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Objective: This study aimed to understand the health of workers exposed to occupational noise and explore the influencing factors related to workers' health, especially the impact of noise on workers' hearing. This work can provide a basis for formulating relevant measures for occupational noise prevention and control in the future., Methods: On the basis of the key occupational disease monitoring project in Chongqing, China, in 2021, the data of 1125 workers exposed to occupational noise were analyzed. Data included demographic information, occupational history, clinical physical examination information, and noise detection information of the working environment. Chi-square test and multifactorial logistic regression were used for statistical analysis., Results: The prevalence rates of abnormal electrocardiogram (ECG), blood pressure (BP), and pure tone audiometry (PTA) were 21.9% (246/1125), 27.8% (313/1125), and 18.0% (202/1125), respectively. Male workers accounted for 78.8%. Compared with male workers, female workers had a lower prevalence of abnormal PTA (OR = 0.28, 95% CI = 0.16-0.50). Workers working in medium enterprises had a lower prevalence of abnormal BP than workers in micro enterprises (OR = 0.36, 95% CI = 0.19-0.66). The prevalence of abnormal BP and PTA of workers increased with age. After adjusting for age, sex, and body mass index, the prevalence of abnormal ECG of mining workers was higher than that of manufacturing workers (OR = 1.54, 95% CI = 1.07-2.24), and the prevalence of abnormal PTA had a rising trend with the increase in noise exposure value., Conclusion: Noise-exposed workers have a high prevalence of abnormal ECG, BP, and PTA, and factors such as age, enterprise size, and workplace noise exposure are correlated with the aberrant health of workers. Governments, enterprises, and individuals need to attach great importance to the possible adverse effects of noise. They must also actively adopt various effective measures to protect the occupational safety and health of workers., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Jin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Because the complexity of the external environment has put great pressure on the agricultural economy, making it vulnerable, it is necessary to promote a system of resilience in the agricultural economy so that Chinese agriculture can continue to persevere in the face of serious external uncertainties. Therefore, this paper investigates the spatio-temporal pattern and evolution of the distributional dynamics of China's county-level agricultural economic resilience based on 2000-2020 data covering 2,545 counties. The results are as follows: first, from 2000 to 2020, the mean value of China's county-level agricultural economic resilience showed an obvious upward trend, which indicates that China's agricultural economy gradually increased its ability to resist risks and continued to develop in a favourable manner. Specifically, the county-level agricultural economic resilience index of the northeast region grew the most significantly, while the index of county units in the western region was relatively low. Second, the centre of gravity of the spatial distribution of China's agricultural economic resilience gradually migrated to the northwest, showing a dominant direction from northeast to southwest and a tendency to develop from southeast to northwest. Third, the spatial differences in China's agricultural economic resilience generally showed an upward trend, while county-level differences were the main source of the overall differences, followed by inter-provincial differences, inter-municipal differences and inter-regional differences. Additionally, the contribution of county-level differences to the overall differences fluctuated within the range of 54%-58%. Fourth, there is a possibility of localized convergence in China's agricultural economic resilience, which is continuous in spatial effects and has obvious positively correlated spatial effects at different times and in different county spaces., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: To explore the feasibility and validity of machine learning models in determining causality in medical malpractice cases and to try to increase the scientificity and reliability of identification opinions., Methods: We collected 13,245 written judgments from PKULAW.COM, a public database. 963 cases were included after the initial screening. 