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1.
Artigo em Inglês | MEDLINE | ID: mdl-35050846

RESUMO

BACKGROUND: Longitudinal modelling of current wheezing identified similar phenotypes, but their characteristics often differ between studies. We propose that more comprehensive description of wheeze may better describe trajectories than binary information on presence/absence of wheezing. METHODS: We derived 6 multi-dimensional variables of wheezing spells from birth to adolescence (including duration, temporal sequencing, and the extent of persistence/recurrence). We applied Partition-Around-Medoids clustering on these variables to derive phenotypes in five birth cohorts. We investigated within- and between-phenotype differences compared to binary latent class analysis models (LCA-phenotypes), and ascertained associations of these phenotypes with asthma and lung function, and with polymorphisms in asthma loci 17q12-21 and CDHR3. FINDINGS: Analysis among 7719 participants with complete data identified 5 spell-based wheeze phenotypes with high degree of certainty: Never (NWZ-54.1%), Early-transient (ETW-23.7%), Late-onset (LOW-6.9%), Persistent (PEW-8.3%), and a novel phenotype, Intermittent wheeze (INT-6.9%). FEV1/FVC was lower in PEW and INT compared to ETW and LOW, and declined from age 8 years to adulthood in INT. 17q12-21 and CDHR3 polymorphisms were associated with higher odds of PEW and INT, but not ETW or LOW. LCA- and spell-based-phenotypes appeared similar, but within-phenotype individual trajectories and phenotype allocation differed substantially. The spell-based approach was much more robust in dealing with missing data, and the derived clusters more stable and internally homogenous. CONCLUSIONS: Modelling of spell variables identified a novel intermittent wheeze phenotype associated with lung function decline to early adulthood. Using multi-dimensional spells variables may better capture wheeze development and provide a more robust input for phenotype derivation.

2.
J Pers Med ; 12(1)2022 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-35055391

RESUMO

Genome-wide and epigenome-wide association studies have identified genetic variants and differentially methylated nucleotides associated with childhood asthma. Incorporation of such genomic data may improve performance of childhood asthma prediction models which use phenotypic and environmental data. Using genome-wide genotype and methylation data at birth from the Isle of Wight Birth Cohort (n = 1456), a polygenic risk score (PRS), and newborn (nMRS) and childhood (cMRS) methylation risk scores, were developed to predict childhood asthma diagnosis. Each risk score was integrated with two previously published childhood asthma prediction models (CAPE and CAPP) and were validated in the Manchester Asthma and Allergy Study. Individually, the genomic risk scores demonstrated modest-to-moderate discriminative performance (area under the receiver operating characteristic curve, AUC: PRS = 0.64, nMRS = 0.55, cMRS = 0.54), and their integration only marginally improved the performance of the CAPE (AUC: 0.75 vs. 0.71) and CAPP models (AUC: 0.84 vs. 0.82). The limited predictive performance of each genomic risk score individually and their inability to substantially improve upon the performance of the CAPE and CAPP models suggests that genetic and epigenetic predictors of the broad phenotype of asthma are unlikely to have clinical utility. Hence, further studies predicting specific asthma endotypes are warranted.

3.
iScience ; 25(1): 103672, 2022 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-34957382

RESUMO

Inflammatory cytokines and chemokines (CC) drive COVID-19 pathology. Yet, patients with similar circulating CC levels present with different disease severity. Here, we determined 171 microRNAomes from 58 hospitalized COVID-19 patients (Cohort 1) and levels of 25 cytokines and chemokines (CC) in the same samples. Combining microRNA (miRNA) and CC measurements allowed for discrimination of severe cases with greater accuracy than using miRNA or CC levels alone. Severity group-specific associations between miRNAs and COVID-19-associated CC (e.g., IL6, CCL20) or clinical hallmarks of COVID-19 (e.g., neutrophilia, hypoalbuminemia) separated patients with similar CC levels but different disease severity. Analysis of an independent cohort of 108 patients from a different center (Cohort 2) demonstrated feasibility of CC/miRNA profiling in leftover hospital blood samples with similar severe disease CC and miRNA profiles, and revealed CCL20, IL6, IL10, and miR-451a as key correlates of fatal COVID-19. These findings highlight that systemic miRNA/CC networks underpin severe COVID-19.

