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Background: Weak grip strength is associated with a range of adverse health outcomes and an accelerated decline in grip strength confers an even greater risk. The factors associated with change in grip strength in mid-life remain ...
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Background: Weak grip strength is associated with a range of adverse health outcomes and an accelerated decline in grip strength confers an even greater risk. The factors associated with change in grip strength in mid-life remain to be fully determined. Methods: We used data from 44,315 UK Biobank participants who had grip strength measured at baseline (2006-10) and a subsequent visit approximately nine years later. At baseline, participants' long-term conditions (LTCs) were categorised against a hierarchy, with multimorbidity characterised by the number of LTC categories. Lifestyle factors were assessed. Change in grip strength was grouped into four patterns: decline, stable low, stable high or reference (no change or increase) and used as the outcome in multinomial logistic regression. Results: Most LTC categories were associated with adverse patterns of change in grip strength (stable low and/or decline): for example, musculoskeletal/trauma conditions were associated with an increased risk of the stable low pattern (Relative Risk Ratio [RRR] = 1.63; 95% confidence interval [CI]: 1.49-1.79). Multimorbidity and lifestyle factors had independent associations with grip strength change. Those with 3+ categories of LTCs were more likely to experience decline in grip strength (RRR = 1.18; 95% CI: 1.08-1.28) compared to those with none. Low physical activity was associated with adverse patterns of grip strength, while raised body mass index (BMI) had divergent associations. Conclusions: Individuals living with multimorbidity and those with lifestyle risk factors such as low physical activity are at increased risk of low muscle strength and the loss of strength over time.
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Dental procedures produce aerosols that may remain suspended and travel significant distances from the source. Dental aerosols and droplets contain oral microbes, and there is potential for infectious disease transmission and majo...
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Dental procedures produce aerosols that may remain suspended and travel significant distances from the source. Dental aerosols and droplets contain oral microbes, and there is potential for infectious disease transmission and major disruption to dental services during infectious disease outbreaks. One method to control hazardous aerosols often used in industry is local exhaust ventilation (LEV). The aim of this study was to investigate the effect of LEV on aerosols and droplets produced during dental procedures. Experiments were conducted on dental mannequins in an 825.4-m(3) open-plan clinic and a 49.3-m(3) single surgery. Ten-minute crown preparations were performed with an air-turbine handpiece in the open-plan clinic and 10-min full-mouth ultrasonic scaling in the single surgery. Fluorescein was added to instrument irrigation reservoirs as a tracer. In both settings, optical particle counters (OPCs) were used to measure aerosol particles between 0.3 and 10.0 mu m, and liquid cyclone air samplers were used to capture aerosolized fluorescein tracer. In addition, in the open-plan setting, fluorescein tracer was captured by passive settling onto filter papers in the environment. Tracer was quantified fluorometrically. An LEV device with high-efficiency particulate air filtration and a flow rate of 5,000 L/min was used. LEV reduced aerosol production from the air-turbine handpiece by 90% within 0.5 m, and this was 99% for the ultrasonic scaler. OPC particle counts were substantially reduced for both procedures and air-turbine settled droplet detection reduced by 95% within 0.5 m. The effect of LEV was substantially greater than suction alone for the air-turbine and was similar to the effect of suction for the ultrasonic scaler. LEV reduces aerosol and droplet contamination from dental procedures by at least 90% in the breathing zone of the operator, and it is therefore a valuable tool to reduce the dispersion of dental aerosols.
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Background: inequalities and gaps in post-diagnostic support (PDS) for people with dementia persist despite a policy focus on dementia in England and Wales. Understanding and overcoming the factors contributing to these inequaliti...
