Long-term Treatment With Tenofovir Alafenamide for Chronic Hepatitis B Results in High Rates of Viral Suppression and Favorable Renal and Bone Safety.

OBJECTIVES: Results from two Phase 3 studies, through 2 years, in chronic hepatitis B infection (CHB) showed tenofovir alafenamide (TAF) had similar efficacy to tenofovir disoproxil fumarate (TDF) with superior renal and bone safety. Here, we report updated results through 5 years. METHODS: Patients with HBeAg-negative or -positive CHB with or without compensated cirrhosis were randomized (2:1) to TAF 25 mg or TDF 300 mg once daily in double-blind (DB) fashion for up to 3 years, followed by open-label (OL) TAF up to 8 years. Efficacy (antiviral, biochemical, serologic), resistance (deep sequencing of polymerase/reverse transcriptase and phenotyping), and safety, including renal and bone parameters, were evaluated by pooled analyses. RESULTS: Of 1298 randomized and treated patients, 866 receiving TAF (DB and OL) and 432 receiving TDF with rollover to OL TAF at year 2 (n = 180; TDF→TAF3y) or year 3 (n = 202; TDF→TAF2y) were included. Fifty (4%) TDF patients who discontinued during DB were excluded. At year 5, 85%, 83%, and 90% achieved HBV DNA < 29 IU/mL (missing = failure) in the TAF, TDF→TAF3y, and TDF→TAF2y groups, respectively; no patient developed TAF or TDF resistance. Median eGFR (by Cockcroft-Gault) declined < 2.5 mL/min, and mean declines of < 1% in hip and spine bone mineral density were seen at year 5 in the TAF group; patients in the TDF→TAF groups had improvements in these parameters at year 5 after switching to OL TAF. CONCLUSIONS: Long-term TAF treatment resulted in high rates of viral suppression, no resistance, and favorable renal and bone safety.

Real-world effectiveness and factors associated with effectiveness of inactivated SARS-CoV-2 vaccines: a systematic review and meta-regression analysis.

BACKGROUND: The two inactivated SARS-CoV-2 vaccines, CoronaVac and BBIBP-CorV, have been widely used to control the COVID-19 pandemic. The influence of multiple factors on inactivated vaccine effectiveness (VE) during long-term use and against variants is not well understood. METHODS: We selected published or preprinted articles from PubMed, Embase, Scopus, Web of Science, medRxiv, BioRxiv, and the WHO COVID-19 database by 31 August 2022. We included observational studies that assessed the VE of completed primary series or homologous booster against SARS-CoV-2 infection or severe COVID-19. We used DerSimonian and Laird random-effects models to calculate pooled estimates and conducted multiple meta-regression with an information theoretic approach based on Akaike's Information Criterion to select the model and identify the factors associated with VE. RESULTS: Fifty-one eligible studies with 151 estimates were included. For prevention of infection, VE associated with study region, variants, and time since vaccination; VE was significantly decreased against Omicron compared to Alpha (P = 0.021), primary series VE was 52.8% (95% CI, 43.3 to 60.7%) against Delta and 16.4% (95% CI, 9.5 to 22.8%) against Omicron, and booster dose VE was 65.2% (95% CI, 48.3 to 76.6%) against Delta and 20.3% (95% CI, 10.5 to 28.0%) against Omicron; primary VE decreased significantly after 180 days (P = 0.022). For the prevention of severe COVID-19, VE associated with vaccine doses, age, study region, variants, study design, and study population type; booster VE increased significantly (P = 0.001) compared to primary; though VE decreased significantly against Gamma (P = 0.034), Delta (P = 0.001), and Omicron (P = 0.001) compared to Alpha, primary and booster VEs were all above 60% against each variant. CONCLUSIONS: Inactivated vaccine protection against SARS-CoV-2 infection was moderate, decreased significantly after 6 months following primary vaccination, and was restored by booster vaccination. VE against severe COVID-19 was greatest after boosting and did not decrease over time, sustained for over 6 months after the primary series, and more evidence is needed to assess the duration of booster VE. VE varied by variants, most notably against Omicron. It is necessary to ensure booster vaccination of everyone eligible for SARS-CoV-2 vaccines and continue monitoring virus evolution and VE. TRIAL REGISTRATION: PROSPERO, CRD42022353272.

