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Objectives: Knee osteoarthritis (OA) is thought to be a slowly evolving disease with glacial changes in cartilage morphology necessitating trials of potential treatments lasting 1-2 years with evidence that over 6 months change in cartilage is not detectable. In contrast to cartilage, bone has the capacity to adapt rapidly, such as after fracture. We tested whether bone marrow lesions (BMLs) change in volume in 6 and 12 weeks, suggesting they may provide evidence of short term fluctuations of joint damage.Methods: In 62 patients with patellofemoral knee OA (mean age 55.7 years, 59.7% women, mean BMI 31.0), we obtained baseline, 6 and 12 week knee MRIs with contrast enhancement. Of those with BMLs at baseline, we assessed BML volume on the axial proton density fat saturated (FS) images and postcontrast sagittal T1 weighted FS images. We manually segmented BML volumes, testing repeatability of BML volumes in knees remeasured. Using the standard deviation of the difference between repeated measurements to calculate Bland-Altman Limits of Agreement, we determined how much BML volume change represented a change greater than due to chance.Results: Fifty-two patients had BMLs at baseline. Test-retest reliability for BML volume was high (ICC 0.89, 95% CI 0.80-0.97). All knees showed at least some change in BML volume by 6 and 12 weeks. On the axial view at 6 weeks, 20/49 (40.8%) knees showed BML volume changes greater than the limits of agreement with similar results at 12 weeks. BML changes were evenly divided among knees with enlarging and shrinking BMLs. 63.3% of the knees had more than 50% change in BML volume at either 6 or 12 weeks on the axial view and 48.7% on the sagittal view.Conclusions: Knee BML volumes change in several weeks in many persons with knee OA. To the extent that they could be regarded as treatment targets, trials testing BML effects could avoid the usual prolonged structure modification trials. [ABSTRACT FROM AUTHOR]

Purpose: Accurate radiation therapy (RT) for lung cancer is challenging because of the respiratory motion of the tumor and surrounding organs at risk. Recently, non-invasive mechanical ventilation (NIMV) has been investigated as a novel respiratory motion management strategy. Using NIMV, respiratory motion can be minimized, while a larger lung volume yields less overall lung dose. The purpose of this study was to determine the potential benefit of NIMV to improve lung cancer RT using magnetic resonance imaging (MRI) data of healthy volunteers., Methods and Materials: Twelve healthy volunteers practiced NIMV at 60 breaths per minute (NIMV 60 ) with added positive end-expiratory pressure (PEEP) in 2 sessions and subsequently underwent NIMV 60 in 2 MRI sessions. We acquired single-slice sagittal 2-dimensional MRI images at 2.6 Hz for 6 minutes during free breathing and NIMV 60 . We quantified the motion of all visible cross-sections of lung arteries, as a surrogate for lung tumors, in cranio-caudal and anterior-posterior directions using deformable image registration, distinguishing between 4 quadrants in the lungs (posterior-cranial, posterior-caudal, anterior-caudal, and anterior-cranial). Also, we analyzed average lung area, as a surrogate for lung volume, on the sagittal images using automatic segmentation., Results: All volunteers were successfully trained to be ventilated with NIMV 60 , and completed all sessions. The reduction of the median lung artery motion in each of the quadrants varied from 61% to 67% (from 10.7-29.9 to 3.8-11.7 mm) in cranio-caudal direction and from 51% to 68% (from 8.0-13.7 to 3.0-5.1 mm) in anterior-posterior direction using NIMV 60 . NIMV 60 increased the sagittal lung area by 35% compared with free breathing., Conclusions: NIMV 60 with added PEEP is a promising way to improve lung cancer RT because of reduced respiratory motion and increased lung area compared with free breathing., Competing Interests: Johannes Kornelis Veldman-Landegent reports financial support from Dutch Cancer Foundation (KWF). Michael J. Parkes reports financial support from Marie Sklodowska Cure Individual Fellowship. Arjan Bel reports research grants from General Electric, Varian Medical Systems Inc Elekta, and Karl Reiner. Zdenko van Kesteren reports a non-financial support from General Electric, Varian Medical Systems Inc, and Philips Healthcare. Irma van Dijk reports research grants from Varian Medical Systems Inc and Karl Reiner. The remaining authors do not have any relevant financial disclosures to report., (© 2024 The Authors.)