21 medical and ten patient factors were selected as characteristic variables by summarising previous literature and cases. Random Forest, eXtreme Gradient Boosting (XGBoost) and Light Gradient Boosting Machine (LightGBM) were used to establish prediction models of causality for the two data sets, respectively. Finally, the optimal model is obtained by hyperparameter tuning of the six models., Results: We built three real data set models and three virtual data set models by three algorithms, and their confusion matrices differed. XGBoost performed best in the real data set, with a model accuracy of 66%. In the virtual data set, the performance of XGBoost and LightGBM was basically the same, and the model accuracy rate was 80%. The overall accuracy of external verification was 72.7%., Conclusions: The optimal model of this study is expected to predict the causality accurately., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Psoriasis vulgaris is a chronic dermatological disease with a high global prevalence. It significantly reduces patients' quality of life and is associated with a substantial economic burden. Conventional therapies for mild-to-moderate psoriasis are often associated with insufficient long-term symptomatic relief and side effects. Chinese herbal medicine (CHM) is commonly used for psoriasis management. A CHM formula, namely Fu zheng he fu zhi yang (FZHFZY), has shown promising treatment effects in clinical practice when used as a bath therapy. However, its efficacy and safety has not been evaluated by a rigorous randomized controlled trial (RCT). Therefore, we designed a double-blinded pilot RCT embedded with a qualitative study on CHM formula FZHFZY plus topical urea for mild-to-moderate psoriasis vulgaris to advance the evidence development and practice of CHM external application for psoriasis. This will be a mixed-method design consisting of a pilot RCT and a qualitative study. The pilot RCT is a two-arm, parallel, placebo-controlled, double-blinded trial. Sixty eligible participants will be randomized at a 1:1 ratio to receive eight weeks' treatment of either FZHFZY plus 10% urea cream, or placebo plus 10% urea cream, with 12-week follow-up visits after the treatment phase. The CHM or placebo will be administered externally as a bath therapy. Outcome measures include trial feasibility, efficacy and safety. The primary efficacy outcome will be Psoriasis Area Severity Index (PASI). Secondary efficacy outcomes include Physician Global Assessment, PASI-75, PASI-50, Body Surface Area, Dermatology Life Quality Index, Skindex-16, itch visual analogue scale and relapse. The qualitative study will be conducted to collect participants' feedback on CHM external application and their experience with the pilot RCT. This study will advance the evidence-based clinical practice of using CHM for psoriasis vulgaris and then to support translation of findings into clinical practice in the future. Trial registration number: ChiCTR2200064092., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Aim: Primarily, this study compares the efficacy of probiotic and acceptance and commitment therapy (ACT) in alleviating the severity of alcohol craving and alcohol use disorder (AUD) among patients who had undergo two weeks of in-patient detoxification. Secondarily, this study compares the efficacy of probiotic and ACT in mitigating the severity of comorbid depression and anxiety symptoms; decreasing serum level of pro-inflammatory cytokines, such as interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α); changing the event-related potential in electroencephalogram (EEG) and restoring microbiota flora in the gut of AUD patients., Methods and Analysis: Initially, during Phase I of the study, the serum level of IL-1β, IL-6 and TNF-α; ERP changes in the EEG and fecal microbiota content will be compared between 120 AUD patients and 120 healthy controls. Subsequently in Phase II of the study, 120 AUD patients will be randomized by stratified permuted block randomization into the probiotic, ACT and placebo groups in a 1:1:1 ratio. Participants in the probiotic and placebo groups will be administered one sachet per day of Lactobacillus spp. probiotic and placebo, respectively for 12 weeks. While those in the ACT group will receive one session per week of ACT for 8 weeks. Outcome measures will be administered at four timepoints, such as t0 = baseline assessment prior to intervention, t1 = 8 weeks after intervention began, t2 = 12 weeks after intervention and t3 = 24 weeks after intervention. Primary outcomes are the degrees of alcohol craving, alcohol withdrawal during abstinence and AUD. Secondary outcomes to be assessed are the severity of co-morbid depression and anxiety symptoms; the serum levels of IL-1β, IL-6 and TNF-α; changes in ERP and fecal microbiota content., Trial Registration Number: NCT05830708 (ClinicalTrials.gov). Registered on April 25, 2023., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Sepsis is characterized by upregulated lipolysis in adipose tissue and a high blood triglyceride (TG) level. It is still