Objectives This phase III study evaluated the efficacy and safety of rituximab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to MTX and who ...were naïve to prior biological treatment. Methods Patients with active disease on stable MTX (10–25 mg/week) were randomised to rituximab 2×500 mg (n=168), rituximab 2×1000 mg (n=172), or placebo (n=172). From week 24, patients not in remission (Disease Activity Score (28 joints) ≥2.6) received a second course of rituximab; patients initially assigned to placebo switched to rituximab 2×500 mg. The primary end point was American College of Rheumatology 20 (ACR20) response at week 24. All patients were followed until week 48. Results At week 24, both doses of rituximab showed statistically superior efficacy (p<0.0001) to placebo (ACR20: 54%, 51% and 23%; rituximab (2×500 mg) + MTX, rituximab (2×1000 mg) + MTX and placebo + MTX, respectively). Secondary end points were also significantly improved for both rituximab groups compared with placebo. Further improvements in both rituximab arms were observed from week 24 to week 48. Rituximab + MTX was well tolerated, demonstrating comparable safety to placebo + MTX through to week 24, and between rituximab doses through to week 48. Conclusions Rituximab (at 2×500 mg and 2×1000 mg) plus MTX significantly improved clinical outcomes at week 24, which were further improved by week 48. No significant differences in either clinical or safety outcomes were apparent between the rituximab doses.
, a gram-negative anaerobe, is a leading etiological agent in periodontitis. This infectious pathogen can induce a dysbiotic, proinflammatory state within the oral cavity by disrupting commensal ...interactions between the host and oral microbiota. It is advantageous for
to avoid complete host immunosuppression, as inflammation-induced tissue damage provides essential nutrients necessary for robust bacterial proliferation. In this context,
can gain access to the systemic circulation, where it can promote a prothrombotic state.
expresses a number of virulence factors, which aid this pathogen toward infection of a variety of host cells, evasion of detection by the host immune system, subversion of the host immune responses, and activation of several humoral and cellular hemostatic factors.
Autonomous driving relies on high accuracy point vector map, which was generated by the point cloud map, and pre-provides the vehicle preliminary road environment information. Lidar Odometry and ...Mapping (LOAM) has always been a promising research topic in the field of robotics, environment sensing, and currently autonomous driving. However, in certain urban environments like basement parking lot, tunnels, highways, or other similar settings, the geometric features are not clearly discernible. As a result, algorithms resembling the LOAM framework may encounter difficulties in accurately mapping these areas. The paper utilized relative low-cost LiDAR expecting to propose a state-of-the-art point cloud mapping/update scheme. We compared the GNSS-challenge area with straight line and loop area separately, simultaneously considered the DG, ICP, NDT matching algorithm for the low-cost mapping/update strategy. With the realistic experiment conduction, our result evaluated by point to point corresponding mean error and standard error. For the straight line environment, ICP has the fastest convergence in empirical cumulative distribution under 0.4 meters. For the loop scenario, point-to-point ICP still has the fastest convergence in empirical cumulative distribution under 0.22 meters. Yet both of them still suffer from the fault matching.
Little is known about how changes in DNA methylation mediate risk for human diseases including dementia. Analysis of genome-wide methylation patterns in patients with two forms of tau-related ...dementia--progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD)--revealed significant differentially methylated probes (DMPs) in patients versus unaffected controls. Remarkably, DMPs in PSP were clustered within the 17q21.31 region, previously known to harbor the major genetic risk factor for PSP. We identified and replicated a dose-dependent effect of the risk-associated H1 haplotype on methylation levels within the region in blood and brain. These data reveal that the H1 haplotype increases risk for tauopathy via differential methylation at that locus, indicating a mediating role for methylation in dementia pathophysiology.
The International Olympic Committee (IOC) recently published a framework on fairness, inclusion, and nondiscrimination on the basis of gender identity and sex variations. Although we appreciate the ...IOC's recognition of the role of sports science and medicine in policy development, we disagree with the assertion that the IOC framework is consistent with existing scientific and medical evidence and question its recommendations for implementation. Testosterone exposure during male development results in physical differences between male and female bodies; this process underpins male athletic advantage in muscle mass, strength and power, and endurance and aerobic capacity. The IOC's “no presumption of advantage” principle disregards this reality. Studies show that transgender women (male‐born individuals who identify as women) with suppressed testosterone retain muscle mass, strength, and other physical advantages compared to females; male performance advantage cannot be eliminated with testosterone suppression. The IOC's concept of “meaningful competition” is flawed because fairness of category does not hinge on closely matched performances. The female category ensures fair competition for female athletes by excluding male advantages. Case‐by‐case testing for transgender women may lead to stigmatization and cannot be robustly managed in practice. We argue that eligibility criteria for female competition must consider male development rather than relying on current testosterone levels. Female athletes should be recognized as the key stakeholders in the consultation and decision‐making processes. We urge the IOC to reevaluate the recommendations of their Framework to include a comprehensive understanding of the biological advantages of male development to ensure fairness and safety in female sports.
Demographic changes increase the necessity to base the pension system more and more on the second and the third pillars, namely the occupational and private pension plans; this paper deals with ...Target Date Funds (TDFs), which are a typical investment opportunity for occupational pension planners. TDFs are usually identified with a decreasing fraction of wealth invested in equity (a so-called glide path) as retirement comes closer, i.e. wealth is invested more riskily the younger the saver is. We investigate whether this is actually optimal in the presence of non-tradable income risk in a stochastic volatility environment. The retirement planning procedure is formulated as a stochastic optimization problem. We find it is the (random) contributions that induce the optimal path exhibiting a glide path structure, both in the constant and stochastic volatility environment. Moreover, the initial wealth and the initial contribution made to a retirement account strongly influence the fraction of wealth invested in risky assets. The risk aversion of an individual mainly determines the shape of the glide path, while the ratio of the wealth and income influences the steepness of the glide path.
