Critical impact of patient knowledge and bone density testing on starting osteoporosis treatment after fragility fracture: secondary analyses from two controlled trials.

UNLABELLED: Most patients are not treated for osteoporosis after their fragility fracture "teachable moment." Among almost 400 consecutive wrist fracture patients, we determined that better-than-average osteoporosis knowledge (adjusted odds = 2.6) and BMD testing (adjusted odds = 6.5) were significant modifiable facilitators of bisphosphonate treatment while male sex, working outside the home, and depression were major barriers. INTRODUCTION: In the year following fragility fracture, fewer than one quarter of patients are treated for osteoporosis. Although much is known regarding health system and provider barriers and facilitators to osteoporosis treatment, much less is understood about modifiable patient-related factors. METHODS: Older patients with wrist fracture not treated for osteoporosis were enrolled in trials that compared a multifaceted intervention with usual care controls. Baseline data included a test of patient osteoporosis knowledge. We then determined baseline factors that independently predicted starting bisphosphonate treatment within 1 year. RESULTS: Three hundred seventy-four patients were enrolled; mean age 64 years, 78 % women, 90 % white, and 54 % with prior fracture. Within 1 year, 86 of 374 (23 %) patients were treated with bisphosphonates. Patients who were treated had better osteoporosis knowledge at baseline (70 % correct vs 57 % for untreated, p < 0.001) than patients who remained untreated; conversely, untreated patients were more likely to be male, still working, and report depression. In fully adjusted models, osteoporosis knowledge was independently associated with starting bisphosphonates (adjusted OR 2.6, 95 %CI 1.3-5.3). Obtaining a BMD test (aOR 6.5, 95 %CI 3.4-12.2) and abnormal BMD results (aOR 34.5, 95 %CI 16.8-70.9) were strongly associated with starting treatment. CONCLUSIONS: The most important modifiable facilitators of osteoporosis treatment in patients with fracture were knowledge and BMD testing. Specifically targeting these two patient-level factors should improve post-fracture treatment rates.

A prototype low-cost secondary standard calorimeter for reference dosimetry with ultra-high pulse dose rates.

OBJECTIVES: Ultra-high pulse dose rate modalities present significant dosimetry challenges for ionisation chambers due to significant ion recombination. Conversely, calorimeters are ideally suited to measure high dose, short duration dose deliveries and this work describes a simple calorimeter as an alternative dosemeter for use in the clinic. METHODS: Calorimeters were constructed featuring a disc-shaped core and single sensing thermistor encased in a 3D-printed body shaped like a Roos ionisation chamber. The thermistor forms one arm of a DC Wheatstone bridge, connected to a standard DMM. The bridge-out-of-balance voltage was calibrated in terms of temperature. A graphite-core calorimeter was calibrated in terms of absorbed dose to water (J/kg) in Co-60 and conventional 6, 10 and 15 MV X-rays. Similarly, an aluminium-core calorimeter was calibrated in a conventional 20 MeV electron beam and tested in a research high dose per pulse 6 MeV electron beam. RESULTS: Calorimeters were successfully calibrated in terms of absorbed dose to water in conventional radiotherapy beams at approximately 5 Gy/min with an estimated uncertainty of ±2-2.5% (k = 2), and performed similarly in a 6 MeV electron beam delivering approximately 180 Gy/s. CONCLUSIONS: A simple, low-cost calorimeter traceably calibrated to existing primary standards of absorbed dose could be used as a secondary standard for dosimetry for ultra-high pulse dose rates in the clinic. ADVANCES IN KNOWLEDGE: Secondary standard calorimeters for routine measurements are not available commercially; this work presents the basis of a simple, low-cost solution for reference dosimetry for ultra-high pulse dose rate beams.

Cost-effectiveness of a multifaceted intervention to improve quality of osteoporosis care after wrist fracture.