Objective: To establish proof-of-concept for the dynamic prediction of adverse pregnancy outcome in women with a history of stillbirth or perinatal death, repeatedly throughout the pregnancy., Methods: A retrospective cohort study of women in a subsequent pregnancy following previous perinatal loss, who received antenatal care at a tertiary hospital between January 2014 and December 2017, was used as the basis for exploratory prognostic model development. Models were developed to repeatedly predict a composite adverse outcome (stillbirth or neonatal death, 5-min Apgar score < 7, umbilical artery pH ≤ 7.05, admission to the neonatal intensive care unit for longer than 24 h, preterm birth (< 37 completed weeks) or birth weight < 10 th centile) using the findings of sequential ultrasound scans for fetal biometry and umbilical and uterine artery Doppler., Results: In total, 506 participants were eligible, of whom 504 were included in the analysis. An adverse pregnancy outcome was experienced by 110 (22%) participants. The ability to predict the composite outcome using repeated head circumference and estimated fetal weight measurements improved as the pregnancy progressed (e.g. area under the receiver-operating-characteristics curve improved from 0.59 at 24 weeks' gestation to 0.74 at 36 weeks' gestation), supporting proof-of-concept. Predictors to include in dynamic prediction models were identified, including ultrasound measurements of fetal biometry, umbilical and uterine artery Doppler and placental size and shape., Conclusion: The present study supports proof-of-concept for dynamic prediction of adverse outcome in pregnancy following prior stillbirth or perinatal death, which could be used to identify risks earlier in pregnancy, while highlighting methodological challenges and requirements for subsequent large-scale model development studies. © 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

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., (© 2024. The Author(s).)

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., (© 2023. The Author(s).)

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 (BED 10 )=100 Gy), 39 Gy in three (BED 10 =90 Gy) or 25 Gy in a single fraction (BED 10 =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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

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., (© 2023. The Author(s).)

Background: Respiratory motion presents a challenge in radiotherapy of thoracic and upper abdominal tumors. Techniques to account for respiratory motion include tracking. Using magnetic resonance imaging (MRI) guided radiotherapy systems, tumors can be tracked continuously. Using conventional linear accelerators, tracking of lung tumors is possible by determining tumor motion on kilo voltage (kV) imaging. But tracking of abdominal tumors with kV imaging is hampered by limited contrast. Therefore, surrogates for the tumor are used. One of the possible surrogates is the diaphragm. However, there is no universal method for establishing the error when using a surrogate and there are particular challenges in establishing such errors during free breathing (FB). Prolonged breath-holding might address these challenges., Purpose: The aim of this study was to quantify the error when using the right hemidiaphragm top (RHT) as surrogate for abdominal organ motion during prolonged breath-holds (PBH) for possible application in radiation treatments., Methods: Fifteen healthy volunteers were trained to perform PBHs in two subsequent MRI sessions (PBH-MRI1 and PBH-MRI2). From each MRI acquisition, we selected seven images (dynamics) to determine organ displacement during PBH by using deformable image registration (DIR). On the first dynamic, the RHT, right and left hemidiaphragm, liver, spleen and right and left kidney were segmented. We used the deformation vector fields (DVF), generated by DIR, to determine the displacement of each organ between two dynamics in inferior-superior (IS), anterior-posterior (AP), left-right (LR) direction and we calculated the 3D vector magnitude (|d|). The displacements of the RHT, both hemidiaphragms and the abdominal organs were compared using a linear fit to determine the correlation (R 2 of the fit) and the displacement ratio (DR, slope of the fit) between displacements of the RHT and each organ. We quantified the median difference between the DRs of PBH-MRI1 and PBH-MRI2 for each organ. Additionally, we estimated organ displacement in the second PBH by applying the DR from the first PBH to the displacement of the RHT measured during the second PBH. We compared the estimated organ displacement to the measured organ displacement during the second PBH. The difference between the two values was defined as the estimation error of using the RHT as a surrogate and assuming a constant DR over MRI sessions., Results: The linear relationships were confirmed by the high R 2 values of the linear fit between the displacements of the RHT and the abdominal organs (R 2 > 0.96) in the IS and AP direction and |d|, and high to moderate correlations in the LR direction (0.93 > R 2 > 0.64). The median DR difference between PBH-MRI1 and PBH-MRI2 varied between 0.13 and 0.31 for all organs. The median estimation error of the RHT as a surrogate varied between 0.4 and 0.8 mm/min for all organs., Conclusion: The RHT could serve as an accurate surrogate for abdominal organ motion during radiation treatments, for example, in tracking, provided the error of the RHT as motion surrogate is taken into account in the margins., Trial Registration: The study was registered in the Netherlands Trial Register (NL7603)., (© 2023 Amsterdam UMC - location AMC. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

