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ObjectiveTo assess the feasibility of conducting a definitive randomised controlled trial (RCT) to test the clinical and cost-effectiveness of a tailored exercise intervention compared with usual care for people aged 80 years and older with hip and/or knee osteoarthritis (OA) and comorbidities.DesignTwo-arm, parallel-design, multicentre, pragmatic, feasibility RCT.SettingFour National Health Service outpatient physiotherapy services across England.ParticipantsAdults aged 80 years and over with clinical hip and/or knee OA and ≥1 comorbidity.InterventionsParticipants were randomised 1:1 via a central web-based system to be offered: (1) a 12-week tailored exercise programme or (2) usual care. Participants and outcome assessors were not blinded to treatment allocation.Feasibility objectives(1) Ability to screen and recruit participants; (2) retention of participants at 14-week follow-up; (3) intervention fidelity (proportion of participants who received ≥4 intervention sessions as per protocol) and (4) participant engagement (assessed by home exercise adherence).ResultsBetween 12 May 2022 and 26 January 2023, 133 potential participants were screened, of whom 94 were eligible. The main reasons for ineligibility were symptoms not consistent with hip or knee OA (10/39, 25.6%) or already having had a physiotherapy appointment (8/39, 20.5%). 51 of 94 (54%) eligible participants were recruited. Participants had a mean age of 84 years (SD 3.5), 31 (60.8%) were female and 96.1% reported their ethnicity as White British (n=49/51). 45 of 51 participants (88%) provided outcome data at the 14-week follow-up time point. Four or more intervention sessions were attended by 13/25 (52%) participants. Home exercise log completion declined over time: 6/23 participants (26.1%) returned completed exercise logs for all 12 weeks. The median number of days home exercises were recorded each week was 5 (range 0–7).ConclusionsThis study demonstrated that a definitive trial would be feasible. Before proceeding, modifications to ensure recruitment of a diverse population and intervention fidelity should be addressed.Trial registration numberISRCTN75983430.

A building society has commissioned research to help lenders, surveyors and valuers deal with the challenges of predicting the impacts of climate change at the level of individual properties over the coming decades While, large-scale intergovernmental modelling of climate change in the atmosphere and ocean is already well established, initiatives that address impacts at the level of the individual property are less developed. At this letterbox level, property professionals in the UK are not yet ready to assess the risk of climate change over the coming decades. [...]the property risk team at the Nationwide Building Society has since 2014 been collecting best-in-class data on such perils. Any new approach to climate change must address: * investigation of reliable big data resources as the basis for improved decision-making * appointment of data provider partners * use and evolution of geospatial big data systems * improving internal use of data * developing new operational systems and approaches to increase the accuracy and resilience of the mortgage-lending process * planned research, development and implementation of appropriate mortgage-lending policies * links with, and the inclusion of, insurance as a financial safety net for the present and future.

Corticosteroid injections and physiotherapy exercise programmes are commonly used to treat rotator cuff disorders but the treatments' effectiveness is uncertain. We aimed to compare the clinical effectiveness and cost-effectiveness of a progressive exercise programme with a single session of best practice physiotherapy advice, with or without corticosteroid injection, in adults with a rotator cuff disorder. In this pragmatic, multicentre, superiority, randomised controlled trial (2 × 2 factorial), we recruited patients from 20 UK National Health Service trusts. We included patients aged 18 years or older with a rotator cuff disorder (new episode within the past 6 months). Patients were excluded if they had a history of significant shoulder trauma (eg, dislocation, fracture, or full-thickness tear requiring surgery), neurological disease affecting the shoulder, other shoulder conditions (eg, inflammatory arthritis, frozen shoulder, or glenohumeral joint instability), received corticosteroid injection or physiotherapy for shoulder pain in the past 6 months, or were being considered for surgery. Patients were randomly assigned (centralised computer-generated system, 1:1:1:1) to progressive exercise (≤6 sessions), best practice advice (one session), corticosteroid injection then progressive exercise, or corticosteroid injection then best practice advice. The primary outcome was the Shoulder Pain and Disability Index (SPADI) score over 12 months, analysed on an intention-to-treat basis (statistical significance set at 1%). The trial was registered with the International Standard Randomised Controlled Trial Register, ISRCTN16539266, and EuDRACT, 2016-002991-28. Between March 10, 2017, and May 2, 2019, we screened 2287 patients. 708 patients were randomly assigned to progressive exercise (n=174), best practice advice (n=174), corticosteroid injection then progressive exercise (n=182), or corticosteroid injection then best practice advice (n=178). Over 12 months, SPADI data were available for 166 (95%) patients in the progressive exercise group, 164 (94%) in the best practice advice group, 177 (97%) in the corticosteroid injection then progressive exercise group, and 175 (98%) in the corticosteroid injection then best practice advice group. We found no evidence of a difference in SPADI score between progressive exercise and best practice advice when analysed over 12 months (adjusted mean difference −0·66 [99% CI −4·52 to 3·20]). We also found no evidence of a difference between corticosteroid injection compared with no injection when analysed over 12 months (−1·11 [–4·47 to 2·26]). No serious adverse events were reported. Progressive exercise was not superior to a best practice advice session with a physiotherapist in improving shoulder pain and function. Subacromial corticosteroid injection provided no long-term benefit in patients with rotator cuff disorders. UK National Institute for Health Research Technology Assessment Programme.

