In a phase 3 randomized trial of 1307 patients with rheumatoid arthritis receiving background methotrexate, the oral JAK1 and JAK2 inhibitor baricitinib showed superior efficacy to placebo and to the ...anti–tumor necrosis factor α monoclonal antibody adalimumab.
Rheumatoid arthritis is a systemic autoimmune disease characterized by inflammatory synovitis and progressive joint destruction, which are associated with severe disability and increased mortality. Progress in treatment with the use of conventional synthetic disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, and biologic DMARDs that target tumor necrosis factor (TNF) has made clinical remission a realistic target.
1
Activated Janus kinases (JAKs) play pivotal roles in intracellular signaling from cell-surface receptors for multiple cytokines implicated in the pathologic processes of rheumatoid arthritis.
2
Baricitinib, an orally available small molecule, provides reversible inhibition of JAK1 and JAK2 and has shown clinical efficacy in studies . . .
This paper conducts a selective review of various estimates for energy demand responses focused specially upon lower-income industrializing economies rather than richer mature nations. It emphasizes ...recent trends from empirical studies that have been published after 2000. Emphasis is placed on the five major emerging or transitional economies in Brazil, China, India, Mexico and Russia, although other important nations like Chile and South Korea are also discussed when studies are available. The review focuses attention on the long-run responses to changes in prices and income after capital stock turnover has been completed. The terminology often refers to elasticities, or the percentage change in energy use divided by the percentage change in price (or income), holding constant all other factors that could influence energy-use decisions. Estimates cover petroleum products, natural gas and electricity, although the available studies often ignore coal. They also include the economy-wide impacts (real GDP) to price changes. Most studies have focused upon household and transportation use of liquid fuels; many fewer studies have investigated fuels used by industry or commerce or for electric generation. Based upon the available estimates, price and income elasticities for liquid fuels are generally less than one (unity) for many countries and sectors, except for the long-run income effect for transportation purposes, which can range widely by country between 0.24 and 1.75 while averaging 0.94 for all countries.
•Reviews estimated demand responses in major emerging economies.•Focuses upon petroleum products, natural gas and electricity.•Price and income elasticities for liquid fuels are generally less than one.•Energy price impacts on economy are small except for energy producers.•Responses are often similar to OECD estimates with some exceptions.
Endoscopic disease activity scoring in ulcerative colitis (UC) is useful in clinical practice but done infrequently. It is required in clinical trials, where it is expensive and slow because human ...central readers are needed. A machine learning algorithm automating the process could elevate clinical care and facilitate clinical research. Prior work using single-institution databases and endoscopic still images has been promising.
Seven hundred and ninety-five full-length endoscopy videos were prospectively collected from a phase 2 trial of mirikizumab with 249 patients from 14 countries, totaling 19.5 million image frames. Expert central readers assigned each full-length endoscopy videos 1 endoscopic Mayo score (eMS) and 1 Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score. Initially, video data were cleaned and abnormality features extracted using convolutional neural networks. Subsequently, a recurrent neural network was trained on the features to predict eMS and UCEIS from individual full-length endoscopy videos.
The primary metric to assess the performance of the recurrent neural network model was quadratic weighted kappa (QWK) comparing the agreement of the machine-read endoscopy score with the human central reader score. QWK progressively penalizes disagreements that exceed 1 level. The model’s agreement metric was excellent, with a QWK of 0.844 (95% confidence interval, 0.787–0.901) for eMS and 0.855 (95% confidence interval, 0.80–0.91) for UCEIS.
We found that a deep learning algorithm can be trained to predict levels of UC severity from full-length endoscopy videos. Our data set was prospectively collected in a multinational clinical trial, videos rather than still images were used, UCEIS and eMS were reported, and machine learning algorithm performance metrics met or exceeded those previously published for UC severity scores.
In two phase 3 trials, mirikizumab, a p19-directed anti–interleukin-23 antibody, was superior to placebo with regard to clinical remission of ulcerative colitis at 12 weeks (induction) and 40 weeks ...(maintenance).
