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Aims To describe type 1 diabetes incidence in Scotland between 2006 and 2019.Methods Repeated annual cross-sectional studies of type 1 diabetes incidence were conducted. Incident cases were identified from the Scottish Care Information – Diabetes Collaboration (SCI-DC), a population-based register of people with diagnosed diabetes derived from primary and secondary care data. Mid-year population estimates for Scotland were used as the denominator to calculate annual incidence with stratification by age and sex. Joinpoint regression was used to investigate whether incidence changed during the study period. Age and sex-specific type 1 diabetes incidence over the whole time period was estimated by quintile of the Scottish Index of Multiple Deprivation (SIMD), an area-based measure, in which Q1 and Q5 denote the most and least deprived fifths of the population respectively with quasi-Poisson regression used to compare incidence for Q5 compared to Q1.Results The median (IQR) age of the study population of 14,564 individuals with incident type 1 diabetes was 24.1 (12.3−42.4) years, 56% were male, 23% were in Q1 and 16% were in Q5. Incidence of T1DM was higher in males than females overall (at around 22 and 17 per 100,000 respectively) and in under 15 year-olds (approximately 40 per 100, 000 in both sexes) than other age groups and was similar across the study period in all strata. There was an inverse association between socio-economic status and type 1 diabetes incidence for 15−29, 30−49 and 50+ year-olds [incidence rate ratio (IRR) for Q5 compared to Q1; IRR (95% CI) 0.52 (0.47 − 0.58), 0.68 (0.61 − 0.76) and 0.53(0.46 − 0.61), respectively] but not for under 15 year-olds [1.02 (0.92 − 1.12)].Conclusion Incidence of type 1 diabetes varies by age, sex and socio-economic status and has remained approximately stable from 2006 to 2019 in Scotland.

The ontology-based modelling system (OBMS) is a formal system for representing theories of behaviour change. A searchable database of 76 theories specified using this system is available at humanbehaviourchange.org/theory-database

Optimization of a previously reported lead series of PI3Kδ inhibitors with a novel binding mode led to the identification of a clinical candidate compound 31 (GSK251). Removal of an embedded Ames-positive heteroaromatic amine by reversing a sulfonamide followed by locating an interaction with Trp760 led to a highly selective compound 9. Further optimization to avoid glutathione trapping, to enhance potency and selectivity, and to optimize an oral pharmacokinetic profile led to the discovery of compound 31 (GSK215) that had a low predicted daily dose (45 mg, b.i.d) and a rat toxicity profile suitable for further development.

RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurological diseases. Currently, RIP1 kinase inhibitors have advanced into early clinical trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis, and ulcerative colitis and neurological diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. In this paper, we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the lead-optimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species. Additionally, we identified a potent murine RIP1 kinase inhibitor 76 as a valuable in vivo tool molecule suitable for evaluating the role of RIP1 kinase in chronic models of disease. DHP 76 showed efficacy in mouse models of both multiple sclerosis and human retinitis pigmentosa.

Background: Better information on the typical course and management of acute common infections in the community could inform antibiotic stewardship campaigns. We aimed to investigate the incidence, management, and natural history of a range of infection syndromes (respiratory, gastrointestinal, mouth/dental, skin/soft tissue, urinary tract, and eye). Methods: Bug Watch was an online prospective community cohort study of the general population in England (2018–2019) with weekly symptom reporting for 6 months. We combined symptom reports into infection syndromes, calculated incidence rates, described the proportion leading to healthcare-seeking behaviours and antibiotic use, and estimated duration and severity. Results: The cohort comprised 873 individuals with 23,111 person-weeks follow-up. The mean age was 54 years and 528 (60%) were female. We identified 1422 infection syndromes, comprising 40,590 symptom reports. The incidence of respiratory tract infection syndromes was two per person year; for all other categories it was less than one. 194/1422 (14%) syndromes led to GP (or dentist) consultation and 136/1422 (10%) to antibiotic use. Symptoms usually resolved within a week and the third day was the most severe. Conclusions: Most people reported managing their symptoms without medical consultation. Interventions encouraging safe self-management across a range of acute infection syndromes could decrease pressure on primary healthcare services and support targets for reducing antibiotic prescribing.

Inhibitors of CDK4 and CDK6 have emerged as important FDA-approved treatment options for breast cancer patients. The properties and pharmacology of CDK4/6 inhibitor medicines have been extensively profiled, and investigations into the degradation of these targets via a PROTAC strategy have also been reported. PROTACs are a novel class of small-molecules that offer the potential for differentiated pharmacology compared to traditional inhibitors by redirecting the cellular ubiquitin-proteasome system to degrade target proteins of interest. We report here the preparation of palbociclib-based PROTACs that incorporate binders for three different E3 ligases, including a novel IAP-binder, which effectively degrade CDK4 and CDK6 in cells. In addition, we show that the palbociclib-based PROTACs in this study that recruit different E3 ligases all exhibit preferential CDK6 vs. CDK4 degradation selectivity despite employing a selection of linkers between the target binder and the E3 ligase binder.

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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 αvβ1, αvβ3, αvβ5, αvβ6, and αvβ8 integrins. Numerous analogs with high affinity and selectivity for the αvβ6 integrin were identified. The analog (S)-3-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid hydrochloride salt was found to have very high affinity for αvβ6 integrin in a radioligand binding assay (pKi = 11), a long dissociation half-life (7 h), very high solubility in saline at pH 7 (>71 mg/mL), and pharmacokinetic properties commensurate with inhaled dosing by nebulization. It wa...