The western part of the Kuroshio Intermediate Water originates from the nutrient‐rich South China Sea intermediate water which upwells onto the East China Sea (ECS) continental shelf and contributes ...a large amount of nutrients to the ECS. This contribution, especially for phosphorus, is far more than the inputs from the phosphorus‐deficient Yangtze and Yellow Rivers. Mass balance calculations reveal that the net denitrification rate in the ECS shelf is 95 ± 50 × 109 mol N yr−1, which is more than the total riverine supply of nitrogen. The nutrient supply allows the ECS to produce 1030 ± 310 × 109 moles dissolved organic carbon and 709 ± 280 × 109 mol particulate organic carbon for a total of 1739 ± 870 × 109 mol organic carbon per year, which translates to a new production rate of phytoplankton as 64 ± 32 mg C m−2 d−1 or 15% of the average primary production rate. The downslope transport of modern particulate carbon is 2547 ± 1250 × 109 mol yr−1, of which 695 ± 350 × 109 mol yr−1 is organic. This value is only 12% of the offshore dissolved organic carbon transport of 5563 ± 1700 × 109 mol yr−1. The alkalinity budget, never attempted before, indicates that there is a substantial amount of alkalinity generation in the sediments (3.9 ± 3.9 mmol m−2 d−1) due to anaerobic respiration such as by iron and sulfate reductions.
Invasive fungal disease (IFD) associated with Coronavirus Disease 2019 (COVID-19) has focussed predominantly on invasive pulmonary aspergillosis. However, increasingly emergent are non-
fungal ...infections including candidiasis, mucormycosis, pneumocystosis, cryptococcosis, and endemic mycoses. These infections are associated with poor outcomes, and their management is challenged by delayed diagnosis due to similarities of presentation to aspergillosis or to non-specific features in already critically ill patients. There has been a variability in the incidence of different IFDs often related to heterogeneity in patient populations, diagnostic protocols, and definitions used to classify IFD. Here, we summarise and address knowledge gaps related to the epidemiology, risks, diagnosis, and management of COVID-19-associated fungal infections other than aspergillosis.
Acute myeloid leukemia (AML) is a hematological malignancy that is characterized by an expansion of immature myeloid precursors. Despite therapeutic advances, the prognosis of AML patients remains ...poor and there is a need for the evaluation of promising therapeutic candidates to treat the disease. The objective of this study was to evaluate the efficacy of duocarmycin Stable A (DSA) in AML cells in vitro. We hypothesized that DSA would induce DNA damage in the form of DNA double-strand breaks (DSBs) and exert cytotoxic effects on AML cells within the picomolar range. Human AML cell lines Molm-14 and HL-60 were used to perform 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT), DNA DSBs, cell cycle, 5-ethynyl-2-deoxyuridine (EdU), colony formation unit (CFU), Annexin V, RNA sequencing and other assays described in this study. Our results showed that DSA induced DNA DSBs, induced cell cycle arrest at the G2M phase, reduced proliferation and increased apoptosis in AML cells. Additionally, RNA sequencing results showed that DSA regulates genes that are associated with cellular processes such as DNA repair, G2M checkpoint and apoptosis. These results suggest that DSA is efficacious in AML cells and is therefore a promising potential therapeutic candidate that can be further evaluated for the treatment of AML.
The vestibular end-organs encode for linear and angular head accelerations in space contributing to our internal representation of self-motion. Activation of the vestibular system with transmastoid ...electrical current has recently grown in popularity; however, a direct relationship between electrically evoked and mechanically evoked vestibular responses remains elusive in humans. We have developed and tested a mechanical-to-electrical vestibular stimulus conversion model incorporating physiological activation of primary vestibular afferents identified in nonhuman primates. We compared ocular torsional responses between mechanical (chair rotation) and model-derived electrical (binaural-bipolar) stimuli in separate experiments for an angular velocity step change (±10 deg/s over 1 s, ±4-mA peak amplitude;
= 10) and multisine angular velocities (±10 deg/s, 9.7 mA peak to peak, 0.05-1 Hz;
= 5), respectively. Perception of whole body rotation (
= 18) to our step-change stimuli was also evaluated. Ocular torsional slow-phase velocity responses between stimulation types were similar (paired two one-sided tests of equivalence: multiple
< 0.002; one-sample
test:
= 0.178) and correlated (Pearson's coefficient: multiple
< 0.001). Bootstrap analysis of perceived angular velocity likewise showed similarity in perceptual decay dynamics. These data suggest that central processing between stimuli was similar, and our vestibular stimulus conversion model with a conversion factor of ∼0.4 mA per deg/s for an angular velocity step change can generate electrical stimuli that replicates dynamic vestibular activation elicited by mechanical whole body rotations. This proposed vestibular conversion model represents an initial framework for using electrical stimuli to generate mechanically equivalent activation of primary vestibular afferents for use in biomedical applications and immersive reality technologies.
With the growing popularity of electrical vestibular stimulation in biomedical and immersive reality applications, a direct conversion model between electrical and mechanical vestibular stimuli is needed. We developed a model to generate electrical stimuli mimicking the physiological activation of vestibular afferents evoked by mechanical rotations. Ocular and perceptual responses evoked by mechanical and model-derived electrical stimuli were similar, thus providing a critical first step toward generation of electrically induced vestibular responses that have a realistic mechanical equivalent.
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