Summary
What is known and objective
Roxadustat is a hypoxia‐inducible factor prolyl hydroxylase inhibitor currently being investigated for the treatment of anemia in chronic kidney disease. Lanthanum ...carbonate is a phosphate binder that is commonly used to treat hyperphosphatemia in patients with chronic kidney disease. This study investigated the effect of lanthanum carbonate on the pharmacokinetics, safety and tolerability of a single oral dose of roxadustat in healthy non‐elderly adult male subjects.
Methods
This was an open‐label, randomized, two‐period, two‐sequence crossover study in non‐elderly healthy adult males. Subjects randomized to Group 1 received roxadustat alone during Period 1 and roxadustat concomitantly with lanthanum carbonate during Period 2; subjects randomized to Group 2 received roxadustat concomitantly with lanthanum carbonate during Period 1 and roxadustat alone during Period 2. All subjects received a single oral dose of 100 mg roxadustat on Day 1 in both periods. Subjects receiving concomitant lanthanum carbonate received 750 mg lanthanum carbonate three times daily on Days 1 and 2. Pharmacokinetic assessments were conducted on Days 1‐4 in both periods. The primary study outcomes were the area under the concentration‐time curve from the time of dosing extrapolated to infinity (AUCinf), and maximum concentration (Cmax); the geometric least squares mean ratio (GMR; roxadustat + lanthanum carbonate/roxadustat alone) and corresponding 90% confidence interval (CI) was calculated for AUCinf and Cmax. Safety was assessed by the occurrence of treatment‐emergent adverse events (TEAEs), laboratory test results, vital signs and standard 12‐lead electrocardiogram.
Results and discussion
A total of 18 subjects were enrolled (Group 1, n = 9; Group 2, n = 9); no subjects discontinued from the study. Roxadustat was rapidly absorbed, reaching maximum plasma concentration between 1 and 4 hours. The GMRs for AUCinf and Cmax were 88.00% (90% CI: 84.01, 92.17) and 98.58% (90% CI: 92.92, 104.58), respectively. The 90% CIs for both parameters were within the no‐effect boundaries of 80% and 125%, indicating a lack of effect of lanthanum carbonate on roxadustat absorption. No deaths or serious TEAEs occurred.
What is new and conclusions
Concomitant administration of a single oral dose of 100 mg roxadustat and 750 mg lanthanum carbonate three times daily did not impact the AUCinf or Cmax of roxadustat and was considered safe and well tolerated in non‐elderly healthy adult male Japanese subjects.
Roxadustat is currently being investigated for the treatment of anaemia in chronic kidney disease. This study investigated the effect of lanthanum carbonate, a phosphate binder, on the pharmacokinetics, safety, and tolerability of a single oral dose of roxadustat in healthy nonelderly adult male subjects. Concomitant administration of roxadustat and lanthanum carbonate did not impact the AUCinf or Cmax of roxadustat.
A new scenario is presented for the cause of magnetospheric relativistic electron decreases (REDs) and potential effects in the atmosphere and on climate. High‐density solar wind heliospheric ...plasmasheet (HPS) events impinge onto the magnetosphere, compressing it along with remnant noon‐sector outer‐zone magnetospheric ~10‐100 keV protons. The betatron accelerated protons generate coherent electromagnetic ion cyclotron (EMIC) waves through a temperature anisotropy (T⊥/T|| > 1) instability. The waves in turn interact with relativistic electrons and cause the rapid loss of these particles to a small region of the atmosphere. A peak total energy deposition of ~3 × 1020 ergs is derived for the precipitating electrons. Maximum energy deposition and creation of electron‐ion pairs at 30‐50 km and at < 30 km altitude are quantified. We focus the readers' attention on the relevance of this present work to two climate change mechanisms. Wilcox et al. (1973) noted a correlation between solar wind heliospheric current sheet (HCS) crossings and high atmospheric vorticity centers at 300 mb altitude. Tinsley et al. () has constructed a global circuit model which depends on particle precipitation into the atmosphere. Other possible scenarios potentially affecting weather/climate change are also discussed.
