Safety and Efficacy of Radiosynoviorthesis: A Prospective Canadian Multicenter Study.

Radiosynoviorthesis is approved in several European countries and the United States to treat refractory synovitis in many inflammatory joint diseases, such as rheumatoid arthritis, spondyloarthropathies, and other arthritic joint diseases. No radiopharmaceuticals for radiosynoviorthesis are currently approved in Canada. The aim of this Health Canada-approved trial was to demonstrate the safety and efficacy of radiosynoviorthesis. Methods: Between July 2012 and November 2017, we conducted a multicenter, prospective, interventional Canadian trial. Patients (n = 360) with synovitis refractory to standard treatments after failing 2 intraarticular glucocorticoid injections were included. They were followed up at 3, 6, and 12 mo. Outcome measures included adverse events (AEs) and clinical signs of synovitis (pain, swelling, and joint effusion) measured with the Health Assessment Questionnaire Disability Index, the Disease Activity Score, and the Visual Analog Scale. Results: In total, 392 joints were treated, including those reinjected after 6 mo (n = 34). Of these, 83.4% (327/392) were injected with [90Y]Y-citrate for the knees and 9.9% (39/392) with [186Re]Re-sulfide for medium-sized joints. Of the joints treated, 82.7% (324/392) were knees. Fifty-five AEs, most of them of mild grade, occurred and resolved without sequelae and were not life-threatening. The incidence of radiosynoviorthesis-related AEs was 9.4% (34/360). The proportion of patients showing an improvement in synovitis symptoms after radiosynoviorthesis was significant at 3 mo and was maintained up to 12 mo (P < 0.001). Conclusion: This study confirmed the safety of radiosynoviorthesis in the treatment of patients with synovitis refractory to standard treatments. There is evidence of sustained clinical efficacy at 12 mo, suggesting that radiosynoviorthesis is an effective treatment for improving synovitis symptoms.

Achieving ultra-low and -uniform residual magnetic fields in a very large magnetically shielded room for fundamental physics experiments.

High-precision searches for an electric dipole moment of the neutron (nEDM) require stable and uniform magnetic field environments. We present the recent achievements of degaussing and equilibrating the magnetically shielded room (MSR) for the n2EDM experiment at the Paul Scherrer Institute. We present the final degaussing configuration that will be used for n2EDM after numerous studies. The optimized procedure results in a residual magnetic field that has been reduced by a factor of two. The ultra-low field is achieved with the full magnetic-field-coil system, and a large vacuum vessel installed, both in the MSR. In the inner volume of ∼1.4m3, the field is now more uniform and below 300 pT. In addition, the procedure is faster and dissipates less heat into the magnetic environment, which in turn, reduces its thermal relaxation time from 12h down to 1.5h.

A large 'Active Magnetic Shield' for a high-precision experiment: nEDM collaboration.

We present a novel Active Magnetic Shield (AMS), designed and implemented for the n2EDM experiment at the Paul Scherrer Institute. The experiment will perform a high-sensitivity search for the electric dipole moment of the neutron. Magnetic-field stability and control is of key importance for n2EDM. A large, cubic, 5 m side length, magnetically shielded room (MSR) provides a passive, quasi-static shielding-factor of about 105 for its inner sensitive volume. The AMS consists of a system of eight complex, feedback-controlled compensation coils constructed on an irregular grid spanned on a volume of less than 1000 m3 around the MSR. The AMS is designed to provide a stable and uniform magnetic-field environment around the MSR, while being reasonably compact. The system can compensate static and variable magnetic fields up to ±50µT (homogeneous components) and ±5µT/m (first-order gradients), suppressing them to a few µT in the sub-Hertz frequency range. The presented design concept and implementation of the AMS fulfills the requirements of the n2EDM experiment and can be useful for other applications, where magnetically silent environments are important and spatial constraints inhibit simpler geometrical solutions.

The Effects of Continuity of Rheumatology Care on Emergency Department Utilization and Hospitalizations for Individuals With Early Rheumatoid Arthritis: A Population-Based Study.

