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  • Myotonic dystrophy type 1: palliative care guidelines

    Willis, Derek; Willis, Tracey; Bassie, Claire; Eglon, Gail; Ashley, Emma-Jayne; Turner, Chris; University of Chester; Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Foundation Trust; Newcastle Upon Tyne Hospitals NHS Foundation Trust; Cure Myotonic Dystrophy UK; University College London Hospitals NHS Foundation Trust (BMJ Publishing Group, 2024-01-22)
    Palliative care for adults with neuromuscular conditions is an emerging field. Previous guidelines regarding myotonic dystrophy and palliative care have only mentioned end-of-life care and little else. The following guidelines have been written using national experts as a description of best practice as part of the Dystrophia Myotonica National Care Guidelines Consortium. [Abstract copyright: © Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.]
  • Do sociodemographic and clinical characteristics affect mortality rates in people with intellectual disability and dysphagia who have a percutaneous endoscopic gastrostomy? A cohort study between 2000 and 2022

    Broad, Laura; Wee, Christine; Harries, Anthony D. (Wiley, 2024-01-22)
    Background: People with intellectual disability frequently have eating, drinking and swallowing difficulties (dysphagia) and are at greater risk of premature mortality, particularly from aspiration and respiratory infections. The insertion of a percutaneous endoscopic gastrostomy (PEG), as part of a multidisciplinary management plan, may help to maintain and improve nutrition. This study included people with intellectual disability who had ever had a PEG inserted and who presented to the specialist Speech and Language Therapy team in one Greater Manchester borough between 2000 and 2022 and assessed the risk of death and sociodemographic and clinical factors associated with this. Methods: This was a cohort study using secondary data. Kaplan–Meier estimates were used to construct the probability of mortality curves. Cox proportional hazards were used to compare death rates in the different sociodemographic and clinical characteristic groups and were presented as hazard ratios and 95% confidence intervals. Findings: Of 42 people included in the study, 18 (43%) died from the point of PEG insertion to the end of the study (December 2022). The median (interquartile range) time to death from PEG insertion was 5 (2–10) years, with four people (10%) dying in the first year. Aspiration pneumonia and unspecified pneumonia were responsible for seven (39%) deaths. No significant associations were found between sociodemographic and clinical factors and risk of death. Conclusion: In persons with intellectual disability and a PEG who were followed up between 2000 and 2022, the mortality was around 40% with deaths occurring in the first year and respiratory conditions being an important cause. The lack of association with sociodemographic and clinical characteristics may have been due to a limited sample size. Further research is needed with larger samples and more variables, including quality of life data, to help understand and improve clinical practice in this area.
  • The Influence of Polycystic Ovary Syndrome (PCOS) and Other Related Factors upon Health-Related Quality of Life in Women of Reproductive Age: A Case-Control Study

    Kite, Chris; Brown, James E. P.; Lahart, Ian M.; Randeva, Harpal S.; Kyrou, Ioannis; University of Wolverhampton; Aston University; University Hospitals Coventry and Warwickshire NHS Trust; Coventry University; University of Chester; University of Warwick; University of Athens (Taylor & Francis, 2024-01-09)
    This study aimed to assess the impact of a polycystic ovary syndrome (PCOS) diagnosis and other factors on health-related quality of life (HRQoL) in women of reproductive age. Online questionnaires were completed and study groups compared. Potential causal relationships were evaluated using path analysis. Analyses revealed that a PCOS diagnosis alongside BMI had the largest effect on HRQoL. Higher levels of physical activity (PA) were not associated with greater HRQoL, and PA was not directly affected by any other outcome. However, reduced self-esteem was identified as a key factor in the promotion of physical and mental health.
  • Novel lactoferrin-conjugated gallium complex to treat Pseudomonas aeruginosa wound infection