Construction of a backpropagation starlight atmospheric refraction model based on ray tracing.

The atmospheric refraction model is a vital part of the refraction navigation system. A more accurate model needs to be constructed for the navigation algorithm design and simulation verification. Based on the Thermosphere, Ionosphere, Mesosphere Energetics and Dynamics/Sounding of the Atmosphere using Broadband Emission Radiometry (TIMED/SABER) dataset and the geometrical ray propagation law, a ray tracing algorithm is proposed to calculate the atmospheric refraction angles. Moreover, a neural network starlight atmospheric refraction model (BP model) is constructed to better describe the relationship between time, location, and refraction angle. Compared with the experimental data, the bias error of the backpropagation (BP) model is 1.06 ' ' , which is better than the 3.75 ' ' of the traditional model. It indicates that the BP model is exact and has important guiding significance for the starlight refraction navigation technology.

Detachment of Dodecane from Silica Surfaces with Variable Surface Chemistry Studied Using Molecular Dynamics Simulation.

The adsorption and detachment processes of n-dodecane (C12H26) molecules were studied on silica surfaces with variable surface chemistry (Q2, Q3, Q4 environments), using molecular dynamics simulations. The area density of the silanol groups varied from 9.4 to 0 per nm2. The shrinking of the oil-water-solid contact line was a key step for the oil detachment, due to water diffusion on the three-phase contact line. The simulation results showed that oil detachment was easier and faster on a perfect Q3 silica surface which had (≡Si(OH))-type silanol groups, due to the H-bond formation between the water and silanol groups. When the surfaces contained more Q2 crystalline type which had (≡Si(OH)2)-type silanol groups, less oil detached, due to the formations of H-bonds among the silanol groups. There were no silanol groups on the Si-OH 0 surface. Water cannot diffuse on the water-oil-silica contact line, and oil cannot detach from the Q4 surface. The detachment efficiency of oil from the silica surface not only depended on the area density, but also on the types of silanol groups. The density and type of silanol groups depend on the crystal cleavage plane, particle size, roughness, and humidity.

Imaging simulation of the AMCW ToF camera based on path tracking.

The time-of-flight (ToF) camera suffers from many error factors, such as multiple reflection or multipath interference and electronic and optical shot noise, making it difficult to simulate its imaging process. Aiming to test the ToF camera algorithm, it is important to obtain a depth image affected by these error factors. In order to model the light propagation behavior and the sensor effect in the imaging process of the ToF camera, an amplitude modulated continuous-wave (AMCW) ToF camera imaging simulation method based on path tracking is presented by deducing the path tracking algorithm model in the AMCW ToF camera theoretically and by realizing the physically based simulation by introducing the infrared bidirectional reflectance distribution function (BRDF) data of the actual materials. According to the constructed error evaluation indexes, the correctness of the imaging simulation method is verified based on the ground experiment. The mean absolute error (MAE) and root mean square error (RMSE) are 10.32 mm and 15.12 mm, respectively, which are less than the error results of the other two comparative simulation methods. The results show that the proposed method is reasonable and can provide reliable data support for AMCW ToF hardware development and algorithm testing.

On the Design and Implementation of the External Data Integrity Tracking and Verification System for Stream Computing System in IoT.

Data integrity is a prerequisite for ensuring data availability of IoT data and has received extensive attention in the field of IoT big data security. Stream computing systems are widely used in the field of IoT for real-time data acquisition and computing. However, the real-time, volatility, suddenness, and disorder of stream data make data integrity verification difficult. According to the survey, there is no mature and universal solution. To solve this issue, we constructed a data integrity verification algorithm scheme of the stream computing system (S-DIV) by utilizing homomorphic message authentication code and pseudo-random function security assumption. Furthermore, based on S-DIV, an external data integrity tracking and verification system is constructed to track and analyze the message data stream in real time. By verifying the data integrity of message during the whole life cycle, the problem of data corruption or data loss can be found in time, and error alarm and message recovery can be actively implemented. Then, we conduct the formal security analysis under the standard model and, finally, implement the S-DIV scheme in simulation environment. Experimental results show that the scheme can guarantee data integrity in an acceptable time without affecting the efficiency of the original system.