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., Competing Interests: Competing interests: WD has received consultancy fees from Google and Abbvie., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: Due to respiratory motion, accurate radiotherapy delivery to thoracic and abdominal tumors is challenging. We aimed to quantify the ability of mechanical ventilation to reduce respiratory motion, by measuring diaphragm motion magnitudes in the same volunteers during free breathing (FB), mechanically regularized breathing (RB) at 22 breaths per minute (brpm), variation in mean diaphragm position across multiple deep inspiration breath-holds (DIBH) and diaphragm drift during single prolonged breath-holds (PBH) in two MRI sessions., Methods: In two sessions, MRIs were acquired from fifteen healthy volunteers who were trained to be mechanically ventilated non-invasively We measured diaphragm motion amplitudes during FB and RB, the inter-quartile range (IQR) of the variation in average diaphragm position from one measurement over five consecutive DIBHs, and diaphragm cranial drift velocities during single PBHs from inhalation (PIBH) and exhalation (PEBH) breath-holds., Results: RB significantly reduced the respiratory motion amplitude by 39%, from median (range) 20.9 (10.6-41.9) mm during FB to 12.8 (6.2-23.8) mm. The median IQR for variation in average diaphragm position over multiple DIBHs was 4.2 (1.0-23.6) mm. During single PIBHs with a median duration of 7.1 (2.0-11.1) minutes, the median diaphragm cranial drift velocity was 3.0 (0.4-6.5) mm/minute. For PEBH, the median duration was 5.8 (1.8-10.2) minutes with 4.4 (1.8-15.1) mm/minute diaphragm drift velocity., Conclusions: Regularized breathing at a frequency of 22 brpm resulted in significantly smaller diaphragm motion amplitudes compared to free breathing. This would enable smaller treatment volumes in radiotherapy. Furthermore, prolonged breath-holding from inhalation and exhalation with median durations of six to seven minutes are feasible., Trial Registration: Medical Ethics Committee protocol NL.64693.018.18., (© 2022. The Author(s).)

Objective: Single prolonged breath-holds of >5 min can be obtained in cancer patients. Currently, however, the preparation time in each radiotherapy session is a practical limitation for clinical adoption of this new technique. Here, we show by how much our original preparation time can be shortened without unduly compromising breath-hold duration., Methods: 44 healthy subjects performed single prolonged breath-holds from 60% O 2 and mechanically induced hypocapnia. We tested the effect on breath-hold duration of shortening preparation time (the durations of acclimatization, hyperventilation and hypocapnia) by changing these durations and or ventilator settings., Results: Mean original breath-hold duration was 6.5 ± 0.2 (standard error) min. The total original preparation time (from connecting the facemask to the start of the breath-hold) was 26 ± 1 min. After shortening the hypocapnia duration from 16 to 5 min, mean breath-hold duration was still 6.1 ± 0.2 min ( ns vs the original). After abolishing the acclimatization and shortening the hypocapnia to 1 min (a total preparation time now of 9 ± 1 min), a mean breath-hold duration of >5 min was still possible (now significantly shortened to 5.2 ± 0.6 min, p < 0.001). After shorter and more vigorous hyperventilation (lasting 2.7 ± 0.3 min) and shorter hypocapnia (lasting 43 ± 4 s), a mean breath-hold duration of >5 min (5.3 ± 0.2 min, p < 0.05) was still possible. Here, the final total preparation time was 3.5 ± 0.3 min., Conclusions: These improvements may facilitate adoption of the single prolonged breath-hold for a range of thoracic and abdominal radiotherapies especially involving hypofractionation., Advances in Knowledge: Multiple short breath-holds improve radiotherapy for thoracic and abdominal cancers. Further improvement may occur by adopting the single prolonged breath-hold of >5 min. One limitation to clinical adoption is its long preparation time. We show here how to reduce the mean preparation time from 26 to 3.5 min without compromising breath-hold duration.

