Pharmacovigilance of pregnancy exposures to medicinal products focusing on the risk of orofacial clefts

Background: It is important to obtain robust scientific information on possible safety concerns related to the use of drugs during pregnancy in post-approval settings. Since pregnant women are actively excluded from trials in the clinical development of most products, at the time of the drug entry in the market meaningful human data on the effects of that drug during pregnancy are rarely available. There are approximately 5 million pregnancies in the EU each year, and about 1 in every 10 women of childbearing age is pregnant each year. Insufficient information for management of maternal disease during pregnancy can have teratogenic impact on fetus. Aim and objectives: This reach comprises three studies, in the first study; the goal was to evaluate the maternal use of medicines and the associated risks of cleft lip and/or palate in fetus and to link this to the accuracy and currency of safety information available in prescribing information. The second area of research was aimed at identifying and exploring social and digital media to understand patients’ experiences regarding medicine use during pregnancy. Last, but not least, I contributed to the development of an enhanced pharmacovigilance programme for analysing drug exposure during pregnancy and outcomes in neonate. Method: Firstly, I identified medication-induced risk factors for oral clefts with safety signal detection and safety signal evaluation techniques. Then I assessed the completeness of the safety information for pregnancy exposures in the Summary of Product Characteristics and the Patient Information in the UK and the US. In second study, the content of posts concerning pregnancy and use of medicines in online pregnancy forums was analysed using artificial intelligence in the form of natural language processing and machine learning algorithms. Third, the PRIM (PRegnancy outcomes Intensive Monitoring) system was developed as an enhanced pharmacovigilance data collection method. This was used to improve the quality and content of prospective case reports using sets of targeted checklists, structured follow-up, a rigorous process of data entry and data quality control, and programmed aggregate analysis. Results: For 12 antiepileptic drugs studied there was a statistical disproportionality in individual case safety reports indicative of an increased risk of cleft lip and/or palate. There are inconsistencies between the UK and US safety labels, despite the same evidence being available for assessment. The second study showed that in social media forums many pregnant women with MS shared profound uncertainties and specific concerns about taking medicines during the reproductive period. There was evidence of concealment of information with health care professionals; however, the same evidence was shared with a peer group. The PRIM method of enhanced pharmacovigilance has yielded substantially more information on the safety of fingolimod exposure during pregnancy than has been achieved via the regulatory authority-mandated pregnancy registry. Conclusion: Use of medicines during pregnancy is an important topic for public health. There is a significant need to provide inclusive, unbiased, up to- date information to prescribers and women of childbearing age concerning the use of medicines in pregnancy and postpartum during breastfeeding. Information must be provided in a timely manner by a trusted source and patients should have access to health care professionals with the relevant expertise and knowledge. It is important that the full anonymised data set, along with evidence-based conclusions are made publicly available to inform decision-making

Contributions towards understanding and building sustainable science

This dissertation focuses on either understanding and detecting threats to the epistemology of science (chapters 1-6) or making practical advances to remedy epistemological threats (chapters 7-9). Chapter 1 reviews the literature on responsible conduct of research, questionable research practices, and research misconduct. Chapter 2 reanalyzes Head et al (2015) their claims about widespread p-hacking for robustness. Chapter 3 examines 258,050 test results across 30,710 articles from eight high impact journals to investigate the existence of a peculiar prevalence of $p$-values just below .05 (i.e., a bump) in the psychological literature, and a potential increase thereof over time. Chapter 4 examines evidence for false negatives in nonsignificant results throughout psychology, gender effects, and the Reproducibility Project: Psychology. Chapter 5 describes a dataset that is the result of content mining 167,318 published articles for statistical test results reported according to the standards prescribed by the American Psychological Association (APA). In Chapter 6, I test the validity of statistical methods to detect fabricated data in two studies. Chapter 7 tackles the issue of data extraction from figures in scholarly publications. In Chapter 8 I argue that "after-the-fact" research papers do not help alleviate issues of access, selective publication, and reproducibility, but actually cause some of these threats because the chronology of the research cycle is lost in a research paper. I propose to give up the academic paper and propose a digitally native "as-you-go" alternative. In Chapter 9 I propose a technical design for this

Patient-oriented Evidence-based Treatment Decision Support System (TreatQuest®) for Lung Cancer

Involving patients in healthcare decisions makes a significant and enduring difference to healthcare outcomes. One challenge for patients is the lack of evidence-based information and tools to support their decision making. Although patients have access to significant information through internet and other sources, it is not personalized for their specific situation. This dissertation attempts to help patients acquire evidence-based information relevant to their own situation, so they can make a more informed decision in co-operation with their physicians. Lung cancer has been selected as a focus for this study because lung cancer presents very complex decision making situation and is the leading cause of cancer deaths in both men and woman in every ethnic group worldwide. The prototype decision support system for lung cancer is called TreatQuest®. This system allows users to create their own profile, access cases similar to their case, and learn about treatment options. The evidences for the treatment were extracted from public data and knowledge gained from guideline. The effectiveness of patient-oriented evidence-based approach was validated by having a group of patient use the system. TreatQuest® is one of the first system developed to support patient\u27s treatment decision process, which represent the most recent trend in delivery of healthcare services. Results from this study show that such a patient-oriented decision support system provides an effective way to help patient receive more personalized information and make informed treatments. In summary, patient-oriented evidence-based decision support systems such as TreatQuest®, can improve the decision quality for patients. Also, such systems can improve health care decisions that are made with the active participation of fully informed patients. Therefore, patient-oriented evidence-based decision support systems can have significant impact on the healthcare industry

