Summary
Romosozumab is a therapy that stimulates bone formation and reduces bone resorption. In this study of postmenopausal women with low BMD, a second course of romosozumab following a period off ...treatment or on denosumab increased or maintained BMD, respectively, and was well tolerated, providing insight into treatment sequence options.
Introduction
In patients with high fracture risk, therapies that stimulate bone formation provide rapid BMD gains; currently available agents, parathyroid hormone receptor agonists, are limited to a 2-year lifetime exposure and generally used for a single treatment course. However, for long-term osteoporosis management, a second treatment course may be appropriate. Romosozumab, a therapy with the dual effect of increasing bone formation and decreasing bone resorption, reduces fracture risk within 12 months. Here, we report efficacy and safety of a second romosozumab course.
Methods
In this phase 2, dose-finding study, postmenopausal women with low bone mass (T-score ≤ − 2.0 and ≥ − 3.5) received romosozumab or placebo (month 0–24) followed by placebo or denosumab (month 24–36); participants then received a year of romosozumab (month 36–48).
Results
Of 167 participants who entered the month 36–48 period, 35 had been initially randomized to romosozumab 210 mg monthly. In participants who received romosozumab 210 mg monthly followed by placebo, a second romosozumab course (
n
= 19) increased BMD by amounts similar to their initial treatment (month 0–12) at the lumbar spine (12.4%; 12.0%, respectively) and total hip (6.0%; 5.5%, respectively). Following denosumab, a second romosozumab course (
n
= 16) increased BMD at the lumbar spine (2.3%) and maintained BMD at the total hip. Safety profiles were similar between first and second romosozumab courses.
Conclusions
After 12 months off-treatment, a second romosozumab course again led to rapid and large BMD gains. Following denosumab, BMD gains with romosozumab were smaller than with initial treatment. No new safety findings were observed during the second course.
Real-time device-level hardware-in-the-loop (HIL) emulation of a complete high-speed rail system is challenging due to its complex modeling and high computing demand. With higher energy-efficient and ...switching frequency semiconductor material being found and adopted in the power electronic electrified traction application, there is a need to develop such new material based real-time device-level power electronic models in the modern and future traction system to estimate and verify the device switching transients, energy efficiency, and power quality improvement capability. This paper proposes a real-time SiC IGBT model based on the Wiener-Hammerstein configuration. A complete Beijing-Shanghai AC traction application is utilized as the study case, implemented on the hybrid multiprocessor system-on-chip (MPSoC) and field-programmable gate array (FPGA) platform, to verify both the system-level and device-level performance of the proposed model with comparisons to commercial software PSCAD/EMTDC and SaberRD. The dedicated hardware implementation enabled model execution at 10~ns for device-level transients and 10 μs for system-level transients.
Real-time device-level multi-domain emulation can provide an accurate insight into behavioral transients of the hydrogen fuel-cell hybrid electric bus (HEB). However, the conventional electromagnetic ...transient (EMT) simulation suffers from the computation burden caused by the complex multi-domain subsystems. This paper develops a hybrid recurrent neural network (RNN) and EMT method for device-level multi-domain emulation for fuel-cell and battery HEB. Two recurrent neural networks (RNN) are designed and trained to create device-level models of permanent magnet synchronous motor (PMSM) and the modular multilevel converter (MMC), respectively. The IGBTs' behavioral transients and thermal performance are integrated into the RNN-based MMC model. Moreover, the EMT models represent the energy behaviour of onboard fuel-cell stacks and battery stacks. The proposed multi-domain hybrid models are implemented on the Xilinx Versal™ adaptive compute acceleration platform (ACAP), where multiple AI engines and the programmable logic deal with the RNN and EMT models, respectively. The real-time hardware emulation is carried out at the time-step of 0.1<inline-formula> <tex-math notation="LaTeX">\mu \text{s} </tex-math></inline-formula> for device-level transients. The results show that the hybrid model has 96.3% accuracy; furthermore, it significantly reduces the HEB emulation time compared to conventional EMT methods.
Depletional induction therapies are routinely used to prevent acute rejection and improve transplant outcome. The effects of depleting agents on T‐cell subsets and subsequent T‐cell reconstitution ...are incompletely defined. We used flow cytometry to examine the effects of rabbit antithymocyte globulin (rATG) on the peripheral T‐cell repertoire of pediatric and adult renal transplant recipients. We found that while rATG effectively depleted CD45RA+CD27+ naïve and CD45RO+CD27+ central memory CD4+ T cells, it had little effect on CD45RO+CD27− CD4+ effector memory or CD45RA+CD31−, CD45RO+CD27+ and CD45RO+CD27− CD8+ T cell subsets. When we performed a kinetic analysis of CD31+ recent thymic emigrants and CD45RA+/RO+ T cells, we found evidence for both thymopoiesis and homeostatic proliferation contributing to immune reconstitution. We additionally examined the impact of rATG on peripheral CD4+Foxp3+ T cells. We found that in adults, administration of rATG‐induced peripheral expansion and new thymic emigration of T cells with a Treg phenotype, while CD4+Foxp3+ T cells of thymic origin predominated in children, providing the first evidence that rATG induces Treg in vivo. Collectively our data indicate that rATG alters the balance of regulatory to memory effector T cells posttransplant, providing an explanation for how it positively impacts transplant outcome.