    Valappil, Sabeel P.; Abou Neel, Ensanya A.; Zakir Hossain, Kazi M.; Paul, Willi; Cherukaraveedu, Durgadas; Wade, Benjamin; Ansari, Tahera I; Hope, Christopher K.; Higham, Susan M.; Sharma, Chandra P.; et al. (Elsevier, 2023-12-19)
    Pseudomonas aeruginosa is one of the leading causes of opportunistic infections such as chronic wound infection that could lead to multiple organ failure and death. Gallium (Ga3+) ions are known to inhibit P. aeruginosa growth and biofilm formation but require carrier for localized controlled delivery. Lactoferrin (LTf), a two-lobed protein, can deliver Ga3+ at sites of infection. This study aimed to develop a Ga-LTf complex for the treatment of wound infection. The characterisation of the Ga-LTf complex was conducted using differential scanning calorimetry (DSC), Infra-Red (FTIR) and Inductive Coupled Plasma Optical Emission Spectrometry (ICP-OES). The antibacterial activity was assessed by agar disc diffusion, liquid broth and biofilm inhibition assays using the colony forming units (CFUs). The healing capacity and biocompatibility were evaluated using a P.aeruginosa infected wound in a rat model. DSC analyses showed thermal transition consistent with apo-lactoferrin; FTIR confirmed the complexation of gallium to lactoferrin. ICP-OES confirmed the controlled local delivery of Ga3+. Ga-LTf showed a 0.57 log10 CFUs reduction at 24 h compared with untreated control in planktonic liquid broth assay. Ga-LTf showed the highest antibiofilm activity with a 2.24 log10 CFUs reduction at 24 h. Furthermore, Ga-LTf complex is biocompatible without any adverse effect on brain, kidney, liver and spleen of rats tested in this study. Ga-LTf can be potentially promising novel therapeutic agent to treat pathogenic bacterial infections.
  • Lifelong dietary protein restriction accelerates skeletal muscle loss and reduces muscle fibre size by impairing proteostasis and mitochondrial homeostasis

    Ersoy, Ufuk; Kanakis, Ioannis; Alameddine, Moussira; Pedraza-Vazquez, Gibran; Ozanne, Susan E.; Peffers, Mandy Jayne; Jackson, Malcolm J.; Goljanek-Whysall, Katarzyna; Vasilaki, Aphrodite; University of Liverpool; NUI Galway; University of Chester; University of Cambridge (Elsevier, 2023-12-02)
    The early life environment significantly affects the development of age-related skeletal muscle disorders. However, the long-term effects of lactational protein restriction on skeletal muscle are still poorly defined. Our study revealed that male mice nursed by dams fed a low-protein diet during lactation exhibited skeletal muscle growth restriction. This was associated with a dysregulation in the expression levels of genes related to the ribosome, mitochondria and skeletal muscle development. We reported that lifelong protein restriction accelerated loss of type-IIa muscle fibres and reduced muscle fibre size by impairing mitochondrial homeostasis and proteostasis at 18 months of age. However, feeding a normal-protein diet following lactational protein restriction prevented accelerated fibre loss and fibre size reduction in later life. These findings provide novel insight into the mechanisms by which lactational protein restriction hinders skeletal muscle growth and includes evidence that lifelong dietary protein restriction accelerated skeletal muscle loss in later life.
  • A comprehensive review on the risks assessment and treatment options for Sarcopenia in people with diabetes

    Johri, Nishant; Vengat, Maheshwari; Kumar, Deepanshu; Nagar, Priya; John, Davis; Dutta, Shubham; Mittal, Piyush; Teerthanker Mahaveer College of Pharmacy; University of Chester (Springer Nature, 2023-07-30)
    This comprehensive review aims to examine the reciprocal interplay between Type 2 diabetes mellitus (T2DM) and sarcopenia, identify prevailing research gaps, and discuss therapeutic approaches and measures to enhance healthcare practices within hospital settings. A thorough literature review was conducted to gather relevant studies and articles on the relationship between T2DM and sarcopenia. Various databases were searched, including Google Scholar, PubMed, Scopus, and Science Direct databases. The search terms included T2DM, sarcopenia, inflammation, insulin resistance, advanced glycation end products, oxidative stress, muscle dimensions, muscle strength, muscle performance, aging, nutrition, hormone levels, and physical activity. The collected articles were critically analysed to extract key findings and identify gaps in current research. The prevalence and incidence of metabolic and musculoskeletal disorders, notably T2DM and sarcopenia, have surged in recent years. T2DM is marked by inflammation, insulin resistance, accumulation of advanced glycation end products, and oxidative stress, while sarcopenia involves a progressive decline in skeletal muscle mass and function. The review underscores the age-related correlation between sarcopenia and adverse outcomes like fractures, falls, and mortality. Research gaps regarding optimal nutritional interventions for individuals with T2DM and sarcopenia are identified, emphasizing the necessity for further investigation in this area. The reciprocal interplay between T2DM and sarcopenia holds significant importance. Further research is warranted to address knowledge gaps, particularly in utilizing precise measurement tools during clinical trials. Lifestyle modifications appear beneficial for individuals with T2DM and sarcopenia. Additionally, practical nutritional interventions require investigation to optimize healthcare practices in hospital settings. The online version contains supplementary material available at 10.1007/s40200-023-01262-w. [Abstract copyright: © The Author(s), under exclusive licence to Tehran University of Medical Sciences 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.]
  • An assessment of interventions following moderate and high scores on the dynamic appraisal of situational aggression risk assessment tool in a forensic mental health unit

