A framework for young people with neurodisability who engage in antisocial behaviour: Introducing the PAM-NEXT

<p>In recent times there has been greater recognition of the over representation of young people with neurodisability within youth justice systems worldwide. This poses a problem for practitioners and suggests that current treatments based on addressing dynamic risk factors may be inadequate for addressing the needs of this group. This thesis elucidates these challenges and extends the Predictive Agency Model (PAM; Heffernan & Ward, 2017) into the Predictive Agency Model-Neurodisability Extension (PAM-NEXT). This extension considers how neurodisability can contribute to a maladaptive developmental history for young people which, in some cases, can lead to exposure to dynamic risk factors. The PAM-NEXT provides a framework to consider how these factors can be operationalised within the process of antisocial behaviour for young people with neurodisabilities. The PAM-NEXT is then applied to composite cases of young people who have engaged in antisocial behaviour to demonstrate its utility. Lastly the PAM-NEXT is evaluated and future directions discussed. The PAM-NEXT can provide practitioners options to adequately target treatment for young people with neurodisability who engage in antisocial behaviour.</p>

A framework for young people with neurodisability who engage in antisocial behaviour: Introducing the PAM-NEXT

<p>In recent times there has been greater recognition of the over representation of young people with neurodisability within youth justice systems worldwide. This poses a problem for practitioners and suggests that current treatments based on addressing dynamic risk factors may be inadequate for addressing the needs of this group. This thesis elucidates these challenges and extends the Predictive Agency Model (PAM; Heffernan & Ward, 2017) into the Predictive Agency Model-Neurodisability Extension (PAM-NEXT). This extension considers how neurodisability can contribute to a maladaptive developmental history for young people which, in some cases, can lead to exposure to dynamic risk factors. The PAM-NEXT provides a framework to consider how these factors can be operationalised within the process of antisocial behaviour for young people with neurodisabilities. The PAM-NEXT is then applied to composite cases of young people who have engaged in antisocial behaviour to demonstrate its utility. Lastly the PAM-NEXT is evaluated and future directions discussed. The PAM-NEXT can provide practitioners options to adequately target treatment for young people with neurodisability who engage in antisocial behaviour.</p>

A platform of patient-derived microtumors identifies treatment response and therapeutic vulnerabilities of ovarian cancer

Ovarian cancer (OvCa) is an insidious disease: due to nonspecific symptoms, these tumors are usually diagnosed at advanced stage with correspondingly devastating consequences for treatment outcome and patient survival. The broad heterogeneity of OvCa manifests itself in the complex composition of the tumor microenvironment. Given the frequent development of therapeutic resistance, there is a strong need for model systems accurately representing OvCa heterogeneity, while enabling parallel drug testing and prediction of appropriate treatment responses in individual patients. Here, we demonstrate the efficient isolation of highly viable OvCa patient-derived microtumors (OvCa PDM). Importantly, our data demonstrate histopathological comparability of OvCa PDM with corresponding patient tumor tissue. Reverse phase protein array (RPPA)-based analyses of >110 total and phospho-proteins enabled the identification of sensitivities to standard, platinum-based as well as experimental, selumetinib-based therapy, and thereby the prediction of treatment-responder. Parallelized drug testing in OvCa PDM allowed functional validation of RPPA data and detection of on- and off-target treatment effects. Strikingly, clinical follow-up of corresponding patients confirmed significantly increased metastasis-free survival of identified carboplatin-responder. Furthermore, flow cytometry-based characterization of autologous TIL populations confirmed the presence of tumor-specific, cytotoxic TILs with stem-like CD39-PD1+ and terminally differentiated CD39+PD1+ phenotypes. Interestingly, our results showed a significant correlation between the presence of CD8+CD39+ Tils and lymph node metastasis in the associated patients. Finally, combining OvCa PDM and autologous TILs for efficacy testing of immune checkpoint inhibitors demonstrated the potential for patient-specific enhancement of cytotoxic TIL activity by this therapeutic approach.

Comparison of Effectiveness of Phonological and Whole-Word Treatment Programmes within Two Dyslexia Subtypes

<p>This thesis compares the effectiveness of two reading treatment programmes, each developed to address the key difficulties of two subtypes of developmental dyslexia - phonological and surface dyslexia, respectively. Previous cognitive neuropsychological research has commonly administered a single tailored treatment programme to each individual. However, this research administers both programmes to individuals from each subtype, and compares their effectiveness. In Experiment 1, a large group of reading-delayed children was screened, and, using Coltheart and Leahy's (1996) criteria, three children were identified as surface dyslexic and seven as phonological dyslexic. All were aged between 9 and 13 years. Following completion of a range of background tests to assess cognitive abilities potentially correlated with dyslexia, each child received two treatment programmes: 1) a phonologically-based programme training grapheme-to-phoneme correspondences (based on Broom and Doctor, 1995b) and 2) a whole-word programme (specifically designed for the current research), with pre- and post-tests throughout. Results indicated that all children significantly improved their reading of the trained words following both training programmes, regardless of subtype. For both subtypes, generalisation to untrained words was observed following the Phonological Programme, but not the Whole-word Programme. In Experiment 2, a second, more case-based investigation was conducted, focussing on one phonological dyslexic and one surface dyslexic, who were selected following extensive screening. Both were aged 10 years 11 months. Experiment 2 also examined the effectiveness of specific whole-word techniques. Results indicated a clear distinction between the responsiveness of the two participants, with each favouring their target treatment programme: the Phonological Programme was more effective for the phonological dyslexic than the Whole-word Programme, and vice versa for the surface dyslexic. The implications are discussed, with particular reference to suggestions for remediating reading disorders.</p>

