence of having a child with a life-limiting condition, especially at the end of life, and adds considerable stress to an already painful situation, with the aftermaths continuing into bereavement. The impact is exacerbated by parents' need to reduce work so they can spend time caring for their dying child, leaving families in a financially and emotionally vulnerable position. There needs to be a consistent approach to immediate practical support from healthcare providers; a review of benefit system delays and the abrupt stopping of Disability Living Allowance; and the development of tailored employment support for parents to remain in or rejoin the workforce
High-light-inducible proteins control associations between chlorophyll synthase and the Photosystem II biogenesis factor Ycf39
Get PDFThe biogenesis of Photosystem II is a complicated process requiring numerous auxiliary factors to assist in all steps of its assembly. The cyanobacterial protein Ycf39 forms a stress-induced complex with 2 small chlorophyll-binding, High-light-inducible proteins C and D (HliC and HliD), and has been reported to participate in the insertion of chlorophyll molecules into the central D1 subunit of Photosystem II. However, how this process is organized remains unknown. Here, we show that Ycf39 and both HliC and HliD can form distinct complexes with chlorophyll synthase (ChlG) in the model cyanobacterium Synechocystis sp. PCC 6803. We isolated and characterized ChlG complexes from various strains grown under different conditions and provide a mechanistic view of the docking of Ycf39 to ChlG via HliD and the structural role of HliC. In the absence of stress, chlorophyll is produced by the ChlG-HliD2-ChlG complex, which is stabilized by chlorophyll and zeaxanthin molecules bound to the HliD homodimer. The switch to high light leads to stress pressure and greatly elevated synthesis of HliC, resulting in the replacement of HliD homodimers with HliC-HliD heterodimers. Unlike HliD, HliC cannot interact directly with ChlG or Ycf39. Therefore, the original ChlG-HliD2-ChlG complex is converted into a ChlG-HliD-HliC hetero-trimer that presumably binds transiently to Ycf39 and the nascent D1 polypeptide. We speculate that this molecular machinery promotes the delivery of chlorophyll to D1 upon high-light-induced chlorophyll deficiency. The HliD homodimers formed under standard, nonstress growth conditions and attached to ChlG could serve as an emergency chlorophyll reserve
Efficacy and safety of dupilumab in pediatric patients aged 6 months to 11 years with erythrodermic atopic dermatitis: A post-hoc analysis of three clinical trials
No full textKindness and curious kinships in the lives of family carers of adults with learning disabilities
No full textThis paper engages with the transcripts of 12 family carers to explore kindness in the lives of family carers and adults with learning disabilities. Knowing that kindness matters and understanding kindness to be inextricably linked to an expansive notion of kinship that extends beyond familial ties, we examine the presence and absence of kindness and kinship in the interactions family carers have with health and social care professionals, services, and systems. This study forms part of a wider research project undertaken in England exploring how family carers of adults with learning disabilities conceptualise and experience mental health, services and support
The illicit cigarette market in the Democratic Republic of the Congo (DRC):findings from a cross-sectional study of empty cigarette packs
Get PDFThis study aimed to estimate the proportion of cigarettes consumed in the Democratic Republic of the Congo (DRC) that are illicit and the extent of cigarette tax evasion; and to identify the origins of and factors associated with illicit cigarettes. Data were collected from May 15 to June 9, 2023. Stratified, multistage sampling was used to select 32 health areas from which empty cigarette packs were collected. Each collected pack was examined and classified as licit if it complied, or illicit if it did not comply, with the DRC’s tax stamp or written health warning requirements, or the requirements to have a notice indicating the prohibition of sale by/to minors or information on tar and nicotine content. We reported frequencies as numbers and percentages, and continuous variables as means or medians. We performed regression analysis and used adjusted odds ratios (aOR) and their 95% confidence intervals (CI) to measure associations. 8.6% (95% CI: 8.1, 9.2) of the 10622 empty cigarette packs collected were illicit, and had also evaded cigarette tax. 8.0% of the collected packs did not comply with written health warning requirements, 5.6% did not indicate the prohibition of sale by/to minors, and 4.5% did not have information on tar and nicotine content. Packs from low-income areas were more likely to be illicit than those collected from high-income areas (aOR 1.90; [95% CI: 1.48-2.43]). The likelihood of being an illicit cigarette increased with increasing susceptibility to armed conflict/insecurity. Packs from border provinces were less likely to be illicit than those from non-border provinces (aOR 0.48; [95% CI: 0.25-0.90]). All illicit cigarettes were imports from other countries. There is, therefore, a need to secure the cigarette supply chain, strengthening border controls and enforcement and compliance monitoring, and strengthening political commitment by Ratifying the WHO Protocol on Illicit Tobacco Trade
