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Introduction For patients with asthma who remain symptomatic on medium-dose inhaled corticosteroid/long-acting β2-agonist, add-on long-acting muscarinic antagonist is a treatment option, which can be administered as multiple-inhaler triple therapy (MITT). A high proportion of patients (61.5%–88.2%) discontinue MITT use within 1 year postinitiation; however, which patients discontinue and their treatment patterns at initiation are unknown. This study aimed to understand the demographic, clinical and treatment-related characteristics of patients with asthma who newly initiated MITT, by discontinuation status.Methods This retrospective cohort study used administrative data from IBM Truven MarketScan Commercial Claims and Encounters Database with Medicare supplement between 1 January 2016 and 31 December 2019. Adult patients with asthma who initiated MITT between 1 January 2017 and 31 March 2019 were included and were classified based on their discontinuation status. ‘Continuous users’ had continuous use of MITT and ‘discontinuers’ discontinued treatment within the 6-month period postinitiation. Demographics and clinical characteristics, asthma treatment use prior to MITT initiation (12-month baseline period), mode of MITT initiation and complexity of regimen were described.Results Of 4132 patients (mean age: 49.0 years, 67.9% female), 78.0% (n=3224) were discontinuers; 22.0% (n=908) were continuous users. Demographic and other clinical and treatment-related characteristics during baseline were broadly similar between cohorts. A significantly higher proportion of continuous users versus discontinuers had ≥6 dispensed claims for short-acting β2-agonist canisters (16.0% vs 12.5%; p=0.006) during baseline and initiated a once-daily MITT regimen (35.2% vs 26.2%; p

Abstract Introduction Chronic hepatitis B virus (HBV) infection is associated with significant global morbidity and mortality. Low treatment rates are observed in patients living with HBV; the reasons for this are unclear. This study sought to describe patients’ demographic, clinical and biochemical characteristics across three continents and their associated treatment need. Methods This retrospective cross-sectional post hoc analysis of real-world data used four large electronic databases from the United States, United Kingdom and China (specifically Hong Kong and Fuzhou). Patients were identified by first evidence of chronic HBV infection in a given year (their index date) and characterized. An algorithm was designed and applied, wherein patients were categorized as treated, untreated but indicated for treatment and untreated and not indicated for treatment based on treatment status and demographic, clinical, biochemical and virological characteristics (age; evidence of fibrosis/cirrhosis; alanine aminotransferase [ALT] levels, HCV/HIV coinfection and HBV virology markers). Results In total, 12,614 US patients, 503 UK patients, 34,135 patients from Hong Kong and 21,614 from Fuzhou were included. Adults (99.4%) and males (59.0%) predominated. Overall, 34.5% of patients were treated at index (range 15.9–49.6%), with nucleos(t)ide analogue monotherapy most commonly prescribed. The proportion of untreated-but-indicated patients ranged from 12.9% in Hong Kong to 18.2% in the UK; almost two-thirds of these patients (range 61.3–66.7%) had evidence of fibrosis/cirrhosis. A quarter (25.3%) of untreated-but-indicated patients were aged ≥ 65 years. Conclusion This large real-world dataset demonstrates that chronic hepatitis B infection remains a global health concern; despite the availability of effective suppressive therapy, a considerable proportion of predominantly adult patients apparently indicated for treatment are currently untreated, including many patients with fibrosis/cirrhosis. Causes of disparity in treatment status warrant further investigation.