4.
Handb Exp Pharmacol ; 268: 313-329, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34085121

RESUMO

Asthma genes have been identified through a range of approaches, from candidate gene association studies and family-based genome-wide linkage analyses to genome-wide association studies (GWAS). The first GWAS of asthma, reported in 2007, identified multiple markers on chromosome 17q21 as associates of the childhood-onset asthma. This remains the best replicated asthma locus to date. However, notwithstanding undeniable successes, genetic studies have produced relatively heterogeneous results with limited replication, and despite considerable promise, genetics of asthma and allergy has, so far, had limited impact on patient care, our understanding of disease mechanisms, and development of novel therapeutic targets. The paucity of precise replication in genetic studies of asthma is partly explained by the existence of numerous gene-environment interactions. Another important issue which is often overlooked is that of time of the assessment of the primary outcome(s) and the relevant environmental exposures. Most large GWASs use the broadest possible definition of asthma to increase the sample size, but the unwanted consequence of this is increased phenotypic heterogeneity, which dilutes effect sizes. One way of addressing this is to precisely define disease subtypes (e.g. by applying novel mathematical approaches to rich phenotypic data) and use these latent subtypes in genetic studies.


Assuntos
Asma , Hipersensibilidade , Asma/genética , Criança , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Hipersensibilidade/genética
5.
ERJ Open Res ; 7(4)2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34881328

RESUMO

Background: The prevalences of obstructive and restrictive spirometric phenotypes, and their relation to early-life risk factors from childhood to young adulthood remain poorly understood. The aim was to explore these phenotypes and associations with well-known respiratory risk factors across ages and populations in European cohorts. Methods: We studied 49 334 participants from 14 population-based cohorts in different age groups (≤10, >10-15, >15-20, >20-25 years, and overall, 5-25 years). The obstructive phenotype was defined as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) z-score less than the lower limit of normal (LLN), whereas the restrictive phenotype was defined as FEV1/FVC z-score ≥LLN, and FVC z-score

6.
Sci Rep ; 11(1): 23741, 2021 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-34887467

RESUMO

The mechanisms explaining excess morbidity and mortality in respiratory infections among males are poorly understood. Innate immune responses are critical in protection against respiratory virus infections. We hypothesised that innate immune responses to respiratory viruses may be deficient in males. We stimulated peripheral blood mononuclear cells from 345 participants at age 16 years in a population-based birth cohort with three live respiratory viruses (rhinoviruses A16 and A1, and respiratory syncytial virus) and two viral mimics (R848 and CpG-A, to mimic responses to SARS-CoV-2) and investigated sex differences in interferon (IFN) responses. IFN-α responses to all viruses and stimuli were 1.34-2.06-fold lower in males than females (P = 0.018 - < 0.001). IFN-ß, IFN-γ and IFN-induced chemokines were also deficient in males across all stimuli/viruses. Healthcare records revealed 12.1% of males and 6.6% of females were hospitalized with respiratory infections in infancy (P = 0.017). In conclusion, impaired innate anti-viral immunity in males likely results in high male morbidity and mortality from respiratory virus infections.

