Synovial changes detected by ultrasound in community-derived people with knee pain

Background: Knee pain, the main symptom of knee osteoarthritis (OA), affects one in 4 people aged over 55 years, of whom 10% have mild to moderate disability. The aetiology of knee pain is heterogeneous and its relationship with structural changes and function is unclear. An important role for synovial pathology in the initiation and progression of knee OA has been emphasised. However, the normal values of synovial changes detected on ultrasound (US) in the general population and their association with knee pain in community-based people with knee pain or OA remain largely unknown. Objectives: [1] to systematically review the literature on synovial changes detected on US in people with knee pain/OA and/or in the general population. [2] to establish the normal ranges for synovial thickness and effusion and determine an optimal cut-off associated with knee pain and radiographic osteoarthritis (ROA) in community-derived men and women over 40 years old. [3] to examine whether community-derived people with early and chronic established knee pain have different risks of having effusion, synovial hypertrophy and Power Doppler signal (PDS), and to explore whether synovial changes detected on US predict/associate with subsequent knee pain worsening. [4] to explore the role of peripheral and central risk factors of knee pain, including the role of synovial changes detected on US in different types of knee pain. Methods: A systematic literature search was undertaken in Medline, EMBASE, Allied and Complementary Medicine, PubMed Web of Science, and SCOPUS databases in May 2015. Frequencies of US abnormalities in people with knee OA/pain, in the general population or asymptomatic controls were pooled using the random effects model. Publication bias and heterogeneity between studies were examined. The source population was the Knee Pain and Related Health in the Community (KPIC, n=9506) survey in Nottingham, UK. All participants had bilateral US and radiographic examination. Synovial changes detected on US were measured by two observers (inter-observer concordance correlation was 0.8 (0.6 to 0.9) for effusion and 0.7 (0.5 to 0.9) for synovial hypertrophy). OA structural changes were measured by standardised radiographs (semi-flexed weight-bearing and flexed skyline views) using the Nottingham Line Drawing Atlas (NLDA). A cross-sectional study comprised of 299 randomly selected adults ≥40 years old (147 women, 152 men). The normal range (95% quintile) for effusion and synovial hypertrophy was calculated in the healthy sample (no current knee pain and no ROA, n=163). The optimal cut-off was established using ROC curve analysis. A case-control study compared community-derived participants with early knee pain (n=298), chronic established knee pain (n=100) and no knee pain (n=94) at baseline. 166 early knee pain participants were followed-up at one year for changes in knee pain and synovial changes detected on US. Relationships between changes in synovial changes detected on US and pain severity were examined using correlation analysis. 255 participants with early and established knee pain replied to a one-year follow-up questionnaire. Predictors of knee pain worsening were determined using logistic regression. Central and peripheral risk factors for knee pain were examined using participants from both the cross-sectional and case-control studies (n=736). The contribution of each was presented using ROC curves. Subgroup analysis was undertaken according to the presence/absence of ROA and widespread pain (WSP) for the association between synovial changes detected on US and knee pain. A within-person analysis in participants with unilateral knee pain was also undertaken. Results:Systematic review and meta-analysis: 29 studies (4720 patients) were identified from the literature. The pooled prevalence of US effusion, synovial hypertrophy and PDS in people with knee OA/pain were 51.5% (95%CI 40.2 to 62.8), 41.5% (26.3 to 57.5) and 32.7% (8.34 to 63.24), respectively, which were higher than those in the general population or asymptomatic controls (19.9% (95%CI 7.8 to 35.3), 14.5% (0 to 58.81), and 15.8% (3.08 to 35.36), respectively). People with knee OA (ACR criteria or ROA) had greater prevalence of synovial changes detected on US than people with knee pain (p=0.037, p=0.010 and p=0.009, respectively). Cross-sectional study: Synovial changes detected on US were different between men and women, therefore, gender-specific reference limits were estimated. In people without KP and structural OA the normal range for effusion was between 0 to 10.3 mm for men and between 0 to 9.8 mm for women and the normal range for synovial hypertrophy was between 0 and 6.8 mm for men and between 0 and 5.4 mm for women. The effusion cut-off able to distinguish a subgroup of people with knee pain and ROA (i.e. “symptomatic OA”) with high specificity was 8.9 mm for men and 7.8 mm for women, and for synovial hypertrophy it was 5.8 mm for men and 4.2 mm for women. Case-control study: At baseline, effusion was associated with early (OR 2.64, 95%CI 1.57 to 4.45) and established KP (OR 5.07, 95%CI 2.74 to 9.38). Synovial hypertrophy was also associated with early (OR 5.43, 95%CI 2.12 to 13.92) and established KP (OR 13.27, 95%CI 4.97 to 35.43). However, the association with effusion diminished when adjusted for ROA. PDS was uncommon (early KP 3%, established KP 2%, controls 0%). Changes in effusion or synovial hypertrophy did not correlate with changes in KP in one year. Effusion and ROA predicted worsening of knee pain at one year (aOR 1.95, 95% CI 1.05 to 3.64, and aOR 3.52 95%CI 1.37 to 9.09, respectively). Central versus peripheral risk factors: A number of central and peripheral risk factors associated with knee pain, including WSP, pain catastrophising, knee injury, ROA, effusion and synovial hypertrophy. Although 25% of knee pain was explained by peripheral risk factors, only 5% was explained by central risk factors. Knee pain was stratified into 4 subgroups according to ROA and WSP. The association between synovial changes detected on US and knee pain varied between subgroups, being strongest in people with isolated ROA (e.g., aOR for hypertrophy 9.99, 95%CI 5.06 to 19.03), moderate in people with ROA plus WSP (aOR 7.24, 95%CI 3.04 to 17.25), weak in people with neither ROA nor WSP (aOR 2.25, 95%CI 1.19 to 4.22) and statistically insignificant in people with isolated WSP (aOR 2.21 95%CI 0.99 to 4.93). This was confirmed by the “one-person two knee” analysis where WSP was fully balanced between painful knees and pain-free knees. The association between synovial changes detected on US and knee pain was stronger when the knees had underlying structure OA changes. Conclusions: Effusion and synovial hypertrophy but not PDS are common in community-derived people with knee pain. These features differ in men and women, requiring different thresholds for abnormality. Synovial changes detected on US are associated knee pain, especially in people with ROA but no WSP. However, changes in effusion and synovial hypertrophy do not correlate with changes in knee pain, and effusion but not synovial hypertrophy predicts pain progression at one year. Further study of the causality between synovial changes detected on US and structural OA, and between peripheral and central risk factors for knee pain is needed

