text:
Raj Sengupta
Royal National Hospital for Rheumatic Diseases, United Kingdom
Arti Mahto
King's College Hospital NHS Foundation Trust, United Kingdom
Jose Inciarte-Mundo
Hospital Clinic of Barcelona, Spain
Front. Med., 30 October 2020
Sec. Rheumatology
Volume 7 - 2020 | https://doi.org/10.3389/fmed.2020.587827
The Role of Ultrasound Across the Inflammatory Arthritis Continuum: Focus on "At-Risk" Individuals
Laurence Duquenne1,2*†, Rahaymin Chowdhury3†, Kulveer Mankia1,2 and Paul Emery1,2
1Leeds Biomedical Research Centre—NIHR, Leeds, United Kingdom
2Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom
3Leeds Teaching Hospital Trust, Leeds, United Kingdom
In individuals at-risk of developing inflammatory arthritis, the value of an ultrasound (US) scan assessment to predict progression has been demonstrated repeatedly. However, depending on recruitment criteria, these individuals may be at different stages in the arthritis development continuum, therefore representing a heterogeneous population. As a consequence, the predictive value of ultrasound results may differ between cohorts. As other reviews have focused on the challenges in population recruitment or have combined biomarkers predicting value according to one recruitment pathway, we wanted to focus on the sole use of ultrasound assessment and its variation according to population recruitment criteria. In this review, we discuss the use of ultrasound in the different at-risk populations across the inflammatory arthritis disease continuum. This review demonstrates that although some sub-population data is scarce, ultrasound is best predictive in three at-risk populations: those with a positive ACPA test in the context of non-specific MSK symptoms, those with clinically suspect arthralgia and those with palindromic rheumatism. We consider that ultrasound assessment will be a cornerstone in prediction risk modeling and prevention studies of the preclinical phases of IA in the future.
Since the availability of biologic therapies, rheumatology practice has entered a new era where achieving damage free remission in rheumatoid arthritis (RA) is not only feasible, but common. As early treatment decreases long term joint damage and impaired quality of life, much effort has been made to refer, diagnose and treat patients early (1). We are now evolving toward the next stage of inflammatory arthritis management: prevention. The new priority is to identify individuals that might eventually develop inflammatory arthritis (IA): the "At-risk" individuals and treat them before arthritis occurs thereby preventing progression to RA. At-risk individuals with subclinical inflammation are at increased risk of arthritis development. It is therefore logical to suggest that this population should be considered for treatment, therefore should be included in the "window of opportunity" (2).
One of the many challenges is that arthritis development is a late step in a long process sometimes called "the inflammatory arthritis disease continuum" (3), where the preclinical phase includes, genetic, environmental, and systemic factors which may arise years before arthritis occurs (4, 5). When recruited into research cohorts, at-risk individuals might be at different stages of the continuum therefore representing heterogeneous populations, with differing risks of progression to IA.
In this review, we discuss the use of ultrasound (US) in the different at-risk populations across the arthritis disease continuum (see Figure 1). The populations in which US may be most informative will be discussed. We included peer-reviewed, published research including, retrospective and prospective analyses, observational, and interventional studies that were relevant for research and clinical practice. Only articles in English language were included.
Figure 1. Evolution toward rheumatoid arthritis (RA) can be considered as a disease continuum encompassing pathogenic phases which conclude in the development of arthritis. Preclinical phases can comprise of a symptomatic at-risk individuals with genetic risk (e.g. an affected first degree relative), environmental risk (including smoking and mucosal inflammation), and RA-related systematic autoimmunity (e.g. ACPA antibodies). Subclinical synovitis is more often found in symptomatic at-risk individuals, either in the presence of RA associated autoantibodies, or clinically suspect arthralgia (CSA).
US Findings in Healthy Subjects
As the aim of this review is to describe the evidence of US abnormalities in the preclinical phase of IA, it seems important to first consider their prevalence in healthy subjects. A first analysis found a power Doppler (PD) signal in 11% of hands and wrists of 27 healthy volunteers, especially in the wrists (6). Using the OMERACT consensus, analysis of 127 healthy controls (HC) matched with another 127 patients with early arthritis from the ESPOIR cohort found that 11% of the MCP joints 2–4 and fifth MTP joints analyzed had bone erosions (BE), 22% had synovial hypertrophy (SH) ≥ grade 1 and 9% ≥ grade 2 (7). Another study showed high prevalence of SH grade 1 in healthy subjects (15%) as well as in RA patients (56%), and no association with PD, tenderness or swelling, suggesting that only Grade ≥ 2 should be considered pathological (8). This is also suggested by a analysis on 46 young healthy subject who showed SE in almost 20% of them (9).
The most comprehensive analysis included 32 joints of 207 HC subjects (6,621 joints in total) (10), showing that the prevalence of US abnormalities was low at joint level but high at individual level 9 vs. 88%), and most commonly synovial effusion (SE) (69% of joints with an abnormality). BE were found only in first metatarso-phalangeal (MTP1) joints (n = 4) and always with PD. The most prevalent joints with US findings were the MTP1 joints followed by MTP joints 2 to 5, then wrists, metacarpo-phalangeal (MCP) joints (especially the third), and finally proximal inter-phalangeal (PIP) joints which were almost never involved. Grade 1 was the most commonly score found, higher grades were only found in feet (10). Grade 1 SE and SH were highly prevalent in healthy subjects, the authors suggested excluding these parameters from the OMERACT ultrasound protocols (7, 10). None of the analyses showed differences between men and women. Only one study showed significant effect of age, especially in the feet (10). While all of the above studies used semi-quantitative measurement, another analysis of 78 individuals determined quantitative measurement of the radio-carpal abnormalities with a greater chance to indicate RA (11).
Taken together the above studies suggest that the presence of low grade US abnormalities (especially grade 1 SE and SH and feet localization) are often present and therefore should not be considered pathognomonic for inflammatory arthritis. It is interesting to notice differences between each MTP, the first and fifth showing the most abnormalities and that larger joints such as elbows, ankles and shoulders have not been analyzed. Also, midfoot joints are not considered in any of the studies. The EULAR-OMERACT combined score defined synovitis as both PD and GS≥1 (GS including SH and SE), including only small joints, with no difference of scoring between joints (12).
The Use of US in First Degree Relatives of Patients With RA
Because a family history of RA has been shown to increase the risk of developing this disease, the use of US as a prediction tool for the development of arthritis in first degree relatives (FDRs) of RA probands has been investigated.
A small study of 20 patients with RA and 25 of their FDRs was undertaken to explore the presence of abnormal US findings in FDRs without clinical arthritis (13, 14). Eight FDRs had arthralgia symptoms, but all were negative for RF and ACPA. The study confirmed the presence on US of inflammatory activity in FDRs (10/25 patients, 40%) and offers support for the use of US as a screening tool in this at-risk population. This study was limited by the small number of participants and did not present the US findings in detail.
A large prospective study investigated a cohort of 237 FDRs of RA patients (15). The population included a spread across the spectrum of RA development and was classified into four groups (three preclinical and one clinical). The first group were those "without risk factors," meaning those negative for the shared epitope, anti-citrullinated protein antibody (ACPA) or rheumatoid factor (RF) and had no symptoms of possible RA (n = 45). The second group had risk factors, with either presence of one or two copies of the shared epitope or an ACPA positive test but no symptoms associated with possible RA (n = 38). The third group included subjects with inflammatory arthralgia, or self-reported symptoms associated with possible RA (n = 132) and the fourth group had features of unclassified arthritis (UA) (n = 58). The authors found that active US findings were associated with the presence of UA on examination but not with the earlier preclinical phases of RA development, including those who had genetic risk factors but were asymptomatic. There was no statistical significance between the US results of ACPA positive and negative FDRs, however it is worth noting that the US scores for these groups were quite low, [mean B-mode score (SD): 6.7 (3.6) vs 6.8 (3.6)], OR: 1.0 (95% CI: 0.9 to 1.1); mean Doppler score (SD): 0.8 (1.3) vs. 1.2 (1.9), OR: 1.2 [95% CI: (0.9 to 1.6]). In addition, there were no demographic or clinical risk factors significantly associated with active US findings except for older age.