Lipid nanoparticles biocompatibility and cellular uptake in a 3D human lung model

Aim: Design nanostructured lipid carriers (NLC) to facilitate drug delivery to tuberculosis-infected areas, exploiting macrophage mannose receptors and assess their uptake in a 3D human lung model. Materials & methods: NLCs and mannosylated-NLCs were synthetized and characterized. Their uptake and biocompatibility were tested in a 3D human lung model. Results: The formulations have appropriate size (170-202 nm) and morphology for lung deposition. Cell membrane integrity was maintained and no significant pro-inflammatory cytokine (IL-1β, IL-8 and TNF-α) secretion or morphological changes were observed 24 h post nanoparticles exposure. NLCs and mannosylated NLCs were distributed in the apical side of the lung tissue, both in macrophages and in epithelial cells. Conclusion: NLCs are biocompatible carriers and can be used for pulmonary drug delivery.Aim: Design nanostructured lipid carriers (NLC) to facilitate drug delivery to tuberculosis-infected areas, exploiting macrophage mannose receptors and assess their uptake in a 3D human lung model. Materials & methods: NLCs and mannosylated-NLCs were synthetized and characterized. Their uptake and biocompatibility were tested in a 3D human lung model. Results: The formulations have appropriate size (170-202 nm) and morphology for lung deposition. Cell membrane integrity was maintained and no significant pro-inflammatory cytokine (IL-1β, IL-8 and TNF-α) secretion or morphological changes were observed 24 h post nanoparticles exposure. NLCs and mannosylated NLCs were distributed in the apical side of the lung tissue, both in macrophages and in epithelial cells. Conclusion: NLCs are biocompatible carriers and can be used for pulmonary drug delivery

Applications of Medical Physics

Applications of Medical Physics” is a Special Issue of Applied Sciences that has collected original research manuscripts describing cutting-edge physics developments in medicine and their translational applications. Reviews providing updates on the latest progresses in this field are also included. The collection includes a total of 20 contributions by authors from 9 different countries, which cover several areas of medical physics, spanning from radiation therapy, nuclear medicine, radiology, dosimetry, radiation protection, and radiobiology

Multimodal sentiment analysis in real-life videos

This thesis extends the emerging field of multimodal sentiment analysis of real-life videos, taking two components into consideration: the emotion and the emotion's target. The emotion component of media is traditionally represented as a segment-based intensity model of emotion classes. This representation is replaced here by a value- and time-continuous view. Adjacent research fields, such as affective computing, have largely neglected the linguistic information available from automatic transcripts of audio-video material. As is demonstrated here, this text modality is well-suited for time- and value-continuous prediction. Moreover, source-specific problems, such as trustworthiness, have been largely unexplored so far. This work examines perceived trustworthiness of the source, and its quantification, in user-generated video data and presents a possible modelling path. Furthermore, the transfer between the continuous and discrete emotion representations is explored in order to summarise the emotional context at a segment level. The other component deals with the target of the emotion, for example, the topic the speaker is addressing. Emotion targets in a video dataset can, as is shown here, be coherently extracted based on automatic transcripts without limiting a priori parameters, such as the expected number of targets. Furthermore, alternatives to purely linguistic investigation in predicting targets, such as knowledge-bases and multimodal systems, are investigated. A new dataset is designed for this investigation, and, in conjunction with proposed novel deep neural networks, extensive experiments are conducted to explore the components described above. The developed systems show robust prediction results and demonstrate strengths of the respective modalities, feature sets, and modelling techniques. Finally, foundations are laid for cross-modal information prediction systems with applications to the correction of corrupted in-the-wild signals from real-life videos

The design and evaluation of targeted patient-centred health information to improve knowledge and behavioural outcomes in tuberculosis patients with limited literacy

