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كتاب النجار قصة حول أعظم استراتيجيات النجاح على الإطلاق جون جوردن، في حوالي 139 صفحة من القطع المتوسط، الموضوع (النجاح الشخصي) وقد جاء فيه (أغلب الناس بمن فيهم المديرون يعتقدون أن القيادة باللقب أو المنصب الذي يشغلونهالهدف من الكتاب سيعلمكم أن أي إنسان محب للناس ومهتم بالناس سيكون قائدا... ؟)

There is an unmet need for a treatment for psoriasis that results in complete skin clearance with a reliably quick response. Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A. We aimed to compare the efficacy and safety of bimekizumab with placebo and ustekinumab in patients with moderate to severe plaque psoriasis over 52 weeks. BE VIVID was a multicentre, randomised, double-blind, active comparator and placebo controlled phase 3 trial done across 105 sites (clinics, hospitals, research units, and private practices) in 11 countries in Asia, Australia, Europe, and North America. Adults aged 18 years or older with moderate to severe plaque psoriasis (Psoriasis Area and Severity Index [PASI] score ≥12, ≥10% body surface area affected by psoriasis, and Investigator's Global Assessment [IGA] score ≥3 on a five point scale) were included. Randomisation was stratified by geographical region and previous exposure to biologics; patients, investigators, and sponsors were masked to treatment assignment. Patients were randomly assigned (4:2:1) using an interactive response technology to bimekizumab 320 mg every 4 weeks, ustekinumab 45 mg or 90 mg (baseline weight-dependent dosing) at weeks 0 and 4, then every 12 weeks, or placebo every 4 weeks. At week 16, patients receiving placebo switched to bimekizumab 320 mg every 4 weeks. All study treatments were administered as two subcutaneous injections. Coprimary endpoints were the proportion of patients with 90% improvement in the PASI (PASI90) and the proportion of patients with an IGA response of clear or almost clear (score 0 or 1) at week 16 (non-responder imputation). Efficacy analyses included the intention-to-treat population; safety analysis included patients who received at least one dose of study treatment. This trial was registered at ClinicalTrials.gov, NCT03370133 (completed). Between Dec 6, 2017, and Dec 13, 2019, 735 patients were screened and 567 were enrolled and randomly assigned (bimekizumab 320 mg every 4 weeks n=321, ustekinumab 45 mg or 90 mg every 12 weeks n=163, placebo n=83). At week 16, 273 (85%) of 321 patients in the bimekizumab group had PASI90 versus 81 (50%) of 163 in the ustekinumab group (risk difference 35 [95% CI 27–43]; p<0·0001) and four (5%) of 83 in the placebo group (risk difference 80 [74–86]; p<0·0001). At week 16, 270 (84%) patients in the bimekizumab group had an IGA response versus 87 (53%) in the ustekinumab group (risk difference 30 [95% CI 22–39]; p<0·0001) and four (5%) in the placebo group (risk difference 79 [73–85]; p<0·0001). Over 52 weeks, serious treatment-emergent adverse events were reported in 24 (6%) of 395 patients in the bimekizumab group (including those who switched from placebo at week 16) and 13 (8%) of 163 in the ustekinumab group. Bimekizumab was more efficacious than ustekinumab and placebo in the treatment of moderate to severe plaque psoriasis. The bimekizumab safety profile was consistent with that observed in previous studies. UCB Pharma.

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.

The results of this phase 2 randomized trial suggest that guselkumab, an anti–interleukin-23 monoclonal antibody, may be an effective therapy for psoriasis and that control of psoriasis can be achieved through specific anti–interleukin-23 therapy. Psoriasis is a chronic skin disease that is characterized by the infiltration of inflammatory cells into the skin and excessive keratinocyte proliferation, which result in raised, well-demarcated erythematous lesions 1 ; the disease has a substantial effect on quality of life. 2 , 3 The pathogenesis of psoriasis involves environmental factors and immune dysregulation in persons with a genetic predisposition. 4 The proinflammatory interleukin-12–mediated type 1 helper T (Th1) cell and interleukin-23–mediated type 17 helper T (Th17) cell signaling pathways 5 , 6 are up-regulated in psoriatic lesions; antibodies that inhibit both interleukin-12 and interleukin-23 7 , 8 and those that inhibit interleukin-17 9 – 13 inhibit the expression of . . .

