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Upadacitinib, an oral selective Janus kinase (JAK) inhibitor, is under investigation for the treatment of Crohn's disease. In two phase 3 induction trials (U-EXCEL and U-EXCEED), we randomly assigned patients with moderate-to-severe Crohn's disease to receive 45 mg of upadacitinib or placebo (2:1 ratio) once daily for 12 weeks. Patients who had a clinical response to upadacitinib induction therapy were randomly assigned in the U-ENDURE maintenance trial to receive 15 mg of upadacitinib, 30 mg of upadacitinib, or placebo (1:1:1 ratio) once daily for 52 weeks. The primary end points for induction (week 12) and maintenance (week 52) were clinical remission (defined as a Crohn's Disease Activity Index score of <150 [range, 0 to 600, with higher scores indicating more severe disease activity]) and endoscopic response (defined as a decrease in the Simple Endoscopic Score for Crohn's Disease [SES-CD; range, 0 to 56, with higher scores indicating more severe disease] of >50% from baseline of the induction trial [or for patients with an SES-CD of 4 at baseline, a decrease of ≥2 points from baseline]). A total of 526 patients underwent randomization in U-EXCEL, 495 in U-EXCEED, and 502 in U-ENDURE. A significantly higher percentage of patients who received 45-mg upadacitinib than those who received placebo had clinical remission (in U-EXCEL, 49.5% vs. 29.1%; in U-EXCEED, 38.9% vs. 21.1%) and an endoscopic response (in U-EXCEL, 45.5% vs. 13.1%; in U-EXCEED, 34.6% vs. 3.5%) (P<0.001 for all comparisons). At week 52 in U-ENDURE, a higher percentage of patients had clinical remission with 15-mg upadacitinib (37.3%) or 30-mg upadacitinib (47.6%) than with placebo (15.1%), and a higher percentage had an endoscopic response with 15-mg upadacitinib (27.6%) or 30-mg upadacitinib (40.1%) than with placebo (7.3%) (P<0.001 for all comparisons). Herpes zoster infections occurred more frequently in the 45-mg and 30-mg upadacitinib groups than in the respective placebo groups, and hepatic disorders and neutropenia were more frequent in the 30-mg upadacitinib group than in the other maintenance groups. Gastrointestinal perforations developed in 4 patients who received 45-mg upadacitinib and in 1 patient each who received 30-mg or 15-mg upadacitinib. Upadacitinib induction and maintenance treatment was superior to placebo in patients with moderate-to-severe Crohn's disease. (Funded by AbbVie; U-EXCEL, U-EXCEED, and U-ENDURE ClinicalTrials.gov numbers, NCT03345849, NCT03345836, and NCT03345823.).

Background As long-term treatment with antitumour necrosis factor (TNF) drugs becomes accepted practice, the risk assessment requires an understanding of anti-TNF long-term safety. Registry safety data in rheumatoid arthritis (RA) are available, but these patients may not be monitored as closely as patients in a clinical trial. Cross-indication safety reviews of available anti-TNF agents are limited. Objective To analyse the long-term safety of adalimumab treatment. Methods This analysis included 23 458 patients exposed to adalimumab in 71 global clinical trials in RA, juvenile idiopathic arthritis, ankylosing spondylitis (AS), psoriatic arthritis, psoriasis (Ps) and Crohn's disease (CD). Events per 100 patient-years were calculated using events reported after the first dose through 70 days after the last dose. Standardised incidence rates for malignancies were calculated using a National Cancer Institute database. Standardised death rates were calculated using WHO data. Results The most frequently reported serious adverse events across indications were infections with greatest incidence in RA and CD trials. Overall malignancy rates for adalimumab-treated patients were as expected for the general population; the incidence of lymphoma was increased in patients with RA, but within the range expected in RA without anti-TNF therapy; non-melanoma skin cancer incidence was raised in RA, Ps and CD. In all indications, death rates were lower than, or equivalent to, those expected in the general population. Conclusions Analysis of adverse events of interest through nearly 12 years of adalimumab exposure in clinical trials across indications demonstrated individual differences in rates by disease populations, no new safety signals and a safety profile consistent with known information about the anti-TNF class.

