16 research outputs found

    Defining the Newborn Blood Spot Screening Reference Interval for TSH: Impact of Ethnicity

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    CONTEXT: There is variability in the congenital hypothyroidism (CH) newborn screening TSH cutoff across the United Kingdom. OBJECTIVE: To determine the influences of year, gender, and ethnicity on screening variability and examine whether there is an optimal operational TSH cutoff. DESIGN AND SETTING: Single center, retrospective population study using blood spot TSH cards received by the Great Ormond Street Hospital Screening Laboratory between 2006 and 2012. PATIENTS: A total of 824 588 newborn screening blood spot TSH cards. INTERVENTION: Blood spot TSH results were recorded with demographic data including the Ethnic Category Code. MAIN OUTCOME MEASURES: The proportions of samples exceeding different TSH cutoffs, ranked by ethnicity. RESULTS: The proportion of samples exceeding the TSH cutoff increased over time, with the cutoff at 4 mU/L, but not at 6 mU/L. There was a consistent trend with ethnicity, irrespective of cutoff, with the odds ratio of exceeding the TSH cutoff lowest (∼1.0) in White babies, higher in Pakistani and Bangladeshi (>2.0), and highest in Chinese (>3.5). CONCLUSIONS: The blood spot TSH screening data demonstrate a clear ranking according to ethnicity for differences in mean TSH. This suggests that there may be ethnic differences in thyroid physiology. Ethnic diversity within populations needs to be considered when establishing and interpreting screening TSH cutoffs

    Parental views on informed consent for expanded newborn screening

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    Background  An increasing array of rare inherited conditions can be detected as part of the universal newborn screening programme. The introduction and evaluation of these service developments require consideration of the ethical issues involved and appropriate mechanisms for informing parents and gaining consent if required. Exploration of parental views is needed to inform the debate and specifically consider whether more flexible protocols are needed to fit with the public perception of new developments in this context. Objective  This study has been undertaken to explore perceptions and attitudes of parents and future parents to an expanded newborn screening programme in the United Kingdom and the necessary information provision and consent processes. Design and participants  A mixed methods study involving focus groups (n = 29) and a web‐survey (n = 142) undertaken with parents and future parents. Results and conclusions  Parents want guaranteed information provision with clear decision‐making powers and an awareness of the choices available to them. The difference between existing screening provision and expanded screening was not considered to be significant enough by participants to warrant formal written, informed consent for expanded screening. It is argued that the ethical review processes need to be more flexible towards the provision of information and consent processes for service developments in newborn screening

    Hemoglobinopathy prevention in primary care: a reflection of underdetection and difficulties with accessibility of medical care, a quantitative study

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    As in most Northern European countries, the prevalence of hemoglobinopathies in The Netherlands is increasing due to migration. Although hemoglobinopathies are severe chronic diseases with few treatment options, timely detection of carriers allows at-risk couples to make informed reproductive choices such as pre-implantation diagnosis, prenatal diagnosis or termination of affected pregnancies. Using a quantitative design, we evaluated the prevalence of hemoglobinopathies in The Hague region, The Netherlands. Patient and carrier registries from hospital, laboratory and general practitioners allowed this quantitative analysis. The highest prevalence of hemoglobinopathies was seen in immigrant neighborhoods, and a large gap was noted between estimated carrier prevalence and the actual registration of carriers in electronic patient records. Carrier prevalence was estimated to be 13,704; however, the ELAN database contains only 1542 cases with ICPC codes for sickle cell disease or thalassemia. Although more research is needed to define the requirements of the healthcare system to address this challenge, this study clearly shows the gap between estimated carrier prevalence and registration and thereby the pressing need for action.Genetics of disease, diagnosis and treatmen

    Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight

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    Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (P-Bonferroni <1.06 x 10(-7)). In additional analyses in 7,278 participants,Peer reviewe

    The Production of Monoclonal Antibodies to Human TSH and Their Use in the Design of Immunometric Assays for Serum and Neonatal Blood Spot TSH

