Sensory experience remodels genome architecture in neural circuit to drive motor learning.

Neuronal-activity-dependent transcription couples sensory experience to adaptive responses of the brain including learning and memory. Mechanisms of activity-dependent gene expression including alterations of the epigenome have been characterized1-8. However, the fundamental question of whether sensory experience remodels chromatin architecture in the adult brain in vivo to induce neural code transformations and learning and memory remains to be addressed. Here we use in vivo calcium imaging, optogenetics and pharmacological approaches to show that granule neuron activation in the anterior dorsal cerebellar vermis has a crucial role in a delay tactile startle learning paradigm in mice. Of note, using large-scale transcriptome and chromatin profiling, we show that activation of the motor-learning-linked granule neuron circuit reorganizes neuronal chromatin including through long-distance enhancer-promoter and transcriptionally active compartment interactions to orchestrate distinct granule neuron gene expression modules. Conditional CRISPR knockout of the chromatin architecture regulator cohesin in anterior dorsal cerebellar vermis granule neurons in adult mice disrupts enhancer-promoter interactions, activity-dependent transcription and motor learning. These findings define how sensory experience patterns chromatin architecture and neural circuit coding in the brain to drive motor learning.

Publisher Correction: Sensory experience remodels genome architecture in neural circuit to drive motor learning.

In this Letter, '≥' should be '≤' in the sentence: "Intra-chromosomal reads were further split into short-range reads (≥1 kb) and long-range reads (>1 kb)". This error has been corrected online.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Comparative risk of acute myocardial infarction for anti-osteoporosis drugs in primary care: a meta-analysis of propensity-matched cohort findings from the UK Clinical Practice Research Database and the Catalan SIDIAP Database.

The aim of this study was to evaluate the risk of acute myocardial infarction in patients taking osteoporosis medication. Patients were taken from the SIDIAP or CPRD database and were matched using propensity scores. Patients with diabetes and chronic kidney disease taking SERMs were at an increased risk. The results favour the cardiovascular safety of alendronate as a first-line choice for osteoporosis treatment. INTRODUCTION: This study aims to evaluate the comparative safety of anti-osteoporosis drugs based on the observed risk of acute myocardial infarction while on treatment in a primary care setting. METHODS: This is a propensity-matched cohort study and meta-analysis. This study was conducted in two primary care record databases covering UK NHS (CPRD) and Catalan healthcare (SIDIAP) patients during 1995-2014 and 2006-2014, respectively. The outcome was acute myocardial infarction while on treatment. Users of alendronate (reference group) were compared to those of (1) other oral bisphosphonates (OBP), (2) strontium ranelate (SR), and (3) selective oestrogen receptor modulator (SERM), after matching on baseline characteristics (socio-demographics, fracture risk factors, comorbidities, and concomitant drug use) using propensity scores. Multiple imputation was used to handle missing data on confounders and competing risk modelling for the calculation of relative risk (sub-distribution hazard ratios (SHR)) according to therapy. Country-specific data were analysed individually and meta-analysed. RESULTS: A 10% increased risk of acute myocardial infarction was found in users of other bisphosphonates as compared to alendronate users within CPRD. The meta-analysis of CPRD and SIDIAP results showed a 9% increased risk in users of other bisphosphonate as compared to alendronate users. Sensitivity analysis showed SERMS users with diabetes and chronic kidney disease were at an elevated risk. CONCLUSIONS: This study provides additional data on the risk of acute myocardial infarction in patients receiving osteoporosis treatment. The results favour the cardiovascular safety of alendronate as a first-line choice for osteoporosis treatment.

Statistical shape modeling of the hip and the association with hip osteoarthritis: a systematic review.

