How do people perceive different advice for rotator cuff disease? A content analysis of qualitative data collected in a randomised experiment.

OBJECTIVES: To explore how people perceive different advice for rotator cuff disease in terms of words/feelings evoked by the advice and treatment needs. SETTING: We performed a content analysis of qualitative data collected in a randomised experiment. PARTICIPANTS: 2028 people with shoulder pain read a vignette describing someone with rotator cuff disease and were randomised to: bursitis label plus guideline-based advice, bursitis label plus treatment recommendation, rotator cuff tear label plus guideline-based advice and rotator cuff tear label plus treatment recommendation. Guideline-based advice included encouragement to stay active and positive prognostic information. Treatment recommendation emphasised that treatment is needed for recovery. PRIMARY AND SECONDARY OUTCOMES: Participants answered questions about: (1) words/feelings evoked by the advice; (2) treatments they feel are needed. Two researchers developed coding frameworks to analyse responses. RESULTS: 1981 (97% of 2039 randomised) responses for each question were analysed. Guideline-based advice (vs treatment recommendation) more often elicited words/feelings of reassurance, having a minor issue, trust in expertise and feeling dismissed, and treatment needs of rest, activity modification, medication, wait and see, exercise and normal movements. Treatment recommendation (vs guideline-based advice) more often elicited words/feelings of needing treatment/investigation, psychological distress and having a serious issue, and treatment needs of injections, surgery, investigations, and to see a doctor. CONCLUSIONS: Words/feelings evoked by advice for rotator cuff disease and perceived treatment needs may explain why guideline-based advice reduces perceived need for unnecessary care compared to a treatment recommendation.

A unified strategy to prostaglandins: chemoenzymatic total synthesis of cloprostenol, bimatoprost, PGF2α, fluprostenol, and travoprost guided by biocatalytic retrosynthesis.

Development of efficient and stereoselective synthesis of prostaglandins (PGs) is of utmost importance, owing to their valuable medicinal applications and unique chemical structures. We report here a unified synthesis of PGs cloprostenol, bimatoprost, PGF2α, fluprostenol, and travoprost from the readily available dichloro-containing bicyclic ketone 6a guided by biocatalytic retrosynthesis, in 11-12 steps with 3.8-8.4% overall yields. An unprecedented Baeyer-Villiger monooxygenase (BVMO)-catalyzed stereoselective oxidation of 6a (99% ee), and a ketoreductase (KRED)-catalyzed diastereoselective reduction of enones 12 (87 : 13 to 99 : 1 dr) were utilized in combination for the first time to set the critical stereochemical configurations under mild conditions. Another key transformation was the copper(ii)-catalyzed regioselective p-phenylbenzoylation of the secondary alcohol of diol 10 (9.3 : 1 rr). This study not only provides an alternative route to the highly stereoselective synthesis of PGs, but also showcases the usefulness and great potential of biocatalysis in construction of complex molecules.

Organocatalytic Asymmetric Domino Oxa-Michael-Mannich-[1,3]-Amino Rearrangement Reaction of N-Tosylsalicylimines to α,ß-Unsaturated Aldehydes by Diarylprolinol Silyl Ethers.

An organocatalytic asymmetric enantioselective domino oxa-Michael-Mannich-[1,3]-amino rearrangement reaction of N-tosylsalicylimines with a wide range of α,ß-unsaturated aldehydes utilizing diarylprolinol silyl ether catalysis is described. The catalytic reactions proceed with excellent enantioselectivity (up to 99% ee) to produce the corresponding chair N-tosylimines-chromenes with a yield of up to 99%, tolerating a range of functional groups. This methodology offers a new method with great potential to further extend the synthetic power and versatility of chiral aminocatalysis.

Access to a Key Building Block for the Prostaglandin Family via Stereocontrolled Organocatalytic Baeyer-Villiger Oxidation.

A new protocol for the construction of a crucial bicyclic lactone of prostaglandins using a stereocontrolled organocatalytic Baeyer-Villiger (B-V) oxidation was developed. The key B-V oxidation of a racemic cyclobutanone derivative with aqueous hydrogen peroxide has enabled an early-stage construction of a bicyclic lactone skeleton in high enantiomeric excess (up to 95 %). The generated bicyclic lactone is fully primed with two desired stereocenters and enabled the synthesis of the entire family of prostaglandins according to Corey's route. Furthermore, the reactivity and enantioselectivity of B-V oxidation of racemic bicyclic cyclobutanones were evaluated and 90-99 % ee was obtained, representing one of the most efficient routes to chiral lactones. This study further facilitates the synthesis of prostaglandins and chiral lactone-containing natural products to promote drug discovery.

Synthesis and structure-activity relationship studies of MI-2 analogues as MALT1 inhibitors.

Recent studies revealed that MALT1 is a promising therapeutic target for the treatment of ABC-DLBCL. Among several reported MALT1 inhibitors, MI-2 as an irreversible inhibitor represents a new class of ABC-DLBCL therapeutics. Due to its inherent potential cross-reactivity, further structure-activity relationship (SAR) study is imperative. In this work, five focused compound libraries based on the chemical structure of MI-2 are designed and synthesized. The systematic SARs revealed that the side chain of 2-methoxyethoxy has little impact on the activity and can be replaced by other functionalized groups, providing new MI-2 analogues with retained or enhanced potency. Compounds 81-83 with terminal hydroxyl group as side chain displayed enhanced activities against MALT1. Replacement of triazole core with pyrazole is also tolerant, while structural modifications on other sites are detrimental. These findings will facilitate further development of small-molecule MALT1 inhibitors.