• ‘Radial force’ of colonic stents: A parameter without consistency, definition or standard

      Laasch, Hans-Ulrich; orcid: 0000-0003-3109-6933; Milward, Graham D.; orcid: 0000-0002-0980-6567; Edwards, Derek W.; orcid: 0000-0001-6192-5056 (Society of Gastrointestinal Intervention, 2020-07-31)
    • Radical hydroxymethylation of alkyl iodides using formaldehyde as a C1 synthon.

      Caiger, Lewis; orcid: 0000-0001-5156-9684; Sinton, Conar; orcid: 0000-0002-5588-7548; Constantin, Timothée; orcid: 0000-0001-5376-1557; Douglas, James J; Sheikh, Nadeem S; Juliá, Fabio; orcid: 0000-0001-8903-4482; Leonori, Daniele; orcid: 0000-0002-7692-4504 (2021-07-06)
      Radical hydroxymethylation using formaldehyde as a C1 synthon is challenging due to the reversible and endothermic nature of the addition process. Here we report a strategy that couples alkyl iodide building blocks with formaldehyde through the use of photocatalysis and a phosphine additive. Halogen-atom transfer (XAT) from α-aminoalkyl radicals is leveraged to convert the iodide into the corresponding open-shell species, while its following addition to formaldehyde is rendered irreversible by trapping the transient O-radical with PPh<sub>3</sub>. This event delivers a phosphoranyl radical that re-generates the alkyl radical and provides the hydroxymethylated product.
    • Radical hydroxymethylation of alkyl iodides using formaldehyde as a C1 synthon.

      Caiger, Lewis; orcid: 0000-0001-5156-9684; Sinton, Conar; orcid: 0000-0002-5588-7548; Constantin, Timothée; orcid: 0000-0001-5376-1557; Douglas, James J; Sheikh, Nadeem S; Juliá, Fabio; orcid: 0000-0001-8903-4482; Leonori, Daniele; orcid: 0000-0002-7692-4504 (2021-07-06)
      Radical hydroxymethylation using formaldehyde as a C1 synthon is challenging due to the reversible and endothermic nature of the addition process. Here we report a strategy that couples alkyl iodide building blocks with formaldehyde through the use of photocatalysis and a phosphine additive. Halogen-atom transfer (XAT) from α-aminoalkyl radicals is leveraged to convert the iodide into the corresponding open-shell species, while its following addition to formaldehyde is rendered irreversible by trapping the transient O-radical with PPh . This event delivers a phosphoranyl radical that re-generates the alkyl radical and provides the hydroxymethylated product. [Abstract copyright: This journal is © The Royal Society of Chemistry.]
    • Raising the bar? The impact of the UNISON ethical care campaign in UK domiciliary care

      Johnson, Mathew; email: Mathew.johnson@manchester.ac.uk; Rubery, Jill; Egan, Matthew (SAGE Publications, 2021-07-15)
      This article critically analyses a major trade union initiative in the United Kingdom to raise standards in public contracts for domiciliary care, and in turn to improve wages and working conditions for outsourced care workers. The campaign successfully built alliances with national employer representatives, and around 25 per cent of commissioning bodies in England, Scotland and Wales have signed a voluntary charter that guarantees workers an hourly living wage, payment for travel time and regular working hours. The campaign overall, however, has had only limited effects on standards across the sector, in which low wages, zero-hours contracts and weak career paths predominate. Furthermore, the campaign has not yet yielded significant gains in terms of union recruitment, although there are signs of sporadic mobilisations of care workers in response to localised disputes.
    • Rapid compensatory evolution can rescue low fitness symbioses following partner switching.

