Development of a measure to assess the quality of proxy decisions about research participation on behalf of adults lacking capacity to consent : the Combined Scale for Proxy Informed Consent Decisions (CONCORD scale)

Acknowledgements We would like to thank the participants who generously volunteered their time to participate in the interviews and the lay advisory group who provide invaluable insight and support for this research programme. Funding This study was conducted as part of a National Institute of Health Research Advanced Fellowship (CONSULT) held by VS and funded by the Welsh Government through Health and Care Research Wales (NIHR-FS(A)-2021). The funding body did not participate in the study design, data collection, analysis, or interpretation in writing this manuscript. Primary and Emergency Care (PRIME) Research Centre Wales) is funded by the Welsh Government through Health and Care Research Wales and the Centre for Trials Research is funded by Health and Care Research Wales and Cancer Research UK.Peer reviewedPublisher PD

Feasibility, effectiveness and costs of a decision support intervention for consultees and legal representatives of adults lacking capacity to consent (CONSULT) : protocol for a randomised Study Within a Trial

Acknowledgements We would like to thank the lay advisory group who provide invaluable insight and support for this research programme. Funding This research was funded by Health and Care Research Wales as part of an NIHR Advanced Fellowship (NIHR-FS(A)-2021). For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising. Primary and Emergency Care (PRIME) Research Centre Wales) is funded by the Welsh Government through Health and Care Research Wales and the Centre for Trials Research is funded by Health and Care Research Wales and Cancer Research UK. © 2022. The Author(s).Peer reviewedPublisher PD

PL-009 Not just a one HIIT wonder: two popular HIIT protocols elicit similar health benefits in a controlled but real world environment

Objective Currently 40% of the UK do not meet the physical activity guidelines with a ‘lack of time’ the most commonly cited barrier to sufficient physical activity. In laboratory based training interventions, high intensity interval training (HIT) offers a time-efficient alternative to moderate intensity continuous training (MICT) but its success requires expensive specialised cycle ergometers and vigorous encouragement from the researchers. To investigate whether two popular HIT protocols, performed using readily available cycle ergometers and without encouragement, can improve aerobic exercise capacity, arterial stiffness and body composition. Methods Eighty-two sedentary males (n=26) and females (n=56) aged 18-65 participated in the study (28±1 y, BMI 25±0.4 kg.m-2). In a randomised cross-over design, participants completed either 6 weeks of 30HIT (4-8x30s sprint with 120s active recovery) or 60HIT (6-10x60s sprint with 60s active recovery). Training sessions were completed on a Wattbike, 3 times per week. VO2peak, body composition (DXA scan), blood glucose (oral glucose tolerance test (OGTT)) and arterial stiffness (pulse wave velocity (PWV)) were assessed pre and post each 6-week training phase, with 4-6 weeks washout period between interventions. Results VO2peakincreased post intervention in 30HIT (36±1 to 39±1 ml.min-1.kg-1) and 60HIT (36±1 to 39±1 ml.min-1.kg-1) (P<0.001), with no difference between intervention group (P=0.208). Body fat percentage decreased pre to post training in both conditions (P=0.001). PWV decreased in 30HIT (2%) and 60HIT (4%) (P<0.005). During the OGTT, there was a trend towards decreasing area under the curve pre to post (P=0.083). When normalized to Watt maxthe participants producing a higher mean power output improved their VO2peakmore than those producing a low MPO (P<0.05). Following further analysis this was only true in 60HIT (P<0.05). Conclusions Both 30HIT and 60HIT could be effective real world strategies to improve aerobic capacity, body composition, arterial stiffness and insulin sensitivity. Improvements were seen even though the time spent sprinting was less in 30HIT (4mins compared to 10mins in 60HIT). In addition, how the 30HIT protocol is executed does not seem to have an effect on physiological outcomes. This suggests 30HIT may be a more applicable training intervention in the real world

Expansion of the Knockdown Resistance Frequency Map for Human Head Lice (Phthiraptera: Pediculidae) in the United States Using Quantitative Sequencing

Pediculosis is a prevalent parasitic infestation of humans, which is increasing due, in part, to the selection of lice resistant to either the pyrethrins or pyrethroid insecticides by the knockdown resistance (kdr) mechanism. To determine the extent and magnitude of thekdr-type mutations responsible for this resistance, lice were collected from 138 collection sites in 48 U.S. states from 22 July 2013 to 11 May 2015 and analyzed by quantitative sequencing. Previously published data were used for comparisons of the changes in the frequency of thekdr-type mutations over time. Mean percent resistance allele frequency (mean % RAF) values across the three mutation loci were determined from each collection site. The overall mean % RAF (+/-SD) for all analyzed lice was 98.3 +/- 10%. 132/138 sites (95.6%) had a mean % RAF of 100%, five sites (3.7%) had intermediate values, and only a single site had no mutations (0.0%). Forty-two states (88%) had a mean % RAF of 100%. The frequencies ofkdr-type mutations did not differ regardless of the human population size that the lice were collected from, indicating a uniformly high level of resistant alleles. The loss of efficacy of the Nix formulation (Prestige Brand, Tarrytown, NY) from 1998 to 2013 was correlated to the increase inkdr-type mutations. These data provide a plausible reason for the decrease in the effectiveness of permethrin in the Nix formulation, which is the parallel increase ofkdr-type mutations in lice over time

