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.
To analyse the long-term safety of adalimumab treatment.
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.
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.
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.
Comets are remnants of the icy planetesimals that formed beyond the ice line in the solar nebula. Growing from mu m-sized dust and ice particles to km-sized objects is, however, difficult because of ...growth barriers and time scale constraints. We study the collisional compression of silica, ice, and silica/ice-mixed pebbles during gravitational collapse of pebble clouds. Using the initial volume-filling factor and the dust-to-ice ratio of the pebbles as free parameters, we constrain the dust-to-ice mass ratio of the formed comet and the resulting volume-filling factor of the pebbles, depending on the cloud mass. We use the representative particle approach, which is a Monte Carlo method, to follow cloud collapse and collisional evolution of an ensemble of ice, silica, and silica/ice-mixed pebbles. Except for the very low-mass cloud, silica pebbles are always compressed during the collapse and attain volume-filling factors in the range from f V ~ 0.22 to 0.43, regardless of f0.
Abstract
We report new light curves and phase functions for nine Jupiter-family comets (JFCs). They were observed in the period 2004–2015 with various ground telescopes as part of the Survey of ...Ensemble Physical Properties of Cometary Nuclei as well as during devoted observing campaigns. We add to this a review of the properties of 35 JFCs with previously published rotation properties. The photometric time series were obtained in Bessel R, Harris R and SDSS r
΄ filters and were absolutely calibrated using stars from the Pan-STARRS survey. This specially developed method allowed us to combine data sets taken at different epochs and instruments with absolute-calibration uncertainty down to 0.02 mag. We used the resulting time series to improve the rotation periods for comets 14P/Wolf, 47P/Ashbrook–Jackson, 94P/Russell and 110P/Hartley 3 and to determine the rotation rates of comets 93P/Lovas and 162P/Siding Spring for the first time. In addition to this, we determined the phase functions for seven of the examined comets and derived geometric albedos for eight of them. We confirm the known cut-off in bulk densities at ∼0.6 g cm−3 if JFCs are strengthless. Using a model for prolate ellipsoids with typical density and elongations, we conclude that none of the known JFCs requires tensile strength larger than 10–25 Pa to remain stable against rotational instabilities. We find evidence for an increasing linear phase function coefficient with increasing geometric albedo. The median linear phase function coefficient for JFCs is 0.046 mag deg−1 and the median geometric albedo is 4.2 per cent.
Context.
A large fraction of transneptunian objects are found in binary pairs, ~30% in the cold classical population between
a
hel
~ 39 and ~48 AU. Observationally, these binaries generally have ...components of similar size and colour. Previous work has shown that gravitational collapse of a pebble cloud is an efficient mechanism for producing such systems. Since the bi-lobate nature of 2014 MU
69
(Arrokoth) was discovered, interest in gravitational collapse as a pathway for forming contact binaries has also grown.
Aims.
We investigate the formation of binary systems through gravitational collapse by considering a wider range of binary masses than previous studies. We analysed in detail the properties of the bound systems that are formed and compared them to observations.
Methods.
We performed
N
-body simulations of gravitational collapse of a pebble cloud using the
REBOUND
package, with an integrator designed for rotating reference frames and robust collision detection. We conducted a deep search for gravitationally bound particles at the end of the gravitational collapse phase and tested their stability. For all systems produced, not just for the most massive binaries, we investigated the population characteristics of their mass and orbital parameters.
Results.
We found that gravitational collapse is an efficient producer of bound planetesimal systems. On average, about 1.5 bound systems were produced per cloud in the mass range studied here. In addition to large equal-sized binaries, we found that gravitational collapse produces massive bodies with small satellites and low-mass binaries with a high mass ratio. Our results disfavour the collapse of high-mass clouds, in line with reported upper mass limits of clouds formed by the streaming instability. Gravitational collapse can create binary systems analogous to Arrokoth, and collisions in a collapsing cloud should be gentle enough to preserve a bi-lobed structure.
The Photovoltaic (PV) solar energy is an essential source for the transition of non-renewable energy generation to clean energy generation worldwide. One of the options to increase participation of ...PV in the Brazilian energy matrix is to invest in Small-scale Distributed Generation (DG). However, this generation represents less than 0.3% of the demand consumed in the captive market of the country. Even though Brazilian consumers are interested in purchasing PV systems, selling the system is still a challenge for the industry, since the sale conversion rate represented only 6.88% in 2018. In this context, this research aims to discuss what are the Critical Success Factors (CSFs) for the growth of the of photovoltaic solar energy in small scale in Brazil. The results of the study provided a total of 43 CSFs, which were cited 165 times by the selected articles, capable of explaining the success of the PV energy in Brazil. A hierarchical structure was structured, grouping the CSFs into six Fundamental Viewpoints (FV): economic; environmental; marketing; political; social, and technological. Through this analysis, it was possible to determine which CSFs are favorable aspects and barriers to the success of this technology, which may not enable the operation of productive systems with cleaner sources of energy.