    Challinor, Alexander; Briggs, Patrick; Brennan, Faye; Daniels, Charles; Hurst, George; Thorpe, Mark; Xavier, Panchu; Nathan, Rajan; University of Liverpool; Mersey Care NHS Foundation Trust; Liverpool University Hospitals NHS Foundation Trust; Cheshire and Wirral Partnership NHS Trust; University of Chester; Liverpool John Moores University (Taylor & Francis, 2023-11-14)
    The Dynamic Appraisal of Situational Aggression (DASA) provides a quick and systematic assessment of short-term violence risk. Risk assessment should be closely aligned to management and result in interventions aimed to reduce risk. The aim of this study was to investigate what interventions followed a moderate/high DASA score and whether they reduced risk. The impact of staff training was also assessed. The study was a retrospective analysis of health records within a medium secure hospital over 6 months. Data was gathered on tool adherence and interventions that were used to reduce risk following a moderate/high score. The change in DASA score following the intervention was recorded. There were 70 patients covering 8224 bed days. There were 24 occasions where a moderate score led to an intervention (n = 24/40%), and 26 occasions for a high score (n = 26/87%). A moderate score was mostly followed by no intervention (n = 35/59%), a high score was mostly followed by seclusion (n = 9/29%). The intervention that led to the largest reduction in DASA score was pro re nata medication following a moderate score and seclusion following a high score. The training of staff led to a reduction in tool adherence and increased intervention use. These results support the need for combining the DASA assessment with operationalised systems to link assessment with risk prevention to help reduce aggression and restrictive practices.
  • Asthma and COPD as co-morbidities in patients hospitalised with Covid-19 disease: a global systematic review and meta-analysis

    Finnerty, James P.; Hussain, A. B. M. Arad; Ponnuswamy, Aravind; Kamil, Hafiz Gulzeb; Abdelaziz, Ammar; Countess of Chester Hospital NHS Trust; Worcestershire Acute Hospital NHS Trust; University of Chester (BMC, 2023-11-22)
    Background: Factors predisposing to increased mortality with COVID-19 infection have been identified as male sex, hypertension, obesity, and increasing age. Early studies looking at airway diseases gave some contradictory results. The purpose of our study was to determine global variation in studies in patients hospitalized with COVID-19 in the prevalence of COPD and asthma; and to determine whether the presence of asthma or COPD affected mortality in the same hospital population. Methods: A systematic review and meta-analysis of the published literature of COPD and asthma as co-morbidities in patients hospitalized with COVID-19 was performed, looking firstly at the prevalence of these diseases in patients hospitalized with COVID-19, and secondly at the relative risk of death from any cause for patients with asthma or COPD. Results: Prevalence of both airway diseases varied markedly by region, making meaningful pooled global estimates of prevalence invalid and not of clinical utility. For individual studies, the interquartile range for asthma prevalence was 4.21 to 12.39%, and for COPD, 3.82 to 11.85%. The relative risk of death with COPD for patients hospitalized with COVID-19 was 1.863 (95% CI 1.640–2.115), while the risk with asthma was 0.918 (95% CI 0.767 to 1.098) with no evidence of increased mortality. Conclusions: For asthma and COPD, prevalence in patients hospitalized with COVID-19 varies markedly by region. We found no evidence that asthma predisposed to increased mortality in COVID-19 disease. For COPD, there was clear evidence of an association with increased mortality. Trial registration: The trial was registered with PROSPERO: registration number CRD42021289886.
  • Effects of a transoceanic rowing challenge on cardiorespiratory function and muscle fitness

