The characterisation and manipulation of a novel subset of tumour-reactive CD4+ cytotoxic T lymphocytes in human cancer

The ability of cytotoxic CD4+ T lymphocytes (CD4+ CTLs) to exert anti-tumour effects has been demonstrated in murine models of melanoma and an increase in the number of CD4+CTLs has previously been identified in the peripheral blood of patients with Chronic Lymphocytic Leukaemia (CLL) as well as in Hepatocellular Carcinoma. The project’s objective was to further characterise CD4+ CTLs in human cancer and in particular in haematological malignancies. CD4+ CTLs were identified in the peripheral blood, lymph nodes and bone marrow trephine biopsies of patients with CLL. There was a significant increase in the percentage of CD4+ CTLs in the blood of Cytomegalovirus (CMV) seropositive patients with CLL. The immunophenotype of the cells was similar to CD8+ CTLs with respect to the expression of EOMES, CD57 and loss of CD27 and CD28. CD4+ CTLs were also identified in other haematological malignancies, including in the bone marrow aspirates of patients with Multiple Myeloma and in the lymph node biopsies of patients with Non-Hodgkin and Hodgkin Lymphoma. We were able to isolate CD4+ CTLs, rapidly expand them and show that they have the ability to secrete Interferon gamma as well as Granzyme B. We also performed an extensive phenotyping of the cells with CyTOF (mass cytometry) technology. Further study is required to examine the molecular and cellular determinants of their cytotoxic activity prior to exploring the potential to manipulate them for therapeutic benefit

Demodulator techniques in satellite communication systems for direct broadcast systems

This thesis is concerned with the FM demodulator techniques used in terrestrial TV receiver designs for Direct Broadcast Systems (DBS) from satellites. The various MAC/Packet schemes intended for DBS applications are described and the international standards that apply to them considered, with particular emphasis on the D2-MAC system. Noise in FM systems is discussed and a suitable threshold noise model is chosen for use in DBS TV demodulator systems. The characteristics of the various types of noise effects are considered in terms of their effect upon the TV picture. The threshold performance of a conventional FM demodulator for differing types of modulation is reviewed and it is shown how the threshold characteristic depends upon the nature of the modulation. The literature review carried out represents a significant component of the thesis and combines material from patent literature with more conventional source materials from professional journals, conferences, textbooks, etc. Some ten existing demodulator concepts that exhibit threshold extension characteristics are examined, and where relevant their potential performance in D2-MAC format systems is assessed. The demodulator characteristics that limit their performance in TV systems are identified. It is concluded that designing a threshold extension demodulator, with reliable operation, for all picture contents and for a wide range of input carrier-to-noise ratios, is a formidable task using existing design techniques. On the basis of this examination an adaptive threshold extension demodulator concept is proposed, that utilises information contained within the signal structure to achieve an improved performance over a wide range of input carrier-to-noise ratios and picture content. It is shown how the relevant signal structures may be derived from conventional (PAL, SECAM and NTSC), MAC format and all-digital television systems. Illustrations are given that show how the adaptive demodulator concept can be applied to certain existing threshold extension demodulators, enhancing their performance for television picture reception. Future trends in all-digital DBS TV systems intended ultimately for DBS applications are briefly discussed together with their demodlilation requirements

A systematic review and meta-analysis on the prevalence of dementia in europe. estimates from the highest-quality studies adopting the dsm iv diagnostic criteria

BACKGROUND: Dementia, including Alzheimer's disease (AD), is one of the most burdensome medical conditions. Usually, the reviews that aim at calculating the prevalence of dementia include estimates from studies without assessing their methodological quality. Alzheimer's Disease International (ADI) proposed a score to assess the methodological quality of population-based studies aimed at estimating the prevalence of dementia. During the last three years, the European Commission has funded three projects (Eurodem, EuroCoDe, and ALCOVE) in order to estimate the prevalence of dementia in Europe. OBJECTIVE: The aim of this study was to perform a systematic review and meta-analysis of data on the prevalence of dementia in Europe derived from studies that included only subjects with a diagnosis of dementia according to the DSM IV criteria, and that had a high quality score according to ADI criteria. METHODS: We considered the studies selected by the two projects EuroCoDe (1993-2007) and Alcove (2008-2011), and we performed a new bibliographic search. For the systematic review, we only selected the subset of articles that included subjects with a diagnosis of dementia according to the DSM IV criteria. The studies were qualitatively assessed using the ADI tool. RESULTS: The meta-analysis considered 9 studies that were carried out in Europe between 1993 and 2018 including a total of 18,263 participants, of which 2,137 were diagnosed with dementia. The prevalence rate standardized for age and sex resulted 7.1%. DISCUSSION: This is the first systematic review on the prevalence of dementia in Europe considering only high-quality studies adopting the same diagnostic criteria (i.e., DSM IV)

Physiologically-Based Pharmacokinetic Modeling to Support the Clinical Management of Drug-Drug Interactions With Bictegravir

