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Abstract Background The relationship between diabetes mellitus (DM) and chronic musculoskeletal complaints (MSCs) is unclear. The aim of this study was to investigate the association between DM, non-fasting glucose and chronic MSCs defined as pain and/or stiffness ≥ 3 months during the past year in the general adult population. Methods The results were based on cross-sectional data from 64,785 men and women (aged ≥ 20 years) who participated in the Nord-Trøndelag Health Survey, which included 1,940 individuals with known DM. Associations were assessed using multiple logistic regression, estimating prevalence odds ratio (OR) with 95% confidence intervals (CIs). Results High non-fasting glucose was associated with a lower prevalence of chronic MSCs compared to a low glucose level. DM was associated with higher prevalence of chronic MSCs, in particular chronic widespread MSCs. In the multivariate analysis, adjusting for glucose level, BMI, age, gender and physical activity, chronic widespread MSCs was 1.6 times more likely (OR = 1.6, 95% CI 1.2–2.2) among individuals < 60 years of age with DM than among those without DM. The association between chronic widespread MSCs and DM was most evident among the group of individuals aged < 60 years with either type 2 DM or unclassified DM (OR = 1.8, 95% CI 1.3–2.5). Conclusion In this cross-sectional study a high non-fasting glucose was associated with lower prevalence of chronic MSCs. Among individuals with known DM chronic widespread MSCs were more likely.

Bivalent proximity-inducing compounds represent a novel class of small molecule therapeutics with exciting potential and new challenges. The most prominent examples of such compounds are utilized in targeted protein degradation where E3 ligases are hijacked to recruit a substrate protein to the proteasome via ubiquitination. In this review we provide an overview of the current state of E3 ligases used in targeted protein degradation, their respective ligands as well as challenges and opportunities that present themselves with these compounds.

In this work an approach for the synthesis of furanocembranoid natural products containing the C-7,8-diol moiety is disclosed. This culminated in the first total synthesis of the natural product molestin E, together with ent-sinulacembranolide A and ent-sinumaximol A as well as a thorough exploration of their chemistry. Late-stage ring-closure of the C-7,8-diols to the corresponding epoxides was also demonstrated. Key features of this synthetic strategy include a stereoselective Baylis-Hillman reaction, ring-closing metathesis and Shiina macrolactonisation. Chiral-pool materials were deployed to ensure the desired absolute stereochemistry which was confirmed by late-stage single crystal X-ray diffraction., (© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Hydrogen-borrowing catalysis represents a powerful method for the alkylation of amine or enolate nucleophiles with non-activated alcohols. This approach relies upon a catalyst that can mediate a strategic series of redox events, enabling the formation of C-C and C-N bonds and producing water as the sole by-product. In the majority of cases these reactions have been employed to target achiral or racemic products. In contrast, the focus of this Minireview is upon hydrogen-borrowing-catalysed reactions in which the absolute stereochemical outcome of the process can be controlled. Asymmetric hydrogen-borrowing catalysis is rapidly emerging as a powerful approach for the synthesis of enantioenriched amine and carbonyl containing products and examples involving both C-N and C-C bond formation are presented. A variety of different approaches are discussed including use of chiral auxiliaries, asymmetric catalysis and enantiospecific processes., (© 2020 The Authors. Published by Wiley-VCH GmbH.)

Bacterial 5'-methylthioadenosine/ S-adenosylhomocysteine nucleosidase (MTAN) hydrolyzes adenine from its substrates to form S-methyl-5-thioribose and S-ribosyl-l-homocysteine. MTANs are involved in quorum sensing, menaquinone synthesis, and 5'-methylthioadenosine recycling to S-adenosylmethionine. Helicobacter pylori uses MTAN in its unusual menaquinone pathway, making H. pylori MTAN a target for antibiotic development. Human 5'-methylthioadenosine phosphorylase (MTAP), a reported anticancer target, catalyzes phosphorolysis of 5'-methylthioadenosine to salvage S-adenosylmethionine. Transition-state analogues designed for HpMTAN and MTAP show significant overlap in specificity. Fifteen unique transition-state analogues are described here and are used to explore inhibitor specificity. Several analogues of HpMTAN bind in the picomolar range while inhibiting human MTAP with orders of magnitude weaker affinity. Structural analysis of HpMTAN shows inhibitors extending through a hydrophobic channel to the protein surface. The more enclosed catalytic sites of human MTAP require the inhibitors to adopt a folded structure, displacing the phosphate nucleophile from the catalytic site.

A visible light mediated iridium photocatalysed reverse polarity Povarov reaction of aryl imines and electron deficient alkenes is described. Operating via a putative nucleophilic α-amino radical, generated by a proton coupled electron transfer process, addition to a range of conjugated electron deficient alkene substrates affords substituted tetrahydroquinoline products in high yields and with typically good to excellent diastereoselectivity in favor of the trans diastereoisomer. Sub-stoichiometric quantities of Hantzsch ester were found to be key to initiate the overall redox-neutral, free radical cyclization cascade. This new reaction complements existing two electron Lewis acid mediated variants and expands the capabilities of imine umpolung chemistry to synthetically relevant cyclisation methodology.

Aims: To examine the nature, frequency and determinants of prescription modifications in Dutch community pharmacies., Methods: A prospective case-control study comparing modified prescriptions with nonmodified prescriptions was carried out in 141 Dutch community pharmacies. 2014 modified prescriptions (cases), collected in the selected pharmacies on a predetermined day in a specific period (25th February until 12th March 1999) and 2581 nonmodified prescriptions (controls) randomly selected on the same day were studied. The nature and frequency of prescription modifications and patient, drug and prescriber related determinants for a modified prescription were assessed., Results: The overall incidence of prescription modifications was 4.3%, with a mean of 14.3 modifications per pharmacy per day. For prescription only medicines (POM) the incidence was 4.9%. The majority of POM modifications concerned a clarification (71.8%). In 22.2% a prescription could potentially have had clinical consequences when not altered; in more than half of the latter it concerned a dose error (13.7% of all cases). POM prescriptions of patients of 40-65 years had a significantly lower chance of modification compared with those of younger people (OR = 0.74 [0.64-0.86]). With respect to medication-class, we found a higher chance of POM modifications in the respiratory domain (OR = 1.48 [1.23-1.79]) and a decreased chance for nervous system POMs (OR = 0.71 [0.61-0.83]). With regard to prescriber-related determinants modifications were found three times more often in non printed prescriptions than in printed ones (OR = 3.30 [2.90-3.75]). Compared with prescriptions by the patient's own GP, prescriptions of specialists (OR = 1.82 [1.57-2.11]), other GP's (OR = 1.49 [1.02-2.17]) and other prescribers such as dentists and midwives (OR = 1.95 [1.06-3.57]) gave a higher probability of prescription modifications. When a GP had no on-line access to the computer of the pharmacy the chance of a modification was also higher (OR = 1.61 [1.33-1.94]). Multivariate analysis revealed that a nonprinted prescription was the strongest independent determinant of prescription modifications (OR = 3.32 [2.87-3.84]), remaining so after adjustment for GP computer link to the pharmacy and for type of prescriber., Conclusions: At least 30% of Dutch community pharmacies corrected 2.8 POM prescriptions per pharmacy per working day, which could potentially have had clinical consequences if not altered. If the study sample is representative for The Netherlands, Dutch community pharmacies correct a total of approximately 4400 of these prescriptions per working day. Using computerized systems to generate prescriptions is an important strategy to reduce the incidence of prescription errors.