Evaluation of the trends and outcomes for women screened for and diagnosed with cervical precursor lesions: A Western Australian perspective

Background - Specific questions regarding the management of cervical cancer precursor lesions still exist. Aims - Identify areas for improvement in the management of cervical abnormalities. Methods - A retrospective population-based cohort study was conducted for women diagnosed with a low-grade glandular or a high-grade cervical lesion. Conclusion - Findings support the revision of management guidelines supported by educational sessions would improve the efficacy of conservative treatment modalities and the importance of post-treatment surveillance

Extraction and Detection of Fetal Electrocardiograms from Abdominal Recordings

The non-invasive fetal ECG (NIFECG), derived from abdominal surface electrodes, offers novel diagnostic possibilities for prenatal medicine. Despite its straightforward applicability, NIFECG signals are usually corrupted by many interfering sources. Most significantly, by the maternal ECG (MECG), whose amplitude usually exceeds that of the fetal ECG (FECG) by multiple times. The presence of additional noise sources (e.g. muscular/uterine noise, electrode motion, etc.) further affects the signal-to-noise ratio (SNR) of the FECG. These interfering sources, which typically show a strong non-stationary behavior, render the FECG extraction and fetal QRS (FQRS) detection demanding signal processing tasks. In this thesis, several of the challenges regarding NIFECG signal analysis were addressed. In order to improve NIFECG extraction, the dynamic model of a Kalman filter approach was extended, thus, providing a more adequate representation of the mixture of FECG, MECG, and noise. In addition, aiming at the FECG signal quality assessment, novel metrics were proposed and evaluated. Further, these quality metrics were applied in improving FQRS detection and fetal heart rate estimation based on an innovative evolutionary algorithm and Kalman filtering signal fusion, respectively. The elaborated methods were characterized in depth using both simulated and clinical data, produced throughout this thesis. To stress-test extraction algorithms under ideal circumstances, a comprehensive benchmark protocol was created and contributed to an extensively improved NIFECG simulation toolbox. The developed toolbox and a large simulated dataset were released under an open-source license, allowing researchers to compare results in a reproducible manner. Furthermore, to validate the developed approaches under more realistic and challenging situations, a clinical trial was performed in collaboration with the University Hospital of Leipzig. Aside from serving as a test set for the developed algorithms, the clinical trial enabled an exploratory research. This enables a better understanding about the pathophysiological variables and measurement setup configurations that lead to changes in the abdominal signal's SNR. With such broad scope, this dissertation addresses many of the current aspects of NIFECG analysis and provides future suggestions to establish NIFECG in clinical settings.:Abstract Acknowledgment Contents List of Figures List of Tables List of Abbreviations List of Symbols (1)Introduction 1.1)Background and Motivation 1.2)Aim of this Work 1.3)Dissertation Outline 1.4)Collaborators and Conflicts of Interest (2)Clinical Background 2.1)Physiology 2.1.1)Changes in the maternal circulatory system 2.1.2)Intrauterine structures and feto-maternal connection 2.1.3)Fetal growth and presentation 2.1.4)Fetal circulatory system 2.1.5)Fetal autonomic nervous system 2.1.6)Fetal heart activity and underlying factors 2.2)Pathology 2.2.1)Premature rupture of membrane 2.2.2)Intrauterine growth restriction 2.2.3)Fetal anemia 2.3)Interpretation of Fetal Heart Activity 2.3.1)Summary of clinical studies on FHR/FHRV 2.3.2)Summary of studies on heart conduction 2.4)Chapter Summary (3)Technical State of the Art 3.1)Prenatal Diagnostic and Measuring Technique 3.1.1)Fetal heart monitoring 3.1.2)Related metrics 3.2)Non-Invasive Fetal ECG Acquisition 3.2.1)Overview 3.2.2)Commercial equipment 3.2.3)Electrode configurations 3.2.4)Available NIFECG databases 3.2.5)Validity and usability of the non-invasive fetal ECG 3.3)Non-Invasive Fetal ECG Extraction Methods 3.3.1)Overview on the non-invasive fetal ECG extraction methods 3.3.2)Kalman filtering basics 3.3.3)Nonlinear Kalman filtering 3.3.4)Extended Kalman filter for FECG estimation 3.4)Fetal QRS Detection 3.4.1)Merging multichannel fetal QRS detections 3.4.2)Detection performance 3.5)Fetal Heart Rate Estimation 3.5.1)Preprocessing the fetal heart rate 3.5.2)Fetal heart rate statistics 3.6)Fetal ECG Morphological Analysis 3.7)Problem Description 3.8)Chapter Summary (4)Novel Approaches for Fetal ECG Analysis 4.1)Preliminary Considerations 4.2)Fetal ECG Extraction by means of Kalman Filtering 4.2.1)Optimized Gaussian approximation 4.2.2)Time-varying covariance matrices 4.2.3)Extended Kalman filter with unknown inputs 4.2.4)Filter calibration 4.3)Accurate Fetal QRS and Heart Rate Detection 4.3.1)Multichannel evolutionary QRS correction 4.3.2)Multichannel fetal heart rate estimation using Kalman filters 4.4)Chapter Summary (5)Data Material 5.1)Simulated Data 5.1.1)The FECG Synthetic Generator (FECGSYN) 5.1.2)The FECG Synthetic Database (FECGSYNDB) 5.2)Clinical Data 5.2.1)Clinical NIFECG recording 5.2.2)Scope and limitations of this study 5.2.3)Data annotation: signal quality and fetal amplitude 5.2.4)Data annotation: fetal QRS annotation 5.3)Chapter Summary (6)Results for Data Analysis 6.1)Simulated Data 6.1.1)Fetal QRS detection 6.1.2)Morphological analysis 6.2)Own Clinical Data 6.2.1)FQRS correction using the evolutionary algorithm 6.2.2)FHR correction by means of Kalman filtering (7)Discussion and Prospective 7.1)Data Availability 7.1.1)New measurement protocol 7.2)Signal Quality 7.3)Extraction Methods 7.4)FQRS and FHR Correction Algorithms (8)Conclusion References (A)Appendix A - Signal Quality Annotation (B)Appendix B - Fetal QRS Annotation (C)Appendix C - Data Recording GU