      Sørensen, Megan E S; Wood, A Jamie; Cameron, Duncan D; Brockhurst, Michael A; email: michael.brockhurst@manchester.ac.uk (2021-07-01)
      Partner switching plays an important role in the evolution of symbiosis, enabling local adaptation and recovery from the breakdown of symbiosis. Because of intergenomic epistasis, partner-switched symbioses may possess novel combinations of phenotypes but may also exhibit low fitness due to their lack of recent coevolutionary history. Here, we examine the structure and mechanisms of intergenomic epistasis in the Paramecium-Chlorella symbiosis and test whether compensatory evolution can rescue initially low fitness partner-switched symbioses. Using partner-switch experiments coupled with metabolomics, we show evidence for intergenomic epistasis wherein low fitness is associated with elevated symbiont stress responses either in dark or high irradiance environments, potentially owing to mismatched light management traits between the host and symbiont genotypes. Experimental evolution under high light conditions revealed that an initially low fitness partner-switched non-native host-symbiont pairing rapidly adapted, gaining fitness equivalent to the native host-symbiont pairing in less than 50 host generations. Compensatory evolution took two alternative routes: either hosts evolved higher symbiont loads to mitigate for their new algal symbiont's poor performance, or the algal symbionts themselves evolved higher investment in photosynthesis and photoprotective traits to better mitigate light stress. These findings suggest that partner switching combined with rapid compensatory evolution can enable the recovery and local adaptation of symbioses in response to changing environments. [Abstract copyright: Copyright © 2021 Elsevier Inc. All rights reserved.]
    • Rare GATA6 variants associated with risk of congenital heart disease phenotypes in 200,000 UK Biobank exomes.

      Williams, Simon G; Byrne, Dominic J F; Keavney, Bernard D; orcid: 0000-0001-9573-0812; email: bernard.keavney@manchester.ac.uk (2021-09-07)
      Congenital heart disease (CHD) has a complex and largely uncharacterised genetic etiology. Using 200,000 UK Biobank (UKB) exomes, we assess the burden of ultra-rare, potentially pathogenic variants in the largest case/control cohort of predominantly mild CHD to date. We find an association with GATA6, a member of the GATA family of transcription factors that play an important role during heart development and has been linked with several CHD phenotypes previously. Several identified GATA6 variants are previously unreported and their roles in conferring risk to CHD warrants further study. We demonstrate that despite limitations regarding detailed familial phenotype information in large-scale biobank projects, through careful consideration of case and control cohorts it is possible to derive important associations. [Abstract copyright: © 2021. The Author(s).]
    • Rates of turnover among general practitioners: a retrospective study of all English general practices between 2007 and 2019.

      Parisi, Rosa; Lau, Yiu-Shing; Bower, Peter; Checkland, Kath; Rubery, Jill; Sutton, Matt; Giles, Sally J; Esmail, Aneez; Spooner, Sharon; orcid: 0000-0001-6965-3673; Kontopantelis, Evangelos; orcid: 0000-0001-6450-5815; email: e.kontopantelis@manchester.ac.uk (2021-08-22)
      To quantify general practitioners' (GPs') turnover in England between 2007 and 2019, describe trends over time, regional differences and associations with social deprivation or other practice characteristics. A retrospective study of annual cross-sectional data. All general practices in England (8085 in 2007, 6598 in 2019). We calculated turnover rates, defined as the proportion of GPs leaving a practice. Rates and their median, 25th and 75th percentiles were calculated by year and region. The proportion of practices with persistent high turnover (>10%) over consecutive years were also calculated. A negative binomial regression model assessed the association between turnover and social deprivation or other practice characteristics. Turnover rates increased over time. The 75th percentile in 2009 was 11%, but increased to 14% in 2019. The highest turnover rate was observed in 2013-2014, corresponding to the 75th percentile of 18.2%. Over time, regions experienced increases in turnover rates, although it varied across English regions. The proportion of practices with high (10% to 40%) turnover within a year almost doubled from 14% in 2009 to 27% in 2019. A rise in the number of practices with persistent high turnover (>10%) for at least three consecutive years was also observed, from 2.7% (2.3%-3.1%) in 2007 to 6.3% (5.7%-6.9%) in 2017. The statistical analyses revealed that practice-area deprivation was moderately associated with turnover rate, with practices in the most deprived area having higher turnover rates compared with practices in the least deprived areas (incidence rate ratios 1.09; 95% CI 1.06 to 1.13). GP turnover has increased in the last decade nationally, with regional variability. Greater attention to GP turnover is needed, in the most deprived areas in particular, where GPs often need to deal with more complex health needs. There is a large cost associated with GP turnover and practices with very high persistent turnover need to be further researched, and the causes behind this identified, to allow support strategies and policies to be developed. [Abstract copyright: © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.]
    • Ratings of perceived exertion at the ventilatory anaerobic threshold in people with coronary heart disease: A CARE CR study.