    Ellis, Chris; Ingram, Thomas; Kite, Chris; Taylor, Sue; Howard, Liz; Pike, Joanna; Lee, Eveline; Buckley, John; Shrewsbury and Telford Hospital NHS Trust; University of Chester; University of Wolverhampton; Perform at St Georges Park, Spire Healthcare; Keele University (Thieme, 2023-11-06)
    Ultra-endurance sports and exercise events are becoming increasingly popular for older age groups. We aimed to evaluate changes in cardiac function and physical fitness in males aged 50-60 years who completed a 50-day transoceanic rowing challenge. This case account of four self-selected males included electro- and echo-cardiography (ECG, echo), cardiorespiratory and muscular fitness measures recorded nine-months prior to and three weeks after a transatlantic team-rowing challenge. No clinically significant changes to myocardial function were found over the course of the study. The training and race created expected functional changes to left ventricular and atrial function; the former associated with training, the latter likely due to dehydration, both resolving towards baseline within three weeks post-event. From race-start to finish all rowers lost 8.4-15.6 kg of body mass. Absolute cardiorespiratory power and muscular strength were lower three weeks post-race compared to pre-race, but cardiorespiratory exercise economy improved in this same period. A structured programme of moderate-vigorous aerobic endurance and muscular training for >6 months, followed by 50-days of transoceanic rowing in older males proved not to cause any observable acute or potential long-term risks to cardiovascular health. Pre-event screening, fitness testing, and appropriate training is recommended, especially in older participants where age itself is an increasingly significant risk factor.
  • SET-PP2A complex as a new therapeutic target in KMT2A (MLL) rearranged AML

    Di Mambro, Antonella; Arroyo-Berdugo, Yoana; Fioretti, Tiziana; Randles, Michael; Cozzuto, Luca; Rajeeve, Vinothini; Cevenini, Armando; Austin, Michael; Esposito, Gabriella; Ponomarenko, Julia; et al. (Springer Nature, 2023-10-27)
    KMT2A-rearranged (KMT2A-R) is an aggressive and chemo-refractory acute leukemia which mostly affects children. Transcriptomics-based characterization and chemical interrogation identified kinases as key drivers of survival and drug resistance in KMT2A-R leukemia. In contrast, the contribution and regulation of phosphatases is unknown. In this study we uncover the essential role and underlying mechanisms of SET, the endogenous inhibitor of Ser/Thr phosphatase PP2A, in KMT2A-R-leukemia. Investigation of SET expression in acute myeloid leukemia (AML) samples demonstrated that SET is overexpressed, and elevated expression of SET is correlated with poor prognosis and with the expression of MEIS and HOXA genes in AML patients. Silencing SET specifically abolished the clonogenic ability of KMT2A-R leukemic cells and the transcription of KMT2A targets genes HOXA9 and HOXA10. Subsequent mechanistic investigations showed that SET interacts with both KMT2A wild type and fusion proteins, and it is recruited to the HOXA10 promoter. Pharmacological inhibition of SET by FTY720 disrupted SET-PP2A interaction leading to cell cycle arrest and increased sensitivity to chemotherapy in KMT2A-R-leukemic models. Phospho-proteomic analyses revealed that FTY720 reduced the activity of kinases regulated by PP2A, including ERK1, GSK3β, AURB and PLK1 and led to suppression of MYC, supporting the hypothesis of a feedback loop among PP2A, AURB, PLK1, MYC, and SET. Our findings illustrate that SET is a novel player in KMT2A-R leukemia and they provide evidence that SET antagonism could serve as a novel strategy to treat this aggressive leukemia. [Abstract copyright: © 2023. The Author(s).]
  • 'I just need to know what they are and if you can help me': Medicalization and the search for legitimacy in people diagnosed with non-epileptic attack disorder

