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Large-scale genetic studies of traumatic brain injury (TBI) are lacking; thus, our understanding of the influence of genetic factors on TBI risk and recovery is incomplete. This study aimed to conduct a genome-wide association study (GWAS) of TBI in VA Million Veteran Program (MVP) enrollees. Participants included a multi-ancestry cohort (European, African, and Hispanic ancestries; N = 304,485; 111,494 TBI cases, 192,991 controls). TBI was assessed using MVP survey data and International Classification of Diseases (ICD) codes from the Veterans Health Administration's electronic health record. GWAS was performed using logistic regression in PLINK, and meta-analyzed in METAL. FUMA was used for post-GWAS analysis. Genomic structural equation modeling (gSEM) was conducted to investigate underlying genetic associations with TBI, and bivariate MiXeR was used to estimate phenotype specific and shared polygenicity. SNP-based heritability was 0.060 (SE = 0.004, p = 7.83×10-66). GWAS analysis identified 15 genome-wide significant (GWS) loci at p < 5×10-8. Gene-based analyses revealed 14 gene-wide significant genes; top genes included NCAM1, APOE, FTO, and FOXP2. Gene tissue expression analysis identified the brain as significantly enriched, particularly in the frontal cortex, anterior cingulate cortex, and nucleus accumbens. Genetic correlations with TBI were significant for risk-taking behaviors and psychiatric disorders, but generally not significant for the neurocognitive variables investigated. gSEM analysis revealed stronger associations with risk-taking traits than with psychiatric traits. Finally, the genetic architecture of TBI was similar to polygenic psychiatric disorders. Neurodegenerative disorders including Alzheimer's and Parkinson's disease showed much less polygenicity, however, the proportion of shared variance with TBI was high. This first well-powered GWAS of TBI identified 15 loci including genes relevant to TBI biology, and showed that TBI is a heritable trait with comparable genetic architecture and high genetic correlation with psychiatric traits. Our findings set the stage for future TBI GWASs that focus on injury severity and diversity and chronicity of symptom sequelae.
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OBJECTIVE: Neuropsychological criteria for mild cognitive impairment (MCI) more accurately predict progression to Alzheimer's disease (AD) and are more strongly associated with AD biomarkers and neuroimaging profiles than ADNI criteria. However, research to date has been conducted in relatively healthy samples with few comorbidities. Given that history of traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) are risk factors for AD and common in Veterans, we compared neuropsychological, typical (Petersen/Winblad), and ADNI criteria for MCI in Vietnam-era Veterans with histories of TBI or PTSD. METHOD: 267 Veterans (mean age = 69.8) from the DOD-ADNI study were evaluated for MCI using neuropsychological, typical, and ADNI criteria. Linear regressions adjusting for age and education assessed associations between MCI status and AD biomarker levels (cerebrospinal fluid [CSF] p-tau181, t-tau, and Aß42) by diagnostic criteria. Logistic regressions adjusting for age and education assessed the effects of TBI severity and PTSD symptom severity simultaneously on MCI classification by each criteria. RESULTS: Agreement between criteria was poor. Neuropsychological criteria identified more Veterans with MCI than typical or ADNI criteria, and were associated with higher CSF p-tau181 and t-tau. Typical and ADNI criteria were not associated with CSF biomarkers. PTSD symptom severity predicted MCI diagnosis by neuropsychological and ADNI criteria. History of moderate/severe TBI predicted MCI by typical and ADNI criteria. CONCLUSIONS: MCI diagnosis using sensitive neuropsychological criteria is more strongly associated with AD biomarkers than conventional diagnostic methods. MCI diagnostics in Veterans would benefit from incorporation of comprehensive neuropsychological methods and consideration of the impact of PTSD.