OBJECTIVE: To determine if continuity of rheumatology care influences rates of emergency department (ED) visits and hospitalizations in patients with rheumatoid arthritis (RA). METHODS: A closed inception cohort of patients with RA diagnosed between 2000 and 2009 were followed until December 31, 2019. During the first 5 years following diagnosis, we categorized patients into 3 rheumatology care continuity groups (high, intermediate, and not retained in rheumatology care). Using a landmark analysis, we compared rates of ED visits and hospitalizations during follow-up. Multivariable Poisson regression models were used to estimate rate ratios (RRs), adjusting for demographics, comorbidities, and health services access and supply measures. RESULTS: The cohort included 38,528 patients, of which 57.7% (n = 22,221) were classified in the high rheumatology continuity group, 17.2% (n = 6636) were in the intermediate group, and 25.1% (n = 9671) were not retained in rheumatology care. Relative to the high continuity group, both the intermediate and nonretention groups had higher ED rates (RR 1.14, 95% CI 1.08-1.20, and RR 1.12, 95% CI 1.08-1.16, respectively). The intermediate group also experienced higher adjusted hospitalization rates (207.4, 95% CI 203.0-211.8 per 1000 person-years [PY]) than the high continuity group (193.5, 95% CI 191.4-195.6 per 1000 PY). CONCLUSION: Patients with RA with higher continuity of rheumatology care had lower rates of ED visits and hospitalizations compared to those who did not receive continuous rheumatology care during the first 5 years of follow-up. These findings provide evidence to support the value of early and continuous rheumatology care for reducing hospitalizations and ED visits.

Stricter treat-to-target in RA does not result in less radiographic progression: a longitudinal analysis in RA BIODAM.

OBJECTIVES: To investigate whether meticulously following a treat-to-target (T2T)-strategy in daily clinical practice will lead to less radiographic progression in patients with active RA who start (new) DMARD-therapy. METHODS: Patients with RA from 10 countries starting/changing conventional synthetic or biologic DMARDs because of active RA, and in whom treatment intensification according to the T2T principle was pursued, were assessed for disease activity every 3 months for 2 years (RA-BIODAM cohort). The primary outcome was the change in Sharp-van der Heijde (SvdH) score, assessed every 6 months. Per 3-month interval DAS44-T2T could be followed zero, one or two times (in a total of two visits). The relation between T2T intensity and change in SvdH-score was modelled by generalized estimating equations. RESULTS: In total, 511 patients were included [mean (s.d.) age: 56 (13) years; 76% female]. Mean 2-year SvdH progression was 2.2 (4.1) units (median: 1 unit). A stricter application of T2T in a 3-month interval did not reduce progression in the same 6-month interval [parameter estimates (for yes vs no): +0.15 units (95% CI: -0.04, 0.33) for 2 vs 0 visits; and +0.08 units (-0.06; 0.22) for 1 vs 0 visits] nor did it reduce progression in the subsequent 6-month interval. CONCLUSIONS: In this daily practice cohort, following T2T principles more meticulously did not result in less radiographic progression than a somewhat more lenient attitude towards T2T. One possible interpretation of these results is that the intention to apply T2T already suffices and that a more stringent approach does not further improve outcome.

Changes in Service Delivery and Access to Rheumatologists Before and During the COVID-19 Pandemic in a Canadian Universal Healthcare Setting.

