Statistical analysis plan for the TRANSLATE (TRANSrectal biopsy versus Local Anaesthetic Transperineal biopsy Evaluation of potentially clinically significant prostate cancer) multicentre randomised controlled trial.

BACKGROUND: The TRANSLATE (TRANSrectal biopsy versus Local Anaesthetic Transperineal biopsy Evaluation) trial assesses the clinical and cost-effectiveness of two biopsy procedures in terms of detection of clinically significant prostate cancer (PCa). This article describes the statistical analysis plan (SAP) for the TRANSLATE randomised controlled trial (RCT). METHODS/DESIGN: TRANSLATE is a parallel, superiority, multicentre RCT. Biopsy-naïve men aged ≥ 18 years requiring a prostate biopsy for suspicion of possible PCa are randomised (computer-generated 1:1 allocation ratio) to one of two biopsy procedures: transrectal (TRUS) or local anaesthetic transperineal (LATP) biopsy. The primary outcome is the difference in detection rates of clinically significant PCa (defined as Gleason Grade Group ≥ 2, i.e. any Gleason pattern ≥ 4 disease) between the two biopsy procedures. Secondary outcome measures are th eProBE questionnaire (Perception Part and General Symptoms) and International Index of Erectile Function (IIEF, Domain A) scores, International Prostate Symptom Score (IPSS) values, EQ-5D-5L scores, resource use, infection rates, complications, and serious adverse events. We describe in detail the sample size calculation, statistical models used for the analysis, handling of missing data, and planned sensitivity and subgroup analyses. This SAP was pre-specified, written and submitted without prior knowledge of the trial results. DISCUSSION: Publication of the TRANSLATE trial SAP aims to increase the transparency of the data analysis and reduce the risk of outcome reporting bias. Any deviations from the current SAP will be described and justified in the final study report and results publication. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number ISRCTN98159689, registered on 28 January 2021 and registered on the ClinicalTrials.gov (NCT05179694) trials registry.

A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301).

PURPOSE: 5-fluorouracil (5-FU) is inefficiently converted to the active anti-cancer metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), is associated with dose-limiting toxicities and challenging administration schedules. NUC-3373 is a phosphoramidate nucleotide analog of fluorodeoxyuridine (FUDR) designed to overcome these limitations and replace fluoropyrimidines such as 5-FU. PATIENTS AND METHODS: NUC-3373 was administered as monotherapy to patients with advanced solid tumors refractory to standard therapy via intravenous infusion either on Days 1, 8, 15 and 22 (Part 1) or on Days 1 and 15 (Part 2) of 28-day cycles until disease progression or unacceptable toxicity. Primary objectives were maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) and schedule of NUC-3373. Secondary objectives included pharmacokinetics (PK), and anti-tumor activity. RESULTS: Fifty-nine patients received weekly NUC-3373 in 9 cohorts in Part 1 (n = 43) and 3 alternate-weekly dosing cohorts in Part 2 (n = 16). They had received a median of 3 prior lines of treatment (range: 0-11) and 74% were exposed to prior fluoropyrimidines. Four experienced dose-limiting toxicities: two Grade (G) 3 transaminitis; one G2 headache; and one G3 transient hypotension. Commonest treatment-related G3 adverse event of raised transaminases occurred in < 10% of patients. NUC-3373 showed a favorable PK profile, with dose-proportionality and a prolonged half-life compared to 5-FU. A best overall response of stable disease was observed, with prolonged progression-free survival. CONCLUSION: NUC-3373 was well-tolerated in a heavily pre-treated solid tumor patient population, including those who had relapsed on prior 5-FU. The MTD and RP2D was defined as 2500 mg/m2 NUC-3373 weekly. NUC-3373 is currently in combination treatment studies. TRIAL REGISTRATION: Clinicaltrials.gov registry number NCT02723240. Trial registered on 8th December 2015. https://clinicaltrials.gov/study/NCT02723240 .

COHESION: a core outcome set for the treatment of neonatal encephalopathy.