debated whether serum TG level is related to mortality in septic patients. The aim of this study is to investigate the association between serum TG level and mortality in septic patients admitted to the intensive care unit (ICU)., Methods: Data from adult septic patients (≥18 years) admitted to the ICU for the first time were obtained from the Multiparameter Intelligent Monitoring in Intensive Care IV (MIMIC-IV) database. The patients' serum TG levels that were measured within the first week after ICU admission were extracted for statistical analysis. The endpoints were 28-day, ICU and in-hospital mortality., Results: A total of 2,782 septic patients were included. Univariate analysis indicated that the relationship between serum TG levels and the risk of mortality was significantly nonlinear. Both the Lowess smoothing technique and restricted cubic spline analyses revealed a U-shaped association between serum TG levels and mortality among septic patients. The lowest mortality rate was associated with a serum TG level of 300-500 mg/dL. Using 300∼500 mg/dL as the reference range, we found that both hypo-TG (<300 mg/dL) and hyper-TG (≥500 mg/dL) were associated with increased mortality. The result was further adjusted by Cox regression with and without the inclusion of some differential covariates., Conclusions: There was a U-shaped association between serum TG and mortality in septic ICU patients. The optimal concentration of serum TG levels in septic ICU patients is 300-500 mg/dL., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Xiao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

General practitioners are crucial in the primary healthcare system as well as for epidemic prevention and control. However, few researchers have examined their professional identity. This study investigated the current status of the professional identity of general practitioners in Chongqing, China and explored the effects of psychological capital and patient's contempt on their professional identity. From December 2021 to January 2022, randomized cluster sampling was used to conduct a cross-sectional online self-assessment questionnaire survey among general practitioners in Chongqing. In total, 2,180 general practitioners working for more than one year were selected. General practitioners' sense of professional identity, mental health, and sense of patients' disrespect were measured using the Professional Identity Scale, Psychological Capital Questionnaire, and Patient's Contempt Questionnaire. Sociodemographic characteristics were also collected. A multiple linear regression model was used to analyze the association between professional identity, psychological capital, and patient's contempt. The average score for professional identity among general practitioners was 53.59 (SD = 6.42). The scores for self-efficacy, hope, resilience, and optimism (subscales of psychological capital) were 26.87 (SD = 5.70), 26.47 (SD = 5.74), 26.97 (SD = 5.55), and 26.86 (SD = 5.59), respectively. The score for perceived contempt was 34.19 (SD = 7.59). An average monthly income greater than CNY 8,000 (β = 1.018, p < 0.001), work tenure of more than 15 years (β = 0.440, p = 0.001), hope (β = 0.249, p < 0.001) and a higher optimism score (β = 0.333, p < 0.001) were positively correlated with professional identity. Having a bachelor's degree and above (β = -0.720, p = 0.014), an administrative role (β = -1.456, p < 0.001), self-efficacy (β = -0.122, p < 0.001), and higher patient's contempt (β = -0.103, p < 0.001) were negatively associated with professional identity. General practitioners in Chongqing demonstrated high professional identity and a strong psychological status during the COVID-19 pandemic. Psychological capital and patient's contempt were associated with professional identity. To improve general practitioners' professional identity, stakeholders should promote practitioners' mental health and physician-patient relationships in China., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Deng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: NOP2/Sun RNA methyltransferase 2 (NSUN2), an important methyltransferase of m5C, has been poorly studied in cancers, and the relationship between NSUN2 and immunity remains largely unclear. Therefore, the purpose of this study was to explore the expression and prognostic value of NSUN2 and the role of NSUN2 in immunity in cancers., Methods: The TIMER, CPTAC and other databases were used to analyze the expression of NSUN2, its correlation with clinical stage and its prognostic value across cancers. Moreover, the TISIDB, TIMER2.0 and Sangerbox platform were used to depict the relationships between NSUN2 and immune molecular subtypes, tumor-infiltrating lymphocytes (TILs), immune checkpoints (ICPs) and immunoregulatory