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Within the Cystic Fibrosis (CF) literature it is acknowledged that parents play a significant role in supporting children with treatment procedures. Furthermore, a number of parenting variables have been associated with treatment adherence within the paediatric CF population. Interventions that target parenting practices may therefore have the potential to improve CF treatment adherence. Paper one presents a systematic literature review of parenting interventions targeting treatment adherence in children and adolescents with CF. The majority of studies focussed on dietary adherence and overall findings from these studies suggested that combined behavioural and nutritional counselling parenting interventions led to improvements in calorie intake and positive parenting practices. Interventions specifically targeting exercise adherence and interventions targeting multiple aspects of the CF treatment regimen were also shown to improve treatment adherence. The review highlighted that interventions targeting some of the more laborious treatments (i.e. chest physiotherapy) were lacking, as were interventions specifically tailored to the needs of adolescents and their parents. Over recent years, CF life expectancy has increased substantially due to medical advances. As a result, more children are living into adulthood, therefore needing to adhere to an increasingly complex treatment regime in order to manage increasing symptoms. Adolescence is a particularly challenging time for treatment adherence as children increase their independence and parents begin to allow the child to manage their own disease management. The study described in Paper 2 aimed to explore the acceptability and feasibility of the Self-Directed Teen Triple P parenting intervention within the adolescent CF population. It also explored whether parent-reported treatment adherence, positive parenting practices, parent wellbeing, and child emotional and behavioural functioning were increased as a result of this intervention. Whilst data from two cases indicated increasing trends in treatment adherence and positive parenting practices following the onset of the parenting intervention, uptake and retention to the intervention was poor. Interviews with parents and CF nurses indicated low acceptability and feasibility of the intervention in its current form and a number of adaptations were reported. The study concludes that researchers need to include parents within the design of tailored parenting interventions within this population in order to increase acceptability. Following this, larger scale studies are required to increase the reliability and rigor of research findings in this area. Paper 3 is a critical reflection and considers both Paper 1 and Paper 2. Within this paper the approaches used, the challenges encountered, and future research are considered.

Orientador: Carmen Silvia Bertuzzo / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-13T02:33:23Z (GMT). No. of bitstreams: 1 Correia_CyntiaArivabenideAraujo_D.pdf: 1775265 bytes, checksum: 99ecfece81f00d7833282ae41bae5731 (MD5) Previous issue date: 2009 / Resumo: A Fibrose Cística (FC) possui uma grande variabilidade de expressão fenotípica, o que significa que crianças com o mesmo genótipo podem diferir quanto à sua apresentação. A proteína defeituosa formada é chamada CFTR (proteína reguladora da conductância iônica), causa transporte anormal de sódio e cloro através da membrana apical das células epiteliais das vias aéreas, pâncreas, intestino e aparelho reprodutor. Essa proteína é codificada por um único gene que recebe o mesmo nome da proteína, CFTR, e localiza-se no braço longo do cromossomo 7, região 7q3.1. Gêmeos monozigóticos apresentam maior concordância em relação à gravidade da doença pulmonar que os dizigóticos, sugerindo que a FC seja modulada por fatores genéticos secundários - genes modificadores - além do gene CFTR. A característica mais importante na FC é a sobrevida que é influenciada pela doença pulmonar. Portanto, genes que estejam envolvidos na imunidade, inflamação, reparação do epitélio e produção de muco são candidatos a genes modificadores da doença. Os objetivos foram: 1) determinar a prevalência dos polimorfismos -308G/A e -238G/A do gene TNF a entre portadores de FC e verificar existência de associação entre esses polimorfismos e a gravidade do quadro pulmonar, 2) identificar alterações de sequencia nos exons e junções exon/ intron dos genes ADIPOQ e STATH e verificar existência de associação entre possíveis variações nesses genes e a gravidade da FC. Foi realizada PCR seguida por digestão enzimática para o polimorfismo -308G/A do gene TNF a, reação em cadeia da polimerase ARMS para o polimorfismo -238G/A do gene TNF a, e para os genes ADIPOQ e STATH foi feita a triagem de mutações através de cromatografia