These results do not support a role for US in FDRs without symptoms, as part of a screening strategy for preclinical RA detection in FDRs, with the possible exception of those with UA features. Further analysis on the individuals who are positive with the shared epitope and/or an ACPA tests would improve categorizing risk populations.
The Use of US in Individuals With Clinically Suspect Arthralgia
Other studies have explored the use of ultrasound in predicting IA in patients with clinically suspect arthralgia (CSA). CSA was defined by EULAR as a set of characteristics to be used in patients with arthralgia without clinical arthritis and without other diagnosis or explanation for the arthralgia (16).
Although many of the following studies were performed prior to this definition, they do follow the same theme of including patients who had inflammatory arthralgia but had no clinical synovitis (CS). An example of this is a large multicentre study which included patients who presented with at least two painful joints but no CS, with symptoms that lasted less than a year (17). Of the 196 patients who were included, 159 patients completed follow up over a 1 year period, only 15% were ACPA positive. The authors defined US synovitis as GS ≥ 2 and PD ≥ 1 and reported a statistically significant association between US synovitis and prediction of IA (OR 3.03, 95% [CI: 1.69–5.41]). They concluded that the lack of US synovitis was a strong negative predictor for IA. These findings were further supported by a retrospective analysis of 80 consecutive patients using SONAR B-mode criteria to determine significant synovitis (18, 19). They found that significant US GS synovitis appeared to be the only independent predictor of RA on multivariate analysis (OR 7.4 [95%CI: 1.19–42.8]) in ACPA negative patients who presented with poly-arthralgia and no CS.
A recent study compared the US and MRI results of 70 individuals with CSA (n = 40) and early IA (n = 30). They showed an overall significant correlation between both imaging techniques regarding synovitis and tenosynovitis, especially in the MCP and wrists joints, although MRI was more sensitive. Although less frequently present in the CSA subgroup, similar results of concordance were found, but with a lower sensitivity (20).
Thus, the literature would suggest that US does add additional value to clinical and laboratory investigations in predicting IA in those with CSA. However, there are a paucity of data on US as MRI has been preferred and further US investigation is recommended.
The Use of US in ACPA (and/or RF) Positive Individuals With Musculoskeletal Symptoms
There have been various studies on the use of US to predict RA in at-risk populations who have been selected on the base of an ACPA and/or RF positive, with MSK symptoms (including arthralgia), but no CS.
An important observational cohort study investigating US as a predictor for IA in ACPA positive at-risk individuals was conducted by a group in Leeds (21). The 100 consecutive participants included were ACPA positive, had a new non-specific musculoskeletal (MSK) symptom, but no CS. They demonstrated in multivariable analysis a significant association between PD at the patient level and the development of IA (HR 1.88 [95% CI 1.07–3.29]) and incorporated it in a prediction model including serological and clinical measures. In Amsterdam, a prospective cohort study of 192 participants who were ACPA and/or RF positive, found that Gray Scale (GS) and PD were predictive for IA at the joint level, but this did not reach statistical significance at the patient level, meaning that there was a significance in US findings predicting which joint would progress to clinical arthritis, but not which patients would progress to IA (22). It is useful to note that US protocols varied between both studies; while Amsterdam's US protocol included only painful, adjacent, and contralateral joints if hands were involved, the Leeds study included all MCP joints, PIP joints and both wrists. A follow up study in Leeds included 136 individuals and added MTP joints to the analysis (23), they concluded that all US findings (BE grade ≥ 1, GS grade ≥ 2 and PD grade ≥ 1) could predict progression to IA and its timing, with the risk being greatest in those patients with at least one joint with PD signal on US. Unlike the Amsterdam cohort, the predictive value of PD was significant at both the joint and patient level. The discrepancy in findings may have been due to the differing inclusion criteria in the studies. While the Amsterdam cohort included about a third of RF positive—ACPA negative individuals, Leeds group included only ACPA positivity, suggesting that individuals in the two cohorts could have been at different level of progression risk. Additionally, the US protocols in both studies were different, Leeds scanned 32 joints including bilateral wrists, MCPs, PIPs and MTPs. Both studies were amongst the first to include only patients without CS.
A follow up prospective cohort study from Amsterdam (24) included a cohort of 163 seropositive (RF and/or ACPA) patients who had arthralgia but no CS in a prospective cohort. After excluding metatarsophalangeal joints (MTPs), they showed that GS had a significant predictive value to progression to IA (OR 6.6 [95%CI 1.9–22]). Unlike the other above studies, PD was not found to be predictive in this study. The authors attributed this main difference to the alternative scanning protocol and technical differences in US machines. Differences can also be ascribed to the inclusion criteria, as Nam et al. included ACPA positive patients only (18).
In two further analyses, the first (25) analyzed US images from 319 patients and found that the number of joints with PD or tenosynovitis (TSV) was predictive of progression to IA with high specificity and moderate sensitivity with respective hazard ratios of 1.2 (p = 0.026) and 1.13 (p = 0.025), the addition of ACPA titer improved the predictive value of the number of joints with PD with a specificity/sensitivity of 0.92/0.34 (AUC 0.964). The authors also suggested that a selection of joints—mainly in the hands and feet—with better predictive power could improve US sensitivity. Another multivariable analysis on the same population (n = 488) showed that individuals with 1–3 joints with a PD signal or 1–2 with BE were twice as likely to develop IA, those with ≥ 4 joints with a PD signal were more than six times more likely (26). A more recent study (27) analyzed baseline US scans of a further 419 CCP positive at-risk individuals from the Leeds CCP cohort. In this analysis, the most predictive features for the development of clinical arthritis on US were BE in >1 joint or BE combined with synovitis in the MTP5 joint (OR 10.6 [95% CI 1.9 to 60.4] p < 0.01) and 5.1 [95% CI 1.4 to 18.9] p = 0.02] respectively. While presence of BE in any joint was previously described predictive of progression to IA (23), this study suggests that some joints might be more specific for progression.
Overall, the discrepancies in some of the findings are likely due to population variability: whether selected individuals are tested positive for RF and/or ACPA, associated symptoms and set of joints analyzed, but also the factors around how to perform the US itself, defining US synovitis, the optimum number and specific joints to be incorporated in the US protocol and the use of different scoring systems.
The above studies demonstrate that there is strong evidence that all US features including GS, BE, TSV, and especially PD presence, have an important part to play in predicting IA in seropositive at-risk individuals with MSK symptoms. They also discussed scanning protocols, while a limited, focused joint set can be used to identify erosions and predict arthritis; pragmatic scanning protocol could be easily incorporated into clinical practice. Ideally future studies should use standardized US protocols and scoring systems.
The Use of US in Individuals With Palindromic Rheumatism
Some individuals—ACPA positive or not—present with intermittent inflammatory flares, alternating between short attacks of pain and swelling and asymptomatic periods. Specific clinical and US features found in these individuals suggest that palindromic rheumatism (PR) could be a discrete pathological entity (28). However, shared risk factors with RA suggest PR could also be considered a phase of the RA continuum (3). Different studies have focused on this population, whether it be during or in-between flares of joint symptoms. In all these analyses, the proportion of ACPA positive patients ranges between 13 and 66.7%.
