Objective: The present study examined the potential roles of externalizing and depressive co-occurring psychopathology on the time-course to anxiety treatment response among youth receiving different treatment conditions. Method: Participants were 488 youth (aged 7-17 years) who received either Cognitive-Behavioral Therapy (CBT) (N = 139), sertraline (SRT) (N = 133), CBT+sertraline (COMB; N = 140), or pill placebo (PLB; N = 76) in the Child/Adolescent Anxiety Multimodal Study (CAMS; Walkup et al., 2008). Results: Findings did not demonstrate a significant relation of comorbid psychopathology with treatment response time-course. Participants in CBT and SRT had significantly different overall treatment response trajectories, though comorbid psychopathology did not significantly relate to the observed treatment response trajectories. Exploratory analyses revealed that parental treatment assignment reaction to CBT was positively associated with more favorable treatment response time course, whereas parental treatment assignment reaction to SRT did not significantly relate to treatment response time course. Conclusions: Our results are consistent with the notion that current interventions (CBT, SRT) produce improvements that generalize across co-occurring depressive and externalizing psychopathology. Clinical implications for the treatment of anxious youth with regard to comorbidity and contextual factors are discussed and suggestions for future research are offered. / Psychology

Hepatitis C Virus (HCV) infects 170 million people worldwide. The current treatment regimen, which is combination therapy with pegylated interferon (PegIFN) and Ribavirin (Rib), cures only 50% of the patients infected with the most prevalent HCV genotype. Therefore, there is a pressing need to understand the molecular mechanism of interferon resistance and to develop a prognostic tool to predict who will respond to treatment before initiation of therapy. It has been firmly established that the virus-host interaction plays an important role in determining treatment outcomes. My thesis investigated the host factors that are involved in interferon resistance with an aim to provide insights into the molecular mechanism of IFN resistance. cDNA microarray analysis identified 18 differentially expressed hepatic genes from pretreatment liver tissues of responders (Rs) and non-responders (NRs). Based on the differential expression levels of these 18 genes, a prognostic tool was developed to predict who will respond to therapy, with a positive predicting value (PPV) of 96%. Most of these 18 genes are interferon stimulated genes (ISGs) and they are more highly expressed in NR livers, indicating that preactivation of interferon signaling in the pre-treatment liver tissues contributes to NR. 3 out of the 18 genes are involved in an ubiquitin-like ISG15/USP18 signaling pathway that plays an important role in interferon response. Over-expression of USP18 and ISG15 in the pretreatment liver tissues of NR promotes HCV production and blunts interferon anti-HCV activity. There exists a distinct cell-type specific ISG activation in the pretreatment liver tissues of Rs and NRs. Up-regulation of the two ISGs that I tested (ISG15 and MxA) was found mainly in hepatocytes in NRs while ISG activation was preferentially observed in macrophages in Rs. Taking all these data together, pre-activation of interferon signaling and cell-type specific gene activation in the pretreatment liver tissues of patients infected with HCV are associated with treatment non-response. HCV exploits the host interferon system to favour its persistence by enhanced replication /secretion stimulated by a few ISGs (ISG15, USP18) in response to IFN. The developed prognostic tool can be used to stratify patients for treatment and the novel insights of the molecular mechanism of IFN resistance in HCV patients offer potential drug targets for future development.

Submitted by Maria Aparecida (cidazen@gmail.com) on 2017-11-13T14:21:15Z No. of bitstreams: 1 Fábio Gomes Teixeira.pdf: 415617 bytes, checksum: 372db933a02a007f513b9a2d77a17362 (MD5) / Made available in DSpace on 2017-11-13T14:21:15Z (GMT). No. of bitstreams: 1 Fábio Gomes Teixeira.pdf: 415617 bytes, checksum: 372db933a02a007f513b9a2d77a17362 (MD5) Previous issue date: 2011-10-18 / Cohort study using retrospective data to evaluate the effectiveness of the treatment program for chronic hepatitis C in users of Farmácia Estadual de Medicamentos Excepcionais do Maranhão (FEME) to determine the rate of sustained virologic response (SVR) and correlate it with demographic, clinical, laboratory, histological and virological features of patients and to identify the rates of discontinuation of treatment. We analyzed data from 256 patients treated for chronic hepatitis C in FEME for the period January 2005 to July 2009, being an SVR by intention to treat 57%. Males predominated (66%). The mean age was 52.5 years, with a predominance of non-white individuals in relation to whites. Genotype 1 was the most common (77%) and 150 (58.6%) patients had viral load above 400,000 UI/ml. With respect to the treatment regimen, pegylated interferon associated with ribavirin was used by 80.5% of patients, the rate of discontinuation of treatment of 13,3%. They were identified as factors independently associated with SVR: white, non-cirrhotic, have not a genotype 1 and viral load below 400,000 IU / ml. These findings demonstrate the effectiveness of treatment provided by FEME, which makes it possible to cure most patients, preventing progression to end-stage liver disease and its disastrous consequences. The factors associated with SVR have seen in other studies, leads us to believe that the results are reliable and that the program is fulfilling the role it has set itself. / Estudo de coorte com dados retrospectivos com o objetivo de avaliar a efetividade do programa de tratamento da hepatite C crônica em usuários da Farmácia Estadual de Medicamentos Excepcionais do Maranhão (FEME), determinar a taxa de resposta virológica sustentada (RVS) e correlacioná-la com características demográficas, clínicas, laboratoriais, histológicas e virológicas dos pacientes, além de identificar as taxas de interrupção do tratamento. Foram analisados os dados de 256 pacientes, tratados para hepatite C crônica na FEME no período de Janeiro de 2005 a Julho de 2009, encontrando-se uma RVS por intenção de tratar de 57%. O sexo masculino foi predominante (66%). A média de idade encontrada foi de 52,5 anos, havendo predomínio de indivíduos não brancos em relação aos brancos. O genótipo 1 foi o mais comum (77%) e 150 (58,6%) pacientes apresentaram carga viral superior a 400.000 UI/ml. Com relação ao esquema de tratamento, o interferon peguilado associado ribavirina foi utilizado por 80,5% dos pacientes, sendo a taxa de interrupção do tratamento de 13,3%. Foram identificados como fatores independentemente associados à RVS : cor branca, não cirróticos, ter genótipo não 1 e carga viral abaixo de 400.000 UI/ml. Estes achados demonstram a efetividade do tratamento fornecido pela FEME, que possibilita a cura da maioria dos pacientes, prevenindo a progressão para doença hepática terminal e suas consequências desastrosas. A RVS associada a fatores já vistos em outros estudos, nos faz acreditar que os resultados são confiáveis e que o programa está cumprindo o papel a que se propôs.

