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1.
PLoS One ; 16(1): e0244873, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33400700

RESUMO

BACKGROUND: Multiple studies have highlighted the negative impact of COVID-19 and its particular effects on vulnerable sub-populations. Complementing this work, here, we report on the social patterning of self-reported positive changes experienced during COVID-19 national lockdown in Scotland. METHODS: The CATALYST study collected data from 3342 adults in Scotland during weeks 9-12 of a national lockdown. Using a cross-sectional design, participants completed an online questionnaire providing data on key sociodemographic and health variables, and completed a measure of positive change. The positive change measure spanned diverse domains (e.g., more quality time with family, developing new hobbies, more physical activity, and better quality of sleep). We used univariate analysis and stepwise regression to examine the contribution of a range of sociodemographic factors (e.g., age, gender, ethnicity, educational attainment, and employment status) in explaining positive change. RESULTS: There were clear sociodemographic differences across positive change scores. Those reporting higher levels of positive change were female, from younger age groups, married or living with their partner, employed, and in better health. CONCLUSION: Overall our results highlight the social patterning of positive changes during lockdown in Scotland. These findings begin to illuminate the complexity of the unanticipated effects of national lockdown and will be used to support future intervention development work sharing lessons learned from lockdown to increase positive health change amongst those who may benefit.


Assuntos
/psicologia , Quarentena/psicologia , Isolamento Social/psicologia , Adulto , Ansiedade/epidemiologia , Ansiedade/prevenção & controle , /prevenção & controle , Controle de Doenças Transmissíveis/métodos , Estudos Transversais , Exercício Físico/psicologia , Família/psicologia , Feminino , Humanos , Masculino , Escócia/epidemiologia , Sono/fisiologia , Higiene do Sono , Estresse Psicológico/prevenção & controle , Estresse Psicológico/psicologia , Inquéritos e Questionários
2.
J Autoimmun ; 118: 102597, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33493980

RESUMO

The role of the innate immune system has been established in the initiation and perpetuation of inflammatory disease, but less attention has been paid to its role in the resolution of inflammation and return to homeostasis. Toll-like receptor (TLR) expression profiles were analysed in tissues with differing disease status in rheumatoid arthritis (RA), ankylosing spondylitis (AS), and in experimental arthritis. TLR gene expression was measured in whole blood and monocytes, before and after TNF blockade. In RA and osteoarthritis synovia, the expression of TLRs was quantified by standard curve qPCR. In addition, four distinct stages of disease were defined and validated in collagen-induced arthritis (CIA), the gold standard animal model for RA - pre-onset, early disease, late disease and immunised mice that were resistant to the development of disease. TLR expression was measured in spleens, lymph nodes, blood cells, liver and the paws (inflamed and unaffected). In RA whole blood, the expression of TLR1, 4 and 6 was significantly reduced by TNF blockade but the differences in TLR expression profiles between responders and non-responders were less pronounced than the differences between RA and AS patients. In RA non-responders, monocytes had greater TLR2 expression prior to therapy compared to responders. The expression of TLR1, 2, 4 and 8 was higher in RA synovium compared to control OA synovium. Circulating cytokine levels in CIA resistant mice were similar to naïve mice, but anti-collagen antibodies were similar to arthritic mice. Distinct profiles of inflammatory gene expression were mapped in paws and organs with differing disease status. TLR expression in arthritic paws tended to be similar in early and late disease, with TLR1 and 2 moderately higher in late disease. TLR expression in unaffected paws varied according to gene and disease status but was generally lower in resistant paws. Disease status-specific profiles of TLR expression were observed in spleens, lymph nodes, blood cells and the liver. Notably, TLR2 expression rose then fell in the transition from naïve to pre-onset to early arthritis. TLR gene expression profiles are strongly associated with disease status. In particular, increased expression in the blood precedes clinical manifestation.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33327556

RESUMO

We examine the impact of the COVID-19 outbreak and concomitant restrictions (i.e., lockdown) on 24-hour movement behaviors (i.e., physical activity, sitting, sleep) in a purposive sample of people (n = 3230) reporting change recruited online. Participants' self-reported time spent in moderate-to-vigorous physical activity (MVPA), walking, sitting and sleep prior to lockdown (T1), during the first national lockdown (T2) and as restrictions initially started to ease (T3). For each 24-hour movement behavior, category-shifts are reported (positive, negative or did not change), as well as the percentage of participants recording positive/negative changes across clusters of behaviors and the percentage of participants recording improvement or maintenance of change across time. From T1 to T2 walking decreased, whereas MVPA, sitting and sleep increased, from T2 to T3 levels returned to pre-lockdown for all but MVPA. Participants who changed one behavior positively were more likely to report a positive change in another and 50% of those who reported positive changes from T1 to T2 maintained or improved further when restrictions started to ease. The current study showed that a large proportion of the sample reported positive changes, most notably those displaying initially poor levels of each behavior. These findings will inform salutogenic intervention development.


