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1.
PLoS Genet ; 15(7): e1008229, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31269066

RESUMO

While many disease-associated single nucleotide polymorphisms (SNPs) are associated with gene expression (expression quantitative trait loci, eQTLs), a large proportion of complex disease genome-wide association study (GWAS) variants are of unknown function. Some of these SNPs may contribute to disease by regulating gene splicing. Here, we investigate whether SNPs that are associated with alternative splicing (splice QTL or sQTL) can identify novel functions for existing GWAS variants or suggest new associated variants in chronic obstructive pulmonary disease (COPD). RNA sequencing was performed on whole blood from 376 subjects from the COPDGene Study. Using linear models, we identified 561,060 unique sQTL SNPs associated with 30,333 splice sites corresponding to 6,419 unique genes. Similarly, 708,928 unique eQTL SNPs involving 15,913 genes were detected at 10% FDR. While there is overlap between sQTLs and eQTLs, 55.3% of sQTLs are not eQTLs. Co-localization analysis revealed that 7 out of 21 loci associated with COPD (p<1x10-6) in a published GWAS have at least one shared causal variant between the GWAS and sQTL studies. Among the genes identified to have splice sites associated with top GWAS SNPs was FBXO38, in which a novel exon was discovered to be protective against COPD. Importantly, the sQTL in this locus was validated by qPCR in both blood and lung tissue, demonstrating that splice variants relevant to lung tissue can be identified in blood. Other identified genes included CDK11A and SULT1A2. Overall, these data indicate that analysis of alternative splicing can provide novel insights into disease mechanisms. In particular, we demonstrated that SNPs in a known COPD GWAS locus on chromosome 5q32 influence alternative splicing in the gene FBXO38.

2.
Hum Mol Genet ; 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-31152171

RESUMO

Many workers are daily exposed to occupational agents like gases/fumes, mineral dust or biological dust, which could induce adverse health effects. Epigenetic mechanisms, such as DNA methylation, have been suggested to play a role. We therefore aimed to identify differentially methylated regions (DMRs) upon occupational exposures in never-smokers and investigated if these DMRs associated with gene expression levels. To determine the effects of occupational exposures independent of smoking, 903 never-smokers of the LifeLines cohort study were included. We performed three genome-wide methylation analyses (Illumina 450 K), one per occupational exposure being gases/fumes, mineral dust and biological dust, using robust linear regression adjusted for appropriate confounders. DMRs were identified using comb-p in Python. Results were validated in the Rotterdam Study (233 never-smokers) and methylation-expression associations were assessed using Biobank-based Integrative Omics Study data (n = 2802). Of the total 21 significant DMRs, 14 DMRs were associated with gases/fumes and 7 with mineral dust. Three of these DMRs were associated with both exposures (RPLP1 and LINC02169 (2×)) and 11 DMRs were located within transcript start sites of gene expression regulating genes. We replicated two DMRs with gases/fumes (VTRNA2-1 and GNAS) and one with mineral dust (CCDC144NL). In addition, nine gases/fumes DMRs and six mineral dust DMRs significantly associated with gene expression levels. Our data suggest that occupational exposures may induce differential methylation of gene expression regulating genes and thereby may induce adverse health effects. Given the millions of workers that are exposed daily to occupational exposures, further studies on this epigenetic mechanism and health outcomes are warranted.

3.
Int J Methods Psychiatr Res ; : e1785, 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31206911

RESUMO

OBJECTIVES: If patients change their perspective due to treatment, this may alter the way they conceptualize, prioritize, or calibrate questionnaire items. These psychological changes, also called "response shifts," may pose a threat to the measurement of therapeutic change in patients. Therefore, it is important to test the occurrence of response shift in patients across their treatment. METHODS: This study focused on self-reported psychological distress/psychopathology in a naturalistic sample of 206 psychiatric outpatients. Longitudinal measurement invariance tests were computed across treatment in order to detect response shifts. RESULTS: Compared with before treatment, post-treatment psychopathology scores showed an increase in model fit and factor loading, suggesting that symptoms became more coherently interrelated within their psychopathology domains. Reconceptualization (depression/mood) and reprioritization (somatic and cognitive problems) response shift types were found in several items. We found no recalibration response shift. CONCLUSION: This study provides further evidence that response shift can occur in adult psychiatric patients across their mental health treatment. Future research is needed to determine whether response shift implies an unwanted potential bias in treatment evaluation or a desired cognitive change intended by treatment.