7.
Clin Transl Allergy ; 11(9): e12076, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34841728

RESUMO

BACKGROUND: Respiratory symptoms are common in early life and often transient. It is difficult to identify in which children these will persist and result in asthma. Machine learning (ML) approaches have the potential for better predictive performance and generalisability over existing childhood asthma prediction models. This study applied ML approaches to predict school-age asthma (age 10) in early life (Childhood Asthma Prediction in Early life, CAPE model) and at preschool age (Childhood Asthma Prediction at Preschool age, CAPP model). METHODS: Clinical and environmental exposure data was collected from children enrolled in the Isle of Wight Birth Cohort (N = 1368, ∼15% asthma prevalence). Recursive Feature Elimination (RFE) identified an optimal subset of features predictive of school-age asthma for each model. Seven state-of-the-art ML classification algorithms were used to develop prognostic models. Training was performed by applying fivefold cross-validation, imputation, and resampling. Predictive performance was evaluated on the test set. Models were further externally validated in the Manchester Asthma and Allergy Study (MAAS) cohort. RESULTS: RFE identified eight and twelve predictors for the CAPE and CAPP models, respectively. Support Vector Machine (SVM) algorithms provided the best performance for both the CAPE (area under the receiver operating characteristic curve, AUC = 0.71) and CAPP (AUC = 0.82) models. Both models demonstrated good generalisability in MAAS (CAPE 8-year = 0.71, 11-year = 0.71, CAPP 8-year = 0.83, 11-year = 0.79) and excellent sensitivity to predict a subgroup of persistent wheezers. CONCLUSION: Using ML approaches improved upon the predictive performance of existing regression-based models, with good generalisability and ability to rule in asthma and predict persistent wheeze.

8.
Lancet Respir Med ; 2021 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-34843665

RESUMO

BACKGROUND: Spirometric restriction, defined as a reduced forced vital capacity (FVC) with a preserved FEV1/FVC ratio, is associated with increased respiratory and non-respiratory comorbidities and all-cause mortality in adulthood. Little is known about the early origins of this condition. We sought to identify early-life risk factors for spirometric restriction in adult life. METHODS: In this longitudinal, multicohort, population-based study, we used data from the Tucson Children's Respiratory Study (TCRS), which recruited 1246 healthy infants at birth between April 1980, and October 1984, in Tucson, AZ, USA. Questionnaires were answered by the primary caregiver at enrolment, immediately after the child's birth, and multiple follow-up questionnaires were completed through childhood and adulthood. At the age of 22, 26, 32, and 36 years, lung function was measured with spirometry. At each survey, three mutually exclusive spirometric patterns were defined: (1) normal (FEV1/FVC ≥10th percentile and FVC ≥10th percentile); (2) restrictive (FEV1/FVC ≥10th percentile and FVC <10th percentile); and (3) obstructive (FEV1/FVC <10th percentile, independent of FVC). Data on demographic features and parental health factors were collected from questionnaires; pregnancy and perinatal data (including nutritional problems) and birth measurements were obtained from medical records; and weight, height, and body-mass index (BMI) during childhood (age 6-16 years) were measured by study nurses. The associations between early-life risk factors and spirometric patterns were assessed by multivariate multinomial logistic regression analysis, adjusted for survey year, sex, and race-ethnicity. Significant risk factors were further tested for replication in the Swedish Child (Barn), Allergy, Milieu, Stockholm, Epidemiological (BAMSE; n=1817; spirometry surveys were done at age 24 years) survey and the UK Manchester Asthma and Allergy Study (MAAS; n=411; spirometry surveys were done at age 18 years) birth cohorts, and fixed-effect meta-analyses of relative risk ratios (RRRs) from multinomial logistic regression models were done to generate a pooled estimate of the effect across the three cohorts. Measurements of body composition (MAAS; n=365) and total lung capacity (TCRS; n=173 and MAAS; n=407) were also available for a subset of participants. FINDINGS: Of 1246 healthy infants included in TCRS, for the present study we included data for 652 participants who had at least one set of spirometry data, contributing up to 1668 observations. In the TCRS cohort, results from the multivariate models showed that maternal nutritional problems during pregnancy (RRR 2·48 [95% CI 1·30-4·76]; p=0·0062), being born small for gestational age (birthweight <10th percentile; 3·26 [1·34-7·93]; p=0·0093), and being underweight in childhood (BMI-for-age <5th percentile; 3·54 [1·35-9·26]; p=0·010) were independent predictors of spirometric restriction in adult life. Associations between being small for gestational age (p=0·0028) and underweight in childhood (p<0·0001) with adult spirometric restriction were supported by the results of meta-analysis of data from all three cohorts. In the MAAS cohort, having a low lean BMI (ie, <10th percentile) at age 11 years predicted adult (age 18 years) spirometric restriction (RRR 3·66 [1·48-9·02]; p=0·0048). These associations of spirometric restriction with small for gestational age, childhood underweight, and low lean BMI in childhood were verified in participants with spirometric restriction who had diminished total lung capacity, indicating that these factors specifically increase the risk of lung restriction. INTERPRETATION: Poor growth and nutritional deficits in utero and throughout childhood precede and predict the development of spirometric restriction in adult life. Strategies to improve prenatal and childhood growth trajectories could help to prevent spirometric restriction and its associated morbidity and mortality burden. FUNDING: National Institutes of Health.

