Modelling neoplastic progression in epithelial ovarian cancer

A national screening programme could significantly reduce mortality from epithelial ovarian cancer (EOC). The biological events that occur in the early stages of development of EOCs remain poorly understood, thus hindering the discovery of biomarkers of early disease. This thesis describes the development of a three-dimensional heterotypic genetic model of neoplastic transformation of normal ovarian surface epithelial (NOSE) cells. hTERT, C-MYC, KRAS and BRAF are genes that are commonly mutated or overexpressed in EOCs. Ectopic expression of hTERT increased in vitro lifespan of NOSE cells without inducing neoplastic transformation. Subsequent overexpression of CMYC +/- KRASG12V /BRAFV 600E in immortalised NOSE (IOSE) cells induced a significant increase in anchorage-independent growth and invasive ability. In in vitro assays and gene expression microarrays, phenotypic and molecular heterogeneity was associated with differential oncogene expression. Physiological and biological features of NOSE cells grown in 3D more closely resembled characteristics of NOSE cells in vivo than when grown by classical two-dimensional (2D) approaches. 3D models of oncogene-expressing clones revealed characteristics of malignant cells in vivo that could not be detected in 2D monolayer cultures. Gene expression microarrrays profiles of ~25,000 genes were generated to identify novel genes that are altered synergistically with the oncogenes that were introduced. A panel of genes has been identified that provides novel candidates for detecting ovarian carcinomas at the earliest, most treatable, stages of disease. Finally, a role for ageing fibroblasts in the initiation of EOC development was explored. In 2D and 3D in vitro co-culture assays, pre-senescent and senescent ovarian fibroblasts differentially affected proliferation, anchorage-independent growth, migration and invasion of IOSECMYC cell lines but not of IOSE cells. These data provide in vitro evidence that the ageing microenvironment can promote transformation of ovarian epithelial cells, and that this is conditional upon mutation in the OSE

Oral omega-6 essential fatty acid treatment in contact lens associated dry eye.

Symptoms of dry eye are commonly reported in contact lens wearers and are a frequent cause of non-tolerance. The purpose of the present study is to evaluate the effects of oral treatment with particular omega-6 fatty acids in the form of evening primrose oil (EPO) on subjective symptoms, ocular surface signs and tear film characteristic in patients with contact lens associated dry eye

Audit of paediatric cardiac services in South Africa

Objective: To evaluate paediatric cardiac services in South Africa with respect to referral base, services provided and human resources.Study design: A descriptive study design was used. An audit of the referral base, personnel and activity of paediatric cardiac units throughout South Africa was conducted by means of a questionnaire. A specialist from each centre was asked to provide the relevant data. Where accurate data was not available, estimates were provided by practitioners within each centre.Results: All identified units participated in the audit. Three were private sector units while the other five were primarily public sector units. Twenty four paediatric cardiologists, equally distributed between public and private sector units, were practicing in the country as at end 2008, with a further eight paediatricians undergoing training in paediatric cardiology. This is significantly less than the 88 paediatric cardiologists required for the population of South Africa. Eight paediatric cardiac surgeons were operating predominantly on children in public hospitals and five in private institutions. An estimated 1370 operations for congenital heart disease were performed over a one year period, with 800 of these in the public sector. Extrapolating from accepted estimates of congenital heart disease incidence, this represents conservatively, less that 40% of operations required for the population. Additionally, only 26% of the estimated 114 simple transposition of great arteries born annually were operated on, indicating serious deficiencies in the ability to adequately detect and intervene in serious congenital heart disease presenting in the neonatal period. Conclusion: The infrastructure and resources to detect and manage heart disease in children in South Africa, particularly within the public sector, are grossly inadequate

Optimal paediatric cardiac services in South Africa – what do we need?

Most children with congenital heart disease have a good outcome if treated appropriately, however the majority of children with heart disease in South Africa do not receive appropriate care. This is related to serious deficiencies in the mechanisms and training for early detection as well as a major shortage of skilled personnel to care for these children at all levels. Most public sector hospitals are unable to cope with the number of patients requiring surgery, mainly due to inadequate theatre time allocation and intensive care facilities. Key interventions to address these deficiencies include: 1. Strategies to improve both the training and the retention of all professionals involved in the care of congenital heart disease. 2. Programmes to increase awareness of both congenital and acquired heart disease in children among health care personnel. 3. Ensuring appropriate infrastructure and equipment designed for children with congenital heart disease are available. 4. Development of congenital heart surgery as an independent subspecialty with dedicated resources and personnel. 5. Dedicated intensive care facilities for paediatric heart surgery. In addition, development of appropriate patterns of referral, stimulation of research and positive private-public partnerships are all necessary to ensure that appropriate care is delivered

Time spent outdoors as an intervention for myopia prevention and control in children: an overview of systematic reviews