4.
Eur Respir J ; 54(1)2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31073081

RESUMO

Previous reports link differential DNA methylation (DNAme) to environmental exposures that are associated with lung function. Direct evidence on lung function DNAme is, however, limited. We undertook an agnostic epigenome-wide association study (EWAS) on pre-bronchodilation lung function and its change in adults.In a discovery-replication EWAS design, DNAme in blood and spirometry were measured twice, 6-15 years apart, in the same participants of three adult population-based discovery cohorts (n=2043). Associated DNAme markers (p<5×10-7) were tested in seven replication cohorts (adult: n=3327; childhood: n=420). Technical bias-adjusted residuals of a regression of the normalised absolute ß-values on control probe-derived principle components were regressed on level and change of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and their ratio (FEV1/FVC) in the covariate-adjusted discovery EWAS. Inverse-variance-weighted meta-analyses were performed on results from discovery and replication samples in all participants and never-smokers.EWAS signals were enriched for smoking-related DNAme. We replicated 57 lung function DNAme markers in adult, but not childhood samples, all previously associated with smoking. Markers not previously associated with smoking failed replication. cg05575921 (AHRR (aryl hydrocarbon receptor repressor)) showed the statistically most significant association with cross-sectional lung function (FEV1/FVC: pdiscovery=3.96×10-21 and pcombined=7.22×10-50). A score combining 10 DNAme markers previously reported to mediate the effect of smoking on lung function was associated with lung function (FEV1/FVC: p=2.65×10-20).Our results reveal that lung function-associated methylation signals in adults are predominantly smoking related, and possibly of clinical utility in identifying poor lung function and accelerated decline. Larger studies with more repeat time-points are needed to identify lung function DNAme in never-smokers and in children.

5.
BMJ Open ; 9(5): e025701, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31092647

RESUMO

INTRODUCTION: The Partners for Change Outcome Management System (PCOMS) is a client feedback-system built on two brief visual analogue self-report scales. Prior studies of PCOMS have found effects varying from significant positive to negative. Aims of present study are; to test the predicted beneficial impact of PCOMS, while accounting for methodological flaws in prior studies and to clarify under which circumstances the addition of PCOMS to therapy has a beneficial effect. METHODS AND ANALYSIS: This study focuses on patients applying for brief, time-limited treatments. Four centres will be randomised to either treatment as usual (TAU) or TAU with PCOMS. All participating patients will be assessed four times. The full staff in the experimental condition will be trained in PCOMS. In the second part of this study, all therapists in the PCOMS condition will fill in a questionnaire concerning the influence of regulatory focus, self-efficacy, external or internal feedback orientation and perceived feedback validity of PCOMS. Finally, patients in the PCOMS condition will be asked to give feedback through a structured interview.The primary outcome measure is the Outcome Questionnaire over the period from beginning to end of therapy. The Mental Health Continuum-Short Form and Consumer Quality Index are also completed. In the primary analysis, outcomes of the two treatment conditions on treatment outcome, patient satisfaction, costs, drop-out and duration will be examined with a three-level (within patient, between patients and between therapists) multilevel analysis. The DSM-classification, sex, education level, age of each patient and therapist factors will be included as covariates. ETHICS AND DISSEMINATION: The Medical Ethics Committee of the University of Twente approved this study (K15-11, METC Twente). Data will be included from 1 January 2016 to 1 July 2019. Study results will be disseminated through peer-reviewed journals and conferences. TRIAL REGISTRATION NUMBER: NTR5466; Pre-results.