OBJECTIVE: To describe changes in service delivery and access to rheumatologists before and during the coronavirus disease 2019 (COVID-19) pandemic periods. METHODS: We conducted a population-based study in Ontario, Canada. Patient visits with rheumatologists were ascertained using billing claims data. Contact with rheumatologists was defined separately by the type of patient encounter (including office visits, telemedicine visits, and new patient consultations). Changes in the total weekly volume of encounters and monthly rates after COVID-19 public health measures were imposed were compared to expected baseline rates determined before pandemic onset (March 17, 2020). RESULTS: In the year prior to the pandemic, there were 289,202 patients (of which 96,955 were new consults) seen by 239 rheumatologists. In the 1 year following the pandemic onset, there were 276,686 patients (of which 86,553 were new consults) seen by 247 rheumatologists. In March 2020, there was an immediate 75.9% decrease in outpatient office visits and a rapid rise in telemedicine visits. By September 2021, 49.7% of patient encounters remained telemedicine visits. For new patient consultations, there was an immediate 50% decrease in visits at the pandemic onset, with 54.8% diverted to telemedicine visits in the first year of the pandemic versus 37.4% by September 2021. New rheumatology consultation rates continued decreasing over the study period. CONCLUSION: Rheumatology care delivery has shifted due to the pandemic, with telemedicine increasing sharply early in the pandemic and persisting over time. The pandemic also negatively affected access to rheumatologists, resulting in fewer new consultations and raising concerns for potential delays to diagnosis.

The very large n2EDM magnetically shielded room with an exceptional performance for fundamental physics measurements.

We present the magnetically shielded room (MSR) for the n2EDM experiment at the Paul Scherrer Institute, which features an interior cubic volume with each side of length 2.92 m, thus providing an accessible space of 25 m3. The MSR has 87 openings of diameter up to 220 mm for operating the experimental apparatus inside and an intermediate space between the layers for housing sensitive signal processing electronics. The characterization measurements show a remanent magnetic field in the central 1 m3 below 100 pT and a field below 600 pT in the entire inner volume, up to 4 cm to the walls. The quasi-static shielding factor at 0.01 Hz measured with a sinusoidal 2 µT peak-to-peak signal is about 100 000 in all three spatial directions and increases rapidly with frequency to reach 108 above 1 Hz.

Canadian Rheumatology Association Living Guidelines for the Pharmacological Management of Rheumatoid Arthritis With Disease-Modifying Antirheumatic Drugs.

OBJECTIVE: To provide the initial installment of a living guideline that will provide up-to-date guidance on the pharmacological management of patients with rheumatoid arthritis (RA) in Canada. METHODS: The Canadian Rheumatology Association (CRA) formed a multidisciplinary panel composed of rheumatologists, researchers, methodologists, and patients. In this first installment of our living guideline, the panel developed a recommendation for the tapering of biologic and targeted synthetic disease-modifying antirheumatic drug (b/ts DMARD) therapy in patients in sustained remission using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach, including a health equity framework developed for the Canadian RA population. The recommendation was adapted from a living guideline of the Australia & New Zealand Musculoskeletal Clinical Trials Network. RESULTS: In people with RA who are in sustained low disease activity or remission for at least 6 months, we suggest offering stepwise reduction in the dose of b/tsDMARD without discontinuation, in the context of a shared decision, provided patients are able to rapidly access rheumatology care and reestablish their medications if needed. In patients where rapid access to care or reestablishing access to medications is challenging, we conditionally recommend against tapering. A patient decision aid was developed to complement the recommendation. CONCLUSION: This living guideline will provide contemporary RA management recommendations for Canadian practice. New recommendations will be added over time and updated, with the latest recommendation, evidence summaries, and Evidence to Decision summaries available through the CRA website (www.rheum.ca).

A New Frontier in Temporal Bone Imaging: Photon-Counting Detector CT Demonstrates Superior Visualization of Critical Anatomic Structures at Reduced Radiation Dose.

