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Transparent reporting of observational studies emulating a target trial: the TARGET Statement
No full textImportance: when randomized trials are unavailable or not feasible, observational studies can be used to answer causal questions about the comparative effects of interventions by attempting to emulate a hypothetical pragmatic randomized trial (target trial). Published guidance to aid reporting of these studies is not available. Objective: to develop consensus based guidance for reporting observational studies performed to estimate causal effects by explicitly emulating a target trial. Design, setting, and participants: the Transparent Reporting of Observational Studies Emulating a Target Trial (TARGET) guideline was developed using the Enhancing the Quality and Transparency of Health Research (EQUATOR) framework. The development included (1) a systematic review of reporting practices in published studies that had explicitly aimed to emulate a target trial; (2) a two round online survey (August 2023 to March 2024; 18 expert participants from six countries) to assess the importance of candidate items selected from previous research and to identify additional items; (3) a three day, expert consensus meeting (June 2024; 18 panelists) to refine the scope of the guideline and draft the checklist; and (4) pilot of the draft checklist with stakeholders (n=108; September 2024 to February 2025). The checklist was further refined based on feedback on successive drafts. Findings: the 21-item TARGET checklist is organized into six sections (abstract, introduction, methods, results, discussion, other information). TARGET provides guidance for reporting observational studies of interventions explicitly emulating a parallel group, individually randomized target trial, with adjustment for baseline confounders. Key recommendations are to (1) identify the study as an observational emulation of a target trial; (2) summarize the causal question and reason for emulating a target trial; (3) clearly specify the target trial protocol (ie, the causal estimand, identifying assumptions, data analysis plan) and how it was mapped to the observational data; and (4) report the estimate obtained for each causal estimand, its precision, and findings from additional analyses to assess the sensitivity of the estimates to assumptions, and design and analysis choices. Conclusions and relevance: application of the TARGET guideline recommendations aims to improve reporting transparency and peer review and help researchers, clinicians, and other readers interpret and apply the results.</p
Liver fat accumulation within the ‘normal range’ is associated with the presence of metabolic syndrome traits
No full textAims: the primary objective of this cross-sectional study was to re-examine the liver fat thresholds associated with metabolic health and number of metabolic syndrome (MetS) traits.Methods: in this cross-sectional study, 597 participants (99.7 % white European) underwent assessment of i) cardiometabolic health with individual MetS traits ii) alcohol consumption and iii) steatotic liver disease (SLD), defined by MRI-PDFF or proton spectroscopy (1H-MRS) liver fat ≥5.56 %.Results: the median (IQR) liver fat was 0.4 % (0.9) in 30 subjects without MetS traits and 6.7 % (15.4) and 16.7 % (20.1) in 117 and 108 subjects with 3 and 5 MetS traits respectively. SLD was associated with each MetS trait (increased blood pressure, central obesity, dysglycaemia, high triglyceride and low HDL-C concentrations; all p < 0.001). There was an increase in liver fat (%) according to increasing number of MetS traits (p < 0.001). There was an increase in every MetS trait with liver fat categories below 5.56 % (i.e. ≥1 % and ≤1.85 %, >1.85 % and <5.56 %).Conclusions: previously defined normal levels of liver fat are not associated with optimal metabolic health (no MetS traits). Small increments in liver fat, even within a pre-defined normal range, are associated with a progressive increase in the number of MetS traits
Cost-utility analysis of TAVI versus surgery in low-risk patients with severe aortic stenosis in the UK
No full textBackground and objective: European guidelines recommend transcatheter aortic valve implantation (TAVI; class IA) for symptomatic severe aortic stenosis (sSAS) in patients aged ≥ 75 years, if a transfemoral approach is possible. Recent cost-utility analyses based on the PARTNER 3 trial have suggested that TAVI with the SAPIEN 3 device is cost effective versus surgical aortic valve replacement (SAVR) in patients at low risk of surgical mortality in several European countries. This cost-utility analysis compares TAVI with SAPIEN 3 versus SAVR in patients with sSAS at low risk of surgical mortality from the UK healthcare system perspective, using 5-year PARTNER 3 trial data.Methods: a two-stage, Markov-based, cost-utility analysis was performed using published and validated methodology to estimate changes in both direct healthcare costs and health-related quality of life for TAVI with SAPIEN 3 versus SAVR in patients with sSAS at low surgical risk from the perspective of the UK healthcare system. The model used a lifetime horizon with a 3.5% yearly discounting factor. Uncertainty was addressed using deterministic and probabilistic sensitivity analyses.Results: transcatheter aortic valve implantation with SAPIEN 3 generated an incremental health benefit of 0.47 (90% credible interval 0.35–0.60) quality-adjusted life-years per patient compared with SAVR, at an increased cost of £7999 (£852–£15,035 90% credible interval) per patient over a lifetime horizon (incremental cost-effectiveness ratio: £16,979 per quality-adjusted life-year gained). Transcatheter aortic valve implantation has a 63–90% probability of cost effectiveness based on a £20,000–£30,000 willingness-to-pay threshold. Transcatheter aortic valve implantation remained cost effective across most deterministic sensitivity analyses, confirming the relative robustness of the results.Conclusions: transcatheter aortic valve implantation with SAPIEN 3 has a 63–90% probability of being cost effective compared with SAVR for low-surgical-risk patients with sSAS. These findings may inform policy decision making in the management of this patient group.<br/