Assuntos
Exercício Físico , Pandemias , Comportamento Sedentário , Sono , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escócia , Postura Sentada , Adulto Jovem
4.
Br J Health Psychol ; 25(4): 1039-1054, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32889759

RESUMO

OBJECTIVES: Development of a vaccine against COVID-19 will be key to controlling the pandemic. We need to understand the barriers and facilitators to receiving a future COVID-19 vaccine so that we can provide recommendations for the design of interventions aimed at maximizing public acceptance. DESIGN: Cross-sectional UK survey with older adults and patients with chronic respiratory disease. METHODS: During the UK's early April 2020 'lockdown' period, 527 participants (311 older adults, mean age = 70.4 years; 216 chronic respiratory participants, mean age = 43.8 years) completed an online questionnaire assessing willingness to receive a COVID-19 vaccine, perceptions of COVID-19, and intention to receive influenza and pneumococcal vaccinations. A free text response (n = 502) examined barriers and facilitators to uptake. The Behaviour Change Wheel informed the analysis of these responses, which were coded to the Theoretical Domains Framework (TDF). Behaviour change techniques (BCTs) were identified. RESULTS: Eighty-six per cent of respondents want to receive a COVID-19 vaccine. This was positively correlated with the perception that COVID-19 will persist over time, and negatively associated with perceiving the media to have over-exaggerated the risk. The majority of barriers and facilitators were mapped onto the 'beliefs about consequences' TDF domain, with themes relating to personal health, health consequences to others, concerns of vaccine safety, and severity of COVID-19. CONCLUSIONS: Willingness to receive a COVID-19 vaccination is currently high among high-risk individuals. Mass media interventions aimed at maximizing vaccine uptake should utilize the BCTs of information about health, emotional, social and environmental consequences, and salience of consequences.


Assuntos
Betacoronavirus , Infecções por Coronavirus , Pandemias , Pneumonia Viral , Vacinação , Infecções por Coronavirus/prevenção & controle , Estudos Transversais , Humanos , Vacinas Virais
5.
Proc Natl Acad Sci U S A ; 117(34): 20753-20763, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32759223

RESUMO

Fibrotic diseases remain a major cause of morbidity and mortality, yet there are few effective therapies. The underlying pathology of all fibrotic conditions is the activity of myofibroblasts. Using cells from freshly excised disease tissue from patients with Dupuytren's disease (DD), a localized fibrotic disorder of the palm, we sought to identify new therapeutic targets for fibrotic disease. We hypothesized that the persistent activity of myofibroblasts in fibrotic diseases might involve epigenetic modifications. Using a validated genetics-led target prioritization algorithm (Pi) of genome wide association studies (GWAS) data and a broad screen of epigenetic inhibitors, we found that the acetyltransferase CREBBP/EP300 is a major regulator of contractility and extracellular matrix production via control of H3K27 acetylation at the profibrotic genes, ACTA2 and COL1A1 Genomic analysis revealed that EP300 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, and broad transcriptomic and proteomic profiling of CREBBP/EP300 inhibition by the chemical probe SGC-CBP30 identified collagen VI (Col VI) as a prominent downstream regulator of myofibroblast activity. Targeted Col VI knockdown results in significant decrease in profibrotic functions, including myofibroblast contractile force, extracellular matrix (ECM) production, chemotaxis, and wound healing. Further evidence for Col VI as a major determinant of fibrosis is its abundant expression within Dupuytren's nodules and also in the fibrotic foci of idiopathic pulmonary fibrosis (IPF). Thus, Col VI may represent a tractable therapeutic target across a range of fibrotic disorders.