      Nichols, Simon; email: s.j.nichols@shu.ac.uk; Engin, Buket; Carroll, Sean; Buckley, John; Ingle, Lee (2020-12-04)
      Exercise prescription guidelines for individuals undergoing cardiovascular rehabilitation (CR) are based on heart rate training zones and rating of perceived exertion (RPE). United Kingdom guidelines indicate that patients should exercise at an intensity of RPE 11 to 14. We aimed to determine the accuracy of this approach by comparing this RPE range with an objectively measured marker of exercise intensity, the ventilatory anaerobic threshold (VAT), and examine whether baseline directly determined cardiorespiratory fitness (CRF) affects the association between VAT and RPE. Participants underwent a maximal cardiopulmonary exercise test before an 8-week community-based CR programme. Peak oxygen uptake (V̇O2peak) and VAT were recorded, and RPE at the workload at which VAT was identified was recorded. Data were then split into tertiles, based on V̇O2peak, to determine whether RPE at the VAT differed in participants with low, moderate or higher CRF. We included 70 individuals [mean (SD) age 63.1 (10.0) years; body mass index 29.4 (4.0) kg/m2; 86% male]. At baseline, the mean RPE at the VAT (RPE@VAT) was 11.8 (95% confidence interval 11-12.6) and significantly differed between low and high CRF groups (P<0.001). The mean RPE@VAT was 10.1 (8.7-11.5), 11.8 (10.5-13.0), and 13.7 (12.5-14.9) for low, moderate and high CRF groups, respectively. When using RPE to guide exercise intensity in CR populations, one must consider the effect of baseline CRF. Mean RPEs of ∼10, 12 and 14 correspond to the VAT in low, moderate and higher-fit patients, respectively. [Abstract copyright: Copyright © 2020 Elsevier Masson SAS. All rights reserved.]
    • Reading Hilary Mantel: Haunted Decades

      Pollard, Eileen (Oxford University Press (OUP), 2021-07-10)
    • Real-time monitoring of crystallization from solution by using an interdigitated array electrode sensor.

      Tong, Jincheng; orcid: 0000-0001-7762-1460; Doumbia, Amadou; orcid: 0000-0002-4136-9029; Turner, Michael L; orcid: 0000-0003-2853-5632; Casiraghi, Cinzia; orcid: 0000-0001-7185-0377 (2021-04-27)
      Monitoring crystallization events in real-time is challenging but crucial for understanding the molecular dynamics associated with nucleation and crystal growth, some of nature's most ubiquitous phenomena. Recent observations have suggested that the traditional nucleation model, which describes the nucleus having already the final crystal structure, may not be valid. It appears that the molecular assembly can range during nucleation from crystalline to partially ordered to totally amorphous phases, and can change its structure during the crystallization process. Therefore, it is of critical importance to develop methods that are able to provide real-time monitoring of the molecular interactions with high temporal resolution. Here, we demonstrate that a simple and scalable approach based on interdigitated electrode array sensors (IESs) is able to provide insights on the dynamics of the crystallization process with a temporal resolution of 15 ms.
    • Reasons for indoor tanning use and the acceptability of alternatives: A qualitative study.