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Disfunção Cognitiva , Testes Neuropsicológicos , Transtornos de Estresse Pós-Traumáticos , Veteranos , Guerra do Vietnã , Proteínas tau , Humanos , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Masculino , Idoso , Pessoa de Meia-Idade , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Testes Neuropsicológicos/normas , Proteínas tau/líquido cefalorraquidiano , Feminino , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/diagnóstico , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fragmentos de Peptídeos/sangue , Idoso de 80 Anos ou maisRESUMO
OBJECTIVE: The authors examined the interaction between apolipoprotein E (APOE) ε4 and brain-derived neurotrophic factor (BDNF) Val66Met alleles on neuropsychological functioning among veterans with histories of mild traumatic brain injury (mTBI). METHODS: Participants were 78 veterans with mTBI (85% males; mean±SD age=32.95±7.00 years; mean time since injury=67.97±34.98 months) who completed a structured clinical interview and underwent a comprehensive neuropsychological assessment. Participants also provided a buccal swab for determination of their APOE and BDNF genotypes. Three cognitive composite scores were calculated from the neuropsychological assessment, reflecting visuospatial speed (seven variables), executive functioning (10 variables), and memory (eight variables). Two-way analyses of covariance (ANCOVAs) adjusted for age, sex, and race-ethnicity were used to assess the effects of APOE (ε4+ vs. ε4-) and BDNF (Met+ vs. Met-) on cognitive functioning. RESULTS: ANCOVAs revealed no significant main effects of APOE or BDNF genotypes on cognitive functioning; however, there was a significant APOE-by-BDNF genotype interaction for all three cognitive composite measures (visuospatial speed: ηp2=0.055; executive functioning: ηp2=0.064; and memory: ηp2=0.068). Specifically, the ε4+/Met+ (N=8) subgroup demonstrated the poorest cognitive functioning relative to all other allele subgroups (ε4+/Met-: N=12, ε4-/Met+: N=23, and ε4-/Met-: N=35). CONCLUSIONS: This exploratory study is the first to show that, compared with other allele subgroups assessed, veterans with both ε4 and Met alleles demonstrated the poorest cognitive functioning across several cognitive domains known to be negatively affected in the context of mTBI. Further research with larger sample sizes is needed to replicate these findings.
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There is a substantial research base for addictive eating with development of interventions. The current 3-arm RCT aimed to investigate the efficacy of the TRACE (Targeted Research for Addictive and Compulsive Eating) program to decrease addictive eating symptoms and improve mental health. Participants (18-85 yrs) endorsing ≥3 addictive eating symptoms were randomly allocated to 1) active intervention, 2) passive intervention, or 3) control group. Primary outcome was change in addictive eating symptoms 3-months post-baseline measured by the Yale Food Addiction Scale. Depression, anxiety and stress were also assessed. A total of 175 individuals were randomised. Using Linear Mixed Models, from baseline to 3-months, there was significant improvement in symptom scores in all groups with mean decrease of 4.7 (95% CI: -5.8, -3.6; p < 0.001), 3.8 (95% CI: -5.2, -2.4; p < 0.001) and 1.5 (95% CI: -2.6, -0.4; p = 0.01) respectively. Compared with the control group, participants in the active intervention were five times more likely to achieve a clinically significant change in symptom scores. There was a significant reduction in depression scores in the active and passive intervention groups, but not control group [-2.9 (95% CI: -4.5, -1.3); -2.3 (95% CI: -4.3, -0.3); 0.5 (95% CI: -1.1, 2.1), respectively]; a significant reduction in stress scores within the active group, but not passive intervention or control groups [-1.3 (95% CI: -2.2, -0.5); -1.0 (95% CI: -2.1, 0.1); 0.4 (95% CI: -0.5, 1.2), respectively]; and the reduction in anxiety scores over time was similar for all groups. A dietitian-led telehealth intervention for addictive eating in adults was more effective than a passive or control condition in reducing addictive eating scores from baseline to 6 months. Trial registration: Australia New Zealand Clinical Trial Registry ACTRN12621001079831.
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Comportamento Aditivo , Telemedicina , Adulto , Humanos , Austrália , Ansiedade/terapia , Ansiedade/psicologia , Transtornos de AnsiedadeRESUMO
BACKGROUND: Homelessness is associated with significant health disparities. Conventional health services often fail to address the unique needs and lived experience of homeless individuals and fail to include participatory design when planning health services. This scoping review aimed to examine areas of patient experience that are most frequently reported by people experiencing homelessness when seeking and receiving healthcare, and to identify existing surveys used to measure patient experience for this cohort. METHODS: A scoping review was undertaken reported according to the PRISMA-ScR 2020 Statement. Databases were searched on 1 December 2022: MEDLINE, EMBASE, APA PsychINFO and CINAHL. Included studies focused on people experiencing homelessness, healthcare services and patient experience, primary research, published in English from 2010. Qualitative papers and findings were extracted and synthesized against a modified framework based on the National Institute for Health and Care Excellence guidelines for care for people experiencing homelessness, the Institute of Medicine Framework and Lachman's multidimensional quality model. People with lived experience of homelessness were employed as part of the research team. RESULTS: Thirty-two studies were included. Of these, 22 were qualitative, seven quantitative and three mixed methods, from the United States of America (n = 17), United Kingdom (n = 5), Australia (n = 5) and Canada (n = 4). Health services ranged from primary healthcare to outpatient management, acute care, emergency care and hospital based healthcare. In qualitative papers, the domains of 'accessible and timely', 'person-centred', and values of 'dignity and respect' and 'kindness with compassion' were most prevalent. Among the three patient experience surveys identified, 'accessible and timely' and 'person-centred' were the most frequent domains. The least frequently highlighted domains and values were 'equitable' and 'holistic'. No questions addressed the 'safety' domain. CONCLUSIONS: The Primary Care Quality-Homeless questionnaire best reflected the priorities for healthcare provision that were highlighted in the qualitative studies of people experiencing homelessness. The most frequently cited domains and values that people experiencing homelessness expressed as important when seeking healthcare were reflected in each of the three survey tools to varying degrees. Findings suggest that the principles of 'Kindness and compassion' require further emphasis when seeking feedback on healthcare experiences and the domains of 'safety', 'equitable', and 'efficiency' are not adequately represented in existing patient experience surveys.