Assuntos
Proteína de Ligação a CREB/genética , Colágeno Tipo VI/metabolismo , Proteína p300 Associada a E1A/metabolismo , Proteína de Ligação a CREB/metabolismo , Proliferação de Células/efeitos dos fármacos , Colágeno/metabolismo , Colágeno Tipo VI/fisiologia , Proteína p300 Associada a E1A/genética , Epigênese Genética/genética , Epigenômica/métodos , Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Fibrose/genética , Fibrose/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Miofibroblastos/metabolismo , Miofibroblastos/fisiologia , Proteômica , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
6.
Nat Commun ; 11(1): 2768, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32488016

RESUMO

Fibrotic disorders are some of the most devastating and poorly treated conditions in developed nations, yet effective therapeutics are not identified for many of them. A major barrier for the identification of targets and successful clinical translation is a limited understanding of the human fibrotic microenvironment. Here, we construct a stromal cell atlas of human fibrosis at single cell resolution from patients with Dupuytren's disease, a localized fibrotic condition of the hand. A molecular taxonomy of the fibrotic milieu characterises functionally distinct stromal cell types and states, including a subset of immune regulatory ICAM1+ fibroblasts. In developing fibrosis, myofibroblasts exist along an activation continuum of phenotypically distinct populations. We also show that the tetraspanin CD82 regulates cell cycle progression and can be used as a cell surface marker of myofibroblasts. These findings have important implications for targeting core pathogenic drivers of human fibrosis.


Assuntos
Contratura de Dupuytren/imunologia , Contratura de Dupuytren/metabolismo , Fibrose/imunologia , Fibrose/metabolismo , Células Estromais/metabolismo , Actinas/metabolismo , Biomarcadores/metabolismo , Quimiocinas CXC/metabolismo , Contratura de Dupuytren/patologia , Fibrose/patologia , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Medicina Molecular , Miofibroblastos/metabolismo , Tetraspaninas/metabolismo , Microambiente Tumoral/fisiologia
7.
Sci Rep ; 10(1): 8830, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483203

RESUMO

We profiled gene expression signatures to distinguish rheumatoid arthritis (RA) from non-inflammatory arthralgia (NIA), self-limiting arthritis (SLA), and undifferentiated arthritis (UA) as compared to healthy controls as novel potential biomarkers for therapeutic responsiveness. Global gene expression profiles of PBMCs from 43 drug-naïve patients presenting with joint symptoms were evaluated and differentially expressed genes identified by comparative analysis with 24 healthy volunteers. Patients were assessed at presentation with follow up at 6 and 12 months. Gene ontology and network pathway analysis were performed using DAVID Bioinformatics Resources v6.7. Gene expression profiles were also determined after disease-modifying anti-rheumatic drug (DMARD) treatment in the inflammatory arthritis groups (i.e. RA and UA) and confirmed by qRT-PCR. Receiver operating characteristic (ROC) curves analysis and Area Under the Curve (AUC) estimation were performed to assess the diagnostic value of candidate gene expression signatures. A type I interferon (IFN) gene signature distinguished DMARD-naïve patients who will subsequently develop persistent inflammatory arthritis (i.e. RA and UA) from those with NIA. In patients with RA, the IFN signature is characterised by up-regulation of SIGLEC1 (p = 0.00597) and MS4A4A (p = 0.00000904). We also identified, EPHB2 (p = 0.000542) and PDZK1IP1 (p = 0.0206) with RA-specific gene expression profiles and elevated expression of the ST6GALNAC1 (p = 0.0023) gene in UA. ROC and AUC risk score analysis suggested that MSA4A (AUC: 0.894, 0.644, 0.720), PDZK1IP1 (AUC: 0.785, 0.806, 0.977), and EPHB2 (AUC: 0.794, 0.723, 0.620) at 0, 6, and 12 months follow-up can accurately discriminate patients with RA from healthy controls and may have practical value for RA diagnosis. In patients with early inflammatory arthritis, ST6GALNAC1 is a potential biomarker for UA as compared with healthy controls whereas EPHB2, MS4A4A, and particularly PDZK1IP1 may discriminate RA patients. SIGLEC1 may also be a useful marker of disease activity in UA.

10.
Biol Open ; 9(3)2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-32139395

RESUMO

Mechanical force is a fundamental regulator of cell phenotype. Myofibroblasts are central mediators of fibrosis, a major unmet clinical need characterised by the deposition of excessive matrix proteins. Traction forces of myofibroblasts play a key role in remodelling the matrix and modulate the activities of embedded stromal cells. Here, we employ a combination of unsupervised computational analysis, cytoskeletal profiling and single cell traction force microscopy as a functional readout to uncover how the complex spatiotemporal dynamics and mechanics of living human myofibroblast shape sub-cellular profiling of traction forces in fibrosis. We resolve distinct biophysical communities of myofibroblasts, and our results provide a new paradigm for studying functional heterogeneity in human stromal cells.