      Lyons, Stephanie; Lorigan, Paul; Green, Adele C; Ferguson, Ashley; Epton, Tracy; email: tracy.epton@manchester.ac.uk (2021-08-20)
      Using indoor tanning devices is associated with substantial health consequences, such as an increased risk of melanoma and other skin cancers. Many people including minors and some at high risk of skin cancer continue to use these devices. In the absence of effective restrictions on use, it is important that behaviour change interventions are designed to reduce indoor tanning. To explore reasons for use of indoor tanning devices and the acceptability of alternatives in adult users residing in North-West England. Participants were required to be current indoor tanners aged 18 years and above and were recruited online. Twenty-one participants took part in either a focus group or semi-structured interview. An inductive thematic analysis was conducted. Six themes were identified: psychological benefits; improving physical health; denial of health risks; alternatives do not meet psychological needs; alternatives do not meet physical needs; and perceived side-effects. Participants used indoor tanning devices to improve their self-esteem and to prevent sun damage to their skin (by gaining a 'base tan'). Participants appeared to justify their usage by responding defensively to avoid accepting they were at risk, exaggerating the benefits of indoor tanning, and discounting alternatives to indoor tanning. Alternatives to indoor tanning were perceived as risky for health, inadequate to provide the desired aesthetic, and incapable of meeting their self-esteem needs. Interventions to reduce indoor tanning behaviour should increase sources of self-esteem other than appearance, increase media literacy and address defensive responses to information around indoor tanning and alternatives. Further research is needed to develop these interventions and assess their feasibility. [Abstract copyright: Copyright © 2021. Published by Elsevier Ltd.]
    • Reasons for success and lessons learnt from nanoscale vaccines against COVID-19.

      Kisby, Thomas; orcid: 0000-0002-8432-7910; Yilmazer, Açelya; orcid: 0000-0003-2712-7450; Kostarelos, Kostas; orcid: 0000-0002-2224-6672; email: kostas.kostarelos@manchester.ac.uk (2021-08)
    • Reciprocal transcription factor networks govern tissue-resident ILC3 subset function and identity.

      Fiancette, Rémi; orcid: 0000-0003-1531-9770; Finlay, Conor M; Willis, Claire; Bevington, Sarah L; Soley, Jake; orcid: 0000-0001-7131-2560; Ng, Sky T H; Baker, Syed Murtuza; orcid: 0000-0002-6633-333X; Andrews, Simon; orcid: 0000-0002-5006-3507; Hepworth, Matthew R; orcid: 0000-0002-9613-7858; email: matthew.hepworth@manchester.ac.uk; Withers, David R; orcid: 0000-0003-3757-7594; email: d.withers@bham.ac.uk (2021-09-23)
      Innate lymphoid cells (ILCs) are guardians of mucosal immunity, yet the transcriptional networks that support their function remain poorly understood. We used inducible combinatorial deletion of key transcription factors (TFs) required for ILC development (RORγt, RORα and T-bet) to determine their necessity in maintaining ILC3 identity and function. Both RORγt and RORα were required to preserve optimum effector functions; however, RORα was sufficient to support robust interleukin-22 production among the lymphoid tissue inducer (LTi)-like ILC3 subset, but not natural cytotoxicity receptor (NCR) ILC3s. Lymphoid tissue inducer-like ILC3s persisted with only selective loss of phenotype and effector functions even after the loss of both TFs. In contrast, continued RORγt expression was essential to restrain transcriptional networks associated with type 1 immunity within NCR ILC3s, which coexpress T-bet. Full differentiation to an ILC1-like population required the additional loss of RORα. Together, these data demonstrate how TF networks integrate within mature ILCs after development to sustain effector functions, imprint phenotype and restrict alternative differentiation programs. [Abstract copyright: © 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.]
    • Recommendations for Transdisciplinary Professional Competencies and Ethics for Animal-Assisted Therapies and Interventions.