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Pessoas Mal Alojadas , Pessoas Mal Alojadas/psicologia , Humanos , Satisfação do Paciente , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Acessibilidade aos Serviços de SaúdeRESUMO
BACKGROUND: Microbiota are recognized to play a major role in regulation of immunity through release of immunomodulatory metabolites such as short-chain fatty acids (SCFAs). Rhinoviruses (RVs) induce upper respiratory tract illnesses and precipitate exacerbations of asthma and chronic obstructive pulmonary disease through poorly understood mechanisms. Local interactions between SCFAs and antiviral immune responses in the respiratory tract have not been previously investigated. OBJECTIVE: We sought to investigate whether pulmonary metabolite manipulation through lung-delivered administration of SCFAs can modulate antiviral immunity to RV infection. METHODS: We studied the effects of intranasal administration of the SCFAs acetate, butyrate, and propionate on basal expression of antiviral signatures, and of acetate in a mouse model of RV infection and in RV-infected lung epithelial cell lines. We additionally assessed the effects of acetate, butyrate, and propionate on RV infection in differentiated human primary bronchial epithelial cells. RESULTS: Intranasal acetate administration induced basal upregulation of IFN-ß, an effect not observed with other SCFAs. Butyrate induced RIG-I expression. Intranasal acetate treatment of mice increased interferon-stimulated gene and IFN-λ expression during RV infection and reduced lung virus loads at 8 hours postinfection. Acetate ameliorated virus-induced proinflammatory responses with attenuated pulmonary mucin and IL-6 expression observed at day 4 and 6 postinfection. This interferon-enhancing effect of acetate was confirmed in human bronchial and alveolar epithelial cell lines. In differentiated primary bronchial epithelial cells, butyrate treatment better modulated IFN-ß and IFN-λ gene expression during RV infection. CONCLUSIONS: SCFAs augment antiviral immunity and reduce virus load and proinflammatory responses during RV infection.
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Infecções por Enterovirus , Infecções por Picornaviridae , Humanos , Camundongos , Animais , Antivirais/uso terapêutico , Rhinovirus , Propionatos/farmacologia , Propionatos/uso terapêutico , Interferons , Brônquios , Células Epiteliais , Acetatos/farmacologia , Acetatos/uso terapêutico , Butiratos/farmacologia , Butiratos/uso terapêuticoRESUMO
INTRODUCTION: Data-driven neuropsychological methods can identify mild cognitive impairment (MCI) subtypes with stronger associations to dementia risk factors than conventional diagnostic methods. METHODS: Cluster analysis used neuropsychological data from participants without dementia (mean age = 71.6 years) in the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (n = 26,255) and the "normal cognition" subsample (n = 16,005). Survival analyses examined MCI or dementia progression. RESULTS: Five clusters were identified: "Optimal" cognitively normal (oCN; 13.2%), "Typical" CN (tCN; 28.0%), Amnestic MCI (aMCI; 25.3%), Mixed MCI-Mild (mMCI-Mild; 20.4%), and Mixed MCI-Severe (mMCI-Severe; 13.0%). Progression to dementia differed across clusters (oCN < tCN < aMCI < mMCI-Mild < mMCI-Severe). Cluster analysis identified more MCI cases than consensus diagnosis. In the "normal cognition" subsample, five clusters emerged: High-All Domains (High-All; 16.7%), Low-Attention/Working Memory (Low-WM; 22.1%), Low-Memory (36.3%), Amnestic MCI (16.7%), and Non-amnestic MCI (naMCI; 8.3%), with differing progression rates (High-All < Low-WM = Low-Memory < aMCI < naMCI). DISCUSSION: Our data-driven methods outperformed consensus diagnosis by providing more precise information about progression risk and revealing heterogeneity in cognition and progression risk within the NACC "normal cognition" group.