Partial undersampling of imbalanced data for cyber threats detection

Real-time detection of cyber threats is a challenging task in cyber security. With the advancement of technology and ease of access to the internet, more and more individuals and organizations are becoming the target for various cyber attacks such as malware, ransomware, spyware. The target of these attacks is to steal money or valuable information from the victims. Signature-based detection methods fail to keep up with the constantly evolving new threats. Machine learning based detection has drawn more attention of researchers due to its capability of detecting new and modified attacks based on previous attack's behaviour. The number of malicious activities in a certain domain is significantly low compared to the number of normal activities. Therefore, cyber threats detection data sets are imbalanced. In this paper, we proposed a partial undersampling method to deal with imbalanced data for detecting cyber threats. © 2020 ACM.E

Synovial changes detected by ultrasound in community-derived people with knee pain

Background: Knee pain, the main symptom of knee osteoarthritis (OA), affects one in 4 people aged over 55 years, of whom 10% have mild to moderate disability. The aetiology of knee pain is heterogeneous and its relationship with structural changes and function is unclear. An important role for synovial pathology in the initiation and progression of knee OA has been emphasised. However, the normal values of synovial changes detected on ultrasound (US) in the general population and their association with knee pain in community-based people with knee pain or OA remain largely unknown. Objectives: [1] to systematically review the literature on synovial changes detected on US in people with knee pain/OA and/or in the general population. [2] to establish the normal ranges for synovial thickness and effusion and determine an optimal cut-off associated with knee pain and radiographic osteoarthritis (ROA) in community-derived men and women over 40 years old. [3] to examine whether community-derived people with early and chronic established knee pain have different risks of having effusion, synovial hypertrophy and Power Doppler signal (PDS), and to explore whether synovial changes detected on US predict/associate with subsequent knee pain worsening. [4] to explore the role of peripheral and central risk factors of knee pain, including the role of synovial changes detected on US in different types of knee pain. Methods: A systematic literature search was undertaken in Medline, EMBASE, Allied and Complementary Medicine, PubMed Web of Science, and SCOPUS databases in May 2015. Frequencies of US abnormalities in people with knee OA/pain, in the general population or asymptomatic controls were pooled using the random effects model. Publication bias and heterogeneity between studies were examined. The source population was the Knee Pain and Related Health in the Community (KPIC, n=9506) survey in Nottingham, UK. All participants had bilateral US and radiographic examination. Synovial changes detected on US were measured by two observers (inter-observer concordance correlation was 0.8 (0.6 to 0.9) for effusion and 0.7 (0.5 to 0.9) for synovial hypertrophy). OA structural changes were measured by standardised radiographs (semi-flexed weight-bearing and flexed skyline views) using the Nottingham Line Drawing Atlas (NLDA). A cross-sectional study comprised of 299 randomly selected adults ≥40 years old (147 women, 152 men). The normal range (95% quintile) for effusion and synovial hypertrophy was calculated in the healthy sample (no current knee pain and no ROA, n=163). The optimal cut-off was established using ROC curve analysis. A case-control study compared community-derived participants with early knee pain (n=298), chronic established knee pain (n=100) and no knee pain (n=94) at baseline. 166 early knee pain participants were followed-up at one year for changes in knee pain and synovial changes detected on US. Relationships between changes in synovial changes detected on US and pain severity were examined using correlation analysis. 