The association between sperm aneuploidy and male infertility: Screening, aetiology and possible routes to alternative therapy

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.One in six couples wishing to start a family are infertile. The many causes of infertility include genetic defects that can be single gene, multifactorial or chromosomal (including Y deletions, karyotype abnormalities and gamete aneuploidy). This thesis is concerned with the association between infertility and increased sperm aneuploidy. Specific questions are: should males be screened for sperm aneuploidy before intracytoplasmic sperm injection (ICSI)? Is there a relationship between individual semen parameters and sperm aneuploidy for specific chromosome pairs? What is the role of genome organisation in male gametes and its association with infertility? Whether use of alternative therapy (in this case, traditional Chinese Medicine (TCM)) can be used to improve sperm disomy levels. Statistical analysis of questionnaire data revealed that infertility specialists believed there to be merit in screening sperm aneuploidy levels before ICSI. Evidence is presented for possible chromosome-specific and semen parameter specific mechanisms for sperm aneuploidy as is evidence of genome organisation that may be perturbed in infertile males. Finally, in six males studied, sperm aneuploidy levels improved significantly coincident with TCM. Closer investigation of the biological activity of individual therapeutic herbs and treatment cocktails revealed strong anti-oestrogenic and anti-oxidant properties. This suggests a possible mechanism of action of the herbs and provides the basis from which future placebo controlled clinical trials might continue. Possible criticisms of the work presented here include the unavailability of blood samples from many of the patients (thus preventing karyotype analysis) and the absence of a second control group in our studies on semen parameters. Nevertheless significant steps have been made towards establishing the need for, and the implementation of, a pre-ICSI screening test. Moreover progress has been made towards further understanding the aetiology of sperm aneuploidy and towards the implementation of a new treatment that may, ultimately, augment, or even replace ICSI

Antiretroviral therapy, drug resistance in pregnancy, and preventing mother-to-child HIV transmission in the UK

