• Macclesfield Baths and Washhouses and its patrons in the nineteenth century

      Griffiths, Sarah; University of Chester (Cheshire Local History Association, 2021-12-31)
      The East Cheshire market town of Macclesfield had grown to become the leading centre of the English silk industry by the mid nineteenth century and this resulted in severe pressure on the town’s inadequate services. One element of the national campaign to improve sanitary conditions in urban areas was the public baths and washhouses movement from the 1840s, which resulted in the Public Baths and Wash-houses Acts in 1846 and 1847. Macclesfield’s Baths and Washhouses opened in January 1850 and it was one of the first provincial towns after Liverpool to provide such facilities. This article will therefore explore the national baths and washhouses movement, the impact of industrialisation on living conditions in Macclesfield, the history of the town’s Baths and Washhouses in the nineteenth century, the people active in its development and the range of motives which may have encouraged their support for this early addition to the public services for inhabitants.
    • Co-designing new tools for collecting, analysing and presenting patient experience data in NHS services: working in partnership with patients and carers

      Small, Nicola; orcid: 0000-0002-7879-7967; email: nicola.small@manchester.ac.uk; Ong, Bie Nio; orcid: 0000-0001-8138-8139; Lewis, Annmarie; Allen, Dawn; Bagshaw, Nigel; Nahar, Papreen; orcid: 0000-0002-5817-8093; Sanders, Caroline; orcid: 0000-0002-0539-928X; Hodgson, Damian; Dehghan, Azad; Sharp, Charlotte; et al. (BioMed Central, 2021-11-27)
      Abstract: Background: The way we collect and use patient experience data is vital to optimise the quality and safety of health services. Yet, some patients and carers do not give feedback because of the limited ways data is collected, analysed and presented. In this study, we worked together with researchers, staff, patient and carer participants, and patient and public involvement and engagement (PPIE) contributors, to co-design new tools for the collection and use of patient experience data in multiple health settings. This paper outlines how the range of PPIE and research activities enabled the co-design of new tools to collect patient experience data. Methods: Eight public contributors represented a range of relevant patient and carer experiences in specialist services with varied levels of PPIE experience, and eleven members of Patient and Participation Groups (PPGs) from two general practices formed our PPIE group at the start of the study. Slide sets were used to trigger co-design discussions with staff, patient and carer research participants, and PPIE contributors. Feedback from PPIE contributors alongside verbatim quotes from staff, patient and carer research participants is presented in relation to the themes from the research data. Results: PPIE insights from four themes: capturing experience data; adopting digital or non-digital tools; ensuring privacy and confidentiality; and co-design of a suite of new tools with guidance, informed joint decisions on the shaping of the tools and how these were implemented. Our PPIE contributors took different roles during co-design and testing of the new tools, which supported co-production of the study. Conclusions: Our experiences of developing multiple components of PPIE work for this complex study demonstrates the importance of tailoring PPIE to suit different settings, and to maximise individual strengths and capacity. Our study shows the value of bringing diverse experiences together, putting patients and carers at the heart of improving NHS services, and a shared approach to managing involvement in co-design, with the effects shown through the research process, outcomes and the partnership. We reflect on how we worked together to create a supportive environment when unforeseen challenges emerged (such as, sudden bereavement).
    • Renal hemofiltration prevents metabolic acidosis and reduces inflammation during normothermic machine perfusion of the vascularized composite allograft—A preclinical study

      Stone, John P.; orcid: 0000-0001-9452-2843; Amin, Kavit R.; Geraghty, Abbey; Kerr, Jak; Shaw, Matthew; Dabare, Dilan; Wong, Jason K.; Brough, David; Entwistle, Timothy R.; Montero‐Fernandez, Angeles; et al. (2021-11-26)
      Abstract: Introduction: Recent experimental evidence suggests normothermic machine perfusion of the vascularized composite allograft results in improved preservation compared to static cold storage, with less reperfusion injury in the immediate post‐operative period. However, metabolic acidosis is a common feature of vascularized composite allograft perfusion, primarily due to the inability to process metabolic by‐products. We evaluated the impact of combined limb‐kidney perfusion on markers of metabolic acidosis and inflammation in a porcine model. Methods: Ten paired pig forelimbs were used for this study, grouped as either limb‐only (LO, n = 5) perfusion, or limb‐kidney (LK, n = 5) perfusion. Infrared thermal imaging was used to determine homogeneity of perfusion. Lactate, bicarbonate, base, pH, and electrolytes, along with an inflammatory profile generated via the quantification of cytokines and cell‐free DNA in the perfusate were recorded. Results: The addition of a kidney to a limb perfusion circuit resulted in the rapid stabilization of lactate, bicarbonate, base, and pH. Conversely, the LO circuit became progressively acidotic, correlating in a significant increase in pro‐inflammatory cytokines. Global perfusion across the limb was more homogenous with LK compared to LO. Conclusion: The addition of a kidney during limb perfusion results in significant improvements in perfusate biochemistry, with no evidence of metabolic acidosis.
    • Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes

      Ansari-Pour, Naser; orcid: 0000-0003-0908-0484; Zheng, Yonglan; orcid: 0000-0001-6597-7072; Yoshimatsu, Toshio F.; orcid: 0000-0003-2674-8159; Sanni, Ayodele; Ajani, Mustapha; orcid: 0000-0001-5758-5773; Reynier, Jean-Baptiste; Tapinos, Avraam; Pitt, Jason J.; Dentro, Stefan; Woodard, Anna; et al. (Nature Publishing Group UK, 2021-11-26)
      Abstract: Black women across the African diaspora experience more aggressive breast cancer with higher mortality rates than white women of European ancestry. Although inter-ethnic germline variation is known, differential somatic evolution has not been investigated in detail. Analysis of deep whole genomes of 97 breast cancers, with RNA-seq in a subset, from women in Nigeria in comparison with The Cancer Genome Atlas (n = 76) reveal a higher rate of genomic instability and increased intra-tumoral heterogeneity as well as a unique genomic subtype defined by early clonal GATA3 mutations with a 10.5-year younger age at diagnosis. We also find non-coding mutations in bona fide drivers (ZNF217 and SYPL1) and a previously unreported INDEL signature strongly associated with African ancestry proportion, underscoring the need to expand inclusion of diverse populations in biomedical research. Finally, we demonstrate that characterizing tumors for homologous recombination deficiency has significant clinical relevance in stratifying patients for potentially life-saving therapies.
    • The effect of hypoxia on PD-L1 expression in bladder cancer

      Smith, Vicky; email: victoria.smith-15@postgrad.manchester.ac.uk; Mukherjee, Debayan; Lunj, Sapna; Choudhury, Ananya; Hoskin, Peter; West, Catharine; Illidge, Tim (BioMed Central, 2021-11-25)
      Abstract: Introduction: Recent data has demonstrated that hypoxia drives an immunosuppressive tumour microenvironment (TME) via various mechanisms including hypoxia inducible factor (HIF)-dependent upregulation of programmed death ligand 1 (PD-L1). Both hypoxia and an immunosuppressive TME are targetable independent negative prognostic factors for bladder cancer. Therefore we sought to investigate whether hypoxia is associated with upregulation of PD-L1 in the disease. Materials and methods: Three human muscle-invasive bladder cancer cell lines (T24, J82, UMUC3) were cultured in normoxia (20% oxygen) or hypoxia (1 and 0.1% oxygen) for 24 h. Differences in PD-L1 expression were measured using Western blotting, quantitative polymerase chain reaction (qPCR) and flow cytometry (≥3 independent experiments). Statistical tests performed were unpaired t tests and ANOVA. For in silico work an hypoxia signature was used to apply hypoxia scores to muscle-invasive bladder cancers from a clinical trial (BCON; n = 142) and TCGA (n = 404). Analyses were carried out using R and RStudio and statistical tests performed were linear models and one-way ANOVA. Results: When T24 cells were seeded at < 70% confluence, there was decreased PD-L1 protein (p = 0.009) and mRNA (p < 0.001) expression after culture in 0.1% oxygen. PD-L1 protein expression decreased in both 0.1% oxygen and 1% oxygen in a panel of muscle-invasive bladder cancer cells: T24 (p = 0.009 and 0.001), J82 (p = 0.008 and 0.013) and UMUC3 (p = 0.003 and 0.289). Increasing seeding density decreased PD-L1 protein (p < 0.001) and mRNA (p = 0.001) expression in T24 cells grown in both 20 and 1% oxygen. Only when cells were 100% confluent, were PD-L1 protein and mRNA levels higher in 1% versus 20% oxygen (p = 0.056 and p = 0.037). In silico analyses showed a positive correlation between hypoxia signature scores and PD-L1 expression in both BCON (p = 0.003) and TCGA (p < 0.001) cohorts, and between hypoxia and IFNγ signature scores (p < 0.001 for both). Conclusion: Tumour hypoxia correlates with increased PD-L1 expression in patient derived bladder cancer tumours. In vitro PD-L1 expression was affected by cell density and decreased PD-L1 expression was observed after culture in hypoxia in muscle-invasive bladder cancer cell lines. As cell density has such an important effect on PD-L1 expression, it should be considered when investigating PD-L1 expression in vitro.
    • Gene editing enables rapid engineering of complex antibiotic assembly lines