OBJECTIVE: To summarize available evidence on the association between hip shape as quantified by statistical shape modeling (SSM) and the incidence or progression of hip osteoarthritis. DESIGN: We conducted a systematic search of five electronic databases, based on a registered protocol (available: PROSPERO CRD42020145411). Articles presenting original data on the longitudinal relationship between radiographic hip shape (quantified by SSM) and hip OA were eligible. Quantitative meta-analysis was precluded because of the use of different SSM models across studies. We used the Newcastle-Ottawa Scale (NOS) for risk of bias assessment. RESULTS: Nine studies (6,483 hips analyzed with SSM) were included in this review. The SSM models used to describe hip shape ranged from 16 points on the femoral head to 85 points on the proximal femur and hemipelvis. Multiple hip shape features and combinations thereof were associated with incident or progressive hip OA. Shape variants that seemed to be consistently associated with hip OA across studies were acetabular dysplasia, cam morphology, and deviations in acetabular version (either excessive anteversion or retroversion). CONCLUSIONS: Various radiographic, SSM-defined hip shape features are associated with hip OA. Some hip shape features only seem to increase the risk for hip OA when combined together. The heterogeneity of the used SSM models across studies precludes the estimation of pooled effect sizes. Further studies using the same SSM model and definition of hip OA are needed to allow for the comparison of outcomes across studies, and to validate the found associations.

Association between Bone marrow lesions & synovitis and symptoms in symptomatic knee osteoarthritis.

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.

Differences between race and sex in measures of hip morphology: a population-based comparative study.

OBJECTIVE: This paper aims to (i) identify differences in measures of hip morphology between four racial groups using anteroposterior (AP) hip x-rays, and (ii) examine whether these differences vary by sex. METHODS: 912 hip x-rays (456 individuals) from four racial groups (European Caucasians, American Caucasians, African Americans and Chinese) were obtained. Males and females (45-75 years) with no radiographic hip OA (Kellgren and Lawrence < Grade 2 or Croft < Grade 1) were included. Eleven features of hip joint morphology were analysed. Linear regression with generalised estimating equations (GEE) was used to determine race and sex differences in hip morphology. Post-hoc Bonferroni procedure was used to adjust for multiple comparisons. RESULTS: The final analysis included 875 hips. Chinese hips showed significant differences for the majority of measures to other racial groups. Chinese were characterised by more shallow and narrow acetabular sockets, reduced femoral head coverage, smaller femoral head diameter, and a lesser angle of alignment between the femoral neck and shaft. Variation was found between other racial groups, but with few statistically significant differences. The average of lateral centre edge angle, minimum neck width and neck length differed between race and sex (p-value for interaction < 0.05). CONCLUSIONS: Significant differences were found in measures of morphology between Chinese hips compared to African Americans or Caucasian groups; these may explain variation in hip OA prevalence rates between these groups and the lower rate of hip OA in Chinese. Sex differences were also identified, which may further explain male-female prevalence differences for OA.

The impact of BMI and smoking on risk of revision following knee and hip replacement surgery: evidence from routinely collected data.

OBJECTIVE: The aim of this study was to assess the association of body mass index (BMI) and smoking with risk of revision following total knee replacement (TKR) and total hip replacement (THR). DESIGN: Primary care data, from the Clinical Practice Research Datalink (CPRD), was linked to inpatient hospital records, from Hospital Episode Statistics Admitted Patient Care (HES APC), and covered 1997 to 2014. Parametric survival models, with BMI and smoking status included as explanatory variables, were estimated for 10-year risk of revision and mortality, and were extrapolated to estimate lifetime risk of revision. FINDINGS: TKR and THR cohorts included 10,260 and 10,961 individuals, respectively. For a change in BMI from 25 to 35, the 10-year risk of revision is expected change from 4.6% (3.3-6.4%) to 3.7% (2.6-5.1%) for TKR and 3.7% (2.8-5.1%) to 4.0% (2.8-5.7%) for THR for an otherwise average patient profile. Meanwhile, changing from a non-smoker to a current smoker is expected to change the risk of revision from 4.1% (3.1-5.5%) to 2.8% (1.7-4.7%) for TKR and from 3.8% (2.8-5.3%) to 2.9% (1.9-4.7%) for THR for an otherwise average patient profile. Estimates of lifetime risk were also similar for different values of BMI or smoking status. CONCLUSIONS: Obesity and smoking do not appear to have a meaningful impact on the risk of revision following TKR and THR.

Impact of a national enhanced recovery after surgery programme on patient outcomes of primary total knee replacement: an interrupted time series analysis from "The National Joint Registry of England, Wales, Northern Ireland and the Isle of Man".