255 participants with early and established knee pain replied to a one-year follow-up questionnaire. Predictors of knee pain worsening were determined using logistic regression. Central and peripheral risk factors for knee pain were examined using participants from both the cross-sectional and case-control studies (n=736). The contribution of each was presented using ROC curves. Subgroup analysis was undertaken according to the presence/absence of ROA and widespread pain (WSP) for the association between synovial changes detected on US and knee pain. A within-person analysis in participants with unilateral knee pain was also undertaken. Results:Systematic review and meta-analysis: 29 studies (4720 patients) were identified from the literature. The pooled prevalence of US effusion, synovial hypertrophy and PDS in people with knee OA/pain were 51.5% (95%CI 40.2 to 62.8), 41.5% (26.3 to 57.5) and 32.7% (8.34 to 63.24), respectively, which were higher than those in the general population or asymptomatic controls (19.9% (95%CI 7.8 to 35.3), 14.5% (0 to 58.81), and 15.8% (3.08 to 35.36), respectively). People with knee OA (ACR criteria or ROA) had greater prevalence of synovial changes detected on US than people with knee pain (p=0.037, p=0.010 and p=0.009, respectively). Cross-sectional study: Synovial changes detected on US were different between men and women, therefore, gender-specific reference limits were estimated. In people without KP and structural OA the normal range for effusion was between 0 to 10.3 mm for men and between 0 to 9.8 mm for women and the normal range for synovial hypertrophy was between 0 and 6.8 mm for men and between 0 and 5.4 mm for women. The effusion cut-off able to distinguish a subgroup of people with knee pain and ROA (i.e. “symptomatic OA”) with high specificity was 8.9 mm for men and 7.8 mm for women, and for synovial hypertrophy it was 5.8 mm for men and 4.2 mm for women. Case-control study: At baseline, effusion was associated with early (OR 2.64, 95%CI 1.57 to 4.45) and established KP (OR 5.07, 95%CI 2.74 to 9.38). Synovial hypertrophy was also associated with early (OR 5.43, 95%CI 2.12 to 13.92) and established KP (OR 13.27, 95%CI 4.97 to 35.43). However, the association with effusion diminished when adjusted for ROA. PDS was uncommon (early KP 3%, established KP 2%, controls 0%). Changes in effusion or synovial hypertrophy did not correlate with changes in KP in one year. Effusion and ROA predicted worsening of knee pain at one year (aOR 1.95, 95% CI 1.05 to 3.64, and aOR 3.52 95%CI 1.37 to 9.09, respectively). Central versus peripheral risk factors: A number of central and peripheral risk factors associated with knee pain, including WSP, pain catastrophising, knee injury, ROA, effusion and synovial hypertrophy. Although 25% of knee pain was explained by peripheral risk factors, only 5% was explained by central risk factors. Knee pain was stratified into 4 subgroups according to ROA and WSP. The association between synovial changes detected on US and knee pain varied between subgroups, being strongest in people with isolated ROA (e.g., aOR for hypertrophy 9.99, 95%CI 5.06 to 19.03), moderate in people with ROA plus WSP (aOR 7.24, 95%CI 3.04 to 17.25), weak in people with neither ROA nor WSP (aOR 2.25, 95%CI 1.19 to 4.22) and statistically insignificant in people with isolated WSP (aOR 2.21 95%CI 0.99 to 4.93). This was confirmed by the “one-person two knee” analysis where WSP was fully balanced between painful knees and pain-free knees. The association between synovial changes detected on US and knee pain was stronger when the knees had underlying structure OA changes. Conclusions: Effusion and synovial hypertrophy but not PDS are common in community-derived people with knee pain. These features differ in men and women, requiring different thresholds for abnormality. Synovial changes detected on US are associated knee pain, especially in people with ROA but no WSP. However, changes in effusion and synovial hypertrophy do not correlate with changes in knee pain, and effusion but not synovial hypertrophy predicts pain progression at one year. Further study of the causality between synovial changes detected on US and structural OA, and between peripheral and central risk factors for knee pain is needed