BACKGROUND AND PURPOSE: Photon-counting detector CT is a new technology with a limiting spatial resolution of ≤150 µm. In vivo comparisons between photon-counting detector CT and conventional energy-integrating detector CT are needed to determine the clinical impact of photon counting-detector CT in temporal bone imaging. MATERIALS AND METHODS: Prospectively recruited patients underwent temporal bone CT examinations on an investigational photon-counting detector CT system after clinically indicated temporal bone energy-integrating detector CT. Photon-counting detector CT images were obtained at an average 31% lower dose compared with those obtained on the energy-integrating detector CT scanner. Reconstructed images were evaluated in axial, coronal, and Pöschl planes using the smallest available section thickness on each system (0.4 mm on energy-integrating detector CT; 0.2 mm on photon-counting detector CT). Two blinded neuroradiologists compared images side-by-side and scored them using a 5-point Likert scale. A post hoc reassignment of readers' scores was performed so that the scores reflected photon-counting detector CT performance relative to energy-integrating detector CT. RESULTS: Thirteen patients were enrolled, resulting in 26 image sets (left and right sides). The average patient age was 63.6 [SD, 13.4] years; 7 were women. Images from the photon-counting detector CT scanner were significantly preferred by the readers in all reconstructed planes (P < .001). Photon-counting detector CT was rated superior for the evaluation of all individual anatomic structures, with the oval window (4.79) and incudostapedial joint (4.75) receiving the highest scores on a Likert scale of 1-5. CONCLUSIONS: Temporal bone CT images obtained on a photon-counting detector CT scanner were rated as having superior spatial resolution and better critical structure visualization than those obtained on a conventional energy-integrating detector scanner, even with a substantial dose reduction.

Results From the 2020 Canadian Rheumatology Association's Workforce and Wellness Survey.

OBJECTIVE: The Canadian Rheumatology Association (CRA) launched the Workforce and Wellness Survey to update the Canadian rheumatology workforce characteristics. METHODS: The survey included demographic and practice information, pandemic effects, and the Mini Z survey to assess burnout. French and English survey versions were distributed to CRA members electronically between October 14, 2020, and March 5, 2021. The number of full-time equivalent (FTE) rheumatologists per 75,000 population was estimated from the median proportion of time in clinical practice multiplied by provincial rheumatologist numbers from the Canadian Medical Association. RESULTS: Forty-four percent (183/417) of the estimated practicing rheumatologists (149 adult; 34 pediatric) completed the survey. The median age was 47 years, 62% were female, and 28% planned to retire within the next 5-10 years. Respondents spent a median of 65% of their time in clinical practice. FTE rheumatologists per 75,000 population were 0.62 nationally and ranged between 0.00 and 0.70 in each province/territory. This represents a deficit of 1-78 FTE rheumatologists per province/territory and 194 FTE rheumatologists nationally to meet the CRA's workforce benchmark. Approximately half of survey respondents reported burnout (51%). Women were more likely to report burnout (OR 2.86, 95% CI 1.42-5.93). Older age was protective against burnout (OR 0.95, 95% CI 0.92-0.99). As a result of the pandemic, 97% of rheumatologists reported spending more time engaged in virtual care. CONCLUSION: There is a shortage of rheumatologists in Canada. This shortage may be compounded by the threat of burnout to workforce retention and productivity. Strategies to address these workforce issues are needed urgently.

Evolution of the sheep industry and genetic research in the United States: opportunities for convergence in the twenty-first century.

The continuous development and application of technology for genetic improvement is a key element for advancing sheep production in the United States. The US sheep industry has contracted over time but appears to be at a juncture where a greater utilization of technology can facilitate industry expansion to new markets and address inefficiencies in traditional production practices. Significant transformations include the increased value of lamb in relation to wool, and a downtrend in large-scale operations but a simultaneous rise in small flocks. Additionally, popularity of hair breeds not requiring shearing has surged, particularly in semi-arid and subtropical US environments. A variety of domestically developed composite breeds and newly established technological approaches are now widely available for the sheep industry to use as it navigates these ongoing transformations. These genetic resources can also address long-targeted areas of improvement such as growth, reproduction and parasite resistance. Moderate progress in production efficiency has been achieved by producers who have employed estimated breeding values, but widespread adoption of this technology has been limited. Genomic marker panels have recently shown promise for reducing disease susceptibility, identifying parentage and providing a foundation for marker-assisted selection. As the ovine genome is further explored and genomic assemblies are improved, the sheep research community in the USA can capitalize on new-found information to develop and apply genetic technologies to improve the production efficiency and profitability of the sheep industry.

A Population-Based Approach to Reporting System-Level Performance Measures for Rheumatoid Arthritis Care.