    Peacock, Marian; Bissell, Paul; Ellis, Julie; Dickson, Jon M.; Wardrope, Alistair; Grünewald, Richard; Reuber, Markus; Edge Hill University; University of Chester; University of Huddersfield; University of Sheffield; Sheffield Teaching Hospitals NHS Foundation Trust (Elsevier, 2023-10-17)
    This paper focuses on the struggles for legitimacy expressed by people with non-epileptic attack disorder (NEAD), one of the most common manifestations of functional neurological disorder presenting to emergency and secondary care services. Nonepileptic attacks are episodes of altered experience, awareness, and reduced self-control that superficially resemble epileptic seizures or other paroxysmal disorders but are not associated with physiological abnormalities sufficient to explain the semiological features. "Organic" or medicalized explanations are frequently sought by patients as the only legitimate explanation for symptoms, and consequently, a diagnosis of NEAD is often contested. Drawing on narrative interviews with patients from a small exploratory study and using a sociological perspective, we propose that a psychological account of NEAD does not provide a sufficiently legitimate path into a socially sanctioned sick role. This is a reflection of the dominance of biomedicine and the associated processes of medicalization. These processes are, we argue, the sole route to achieving legitimacy. The stress-based or psychologically oriented explanations offered to patients in contemporary medical models of the etiology of NEAD engender an uncertain identity and social position and fail to provide many patients with an account of the nature or origin of their symptoms that they find satisfactory or convincing. These struggles for legitimacy (shared by others with functional or somatoform conditions) are sharpened by key features of the contemporary healthcare landscape, such as the increasing framing of health through a lens of 'responsibilization'. [Abstract copyright: Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.]
  • Causation, historiographic approaches and the investigation of serious adverse incidents in mental health settings

    Bhandari, Sahil; Thomassen, Øyvind; Nathan, Rajan; Health Education England North West; Cheshire and Wirral Partnerships NHS Foundation Trust; Norwegian University of Science and Technology; St Olavs Hospital, Norway; University of Chester; University of Liverpool; Liverpool John Moores University (SAGE Publications, 2022-05-03)
    To improve the safety of healthcare systems, it is necessary to understand harm-related events that occur in these systems. In mental health services, particular attention is paid to harm arising from the actions of patients against themselves or others. The primary intention of examining these adverse events is to inform changes to care provision so as to reduce the likelihood of the recurrence of such events. The predominant approach to investigating adverse incidents has relied on the cause-and-effect conceptualisation of past events. Whilst the merits of approaches which are reliant on cause-and-effect narratives have been questioned, alternatives models to explain adverse incidents in health settings have not been theoretically or empirically tested. This novel article (i) examines the notion of causation (and the related notion of omission) in the context of explaining adverse events in mental health settings, and (ii) draws on a long-established discipline devoted to the study of how the past is interpreted (namely historiography) to theoretically investigate the innovative application of two historiographical approaches (i.e. counterfactual analysis and historical materialism) to understanding adverse events in mental health settings.
  • Predicted Structure and Potential Binding of the Nematode Tetraspanin 7 Protein (tsp-7) With Human Tissue Inhibitor Metalloprotease 1 (TIMP-1): a Possible Role In Parasite- Host Interactions