BACKGROUND: Heterogeneity in outcomes reported in trials of interventions for the treatment of neonatal encephalopathy (NE) makes evaluating the effectiveness of treatments difficult. Developing a core outcome set for NE treatment would enable researchers to measure and report the same outcomes in future trials. This would minimise waste, ensure relevant outcomes are measured and enable evidence synthesis. Therefore, we aimed to develop a core outcome set for treating NE. METHODS: Outcomes identified from a systematic review of the literature and interviews with parents were prioritised by stakeholders (n = 99 parents/caregivers, n = 101 healthcare providers, and n = 22 researchers/ academics) in online Delphi surveys. Agreement on the outcomes was achieved at online consensus meetings attended by n = 10 parents, n = 18 healthcare providers, and n = 13 researchers/ academics. RESULTS: Seven outcomes were included in the final core outcome set: survival; brain injury on imaging; neurological status at discharge; cerebral palsy; general cognitive ability; quality of life of the child, and adverse events related to treatment. CONCLUSION: We developed a core outcome set for the treatment of NE. This will allow future trials to measure and report the same outcomes and ensure results can be compared. Future work should identify how best to measure the COS. IMPACT: We have identified seven outcomes that should be measured and reported in all studies for the treatment of neonatal encephalopathy. Previously, a core outcome set for neonatal encephalopathy treatments did not exist. This will help to reduce heterogeneity in outcomes reported in clinical trials and other studies, and help researchers identify the best treatments for neonatal encephalopathy.

Evaluation of hypofractionated adaptive radiotherapy using the MR Linac in localised pancreatic cancer: protocol summary of the Emerald-Pancreas phase 1/expansion study located at Oxford University Hospital, UK.

INTRODUCTION: Online adaptive MR-guided radiotherapy allows for dose escalation to pancreatic cancer while sparing surrounding critical organs. We seek to evaluate the safety of delivering hypofractionated five-fraction, three-fraction and single-fraction MR-guided stereotactic ablative radiotherapy (SABR) to the pancreas. METHODS AND ANALYSIS: This is a single-centre three-arm phase 1 non-randomised safety study. Patients with localised pancreatic cancer will receive either 50 Gy in five (biological equivalent dose (BED10)=100 Gy), 39 Gy in three (BED10=90 Gy) or 25 Gy in a single fraction (BED10=87.5 Gy) MR-guided daily online adaptive radiotherapy. Each fractionation regimen will be assessed as independent cohorts to determine tolerability, assessed continuously using Bayesian conjugate posterior beta distributions. The primary endpoint of the study is to establish the safety of five-fraction, three-fraction and single-fraction MR-guided hypofractionation SABR in localised pancreatic cancer by assessing dose-limiting toxicities. Secondary endpoints include overall survival, progression-free survival, local control rates, overall control rate, resection rates, long-term toxicities and freedom from second-line chemotherapy. This study plans to also explore imaging and immune biomarkers that may be useful to predict outcome and personalise treatment. The trial will recruit up to 60 patients with a safety run-in. ETHICS AND DISSEMINATION: The trial is approved by the West Midlands-Black Country Research Ethics Committee 22/WM/0122. The results will be disseminated via conference presentations, peer-reviewed scientific journals and submission to regulatory authorities. The data collected for the study, including individual participant data, will be made available to researchers on request to the study team and with appropriate reason, via octo-enquiries@oncology.ox.ac.uk. The shared data will be deidentified participant data and will be available for 3 years following publication of the study. Data will be shared with investigator support, after approval of a proposal and with a signed data access agreement. TRIAL REGISTRATION NUMBER: ISRCTN10557832.

Multi-Round versus Real-Time Delphi survey approach for achieving consensus in the COHESION core outcome set: a randomised trial.

BACKGROUND: Delphi surveys are commonly used to prioritise critical outcomes in core outcome set (COS) development. This trial aims to compare a three-round (Multi-Round) Delphi (MRD) with a Real-Time Delphi (RTD) in the prioritisation of outcomes for inclusion in a COS for neonatal encephalopathy treatments and explore whether 'feedback', 'iteration', and 'initial condition' effects may occur in the two survey methods. METHODS: We recruited 269 participants (parents/caregivers, healthcare providers and researchers/academics) of which 222 were randomised to either the MRD or the RTD. We investigated the outcomes prioritised in each survey and the 'feedback', 'iteration', and 'initial condition' effects to identify differences between the two survey methods. RESULTS: In the RTD, n = 92 participants (83%) fully completed the survey. In the MRD, n = 60 participants (54%) completed all three rounds. Of the 92 outcomes presented, 26 (28%) were prioritised differently between the RTD and MRD. Significantly fewer participants amended their scores when shown stakeholder responses in the RTD compared to the MRD ('feedback effect'). The 'iteration effect' analysis found most experts appeared satisfied with their initial ratings in the RTD and did not amend their scores following stakeholder response feedback. Where they did amend their scores, ratings were amended substantially, suggesting greater convergence. Variance in scores reduced with subsequent rounds of the MRD ('iteration effect'). Whilst most participants did not change their initial scores in the RTD, of those that did, later recruits tended to align their final score more closely to the group mean final score than earlier recruits (an 'initial condition' effect). CONCLUSION: The feedback effect differed between the two Delphi methods but the magnitude of this difference was small and likely due to the large number of observations rather than because of a meaningfully large difference. It did not appear to be advantageous to require participants to engage in three rounds of a survey due to the low change in scores. Larger drop-out through successive rounds in the MRD, together with a lesser convergence of scores and longer time to completion, indicate considerable benefits of the RTD approach. TRIAL REGISTRATION: NCT04471103. Registered on 14 July 2020.