9.
Nat Commun ; 12(1): 6618, 2021 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-34785669

RESUMO

Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema.

10.
Allergy ; 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34716996

RESUMO

BACKGROUND: The heterogeneity and lack of validation of existing severity scores for food allergic reactions limit standardization of case management and research advances. We aimed to develop and validate a severity score for food allergic reactions. METHODS: Following a multidisciplinary experts consensus, it was decided to develop a food allergy severity score (FASS) with ordinal (oFASS) and numerical (nFASS) formats. oFASS with 3 and 5 grades were generated through expert consensus, and nFASS by mathematical modeling. Evaluation was performed in the EuroPrevall outpatient clinic cohort (8232 food reactions) by logistic regression with request of emergency care and medications used as outcomes. Discrimination, classification, and calibration were calculated. Bootstrapping internal validation was followed by external validation (logistic regression) in 5 cohorts (3622 food reactions). Correlation of nFASS with the severity classification done by expert allergy clinicians by Best-Worst Scaling of 32 food reactions was calculated. RESULTS: oFASS and nFASS map consistently, with nFASS having greater granularity. With the outcomes emergency care, adrenaline and critical medical treatment, oFASS and nFASS had a good discrimination (receiver operating characteristic area under the curve [ROC-AUC]>0.80), classification (sensitivity 0.87-0.92, specificity 0.73-0.78), and calibration. Bootstrapping over ROC-AUC showed negligible biases (1.0 × 10-6 -1.23 × 10-3 ). In external validation, nFASS performed best with higher ROC-AUC. nFASS was strongly correlated (R 0.89) to best-worst scoring of 334 expert clinicians. CONCLUSION: FASS is a validated and reliable method to measure severity of food allergic reactions. The ordinal and numerical versions that map onto each other are suitable for use by different stakeholders in different settings.

11.
Healthcare (Basel) ; 9(8)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34442138

RESUMO

The research aim was to evaluate the rationale of undergraduate final-year student nurses to undertake paid clinical placements during COVID-19 (Wave 1). The nursing profession reacted innovatively to meet demands placed on the National Health Service during COVID-19. Temporary changes to professional regulation enabled final-year United Kingdom nursing students to voluntarily undertake paid placements in the National Health Service. Neither full-time employees nor full-time students, volunteers undertook a unique hybrid role bolstering the front-line health workforce. Using reflective qualitative inquiry, 17 volunteers evaluated reasoning for entering practice in acute hospitals. Online surveys based around the UK Nursing and Midwifery Council Competency Framework (NMC 2012) were completed weekly for 6 weeks. Data were thematically analysed. Six themes were identified, including sense of duty, and opting-in or out. These highlighted the importance of collaboration and the tripartite relationship between University, host and student during placement, and the influence of these on the learning experience. Several significant insights emerged for nurse education and curricula during pandemics related to patient safety, safety climate and governance. The insights were used to develop a "Student Nurses Placement Framework" with recommendations for Pre-During-Post placement, offering a guide for future nursing workforce recruitment and retention.