Paediatric low vision service evaluation: Sheffield teaching hospitals NHS foundation trust
Get PDFThis retrospective service evaluation was conducted to evaluate the low vision (LV) clinic and its impact for children attending Sheffield Teaching Hospitals (STH) between 2012 and 2022. The main cause of vision impairment (VI), LV aids used and their impact on distance and near visual acuity (VA), was extracted from medical records. Index of multiple deprivation (IMD) was determined using each child’s postal code. The most common causes of VI were retinal disease (32%), albinism (16%), and nystagmus (12%). One third of children with VI lived in areas of the lowest decile IMD. Two thirds were certified as sight impaired (SI) or severely sight impaired (SSI). LV aids significantly improved near and distance vision (p < .001). Given that the high number of children with VI lived in socioeconomically deprived areas, LV clinic and LV aids should be available for all children with VI regardless of their socioeconomic or registration status
The Genomic Signature of Demographic Decline in a Long-Distance Migrant in a Range-Extreme Population
Get PDFMigratory birds are inherently vagile, a strategy that may reduce the impacts of habitat loss and fragmentation on genetic diversity. However, specialist resource requirements and range-edge distribution can counteract these benefits. The European nightjar (Caprimulgus europaeus) is a long-distance migratory bird and resource specialist. Like other long-distance migrants, nightjar populations have declined across the British Isles and Northwestern Europe over the past century. With this decline well documented in the British Isles, there is a need to quantify its genetic impacts. We applied full genome resequencing to 60 historic (1841-1980) and 36 contemporary British nightjars. Nightjars exhibited a statistically significant 34.8% loss in heterozygosity and an increase in inbreeding over the last ~180 years, showing a departure from panmixia towards weak spatial structure in the modern population. Such fine-scale structuring in migratory birds is rare. Our results provide a case study of fragmentation's impact on a species with specialist resource requirements at its range limit. Similar demographic declines in nightjars and other long-distance migrants across Northern and Western Europe suggest that genetic patterns seen in the British population may reflect those in other nightjar populations and European avifauna. Whilst our results indicate no immediate conservation concern, they depict a trajectory of declining genetic diversity, increasing inbreeding and genetic structure, potentially shared with other migratory species. Our study highlights the value of applying spatiotemporal population genetics analysis to migratory birds, despite their inherent vagility
Deep Learning-Based Exposure Asymmetry Multispectral Reconstruction from Digital RGB Images
Get PDFMultispectral reconstruction is an important way to acquire spectral images with a high spatial resolution as snapshots. Current deep learning-based multispectral reconstruction models perform well under symmetric conditions, where the exposure of training and testing images is consistent. However, further research has shown that these models are sensitive to exposure changes. When the exposure symmetry is not maintained and testing images are input into the multispectral reconstruction model under different exposure conditions, the reconstructed multispectral images tend to deviate from the real ground truth to varying degrees. This limitation restricts the robustness and applicability of the model in practical scenarios. To address this challenge, we propose an exposure estimation multispectral reconstruction model of EFMST++ with data augmentation and optimized deep learning architecture, where Retinex decomposition and a wavelet transform are introduced into the proposed model. Based on the currently available dataset in this field, a comprehensive comparison is made between the proposed and existing models. The results show that after the current multispectral reconstruction models are retrained using the augmented datasets, the average MRAE and RMSE of the current most advanced model of MST++ are reduced from 0.570 and 0.064 to 0.236 and 0.040, respectively. The proposed method further reduces the average MRAE and RMSE to 0.229 and 0.037, with the average PSNR increasing from 27.94 to 31.43. The proposed model supports the use of multispectral reconstruction in open environments
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