genes. Furthermore, the NSUN2-interacting proteins and related genes as well as the coexpression networks of NSUN2 in LIHC, LUAD and HNSC were explored with the STRING, DAVID, GEPIA2 and LinkedOmics databases. Finally, the subcellular location and function of NSUN2 in HepG2, A549 and 5-8F cells were investigated by performing immunofluorescence, CCK-8 and wound healing assays., Results: Overall, NSUN2 was highly expressed and related to a poor prognosis in most types of cancers and was also significantly associated with immune molecular subtypes in some cancer types. Furthermore, NSUN2 was significantly associated with the levels of ICPs and immunoregulatory genes. In addition, NSUN2 was found to be involved in a series of immune-related biological processes, such as the humoral immune response in LIHC and LUAD and T-cell activation and B-cell activation in HNSC. Immunofluorescence and CCK-8 assays also confirmed that NSUN2 was widely expressed in the nucleus and cytoplasm, and overexpression of NSUN2 promoted the proliferation and migration of HepG2, A549 and 5-8F cells. NSUN2 was also confirmed to positively regulate the expression of PD-L1., Conclusion: NSUN2 serves as a pan-cancer prognostic biomarker and is correlated with the immune infiltration of tumors., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Zheng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

We have used bias-corrected data from CMIP6 models to drive a regional climate model and project climate on the Tibetan Plateau (TP) in the 21st century. Changes in two background fields, namely, 2-meter air temperature and total precipitation, were analyzed. The results show that the WRF simulations capture the terrain effect that cannot be represented in low-resolution models. The simulation of temperature is better in summer than in winter, while the simulated precipitation is the opposite. By the end of the 21st century, the entire TP region experiences significant warming, with an average warming of 3°C and 7°C in the SSP245 and SSP585 scenarios, respectively. The western region shows a greater warming amplitude, with a maximum of more than 10°C in the SSP585 scenario. Most regions of the TP had significant increases in precipitation by the end of the 21st century, with precipitation increasing by 90 mm and 200 mm in the two scenarios, respectively. However, in the low-altitude areas of southeastern TP, total winter precipitation is significantly reduced in the SSP585 scenario. The strengthening of the East Asian summer monsoon and westerly disturbances collectively leads to a significant increase in precipitation within the TP region. By the end of the 21st century, the average annual precipitation in the TP is projected to reach approximately 600 millimeters., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Deng, Ji. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Aim: Implantable cardiac monitors (ICM) can facilitate the detection of asymptomatic atrial fibrillation episodes. We performed a systematic review and meta-analysis to investigate whether ICM can prevent stroke in patients with prior stroke and risk factors for stroke., Methods: This study included randomized controlled trials comparing ICM with conventional (non-ICM) external cardiac monitoring in patients with prior stroke and risk factors for stroke. We searched Medline, Embase, and CENTRAL from inception until January 5, 2022, without language restriction. Quantitative pooling of the data was undertaken using a random-effects model. The primary outcome was ischemic stroke at the longest follow-up., Results: Four trials comprising 7237 patients were included. ICM was significantly associated with decreased risk of ischemic stroke (RR 0.76; 95% CI, 0.59-0.97; moderate-quality evidence) in patients with prior stroke and risk factors for stroke. ICM was associated with higher detection of atrial fibrillation (RR 4.21, 95% CI 2.26-7.85) and use of oral anticoagulants (RR 2.29, 95% CI 2.07-2.55)., Conclusions: ICM results in a significantly lower risk of ischemic stroke than conventional (non-ICM) external cardiac monitoring in patients with prior stroke and risk factors for stroke. Due to the clinical heterogeneity of study population and limited related studies, more trials were needed to furtherly explore the topic in patients with prior stroke or high risk of stroke., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 He et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To compare the rerupture rate after conservative treatment, open repair, and minimally invasive surgery management of acute Achilles tendon ruptures., Design: Systematic review and network meta-analysis., Data Sources: We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to August 2022., Methods: Randomised controlled