Hepatitis C Virus (HCV) infects 170 million people worldwide. The current treatment regimen, which is combination therapy with pegylated interferon (PegIFN) and Ribavirin (Rib), cures only 50% of the patients infected with the most prevalent HCV genotype. Therefore, there is a pressing need to understand the molecular mechanism of interferon resistance and to develop a prognostic tool to predict who will respond to treatment before initiation of therapy. It has been firmly established that the virus-host interaction plays an important role in determining treatment outcomes. My thesis investigated the host factors that are involved in interferon resistance with an aim to provide insights into the molecular mechanism of IFN resistance. cDNA microarray analysis identified 18 differentially expressed hepatic genes from pretreatment liver tissues of responders (Rs) and non-responders (NRs). Based on the differential expression levels of these 18 genes, a prognostic tool was developed to predict who will respond to therapy, with a positive predicting value (PPV) of 96%. Most of these 18 genes are interferon stimulated genes (ISGs) and they are more highly expressed in NR livers, indicating that preactivation of interferon signaling in the pre-treatment liver tissues contributes to NR. 3 out of the 18 genes are involved in an ubiquitin-like ISG15/USP18 signaling pathway that plays an important role in interferon response. Over-expression of USP18 and ISG15 in the pretreatment liver tissues of NR promotes HCV production and blunts interferon anti-HCV activity. There exists a distinct cell-type specific ISG activation in the pretreatment liver tissues of Rs and NRs. Up-regulation of the two ISGs that I tested (ISG15 and MxA) was found mainly in hepatocytes in NRs while ISG activation was preferentially observed in macrophages in Rs. Taking all these data together, pre-activation of interferon signaling and cell-type specific gene activation in the pretreatment liver tissues of patients infected with HCV are associated with treatment non-response. HCV exploits the host interferon system to favour its persistence by enhanced replication /secretion stimulated by a few ISGs (ISG15, USP18) in response to IFN. The developed prognostic tool can be used to stratify patients for treatment and the novel insights of the molecular mechanism of IFN resistance in HCV patients offer potential drug targets for future development.

Complex regional pain syndrome (CRPS) is a chronic neuropathic pain disorder characterized by both central and peripheral symptoms that can be debilitating in children. CRPS treatment typically consists of intensive physical, occupational, and psychological therapy with evidence supporting the efficacy of this approach. Among these outcomes, some patients report significant improvements in pain while others report no change. Identifying baseline predictors of treatment resistance would refine our treatment approach and provide additional targets for intervention. The current study examined baseline brain structure via cortical thickness and gray matter volume (GMV) in 29 pediatric CRPS patients enrolled in an intensive pain rehabilitation program. All participants underwent MRI using a high-resolution T1-weighted sequence. Patients were categorized as pain treatment “responders” (n=19) or “non-responders” (n=10) based on change in reported pain levels from admission to follow up. Compared to treatment responders, non-responders demonstrated significantly less GMV in the bilateral nucleus accumbens p<0.05 and right: putamen p<0.01, pallidum p<0.05, and amygdala p<0.05. Furthermore, treatment non-responders exhibited significant cortical thickening in the left anterior insular cortex and medial frontal gyrus, and cortical thinning in the bilateral precentral gyrus and superior frontal gyrus; right: middle frontal gyrus, fusiform gyrus, inferior temporal gyrus, middle temporal gyrus, and anterior prefrontal cortex; and left: parahippocampal gyrus. Though we did see significant thinning of the primary motor cortex in treatment non-responders compared to responders, the majority of our findings were localized to regions associated with reward, motivation, learning, and emotion. We, therefore, postulate that treatment non-responders, when compared to responders, likely have an intrinsically reduced reward responsiveness, diminished motivation, and impaired learning, overall contributing to their negative treatment outcomes and chronification of pain. In conclusion, these baseline differences overall suggest these regional morphometric alterations may potentially serve as predictors of treatment response in pediatric CRPS. Furthermore, these areas may also indicate possible targets for future treatment.