      Thong, Wei Li; Zhang, Yingxin; Zhuo, Ying; Robins, Katherine J.; orcid: 0000-0001-5049-4246; Fyans, Joanna K.; Herbert, Abigail J.; Law, Brian J. C.; Micklefield, Jason; orcid: 0000-0001-8951-4873; email: jason.micklefield@manchester.ac.uk (Nature Publishing Group UK, 2021-11-25)
      Abstract: Re-engineering biosynthetic assembly lines, including nonribosomal peptide synthetases (NRPS) and related megasynthase enzymes, is a powerful route to new antibiotics and other bioactive natural products that are too complex for chemical synthesis. However, engineering megasynthases is very challenging using current methods. Here, we describe how CRISPR-Cas9 gene editing can be exploited to rapidly engineer one of the most complex megasynthase assembly lines in nature, the 2.0 MDa NRPS enzymes that deliver the lipopeptide antibiotic enduracidin. Gene editing was used to exchange subdomains within the NRPS, altering substrate selectivity, leading to ten new lipopeptide variants in good yields. In contrast, attempts to engineer the same NRPS using a conventional homologous recombination-mediated gene knockout and complementation approach resulted in only traces of new enduracidin variants. In addition to exchanging subdomains within the enduracidin NRPS, subdomains from a range of NRPS enzymes of diverse bacterial origins were also successfully utilized.
    • Structure of ABCB1/P-Glycoprotein in the Presence of the CFTR Potentiator Ivacaftor

      Barbieri, Alessandro; orcid: 0000-0002-0135-9977; email: alessandro.barbieri@postgrad.manchester.ac.uk; Thonghin, Nopnithi; orcid: 0000-0001-5656-5973; email: nopnithi@g.swu.ac.th; Shafi, Talha; email: talha.shafi@manchester.ac.uk; Prince, Stephen M.; email: steve.prince@manchester.ac.uk; Collins, Richard F.; email: Richard.Collins@manchester.ac.uk; Ford, Robert C.; orcid: 0000-0002-0958-1505; email: robert.ford@manchester.ac.uk (MDPI, 2021-11-25)
      ABCB1/P-glycoprotein is an ATP binding cassette transporter that is involved in the clearance of xenobiotics, and it affects the disposition of many drugs in the body. Conformational flexibility of the protein within the membrane is an intrinsic part of its mechanism of action, but this has made structural studies challenging. Here, we have studied different conformations of P-glycoprotein simultaneously in the presence of ivacaftor, a known competitive inhibitor. In order to conduct this, we used high contrast cryo-electron microscopy imaging with a Volta phase plate. We associate the presence of ivacaftor with the appearance of an additional density in one of the conformational states detected. The additional density is in the central aqueous cavity and is associated with a wider separation of the two halves of the transporter in the inward-facing state. Conformational changes to the nucleotide-binding domains are also observed and may help to explain the stimulation of ATPase activity that occurs when transported substrate is bound in many ATP binding cassette transporters.
    • First observation of radiolytic bubble formation in unstirred nano-powder sludges and a consistent model thereof