Correlation between imaging-detected and pathological extranodal extension in a randomised trial in Human Papillomavirus-positive oropharyngeal cancer
No full textBackground Imaging-detected and pathological extranodal extension (iENE, pENE) negatively impact prognosis in Human Papillomavirus (HPV)-positive oropharyngeal cancer (OPSCC), as reflected in future TNM staging updates. Correlation between iENE and pENE in HPV-positive OPSCC is currently unknown yet is vital to determine how iENE should be used to influence treatment decisions. Methods PATHOS is a trial of de-intensified adjuvant treatment after transoral surgery for HPV-positive OPSCC. 291 consecutively recruited patients undergoing surgery at three UK centres were included. Pre-operative cross-sectional imaging (CT and/or MRI) was independently scored for iENE by 2 expert radiologists; pENE was scored by 2 expert pathologists. Results Inter-rater agreement for iENE was fair in round 1 (Gwet’s AC: 0.34 (95%CI:0.26–0.41)) but improved to very good after second review (Gwet’s AC: 0.88 (95%CI:0.85–0.93), Agreement: 0.91 (95%CI:0.87–0.94)). Sensitivity of iENE for predicting pENE was relatively low (at best: 56.4% (95%CI:42.3–69.7) and specificity was high (at worst: 70.9% (95%CI:65.0–76.3)). Excluding cases with suboptimal image quality and recent core biopsy produced modest improvements in sensitivity (up to 59.4% (95%CI:40.6–76.3)) and specificity (up to 87.8% (95%CI:80.4–93.2)). Discussion The high specificity could help select iENE-negative patients for surgery, but higher sensitivity is required before excluding surgery based solely on iENE positivity
Recipient-focused interventions to increase vaccine uptake in high and upper-middle income countries: a systematic review and network meta-analysis
No full textBackground Vaccination is a highly effective public health tool. However, uptake of many vaccines has declined globally over the past decade, exacerbated by the COVID-19 pandemic, with coverage often falling short of critical thresholds. There is a large evidence-base of vaccine uptake interventions targeting vaccine recipients. Here we aim to synthesise evidence on the comparative effectiveness of these interventions, assess variations by age, and evaluate the impact of the COVID-19 pandemic on intervention effectiveness.Methods We conducted a systematic review, searching nine databases and grey literature for randomised controlled trials from high and upper-middle income countries, published from 2000 to April 2024. We included interventions targeted at vaccine recipients of any age (or their caregivers) living in the community, aimed at increasing uptake of routine or selective/targeted vaccinations on the UK schedule and categorised them into six intervention categories (access, affordability, education, reminder, education and reminder, and multi-component). Our outcome was number vaccinated. We estimated odds ratios (ORs) using Bayesian random effects network meta-analysis (NMA) combining all direct and indirect evidence on relative intervention effects in a single coherent analysis. Risk of bias was assessed using the Cochrane RoB 2 tool and certainty in the evidence using CINeMA. This review is registered with PROPSERO (CRD42022369139).Findings We included 268 studies (6,243,118 participants; 39% male, 61% female) with 223 eligible for analysis. Studies not eligible for analysis are narratively reported. Of those eligible for analysis, we assessed 105 studies as low risk of bias, 87 as some concerns, and 31 as high risk. Our NMA produced ORs and 95% credible intervals (CrI) > 1 for all six intervention categories, indicating favourable vaccine uptake compared to control (standard practice, no intervention, or attention placebo), with multicomponent (OR: 2.09, 95% CrI: 1.66–2.63), access (OR: 1.74, 95% CrI: 1.35–2.26), and affordability (OR: 1.87, 95% CrI: 1.47–2.40) interventions appearing most effective followed by education and reminder (OR: 1.47, 95% CrI: 1.29–1.67), reminder (OR: 1.36, 95% CrI: 1.22–1.50), and education (OR: 1.33, 95% CrI: 1.19–1.49). We judged the evidence for all six interventions as moderate certainty. Subgroup analyses exploring the effect of the COVID-19 pandemic suggest that affordability interventions may be less effective post-2020 (OR: 1.35, 95% CrI: 0.94–1.94) than pre-2020 (OR: 2.32, 95% CrI:1.72–3.19), similarly multicomponent interventions appear less effective post-2020 (OR: 1.45, 95% CrI: 1.00–2.10) than pre-2020 (OR: 2.50, 95% CrI: 1.89–3.33) whilst access, education, reminder, and education and reminder intervention effects remained stable.Interpretation Vaccination programmes in high and upper-middle income countries should prioritise ensuring vaccines are accessible, convenient, and affordable for the recipient. Efforts should be directed towards further investigating and optimising access and affordability interventions. The possible negative impacts of the COVID-19 pandemic on the effectiveness of affordability and multicomponent interventions should be monitored.Funding NIHR Public Health Research Programme (NIHR135130
Goldilocks and the three laws: competition law, the Digital Markets Act, and the Digital Service Act: regulation of online safety
