Protocol for a feasibility and acceptability study for UK general population paediatric type 1 diabetes screening-the EarLy Surveillance for Autoimmune diabetes (ELSA) study.

Aim: The EarLy Surveillance for Autoimmune (ELSA) study aims to explore the feasibility and acceptability of UK paediatric general population screening for type 1 diabetes.

Methods: We aim to screen 20,000 children aged 3-13 years for islet-specific autoantibodies through dried blood spot sample collection at home, hospital or community settings. Children with two or more autoantibodies are offered metabolic staging via oral glucose challenge testing.

Core Modifications of GSK3335103 toward Orally Bioavailable αβ Inhibitors with Improved Synthetic Tractability.

The αβ integrin has been identified as a target for the treatment of fibrotic diseases, based on the role it has in activating TGF-β, a protein implicated in the pathogenesis of fibrosis. However, the development of orally bioavailable αβ inhibitors has proven challenging due to the zwitterionic pharmacophore required to bind to the RGD binding site. This work describes the design and development of a novel, orally bioavailable series of αβ inhibitors, developing on two previously published αβ inhibitors, GSK3008348 and GSK3335103.

Discovery and Development of Highly Potent and Orally Bioavailable Nonpeptidic αβ Integrin Inhibitors.

A series of 3-aryl(()-3-fluoropyrrolidin-1-yl)butanoic acids were developed as potent orally bioavailable αβ integrin inhibitors. Starting from a zwitterionic peptidomimetic series optimized for inhaled administration, the balancing of potency and passive permeability to achieve suitable oral agents through modification and exploration of aryl substituents and p of the central cyclic amine is described. ()-4-(()-3-Fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-3-(3-(2-methoxyethoxy)phenyl)butanoic acid was found to have highly desirable oral pharmacokinetic profiles in rat, dog, and minipig, with low to moderate clearance (26%, 7%, and 18% liver blood flow, respectively), moderate volumes of distribution (3.

Current evidence for designing self-management support for underserved populations: an integrative review using the example of diabetes.

Aims: With numerous and continuing attempts at adapting diabetes self-management support programmes to better account for underserved populations, its important that the lessons being learned are understood and shared. The work we present here reviews the latest evidence and best practice in designing and embedding culturally and socially sensitive, self-management support programmes.

Methods: We explored the literature with regard to four key design considerations of diabetes self-management support programmes: Composition - the design and content of written materials and digital tools and interfaces; Structure - the combination of individual and group sessions, their frequency, and the overall duration of programmes; Facilitators - the combination of individuals used to deliver the programme; and Context - the influence and mitigation of a range of individual, socio-cultural, and environmental factors.

Enhancing the health of NHS staff: eTHOS - protocol for a randomised controlled pilot trial of an employee health screening clinic for NHS staff to reduce absenteeism and presenteeism, compared with usual care.

Background: Staff absenteeism and presenteeism incur high costs to the NHS and are associated with adverse health outcomes. The main causes are musculoskeletal complaints and mental ill-health, which are potentially modifiable, and cardiovascular risk factors are also common. We will test the feasibility of an RCT to evaluate the clinical and cost-effectiveness of an employee health screening clinic on reducing sickness absenteeism and presenteeism.

EarLy Surveillance for Autoimmune diabetes: protocol for a qualitative study of general population and stakeholder perspectives on screening for type 1 diabetes in the UK (ELSA 1).

Objective: Type 1 diabetes (T1D) is the most common form of diabetes in children, accounting for 96% of cases, with 29 000 children affected in the UK. Studies have recently identified immunotherapies that safely delay the development of T1D for at least 3 years, and further therapies are in development. General population screening programs in other countries can now accurately identify children with presymptomatic T1D who can be entered into prevention studies.

Structure-Based Design of a Novel Class of Autotaxin Inhibitors Based on Endogenous Allosteric Modulators.

Autotaxin (ATX) facilitates the hydrolysis of lysophosphatidylcholine to lysophosphatidic acid (LPA), a bioactive phospholipid, which facilitates a diverse range of cellular effects in multiple tissue types. Abnormal LPA expression can lead to the progression of diseases such as cancer and fibrosis. Previously, we identified a potent ATX steroid-derived hybrid (partially orthosteric and allosteric) inhibitor which did not form interactions with the catalytic site.