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Disfunção Cognitiva , Progressão da Doença , Testes Neuropsicológicos , Humanos , Disfunção Cognitiva/diagnóstico , Idoso , Feminino , Masculino , Testes Neuropsicológicos/estatística & dados numéricos , Análise por Conglomerados , Idoso de 80 Anos ou mais , Fatores de RiscoRESUMO
There is a need to identify the outcomes of changes in loneliness during adolescence, and to consider this within a multidimensional framework of loneliness. This study considered the effects of different trajectories of change in Isolation Loneliness and in Friendship Loneliness upon both positive wellbeing and symptoms of depression. To achieve this, 1782 (43% female; 12.92 years old at the start of the study, SD = 1.60) young people took part in a longitudinal study with four data points across 2 years. Four Isolation Loneliness trajectories and five Friendship Loneliness trajectories were identified. Youth who experienced low levels of Isolation Loneliness that subsequently increased appear to be at particular risk for poor outcomes. Similarly, initially high levels of Friendship Loneliness that decreased rapidly, or which began at a low level and only increased marginally, seem to also be a risk. Loneliness is a multi-dimensional construct and its development during adolescence impacts upon young people's depressive symptomatology and positive mental wellbeing.
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Depressão , Solidão , Humanos , Adolescente , Feminino , Criança , Masculino , Estudos Longitudinais , AmigosRESUMO
BACKGROUND: Mental health crisis rates in the United Kingdom are on the rise. The emergence of community mental health models, such as Crisis Resolution Home Treatment Teams (CRHTTs), offers a vital pathway to provide intensive assessment and treatment to individuals in their homes, including psychological interventions. Previous qualitative literature has identified facilitators and barriers to the implementation of psychological interventions within CRHTT settings; however, a synthesis of this literature has not yet been conducted. To address this gap, a systematic review was undertaken with the aim of identifying the reported facilitators and barriers of implementing evidence-based psychological interventions in CRHTTs. METHOD: A systematic review and narrative synthesis were conducted. Studies were included if they examined the implementation of evidence-based psychological interventions in a CRHTT setting. The study population had to be 18 and over and could include healthcare professionals working in CRHTTs, service users of CRHTTs, or family and carers of CRHTT service users. Studies of any formal research methodology were included. Four databases were searched (MEDLINE, CINAHL Plus, Embase and PsycINFO), along with Google Scholar, to identify eligible studies. RESULTS: Six studies were identified, using mixed qualitative and quantitative methodologies, with the predominant focus being the exploration of stakeholder perspectives on care implementation within CRHTTs, encompassing aspects including but not restricted to psychological care implementation. The literature was deemed to be of moderate to high quality. Facilitators included adapting psychological therapies, prioritizing the therapeutic relationship, increasing psychological skills and training of CRHTT staff and psychologically informed CRHTT models. The barriers identified included a medical model bias within teams, resource constraints and elements pertaining to CRHTT services. CONCLUSIONS: Further robust research in this area is imperative. We recommend that future research be implemented in the form of service evaluations and randomized controlled trials (RCTs) and that the principles of implementation science be used to assess and develop the evidence base for psychological intervention delivery in CRHTTs.
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Intervenção em Crise , Serviços de Assistência Domiciliar , Transtornos Mentais , Intervenção Psicossocial , Humanos , Intervenção em Crise/métodos , Intervenção Psicossocial/métodos , Transtornos Mentais/terapia , Transtornos Mentais/psicologia , Serviços Comunitários de Saúde Mental/métodos , Reino Unido , Equipe de Assistência ao PacienteRESUMO
Cognitive behaviour therapy for psychosis (CBTp) should be offered to patients receiving psychiatric inpatient care, yet very little is known about patients' perspectives on this. The aim of this study was to examine patients' experiences of a CBTp-informed intervention delivered in inpatient settings. We recruited 10 participants from the intervention arm of a randomised controlled trial examining the feasibility and acceptability of a CBTp-informed intervention for psychiatric inpatient settings. We undertook semistructured interviews examining their experiences of the intervention and analysed them using thematic analysis. The study was conducted in partnership with a coproduction group of key stakeholders (people with lived experience, family and carers, and clinicians). The intervention was found helpful by almost all participants, and all participants would recommend it to others in similar situations to themselves. The results demonstrated that participants valued the therapist's professionalism and emphasised the importance of the therapeutic relationship. Participants highlighted the importance of the therapy focusing on navigating admission and developing skills to manage the crisis experience so they could return to their normal lives. Participants described challenges to having psychological therapy in the acute crisis context including therapy interruptions and ongoing distressing experiences of psychosis. The study demonstrated the importance of prioritising the therapeutic relationship, that therapy was a valued process to navigate admission and discharge, but that some environmental and patient-level challenges were present. Further research is needed to explore inpatients' experiences of psychological interventions in this setting. TRIAL REGISTRATION: ISRCTN trial registry: ISRCTN59055607.
