Chemical Classification of Spherules Recovered From The Pacific Ocean Site of The CNEOS 2014-01-08 (IM1) Bolide

We have conducted an extensive towed-magnetic-sled survey during the period of June 14-28, 2023, over the seafloor about 85 km north of Manus Island, Papua New Guinea, centered around the calculated path of the bolide CNEOS 2014-01-08 (IM1). We found about 850 spherules of diameter 0.1-1.3 millimeters in our samples. The samples were analyzed by micro-XRF, Electron Probe Microanalyzer and ICP Mass spectrometry. Here we report major and trace element compositions of the samples and classify spherules based on that analysis. We identified 78% of the spherules as primitive, in that their compositions have not been affected by planetary differentiation. We divided these into four groups corresponding to previously described cosmic spherule types. The remaining 22% appear to all reflect planetary igneous differentiation and are all different from previously described spherules. We call them D-type spherules. A portion of the D-spherules show an excess of Be, La and U, by up to three orders of magnitude relative to the solar system standard of CI chondrites. Detailed mass spectroscopy of 12 of these BeLaU-type spherules, the population of which may constitute up to ~10% of our entire collected sample, suggests that they are derived from material formed by planetary igneous fractionation. Their chemical composition is unlike any known solar system material. We compare these compositions to known differentiated bodies in the solar system and find them similar to evolved planetary materials - with lunar KREEP the closest in terms of its trace element enrichment pattern, but unusual in terms of their elevated CI-normalized incompatible elements. The BeLaU-type spherules reflect a highly differentiated, extremely evolved composition of an unknown source.Comment: 26 pages, 20 figures, submitted for publicatio

Two-year results of disease activity score (DAS)-remission-steered treatment strategies aiming at drug-free remission in early arthritis patients (the IMPROVED-study)

Background: Early suppression of disease activity in (rheumatoid) arthritis (RA) patients may result in drug-free remission and prevent damage. We assessed 2-year clinical and radiological outcomes of two disease activity score (DAS)-remission-steered treatment strategies in early arthritis patients.Methods: Patients (n = 610) with early RA or undifferentiated arthritis (UA) were treated with methotrexate (MTX) and tapered high dose of prednisone. Patients in early remission (44/53 joints DAS <1.6) after 4 months tapered and stopped medication. Patients who did not achieve early DAS-remission were randomized to either MTX plus hydroxychloroquine plus sulphasalazine plus low dose prednisone (arm 1) or to MTX + adalimumab (arm 2). At four-monthly intervals, medication was tapered and stopped if DAS was <1.6 but restarted, increased or switched if DAS was ≥1.6. Proportions of (drug-free) DAS-remission (DFR) after 2 years and Sharp-van der Heijde scores (SHS) were analyzed separately for the treatment strategies and patients with RA and UA.Results: After 2 years, 301/610 (49 %) patients were in DAS-remission and 131/610 (21 %) in DFR. In the early remission group 241/387 patients (62 %) were in DAS-remission and 111/387 (29 %) DFR. In arm 1 22/83 (27 %) and in arm 2 24/78 (31 %) were in DAS-remission, and 6/83 (7 %) and 7/78 (9 %), respectively, were in DFR. RA and UA patients achieved DAS-remission in comparable percentages (RA: 234/479 (49 %), UA: 64/122 (52 %), p = 0.25). More UA patients achieved DFR (41/122 (34 %)) compared to RA patients (89/479 (19 %), p<0.001). Mean (SD) DAS over time was 1.74 (0.58) across all patients, and median (IQR) SHS progression was 0 (0–0).Conclusions: After 2 years remission-steered treatment in early RA and UA patients, DAS-remission and DFR percentages were relatively low. Patients who achieved early remission more often achieved (drug-free) remission after 2 years than patients who needed additional treatment steps in the randomization arms, and more UA than RA patients achieved DFR. Overall, disease activity and radiologic damage progression in all patients were well suppressed.Trial registration: http://www.controlled-trials.com/ISRCTN11916566 Registered 07/11/2006 and EudraCT number 2006-06186-16 Registered 16/07/2007

Topical microbicides to prevent the transmission of HIV: formulation gaps and challenges

The efforts of the topical microbicide field to identify a safe and effective topical microbicide were realized in July of 2010 with the reporting of the results of the Centre for the AIDS Programme of Research in South Africa 004 trial. In this trial, a 1% tenofovir gel was found to reduce women’s risk for HIV acquisition by 39% compared to placebo. To understand the impact of this trial on future microbicide development, we must view it from the historical perspective of previous phases 2 and 3 clinical trials with detergents and sulfated polyanions. This knowledge and emerging information must then be parlayed into the next steps needed to create a safe, effective, and acceptable topical microbicide. This review will look at the lessons learned from preclinical and clinical development of topical microbicides, focusing on two significant future challenges: (1) topical microbicide formulation safety and (2) the critical role that adherence to product use has in determining safety and efficacy in clinical trials and ultimately commercial viability of the licensed product. In addition to framing these issues within our current understanding of formulation and prevention of HIV acquisition, recent advances in our understanding of the mechanism of HIV transmission and how it informs on future formulation strategies will be briefly discussed

Management of rheumatoid arthritis: consensus recommendations from the Hong Kong Society of Rheumatology

Given the recent availability of novel biologic agents for the treatment of rheumatoid arthritis (RA), the Hong Kong Society of Rheumatology has developed consensus recommendations on the management of RA, which aim at providing guidance to local physicians on appropriate, literature-based management of this condition, specifically on the indications and monitoring of the biologic disease-modifying anti-rheumatic drugs (DMARDs). The recommendations were developed using the European League Against Rheumatism (EULAR) recommendations for the management of early arthritis as a guide, along with local expert opinion. As significant joint damage occurs early in the course of RA, initiating therapy early is key to minimizing further damage and disability. Patients with serious disease or poor prognosis should receive early, aggressive therapy. Because of its good efficacy and safety profile, methotrexate is considered the standard first-line DMARD for most treatment-naïve RA patients. Patients with a suboptimal response to methotrexate monotherapy should receive step-up (combination) therapy with either the synthetic or biologic DMARDs. In recent years, combinations of methotrexate with tocilizumab, abatacept, or rituximab have emerged as effective therapies in patients who are unresponsive to traditional DMARDs or the anti-tumor necrosis factor (TNF)-α agents. As biologic agents can increase the risk of infections such as tuberculosis and reactivation of viral hepatitis, screening for the presence of latent tuberculosis and chronic viral hepatitis carrier state is recommended before initiating therapy

Thrombocytogenesis by megakaryocyte; Interpretation by protoplatelet hypothesis

Serial transmission electron microscopy of human megakaryocytes (MKs) revealed their polyploidization and gradual maturation through consecutive transition in characteristics of various organelles and others. At the beginning of differentiation, MK with ploidy 32N, e.g., has 16 centrosomes in the cell center surrounded by 32N nucleus. Each bundle of microtubules (MTs) emanated from the respective centrosome supports and organizes 16 equally volumed cytoplasmic compartments which together compose one single 32N MK. During the differentiation, single centriole separated from the centriole pair, i.e., centrosome, migrates to the most periphery of the cell through MT bundle, corresponding to a half of the interphase array originated from one centrosome, supporting one “putative cytoplasmic compartment” (PCC). Platelet demarcation membrane (DM) is constructed on the boundary surface between neighbouring PCCs. Matured PCC, composing of a tandem array of platelet territories covered by a sheet of DM is designated as protoplatelet. Eventually, the rupture of MK results in release of platelets from protoplatelets