OBJECTIVE: We aimed to test whether a national Enhanced Recovery After Surgery (ERAS) Programme in total knee replacement (TKR) had an impact on patient outcomes. DESIGN: Natural-experiment (April 2008-December 2016). Interrupted time-series regression assessed impact on trends before-during-after ERAS implementation. SETTING: Primary operations from the UK National Joint Registry (NJR) were linked with Hospital Episode Statistics (HES) data which contains inpatient episodes undertaken in National Health Service (NHS) trusts in England, and Patient Reported Outcome Measures (PROMs). PARTICIPANTS: Patients undergoing primary planned TKR aged ≥18 years. INTERVENTION: ERAS implementation (April 2009-March 2011). OUTCOMES: Regression coefficients of monthly means of Length of stay (LOS), bed day costs, change in Oxford knee scores (OKS) 6-months after surgery, complications (at 6 months), and rates of revision surgeries (at 5 years). RESULTS: 486,579 primary TKRs were identified. Overall LOS and bed-day costs decreased from 5.8 days to 3.7 and from £7607 to £5276, from April 2008 to December 2016. Oxford knee score (OKS) change improved from 15.1 points in April 2008 to 17.1 points in December 2016. Complications decreased from 4.1 % in April 2008 to 1.7 % in March 2016. 5-year revision rates remained stable at 4.8 per 1000 implants years in April 2008 and December 2011. After ERAS, declining trends in LOS and bed costs slowed down; OKS improved, complications remained stable, and revisions slightly increased. CONCLUSIONS: Different secular trends in outcomes for patients having TKR have been observed over the last decade. Although patient outcomes are better than a decade ago ERAS did not improve them at national level.

OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis.

OBJECTIVE: To update and expand upon prior Osteoarthritis Research Society International (OARSI) guidelines by developing patient-focused treatment recommendations for individuals with Knee, Hip, and Polyarticular osteoarthritis (OA) that are derived from expert consensus and based on objective review of high-quality meta-analytic data. METHODS: We sought evidence for 60 unique interventions. A systematic search of all relevant databases was conducted from inception through July 2018. After abstract and full-text screening by two independent reviewers, eligible studies were matched to PICO questions. Data were extracted and meta-analyses were conducted using RevMan software. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Evidence Profiles were compiled using the GRADEpro web application. Voting for Core Treatments took place first. Four subsequent voting sessions took place via anonymous online survey, during which Panel members were tasked with voting to produce recommendations for all joint locations and comorbidity classes. We designated non-Core treatments to Level 1A, 1B, 2, 3, 4A, 4B, or 5, based on the percentage of votes in favor, in addition to the strength of the recommendation. RESULTS: Core Treatments for Knee OA included arthritis education and structured land-based exercise programs with or without dietary weight management. Core Treatments for Hip and Polyarticular OA included arthritis education and structured land-based exercise programs. Topical non-steroidal anti-inflammatory drugs (NSAIDs) were strongly recommended for individuals with Knee OA (Level 1A). For individuals with gastrointestinal comorbidities, COX-2 inhibitors were Level 1B and NSAIDs with proton pump inhibitors Level 2. For individuals with cardiovascular comorbidities or frailty, use of any oral NSAID was not recommended. Intra-articular (IA) corticosteroids, IA hyaluronic acid, and aquatic exercise were Level 1B/Level 2 treatments for Knee OA, dependent upon comorbidity status, but were not recommended for individuals with Hip or Polyarticular OA. The use of Acetaminophen/Paracetamol (APAP) was conditionally not recommended (Level 4A and 4B), and the use of oral and transdermal opioids was strongly not recommended (Level 5). A treatment algorithm was constructed in order to guide clinical decision-making for a variety of patient profiles, using recommended treatments as input for each decision node. CONCLUSION: These guidelines offer comprehensive and patient-centered treatment profiles for individuals with Knee, Hip, and Polyarticular OA. The treatment algorithm will facilitate individualized treatment decisions regarding the management of OA.

Considering "clonality": A regulatory perspective on the importance of the clonal derivation of mammalian cell banks in biopharmaceutical development.