Effective interventions have reduced the HIV vertical transmission rate in high-income countries to very low levels; the goal is now to eliminate new paediatric HIV infections. The aim of this thesis was to examine the role of antiretroviral therapy (ART) and other interventions to reduce vertical HIV transmission in the UK and Ireland in the current treatment era. I used data from the National Study of HIV in Pregnancy and Childhood (NSHPC), a national surveillance study of all pregnancies in women living with HIV and their children in the UK and Ireland; the UK HIV drug resistance database and a national survey on the management of women who decline antenatal HIV testing. The NSHPC dataset included all pregnancies reported 2000-2014. Results highlight substantial changes in the demographics of women with reported pregnancies. There was wide variation in the management of women who decline HIV testing in pregnancy. Women with perinatal HIV in the UK had a first pregnancy incidence of 13 per 1000 woman-years (95% CI: 9 to 17 per 1000 woman-years). Perinatal HIV was an independent risk factor for detectable viral load near delivery (aOR 3.22 95% CI: 1.22-8.48), as was lower age at conception, no ART at conception, and PI-containing cART. The prevalence of transmitted drug resistance was 5.3% in women diagnosed during pregnancy (95% CI: 4.3% to 6.5%), similar to other estimates in non-B HIV-1 subtypes in the UK. Key contributing factors were identified in the 108 cases of perinatal HIV in infants born in the UK 2006-2014, including women who declined HIV testing in pregnancy; difficulties with engagement and adherence to ART during pregnancy; HIV acquisition during pregnancy or postnatal period after a negative test in early pregnancy. This thesis identifies key improvements which can still be made on the road to eliminating paediatric HIV

Human Papillomavirus and Related Diseases

Cervical cancer is the second most prevalent cancer among women worldwide, and infection with Human Papilloma Virus (HPV) has been identified as the causal agent for this condition. The natural history of cervical cancer is characterized by slow disease progression, rendering the condition in essence preventable and even treatable when diagnosed in early stages. Pap smear and the recently introduced prophylactic vaccines are the most prominent prevention options, but despite the availability of these primary and secondary screening tools, the global burden of disease is unfortunately still very high This book will focus on the clinical and diagnostic aspects of HPV and related disease, highlighting the latest developments in this field

A comprehensive integrative approach to investigate factors associated with preterm birth, related perinatal outcomes and its prediction using metabolomic markers