Cadmium has been reported to accumulate primarily in spermatogonia and spermatocytes. Exposure to cadmium results in male reproductive toxicity via germ-cell apoptosis and impaired autophagy. Apoptosis and autophagy are two physiologically conserved events that maintain cellular homeostasis. However, the precise role of autophagy in cadmium-induced apoptosis of male germ cells has yet to be addressed. The present study aimed to investigate the impact of cadmium exposure on the cytotoxicity of GC-2 spd cells, a mouse spermatocyte cell line. The results showed that cadmium exposure caused apoptotic cell death and the accumulation of autophagosomes, along with the up-regulation of ATG proteins in GC-2 spd cells. It was demonstrated that the cadmium-induced accumulation of autophagosomes contributes to the apoptosis of GC-2 spd cells. This notion is supported by the findings that the autophagy inhibitor 3-MA reduced accumulation of autophagosomes and apoptotic cell death. Conversely, the apoptosis inhibitor Z-VAD-FMK inhibited apoptosis but had little effect on the accumulation of autophagosomes. Cadmium may impede the fusion of autophagosomes with lysosomes, leading to the autophagosome buildup. Additionally, we found that the JNK pathway mediates transcriptional induction of several autophagy-related (ATG) genes involved in autophagosome formation. The cadmium-activated JNK pathway regulates apoptosis by mediating the autophagosome formation. Treatment of cells with the JNK inhibitor SP600125 attenuated the accumulation of autophagosomes, the upregulated expression of autophagosome-associated proteins and apoptotic cell death induced by cadmium. Overall, these findings suggest that cadmium enhances apoptosis of GC-2 spd cells by activating the JNK pathway and inhibiting autophagic flux.

Abstract Cadmium is one of the environmental and occupational pollutants and its potential adverse effects on human health have given rise to substantial concern. Cadmium causes damage to the male reproductive system via induction of germ-cell apoptosis; however, the underlying mechanism of cadmium-induced reproductive toxicity in Leydig cells remains unclear. In this study, twenty mice were divided randomly into four groups and exposed to CdCl2 at concentrations of 0, 0.5, 1.0 and 2.0 mg/kg/day for four consecutive weeks. Testicular injury, abnormal spermatogenesis and apoptosis of Leydig cells were observed in mice. In order to investigate the mechanism of cadmium-induced apoptosis of Leydig cells, a model of mouse Leydig cell line (i.e. TM3 cells) was subjected to treatment with various concentrations of CdCl2. It was found that mitochondrial function was disrupted by cadmium, which also caused a significant elevation in levels of mitochondrial superoxide and cellular ROS. Furthermore, while cadmium increased the expression of mitochondrial fission proteins (DRP1 and FIS1), it reduced the expression of mitochondrial fusion proteins (OPA1 and MFN1). This led to excessive mitochondrial fission, the release of cytochrome c and apoptosis. Conversely, cadmium-induced accumulation of mitochondrial superoxide was decreased by the inhibition of mitochondrial fission through the use of Mdivi-1 (an inhibitor of DRP1). Mdivi-1 also partially prevented the release of cytochrome c from mitochondria to cytosol and attenuated cell apoptosis. Finally, given the accumulation of LC3II and SQSTM1/p62 and the obstruction of Parkin recruitment into damaged mitochondria in TM3 cells, the autophagosome-lysosome fusion was probably inhibited by cadmium. Overall, these findings suggest that cadmium induces apoptosis of mouse Leydig cells via the induction of excessive mitochondrial fission and inhibition of mitophagy.

Online traveling community is initiated by companies, but its survival is inextricably linked to consumer citizenship behavior (e.g., out-group recommendation, in-group helping, and inward response). The majority of researches have investigated consumer behavior of brand community such as consumer satisfaction, brand loyalty, and purchase intention. A few scholars try to explore consumer behaviors beyond the purchase, like participation, which was concerned as the value co-creation. However, the value co-creation of the community should depend on consumers’ citizenship behaviors instead of their pure participation. Therefore, this study empirically examines the effect of consumer interaction on consumer psychology and citizenship behaviors of the online travel community. The findings demonstrated that consumer interaction facilitated participants’ self-identity and their perceived social support, which enhanced their community identification and thus their citizenship behaviors. Furthermore, the motivation of participation plays a moderator in this process. Specifically, symbolic motivation moderates the relationship between consumer interaction and their self-identity, while utilitarian motivation moderates the effect of consumer interaction on their perceived social support. These findings contributed to the intervention of consumer citizenship behavior in online traveling community and provide insights into the management of the online travel community from the perspective of the value co-creation.