      Trevathan-Minnis, Melissa; Johnson, Amy; orcid: 0000-0003-3536-9193; Howie, Ann R (2021-12-02)
      AAI is a transdisciplinary field that has grown exponentially in recent decades. This growth has not always been synergistic across fields, creating a need for more consistent language and standards, a call for which many professionals in the field have made. Under the umbrella of human-animal interactions (HAI) is animal-assisted interventions (AAIs), which have a more goal-directed intention with animals who have been assessed for therapeutic, educational, or vocational work. The current article offers a brief history and efficacy of HAI, describes the limitations and gaps within the field and recommends a new set of competencies and guidelines that seek to create some of the needed common language and standards for AAI work to address these limitations.
    • Recomposing persons: Scavenging and storytelling in a birth cohort archive

      Tinkler, Penny; orcid: 0000-0002-9918-9821; email: penny.tinkler@manchester.ac.uk; Cruz, Resto; orcid: 0000-0003-2621-6232; Fenton, Laura (SAGE Publications, 2021-03-08)
      Birth cohort studies can be used not only to generate population-level quantitative data, but also to recompose persons. The crux is how we understand data and persons. Recomposition entails scavenging for various (including unrecognised) data. It foregrounds the perspective and subjectivity of survey participants, but without forgetting the partiality and incompleteness of the accounts that it may generate. Although interested in the singularity of individuals, it attends to the historical and relational embeddedness of personhood. It examines the multiple and complex temporalities that suffuse people’s lives, hence departing from linear notions of the life course. It implies involvement, as well as reflexivity, on the part of researchers. It embraces the heterogeneity and transformations over time of scientific archives and the interpretive possibilities, as well as incompleteness, of birth cohort studies data. Interested in the unfolding of lives over time, it also shines light on meaningful biographical moments.
    • Recovery of free volume in PIM-1 membranes through alcohol vapor treatment

      Almansour, Faiz; Alberto, Monica; Bhavsar, Rupesh S.; Fan, Xiaolei; Budd, Peter M.; Gorgojo, Patricia; email: p.gorgojo@manchester.ac.uk (Higher Education Press, 2021-02-10)
      Abstract: Physical aging is currently a major obstacle for the commercialization of PIM-1 membranes for gas separation applications. A well-known approach to reversing physical aging effects of PIM-1 membranes at laboratory scale is soaking them in lower alcohols, such as methanol and ethanol. However, this procedure does not seem applicable at industrial level, and other strategies must be investigated. In this work, a regeneration method with alcohol vapors (ethanol or methanol) was developed to recover permeability of aged PIM-1 membranes, in comparison with the conventional soaking-in-liquid approach. The gas permeability and separation performance, before and post the regeneration methods, were assessed using a binary mixture of CO2 and CH4 (1:1, v:v). Our results show that an 8-hour methanol vapor treatment was sufficient to recover the original gas permeability, reaching a CO2 permeability > 7000 barrer.
    • Recurrent KCNT2 missense variants affecting p.Arg190 result in a recognizable phenotype

      Jackson, Adam; orcid: 0000-0002-3674-3960; email: adam.jackson-5@postgrad.manchester.ac.uk; Banka, Siddharth; orcid: 0000-0002-8527-2210; Stewart, Helen; orcid: 0000-0002-1196-3000; Genomics England Research Consortium; Robinson, Hannah; Lovell, Simon; Clayton‐Smith, Jill (John Wiley & Sons, Inc., 2021-06-01)
      Abstract: KCNT2 variants resulting in substitutions affecting the Arg190 residue have been shown to cause epileptic encephalopathy and a recognizable facial gestalt. We report two additional individuals with intellectual disability, dysmorphic features, hypertrichosis, macrocephaly and the same de novo KCNT2 missense variants affecting the Arg190 residue as previously described. Notably, neither patient has epilepsy. Homology modeling of these missense variants revealed that they are likely to disrupt the stabilization of a closed channel conformation of KCNT2 resulting in a constitutively open state. This is the first report of pathogenic variants in KCNT2 causing a developmental phenotype without epilepsy.
    • Reduced physiologically-based pharmacokinetic model of dabigatran etexilate-dabigatran and its application for prediction of intestinal P-gp-mediated drug-drug interactions.