Orientador: José Guilherme CecattiTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: Introdução: O parto prematuro é uma das principais causas de morbimortalidade perinatal, neonatal e de crianças até 5 anos de idade e suas causas e fisiopatologia ainda são pouco conhecidas. Identificar quais são as mulheres de maior risco e desenvolver modelos de predição é ainda um grande desafio, potencialmente impactando nas medidas preventivas. Objetivo: Desenvolver uma abordagem abrangente com diferentes estudos e produtos relacionados aos fatores clínicos e epidemiológicos associados ao parto prematuro, seus preditores metabolômicos e respectivos desfechos perinatais. Métodos: Diferentes projetos de pesquisa e métodos foram utilizados, incluindo: duas análises secundárias de um estudo multicêntrico de corte transversal avaliando a associação do índice de massa corpórea (IMC), o ganho de peso gestacional por semana e fenótipos maternos com a ocorrência de prematuridade e desfechos maternos e perinatais; uma revisão narrativa sobre ciência ômica aplicada na área de saúde materna e perinatal, com enfoque na metabolômica; uma revisão sistemática e seu respectivo artigo de protocolo sobre a performance da metabolômica em predizer prematuridade espontânea em mulheres assintomáticas; dois artigos abordando o desenvolvimento do método e dos procedimentos técnicos para um estudo multicêntrico prospectivo para investigar parto prematuro; um estudo caso-controle aninhado a uma coorte multicêntrica internacional para identificar preditores clínicos e metabolômicos para prematuridade espontânea; dois artigos originais abordando a incidência, fatores clínicos e epidemiológicos e os desfechos maternos e perinatais associados ao parto prematuro em uma coorte multicêntrica no Brasil com gestantes nulíparas de baixo risco. Resultados: Nas análises secundárias do EMIP, observou-se que independente do IMC inicial, quanto maior o ganho de peso materno, maior a probabilidade para todos os subtipos de prematuridade, exceto para prematuridade espontânea em mulheres com IMC normal ou sobrepeso. Foram identificados três clusters de mulheres com parto prematuro, sendo um caracterizado principalmente por mulheres sem nenhuma das condições de risco, o segundo por mulheres com várias condições (cluster misto) e o terceiro por mulheres que tiveram pré-eclâmpsia, eclâmpsia, síndrome HELLP e/ou restrição de crescimento fetal. A revisão narrativa aborda os métodos e o embasamento teórico das ciências ômicas, como a genômica, transcriptômica, proteômica e metabolômica, dando enfoque especial à aplicação dessa última técnica na área de saúde materna e perinatal. A identificação e validação de marcadores pode auxiliar na predição e também no entendimento da fisiopatologia de doenças complexas como a prematuridade. A técnica de metabolômica identificou mais de 140 metabólitos nas amostras de soro de gestantes nulíparas e três destes foram significativamente associados com parto prematuro espontâneo nas amostras de Cork, Irlanda. Modelos preditores usando marcadores clínicos e metabolômicos mostraram uma área sob a curva ROC de 0,73 e 0,85 para parto prematuro abaixo de 37 e 34 semanas, respectivamente. Conclusão: O ganho de peso gestacional, um fator modificável, mostrou diferentes associações com a probabilidade de parto prematuro, a depender do IMC inicial. Possíveis investigações de risco e de prevenção devem considerar essa evidência. A utilização de critérios clínicos no rastreamento e predição do parto prematuro ainda mostra limitações. A análise por cluster, por exemplo, mostrou que um número considerável não possui nenhuma das condições pré-definidas como potencialmente associadas ao parto prematuro. A aplicação de estudos da ciência Ômica parece ser uma abordagem adequada para a identificação da etiologia e de marcadores para predição de complicações maternas e perinatais, embora ainda necessitem de sucessivas validações e evidência de reprodutibilidade. O desenvolvimento, implementação e coordenação de um estudo multicêntrico para estudar preditores e fatores associados ao parto prematuro requer recursos humanos qualificados, infraestrutura para pesquisa adequada, comprometimento institucional e envolvimento de agências de fomento e desenvolvimento de pesquisa. O modelo preditor para parto prematuro espontâneo em mulheres nulíparas mostra resultados de boa performance, entretanto requer futuras validações antes de qualquer uso clínico. É provável que os metabólitos que compõem o modelo não sejam identificados da mesma forma em outras populaçõesAbstract: Introduction: Preterm birth is the leading cause of perinatal, neonatal and under-5 year¿s morbidity and mortality. Identifying women at higher risk and developing prediction models remains a great challenge, potentially affecting preventive interventions. Objectives: To develop a comprehensive approach including diverse study designs to investigate clinical and epidemiological risk factors associated with preterm birth, its metabolomics predictors and respective perinatal outcomes. Methods: Different projects and methods were applied in this thesis, including: two secondary analysis of a multicentre cross-sectional with a nested case-control study addressing the association of maternal body mass index (BMI), gestational weight gain per week and phenotypes with the occurrence of preterm birth and maternal and perinatal outcomes; an integrative review about omics sciences applied to maternal and perinatal health, focusing on metabolomics; a systematic review and respective protocol investigating the performance of metabolomics to predict spontaneous preterm birth (sPTB) in asymptomatic women; two articles describing the methods, clinical protocol, technical procedures for the development and implementation of a multicentre prospective cohort study to investigate preterm birth and other maternal and perinatal complications; a nested case-control from a multicentre international cohort to identify clinical and metabolomics predictors for sPTB; two articles addressing incidence, clinical and epidemiological risk factors and maternal and perinatal outcomes associated with sPTB in a Brazilian multicentre cohort of low-risk nulliparous pregnant women. Results: According to the EMIP secondary analyses, the greater the rate of weight gain, the higher the predicted probability for all preterm birth subtypes regardless the initial BMI, except in normal BMI or overweight women and sPTB. Three clusters of women with preterm birth were identified; cluster one of women without any pre-defined conditions, cluster two with mixed conditions and cluster three with women who had preeclampsia, eclampsia, HELLP syndrome and/or fetal growth restriction. Maternal and perinatal outcomes did not differ between clusters. An integrative review addressed Omis Science's methods and theoretical background, as genomics, transcriptomics, proteomics and metabolomics, focusing on the application on maternal and perinatal health. Metabolomics approach has been applied to better understand the pathophysiology and to identify and validate predictors for complex diseases as preterm birth. Metabolomics technique identified more than 140 metabolites in serum samples of nulliparous pregnant women and three of them were significantly associated with sPTB in samples from Cork, Ireland. Predictive models associating metabolites and clinical markers showed an area under ROC curve of 0.73 and 0.85 for sPTB below 37 and 34 weeks, respectively. Conclusion: Gestational weight gain, a modifiable factor, showed to have different associations with the predicted probability for preterm birth, depending on the initial BMI. The use of clinical criteria in the screening of preterm birth still shows limited performance. Cluster analysis, for instance, showed that a substantial number of women does not present the predefined potential conditions associated with preterm birth. Omics science studies might be a reasonable approach to investigate the aetiology and predictive markers for maternal and perinatal complications. Metabolomic studies addressing the prediction for sPTB, preeclampsia, gestational diabetes mellitus and fetal growth restriction show promising findings, although they still require repeated validations and reproducibility. The development, implementation and management of a multicenter study to investigate factors associated with sPTB requires qualified human resources, adequate infrastructure, institutional commitment and the involvement of funding and research agencies. The predictive model for sPTB in nulliparous women showed a good performance, although further validation is required before clinical application. Possibly, reproducibility of the predictive model is limited, once metabolites comprising the model were only identified in one of the subsetDoutoradoSaúde Materna e PerinatalDoutor em Ciências da SaúdeCAPE