6.
BMC Pulm Med ; 19(1): 58, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30845926

RESUMO

BACKGROUND: Airflow obstruction is a hallmark of chronic obstructive pulmonary disease (COPD), and is defined as either the ratio between forced expiratory volume in one second and forced vital capacity (FEV1/FVC) < 70% or < lower limit of normal (LLN). This study aimed to assess the overlap between genome-wide association studies (GWAS) on airflow obstruction using these two definitions in the same population stratified by smoking. METHODS: GWASes were performed in the LifeLines Cohort Study for both airflow obstruction definitions in never-smokers (NS = 5071) and ever-smokers (ES = 4855). The FEV1/FVC < 70% models were adjusted for sex, age, and height; FEV1/FVC < LLN models were not adjusted. Ever-smokers models were additionally adjusted for pack-years and current-smoking. The overlap in significantly associated SNPs between the two definitions and never/ever-smokers was assessed using several p-value thresholds. To quantify the agreement, the Pearson correlation coefficient was calculated between the p-values and ORs. Replication was performed in the Vlagtwedde-Vlaardingen study (NS = 432, ES = 823). The overlapping SNPs with p < 10- 4 were validated in the Vlagtwedde-Vlaardingen and Rotterdam Study cohorts (NS = 1966, ES = 3134) and analysed for expression quantitative trait loci (eQTL) in lung tissue (n = 1087). RESULTS: In the LifeLines cohort, 96% and 93% of the never- and ever-smokers were classified concordantly based on the two definitions. 26 and 29% of the investigated SNPs were overlapping at p < 0.05 in never- and ever-smokers, respectively. At p < 10- 4 the overlap was 4% and 6% respectively, which could be change findings as shown by simulation studies. The effect estimates of the SNPs of the two definitions correlated strongly, but the p-values showed more variation and correlated only moderately. Similar observations were made in the Vlagtwedde-Vlaardingen study. Two overlapping SNPs in never-smokers (NFYC and FABP7) had the same direction of effect in the validation cohorts and the NFYC SNP was an eQTL for NFYC-AS1. NFYC is a transcription factor that binds to several known COPD genes, and FABP7 may be involved in abnormal pulmonary development. CONCLUSIONS: The definition of airflow obstruction and the population under study may be important determinants of which SNPs are associated with airflow obstruction. The genes FABP7 and NFYC(-AS1) could play a role in airflow obstruction in never-smokers specifically.


Assuntos
Fator de Ligação a CCAAT/genética , Proteína 7 de Ligação a Ácidos Graxos/genética , Estudo de Associação Genômica Ampla , Doença Pulmonar Obstrutiva Crônica/genética , Fumar/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Volume Expiratório Forçado , Homologia de Genes/genética , Predisposição Genética para Doença , Humanos , Modelos Lineares , Modelos Logísticos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Fumar/efeitos adversos , Espirometria , Capacidade Vital , Adulto Jovem
7.
J Surg Oncol ; 119(7): 903-908, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30737791

RESUMO

BACKGROUND AND OBJECTIVES: Recent studies show that whole specimen intraoperative frozen section analysis (WIFSA) is a reliable method for margin analysis in basal cell carcinoma (BCC) and has low recurrence rates after five-years follow-up. There are no studies with longer follow-up. Our aim is to present long-term recurrence rates after WIFSA. MATERIALS AND METHODS: All patients with a facial BCC receiving excision with WIFSA between 1992 and 2007 were evaluated. Recurrence rates were examined for primary BCC (pBCC), recurrent BCCs (rBCC), and the different histological subtypes. The accuracy of WIFSA was assessed by comparing with formalin-fixed paraffin-embedded section analysis. RESULTS: A total of 1140 patients with 1265 BCCs underwent excision with WIFSA, with a median and maximum follow-up of 10 and 25.3 years, respectively. Of all tumors, 90.0% were primary. Excisions were radical after an average of 1.4 excision rounds;5, 10, and 15-year recurrence rates for pBCCs are 3.3%, 5.1%, and 7.3%, respectively. An aggressive growth pattern and rBCCs are associated with more recurrences. The accuracy of WIFSA is 98.4%. CONCLUSIONS: WIFSA provides a highly accurate analysis and has a low recurrence rate for primary BCCs. The increasing recurrence rates over time imply 5 years of follow-up may be insufficient.


Assuntos
Carcinoma Basocelular/patologia , Carcinoma Basocelular/cirurgia , Recidiva Local de Neoplasia/patologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Faciais/patologia , Neoplasias Faciais/cirurgia , Feminino , Seguimentos , Secções Congeladas/métodos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Monitorização Intraoperatória/métodos , Valor Preditivo dos Testes , Estudos Retrospectivos , Adulto Jovem
8.
Nat Genet ; 51(3): 494-505, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804561

RESUMO

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 × 10-8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.