Comorbidities in Osteoarthritis: a systematic review and meta-analysis of observational studies

ObjectivesOsteoarthritis (OA) is a common chronic condition in older people but its association with other chronic conditions is largely unknown. This study aimed to systematically review the literature on comorbidities in people with OA compared to those without.MethodsWe searched four databases for observational studies on comorbidities in people with OA. Studies of OA only or in comparison with non‐OA controls were included. Risk of bias and study quality was assessed using the Newcastle‐Ottawa Scale (NOS). The prevalence of comorbidities in the OA group and prevalence ratio (PR) and 95% confidence interval (CI) between OA and non‐OA groups were calculated.ResultsForty‐two studies from 16 countries (27 case‐only and 15 comparative studies) met the inclusion criteria. Mean age of participants varied from 51 to 76 years. Pooled prevalence of any comorbidity was 67% (95%CI: 57%‐74%) in people with OA versus 56% (95%CI: 44%‐68%) in people without OA. The pooled PR for any comorbidity was 1.21 (95%CI: 1.02‐1.45). The PR increased from 0.73 (95%CI: 0.43‐1.25) for one comorbidity, to 1.58 (95%CI: 1.03‐2.42) for two, and 1.94 (95%CI 1.45‐ 2.59) for three or more comorbidities. The key comorbidities associated with OA were stroke (PR 2.61; 95%CI: 2.13‐3.21), peptic ulcer (PR 2.36; 95%CI: 1.71‐3.27) and metabolic syndrome (PR 1.94; 95%CI 1.21‐3.12).ConclusionsPeople with OA are more likely to have other chronic conditions. The association is dose‐dependent in terms of the number of comorbidities, suggesting multimorbidities. Further studies on the causality of this association and clinical implications are needed

Flash Joule heating for ductilization of metallic glasses

Metallic glasses (MGs) inherit their amorphous structure from the liquid state, which predetermines their ability to withstand high loads approaching the theoretical limit. However, the absence of slip systems makes them very sensitive to the type of loading and extremely brittle in tension. The latter can be improved by precipitation of ductile crystals, which suppress a catastrophic propagation of shear bands in a glassy matrix. Here we report a novel approach to obtain MG-matrix composites with tensile ductility by flash Joule heating applied to Cu47.5Zr47.5Al5 (at.%) metallic glass. This homogeneous, volumetric and controllable rapid heat treatment allows achieving uniformly distributed metastable B2 CuZr crystals in the glassy matrix. It results in a significant tensile strain of 6.8±0.5%. Moreover, optimized adjustment of the heat-treatment conditions enables tuning of microstructure to achieve desired mechanical properties

Proportion of contextual effects in the treatment of fibromyalgia - a meta-analysis of randomised controlled trials

Objectives: To examine the proportion of the total treatment effect that is attributable to contextual effects in randomised controlled trials (RCTs) of treatments for fibromyalgia. Methods: A systematic literature search was undertaken in Medline, Web of Science, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Allied and Complementary Medicine in September 2015. The proportion of contextualeffect (PCE) was calculated by dividing the improvement in the placebo arm by the improvement in the treatment arm. The measure was log-transformed for each trial and the random effects model was used to pool data. The primary outcome was pain. Secondary outcomes were fibromyalgia impact questionnaire (FIQ) total and fatigue. Heterogeneity was quantified using I2. Publication bias was assessed using a funnel plot and Egger's test. Subgroup analysis was undertaken to explore heterogeneity and potential determinants of the PCE. Results: 51 eligible trials (9599 participants) were identified. The PCE was 0.60 (95% CI0·56 to 0·64) for pain, 0·57 (95% CI 0·53 to 0·61) for FIQ total, and 0·63 (95% CI 0·59 to 0·68) for fatigue. The I2 was 99.4% for pain, 99.2% for FIQ total, and 97.6% for fatigue. Conclusion: More than half of the treatment effect in fibromyalgia RCTs results from non-specific contextual factors. Reporting the total treatment effect and the proportion of contextual effect in trials may help to better translate research evidence into clinical practice