      O’Leary, Mel; email: mel.oleary@manchester.ac.uk; Baidak, Aliaksandr; Barnes, Martyn; Donoclift, Thomas; Emerson, Christopher; Figueira, Catarina; Fox, Oliver; Kleppe, Annette; McCulloch, Aaron; Messer, Darryl; et al. (Nature Publishing Group UK, 2021-11-24)
      Abstract: Experiments involving the irradiation of water contained within magnesium hydroxide and alumina nanoparticle sludges were conducted and culminated in observations of an increased yield of molecular hydrogen when compared to the yield from the irradiation of bulk water. We show that there is a relationship linking this increased yield to the direct nanoscale ionization mechanism in the nanoparticles, indicating that electron emission from the nanoparticles drives new radiative pathways in the water. Because the chemical changes in these sludges are introduced by irradiation only, we have a genuinely unstirred system. This feature allows us to determine the diffusivity of the dissolved gas. Using the measured gas production rate, we have developed a method for modelling when hydrogen bubble formation will occur within the nanoparticle sludges. This model facilitates the determination of a consistent radiolytic consumption rate coinciding with the observations of bubble formation. Thus, we demonstrate a nanoscale radiation effect directly influencing the formation of molecular hydrogen.
    • Metacognitive Beliefs and Suicidal Ideation: An Experience Sampling Study

      Aadahl, Vikki; email: vikkiaadahl@gmail.com; Wells, Adrian; orcid: 0000-0001-7713-1592; email: adrian.wells@manchester.ac.uk; Hallard, Robert; email: Robert.Hallard@cntw.nhs.uk; Pratt, Daniel; orcid: 0000-0001-8843-1224; email: daniel.pratt@manchester.ac.uk (MDPI, 2021-11-24)
      The current study aimed to examine the relationship between metacognitive beliefs about suicidal ideation and the content and process of suicidal ideation. This was to examine the potential contribution of the Self-Regulatory Executive Function (S-REF) model (Wells and Matthew, 2015) to suicidal ideation. Twenty-seven participants completed both trait and state-level measures of suicidal ideation, negative affect, defeat, hopelessness, entrapment and metacognitive beliefs. Experience Sampling Methodology (ESM) was adopted to measure state-level measurements with participants invited to complete an online diary up to seven times a day for six days. Multi-level modelling enabled a detailed examination of the relationships between metacognitive beliefs and suicidal ideation. Positive (β = 0.241, p 0.001) and negative (β = 0.167, p 0.001) metacognitive beliefs about suicidal ideation were positively associated with concurrent suicidal ideation even when known cognitive correlates of suicide were controlled for. The results have important clinical implications for the assessment, formulation and treatment of suicidal ideation. Novel meta-cognitive treatments targeting beliefs about suicidal ideation are now indicated. A limited range of characteristics reported by participants affects the generalizability of findings. Future research is recommended to advance understanding of metacognition and suicide but results demonstrate an important contribution of the S-REF model.
    • Data protection, information governance and the potential erosion of ethnographic methods in health care?

      Lee, Rebecca R.; orcid: 0000-0002-4559-1647; email: rebecca.lee-4@manchester.ac.uk; McDonagh, Janet E.; Farre, Albert; Peters, Sarah; Cordingley, Lis; Rapley, Tim (2021-11-23)
      Abstract: With the most recent developments to the European General Data Protection Regulations (GDPR) introduced in May 2018, the resulting legislation meant a new set of considerations for study approvers and health‐care researchers. Compared with previous legislation in the UK (The Data Protection Act, 1998), it introduced more extensive and directive principles, requiring anybody ‘processing’ personal data to specifically define how this data will be obtained, stored, used and destroyed. Importantly, it also emphasised the principle of accountability, which meant that data controllers and processors could no longer just state that they planned to adhere to lawful data protection principles, they also had to demonstrate compliance. New questions and concerns around accountability now appear to have increased levels of scrutiny in all areas of information governance (IG), especially with regards to processing confidential patient information. This article explores our experiences of gaining required ethical and regulatory approvals for an ethnographic study in a UK health‐care setting, the implications that the common law duty of confidentiality had for this research, and the ways in which IG challenges were overcome. The purpose of this article was to equip researchers embarking on similar projects to be able to navigate the potentially problematic and complex journey to approval.
    • Resurgence of a Nation’s Radiation Science Driven by Its Nuclear Industry Needs