12.
J Allergy Clin Immunol Pract ; 9(12): 4243-4251.e7, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34303020

RESUMO

BACKGROUND: Asthma diagnostic guidelines require procedures with aerosol-generating potential (aerosol-generating procedures [AGPs]) to guide decision making. Restricted access to AGPs poses significant challenges in primary care and resource-poor countries, further amplified during the coronavirus disease 2019 pandemic. OBJECTIVE: To establish an approach to asthma diagnosis that does not require AGPs. METHOD: Symptomatic yet untreated (beyond as-required bronchodilator use) adults with clinician-suspected asthma and maximum 10 pack year smoking history were recruited. Clinical history, physical examination, spirometry with bronchodilator reversibility, home peak flow monitoring, and bronchial challenges were performed, and fractional exhaled nitric oxide and serum eosinophils measured. Tests were then repeated following treatment with inhaled corticosteroids before an asthma diagnosis was confirmed or refuted by an expert panel. RESULTS: A total of 65 adults (mean age, 34.8 ± 12.2 years) were recruited. Five were excluded as "unclassifiable," because of borderline results or missing data. Of the remainder, 36 were diagnosed with asthma and 24 were not. Using data from non-AGPs only (wheeze on auscultation and blood eosinophilia) and home peak flow variability, a "rule-in" diagnostic model provided comparable discriminative ability to the application of established guidelines. Clinical suspicion of asthma together with at least 1 positive non-AGP test result provided a sensitivity of 55%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 60%. Application of this model reduced the need for spirometry-based tests by one-third. CONCLUSIONS: The proposed diagnostic algorithm may be clinically useful in "ruling-in" asthma in adults when access to AGPs is limited. This algorithm is not suitable for those with low clinical probability, with a significant smoking history, or where alternative diagnoses are more likely. This pragmatic approach to asthma diagnosis merits prospective validation.

13.
Pediatr Allergy Immunol ; 32(8): 1824-1832, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34101271

RESUMO

BACKGROUND: Chemokines are important mediators in immune cell recruitment, contributing to allergy development. However, extensive studies of chemokines in the circulation in relation to the presence and development of allergic diseases remain scarce. Our aim was to investigate associations of circulating allergy-related chemokines with the development of asthma and sensitization cross-sectionally and longitudinally in a population-based cohort. METHODS: The chemokines CCL17, CCL22, CXCL10, CXCL11 and CCL18 were measured in plasma samples from children in the Manchester Asthma and Allergy Study. Samples were available from cord blood at birth (n = 376), age 1 (n = 195) and age 8 (n = 334). Cross-sectional and longitudinal association analyses were performed in relation to asthma and allergic sensitization, as well as allergic phenotype clusters previously derived using machine learning in the same study population. RESULTS: In children with asthma and/or allergic sensitization, CCL18 levels were consistently elevated at 1 and/or 8 years of ages. In a longitudinal model including information on asthma from 4 time points (5, 8, 11 and 16 years of ages), we observed a significant association between increasing CCL18 levels at age 1 and a higher risk of asthma from early school age to adolescence (OR = 2.9, 95% CI 1.1-7.6, p = .028). We observed similar associations in longitudinal models for allergic sensitization. Asthma later in life was preceded by increased CXCL10 levels after birth and decreased CXCL11 levels at birth. CONCLUSION: Elevated CCL18 levels throughout childhood precede the development of asthma and allergic sensitization. The Th1-associated chemokines CXCL10 and CXCL11 also associated with the development of both outcomes, with differential temporal effects.

14.
Food Chem ; 362: 129879, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34118511

RESUMO

Baked matrices, such as muffin, may help to promote tolerance to food allergens by modifying allergen structure, digestibility, and capacity to stimulate the immune responses. However, the impact of the muffin matrix on the bioaccessibility of allergens in the gastrointestinal tract is not well understood. Muffin containing egg and peanut was subjected to in vitro oral-gastro-duodenal digestion. During gastric digestion, the majority of the egg allergen Gal d 2 and the peanut allergens Ara h 1 and 3 were not bioaccessible. Subsequent duodenal digestion increased allergen bioaccessibility with Gal d 2 and the peanut allergen Ara h 2 proving highly resistant to digestion. The IgE reactivity of bioaccessible peanut allergens was retained to a greater extent than that of egg allergens after oral-gastric digestion. The starch and gluten-rich muffin matrix modifies allergen bioaccessiblity in a manner more similar to baked matrices such as bread, than low water activity matrices such as cookies.