11.
Psychol Health ; 35(7): 811-823, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31637928

RESUMO

Objective: An individual's own personality traits are powerful predictors of their health outcomes (actor effects). However, the effect of personality on health may also occur at an interpersonal level, whereby the personalities of people close to the individual also affect his or her health outcomes (partner effects). Our objective was to examine the actor and partner effects of Type D personality on health in romantic couples for the first time.Design: Cross-sectional questionnaire-based study (N = 364), consisting of 182 romantic couples from the general population (mean age = 35.7 years).Main outcome measures: Each participant completed self-report measures of Type D personality (DS14), health behaviours (GPHB), mood (DASS-21) and quality of life (WHOQOL-BREF).Results: Data were analysed using the Actor-Partner Interdependence Model (APIM). The APIM showed no actor or partner effects of the overall Type D construct. However, there were actor effects of negative affect for both males and females on depression and quality of life, a male actor effect of social inhibition on quality of life, and a female partner effect of social inhibition on depression.Conclusions: These findings suggest that there are both actor and partner effects of the Type D components on some health outcomes.


Assuntos
Afeto , Comportamentos Relacionados com a Saúde , Qualidade de Vida/psicologia , Parceiros Sexuais/psicologia , Personalidade Tipo D , Adolescente , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Autorrelato , Inquéritos e Questionários , Adulto Jovem
12.
Sci Adv ; 5(12): eaay0370, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31840071

RESUMO

Dissecting the molecular landscape of fibrotic disease, a major unmet need, will inform the development of novel treatment strategies to target disease progression and identify desperately needed therapeutic targets. Here, we provide a detailed single-cell analysis of the immune landscape in Dupuytren's disease, a localized fibrotic condition of the hand, and identify a pathogenic signaling circuit between stromal and immune cells. We demonstrate M2 macrophages and mast cells as key cellular sources of tumor necrosis factor (TNF) that promotes myofibroblast development. TNF acts via the inducible TNFR2 receptor and stimulates interleukin-33 (IL-33) secretion by myofibroblasts. In turn, stromal cell IL-33 acts as a potent stimulus for TNF production from immune cells. Targeting this reciprocal signaling pathway represents a novel therapeutic strategy to inhibit the low-grade inflammation in fibrosis and the mechanism that drives chronicity.


Assuntos
Contratura de Dupuytren/genética , Fibrose/genética , Interleucina-33/genética , Receptores Tipo II do Fator de Necrose Tumoral/genética , Fator de Necrose Tumoral alfa/genética , Linhagem Celular , Contratura de Dupuytren/tratamento farmacológico , Contratura de Dupuytren/imunologia , Contratura de Dupuytren/patologia , Fibrose/tratamento farmacológico , Fibrose/imunologia , Fibrose/patologia , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Macrófagos/imunologia , Macrófagos/patologia , Terapia de Alvo Molecular , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Transdução de Sinais/genética , Análise de Célula Única/métodos , Fator de Necrose Tumoral alfa/imunologia
13.
Cell Rep ; 29(11): 3385-3393.e6, 2019 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-31825823

RESUMO

p21-Activated kinase 4 (PAK4), a serine/threonine kinase, is purported to localize to podosomes: transient adhesive structures that degrade the extracellular matrix to facilitate rapid myeloid cell migration. We find that treatment of transforming growth factor ß (TGF-ß)-differentiated monocytic (THP-1) cells with a PAK4-targeted inhibitor significantly reduces podosome formation and induces the formation of focal adhesions. This switch in adhesions confers a diminution of matrix degradation and reduced cell migration. Furthermore, reduced PAK4 expression causes a significant reduction in podosome number that cannot be rescued by kinase-dead PAK4, supporting a kinase-dependent role. Concomitant with PAK4 depletion, phosphorylation of Akt is perturbed, whereas a specific phospho-Akt signal is detected within the podosomes. Using superresolution analysis, we find that PAK4 specifically localizes in the podosome ring, nearer to the actin core than other ring proteins. We propose PAK4 kinase activity intersects with the Akt pathway at the podosome ring:core interface to drive regulation of macrophage podosome turnover.


