• Recent Advances in Enzymatic and Non-Enzymatic Electrochemical Glucose Sensing

      Hassan, Mohamed H.; orcid: 0000-0002-0832-8559; email: Mohamed.hassan@manchester.ac.uk; Vyas, Cian; orcid: 0000-0001-6030-1962; email: cian.vyas@manchester.ac.uk; Grieve, Bruce; orcid: 0000-0002-5130-3592; email: bruce.grieve@manchester.ac.uk; Bartolo, Paulo; orcid: 0000-0003-3683-726X; email: paulojorge.dasilvabartolo@manchester.ac.uk (MDPI, 2021-07-08)
      The detection of glucose is crucial in the management of diabetes and other medical conditions but also crucial in a wide range of industries such as food and beverages. The development of glucose sensors in the past century has allowed diabetic patients to effectively manage their disease and has saved lives. First-generation glucose sensors have considerable limitations in sensitivity and selectivity which has spurred the development of more advanced approaches for both the medical and industrial sectors. The wide range of application areas has resulted in a range of materials and fabrication techniques to produce novel glucose sensors that have higher sensitivity and selectivity, lower cost, and are simpler to use. A major focus has been on the development of enzymatic electrochemical sensors, typically using glucose oxidase. However, non-enzymatic approaches using direct electrochemistry of glucose on noble metals are now a viable approach in glucose biosensor design. This review discusses the mechanisms of electrochemical glucose sensing with a focus on the different generations of enzymatic-based sensors, their recent advances, and provides an overview of the next generation of non-enzymatic sensors. Advancements in manufacturing techniques and materials are key in propelling the field of glucose sensing, however, significant limitations remain which are highlighted in this review and requires addressing to obtain a more stable, sensitive, selective, cost efficient, and real-time glucose sensor.
    • Recent advances in the chemistry of ketyl radicals.

      Péter, Áron; email: david.j.procter@manchester.ac.uk; Agasti, Soumitra; Knowles, Oliver; Pye, Emma; Procter, David J (2021-03-23)
      Ketyl radicals are valuable reactive intermediates for synthesis and are used extensively to construct complex, functionalized products from carbonyl substrates. Single electron transfer (SET) reduction of the C[double bond, length as m-dash]O bond of aldehydes and ketones is the classical approach for the formation of ketyl radicals and metal reductants are the archetypal reagents employed. The past decade has, however, witnessed significant advances in the generation and harnessing of ketyl radicals. This tutorial review highlights recent, exciting developments in the chemistry of ketyl radicals by comparing the varied contemporary - for example, using photoredox catalysts - and more classical approaches for the generation and use of ketyl radicals. The review will focus on different strategies for ketyl radical generation, their creative use in new synthetic protocols, strategies for the control of enantioselectivity, and detailed mechanisms where appropriate.
    • Recent Progress on Semiconductor-Interface Facing Clinical Biosensing

      Zhang, Mingrui; email: mingrui.zhang-2@student.manchester.ac.uk; Adkins, Mitchell; email: mitchelladkins@oakland.edu; Wang, Zhe; orcid: 0000-0003-3762-3167; email: zhewang@oakland.edu (MDPI, 2021-05-16)
      Semiconductor (SC)-based field-effect transistors (FETs) have been demonstrated as amazing enhancer gadgets due to their delicate interface towards surface adsorption. This leads to their application as sensors and biosensors. Additionally, the semiconductor material has enormous recognizable fixation extends, high affectability, high consistency for solid detecting, and the ability to coordinate with other microfluidic gatherings. This review focused on current progress on the semiconductor-interfaced FET biosensor through the fundamental interface structure of sensor design, including inorganic semiconductor/aqueous interface, photoelectrochemical interface, nano-optical interface, and metal-assisted interface. The works that also point to a further advancement for the trademark properties mentioned have been reviewed here. The emergence of research on the organic semiconductor interface, integrated biosensors with Complementary metal–oxide–semiconductor (CMOS)-compatible, metal-organic frameworks, has accelerated the practical application of biosensors. Through a solid request for research along with sensor application, it will have the option to move forward the innovative sensor with the extraordinary semiconductor interface structure.
    • Reciprocal priming between receptor tyrosine kinases at recycling endosomes orchestrates cellular signalling outputs