trials involving different treatments for Achilles tendon rupture were included. The primary outcome was rerupture. Bayesian network meta-analysis with random effects was used to assess pooled relative risks (RRs) and 95% confidence intervals. We evaluated the heterogeneity and publication bias., Results: Thirteen trials with 1465 patients were included. In direct comparison, there was no difference between open repair and minimally invasive surgery for rerupture rate (RR, 0.72, 95% CI 0.10-4.4; I2 = 0%; Table 2). Compared to the conservative treatment, the RR was 0.27 (95% CI 0.10-0.62, I2 = 0%) for open repair and 0.14 (95% CI 0.01-0.88, I2 = 0%) for minimally invasive surgery. The network meta-analysis had obtained the similar results as the direct comparison., Conclusion: Both open repair and minimally invasive surgery were associated with a significant reduction in rerupture rate compared with conservative management, but no difference in rerupture rate was found comparing open repair and minimally invasive surgery., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Deng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The feeding amount of bass farming is closely related to the number of bass. It is of great significance to master the number of bass to achieve accurate feeding and improve the economic benefits of the farm. In view of the interference caused by the problems of multiple targets and target occlusion in bass data for bass detection, this paper proposes a bass target detection model based on improved YOLOV5 in circulating water system. Firstly, acquiring by HD cameras, Mosaic-8, a data augmentation method, is utilized to expand datasets and improve the generalization ability of the model. And K-means clustering algorithm is applied to generate suitable coordinates of prior boxes to improve training efficiency. Secondly, Coordinate Attention mechanism (CA) is introduced into backbone feature extraction network and neck feature fusion network to enhance attention to targets of interest. Finally, Soft-NMS algorithm replaces Non-Maximum Suppression algorithm (NMS) to re-screen prediction boxes and keep targets with higher overlap, which effectively solves the problems of missed detection and false detection. The experiments show that the proposed model can reach 98.09% in detection accuracy and detection speed reaches 13.4ms. The proposed model can help bass farmers under the circulating water system to accurately grasp the number of bass, which has important application value to realize accurate feeding and water conservation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Xu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: The relationship between physical activity (PA) and the risk of frailty has not reached a conclusive result. This systematic review with meta-analysis aimed to evaluate the effect of PA on the onset of frailty in the community-dwelling middle and older age adults by pooling data from cohort studies., Methods: A systematic literature search was performed via PubMed, Embase, and Web of Science up to June 01, 2021. Pooled adjusted effect estimates (ES) with 95% confidence interval (CI) were calculated by using the random-effect model and by comparing the highest with lowest levels of PA. Heterogeneity was tested using the I2 statistic and Q-test. The quality of evidence was evaluated by using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach., Results: A total of ten cohort studies with 14 records were selected, and the GRADE approach classified the quality of evidence as low. In comparison with the lowest level of PA, the highest level of PA was associated with 41% decreased odds of frailty (ES: 0.59, 95% CI: 0.51-0.67; I2 = 70.0%, P-heterogeneity < 0.001) after pooling results from included studies. In stratified analysis by frailty assessment approach, the highest level of PA was significantly associated with 37% (ES 0.63, 95% CI: 0.52-0.77, 49% (ES: 0.51, 95% CI: 0.41-0.63), and 30% (ES: 0.70, 95% CI: 0.65-0.75) reduced odds of frailty when pooling studies using criteria of physical frailty, multidimensional model, and accumulation of disability, respectively. Stratified analyses further by PA indicators and PA assessment tools yielded similar protective effects in any subgroups., Conclusions: This study with moderate-certainty evidence shows that a higher level of PA was associated with lower odds of frailty, and the benefits of PA for frailty prevention were independent of frailty assessment tools, PA indicators, and PA assessment methods. Findings from this study may help implement active exercise strategies to prevent frailty., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Zhao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Cutaneous melanoma (CM) is the most common