Assuntos
Alérgenos/imunologia , Hipersensibilidade a Ovo , Imunoglobulina E/imunologia , Hipersensibilidade a Amendoim , Albuminas 2S de Plantas/imunologia , Antígenos de Plantas/imunologia , Arachis/química , Culinária , Digestão , Hipersensibilidade Alimentar , Humanos , Proteínas de Membrana/imunologia , Proteínas de Plantas/imunologia
15.
Med (N Y) ; 2(6): 720-735.e4, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-33821250

RESUMO

Background: Emerging studies indicate that some coronavirus disease 2019 (COVID-19) patients suffer from persistent symptoms, including breathlessness and chronic fatigue; however, the long-term immune response in these patients presently remains ill-defined. Methods: Here, we describe the phenotypic and functional characteristics of B and T cells in hospitalized COVID-19 patients during acute disease and at 3-6 months of convalescence. Findings: We report that the alterations in B cell subsets observed in acute COVID-19 patients were largely recovered in convalescent patients. In contrast, T cells from convalescent patients displayed continued alterations with persistence of a cytotoxic program evident in CD8+ T cells as well as elevated production of type 1 cytokines and interleukin-17 (IL-17). Interestingly, B cells from patients with acute COVID-19 displayed an IL-6/IL-10 cytokine imbalance in response to Toll-like receptor activation, skewed toward a pro-inflammatory phenotype. Whereas the frequency of IL-6+ B cells was restored in convalescent patients irrespective of clinical outcome, the recovery of IL-10+ B cells was associated with the resolution of lung pathology. Conclusions: Our data detail lymphocyte alterations in previously hospitalized COVID-19 patients up to 6 months following hospital discharge and identify 3 subgroups of convalescent patients based on distinct lymphocyte phenotypes, with 1 subgroup associated with poorer clinical outcome. We propose that alterations in B and T cell function following hospitalization with COVID-19 could affect longer-term immunity and contribute to some persistent symptoms observed in convalescent COVID-19 patients. Funding: Provided by UKRI, Lister Institute of Preventative Medicine, the Wellcome Trust, The Kennedy Trust for Rheumatology Research, and 3M Global Giving.

16.
Front Psychol ; 12: 554100, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33868064

RESUMO

Objective: There is a demonstrated link between the mental health and substance use comorbidities experienced by young adults, however the vast majority of psychological interventions are disorder specific. Novel psychological approaches that adequately acknowledge the psychosocial complexity and transdiagnostic needs of vulnerable young people are urgently needed. A modular skills-based program for emotion regulation and impulse control (ERIC) addresses this gap. The current one armed open trial was designed to evaluate the impact that 12 weeks exposure to ERIC alongside usual care had on young people's ability to regulate emotions, as well as examine potential moderating mechanisms. Methods: Seventy nine young people (50.6% male; M = 19.30; SD = 2.94) were enrolled to the 12 week intervention period. Twenty one practitioners from youth and community health services delivered relevant ERIC modules adjunct to usual care. Linear mixed effects regression (with random intercept) was used to examine change over time across the primary outcome of emotion dysregulation and secondary outcomes of depression, anxiety, stress, experiential avoidance and mindfulness. Moderation analyses were conducted to test whether the magnitude of change in emotion dysregulation moderated change over time in secondary outcomes. Results: Analyses revealed significant improvement in the primary outcome of emotion dysregulation with a moderate effect size (Mean Change = -10.24, 95% CI (-14.41, -6.06; Cohen's dav = -0.53), in addition to decreases in the secondary outcomes of depression, anxiety, stress and experiential avoidance. No improvements in mindfulness were reported. Moderation analyses revealed that the residualised change over time in emotion dysregulation moderated the change over time in symptoms of distress, depression, anxiety, stress, experiential avoidance, and mindfulness. Conclusion: Reductions in the severity of emotion dysregulation, depression, anxiety, stress and experiential avoidance are promising, and were evident despite the complexity of the participants and the diversity of the service setting. The improvements found in each outcome were only observed for those young people whose emotion regulation also improved, providing preliminary evidence for the role of emotion regulation as a key treatment target in this population.