UNLABELLED: In a randomized trial, a multifaceted intervention tripled rates of osteoporosis treatment in older patients with wrist fracture. An economic analysis of the trial now demonstrates that the intervention tested "dominates" usual care: over a lifetime horizon, it reduces fracture, increases quality-adjusted life years, and saves the healthcare system money. INTRODUCTION: In a randomized trial (N = 272), we reported a multifaceted quality improvement intervention directed at older patients and their physicians could triple rates of osteoporosis treatment within 6 months of a wrist fracture when compared with usual care (22% vs 7%). Alongside the trial, we conducted an economic evaluation. METHODS: Using 1-year outcome data from our trial and micro-costing time-motion studies, we constructed a Markov decision-analytic model to determine cost-effectiveness of the intervention compared with usual care over the patients' remaining lifetime. We took the perspective of third-party healthcare payers. In the base case, costs and benefits were discounted at 3% and expressed in 2006 Canadian dollars. One-way deterministic and probabilistic sensitivity analyses were conducted. RESULTS: Median age of patients was 60 years, 77% were women, and 72% had low bone mineral density (BMD). The intervention cost $12 per patient. Compared with usual care, the intervention strategy was dominant: for every 100 patients receiving the intervention, three fractures (one hip fracture) would be prevented, 1.1 quality-adjusted life year gained, and $26,800 saved by the healthcare system over their remaining lifetime. The intervention dominated usual care across numerous one-way sensitivity analyses: with respect to cost, the most influential parameter was drug price; in terms of effectiveness, the most influential parameter was rate of BMD testing. The intervention was cost saving in 80% of probabilistic model simulations. CONCLUSIONS: For outpatients with wrist fractures, our multifaceted osteoporosis intervention was cost-effective. Healthcare systems implementing similar interventions should expect to save money, reduce fractures, and gain quality-adjusted life expectancy.

Nurse case-manager vs multifaceted intervention to improve quality of osteoporosis care after wrist fracture: randomized controlled pilot study.

UNLABELLED: Few outpatients with fractures are treated for osteoporosis in the years following fracture. In a randomized pilot study, we found a nurse case-manager could double rates of osteoporosis testing and treatment compared with a proven efficacious quality improvement strategy directed at patients and physicians (57% vs 28% rates of appropriate care). INTRODUCTION: Few patients with fractures are treated for osteoporosis. An intervention directed at wrist fracture patients (education) and physicians (guidelines, reminders) tripled osteoporosis treatment rates compared to controls (22% vs 7% within 6 months of fracture). More effective strategies are needed. METHODS: We undertook a pilot study that compared a nurse case-manager to the multifaceted intervention using a randomized trial design. The case-manager counseled patients, arranged bone mineral density (BMD) tests, and prescribed treatments. We included controls from our first trial who remained untreated for osteoporosis 1-year post-fracture. Primary outcome was bisphosphonate treatment and secondary outcomes were BMD testing, appropriate care (BMD test-treatment if bone mass low), and costs. RESULTS: Forty six patients untreated 1-year after wrist fracture were randomized to case-manager (n = 21) or multifaceted intervention (n = 25). Median age was 60 years and 68% were female. Six months post-randomization, 9 (43%) case-managed patients were treated with bisphosphonates compared with 3 (12%) multifaceted intervention patients (relative risk [RR] 3.6, 95% confidence intervals [CI] 1.1-11.5, p = 0.019). Case-managed patients were more likely than multifaceted intervention patients to undergo BMD tests (81% vs 52%, RR 1.6, 95%CI 1.1-2.4, p = 0.042) and receive appropriate care (57% vs 28%, RR 2.0, 95%CI 1.0-4.2, p = 0.048). Case-management cost was $44 (CDN) per patient vs $12 for the multifaceted intervention. CONCLUSIONS: A nurse case-manager substantially increased rates of appropriate testing and treatment for osteoporosis in patients at high-risk of future fracture when compared with a multifaceted quality improvement intervention aimed at patients and physicians. Even with case-management, nearly half of patients did not receive appropriate care. TRIAL REGISTRY: clinicaltrials.gov identifier: NCT00152321.