Summary Background Biological agents offer good control of rheumatoid arthritis, but the long-term benefits of achieving low disease activity with a biological agent plus methotrexate or methotrexate ...alone are unclear. The OPTIMA trial assessed different treatment adjustment strategies in patients with early rheumatoid arthritis attaining (or not) stable low disease activity with adalimumab plus methotrexate or methotrexate monotherapy. Methods This trial was done at 161 sites worldwide. Patients with early (<1 year duration) rheumatoid arthritis naive to methotrexate were randomly allocated (by interactive voice response system, in a 1:1 ratio, block size four) to adalimumab (40 mg every other week) plus methotrexate (initiated at 7·5 mg/week, increased by 2·5 mg every 1–2 weeks to a maximum weekly dose of 20 mg by week 8) or placebo plus methotrexate for 26 weeks (period 1). Patients in the adalimumab plus methotrexate group who completed period 1 and achieved the stable low disease activity target (28-joint disease activity score with C-reactive protein DAS28<3·2 at weeks 22 and 26) were randomised to adalimumab-continuation or adalimumab-withdrawal for an additional 52 weeks (period 2). Patients achieving the target with initial methotrexate continued methotrexate-monotherapy. Inadequate responders were offered adalimumab plus methotrexate. All patients and investigators were masked to treatment allocation in period 1. During period 2, treatment reallocation of patients who achieved the target was masked to patients and investigators; patients who did not achieve the target remained masked to original randomisation, but were aware of the subsequent assignment. The primary endpoint was a composite measure of DAS28 of less than 3·2 at week 78 and radiographic non-progression from baseline to week 78, compared between adalimumab-continuation and methotrexate-monotherapy. Adverse events were monitored throughout period 2. This trial is registered with ClinicalTrials.gov , number NCT00420927. Findings The study was done between Dec 28, 2006, and Aug 3, 2010. 1636 patients were assessed and 1032 were randomised in period 1 (515 to adalimumab plus methotrexate; 517 to placebo plus methotrexate). 466 patients in the adalimumab plus methotrexate group completed period 1; 207 achieved the stable low disease activity target, of whom 105 were rerandomised to adalimumab-continuation. 460 patients in the placebo plus methotrexate group completed period 1; 112 achieved the stable low disease activity target and continued methotrexate-monotherapy. 73 of 105 (70%) patients in the adalimumab-continuation group and 61 of 112 (54%) patients in the methotrexate-monotherapy group achieved the primary endpoint at week 78 (mean difference 15% 95% CI 2–28%, p=0·0225). Patients achieving the stable low disease activity target on adalimumab plus methotrexate who withdrew adalimumab mostly maintained their good responses. Overall, 706 of 926 patients in period 2 had an adverse event, of which 82 were deemed serious; however, distribution of adverse events did not differ between groups. Interpretation Treatment to a stable low disease activity target resulted in improved clinical, functional, and structural outcomes, with both adalimumab-continuation and methotrexate-monotherapy. However, a higher proportion of patients treated with initial adalimumab plus methotrexate achieved the low disease activity target compared with those initially treated with methotrexate alone. Outcomes were much the same whether adalimumab was continued or withdrawn in patients who initially responded to adalimumab plus methotrexate. Funding AbbVie.
Introduction:
An apparent clinical relationship between pain and depression has long been recognized, which makes an enormous impact on the individual health care. At present, the practical ...implication of such overlapping symptomatology between pain and depression is not clear, but the prevalence estimates for depression are substantially inflated among patients with chronic pain and vice versa. This interaction has been labeled as the depression-pain syndrome or depression-pain dyad.
Areas covered:
This article discusses the neurobiological substrates and neuroanatomical pathways involved in pain-depression dyad along with newer therapeutic targets.
Expert opinion:
Several key themes emerged from our review of the relationship between depression and pain. First, the diagnosis of depression in pain or vice versa is particularly challenging, and the development of better diagnostic framework that involves both pain and depression is particularly required. Secondly, the entwined relationship between pain and depression supports the possibility of common coactivating factors that results in their neurophysiological overlap. A broad understanding of the role played by the central nervous system (CNS) in the processing of pain and depression may eventually lead to the introduction of triple reuptake inhibitors, agomelatine, vilazodone and ketamine with novel mechanism of action, hence appear to be of promising potential for pain with depression.
Background
Bowel urgency, the sudden or immediate need to have a bowel movement, is a common, bothersome and disruptive symptom of ulcerative colitis (UC). UC treatment goals include control of ...urgency; however, it is not consistently assessed in UC clinical trials. The Urgency Numeric Rating Scale (NRS) is a new patient-reported measure to assess severity of bowel urgency in adults with UC developed in accordance with Food and Drug Administration guidelines.