Effects of molecular weight of polyaspartic acid on nitrogen use efficiency and crop yield.

BACKGROUND: In the past decades, ever-increasing fertilizer use has led to a continuous increase in agricultural output. However, serious waste of resources occurs because of the low utilization of fertilizers. Polyaspartic acid (PASP) is a biodegradable polymer that can be used as a fertilizer synergist in agricultural production to improve the nutrient utilization capacity of plants. For polymers, the molecular weight (MW) often affects their effectiveness. However, little information is available on the effects of PASP MW in agriculture, especially on nitrogen leaching and plant element uptake. RESULTS: This work was conducted to identify the effect of PASPs with three different MWs - PASP-1 (MW: 5517), PASP-2 (MW: 6934), and PASP-3 (MW: 7568) - on nitrogen leaching, lettuce growth, and wheat cultivation. The results revealed that PASP favored plant growth and nitrogen accumulation in the soil, independent of crop species. PASP with a higher MW improved yields and the agronomic characteristics of lettuce and wheat. Furthermore, apparent amelioration of nitrogen use efficiency for lettuce (7.6%, 12.8%, and 15.0%) and wheat (4.6%, 8.1%, and 9.2%) was observed in the treatments with PASP addition. The effects and merits of PASPs on preventing ammonium nitrogen leaching and improving lettuce and wheat productivity were as follows: PASP-3 > PASP-2 > PASP-1. CONCLUSION: The MW of PASP is an essential factor affecting inorganic nitrogen leaching and crop productivity, and PASP with a higher MW (7568) is recommended for application in agriculture. © 2022 Society of Chemical Industry.

Gallic acid-gold nanoparticles enhance radiation-induced cell death of human glioma U251 cells.

Glioblastoma multiforme (GBM) is among the most common adult brain tumors with invariably fatal character. Following the limited conventional therapies, almost all patients, however, presented with symptoms at the time of recurrence. It is dire to develop novel therapeutic strategies to improve the current treatment of GBM. Gallic acid is a well-established antioxidant, presenting a promising new selective anti-cancer drug, while gold nanoparticles (GNPs) can be developed as versatile nontoxic carriers for anti-cancer drug delivery. Here, we prepared gallic acid-GNPs (GA-GNPs) by loading gallic acid onto GNPs, reduction products of tetrachloroauric acid by sodium citrate, through physical and agitation adsorption. GA-GNPs, rather than GNPs alone, significantly inhibited the survival of U251 GBM cells, as well as enhanced radiation-induced cell death. Moreover, GA-GNPs plus radiation arrested the cell cycle of U251 at the S and G2/M phases and triggered apoptotic cell death, which is supported by increased BAX protein levels and decreased expression of BCL-2. Thus, GA-GNPs have great potential in the combination with radiation therapy in future studies for GBM treatment.

Automatic underwater polarization imaging without background region or any prior.

Previous polarization underwater imaging methods based on the physical scattering model usually require background region included in the image and the prior knowledge, which hinders its practical application. In this paper, we analyze and optimize the physically feasible region and propose an improved method by degenerating intermediate variables, which can realize automatic underwater image recovery without background region or any prior. The proposed method does not need to estimate the intermediate variables in the traditional underwater imaging model and is adaptable to the underwater image with non-uniform illumination, which avoids the poor and unstable image recovery performance caused by inaccurate estimation of intermediate parameters due to the improper identification of the background region. Meanwhile, our method is effective for both images without background region and images in which the background region is hard to be identified. In addition, our method solves the significant variation in recovery results caused by the different selection of background regions and the inconsistency of parameter adjustment. The experimental results of different underwater scenes show that the proposed method can enhance image contrast while preserving image details without introducing considerable noise, and the proposed method is effective for the dense turbid medium.

Multiple Magnetic Topological Phases in Bulk van der Waals Crystal MnSb_{4}Te_{7}.