      Leay, Laura; email: laura.leay@outlook.com; Baidak, Aliaksandr; email: aliaksandr.baidak@manchester.ac.uk; Anderson, Christopher; orcid: 0000-0003-4452-4378; email: christopher.anderson-3@postgrad.manchester.ac.uk; Chan, Choen May; email: ChoenMay.Chan@jacobs.com; Daubney, Aaron; email: aaron.daubney@sellafieldsites.com; Donoclift, Thomas; email: Thomas.Donoclift@glasgow.ac.uk; Draper, Gemma; email: gemma.draper@stfc.ac.uk; Edge, Ruth; orcid: 0000-0002-9144-041X; email: ruth.edge@manchester.ac.uk; Hobbs, Jeff; email: jeff.w.hobbs@sellafieldsites.com; Jones, Luke; email: Luke.Jones@uknnl.com; et al. (MDPI, 2021-11-23)
      This article describes the radiation facilities and associated sample preparation, management, and analysis equipment currently in place at the Dalton Cumbrian Facility, a facility which opened in 2011 to support the UK’s nuclear industry. Examples of measurements performed using these facilities are presented to illustrate their versatility and the breadth of research they make possible. Results are presented from research which furthers our understanding of radiation damage to polymeric materials, radiolytic yield of gaseous products in situations relevant to nuclear materials, radiation chemistry in light water reactor cooling systems, material chemistry relevant to immobilization of nuclear waste, and radiation-induced corrosion of fuel cladding elements. Applications of radiation chemistry relevant to health care are also described. Research concerning the mechanisms of radioprotection by dietary carotenoids is reported. An ongoing open-labware project to develop a suite of modular sample handling components suited to radiation research is described, as is the development of a new neutron source able to provide directional beams of neutrons.
    • Oxygen Depletion in Proton Spot Scanning: A Tool for Exploring the Conditions Needed for FLASH

      Rothwell, Bethany C.; orcid: 0000-0002-3323-671X; email: bethany.rothwell@postgrad.manchester.ac.uk; Lowe, Matthew; orcid: 0000-0002-7685-8156; email: matthew.lowe11@nhs.net; Kirkby, Norman F.; orcid: 0000-0001-5352-8069; email: norman.kirkby@manchester.ac.uk; Merchant, Michael J.; orcid: 0000-0001-8422-5255; email: michael.merchant@manchester.ac.uk; Chadwick, Amy L.; orcid: 0000-0002-7841-0507; email: amy.chadwick@manchester.ac.uk; Mackay, Ranald I.; orcid: 0000-0002-7329-6127; email: ranald.mackay@nhs.net; Hendry, Jolyon H.; email: jolyon.hendry@manchester.ac.uk; Kirkby, Karen J.; orcid: 0000-0002-0901-210X; email: karen.kirkby@manchester.ac.uk (MDPI, 2021-11-22)
      FLASH radiotherapy is a rapidly developing field which promises improved normal tissue protection compared to conventional irradiation and no compromise on tumour control. The transient hypoxic state induced by the depletion of oxygen at high dose rates provides one possible explanation. However, studies have mostly focused on uniform fields of dose and there is a lack of investigation into the spatial and temporal variation of dose from proton pencil-beam scanning (PBS). A model of oxygen reaction and diffusion in tissue has been extended to simulate proton PBS delivery and its impact on oxygen levels. This provides a tool to predict oxygen effects from various PBS treatments, and explore potential delivery strategies. Here we present a number of case applications to demonstrate the use of this tool for FLASH-related investigations. We show that levels of oxygen depletion could vary significantly across a large parameter space for PBS treatments, and highlight the need for in silico models such as this to aid in the development and optimisation of FLASH radiotherapy.
    • Behavioural Indicators of Intra- and Inter-Specific Competition: Sheep Co-Grazing with Guanaco in the Patagonian Steppe

      Fernández, Tomás; email: tomas.fv@gmail.com; Lancaster, Alex; email: 1821496@chester.ac.uk; Moraga, Claudio A.; email: clmoraga@gmail.com; Radic-Schilling, Sergio; email: sergio.radic@umag.cl; von Hardenberg, Achaz; email: a.vonhardenberg@chester.ac.uk; Corti, Paulo; orcid: 0000-0002-8253-2195; email: pcorti@uach.cl (MDPI, 2021-11-22)
      In extensive livestock production, high densities may inhibit regulation processes, maintaining high levels of intraspecific competition over time. During competition, individuals typically modify their behaviours, particularly feeding and bite rates, which can therefore be used as indicators of competition. Over eight consecutive seasons, we investigated if variation in herd density, food availability, and the presence of a potential competitor, the guanaco (Lama guanicoe), was related with behavioural changes in domestic sheep in Chilean Patagonia. Focal sampling, instantaneous scan sampling, measures of bite and movement rates were used to quantify behavioural changes in domestic sheep. We found that food availability increased time spent feeding, while herd density was associated with an increase in vigilant behaviour and a decrease in bite rate, but only when food availability was low. Guanaco presence appeared to have no impact on sheep behaviour. Our results suggest that the observed behavioural changes in domestic sheep are more likely due to intraspecific competition rather than interspecific competition. Consideration of intraspecific competition where guanaco and sheep co-graze on pastures could allow management strategies to focus on herd density, according to rangeland carrying capacity.
    • A Decade and a Half of Fast Radio Burst Observations