Biospectroscopy towards screening and diagnosis of cancer

Systems biology is an emerging science that combines high throughput investigation techniques to define the dynamic interplay between different biological regulatory systems in response to internal and external cues. Related technologies, genomics, epigenomics, transcriptomics, proteomics, metabolomics and toponomics have been applied to investigate models of carcinogenesis to identify committing initiating events. Vibrational spectroscopy has the potential to play an integral role within systems biology research approaches, as it is able to identify chemical bond alterations within molecules independent of where these molecules reside. Its integration with current “systems biology” methodologies can contribute in the identification of potential biomarkers of carcinogenesis and assist in their incorporation into clinical practice. Breast tissue undergoes cyclical and longitudinal molecular and histological alterations that are influenced by environmental factors. These factors may include diet and lifestyle in addition to parity, lactation and menopausal status and are implicated in carcinogenesis. Breast cancer may appear decades after the initial carcinogenic event. Available research in this area is limited to when early histological changes occur due to the difficulties imposed by the molecular and histological diversity of breast tissue. Vibrational spectroscopy in combination with powerful chemometric techniques has identified spatial and temporal mammary alterations in benign tissue. Prostate cancer is influenced by environmental factors. Its incidence is higher in populations adopting a Westernised lifestyle and diet and has increased over the past generation. This leads to the assumption that prostatic tissue composition may exhibit chronological alterations. Vibrational spectroscopy techniques were applied to matching prostatic tissues with benign prostatic hyperplasia collected from 1983 to 2013. Significant trans-generational segregation was identified. Spectral areas responsible for this segregation pointed towards epigenetic changes. Immunohistochemical studies for DNA methylation and hypomethylation supported these results. Vibrational spectroscopy techniques were also implemented to explore molecular changes between normal ovarian tissue, borderline ovarian tumours and malignant ovarian carcinomas. Different chemometric techniques were applied to discriminate cancers from controls. Similar techniques were able to segregate different types of epithelial ovarian carcinomas. The accurate diagnosis obtained using ATR-FTIR spectroscopy demonstrates its potential for development as an assisting tool for histopathological diagnosis. The endometrial-myometrial junction areas of benign uterine tissues were scrutinised by Synchrotron FTIR and FPA. These techniques in combination with multivariate analysis revealed clear segregation between the functionalis and basalis layers within the uterine crypts. The same techniques illustrated potential areas within these epithelial surfaces where different stem cell types may reside. Targeting the activation/ inactivation of these stem cells may have applications in the diagnosis and treatment of early uterine cancer

Primary Health Care

This book presents examples from various countries about the provision of health services at the primary care level. Chapters examine the role of professionals in primary healthcare services and how they can work to improve the health of individuals and communities. Written by authors from Africa, Asia, America, Europe, and Australia, this book provides up-to-date information on primary health care, including telehealth services in the era of COVID-19