líquida de alta resolução por desnaturação - DHPLC com posterior sequenciamento da região onde foi encontrada alteração. Foram analisados 49 pacientes com FC em seguimento no Ambulatório de Mucoviscidose do HC/UNICAMP, homozigotos para a mutação F508 ou heterozigotos compostos para mutações de classe I ou II ou homozigotos para mutações de classe II, que são alterações que não levam à formação de proteína funcional. Além disso, foram selecionados indivíduos que apresentem alteração de eletrólitos no suor. Para o polimorfismo -308G/A do gene TNFa os genótipos GG, AA e GA foram encontrados com as seguintes frequencias: 14,28, 67,35 e 18,36% respectivamente. Estes dados se opõem ao relatado na literatura. Tal diferença deve ocorrer pelas características populacionais da população brasileira. Para o polimorfismo -238G/A do gene TNFa, os genótipos GG e AG tiveram as seguintes frequencias: 79,59 e 20,41% respectivamente. O genótipo AA não foi encontrado na amostra analisada. A alta frequencia do genótipo GG comparado com o AA, concorda com a literatura. Não foi encontrada alteração na sequencia dos genes STATH e ADIPOQ. Não foi possível estabelecer uma associação entre a gravidade da FC e os genes TNFa, STATH e ADIPOQ, nas regiões analisadas. / Abstract: Cystic Fibrosis (CF) has a great variety expression, which means that the seriousness of the disease can vary a lot among people who have it. The defective protein, called CFTR (Cystic Fibrosis Transmenbrane Regulator), causes abnormal transportation of chloride and sodium through the apical membrane of the epithelial cells of the airway, liver, intestine and masculine reproductive tract. This protein is encoded by a single gene which has the same name, CFTR, and is located within the long arm of chromosome 7, region 7q3.1. CF is a disease which expressivity is much variable, with different degrees of damage and the age when the symptoms begins is also much variable, even within individuals of the same family, like twins. Because of it, it is been said that others genetic factors besides CFTR, can be modulating the clinical presentation. As the pulmonary state is the great responsible for the mortality of the disease genes that are involved in host defense, inflammation, epithelial repair, mucin production, and airway reponsiveness are of great interest. Base on this the objectives of this work were: determine the prevalence of the polymorphisms -308G/A e -238G/A from the TNF a gene and verify if there is an association between these polymorphisms pulmonary disease severity, and identify alterations on ADIPOQ and STATH genes and verify if there is an association between these polymorphisms and CF severity. PCR followed by restriction enzyme digestion was performed to detect the polymorphism -308G/A from the TNF a gene, ARMS PCR to the polymorphism -238G/A from the TNF a gene the DHPLC method associated to the sequencing to analyze ADIPOQ and STATH genes, were used. We performed analyses of 49 cystic fibrosis patients that are followed in a Cystic Fibrosis center from HC/UNICAMP, that are \F508 homozygous or compound heterozygous to mutations from class I or II, or that are homozygous to class II mutations, which are alterations that do not produce functional protein. Besides this, were selected individuals that have sweat test altered. To the polymorphism 308G/A from TNFa gene the genotypes GG, AA e AG were in the following frequencies: 14,28, 67,35 e 18,36%. This data is contradictory to the literature and may occur because of the racial admixture of the Brazilian population. To the polymorphism -238G/A from TNFa gene, the genotypes GG AG were in the following frequencies 79,59 e 20,41%. The genotype AA was not found in the analyzed group. The high frequency of the genotype GG is in agreement of the data. It was not possible to find any alteration on ADIPOQ and STATH genes. And also it was not possible to make any correlation between the severity of the CF disease and the genes TNFa, STATH and ADIPOQ between the analyzed regions. / Doutorado / Ciencias Biomedicas / Doutor em Ciências Médicas

ABSTRACT Cystic fibrosis (CF) is an autosomal recessive disorder that occurs in all ethnic groups. Mutations in the cystic fibrosis transmembrane regulator (CFTR) gene are responsible for pulmonary obstruction, chronic lung infections, pancreatic insufficiency, meconium ileus, failure to thrive and infertility. Genetic testing for CF at the DNA level is available. A diagnosis of CF in an individual has implications for other family members and so genetic counselling should form part of CF management. Genetic counselling has been offered by the Clinical Unit of the Division of Human Genetics, National Health Laboratory Service and the University of the Witwatersrand, Johannesburg, for many years. At the beginning of 2006, genetic services were introduced into