South Africa carries a significant TB burden as evidenced in the 2013 statistics which report 450 000 new active TB cases and 890 000 TB-related mortalities. For successful treatment outcomes, 90% adherence is necessary, but many patients prematurely discontinue treatment due to poor knowledge and understanding of their complex TB medicines. Patient education is pivotal in improving knowledge, health literacy and behavioural outcomes such as health information seeking, self-efficacy and adherence. In the under-resourced South African healthcare system, time and capacity to adequately counsel patients are limited. The value of written medicine information (WMI) to supplement the verbal information provided by healthcare professionals (HCPs) has been widely investigated but minimal South African research is available. Current WMI distributed in South Africa is mainly generated by pharmaceutical manufacturers and is complex, incomprehensible and undesirable to patients. TB-related WMI focuses mainly on the disease, with little information relating to TB medicines and their use. The overall aim of this project was to improve patient knowledge about their TB medicines through the use of a simple illustrated patient information leaflet (PIL). Objectives to achieve this aim included: investigation of the medicine information seeking behaviour (MISB) of long term patients attending public health sector facilities; the development and validation of a medicine literacy test (MLT) to identify patients with limited health literacy requiring additional support and counselling; the development and evaluation of a patient-centred illustrated PIL for first-line TB treatment; the assessment of self-efficacy and adherence using modified versions of the HIV Treatment Adherence Self-Efficacy Scale (HIV-ASES) and Morisky 8-item Medicine Adherence Scale (MMAS-8), respectively, and the investigation of the impact of the PIL on patient knowledge and these health-related behaviours. Six focus group discussions (FGDs) conducted in 34 isiXhosa-speaking patients with limited formal education taking long-term treatment explored themes related to information needs, information-seeking practices and awareness of and ability to utilize information sources. Codes were analysed and potential themes and subthemes were identified and refined. The findings of this study reflected a passive, disempowered patient due to both patient-related and systemic healthcare factors. Poor awareness of information sources, lack of health-related knowledge, stigma and lack of awareness of the importance of appropriate medicine-related knowledge contributed to a lack of information-seeking practice. Patients neither asked questions nor were encouraged to do so. All expressed an unmet need for information and a desire for receiving relevant, appropriate, written medicine-related information. Feedback from this phase of the study was used to inform the development of the targeted patientcentred PIL. A double-sided A4 PIL containing information about TB medicines was designed giving careful consideration to content, format and layout features. Twenty five pictograms were designed through a rigorous, iterative design process and were included in the PIL that was evaluated in a randomised control trial (RCT) conducted amongst 120 TB patients attending a high burden TB clinic in South Africa. Interviews were conducted in either isiXhosa or Afrikaans via a trained interpreter. Patients were randomly allocated to either a control (standard care) or an experimental group (standard care plus brief counselling using the PIL). Two interviews were conducted using a prepared questionnaire; one at baseline followed by a 4-week follow-up. Baseline data included demographics, medicine literacy test, health information sources, knowledge of TB medicines, self-reported adherence and self-efficacy. Data collected at the 4-week follow-up interview included TB knowledge, self-reported adherence, self-efficacy, opinion of TB medicine information and interpretation of pictograms. Data were analysed using t-test, correlations, chi-square and ANOVA tests at a 0.05 level of significance. The PIL was successful in improving patient knowledge of the disease, TB medicine-taking, side effects, drug-resistant TB and HIV and TB co-infection. At baseline, there was no significant difference in the overall mean percentage knowledge score between the control and experimental groups (p=0.074). At follow-up, the percentage knowledge score for the experimental group increased significantly from 59.0% to 84.6% (p<0.001) and showed a significantly higher score than the control group (p<0.001), displaying evidence of the impact of the PIL as a counselling tool on patient knowledge. The PIL generated a highly positive response in the experimental group who indicated that they had referred to the leaflet over the last month and that it had played an important role in improving their TB medicine-related knowledge. This was reflected in the experimental group knowledge score of greater than 80% for almost three quarters of the patients whereas only 14% in the control group achieved this score. Patients appreciated the inclusion of pictograms and strongly felt that they helped them to recall and understand the textual PIL content. The study found that patients want side effect information and, interestingly, did not perceive the presentation of side effects in pictorial form to constitute a risk factor for nonadherence. Use of the illustrated PIL (experimental group) resulted in a significant improvement in patient self-efficacy (p=0.002), but showed no effect on self-reported adherence (p=0.563). Neither self-efficacy nor adherence was influenced by gender, age or education. An education effect on knowledge was only observed in the control group at baseline. The newly developed MLT was shown to be a valid and reliable tool and a moderate, positive and significant correlation was noted between the MLT score and baseline TB medicine-related knowledge in both the control and experimental groups. As there is a paucity of studies investigating the influence of take-home written leaflets on TB medicine knowledge and on patient behaviour, this study represents a significant knowledge contribution. It is the first study to report the development and evaluation of a patient-centred PIL to address the dearth of available TB medicine information. The use of targeted user-friendly, illustrated information leaflets can be a valuable counselling aid to improve patient knowledge and self-efficacy, particularly among patients with limited literacy. However, careful consideration of the design and content, with input from the endusers at all stages of the process, will optimise its effectiveness. The proposed framework for the development and implementation of patient-centred health and medicines information in a developing country context presented in this thesis could be used as a theoretical basis for informing the development of effective information materials targeting other disease states. Local patients taking TB medicines identified nurses, WMI and media as their current sources of information but they expressed a strong desire to know more about their treatment. Targeted public health interventions that focus on medicine-taking information and behaviours and encourage patients to adopt a more active, questioning role in health consultations could improve health literacy and empower patients in their medicine-taking practices.Thesis (PhD) -- Faculty of Pharmacy, Pharmacy, 201