Sarilumab for Relapse of Polymyalgia Rheumatica during Glucocorticoid Taper.

BACKGROUND: More than half of patients with polymyalgia rheumatica have a relapse during tapering of glucocorticoid therapy. Previous studies have suggested that interleukin-6 blockade may be clinically useful in the treatment of polymyalgia rheumatica. Sarilumab, a human monoclonal antibody, binds interleukin-6 receptor α and efficiently blocks the interleukin-6 pathway. METHODS: In this phase 3 trial, we randomly assigned patients in a 1:1 ratio to receive 52 weeks of a twice-monthly subcutaneous injection of either sarilumab (at a dose of 200 mg) plus a 14-week prednisone taper or placebo plus a 52-week prednisone taper. The primary outcome at 52 weeks was sustained remission, which was defined as the resolution of signs and symptoms of polymyalgia rheumatica by week 12 and sustained normalization of the C-reactive protein level, absence of disease flare, and adherence to the prednisone taper from weeks 12 through 52. RESULTS: A total of 118 patients underwent randomization (60 to receive sarilumab and 58 to receive placebo). At week 52, sustained remission occurred in 28% (17 of 60 patients) in the sarilumab group and in 10% (6 of 58 patients) in the placebo group (difference, 18 percentage points; 95% confidence interval, 4 to 32; P = 0.02). The median cumulative glucocorticoid dose at 52 weeks was significantly lower in the sarilumab group than in the placebo group (777 mg vs. 2044 mg; P<0.001). The most common adverse events with sarilumab as compared with placebo were neutropenia (15% vs. 0%), arthralgia (15% vs. 5%), and diarrhea (12% vs. 2%). More treatment-related discontinuations were observed in the sarilumab group than in the placebo group (12% vs. 7%). CONCLUSIONS: Sarilumab showed significant efficacy in achieving sustained remission and reducing the cumulative glucocorticoid dose in patients with a relapse of polymyalgia rheumatica during glucocorticoid tapering. (Funded by Sanofi and Regeneron Pharmaceuticals; SAPHYR ClinicalTrials.gov number, NCT03600818.).

A phase 3 randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of sarilumab in patients with giant cell arteritis.

BACKGROUND: Giant cell arteritis (GCA) is primarily treated with glucocorticoids (GCs), which have substantial toxicity. Tocilizumab, an interleukin-6-receptor inhibitor (IL-6Ri), showed beneficial effects in GCA, leading to its approval. This study investigated the efficacy and safety of sarilumab (another IL-6Ri) in GCA. METHODS: This Phase 3, double-blind study comprised a 52-week treatment period and a 24-week follow-up phase. Eligible GCA patients were randomized to receive sarilumab 200 mg (SAR200 + 26W) or 150 mg (SAR150 + 26W) with a 26-week GC taper, or placebo with a 52-week (PBO + 52W) or 26-week (PBO + 26W) GC taper. The primary efficacy endpoint was sustained remission (SR) at week 52. Additional endpoints were SR at week 24, cumulative GC dose, and safety. The study was discontinued prematurely due to protracted recruitment timelines, because of the impact of COVID-19. Therefore, only descriptive statistics were summarized. RESULTS: Of the planned 360 subjects, only 83 were randomized and 36 were included in the week 52 analysis. At week 52, 46% (n = 6/13) of patients in SAR200 + 26W, 43% (n = 3/7) in SAR150 + 26W, 30% (n = 3/10) in PBO + 52W, and 0 (n = 0/6) in PBO + 26W taper groups achieved SR. Sensitivity analyses, excluding acute-phase reactants from the SR definition, showed similar results for SAR groups, but 60% (n = 6/10) in PBO + 52W and 17% (n = 1/6) in PBO + 26W taper groups achieved SR at week 52. Similar findings were noted at week 24. The proportions of patients who adhered to GC taper from week 12 through week 52 in each group were as follows: 46% (n = 6/13, SAR200 + 26W), 43% (n = 3/7, SAR150 + 26W), 60% (n = 6/10, PBO + 52W), and 33% (n = 2/6, PBO + 26W). The median actual cumulative GC dose received in the SAR200 + 26W group was lower than other groups. Most patients (80-100%) experienced treatment-emergent adverse events, with similar incidences reported across groups. CONCLUSIONS: Owing to the small sample size due to the early termination, it is difficult to draw clear conclusions from this study. There were no unexpected safety findings. TRIAL REGISTRATION: ClinicalTrials.gov NCT03600805. Registered on July 26, 2018.

Managing Interruptions to Improve Diagnostic Decision-Making: Strategies and Recommended Research Agenda.

Interruptions are an inevitable occurrence in health care. Interruptions in diagnostic decision-making are no exception and can have negative consequences on both the decision-making process and well-being of the decision-maker. This may result in inaccurate or delayed diagnoses. To date, research specific to interruptions on diagnostic decision-making has been limited, but strategies to help manage the negative impacts of interruptions need to be developed and implemented. In this perspective, we first present a modified model of interruptions to visualize the interruption process and illustrate where potential interventions can be implemented. We then consider several empirically tested strategies from the fields of health care and cognitive psychology that can lay the groundwork for additional research to mitigate effects of interruptions during diagnostic decision-making. We highlight strategies to minimize the negative impacts of interruptions as well as strategies to prevent interruptions altogether. Additionally, we build upon these strategies to propose specific research priorities within the field of diagnostic safety. Identifying effective interventions to help clinicians better manage interruptions has the potential to minimize diagnostic errors and improve patient outcomes.