There has been much recent focus on the regulatory emphasis and the relative importance surrounding clonal derivation of mammalian production cell lines used in the manufacture of recombinant DNA-derived biopharmaceuticals. This interest has led to an ongoing discussion between regulators and industry on how this topic is evaluated and the role it plays in the development of a new biopharmaceutical. Herein the authors describe that the clonal derivation of the production cell line is a factor with potential impact on product quality, and thus should not be considered separately from, but rather in the context of all elements comprising the control strategy necessary to support approval of a regulatory application. Considerations for how clonal derivation of cell banks and clonal variation thereof may be viewed during the lifecycle of a biopharmaceutical product is provided.

Population-based prevalence of multiple radiographically-defined hip morphologies: the Johnston County Osteoarthritis Project.

OBJECTIVE: To provide the first prevalence estimates of different radiographic hip morphologies relevant to dysplasia and femoroacetabular impingement in a well-characterized USA population-based cohort. METHODS: Cross-sectional data were from the baseline examination (1991-1997) of a large population-based prospective longitudinal cohort study (The Johnston County Osteoarthritis Project). HipMorf software (Oxford, UK) was used to assess hip morphology on anteroposterior (AP) pelvis radiographs. Weighted, sex-stratified prevalence estimates and 95% confidence intervals for four key hip morphologies (AP alpha angle, triangular index sign, lateral center edge angle (LCEA), and protrusio acetabula) were derived and further stratified by age, race and body mass index (BMI). RESULTS: A total of 5192 hips from 2596 individuals were included (31% African American, 43% male, mean age 63 years, mean BMI 29 kg/m2). Cam morphology was seen in more than 25% of men and 10% of women. Mild dysplasia was present in about 1/3 of men and women, while pincer morphology was identified in 7% of men and 10% of women. Femoral side (cam) morphologies were more common and more frequently bilateral among men, while pincer morphologies were more common in women; mixed morphologies were infrequent. African-Americans were more likely to have protrusio acetabula than whites. CONCLUSION: We report the first population-based prevalence estimates of radiographic hip morphologies relevant to femoroacetabular impingement (FAI) and dysplasia in the USA. These morphologies are very common, with » men and 1/10 women having cam morphology, 1/3 of all adults having mild dysplasia, and 1/15 men and 1/10 women having pincer morphology in at least one hip.

Harmonising measures of knee and hip osteoarthritis in population-based cohort studies: an international study.

OBJECTIVE: Population-based osteoarthritis (OA) cohorts provide vital data on risk factors and outcomes of OA, however the methods to define OA vary between cohorts. We aimed to provide recommendations for combining knee and hip OA data in extant and future population cohort studies, in order to facilitate informative individual participant level analyses. METHOD: International OA experts met to make recommendations on: 1) defining OA by X-ray and/or pain; 2) compare The National Health and Nutrition Examination Survey (NHANES)-type OA pain questions; 3) the comparability of the Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) scale to NHANES-type OA pain questions; 4) the best radiographic scoring method; 5) the usefulness of other OA outcome measures. Key issues were explored using new analyses in two population-based OA cohorts (Multicenter Osteoarthritis Study; MOST and Osteoarthritis Initiative OAI). RESULTS: OA should be defined by both symptoms and radiographs, with symptoms alone as a secondary definition. Kellgren and Lawrence (K/L) grade ≥2 should be used to define radiographic OA (ROA). The variable wording of pain questions can result in varying prevalence between 41.0% and 75.4%, however questions where the time anchor is similar have high sensitivity and specificity (91.2% and 89.9% respectively). A threshold of 3 on a 0-20 scale (95% CI 2.1, 3.9) in the WOMAC pain subscale demonstrated equivalence with the preferred NHANES-type question. CONCLUSION: This research provides recommendations, based on expert agreement, for harmonising and combining OA data in existing and future population-based cohorts.

Do foot & ankle assessments assist the explanation of 1 year knee arthroplasty outcomes?