OBJECTIVE: To operationalize and report on nationally endorsed rheumatoid arthritis (RA) performance measures (PMs) using health administrative data for British Columbia (BC), Canada. METHODS: All patients with RA in BC ages ≥18 years were identified between January 1, 1997 and December 31, 2009 using health administrative data and followed until December 2014. PMs tested include: the percentage of incident patients with ≥1 rheumatologist visit within 365 days; the percentage of prevalent patients with ≥1 rheumatologist visit per year; the percentage of prevalent patients dispensed disease-modifying antirheumatic drug (DMARD) therapy; and time from RA diagnosis to DMARD therapy. Measures were reported on patients seen by rheumatologists, and in the total population. RESULTS: The cohort included 38,673 incident and 57,922 prevalent RA cases. The percentage of patients seen by a rheumatologist within 365 days increased over time (35% in 2000 to 65% in 2009), while the percentage of RA patients under the care of a rheumatologist seen yearly declined (79% in 2001 to 39% in 2014). The decline was due to decreasing visit rates with increasing follow-up time rather than calendar effect. The percentage of RA patients dispensed a DMARD was suboptimal over follow-up (37% in 2014) in the total population but higher (87%) in those under current rheumatologist care. The median time to DMARD in those seen by a rheumatologist improved from 49 days in 2000 to 23 days in 2009, with 34% receiving treatment within the 14-day benchmark. CONCLUSION: This study describes the operationalization and reporting of national PMs using administrative data and identifies gaps in care to further examine and address.

Advances in understanding and in multi-disciplinary methodology used to assess lipid regulation of signalling cascades from the cancer cell plasma membrane.

The lipid bilayer is a functional component of cells, forming a stable platform for the initiation of key biological processes, including cell signalling. There are distinct changes in the lipid composition of cell membranes during oncogenic transformation resulting in aberrant activation and inactivation of signalling transduction pathways. Studying the role of the cell membrane in cell signalling is challenging, since techniques are often limited to by timescale, resolution, sensitivity, and averaging. To overcome these limitations, combining 'computational', 'wet-lab' and 'semi-dry' approaches offers the best opportunity to resolving complex biological processes involved in membrane organisation. In this review, we highlight analytical tools that have been applied for the study of cell signalling initiation from the cancer cell membranes through computational microscopy, biological assays, and membrane biophysics. The cancer therapeutic potential of extracellular membrane-modulating agents, such as cholesterol-reducing agents is also discussed, as is the need for future collaborative inter-disciplinary research for studying the role of the cell membrane and its components in cancer therapy.

Is treat-to-target really working in rheumatoid arthritis? a longitudinal analysis of a cohort of patients treated in daily practice (RA BIODAM).

OBJECTIVES: To investigate whether following a treat-to-target (T2T)-strategy in daily clinical practice leads to more patients with rheumatoid arthritis (RA) meeting the remission target. METHODS: RA patients from 10 countries starting/changing conventional synthetic or biological disease-modifying anti-rheumatic drugs were assessed for disease activity every 3 months for 2 years (RA BIODAM (BIOmarkers of joint DAMage) cohort). Per visit was decided whether a patient was treated according to a T2T-strategy with 44-joint disease activity score (DAS44) remission (DAS44 <1.6) as the target. Sustained T2T was defined as T2T followed in ≥2 consecutive visits. The main outcome was the achievement of DAS44 remission at the subsequent 3-month visit. Other outcomes were remission according to 28-joint disease activity score-erythrocyte sedimentation rate (DAS28-ESR), Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI) and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean definitions. The association between T2T and remission was tested in generalised estimating equations models. RESULTS: In total 4356 visits of 571 patients (mean (SD) age: 56 (13) years, 78% female) were included. Appropriate application of T2T was found in 59% of the visits. T2T (vs no T2T) did not yield a higher likelihood of DAS44 remission 3 months later (OR (95% CI): 1.03 (0.92 to 1.16)), but sustained T2T resulted in an increased likelihood of achieving DAS44 remission (OR: 1.19 (1.03 to 1.39)). Similar results were seen with DAS28-ESR remission. For more stringent definitions (CDAI, SDAI and ACR/EULAR Boolean remission), T2T was consistently positively associated with remission (OR range: 1.16 to 1.29), and sustained T2T had a more pronounced effect on remission (OR range: 1.49 to 1.52). CONCLUSION: In daily clinical practice, the correct application of a T2T-strategy (especially sustained T2T) in patients with RA leads to higher rates of remission.