Recruitment interventions for trials involving adults lacking capacity to consent: methodological and ethical considerations for designing Studies Within a Trial (SWATs)

Background: The number of interventions to improve recruitment and retention of participants in trials is rising, with a corresponding growth in randomised Studies Within Trials (SWATs) to evaluate their (cost-)efectiveness. Despite recognised challenges in conducting trials involving adults who lack capacity to consent, until now, no individual-level recruitment interventions have focused on this population. Following the development of a decision aid for family members making non-emergency trial participation decisions on behalf of people with impaired capacity, we have designed a SWAT to evaluate the decision aid in a number of host trials (CONSULT). Unlike in recruitment SWATs to date, the CONSULT intervention is aimed at a ‘proxy’ decision-maker (a family member) who is not a participant in the host trial and does not receive the trial intervention. This commentary explores the methodological and ethical considerations encountered when designing such SWATs, using the CONSULT SWAT as a case example. Potential solutions to address these issues are also presented. Discussion: We encountered practical issues around informed consent, data collection, and follow-up which involves linking the intervention receiver (the proxy) with recruitment and retention data from the host trial, as well as issues around randomisation level, resource use, and maintaining the integrity of the host trial. Unless addressed, methodological uncertainty about diferential recruitment and heterogeneity between trial populations could potentially limit the scope for drawing robust inferences and harmonising data from diferent SWAT host trials. Proxy consent is itself ethically complex, and so when conducting a SWAT which aims to disrupt and enhance proxy consent decisions, there are additional ethical issues to be considered. Conclusions: Designing a SWAT to evaluate a recruitment intervention for non-emergency trials with adults lacking capacity to consent has raised a number of methodological and ethical considerations. Explicating these challenges, and some potential ways to address them, creates a starting point for discussions about conducting these potentially more challenging SWATs. Increasing the evidence base for the conduct of trials involving adults lacking capacity to consent is intended to improve both the ability to conduct these trials and their quality, and so help build research capacity for this under-served populatio

Storylines of UK drought based on the 2010–2012 event

Spatially extensive multi-year hydrological droughts cause significant environmental stress. The UK is expected to remain vulnerable to future multi-year droughts under climate change. Existing approaches to quantify hydrological impacts of climate change often rely solely on global climate model (GCM) projections following different emission scenarios. This may miss out low-probability events with significant impacts. As a means of exploring such events, physical climate storyline approaches aim to quantify physically coherent articulations of how observed events could hypothetically have unfolded in alternative ways. This study uses the 2010–2012 drought, the most recent period of severe hydrological drought in the UK, as a basis and analyses storylines based on changes to (1) precondition severity, (2) temporal drought sequence, and (3) climate change. Evidence from multiple storylines shows that the maximum intensity, mean deficit, and duration of the 2010–2012 drought were highly influenced by its meteorological preconditions prior to drought inception, particularly for northern catchments at shorter timescales. The influence of progressively drier preconditions reflects both the spatial variation in drought preconditions and the role of physical catchment characteristics, particularly hydrogeology in the propagation of multi-year droughts. There are two plausible storylines of an additional dry year with dry winter conditions repeated either before the observed drought or replacing the observed dramatic drought termination confirm the vulnerability of UK catchments to a “third dry winter” storyline. Applying the UKCP18 climate projections, we find that drought conditions worsen with global warming with a mitigation of drought conditions by wetter winters in northern catchments at high warming levels. Comparison of the storylines with a benchmark drought (1975–1976) and a protracted multi-year drought (1989–1993) shows that, for each storyline (including the climate change storylines), drought conditions could have matched and exceeded those experienced during the past droughts at catchments across the UK, particularly for southern catchments. The construction of storylines based on observed events can complement existing methods to stress test UK catchments against plausible unrealised droughts