Multi-institutional dosimetric delivery assessment of intracranial stereotactic radiosurgery on different treatment platforms.

BACKGROUND AND PURPOSE: Assessment of dosimetric accuracy of radiosurgery on different treatment platforms. MATERIAL AND METHODS: Thirty-three single fraction treatment plans were assessed at thirty centres using an anthropomorphic head phantom with target and brainstem structures. The target being a single irregular shaped target, ~8 cc, 10 mm from the brainstem. The phantom was "immobilised", scanned, planned and treated following the local protocols. EBT-XD films and alanine pellets were used to measure absolute dose, inside both the target and the brainstem, and compared with TPS predicted dose distributions. RESULTS: PTV alanine measurements from gantry-based linacs showed a median percentage difference to the TPS of 0.65%. Cyberknife (CK) had the highest median difference of 2.3% in comparison to the other platforms. GammaKnife (GK) showed the smallest median of 0.3%. Similar trends were observed in the OAR with alanine measurements showing median percentage differences of1.1%, 2.0% and 0.4%, for gantry-based linacs, CK and GK respectively. All platforms showed comparable gamma passing rates between axial and sagittal films. CONCLUSIONS: This comparison has highlighted the dosimetric variation between measured and TPS calculated dose for each delivery platform. The results suggest that clinically acceptable agreement with the predicted dose distributions is achievable by all treatment delivery systems.

PANLAR consensus statement on biosimilars.

INTRODUCTION: Biologics have improved the treatment of rheumatic diseases, resulting in better outcomes. However, their high cost limits access for many patients in both North America and Latin America. Following patent expiration for biologicals, the availability of biosimilars, which typically are less expensive due to lower development costs, provides additional treatment options for patients with rheumatic diseases. The availability of biosimilars in North American and Latin American countries is evolving, with differing regulations and clinical indications. OBJECTIVE: The objective of the study was to present the consensus statement on biosimilars in rheumatology developed by Pan American League of Associations for Rheumatology (PANLAR). METHODS: Using a modified Delphi process approach, the following topics were addressed: regulation, efficacy and safety, extrapolation of indications, interchangeability, automatic substitution, pharmacovigilance, risk management, naming, traceability, registries, economic aspects, and biomimics. Consensus was achieved when there was agreement among 80% or more of the panel members. Three Delphi rounds were conducted to reach consensus. Questionnaires were sent electronically to panel members and comments about each question were solicited. RESULTS: Eight recommendations were formulated regarding regulation, pharmacovigilance, risk management, naming, traceability, registries, economic aspects, and biomimics. CONCLUSION: The recommendations highlighted that, after receiving regulatory approval, pharmacovigilance is a fundamental strategy to ensure safety of all medications. Registries should be employed to monitor use of biosimilars and to identify potential adverse effects. The price of biosimilars should be significantly lower than that of reference products to enhance patient access. Biomimics are not biosimilars and, if they are to be marketed, they must first be evaluated and approved according to established regulatory pathways for novel biopharmaceuticals. KEY POINTS: • Biologics have improved the treatment of rheumatic diseases. • Their high cost limits access for many patients in both North America and Latin America. • Biosimilars typically are less expensive, providing additional treatment options for patients with rheumatic diseases. • PANLAR presents its consensus on biosimilars in rheumatology.

Correction to: PANLAR consensus statement on biosimilars.

The two co-authors of the mentioned above article were incorrect. The correct are authors should have been "P. A. Beltrán" instead of "P. A. B. Roa" and "J. F. Diaz-Coto" instead of "L. Diaz Soto".

Hot joints: myth or reality? A thermographic joint assessment of inflammatory arthritis patients.