Day-to-day variability of knee pain and the relationship with physical activity in people with knee osteoarthritis: an observational, feasibility study using consumer smartwatches.

OBJECTIVE: To assess the feasibility of using smartwatches in people with knee osteoarthritis (OA) to determine the day-to-day variability of pain and the relationship between daily pain and step count. DESIGN: Observational, feasibility study. SETTING: In July 2017, the study was advertised in newspapers, magazines and, on social media. Participants had to be living/willing to travel to Manchester. Recruitment was in September 2017 and data collection was completed in January 2018. PARTICIPANTS: 26 participants aged>50 years with self-diagnosed symptomatic knee OA were recruited. OUTCOME MEASURES: Participants were provided with a consumer cellular smartwatch with a bespoke app that triggered a series of daily questions including two times per day questions about level of knee pain and one time per month question from the pain subscale of the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire. The smartwatch also recorded daily step counts. RESULTS: Of the 25 participants, 13 were men and their mean age was 65 years (standard deviation (SD) 8 years). The smartwatch app was successful in simultaneously assessing and recording data on knee pain and step count in real time. Knee pain was categorised into sustained high/low or fluctuating levels, but there was considerable day-to-day variation within these categories. Levels of knee pain in general correlated with pain assessed by KOOS. Those with sustained high/low levels of pain had a similar daily step count average (mean 3754 (SD 2524)/4307 (SD 2992)), but those with fluctuating pain had much lower step count levels (mean 2064 (SD 1716)). CONCLUSIONS: Smartwatches can be used to assess pain and physical activity in knee OA. Larger studies may help inform a better understanding of causal links between physical activity patterns and pain. In time, this could inform development of personalised physical activity recommendations for people with knee OA.

Protocol for the TRANSLATE prospective, multicentre, randomised clinical trial of prostate biopsy technique.

OBJECTIVES: Primary objectives: to determine whether local anaesthetic transperineal prostate (LATP) biopsy improves the detection of clinically significant prostate cancer (csPCa), defined as International Society of Urological Pathology (ISUP) Grade Group ≥2 disease (i.e., any Gleason pattern 4 disease), compared to transrectal ultrasound-guided (TRUS) prostate biopsy, in biopsy-naïve men undergoing biopsy based on suspicion of csPCa. SECONDARY OBJECTIVES: to compare (i) infection rates, (ii) health-related quality of life, (iii) patient-reported procedure tolerability, (iv) patient-reported biopsy-related complications (including bleeding, bruising, pain, loss of erectile function), (v) number of subsequent prostate biopsy procedures required, (vi) cost-effectiveness, (vii) other histological parameters, and (viii) burden and rate of detection of clinically insignificant PCa (ISUP Grade Group 1 disease) in men undergoing these two types of prostate biopsy. PATIENTS AND METHODS: The TRANSLATE trial is a UK-wide, multicentre, randomised clinical trial that meets the criteria for level-one evidence in diagnostic test evaluation. TRANSLATE is investigating whether LATP biopsy leads to a higher rate of detection of csPCa compared to TRUS prostate biopsy. Both biopsies are being performed with an average of 12 systematic cores in six sectors (depending on prostate size), plus three to five target cores per multiparametric/bi-parametric magnetic resonance imaging lesion. LATP biopsy is performed using an ultrasound probe-mounted needle-guidance device (either the 'Precision-Point' or BK UA1232 system). TRUS biopsy is performed according to each hospital's standard practice. The study is 90% powered to detect a 10% difference (LATP biopsy hypothesised at 55% detection rate for csPCa vs 45% for TRUS biopsy). A total of 1042 biopsy-naïve men referred with suspected PCa need to be recruited. CONCLUSIONS: This trial will provide robust prospective data to determine the diagnostic ability of LATP biopsy vs TRUS biopsy in the primary diagnostic setting.