The magnetic van der Waals crystals MnBi_{2}Te_{4}/(Bi_{2}Te_{3})_{n} have drawn significant attention due to their rich topological properties and the tunability by external magnetic field. Although the MnBi_{2}Te_{4}/(Bi_{2}Te_{3})_{n} family have been intensively studied in the past few years, their close relatives, the MnSb_{2}Te_{4}/(Sb_{2}Te_{3})_{n} family, remain much less explored. In this work, combining magnetotransport measurements, angle-resolved photoemission spectroscopy, and first principles calculations, we find that MnSb_{4}Te_{7}, the n=1 member of the MnSb_{2}Te_{4}/(Sb_{2}Te_{3})_{n} family, is a magnetic topological system with versatile topological phases that can be manipulated by both carrier doping and magnetic field. Our calculations unveil that its A-type antiferromagnetic (AFM) ground state stays in a Z_{2} AFM topological insulator phase, which can be converted to an inversion-symmetry-protected axion insulator phase when in the ferromagnetic (FM) state. Moreover, when this system in the FM phase is slightly carrier doped on either the electron or hole side, it becomes a Weyl semimetal with multiple Weyl nodes in the highest valence bands and lowest conduction bands, which are manifested by the measured notable anomalous Hall effect. Our work thus introduces a new magnetic topological material with different topological phases that are highly tunable by carrier doping or magnetic field.

Comparison of in vitro biocompatibility and antibacterial activity of two calcium silicate-based materials.

This study is aimed at comparing and evaluating the biocompatibility and antibacterial activities of mineral trioxide aggregate (MTA) and iRoot BP Plus as novel retro-filling materials. Discs of both materials were prepared and incubated for 72 h to obtain material extracts in medium. Flow cytometry and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay were used to assess the rate of apoptosis and proliferation of human periodontal ligament stem cells (hPDLSCs) when exposed to eluates of both materials. The expression levels of alkaline phosphatase, collagen type I, osteocalcin, Runt-related transcription factor-2, and Osterix were tested for evaluating the osteogenic differentiation of hPDLSCs. The antibacterial activities of both materials were compared by the direct contact test. The hPDLSCs stimulated by MTA or iRoot BP Plus eluates showed significantly higher cell viability than that of the control group with no eluates. No significant differences were observed among the percentages of necrotic and apoptotic cells stimulated by MTA and iRoot BP Plus eluates and the control group. The expression of all osteogenic differentiation markers of hPDLSCs in both experimental groups were significantly higher than those of the control group, while the increment values in MTA group were significantly higher than those of the iRoot BP Plus group. The antibacterial activity against Enterococcus faecalis showed no significant difference between MTA and iRoot BP Plus. Therefore, both materials may be suitable for retro-filling applications.

Copper-induced sublethal effects in Bufo gargarizans tadpoles: growth, intestinal histology and microbial alternations.

Copper (Cu) is one of the environmental contaminations which can pose significant risks for organisms. The current study explores the effects of Cu exposure on the growth, intestinal histology and microbial ecology in Bufo gargarizans. The results revealed that 0.5-1 µM Cu exposure induced growth retardation (including reduction of total body length and wet weight) and intestinal histological injury (including disordered enterocyte, changes in the villi and vacuoles) of tadpoles. Also, high-throughput sequencing analysis showed that Cu exposure caused changes in richness, diversity and structure of intestinal microbiota. Moreover, the composition of intestinal microbiota was altered in tadpoles exposed to different concentrations of Cu. At the phylum level, we observed the abundance of proteobacteria was increased, while the abundance of fusobacteria was decreased in the intestinal microbiota of tadpoles exposed to 1 µM Cu. At the genus level, a reduced abundance of kluyvera and aeromonas was observed in the intestinal microbiota of tadpoles under the exposure of 0-0.5 µM Cu. Finally, functional predictions revealed that tadpoles exposed to copper may be at a higher risk of developing metabolic disorders or diseases. Above all, our results will develop a comprehensive view of the Cu exposure in amphibians and will yield a new consideration for sublethal effects of Cu on aquatic organisms.

Altered temperature affect body condition and endochondral ossification in Bufo gargarizans tadpoles.