When biochars are produced, feedstock is a crucial factor that determines their physicochemical properties. However, the characteristics of tropical crop waste-derived biochar have not been described and limit its availability. In this study, pineapple leaf (PAL), banana stem (BAS), sugarcane bagasse (SCB) and horticultural substrate (HCS), were used to prepare biochar at 300, 500 and 700 °C. Properties of biochars and their applications were analysed. The results indicated that hydrophobicity, nonpolarity and aromaticity of SCB biochar (SCBB) were higher than other biochars due to the loss of H (hydrogen), O (oxygen), and N (nitrogen). The pH of PAL biochar (PALB) and BAS biochar (BASB) ranged from 9.69 to 10.30 higher than that of SCBB and HCS biochar (HCSB) with 7.17–9.77. In PALB and BASB, sylvite was the dominant crystal structure. With temperature rising, C–H stretching, C=C stretching and H–O in alcohol groups decreased, and Si–O stretching in HCSB and SCBB strengthened. Biochars obtained at 500 °C, especially SCBB and HCSB, significantly promoted the growth of maize. The PALB and BASB greatly increased the soil pH/EC to 6.90–7.35 and 0.67–0.95 ms/cm, while those of SCBB and HCSB were 5.97–6.74 and 0.23–0.45 ms/cm. The application of the biochars to the soil increased soil pH, reducing the acidic soil stress in maize growth, especially PAL and BAS biochars prepared at 300 °C. Biochar prepared at lower temperature will greatly reduce energy consumption and increase the utilization efficiency of tropical agricultural waste resources.

Rapeseed (Brassica napus) is an important oilseed crop widely planted in the world, providing substantial edible oil and other nutrients for mankind. The composition of fatty acids affects the edible and processing quality of vegetable oils, among which erucic acid (EA) is potentially to cause health problems. Therefore, low erucic acid (LEA) has always been a breeding trait of B. napus. Fatty acid elongase 1 (FAE1) plays a decisive role in the synthesis of EA. There are two functional homologous copies of FAE1 on the A08 and C03 chromosomes in B. napus. In this study, we used CRISPR/Cas9 technology to create targeted mutations on these two homologous copies of BnaFAE1 in three B. napus germplasms with high EA (>30%) and high oil (>50%). Our results show that the EA content was significantly reduced by more than 10 percentage points in the mutant of BnaC03.FAE1 (c03), while the double mutation of BnaA08.FAE1 and BnaC03.FAE1 (a08c03) resulted in nearly zero EA in three BnaFAE1-edited germplasms, and the oleic acid content was increased in different degrees. In addition, knockout of BnaA08.FAE1 or/and BnaC03.FAE1 mildly decreased seed oil content, but had no significant effect on other agronomic traits. In general, we successfully created low EA germplasms of B. napus, which provides a feasible way for future low EA breeding.

Cadmium is a component of ambient metal pollution, which is linked to diverse health issues globally, including male reproductive impairment. Assessments of the acute effects of cadmium on male reproduction systems, such as testes, tend to be based on frank adverse effects, with particular molecular pathways also involved. The relationship between cytotoxicity potential and cellular stress response has been suggested to be one of the many possible drivers of the acute effects of cadmium, but the link remains uncertain. In consequence, there is still much to be learned about the cellular stress response induced by a non-lethal concentration of cadmium in male reproductive cells. The present study used temporal assays to evaluate cellular stress response upon exposure to non-lethal concentrations of Cadmium chloride (CdCl2) in the Sertoli cell line (TM4). The data showed alternations in the expression of genes intimated involved in various cellular stress responses, including endoplasmic reticulum (ER) stress, endoplasmic unfolded protein stress (UPRmt), endoplasmic dynamics, Nrf2-related antioxidative response, autophagy, and metallothionein (MT) expression. Furthermore, these cellular responses interacted and were tightly related to oxidative stress. Thus, the non-lethal concentration of cadmium perturbed the homeostasis of the Sertoli cell line by inducing pleiotropic cellular stresses.