In 2014, a group analyzed 11 joints in the hands of 54 patients outside of a flare (29). The joints reported to be involved in the first flare varied according to ACPA status, with an increased ratio of small joints involvement in ACPA positive participants. This antibody based discrepancy was confirmed on US performed between flares. At the joint level, they found that only 2.8% of the 1,188 joints analyzed had SH≥2, with PD≥1 in 1.4% of these, mostly wrists and MCP. At the patient level, 25.9% of them presented US synovitis in at least one joint (SH≥2, or PD≥1). Patients in this cohort had long disease duration (mean duration of 11.6 years) and 61.1% were on DMARDs (mainly hydroxychloroquine). Ten patients of this study were also assessed during a flare, none of them showed periarticular US abnormalities, seven showed an intra-articular PD signal.
In a small cohort (n = 15), analysis of US scans taken during flares in the hands and wrists showed US synovitis in 60% of individuals (n = 9/15), with PD in 6 of them (30). The largest analysis to date was based on 84 PR patients during a flare (31). While 78% of the participants had signs of PD presence, only 31% of these were intra-articular PD, the rest were features of TSV and/or periarticular soft tissue inflammation. Moreover, Intra-articular PD presence and ACPA positivity were both recognized as predictors of progression to RA (respectively: OR = 2.28 [95%CI: 0.67–7.68] and OR = 6.18 [95% CI: 1.50–25.52]).
The most recent imaging analysis in PR was performed on 79 individuals comparing US and MRI (32). This analysis was the first to include treatment-naïve individuals, with a short duration of symptoms. The authors compared US examinations taken during and between flares, and showed US of the flaring area showed significantly more TSV (23 vs. 4%), more signs of extra-capsular inflammation (61 vs. 15%), particularly periarticular inflammation (39 vs. 4%), (and non-significantly different PD synovitis [23 vs. 7%]) than in-between flares. Interestingly, there was no influence of the antibody status on the US features. These results suggest that palindromic rheumatism has a discrete imaging phenotype and that some features such as ACPA positivity and intra-articular inflammation during a flare may increase the risk of developing RA.
These studies all included individuals with PR, which US has revealed some specific features such as higher proportion of extra-capsular abnormalities compared to at-risk and RA individuals. Discrepancies can be explained by recruitment criteria differences such as the use of previous medication, proportion of ACPA positive individuals and symptoms duration. Two analyses showed predominance of US extra-articular inflammation while all showed presence of sub-clinical inflammation.
Ultrasound in Undifferentiated Arthritis
Early diagnosis is a priority, it is therefore essential to improve diagnostic success rates at first referral. Because of its power and accessibility, US is now recognized as an essential tool for IA diagnosis and management. We have discussed US findings and implication in individuals with no CS (the at-risk populations), individuals with intermittent CS (palindromic rheumatism). Here we discuss how US use has been a major tool in assessing patients at CS onset. This chapter will not focus on RA patients but those with undifferentiated arthritis (UA) who are presenting with early CS but do not meet classification criteria for a specific rheumatic disease."
Many studies have shown US superiority to clinical examination in detecting synovitis (33–35). In a cohort of 50 ACPA and RF negative patients with UA from early arthritis clinics, they showed that IA probability increased from 6 to 8–85% depending on which two US features were present (GS = 3, PD ≥ 1 or BE presence) (36). This was confirmed in a large study (n = 831) where 31% of patients progressed to persistent IA, baseline serological and clinical biomarkers were already predictive of progression, but US improved all predictive values, particularly in the seronegative patients (AUC increase of 9%, p < 0.001) (37). Another study focused on EULAR classification criteria for RA, with the same recruitment criteria (n = 109), 61% of participants presented with a swollen joint, 30% were ACPA+ (compared to 15.4% in the previous study). They showed that GS≥1 improved the sensitivity of the 2010 criteria from 58 up to 78% without decreasing specificity (AUC 0.868), which was 93.7% if GS ≥ 2 or PD ≥ 1 were present, but at the price of decreased specificity which went down to 56.1% (AUC 0.844) (38). US was also shown to be especially useful in RA diagnosis in CCP negative very early UA. Indeed, in a study recruiting only CCP negative individuals with suspected UA, US synovitis significantly improved the sensitivity of the 2010 classification criteria up to 86.2% (39), meaning that US could counterbalance the absence of specific serology findings. While using a probabilistic approach depending on the practitioner's impression, another group showed that the addition of US to routine investigations increased the diagnostic certainty of UA from 31.1 to 61.2% (p < 0.001) (40). It is interesting that in these studies, more than half of patients presented abnormalities on first US but not all developed a persistent disease, suggesting that, focusing on the most specific US features such as PD presence and/or GS ≥ 2 might improve US accuracy. Another study showed that GS was more effective at showing synovitis than clinical examination, laboratory investigation (p = 0.00015), and plain film radiography (p = 0.0002) (41). In a study recruiting individuals with at least one swollen joint, the same improvement of the AUC for RA diagnosis was found, they also showed that MCP joints were highly specific for IA (42). Others found that selecting PD grade 2 increased discriminative ability (43).
Interestingly, in a large (n = 379) retrospective analysis on a cohort of patients referred to early arthritis clinic and followed for minimum 12 months, US parameters did not show significant predictive value for persistent IA in comparison to clinical parameters alone, (AUC curve both metrics: 0.91; [95% CI 0.89–0.94] [95% CI 0.88 to 0.94] respectively) (44). This same group did a further study with different scanning protocol and comparison methodology between clinical and US variables, which did show improvement of predictive values when comparing to clinical parameters alone (37).
The same team developed two "risk metrics" computerized tools using logistic regression to predict the development of persistent IA whereas the first models used multivariate and ROC curve analysis to identify discriminators of IA and the added value of US parameters (44). Another diagnostic model for progression from UA to RA was designed combining symptoms and morning stiffness durations, raised inflammatory markers, CCP and or RF positivity and PDUS presence in 1, 2 or ≥3 joints, which provided an impressive AUC of 0.919 (n = 149) (45).
After a RA diagnosis has been made, US has also shown a good correlation with composite scores of disease activity at all points of disease evolution, as well as with radiological damage (33, 46–48). It is suggested for use in the assessment of remission, prediction of flares, and to assess risk of relapse when tapering treatment as well as to inform the need to intensify treatment (49–55). PROMPT trial randomized 110 UA individuals to receive methotrexate (MTX) vs. placebo for 1 year depending on US results. At 5 years, they showed no difference in progression rates to RA, only a delay in progression in the treated ACPA positive participants (56).
Overall, US has proved its place in diagnosis, disease activity and remission assessment while, for now, US driven trials have shown variable results.
The main challenge in populations at-risk of RA is to categorize biomarkers that are specific, sensitive, and reproducible in predicting disease progression. Some of them may be present years before progression and remain stable—such as specific antibodies or genetic predisposition—whilst others may vary with time or only appear closer to the clinical phase of the disease such as abnormalities on high-resolution imaging, for example, US. Defining the phase where sub-clinical inflammation on imaging appears is particularly important, as it represents the initial onset of articular inflammation and as such, the phase where clinical arthritis is imminent. Indeed, as one RCT has shown to delay the onset of RA (57), the preclinical phase of RA could be the optimal time point to initiate treatment as damages have not occurred yet, thus re-defining the window of opportunity. Delaying or even preventing the onset of RA will have major social, financial, and personal impact on patients and society.