Purpose: Outdoor light exposure is considered a safe and effective strategy to reduce myopia development and aligns with existing public health initiatives to promote healthier lifestyles in children. However, it is unclear whether this strategy reduces myopia progression in eyes that are already myopic. This study aims to conduct an overview of systematic reviews (SRs) reporting time spent outdoors as a strategy to prevent myopia or slow its progression in children. Methods: We searched the Cochrane Library, EMBASE, MEDLINE and CINAHL from inception to 1 November 2020 to identify SRs that evaluated the association between outdoor light exposure and myopia development or progression in children. Outcomes included incident myopia, prevalent myopia and change in spherical equivalent refractive error (SER) and axial length (AL) to evaluate annual rates of myopia progression. The methodological quality and risk of bias of included SRs were assessed using the AMSTAR-2 and ROBIS tools, respectively. Results: Seven SRs were identified, which included data from 47 primary studies with 63,920 participants. Pooled estimates (risk or odds ratios) consistently demonstrated that time outdoors was associated with a reduction in prevalence and incidence of myopia. In terms of slowing progression in eyes that were already myopic, the reported annual reductions in SER and AL from baseline were small (0.13–0.17 D) and regarded as clinically insignificant. Methodological quality assessment using AMSTAR-2 found that all reviews had one or more critical flaws and the ROBIS tool identified a low risk of bias in only two of the included SRs. Conclusion: This overview found that increased exposure to outdoor light reduces myopia development. However, based on annual change in SER and AL, there is insufficient evidence for a clinically significant effect on myopia progression. The poor methodological quality and inconsistent reporting of the included systematic reviews reduce confidence in the estimates of effect

Health services research in the public healthcare system in Hong Kong: An analysis of over 1 million antihypertensive prescriptions between 2004-2007 as an example of the potential and pitfalls of using routinely collected electronic patient data

<b>Objectives</b> Increasing use is being made of routinely collected electronic patient data in health services research. The aim of the present study was to evaluate the potential usefulness of a comprehensive database used routinely in the public healthcare system in Hong Kong, using antihypertensive drug prescriptions in primary care as an example.<p></p> <b>Methods</b> Data on antihypertensive drug prescriptions were retrieved from the electronic Clinical Management System (e-CMS) of all primary care clinics run by the Health Authority (HA) in the New Territory East (NTE) cluster of Hong Kong between January 2004 and June 2007. Information was also retrieved on patients’ demographic and socioeconomic characteristics, visit type (new or follow-up), and relevant diseases (International Classification of Primary Care, ICPC codes). <p></p> <b>Results</b> 1,096,282 visit episodes were accessed, representing 93,450 patients. Patients’ demographic and socio-economic details were recorded in all cases. Prescription details for anti-hypertensive drugs were missing in only 18 patients (0.02%). However, ICPC-code was missing for 36,409 patients (39%). Significant independent predictors of whether disease codes were applied included patient age > 70 years (OR 2.18), female gender (OR 1.20), district of residence (range of ORs in more rural districts; 0.32-0.41), type of clinic (OR in Family Medicine Specialist Clinics; 1.45) and type of visit (OR follow-up visit; 2.39). <p></p> In the 57,041 patients with an ICPC-code, uncomplicated hypertension (ICPC K86) was recorded in 45,859 patients (82.1%). The characteristics of these patients were very similar to those of the non-coded group, suggesting that most non-coded patients on antihypertensive drugs are likely to have uncomplicated hypertension. <p></p> <b>Conclusion</b> The e-CMS database of the HA in Hong Kong varies in quality in terms of recorded information. Potential future health services research using demographic and prescription information is highly feasible but for disease-specific research dependant on ICPC codes some caution is warranted. In the case of uncomplicated hypertension, future research on pharmaco-epidemiology (such as prescription patterns) and clinical issues (such as side-effects of medications on metabolic parameters) seems feasible given the large size of the data set and the comparability of coded and non-coded patients

Determining the date of diagnosis – is it a simple matter? The impact of different approaches to dating diagnosis on estimates of delayed care for ovarian cancer in UK primary care

Background Studies of cancer incidence and early management will increasingly draw on routine electronic patient records. However, data may be incomplete or inaccurate. We developed a generalisable strategy for investigating presenting symptoms and delays in diagnosis using ovarian cancer as an example. Methods The General Practice Research Database was used to investigate the time between first report of symptom and diagnosis of 344 women diagnosed with ovarian cancer between 01/06/2002 and 31/05/2008. Effects of possible inaccuracies in dating of diagnosis on the frequencies and timing of the most commonly reported symptoms were investigated using four increasingly inclusive definitions of first diagnosis/suspicion: 1. "Definite diagnosis" 2. "Ambiguous diagnosis" 3. "First treatment or complication suggesting pre-existing diagnosis", 4 "First relevant test or referral". Results The most commonly coded symptoms before a definite diagnosis of ovarian cancer, were abdominal pain (41%), urogenital problems(25%), abdominal distension (24%), constipation/change in bowel habits (23%) with 70% of cases reporting at least one of these. The median time between first reporting each of these symptoms and diagnosis was 13, 21, 9.5 and 8.5 weeks respectively. 19% had a code for definitions 2 or 3 prior to definite diagnosis and 73% a code for 4. However, the proportion with symptoms and the delays were similar for all four definitions except 4, where the median delay was 8, 8, 3, 10 and 0 weeks respectively. Conclusion Symptoms recorded in the General Practice Research Database are similar to those reported in the literature, although their frequency is lower than in studies based on self-report. Generalisable strategies for exploring the impact of recording practice on date of diagnosis in electronic patient records are recommended, and studies which date diagnoses in GP records need to present sensitivity analyses based on investigation, referral and diagnosis data. Free text information may be essential in obtaining accurate estimates of incidence, and for accurate dating of diagnoses