17.
Thorax ; 76(6): 624-631, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33504564

RESUMO

Asthma is the most common chronic respiratory disease in the UK; however, the misdiagnosis rate is substantial. The lack of consistency in national guidelines and the paucity of data on the performance of diagnostic algorithms compound the challenges in asthma diagnosis. Asthma is a highly rhythmic disease, characterised by diurnal variability in clinical symptoms and pathogenesis. Asthma also varies day to day, seasonally and from year to year. As much as it is a hallmark for asthma, this variability also poses significant challenges to asthma diagnosis. Almost all established asthma diagnostic tools demonstrate diurnal variation, yet few are performed with standardised timing of measurements. The dichotomous interpretation of diagnostic outcomes using fixed cut-off values may further limit the accuracy of the tests, particularly when diurnal variability straddles cut-off values within a day, and careful interpretation beyond the 'positive' and 'negative' outcome is needed. The day-to-day and more long-term variations are less predictable and it is unclear whether performing asthma diagnostic tests during asymptomatic periods may influence diagnostic sensitivities. With the evolution of asthma diagnostic tools, home monitoring and digital apps, novel strategies are needed to bridge these gaps in knowledge, and circadian variability should be considered during the standardisation process. This review summarises the biological mechanisms of circadian rhythms in asthma and highlights novel data on the significance of time (the fourth dimension) in asthma diagnosis.


Assuntos
Asma/diagnóstico , Diagnóstico por Imagem/métodos , Processamento de Imagem Assistida por Computador/métodos , Humanos
18.
J Allergy Clin Immunol ; 147(1): 144-157, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32442646

RESUMO

BACKGROUND: Asthma is a complex disease with multiple phenotypes that may differ in disease pathobiology and treatment response. IL33 single nucleotide polymorphisms (SNPs) have been reproducibly associated with asthma. IL33 levels are elevated in sputum and bronchial biopsies of patients with asthma. The functional consequences of IL33 asthma SNPs remain unknown. OBJECTIVE: This study sought to determine whether IL33 SNPs associate with asthma-related phenotypes and with IL33 expression in lung or bronchial epithelium. This study investigated the effect of increased IL33 expression on human bronchial epithelial cell (HBEC) function. METHODS: Association between IL33 SNPs (Chr9: 5,815,786-6,657,983) and asthma phenotypes (Lifelines/DAG [Dutch Asthma GWAS]/GASP [Genetics of Asthma Severity & Phenotypes] cohorts) and between SNPs and expression (lung tissue, bronchial brushes, HBECs) was done using regression modeling. Lentiviral overexpression was used to study IL33 effects on HBECs. RESULTS: We found that 161 SNPs spanning the IL33 region associated with 1 or more asthma phenotypes after correction for multiple testing. We report a main independent signal tagged by rs992969 associating with blood eosinophil levels, asthma, and eosinophilic asthma. A second, independent signal tagged by rs4008366 presented modest association with eosinophilic asthma. Neither signal associated with FEV1, FEV1/forced vital capacity, atopy, and age of asthma onset. The 2 IL33 signals are expression quantitative loci in bronchial brushes and cultured HBECs, but not in lung tissue. IL33 overexpression in vitro resulted in reduced viability and reactive oxygen species-capturing of HBECs, without influencing epithelial cell count, metabolic activity, or barrier function. CONCLUSIONS: We identify IL33 as an epithelial susceptibility gene for eosinophilia and asthma, provide mechanistic insight, and implicate targeting of the IL33 pathway specifically in eosinophilic asthma.