      Smith, Michael P; Ferguson, Harriet R; orcid: 0000-0002-0283-4629; Ferguson, Jennifer; Zindy, Egor; Kowalczyk, Katarzyna M; Kedward, Thomas; Bates, Christian; Parsons, Joseph; Watson, Joanne; Chandler, Sarah; orcid: 0000-0003-3981-8590; et al. (2021-06-04)
      Abstract: Integration of signalling downstream of individual receptor tyrosine kinases (RTKs) is crucial to fine‐tune cellular homeostasis during development and in pathological conditions, including breast cancer. However, how signalling integration is regulated and whether the endocytic fate of single receptors controls such signalling integration remains poorly elucidated. Combining quantitative phosphoproteomics and targeted assays, we generated a detailed picture of recycling‐dependent fibroblast growth factor (FGF) signalling in breast cancer cells, with a focus on distinct FGF receptors (FGFRs). We discovered reciprocal priming between FGFRs and epidermal growth factor (EGF) receptor (EGFR) that is coordinated at recycling endosomes. FGFR recycling ligands induce EGFR phosphorylation on threonine 693. This phosphorylation event alters both FGFR and EGFR trafficking and primes FGFR‐mediated proliferation but not cell invasion. In turn, FGFR signalling primes EGF‐mediated outputs via EGFR threonine 693 phosphorylation. This reciprocal priming between distinct families of RTKs from recycling endosomes exemplifies a novel signalling integration hub where recycling endosomes orchestrate cellular behaviour. Therefore, targeting reciprocal priming over individual receptors may improve personalized therapies in breast and other cancers.
    • 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.]
    • Recognition of Design Fixation via Body Language Using Computer Vision

      Academic Editor: Zhang, Kai; Yang, Zhongliang; email: yzl@dhu.edu.cn; Chen, Yumiao; orcid: 0000-0002-2702-4649; email: 181603042@qq.com; Zhang, Song; email: zhangrime@gmail.com (Hindawi, 2021-08-27)
      The main objective of this study is to recognize design fixation accurately and effectively. First, we conducted an experiment to record the videos of design process and design sketches from 12 designers for 15 minutes. Then, we executed a video analysis of body language in designers, correlating body language to the presence of design fixation, as judged by a panel of six experts. We found that three body language types were significantly correlated to fixation. A two-step hybrid recognition model of design fixation based on body language was proposed. The first-step recognition model of body language using transfer learning based on a pretrained VGG-16 convolutional neural network was constructed. The average recognition rate achieved by the VGG-16 model was 92.03%. Then, the frames of recognized body language were used as input vectors to the second-step fixation classification model based on support vector machine (SVM). The average recognition rate for the fixation state achieved by the SVM model was 79.11%. The impact of the work could be that the fixation can be detected not only by the sketch outcomes but also by monitoring the movements, expressions, and gestures of designers, as it is happening by monitoring the movements, expressions, and gestures of designers.
    • Recommendations for Transdisciplinary Professional Competencies and Ethics for Animal-Assisted Therapies and Interventions

      Trevathan-Minnis, Melissa; email: drtrevathanminnis@gmail.com; Johnson, Amy; orcid: 0000-0003-3536-9193; email: dramyjohnsonlpc@gmail.com; Howie, Ann R.; email: humananimalsolutions@comcast.net (MDPI, 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.
    • 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.
    • Reconciling Egg- and Antigen-Based Estimates of Schistosoma mansoni Clearance and Reinfection: A Modeling Study