skin cancer and one of the most aggressive cancers and its incidence has risen dramatically over the past few decades. The tumor microenvironment (TME) plays a crucial role in the occurrence and development of cutaneous melanoma. Nevertheless, the dynamics modulation of the immune and stromal components in the TME is not fully understood. In this study, 471 CM samples were obtained from TCGA database, and the ratio of tumor-infiltrating immune cells (TICs) in the TME were estimated using the ESTIMATE algorithms and CIBERSORT computational method. The differently expressed genes (DEGs) were applied to GO and KEGG function enrichment analysis, establishment of protein-protein interaction (PPI) network and univariate Cox regression analysis. Subsequently, we identified a predictive factor: HLA-DRB1 (major histocompatibility complex, class II, DR beta 1) by the intersection analysis of the hub genes of PPI network and the genes associated with the prognosis of the CM patients obtained by univariate Cox regression analysis. Correlation analysis and survival analysis showed that the expression level of HLA-DRB1 was negatively correlated with the Stage of the patients while positively correlated with the survival, prognosis and TME of melanoma. The GEPIA web server and the representative immunohistochemical images of HLA-DRB1 in the normal skin tissue and melanoma tissue from the Human Protein Atlas (HPA) database were applied to validate the expression level of HLA-DRB1. CIBERSORT analysis for the ratio of TICs indicated that 9 types of TICs were positively correlated with the expression level of HLA-DRB1 and only 4 types of TICs were negatively correlated with the expression level of HLA-DRB1. These results suggested that the expression level of HLA-DRB1 may be related to the immune activity of the TME and may affect the prognosis of CM patients by changing the status of the TME., Competing Interests: The authors have declared that no competing interests exist.

Background: Vitamin E has long been linked to skin health, including all of its possible functions in cosmetic products, to its roles in membrane integrity and even the aging process. However, reports on the relationship between serum vitamin E levels and the risk of chronic inflammatory skin diseases have been inconsistent. We performed a systematic review and meta-analysis to evaluate the association between serum vitamin E levels and chronic inflammatory skin diseases., Methods: We searched the PubMed, Web of Science and Scopus databases, with no time limit up to 30.06.2021. Studies examining serum vitamin E levels in patients with chronic inflammatory skin diseases were selected., Results: Twenty articles met the inclusion criteria. Compared with controls, a lower vitamin E level was found in patients with vitiligo (SMD: -0.70, 95% CI: -1.21 to -0.19), psoriasis (SMD: -2.73, 95% CI: -3.57 to -1.18), atopic dermatitis (SMD: -1.08, 95% CI: -1.80 to -0.36) and acne (SMD: -0.67, 95% CI: -1.05 to -0.30)., Conclusions: Our meta-analysis showed that serum vitamin E levels were lower in patients suffering from vitiligo, psoriasis, atopic dermatitis and acne. This study highlights the need to evaluate vitamin E status to improve its level in patients with skin diseases., Competing Interests: The authors have declared that no competing interests exist.

This study investigates international students' acculturation attitude preference and the influence factors (i.e., gender, duration in China, host and English proficiency, adult attachment style and social ties) on each acculturation attitude (i.e, integration, assimilation, separation and marginalization attitude) in China. A group of 229 international students within China responded online. Results from cluster analysis based on process model of acculturation revealed that, integration was the most prevalent acculturation attitude of international students in China. Additionally, logistic regressions analysis indicated that duration in China was negatively associated with adoption of separation and marginalization attitude also higher level of English proficiency predicted the preference of marginalization attitude. However, Chinese proficiency was positively associated with integration attitude adoption, host ties were positively and significantly associated with adoption of assimilation and integration attitude, but negatively associated with the usage of marginalization attitude. Lastly, avoidance attachment was found negatively associating with the integration attitude. This study provides valuable insights for international student education policymakers to assist international students in order to adapt to a new environment quickly and effectively., Competing Interests: The authors have declared that no competing interests exist.

