Medicine
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This repository contains the published and unpublished research of the Faculty of Medicine by the staff members of the faculty
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Item Elective cholecystectomy is associated with increased morbidity and mortality in patients with severe Thalassemia: A retrospective case control study.(Ferrata Storti Foundation, 2015) Premawardhena, A.; Fernando, R.; Kumarage, S.; Nishad, N.; de Silva, I.BACKGROUND: Haemoglobin disorders including thalassemia and sickle cell disease are often complicated with gall stone formation. The co-existence of Gilbert's syndrome together with these diseases further increases the risk of gall bladder disease. Some of these patients develop symptomatic disease which necessitates surgical intervention. At present the timing of cholecystectomy for thalassemia is no different from that of the general population with the exception of removal of the gall bladder at the time of splenectomy. This is no longer the case in sickle cell disease where, laparoscopic cholecystectomy is recommended even in asymptomatic patients. This practice however has not been extended to other types of haemoglobin disorders. AIM(S): 1.To assess the perioperative complications of patients with thalassaemia during cholecytetomy and to compare it with non thalassaemics who undergo the procedure. 2. To see if there is enough evidence to recommend elective cholecystectomy for thalassaemics. METHOD(S): We retrospectively studied case notes of thalassemia patients who had cholecystectomy (cases) in two of the biggest thalassaemia centres in Sri Lanka and also of 62 non-thalassaemics (controls) with gall bladder disease who had been scheduled to have gall bladder surgery in the same hospitals and looked at their peri-operative complications. RESULT(S): 98 out of 540 (18%) thalassaemics in the two centres had gall stones. Mean age of cases was 26.8 (SD 10.9) years and of controls 47.5 (SD 19.7) years. 19 (19%) thalassaemics with gall stones had undergone cholecystectomy. Ten patients had cholecystectomy simultaneously with splenectomy. The majority of non-thalassaemic "controls" had laparoscopic cholecystectomy 53/55 (96.3%) whilst the patients with thalassaemia were mostly operated with laparotomy 13/19 (68%). There was a significant excess complications occurring in both early (42.11 vs. 18.1%) and late (31.5 vs. 12.7%) phases in the thalassaemic patients compared with the controls. Among the early complications, sepsis (10.5% vs. 1.8%) and liver abscess formation (5.2 vs. 0%) was significantly different in the groups, adversely affecting the thalassaemics. Recurrent abdominal pain was more common among the thalassaemics as a late complication (P<0.05). Six thalassaemic patients with gall stone disease died during this study, 5(5%) while awaiting surgery and 1(1%) after surgery. There were no deaths among the controls. Out of the deaths, 3 (50%) were directly attributable to gallstone disease. In all three septicemia precipitated heart failure. We found a significant increase of both early and late post-surgical complications in the thalassemia group and also increased mortality most of which was related to severe sepsis. Higher perioperative mortality and morbidity were seen among symptomatic thalassaemic patients with gall stone disease undergoing cholecystectomy. This seems to suggest a strong case for supporting elective cholecystectomy in thalassemics before they develop symptoms. SUMMARY AND CONCLUSION(S): We suggest that laparoscopic elective cholecystectomy be considered for non-sickle, thalassemia patients too who have asymptomatic gall bladder disease, in an attempt to reduce this morbidity and mortality.Item Alpha thalassaemia and extended alpha globin genes in Sri Lanka(Elsevier-Academic Press, 2013) Suresh, S.; Fisher, C.; Ayyub, H.; Premawardhena, A.; Allen, A.; Perera, A.; Bandara, D.; Olivieri, N.; Weatherall, D.The α-globin genes were studied in nine families with unexplained hypochromic anaemia and in 167 patients with HbE β thalassaemia in Sri Lanka. As well as the common deletion forms of α(+) thalassaemia three families from an ethnic minority were found to carry a novel form of α(0) thalassaemia, one family carried a previously reported form of α(0) thalassaemia, --(THAI), and five families had different forms of non-deletional thalassaemia. The patients with HbE β thalassaemia who had co-inherited α thalassaemia all showed an extremely mild phenotype and reduced levels of HbF and there was a highly significant paucity of α(+) thalassaemia in these patients compared with the normal population. Extended α gene arrangements, including ααα, αααα and ααααα, occurred at a low frequency and were commoner in the more severe phenotypes of HbE β thalassaemia. As well as emphasising the ameliorating effect of α thalassaemia on HbE β thalassaemia the finding of a novel form of α(0) thalassaemia in an ethnic minority, together with an unexpected diversity of forms of non-deletion α thalassaemia in Sri Lanka, further emphasises the critical importance of micro-mapping populations for determining the frequency of clinically important forms of the