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Terapia Cognitivo-Comportamental , Intervenção em Crise , Pacientes Internados , Transtornos Psicóticos , Pesquisa Qualitativa , Humanos , Transtornos Psicóticos/terapia , Transtornos Psicóticos/psicologia , Feminino , Masculino , Terapia Cognitivo-Comportamental/métodos , Adulto , Intervenção em Crise/métodos , Pessoa de Meia-Idade , Pacientes Internados/psicologia , Satisfação do Paciente/estatística & dados numéricosRESUMO
BACKGROUND: Obesity is associated with more severe asthma, however, the mechanisms responsible are poorly understood. Obesity is also associated with low-grade systemic inflammation; it is possible that this inflammation extends to the airways of adults with asthma, contributing to worse asthma outcomes. Accordingly, the aim of this review was to examine whether obesity is associated with increased airway and systemic inflammation and adipokines, in adults with asthma. METHODS: Medline, Embase, CINAHL, Scopus and Current Contents were searched till 11 August 2021. Studies reporting measures of airway inflammation, systemic inflammation and/or adipokines in obese versus non-obese adults with asthma were assessed. We conducted random effects meta-analyses. We assessed heterogeneity using the I2 statistic and publication bias using funnel plots. RESULTS: We included 40 studies in the meta-analysis. Sputum neutrophils were 5% higher in obese versus non-obese asthmatics (mean difference (MD)=5.0%, 95% CI: 1.2 to 8.9, n=2297, p=0.01, I2=42%). Blood neutrophil count was also higher in obesity. There was no difference in sputum %eosinophils; however, bronchial submucosal eosinophil count (standardised mean difference (SMD)=0.58, 95% CI=0.25 to 0.91, p<0.001, n=181, I2=0%) and sputum interleukin 5 (IL-5) (SMD=0.46, 95% CI=0.17 to 0.75, p<0.002, n=198, I2=0%) were higher in obesity. Conversely, fractional exhaled nitric oxide was 4.5 ppb lower in obesity (MD=-4.5 ppb, 95% CI=-7.1 ppb to -1.8 ppb, p<0.001, n=2601, I2=40%). Blood C reactive protein, IL-6 and leptin were also higher in obesity. CONCLUSIONS: Obese asthmatics have a different pattern of inflammation to non-obese asthmatics. Mechanistic studies examining the pattern of inflammation in obese asthmatics are warranted. Studies should also investigate the clinical relevance of this altered inflammatory response. PROSPERO REGISTERATION NUMBER: CRD42021254525.
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Asma , Adulto , Humanos , Asma/metabolismo , Inflamação/metabolismo , Eosinófilos/metabolismo , Obesidade/complicações , Contagem de Leucócitos , Escarro/metabolismoRESUMO
BACKGROUND: There is limited research on what, when and how outcomes should be measured in psychological therapy trials in acute mental health inpatient wards. OBJECTIVES: This study aimed to consider what outcomes service users think are important to measure. METHODS: This qualitative study explored the views of 14 participants, who had an inpatient admission within the last year, on outcomes of psychological therapies using semistructured interviews. Data were analysed using thematic analysis from a critical realist perspective with both inductive and deductive coding. RESULTS: The 126 outcomes that were important to participants were mapped onto an established taxonomy of outcomes across different health areas and the socioecological framework to consider the wider context and help summarise the outcomes. Most of the outcomes were mapped to the intrapersonal and interpersonal level. In addition to the outcome mapping, three themes were constructed from the qualitative data: (1) I am not a problem I am a person, (2) Feeling cared for and loved, (3) What does getting better look like. CONCLUSIONS: Our results highlight the need for patient-reported outcomes which are cocreated with service users, disseminating research and training on preventing dehumanising experiences, enhancing psychological safety and therapeutic relationships and improving access to psychological therapy. PATIENT OR PUBLIC CONTRIBUTION: The wider People with Personal Experience Involvement Committee at the University of Bath were consulted which included a focus group during the early planning stages. We also collaborated with a person with personal experience, at every stage of the research. This included developing our research question and aims, protocol, participant documents (e.g., information and debrief forms), advertisement and recruitment strategy, interview topic guide, the codes, the final themes and quotes and reviewing the manuscript. People with lived experience of being admitted to an acute mental health inpatient ward participated in our study.