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) T 1 W FS, and 3D T 1 W 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 T 1 W FFE sequence was significantly smaller (224.7 mm 3 , interquartile range [IQR] 82.50-607.95) than the other three sequences. BML volume was greatest on the CE sequence (1129.8 mm 3 , 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 T 1 W FS sequences (ρ s = 0.98). Correlations were lower between these three sequences and T 1 W FFE (ρ s = 0.80-0.81). Intraclass correlation coefficients were excellent for proton density fat-suppressed, short-tau inversion recovery, and CE T 1 W FS sequences (0.991-0.995), while the ICC for T 1 W FFE was good at 0.88. We found no significant association between BML volumes assessed using any of the sequences and knee pain., Conclusion: T 1 W 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 T 1 W 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.

We report on a comparative dosimetrical study between deep inspiration breath hold (DIBH) and shallow breathing (SB) in prone crawl position for photon and proton radiotherapy of whole breast (WB) and locoregional lymph node regions, including the internal mammary chain (LN&#95;MI). We investigate the dosimetrical effects of DIBH in prone crawl position on organs-at-risk for both photon and proton plans. For each modality, we further estimate the effects of lung and heart doses on the mortality risks of different risk profiles of patients. Thirty-one patients with invasive carcinoma of the left breast and pathologically confirmed positive lymph node status were included in this study. DIBH significantly decreased dose to heart for photon and proton radiotherapy. DIBH also decreased lung doses for photons, while increased lung doses were observed using protons because the retracting heart is displaced by low-density lung tissue. For other organs-at-risk, DIBH resulted in significant dose reductions using photons while minor differences in dose deposition between DIBH and SB were observed using protons. In patients with high risks for cardiac and lung cancer mortality, average thirty-year mortality rates from radiotherapy-related cardiac injury and lung cancer were estimated at 3.12% (photon DIBH), 4.03% (photon SB), 1.80% (proton DIBH) and 1.66% (proton SB). The radiation-related mortality risk could not outweigh the ~ 8% disease-specific survival benefit of WB + LN&#95;MI radiotherapy in any of the assessed treatments.

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., (© 2020 The Authors.)

Objective: Bone marrow lesions (BMLs) on MRI are typically subchondral in location, however, a proportion occur at knee ligament attachments and also include a cyst-like component. Our aim was to determine whether the volume of BML subtypes and synovial tissue volume (STV) was associated with symptoms in symptomatic knee OA., Method: Images were acquired in a sub-sample who had taken part in a randomised trial of vitamin D therapy in knee OA (UK-VIDEO). Contrast-enhanced (CE) MRI was performed annually. In those who had ≥1 follow-up and a baseline scan (N = 50), STV and BML volume was assessed. BMLs were categorised by location and by the presence/absence of a cyst-like component. WOMAC was assessed annually. We used fixed-effects panel-regression modelling to examine the association between volume and symptoms., Results: There was no association between knee pain and total subchondral BML volume (b = 0.3 WOMAC units, 95% CI -0.3 to 1.0) or total ligament-based BML volume (b = 1.9, 95% CI -1.6 to 5.3). The volume of subchondral BMLs with a cyst-like component was not associated with pain (b = 0.8, 95% CI -0.5 to 2.1) however, the volume of the cyst-like component itself was associated with pain (b = 51.8, 95% CI 14.2 to 89.3). STV was associated with pain (b = 2.2, 95% CI 0.6 to 3.7)., Conclusion: The volume of the cyst-like component from subchondral BMLs with a cyst-like component was associated with knee pain. BML location, however, did not influence symptoms. STV was also associated with knee symptoms., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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.