      Lang, Jennifer; Vincent, Ludwig; Chenel, Marylore; Ogungbenro, Kayode; Galetin, Aleksandra; email: aleksandra.galetin@manchester.ac.uk (2021-07-11)
      Dabigatran etexilate (DABE) has been suggested as a clinical probe for intestinal P-glycoprotein (P-gp)-mediated drug-drug interaction (DDI) studies and, as an alternative to digoxin. Clinical DDI data with various P-gp inhibitors demonstrated a dose-dependent inhibition of P-gp with DABE. The aims of this study were to develop a joint DABE (prodrug)-dabigatran reduced physiologically-based-pharmacokinetic (PBPK) model and to evaluate its ability to predict differences in P-gp DDI magnitude between a microdose and a therapeutic dose of DABE. A joint DABE-dabigatran PBPK model was developed with a mechanistic intestinal model accounting for the regional P-gp distribution in the gastrointestinal tract. Model input parameters were estimated using DABE and dabigatran pharmacokinetic (PK) clinical data obtained after administration of DABE alone or with a strong P-gp inhibitor, itraconazole, and over a wide range of DABE doses (from 375 µg to 400 mg). Subsequently, the model was used to predict extent of DDI with additional P-gp inhibitors and with different DABE doses. The reduced DABE-dabigatran PBPK model successfully described plasma concentrations of both prodrug and metabolite following administration of DABE at different dose levels and when co-administered with itraconazole. The model was able to capture the dose dependency in P-gp mediated DDI. Predicted magnitude of itraconazole P-gp DDI was higher at the microdose (predicted vs. observed median fold-increase in AUC /AUC (min-max) = 5.88 (4.29-7.93) vs. 6.92 (4.96-9.66) ng.h/mL) compared to the therapeutic dose (predicted median fold-increase in AUC /AUC  = 3.48 (2.37-4.84) ng.h/mL). In addition, the reduced DABE-dabigatran PBPK model predicted successfully the extent of DDI with verapamil and clarithromycin as P-gp inhibitors. Model-based simulations of dose staggering predicted the maximum inhibition of P-gp when DABE microdose was concomitantly administered with itraconazole solution; simulations also highlighted dosing intervals required to minimise the DDI risk depending on the DABE dose administered (microdose vs. therapeutic). This study provides a modelling framework for the evaluation of P-gp inhibitory potential of new molecular entities using DABE as a clinical probe. Simulations of dose staggering and regional differences in the extent of intestinal P-gp inhibition for DABE microdose and therapeutic dose provide model-based guidance for design of prospective clinical P-gp DDI studies. [Abstract copyright: Copyright © 2021. Published by Elsevier B.V.]
    • Reducing bias in trials due to reactions to measurement: experts produced recommendations informed by evidence.

      French, David P; email: david.french@manchester.ac.uk; Miles, Lisa M; Elbourne, Diana; Farmer, Andrew; Gulliford, Martin; Locock, Louise; Sutton, Stephen; McCambridge, Jim; MERIT Collaborative group (2021-07-03)
      This study (MEasurement Reactions In Trials) aimed to produce recommendations on how best to minimise bias from measurement reactivity in randomised controlled trials of interventions to improve health. The MERIT study consisted of: (a) an updated systematic review that examined whether measuring participants had effects on participants' health-related behaviours, relative to no-measurement controls, and three rapid reviews to identify: (i) existing guidance on measurement reactivity; (ii) existing systematic reviews of studies that have quantified the effects of measurement on behavioural or affective outcomes; and (iii) studies that have investigated the effects of objective measurements of behaviour on health-related behaviour; (b) an Delphi study to identify the scope of the recommendations; and (c) an expert workshop in October 2018 to discuss potential recommendations in groups. Fourteen recommendations were produced by the expert group to: (a) identify whether bias is likely to be a problem for a trial; (b) decide whether to collect data about whether bias is likely to be a problem; (c) design trials to minimise the likelihood of this bias. These recommendations raise awareness of how and where taking measurements can produce bias in trials, and are thus helpful for trial design. [Abstract copyright: Copyright © 2021. Published by Elsevier Inc.]
    • Refining the blank line‐up procedure: How should we instruct eyewitnesses?

      Kucina, Talira; Sauer, James D.; Holt, Glenys A.; Brewer, Neil; Palmer, Matthew A.; orcid: 0000-0002-3467-3364 (Wiley, 2020-08-19)