Bictegravir is equally metabolized by cytochrome P450 (CYP)3A and uridine diphosphate-glucuronosyltransferase (UGT)1A1. Drug-drug interaction (DDI) studies were only conducted for strong inhibitors and inducers, leading to some uncertainty whether moderate perpetrators or multiple drug associations can be safely coadministered with bictegravir. We used physiologically-based pharmacokinetic (PBPK) modeling to simulate DDI magnitudes of various scenarios to guide the clinical DDI management of bictegravir. Clinically observed DDI data for bictegravir coadministered with voriconazole, darunavir/cobicistat, atazanavir/cobicistat, and rifampicin were predicted within the 95% confidence interval of the PBPK model simulations. The area under the curve (AUC) ratio of the DDI divided by the control scenario was always predicted within 1.25-fold of the clinically observed data, demonstrating the predictive capability of the used modeling approach. After the successful verification, various DDI scenarios with drug pairs and multiple concomitant drugs were simulated to analyze their effect on bictegravir exposure. Generally, our simulation results suggest that bictegravir should not be coadministered with strong CYP3A and UGT1A1 inhibitors and inducers (e.g., atazanavir, nilotinib, and rifampicin), but based on the present modeling results, bictegravir could be administered with moderate dual perpetrators (e.g., efavirenz). Importantly, the inducing effect of rifampicin on bictegravir was predicted to be reversed with the concomitant administration of a strong inhibitor such as ritonavir, resulting in a DDI magnitude within the efficacy and safety margin for bictegravir (0.5-2.4-fold). In conclusion, the PBPK modeling strategy can effectively be used to guide the clinical management of DDIs for novel drugs with limited clinical experience, such as bictegravir

Magnitude of Drug-Drug Interactions in Special Populations

Drug-drug interactions (DDIs) are one of the most frequent causes of adverse drug reactions or loss of treatment efficacy. The risk of DDIs increases with polypharmacy and is therefore of particular concern in individuals likely to present comorbidities (i.e., elderly or obese individuals). These special populations, and the population of pregnant women, are characterized by physiological changes that can impact drug pharmacokinetics and consequently the magnitude of DDIs. This review compiles existing DDI studies in elderly, obese, and pregnant populations that include a control group without the condition of interest. The impact of physiological changes on the magnitude of DDIs was then analyzed by comparing the exposure of a medication in presence and absence of an interacting drug for the special population relative to the control population. Aging does not alter the magnitude of DDIs as the related physiological changes impact the victim and perpetrator drugs to a similar extent, regardless of their elimination pathway. Conversely, the magnitude of DDIs can be changed in obese individuals or pregnant women, as these conditions impact drugs to different extents depending on their metabolic pathway

Applications of physiologically based pharmacokinetic modeling for the optimization of anti-infective therapies

Introduction: The pharmacokinetic properties of anti-infective drugs are a determinant part of treatment success. Pathogen replication is inhibited if adequate drug levels are achieved in target sites, whereas excessive drug concentrations linked to toxicity are to be avoided. Anti-infective distribution can be predicted by integrating in vitro drug properties and mathematical descriptions of human anatomy in physiologically based pharmacokinetic models. This method reduces the need for animal and human studies and is used increasingly in drug development and simulation of clinical scenario such as, for instance, drug–drug interactions, dose optimization, novel formulations and pharmacokinetics in special populations. Areas covered: We have assessed the relevance of physiologically based pharmacokinetic modeling in the anti-infective research field, giving an overview of mechanisms involved in model design and have suggested strategies for future applications of physiologically based pharmacokinetic models. Expert opinion: Physiologically based pharmacokinetic modeling provides a powerful tool in anti-infective optimization, and there is now no doubt that both industry and regulatory bodies have recognized the importance of this technology. It should be acknowledged, however, that major challenges remain to be addressed and that information detailing disease group physiology and anti-infective pharmacodynamics is required if a personalized medicine approach is to be achieved

An estimate of attributable cases of alzheimer disease and vascular dementia due to modifiable risk factors. the impact of primary prevention in europe and in italy

Background: Up to 53.7% of all cases of dementia are assumed to be due to Alzheimer disease (AD), while 15.8% are considered to be due to vascular dementia (VaD). In Europe, about 3 million cases of AD could be due to 7 potentially modifiable risk factors: diabetes, midlife hypertension and/or obesity, physical inactivity, depression, smoking, and low educational level. Aims: To estimate the number of VaD cases in Europe and the number of AD and VaD cases in Italy attributable to these 7 potentially modifiable risk factors. Methods: Assuming the nonindependence of the 7 risk factors, the adjusted combined population attributable risk (PAR) was estimated for AD and VaD. Results: In Europe, adjusted combined PAR was 31.4% for AD and 37.8% for VaD. The total number of attributable cases was 3,033,000 for AD and 873,000 for VaD. In Italy, assuming a 20% reduction of the prevalence of each risk factor, adjusted combined PAR decreased from 45.2 to 38.9% for AD and from 53.1 to 46.6% for VaD, implying a 6.4 and 6.5% reduction in the prevalence of AD and VaD, respectively. Conclusion: A relevant reduction of AD and VaD cases in Europe and Italy could be obtained through primary prevention