    Michelangeli, Frank; Jones, Brogan (University of Chester, 2023-02)
    Human parasitic nematodes evade the host immune system through cross communication by unknown mechanisms. The proteins of the parasitic nematodes are still poorly annotated. CD63 is a human tetraspanin and binds to TIMP-1 a metalloproteinase inhibitor, which has recently been found to play an active role in inflammation by acting as a cytokine when bound to CD63. Caenorhabditis elegans is a free-living nematode, a model organism for both human and parasitic nematodes. C. elegans tetraspanin protein -7 (tsp-7) is an orthologue of human CD63. The model organism used can provide information about potential tetraspanin proteins from parasitic nematodes, which are believed to play a role in the cross communication between parasite and host. The tsp-7 protein sequence from C. elegans shares a high percentage similarity, identity, and homology with a variety of human parasitic nematode proteins. Using a number of computer-based programmes including ‘Alpha-Fold,’ which is currently the most powerful Artificial Intelligence protein structure prediction programme, the structure of the C. elegans tsp-7 was determined. From the predicted structure, the tsp-7 protein has one highly likely, membrane exposed tyrosine phosphorylation site, with implications of its potential involvement in signalling pathways and immune responses. Using multiple protein docking databases and programmes, tsp-7 has been shown to theoretically bind to human TIMP-1. Two mutant strains of C. elegans were obtained from Caenorhabditis Genetics Centre, University of Minnesota, USA, with amino acid deletions within the tsp-7 protein (mutant tm5046 and mutant tm5761). These tsp-7 mutant strains were shown to have an overall longer life span than the wild type C. elegans (N2). The mutant tm5761 showed a greater stress response compared to the N2 wild-type, when exposed to various chemical stimuli, however, mutant tm5046 was more similar to wild type C. elegans. Under heat stress, mutant tm5761 and wild type N2, were less tolerant to heat compared to the tm5046 mutant. In general, mutant tm5046 was more stable and displayed a reduced stress behavioural response compared to mutant tm5761. A primary polyclonal antibody was produced against the tsp-7 large extracellular loop domain, believed to be the key active site in protein-protein interactions. The expression of tsp-7 in mutant tm5761 was detected at lower concentrations than the wild type and mutant tm5046 in an ELISA assay and it also could not be detected by western blotting. Mutant tm5046 was detected weakly by western blotting. Cos-7 cells transfected with the tsp-7 protein-GFP tagged plasmid were incubated with active human TIMP-1. The tsp-7 tagged cells showed co-localisation with TIMP-1, using immuno-fluorescence microscopy, thus adding to the evidence that tsp-7 could interact with human TIMP-1. Such an interaction may well play a role in parasite-host interactions and its effects on the immune response. As C. elegans tsp-7 shares high similarity with many parasitic nematodes that are known to infect humans, it is a good protein candidate to further explore the potential interactions of parasitic nematodes with humans, in terms of cross communication and interaction with the host immune system.
  • Lysophosphatidic Acid Signalling in Diabetes Mellitus

    Johnson, Eustace; Hamdallah, Hanady; Asiamah, Prince (University of Chester, 2023-08)
    Driven by obesity, the incidence of type 2 diabetes mellitus (T2DM) has escalated, reaching unprecedented levels worldwide. This has led to a change in approach from treatment to prevention or delaying the onset of the disease. While current treatment of the disease has been successful in increasing patients’ quality of life, it has substantially increased the financial burden on healthcare systems worldwide. In view of this, the NHS, in partnership with Diabetes UK and Public Health England, has launched a diabetes prevention programme to target people at risk of the disease and provide targeted support to prevent its development. A prelude to this strategy is to identify robust risk factors that will enable the capture of people at increased risk of developing the disease. The phospholipid lysophosphatidic acid (LPA), upregulated during obesity, has been shown to be a potent regulator of glucose homeostasis and insulin secretion in animal models. This thesis is the first to assess circulating levels of LPA in human T2DM patients versus non-DM control. The thesis aims to assess the usefulness of LPA as a biomarker for T2DM screening and has three major objectives: (1) to determine plasma LPA concentration in T2DM patients compared with non-diabetic controls and assess LPA correlation with current diagnostic markers for T2DM. (2) to determine LPA correlation with pathological markers known to lead to DM complications; (3) to develop an immunofluorescence assay to assess LPA signalling of glucose homoeostasis using a mammalian cell line. (4) to assess LPA regulations of GLUT4, PKC and α2a adrenergic receptor (α2aAR) using the developed assay.
  • Prevalence of SARS-CoV-2 Omicron Sublineages and Spike Protein Mutations Conferring Resistance against Monoclonal Antibodies in a Swedish Cohort during 2022–2023

