Can we do better? A qualitative study in the East of England investigating patient experience and acceptability of using the faecal immunochemical test in primary care.

OBJECTIVES: The faecal immunochemical test (FIT) is increasingly used in UK primary care to triage patients presenting with symptoms and at different levels of colorectal cancer risk. Evidence is scarce on patients' views of using FIT in this context. We aimed to explore patients' care experience and acceptability of using FIT in primary care. DESIGN: A qualitative semi-structured interview study. Interviews were conducted via Zoom between April and October 2020. Transcribed recordings were analysed using framework analysis. SETTING: East of England general practices. PARTICIPANTS: Consenting patients (aged ≥40 years) who presented in primary care with possible symptoms of colorectal cancer, and for whom a FIT was requested, were recruited to the FIT-East study. Participants were purposively sampled for this qualitative substudy based on age, gender and FIT result. RESULTS: 44 participants were interviewed with a mean age 61 years, and 25 (57%) being men: 8 (18%) received a positive FIT result. Three themes and seven subthemes were identified. Participants' familiarity with similar tests and perceived risk of cancer influenced test experience and acceptability. All participants were happy to do the FIT themselves and to recommend it to others. Most participants reported that the test was straightforward, although some considered it may be a challenge to others. However, test explanation by healthcare professionals was often limited. Furthermore, while some participants received their results quickly, many did not receive them at all with the common assumption that 'no news is good news'. For those with a negative result and persisting symptoms, there was uncertainty about any next steps. CONCLUSIONS: While FIT is acceptable to patients, elements of communication with patients by the healthcare system show potential for improvement. We suggest possible ways to improve the FIT experience, particularly regarding communication about the test and its results

The Common Representative Intermediates Mechanism Version 2 in the United Kingdom Chemistry and Aerosols Model

Funder: Met Office and the Natural Environment Research CouncilFunder: ESA Climate Change InitiativeAbstract: We document the implementation of the Common Representative Intermediates Mechanism version 2, reduction 5 into the United Kingdom Chemistry and Aerosol model (UKCA) version 10.9. The mechanism is merged with the stratospheric chemistry already used by the StratTrop mechanism, as used in UKCA and the UK Earth System Model, to create a new CRI‐Strat mechanism. CRI‐Strat simulates a more comprehensive treatment of non‐methane volatile organic compounds (NMVOCs) and provides traceability with the Master Chemical Mechanism. In total, CRI‐Strat simulates the chemistry of 233 species competing in 613 reactions (compared to 87 species and 305 reactions in the existing StratTrop mechanism). However, while more than twice as complex than StratTrop, the new mechanism is only 75% more computationally expensive. CRI‐Strat is evaluated against an array of in situ and remote sensing observations and simulations using the StratTrop mechanism in the UKCA model. It is found to increase production of ozone near the surface, leading to higher ozone concentrations compared to surface observations. However, ozone loss is also greater in CRI‐Strat, leading to less ozone away from emission sources and a similar tropospheric ozone burden compared to StratTrop. CRI‐Strat also produces more carbon monoxide than StratTrop, particularly downwind of biogenic VOC emission sources, but has lower burdens of nitrogen oxides as more is converted into reservoir species. The changes to tropospheric ozone and nitrogen budgets are sensitive to the treatment of NMVOC emissions, highlighting the need to reduce uncertainty in these emissions to improve representation of tropospheric chemical composition

Identification and Clonal Characterisation of a Progenitor Cell Sub-Population in Normal Human Articular Cartilage

Background: Articular cartilage displays a poor repair capacity. The aim of cell-based therapies for cartilage defects is to repair damaged joint surfaces with a functional replacement tissue. Currently, chondrocytes removed from a healthy region of the cartilage are used but they are unable to retain their phenotype in expanded culture. The resulting repair tissue is fibrocartilaginous rather than hyaline, potentially compromising long-term repair. Mesenchymal stem cells, particularly bone marrow stromal cells (BMSC), are of interest for cartilage repair due to their inherent replicative potential. However, chondrocyte differentiated BMSCs display an endochondral phenotype, that is, can terminally differentiate and form a calcified matrix, leading to failure in long-term defect repair. Here, we investigate the isolation and characterisation of a human cartilage progenitor population that is resident within permanent adult articular cartilage. Methods and Findings: Human articular cartilage samples were digested and clonal populations isolated using a differential adhesion assay to fibronectin. Clonal cell lines were expanded in growth media to high population doublings and karyotype analysis performed. We present data to show that this cell population demonstrates a restricted differential potential during chondrogenic induction in a 3D pellet culture system. Furthermore, evidence of high telomerase activity and maintenance of telomere length, characteristic of a mesenchymal stem cell population, were observed in this clonal cell population. Lastly, as proof of principle, we carried out a pilot repair study in a goat in vivo model demonstrating the ability of goat cartilage progenitors to form a cartilage-like repair tissue in a chondral defect. Conclusions: In conclusion, we propose that we have identified and characterised a novel cartilage progenitor population resident in human articular cartilage which will greatly benefit future cell-based cartilage repair therapies due to its ability to maintain chondrogenicity upon extensive expansion unlike full-depth chondrocytes that lose this ability at only seven population doublings