Bufo gargarizans is one kind of economic animals with higher medicinal value in China. In this study, B. gargarizans (Bufo gargarizans) tadpoles were reared at three different water temperature (15, 22 and 29 °C) from Gosner stages 28-46. We investigated the effects of temperature on growth, development, survival, metamorphic duration, size and skeletal ossification at Gosner stage 40, 42, and 46, as well as thyroid tissue reached metamorphic climax (Gs42). Besides, we examined the transcription levels of endochondral ossification-related genes in hind limb at metamorphic climax (Gs42). Our results showed that the growth and development of tadpoles conform to the temperature-size rule (TSR). While warm temperature resulted in the decrease in body size and hind limb length, and shorten larval period, cold temperature led to increase in body size and hind limb length but prolonged larval period. Histological examinations revealed that warm and cold temperatures caused damage to thyroid tissue. Also, warm and cold temperatures inhibited the degree of ossification with the double staining methodology. Additionally, the real-time PCR results suggested that warm and cold temperatures significantly up-regulated Runx2, VEGF and VEGFR mRNA levels, and down-regulated TRß, MMP9, MMP13 and Runx3 mRNA levels. The up-regulation of Dio2 level and down-regulation of Dio3 level were observed in warm temperature. TRα mRNA level was significantly increased in warm temperature, but decreased in cold temperature. Collectively, these observations demonstrated that warm and cold temperatures affected endochondral ossification in B. gargarizans tadpoles, which might influence their capacity to terrestrial locomotion.

Effects of temperature on growth, development and the leptin signaling pathway of Bufo gargarizans.

Climate change is one of the most important causes of the decline in amphibians. Changes in temperature have an important effect on the growth and development and energy metabolism of amphibians. The aim of this study is to unravel the effects of temperature on the leptin signaling pathway of Bufo gargarizans and its molecular mechanisms. Our results showed that high temperature accelerated the development rate of tadpoles, but reduced body size and mass, while low temperature deferred the development of tadpoles, but increased size and mass. Both high temperature and low temperature exposure caused pathological damage of the liver in B. gargarizans. The results of RT-qPCR revealed that the high temperature treatment significantly upregulated the transcript levels of genes related to thyroid hormone (DIO2 (D2), Thyroid Hormone Receptor-α (TRα)) and the leptin signaling pathway (Leptin Receptor (LepR), Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Tyrosine kinase 2 (TYK2), Signal Transducer And Activator Of Transcription 3 (STAT3), Signal Transducer And Activator Of Transcription 3.1 (STAT3.1), and Signal Transducer And Activator Of Transcription 6 (STAT6)), while there was a decrease of mRNA expression of these genes (TRα, Thyroid Hormone Receptor-Beta (TRß), LepR, JAK1, and TYK2) in the liver of tadpoles exposed to high temperature compared with the intermediate temperature treatment. Therefore, our results suggested that temperature extremes might interfere with the thyroid and leptin signaling pathways and affect the growth and development of B. gargarizans. Furthermore, tissue injury of the liver could occur due to exposure to temperature extremes. This work promotes public awareness of environmental protection and species conservation needs, also provides valuable experimental data and a theoretical basis for the protection of amphibians.

Temperature compensation of optical alternating magnetic field sensor via a novel method for on-line measuring.

The variation of environment temperature is a crucial problem for optical magnetic field sensors based on the magneto-optical crystal. In this paper, we propose a novel temperature compensation method for optical alternating magnetic field measuring by analyzing the demodulation principle and establishing the temperature compensation model, which can implement the functions of temperature compensation and on-line measuring simultaneously. Both the temperature and the alternating magnetic field flux density can be obtained only by adding two magnet rings on the magnetic field sensor. The experimental phenomenon agrees well with the temperature characteristics of the magneto-optical crystal and the theoretical compensation model. The experimental results demonstrate that this sensor has excellent stability whose max relative fluctuation is only 0.7402% in the range of 0-4 mT under a constant temperature. In the temperature compensation experiment of 0 °C, 20 °C and 40 °C, the sensor shows strong temperature robustness that the max absolute and relative errors are 0.07 mT and 3.50%, respectively. Meanwhile, compensation efficiency reaches 83.968%, which can effectively avoid temperature crosstalk to a large extent. Additionally, it has a better compensation performance whose max absolute and relative errors are 0.15 mT and 1.66% in the broader range of 0-16 mT when the actual temperature is accurately known.