Assuntos
Predisposição Genética para Doença/genética , Doença Pulmonar Obstrutiva Crônica/genética , Adulto , Idoso , Asma/genética , Estudos de Casos e Controles , Feminino , Expressão Gênica/genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fibrose Pulmonar/genética , Fumar/genética
9.
Eur Respir J ; 53(4)2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30679190

RESUMO

INTRODUCTION: Dynamic hyperinflation has been documented in asthma, yet its impact on overall health and daily life activities is unclear. We assessed the prevalence of dynamic hyperinflation in moderate to severe asthma and its relationship with the scores of a set of specific and general respiratory health questionnaires. METHODS: 77 nonsmoking asthma patients (Global Initiative for Asthma steps 4-5) were recruited consecutively and completed five questionnaires: Asthma Control Questionnaire, Clinical COPD (chronic obstructive pulmonary disease) Questionnaire, St George's Respiratory Questionnaire, London Chest Activity of Daily Living scale (LCADL) and Shortness of Breath with Daily Activities (SOBDA). Dynamic hyperinflation was defined as ≥10% reduction in inspiratory capacity induced by standardised metronome-paced tachypnoea. Associations between level of dynamic hyperinflation and questionnaire scores were assessed and adjusted for asthma severity. RESULTS: 81% (95% CI 71.7-89.4%) of patients showed dynamic hyperinflation. Higher levels of dynamic hyperinflation were related to poorer scores on all questionnaires (r=0.228-0.385, p<0.05). After adjustment for asthma severity, dynamic hyperinflation remained associated with poorer scores on LCADL (p=0.027) and SOBDA (p=0.031). CONCLUSION: Dynamic hyperinflation is associated with poorer overall health and impaired daily life activities, independent of asthma severity. Because of its major impact on everyday life activities, dynamic hyperinflation is an important target for treatment in asthma.

10.
Environ Int ; 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30449631

RESUMO

Respiratory symptoms are important indicators of respiratory diseases. Both genetic and environmental factors contribute to respiratory symptoms development but less is known about gene-environment interactions. We aimed to assess interactions between single nucleotide polymorphisms (SNPs) and occupational exposures on respiratory symptoms cough, dyspnea and phlegm. As identification cohort LifeLines I (n = 7976 subjects) was used. Job-specific exposure was estimated using the ALOHA + job exposure matrix. SNP-by-occupational exposure interactions on respiratory symptoms were tested using logistic regression adjusted for gender, age, and current smoking. SNP-by-exposure interactions with a p-value <10-4 were tested for replication in two independent cohorts: LifeLines II (n = 5260) and the Vlagtwedde-Vlaardingen cohort (n = 1529). The interaction estimates of the replication cohorts were meta-analyzed using PLINK. Replication was achieved when the meta-analysis p-value was <0.05 and the interaction effect had the same direction as in the identification cohort. Additionally, we assessed whether replicated SNPs associated with gene expression by analyzing if they were cis-acting expression quantitative trait loci (eQTL) in lung tissue. In the replication meta-analysis, sixteen out of 477 identified SNP-by-occupational exposure interactions had a p-value <0.05 and 9 of these interactions had the same direction as in the identification cohort. Several identified loci were plausible candidates for respiratory symptoms, such as TMPRSS9, SERPINH1, TOX3, and ARHGAP18. Three replicated SNPs were cis-eQTLs for FCER1A, CHN1, and TIMM13 in lung tissue. Taken together, this genome-wide SNP-by-occupational exposure interaction study in relation to cough, dyspnea, and phlegm identified several suggestive susceptibility genes. Further research should determine if these genes are true susceptibility loci for respiratory symptoms in relation to occupational exposures.