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Background: inequalities and gaps in post-diagnostic support (PDS) for people with dementia persist despite a policy focus on dementia in England and Wales. Understanding and overcoming the factors contributing to these inequalities is vital to improve care for people living with dementia (PLWD) and their families. Objective: to explore common barriers to the delivery of PDS in England and Wales and describe successful strategies to address them, drawing on examples from current practice. Design: qualitative semi-structured interviews, focus groups and observation. Settings: Phase 1: interviewees were drawn from multiple sectors across England and Wales, including NHS clinical commissioning groups and social care. Phase 2: six case study sites based in different sectors (primary care, secondary mental health and third sector) in England. Participants: Phase 1: 61 professionals, including commissioners and service managers. Phase 2: 68 professionals, including frontline staff and those working in related services; 17 PLWD; 31 carers. Results: barriers to implementing PDS in dementia were an unsupportive infrastructure, limited proactive review and limited capacity and capability particularly in primary care. Strategies used successfully in practice to address these challenges included creating opportunities for service development, improving joint working, supporting non-specialists and developing ongoing, holistic review and care planning. Conclusion: a range of practical strategies have been identified to address many of the common barriers to PDS in dementia. To achieve policy goals of a task-shifted and task-shared approach to PDS, widespread use of these strategies is recommended.
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The success of atezolizumab plus bevacizumab treatment contributed to a shift in systemic therapies for hepatocellular carcinoma (HCC) towards combinations that include cancer immunotherapeutic agents. Thus far, the principal focu...
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The success of atezolizumab plus bevacizumab treatment contributed to a shift in systemic therapies for hepatocellular carcinoma (HCC) towards combinations that include cancer immunotherapeutic agents. Thus far, the principal focus of cancer immunotherapy has been on interrupting immune checkpoints that suppress antitumour lymphocytes. As well as lymphocytes, the HCC environment includes numerous other immune cell types, among which neutrophils are emerging as an important contributor to the pathogenesis of HCC. A growing body of evidence supports neutrophils as key mediators of the immunosuppressive environment in which some cancers develop, as well as drivers of tumour progression. If neutrophils have a similar role in HCC, approaches that target or manipulate neutrophils might have therapeutic benefits, potentially including sensitization of tumours to conventional immunotherapy. Several neutrophil-directed therapies for patients with HCC (and other cancers) are now entering clinical trials. This Review outlines the evidence in support of neutrophils as drivers of HCC and details their mechanistic roles in development, progression and metastasis, highlighting the reasons that neutrophils are well worth investigating despite the challenges associated with studying them. Neutrophil-modulating anticancer therapies entering clinical trials are also summarized. Growing evidence indicates that neutrophils are involved in tumorigenesis, progression and metastasis of hepatocellular carcinoma (HCC). Here, Geh and colleagues summarize neutrophil phenotypes in HCC, describe the pathogenetic mechanisms underlying these contributions of neutrophils to HCC and highlight emerging neutrophil-targeted therapies.
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Background Gastric adenocarcinoma is common and consequent mortality high. Presentation and mortality are increased in obese individuals, many of whom have elevated circulating insulin concentrations. High plasma insulin concentra...
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Background Gastric adenocarcinoma is common and consequent mortality high. Presentation and mortality are increased in obese individuals, many of whom have elevated circulating insulin concentrations. High plasma insulin concentrations may promote, and increase mortality from, gastric adenocarcinoma. Tumour promotion activities of insulin and its receptor are untested in gastric cancer cells. Methods Tumour gene amplification and expression were computed from sequencing and microarray data. Associations with patient survival were assessed. Insulin-dependent signal transduction, growth, apoptosis and anoikis were analysed in metastatic cells from gastric adenocarcinoma patients and in cell lines. Receptor involvement was tested by pharmacological inhibition and genetic knockdown. RNA was analysed by RT-PCR and proteins by western transfer and immunofluorescence. Results INSR expression was higher in tumour than in normal gastric tissue. High tumour expression was associated with worse patient survival. Insulin receptor was detected readily in metastatic gastric adenocarcinoma cells and cell lines. Isoforms B and A were expressed. Pharmacological inhibition prevented cell growth and division, and induced caspase-dependent cell death. Rare tumour INS expression indicated tumours would be responsive to pancreatic or therapeutic insulins. Insulin stimulated gastric adenocarcinoma cell PI3-kinase/Akt signal transduction, proliferation, and survival. Insulin receptor knockdown inhibited proliferation and induced programmed cell death. Type I IGF receptor knockdown did not induce cell death. Conclusions The insulin and IGF signal transduction pathway is dominant in gastric adenocarcinoma. Gastric adenocarcinoma cell survival depends upon insulin receptor. That insulin has direct cancer-promoting effects on tumour cells has implications for clinical management of obese and diabetic cancer patients.