Plastic pollution in croplands threatens long-term food security.

Plastic pollution is a global concern given its prevalence in aquatic and terrestrial ecosystems. Studies have been conducted on the distribution and impact of plastic pollution in marine ecosystems, but little is known on terrestrial ecosystems. Plastic mulch has been widely used to increase crop yields worldwide, yet the impact of plastic residues in cropland soils to soil health and crop production in the long term remained unclear. In this paper, using a global meta-analysis, we found that the use of plastic mulch can indeed increase crop yields on average by 25%-42% in the immediate season due to the increase of soil temperature (+8%) and moisture (+17%). However, the unabated accumulation of film residues in the field negatively impacts its physicochemical properties linked to healthy soil and threatens food production in the long term. It has multiple negative impacts on plant growth including crop yield (at the mean rate of -3% for every additional 100 kg/ha of film residue), plant height (-2%) and root weight (-5%), and soil properties including soil water evaporation capacity (-2%), soil water infiltration rate (-8%), soil organic matter (-0.8%) and soil available phosphorus (-5%) based on meta-regression. Using a nationwide field survey of China, the largest user of plastic mulch worldwide, we found that plastic residue accumulation in cropland soils has reached 550,800 tonnes, with an estimated 6%-10% reduction in cotton yield in some polluted sites based on current level of plastic residue content. Immediate actions should be taken to ensure the recovery of plastic film mulch and limit further increase in film residue loading to maintain the sustainability of these croplands.

Effects of sodium perchlorate and exogenous L-thyroxine on growth, development and leptin signaling pathway of Bufo gargarizans tadpoles during metamorphosis.

Sodium perchlorate (NaClO4) and exogenous L-thyroxine (T4), two kinds of endocrine-disrupting chemicals (EDCs), mainly affect the circulating thyroid hormones, which regulate the initiation and rate of metamorphosis in amphibian. The aim of this study is to evaluate the potential role of EDCs in regulating the development of tadpoles and leptin signaling pathway of liver during the metamorphosis of Bufo gargarizans. There was completely opposite result of average development stage of tadpoles and morphological parameters between the NaClO4 and T4 exposure groups. Histological analysis revealed that NaClO4 and T4 exposure both caused liver injury, such as the decreased size of hepatocytes, atrophy of nucleus, increased melanomacrophage centres and disappearance of hepatocyte membranes. In addition, the results of RT-qPCR revealed that NaClO4 treatment significantly inhibited the transcript levels of genes related to thyroid hormone (D2, TRα and TRß) and leptin signaling pathway (LepR, JAK1, JAK2, and TYK2), while there was an increase of mRNA expression of these genes in the liver of tadpoles administrated with T4 compared with control. This work lays an important foundation for assessing the risk of EDCs in relation to amphibian development during metamorphosis.

The effects of chronic cadmium exposure on the gut of Bufo gargarizans larvae at metamorphic climax: Histopathological impairments, microbiota changes and intestinal remodeling disruption.

Cadmium (Cd) is carcinogenic to human and it also has adverse effects on aquatic life such as amphibian larvae. However, its influences on amphibian gut morphology and development as well as intestinal microbiota are still hardly understood. In this study, we examined the effects of chronic cadmium exposure on the gut of tadpoles at Gosner stage 42 of metamorphic climax by using Bufo gargarizans as a model species. Tadpoles were exposed to cadmium concentrations at 0, 5, 100 and 200 µg L-1 from Gosner stage 26-42. The results showed that high cadmium (100 and 200 µg L-1) exposure caused significant decrease of body length and weight but significant increase of intestinal length and weight. Moreover, severe histopathological damages were induced by high Cd exposure. In addition, microbial communities in the gut of tadpoles in high cadmium exposure groups were remarkably different from those in control group. Unexpectedly, species diversity and richness were higher in the intestinal microbiota of 200 µg L-1 cadmium exposure group. Furthermore, the abundance of prevalent phyla, families and genera of intestinal microbiota were changed by cadmium exposure. Meanwhile, cadmium exposure perturbed gut renewal functions and the relative mRNA expression of genes involved in canonical and non-canonical Wnt signaling pathway was seriously affected by high cadmium exposure. We concluded that cadmium could be harmful to tadpole health by inducing intestinal histopathological damages, gut remodeling inhibition and intestinal microbiota alterations.

Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial.

Importance: Remdesivir demonstrated clinical benefit in a placebo-controlled trial in patients with severe coronavirus disease 2019 (COVID-19), but its effect in patients with moderate disease is unknown. Objective: To determine the efficacy of 5 or 10 days of remdesivir treatment compared with standard care on clinical status on day 11 after initiation of treatment. Design, Setting, and Participants: Randomized, open-label trial of hospitalized patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and moderate COVID-19 pneumonia (pulmonary infiltrates and room-air oxygen saturation >94%) enrolled from March 15 through April 18, 2020, at 105 hospitals in the United States, Europe, and Asia. The date of final follow-up was May 20, 2020. Interventions: Patients were randomized in a 1:1:1 ratio to receive a 10-day course of remdesivir (n = 197), a 5-day course of remdesivir (n = 199), or standard care (n = 200). Remdesivir was dosed intravenously at 200 mg on day 1 followed by 100 mg/d. Main Outcomes and Measures: The primary end point was clinical status on day 11 on a 7-point ordinal scale ranging from death (category 1) to discharged (category 7). Differences between remdesivir treatment groups and standard care were calculated using proportional odds models and expressed as odds ratios. An odds ratio greater than 1 indicates difference in clinical status distribution toward category 7 for the remdesivir group vs the standard care group. Results: Among 596 patients who were randomized, 584 began the study and received remdesivir or continued standard care (median age, 57 [interquartile range, 46-66] years; 227 [39%] women; 56% had cardiovascular disease, 42% hypertension, and 40% diabetes), and 533 (91%) completed the trial. Median length of treatment was 5 days for patients in the 5-day remdesivir group and 6 days for patients in the 10-day remdesivir group. On day 11, patients in the 5-day remdesivir group had statistically significantly higher odds of a better clinical status distribution than those receiving standard care (odds ratio, 1.65; 95% CI, 1.09-2.48; P = .02). The clinical status distribution on day 11 between the 10-day remdesivir and standard care groups was not significantly different (P = .18 by Wilcoxon rank sum test). By day 28, 9 patients had died: 2 (1%) in the 5-day remdesivir group, 3 (2%) in the 10-day remdesivir group, and 4 (2%) in the standard care group. Nausea (10% vs 3%), hypokalemia (6% vs 2%), and headache (5% vs 3%) were more frequent among remdesivir-treated patients compared with standard care. Conclusions and Relevance: Among patients with moderate COVID-19, those randomized to a 10-day course of remdesivir did not have a statistically significant difference in clinical status compared with standard care at 11 days after initiation of treatment. Patients randomized to a 5-day course of remdesivir had a statistically significant difference in clinical status compared with standard care, but the difference was of uncertain clinical importance. Trial Registration: ClinicalTrials.gov Identifier: NCT04292730.

Response Patterns of Biomarkers as Tools to Identify Toxic Effects of Cadmium and Lead on Bufo gargarizans Embryo.

Molecular biomarkers play an increasing crucial role in evaluating and predicting toxicity of metals. Expressions patterns of genes related to oxidative stress, apoptosis, immune and inflammation response in the Bufo gargarizans embryo exhibited a development dependent manner. The genes related to oxidative stress (HSP, GPx and SOD) are the first response in the development of embryo, followed by the apoptosis (Bax, BCLAF1 and TRAIL) and inflammation and immune response (SOCS3, IL-27 and IL-17D), respectively. Then, we have verified the HSP, Bax and SOCS3 IL-27 (expressed highest in their respective processes) exhibited the most significant changes in Cd-Pb mixed group compared with control. In addition, we found exposure of Cd-Pb mixed metals causes greater adverse effects than Cd, Pb alone on development and morphology of embryo. Overall, our results provide a useful tool to use the sensitive molecular biomarkers as indicators of developmental toxicity in amphibian embryo.