Trends in incidence and prevalence of osteoarthritis in the United Kingdom:findings from the Clinical Practice Research Datalink (CPRD)

Objective: This study aimed to explore the incidence and prevalence of OA in the UK in 2017 and their trends from 1997 to 2017 using a large nationally representative primary care database. Design: The UK Clinical Practice Research Datalink (CPRD) comprising data on nearly 17.5 million patients was used for the study. The incidence and prevalence of general practitioner diagnosed OA over a 20 years period (1997-2017) were estimated and age-sex and length of data contribution standardized using the 2017 CPRD population structure. Cohort effects were examined through Age-period-cohort analysis. Results: During 1997-2017, there were 494,716 incident OA cases aged ≥20 years. The standardised incidence of any OA in 2017 was 6.8 per 1000 person-years (95% CI 6.7 to 6.9) and prevalence was 10.7% (95% CI 10.7-10.8%). Both incidence and prevalence were higher in women than men. The incidence of any-OA decreased gradually in the past 20 years at an annual rate of -1.6% (95%CI -2.0 to -1.1%), and the reduction speeded up for people born after 1960. The prevalence of any-OA increased gradually at an annual rate of 1.4% (95% CI 1.3-1.6%). Although the prevalence was highest in Scotland and Northern Ireland, incidence was highest in the East Midlands. Both incidence and prevalence reported highest in the knee followed by hip, wrist/hand and ankle/foot. Conclusion: In the UK approximately one in 10 adults have symptomatic clinically diagnosed OA, the knee being the commonest. While prevalence has increased and become static after 2008, incidence is slowly declining. Further research is required to understand these changes

Comment on: Conventional and biologic disease-modifying anti-rheumatic drugs for osteoarthritis: a meta-analysis of randomized controlled trials: Reply

MD reports a grant from AstraZeneca funding a non-drug PI-led study in Nottingham (Sons of Gout study) and honoraria for Advisory boards on osteoarthritis and gout for AstraZeneca, Grunenthal, Mallinckrodt, and Roche, outside the submitted work. WZ reports honoraria for Grunenthal and speaker fees for Bioiberica and Hisun, outside the submitted work. All other authors have declared no conflicts of interest

Conventional and biologic disease-modifying anti-rheumatic drugs for osteoarthritis:a meta-analysis of randomized controlled trials

ObjectivesThe role of inflammation in OA is controversial and it is unclear whether suppressing inflammation with conventional or biologic DMARDs is effective. A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to compare DMARDs with placebo in participants with symptomatic OA.MethodsDatabases (Medline, Embase, Allied and Complementary Medicine Database, Web of Science and Cochrane Library), conference abstracts and ClinicalTrials.gov were searched to end of November 2017 for placebo-controlled RCTs of DMARDs, including biologics, in symptomatic OA. Pain data at treatment peak time point were extracted and combined using a random-effects meta-analysis. Markers of inflammation and adverse events were extracted and reviewed. Risk of bias assessment was conducted using Cochrane’s tool.ResultsEleven RCTs (1205 participants) were meta-analysed, including six for conventional DMARDs (757 participants) and five for biologics (448 participants). Overall, DMARDs were statistically superior to placebo [effect size (ES) = 0.18, 95% CI: 0.03, 0.34], although the difference was not clinically significant (0.5 ES threshold). Furthermore, no statistically significant differences were observed in sub-analysis of high-quality trials (ES = 0.11, 95% CI : −0.06, 0.28), biologics (ES = 0.16, 95% CI: −0.02, 0.34) or conventional DMARDs (ES = 0.24, 95% CI: −0.05, 0.54). No difference was found between erosive vs non-erosive hand OA, hand vs knee OA or anti-IL1 vs anti-TNF biologics.ConclusionDMARDs did not offer clinically significant pain relief above placebo in OA. This poor efficacy indicates that inflammation may not be a prime driver for OA pain