      Clark, Jessica; orcid: 0000-0003-1692-899X; Moses, Arinaitwe; Nankasi, Andrina; Faust, Christina L; Moses, Adriko; Ajambo, Diana; Besigye, Fred; Atuhaire, Aaron; Wamboko, Aidah; Carruthers, Lauren V; et al. (Oxford University Press (OUP), 2021-08-06)
      Abstract Background Despite decades of interventions, 240 million people have schistosomiasis. Infections cannot be directly observed, and egg-based Kato-Katz thick smears lack sensitivity, affected treatment efficacy and reinfection rate estimates. The point-of-care circulating cathodic antigen (referred to from here as POC-CCA+) test is advocated as an improvement on the Kato-Katz method, but improved estimates are limited by ambiguities in the interpretation of trace results. Method We collected repeated Kato-Katz egg counts from 210 school-aged children and scored POC-CCA tests according to the manufacturer’s guidelines (referred to from here as POC-CCA+) and the externally developed G score. We used hidden Markov models parameterized with Kato-Katz; Kato-Katz and POC-CCA+; and Kato-Katz and G-Scores, inferring latent clearance and reinfection probabilities at four timepoints over six-months through a more formal statistical reconciliation of these diagnostics than previously conducted. Our approach required minimal but robust assumptions regarding trace interpretations. Results Antigen-based models estimated higher infection prevalence across all timepoints compared with the Kato-Katz model, corresponding to lower clearance and higher reinfection estimates. Specifically, pre-treatment prevalence estimates were 85% (Kato-Katz; 95% CI: 79%–92%), 99% (POC-CCA+; 97%–100%) and 98% (G-Score; 95%–100%). Post-treatment, 93% (Kato-Katz; 88%–96%), 72% (POC-CCA+; 64%–79%) and 65% (G-Score; 57%–73%) of those infected were estimated to clear infection. Of those who cleared infection, 35% (Kato-Katz; 27%–42%), 51% (POC-CCA+; 41%–62%) and 44% (G-Score; 33%–55%) were estimated to have been reinfected by 9-weeks. Conclusions Treatment impact was shorter-lived than Kato-Katz–based estimates alone suggested, with lower clearance and rapid reinfection. At 3 weeks after treatment, longer-term clearance dynamics are captured. At 9 weeks after treatment, reinfection was captured, but failed clearance could not be distinguished from rapid reinfection. Therefore, frequent sampling is required to understand these important epidemiological dynamics.
    • Reconciling egg- and antigen-based estimates of Schistosoma mansoni clearance and reinfection: a modelling study

      Clark, Jessica; orcid: 0000-0003-1692-899X; Arinaitwe, Moses; Nankasi, Andrina; Faust, Christina L; Moses, Adriko; Ajambo, Diana; Besigye, Fred; Atuhaire, Alon; Wamboko, Aidah; Carruthers, Lauren V; et al. (Oxford University Press (OUP), 2021-08-06)
      Abstract Background 240-million people have schistosomiasis despite decades of interventions. Infections cannot be directly observed, and egg-based Kato-Katz thick smears lack sensitivity, impacting treatment efficacy and reinfection rate estimates. The Point-of-Care Circulating Cathodic Antigen test (POC-CCA) is advocated as an improvement upon the Kato-Katz, however improved estimates are limited by ambiguities in the interpretation of Trace results. Method We collected repeated Kato-Katz counts from 210 school-aged children and scored POC-CCAs according to manufacturer’s guidelines (POC-CCA+) and the externally developed G-Score. We used Hidden Markov Models parameterised with Kato-Katz; Kato-Katz and POC-CCA+; and Kato-Katz and G-Scores, inferring latent clearance and reinfection probabilities at four timepoints over six-months through a more formal statistical reconciliation of these diagnostics than previously conducted. Our approach required minimal but robust assumptions regarding Trace interpretations. Results Antigen-based models estimated higher infection prevalence across all timepoints compared with the Kato-Katz model, corresponding to lower clearance and higher reinfection estimates. Specifically, pre-treatment prevalence estimates were 85% (Kato-Katz; 95% CI: 79-92%), 99% (POC-CCA+; 97-100%) and 98% (G-Score; 95-100%). Post-treatment, 93% (Kato-Katz; 88-96%), 72% (POC-CCA+; 64-79%) and 65% (G-Score; 57-73%) of those infected were estimated to clear infection. Of those who cleared infection, 35% (Kato-Katz; 27-42%), 51% (POC-CCA+; 41-62%) and 44% (G-Score; 33-55%) were estimated to have been reinfected by nine-weeks. Conclusion Treatment impact was shorter-lived than only Kato-Katz-based estimates suggested, with lower clearance and rapid reinfection. Three-weeks-post-treatment captured longer-term clearance dynamics. Nine-weeks-post-treatment captured reinfection, but alone could not discern between failed clearance and rapid reinfection. Therefore, frequent sampling is required to understand these important epidemiological dynamics.
    • Reconciling egg- and antigen-based estimates of Schistosoma mansoni clearance and reinfection: a modelling study.

