Contribuições para o entendimento da heterogeneidade na sintomatologia e nas taxas de tratamento do transtorno de déficit de atenção/hiperatividade

Transtorno de Déficit de Atenção/Hiperatividade (TDAH) é um transtorno neurodesenvolvimental prevalente que se caracteriza por sintomas de desatenção e/ou de hiperatividade/impulsividade inapropriados para a faixa etária do indivíduo, causando-lhe prejuízo. Apesar de ser um dos transtornos psiquiátricos mais pesquisados da literatura mundial, seguem existindo debates quanto à sua existência, sobre a existência de sub ou sobrediagnóstico do transtorno, assim como um sub ou sobretratamento farmacológico dos pacientes. Estes questionamentos são alavancados pela notória heterogeneidade do TDAH, cujas apresentações variam amplamente em razão de fatores etiológicos (genéticos e ambientais), perfis e gravidade de comorbidades, evolução de sintomas ao longo do tempo, e resposta às terapias farmacológicas ou não farmacológicas. Neste trabalho, buscamos contribuir para o entendimento da heterogeneidade do TDAH, abordando a psicometria de seus sintomas sob a ótica das análises de rede e abordando a questão do sub ou sobretratamento do TDAH em nível mundial por meio de uma metanálise. Munidos das últimas atualizações e desenvolvimentos no campo de Análise de Redes, avaliamos as inter-relações de sintomas de TDAH e comparamos as estruturas de sintomas em diferentes contextos etários e amostrais. Além disso, abordamos a questão de sub e sobretratamento medicamentoso do transtorno em crianças e adolescentes através de uma revisão sistemática e metanálise de todos os estudos na literatura que avaliam o tratamento farmacológico do TDAH. Para tal, incluímos estudos baseados em prescrições, questionamentos ou registros em prontuários, de pacientes avaliados direta ou indiretamente para o diagnóstico ou ausência de diagnóstico de TDAH. As análises de rede demonstraram um bom agrupamento dos sintomas sob o formato bidimensional típico do TDAH. Os testes de estabilidade indicaram que somente o índice de força foi estável o suficiente para avaliação e, mesmo assim, apresentou alta variabilidade dentre sintomas de acordo com o contexto amostral. Encontraram-se diferenças estruturais e globais entre as amostras de crianças e adultos. Nossos achados condizem com estudos psicométricos clássicos, corroborando a alta heterogeneidade sintomática do TDAH. Os achados reforçam a importância de aplicar análises de estabilidade de rede antes de interpretações dos achados em estudos subsequentes. Apontamos diferenças nesta nova abordagem que podem contribuir para o entendimento do transtorno e para o desenvolvimento futuro de novas estratégias diagnósticas. A revisão sistemática e metanálise de toda a literatura disponível a respeito de tratamento farmacológico do TDAH focou-se primeiramente em amostras de crianças e adolescentes que usaram métodos validados de diagnóstico. Nestes, 19,1% (IC 95%: 11,5 - 29,9) dos diagnosticados com TDAH recebem tratamento farmacológico, enquanto 0,9% (IC 95%: 0,5 - 1,7) dos que possuem diagnóstico negativo também recebem tratamento farmacológico para o TDAH. Encontramos alta heterogeneidade, conforme esperado, influenciada principalmente pela avaliação da qualidade, país e desenho dos estudos incluídos. Nossos achados demonstram claramente a existência concomitante dos fenômenos de sub e sobretratamento do Transtorno de Déficit de Atenção/Hiperatividade e que tais estão presentes difusamente por países culturalmente distintos.Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention and/or hyperactivity/impulsivity, causing impairment. Albeit being one of the world's most studied psychiatric disorders, controversies remain regarding the existence of the disorder, it's under or over diagnosis, as well as under or over treatment of affected ones. Such controversies are fueled by ADHD's notorious heterogeneity, as presentation of the disorder is highly variable by function of etiological factors (genetic or environmental), profiles and severity of comorbidities, evolution of symptoms through lifespan, and response to pharmacological and nonpharmacological therapies. In this work, we aim to contribute to the understanding of ADHD's heterogeneity, addressing its symptoms psychometrics under the perspective of network analysis, and addressing the issue of under or overtreatment of ADHD worldwide through a meta-analysis. Armed with the last updates and developments in the Network Analysis field, we evaluate the inter-relations between ADHD symptoms and compare symptom structure in different age and sampling contexts. Furthermore, we evaluate the issue of ADHD's pharmacological under or over treatment among children and adolescents through a systematic review and meta-analysis of all available studies in the literature evaluating pharmacological treatment of ADHD. We included studies based on prescriptions, questioning or medical registry, of patients directly or indirectly screened for ADHD diagnosis or its absence. The network analysis demonstrated a good cluster of symptoms under the typical bidimensional structure of ADHD. Stability tests indicated that strength was the single measurement stable for evaluation, and even such measurement presented high variability according to sampling contexts. Comparative analysis demonstrated structural variability between youth and adult samples. Our findings agree with classical psychometric studies, confirming the high symptomatological heterogeneity of ADHD. The findings reinforce the importance of applying stability analysis of networks before inferences over findings in subsequent studies. We indicate differences in this new approach that might contribute to the understanding of the disorder and future development of new diagnostic strategies. The systematic review and meta-analysis of all available literature on the pharmacological treatment of ADHD focused primarily on children and adolescents identified through validated diagnostic methods. Among those, 19,1% (CI 95%: 11,5 - 29,9) of diagnosed individuals received pharmacological treatment, while 0,9% (CI 95%: 0,5 - 1,7) of those with a negative diagnosis were also receiving pharmacological treatment for ADHD. We found high heterogeneity among studies as predicted, influenced mainly by the quality of assessment, country of origin and study design. Our findings demonstrate a clear coexistence of the phenomena of undertreatment and overtreatment of ADHD, and such are present across distinct countries