11.
Med Teach ; : 1-7, 2018 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-30394166

RESUMO

PURPOSE: To examine the associations between residents' personality traits, type of specialty, and symptoms of burnout. METHOD: A cross-sectional online survey among Dutch residents was conducted (see Supplementary Material ). The 20-item Dutch translation of the Maslach Burnout Inventory was used to ascertain burnout. Personality traits were assessed with the 44-item Dutch Big Five Inventory. Logistic regression analyses, including all five personality traits, were used to assess associations with burnout. Analyses were stratified by specialties. RESULTS: One thousand two hundred thirty one residents participated, 185 (15.0%) of whom met the criteria for burnout. Neuroticism was significantly associated with resident burnout in all specialties, more strongly in supportive (odds ratio (OR) 6.19, 95% CI 2.12-18.12) and surgical (OR 4.37, 95% CI 1.76-10.86) than in medical residents (OR 1.99, 95% CI 1.22-3.24). Extraversion was significantly associated with less burnout in surgical residents (OR 0.26, 95% CI 0.13-0.58). These findings remained highly significant after controlling for gender, overtime, autonomy at work, satisfaction between work and private life, and the perceived quality of the learning environment. CONCLUSIONS: Burnout risk was associated with personality traits in residents. Consistently, residents scoring high on neuroticism reported more burnout. Extraverted surgical residents were less susceptible to burnout. Residents scoring high on neuroticism may require more intense monitoring during their training years.

12.
Pediatr Dermatol ; 2018 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-30338542

RESUMO

BACKGROUND: Adherence to topical corticosteroids is low among atopic dermatitis patients and their parents. This can lead to treatment failure and decreased quality of life. OBJECTIVE: To assess and compare the worries and beliefs concerning topical corticosteroids among parents of children with atopic dermatitis, involved health care professionals, and between different professionals. Also, we identify factors associated with corticosteroid phobia (corticophobia) in professionals. METHODS: Parents and health care professionals were invited to complete a questionnaire about corticophobia (Topicop). Higher questionnaire scores, expressed as a percentage, indicate more severe corticophobia. Professionals were asked to answer the questions as though they were using topical corticosteroids on their own child. RESULTS: The scores for 29 parents and 31 public health care nurses were equal: 44%. The score for 51 general practitioners was 39%. The score for 33 public health care physicians and of 47 pediatricians was 31%. The differences between parents and these professionals were statistically significantly different (P = 0.001). Type of profession and having a child with atopic dermatitis were significantly associated factors for the score. CONCLUSION: Corticophobia is present among parents of children with atopic dermatitis and among health care professionals involved in caring for children with atopic dermatitis. Health care nurses express the same level of corticophobia as parents. The presence of corticophobia among health care professionals may affect parental perspectives and topical corticosteroids adherence negatively.

13.
Nat Commun ; 9(1): 2976, 2018 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-30061609

RESUMO

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.

14.
Lancet Psychiatry ; 5(7): 564-572, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29937396

RESUMO

BACKGROUND: Previous research suggests that the use of outcome feedback technology can enable psychological therapists to identify and resolve obstacles to clinical improvement. We aimed to assess the effectiveness of an outcome feedback quality assurance system applied in stepped care psychological services. METHODS: This multisite, open-label, cluster randomised controlled trial was done at eight National Health Service (NHS) Trusts in England, involving therapists who were qualified to deliver evidence-based low-intensity or high-intensity psychological interventions. Adult patients (18 years or older) who accessed individual therapy with participating therapists were eligible for inclusion, except patients who accessed group therapies and those who attended less than two individual therapy sessions. Therapists were randomly assigned (1:1) to an outcome feedback intervention group or a treatment-as-usual control group by use of a computer-generated randomisation algorithm. The allocation of patients to therapists was quasi-random, whereby patients on waiting lists were allocated sequentially on the basis of therapist availability. All patients received low-intensity (less than eight sessions) or high-intensity (up to 20 sessions) psychological therapies for the duration of the 1-year study period. An automated computer algorithm alerted therapists in the outcome feedback group to patients who were not on track, and primed them to review these patients in clinical supervision. The primary outcome was symptom severity on validated depression (Patient Health Questionnaire-9 [PHQ-9]) and anxiety (Generalised Anxiety Disorder-7 [GAD-7]) measures after treatment of varying durations, which were compared between groups with multilevel modelling, controlling for cluster (therapist) effects. We used an intention-to-treat approach. This trial was prospectively registered with ISRCTN, number ISRCTN12459454. FINDINGS: In total, 79 therapists were recruited to the study between Jan 8, 2016, and July 15, 2016, but two did not participate. Of these participants, 39 (51%) were randomly assigned to the outcome feedback group and 38 (49%) to the control group. Overall, 2233 patients were included in the trial (1176 [53%] were treated by therapists in the outcome feedback group, and 1057 [47%] by therapists in the control group). Patients classified as not on track had less severe symptoms after treatment if they were allocated to the outcome feedback group than those in the control group (PHQ-9 d=0·23, B=-1·03 [95% CI -1·84 to -0·23], p=0·012; GAD-7 d=0·19, B=-0·85 [-1·56 to -0·14], p=0·019). INTERPRETATION: Supplementing psychological therapy with low-cost feedback technology can reduce symptom severity in patients at risk of poor response to treatment. This evidence supports the implementation of outcome feedback in stepped care psychological services. FUNDING: English NHS and Department of Health Sciences, University of York, York, UK.