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BACKGROUND: Obesity-related complications including visceral fat, metabolic abnormalities, nutrient deficiencies, and immune perturbations are interdependent but have been individually associated with childhood asthma. OBJECTIVE: We sought to endotype childhood obesity-related asthma by quantifying contributions of obesity-related complications to symptoms and pulmonary function. METHODS: Multiomics analysis using Similarity Network Fusion followed by mediation analysis were performed to quantify prediction of obese asthma phenotype by different combinations of anthropometric, metabolic, nutrient, and TH-cell transcriptome and DNA methylome data sets. RESULTS: Two clusters (n = 28 and 26) distinct in their anthropometric (neck and midarm circumference, waist to hip ratio [WHR], and body mass index [BMI] z score), metabolic, nutrient, and TH-cell transcriptome and DNA methylome footprint predicted 5 or more pulmonary function indices across 7 different data set combinations. Metabolic measures attenuated the association of neck, WHR, and BMI z score with FEV1/forced vital capacity (FVC) ratio and expiratory reserve volume (ERV), of neck, midarm, and BMI z score with functional residual capacity, but only of WHR with inspiratory capacity. Nutrient levels attenuated the association of neck, midarm circumference, and BMI z score with functional residual capacity, and of WHR with FEV1/FVC ratio, ERV, and inspiratory capacity. TH-cell transcriptome attenuated the association of all 4 anthropometric measures with FEV1/FVC ratio, but only of WHR with ERV and inspiratory capacity. The DNA methylome attenuated the association of all 4 anthropometric measures with FEV1/FVC ratio and ERV, but only of WHR with inspiratory capacity. CONCLUSIONS: Anthropometric, metabolic, nutrient, and immune perturbations have individual but interdependent contributions to obese asthma phenotype, with the most consistent effect of WHR, highlighting the role of truncal adiposity in endotyping childhood obesity-related asthma.
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Asma , Obesidade Infantil , Adiposidade , Índice de Massa Corporal , Linfócitos T CD4-Positivos , Humanos , Nutrientes , Obesidade Infantil/complicações , Relação Cintura-QuadrilRESUMO
BACKGROUND: Obesity is a risk factor for asthma, and obese asthmatic individuals are more likely to have severe, steroid-insensitive disease. How obesity affects the pathogenesis and severity of asthma is poorly understood. Roles for increased inflammasome-mediated neutrophilic responses, type 2 immunity, and eosinophilic inflammation have been described. OBJECTIVE: We investigated how obesity affects the pathogenesis and severity of asthma and identified effective therapies for obesity-associated disease. METHODS: We assessed associations between body mass index and inflammasome responses with type 2 (T2) immune responses in the sputum of 25 subjects with asthma. Functional roles for NLR family, pyrin domain-containing (NLRP) 3 inflammasome and T2 cytokine responses in driving key features of disease were examined in experimental high-fat diet-induced obesity and asthma. RESULTS: Body mass index and inflammasome responses positively correlated with increased IL-5 and IL-13 expression as well as C-C chemokine receptor type 3 expression in the sputum of subjects with asthma. High-fat diet-induced obesity resulted in steroid-insensitive airway hyperresponsiveness in both the presence and absence of experimental asthma. High-fat diet-induced obesity was also associated with increased NLRP3 inflammasome responses and eosinophilic inflammation in airway tissue, but not lumen, in experimental asthma. Inhibition of NLRP3 inflammasome responses reduced steroid-insensitive airway hyperresponsiveness but had no effect on IL-5 or IL-13 responses in experimental asthma. Depletion of IL-5 and IL-13 reduced obesity-induced NLRP3 inflammasome responses and steroid-insensitive airway hyperresponsiveness in experimental asthma. CONCLUSION: We found a relationship between T2 cytokine and NLRP3 inflammasome responses in obesity-associated asthma, highlighting the potential utility of T2 cytokine-targeted biologics and inflammasome inhibitors.