Efficacious and well-tolerated systemic, oral treatments for psoriasis are needed. We report preclinical and phase 1c (NCT06808815) results for DC-806, a small molecule interleukin (IL)-17 inhibitor, for the treatment of mild-to-moderate psoriasis. Preclinical results demonstrated DC-806 targets IL-17AA and IL-17AF with secukinumab-like therapeutic efficacy. In the phase 1c trial, 32 patients consented to receive twice daily (BID) doses of placebo or DC-806 (200 mg or 800 mg) for 28 days. No serious adverse events (SAEs) or discontinuations due to treatment-related adverse events (TRAEs) occurred. In an exploratory analysis, adjusted mean percentage reductions from baseline in psoriasis area and severity indices (PASI) at Day 29 were 43.7%, 15.1%, and 13.3% for 800 mg BID, 200 mg BID, and placebo arms, respectively (800 mg BID vs placebo, P value = 0.0008). DC-806 was found to be well tolerated with an acceptable safety profile and preliminary signals of clinical efficacy in mild-to-moderate psoriasis. EudraCT Identifier: 2021-002888-21.

Interleukins 12 and 23 have important roles in the pathophysiology of psoriasis. We assessed ustekinumab, a human monoclonal antibody directed against these cytokines, for the treatment of psoriasis. In this phase III, parallel, double-blind, placebo-controlled study, 766 patients with moderate-to-severe psoriasis were randomly assigned to receive ustekinumab 45 mg (n=255) or 90 mg (n=256) at weeks 0 and 4 and then every 12 weeks; or placebo (n=255) at weeks 0 and 4, with subsequent crossover to ustekinumab at week 12. Patients who were initially randomised to receive ustekinumab at week 0 who achieved long-term response (at least 75% improvement in psoriasis area and severity index [PASI 75] at weeks 28 and 40) were re-randomised at week 40 to maintenance ustekinumab or withdrawal from treatment until loss of response. Both randomisations were done with a minimisation method via a centralised interactive voice response system. The primary endpoint was the proportion of patients achieving PASI 75 at week 12. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00267969. All randomised patients were included in the efficacy analysis. 171 (67·1%) patients receiving ustekinumab 45 mg, 170 (66·4%) receiving ustekinumab 90 mg, and eight (3·1%) receiving placebo achieved PASI 75 at week 12 (difference in response rate vs placebo 63·9%, 95% CI 57·8–70·1, p<0·0001 for 45 mg and 63·3%, 57·1–69·4, p<0·0001 for 90 mg). At week 40, long-term response had been achieved by 150 patients in the 45 mg group and 172 patients in the 90 mg group. Of these, 162 patients were randomly assigned to maintenance ustekinumab and 160 to withdrawal. PASI 75 response was better maintained to at least 1 year in those receiving maintenance ustekinumab than in those withdrawn from treatment at week 40 (p<0·0001 by log-rank test). During the placebo-controlled phase, adverse events occurred in 278 (54·5%) of the 510 patients receiving ustekinumab and 123 (48·2%) of the 255 receiving placebo. Serious adverse events occurred in six (1·2%) of 510 patients receiving ustekinumab and in two (0·8%) of 255 receiving placebo in this phase. The pattern of adverse events was much the same in the placebo crossover and randomised withdrawal phases as it was in the placebo-controlled phase. Ustekinumab seems to be efficacious for the treatment of moderate-to-severe psoriasis; dosing every 12 weeks maintains efficacy for at least a year in most patients. Centocor Inc.