ObjectiveTo evaluate the long-term safety profile for upadacitinib across rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS) and atopic dermatitis (AD).MethodsSafety data from clinical trials of upadacitinib 15 mg and upadacitinib 30 mg (AD only) for treating RA, PsA, AS and AD as of 30 June 2021 were analysed; some RA and PsA studies included adalimumab and methotrexate as active comparators. Treatment-emergent adverse events (TEAEs) were presented by disease as exposure-adjusted event rates per 100 patient years (E/100 PY).ResultsThe analysis included 6991 patients (RA, n=3209; PsA, n=907; AS, n=182; AD, n=2693) who received at least one dose of upadacitinib, representing 15 425 PY of exposure (maximum duration 2.75–5.45 years) across diseases. Rates (E/100 PY) of any TEAE (205.5–278.1) and TEAE leading to discontinuation (4.5–5.4) were similar across diseases; serious TEAEs were numerically higher in patients with RA and PsA. Rates of herpes zoster (1.6–3.6), non-melanoma skin cancer (0–0.8) and elevations in creatine phosphokinase levels (4.4–7.9) were higher with upadacitinib than with active comparators in the RA and PsA populations. Deaths (0–0.8), serious infections (0–3.9), major adverse cardiovascular events (0–0.4), venous thromboembolism (<0.1–0.4) and malignancies (0.3–1.4) were observed, with rates generally lowest in AS and AD. Increased rates of acne were observed in patients with AD only.ConclusionsFindings from this analysis demonstrate that upadacitinib is generally well tolerated with observed differences in safety profiles likely reflective of varying patient characteristics across RA, PsA, AS and AD populations.Trial registration numbersNCT02675426, NCT02706951, NCT02706847, NCT02629159, NCT02706873, NCT03086343, NCT03104374, NCT03104400, NCT03178487, NCT03569293, NCT03568318 and NCT03607422.

Increased demand for a greater variety of products has forced many companies to rethink their strategies to offer more product variants without sacrificing production efficiency. In this context, research has found that such a trade-off can be properly managed by exploiting the module-based product family (MBPF) design. Over the years, active work in developing methods to design MBPFs has been carried out. Nevertheless, many of them have been created, and consequently exist, in isolation from one other. As a result, the adoption of these methods in industry and academy alike is inhibited by the seemingly broad array of material without a coherent organizing structure. To bridge this gap, this paper performs a systematic literature review and a meta-synthesis, wherein 72 methods to design MBPFs and their respective instances are connected in the form of a functional model and structured classes of design problems. These entities together serve as a meta-method for organizing the research on MBPF design, from which it was possible to identify the common underlying structure among the methods developed over the past 20 years. The main contributions of this work include: (1) constructing a functional model that connects the design methods for MBPFs; (2) suggesting structured classes of design problems that complement the functional model by cataloging the techniques meant to execute each sub-function of the model; (3) proposing a construction heuristic to build and assess functional models and classes of design problems.

Pathogen infections have been associated with autoimmunity, which in turn has been implicated in the pathogenesis of vitiligo. However, the association between pathogen infections and vitiligo remains elusive. This study aimed to assess the proportion of individuals who tested positive for specific IgG antibodies against selected pathogens in patients with vitiligo and control subjects. Plasma from 51 patients with vitiligo and 51 age- and gender-matched controls were tested for anti- IgG, anti-herpes simplex types 1 and 2 (HSV-1/2) IgG, anti-cytomegalovirus (CMV) IgG and anti-hepatitis C virus IgG. Among all participants ( = 102), 63%, 84% and 87% tested positive for anti- , anti-HSV-1/2 and anti-CMV IgG antibodies, respectively. Anti-hepatitis C virus IgG was negative in all samples tested. Positive anti- IgG was detected in plasma samples of 39 (78%) patients with vitiligo and 25 (49%) controls (odds ratio [OR] 3.68, 95% confidence interval [CI] 1.55-8.76, = 0.0036). Anti-HSV-1/2 IgG was detected in samples of 47 (92%) patients with vitiligo and 38 (76%) controls (OR 3.71, 95% CI 1.11-12.44, = 0.031). Differences in frequencies of positive results for anti- IgG and anti-HSV-1/2 IgG were only significant in samples from female patients with vitiligo when compared with controls ( = 0.036 and 0.024, respectively). Anti-CMV IgG was detected in samples from 46 patients with vitiligo (90%) and 41 (84%) controls ( = 0.384). IgG and HSV-1/2 IgG were significantly more frequent in patients with vitiligo, especially in women, when compared with age- and gender-matched controls. Since and HSV-1/2 infections can trigger autoimmune events, past exposure to these pathogens may be a risk factor for the development of vitiligo.