Retrospective studies on RA patients were highly useful initially to find out biomarkers that were present before symptoms, but these are limited in the quantity and quality of the data. For example, not all analysis was possible on frozen blood samples, no imaging was performed, and clinical data were absent. Therefore, observational studies on RA prediction should now be all prospective. Another important challenge in at-risk population studies are the discrepancies between and within cohorts depending on the recruitment criteria. This implies that results are difficult to replicate and/or compare between populations. We discussed above the various pathways of prospective recruitment, for example, CSA and ACPA+ individuals, with a usual progression to IA rate of around one third of participants. This low progression rate increases duration of follow-up needed, tests and visits to be repeated, and the need for large cohorts to get significant results. Only a few centers are able to support this.
Identifying individuals who would benefit the most from an US assessment is of major importance. Indeed, although US sub-clinical inflammation can be found throughout the whole disease continuum toward RA, US abnormalities have shown—at present—only of predictive value for disease development in specific populations. The most representative are symptomatic at-risk individuals who have been identified by antibody positivity while in some populations, for example, in FDRs and CSA individuals, data are sparse and would benefit from further study. Another limitation is that not all analysis used the same US protocols. Even if we nowadays tend to follow EULAR/OMERACT recommendation, this has not always been the case. Although some US protocols focusing on specific joint sets are suggested in RA to improve US pragmatic use in clinic (58, 59), no joint based analysis have been performed on at-risk individuals yet. Nevertheless, focus is often on the small joints such as MCP, PIP, MTP, and wrists.
The studies investigating the role of US in FDRs do not support its use in those without symptoms. There is however a paucity of data in this area and further exploration is needed. On the other hand, the predictive value of US for IA development was greater in the individuals with MSK symptoms identified by a positive ACPA test. In this group particularly, depending on the US scan protocols and the recruitment criteria, US features have shown significant predictive value at the joint and patient level, for GS, BE, TSV, and especially for PD presence. This is more consistent if we consider the studies of individuals with more stringent inclusion criteria, with cohorts more likely to be at imminent risk of progression. In individuals with CSA, MRI-US comparison has shown good correlation, mainly for specificity. At diagnosis of early UA, some studies showed US superiority to clinical examination, efficacy in RA diagnosis, disease activity assessment, and treatment efficacy. In this population, efficacy is not dependent on the serological results and might be of more value in the seronegative individuals. It has good discriminative value, improving the classification criteria's sensitivity. In established RA, although it has been shown to be a good predictor in treatment response, remission assessment, and flare prediction, two trials comparing conventional T2T approach with US lead approach did not show significant differences in DAS28 remission, and lead to an increased treatment regimen is the US groups (60, 61). Nevertheless, secondary analysis showed that Boolean remission was more often reached in the US arm (61).
At present without guidance, rheumatologists have different approaches to managing at-risk individuals. A survey conducted in 2019 across the UK showed that 73% of practitioners would treat ACPA positive individuals if at least one joint showed PD presence on US (62). This reflects the pragmatic approach used due to the lack evidence on which treatment is the most appropriate, which population would respond well and what is the most appropriate timing to start treatment. This lack of global consensus emphasizes the need for research studies to assess these questions (63). Although individuals followed in preventive observational cohorts showed milder disease activity at progression (64), long term impact of prevention clinics have not been assessed yet. A few randomized controlled trials have been designed on individuals without CS. While one used the presence of US inflammation as part of the recruitment criteria (57), another one collected US data along the study for secondary analysis, results are not published yet (65), none of the others included US as an outcome or collected longitudinal data (66–68). Some RA treatments have been tested on individuals with UA (56) or even before CS occurs (65), the complexity here is to define the optimal high risk individuals who may benefit from treatment as well as the participant acceptance for a medication without confirmed disease (69, 70). At present, no formal economic analyses for use of US or treatment in at-risk individuals have been conducted, it therefore represents an important area for future work.
All aspects of US findings throughout the RA continuum have shown its high predictive value for progression to clinical synovitis, perhaps with PD standing out to be most predictive. However, it is difficult to compare these aspects due to the different definitions of US synovitis and scanning protocols through the studies. Overall, US does offer clear assistance in identifying sub-clinical inflammation in individuals at-risk of IA. However, we have to consider the time and resources needed for systemic prevention to be put in place. All populations considered, it appears that the greatest impact on IA prediction of US examination can be found in three at-risk populations: those with a positive ACPA test in the context of non-specific MSK symptom, those with CSA, and those with palindromic rheumatism. Since it has shown such good predictive value in IA and in the preclinical phases of IA, it is expected that US will be a cornerstone in prediction risk modeling and prevention studies. Nonetheless, further studies with unified selection criteria, specific joints and/or feature selections are still needed to improve US impact relevance.
LD and RC have participated with equal contribution and would like to share first authorship. KM: important part in topic choices, discussion, proof reading, and time input. PE: topic choices, discussion, and final approval for submission. All authors contributed to the article and approved the submitted version.
KM reports personal fees from Abbvie, UCB, and Eli Lilly, outside the submitted work and research grants from BMS, Eli Lilly. PE reports consultant fees from BMS, AbbVie, Gilead, Galapagos, Lilly, MSD, Pfizer, Novartis, Roche, Samsung outside the submitted work and research grants from UCB, AbbVie, Lilly, Novartis, BMS, Pfizer, MSD, and Roche, outside the submitted work.
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14. Soliman E, Ohrndorf S, Zehairy M, Matrawy K, Alhadidy A, Abdelati A. Osteopontin, osteoprotegerin and musculoskeletal ultrasound findings in first-degree relatives of rheumatoid arthritis: potential markers of preclinical disease. Preprint. (2020). doi: 10.21203/rs.3.rs-20512/v1
15. Brulhart L, Alpízar-Rodríguez D, Nissen MS, Zufferey P, Ciubotariu I, Fleury G, et al. Ultrasound is not associated with the presence of systemic autoimmunity or symptoms in individuals at-risk for rheumatoid arthritis. RMD Open. (2019) 5:e000922. doi: 10.1136/rmdopen-2019-000922
16. van Steenbergen HW, Aletaha D, Beaart-van de Voorde LJ, Brouwer E, Codreanu C, Combe B, et al. Eular definition of arthralgia suspicious for progression to rheumatoid arthritis. Ann Rheum Dis. (2017) 76:491–6. doi: 10.1136/annrheumdis-2016-209846
17. van der Ven M, van der Veer-Meerkerk M, Ten Cate DF, Rasappu N, Kok MR, Csakvari D, et al. Absence of ultrasound inflammation in patients presenting with arthralgia rules out the development of arthritis. Arthritis Res Ther. (2017) 19:202. doi: 10.1186/s13075-017-1405-y
18. Zufferey P, Rebell C, Benaim C, Ziswiler HR, Dumusc A, So A. Ultrasound can be useful to predict an evolution towards rheumatoid arthritis in patients with inflammatory polyarthralgia without anticitrullinated antibodies. Joint, Bone, Spine. (2017) 84:299–303. doi: 10.1016/j.jbspin.2016.05.011
19. Zufferey P, Brulhart L, Tamborrini G, Finckh A, Scherer A, Moller B, et al. Ultrasound evaluation of synovitis in RA: correlation with clinical disease activity and sensitivity to change in an observational cohort study. Joint Bone Spine. (2014) 81:222–7. doi: 10.1016/j.jbspin.2013.08.006
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22. van de Stadt LA, Bos WH, Meursinge Reynders M, Wieringa H, Turkstra F, van der Laken CJ, et al. The value of ultrasonography in predicting arthritis in auto-antibody positive arthralgia patients: a prospective cohort study. Arthritis Res Ther. (2010) 12:R98. doi: 10.1186/ar3028
23. Nam JL, Hensor EM, Hunt L, Conaghan PG, Wakefield RJ, Emery P. Ultrasound findings predict progression to inflammatory arthritis in anti-CCP antibody-positive patients without clinical synovitis. Ann Rheum Dis. (2016) 75:2060–7. doi: 10.1136/annrheumdis-2015-208235
24. van Beers-Tas MH, Blanken AB, Nielen MMJ, Turkstra F, van der Laken CJ, Meursinge Reynders M, et al. The value of joint ultrasonography in predicting arthritis in seropositive patients with arthralgia: a prospective cohort study. Arthritis Res Ther. (2018) 20:279. doi: 10.1186/s13075-018-1767-9
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26. Duquenne L. MK, Di Matteo A, Garcia-Montoya L, Nam J, Emery P. ACPA positive At-risk individuals without clinical arthritis, is ultrasound sufficiently accurate to predict progression to inflammatory arthritis? Ann Rheum Dis. (2020) 79:260.