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., (©Anna L L Beukenhorst, Kelly Howells, Louise Cook, John McBeth, Terence W O'Neill, Matthew J Parkes, Caroline Sanders, Jamie C Sergeant, Katy S Weihrich, William G Dixon. Originally published in JMIR mHealth and uHealth (http://mhealth.jmir.org), 29.01.2020.)

Background: There is still an urgent clinical need to develop non-invasive diagnostic tests for early ischemic heart disease because, once angina occurs, it is too late. Hypocapnia has long been known to cause coronary artery vasoconstriction. Some new cardiology tests are accompanied by the claim that they must have potential diagnostic value if hypocapnia enhances their cardiac effects in healthy subjects. But no previous study has tested whether hypocapnia produces bigger cardiac effects in patients with angina than in healthy subjects., Methods: Severe hypocapnia (a PetCO 2 level of 20 mmHg) lasting >15 min was mechanically induced by facemask, while conscious and unmedicated, in 18 healthy subjects and in 10 patients with angina and angiographically confirmed coronary artery disease, awaiting by-pass surgery. Each participant was their own control in normocapnia (where CO 2 was added to the inspirate) and the order of normocapnia and hypocapnia was randomized. Twelve lead electrocardiograms (ECG) were recorded and automated measurements were made on all ECG waveforms averaged over >120 beats. 2D echocardiography was also performed on healthy subjects., Results: In the 18 healthy subjects, we confirm that severe hypocapnia (a mean PetCO 2 of 20 ± 0 mmHg, P < 0.0001) consistently increased the mean T wave amplitude in leads V1-V3, but by only 31% ( P < 0.01), 15% ( P < 0.001) and 11% ( P < 0.05), respectively. Hypocapnia produced no other significant effects ( p > 0.05) on their electro- or echocardiogram. All 10 angina patients tolerated the mechanical hyperventilation well, with minimal discomfort. Hypocpania caused a similar increase in V1 (by 39%, P < 0.05 vs. baseline, but P > 0.05 vs. healthy controls) and did not induce angina. Its effects were no greater in patients who did not take β-blockers, or did not take organic nitrates, or had the worst Canadian Cardiovascular Society scores., Conclusion: Non-invasive mechanical hyperventilation while awake and unmedicated is safe and acceptable, even to patients with angina. Using it to produce severe and prolonged hypocapnia alone does produce significant ECG changes in angina patients. But its potential diagnostic value for identifying patients with coronary stenosis requires further evaluation., (Copyright © 2020 Parkes, Sheppard, Barker, Ranasinghe, Senanayake, Clutton-Brock and Frenneaux.)