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    The potential for the application of antibodies as analytical and preparative reagents was greatly expanded by the development of techniques for the production of monoclonal antibodies (Kohler and Milstein, 1975, 1976). The properties of monoclonal antibodies are particularly suited to application in immunometric assays and indeed overcome all the major problems associated with conventional antisera. Antibodies of only moderate affinity may be used in sensitive immunometric assays with detection limits up to two orders of magnitude greater than can be achieved in competitive immunoassays with the same antibody (Buchegger et al, 1981). The work of this thesis was concerned with the production of monoclonal antibodies to human TSH and their use in the design of immunometric assays for serum and neonatal blood spot TSH. Chapter 3 deals with the production of a variety of monoclonal antibodies to TSH. These antibodies were characterised in terms of affinity, specificity and isotype. The results indicated that 5H8 and 2G2 may be of extreme practical value in the development of a two-site immunoradiometric assay (IRMA) for TSH. A number of such assays for the measurement of TSH in serum and in neonatal blood spots were then developed using both monoclonal and polyclonal antisera. Chapter 4 seeks to illustrate the clinical role and suitability of the monoclonal-polyclonal serum TSH assay developed in this project. The assay successfully distinguished all cases of untreated primary hypothyroidism as having an elevated serum TSH and all cases of untreated hyperthyroidism as having an undetectable serum TSH (<0.2 mU/1). On the basis of this information, together with the performance data described in Chapter 3, the assay was introduced in 1984 as the 'routine" serum TSH assay for the laboratory at Glasgow Royal Infirmary, processing some 20,000 serum specimens per annum. Regarding the Scottish Screening Programme for congenital hypothyroidism, at the end of 1983 the monoclonal - polyclonal IRMA replaced the two-polyclonal IRMA of Sutherland et al (1981). Cumulative statistics and predictive values of the data obtained from The National Screening Programme with the two In-house IRMA TSH assays are recorded in Chapter 5 and they reveal that the monoclonal - polyclonal IRMA has continued to maintain the excellent clinical data obtained from the Scottish Screening Programme. Alternative high specific activity labels and the implications of these developments for the serum TSH assay service in Glasgow Royal Infirmary and the Scottish Screening Programme for congenital hypothyroidism are discussed in Chapter 6. It is almost certain that the clinical value of a serum TSH assay will be enhanced by improving the detection limit from 0.2 mU/1 to 0.02 mU/1. Such an improvement is not possible with the existing monoclonal and polyclonal antibodies and an 125I-label. The most straightforward way to achieve this improvement is to move to a non-isotopic label that is compatible with the available antibodies. The work presented in Chapter 4 of this thesis (Sections V and VI) has shown that many patients receiving thyroxine replacement therapy have undetectable serum TSH levels, both in the in-house IRMA and using the Delfia assay. The interpretation of these results is discussed in Chapter 6. However, the role of sensitive TSH assays in monitoring patients receiving thyroxine replacement has still to be fully evaluated

    Living with cystic fibrosis: Patients' experiences of diagnosis in adulthood

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    There is a paucity of research investigating what it is like to be diagnosed and to live with cystic fibrosis (CF) in adulthood. Understanding the experiences of these adults and the impact of the condition can provide information to help healthcare professionals deliver appropriate support for their patients. This research aimed to address this gap in the literature. In-depth semi-structured interviews were carried out with sixteen participants (ten females and six males) diagnosed with CF in adulthood. Using thematic analysis, four themes were identified “No, you can’t possibly have CF”, Emotions around diagnosis, “It did kind of take over my life” and “I no longer wish to argue with it”. These themes described participants’ frustrations with their contact with healthcare providers before diagnosis, their ambivalence around their diagnosis, the various impact and challenges faced with day-to-day living, work-life, finances, relationships, fertility, life plans, the future, treatment burden and their acceptance and adjustment to their CF. A key finding was the mismatch between patient need and healthcare provision. The main recommendations made included: 1) raising a greater awareness amongst non-CF specialist healthcare professionals and the general public of the possibility of receiving a CF diagnosis in adulthood, 2) ensuring CF healthcare professionals delivering the news of an adult CF diagnosis have the appropriate training and support and 3) ensuring CF healthcare professionals adequately assess individual’s information needs and provide appropriate and relevant information. The implications for health psychology practice include support for patients to help make sense of the diagnosis, develop adaptive coping strategies and adjust to living with a chronic condition. The role of the psychologist would involve working with specialist CF healthcare professionals through providing educative training, reflective practice and supervision

    Significant conversations with parents: a systematic review of interventions to support the communication of bad news in paediatric settings and a qualitative study of parental experiences of receiving a newborn diagnosis of cystic fibrosis

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    Background: Significant conversations with parents are a necessary and important part of healthcare. The delivery of bad or difficult news, such as the diagnosis of a chronic health condition, requires key communication skills. This is especially true for communication between healthcare professionals and parents in paediatric settings. It is important to understand parental experiences of these conversations and what can be done to help support and improve skills in this area. Method: A systematic review evaluates studies assessing the effectiveness of interventions in improving breaking bad news skills. An empirical study uses Interpretative Phenomenological Analysis of interviews with parents to gain an in-depth understanding of parental experiences of receiving a newborn diagnosis of cystic fibrosis (CF). Results: The systematic review identified ten quantitative studies assessed to be of either moderate or high quality. Significant improvements in communication skills were found following nine of the ten interventions. These interventions shared some common features. In the empirical study, three superordinate themes emerged following interview analysis: Cognitive and Emotional Experiences; Connection; and Knowledge. Conclusions: Findings from the review suggest that there are interventions that can improve communication skills in delivering bad news in paediatric settings. Parents in the empirical study clearly recalled the period of receiving a newborn diagnosis of CF as an emotional time. Health professionals’ communication and interpersonal skills seemed to play an important role in providing containment for families. Clinical implications and directions for future research are discussed