15.
Psychotherapy (Chic) ; 55(2): 151-163, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29863395

RESUMO

There is evidence that progress feedback combined with a clinical support tool (CST) improves treatment outcome in individual psychotherapy. This study examined the effect of feedback in combination with a CST in outpatient group psychotherapy. A prospective cohort study was performed with patients meeting diagnostic criteria for a major depressive disorder or an anxiety disorder. Patients received cognitive-behavioral group therapy or interpersonal group therapy and completed the Outcome Questionnaire-45 on a session by session basis. In the control cohort (N = 132), no feedback was provided. In the feedback cohort (N = 137), patients and clinicians received feedback on the treatment progress based on the Outcome Questionnaire-45. If a patient was deteriorating as compared with the start of treatment or the previous session, the CST was offered. Both cohorts showed a significant decrease in symptoms during therapy, but no significant differences existed on treatment outcome. The number of sessions was significantly lower in the feedback cohort. The results suggest that feedback in outpatient group psychotherapy does not improve outcomes but that fewer sessions may be sufficient to obtain outcomes similar to treatment as usual. More research with the use of progress feedback in outpatient group therapy is needed, especially with CSTs. (PsycINFO Database Record

16.
Hum Mol Genet ; 27(10): 1819-1829, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29547942

RESUMO

Causal genes of chronic obstructive pulmonary disease (COPD) remain elusive. The current study aims at integrating genome-wide association studies (GWAS) and lung expression quantitative trait loci (eQTL) data to map COPD candidate causal genes and gain biological insights into the recently discovered COPD susceptibility loci. Two complementary genomic datasets on COPD were studied. First, the lung eQTL dataset which included whole-genome gene expression and genotyping data from 1038 individuals. Second, the largest COPD GWAS to date from the International COPD Genetics Consortium (ICGC) with 13 710 cases and 38 062 controls. Methods that integrated GWAS with eQTL signals including transcriptome-wide association study (TWAS), colocalization and Mendelian randomization-based (SMR) approaches were used to map causality genes, i.e. genes with the strongest evidence of being the functional effector at specific loci. These methods were applied at the genome-wide level and at COPD risk loci derived from the GWAS literature. Replication was performed using lung data from GTEx. We collated 129 non-overlapping risk loci for COPD from the GWAS literature. At the genome-wide scale, 12 new COPD candidate genes/loci were revealed and six replicated in GTEx including CAMK2A, DMPK, MYO15A, TNFRSF10A, BTN3A2 and TRBV30. In addition, we mapped candidate causal genes for 60 out of the 129 GWAS-nominated loci and 23 of them were replicated in GTEx. Mapping candidate causal genes in lung tissue represents an important contribution to the genetics of COPD, enriches our biological interpretation of GWAS findings, and brings us closer to clinical translation of genetic associations.