      Clark, Jessica; orcid: 0000-0003-1692-899X; Arinaitwe, Moses; Nankasi, Andrina; Faust, Christina L; Moses, Adriko; Ajambo, Diana; Besigye, Fred; Atuhaire, Alon; Wamboko, Aidah; Carruthers, Lauren V; et al. (2021-08-06)
      240-million people have schistosomiasis despite decades of interventions. Infections cannot be directly observed, and egg-based Kato-Katz thick smears lack sensitivity, impacting treatment efficacy and reinfection rate estimates. The Point-of-Care Circulating Cathodic Antigen test (POC-CCA) is advocated as an improvement upon the Kato-Katz, however improved estimates are limited by ambiguities in the interpretation of Trace results. We collected repeated Kato-Katz counts from 210 school-aged children and scored POC-CCAs according to manufacturer's guidelines (POC-CCA+) and the externally developed G-Score. We used Hidden Markov Models parameterised with Kato-Katz; Kato-Katz and POC-CCA+; and Kato-Katz and G-Scores, inferring latent clearance and reinfection probabilities at four timepoints over six-months through a more formal statistical reconciliation of these diagnostics than previously conducted. Our approach required minimal but robust assumptions regarding Trace interpretations. Antigen-based models estimated higher infection prevalence across all timepoints compared with the Kato-Katz model, corresponding to lower clearance and higher reinfection estimates. Specifically, pre-treatment prevalence estimates were 85% (Kato-Katz; 95% CI: 79-92%), 99% (POC-CCA+; 97-100%) and 98% (G-Score; 95-100%). Post-treatment, 93% (Kato-Katz; 88-96%), 72% (POC-CCA+; 64-79%) and 65% (G-Score; 57-73%) of those infected were estimated to clear infection. Of those who cleared infection, 35% (Kato-Katz; 27-42%), 51% (POC-CCA+; 41-62%) and 44% (G-Score; 33-55%) were estimated to have been reinfected by nine-weeks. Treatment impact was shorter-lived than only Kato-Katz-based estimates suggested, with lower clearance and rapid reinfection. Three-weeks-post-treatment captured longer-term clearance dynamics. Nine-weeks-post-treatment captured reinfection, but alone could not discern between failed clearance and rapid reinfection. Therefore, frequent sampling is required to understand these important epidemiological dynamics. [Abstract copyright: © The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.]
    • 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.
    • Redevelopment of the Predict: Breast Cancer website and recommendations for developing interfaces to support decision‐making

      Farmer, George D.; orcid: 0000-0003-2882-0310; email: george.farmer@manchester.ac.uk; Pearson, Mike; orcid: 0000-0002-8161-2660; Skylark, William J.; orcid: 0000-0002-3375-2669; Freeman, Alexandra L. J.; orcid: 0000-0002-4115-161X; Spiegelhalter, David J.; orcid: 0000-0001-9350-6745 (2021-06-21)
      Abstract: Objectives: To develop a new interface for the widely used prognostic breast cancer tool: Predict: Breast Cancer. To facilitate decision‐making around post‐surgery breast cancer treatments. To derive recommendations for communicating the outputs of prognostic models to patients and their clinicians. Method: We employed a user‐centred design process comprised of background research and iterative testing of prototypes with clinicians and patients. Methods included surveys, focus groups and usability testing. Results: The updated interface now caters to the needs of a wider audience through the addition of new visualisations, instantaneous updating of results, enhanced explanatory information and the addition of new predictors and outputs. A programme of future research was identified and is now underway, including the provision of quantitative data on the adverse effects of adjuvant breast cancer treatments. Based on our user‐centred design process, we identify six recommendations for communicating the outputs of prognostic models including the need to contextualise statistics, identify and address gaps in knowledge, and the critical importance of engaging with prospective users when designing communications. Conclusions: For prognostic algorithms to fulfil their potential to assist with decision‐making they need carefully designed interfaces. User‐centred design puts patients and clinicians needs at the forefront, allowing them to derive the maximum benefit from prognostic models.
    • Redistribution, power sharing and inequality concern