Assessment of patients' self-reported levels of adherence to postoperative restrictions following total hip replacement.

BACKGROUND: Postoperative precautions that limit hip movement reduce the incidence of postoperative dislocation following total hip replacement (THR). It is assumed that patients adhere to these precautions, but true adherence is unknown. AIMS: To assess adherence to postoperative precautions, including bending, twisting, crossing of legs, sleeping position and sitting position following primary THR surgery. METHODS: A self-reporting questionnaire explored patient adherence to precautions following primary THR. Questionnaires were sent to 120 patients following elective primary THR at two orthopaedic centres in England between November 2016 and April 2017. Patients were also asked to report the duration of adherence and the difficulty associated with adherence to each of the precautions. RESULTS: Eighty-three percent (99/120) of patients responded. Of these, 56% (56/99) were female and 44% (44/99) were male. Mean age was 66.0 (standard deviation 9.4) years. Seventy-six percent of patients were classified as 'highly adherent' to the precautions in hospital, and this reduced to 68% when patients went home. The median duration of adherence to the precaution to avoid crossing legs was 6 weeks [interquartile range (IQR) 6-6]. For the remaining four precautions, the median duration of adherence was consistently 6 weeks (IQR 4-6). CONCLUSION: High levels of adherence to precautions following THR were identified. However, patients reported difficulty adhering to the precautions, which may explain why 24% of patients were not able to adhere to the precautions> 90% of the time. Patients reported that the most difficult precaution to adhere to was supine sleeping, and the least difficult precautions to adhere to were avoiding crossing legs and using a raised chair.

Assessment of bone marrow oedema-like lesions using MRI in patellofemoral knee osteoarthritis: comparison of different MRI pulse sequences.

OBJECTIVE: To compare bone marrow oedema-like lesion (BML) volume in subjects with symptomatic patellofemoral (PF) knee osteoarthritis (OA) using four different MRI sequences and to determine reliability of BML volume assessment using these sequences and their correlation with pain. METHODS: 76 males and females (mean age 55.8 years) with symptomatic patellofemoral knee OA had 1.5 T MRI scans. PD fat suppressed (FS), STIR, contrast-enhanced (CE) T1W FS, and 3D T1W fast field echo (FFE) sequences were obtained. All sequences were assessed by one reader, including repeat assessment of 15 knees using manual segmentation and the measurements were compared. We used random-effects panel linear regression to look for differences in the log-transformed BML volume (due to positive skew in the BML volume distribution) between sequences and to determine associations between BML volumes and knee pain. RESULTS: 58 subjects had PF BMLs present on at least one sequence. Median BML volume measured using T1W FFE sequence was significantly smaller (224.7 mm3, interquartile range [IQR] 82.50-607.95) than the other three sequences. BML volume was greatest on the CE sequence (1129.8 mm3, IQR 467.28-3166.02). Compared to CE sequence, BML volumes were slightly lower when assessed using PDFS (proportional difference = 0.79; 95% confidence interval [CI] 0.62, 1.01) and STIR sequences (proportional difference = 0.85; 95% CI 0.67, 1.08). There were strong correlations between BML volume on PDFS, STIR, and CE T1W FS sequences (ρs = 0.98). Correlations were lower between these three sequences and T1W FFE (ρs = 0.80-0.81). Intraclass correlation coefficients were excellent for proton density fat-suppressed, short-tau inversion recovery, and CE T1W FS sequences (0.991-0.995), while the ICC for T1W FFE was good at 0.88. We found no significant association between BML volumes assessed using any of the sequences and knee pain. CONCLUSION: T1W FFE sequences were less reliable and measured considerably smaller BML volume compared to other sequences. BML volume was larger when assessed using the contrast enhanced T1W FS though not statistically significantly different from BMLs when assessed using PDFS and STIR sequences. ADVANCES IN KNOWLEDGE: This is the first study to assess BMLs by four different MRI pulse sequences on the same data set, including different fluid sensitive sequences and gradient echo type sequence.

Engagement and Participant Experiences With Consumer Smartwatches for Health Research: Longitudinal, Observational Feasibility Study.