27. Di Matteo A, Mankia K, Duquenne L, Cipolletta E, Wakefield RJ, Garcia-Montoya L, et al. Ultrasound erosions in the feet best predict progression to inflammatory arthritis in anti-CCP positive at-risk individuals without clinical synovitis. Ann Rheum Dis. (2020) 79:901–7. doi: 10.1136/annrheumdis-2020-217215
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39. Ji L, Deng X, Geng Y, Song Z, Zhang Z. The additional benefit of ultrasonography to 2010 ACR/EULAR classification criteria when diagnosing rheumatoid arthritis in the absence of anti-cyclic citrullinated peptide antibodies. Clin Rheumatol. (2017) 36:261–7. doi: 10.1007/s10067-016-3465-9
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42. Filer A, de Pablo P, Allen G, Nightingale P, Jordan A, Jobanputra P, et al. Utility of ultrasound joint counts in the prediction of rheumatoid arthritis in patients with very early synovitis. Ann Rheum Dis. (2011) 70:500–7. doi: 10.1136/ard.2010.131573
43. Kawashiri SY, Fujikawa K, Nishino A, Okada A, Aramaki T, Shimizu T, et al. Ultrasound-detected bone erosion is a relapse risk factor after discontinuation of biologic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis whose ultrasound power Doppler synovitis activity and clinical disease activity are well controlled. Arthritis Res Ther. (2017) 19:108. doi: 10.1186/s13075-017-1320-2
44. Pratt AG, Lorenzi AR, Wilson G, Platt PN, Isaacs JD. Predicting persistent inflammatory arthritis amongst early arthritis clinic patients in the UK: is musculoskeletal ultrasound required? Arthritis Res Ther. (2013) 15:R118. doi: 10.1186/ar4298
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48. Ribbens C, Andre B, Marcelis S, Kaye O, Mathy L, Bonnet V, et al. Rheumatoid hand joint synovitis: gray-scale and power Doppler US quantifications following anti-tumor necrosis factor-alpha treatment: pilot study. Radiology. (2003) 229:562–9. doi: 10.1148/radiol.2292020206
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Keywords: arthritis (including rheumatoid arthritis), ultrasound, at risk, prediction, ACPA, anti-cyclic citrullinated peptide antibodies
Citation: Duquenne L, Chowdhury R, Mankia K and Emery P (2020) The Role of Ultrasound Across the Inflammatory Arthritis Continuum: Focus on "At-Risk" Individuals. Front. Med. 7:587827. doi: 10.3389/fmed.2020.587827
Received: 27 July 2020; Accepted: 12 October 2020;
Published: 30 October 2020.
Raj Sengupta, Royal National Hospital for Rheumatic Diseases, United Kingdom
Jose Inciarte-Mundo, Hospital Clínic de Barcelona, Spain
Arti Mahto, King's College Hospital NHS Foundation Trust, United Kingdom
Copyright © 2020 Duquenne, Chowdhury, Mankia and Emery. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Laurence Duquenne, l.duquenne@leeds.ac.uk
†These authors share first authorship
Imaging In Inflammatory Rheumatic Diseases - Recent Advances


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> Uncategorized > Company 'etched' details into paving near memorial
Company 'etched' details into paving near memorial
Published on: 24th October 2018 | By: Jake Levison | Category: Uncategorized
A local pressure washing company stencilled their details on paving surrounding the war memorial on the High Street, which caused quite a stir amongst residents.
The advertisement, which read: "HERTS PRESSURE WASHING DRIVEWAY AND PATIO REMOVAL", along with the company's Facebook page underneath, was brought to the attention of the Aldenham Parish Council by a passing resident, according to Councillor Vivienne Charrett.
The councillor, who is a member of the Parks and Open Spaces Committee, said that when the council received the complaint, it reached out to the company and asked them to remove it or pay the council to remove it for them.
Cllr Charrett said their response was: "All we did was clean a bit of pavement, and since it isn't permanent, no crime has been committed, but please feel free to pursue this line of enquiry if you wish. We shall not be removing or paying for the removal of the stencils."
While the mark on the paving has now reportedly been cleared, many residents were left upset by the advertisement.
When Cllr Charrett opened up a discussion on the Radlett Village Facebook page about the etching, many responded saying they thought it was "disrespectful" and "inappropriate." There were also a number of people who defended the company's actions, saying that the advertisement was impressive and far enough from the memorial to not be offensive.
RadlettNews reached out to Herts Pressure Washing's owner, Alex Bracken, for comment but he declined.
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redpajama_set_name: RedPajamaCommonCrawl


Present coalition Government is committed for imparting quality education and development of educational infrastructure with provision of latest technical expertise to teaching community, for which steps have already been taken at ground level. This was stated by Minister for Education Mr. Naeem Akhtar today while visiting various educational institutions of Anantnag.
Accompanied by Additional Deputy Commissioner Anantnag Mr. Mohammad Younis Malik, Joint Director School Education Mr. Abid Hussain, Chief Education Officer and other concerned officers of R&B and allied Departments Mr. Naeem Akhtar today visited Girls Higher Secondary School Bijbehara & Anantnag and Boys Higher Secondary school Bijbehara and Anantnag.
During a daylong visit the minister reviewed each and every aspect of the said Schools including the damages caused to the infrastructure during September floods. He interacted with students and enquired about their needs and aspiration with regard to available facilities, syllabus and formulation of new Educational Policy.
At Girls Higher Secondary School, Bijbehara, Minister announced introducing Commerce stream from the current academic session. He urged the heads of the institutions to identify the Job-oriented courses and not to remain stick to traditional courses. He urged the teachers to take students outside the traditional classrooms to help them acquire knowledge practically.
Minister announced that these four higher secondary schools will be developed as "Model schools" for the purpose of which all basic facilities for imparting quality education will be provided besides making available the best human resource. He urged the teaching community to come forward and share the social responsibility of transforming the society by giving their best. Minister also announced that toppers of board exams of these four Educational Institutions will be provided free coaching by experts besides arranging exposure visits for them.
Minister further said that the process of rationalization has initiated to streamline the Education department.
Mr. Naeem Akhtar urged all concerned to work with dedication and co-operation so that a new educational system is evolved.
Meanwhile the Minister inspected various schools of Srinagar including Girls High School, Rawalpora. He was accompanied by Joint Director School Education Kashmir, CEO Srinagar and District Planning Officer, Srinagar. During the inspection, the Minister interacted with the students and teachers. He awared about various issues and problems being faced by them on various count. Minister assured full support and directed the officers to make sure that the education in government school is given a fillip.
The Minister also discussed the vision of making government school attractive for the children, so that the education sector can became an engine for growth and development of entire society. Referring to new transfer policy, Naeem said that the policy is just and practical and is aimed at rejuvenating the education system. Naeem Akhtar said that to sort out the abysmal teacher-student ratio in government; school rationalization policy is being initiated.