Display omitted
•We reviewed 123 studies of the Solar PV Energy and extracted 43 Critical Success Factors (CSF)•The CSFs were organized in a Hierarchical Tree with three levels and six Fundamental Viewpoints (FV)•We analyzed the CSF in the context of Brazil through facts published in law, news, reports, and articles•The impeditive and favorable factors in achieving the success of small-scale PV generation was identified
Ever since the very first photometric studies of Centaurs and Kuiper belt objects (KBOs) their visible color distribution has been controversial. This controversy has triggered to a prolific debate ...on the origin of the surface colors of these distant icy objects of the solar system. Two scenarios have been proposed to interpret and explain the large variability of colors, hence surface composition. Are the colors mainly primordial and directly related to the formation region, or are they the result of surface evolution processes? To date, no mechanism has been found that successfully explains why Centaurs, which are escapees from the Kuiper belt, exhibit two distinct color groups, whereas KBOs do not. We readdress this issue using a carefully compiled set of B − R colors and HR(α) magnitudes (as proxy for size) for 253 objects, including data for 10 new small objects. We find that the bimodal color distribution of Centaurs is a size-related phenomenon, common to both Centaurs and small KBOs, i.e. independent of dynamical classification. Furthermore, we find that large KBOs also have a bimodal distribution of surface colors, albeit distinct from the small objects and strongly dependent on the “Haumea collisional family” objects. When plotted in B − R, HR(α) space, the colors of Centaurs and KBOs display a peculiar 𝒩 shape.
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.
Metal complexes based on ruthenium have established excellent activity with less toxicity and great selectivity for tumor cells. This study aims to assess the anticancer potential of ...ruthenium(II)/allopurinol complexes called RuCl
2
(allo)
2
(PPh
3
)
2
(
1
) and RuCl
2
(allo)
2
(dppb) (
2
), where allo means allopurinol, PPh
3
is triphenylphosphine and dppb, 1,4-bis(diphenylphosphino)butane. The complexes were synthesized and characterized by elemental analysis, IR, UV–Vis and NMR spectroscopies, cyclic voltammetry, molar conductance measurements, as well as the X-ray crystallographic analysis of complex
2
. The antitumor effects of compounds were determined by cytotoxic activity and cellular and molecular responses to cell death mechanisms. Complex
2
showed good antitumor profile prospects because in addition to its cytotoxicity, it causes cell cycle arrest, induction of DNA damage, morphological and biochemical alterations in the cells. Moreover, complex
2
induces cell death by p53-mediated apoptosis, caspase activation, increased Beclin-1 levels and decreased ROS levels. Therefore, complex
2
can be considered a suitable compound in antitumor treatment due to its cytotoxic mechanism.
Graphic abstract
In this paper, four new ruthenium complexes, Ru(N-S)(dppm)2PF6 (1), Ru(N-S)(dppe)2PF6 (2), Ru(N-S)2(dppp) (3) and Ru(N-S)2(PPh3)2 (4) dppm = 1,1-bis(diphenylphosphino)methane, dppe = ...1,2-bis(diphenylphosphino)ethane, dppp = 1,3-bis(diphenylphosphino)propane, PPh3 = triphenylphosphine and N-S = 2-mercaptopyrimidine anion were synthesized and characterized using spectroscopy techniques, molar conductance, elemental analysis, electrochemical techniques and X-ray diffraction. The DNA binding studies were investigated using voltammetry and spectroscopy techniques. The results show that all complexes exhibit a weak interaction with DNA. HSA interaction with the complexes was studied using fluorescence emission spectroscopy, where the results indicate a spontaneous interaction between the species by a static quenching mechanism. The cytotoxicity of the complexes was evaluated against A549, MDA-MB-231 and HaCat cells by MTT assay. Complexes (1) and (2), which are very active against triple negative MDA-MB-231, were subjected to further biological tests with this cell line. The cytotoxic activity triggered by the complexes was confirmed by clonogenic assay. Cell cycle analyses demonstrated marked anti-proliferative effects, especially at the G0/G1 and S phases. The morphological detection of apoptosis and necrosis - HO/PI and Annexin V-FITC/PI assay, elucidated that the type of cell death triggered by these complexes was probably by apoptosis. The in vivo toxicological assessment performed on zebrafish embryos revealed that complexes (1) and (2) did not present embryotoxic or toxic effects during embryonic and larval development showing that they are promising new prototypes of safer and more effective drugs for triple negative breast cancer treatment.
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