    Haars, Jonathan; Palanisamy, Navaneethan; Wallin, Frans; Mölling, Paula; Lindh, Johan; Sundqvist, Martin; Ellström, Patrik; Kaden, René; Lennerstrand, Johan; Uppsala University; University of Chester; Örebro University Hospital; SciLifeLab, Uppsala (MDPI, 2023-09-27)
    Monoclonal antibodies (mAbs) are an important treatment option for COVID-19 caused by SARS-CoV-2, especially in immunosuppressed patients. However, this treatment option can become ineffective due to mutations in the SARS-CoV-2 genome, mainly in the receptor binding domain (RBD) of the spike (S) protein. In the present study, 7950 SARS-CoV-2 positive samples from the Uppsala and Örebro regions of central Sweden, collected between March 2022 and May 2023, were whole-genome sequenced using amplicon-based sequencing methods on Oxford Nanopore GridION, Illumina MiSeq, Illumina HiSeq, or MGI DNBSEQ-G400 instruments. Pango lineages were determined and all single nucleotide polymorphism (SNP) mutations that occurred in these samples were identified. We found that the dominant sublineages changed over time, and mutations conferring resistance to currently available mAbs became common. Notable ones are R346T and K444T mutations in the RBD that confer significant resistance against tixagevimab and cilgavimab mAbs. Further, mutations conferring a high-fold resistance to bebtelovimab, such as the K444T and V445P mutations, were also observed in the samples. This study highlights that resistance mutations have over time rendered currently available mAbs ineffective against SARS-CoV-2 in most patients. Therefore, there is a need for continued surveillance of resistance mutations and the development of new mAbs that target more conserved regions of the RBD.
  • An Investigation of the Protein Quality and Temporal Pattern of Peripheral Blood Aminoacidemia following Ingestion of 0.33 g·kg−1 Body Mass Protein Isolates of Whey, Pea, and Fava Bean in Healthy, Young Adult Men

    Kozior, Marta; Davies, Robert W.; Amigo-Benavent, Miryam; Fealy, Ciaran; Jakeman, Philip M.; University of Limerick; University of Chester (MDPI, 2023-09-29)
    An increase in the intake of legumes is recommended in the promotion of plant-sourced (PSP) rather than animal-sourced (ASP) protein intake to produce a more sustainable diet. This study evaluated the quality of novel PSP isolates from pea (PEA) and fava bean (FAVA) and an ASP isolate of whey (WHEY) and compared the magnitude and temporal pattern of peripheral arterial aminoacidemia following ingestion of 0.33 g·kg−1 body mass of protein isolate in healthy young adult men (n = 9). Total indispensable amino acids (IAA) comprised 58% (WHEY), 46% (PEA), and 42% (FAVA) of the total amino acid (AA) composition, with the ingested protein providing 108% (WHEY), 77% (PEA), and 67% (FAVA) of the recommended per diem requirement of IAA. Reflecting the AA composition, the area under the curve (∆AUC0-180), post-ingestion increase in total IAA for WHEY was 41% (p < 0.001) and 57% (p < 0.001) greater than PEA and FAVA, respectively, with PEA exceeding FAVA by 28% (p = 0.003). As a sole-source, single-dose meal-size serving, the lower total IAA for PEA and FAVA would likely evoke a reduced post-prandial anabolic capacity compared to WHEY. Incorporated into a food matrix, the promotion of PSP isolates contributes to a more sustainable diet.
  • Fgf signalling triggers an intrinsic mesodermal timer that determines the duration of limb patterning

    Sedas Peres, Sofia; McQueen, Caitlin; Stainton, Holly; Pickering, Joseph; Chinnaiya, Kavitha; Saiz Lopez, Patricia; Placzek, Marysia; Ros, Maria; Towers, Matthew; University of Sheffield; University of Chester; Universidad de Cantabria (Nature Research, 2023-09-20)
    Complex signalling between the apical ectodermal ridge (AER - a thickening of the distal epithelium) and the mesoderm controls limb patterning along the proximo-distal axis (humerus to digits). However, the essential in vivo requirement for AER-Fgf signalling makes it difficult to understand the exact roles that it fulfils. To overcome this barrier, we developed an amenable ex vivo chick wing tissue explant system that faithfully replicates in vivo parameters. Using inhibition experiments and RNA-sequencing, we identify a transient role for Fgfs in triggering the distal patterning phase. Fgfs are then dispensable for the maintenance of an intrinsic mesodermal transcriptome, which controls proliferation/differentiation timing and the duration of patterning. We also uncover additional roles for Fgf signalling in maintaining AER-related gene expression and in suppressing myogenesis. We describe a simple logic for limb patterning duration, which is potentially applicable to other systems, including the main body axis.
  • Older adults’ experience of neuropsychological assessments for dementia screening in South India: a qualitative study