Pharmacological characterisation of GSK3335103, an oral αvβ6 integrin small molecule RGD-mimetic inhibitor for the treatment of fibrotic disease.

Fibrosis is the formation of scar tissue due to injury or long-term inflammation and is a leading cause of morbidity and mortality. Activation of the pro-fibrotic cytokine transforming growth factor-β (TGFβ) via the alpha-V beta-6 (αvβ6) integrin has been identified as playing a key role in the development of fibrosis. Therefore, a drug discovery programme to identify an orally bioavailable small molecule αvβ6 arginyl-glycinyl-aspartic acid (RGD)-mimetic was initiated.

Synthesis of Arylethylamines C(sp)-C(sp) Palladium-Catalyzed Cross-Coupling.

Substituted arylethylamines represent a key structural motif in natural, pharmaceutical, and agrochemical compounds. Access to such scaffolds has been the subject of long-standing synthetic interest. Herein, we report the synthesis of such scaffolds a palladium-catalyzed C(sp)-C(sp) coupling between (chloromethyl)aryls and air-/moisture-stable ,-dialkylaminomethyltrifluoroborate salts.

Discovery of the first potent and selective αβ integrin inhibitor based on an amide-containing core.

Integrins αβ and αβ are closely related, proangiogenic members of the wider RGD-binding integrin family. Due to their high sequence homology, the development of αβ-selective compounds has remained elusive to synthetic and medicinal chemists. Herein, we describe a survey of SAR around a series of amide-containing 3-aryl-succinamic acid-based RGD mimetics.

Facile synthesis of 7-alkyl-1,2,3,4-tetrahydro-1,8-naphthyridines as arginine mimetics using a Horner-Wadsworth-Emmons-based approach.

Integrin inhibitors based on the tripeptide sequence Arg-Gly-Asp (RGD) are potential therapeutics for the treatment of idiopathic pulmonary fibrosis (IPF). Herein, we describe an expeditious three-step synthetic sequence of Horner-Wadsworth-Emmons olefination, diimide reduction, and global deprotection to synthesise cores for these compounds in high yields (63-83% over 3 steps) with no need for chromatography. Key to this transformation is the phosphoramidate protecting group, which is stable to metalation steps.

Profile of a Highly Selective Quaternized Pyrrolidine Betaine αβ Integrin Inhibitor-(3)-3-(3-(3,5-Dimethyl-1-pyrazol-1-yl)phenyl)-4-((1 and 1,3)-1-methyl-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-ium-1-yl)butanoate Synthesized by Stereoselective Methylation.

A quaternary ammonium betaine is described which shows exceptional potency and selectivity (1.4 to >3 logs) for the αβ integrin receptor over the other α integrins as determined in cell adhesion assays. is prepared by remarkably stereoselective methylation, the origins of which are discussed.

The Design of Potent, Selective and Drug-Like RGD αvβ1 Small-Molecule Inhibitors Derived from non-RGD α4β1 Antagonists.

Up to 45 % of deaths in developed nations can be attributed to chronic fibroproliferative diseases, highlighting the need for effective therapies. The RGD (Arg-Gly-Asp) integrin αvβ1 was recently investigated for its role in fibrotic disease, and thus warrants therapeutic targeting. Herein we describe the identification of non-RGD hit small-molecule αvβ1 inhibitors.

Discovery of ( S)-3-(3-(3,5-Dimethyl-1 H-pyrazol-1-yl)phenyl)-4-(( R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic Acid, a Nonpeptidic αβ Integrin Inhibitor for the Inhaled Treatment of Idiopathic Pulmonary Fibrosis.

A series of 3-aryl(pyrrolidin-1-yl)butanoic acids were synthesized using a diastereoselective route, via a rhodium catalyzed asymmetric 1,4-addition of arylboronic acids in the presence of ( R)-BINAP to a crotonate ester to provide the ( S) absolute configuration for the major product. A variety of aryl substituents including morpholine, pyrazole, triazole, imidazole, and cyclic ether were screened in cell adhesion assays for affinity against αβ, αβ, αβ, αβ, and αβ integrins. Numerous analogs with high affinity and selectivity for the αβ integrin were identified.

Effectiveness of a childhood obesity prevention programme delivered through schools, targeting 6 and 7 year olds: cluster randomised controlled trial (WAVES study).