17.
Occup Environ Med ; 75(6): 427-435, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29459480

RESUMO

OBJECTIVES: Occupational pesticide exposure is associated with a wide range of diseases, including lung diseases, but it is largely unknown how pesticides influence airway disease pathogenesis. A potential mechanism might be through epigenetic mechanisms, like DNA methylation. Therefore, we assessed associations between occupational exposure to pesticides and genome-wide DNA methylation sites. METHODS: 1561 subjects of LifeLines were included with either no (n=1392), low (n=108) or high (n=61) exposure to any type of pesticides (estimated based on current or last held job). Blood DNA methylation levels were measured using Illumina 450K arrays. Associations between pesticide exposure and 420 938 methylation sites (CpGs) were assessed using robust linear regression adjusted for appropriate confounders. In addition, we performed genome-wide stratified and interaction analyses by gender, smoking and airway obstruction status, and assessed associations between gene expression and methylation for genome-wide significant CpGs (n=2802). RESULTS: In total for all analyses, high pesticide exposure was genome-wide significantly (false discovery rate P<0.05) associated with differential DNA methylation of 31 CpGs annotated to 29 genes. Twenty of these CpGs were found in subjects with airway obstruction. Several of the identified genes, for example, RYR1, ALLC, PTPRN2, LRRC3B, PAX2 and VTRNA2-1, are genes previously linked to either pesticide exposure or lung-related diseases. Seven out of 31 CpGs were associated with gene expression levels. CONCLUSIONS: We show for the first time that occupational exposure to pesticides is genome-wide associated with differential DNA methylation. Further research should reveal whether this differential methylation plays a role in the airway disease pathogenesis induced by pesticides.

18.
Eur J Hum Genet ; 26(5): 709-722, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29422661

RESUMO

Chronic obstructive pulmonary disease (COPD) is a major health burden in adults and cigarette smoking is considered the most important environmental risk factor of COPD. Chromosome 15q25.1 locus is associated with both COPD and smoking. Our study aims at understanding the mechanism underlying the association of chromosome 15q25.1 with COPD through epigenetic and transcriptional variation in a population-based setting. To assess if COPD-associated variants in 15q25.1 are methylation quantitative trait loci, epigenome-wide association analysis of four genetic variants, previously associated with COPD (P < 5 × 10-8) in the 15q25.1 locus (rs12914385:C>T-CHRNA3, rs8034191:T>C-HYKK, rs13180:C>T-IREB2 and rs8042238:C>T-IREB2), was performed in the Rotterdam study (n = 1489). All four variants were significantly associated (P < 1.4 × 10-6) with blood DNA methylation of IREB2, CHRNA3 and PSMA4, of which two, including IREB2 and PSMA4, were also differentially methylated in COPD cases and controls (P < 0.04). Further additive and multiplicative effects of smoking were evaluated and no significant effect was observed. To evaluate if these four genetic variants are expression quantitative trait loci, transcriptome-wide association analysis was performed in 1087 lung samples. All four variants were also significantly associated with differential expression of the IREB2 3'UTR in lung tissues (P < 5.4 × 10-95). We conclude that regulatory mechanisms affecting the expression of IREB2 gene, such as DNA methylation, may explain the association between genetic variants in chromosome 15q25.1 and COPD, largely independent of smoking.

19.
Environ Health Perspect ; 126(2): 027004, 2018 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-29410382

RESUMO

BACKGROUND: Long-term air pollution exposure is negatively associated with lung function, yet the mechanisms underlying this association are not fully clear. Differential DNA methylation may explain this association. OBJECTIVES: Our main aim was to study the association between long-term air pollution exposure and DNA methylation. METHODS: We performed a genome-wide methylation study using robust linear regression models in 1,017 subjects from the LifeLines cohort study to analyze the association between exposure to nitrogen dioxide (NO2) and particulate matter (PM2.5, fine particulate matter with aerodynamic diameter ≤2.5 µm; PM10, particulate matter with aerodynamic diameter ≤10 µm) and PM2.5absorbance, indicator of elemental carbon content (estimated with land-use-regression models) with DNA methylation in whole blood (Illumina® HumanMethylation450K BeadChip). Replication of the top hits was attempted in two independent samples from the population-based Cooperative Health Research in the Region of Augsburg studies (KORA). RESULTS: Depending on the p-value threshold used, we found significant associations between NO2 exposure and DNA methylation for seven CpG sites (Bonferroni corrected threshold p<1.19×10-7) or for 4,980 CpG sites (False Discovery Rate<0.05). The top associated CpG site was annotated to the PSMB9 gene (i.e., cg04908668). None of the seven Bonferroni significant CpG-sites were significantly replicated in the two KORA-cohorts. No associations were found for PM exposure. CONCLUSIONS: Long-term NO2 exposure was genome-wide significantly associated with DNA methylation in the identification cohort but not in the replication cohort. Future studies are needed to further elucidate the potential mechanisms underlying NO2-exposure-related respiratory disease. https://doi.org/10.1289/EHP2045.

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