Key Points
Heliospheric plasmasheet impingements on the magnetosphere lead to relativistic electron losses
Compressing the magnetosphere causes generation of coherent EMIC waves which confine electron losses to small region of dayside ionosphere
Energy deposition and ionization at low altitudes may cause Wilcox effect and Tinsley effect
This paper describes a phase-locked multicarrier light source that employs a continuous wave (CW) light source, two phase modulators, and a dispersion medium. A sinusoidal phase modulation (PM) with ...a modulation index of ¿/4 and a group velocity dispersion of ±1/(4¿ fm 2 ), where fm is the modulation frequency, are applied to a CW light followed by a large sinusoidal PM. This configuration provides a multicarrier light with a flattened optical power spectrum for any modulation index of the second PM. By adopting a chirped fiber Bragg grating (FBG) as a dispersion medium instead of a long normal dispersion fiber, we can increase the stability of the optical output spectrum and reduce the size of the multicarrier light generator. We have built a prototype with this configuration that generates a 61-carrier light with a 25 GHz interval and a power deviation of less than 8 dB.
Purpose
Tryptophan metabolites have immunomodulatory functions, suggesting possible roles in cancer immunity.
Methods
Plasma tryptophan metabolites were measured using liquid chromatography/mass ...spectrometry before immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer (NSCLC).
Results
The 19 patients with NSCLC had significantly lower levels of tryptophan (
p
= 0.002) and xanthurenic acid (
p
= 0.032), and a significantly higher level of 3-hydroxyanthranilic acid (3-HAA) (
p
= 0.028) compared with the 10 healthy volunteers. The patients achieving objective responses had significantly lower levels of 3-HAA than those who did not (
p
= 0.045). Receiver operating characteristic analyses determined that the cutoff value of 3-HAA for objective response was 35.4 pmol/mL (sensitivity: 87.5% and specificity: 83.3%). The patients with 3-HAA < 35.4 pmol/mL had significantly longer median progression-free survival (7.0 months) than those without (1.6 months,
p
= 0.022).
Conclusions
Tryptophan metabolites may have a potential for predicting the efficacy of ICIs.
Registration number
University Hospital Medical Information Network Clinical Trial Registry 000026140.
The effect of heat treatment on conformational and structural properties of sugar beet pectin (SBP) was investigated using Ubbelohde capillary viscometry and Fourier Transform Infrared (FT-IR) ...spectroscopy. Intrinsic viscosity, η, was estimated from the Rao plot for the Fedors-Rao equation, indicating degradation of SBP by heat treatment. The temperature T dependence of η for both SBPs in an aqueous solution was studied from T = 30–60°C. The value of η was found to decrease with increasing temperature for all samples. This result indicated that the hydrodynamic volume of SBP becomes smaller with increasing T, which could be attributed to an increase in hydrophobic interaction and decreased softening of chain stiffness with increasing temperature. Compositional change due to heat treatment was investigated using FT-IR over the region 4000–400 cm−1, suggesting degradation behavior due to the heat treatment of SBP, which was in agreement with the capillary viscometry results.
Aims
To test the hypothesis that treatment with a sodium‐glucose co‐transporter‐2 inhibitor would reverse ventricular repolarization heterogeneity, a predictor of cardiovascular mortality, in people ...with Type 2 diabetes.
Methods
We retrospectively analysed changes in indices of ventricular repolarization before and after treatment with a sodium‐glucose co‐transporter‐2 inhibitor in 46 people with Type 2 diabetes.
Results
Sodium‐glucose co‐transporter‐2 inhibitor treatment reduced HbA1c concentration 62±13 mmol/mol (7.7±1.2%) vs 59±16 mmol/mol (7.5±1.4%), body weight (77.8±13.9 vs 74.7±12.5 kg) and systolic blood pressure (133±18 vs 126±12 mmHg) in the study participants. Heart rate and QTc interval were not changed by sodium‐glucose co‐transporter‐2 inhibitor treatment, but QTc dispersion was significantly reduced (median, 48.8 vs 44.2 ms). Sodium‐glucose co‐transporter‐2 inhibitor treatment reversed QTc dispersion more in participants who had larger QTc dispersion before the treatment. Changes in systolic blood pressure (Spearman's ρ= 0.319; P=0.031), but not in HbA1c concentration, were correlated with changes in QTc dispersion after sodium‐glucose co‐transporter‐2 inhibitor treatment.
Conclusions
The findings suggest that sodium‐glucose co‐transporter‐2 inhibitor treatment reverses ventricular repolarization heterogeneity in people with Type 2 diabetes, independently of its effect on glycaemic control. The favourable effect on ventricular repolarization heterogeneity could be the mechanism by which empaglifozin reduced cardiovascular events in a recent study.
What's new?
In this study, we found that treatment with a sodium‐glucose co‐transporter‐2 (SGLT2) inhibitor reduced prolonged QTc dispersion in people with Type 2 diabetes, independently of its effect on glycaemic control.