Rheumatoid arthritis is a common inflammatory disease that causes destruction of joints. Accurate recognition of active disease has significant implications in determining appropriate treatment; however, there is significant inter-rater variability in clinical joint assessment. This study aimed to assess the utility of thermographic imaging in the evaluation of inflammatory arthritis activity as an adjunct to clinical assessment. This was a cross-sectional study of 79 subjects recruited from the University of Alberta Outpatient Rheumatology clinic comparing the hand joints of 49 patients with rheumatoid arthritis (RA) diagnosed by American College of Rheumatology (ACR) criteria to 30 healthy volunteers. Convenience sampling of consecutive RA patients was undertaken. The effect of clinical assessment (HAQ and DAS-28) on joint temperature was evaluated using a linear mixed effect model. A thermography camera, FLIR T300 model, 30 Hz, was used to obtain both thermographic and digital images on subjects. Pearson's correlation coefficient was used to assess the correlation of clinical assessments and average joint temperature averaged over all joints. Thermographic analysis did not associate with clinical measures of disease activity. In RA patients, there was no statistically significant relationship between joint temperature and clinical assessment of disease activity including Health Assessment Questionnaire (coefficient estimate - 0.54, p = 0.056), swollen joints (coefficient estimate - 0.09, p = 0.238), or serologic markers of inflammation such as CRP (coefficient estimate - 0.006, p = 0.602) and ESR (coefficient estimate - 0.01, p = 0.503). Evaluation of disease activity requires a multifaceted approach that includes clinical assessment and appropriate imaging. There may be a role for thermography in assessment of larger joints; however, it does not appear to be an effective modality for the small joints of the hand.

Adaptation and validation of a commercial head phantom for cranial radiosurgery dosimetry end-to-end audit.

OBJECTIVE: To adapt and validate an anthropomorphic head phantom for use in a cranial radiosurgery audit. METHODS: Two bespoke inserts were produced for the phantom: one for providing the target and organ at risk for delineation and the other for performing dose measurements. The inserts were tested to assess their positional accuracy. A basic treatment plan dose verification with an ionization chamber was performed to establish a baseline accuracy for the phantom and beam model. The phantom and inserts were then used to perform dose verification measurements of a radiosurgery plan. The dose was measured with alanine pellets, EBT extended dose film and a plastic scintillation detector (PSD). RESULTS: Both inserts showed reproducible positioning (±0.5 mm) and good positional agreement between them (±0.6 mm). The basic treatment plan measurements showed agreement to the treatment planning system (TPS) within 0.5%. Repeated film measurements showed consistent gamma passing rates with good agreement to the TPS. For 2%-2 mm global gamma, the mean passing rate was 96.7% and the variation in passing rates did not exceed 2.1%. The alanine pellets and PSD showed good agreement with the TPS (-0.1% and 0.3% dose difference in the target) and good agreement with each other (within 1%). CONCLUSION: The adaptations to the phantom showed acceptable accuracies. The presence of alanine and PSD do not affect film measurements significantly, enabling simultaneous measurements by all three detectors. Advances in knowledge: A novel method for thorough end-to-end test of radiosurgery, with capability to incorporate all steps of the clinical pathway in a time-efficient and reproducible manner, suitable for a national audit.

Osteoporosis follow-up after wrist fractures following minor trauma.

BACKGROUND: Patients presenting with low-trauma wrist fractures are an ideal target population for early case finding of osteoporosis. We decided to investigate whether this early detection occurred in practice. METHODS: This study was conducted at a single center in Edmonton, Alberta. A structured interview format was used to contact 112 (72%) of 156 patients older than 40 years who were diagnosed as having an atraumatic fracture of the distal radius/ulna from April 1997 to March 1998 and from January 1999 to February 1999. Information on osteoporosis follow-up and drug therapy was obtained from the patient. RESULTS: The time between fracture and telephone interview ranged from 6 months to 3 years, with the majority of the sample being interviewed at least 1 year after fracture. Of the 112 patients in this study, 44 had sustained previous fractures, 17 of which had occurred at the wrist, vertebrae, or hip. Sixteen patients in the sample had already sustained a subsequent clinical fracture before our telephone contact. Thirty-two patients had received treatment for osteoporosis before fracture. A further 24 patients (21%) had undergone osteoporosis follow-up after fracture. After fracture, 42 (38%) of all patients were receiving either hormone replacement therapy or using a bisphosphonate. CONCLUSIONS: Only 50% of the study population had received osteoporosis follow-up after fracture. Few patients had any change in their medication use after fracture. The findings in this study population suggest that recognition of the potential for osteoporosis in such patients is inadequate. Given the magnitude of this public health care problem, it is clear that attention to case finding and treatment of osteoporosis should be increased.