the CF Clinics of Johannesburg Hospital by way of specialist Genetic Counselling Clinics. The study aimed to determine who utilises the CF genetic counselling services and why, to estimate the number of at-risk relatives per family, and how many of them had mutation testing and genetic counselling. Finally, the study explored what impact the specialist Genetic Counselling Clinics had on the overall service of genetic counselling. The files of 153 families seen for CF genetic counselling from 1990 to 2006 were analysed. The majority of counsellees (93%) were white. Most counsellees were parents of CF probands (35%). Relatives with carrier risks of 67% (siblings) and 50% formed only 7% and 6% of all counsellees respectively. Most individuals attended genetic counselling in order to gather information. On average, 5.9 ± 3.45 families were seen for CF genetic counselling per year from 1990 to 2005, whereas in 2006, 58 families were seen. Paediatrician, physician and nurse referrals increased notably during 2006 compared to prior years. In 140 unrelated CF-affected families, 1991 at-risk relatives, with carrier risks above 25%, were identified. Only 11% of these relatives had mutation testing and only 8% attended genetic counselling. Uptake of genetic counselling is greater when the service is integrated into CF treatment clinics than when it is offered externally. The low uptake of mutation testing and genetic counselling by at-risk relatives suggests that new methods of educating individuals for cascade screening and testing are required.

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Background/Objectives: Chronic airway infections, characterized by pulmonary exacerbations, are responsible for >90% of morbidity and mortality in CF. Although conventional CF pathogens are targets of antibiotic therapy, colonization by complex polymicrobial communities is now recognized. Our previous research has observed novel pathogens in CF, and polymicrobial interactions, where increased P. aeruginosa virulence may contribute to airway infections. However, these culture-based findings are not recapitulated in culture-independent microbiome profiling studies. Because expectorated sputum produces highly heterogeneous mucous plugs, only a percentage is representative of the active subpopulation driving the disease. To distinguish populations, culture will be compared with DNA and RNA based molecular profiling. Methods: Spontaneous sputum produced by adult patients attending regular CF clinic visits were obtained within 30 min and processed. Aliquots were treated for quantitative culture and processed for DNA and RNA extraction. Bacterial composition was determined by profiling of the v3 variable region of the 16S rRNA gene (DNA) and 16S rRNA (RNA), and sequenced on an Illumina MiSeq and processed using DADA2. Results: Quantitative culture allowed for recovery of majority of the CF airway microbiome and resulted in distinct cultured organisms at each fractionation conditions for each patient. This individual specific composition was recapitulated in molecular profiles; however, DNA and RNA profiles were dissimilar at each fractionation step. Conclusions: Each bacterial profiling method resulted in distinct bacterial composition. Processing allowed for varying areas of sputum to be isolated resulting in high microbial diversity within the sample, highlighting high sputum microbiome heterogeneity.Incongruent DNA and RNA profiles across sputum suggest viable bacterial populations, represented by the RNA profile, may be more representative of disease state. Overall, the microbiology of sputum is highly patient specific and very difficult to identify a unifying pattern. / Thesis / Master of Science (MSc) / Cystic fibrosis is a deleterious, genetically inherited disease affecting 1 in every 3600 children born in Canada with 4300 individuals attending specialized clinics. CF most severely impacts the lungs, accounting for over 90% of mortality. In an attempt minimize irreversible decline in lung function, patients are prescribed aggressive antibiotic treatments. The issue is that conventional pathogens are targets of treatment and uncommon bacterial populations of low abundance are not of primary concern. Furthermore, expectorated sputum is used as a prognostic tool for estimating disease progression. Sputum is highly heterogeneous, containing mucous and saliva components. By fractionating the sputum, we can characterize active bacterial populations, which potentially contribute to disease progression, and dormant populations, which may be a result of chronic infection. Such analysis has emphasized high heterogeneity both within a single sample and across patient populations. This highlights the need for tailored treatment and management of disease for each individual.

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