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Pathogenic variants in mitochondrial DNA (mtDNA) are associated with significant clinical heterogeneity with neuromuscular involvement commonly reported. Non-syndromic presentations of mtDNA disease continue to pose a diagnostic c...
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Pathogenic variants in mitochondrial DNA (mtDNA) are associated with significant clinical heterogeneity with neuromuscular involvement commonly reported. Non-syndromic presentations of mtDNA disease continue to pose a diagnostic challenge and with genomic testing still necessitating a muscle biopsy in many cases. Here we describe an adult patient who presented with progressive ataxia, neuropathy and exercise intolerance in whom the application of numerous Mendelian gene panels had failed to make a genetic diagnosis. Muscle biopsy revealed characteristic mitochondrial pathology (cytochrome c oxidase deficient, ragged-red fibers) prompting a thorough investigation of the mitochondrial genome. Two heteroplasmic MT-CO2 gene variants (NC_012920.1: m.7887G > A and m.8250G > A) were identified, necessitating single fiber segregation and familial studies - including the biopsy of the patient's clinically-unaffected mother - to demonstrate pathogenicity of the novel m.7887G > A p.(Gly101Asp) variant and establishing this as the cause of the mitochondrial biochemical defects and clinical presentation. In the era of high throughput whole exome and genome sequencing, muscle biopsy remains a key investigation in the diagnosis of patients with non-syndromic presentations of adult-onset mitochondrial disease and fully defining the pathogenicity of novel mtDNA variants. (c) 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )
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BACKGROUND & AIMS: Methyl-CpG binding protein 2, MECP2, which binds to methylated regions of DNA to regulate transcription, is expressed by hepatic stellate cells (HSCs) and is required for development of liver fibrosis in mice. We investigated the effects of MECP2 deletion from HSCs on their transcriptome and of phosphorylation of MECP2 on HSC phenotype and liver fibrosis. METHODS: We isolated HSCs from Mecp2(-/y) mice and wild-type (control) mice. HSCs were activated in culture and used in array analyses of messenger RNAs and long noncoding RNAs. Kyoto Encyclopedia of Genes and Genomes pathway analyses identified pathways regulated by MECP2. We studied mice that expressed a mutated form of Mecp2 that encodes the S80A substitution, MECP2S80, causing loss of MECP2 phosphorylation at serine 80. Liver fibrosis was induced in these mice by administration of carbon tetrachloride, and liver tissues and HSCs were collected and analyzed. RESULTS: MECP2 deletion altered expression of 284 messenger RNAs and 244 long noncoding RNAs, including those that regulate DNA replication; are members of the minichromosome maintenance protein complex family; or encode CDC7, HAS2, DNA2 (a DNA helicase), or RPA2 (a protein that binds single-stranded DNA). We found that MECP2 regulates the DNA repair Fanco...
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BACKGROUND & AIMS: Methyl-CpG binding protein 2, MECP2, which binds to methylated regions of DNA to regulate transcription, is expressed by hepatic stellate cells (HSCs) and is required for development of liver fibrosis in mice. We investigated the effects of MECP2 deletion from HSCs on their transcriptome and of phosphorylation of MECP2 on HSC phenotype and liver fibrosis. METHODS: We isolated HSCs from Mecp2(-/y) mice and wild-type (control) mice. HSCs were activated in culture and used in array analyses of messenger RNAs and long noncoding RNAs. Kyoto Encyclopedia of Genes and Genomes pathway analyses identified pathways regulated by MECP2. We studied mice that expressed a mutated form of Mecp2 that encodes the S80A substitution, MECP2S80, causing loss of MECP2 phosphorylation at serine 80. Liver fibrosis was induced in these mice by administration of carbon tetrachloride, and liver tissues and HSCs were collected and analyzed. RESULTS: MECP2 deletion altered expression of 284 messenger RNAs and 244 long noncoding RNAs, including those that regulate DNA replication; are members of the minichromosome maintenance protein complex family; or encode CDC7, HAS2, DNA2 (a DNA helicase), or RPA2 (a protein that binds single-stranded DNA). We found that MECP2 regulates the DNA repair Fanconi anemia pathway in HSCs. Phosphorylation of MECP2S80 and its putative kinase, HAS2, were induced during transdifferentiation of HSCs. HSCs from MECP2S80 mice had reduced proliferation, and livers from these mice had reduced fibrosis after carbon tetrachloride administration. CONCLUSIONS: In studies of mice with disruption of Mecp2 or that expressed a form of MECP2 that is not phosphorylated at S80, we found phosphorylation of MECP2 to be required for HSC proliferation and induction of fibrosis. In HSCs, MECP2 regulates expression of genes required for DNA replication and repair. Strategies to inhibit MECP2 phosphorylation at S80 might be developed for treatment of liver fibrosis.