OBJECTIVE: Whilst a number of risk factors for poor patient reported outcome measures (PROMs) following knee arthroplasty (KA) have been identified, unexplained variability still remains. The role of pre-operative foot and ankle status on such outcomes has not been investigated. The aim of this study was therefore to determine the association of clinical foot and ankle assessments with patient reported outcomes 1 year following KA. DESIGN: One hundred and fifteen participants from the Clinical Outcomes in Arthroplasty Study (COASt), underwent detailed foot and ankle assessments at baseline, prior to KA (2012-2014) and were followed up for self-reported outcomes 1 year after surgery. RESULTS: Thirty nine percent of subjects reported foot pain at baseline. Mean pre-operative Oxford Knee Score (OKS; 0 [worst] to 48 [best outcome]) was 21 and post-operative OKS score was 38. In fully adjusted analysis pre-operative foot pain was significantly associated with 1 year outcome (risk ratio [RR] 0.78 95% confidence interval [95% CI] 0.62, 0.98). No significant association was observed between ankle dorsiflexion or foot posture and outcome. CONCLUSIONS: Patients with pre-operative foot pain are more likely to have poorer clinically important outcomes 1 year following KA than patients without foot pain. Static ankle dorsiflexion and foot posture do not further explain post-operative KA outcomes. Consideration should also be given to address pre-operative foot pain when attempting to achieve a good clinical outcome for KA.

Bone density and body composition in newly licenced professional jockeys.

The primary objective is the description of bone mineral density (BMD) and body composition in newly licensed jockeys. One in three male, flat jockeys has a very low bone mineral density. Further research is needed to assess the short-term risk of fractures and long-term health implications of these findings. INTRODUCTION: Describe bone mineral density (BMD) and body composition in entry-level male and female, flat and jump jockeys in Great Britain. METHODS: Data was collected on jockeys applying for a professional jockey license between 2013 and 2015. Areal BMD at the spine, femoral neck (FN), total hip and body composition were assessed by dual-energy X-ray absorptiometry (DXA) scan. We examined differences between BMD and body composition by gender and race type (flat or jump). Volumetric bone mineral apparent density (BMAD) of the spine and FN was also calculated to account for group differences in bone size. RESULTS: Seventy-nine male flat jockeys (age 18.5 ± 1.9, BMI 19.0 ± 1.4), 69 male jump (age 20.7 ± 2.0, BMI 20.6 ± 1.3) and 37 female flat jockeys (age 19.3 ± 2.0, BMI 20.8 ± 1.7) took part in this study. Spine BMD Z-scores ≤-2 for male flat, male jump and female flat jockeys were 29, 13 and 2.7%, respectively. Spine BMD was lower in male than female flat jockeys (p<0.001). All BMD scores were lower in male flat compared to male jump jockeys (p<0.001). Body fat percent (BF %) was lower in male flat jockeys compared to male jump and female flat jockeys (p<0.05). Lean mass index (LMI) was lower in male flat compared to male jump jockeys (p<0.001). CONCLUSIONS: Male flat jockeys had a significantly lower BMD, LMI and BF% compared to jump jockeys and female flat jockeys. Male flat jockeys had lower spine BMD scores than females. Individual bone maturation may influence these findings. Further investigation into the relevance of low BMD and altered body composition on jockey health is required.

Physical activity and osteoarthritis: a consensus study to harmonise self-reporting methods of physical activity across international cohorts.

Physical activity (PA) is increasingly recognised as an important factor within studies of osteoarthritis (OA). However, subjective methods used to assess PA are highly variable and have not been developed for use within studies of OA, which creates difficulties when comparing and interpreting PA data in OA research. The aim of this study was, therefore, to gain expert agreement on the appropriate methods to harmonise PA data among existing population cohorts to enable the investigation of the association of PA and OA. The definition of PA in an OA context and methods of harmonization were established via an international expert consensus meeting and modified Delphi exercise using a geographically diverse committee selected on the basis of individual expertise in physical activity, exercise medicine, and OA. Agreement was met for all aims of study: (1) The use of Metabolic Equivalent of Task (MET) minutes per week (MET-min/week) as a method for harmonising PA variables among cohorts; (2) The determination of methods for treating missing components of MET-min/week calculation; a value will be produced from comparable activities within a representative cohort; (3) Exclusion of the domain of occupation from total MET-min/week; (4) The need for a specific measure of joint loading of an activity in addition to intensity and time, in studies of diseases, such as OA. This study has developed a systematic method to classify and harmonise PA in existing OA cohorts. It also provides minimum requirements for future studies intending to include subjective PA measures.

