Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Integrating advanced technologies to uphold security of payment: Data flow diagram

© 2020 Elsevier B.V. Security of payment (SOP) issues still persist in the construction industry despite numerous investigations and incremental reforms. Various solutions and policies have been proposed and analysed in-depth in previous studies. However, limited studies have focused on the integration of advanced technologies to address SOP issues. The aim of this research is to develop a comprehensive framework that integrates practical advanced technologies to address SOP issues in the construction industry. A concurrent mixed-method design was adopted to (a) identify the industry's perspective on what advanced technologies can be accepted to address SOP issues through a questionnaire survey, and (b) identify the use of advanced technologies through a live construction project as a case study. Subsequently, a data flow diagram framework was developed to articulate the whole process flow of how the system delivers automatic payments to subcontractors upon the completion of their contractual obligations and work done. This research contributes new and practical insights into the application and integration of smart sensors, oracles, BIM, blockchain technology and smart contracts in addressing SOP issues in the construction industry

UK cost-utility analysis of rituximab in patients with rheumatoid arthritis that failed to respond adequately to a biologic disease-modifying antirheumatic drug

Objective: To evaluate the incremental cost effectiveness of rituximab in patients with rheumatoid arthritis that failed to respond adequately to tumour necrosis factor-a inhibitors (biologic disease-modifying antirheumatic drugs; bDMARDs). A cost-utility model has been developed to simulate the long-term incremental cost and benefits of rituximab using data from clinical trials and registries. Methods: The model estimates the lifetime disease progression of up to 10 000 hypothetical rheumatoid arthritis (RA) patients that failed one bDMARD. It compares cost and outcomes of two treatment sequences, representing the current UK standard both with and without rituximab. The population characteristics match those of the Randomised Evaluation of Long-term Efficacy of rituximab in RA (REFLEX) phase III randomised control trial. Clinical outcomes were based on an indirect comparison of published American College of Rheumatology response rates, adjusted for differences in placebo. To estimate medical resource use, health assessment questionnaire (HAQ) scores were grouped into five categories with UK registry data informing the average cost for each category. Quality-adjusted life years (QALYs) gained were mapped from disease severity (HAQ scores). Results: Compared to a standard UK treatment sequence (assuming the sequential use of bDMARDs) the introduction of rituximab led to a QALY gain of 0.526 years. The incremental cost-effectiveness ratios (ICEPs) based on total direct medical cost were 11 pound 601. Adding rituximab to a treatment sequence with no sequential use of biologic generates an ICER of 14 pound 690. Conclusion: Rituximab has lower average annual treatment costs compared to other bDMARDs and is a highly cost-effective treatment option for patients who have failed to respond adequately to one bDMARD. The cost per QALY gained of rituximab falls well below commonly accepted thresholds within the UK. Potential weaknesses of the model include the paucity of data on the efficacy of bDMARDs or non-biologic DMARDs when used as second-line options; the lack of consensus about the most appropriate therapy in patients who fail all available bDMARDs; probable underestimation of the non-drug related medical costs; indirect measurement of OALY gains with rituximab therapy; and the necessity of synthesising data from a number of clinical trials with different populations and study drugs

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Cost-effectiveness, Cost-utility, Pioglitazone, Rosiglitazone, Type-2-diabetes-mellitus

A Lifetime Modelled Economic Evaluation Comparing Pioglitazone and Rosiglitazone for the Treatment of Type 2 Diabetes Mellitus in the UK

Introduction: Adding pioglitazone or rosiglitazone to existing therapy are alternative treatment options for patients with type 2 diabetes mellitus who have insufficient glycaemic control while receiving the maximal tolerated dose of metformin monotherapy. Our objective was to develop a lifetime model of type 2 diabetes mellitus and its sequelae in order to compare the costs and benefits of pioglitazone versus rosiglitazone in combination with metformin. Methods: A decision-analytic model employing a first order Monte Carlo simulation of a Markov process was constructed. The model incorporated surrogate outcome measures from a large randomised controlled trial (RCT) [n_=_802] that compared the glycaemic and lipid control of pioglitazone and rosiglitazone monotherapy. These efficacy data were used with a recently validated and peer-reviewed UKPDS (UK Prospective Diabetes Study) algorithm to simulate the progression of these surrogate outcomes to final health outcomes, including quality of life (QOL) and mortality, and to calculate the risks of diabetic complications and death. The model perspective was of the UK NHS and included direct healthcare costs only (Lstg , 2004/5 values). Patient outcomes measured in the model included life-expectancy (LE) and QALYs. The base-case analysis was run for 56-year-old male Caucasions with a haemoglobin A1c (HbA1c) of 7.57% and a body mass index of 33.14 kg/m2. Results: Patients treated with pioglitazone experienced a reduction in the total cholesterol to high-density lipoprotein-cholesterol (TC___HDL-C) ratio of 0.34, whereas the TC___HDL-C ratio increased by 0.65 in those receiving rosiglitazone (p_Cost-effectiveness, Cost-utility, Pioglitazone, Rosiglitazone, Type-2-diabetes-mellitus

Enhancing cancer patient's well-being and health status improvement following treatment using AI methods - project ONCORELIEF

ONCORELIEF improves post-treatment health status, well-being and follow-up care for cancer patients in order to meet their needs and allow for timely suggestions before these patients face increased therapeutic side-effects, emotional distress, or biobehavioural factors promoting cancer progression