He urged the heads of educational institutions to make the government schools attractive to students from nursery level to ensure maximum enrollment in the government schools. He asked the teachers to play their role as real architects of society and be true to their profession.


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C21 Investments' CEO to address Annual Cannabis Conference in New York
C21 Investments Inc. (CSE: CXXI and OTC: CXXIF) today announced that its President and Chief Executive Officer, Robert Cheney, will join other cannabis industry experts at the Canaccord Genuity's 3rd Annual Cannabis Conference and present. C21 Investments Inc. is a vertically integrated cannabis company that cultivates, processes, and distributes quality cannabis and hemp-derived consumer products in the United States.
Mr. Cheney is scheduled to present at 3:00pm EST time on Tuesday, May 14, 2019, and his presentation will be available via webcast at: http://wsw.com/webcast/canaccord34/ctoi/. Mr. Cheney is available for meetings and media interviews during the conference.
C21 Investments recently reported unaudited revenue of US$7.7 million for the 1st quarter ended April 30, 2019. This amount reflects revenue from the Company's operations in Nevada and Oregon. Unaudited gross margin (before fair value adjustments) is estimated to be 54%. During the quarter, C21's retail dispensaries completed 140,000 customer transactions. These figures do not include revenue from Swell Companies.
After the completion of the acquisition of Swell Companies, the C21 Investments group of companies will have 140,000 sq. ft. of cultivation space (both indoor and outdoor) with another 165,000 sq. ft. available for cultivation, extraction or wholesale distribution; 11,000 sq. ft. of wholesale distribution; 13,000 sq. ft. of extraction; and 17,000 sq. ft of retail distribution.
SOURCE C21 Investments Inc.
WAX Solving Voter Apathy Problem Plaguing DPoS-Based Blockchains by Incentivizing Voting
Chicago FinTech Group FinTEx Announces Second Annual FinTEx Forum, Sponsored by Actuate Law
Permissioned blockchain? Private blockchain? Public blockchain? Fret not for YAO Network accepts them all. YAO Network is a cloud service paradise for new blockchain projects looking for a community to nestle in and make their homes there. By integrating cloud computation with decentralized computation, the YAO Network is able to support computation eco-platforms of multiple blockchain networks, maximizing the utility of all participants while helping projects to achieve their technological targets and generate value.
The YAO Network was built for a vision: to benefit developers and to help enterprises achieve much more, freeing the successes of blockchain technologies for all to enjoy. This vision grounds the design of YAO Network's architecture as the platform seeks to establish a comprehensive service and utility computation platform where Pareto optimality is achieved amongst developers, enterprises, and overall public utility.
Like many other blockchain platforms out there, technology remains a key factor in determining a platform's functionality. The YAO Network certainly has a strong pillar of support in its robust technical infrastructure to achieve its goals.
1. YAO Network integrates multiple computation paradigms in utility computation.
The YAO Network platform effectively combines three computational paradigms, cloud computing, decentralized computing and encrypted computing, to meet the demands of different applications and create maximum computation utility.
Cloud computation has been gaining massive popularity as a computational model in many enterprises and the public. The advantages of cloud computation are numerous. It saves cost for enterprises, developers and the public while offering flexible workload deployments, which enhances the overall utility of both individuals and society.
Recognizing the advantages of cloud computation, the YAO Network platform makes cloud computing the only carrier of all service and computation units in the blockchain. Cloud computing is not only utilized for deployments and encrypted computation of centralized applications, but also widely applied in decentralized blockchain networks.
2. YAO Network standardizes decentralized and centralized computation units based on cloud computation.
Different computation units have been designed for various types of applications to promote the usage of blockchains in the public domain. YaoLet is the solution designed by the YAO Network for decentralized applications, while BuildPack is its equivalent for centralized applications designed based on PaaS. The entire architecture is rested on these two solutions alongside other services. As YaoLet and BuildPack are both multiplexed; developers and service providers can participate in the sharing of YaoLet and BuildPack and reap the rewards through corresponding YAO Network reward system.
3. YAO Network allows softwares to define blockchain through topological orchestration and virtualization.
Most computations are no longer an isolated and individual computation unit; they have complex interconnections that are unified by a topological structure. This combination of computational units is achieved through topological orchestration.
On one hand, new services and components can be combined and orchestrated by existing computation units. On the other hand, various infranets in blockchains can also be orchestrated to establish corresponding nodes and services. Most blockchain architectures like YAO Network take on a modularized approach where interledger general blockchain protocols are made viable through plugging and unplugging every component and service as well as modularizing operations. The blockchain network becomes the virtual superposition of peer-to-peer networks, making it possible to define new blockchain network models and service models through virtual and abstract orchestrations.
4. YAO Network supports multiple blockchain network architectures and paradigms including public blockchains, permissioned blockchains and private blockchains.
The blockchain network within YAO Network supports three types of blockchains, namely public blockchain, permissioned blockchain and private blockchain. They can be broken down into shared and exclusive nodes based on the extent of its isolation. Enterprises and developers can build on shared blockchains or create their own exclusive blockchains on the YAO Network platform. Another alternative would be to classify the blockchain network based on its testnet and mainnet, and their applications.
5. YAO Network maximizes utility of developers, enterprises and the general public.
YAO Network is a one-stop blockchain service platform for blockchain service consumers, developers and enterprises to share innovations both in public and private. One of the biggest hurdles blockchain has yet to overcome is its low adoption rate and thus the YAO Network has provided blockchain PaaS services for developers to utilise and a platform where they can release their blockchain products directly to blockchain service providers. This forms a healthy supply and demand ecosystem as iterations of blockchain products are incubated or eliminated based on practicality and impact. Those that are proven viable will unite and form a larger blockchain ecosystem and platform.
Developers even earn the chance to make some profits through the YAO Network. The network rewards developers when their creations are utilised by others. In addition, the YAO Network has three specific function modules in terms of product modality: blockchain marketplace, enterprise aggregation and solutions, and developer community. This forms a trinity that works together to serve both developers and enterprises. Driven by supply, YAO Network solves the scarcity of blockchain comprehensive services by connecting and bridging between developers and enterprises, in order to establish a healthy and organic ecosystem where all participants have maximum utility within the system.
6. YAO Network has high inclusivity in the system.
A well-designed architecture should have open interfaces. Every layer delivers its own functions, and is connected to each other through the same cross layer interface. The YAO Network system is designed based on important principles including openness, security, technology neutrality, verifiability in the future, interoperability, scalability, modularization, manageability and dependability, to achieve inclusivity in the system.
YAO Network embraces existing and future blockchain applications and is committed to establishing a comprehensive computation platform with multiple blockchains, multiple computational paradigms and integrated utilities.
SOURCE YAO Network
Success strategies from top industry leaders, the latest in high-tech devices and a chance to network with other real estate professionals: That's what the Florida Realtors® 2019 Convention & Trade Expo offers – opportunities to boost business and the bottom line.
This year's Convention & Trade Expo takes place Aug. 21-22, 2019, at the Rosen Shingle Creek resort in Orlando, with the popular REBarCamp slated to kick off the event on Tuesday, Aug. 20. Then Realtor members will get down to the business of the state association and wrap up the week with governance meetings, Aug. 23-25, 2019.
"Florida Realtors 2019 Convention and Trade Expo is the one business event this year that every Realtor should attend," says 2019 Florida Realtors President Eric Sain, a Realtor and district sales manager with Illustrated Properties in Palm Beach. "Over the course of just two days, Realtors have the chance to learn successful business strategies from top industry leaders, get new marketing tips, hear inspirational speakers offer advice from the trenches, network with colleagues and enjoy exciting entertainment. Florida Realtors' annual convention provides outstanding value to anyone interested in the latest trends, technology and best practices. I'll be there – will you?"