In the JWST, Extremely Large Telescopes, and LUVOIR era, we expect to characterize a number of potentially habitable Earth-like exoplanets. However, the characterization of these worlds depends crucially on the accuracy of theoretical models. Validating these models against observations of planets with known properties will be key for the future characterization of terrestrial exoplanets. Due to its sensitivity to the micro- and macro-physical properties of an atmosphere, polarimetry will be an important tool that, in tandem with traditional flux-only observations, will enhance the capabilities of characterizing Earth-like planets. In this paper we benchmark two different polarization-enabled radiative-transfer codes against each other and against unique linear spectropolarimetric observations of the earthshine that cover wavelengths from ∼0.4 to ∼2.3 μm. We find that while the results from the two codes generally agree with each other, there is a phase dependency between the compared models. Additionally, with our current assumptions, the models from both codes underestimate the level of polarization of the earthshine. We also report an interesting discrepancy between our models and the observed 1.27 μm O2 feature in the earthshine, and provide an analysis of potential methods for matching this feature. Our results suggest that only having access to the 1.27 μm O2 feature coupled with a lack of observations of the O2 A and B bands could result in a mischaracterization of an Earth-like atmosphere. Providing these assessments is vital to aid the community in the search for life beyond the solar system.

The search for life beyond the solar system remains a primary goal of current and near-future missions, including NASA’s upcoming Habitable Worlds Observatory (HWO). However, research into determining the habitability of terrestrial exoplanets has been primarily focused on comparisons to modern-day Earth. Additionally, current characterization strategies focus on the unpolarized flux from these worlds, taking into account only a fraction of the informational content of the reflected light. Better understanding the changes in the reflected-light spectrum of the Earth throughout its evolution, as well as analyzing its polarization, will be crucial for mapping its habitability and providing comparison templates to potentially habitable exoplanets. Here we present spectropolarimetric models of the reflected light from the Earth at six epochs across all four geologic eons. We find that the changing surface albedos and atmospheric gas concentrations across the different epochs allow the habitable and nonhabitable scenarios to be distinguished, and diagnostic features of clouds and hazes are more noticeable in the polarized signals. We also discuss how using Mie scattering for naturally nonspherical particles, which is a common simplification for exoplanet modeling, affects the resulting planetary signals. Finally, our results suggest that pushing the HWO planet-to-star flux contrast limit down to 1 × 10−13 could allow for the characterization in both unpolarized and polarized light of an Earth-like planet at any stage in its history.

Determining the habitability of terrestrial exoplanets is a complex problem that represents the next major step for the astrophysical community. The majority of current models treat these planets as homogeneous or contain heterogeneity that is constant in time. In reality, habitable exoplanets are expected to contain atmospheric and surface heterogeneities similar to Earth, with diurnal rotation, seasonal changes, and weather patterns resulting in complex, time-dependent signatures. Due to its ability to measure light as a vector, polarimetry provides an important tool that will enhance the characterizations of heterogeneous worlds. Here we model the visible to near-infrared linear spectropolarimetric signatures, as functions of wavelength and planetary phase angle, of various heterogeneous Earth scenarios as well as the first signals of an early wet and potentially habitable Mars. The contributions from the different atmospheric and surface properties result in asymmetric phase curves and variable spectra, with the polarization appearing to be more sensitive than flux to heterogeneities such as patchy clouds and continents moving into and out of view. Our models provide important predictions of expected polarized and unpolarized signatures of heterogeneous exoplanets that will help guide the designs and observing plans of future polarimeters, including those proposed for the upcoming Habitable Worlds Observatory.

For decades, topical corticosteroids have been the mainstay of treatment for mild-to-moderate inflammatory skin diseases, even though only short-term use is approved for these agents and systemic inflammation is not addressed. Increased understanding of the immunopathogenesis of these conditions, especially for psoriasis and atopic dermatitis, has facilitated the development of antibody-based drugs that neutralize single key cytokines or their associated receptors, such as interleukin (IL)-17A/F, IL-23, and IL-17RA in psoriasis and IL-13 and IL-4Rα in atopic dermatitis. However, oral therapy is still preferred by many patients owing to the ease of use and needle-free administration. Phosphodiesterase 4 (PDE4) inhibitors have been approved for both oral and topical use for inflammatory skin diseases. In this review, we present a summary of an emerging class of selective PDE4B/D inhibitors under clinical development and compare the differences in selectivity of this new generation of PDE4 inhibitors with the less selective currently approved PDE4 inhibitors.