      Debowicz, Dario; orcid: 0000-0003-0944-3097; Saporiti, Alejandro; orcid: 0000-0002-9156-464X; email: alejandro.saporiti@manchester.ac.uk; Wang, Yizhi; orcid: 0000-0002-5723-2609 (Springer Berlin Heidelberg, 2021-03-10)
      Abstract: We analyze a political competition model of redistributive policies. We provide an equilibrium existence result and a full characterization of the net transfers to the different income groups. We also derive several testable predictions about the way in which the net group transfers and the after-tax Gini coefficient vary with the main parameters of the model. In accordance with the theory, the empirical evidence from a sample of developed and developing democracies supports a highly statistically significant association between: (i) the net group transfer and the gap between the population and the group mean initial income, and (ii) the net group transfer (and resp., the Gini coefficient) and power sharing disproportionality. In addition, the data also provide some empirical evidence confirming a significant relationship between the net transfers to the poor (and resp., the Gini) and the concern of the political parties with income inequality.
    • 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.]
    • Reducing the burden of orthodontic care for children with clefts: evaluating the effectiveness of pre-alveolar bone graft orthodontics in unilateral non-syndromic cleft patients (PABO study)- A study protocol for a multicentric randomised controlled trial.

      Thiruvenkatachari, Badri; orcid: 0000-0002-7809-8111; email: badri.t@manchester.ac.uk; Hussain, Syed Altaf; Batra, Puneet; Vijayakumar, Charanya; Prathap C, Manoj (2021-08-28)
      <h4>Background</h4>An alveolar cleft commonly affects 75% of cleft lip and palate patients. While it is common practice to provide a course of orthodontic treatment before alveolar bone grafting, there are no previous high-quality studies reporting on the benefits of this type of treatment.<h4>Aim</h4>The aim of the study is to evaluate the effectiveness of pre-alveolar bone graft orthodontics for unilateral non-syndromic cleft palate patients.<h4>Method</h4>The PABO trial is a multicentric, parallel, two-arm, single-blinded randomised controlled trial. The inclusion criteria include unilateral cleft alveolus patients requiring bone graft and between the age group of 8 and 13 years with erupted upper central incisors. Participants will be recruited at three centres across India. Participants will be randomised to orthodontic treatment or no orthodontic treatment group. Both groups of participants will have alveolar bone graft surgery and will be followed up for 6 months after surgery. The primary outcome will be the success of the alveolar bone graft measured by anterior oblique radiograph and secondary outcomes include quality of life, cost analysis and quality of the dento-occlusal outcome. Data analysis will be carried out by an independent statistician at the end of the study.<h4>Discussion</h4>This study is the first to evaluate the effect of orthodontics on alveolar bone graft success. The increased burden of care for these patients with multiple treatments required from multiple specialists from birth to adult life highlights the need for reducing unnecessary treatment provision.<h4>Trial registration</h4>Clinical Trials Registry - India, CTRI/2020/10/028756 . Trial prospectively registered on 29 October 2020. .
    • Reducing the burden of orthodontic care for children with clefts: evaluating the effectiveness of pre-alveolar bone graft orthodontics in unilateral non-syndromic cleft patients (PABO study)— A study protocol for a multicentric randomised controlled trial

      Thiruvenkatachari, Badri; orcid: 0000-0002-7809-8111; email: badri.t@manchester.ac.uk; Hussain, Syed Altaf; Batra, Puneet; Vijayakumar, Charanya; Prathap. C, Manoj (BioMed Central, 2021-08-28)
      Abstract: Background: An alveolar cleft commonly affects 75% of cleft lip and palate patients. While it is common practice to provide a course of orthodontic treatment before alveolar bone grafting, there are no previous high-quality studies reporting on the benefits of this type of treatment. Aim: The aim of the study is to evaluate the effectiveness of pre-alveolar bone graft orthodontics for unilateral non-syndromic cleft palate patients. Method: The PABO trial is a multicentric, parallel, two-arm, single-blinded randomised controlled trial. The inclusion criteria include unilateral cleft alveolus patients requiring bone graft and between the age group of 8 and 13 years with erupted upper central incisors. Participants will be recruited at three centres across India. Participants will be randomised to orthodontic treatment or no orthodontic treatment group. Both groups of participants will have alveolar bone graft surgery and will be followed up for 6 months after surgery. The primary outcome will be the success of the alveolar bone graft measured by anterior oblique radiograph and secondary outcomes include quality of life, cost analysis and quality of the dento-occlusal outcome. Data analysis will be carried out by an independent statistician at the end of the study. Discussion: This study is the first to evaluate the effect of orthodontics on alveolar bone graft success. The increased burden of care for these patients with multiple treatments required from multiple specialists from birth to adult life highlights the need for reducing unnecessary treatment provision. Trial Registration: Clinical Trials Registry – India, CTRI/2020/10/028756. Trial prospectively registered on 29 October 2020. .