BACKGROUND: Wearables provide opportunities for frequent health data collection and symptom monitoring. The feasibility of using consumer cellular smartwatches to provide information both on symptoms and contemporary sensor data has not yet been investigated. OBJECTIVE: This study aimed to investigate the feasibility and acceptability of using cellular smartwatches to capture multiple patient-reported outcomes per day alongside continuous physical activity data over a 3-month period in people living with knee osteoarthritis (OA). METHODS: For the KOALAP (Knee OsteoArthritis: Linking Activity and Pain) study, a novel cellular smartwatch app for health data collection was developed. Participants (age ≥50 years; self-diagnosed knee OA) received a smartwatch (Huawei Watch 2) with the KOALAP app. When worn, the watch collected sensor data and prompted participants to self-report outcomes multiple times per day. Participants were invited for a baseline and follow-up interview to discuss their motivations and experiences. Engagement with the watch was measured using daily watch wear time and the percentage completion of watch questions. Interview transcripts were analyzed using grounded thematic analysis. RESULTS: A total of 26 people participated in the study. Good use and engagement were observed over 3 months: most participants wore the watch on 75% (68/90) of days or more, for a median of 11 hours. The number of active participants declined over the study duration, especially in the final week. Among participants who remained active, neither watch time nor question completion percentage declined over time. Participants were mainly motivated to learn about their symptoms and enjoyed the self-tracking aspects of the watch. Barriers to full engagement were battery life limitations, technical problems, and unfulfilled expectations of the watch. Participants reported that they would have liked to report symptoms more than 4 or 5 times per day. CONCLUSIONS: This study shows that capture of patient-reported outcomes multiple times per day with linked sensor data from a smartwatch is feasible over at least a 3-month period. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/10238.

Change in pain and its relation to change in activity in osteoarthritis.

Objective: Trials testing promising interventions in knee osteoarthritis (OA) often fail to show pain reductions. This may be due to change in activity whereby a person's pain decreases, leading them to increase their activity levels, in turn increasing pain back to baseline levels. Using data from a trial of a beneficial treatment for knee pain, we explored whether activity changes might mask a treatment's effect on pain, by looking at whether activity levels increased with effective treatment and whether change in activity level related to change in pain. Design: During the InRespond trial (ISRCTN55059760) participants wore an accelerometer for 7 days before and during treatments. We assessed change in pain on treatment using scores for overall knee pain and pain in a nominated pain-aggravating activity both in the last week and evaluated change in different types of activity using accelerometer data. Principal components analysis tested whether change in activity and pain outcomes were correlated and created composites combining them. We then tested whether activity, pain or the composites showed a treatment effect, and examined their responsiveness. Results: In the 61 participants (mean age 64.5 years, 38% women, mean overall knee pain score 5.08 (0-10)), activity levels mostly decreased during the trial. Principal component analyses suggested that pain and activity did not correlate highly, loading on different components. Treatment that showed significant effects on pain did not show similar effects on either activity (e.g. the active treatment had a slightly greater reduction in total steps taken than the control treatment (difference 1942.6 steps/week, p = 0.42) nor on composites combining activity and pain. Pain outcomes were the most responsive; static loading (standing) outcomes were the most responsive activity outcome. Conclusion: We found no evidence to support the hypothesis that activity levels increase during effective OA treatment and might account for the negligible pain effects of OA treatments.

Do Clinical Correlates of Knee Osteoarthritis Predict Outcome of Intraarticular Steroid Injections?