No full textThis paper undertakes an analysis of the individual goals of the competition rules, the Digital Service Act and Digital Markets Act and assessing whether as a trio they can cooperate to successfully develop online safety. With the adoption of the DSA and DMA, a necessary shift has taken place of the regulation of online markets, from self-regulation to co-regulation. However, as is argued in the paper, the competition rules will need to follow suit in this shift to avoid conflicts with the goals of the DMA and DSA. The paper demonstrates how the goals of the DMA and DSA are carefully based on core competition law principles, therefore allowing for alignment of the three legislations. Yet the main obstacle to ensure alignment seems to be the consumer welfare approach adopted and heavily relied upon by the Commission over the last two decades. This approach restricts a broader application of the competition rules to socio-economic issues such as online safety and appears at odds with the Commission’s ‘can do attitude' it has regarding the strength of the competition rules. This attitude as illustrated has supported the liberation of certain industries and allowed for second tier regulation of other areas of law indicating that the competition rules can be a useful tool to online safety. With careful tweaking of the competition law goals to allow for the consideration of broader socio-economic issues, this paper argues that cooperation between the DSA, DMA and the competition rules in the online market may be successful
Physical and chemical characterisation of tyre and road wear particles
No full textTyre and road wear particles (TRWPs) are recognised as a significant global pollution threat. The abrasion of tyres during driving generates particles containing tyre and road material, hence termed TRWPs. An increasing number of TRWPs, due to the electrification of cars, potentially pose risks to humans and the ecosystem. Despite the omnipresence of TRWPs, there are uncertainties regarding their quantification and the validation of analytical methods for their identification. This thesis aims to integrate critical reviews and seek to establish a standardised analytical framework for the comprehensive analysis of TRWPs. A lack of a suitable marker for TRWPs remains a significant obstacle in accurately determining their concentration in environmental settings. Here, a marker refers to a unique characteristic of TRWPs that can act as a detectable indicator of their presence in the environment. A thorough review of existing literature shows that relying on a single chemical component as a marker, such as zinc or N-(1,3-dimethylbutyl)-N’-phenyl-p-phenylenediamine (6PPD), may lead to an overestimation of TRWPs. This is because zinc has been linked to brake wear, and 6PPD has been detected in other industrial applications, such as dyes, which limits the specificity of chemical additives as unique markers. The sausage-shaped assembly is distinctive to TRWPs. A suite of physical and chemical characteristics (including organic and elemental constituents), therefore, is recommended to improve their identification in the environment. This approach could serve as an international standard for quantifying TRWPs. Given the heterogeneity of TRWPs, the use of complementary analytical techniques is recommended. This includes microscopy and spectroscopy to examine surface characteristics such as size, shape, and elemental composition. Thermoanalytical methods are recommended to analyse organic additives in TRWPs. Validating these techniques requires environmentally relevant TRWPs. The reference standard for TRWPs was generated using a pin-on-disc tribometer (PoD), providing a reproducible standard for future studies. The critical review established in this thesis emphasises the importance of consistent sampling principles to promote standardisation in future research. This involves employing multiple field blanks (quality control measures) to prevent cross-contamination and careful consideration of the sampling matrix to ensure representativeness. These findings highlight that the reliable identification of TRWP (other than appropriate markers) is intrinsically linked to a standardised approach/workflow. Based on these insights, micro-computerised tomography (µ-CT) was established as a robust analytical method for the analysis of physical properties of TRWPs. 23,540 TRWPs from three commercial tyre brands (Bridgestone, Michelin, and Hankook), comprising approximately 50,000 slices, were assessed. Each particle was reconstructed and analysed through single particle analysis. Here, slices refer to cross-sectional images of TRWPs generated via µ-CT, enabling comprehensive three-dimensional characterisation from all angles/sides. Quantitative analysis shows significant heterogeneity in the shape of TRWPs, with sphericity ranging from 0.25 to 0.75 and aspect ratio from less than 1 to greater than 6. The implications of these findings suggest that TRWPs with an aspect ratio less than 1, due to increased aerodynamic drag, may undergo secondary motion in air. The increased drag may prolong the suspension of TRWPs in air, facilitating their transport to distant locations. These findings show the suitability of µ-CT for the comprehensive physical analysis of TRWPs and considering the physical properties to determine fate and transportation of TRWPs in the environment. A novel analytical framework consisting of a scanning electron microscope with energy-dispersive Xray spectroscopy (SEM-EDS) and two-dimensional gas chromatography-mass spectrometry (2DGC/MS) was established for comprehensive chemical analysis. The presence of per- and polyfluoroalkyl substances (PFAs) in the polymer structure of the particles highlights a potential for long-term risks from the presence (and potential release) of these toxic, persistent components. The employed analytical techniques may help future studies in the quantification of TRWPs present in the environment and their associated risks. Overall, this thesis not only established a methodological foundation but also laid the groundwork for harmonised monitoring efforts for future research. The developed analytical methodologies and frameworks are a significant contribution to the field, emphasising the importance of this research in the study of TRWPs
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