Methods
Qualitative interviews were used to develop Urgency NRS. The scale asks patients to report the immediacy status of their UC symptom over the past 24 h on an 11-point horizontal numeric rating scale 0 (No urgency) to 10 (Worst possible urgency). Higher scores indicate worse urgency severity. A 2-week diary study assessed floor and ceiling effects, test–retest reliability (intraclass correlation coefficient (ICC) (2,1) between Week 1 and 2), and construct validity (Spearman correlation using Week 1 scores). Weekly scores were calculated as mean score over each 7-day period.
Results
Qualitative interviews with 16 UC patients (mean age 37.9 ± 11.6 years; 50% female; 56% White) confirmed relevance, content, and comprehensiveness. The 2-week diary study included 41 UC patients (mean age 44.2 ± 14.6 years; 51% female; 56% White). No ceiling or floor effects were identified. Test–retest reliability was high (ICC = 0.877). Average Urgency NRS and patient global rating of severity scores were highly correlated, with a moderate correlation between average Urgency NRS and stool frequency, demonstrating construct validity.
Conclusions
Bowel urgency is a distinct symptom of UC. The Urgency NRS is a well-defined, content-valid, and reliable measurement of bowel urgency in adults with UC.
Background
Adalimumab is a fully human, monoclonal antibody against tumor necrosis factor that is approved in Western countries for the treatment of moderately to severely active ulcerative colitis ...(UC).
Methods
This 52-week, phase 2/3, randomized, double-blind study evaluated adalimumab for induction and maintenance treatment in 273 anti-TNF–naive Japanese patients with UC who were refractory to corticosteroids, immunomodulators, or both. Patients received placebo, adalimumab 80/40 (80 mg at week 0, then 40 mg every other week), or adalimumab 160/80 (160/80 mg at weeks 0/2, then 40 mg every other week) in addition to background UC therapy.
Results
At week 8, remission rates were similar among treatment arms, but more patients treated with adalimumab 160/80 achieved response (placebo, 35 %; 80/40, 43 %; 160/80, 50 %;
P
= 0.044 for 160/80 vs placebo) and mucosal healing (placebo, 30 %; 80/40, 39 %; 160/80, 44 %;
P
= 0.045 for 160/80 vs placebo) compared with placebo. At week 52, more patients receiving adalimumab 40 mg every other week achieved response (18 vs 31 %;
P
= 0.021), remission (7 vs 23 %;
P
= 0.001), and mucosal healing (16 vs 29 %;
P
= 0.015) compared with placebo. Week 8 response to adalimumab was associated with greater rates of response (61 %), remission (46 %), and mucosal healing (57 %) at week 52 relative to the overall population. Rates of serious adverse events were similar between treatment arms.
Conclusions
Induction with adalimumab 160/80 mg led to early response and mucosal healing. Maintenance adalimumab had greater rates of long-term response, remission, and mucosal healing compared with placebo. No new safety signals were identified.
Abstract
Background
Computed tomography perfusion (CTp), a useful technique in oncology, is not widely utilized due to the high radiation dose delivered from it. It involves scanning the region of ...interest every second for 50 seconds following intravenous contrast administration. Doubling sampling interval (SI) to 2 seconds will half the radiation dose, but may impact its effectiveness, which needs to be evaluated.
Objectives
To evaluate a dose reduction strategy in CTp by determining agreement between standard dose (SD) CTp (acquisition with SI 1 second) and low-dose CTp techniques with SI of 2 seconds (achieved either by reconstruction only or true low-dose acquisition).
Materials and methods
This cross-sectional study was conducted on histopathology-proven head and neck squamous cell carcinoma (HNSCC) patients who underwent CTp on 64 slice multidetector CT. A total of 56 patients had SD and 24 patients underwent true low dose (LD) acquisition. SD data were also reconstructed at SI 2 seconds to obtain a dataset simulating low dose (low-dose reconstruction LDr). Paired
t
-test was applied to compare CTp in SD and LDr groups and the Bland–Altman plot drawn to calculate 95% confidence limit of agreement. The Kolmogorov–Smirnov test compared CTp parameters for LDr and LD groups.
Results
There was no statistical difference in CTp parameters (except blood flow in malignant) in SD and LDr groups for both malignant and normal tissues. CTp of malignant tissue was not statistically different in LDr and LD groups but the radiation dose was half in the LD group.
Conclusion
Reduction of radiation dose to half achieved by doubling the SI does not affect the CTp parameters significantly. So LD acquisitions will increase the use of CTp in HNSCC.
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