Background & Purpose: Multiple, short breath-holds are now used in single radiotherapy treatment sessions. Here we investigated the feasibility and safety of multiple prolonged breath-holds in a single session. We measured how long is a second breath-hold if we prematurely terminate a single, prolonged breath-hold of >5 min either by using a single breath of oxygen (O 2 ), or by reintroducing preoxygenation and hypocapnia. We also investigated the feasibility and safety of undertaking 9 prolonged breath-holds in a row., Materials & Methods: 30 healthy volunteers with no previous breath-holding experience were trained to perform single prolonged breath-holds safely., Results: Their mean single, prolonged breath-hold duration was 6.1 ± 0.3 se minutes (n = 30). In 18/18 subjects, premature termination (at 5.1 ± 0.2 min) with a single breath of 60% O 2 , enabled a 2nd safe breath-hold lasting 3.3 ± 0.2 min. In 18/18 subjects, premature termination at 5.3 ± 0.2 min) by reintroducing preoxygenation and hypocapnia, enabled a 2nd safe breath-hold lasting 5.8 ± 0.3 min. 17/17 subjects could safely perform 9 successive prolonged breath-holds, each terminated (at 4.3 ± 0.2 min) by reintroducing preoxygenation and hypocapnia for 3.1 ± 0.2 min. The 9th unconstrained breath-hold (mean of 6.0 ± 0.3 min) lasted as long as their single breath-hold., Conclusions: Multiple prolonged breath-holds are possible and safe. In a ∼19 min treatment session, it would therefore be possible to have ∼13 min for radiotherapy treatment (3 breath-holds) and ∼6 min for setup and recovery. In a 65 min session, it would be possible to have 41 min for radiotherapy and 25 min for setup and recovery., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Reducing respiratory motion during the delivery of radiation therapy reduces the volume of healthy tissues irradiated and may decrease radiation-induced toxicity. The purpose of this study was to assess the potential for rapid shallow non-invasive mechanical ventilation to reduce internal anatomy motion for radiation therapy purposes., Methods and Materials: Ten healthy volunteers (mean age, 38 years; range, 22-54 years; 6 female and 4 male) were scanned using magnetic resonance imaging during normal breathing and at 2 ventilator-induced frequencies: 20 and 25 breaths per minute for 3 minutes. Sagittal and coronal cinematic data sets, centered over the right diaphragm, were used to measure internal motions across the lung-diaphragm interface. Repeated scans assessed reproducibility. Physiologic parameters and participant experiences were recorded to quantify tolerability and comfort., Results: Physiologic observations and experience questionnaires demonstrated that rapid shallow non-invasive ventilation technique was tolerable and comfortable. Motion analysis of the lung-diaphragm interface demonstrated respiratory amplitudes and variations reduced in all subjects using rapid shallow non-invasive ventilation compared with spontaneous breathing: mean amplitude reductions of 56% and 62% for 20 and 25 breaths per minute, respectively. The largest mean amplitude reductions were found in the posterior of the right lung; 40.0 mm during normal breathing to 15.5 mm (P < .005) and 15.2 mm (P < .005) when ventilated with 20 and 25 breaths per minute, respectively. Motion variations also reduced with ventilation; standard deviations in the posterior lung reduced from 14.8 mm during normal respiration to 4.6 mm and 3.5 mm at 20 and 25 breaths per minute, respectively., Conclusions: To our knowledge, this study is the first to measure internal anatomic motion using rapid shallow mechanical ventilation to regularize and minimize respiratory motion over a period long enough to image and to deliver radiation therapy. Rapid frequency and shallow, non-invasive ventilation both generate large reductions in internal thoracic and abdominal motions, the clinical application of which could be profound-enabling dose escalation (increasing treatment efficacy) or high-dose ablative radiation therapy., (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)

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 mm 3 , 95% CI -1605.0 to 1792.7) and subchondral BML volume (- 313.5 mm 3 , 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/.

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., (©Anna L Beukenhorst, Matthew J Parkes, Louise Cook, Rebecca Barnard, Sabine N van der Veer, Max A Little, Kelly Howells, Caroline Sanders, Jamie C Sergeant, Terence W O'Neill, John McBeth, William G Dixon. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 23.01.2019.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY. Published by BMJ.)

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.

New Findings: What is the topic of this review? One of the major unanswered questions in physiology is that of how breathing matches metabolic rate. Venous chemoreceptors seem to have been dismissed since the 1960s. What advances does it highlight? New evidence shows that their apparent dismissal needs reappraisal. The paper on which this depends has more than one interpretation, and another paper obtained the opposite result. Previous search ignored all locations between skeletal muscle and the right heart. Oxygen sensors other than the arterial chemoreceptors do exist. Heymans and colleagues originally demonstrated some residual breathing response to hypoxia in sino-aortically denervated animals. Similar results occur in humans. One of the major unanswered questions in physiology is that of how breathing matches metabolic rate. The existence in humans of venous chemoreceptors that might control breathing seems to have been dismissed since the 1960s. New evidence has emerged showing that this apparent dismissal needs reappraisal. First, the paper in humans on which this depends has more than one interpretation. Moreover, a previous paper obtained the opposite result and is not cited. Secondly, previous search for venous chemoreceptors failed to examine all venous locations between skeletal muscle and the right heart and lungs. Thirdly, oxygen sensors other than the arterial chemoreceptors do exist. Heymans himself originally demonstrated some residual breathing response to hypoxia in sino-aortically denervated animals. Others confirm a residual breathing response to hypoxia in mammals, including humans. There is now considerable interest in the importance of afferent feedback in controlling the cardiovascular and respiratory systems. Moreover, it is now clear that arterial, aortic and central chemoreceptors have no role in explaining how breathing matches metabolic rate during exercise. These together provide a timely reminder that venous chemoreceptors remain ideal candidates still to be considered as metabolic rate sensors to explain matching in humans. Firstly, this is because venous PO2 and PCO2 values do change appropriately in proportion to metabolic rate, so a metabolic rate signal sufficient to drive breathing might already exist. Secondly, chemoreceptor-like anatomical structures are present in the systemic venous system but remain unexplored. Finally, no extant experimental evidence precludes their existence., (© 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.)