Exploring the association between attention-deficit/hyperactivity disorder and entrepreneurship

Objective: To investigate the association between attention-deficit/hyperactivity disorder (ADHD) symptoms and entrepreneurial profiles and the effects of entrepreneurial characteristics in individuals who screen positive for ADHD and self-identify as entrepreneurs. Methods: We sent 4,341 questionnaires by e-mail to applicants for a career development course for entrepreneurs. We used the propensity score covariate adjustment to balance differences between included and excluded individuals. ADHD symptoms were evaluated with the Adult ADHD Self-Report Scale. The Individual Entrepreneurial Orientation scale was used to assess the entrepreneurial profile of the participants. Impairment from ADHD symptoms was assessed with the Barkley Functional Impairment Scale. Results: Those who screened positive for ADHD had higher risk-taking scores (p-value = 0.016) and lower proactivity (p-value = 0.001) than those who screened negative. Higher inattention scores were related to lower proactivity (p-value o 0.001), while higher hyperactive symptom scores were related to a more generalized entrepreneurial profile (p-value = 0.033). Among ADHD-positive participants, entrepreneurial profile scores were not significantly associated with company profits or impairment. Conclusion: Inattention symptoms were related to less proactivity, whereas hyperactive symptoms were positively associated with a general entrepreneurial orientation. ADHD-positive individuals had a higher risk-taking profile, and these characteristics did not negatively impact their lives

Combinatory effect of BRCA1 and HERC2 expression on outcome in advanced non-small-cell lung cancer

BACKGROUND: BRCA1 is a main component of homologous recombination and induces resistance to platinum in preclinical models. It has been studied as a potential predictive marker in lung cancer. Several proteins modulate the function of BRCA1. The E3 ubiquitin ligase HERC2 facilitates the assembly of the RNF8-UBC13 complex to recruit BRCA1 to DNA damage sites. The combined analysis of multiple components of the pathway leading to the recruitment of BRCA1 at DNA damage sites has the potentiality to improve the BRCA1 predictive model. METHODS: We retrospectively analyzed 71 paraffin-embedded tumor samples from advanced non-small-cell lung cancer patients treated with first-line platinum based chemotherapy and measured the mRNA expression levels of BRCA1, RNF8, UBC13 and HERC2 using real-time PCR. The mRNA expression was categorized using median value as cut-off point. RESULTS: The median progression-free survival of all 71 patients was 7.2 months whereas the median overall survival of the study population was 10.7 months. Among patients with low BRCA1 expression, the median PFS was 7.4 months in the presence of low HERC2 levels and 5.9 months for patients expressing high HERC2 levels (p\u2009=\u20090.01). The median OS was 15.3 months for patients expressing low levels of both genes and 7.4 months for those with low BRCA1 but high HERC2 (p\u2009=\u20090.008). The multivariate analysis showed that among patients with Eastern Cooperative Oncology Group performance status 0-1, the combined low expression of both BRCA1 and HERC2 clearly reduced the risk of progression (p\u2009=\u20090.03) and of death (p\u2009=\u20090.004). CONCLUSIONS: These findings confirm the potentiality of integrated DNA repair components analysis in predicting the sensitivity to platinum in lung cancer. The study indicates a predictive role for HERC2 mRNA expression and paves the way for further refinement of the BRCA1 predictive model

BRCA1, LMO4, and CtIP mRNA Expression in Erlotinib-Treated Non–Small-Cell Lung Cancer Patients with EGFR Mutations