This prospective study examines the contribution of thymopoiesis versus homeostatic proliferation to immune reconstitution following rATG and the influence of rATG on the emergence of Treg in renal transplant recipients.
Summary
Romosozumab, a sclerostin antibody, exerts dual effect to increase bone formation and decrease bone resorption. Among high-risk postmenopausal East Asian women, romosozumab followed by ...alendronate was associated with lower incidences of fractures vs alendronate alone. Romosozumab demonstrates potential to address an unmet need in osteoporosis management in Asia.
Introduction
Romosozumab, a sclerostin antibody, exerts dual effect to increase bone formation and decrease bone resorption. The global ARCH study demonstrated superiority of romosozumab followed by alendronate in reducing fracture risk in high-risk postmenopausal osteoporotic women vs alendronate alone. We report outcomes among ARCH East Asian patients.
Methods
In ARCH, 4093 postmenopausal osteoporotic women with fragility fracture were randomized 1:1 to monthly romosozumab 210 mg or weekly alendronate 70 mg for 12 months, both followed by open-label alendronate. Primary endpoints were incidence of new vertebral fracture (VF) at 24 months and clinical fracture at primary analysis (confirmed fractures in ≥ 330 patients and all patients had opportunity to attend month 24 visit). This post hoc analysis was not powered to detect fracture-rate differences.
Results
This analysis included 275 patients from Hong Kong, Korea, and Taiwan. Romosozumab followed by alendronate reduced risk of new VFs at 24 months by 60% (
P
= 0.11) and clinical fractures at primary analysis by 44% (
P
= 0.15) vs alendronate alone. Romosozumab followed by alendronate significantly increased mean bone mineral density at 24 months from baseline by a further 9.0%, 3.3%, and 3.0% at the lumbar spine, total hip, and femoral neck vs alendronate alone. Adverse event (AE) rates, including positively adjudicated serious cardiovascular AEs (1.6% vs 1.4% at 12 months for romosozumab vs alendronate), were similar across treatment groups.
Conclusions
Consistent with the global analysis, romosozumab followed by alendronate was associated with lower incidences of new vertebral, clinical, non-vertebral, and hip fractures vs alendronate alone among East Asian patients.
With improved survival in the antiretroviral era, data from ongoing studies suggest that HIV patients can be safely transplanted. The disproportionate burden of HIV‐related end‐stage renal disease in ...minority populations may impose additional obstacles to successful completion of the transplant evaluation. We retrospectively reviewed 309 potentially eligible HIV patients evaluated for kidney transplant at our institution since 2000. Only 20% of HIV patients have been listed, compared to 73% of HIV‐negative patients evaluated over the same period (p < 0.00001). Failure to provide documentation of CD4 and viral load (36% of candidates) was the most common reason for failure to progress beyond initial evaluation. Other factors independently associated with failure to complete the evaluation included CD4 < 200 at initial evaluation (OR 15.17; 95% CI 1.94–118.83), black race (OR 2.33; 95% CI 1.07–5.06), and history of drug use (OR 2.56; 95% CI 1.22–5.37). More efficient medical record sharing and an awareness of factors associated with failure to list HIV‐positive transplant candidates may enable transplant centers to more effectively advocate for these patients.
This study retrospectively analyzes the HIV+ patients referred for kidney transplant evaluation and examines the barriers to listing they experience.
Shunt capacitors are extensively used in power systems for voltage support and power factor correction. The proliferation of harmonic-producing loads significantly increases the possibility of ...system-capacitor resonance. As a result, a practical and easy-to-use procedure to estimate the severity of harmonic resonance is of good interest to industry. The objective of this paper is to present such a method. The paper first proposes a harmonic resonance index. By taking into account the IEEE harmonic limits and the capacitor loading limits, a harmonic resonance chart is developed. A detailed harmonic analysis of the system is needed only if the system condition is located in certain regions of the chart. Examples are given to show how the possibility and severity of harmonic resonance can be estimated using the proposed guideline.
This paper presents a new approach for the real-time digital simulation of power electronic controllers in power systems. Digital controllers for power electronic systems present a problem when ...testing in real-time using a digital simulator due to the discrete nature of their outputs which are not necessarily in synchronism with the time step of the simulator. The proposed algorithm combines the variable step-size numerical integration method with linear interpolation for the synchronization of a real-time digital simulator and a digital controller. It is shown that lack of such synchronization leads to inaccurate simulation results, specifically with regard to the fundamental and harmonics of the voltage and current signals. Sampling theory is used to model the interaction between a digital simulator and a digital controller. A pulse width modulated (PWM) voltage source converter (VSC) based reactive power compensator system is used as an illustrative example for the simulation.
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