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Asma , Inflamassomos , Citocinas , Humanos , Inflamassomos/metabolismo , Inflamação/metabolismo , Interleucina-13 , Interleucina-1beta , Interleucina-5 , Proteína 3 que Contém Domínio de Pirina da Família NLR , Obesidade/complicaçõesRESUMO
OBJECTIVES: Psychologists frequently deliver indirect psychological interventions in mental health inpatient settings to support staff to reflect upon and improve their clinical practice. However, research into these interventions is sparse. Therefore, this study aimed to undertake a systematic review and narrative synthesis of the indirect psychological interventions used in mental health inpatient settings. METHODS: MEDLINE, PsycINFO and Embase were searched for eligible studies and forward-citation searching was undertaken. A narrative synthesis was undertaken to synthesize results. The quality of studies was assessed using the Mixed Methods Appraisal Tool. RESULTS: Ten studies were included in the review, and all utilized a small to moderate sample size. We identified five categories of interventions involving a range of methodologies and the studies were assessed to be of good to adequate quality. The most common type of indirect intervention employed was case formulation sessions. Other types of indirect interventions included formal clinical supervision, reflective practice and staff practice-based education sessions. Overall, the utilization of indirect psychological interventions shows promise, particularly case formulation sessions. CONCLUSIONS: The use of indirect psychological interventions within mental health inpatient settings may have benefits for patient care. However, additional larger scale research is required to further develop the evidence base of indirect interventions for this setting.
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Pacientes Internados , Saúde Mental , Humanos , Intervenção Psicossocial , NarraçãoRESUMO
INTRODUCTION: The significance of endoplasmic reticulum (ER) stress in asthma is unclear. Here, we demonstrate that ER stress and the unfolded protein response (UPR) are related to disease severity and inflammatory phenotype. METHODS: Induced sputum (n=47), bronchial lavage (n=23) and endobronchial biopsies (n=40) were collected from participants with asthma with varying disease severity, inflammatory phenotypes and from healthy controls. Markers for ER stress and UPR were assessed. These markers were also assessed in established eosinophilic and neutrophilic murine models of asthma. RESULTS: Our results demonstrate increased ER stress and UPR pathways in asthma and these are related to clinical severity and inflammatory phenotypes. Genes associated with ER protein chaperone (BiP, CANX, CALR), ER-associated protein degradation (EDEM1, DERL1) and ER stress-induced apoptosis (DDIT3, PPP1R15A) were dysregulated in participants with asthma and are associated with impaired lung function (forced expiratory volume in 1 s) and active eosinophilic and neutrophilic inflammation. ER stress genes also displayed a significant correlation with classic Th2 (interleukin-4, IL-4/13) genes, Th17 (IL-17F/CXCL1) genes, proinflammatory (IL-1b, tumour necrosis factor α, IL-8) genes and inflammasome activation (NLRP3) in sputum from asthmatic participants. Mice with allergic airway disease (AAD) and severe steroid insensitive AAD also showed increased ER stress signalling in their lungs. CONCLUSION: Heightened ER stress is associated with severe eosinophilic and neutrophilic inflammation in asthma and may play a crucial role in the pathogenesis of asthma.
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Asma , Animais , Asma/metabolismo , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/patologia , Humanos , Inflamação/metabolismo , Camundongos , Neutrófilos/metabolismo , Transdução de Sinais , Resposta a Proteínas não DobradasRESUMO
BACKGROUND: Neutrophilic asthma (NA) is a clinically important asthma phenotype, the cellular and molecular basis of which is not completely understood. Airway macrophages are long-lived immune cells that exert important homeostatic and inflammatory functions which are dysregulated in asthma. Unique transcriptomic programmes reflect varied macrophage phenotypes in vitro. We aimed to determine whether airway macrophages are transcriptomically altered in NA. METHODS: We performed RNASeq analysis on flow cytometry-isolated sputum macrophages comparing NA (n = 7) and non-neutrophilic asthma (NNA, n = 13). qPCR validation of RNASeq results was performed (NA n = 13, NNA n = 23). Pathway analysis (PANTHER, STRING) of differentially expressed genes (DEGs) was performed. Gene set variation analysis (GSVA) was used to test for enrichment of NA macrophage transcriptomic signatures in whole sputum microarray (cohort 1 - controls n = 16, NA n = 29, NNA n = 37; cohort 2 U-BIOPRED - controls n = 16, NA n = 47, NNA n = 57). RESULTS: Flow cytometry-sorting significantly enriched sputum macrophages (99.4% post-sort, 44.9% pre-sort, p < .05). RNASeq analysis confirmed macrophage purity and identified DEGs in NA macrophages. Selected DEGs (SLAMF7, DYSF, GPR183, CSF3, PI3, CCR7, all p < .05 NA vs. NNA) were confirmed by qPCR. Pathway analysis of NA macrophage DEGs was consistent with responses to bacteria, contribution to neutrophil recruitment and increased expression of phagocytosis and efferocytosis factors. GSVA demonstrated neutrophilic macrophage gene signatures were significantly enriched in whole sputum microarray in NA vs. NNA and controls in both cohorts. CONCLUSIONS: We demonstrate a pathophysiologically relevant sputum macrophage transcriptomic programme in NA. The finding that there is transcriptional activation of inflammatory programmes in cell types other than neutrophils supports the concept of NA as a specific endotype.