Elevated Fibroblast growth factor 21 (FGF21) in obese, insulin resistant states is normalised by the synthetic retinoid Fenretinide in mice

The authors would like to thank undergraduate student Aleksandra Kowalczuk (University of Aberdeen) for assisting in experiments and Dr. Emma K. Lees (School of Health Sciences, Liverpool Hope University, Liverpool, UK) for invaluable discussions concerning the regulation of FGF21. We thank Dr. Calum Sutherland and Dr. Amy Cameron (both Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Scotland, UK) for technical support and expertise in performing hepatocyte studies. Fenretinide was a generous gift of T. Martin (Johnson & Johnson, New Brunswick, NJ) and U. Thumeer (Cilag AG, Schaffhausen, Switzerland), for use completely without restriction or obligation. Quantitative-PCR was carried out using the qPCR Core Facility (Institute of Medical Sciences, University of Aberdeen). RNA-sequencing was carried out at the University of Aberdeen Centre for Genome Enabled Biology and Medicine. Pancreas histology was performed by Dr Linda Davidson (Department of Histology, Aberdeen Royal Infirmary, NHS Grampian, Foresterhill Health Campus, Aberdeen, UK). This study was supported by the British Heart Foundation Intermediate Basic Research Fellowship FS/09/026 to N. Mody, RCUK fellowship to MD, EFSD/Lilly Programme Grant to MD and N. Mody, Tenovus Scotland grants G10/04 and G14/14 to N. Mody, University of Aberdeen Centre for Genome Enabled Biology and Medicine (CGEBM) PhD studentship to N. Morrice and Biotechnology and Biological Sciences Research Council studentship to GDM.Peer reviewedPublisher PD

Genistein Improves Neuropathology and Corrects Behaviour in a Mouse Model of Neurodegenerative Metabolic Disease

BACKGROUND: Neurodegenerative metabolic disorders such as mucopolysaccharidosis IIIB (MPSIIIB or Sanfilippo disease) accumulate undegraded substrates in the brain and are often unresponsive to enzyme replacement treatments due to the impermeability of the blood brain barrier to enzyme. MPSIIIB is characterised by behavioural difficulties, cognitive and later motor decline, with death in the second decade of life. Most of these neurodegenerative lysosomal storage diseases lack effective treatments. We recently described significant reductions of accumulated heparan sulphate substrate in liver of a mouse model of MPSIIIB using the tyrosine kinase inhibitor genistein. METHODOLOGY/PRINCIPAL FINDINGS: We report here that high doses of genistein aglycone, given continuously over a 9 month period to MPSIIIB mice, significantly reduce lysosomal storage, heparan sulphate substrate and neuroinflammation in the cerebral cortex and hippocampus, resulting in correction of the behavioural defects observed. Improvements in synaptic vesicle protein expression and secondary storage in the cerebral cortex were also observed. CONCLUSIONS/SIGNIFICANCE: Genistein may prove useful as a substrate reduction agent to delay clinical onset of MPSIIIB and, due to its multimodal action, may provide a treatment adjunct for several other neurodegenerative metabolic diseases

Amitriptyline-Mediated Cognitive Enhancement in Aged 3×Tg Alzheimer's Disease Mice Is Associated with Neurogenesis and Neurotrophic Activity

Approximately 35 million people worldwide suffer from Alzheimer's disease (AD). Existing therapeutics, while moderately effective, are currently unable to stem the widespread rise in AD prevalence. AD is associated with an increase in amyloid beta (Aβ) oligomers and hyperphosphorylated tau, along with cognitive impairment and neurodegeneration. Several antidepressants have shown promise in improving cognition and alleviating oxidative stress in AD but have failed as long-term therapeutics. In this study, amitriptyline, an FDA-approved tricyclic antidepressant, was administered orally to aged and cognitively impaired transgenic AD mice (3×TgAD). After amitriptyline treatment, cognitive behavior testing demonstrated that there was a significant improvement in both long- and short-term memory retention. Amitriptyline treatment also caused a significant potentiation of non-toxic Aβ monomer with a concomitant decrease in cytotoxic dimer Aβ load, compared to vehicle-treated 3×TgAD controls. In addition, amitriptyline administration caused a significant increase in dentate gyrus neurogenesis as well as increases in expression of neurosynaptic marker proteins. Amitriptyline treatment resulted in increases in hippocampal brain-derived neurotrophic factor protein as well as increased tyrosine phosphorylation of its cognate receptor (TrkB). These results indicate that amitriptyline has significant beneficial actions in aged and damaged AD brains and that it shows promise as a tolerable novel therapeutic for the treatment of AD