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Purpose: The high infection rate of SARS-CoV-2 necessitates the need for multiple studies identifying the molecular mechanisms that facilitate the viral entry and propagation. Currently the potential extra-respiratory transmission...
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Purpose: The high infection rate of SARS-CoV-2 necessitates the need for multiple studies identifying the molecular mechanisms that facilitate the viral entry and propagation. Currently the potential extra-respiratory transmission routes of SARS-CoV-2 remain unclear.
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The interferon gene signature (IGS) is derived from the expression of interferon-regulated genes and is classically increased in response to type I interferon exposure. A raised whole blood IGS has increasingly been reported in rh...
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The interferon gene signature (IGS) is derived from the expression of interferon-regulated genes and is classically increased in response to type I interferon exposure. A raised whole blood IGS has increasingly been reported in rheumatic diseases as sequencing technology has advanced. Although its role remains unclear, we explore how a raised IGS can function as a clinically relevant biomarker, independent of whether it is a bystander effect or a key pathological process. For example, a raised IGS can act as a diagnostic biomarker when predicting rheumatoid arthritis in patients with arthralgia and anti-citrullinated protein antibodies, or predicting systemic lupus erythematous (SLE) in those with antinuclear antibodies; a theragnostic biomarker when predicting response for patients receiving disease modifying therapy, such as rituximab in rheumatoid arthritis; a biomarker of disease activity (early rheumatoid arthritis, dermatomyositis, systemic sclerosis, SLE); or finally a predictor of clinical characteristics, such as lupus nephritis in SLE or disease burden in primary Sjogren's syndrome. A high IGS does not uniformly predict worse clinical phenotypes across all diseases, as demonstrated by a reduced disease burden in primary Sjogren's syndrome, nor does it predict a universally poorer response to all therapies, as shown in rheumatoid arthritis. This dichotomy highlights both the complexity of type I interferon signalling in vivo and the current lack of standardisation when calculating the IGS. The IGS as a biomarker warrants further exploration, with beneficial clinical applications anticipated in multiple rheumatic diseases.
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Introduction: Qualitative research is a well-established branch of scientific enquiry that draws insights from experiences.(1,2) Within social and administrative pharmacy research, interview and focus group methods are a mainstay ...
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Introduction: Qualitative research is a well-established branch of scientific enquiry that draws insights from experiences.(1,2) Within social and administrative pharmacy research, interview and focus group methods are a mainstay of collecting data. However, other disciplines such as sociology, psychology and anthropology, use existing data that is routinely to provide a substance for qualitative inquiry. Drawing on our experiences of using interdisciplinary research methods, this paper presents three case studies where textual data was qualitatively analysed and critically examines the strengths and weaknesses of these method in relation to pharmacy practice. Methods: Three case studies were selected that access different types of existing, routinely collected data from pharmacy practice. This included 1) a study utilising boardroom meeting minutes, 2) a study using incident reports and 3) a study using WhatsApp messages as data. Each case study is described and critically examined. The strengths and weaknesses of this approach are based on our own reflections of completing the studies. Results: Relationships between people, products and organisations can be examined in documents, records and text that is routinely collected. Existing data can also provide insights into culture, working patterns, education and errors. Practical advantages of using existing data include faster data collection and access to first-hand, accounts of experiences of human relationship with pharmaceutical products and practice. Drawbacks of using existing data are that some data may be missing, participants may no longer be accessible for participant checking and the context of language may have changed. Conclusion: This paper critically examined the use of methods rarely used in pharmacy practice research which draw on existing, routinely collected data. Adopting a wider range of data collection methods may will provide new understanding and insights into social and clinical pharmacy practice.
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