disease.Item Efficacy and safety of oral hydroxyurea in transfusion-dependent β-thalassaemia: a protocol for randomised double-blind controlled clinical trial(BMJ Publishing Group Ltd., 2020) Yasara, N.; Wickramarathne, N.; Mettananda, C.; Manamperi, A.; Premawardhena, A.; Mettananda, S.INTRODUCTION: Despite being one of the first diseases to be genetically characterised, β-thalassaemia remains a disorder without a cure in a majority of patients. Most patients with β-thalassaemia receive only supportive treatment and therefore have a poor quality of life and shorter life spans. Hydroxyurea, which has shown to induce fetal haemoglobin synthesis in human erythroid cells, is currently recommended for the treatment of sickle cell disease. However, its clinical usefulness in transfusion-dependent β-thalassaemia is unclear. Here, we present a protocol for a randomised double-blind controlled clinical trial to evaluate the efficacy and safety of oral hydroxyurea in transfusion-dependent β-thalassaemia. METHODS AND ANALYSIS: This single-centre randomised double-blind placebo-controlled clinical trial is conducted at the Thalassaemia Centre of Colombo North Teaching Hospital, Ragama, Sri Lanka. Adult and adolescent patients with haematologically and genetically confirmed transfusion-dependent β-thalassaemia are enrolled and randomised into the intervention or control group. The intervention group receives oral hydroxyurea 10-20 mg/kg daily for 6 months, while the control group receives a placebo which is identical in size, shape and colour to hydroxyurea without its active ingredient. Transfused blood volume, pretransfusion haemoglobin level, fetal haemoglobin percentage and adverse effects of treatment are monitored during treatment and 6 months post-treatment. Cessation or reduction of blood transfusions during the treatment period will be the primary outcome measure. The statistical analysis will be based on intention to treat. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Ethics Committee of Faculty of Medicine, University of Kelaniya (P/116/05/2018) and the trial is approved by the National Medicinal Regulatory Authority of Sri Lanka. Results of the trial will be disseminated in scientific publications in reputed journals.Item A Cost-of-illness analysis of β-Thalassaemia major in children in Sri Lanka - experience from a tertiary level teaching hospital.(BioMed Central., 2020) Reed-Embleton, H.; Arambepola, S.; Dixon, S.; Maldonado, B. N.; Premawardhena, A.; Arambepola, M.; Khan, J. A. M.; Allen, S.BACKGROUND: Sri Lanka has a high prevalence of β-thalassaemia major. Clinical management is complex and long-term and includes regular blood transfusion and iron chelation therapy. The economic burden of β-thalassaemia for the Sri Lankan healthcare system and households is currently unknown. METHODS: A prevalence-based, cost-of-illness study was conducted on the Thalassaemia Unit, Department of Paediatrics, Kandy Teaching Hospital, Sri Lanka. Data were collected from clinical records, consultations with the head of the blood bank and a consultant paediatrician directly involved with the care of patients, alongside structured interviews with families to gather data on the personal costs incurred such as those for travel. RESULTS: Thirty-four children aged 2-17 years with transfusion dependent thalassaemia major and their parent/guardian were included in the study. The total average cost per patient year to the hospital was $US 2601 of which $US 2092 were direct costs and $US 509 were overhead costs. Mean household expenditure was $US 206 per year with food and transport per transfusion ($US 7.57 and $US 4.26 respectively) being the highest cost items. Nine (26.5%) families experienced catastrophic levels of healthcare expenditure (> 10% of income) in the care of their affected child. The poorest households were the most likely to experience such levels of expenditure. CONCLUSIONS: β-thalassaemia major poses a significant economic burden on health services and the families of affected children in Sri Lanka. Greater support is needed for the high proportion of families that suffer catastrophic out-of-pocket costs. KEYWORDS: Children; Cost-of-illness; Sri Lanka; Thalassaemia.Item Genome editing of haemopoietic stem cells for treatment of thalassaemia(Oxford University Press, 2019) Badat, M.; Mettananda, S.; Hua, P.; Schwessinger, R.; Hughes, J.; Higgs, D.; Davies, J.AIM: Thalassaemia is commonly due to mutations at the beta globin (HBB) locus, and this causes transfusion dependent anaemia in severe cases. A key pathophysiological factor is the imbalance of alpha and beta globin production. This results in accumulation of excess alpha globin chains, which are toxic and cause cell death. Patients who co-inherit partial deletions of the alpha globin genes with beta thalassaemia usually have a mild phenotype and are transfusion independent. We aim to develop genome editing strategies of haemopoietic stem cells to exploit this for use as part of an autologous transplant to treat thalassaemia. METHODS: CRISPR-Cas9 was used to edit the most important enhancer of the alpha globin gene to elicit a controlled reduction in alpha globin expression. In silico methods were used to