The mazing race: Effects of interruptions and benefits of interruption lags in a novel maze-like decision-making paradigm.

Interruptions are an inevitable, and often negative, part of everyday life that increase both errors and the time needed to complete even menial tasks. However, existing research suggests that being given time to prepare for a pending interruption-a lag time-can mitigate some of the interruption costs. To understand better why interruption lags are effective, we present a series of three experiments in which we develop and test a novel sequential decision-making paradigm, the mazing race. We find that interruption lags were only beneficial when participants had a clear strategy for how to complete the task, allowing them to avoid specific errors. In the final experiment, we attempted to use what we learned about the kinds of errors introduced by interruptions to develop a feedback-based intervention, aimed at dealing with situations in which interruption lags are not possible. We found that feedback was, only in certain situations, an effective replacement for an interruption lag. Overall, however, because the usefulness of interruption lags depend on the specific strategy a participant adopts, developing generic interventions to replace interruption lags is likely to be difficult. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Adapting to the algorithm: how accuracy comparisons promote the use of a decision aid.

In three experiments, we sought to understand when and why people use an algorithm decision aid. Distinct from recent approaches, we explicitly enumerate the algorithm's accuracy while also providing summary feedback and training that allowed participants to assess their own skills. Our results highlight that such direct performance comparisons between the algorithm and the individual encourages a strategy of selective reliance on the decision aid; individuals ignored the algorithm when the task was easier and relied on the algorithm when the task was harder. Our systematic investigation of summary feedback, training experience, and strategy hint manipulations shows that further opportunities to learn about the algorithm encourage not only increased reliance on the algorithm but also engagement in experimentation and verification of its recommendations. Together, our findings emphasize the decision-maker's capacity to learn about the algorithm providing insights for how we can improve the use of decision aids.

COLOURED PATIENT FOLDERS: THE LITTLE THINGS MAKING A DIFFERENCE FOR THE BEDSIDE NURSE.

Jointly initiated by Monash Children's and The Royal Children's Hospital (RCH), The Victorian Children's Tool for Observation and Response project known as VICTOR (www.victor.org.au) is a sector-led project funded by the Victorian Paediatric Clinical Network.

Using Decision Models to Enhance Investigations of Individual Differences in Cognitive Neuroscience.

There is great interest in relating individual differences in cognitive processing to activation of neural systems. The general process involves relating measures of task performance like reaction times or accuracy to brain activity to identify individual differences in neural processing. One limitation of this approach is that measures like reaction times can be affected by multiple components of processing. For instance, some individuals might have higher accuracy in a memory task because they respond more cautiously, not because they have better memory. Computational models of decision making, like the drift-diffusion model and the linear ballistic accumulator model, provide a potential solution to this problem. They can be fitted to data from individual participants to disentangle the effects of the different processes driving behavior. In this sense the models can provide cleaner measures of the processes of interest, and enhance our understanding of how neural activity varies across individuals or populations. The advantages of this model-based approach to investigating individual differences in neural activity are discussed with recent examples of how this method can improve our understanding of the brain-behavior relationship.

Severe human parechovirus type 3 myocarditis and encephalitis in an adolescent with hypogammaglobulinemia.

Human parechovirus (HPeV) belongs to the Picornaviridae family of RNA viruses. HPeV infections can be asymptomatic, lead to mild respiratory and/or gastrointestinal symptoms, or less frequently cause severe diseases such as sepsis, meningitis, encephalitis, and myocarditis. Severe neurological HPeV infections occur most commonly in infants and neonates. There are currently 16 recognized types of HPeV. HPeV type 3 (HPeV3) has been the predominant type associated with severe central nervous system disease in neonates and newborns since its discovery in 1999. Although HPeV-related infections have been reported in adults, symptomatic HPeV3 infections in adolescents and adults are uncommon. A case of severe HPeV3 myocarditis and encephalitis in an adolescent is described.

Adenosine A1 receptors (A1Rs) play a critical role in osteoclast formation and function.

Adenosine regulates a wide variety of physiological processes via interaction with one or more G-protein-coupled receptors (A(1)R, A(2A)R, A(2B)R, and A(3)R). Because A(1)R occupancy promotes fusion of human monocytes to form giant cells in vitro, we determined whether A(1)R occupancy similarly promotes osteoclast function and formation. Bone marrow cells (BMCs) were harvested from C57Bl/6 female mice or A(1)R-knockout mice and their wild-type (WT) littermates and differentiated into osteoclasts in the presence of colony stimulating factor-1 and receptor activator of NF-kappaB ligand in the presence or absence of the A(1)R antagonist 1,3-dipropyl-8-cyclopentyl xanthine (DPCPX). Osteoclast morphology was analyzed in tartrate-resistant acid phosphatase or F-actin-stained samples, and bone resorption was evaluated by toluidine blue staining of dentin. BMCs from A(1)R-knockout mice form fewer osteoclasts than BMCs from WT mice, and the A(1)R antagonist DPCPX inhibits osteoclast formation (IC(50)=1 nM), with altered morphology and reduced ability to resorb bone. A(1)R blockade increased ubiquitination and degradation of TRAF6 in RAW264.7 cells induced to differentiate into osteoclasts. These studies suggest a critical role for adenosine in bone homeostasis via interaction with adenosine A(1)R and further suggest that A(1)R may be a novel pharmacologic target to prevent the bone loss associated with inflammatory diseases and menopause.