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., Competing Interests: Competing interests: None declared.

Background: Braces are used to treat pain in patellofemoral joint osteoarthritis (PFJOA). In a trial, we previously reported pain improvement after 6-weeks brace use. The pain reduction did not correlate with changes in Magnetic Resonance Imaging (MRI) assessed Bone Marrow Lesion volume or static synovial volume. Studies show that changes in the synovium on dynamic contrast enhanced (DCE) MRI are more closely associated with symptom change than static synovial volume changes. We hypothesised change in synovitis assessed using dynamic imaging could explain the reduction in pain., Method: One hundred twenty-six men and women aged 40-70 years with painful radiographically confirmed PFJOA were randomised to either brace wearing or no brace for 6-weeks. Pain assessment and DCE-MRI were performed at baseline and 6 weeks. DCE data was analysed using Tofts's equation. Pain measures included a VAS of pain on nominated aggravating activity (VAS NA ), and the KOOS pain subscale. Paired t-tests were used to determine within person change in outcome measures and Spearman's correlation coefficients were used to determine the correlation between change in pain and change in the DCE parameters., Results: Mean age of subjects was 55.5 years (SD = 7.5) and 57% were female. There was clear pain improvement in the brace users compared to controls (VAS NA  - 16.87 mm, p = <0.001). There was no significant change to the dynamic synovitis parameters among brace users nor was pain change correlated with change in dynamic synovitis parameters., Conclusion: The reduction in knee pain following brace wearing in patients with PFJOA is not explained by changes in synovitis., Trial Registration: Trial registration number UK. ISRCTN50380458 /Registered 21.5.2010.

Background: The aim was to examine if structural factors could affect response to intra-articular steroid injections (IASI) in knee osteoarthritis (OA)., Method: Persons with painful knee OA participated in an open-label trial of IASI where radiographic joint space narrowing (JSN) and Kellgren-Lawrence (KL) grade, whole-organ magnetic resonance imaging (MRI) scores (WORMS) and quantitative assessment of synovial tissue volume (STV) were assessed on baseline images. Participants completed the Knee Injury and Osteoarthritis Outcome Score (KOOS) and a question about knee pain with a visual analogue scale for pain during nominated activity (VAS NA ), and Outcome Measures in Rheumatology (OMERACT)-Osteoarthritis Research Society International (OARSI) criteria were used to assess responder status within 2 weeks (short term) and 6 months (longer term). Regression models were used to examine predictors of short and longer term response to IASI., Results: Subjects (n = 207) attended and had IASI. Information on responder status was available on 199 participants. Of these, 188 subjects, mean age 63.2 years (standard deviation (SD) 10.3), 97 (51.6%) female, had x-rays and 120 had MRI scans available. Based on the OMERACT-OARSI criteria, 146 (73.4%) participants responded to therapy and 40 (20.1%) were longer term responders. A few factors were associated with a reduced KOOS-pain and VAS NA response though none were associated with OMERACT-OARSI responder status in the short term. Higher MRI meniscal damage (odds ratio (OR) = 0.74; 95% CI 0.55 to 0.98), increasing KL maximal grade (OR = 0.43; 95% CI 0.23 to 0.82) and joint space narrowing (JSN) maximal score (OR = 0.60; 95% CI 0.36 to 0.99) were each associated with a lower odds of longer term responder status. Baseline synovitis was not associated with treatment response. The predicted probability of longer term response decreased from 38% to 12% as baseline maximal JSN increased from grade 0 to 3., Conclusion: Compared with those who have mild structural damage, persons with more severe knee damage on either MRI or x-ray are less likely to respond to knee IASI., Trial Registration: ISRCTN.com, ISRCTN07329370 . Registered 21 May 2010. Retrospectively registered.