OBJECTIVE: To determine whether clinical correlates of knee osteoarthritis (OA) affect the outcome of intraarticular steroid injections (IASI) in symptomatic knee OA. METHODS: Men and women aged ≥ 40 years with painful knee OA who participated in an open-label trial of IASI completed questionnaires and clinical examination. The Outcome Measures in Rheumatology (OMERACT)-Osteoarthritis Research Society International (OARSI) criteria were used to assess response to therapy in the short term (within 2 weeks). Among those who initially responded, those whose pain had not returned to within 20% of the baseline Knee Injury and Osteoarthritis Outcome Score pain score at 6 months were characterized as longer-term responders. Log-binomial regression was used to examine factors associated with outcome. RESULTS: One hundred ninety-nine participants were included, of whom 146 (73.4%) were short-term and 40 (20.1%) longer-term responders. Compared to short-term nonresponders, participants with these characteristics were more likely to be short-term responders: medial joint line tenderness [relative risk (RR) 1.42, 95% CI 1.10-1.82], medial and lateral joint line tenderness (RR 1.38, 95% CI 1.03-1.84), patellofemoral tenderness (RR 1.27, 95% CI 1.04-1.55), anserine tenderness (RR 1.27, 95% CI 1.06-1.52), and a belief that treatment would be effective [RR/unit increase (range 0-10) = 1.05 (1.01-1.09)]. Aspiration of joint fluid (RR 0.79, 95% CI 0.66-0.95) and previous ligament/meniscus injury (RR 0.63, 95% CI 0.44-0.91) were associated with a reduced risk of being a short-term responder. Compared to initial nonresponders and those whose pain recurred within 6 months, participants with a higher number of pain sites [RR/unit increase (range 0-10) = 0.83, 95% CI 0.72-0.97], chronic widespread pain (RR 0.32, 95% CI 0.10-0.98), perceived chronicity of disease [RR/unit increase (range 0-10) = 0.86, 95% CI 0.78-0.94], and a higher depression score [RR/unit increase (range 0-21) = 0.89, 95% CI 0.81-0.99] were less likely to be longer-term responders. CONCLUSION: Among patients with symptomatic knee OA, tenderness around the knee was associated with better short-term outcome of IASI. However, clinical-related factors did not predict longer-term response, while those with chronic widespread pain and depressive symptoms were less likely to obtain longer-term benefits.

Measurement of synovial tissue volume in knee osteoarthritis using a semiautomated MRI-based quantitative approach.

PURPOSE: Synovitis is common in knee osteoarthritis and is associated with both knee pain and progression of disease. Semiautomated methods have been developed for quantitative assessment of structure in knee osteoarthritis. Our aims were to apply a novel semiautomated assessment method using 3D active appearance modeling for the quantification of synovial tissue volume (STV) and to compare its performance with conventional manual segmentation. METHODS: Thirty-two sagittal T1 -weighted fat-suppressed contrast-enhanced MRIs were assessed for STV by a single observer using 1) manual segmentation and 2) a semiautomated approach. We compared the STV analysis using the semiautomated and manual segmentation methods, including the time taken to complete the assessments. We also examined the reliability of STV assessment using the semiautomated method in a subset of 12 patients who had participated in a clinical trial of vitamin D therapy in knee osteoarthritis. RESULTS: There was no significant difference in STV using the semiautomated quantitative method compared to manual segmentation, mean difference = 207.2 mm3 (95% confidence interval -895.2 to 1309.7). The semiautomated method was significantly quicker than manual segmentation (18 vs. 71 min). For the semiautomated method, intraobserver agreement was excellent (intraclass correlation coefficient (3,1) = 0.99) and interobserver agreement was very good (intraclass correlation coefficient (3,1) = 0.83). CONCLUSION: We describe the application of a semiautomated method that is accurate, reliable, and quicker than manual segmentation for assessment of STV. The method may help increase efficiency of image assessment in large imaging studies and may also assist investigation of treatment efficacy in knee osteoarthritis.

Effect of Vitamin D supplementation on synovial tissue volume and subchondral bone marrow lesion volume in symptomatic knee osteoarthritis.

BACKGROUND: Data from a recent clinical trial of vitamin D therapy in knee OA suggests that, compared to placebo, vitamin D therapy may be associated with a reduction in effusion-synovitis. Our aim was, using contrast-enhanced (CE) magnetic resonance imaging (MRI), to examine the effect of vitamin D therapy on synovial tissue volume (STV) and also subchondral bone marrow lesion (BML) volume in men and women with symptomatic knee OA. METHODS: Data was acquired from participants who took part in a randomised placebo-controlled trial (UK VIDEO) investigating the effect of vitamin D therapy (800 IU cholecalciferol daily) on radiographic joint space narrowing. A subsample had serial CE MRI scans acquired during the trial. Subjects with serial images were assessed (N = 50) for STV and subchondral BML volume. The difference in the mean change from baseline in these structural outcomes between intervention and placebo groups was assessed using random-effects modelling. RESULTS: The mean age of the 50 subjects (24 active group, 26 placebo group) who contributed data to the analysis was 63.3 years (SD 6.5) and 74% were female. There was no significant difference at 2 years follow-up between the vitamin D and placebo groups in the mean change from baseline for STV (93.9 mm3, 95% CI -1605.0 to 1792.7) and subchondral BML volume (- 313.5 mm3, 95% CI -4244.7 to 3617.7). CONCLUSIONS: Vitamin D supplementation does not appear to have an effect on synovitis or BML volume in patients with symptomatic knee OA. TRIAL REGISTRATION: VIDEO was registered with EudraCT: ref. 2004-000169-37. The protocol for the trial can be accessed at https://www.ctu.mrc.ac.uk/studies/all-studies/v/video/.