      Caleb, Manisha; email: manisha.caleb@manchester.ac.uk; Keane, Evan; email: evan.keane@gmail.com (MDPI, 2021-11-20)
      Fast radio bursts (FRBs) have a story which has been told and retold many times over the past few years as they have sparked excitement and controversy since their pioneering discovery in 2007. The FRB class encompasses a number of microsecond- to millisecond-duration pulses occurring at Galactic to cosmological distances with energies spanning about 8 orders of magnitude. While most FRBs have been observed as singular events, a small fraction of them have been observed to repeat over various timescales leading to an apparent dichotomy in the population. ∼50 unique progenitor theories have been proposed, but no consensus has emerged for their origin(s). However, with the discovery of an FRB-like pulse from the Galactic magnetar SGR J1935+2154, magnetar engine models are the current leading theory. Overall, FRB pulses exhibit unique characteristics allowing us to probe line-of-sight magnetic field strengths, inhomogeneities in the intergalactic/interstellar media, and plasma turbulence through an assortment of extragalactic and cosmological propagation effects. Consequently, they are formidable tools to study the Universe. This review follows the progress of the field between 2007 and 2020 and presents the science highlights of the radio observations.
    • Exploring Consensus on Preventive Measures and Identification of Patients at Risk of Age-Related Macular Degeneration Using the Delphi Process

      García-Layana, Alfredo; email: aglayana@unav.es; Garhöfer, Gerhard; email: gerhard.garhoefer@meduniwien.ac.at; Aslam, Tariq M.; orcid: 0000-0002-9739-7280; email: tariq.aslam@manchester.ac.uk; Silva, Rufino; orcid: 0000-0001-8676-0833; email: rufino.silva@oftalmologia.co.pt; Delcourt, Cécile; orcid: 0000-0002-2099-0481; email: cecile.delcourt@u-bordeaux.fr; Klaver, Caroline C. W.; email: c.c.w.klaver@erasmusmc.nl; Seddon, Johanna M.; email: johanna.seddon@umassmed.edu; Minnella, Angelo M.; email: angelomaria.minnella@unicatt.it (MDPI, 2021-11-20)
      Background: Early identification of AMD can lead to prompt and more effective treatment, better outcomes, and better final visual acuity; several risk scores have been devised to determine the individual level of risk for developing AMD. Herein, the Delphi method was used to provide recommendations for daily practice regarding preventive measures and follow-up required for subjects at low, moderate, and high risk of AMD evaluated with the Simplified Test AMD Risk-assessment Scale (STARS®) questionnaire. Methods: A steering committee of three experts drafted and refined 25 statements on the approach to be recommended in different clinical situations [general recommendations (n = 2), use of evaluation tools (n = 4), general lifestyle advice (n = 3), and AREDS-based nutritional supplementation (n = 5)] with the help of a group of international experts, all co-authors of this paper. Thirty retinal specialists from Europe and the US were chosen based on relevant publications, clinical expertise, and experience in AMD, who then provided their level of agreement with the statements. Statements for which consensus was not reached were modified and voted upon again. Results: In the first round of voting, consensus was reached for 24 statements. After modification, consensus was then reached for the remaining statement. Conclusion: An interprofessional guideline to support preventive measures in patients at risk of AMD based on STARS® scoring has been developed to aid clinicians in daily practice, which will help to optimize preventive care of patients at risk of AMD.
    • Is there a role for natural desiccated thyroid in the treatment of levothyroxine unresponsive hypothyroidism? Results from a consecutive case series