IntroductionLung adenocarcinoma patients harboring EGFR activating mutations attain improved progression-free survival (PFS) with treatment with epidermal growth factor receptor tyrosine kinase inhibitors. However, patients ultimately relapse, indicating that other genetic factors could influence outcome in such patients. We hypothesized that PFS could be influenced by the expression of genes in DNA repair pathways.MethodsWe examined the mRNA expression of C terminus-binding protein–interacting protein and Lin11, Isl-1, and Mec-3 domain only 4 (LMO4) in pretreatment tumor samples from 91 erlotinib-treated advanced non–small-cell lung cancer patients with EGFR mutations in whom breast cancer gene 1 (BRCA1) expression and the concomitant presence of the EGFR T790M mutation had previously been assessed. Gene expression was analyzed by polymerase chain reaction, using β-actin as endogenous gene. Results were correlated with PFS and overall survival.ResultsIn patients with low LMO4 levels, PFS was 13 months, whereas it was not reached for those with high LMO4 levels (p = 0.03). In patients with low levels of both BRCA1 and LMO4, PFS was 19 months whereas it was not reached in those with low BRCA1 and high LMO4 mRNA levels (p = 0.04). In patients with high BRCA1 and low LMO4 levels, PFS was 8 months, whereas it was 18 months in those with high levels of both genes (p = 0.03).ConclusionsLow BRCA1 and high LMO4 levels were associated with longer PFS to erlotinib. Baseline assessment of BRCA1 and LMO4 mRNA expression can help predict outcome to erlotinib

Detection of EGFR mutations with mutation-specific antibodies in stage IV non-small-cell lung cancer

<p>Abstract</p> <p>Background</p> <p>Immunohistochemistry (IHC) with mutation-specific antibodies may be an ancillary method of detecting EGFR mutations in lung cancer patients.</p> <p>Methods</p> <p>EGFR mutation status was analyzed by DNA assays, and compared with IHC results in five non-small-cell lung cancer (NSCLC) cell lines and tumor samples from 78 stage IV NSCLC patients.</p> <p>Results</p> <p>IHC correctly identified del 19 in the H1650 and PC9 cell lines, L858R in H1975, and wild-type EGFR in H460 and A549, as well as wild-type EGFR in tumor samples from 22 patients. IHC with the mAb against EGFR with del 19 was highly positive for the protein in all 17 patients with a 15-bp (ELREA) deletion in exon 19, whereas in patients with other deletions, IHC was weakly positive in 3 cases and negative in 9 cases. IHC with the mAb against the L858R mutation showed high positivity for the protein in 25/27 (93%) patients with exon 21 EGFR mutations (all with L858R) but did not identify the L861Q mutation in the remaining two patients.</p> <p>Conclusions</p> <p>IHC with mutation-specific mAbs against EGFR is a promising method for detecting EGFR mutations in NSCLC patients. However these mAbs should be validated with additional studies to clarify their possible role in routine clinical practice for screening EGFR mutations in NSCLC patients.</p

BIM and mTOR expression levels predict outcome to erlotinib in EGFR-mutant non-small-cell lung cancer

Altres ajuts: Fellowship Award of the International Association for the Study of Lung Cancer i grant of the Italian Association for Cancer Research (AIRC My First AIRC Grant n° 14282).Abstract.BIM is a proapoptotic protein that initiates apoptosis triggered by EGFR tyrosine kinase inhibitors (TKI). mTOR negatively regulates apoptosis and may influence response to EGFR TKI. We examined mRNA expression of BIM and MTOR in 57 patients with EGFR-mutant NSCLC from the EURTAC trial. Risk of mortality and disease progression was lower in patients with high BIM compared with low/intermediate BIM mRNA levels. Analysis of MTOR further divided patients with high BIM expression into two groups, with those having both high BIM and MTOR experiencing shorter overall and progression-free survival to erlotinib. Validation of our results was performed in an independent cohort of 19 patients with EGFR-mutant NSCLC treated with EGFR TKIs. In EGFR-mutant lung adenocarcinoma cell lines with high BIM expression, concomitant high mTOR expression increased IC50 of gefitinib for cell proliferation. We next sought to analyse the signalling pattern in cell lines with strong activation of mTOR and its substrate P-S6. We showed that mTOR and phosphodiesterase 4D (PDE4D) strongly correlate in resistant EGFR-mutant cancer cell lines. These data suggest that the combination of EGFR TKI with mTOR or PDE4 inhibitors could be adequate therapy for EGFR-mutant NSCLC patients with high pretreatment levels of BIM and mTOR