The Efficacy of a Lateral Wedge Insole for Painful Medial Knee Osteoarthritis After Prescreening: A Randomized Clinical Trial.

OBJECTIVE: Lateral wedge shoe insoles decrease medial knee loading, but trials have shown no effect on pain in medial knee osteoarthritis (OA). However, loading effects of insoles are inconsistent, and they can increase patellofemoral loading. We undertook this study to investigate the hypothesis that insoles would reduce pain in preselected patients. METHODS: Among patients with painful medial knee OA, we excluded those with patellofemoral OA and those with a pain rating of <4 of a possible 10. We further excluded participants who, in a gait analysis using lateral wedges, did not show at least a 2% reduction in knee adduction moment (KAM), compared to wearing their shoes and a neutral insole. We then randomized subjects to lateral wedge versus neutral insole for 8-week periods, separated by an 8-week washout. The primary outcome measure was knee pain (0-10 scale) during the past week, and secondary outcome measures included activity pain and pain rated in the Knee Injury and Osteoarthritis Outcome Score questionnaire. We carried out mixed model analyses adjusted for baseline pain. RESULTS: Of 83 participants, 21 (25.3%) were excluded from analysis because of insufficient reduction in KAM. In the 62 patients included in analysis, the mean ± SD age was 64.2 ± 9.1 years, and 37.1% were women. Lateral wedge insoles produced a greater reduction in knee pain than neutral insoles (mean difference of 0.7 on 0-10 scale [95% confidence interval 0.1, 1.2]) (P = 0.02). Findings for secondary outcome measures were mixed. CONCLUSION: In participants prescreened to eliminate those with patellofemoral OA and biomechanical nonresponders, lateral wedge insoles reduced knee pain, but the effect of treatment was small and is likely of clinical significance in only a minority of patients. Targeting patients may identify those who respond to this treatment.

Collecting Symptoms and Sensor Data With Consumer Smartwatches (the Knee OsteoArthritis, Linking Activity and Pain Study): Protocol for a Longitudinal, Observational Feasibility Study.

BACKGROUND: The Knee OsteoArthritis, Linking Activity and Pain (KOALAP) study is the first to test the feasibility of using consumer-grade cellular smartwatches for health care research. OBJECTIVE: The overall aim was to investigate the feasibility of using consumer-grade cellular smartwatches as a novel tool to capture data on pain (multiple times a day) and physical activity (continuously) in patients with knee osteoarthritis. Additionally, KOALAP aimed to investigate smartwatch sensor data quality and assess whether engagement, acceptability, and user experience are sufficient for future large-scale observational and interventional studies. METHODS: A total of 26 participants with self-diagnosed knee osteoarthritis were recruited in September 2017. All participants were aged 50 years or over and either lived in or were willing to travel to the Greater Manchester area. Participants received a smartwatch (Huawei Watch 2) with a bespoke app that collected patient-reported outcomes via questionnaires and continuous watch sensor data. All data were collected daily for 90 days. Additional data were collected through interviews (at baseline and follow-up) and baseline and end-of-study questionnaires. This study underwent full review by the University of Manchester Research Ethics Committee (#0165) and University Information Governance (#IGRR000060). For qualitative data analysis, a system-level security policy was developed in collaboration with the University Information Governance Office. Additionally, the project underwent an internal review process at Google, including separate reviews of accessibility, product engineering, privacy, security, legal, and protection regulation compliance. RESULTS: Participants were recruited in September 2017. Data collection via the watches was completed in January 2018. Collection of qualitative data through patient interviews is still ongoing. Data analysis will commence when all data are collected; results are expected in 2019. CONCLUSIONS: KOALAP is the first health study to use consumer cellular smartwatches to collect self-reported symptoms alongside sensor data for musculoskeletal disorders. The results of this study will be used to inform the design of future mobile health studies. Results for feasibility and participant motivations will inform future researchers whether or under which conditions cellular smartwatches are a useful tool to collect patient-reported outcomes alongside passively measured patient behavior. The exploration of associations between self-reported symptoms at different moments will contribute to our understanding of whether it may be valuable to collect symptom data more frequently. Sensor data-quality measurements will indicate whether cellular smartwatch usage is feasible for obtaining sensor data. Methods for data-quality assessment and data-processing methods may be reusable, although generalizability to other clinical areas should be further investigated. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/10238.