    Cardiopulmonary exercise testing in the assessment and treatment of young people with cystic fibrosis

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    Cystic fibrosis (CF) is the most common, genetically inherited, life-shortening condition in the Caucasian population, with ~11,000 people in the United Kingdom having the disease. The genetic defect responsible for CF results in accumulation of thick, sticky mucus that blocks the airways and digestive systems. As there is currently no cure for CF, it is a disease that is managed using antibiotics, nutrition, physiotherapy and exercise. Exercise capacity, as measured by peak oxygen uptake (V̇O2peak), and where possible, maximal oxygen uptake (V̇O2max), is reduced in patients with CF and a low V̇O2peak is associated with increased risk of hospitalisation, mortality and low quality of life. As a result, regular exercise testing is recommended, with cardiopulmonary exercise testing (CPET) considered the ‘gold standard’ procedure by leading international clinical organisations. The purpose of this thesis was to further our understanding surrounding the use of CPET in the assessment and treatment of children and adolescents with CF. The first component of this thesis sought to identify and evaluate submaximal parameters of aerobic function derived from CPET, namely the oxygen uptake efficiency slope (OUES) and plateau (OUEP). Findings revealed that allometric scaling for body surface area (BSA) was necessary when evaluating OUES, and a power function of 1.40 (i.e. OUES/BSA1.40) removed residual effects of body size (Chapter 4). Subsequently, results identified that the OUES was not a valid surrogate of aerobic fitness in CF, despite a significant correlation (r = 0.47, p = 0.004) with V̇O2max when expressed relative to body mass, as it was unable to discriminate aerobic fitness within a CF group, nor against a control group (Chapter 5). As OUES was not a valid surrogate of aerobic fitness, the utility of OUEP as an independent marker of aerobic fitness was explored. Whilst the OUEP was correlated with V̇O2peak in CF, when expressed as an absolute value (r = 0.43, p = 0.010) and when allometrically scaled for body mass (r = 0.52, p = 0.001), it was unable to discriminate aerobic fitness to the same extent as V̇O2peak. However, the OUEP was associated with disease status and severity, being significantly (p < 0.001) lower in the CF group, but also significantly and positively correlated with lung function (forced expiratory volume in one-second [FEV1]) in the CF group (r = 0.43, p = 0.010), a finding that warrants further, longitudinal investigation (Chapter 6). The second component of this thesis utilised CPET to investigate musculoskeletal limitations to the reduced V̇O2max that has previously been reported in CF. Parameters of muscle size (thigh cross-sectional area, muscle cross-sectional area and thigh muscle volume) were first quantified using magnetic resonance imaging, alongside the error associated with estimating muscle volume using alternative calculation techniques (Chapter 7). These parameters were then allometrically scaled for, which successfully removes residual effects of muscle size (i.e. muscle ‘quantity’) from V̇O2max. When this scaling is undertaken, V̇O2max is lower in children with CF relative to age- and sex-matched controls, indicating that exercise capacity is not size-dependent in CF and that intrinsic muscular factors (i.e. muscle ‘quality’) are likely responsible for the reduced V̇O2max observed in CF (Chapter 8). Finally, the third component identified applications of CPET for both patients with CF and staff responsible for care. CPET, using a case-study approach, was utilised to describe exercise-related changes in an 11 year old female with CF following surgical insertion of a percutaneous endoscopic gastrostomy and overnight nutritional supplementation. This evaluation identified a maintenance of V̇O2max over one year, in contrast to a fluctuation in FEV1, and increase in body mass index (BMI), therefore highlighting the independent prognostic information afforded by use of CPET (Chapter 9). Following this patient-centred application of CPET, two meetings were held with NHS staff, to provide a platform for exchange of ideas and best practice, but to also survey roles, responsibilities, prevalence of CPET and resources needed for effective implementation of exercise testing and training (Chapter 10). In conclusion, this thesis has further highlighted the utility of CPET in the management of CF. Moreover, it has explored the prognostic and diagnostic properties of CPET, as well as its implementation for patients and staff alike
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