define the key sequences to delete to abrogate transcription factor binding. This allowed us to develop a strategy to disrupt single transcription factor binding sites using Cas9 ribonucleoprotein. RESULTS: Our in silico approaches allowed us to define three key transcription factor binding sites within the enhancer. We were able to achieve indel efficiencies in excess of 75% as measured by next generation sequencing. This resulted in a much more controlled reduction in alpha globin expression than was achieved by deletion of the whole enhancer. DISCUSSION: In silico prediction allows the identification of the sites within enhancers that allow genome editing to be used to reduce gene expression in a highly controlled manner.Item Thalassaemia: In a quest towards an ultimate cure(Sri Lanka College of Paediatricians, 2017) Mettananda, S.Item Correlation of genotype with phenotype in beta thalassaemia intermedia in Sri lanka(Thalassaemia International Federation, 2015) Perera, P.S.; Silva, D.P.S.I.; Hapugoda, M.; Wickramarathne, M.N.; Wijesiriwardena, I.; Efremov, D.G.; Fisher, C.A.; Weatherall, D.J.; Premawardhena, A.Abstract AvailableItem The Thal-index with the BTT prediction.exe to discriminate ß-thalassaemia traits from other microcytic anaemias(Pagepress, Italy, 2012) Nishad, A.A.N.; Pathmeswaran, A.; Wickremasinghe, A.R.; Premawardhena, A.Several attempts have been made previously to differentiate -thalassaemia trait (BTT) from other microcytic anaemias using formulae with red cell (RC) parameters. Presently available formulae have low sensitivity and specificity. We wanted to develop a more precise algorithm, which could be used in situations where the gold-standard test for thalassaemia diagnosis: the high performance liquid chromatography (HPLC) is not available. The study was carried out prospectively from November 2008 to March 2010 from randomly collected blood samples with a mean cell volume (MCV) of less than 80 fL. HbA2 measured by HPLC was used to diagnose BTT. We used Fishers stepwise linear discriminant function analysis to develop an algorithm with RC parameters. Calculated new index Thal-index was then subjected to receiver operating characteristic curve analysis to identify best cutoff to discriminate BTT from other microcytic blood films. Software was developed to predict the BTT status (BTT prediction.exe). New index, referred to as the Thal-index, was calculated using discriminant function analysis and is given as Thal-index=[(0.615MCV) +(0.518mean corpuscular hemoglobin)+ (0.446red cell distribution width)]. A value of 59 for Thal-index has 90% sensitivity and 85% specificity for differentiating BTT from other microcytic anaemias. This showed better sensitivity and specificity compared to other formulae presently used (i.e., Mentzer in Eshani, et al.). Our study gives a better answer to set-up where HPLC is not available. Although this cannot replace HPLC, BTT prediction.exe is useful to predict instantly and is the first ever computer program available for this functionItem Alpha-globin as a molecular target in treatment of beta-thalassemia(American Society of Hematology, 2015) Mettananda, S.; Gibbons, R. J.; Higgs, D. R.The thalassemias together with sickle cell anemia and its variants are the world's most common form of inherited anemia and in economically undeveloped countries still account for tens of thousands of premature deaths every year. In developed countries, treatment of thalassemia is still far from ideal, requiring lifelong transfusion or allogeneic bone marrow transplantation. Clinical and molecular genetic studies over the past 50 years have demonstrated how co-inheritance of modifier genes, which alter the balance of α-like and β-like globin gene expression, may transform severe, transfusion dependent thalassemia into mild forms of anemia. Most attention has been paid to pathways that increase γ-globin expression and hence the production of fetal hemoglobin. Here we review the evidence that reduction of α-globin expression may provide an equally plausible approach to ameliorate clinically severe forms of β-thalassemia, in particular, the very common subgroup of patients with HbE β-thalassemia which make up approximately half of all patients born each year with severe β-thalassemia.Item Is the beta thalassaemia trait of clinical importance?(Wiley-Blackwell, 2008) Premawardhena, A.; Arambepola, M.; Katugaha, N.; Weatherall, D. J.Although the beta thalassaemia trait affects millions of people worldwide, there have been no controlled studies to determine whether it is associated with any clinical disability or abnormal physical signs. To address this question, 402 individuals were studied: 217 with beta thalassaemia trait, of whom 154 were aware of the diagnosis and 63 were unaware until after the completion of the study; 89 normal controls; and 96 controls with mild hypochromic anaemia. There was a significant increase in symptoms ascribable to anaemia and episodes of pyrexia in those with the beta thalassaemia trait that were not influenced by prior knowledge that they had this condition. There was no difference in physical findings, notably splenomegaly, between those with beta thalassaemia trait and either control group