BackgroundAdalimumab has been used in patients with moderately to severely active rheumatoid arthritis (RA) for over 10 years and has a well-established safety profile across multiple indications.ObjectiveTo update adverse events (AEs) of special interest from global adalimumab clinical trials in patients with RA.MethodsThis analysis includes 15 132 patients exposed to adalimumab in global RA clinical trials. AEs of interest included overall infections, laboratory abnormalities and AEs associated with influenza vaccination. Pregnancy outcome data were collected from the Adalimumab Pregnancy Registry.ResultsSerious infections and tuberculosis occurred at a rate of 4.7 and 0.3 events/100 patient-years, respectively. Two patients experienced hepatitis B reactivation. No significant laboratory abnormalities were reported with adalimumab-plus-methotrexate compared with placebo-plus-methotrexate. Influenza-related AEs occurred in 5% of vaccinated patients compared with 14% of patients not vaccinated during the study. Relative risk of major birth defects and spontaneous abortions in adalimumab-exposed women were similar between that of unexposed women with RA and healthy women.ConclusionsThis analysis confirms and expands the known safety profile of adalimumab and reports no additional safety risk of laboratory abnormalities, hepatitis B reactivation and pregnancy outcomes, including spontaneous abortions and birth defects. The benefits of influenza vaccination are reinforced.Trial registration numbersNCT00195663, NCT00195702, NCT00448383, NCT00049751, NCT00234845, NCT00650390, NCT00235859, NCT00647920, NCT00649545, NCT00647491, NCT00649922, NCT00538902, NCT00420927, NCT00870467, NCT00650156, NCT00647270, NCT01185288, NCT01185301.

Essential oils are composed of secondary metabolites derived from medicinal plants and have bioactive properties, such as antiparasitic activity. This study investigated the in vitro anti‐dactylogyridean efficacy of the Zingiber officinale, Curcuma longa and Cymbopogon nardus essential oils, as well as the acute toxicity for Colossoma macropomum (tambaqui). The majority chemical components of the essential oils of Z. officinale (α‐zingiberene, β‐sesquiphellandrene, limonene and geranial), C. longa (ar‐turmerone, α‐turmerone, α‐phellandrene, curlone and 1,8‐cineole) and C. nardus (geraniol, geranial and neral) were analysed. All the essential oils exhibited dose‐dependent efficacy against dactylogyrideans Anacanthorus spathulatus, Notozothecium janauachensis and Mymarothecium boegeri, and the mean effective concentration (EC50) was 16.6 mg L−1 (3 h and 30 min) for Z. officinale essential oil, 30.9 mg L−1 (2 h and 15 min) for C. longa essential oil and 13.7 mg L−1 (30 min) for C. nardus essential oil. Effects of these oils on the ultrastructure of Anacanthorus dactylogyrideans exposed to the essential oils were also evaluated using scanning electron microscopy. This study shows for the first time the potential use of the Z. officinale, C. longa and C. nardus essential oils in controlling dactylogyridean parasites.

TNF-α is essential for induction and maintenance of inflammatory responses and its dysregulation is associated with susceptibility to various pathogens that infect the central nervous system. Activation of both microglia and astrocytes leads to TNF-α production, which in turn triggers further activation of these cells. Astrocytes have been implicated in the pathophysiology of a wide range of neurodegenerative diseases with either harmful or protective roles, as these cells are capable of secreting several inflammatory factors and also promote synapse elimination and remodeling. These responses are possible because they sense their surroundings via several receptors, including the metabotropic glutamate receptor 5 (mGluR5). Under neuroinflammatory conditions, mGluR5 activation in astrocytes can be neuroprotective or have the opposite effect. In the current study, we investigated the role of mGluR5 in hiPSC-derived astrocytes subjected to pro-inflammatory stimulation by recombinant TNF-α (rTNF-α). Our results show that mGluR5 blockade by CTEP decreases the secreted levels of pro-inflammatory cytokines (IL-6 and IL-8) following short rTNF-α stimulation, although this effect subsides with time. Additionally, CTEP enhances synaptoneurosome phagocytosis by astrocytes in both non-stimulated and rTNF-α-stimulated conditions, indicating that mGluR5 blockade alone is enough to drive synaptic material engulfment. Finally, mGluR5 antagonism as well as rTNF-α stimulation augment the expression of the reactivity marker SERPINA3 and reduces the expression of synaptogenic molecules. Altogether, these data suggest a complex role for mGluR5 in human astrocytes, since its blockade may have beneficial and detrimental effects under inflammatory conditions.