      Heald, Adrian H.; email: adrian.heald@manchester.ac.uk; Premawardhana, Lakdasa; Taylor, Peter; Okosieme, Onyebuchi; Bangi, Tasneem; Devine, Holly; Livingston, Mark; Javed, Ahmed; Moreno, Gabriela Y. C.; Watt, Torquil; et al. (2021-11-20)
      Abstract: Introduction: Some levothyroxine unresponsive individuals with hypothyroidism are prescribed a natural desiccated thyroid (NDT) preparation such as Armour Thyroid ® or ERFA Thyroid ® . These contain a mixture of levothyroxine and liothyronine in a fixed ratio. We evaluated the response to NDT in individuals at a single endocrine centre in terms of how the change from levothyroxine to NDT impacted on their lives in relation to quality of life (QOL) and thyroid symptoms. Methods: The ThyPRO39 (thyroid symptomatology) and EQ‐5D‐5L‐related QoL/EQ5D5L (generic QOL) questionnaires were administered to 31 consecutive patients who had been initiated on NDT, before initiating treatment/6 months later. Results: There were 28 women and 3 men. The dose range of NDT was 60‐180 mg daily. Age range was 26‐77 years with length of time since diagnosis with hypothyroidism ranging from 2 to 40 years. One person discontinued the NDT because of lack of response; two because of cardiac symptoms. EQ‐5D‐5L utility increased from a mean (SD) of 0.214 (0.338) at baseline, to 0.606 (0.248) after 6 months; corresponding to a difference of 0.392 (95% CI 0.241‐0.542), t = 6.82, P < .001. EQ‐VAS scores increased from 33.4 (17.2) to 71.1 (17.5), a difference of 37.7 (95% CI 25.2‐50.2), t = −4.9, P < .001. ThyPRO scores showed consistent fall across all domains with the composite QoL‐impact Score improving from 68.3 (95% CI 60.9‐75.7) to 25.2 (95% CI 18.7‐31.7), a difference of 43.1 (95% CI 33‐53.2) (t = 5.6, P < .001). Conclusion: Significant symptomatic benefit and improvement in QOL was experienced by people with a history of levothyroxine unresponsive hypothyroidism treated with NDT, suggesting the need for further evaluation of NDT in this context.
    • Kite-Shaped Molecules Block SARS-CoV-2 Cell Entry at a Post-Attachment Step

      Chan, Shiu-Wan; email: shiu-wan.chan@manchester.ac.uk; Shafi, Talha; email: talha.shafi@manchester.ac.uk; Ford, Robert C.; orcid: 0000-0002-0958-1505; email: robert.ford@manchester.ac.uk (MDPI, 2021-11-19)
      Anti-viral small molecules are currently lacking for treating coronavirus infection. The long development timescales for such drugs are a major problem, but could be shortened by repurposing existing drugs. We therefore screened a small library of FDA-approved compounds for potential severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antivirals using a pseudovirus system that allows a sensitive read-out of infectivity. A group of structurally-related compounds, showing moderate inhibitory activity with IC50 values in the 2–5 μM range, were identified. Further studies demonstrated that these “kite-shaped” molecules were surprisingly specific for SARS-CoV-1 and SARS-CoV-2 and that they acted early in the entry steps of the viral infectious cycle, but did not affect virus attachment to the cells. Moreover, the compounds were able to prevent infection in both kidney- and lung-derived human cell lines. The structural homology of the hits allowed the production of a well-defined pharmacophore that was found to be highly accurate in predicting the anti-viral activity of the compounds in the screen. We discuss the prospects of repurposing these existing drugs for treating current and future coronavirus outbreaks.
    • Preparation, Characterization, and Pharmacological Investigation of Withaferin-A Loaded Nanosponges for Cancer Therapy; In Vitro, In Vivo and Molecular Docking Studies

