Trial Forge Guidance 2: how to decide if a further Study Within A Trial (SWAT) is needed

The evidence base available to trialists to support trial process decisions—e.g. how best to recruit and retain participants, how to collect data or how to share the results with participants—is thin. One way to fill gaps in evidence is to run Studies Within A Trial, or SWATs. These are self-contained research studies embedded within a host trial that aim to evaluate or explore alternative ways of delivering or organising a particular trial process. SWATs are increasingly being supported by funders and considered by trialists, especially in the UK and Ireland. At some point, increasing SWAT evidence will lead funders and trialists to ask: given the current body of evidence for a SWAT, do we need a further evaluation in another host trial? A framework for answering such a question is needed to avoid SWATs themselves contributing to research waste. This paper presents criteria on when enough evidence is available for SWATs that use randomised allocation to compare different interventions

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

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Problem of China in British foreign policy, 1917-1921.

This thesis is not available on this repository until the author agrees to make it public. If you are the author of this thesis and would like to make your work openly available, please contact us: [email protected] Library can supply a digital copy for private research purposes; interested parties should submit the request form here: http://www.lib.cam.ac.uk/collections/departments/digital-content-unit/ordering-imagesPlease note that print copies of theses may be available for consultation in the Cambridge University Library's Manuscript reading room. Admission details are at http://www.lib.cam.ac.uk/collections/departments/manuscripts-university-archive

Jan Wisseman Christie (1947?2021)

10.1080/13639811.2021.1975945Indonesia and the Malay World49145496-50

Workshop report on regulated gambling and problem gambling among aborigines from remote NT communities: A Yolngu case study

Made available by the Northern Territory Library via the Publications (Legal Deposit) Act 2004 (NT).This report is one of a series produced by Charles Darwin University on the phenomenon of gambling in the Northern Territory of Australia. Since 2005, the School for Social and Policy Research and it partners have pursued a structured and ongoing research agenda into commercial gambling which has encompassed gambling prevalence, gambling by the Indigenous population, problem gambling, the geography of gambling accessibility, and mechanisms for harm minimisation.Executive Summary -- Aims -- Methods -- History of gambling -- Motivations for gambling -- Gambling related harm -- Harm minimisation -- The Consultants -- Methodology -- Summary of Findings -- Yol?u non-regulated gambling (dopulu) -- Yol?u participation in regulated gambling in casinos -- Gambling related problems -- What Can be Done? -- Notes on Key Words -- Appendix: Transcription

A new orally bioavailable dual adenosine A2B/A3 receptor antagonist with therapeutic potential.

The synthesis and SAR of 5-heterocycle-substituted aminothiazole adenosine receptor antagonists is described. Several compounds show high affinity and selectivity for the A2B and A3 receptors. One compound (5f) shows good ADME properties in the rat and as such may be an important new compound in testing the current hypotheses proposing a therapeutic role for a dual A2B/A3 antagonist in allergic diseases

Solubility-Driven Optimisation of Phosphodiesterase-4 Inhibitors Leading to a Clinical Candidate

The solubility-driven optimisation of a series of 1,7-napthyridine phosphodiesterase 4 inhibitors is described. Directed structural changes resulted in increased aqueous solubility, enabling superior pharmacokinetic properties, with retention of PDE4 inhibition. A range of potent and orally bioavailable compounds with good in vivo efficacy in animal models of inflammation and reduced emetic potential compared to previously described drugs were synthesised. Compound 2d was taken forward as a clinical candidate for the treatment of COPD

The Discovery And Optimisation of 4-(8-(3-Fluorophenyl)-1,7-naphthyridin-6-yl)cyclohexanecarboxylic acid, An Improved PDE4 Inhibitor For The Treatment of COPD.

Herein we describe the optimisation of a series of PDE4 inhibitors, with special focus on solubility and pharamcokinetics, to clinical compound 2, 4-(8-(3-fluorophenyl)-1,7-naphthyridin-6-yl)cyclohexanecarboxylic acid. Compound 2 was found to have exemplary pharmacokinetics in humans, which enabled a novel dosing regime and the achievement of high plasma drug levels without associated nausea or emesis