Safety and effectiveness of adalimumab in a clinical setting that reflects Canadian standard of care for the treatment of rheumatoid arthritis (RA): Results from the CanACT study

<p>Abstract</p> <p>Background</p> <p>This multicenter, open-label, prospective, single cohort study evaluated the effectiveness and safety of adalimumab in a clinical setting reflecting the Canadian standard of care for the treatment of patients with rheumatoid arthritis (RA).</p> <p>Methods</p> <p>Patients ≥ 18 years of age with a history of active RA ≥ 3 months and fulfilling Canadian requirements for biological therapy received adalimumab 40 mg subcutaneously every other week for 12 weeks. Pre-study DMARD treatment regimens, corticosteroids, or NSAIDs were allowed throughout the study. The primary effectiveness outcome measure was the mean change in 28-joint disease activity score (DAS28) from baseline to Week 12. Secondary measures included the proportion of patients achieving joint remission (DAS28 < 2.6) and low-disease activity (DAS28 < 3.2) at Week 12, and European League Against Rheumatism (EULAR: moderate and good) and American College of Rheumatology (ACR: ACR20, 50, and 70) responses, as well as responses in ACR core components at Weeks 4, 8, and 12. Subgroup analysis included a comparison of patients naïve to biological DMARD (BDMARD) therapy versus BDMARD-experienced patients. Safety was assessed in terms of adverse and serious adverse events.</p> <p>Results</p> <p>A total of 879 patients (mean disease duration > 12 years) were enrolled; 772 (87.9%) completed the 12-week period. Adalimumab treatment was associated with rapid and sustained improvements in the signs and symptoms of RA. Significant improvements in mean DAS28 score were observed as early as Week 4. After 12 weeks of adalimumab treatment, 15.3% and 28.9% of patients achieved clinical remission and low-disease activity, respectively. Similarly, significant improvements in ACR core components were observed as early as Week 4, with continued improvements occurring through 12 weeks. Patients naïve to BDMARD therapy demonstrated numerically greater clinical responses when compared with patients who had experienced prior BDMARD therapy, although both subgroups were associated with significant improvements from baseline. The rates and types of adverse events, as well as the results of laboratory measures, demonstrated that adalimumab was generally safe and well-tolerated.</p> <p>Conclusions</p> <p>This study demonstrated that, under conditions reflective of the normal clinical practice in Canada, adalimumab is an effective and safe treatment for patients with RA.</p> <p>Trial registration</p> <p><a href="http://www.clinicaltrials.gov/ct2/show/NCT00649545">NCT00649545</a>.</p

Relationship between knee and ankle degeneration in a population of organ donors

<p>Abstract</p> <p>Background</p> <p>Osteoarthritis (OA) is a progressive degenerative condition of synovial joints in response to both internal and external factors. The relationship of OA in one joint of an extremity to another joint within the same extremity, or between extremities, has been a topic of interest in reference to the etiology and/or progression of the disease.</p> <p>Methods</p> <p>The prevalence of articular cartilage lesions and osteophytes, characteristic of OA, was evaluated through visual inspection and grading in 1060 adult knee/tali pairs from 545 cadaveric joint donors.</p> <p>Results</p> <p>Joint degeneration increased more rapidly with age for the knee joint, and significantly more knee joints displayed more severe degeneration than ankle joints from as early as the third decade. Women displayed more severe knee degeneration than did men. Severe ankle degeneration did not exist in the absence of severe knee degeneration. The effect of weight on joint degeneration was joint-specific whereby weight had a significantly greater effect on the knee. Ankle grades increasingly did not match within a donor as the grade of degeneration in either the left or the right knee increased.</p> <p>Conclusions</p> <p>Gender and body type have a greater effect on knee joint integrity as compared to the ankle, suggesting that knees are more prone to internal causative effects of degeneration. We hypothesize that the greater variability in joint health between joints within an individual as disease progresses from normal to early signs of degeneration may be a result of mismatched limb kinetics, which in turn might lead to joint disease progression.</p

Integration of a nationally procured electronic health record system into user work practices

