Existing validated clinical prediction rules for predicting response to physiotherapy interventions for musculoskeletal conditions have limited clinical value: a systematic review

Objective: To systematically review clinical prediction rules (CPRs) that have undergone validation testing for predicting response to physiotherapy-related interventions for musculoskeletal conditions. Study design and setting: PubMed, EMBASE, CINAHL and Cochrane Library were systematically searched to September 2020. Search terms included musculoskeletal (MSK) conditions, physiotherapy interventions and clinical prediction rules. Controlled studies that validated a prescriptive CPR for physiotherapy treatment response in musculoskeletal conditions were included. Two independent reviewers assessed eligibility. Original derivation studies of each CPR were identified. Risk of bias was assessed with the PROBAST tool (derivation studies) and the Cochrane Effective Practice and Organisation of Care group criteria (validation studies). Results: Nine studies aimed to validate seven prescriptive CPRs for treatment response for MSK conditions including back pain, neck pain, shoulder pain and carpal tunnel syndrome. Treatments included manipulation, traction and exercise. Seven studies failed to demonstrate an association between CPR prediction and outcome. Methodological quality of derivation studies was poor and for validation studies was good overall. Conclusion: Results do not support the use of any CPRs identified to aid physiotherapy treatment selection for common musculoskeletal conditions, due to methodological shortcomings in the derivation studies and lack of association between CPR and outcome in validation studie

Highly selective inhibition of histone demethylases by de novo macrocyclic peptides.

The JmjC histone demethylases (KDMs) are linked to tumour cell proliferation and are current cancer targets; however, very few highly selective inhibitors for these are available. Here we report cyclic peptide inhibitors of the KDM4A-C with selectivity over other KDMs/2OG oxygenases, including closely related KDM4D/E isoforms. Crystal structures and biochemical analyses of one of the inhibitors (CP2) with KDM4A reveals that CP2 binds differently to, but competes with, histone substrates in the active site. Substitution of the active site binding arginine of CP2 to N-ɛ-trimethyl-lysine or methylated arginine results in cyclic peptide substrates, indicating that KDM4s may act on non-histone substrates. Targeted modifications to CP2 based on crystallographic and mass spectrometry analyses results in variants with greater proteolytic robustness. Peptide dosing in cells manifests KDM4A target stabilization. Although further development is required to optimize cellular activity, the results reveal the feasibility of highly selective non-metal chelating, substrate-competitive inhibitors of the JmjC KDMs