Objective: To assess the effectiveness of a school and family based healthy lifestyle programme (WAVES intervention) compared with usual practice, in preventing childhood obesity.

Design: Cluster randomised controlled trial.

Setting: UK primary schools from the West Midlands.

Quantitative Brain MRI in Congenital Adrenal Hyperplasia: In Vivo Assessment of the Cognitive and Structural Impact of Steroid Hormones.

Context: Brain white matter hyperintensities are seen on routine clinical imaging in 46% of adults with congenital adrenal hyperplasia (CAH). The extent and functional relevance of these abnormalities have not been studied with quantitative magnetic resonance imaging (MRI) analysis.

Objective: To examine white matter microstructure, neural volumes, and central nervous system (CNS) metabolites in CAH due to 21-hydroxylase deficiency (21OHD) and to determine whether identified abnormalities are associated with cognition, glucocorticoid, and androgen exposure.

β-Keto-dioxinones and β,δ-diketo-dioxinones in biomimetic resorcylate total synthesis.

Resorcylates are a large group of bioactive natural products that are biosynthesized from acetate and malonate units via the intermediacy of polyketides. These polyketides undergo cyclization reactions to introduce the aromatic core. The bioactivities of the resorcylates including resorcylate macrocyclic lactones include anticancer, antimalarial, mycotoxicity, antifungal, and antibiotic properties, and several compounds in the series are already in use in medicine.

Cascade polyketide and polyene cyclizations: biomimetic total synthesis of hongoquercin B.

The total synthesis of hongoquercin B was carried out in 9 steps from trans,trans-farnesyl acetate using a palladium catalyzed decarboxylative π-farnesyl rearrangement of a diketo-dioxinone ester, aromatization and cationic diene-epoxide cyclization as key steps. This cascade tetracyclization simplifies the synthesis of terpenoid resorcylate natural products.

Clinical characteristics and management of cranial diabetes insipidus in infants.

Aim: Cranial diabetes insipidus (CDI) is rare in infants with no guidelines on its management. We describe the first case series, characterizing the clinical features and treatment challenges.

Method: Retrospective case note review of infants diagnosed with CDI between April 1992 and February 2011.

Metabolic outcomes in young children with type 1 diabetes differ between treatment centers: the Hvidoere Study in Young Children 2009.

Objective: To investigate whether center differences in glycemic control are present in prepubertal children <11 yr with type 1 diabetes mellitus.

Research Design And Methods: This cross-sectional study involved 18 pediatric centers worldwide. All children, <11 y with a diabetes duration ≥12 months were invited to participate.

Total synthesis of the marine metabolite (±)-polysiphenol via highly regioselective intramolecular oxidative coupling.

(±)-Polysiphenol (1), an atropisomerically stable 4,5-dibrominated 9,10-dihydrophenanthrene from Polysiphonia ferulacea, was prepared by a biomimetically inspired highly regioselective intramolecular oxidative coupling of a dibrominated dihydrostilbene. The installation of the two bromine atoms prior to oxidative coupling prevents further oxidation to a planar aromatized phenanthrene. By this strategy, the synthesis of (±)-polysiphenol was achieved in four steps in 70% overall yield.

A missense mutation in LRR8 of RXFP2 is associated with cryptorchidism.

Using genome-wide mutagenesis with N-ethyl-N-nitrosourea (ENU), a mouse mutant with cryptorchidism was identified. Genome mapping and exon sequencing identified a novel missense mutation (D294G) in Relaxin/insulin-like family peptide receptor 2 (Rxfp2). The mutation impaired testicular descent and resulted in decreased testis weight in Rxfp2 ( DG/DG ) mice compared to Rxfp2 (+/DG ) and Rxfp2 (+/+) mice.

ThOMAs: the other means of assessment.

We describe a pilot study to investigate whether drawing "Thomas the Tank Engine" could be as effective a measure of developmental progress as the Goodenough-Harris Draw A Man test against the ThOMAs test (The Other Means of Assessment), with internal validation. The study included 95 children aged between 3 and 11 years of age, including a subgroup of 13 children with registered special needs from community and general pediatric clinics within Birmingham, UK, as a means of validation. There was no significant evidence that ThOMAS was either culturally or sex biased.