Matrix Development in Self-Assembly of Articular Cartilage

Articular cartilage is a highly functional tissue which covers the ends of long bones and serves to ensure proper joint movement. A tissue engineering approach that recapitulates the developmental characteristics of articular cartilage can be used to examine the maturation and degeneration of cartilage and produce fully functional neotissue replacements for diseased tissue.This study examined the development of articular cartilage neotissue within a self-assembling process in two phases. In the first phase, articular cartilage constructs were examined at 1, 4, 7, 10, 14, 28, 42, and 56 days immunohistochemically, histologically, and through biochemical analysis for total collagen and glycosaminoglycan (GAG) content. Based on statistical changes in GAG and collagen levels, four time points from the first phase (7, 14, 28, and 56 days) were chosen to carry into the second phase, where the constructs were studied in terms of their mechanical characteristics, relative amounts of collagen types II and VI, and specific GAG types (chondroitin 4-sulfate, chondroitin 6-sulfate, dermatan sulfate, and hyaluronan). Collagen type VI was present in initial abundance and then localized to a pericellular distribution at 4 wks. N-cadherin activity also spiked at early stages of neotissue development, suggesting that self-assembly is mediated through a minimization of free energy. The percentage of collagen type II to total collagen significantly increased over time, while the proportion of collagen type VI to total collagen decreased between 1 and 2 wks. The chondroitin 6- to 4- sulfate ratio decreased steadily during construct maturation. In addition, the compressive properties reached a plateau and tensile characteristics peaked at 4 wks.The indices of cartilage formation examined in this study suggest that tissue maturation in self-assembled articular cartilage mirrors known developmental processes for native tissue. In terms of tissue engineering, it is suggested that exogenous stimulation may be necessary after 4 wks to further augment the functionality of developing constructs

Dietary mineral supplies in Malawi: spatial and socioeconomic assessment

Background Dietary mineral deficiencies are widespread globally causing a large disease burden. However, estimates of deficiency prevalence are often only available at national scales or for small population sub-groups with limited relevance for policy makers. Methods This study combines food supply data from the Third Integrated Household Survey of Malawi with locally-generated food crop composition data to derive estimates of dietary mineral supplies and prevalence of inadequate intakes in Malawi. Results We estimate that >50 % of households in Malawi are at risk of energy, calcium (Ca), selenium (Se) and/or zinc (Zn) deficiencies due to inadequate dietary supplies, but supplies of iron (Fe), copper (Cu) and magnesium (Mg) are adequate for >80 % of households. Adequacy of iodine (I) is contingent on the use of iodised salt with 80 % of rural households living on low-pH soils had inadequate dietary Se supplies compared to 55 % on calcareous soils; concurrent inadequate supplies of Ca, Se and Zn were observed in >80 % of the poorest rural households living in areas with non-calcareous soils. Prevalence of inadequate dietary supplies was greater in rural than urban households for all nutrients except Fe. Interventions to address dietary mineral deficiencies were assessed. For example, an agronomic biofortification strategy could reduce the prevalence of inadequate dietary Se supplies from 82 to 14 % of households living in areas with low-pH soils, including from 95 to 21 % for the poorest subset of those households. If currently-used fertiliser alone were enriched with Se then the prevalence of inadequate supplies would fall from 82 to 57 % with a cost per alleviated case of dietary Se deficiency of ~ US$ 0.36 year−1. Conclusions Household surveys can provide useful insights into the prevalence and underlying causes of dietary mineral deficiencies, allowing disaggregation by spatial and socioeconomic criteria. Furthermore, impacts of potential interventions can be modelled

Computational Models of the Notch Network Elucidate Mechanisms of Context-dependent Signaling

The Notch signaling pathway controls numerous cell fate decisions during development and adulthood through diverse mechanisms. Thus, whereas it functions as an oscillator during somitogenesis, it can mediate an all-or-none cell fate switch to influence pattern formation in various tissues during development. Furthermore, while in some contexts continuous Notch signaling is required, in others a transient Notch signal is sufficient to influence cell fate decisions. However, the signaling mechanisms that underlie these diverse behaviors in different cellular contexts have not been understood. Notch1 along with two downstream transcription factors hes1 and RBP-Jk forms an intricate network of positive and negative feedback loops, and we have implemented a systems biology approach to computationally study this gene regulation network. Our results indicate that the system exhibits bistability and is capable of switching states at a critical level of Notch signaling initiated by its ligand Delta in a particular range of parameter values. In this mode, transient activation of Delta is also capable of inducing prolonged high expression of Hes1, mimicking the “ON” state depending on the intensity and duration of the signal. Furthermore, this system is highly sensitive to certain model parameters and can transition from functioning as a bistable switch to an oscillator by tuning a single parameter value. This parameter, the transcriptional repression constant of hes1, can thus qualitatively govern the behavior of the signaling network. In addition, we find that the system is able to dampen and reduce the effects of biological noise that arise from stochastic effects in gene expression for systems that respond quickly to Notch signaling