Assuntos
Células Mieloides/metabolismo , Podossomos/metabolismo , Quinases Ativadas por p21/metabolismo , Células Cultivadas , Dissulfetos/farmacologia , Matriz Extracelular/metabolismo , Adesões Focais/metabolismo , Células HEK293 , Humanos , Células Mieloides/efeitos dos fármacos , Células Mieloides/ultraestrutura , Naftóis/farmacologia , Fosforilação , Podossomos/ultraestrutura , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Células THP-1 , Quinases Ativadas por p21/antagonistas & inibidores
14.
Sci Rep ; 9(1): 17115, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31723212

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

15.
Br J Health Psychol ; 24(1): 66-87, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30221433

RESUMO

OBJECTIVES: In an innovative approach to improve the contribution of health psychology to public health we have analysed the presence and nature of affect within the visual materials deployed in antimicrobial stewardship interventions targeting the public identified through systematic review. DESIGN: A qualitative analysis focused on the affective content of visual materials garnered from a systematic review of antibiotic stewardship (k = 20). METHODS: A novel method was devised drawing on concepts from semiotics to analyse the affective elements within intervention materials. RESULTS: Whilst all studies examined tacitly rely on affect, only one sought to explicitly deploy affect. Three thematic categories of affect are identified within the materials in which specific ideological machinery is deployed: (1) monsters, bugs, and superheroes; (2) responsibility, threat, and the misuse/abuse of antibiotics; (3) the figure of the child. CONCLUSIONS: The study demonstrates how affect is a present but tacit communication strategy of antimicrobial stewardship interventions but has not - to date - been adequately theorized or explicitly considered in the intervention design process. Certain affective features were explored in relation to the effectiveness of antimicrobial resistance interventions and warrant further investigation. We argue that further research is needed to systematically illuminate and capitalize upon the use of affect to effect behaviour change concerning antimicrobial stewardship. Statement of contribution What is already known on this subject? The (mis)use of antibiotics and consequent risk of antimicrobial resistance is a critical public health problem. If sufficient action is not taken, global society will face the 'post-antibiotic' era, in which common infections will lead to death for many millions. Key desirable behavioural changes are decreased patient demands for antibiotics, use of them for targeted purposes alone, and compliance with prescribed dosing. There is a growth of interest in the role of affect in mass media interventions designed to engage publics and produce health-related behavioural change. What does this study add? This article presents a novel analytic approach to understanding and intervening within behaviour change in public health that may complement other types of analysis. We present findings specifically from an 'affective' analysis based on semiotics in which we critically interrogated the visual imagery being deployed in mass media public health interventions concerning antimicrobial stewardship. Three thematic categories of affect are identified within the materials in which specific ideological machinery is deployed and that demonstrate some association with intervention effectiveness worthy of further investigation and testing.


Assuntos
Gestão de Antimicrobianos , Recursos Audiovisuais , Comportamentos Relacionados com a Saúde , Meios de Comunicação de Massa , Comunicação Persuasiva , Humanos , Saúde Pública
16.
Psychol Health ; 34(3): 255-270, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30295089

RESUMO

OBJECTIVES: Research supports the ability of social cognitive theory (SCT) to explain physical activity (PA) behaviour, but most studies have examined this theory between individuals in large group studies. The aim of the present study was to examine the interrelationships between SCT constructs and PA within individuals of varying activity levels. DESIGN: Correlational n-of-1 studies. METHODS: Six adults aged 29-65 with varying levels of PA provided daily measures of PA, and completed probe measures over a four-week period of SCT constructs (e.g. barrier self-efficacy, goal setting, planning, social support, outcome expectations, perceived barriers, enjoyment). Data were analysed using cross-correlational time series analysis. RESULTS: Cross-correlation analysis showed that at least one SCT construct was associated with PA in five participants, although no individual had the same pattern of associations across the study. On some occasions, SCT constructs predicted subsequent PA, but at other times, PA engagement caused a subsequent change in the SCT construct. There were also examples of PA and SCT constructs being concurrently associated. CONCLUSIONS: SCT factors are associated with variations in PA behaviour, but the cause and effect of these relationships within individuals is complex.