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Asma , Transcriptoma , Asma/diagnóstico , Asma/genética , Humanos , Macrófagos , Neutrófilos , EscarroRESUMO
An emerging body of evidence suggests that diet plays an important role in both the development and management of asthma. The relationship between dietary intake and asthma risk has been explored in epidemiological studies, though intervention trials examining the effects of nutrient intake and dietary patterns on asthma management are scarce. Evidence for diets high in fruits and vegetables, antioxidants, omega-3 fatty acids and soluble fiber such as the Mediterranean diet is conflicting. However, some studies suggest that these diets may reduce the risk of asthma, particularly in young children, and could have positive effects on disease management. In contrast, a Westernized dietary pattern, high in saturated fatty acids, refined grains, and sugars may promote an inflammatory environment resulting in the onset of disease and worsening of asthma outcomes. This review will summarize the state of the evidence for the impact of whole dietary patterns, as well as individual nutrients, on the prevalence and management of asthma.
Assuntos
Asma , Ácidos Graxos Ômega-3 , Antioxidantes/uso terapêutico , Asma/epidemiologia , Asma/etiologia , Asma/terapia , Criança , Pré-Escolar , Ácidos Graxos , Ácidos Graxos Ômega-3/uso terapêutico , Humanos , Estado Nutricional , AçúcaresRESUMO
BACKGROUND: One of the opposing arguments to restricting or banning the sale of tobacco products stem from a perception that this would adversely impact on small retail stores that rely on tobacco sales for viability. It has also been argued that purchases of tobacco leads to unplanned purchasing of other items that yield income for small store owners. This study tested the veracity of these arguments in the Australian context. METHODS: Consumer intercept surveys (n=1487) were conducted outside a comprehensive sample of small stores (n=136) selling tobacco in lower socioeconomic suburbs. Data were collected over a 2-hour period outside each store using the same methodology (36% consumer response rate). Descriptive statistics examined the proportion of tobacco and non-tobacco purchases and most common products purchased. RESULTS: Purchasing tobacco was the primary motivation for store visits for only 3% of consumers. The vast majority of products purchased (92%) were not tobacco, with hot food, groceries and lottery tickets most frequent. Only 8% of consumers purchased tobacco. When unplanned purchasing patterns were compared, consumers' who purchased tobacco were no more likely to buy other products. CONCLUSION: Tobacco purchasing was rarely the reason for store visits, indicating that it is not a key driver of consumer foot traffic for small retailers. There was also no evidence that tobacco contributes to spontaneous purchases of other products that might bring retailers profit. Findings suggest that restricting the retail availability of tobacco would be unlikely to have a pronounced negative impact on small retail stores.
Assuntos
Nicotiana , Produtos do Tabaco , Humanos , Austrália , Comércio , Fatores SocioeconômicosRESUMO
BACKGROUND: The negative impact of caregiving on carers' physical and psychological wellbeing is well documented. Carers of mental health inpatients have particularly negative experiences and largely report being dissatisfied with how they and their loved one are treated during inpatient care. It remains unclear why, despite policies intended to improve inpatient experiences. A comprehensive review of carers' inpatient experiences is needed to understand carer needs. As such, we aimed to conduct a systematic review and thematic synthesis of carer experiences of inpatient mental health care. METHODS: We searched MEDLINE, PsycINFO, Embase and CINAHL for qualitative studies examining carer experiences of mental health inpatient care. Searches were supplemented by reference list screening and forward citation tracking of included studies. Results were synthesised using thematic synthesis. Our protocol was registered on PROSPERO (CRD42020197904) and our review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. FINDINGS: Twelve studies were included from 6 countries. Four themes were identified: the emotional journey of inpatient care; invisible experts; carer concerns about quality of care for their loved one; and relationships and partnership between carers, service users and staff. INTERPRETATION: Greater attention should be paid to ensure carers are well-supported, well-informed, and included in care. More emphasis must be placed on fostering positive relationships between carers, service users and staff and in facilitating continuity of care across inpatient and community services to provide carers with a sense of security and predictability. Further research is needed to explore differences in experiences based on carer and service user characteristics and global context, alongside co-production with carers to develop and evaluate future guidelines and policies.