Inter-departmental dosimetry audits - development of methods and lessons learned.

External dosimetry audits give confidence in the safe and accurate delivery of radiotherapy. In the United Kingdom, such audits have been performed for almost 30 years. From the start, they included clinically relevant conditions, as well as reference machine output. Recently, national audits have tested new or complex techniques, but these methods are then used in regional audits by a peer-to-peer approach. This local approach builds up the radiotherapy community, facilitates communication, and brings synergy to medical physics.

Radiotherapy dosimetry audit: three decades of improving standards and accuracy in UK clinical practice and trials.

Dosimetry audit plays an important role in the development and safety of radiotherapy. National and large scale audits are able to set, maintain and improve standards, as well as having the potential to identify issues which may cause harm to patients. They can support implementation of complex techniques and can facilitate awareness and understanding of any issues which may exist by benchmarking centres with similar equipment. This review examines the development of dosimetry audit in the UK over the past 30 years, including the involvement of the UK in international audits. A summary of audit results is given, with an overview of methodologies employed and lessons learnt. Recent and forthcoming more complex audits are considered, with a focus on future needs including the arrival of proton therapy in the UK and other advanced techniques such as four-dimensional radiotherapy delivery and verification, stereotactic radiotherapy and MR linear accelerators. The work of the main quality assurance and auditing bodies is discussed, including how they are working together to streamline audit and to ensure that all radiotherapy centres are involved. Undertaking regular external audit motivates centres to modernize and develop techniques and provides assurance, not only that radiotherapy is planned and delivered accurately but also that the patient dose delivered is as prescribed.

Low-dose methotrexate kinetics in arthritis.

Twelve patients with either rheumatoid or psoriatic arthritis were injected with a 10-mg bolus dose of methotrexate (MTX) either intramuscularly (n = 6) or intravenously (n = 6) and the MTX concentration in their sera was determined by radioimmunoassay. MTX concentration--time data fitted triexponential equations. Doses injected intramuscularly were rapidly and completely absorbed. There were no significant intergroup differences in drug mean t 1/2, volume of distribution, and total body clearance. In nine patients serum MTX concentrations remained above the suggested critical level of 0.01 mumol throughout the 24-hr study irrespective of the route of administration, but MTX did not cumulate in the serum. We conclude that the behavior of low doses of MTX in patients with arthritis closely resembles the pattern in patients receiving intermediate and high doses for the treatment of neoplasia.

Penicillamine-induced myasthenia gravis associated with antibodies to acetylcholine receptor.

A woman with rheumatoid arthritis was treated with penicillamine and developed myasthenia gravis. This drug-induced disease was associated with characteristic autoantibodies to acetycholine receptor. After discontinuing the drug, her symptoms improved and the antibody titers fell. Penicillamine is now being used much more frequently in the treatment of rheumatoid arthritis and it is likely that this complication will become more prevalent.

Factors influencing the autologous mixed leukocyte reaction in normal subjects.

The proliferative response of T cells to autologous non-T cells (autologous mixed leukocyte reaction, AMLR) varies with the duration of incubation as well as the concentration and nature of the stimulator cells. The peak response was generally found on days 6, 7 or 8 of incubation, but with unseparated non-T cells, as well as varying in different individuals this varied in the same individual on different days. Removal of adherent cells from the stimulator population increased the magnitude of the peak response and improved day-to-day consistency both in size of peak response and in the duration of incubation required. Adherent cells were poor stimulators. Some of the variability in AMLR in normals and the differences between normal and disease subjects may relate to inclusion of an adherent cell population in the test and to the use of a fixed time period for incubation.