Because increased repolarization heterogeneity is associated with fatal arrhythmia and sudden cardiac death, these results suggest that improvement in ventricular repolarization heterogeneity is one of the mechanisms by which SGLT2 inhibitor treatment reduced mortality in the EMPA‐REG OUTCOME trial.
ABSTRACT Photon imaging for MeV gammas has serious difficulties due to huge backgrounds and unclearness in images, which originate from incompleteness in determining the physical parameters of ...Compton scattering in detection, e.g., lack of the directional information of the recoil electrons. The recent major mission/instrument in the MeV band, Compton Gamma Ray Observatory/COMPTEL, which was Compton Camera (CC), detected a mere ∼30 persistent sources. It is in stark contrast with the ∼2000 sources in the GeV band. Here we report the performance of an Electron-Tracking Compton Camera (ETCC), and prove that it has a good potential to break through this stagnation in MeV gamma-ray astronomy. The ETCC provides all the parameters of Compton-scattering by measuring 3D recoil electron tracks; then the Scatter Plane Deviation (SPD) lost in CCs is recovered. The energy loss rate (dE/dx), which CCs cannot measure, is also obtained, and is found to be helpful to reduce the background under conditions similar to those in space. Accordingly, the significance in gamma detection is improved severalfold. On the other hand, SPD is essential to determine the point-spread function (PSF) quantitatively. The SPD resolution is improved close to the theoretical limit for multiple scattering of recoil electrons. With such a well-determined PSF, we demonstrate for the first time that it is possible to provide reliable sensitivity in Compton imaging without utilizing an optimization algorithm. As such, this study highlights the fundamental weak-points of CCs. In contrast we demonstrate the possibility of ETCC reaching the sensitivity below 1 × 10−12 erg cm−2 s−1 at 1 MeV.
Summary
During 2013–2015, several and severe outbreaks of African swine fever (ASF) affected domestic pigs in six provinces of Zambia. Genetic characterization of ASF viruses (ASFVs) using ...standardized genotyping procedures revealed that genotypes I, II and XIV were associated with these outbreaks. Molecular and epidemiological data suggest that genotype II ASFV (Georgia 2007/1‐like) detected in Northern Province of Zambia may have been introduced from neighbouring Tanzania. Also, a genotype II virus detected in Eastern Province of Zambia showed a p54 phylogenetic relationship that was inconsistent with that of p72, underscoring the genetic variability of ASFVs. While it appears genotype II viruses detected in Zambia arose from a domestic pig cycle, genotypes I and XIV possibly emerged from a sylvatic cycle. Overall, this study demonstrates the co‐circulation of multiple genotypes of ASFVs, involvement of both the sylvatic and domestic pig cycle in ASF outbreaks in Zambia and possible trans‐boundary spread of the disease in south‐eastern Africa. Indeed, while there is need for regional or international concerted efforts in the control of ASF, understanding pig marketing practices, pig population dynamics, pig housing and rearing systems and community engagement will be important considerations when designing future prevention and control strategies of this disease in Zambia.
X-ray and gamma-ray polarimetry is a promising tool to study the geometry and the magnetic configuration of various celestial objects, such as binary black holes or gamma-ray bursts (GRBs). However, ...statistically significant polarizations have been detected in few of the brightest objects. Even though future polarimeters using X-ray telescopes are expected to observe weak persistent sources, there are no effective approaches to survey transient and serendipitous sources with a wide field of view (FoV). Here we present an electron-tracking Compton camera (ETCC) as a highly sensitive gamma-ray imaging polarimeter. The ETCC provides powerful background rejection and a high modulation factor over an FoV of up to 2π sr thanks to its excellent imaging based on a well-defined point-spread function. Importantly, we demonstrated for the first time the stability of the modulation factor under realistic conditions of off-axis incidence and huge backgrounds using the SPring-8 polarized X-ray beam. The measured modulation factor of the ETCC was 0.65 0.01 at 150 keV for an off-axis incidence with an oblique angle of 30° and was not degraded compared to the 0.58 0.02 at 130 keV for on-axis incidence. These measured results are consistent with the simulation results. Consequently, we found that the satellite-ETCC proposed in Tanimori et al. would provide all-sky surveys of weak persistent sources of 13 mCrab with 10% polarization for a 107 s exposure and over 20 GRBs down to a 6 × 10−6 erg cm−2 fluence and 10% polarization during a one-year observation.
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