Painful knee but not hand osteoarthritis is an independent predictor of mortality over 23†years follow-up of a population-based cohort of middle-aged women.

UNLABELLED: To assess whether joint pain or radiographic osteoarthritis (ROA) of the knee and hand is associated with all-cause and disease-specific mortality in middle-aged women. METHODS: Four subgroups from the prospective community-based Chingford Cohort Study were identified based on presence/absence of pain and ROA at baseline: (Pain-/ROA-; Pain+/ROA-; Pain-/ROA+; Pain+/ROA+). Pain was defined as side-specific pain in the preceding month, while side-specific ROA was defined as Kellgren-Lawrence grade ≥2. All-cause, cardiovascular disease (CVD) and cancer-related mortality over the 23-year follow-up was based on information collected by the Office for National Statistics. Associations between subgroups and all-cause/cause-specific mortality were assessed using Cox regression, adjusting for age, body mass index, typical cardiovascular risk factors, occupation, past physical activity, existing CVD disease, glucose levels and medication use. RESULTS: 821 and 808 women were included for knee and hand analyses, respectively. Compared with the knee Pain-/ROA- group, the Pain+/ROA- group had an increased risk of CVD-specific mortality (HR 2.93 (95% CI 1.47 to 5.85)), while the knee Pain+/ROA+ group had an increased HR of 1.97 (95% CI 1.23 to 3.17) for all-cause and 3.57 (95% CI 1.53 to 8.34) for CVD-specific mortality. We found no association between hand OA and mortality. CONCLUSION: We found a significantly increased risk of all-cause and CVD-specific mortality in women experiencing knee pain with or without ROA but not ROA alone. No relationship was found between hand OA and mortality risk. This suggests that knee pain, more than structural changes of OA is the main driver of excess mortality in patients with OA.

Measures of hip morphology are related to development of worsening radiographic hip osteoarthritis over 6 to 13 year follow-up: the Johnston County Osteoarthritis Project.

OBJECTIVES: We sought to describe the effect of alterations in hip morphology with respect to worsening hip OA in a community-based sample including African American (AA) and white men and women. METHODS: This nested case-control study defined case hips as Kellgren Lawrence grade (KLG) <3 on baseline supine pelvis radiographs and KLG ≥3 or THR for OA at the 1st or 2nd follow-up visit (mean 6 and 13 years, respectively); control hips had KLG <3 at both visits, with gender/race distribution similar to cases. Hip morphology was assessed using HipMorf software (Oxford, UK). Descriptive means and standard errors were obtained from generalized estimating equation (GEE) models. Sex-stratified GEE regression models (accounting for within-person correlation), adjusted for age, race, BMI, and side were then employed. RESULTS: A total of 120 individuals (239 hips; 71 case/168 control) were included (25% male, 26% AA, mean age 62 years, BMI 30 kg/m(2)). Case hips tended to have greater baseline AP alpha angles, smaller minimum joint space width (mJSW) and more frequent triangular index signs. Adjusted results among men revealed that higher AP alpha angle, Gosvig ratio, and acetabular index were positively associated with case hips; coxa profunda was negatively associated. Among women, greater AP alpha angle, smaller mJSW, protrusio acetabuli, and triangular index sign were associated with case hips. CONCLUSIONS: We confirmed an increased risk of worsening hip OA due to baseline features of cam deformity among men and women, as well as protrusio acetabuli among women, and provide the first estimates of these measures in AAs.

The effect of vitamin D supplementation on knee osteoarthritis, the VIDEO study: a randomised controlled trial.