Added value of seasonal hindcasts to create UK hydrological drought storylines

The UK has experienced recurring periods of hydrological droughts in the past, including the drought declared in summer 2022. Seasonal hindcasts, consisting of a large sample of plausible weather sequences, can be used to create drought storylines and add value to existing approaches to water resources planning. In this study, the drivers of winter rainfall in the Anglian region in England are investigated using the ECMWF SEAS5 hindcast dataset, which includes 2850 plausible winters across 25 ensemble members and 3 lead times. Four winter clusters are defined using the hindcast winters based on possible combinations of various atmospheric circulation indices (such as the North Atlantic Oscillation, NAO; East Atlantic, EA, pattern; and El Niño–Southern Oscillation). Using the 2022 drought as a case study, we demonstrate how storylines representing alternative ways the event could have unfolded can be used to explore plausible worst-case scenarios over winter 2022/23 and beyond. The winter clusters span a range of temperature and rainfall response in the study region and represent circulation storylines that could have happened over winter 2022/23. River flow and groundwater level simulations with the large sample of plausible hindcast winters show that drier-than-average winters characterised by predominantly NAO−/EA− and NAO+/EA− circulation patterns could have resulted in the continuation of the drought with a high likelihood of below-normal to low river flows across all selected catchments and boreholes by spring and summer 2023. Catchments in Norfolk were particularly vulnerable to a dry summer in 2023 as river flows were not estimated to recover to normal levels even with wet winters characterised predominantly by NAO−/EA+ and NAO+/EA+ circulation patterns, due to insufficient rainfall to overcome previous dry conditions and the slow response nature of groundwater-dominated catchments. Through this analysis, we aim to demonstrate the added value of this approach to create drought storylines during an ongoing event. Storylines constructed in this way supplement traditional weather forecasts and hydrological outlooks, in order to explore a wider range of plausible outcomes

Passive Heat Therapy in Sedentary Humans Increases Skeletal Muscle Capillarisation and eNOS Content but Not Mitochondrial Density or GLUT4 Content.

Passive heat therapy (PHT) has been proposed as an alternative intervention to traditional moderate intensity continous training (MICT) in individuals who are unable or unwilling to exercise. This study aimed to make the first comparison of the effect of PHT and MICT on 1) skeletal muscle capillarisation and endothelial specific eNOS content and 2) mitochondrial density, GLUT4 and IMTG content. Twenty young sedentary males (21±1years, BMI 25±1kg.m-2) were allocated to either 6 weeks of PHT (n=10; 40-50min at 40°C in a heat chamber, 3x/wk) or MICT (n=10; time matched cycling at ~65% VO2peak). Muscle biopsies were taken from the vastus lateralis muscle pre- and post-training. Immunofluorescence microscopy was used to assess changes in skeletal muscle mitochondrial density, GLUT4 and IMTG content, capillarisation and endothelial specific eNOS content. VO2peak and whole body insulin sensitivity were also assessed. PHT and MICT both increased capillary density and capillary-fibre perimeter exchange index (P<0.05), and endothelial specific eNOS content (P<0.05). However, unlike MICT (P<0.05) PHT did not increase mitochondrial density (P=0.443), GLUT4 (P=0.217) or IMTG content (P=0.957). Both intervention improved aerobic capacity and whole body insulin sensitivity (P<0.05). 6 weeks PHT in young sedentary males increases skeletal muscle capillarisation and eNOS content to a similar extent as MICT, however, unlike MICT PHT does not affect skeletal muscle mitochondrial density, GLUT4 or IMTG content

Effective interventions to increase representation of under-served groups in randomised trials in UK and Ireland: a scoping literature review [version 1; peer review: awaiting peer review]

Background: Participants in clinical trials often do not reflect the populations that could benefit from the treatments being investigated. There are known barriers to trial participation for under-served groups, but limited evidence on strategies to alleviate these barriers to improve representation. This scoping review aimed to identify effective interventions and design features that improve the representation `of under-served groups in trials, focusing on the UK and Ireland. Methods: We included methodological research studies that reported interventions to improve representation of ethnic minority groups, socioeconomically disadvantaged groups, older people, or those with impaired capacity to consent to randomised controlled trials, conducted in the UK and Ireland, published between 2000–2021. Systematic searches were conducted in November 2021 and data were independently extracted by two authors and narratively synthesised. Results: Seven studies were included: one randomised controlled study embedded in five trials, one mixed-methods study, and five studies reporting ‘lessons learnt’ from one trial. We categorised the 47 reported interventions or strategies into nine broad themes: Recruitment sites, recruitment settings, community engagement, and communication with participants, incentives, inclusion criteria, flexibility, patient documentation, and the consent process. Only 28/47 interventions were evaluated, 23 of which were comparison of recruitment pathways. The randomised study found that a £100 incentive mentioned in the invitation letter increased positive responses overall across drug trials in cardiovascular disease and hypertension, but not for older people or those living in the most deprived areas. Invitation letters via GPs and working with communities were reported as successful recruitment pathways in recruiting different under-served populations. Conclusions: Interventions aiming to improve the recruitment of under-served groups in the UK and Ireland were reported across seven papers, but their effectiveness was rarely rigorously evaluated. Included studies were context specific. Using a variety of recruitment methods is likely to help achieve a more diverse cohort