Comparing image analysis approaches versus expert readers: the relation of knee radiograph features to knee pain.

OBJECTIVES: The relationship between radiographic evidence of osteoarthritis and knee pain has been weak. This may be because features that best discriminate knees with pain have not been included in analyses. We tested the correlation between knee pain and radiographic features taking into account both image analysis features and manual scores. METHODS: Using data of the Multicentre Osteoarthritis Study, we tested in a cross-sectional design how well X-ray features discriminated those with frequent knee pain (one question at one time) or consistent frequent knee pain (three questions at three times during the 2 weeks prior to imaging) from those without it. We trained random forest models on features from two radiographic views for classification. RESULTS: X-rays were better at classifying those with pain using three questions compared with one. When we used all manual radiographic features, the area under the curve (AUC) was 73.9%. Using the best model from automated image analyses or a combination of these and manual grades, no improvement over manual grading was found. CONCLUSIONS: X-ray changes of OA are more strongly associated with repeated reports of knee pain than pain reported once. In addition, a fully automated system that assessed features not scored on X-ray performed no better than manual grading of features.

Responsiveness of Single versus Composite Measures of Pain in Knee Osteoarthritis.

OBJECTIVE: In rheumatoid arthritis, composite outcomes constructed from a combination of outcome measures are widely used to enhance responsiveness (sensitivity to change) and comprehensively summarize response. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain is the primary outcome measure in many osteoarthritis (OA) trials. Information from other outcomes, such as rescue medication use and other WOMAC subscales, could be added to create composite outcomes, but the sensitivity of such a composite has not been tested. METHODS: We used data from a completed trial of tanezumab for knee OA (NCT00733902). The WOMAC questionnaire and rescue medication use were measured at several timepoints, up to 16 weeks. Pain and rescue medication outcomes were standardized and combined into 3 composite outcomes through principal components analysis to produce 1 score (composite outcome) and their responsiveness was compared to WOMAC pain, the standard. We pooled all treatment doses of tanezumab into 1 treatment group, for simplicity, and compared this to the control group (placebo). RESULTS: The composite outcomes showed modestly, but not statistically significantly greater responsiveness when compared to WOMAC pain alone. Adding information on rescue medication to the composite improved responsiveness. While improvements in sensitivity were modest, the required sample sizes for trials using composites was 20-40% less than trials using WOMAC pain alone. CONCLUSION: Combining information from related but distinct outcomes considered relevant to a particular treatment improved responsiveness, could reduce sample size requirements in OA trials, and might offer a way to better detect treatment efficacy in OA trials.

Prognostic factors for specific lower extremity and spinal musculoskeletal injuries identified through medical screening and training load monitoring in professional football (soccer): a systematic review.

BACKGROUND: Medical screening and load monitoring procedures are commonly used in professional football to assess factors perceived to be associated with injury. OBJECTIVES: To identify prognostic factors (PFs) and models for lower extremity and spinal musculoskeletal injuries in professional/elite football players from medical screening and training load monitoring processes. METHODS: The MEDLINE, AMED, EMBASE, CINAHL Plus, SPORTDiscus and PubMed electronic bibliographic databases were searched (from inception to January 2017). Prospective and retrospective cohort studies of lower extremity and spinal musculoskeletal injury incidence in professional/elite football players aged between 16 and 40 years were included. The Quality in Prognostic Studies appraisal tool and the modified Grading of Recommendations Assessment, Development and Evaluation synthesis approach was used to assess the quality of the evidence. RESULTS: Fourteen studies were included. 16 specific lower extremity injury outcomes were identified. No spinal injury outcomes were identified. Meta-analysis was not possible due to heterogeneity and study quality. All evidence related to PFs and specific lower extremity injury outcomes was of very low to low quality. On the few occasions where multiple studies could be used to compare PFs and outcomes, only two factors demonstrated consensus. A history of previous hamstring injuries (HSI) and increasing age may be prognostic for future HSI in male players. CONCLUSIONS: The assumed ability of medical screening tests to predict specific musculoskeletal injuries is not supported by the current evidence. Screening procedures should currently be considered as benchmarks of function or performance only. The prognostic value of load monitoring modalities is unknown.