The 2019 convention features more than 40 education sessions from top industry speakers on various topics such as new trends in real estate, disaster recovery planning, Florida's water crisis, how to make the most of the home-share trend, video marketing, Florida's evolving cannabis laws, best practices for brokers and much more.
Convention highlights
REBarCamp: Aug. 20, 9:30 a.m. – 5:30 p.m.; registration sign-in starts at 8:30 a.m.
This year marks the 10th year for the event's peer-to-peer learning and sharing. However, industry powerhouses are on tap to facilitate sessions, including: Sean Carpenter, Jay Thompson, Nick Baldwin and Tristan Ahumada with Lab Coat Agents to name a few. More than 500 Realtors attended last year's REBarCamp. Cost for day, which includes lunch and the After Party, is $15. Register through Eventbrite to guarantee a ticket.
General Session Keynote: Aug. 21, 1:30 – 2:30 p.m.
Songwriter and Grammy-nominated Top 40 singer John Ondrasik, also known as Five for Fighting, brings home his message of "Harnessing Inspiration and Creativity to Design the World You Want" on piano and guitar. One complimentary ticket is included with full convention registration. One additional ticket can be purchased by full convention attendees for $30.
Dance Party with "Party on the Moon": Aug. 21, 8 – 11 p.m.
Returning for the 5th year in a row, American's No. 1 Party Band, Party on the Moon delivers a high-energy evening of the latest dance music, '80s classic rock, Latin, disco/funk, R&B and Motown. This 13-piece band – with singers, musicians and dancers – has performed worldwide. One complimentary ticket for the party is included with full convention registration. Additional tickets can be purchased by any attendee for $30.
Awards Luncheon, featuring entertainment by the Funkywunks: Aug. 22, noon – 1:30 p.m.
Florida Realtors honors Realtor excellence and service at this ticketed event, including recognizing the Humanitarian of the Year and Realtor of the Year and other award winners. Orlando dance troupe the Funkywunks was a contender on the World of Dance TV show in 2018, making it to the third week of the duels. Judges praised their high-energy, funky and entertaining routines, specifically noting the group's commitment and innovative choreography. Tickets for the Awards Luncheon are $50 and will be sold until noon on Aug. 22, or as long as they're available.
Closing Session Keynote with Ryan Serhant: Aug. 22, 4 – 5p.m.
Learn Serhant's professional secrets, as the super sales broker and Bravo TV star tells his rags-to-riches story: "The Four W's: How identifying Your Way, Work, Wall & Win Leads to Success." One complimentary ticket is included with full convention registration. One additional ticket can be purchased by full convention attendees for $30.
The Trade Expo, Aug. 21, 9 a.m. – 6 p.m., and Aug. 22, 8:30 a.m. – 4 pm.
The expo features more than 200 industry experts and exhibitors showcasing the latest marketing and technology products. Attendance to the Trade Expo (Expo only admittance) is free!
Some of the sponsors for the 2019 convention include: Title Sponsor, BoomTown!; Titanium Association Sponsors, RAPB +GFLR, (Realtors Association of the Palm Beaches and Greater Fort Lauderdale Realtors) and Miami Realtors; Titanium Sponsors, Northeast Florida Association of Realtors, RealtyWEB.net, Metro Market Trends and Stellar MLS; Diamond Association Partner, Orlando Regional Realtor Association; Ruby Association Partner Sponsor, Royal Palm Coast Realtor Association; Gold Partners, Century 21 and realtor.com; Sapphire Association Partner Sponsor, Naples Area Board of Realtors; Vehicle Sponsor, FCA – Fiat Chrysler Automobiles; Emerald Association Partner, Greater Tampa Realtors and Realtor Association of Sarasota and Manatee; Popcorn Sponsor, Form Simplicity; Registration Bag Sponsor, Florida Realtors PAC; Notepad Sponsor, Find a Mortgage Broker.com; Interactive Wall Sponsor, wizehire; General Sponsors, American Home Shield, America's Title Corp., gte financial, Realtors Association of Citrus County, Dot Loop, HomeSnap, HomeTeam Inspection Service, Freedomtax International, Loan Genuis, NARPM, Supreme Title and Escrow and Tenantreports.com.
Register online through Aug. 12 for the Florida Realtors convention or by calling 1-800-669-4327. The full event registration fee for members is $150 through July 19 and $160 from July 20 – Aug. 12, 2019. The cost is $175 for non-members through July 19 and $185 from July 20 – Aug. 12. After Aug. 12, registration will be handled at the convention site. For more info, check out http://convention.floridarealtors.org/.
Florida Realtors® serves as the voice for real estate in Florida. It provides programs, services, continuing education, research and legislative representation to its more than 187,000 members in 52 boards/associations. Florida Realtors® Media Center website is available at http://media.floridarealtors.org.
SOURCE Florida Realtors
Knowmatix: An Online Educational Platform for the Cryptocurrency Industry
Knowmatix is an online, in-depth educational platform providing the fundamentals and practical skills necessary to become successful in the Blockchain, Cryptocurrency industry from the comfort of your own home.
By applying our easy to understand, proven methods and applications, it is now easier than ever to successfully become a knowledgeable leader in blockchain technologies industry through our online accelerated educational program. Our comprehensive introductory program provides a fundamental understanding of how various blockchains operate and how easy it is to strategically trade cryptocurrency in today's centralized economy.
Our founder and curriculum developer, Abdulaziz AlYaqout, is currently operating in Miami Beach, Florida. Prior to forming Knowmatix, Mr. AlYaqout took lead as an important consultant for the business analyst team at Ryder Systems, Inc. and the University of Miami Hospital and Clinics. He holds BS Degree and MS in Industrial Engineering, both from the University of Miami.
As lead instructor for Knowmatix, Mr. AlYaqout's first course is a blockchain and digital currency microdegree that provides you the basic tools to start and advance your professional career in the cryptocurrency.
Learn the technical analysis basics and terminology and develop buying strategies and skills to grow your personal finances. Learn how to deconstruct the blockchain technology, and the importance of Hashing. Discover Bitcoin and understand its history and role in the cryptocurrency marketplace.
Knowmatix, seeks to create a Knowmatix Impact Program (KIP) that forms strategic alliances with reputable businesses operating in the Blockchain industry. This involves Knowmatix assigning project managers to given projects, and delegating work per project basis to qualified star students. While forming alliances with businesses, Knowmatix will align itself with schools and institutions to provide a custom backend solutions curriculum to help revamp their online courses. This effort provides colleges and institutions cost saving measures by offering its platform in a software program, which acts as an additional resource to aid students with completing their education, and securing a career through Knowmatix alliances and partners in the ever growing technology field, nationwide.
With Knowmatix' proprietary platform and blockchain-focused training services, Mr. AlYaqout ventures to be part of the governmental effort to Buy American and Hire American with special interest for advancing the careers of woman and Veteran groups nationwide to team up with Knowmatix.
For additional information and preview of our proprietary educational curriculum, please visit our website at www.knowmatix.com.
Cryptocurrency terminology
Deconstructing blockchain technology
Understanding Hashing
Digital Currency and its Future
Bitcoins role and history
Crypto Research tools
Digital Asset Classifications
Blockchain Analysis Basics
SOURCE Knowmatix


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text:
Nvidia's New Tablet (?)
Technology Articles > Gadgets > Tablets > Nvidia's New Tablet (?)
Is Nvidia working on its own tablet? Well, to be fair, Nvidia helped Google and Asus with their Nexus 7 tablet, but that's kind of a secret. This time, though, Nvidia may be branching out on its own to bring the world something called the Nvidia Tegra Tab.