Assuntos
Exercício Físico/psicologia , Teoria Psicológica , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
17.
EBioMedicine ; 33: 282-288, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29983350

RESUMO

BACKGROUND: Dupuytren's disease is a common fibrotic condition of the hand that causes irreversible flexion contractures of the fingers, with no approved therapy for early stage disease. Our previous analysis of surgically-excised tissue defined tumour necrosis factor (TNF) as a potential therapeutic target. Here we assessed the efficacy of injecting nodules of Dupuytren's disease with a TNF inhibitor. METHODS: Patients were randomised to receive adalimumab on one occasion in dose cohorts of 15 mg in 0.3 ml, 35 mg in 0.7 ml, or 40 mg in 0.4 ml, or an equivalent volume of placebo in a 3:1 ratio. Two weeks later the injected tissue was surgically excised and analysed. The primary outcome measure was levels of mRNA expression for α-smooth muscle actin (ACTA2). Secondary outcomes included levels of α-SMA and collagen proteins. The trial was registered with ClinicalTrial.gov (NCT03180957) and the EudraCT (2015-001780-40). FINDINGS: We recruited 28 patients, 8 assigned to the 15 mg, 12 to the 35 mg and 8 to the 40 mg adalimumab cohorts. There was no change in mRNA levels for ACTA2, COL1A1, COL3A1 and CDH11. Levels of α-SMA protein expression in patients treated with 40 mg adalimumab (1.09 ±â€¯0.09 ng per µg of total protein) were significantly lower (p = 0.006) compared to placebo treated patients (1.51 ±â€¯0.09 ng/µg). The levels of procollagen type I protein expression were also significantly lower (p < 0.019) in the sub group treated with 40 mg adalimumab (474 ±â€¯84 pg/µg total protein) compared with placebo (817 ±â€¯78 pg/µg). There were two serious adverse events, both considered unrelated to the study drug. INTERPRETATION: In this dose-ranging study, injection of 40 mg of adalimumab in 0.4 ml resulted in down regulation of the myofibroblast phenotype as evidenced by reduction in expression of α-SMA and type I procollagen proteins at 2 weeks. These data form the basis of an ongoing phase 2b clinical trial assessing the efficacy of intranodular injection of 40 mg adalimumab in 0.4 ml compared to an equivalent volume of placebo in patients with early stage Dupuytren's disease. FUNDING: Health Innovation Challenge Fund (Wellcome Trust and Department of Health) and 180 Therapeutics LP.


Assuntos
Actinas/metabolismo , Adalimumab/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Colágeno Tipo I/metabolismo , Contratura de Dupuytren/tratamento farmacológico , Actinas/genética , Adalimumab/farmacologia , Anti-Inflamatórios/farmacologia , Colágeno Tipo I/genética , Método Duplo-Cego , Regulação para Baixo , Esquema de Medicação , Contratura de Dupuytren/genética , Contratura de Dupuytren/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Injeções , Masculino , Resultado do Tratamento
18.
Br J Health Psychol ; 23(4): 804-819, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29804314

RESUMO

OBJECTIVES: Changing public awareness of antimicrobial resistance (AMR) represents a global public health priority. A systematic review of interventions that targeted public AMR awareness and associated behaviour was previously conducted. Here, we focus on identifying the active content of these interventions and explore potential mechanisms of action. METHODS: The project took a novel approach to intervention mapping utilizing the following steps: (1) an exploration of explicit and tacit theory and theoretical constructs within the interventions using the Theoretical Domains Framework (TDFv2), (2) retrospective coding of behaviour change techniques (BCTs) using the BCT Taxonomy v1, and (3) an investigation of coherent links between the TDF domains and BCTs across the interventions. RESULTS: Of 20 studies included, only four reported an explicit theoretical basis to their intervention. However, TDF analysis revealed that nine of the 14 TDF domains were utilized, most commonly 'Knowledge' and 'Environmental context and resources'. The BCT analysis showed that all interventions contained at least one BCT, and 14 of 93 (15%) BCTs were coded, most commonly 'Information about health consequences', 'Credible source', and 'Instruction on how to perform the behaviour'. CONCLUSIONS: We identified nine relevant TDF domains and 14 BCTs used in these interventions. Only 15% of BCTs have been applied in AMR interventions thus providing a clear opportunity for the development of novel interventions in this context. This methodological approach provides a useful way of retrospectively mapping theoretical constructs and BCTs when reviewing studies that provide limited information on theory and intervention content. Statement of contribution What is already known on this subject? Evidence of the effectiveness of interventions that target the public to engage them with AMR is mixed; the public continue to show poor knowledge and misperceptions of AMR. Little is known about the common, active ingredients of AMR interventions targeting the public and information on explicit theoretical content is sparse. Information on the components of AMR public health interventions is urgently needed to enable the design of effective interventions to engage the public with AMR stewardship behaviour. What does this study add? The analysis shows very few studies reported any explicit theoretical basis to the interventions they described. Many interventions share common components, including core mechanisms of action and behaviour change techniques. The analysis suggests components of future interventions to engage the public with AMR.