No description available.

Background: The hepatitis B and D virus (HBV/HDV) hepatocyte entry inhibitor bulevirtide (BLV) has been available in Europe since July 2020, after the registrational trial MYR202. Real-life data on the efficacy and safety of BLV are sparse. Methods: We have analysed the course of treatment with BLV (2 mg/day) plus tenofovir disoproxil fumarate (TDF) (245 mg/day) in patients with chronic hepatitis delta (CHD). Virologic (≥2 log reduction in HDV RNA or suppression of HDV RNA below the lower limit of detection) and biochemical (normalisation of serum ALT) treatment responses after 24 weeks were defined according to the MYR202 trial. Results: Seven patients were recruited (four with liver cirrhosis Child–Pugh A). After 24 weeks, a virologic response was observed in five of seven and a biochemical response was seen in three of six patients with elevated serum ALT at baseline. Extended treatment data > 48 weeks were available in three cases: two presented with continuous virologic and biochemical responses and in one individual an HDV-RNA breakthrough was observed. Adverse effects were not recorded. Conclusions: The first real-life data of the approved dosage of 2 mg of BLV in combination with TDF confirm the safety, tolerability, and efficacy of the registrational trial MYR202 for a treatment period of 24 weeks and beyond.

Unexpected dramatic changes in psychotherapy have been observed historically and tied to high recovery rates. Many different methodologies that identify these changes are assumed to be capturing similar or identical phenomena. This study compared three methods – Sudden Gains (SG), Percentage Increase – 50% (PI-50%), and Rapid Response (RR) - in a large database looking for similarities and differences. Results suggest that there are significant differences between SG, RR, and PI-50 as methods for operationally defining unexpected dramatic treatment response, and caution should be used when referring to SG, PI-50, and RR as the same phenomenon or interchangeable terms for unexpected dramatic treatment response. In particular, overlap in clients who experienced both a SG and RR was low. Experiencing any of the three phenomenon was associated with higher recovery rates, while differences abound in both which clients experience each of the phenomena and demographic characteristics of those clients. PI-50 identified inconsequential amounts of clients suggesting under its current methodological construction it would have limited useability. These results tying SG, RR, and PI-50 to significant rates of recovery and positive treatment change suggest possible future use as a predictive feedback tool for clients and clinicians alike to be better able to examine the effectiveness of treatment components during treatment.

Cellular heterogeneity is regarded as a major factor for treatment response and resistance in a variety of malignant tumors, including malignant melanoma. More recent developments of single-cell sequencing technology provided deeper insights into this phenomenon. Single-cell data were used to identify prognostic subtypes of melanoma tumors, with a special emphasis on immune cells and fibroblasts in the tumor microenvironment. Moreover, treatment resistance to checkpoint inhibitor therapy has been shown to be associated with a set of differentially expressed immune cell signatures unraveling new targetable intracellular signaling pathways. Characterization of T cell states under checkpoint inhibitor treatment showed that exhausted CD8+ T cell types in melanoma lesions still have a high proliferative index. Other studies identified treatment resistance mechanisms to targeted treatment against the mutated BRAF serine/threonine protein kinase including repression of the melanoma differentiation gene microphthalmia-associated transcription factor (MITF) and induction of AXL receptor tyrosine kinase. Interestingly, treatment resistance mechanisms not only included selection processes of pre-existing subclones but also transition between different states of gene expression. Taken together, single-cell technology has provided deeper insights into melanoma biology and has put forward our understanding of the role of tumor heterogeneity and transcriptional plasticity, which may impact on innovative clinical trial designs and experimental approaches.

In this thesis, we developed prognostic models of clinical outcomes, specific to violent and criminal outcomes in psychiatry, and predictive models of treatment response at an individual level. Overall, we demonstrate that evidence-based risk factors, protective factors, and treatment status variables were able to prognosticate prospective physical aggression at an individual level; 2) prognostic models of clinical and violent outcomes in psychiatry have largely focused on clinical and sociodemographic variables, show similar performance between identifying true positives and true negatives, although the error rate of models are still high, and further refinement is needed; 3) within treatment response prediction models in MDD using EEG, greater performance was observed in predicting response to rTMS, relative to antidepressants, and across models, greater sensitivity (true positives), were observed relative to specificity (true negatives), suggesting that EEG prediction models thus far better identify non-responders than responders; and 4) across randomized clinical trials using data-driven biomarkers in predictive models, based on the consistency of performance across models with large sample sizes, the highest degree of evidence was in predicting response to sertraline and citalopram using fMRI features. / Dissertation / Doctor of Philosophy (PhD)