Comparison of Effectiveness of Phonological and Whole-Word Treatment Programmes within Two Dyslexia Subtypes

<p>This thesis compares the effectiveness of two reading treatment programmes, each developed to address the key difficulties of two subtypes of developmental dyslexia - phonological and surface dyslexia, respectively. Previous cognitive neuropsychological research has commonly administered a single tailored treatment programme to each individual. However, this research administers both programmes to individuals from each subtype, and compares their effectiveness. In Experiment 1, a large group of reading-delayed children was screened, and, using Coltheart and Leahy's (1996) criteria, three children were identified as surface dyslexic and seven as phonological dyslexic. All were aged between 9 and 13 years. Following completion of a range of background tests to assess cognitive abilities potentially correlated with dyslexia, each child received two treatment programmes: 1) a phonologically-based programme training grapheme-to-phoneme correspondences (based on Broom and Doctor, 1995b) and 2) a whole-word programme (specifically designed for the current research), with pre- and post-tests throughout. Results indicated that all children significantly improved their reading of the trained words following both training programmes, regardless of subtype. For both subtypes, generalisation to untrained words was observed following the Phonological Programme, but not the Whole-word Programme. In Experiment 2, a second, more case-based investigation was conducted, focussing on one phonological dyslexic and one surface dyslexic, who were selected following extensive screening. Both were aged 10 years 11 months. Experiment 2 also examined the effectiveness of specific whole-word techniques. Results indicated a clear distinction between the responsiveness of the two participants, with each favouring their target treatment programme: the Phonological Programme was more effective for the phonological dyslexic than the Whole-word Programme, and vice versa for the surface dyslexic. The implications are discussed, with particular reference to suggestions for remediating reading disorders.</p>

Can individualized targets for transcranial magnetic stimulation increase treatment effectiveness in psychiatric disorders? A systematic review and meta-analysis

Background: Transcranial magnetic stimulation (TMS) techniques have developed in recent years in research and clinical treatment. The identification of targets for TMS treatment is increasingly individualized based on morphology or function; however, whether individualized TMS targets could increase the treatment effectiveness of psychiatric disorders remains controversial. Methods: A meta-analysis was conducted to explore whether individualized TMS targets are better than standard targets. A total of 3340 studies were identified in a systematic search, and twelve were included in the quantitative review. Among them, eight used a structure-based individualized target selection method, nine were on depression, and four compared unilateral and bilateral stimulant targets. Results: Meta-analyses showed that: (1) individualized TMS targets increased the effectiveness in treating psychiatric disorders; (2) structural-based TMS targets brought additional treatment effectiveness, and PET-based structural selection methods proved to be valid; (3) there was no significant increase in the treatment effects of individualized targets in EEG-based and task-fMRI-based methods; (4) updated stimulant sequences did not increase the individualized target treatment effect; (5) individualized TMS targets showed increased treatment effectiveness in depression but not in schizophrenia; and (6) bilateral stimuli did not show additional effectiveness compared with unilateral stimuli. Conclusions: The current findings revealed that individualized TMS targets show additional treatment effectiveness compared to standard targets in treating psychiatric disorders, and structure-based selection methods are effective in identifying TMS targets. The current conclusions provide directions for future TMS research and provide valuable references for clinicians treating psychiatric disorders.

The Management of Extrapulmonary Comorbidities and Treatable Traits; Obesity, Physical Inactivity, Anxiety, and Depression, in Adults With Asthma

Asthma is a complex and heterogenous disease characterized by variability in disease expression and severity. Multiple extrapulmonary comorbidities and treatable traits are common in people with asthma, and there is an increasing appreciation of how these may complicate asthma management. This review will discuss the prevalence and impact of extrapulmonary comorbidities/risk factors or “traits,” which have been found to co-exist in asthma (obesity, symptoms of depression and/or anxiety and physical inactivity), the impact these traits have on future outcomes (including exacerbation risk and quality of life) and asthma management, and how we should target treatment in asthma when these extrapulmonary traits are present.

Novel Concepts of Glioblastoma Therapy Concerning Its Heterogeneity

Although treatment outcomes of glioblastoma, the most malignant central nervous system (CNS) tumor, has improved in the past decades, it is still incurable, and survival has only slightly improved. Advances in molecular biology and genetics have completely transformed our understanding of glioblastoma. Multiple classifications and different diagnostic methods were made according to novel molecular markers. Discovering tumor heterogeneity only partially explains the ineffectiveness of current anti-proliferative therapies. Dynamic heterogeneity secures resistance to combined oncotherapy. As tumor growth proceeds, new therapy-resistant sub clones emerge. Liquid biopsy is a new and promising diagnostic tool that can step up with the dynamic genetic change. Getting a ’real-time’ picture of a specific tumor, anti-invasion and multi-target treatment can be designed. During invasion to the peri-tumoral brain tissue, glioma cells interact with the extracellular matrix components. The expressional levels of these matrix molecules give a characteristic pattern, the invasion spectrum, which possess vast diagnostical, predictive and prognostic information. It is a huge leap forward combating tumor heterogeneity and searching for novel therapies. Using the invasion spectrum of a tumor sample is a novel tool to distinguish between histological subtypes, specifying the tumor grades or different prognostic groups. Moreover, new therapeutic methods and their combinations are under trial. These are crucial steps towards personalized oncotherapy.