Artists can learn a great deal from the structure of other artists' paintings and, with this in mind, the author analyses works by Jack Smith and John Bratby

Metabolite profiling of industrially important suspension-cultured mammalian cells is being increasingly used for rational improvement of bioprocesses. This requires the generation of global metabolite profiles that cover a broad range of metabolites and that are representative of the cells at the time of sampling. The protocol described here is a validated method for recovery of physiologically relevant amounts of key metabolites from suspension-cultured mammalian cells. The method is a two-step process consisting of initial quenching of the cells (to stop cellular metabolism and allow isolation of the cells) followed by extraction of the metabolites. The cells are quenched in 60% methanol supplemented with 0.85% (wt/vol) ammonium bicarbonate at −40 °C. Metabolites are then extracted from the quenched cells using two 100% methanol extractions followed by a single water extraction. Metabolite samples generated using this protocol are amenable to analysis by mass spectrometry–based techniques (e.g., gas chromatography–mass spectrometry, liquid chromatography–mass spectrometry), NMR spectroscopy and enzymatic assays.

The tumour suppressor p53 is mutated in cancer, including over 96% of high-grade serous ovarian cancer (HGSOC). Mutations cause loss of wild-type p53 function due to either gain of abnormal function of mutant p53 (mutp53), or absent to low mutp53. Massively parallel sequencing (MPS) enables increased accuracy of detection of somatic variants in heterogeneous tumours. We used MPS and immunohistochemistry (IHC) to characterise HGSOCs for TP53 mutation and p53 expression. TP53 mutation was identified in 94% (68/72) of HGSOCs, 62% of which were missense. Missense mutations demonstrated high p53 by IHC, as did 35% (9/26) of non-missense mutations. Low p53 was seen by IHC in 62% of HGSOC associated with non-missense mutations. Most wild-type TP53 tumours (75%, 6/8) displayed intermediate p53 levels. The overall sensitivity of detecting a TP53 mutation based on classification as ‘Low’, ‘Intermediate’ or ‘High’ for p53 IHC was 99%, with a specificity of 75%. We suggest p53 IHC can be used as a surrogate marker of TP53 mutation in HGSOC; however, this will result in misclassification of a proportion of TP53 wild-type and mutant tumours. Therapeutic targeting of mutp53 will require knowledge of both TP53 mutations and mutp53 expression.

Drug repurposing has emerged as an effective strategy to accelerate drug discovery. Using the pipeline established from a large collaborative drug repurposing project focused on high-grade serous ovarian cancer (HGSOC), we identified ivacaftor, an FDA-approved cystic fibrosis medication, as a drug candidate predicted to interact with the receptor tyrosine kinase-like orphan receptor 1 (ROR1) which we have previously demonstrated as a therapeutic target in ovarian cancer. This study aimed to provide preclinical evidence supporting the potential repurposing of ivacaftor for HGSOC treatment. Ivacaftor was tested in 2D and 3D preclinical models as well as patient-derived organoid models in vitro. Dose-response analysis was undertaken in ROR1 expressing HGSOC cell lines OVCAR4, KURAMOCHI, COV362 and COV318 in both 2D adherent and 3D bioprinted formats. Real-time live/dead and apoptosis cell staining were performed over a 72 h period using the IncuCyte live cell imaging platform. Flow cytometry was used to assess apoptosis, DNA damage and cell proliferation following treatment with either 15 µM ivacaftor or 30 µM carboplatin at 24, 48 and 72 h. Additionally, ROR1-expressing HGSOC patient-derived organoids (OC029, OC043 and OC058) underwent ivacaftor dose-response analysis. Cell apoptosis following 15 µM ivacaftor treatment was measured in real-time using an Annexin V assay in two additional organoid models (OC062 and OC075). Finally, the mechanisms associated with response to ivacaftor were explored in HGSOC cell lines through Western blotting. The IC50 for ivacaftor ranged from 6.5 to 13.2 µM in 2D cultures and 11.6 to 18.2 µM in 3D cultures. Treatment with 10 and 15 µM ivacaftor resulted in significantly increased cell death and reduced live cell counts compared to the vehicle control over 72 h. Organoids displayed IC50 values between 11.2 and 14.1 µM. Ivacaftor treatment induced apoptosis in organoids, with no significant impact on DNA damage or cell cycle in HGSOC cells. ROR1 signalling associated oncogenic pathways including the BMI-1 and the PI3K/AKT pathways were modulated following ivacaftor treatment. In summary, ivacaftor demonstrated significant anti-tumour potential in preclinical HGSOC models, supporting its further investigation as a repurposed therapy for ovarian cancer.

This letter to the editor is in response to the consensus statement from the Ultrasound Subcommittee of the European Society of Radiology, the European Union of Medical Specialists (UEMS) Section of Radiology, and the European Federation of Societies for Ultrasound in Medicine and Biology. It highlights the role of the non-medical sonographer in the UK and the evidence underpinning this safe and effective practice.

In this study we report on the optimisation of the technologies for generation of a global metabolomics profile for intracellular metabolites in Chinese hamster ovary (CHO) cells. We evaluated the effectiveness of a range of different extraction methods applied to CHO cells which had been quenched using a previously optimised approach. The extraction methods tested included cold methanol, hot ethanol, acid, alkali and methanol/chloroform plus combinations of these. The extraction of metabolites using two 100% methanol extractions followed by a final water extraction recovered the largest range of metabolites. For the majority of metabolites, extracts generated in this manner exhibited the greatest recovery with high reproducibility. Therefore, this was the best extraction method for attaining a global metabolic profile from a single sample. However, another parallel extraction method (e.g. alkali) may also be required to maximise the range of metabolites recovered (e.g. non-polar metabolites).