OBJECTIVE: Epidemiological data suggest low serum 25-hydroxyvitamin D3 (25-OH-D3) levels are associated with radiological progression of knee osteoarthritis (OA). This study aimed to assess whether vitamin D supplementation can slow the rate of progression. METHOD: A 3-year, double-blind, randomised, placebo-controlled trial of 474 patients aged over 50 with radiographically evident knee OA comparing 800 IU cholecalciferol daily with placebo. Primary outcome was difference in rate of medial joint space narrowing (JSN). Secondary outcomes included lateral JSN, Kellgren & Lawrence grade, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, function, stiffness and the Get up and Go test. RESULTS: Vitamin D supplementation increased 25-OH-D3 from an average of 20.7 (standard deviation (SD) 8.9) µg/L to 30.4 (SD 7.7) µg/L, compared to 20.7 (SD 8.1) µg/L and 20.3 (SD 8.1) µg/L in the placebo group. There was no significant difference in the rate of JSN over 3 years in the medial compartment of the index knee between the treatment group (average -0.01 mm/year) and placebo group (-0.08 mm/year), average difference 0.08 mm/year (95% confidence interval (CI) [-0.14-0.29], P = 0.49). No significant interaction was found between baseline vitamin D levels and treatment effect. There were no significant differences for any of the secondary outcome measures. CONCLUSION: Vitamin D supplementation did not slow the rate of JSN or lead to reduced pain, stiffness or functional loss over a 3-year period. On the basis of these findings we consider that vitamin D supplementation has no role in the management of knee OA.

The OA Trial Bank: meta-analysis of individual patient data from knee and hip osteoarthritis trials show that patients with severe pain exhibit greater benefit from intra-articular glucocorticoids.

OBJECTIVE: To evaluate the efficacy of intra-articular (IA) glucocorticoids for knee or hip osteoarthritis (OA) in specific subgroups of patients with severe pain and inflammatory signs using individual patient data (IPD) from existing trials. DESIGN: Randomized trials evaluating one or more IA glucocorticoid preparation in patients with knee or hip OA, published from 1995 up to June 2012 were selected from the literature. IPD obtained from original trials included patient and disease characteristics and outcomes measured. The primary outcome was pain severity at short-term follow-up (up to 4 weeks). The subgroup factors assessed included severe pain (≥70 points, 0-100 scale) and signs of inflammation (dichotomized in present or not) at baseline. Multilevel regression analyses were applied to estimate the magnitude of the effects in the subgroups with the individuals nested within each study. RESULTS: Seven out of 43 published randomized clinical trials (n = 620) were included. Patients with severe baseline pain had a significantly larger reduction in short-term pain, but not in mid- and long-term pain, compared to those with less severe pain at baseline (Mean Difference 13.91; 95% Confidence Interval 1.50-26.31) when receiving IA glucocorticoid injection compared to placebo. No statistical significant interaction effects were found between inflammatory signs and IA glucocorticoid injections compared to placebo and to tidal irrigation at all follow-up points. CONCLUSIONS: This IPD meta-analysis demonstrates that patients with severe knee pain at baseline derive more benefit from IA glucocorticoid injection at short-term follow-up than those with less severe pain at baseline.

A comparison of radiographic anatomic axis knee alignment measurements and cross-sectional associations with knee osteoarthritis.

OBJECTIVE: Malalignment is associated with knee osteoarthritis (KOA), however, the optimal anatomic axis (AA) knee alignment measurement on a standard limb radiograph (SLR) is unknown. This study compares one-point (1P) and two-point (2P) AA methods using three knee joint centre locations and examines cross-sectional associations with symptomatic radiographic knee osteoarthritis (SRKOA), radiographic knee osteoarthritis (RKOA) and knee pain. METHODS: AA alignment was measured six different ways using the KneeMorf software on 1058 SLRs from 584 women in the Chingford Study. Cross-sectional associations with principal outcome SRKOA combined with greatest reproducibility determined the optimal 1P and 2P AA method. Appropriate varus/neutral/valgus alignment categories were established using logistic regression with generalised estimating equation models fitted with restricted cubic spline function. RESULTS: The tibial plateau centre displayed greatest reproducibility and associations with SRKOA. As mean 1P and 2P values differed by >2°, new alignment categories were generated for 1P: varus <178°, neutral 178-182°, valgus >182° and for 2P methods: varus <180°, neutral 180-185°, valgus >185°. Varus vs neutral alignment was associated with a near 2-fold increase in SRKOA and RKOA, and valgus vs neutral for RKOA using 2P method. Nonsignificant associations were seen for 1P method for SRKOA, RKOA and knee pain. CONCLUSIONS: AA alignment was associated with SRKOA and the tibial plateau centre had the strongest association. Differences in AA alignment when 1P vs 2P methods were compared indicated bespoke alignment categories were necessary. Further replication and validation with mechanical axis alignment comparison is required.