    Du, Bharath; Jones, Steven; Bailey, Jan; Rao, Poornima; Chandra, Mina; Vaitheswaran, Sridhar; Shaji K. S.; Goswami, Satyapal P.; Spector, Amy; Fisher, Emily; et al. (Wellcome, 2023-09-25)
    Background: In community settings, neuropsychological assessment is the most commonly employed method for early recognition of dementia. However, little is known about the experience and perspectives of older adults when they undertake neuro psychological assessments in low-and middle-income countries (LMICs), including India. Methods: We conducted semi-structured interviews for 11 individuals (aged between 64 and 88 years) who had undergone cognitive assessment in the CST International (Cognitive Stimulation Therapy International) study and were free from dementia. The transcripts were analysed manually utilising Interpretative Phenomenological Analysis to develop key themes. Results: When data were analysed three super-ordinate themes (experiences related to the process, content and outcomes) each with a set of subordinate themes emerged. Conclusions: This study highlights the need for a thorough planning of pre-assessment briefing for equipping participants with adequate information related to the neuro psychological assessment: its indication, length of procedure, contents of the test, possible outcomes, medical implications of those outcomes, possible therapeutic options if diagnosed with lower cognitive function.We discuss our findings in relation to extant knowledge and explore issues clinicians should consider when conducting neuro psychological assessments in LMIC settings.
  • Evaluation of a novel, multicomponent anxiety management programme for people with intellectual disability: protocol for a mixed-methods, quasi-experimental feasibility study

    Jones, Steven; Acton, Danny; Jaydeokar, Sujeet; Lane, Steven; Woodrow, Ceri; Talbot, Grace; Williams, Jonathan; Cheshire and Wirral Partnership NHS Foundation Trust; University of Chester; University of Liverpool (BMJ Publishing Group, 2023-09-20)
    Studies have shown some benefits to single approaches to psychological therapies for the treatment of anxiety in people with intellectual disability such as modified cognitive–behavioural therapy and mindfulness. To our knowledge, no studies have used a multicomponent approach for the individual treatment of anxiety-related disorders in this population group. A co-production group of clinical experts and people with intellectual disability has created a novel multicomponent anxiety management programme (MCAMP-ID). The aims of this study are to investigate (1) the feasibility of this approach in reducing anxiety for people with a mild/moderate intellectual disability, (2) the feasibility of outcome measures and (3) the feasibility of completing a future randomised controlled trial of this programme. The data from this feasibility study will be used to inform trial design and to complete power calculation.
  • ST2-Conditioned Medium Fosters Dorsal Horn Cell Excitability and Synaptic Transmission in Cultured Mouse Spinal Cord

    Juárez, Esri H.; Wood, Chelsea R.; Davies, Rebecca; Kehoe, Oksana; Johnson, William E. B.; Merighi, Adalberto; Ferrini, Francesco; University of Turin; University of Chester; Keele University; Université Laval (Springer, 2023-09-06)
    Conditioned medium obtained from bone marrow-derived stem cells has been proposed as a novel cell-free therapy in spinal cord injury and neuropathic pain, yet the direct effect on spinal neuron function has never been investigated. Here, we adopted spinal cord organotypic cultures (SCOCs) as an experimental model to probe the effect of ST2 murine mesenchymal stem cells-conditioned medium (ST2-CM) on dorsal horn (DH) neuron functional properties. Three days of SCOC exposure to ST2-CM increased neuronal activity measured by Fos expression, as well as spontaneous or induced firing. We showed that the increase in neuronal excitability was associated with changes in both intrinsic membrane properties and an enhanced excitatory drive. The increased excitability at the single-cell level was substantiated at the network level by detecting synchronous bursts of calcium waves across DH neurons. Altogether, SCOCs represent a viable tool to probe mesenchymal cells' effect on intact neuronal networks. Our findings indicate that ST2-CM enhances neuronal activity and synaptic wiring in the spinal dorsal horn. Our data also support the trophic role of mesenchymal cells CM in maintaining network activity in spinal circuits. [Abstract copyright: © 2023. The Author(s).]

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