4 results on '"Conwell, Louise S."'
Search Results
2. Predicted benign and synonymous variants in CYP11A1 cause primary adrenal insufficiency through missplicing
- Author
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Maharaj, Avinaash, Buonocore, Federica, Meimaridou, Eirini, Ruiz-Babot, Gerard, Guasti, Leonardo, Peng, Hwei Ming, Capper, Cameron P., Burgos-Tirado, Neikelyn, Prasad, Rathi, Hughes, Claire R., Maudhoo, Ashwini, Crowne, Elizabeth, Cheetham, Timothy D., Brain, Caroline E., Suntharalingham, Jenifer P., Striglioni, Niccolò, Yuksel, Bilgin, Gurbuz, Fatih, Gupta, Sangay, Lindsay, Robert, Couch, Robert, Spoudeas, Helen A., Guran, Tulay, Johnson, Stephanie, Fowler, Dallas J., Conwell, Louise S., McInerney-Leo, Aideen M., Drui, Delphine, Cariou, Bertrand, Lopez-Siguero, Juan P., Harris, Mark, Duncan, Emma L., Hindmarsh, Peter C., Auchus, Richard J., Donaldson, Malcolm D., Achermann, John C., Metherell, Louise A., Maharaj, Avinaash, Buonocore, Federica, Meimaridou, Eirini, Ruiz-Babot, Gerard, Guasti, Leonardo, Peng, Hwei Ming, Capper, Cameron P., Burgos-Tirado, Neikelyn, Prasad, Rathi, Hughes, Claire R., Maudhoo, Ashwini, Crowne, Elizabeth, Cheetham, Timothy D., Brain, Caroline E., Suntharalingham, Jenifer P., Striglioni, Niccolò, Yuksel, Bilgin, Gurbuz, Fatih, Gupta, Sangay, Lindsay, Robert, Couch, Robert, Spoudeas, Helen A., Guran, Tulay, Johnson, Stephanie, Fowler, Dallas J., Conwell, Louise S., McInerney-Leo, Aideen M., Drui, Delphine, Cariou, Bertrand, Lopez-Siguero, Juan P., Harris, Mark, Duncan, Emma L., Hindmarsh, Peter C., Auchus, Richard J., Donaldson, Malcolm D., Achermann, John C., and Metherell, Louise A.
- Abstract
Primary adrenal insufficiency (PAI) is a potentially life-threatening condition that can present with nonspecific features and can be difficult to diagnose. We undertook next generation sequencing in a cohort of children and young adults with PAI of unknown etiology from around the world and identified a heterozygous missense variant (rs6161, c.940G.A, p.Glu314Lys) in CYP11A1 in 19 individuals from 13 different families (allele frequency within undiagnosed PAI in our cohort, 0.102 vs 0.0026 in the Genome Aggregation Database; P, 0.0001). Seventeen individuals harbored a second heterozygous rare disruptive variant in CYP11A1 and two had very rare synonymous changes in trans (c.990G.A, Thr330 =; c.1173C.T, Ser391 =). Although p.Glu314Lys is predicted to be benign and showed no loss-of-function in an Escherichia coli assay system, in silico and in vitro studies revealed that the rs6161/c.940G.A variant, plus the c.990G.A and c.1173C.T changes, affected splicing and that p.Glu314Lys produces a nonfunctional protein in mammalian cells. Taken together, these findings show that compound heterozygosity involving a relatively common and predicted “benign” variant in CYP11A1 is a major contributor to PAI of unknown etiology, especially in European populations. These observations have implications for personalized management and demonstrate how variants that might be overlooked in standard analyses can be pathogenic when combined with other very rare disruptive changes.
- Published
- 2019
3. Bisphosphonates for osteoporosis in people with cystic fibrosis (Review)
- Author
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Conwell, Louise S., Chang, Anne B., Conwell, Louise S., and Chang, Anne B.
- Abstract
BackgroundOsteoporosis is a bone mineralisation disorder occurring in about one third of adults with cystic fibrosis. Bisphosphonates can increase bone mineral density and decrease the risk of new fractures in post-menopausal women and people receiving long-term oral corticosteroids.ObjectivesTo assess the effects of bisphosphonates on the frequency of fractures, bone mineral density, quality of life, adverse events, trial withdrawals, and survival in people with cystic fibrosis.Search methodsWe searched the Cystic Fibrosis and Genetic Disorders Group Trials Register of references (identified from electronic database searches and handsearches of journals and abstract books) on 13 January 2014.Additional searches of PubMed were performed on 13 January 2014.Selection criteriaRandomised controlled trials of at least six months duration studying bisphosphonates in people with cystic fibrosis.Data collection and analysisTwo authors independently selected trials and extracted data. Trial investigators were contacted to obtain missing data.Main resultsNine trials were identified and seven (with a total of 237 adult participants) were included.Data were combined (when available) from six included studies in participants without a lung transplant. Data showed that there was no significant reduction in fractures between treatment and control groups at 12 months, odds ratio 0.72 (95% confidence interval 0.13 to 3.80). No fractures were reported in studies with follow-up at 24 months. However, in patients taking bisphosphonates after six months the percentage change in bone mineral density increased at the lumbar spine, mean difference 4.61 (95% confidence interval 3.90 to 5.32) and at the hip or femur, mean difference 3.35 (95% confidence interval 1.63 to 5.07); but did not significantly change at the distal forearm, mean difference -0.49 (95% confidence interval -2.42 to 1.45). In patients taking bisphosphonates, at 12 months the percentage change in bone mineral density incr
- Published
- 2014
4. Considering statins for cholesterol-reduction in children if lifestyle and diet changes do not improve their health: a review of the risks and benefits
- Author
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O'Gorman, Clodagh S., O'Neill, Michael B., Conwell, Louise S., O'Gorman, Clodagh S., O'Neill, Michael B., and Conwell, Louise S.
- Abstract
peer-reviewed, Children who appear healthy, even if they have one or more recognized cardiovascular risk factors, do not generally have outcomes of cardiovascular or other vascular disease during childhood. Historically, pediatric medicine has not aggressively screened for or treated cardiovascular risk factors in otherwise healthy children. However, studies such as the P-Day Study (Pathobiological Determinants of Atherosclerosis in Youth), and the Bogalusa Heart Study, indicate that healthy children at remarkably young ages can have evidence of significant atherosclerosis. With the increasing prevalence of pediatric obesity, can we expect more health problems related to the consequences of pediatric dyslipidemia, hypertriglyceridemia, and atherosclerosis in the future? For many years, medications have been available and used in adult populations to treat dyslipidemia. In recent years, reports of short-term safety of some of these medications in children have been published. However, none of these studies have detailed long-term follow-up, and therefore none have described potential late side-effects of early cholesterol-lowering therapy, or potential benefits in terms of reduction of or delay in cardiovascular or other vascular end-points. In 2007, the American Heart Association published a scientific statement on the use of cholesterol-lowering therapy in pediatric patients. In this review paper, we discuss some of the current literature on cholesterol-lowering therapy in children, including the statins that are currently available for use in children, and some of the cautions with using these and other cholesterol-lowering medications. A central tenet of this review is that medications are not a substitute for dietary and lifestyle interventions, and that even in children on cholesterol-lowering medications, physicians should take every opportunity to encourage children and their parents to make healthy diet and lifestyle choices.
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