Assuntos
Asma , Regulação da Expressão Gênica/imunologia , Predisposição Genética para Doença , Interleucina-33 , Polimorfismo de Nucleotídeo Único , Adulto , Asma/genética , Asma/imunologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Interleucina-33/genética , Interleucina-33/imunologia , Masculino , Pessoa de Meia-Idade
19.
Life Sci Alliance ; 3(12)2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33020210

RESUMO

Lung-resident macrophages are crucial to the maintenance of health and in the defence against lower respiratory tract infections. Macrophages adapt to local environmental cues that drive their appropriate function; however, this is often dysregulated in many inflammatory lung pathologies. In mucosal tissues, neuro-immune interactions enable quick and efficient inflammatory responses to pathogenic threats. Although a number of factors that influence the antimicrobial response of lung macrophages are known, the role of neuronal factors is less well understood. Here, we show an intricate circuit involving the neurotrophic factor, neurturin (NRTN) on human lung macrophages that dampens pro-inflammatory cytokine release and modulates the type of matrix metalloproteinases produced in response to viral stimuli. This circuit involves type 1 interferon-induced up-regulation of RET that when combined with the glial cell line-derived neurotrophic factor (GDNF) receptor α2 (GFRα2) allows binding to epithelial-derived NRTN. Our research highlights a non-neuronal immunomodulatory role for NRTN and a novel process leading to a specific antimicrobial immune response by human lung-resident macrophages.


Assuntos
Pulmão/imunologia , Macrófagos Alveolares/metabolismo , Neurturina/farmacologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Humanos , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos Alveolares/imunologia , Neurônios/metabolismo , Neurturina/metabolismo , Proteínas Proto-Oncogênicas c-ret/metabolismo , RNA Mensageiro/metabolismo , Viroses/imunologia , Viroses/metabolismo
20.
Sci Immunol ; 5(51)2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32943497

RESUMO

COVID-19 pathogenesis is associated with an exaggerated immune response. However, the specific cellular mediators and inflammatory components driving diverse clinical disease outcomes remain poorly understood. We undertook longitudinal immune profiling on both whole blood and peripheral blood mononuclear cells (PBMCs) of hospitalized patients during the peak of the COVID-19 pandemic in the UK. Here, we report key immune signatures present shortly after hospital admission that were associated with the severity of COVID-19. Immune signatures were related to shifts in neutrophil to T cell ratio, elevated serum IL-6, MCP-1 and IP-10, and most strikingly, modulation of CD14+ monocyte phenotype and function. Modified features of CD14+ monocytes included poor induction of the prostaglandin-producing enzyme, COX-2, as well as enhanced expression of the cell cycle marker Ki-67. Longitudinal analysis revealed reversion of some immune features back to the healthy median level in patients with a good eventual outcome. These findings identify previously unappreciated alterations in the innate immune compartment of COVID-19 patients and lend support to the idea that therapeutic strategies targeting release of myeloid cells from bone marrow should be considered in this disease. Moreover, they demonstrate that features of an exaggerated immune response are present early after hospital admission suggesting immune-modulating therapies would be most beneficial at early timepoints.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Imunidade Inata , Monócitos/imunologia , Pneumonia Viral/imunologia , Adulto , Idoso , Biomarcadores/sangue , COVID-19 , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Ciclo-Oxigenase 2/imunologia , Ciclo-Oxigenase 2/metabolismo , Progressão da Doença , Feminino , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Mediadores da Inflamação/sangue , Mediadores da Inflamação/imunologia , Antígeno Ki-67/imunologia , Antígeno Ki-67/metabolismo , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Estudos Prospectivos , SARS-CoV-2 , Índice de Gravidade de Doença , Reino Unido/epidemiologia
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