Arginase production by peritoneal macrophages: a new assay.

The arginase activity of murine mononuclear cells was assessed with a new highly sensitive radioassay. Adherent mononuclear cells obtained by peritoneal lavage from normal mice contain significant quantities of enzyme. This was released in culture and continued synthesis could be blocked with cycloheximide. Arginase activity was not found in adherent or non-adherent mononuclear cells from the spleen. Peritoneal cells obtained from mice infected with P. berghei or from mice injected with LPS intraperitoneally had higher arginase activity than cells from control mice.

Cell mediated immunity to herpes simplex in man. IV. A correlation of lymphocyte stimulation and inhibition of leukocyte migration.

The cell mediated immune response to herpes simplex virus was assessed by a modification of the leukocyte migration inhibition test, developed to increase its sensitivity and correlated with the in vitro stimulation of lymphocytes. The introduction of a preincubation step allowed us to demonstrate significant inhibition of leukocyte migration in 15 out of 24 subjects susceptible to recurrent herpes labialis. This was not present in any of the 10 subjects without such infections. However lymphocytes from all 24 subjects demonstrated stimulation in response to herpes virus antigen. The degrees of lymphocyte stimulation and migration inhibition in the susceptible subjects were well correlated and do not support the suggestion that there is a focal defect in this aspect of the cell mediated immune response to herpes simplex virus in those patients.

A follow-up study of 48 patients with Reiter's syndrome.

A follow-up study of 48 patients with Reiter's syndrome was carried out in an attempt to clarify the clinical course of the disease. The mean age at the onset of Reiter's syndrome was 27.1 years (range 15 to 52 years) and when seen at follow-up 32.5 years (range 19 to 58 years). The average time from the onset of the first attack of peripheral arthritis to the time of follow-up was six and a half years (range 0.5 to 27 years). Only three patients had diarrhea prior to the onset of Reiter's syndrome. At follow-up 22 per cent of the patients were asymptomatic, 24 per cent had recurrent minor symptoms, 24 per cent had recurrent moderate symptoms, and 30 per cent had recurrent major symptoms. However, even in the last group, all patients were in functional classes 1 or 2 between the flares of disease. No patients in the series were in functional class 3 or 4, and 30 per cent were in class 1.

The scintigraphic investigation of sacroiliac disease.

Bone scintigraphs obtained with both Technetium-99m polyphosphate and Technetium-99m pyrophosphate have been abnormal at the sacroiliac joints of 44 patients with definite ankylosing spondylitis (AS). Because of the normal registration of the sacroiliac joints on bone scintigraphy, it has been necessary to develop a profile-scan technique to quantify the abnormality that proves to be significantly different from the normal finding. In 17 patients with a strong clinical suspicion of AS but normal radiographs, the sacroiliac joints have frequently been abnormal. This finding is meaningful because there is a common occurence in this group of the histocompatibility antigen HL A-B27, known to be a marker of AS. We also note the frequency of abnormal sacroiliac scinitigrams in 26 patients with rheumatoid arthritis and in a group of other diseases-Crohn's disease, uveitis, psoriasis, ulcerative colitis, and Reiter's disease-all of which share some of the manifestations of AS.

Scintigraphic findings in ankylosing spondylitis.

A prospective study of bone scintigraphic findings has been carried out in 63 patients, firmly diagnosed as having ankylosing spondylitis. In addition to abnormal uptake of the radiotracer at the sacroiliac joints, a peripheral arthropathy has been a common finding, particularly in the proximal joints, occurring in up to 50% of patients. Increased uptake of radiotracer in the spine has also been found both diffusely and focally. Focal increases have been noted at the apophyseal joints in 40% of patients and in three patients with a sterile intervertebral diskitis, an unusual complication of this disease only diagnosed in two patients after bone scintigraphy.