Genetic structure and admixture in sheep from terminal breeds in the United States.

Selection for performance in diverse production settings has resulted in variation across sheep breeds worldwide. Although sheep are an important species to the United States, the current genetic relationship among many terminal sire breeds is not well characterized. Suffolk, Hampshire, Shropshire and Oxford (terminal) and Rambouillet (dual purpose) sheep (n = 248) sampled from different flocks were genotyped using the Applied Biosystems Axiom Ovine Genotyping Array (50K), and additional Shropshire sheep (n = 26) using the Illumina Ovine SNP50 BeadChip. Relationships were investigated by calculating observed heterozygosity, inbreeding coefficients, eigenvalues, pairwise Wright's FST estimates and an identity by state matrix. The mean observed heterozygosity for each breed ranged from 0.30 to 0.35 and was consistent with data reported in other US and Australian sheep. Suffolk from two different regions of the United States (Midwest and West) clustered separately in eigenvalue plots and the rectangular cladogram. Further, divergence was detected between Suffolk from different regions with Wright's FST estimate. Shropshire animals showed the greatest divergence from other terminal breeds in this study. Admixture between breeds was examined using admixture, and based on cross-validation estimates, the best fit number of populations (clusters) was K = 6. The greatest admixture was observed within Hampshire, Suffolk, and Shropshire breeds. When plotting eigenvalues, US terminal breeds clustered separately in comparison with sheep from other locations of the world. Understanding the genetic relationships between terminal sire breeds in sheep will inform us about the potential applicability of markers derived in one breed to other breeds based on relatedness.

Adherence to Treat-to-target Management in Rheumatoid Arthritis and Associated Factors: Data from the International RA BIODAM Cohort.

OBJECTIVE: Compelling evidence supports a treat-to-target (T2T) strategy for optimal outcomes in rheumatoid arthritis (RA). There is limited knowledge regarding the factors that impede implementation of T2T, particularly in a setting where adherence to T2T is protocol-specified. We aimed to assess clinical factors that associate with failure to adhere to T2T. METHODS: Patients with RA from 10 countries who were starting or changing conventional synthetic disease-modifying antirheumatic drugs and/or starting tumor necrosis factor inhibitors were followed for 2 years. Participating physicians were required per protocol to adhere to the T2T strategy. Factors influencing adherence to T2T low disease activity (T2T-LDA; 44-joint count Disease Activity Score ≤ 2.4) were analyzed in 2 types of binomial generalized estimating equations models: (1) including only baseline features (baseline model); and (2) modeling variables that inherently vary over time as such (longitudinal model). RESULTS: A total of 571 patients were recruited and 439 (76.9%) completed 2-year followup. Failure of adherence to T2T-LDA was noted in 1765 visits (40.5%). In the baseline multivariable model, a high number of comorbidities (OR 1.10, 95% CI 1.02-1.19), smoking (OR 1.32, 95% CI 1.08-1.63) and high number of tender joints (OR 1.03, 95% CI 1.02-1.04) were independently associated with failure to implement T2T, while anticitrullinated protein antibody/rheumatoid factor positivity (OR 0.63, 95% CI 0.50-0.80) was a significant facilitator of T2T. Results were similar in the longitudinal model. CONCLUSION: Lack of adherence to T2T in the RA BIODAM cohort was evident in a substantial proportion despite being a protocol requirement, and this could be predicted by clinical features. [Rheumatoid Arthritis (RA) BIODAM cohort; ClinicalTrials.gov: NCT01476956].