In the field of mobile computing, after the placement of sensor nodes, energy efficiency of data transmission in the sensor network is becoming a critical issue as the sensor nodes are battery-operated devices. Most of the proposed protocols implement clustering based methods in order to balance the energy consumption among the sensor nodes through data aggregation. In this paper, a new method named a two-stage RPSO-ACS based protocol is proposed to improve the energy efficiency and network operation quality in the data transmission process, prolonging the lifespan of the network. Firstly, in the process of cluster head (CH) selection, the resampling particle swarm optimization (RPSO) is introduced, which shows better precision and efficiency than particle swarm optimization (PSO) and genetic algorithm (GA). Secondly, after the selection of cluster head, instead of the single-hop transmission from the cluster heads to base station (BS), which is used in many papers, we adopt multi-hop transmission to save energy. The ant colony optimization (ACO) is used to select the relay nodes between the cluster heads and the base station for the purpose of minimizing the energy consumption in the transmission process. In addition, we determine the reasonable threshold based on the energy consumption curve of the transmission. In this way, the nodes within a radius of the threshold from BS communicate with BS directly to save energy. Experimental results show that the proposed methods achieve the goal of improving the energy efficiency and operation quality of the sensor network in comparison to traditional methods.

Early-life exposure to toxicants could affect health outcomes in adulthood. We determined the effects of early-life exposure to the organophosphorus flame-retardant tris (1,3-dichloro-2-propyl) phosphate (TDCIPP) in adult zebrafish. Embryos were exposed to TDCIPP from early embryogenesis (2 h post-fertilization) to 10 days post-fertilization (dpf), and larvae were transferred to clean water until adulthood (150 dpf). TDCIPP showed accumulation in larvae, but returned to control levels after 7 days of depuration. In adult zebrafish exposed to TDCIPP in early life, vulnerability to anxiety-like behavior was observed in females but not males, suggesting gender-dependent neurotoxicity. Decreased dopamine (DA) concentration and down-regulation of dopaminergic signaling related genes were observed in the brains of adult females. Upregulation of DNA methylation transferases (dnmt1, dnmt3a, and dnmt3b) genes were observed in larvae and brains of adult females. Further, the promoter regions of the selected key genes (bdnf, drd4b, zc4h2 and th) showed increased DNA methylation status, accompanied by down-regulation of gene transcription in larvae and brains of adult females. Our results indicate that early-life exposure to TDCIPP could cause delayed neurotoxicity in adult zebrafish. Keywords: Tris (1,3-dichloro-2-propyl) phosphate, Delayed neurotoxicity, Dopaminergic neurons, DNA methylation, Zebrafish

The recent availability of digital traces generated by cellphone calls has significantly increased the scientific understanding of human mobility. Until now, however, based on low time resolution measurements, previous works have ignored to study human mobility under various time scales due to sparse and irregular calls, particularly in the era of mobile Internet. In this paper, we introduced Mobile Flow Records, flow-level data access records of online activity of smartphone users, to explore human mobility. Mobile Flow Records collect high-resolution information of large populations. By exploiting this kind of data, we show the models and statistics of human mobility at a large-scale (3,542,235 individuals) and finer-granularity (7.5min). Next, we investigated statistical variations and biases of mobility models caused by different time scales (from 7.5min to 32h), and found that the time scale does influence the mobility model, which indicates a deep coupling of human mobility and time. We further show that mobility behaviors like transportation modes contribute to the diversity of human mobility, by exploring several novel and refined features (e.g., motion speed, duration, and trajectory distance). Particularly, we point out that 2-hour sampling adopted in previous works is insufficient to study detailed motion behaviors. Our work not only offers a macroscopic and microscopic view of spatial-temporal human mobility, but also applies previously unavailable features, both of which are beneficial to the studies on phenomena driven by human mobility.