BACKGROUND: Evidence suggests that many small- and medium-scale Electronic Health Record (EHR) implementations encounter problems, these often stemming from users' difficulties in accommodating the new technology into their work practices. There is the possibility that these challenges may be exacerbated in the context of the larger-scale, more standardised, implementation strategies now being pursued as part of major national modernisation initiatives. We sought to understand how England's centrally procured and delivered EHR software was integrated within the work practices of users in selected secondary and specialist care settings. METHODS: We conducted a qualitative longitudinal case study-based investigation drawing on sociotechnical theory in three purposefully selected sites implementing early functionality of a nationally procured EHR system. The complete dataset comprised semi-structured interview data from a total of 66 different participants, 38.5 hours of non-participant observation of use of the software in context, accompanying researcher field notes, and hospital documents (including project initiation and lessons learnt reports). Transcribed data were analysed thematically using a combination of deductive and inductive approaches, and drawing on NVivo8 software to facilitate coding. RESULTS: The nationally led "top-down" implementation and the associated focus on interoperability limited the opportunity to customise software to local needs. Lack of system usability led users to employ a range of workarounds unanticipated by management to compensate for the perceived shortcomings of the system. These had a number of knock-on effects relating to the nature of collaborative work, patterns of communication, the timeliness and availability of records (including paper) and the ability for hospital management to monitor organisational performance. CONCLUSIONS: This work has highlighted the importance of addressing potentially adverse unintended consequences of workarounds associated with the introduction of EHRs. This can be achieved with customisation, which is inevitably somewhat restricted in the context of attempts to implement national solutions. The tensions and potential trade-offs between achieving large-scale interoperability and local requirements is likely to be the subject of continuous debate in England and beyond with no easy answers in sight

Direct measurement of the intrinsic electric dipole moment in pear-shaped thorium-228

Atomic nuclei with certain combinations of proton and neutron numbers can adopt reflection-asymmetric or octupole-deformed shapes at low excitation energy. These nuclei present a promising avenue in the search for a permanent atomic electric dipole moment—the existence of which has implications for physics beyond the Standard Model of particle physics. Theoretical studies have suggested that certain thorium isotopes may have large octupole deformation. However, due to experimental challenges, the extent of the octupole collectivity in the low-energy states in these thorium nuclei has not yet been demonstrated. Here, we report measurements of the lifetimes of low-energy states in 228Th (Z = 90) with a direct electronic fast-timing technique, the mirror symmetric centroid difference method. From lifetime measurements of the low-lying Jπ = 1− and Jπ = 3− states, the E1 transition probability rates and the intrinsic dipole moment are determined. The results are in agreement with those of previous theoretical calculations, allowing us to estimate the extent of the octupole deformation of 228Th. This study indicates that the nuclei 229Th and 229Pa (Z = 91) may be good candidates for the search for a permanent atomic electric dipole moment

Managing hyperemesis gravidarum: a multimodal challenge

Up to 90% of pregnant women experience nausea and vomiting. When prolonged or severe, this is known as hyperemesis gravidarum (HG), which can, in individual cases, be life threatening. In this article the aetiology, diagnosis and treatment strategies will be presented based on a selective literature review. Treatment strategies range from outpatient dietary advice and antiemetic drugs to hospitalization and intravenous (IV) fluid replacement in persistent or severe cases. Alternative methods, such as acupuncture, are not yet evidence based but sometimes have a therapeutic effect

Prolonged survival in patients with breast cancer and a history of brain metastases: results of a preplanned subgroup analysis from the randomized phase III BEACON trial

Purpose: Conventional chemotherapy has limited activity in patients with breast cancer and brain metastases (BCBM). Etirinotecan pegol (EP), a novel long-acting topoisomerase-1 inhibitor, was designed using advanced polymer technology to preferentially accumulate in tumor tissue including brain metastases, providing sustained cytotoxic SN38 levels. Methods: The phase 3 BEACON trial enrolled 852 women with heavily pretreated locally recurrent or metastatic breast cancer between 2011 and 2013. BEACON compared EP with treatment of physician’s choice (TPC; eribulin, vinorelbine, gemcitabine, nab-paclitaxel, paclitaxel, ixabepilone, or docetaxel) in patients previously treated with anthracycline, taxane, and capecitabine, including those with treated, stable brain metastases. The primary endpoint, overall survival (OS), was assessed in a pre-defined subgroup of BCBM patients; an exploratory post hoc analysis adjusting for the diagnosis-specific graded prognostic assessment (GPA) index was also conducted. Results: In the trial, 67 BCBM patients were randomized (EP, n = 36; TPC, n = 31). Treatment subgroups were balanced for baseline characteristics and GPA indices. EP was associated with a significant reduction in the risk of death (HR 0.51; P < 0.01) versus TPC; median OS was 10.0 and 4.8 months, respectively. Improvement in OS was observed in both poorer and better GPA prognostic groups. Survival rates at 12 months were 44.4% for EP versus 19.4% for TPC. Consistent with the overall BEACON population, fewer patients on EP experienced grade ≥3 toxicity (50 vs. 70%). Conclusions: The significant improvement in survival in BCBM patients provides encouraging data for EP in this difficult-to-treat subgroup of patients. A phase three trial of EP in BCBM patients is underway (ClinicalTrials.gov NCT02915744)