Reports from Chinese tech sites show something that looks like a new tablet on the horizon. This tablet has all the markings of a Nvidia tab, and even includes the same basic design that we've seen on the Asus tab.
To further solidify those rumors, Nvidia has filed a trademark for the name 'Tegra Tab' in the United States. What does all of this mean? A new Nvidia tablet might be on the horizon - only, will it actually make a dent in the market?
Some Disappointing Numbers
When first released, the Tegra 4 promised great things. However, this tablet fell very short of its promises, and consumers let out a big "meh" at the sight of it. At that point, Nvidia promised that the company would soon be releasing cheaper tablet options, and that might be where the newest Nvidia tablet comes into play.
The big question isn't whether or not a Nvidia Tegra Tab is in the works, but more whether or not it will make it to North America. The Tegra Tab could just be a tablet for the Chinese market. It will be interesting to see whether or not Nvidia can bring down the prices of a new tablet, and how the company's 'Kai' program fits into the whole picture.
The Nvidia Kai Program
Kai is, essentially, a platform built by Nvidia for developing quad-core Android 4.0 tablets. The price? Around $199. Kai tablets are meant to use DDR3L memory, and, originally, the company wanted these new tablets to compete directly with the Kindle Fire. Only, Nvidia openly stated that the Kai tablets would be more powerful than the Kindle Fire, but would also be priced lower.
So, it might make some sense that Nvidia is working on a more powerful tablet that does, indeed, directly compete with the Kindle Fire. Since earlier tablets developed in conjunction with Nvidia did not impact the tablet market as originally suspected, the new tablets may just fill that gap. So far, though, nobody has actually seen these tablets, though early suspected photos include a spot for a Stylus.
Nvidia Weighs In
When contacted by press, Nvidia did not have anything to say about the leaked photographs of a potentially new tablet. When a company remains silent about a possible leaked photo or two, it tends to be for two reasons. The first is that the images are correct, and the second is to keep the public guessing.
Were the rumors to be completely untrue, Nvidia would have stated that there was no truth to the news. This did not happen. When can you expect a new Nvidia tab to hit the market in the US? It's really hard to speculate, but I wouldn't be shocked if this tablet came out sometime this winter.


text: Les échinocandines sont une classe de médicaments antifongiques inhibant la synthèse des β-glucanes de la paroi cellulaire du champignon. La caspofungine, la micafungine et la rézafungine, trois médicaments de cette classe, sont utilisés pour le traitement des mycoses graves.

redpajama_set_name: RedPajamaWikipedia


The Trump Administration is on the brink of putting a cruel price tag on permission to be in this country. Unless an immediate public outcry stops a new policy from becoming effective, many immigrants will be separated from their homes, employers will lose their employees, and most wrenching of all, immigrant parents will be finding themselves across an international border from their U.S.-born children.
Immigrants who don't have a high enough income, or who receive or are likely to receive health, food, or housing supports, may soon not be able to stay in this country. Published last week, the proposed Trump Rule, a radical reinterpretation of who is considered a "public charge," would cover anyone applying for a green card through a family-based petition, or seeking to extend or change their temporary non-immigrant status in the United States.
The direct effect is shocking, but it is just the tip of this appalling iceberg. If it becomes a reality, experience tells us that the Trump Rule would have a powerfully chilling impact on families with at least one non-citizen immigrant member. They'd become nervous about receiving or applying for Medicaid, SNAP (supplemental nutrition assistance, also known as food stamps), Medicare Part D (which covers prescription drugs), or housing assistance – benefits which, for the first time, would fall under the "public charge" definition of those whose green card applications may be denied. Some, we're sure, would even be moved by confusion and fear to dis-enroll from benefit programs. The Fiscal Policy Institute (FPI) estimates that 2.1 million residents of New York State (and as many as 24 million people nationwide) could experience this chilling effect; that's the number of people with a family member who is a non-citizen in which the family has received one of the benefits named in the proposed Trump Rule.
A child's wellbeing is inextricably intertwined with that of the child's parents. In New York State, there are 680,000 children under 18 years old who live in families that have at least one non-citizen family member and that have received one of the benefits specified by the Trump Rule. The large majority, 580,000 of the 680,000, are United States citizens.
Fear around the proposal's interest in Medicaid, not to mention other programs, could lead to 15, 25, or even 35 percent of those experiencing the chilling effect to dis-enroll, all examples modeled in the FPI report as well as in a study from the Kaiser Family Foundation. Disenrollment would mean adults, but also kids—including kids who are U.S. citizens—going without health insurance, with potentially catastrophic consequences. Over the past few months, fear and anxiety aroused by rumors of this proposed change have already caused immigrant families to steer clear of essential public programs, even some not covered by the proposed rule. The proposed Trump Rule has impacted even the youngest of us – infants. This year, providers in New York and around the country have witnessed a decline in enrollment in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC), a program not included in the proposed rule.
Helping kids in immigrant families do well is not only the right thing to do; it's also a sound investment in the future of our state and nation. One of the clearest and most striking findings in a major study by the National Academy of Sciences is that the children of immigrants, once grown, become among the strongest contributors to the country's economy.
But you don't even need to take that long view; the negative economic consequences of the Trump Rule would be felt quickly and sharply. An FPI analysis estimates that New York State would lose $1.8 billion annually in federal benefits if just 25 percent of people experiencing the chilling effect make the wrenching decision to dis-enroll from SNAP and Medicaid benefits they qualify to get. These losses would then ripple out through the economy. That's because withdrawal of SNAP funding means a reduction in spending in grocery stores and supermarkets. When families lose health insurance, hospitals and doctors lose income. And some spending would be reduced in other areas, as families struggle to pay food and health costs. Depending on where we are in the economic cycle, these additional losses could amount to an overall hit to the New York State economy of $3.6 billion – with up to 25,000 jobs statewide lost in the bargain, too.
Over the summer, the nation was outraged to find out that the Trump Administration has been using the forced separation of children from their parents as an inhumane tactic of immigration enforcement. The redefinition of public charge doubles down on making children instruments of repressive policy. The Administration's approach does not include going to Congress for approval, so the only thing that will stop it is a massive public reaction. The Administration has given the public 60 days to submit public comments. Individuals, organizations, businesses, governments, can all do that here: https://www.ouramericanstory.us/. That's your place to say: Enough is enough!
David Dyssegaard Kallick is deputy director of the Fiscal Policy Institute. Jennifer Jones Austin is chief executive officer of the Federation of Protestant Welfare Agencies.
This Urban Matters is part of our ongoing focus on how new federal policy and budget proposals impact children in New York City.


CPABC's annual Business Case Competition showcases the talent and business acumen of post-secondary students throughout British Columbia by challenging students to apply their skills to business case analyses.
This year, 51 post-secondary teams competed in the first round of the competition. Each team consisted of three to four students in different academic years. They were given a 72-hour window to resolve a business case scenario and present their strategic recommendations via video submission.
A total of nine teams from eight post-secondary schools—the British Columbia Institute of Technology, Camosun College, Kwantlen Polytechnic University, Langara College, Selkirk College, Simon Fraser University, the University of British Columbia, and Vancouver Island University were subsequently selected to participate in the final round of the competition.
The final round was hosted on Saturday, March 23, 2019, at the Terminal City Club in Vancouver. Teams were given a tight timeframe of three hours to analyze a new business case focused on finance and technology. By presenting their findings in front of a panel of CPA judges, teams were assessed on their presentation style, case knowledge, strategic implementation, creativity, and a rapid-fire question/answer period.
CPABC congratulates the winning teams once again and thank you to all the teams for participating!
Photos by Raymond Chou Photography. For more photos from this events, visit CPABC's Flickr page here.