Assuntos
Farmacorresistência Bacteriana , Comportamentos Relacionados com a Saúde , Comunicação em Saúde/métodos , Conhecimentos, Atitudes e Prática em Saúde , Promoção da Saúde/métodos , Humanos , Masculino , Estudos Retrospectivos
19.
J Antimicrob Chemother ; 73(6): 1464-1478, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29554263

RESUMO

Background: A global antimicrobial resistance (AMR) awareness intervention targeting the general public has been prioritized. Objectives: To evaluate the effectiveness of interventions that aim to change AMR awareness and subsequent stewardship behaviours amongst the public. Methods: Five databases were searched between 2000 and 2016 for interventions to change the public's AMR awareness and/or antimicrobial stewardship behaviours. Study designs meeting the Cochrane Effective Practice and Organization of Care (EPOC) criteria, non-controlled before-and-after studies and prospective cohort studies were considered eligible. Participants recruited from healthcare settings and studies measuring stewardship behaviours of healthcare professionals were excluded. Quality of studies was assessed using EPOC risk of bias criteria. Data were extracted and synthesized narratively. Registration: PROSPERO international prospective register of systematic reviews (PROSPERO 2016: CRD42016050343). Results: Twenty studies were included in the review with nine meeting the EPOC criteria. The overall risk of bias was high. Nineteen studies were conducted in high-income countries. Mass media interventions were most common (n = 7), followed by school-based (n = 6) and printed material interventions (n = 6). Seventeen studies demonstrated a significant effect on changing knowledge, attitudes or the public's antimicrobial stewardship behaviours. Analysis showed that interventions targeting schoolchildren and parents have notable potential, but for the general public the picture is less clear. Conclusions: Our work provides an in-depth examination of the effectiveness of AMR interventions for the public. However, the studies were heterogeneous and the quality of evidence was poor. Well-designed, experimental studies on behavioural outcomes of such interventions are required.


Assuntos
Gestão de Antimicrobianos/métodos , Farmacorresistência Bacteriana , Conhecimentos, Atitudes e Prática em Saúde , Saúde Pública/métodos , Antibacterianos/farmacologia , Gestão de Antimicrobianos/estatística & dados numéricos , Ensaios Clínicos como Assunto , Humanos , Estudos Prospectivos , Saúde Pública/estatística & dados numéricos
20.
Biochem Biophys Res Commun ; 499(2): 260-266, 2018 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-29567473

RESUMO

Tumour necrosis factor (TNF) is produced by primary human macrophages in response to stimulation by exogenous pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs) via Toll-like receptor (TLR) signalling. However, uncontrolled TNF production can be deleterious and hence it is tightly controlled at multiple stages. We have previously shown that Bruton's tyrosine kinase (Btk) regulates TLR4-induced TNF production via p38 MAP Kinase by stabilising TNF messenger RNA. Using both gene over-expression and siRNA-mediated knockdown we have examined the role of Btk in TLR7/8 mediated TNF production. Our data shows that Btk acts in the TLR7/8 pathway and mediates Ser-536 phosphorylation of p65 RelA and subsequent nuclear entry in primary human macrophages. These data show an important role for Btk in TLR7/8 mediated TNF production and reveal distinct differences for Btk in TLR4 versus TLR7/8 signalling.


Assuntos
NF-kappa B/metabolismo , Proteínas Tirosina Quinases/metabolismo , Receptor 7 Toll-Like/metabolismo , Receptor 8 Toll-Like/metabolismo , Transcrição Genética , Fator de Necrose Tumoral alfa/genética , Regiões 3' não Traduzidas/genética , Tirosina Quinase da Agamaglobulinemia , Pareamento de Bases/genética , Núcleo Celular/metabolismo , Citocinas/biossíntese , Regulação para Baixo/genética , Humanos , Fosforilação , Regiões Promotoras Genéticas/genética , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
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