      Shah, Hamid Saeed; orcid: 0000-0003-4396-5235; email: hamid.saeed@uvas.edu.pk; Nasrullah, Usman; email: nasrullah@em.uni-frankfurt.de; Zaib, Sumera; email: sumera.zaib@ucp.edu.pk; Usman, Faisal; orcid: 0000-0002-8998-9454; email: faisal.usman@bzu.edu.pk; Khan, Ajmal; email: ajmalkhan@unizwa.edu.om; Gohar, Umar Farooq; email: dr.mufgohor@gcu.edu.pk; Uddin, Jalal; orcid: 0000-0002-8613-4493; email: jalaluddinamin@gmail.com; Khan, Imtiaz; orcid: 0000-0001-7359-1727; email: imtiaz.khan@manchester.ac.uk; Al-Harrasi, Ahmed; orcid: 0000-0002-0815-5942; email: aharrasi@unizwa.edu.om (MDPI, 2021-11-19)
      The rapidly growing global burden of cancer poses a major challenge to public health and demands a robust approach to access promising anticancer therapeutics. In parallel, nanotechnology approaches with various pharmacological properties offer efficacious clinical outcomes. The use of new artificial variants of nanosponges (NS) as a transporter of chemotherapeutic drugs to target cells has emerged as a very promising tool. Therefore, in this research, ethylcellulose (EC) NS were prepared using the ultrasonication assisted-emulsion solvent evaporation technique. Withaferin-A (WFA), an active ingredient in Withania somnifera, has been implanted into the nanospongic framework with enhanced anticancer properties. Inside the polymeric structure, WFA was efficiently entrapped (85 ± 11%). The drug (WFA) was found to be stable within polymeric nanosponges, as demonstrated by Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) studies. The WFA-NS had a diameter of 117 ± 4 nm and zeta potential of −39.02 ± 5.71 mV with a polydispersity index (PDI) of 0.419 ± 0.073. In addition, scanning electron microscopy (SEM) revealed the porous surface texture of WFA-NS. In vitro anticancer activity (SRB assay) results showed that WFA–NS exhibited almost twice the anticancer efficacy against MCF-7 cells (IC50 = 1.57 ± 0.091 µM), as quantified by flow cytometry and comet tests. Moreover, fluorescence microscopy with DAPI staining and analysis of DNA fragmentation revealed apoptosis as a mechanism of cancer cell death. The anticancer activity of WFA-NS was further determined in vivo and results were compared to cisplatin. The anticancer activity of WFA-NS was further investigated in vivo, and the data were consistent to those obtained with cisplatin. At Day 10, WFA-NS (10 mg/kg) significantly reduced tumour volume to 72 ± 6%, which was comparable to cisplatin (10 mg/kg), which reduced tumour volume to 78 ± 8%. Finally, the outcomes of molecular modeling (in silico) also suggested that WFA established a stable connection with nanosponges, generating persistent hydrophobic contacts (polar and nonpolar) and helping with the attractive delayed-release features of the formulation. Collectively, all the findings support the use of WFA in nanosponges as a prototype for cancer treatment, and opened up new avenues for increasing the efficacy of natural product-derived medications.
    • Heartburn as a Marker of the Success of Acid Suppression Therapy in Chronic Cough

      Badri, H.; orcid: 0000-0002-6134-4347; email: huda.badri@manchester.ac.uk; Satia, I.; Bansal, V.; Mangi, M. A.; Tangaroonsanti, A.; DeVault, K. R.; Lee, A. S.; Houghton, L. A.; Smith, J. A. (Springer US, 2021-11-19)
      Abstract: Purpose: Gastro-oesophageal reflux disease (GORD) is commonly thought to play an important role in chronic cough and patients are often empirically treated with acid suppression therapy. We sought to investigate the response rate to acid suppression treatment in patients with and without heartburn attending two specialist cough clinics. Methods: A retrospective review of 558 consecutive patients referred to two specialist cough clinics was performed (UK and USA). Patients who were treated with acid suppression were included and their documented response to treatment was collected. Binary logistic regression was used to ascertain the value of reported heartburn in predicting the response of chronic cough to acid suppression therapy. Results: Of 558 consecutive referrals, 238 patients were excluded due to missing data or cough duration of < 8 weeks. The remaining 320 patients were predominantly female (76%), with mean age 61 yrs (± 13) and 96.8% non-smokers, with chronic cough for 36 (18–117) months. Of 72 patients with heartburn, 20 (28%) noted improvement in their cough with acid suppression, whereas of 248 without heartburn, only 35 (14%) responded. Patients reporting heartburn were 2.7 (95% C.I. 1.3–5.6) times more likely to respond to acid suppression therapy (p = 0.007). Conclusion: In specialist cough clinics, few patients report a response of their chronic cough to acid suppression therapy. Nonetheless, heartburn is a useful predictor substantially increasing the likelihood of benefit.