The search for sustainable land use has increased in Brazil due to the important role that agriculture plays in the country. Soil detailed classification is related with texture attribute. How can one discriminate the same soil class with different textures using proximal soil sensing, as to reach surveys, land use planning and increase crop productivity? This study aims to evaluate soil texture using a regional spectral library and its usefulness on classification. We collected 3750 soil samples covering 3 million ha within strong soil class variations in São Paulo State. The spectral analyses of soil samples from topsoil and subsoil were measured in laboratory (400–2500 nm). The potential of a regional soil spectral library was evaluated on the discrimination of soil texture. We considered two types of soil texture systems, one related with soil classification and another with soil managements. The soil line technique was used to assess differentiation between soil textural groups. Soil spectra were summarized by principal component analysis (PCA) to select relevant information on the spectra. Partial least squares regression (PLSR) was used to predict texture. Spectral curves indicated different shapes according to soil texture and discriminated particle size classes from clayey to sandy soils. In the visible region, differences were small because of the organic matter, while the short wave infrared (SWIR) region showed more differences; thus, soil texture variation could be differentiated by quartz. Angulation differences are on a spectral curve from NIR to SWIR. The statistical models predicted clay and sand levels with R2 = 0.93 and 0.96, respectively. Indeed, we achieved a difference of 1.2% between laboratory and spectroscopy measurement for clay. The spectral information was useful to classify Ferralsols with different texture classification. In addition, the spectra differentiated Lixisols from Ferralsols and Arenosols. This work can help the development of computer programs that allow soil texture classification and subsequent digital soil mapping at detailed scales. In addition, it complies with requirements for sustainable land use and soil management.

Abstract Background We evaluated the association of achieving endoscopic outcomes at week 12 of induction with improvements in clinical outcomes and quality of life (QoL) at week 52 of maintenance in patients with moderately to severely active Crohn’s disease (CD) treated with upadacitinib (UPA). Methods This post hoc analysis evaluated data from 2 phase 3 induction trials (NCT03345836 and NCT03345849) and 1 maintenance (NCT03345823) trial. Clinical responders to 12-week induction therapy with UPA who also received 52-week maintenance treatment with UPA were included. Endoscopic response, remission, healing, and ulcer-free endoscopy were assessed at week 12. Meaningful improvements in clinical and QoL outcomes were evaluated at week 52. Results A significantly greater proportion of patients who achieved an endoscopic response at the end of induction, compared with patients who did not, attained Crohn’s Disease Activity Index (CDAI) remission (52.0% vs 34.6%; P ≤ .01), corticosteroid-free CDAI remission (50.0% vs 30.9%), Inflammatory Bowel Disease Questionnaire remission (52.6% vs 30.3%), and meaningful improvements in Functional Assessment of Chronic Illness Therapy—Fatigue response (46.7% vs 25.9%), overall work impairment (47.1% vs 26.5%), and daily activity impairment (53.3% vs 34.1%) (all P < .05) at week 52. Similar findings were observed for patients who achieved endoscopic remission, endoscopic healing, and ulcer-free endoscopy at the end of induction vs those who did not. Conclusions Early improvement in endoscopic outcomes after UPA induction treatment was associated with long-term meaningful improvements in clinical outcomes and QoL in patients with CD. Clinical Registration number U-EXCEED induction trial (NCT03345836), U-EXCEL induction trial (NCT03345849), and U-ENDURE maintenance trial (NCT03345823). Lay Summary In patients with Crohn’s disease treated with 12 weeks of upadacitinib, a greater proportion with early improvements in endoscopic response, remission, healing, and ulcer-free endoscopy, vs those without improvements, attained long-term meaningful improvements in clinical outcomes and quality of life.