Human mobility is crucial to understand the transmission pattern of COVID-19 on spatially embedded geographic networks. This pattern seems unpredictable, and the propagation appears unstoppable, resulting in over 350,000 death tolls in the U.S. by the end of 2020. Here, we create the spatiotemporal inter-county mobility network using 10 TB (Terabytes) trajectory data of 30 million smart devices in the U.S. in the first six months of 2020. We investigate the bond percolation process by removing the weakly connected edges. As we increase the threshold, the mobility network nodes become less interconnected and thus experience surprisingly abrupt phase transitions. Despite the complex behaviors of the mobility network, we devised a novel approach to identify a small, manageable set of recurrent critical bridges, connecting the giant component and the second-largest component. These adaptive links, located across the United States, played a key role as valves connecting components in divisions and regions during the pandemic. Beyond, our numerical results unveil that network characteristics determine the critical thresholds and the bridge locations. The findings provide new insights into managing and controlling the connectivity of mobility networks during unprecedented disruptions. The work can also potentially offer practical future infectious diseases both globally and locally., Competing Interests: The authors have declared that no competing interests exist.

Background: Caudal epidural block (CEB) provides reliable anesthesia for adults undergoing anorectal surgery. Despite the widely utilization, the minimum effective concentration for 90% patients (MEC90) of ropivacaine for CEB remains unknown., Objective: To estimate MEC of ropivacaine for CEB in anorectal surgery., Design: A prospective dose-finding study using biased coin design up-and-down sequential method., Setting: Operating room and postoperative recovery area of Chengdu Shangjin Nanfu Hospital, from October 2019 to January 2020., Patients: 50 males and 51 females scheduled for anorectal surgery., Interventions: We conducted two independent biased coin design up-and down trials by genders. The concentration of ropivacaine administered to the first patient of male and female were 0.25% with fixed volume of 14ml for male and 12ml for female patients based on our previous study. In case of failure, the concentration was increased by 0.05% in the next subject. Otherwise, the next subject was randomized to a concentration 0.05% less with a probability of 0.11, or the same concentration with a probability of 0.89. Success was defined as complete sensory blockade of perineal area 15 min after the block evidenced by the presence of a lax anal sphincter and pain-free surgery., Main Outcome Measures: The MEC of ropivacaine to achieve a successful CEB in 90%(MEC90) of the patients., Results: The MEC90 of ropivacaine for CEB were estimated to be 0.35% (95% CI 0.29 to 0.4%) for male and 0.353% (95%CI 0.22 to 0.4%) for female. By extrapolation to MEC in 99% of subjects (MEC99) and pooled adjacent violators algorithm (PAVA) adjusted responses, it would be optimal to choose 0.4% ropivacaine with a volume of 14ml for male and 12ml for female., Conclusions: A concentration of 0.35% ropivacaine with a volume of 14ml provided a successful CEB in 90% of the male patients, while 0.353% ropivacaine with a volume of 12ml provided a successful CEB in 90% of the female patients. A concentration of 0.4% and a volume of 14ml for male and 12 ml for female would be successful in 99% of the patients., Trial Registration: Chictr.org.cn identifier: No. ChiCTR 1900024315., Competing Interests: The authors have declared that no competing interests exist.

Collagen is the major protein in the extracellular matrix and plays vital roles in tissue development and function. Collagen is also one of the most processed proteins in its biosynthesis. The most prominent post-translational modification (PTM) of collagen is the hydroxylation of Pro residues in the Y-position of the characteristic (Gly-Xaa-Yaa) repeating amino acid sequence of a collagen triple helix. Recent studies using mass spectrometry (MS) and tandem MS sequencing (MS/MS) have revealed unexpected hydroxylation of Pro residues in the X-positions (X-Hyp). The newly identified X-Hyp residues appear to be highly heterogeneous in location and percent occupancy. In order to understand the dynamic nature of the new X-Hyps and their potential impact on applications of MS and MS/MS for collagen research, we sampled four different collagen samples using standard MS and MS/MS techniques. We found considerable variations in the degree of PTMs of the same collagen from different organisms and/or tissues. The rat tail tendon type I collagen is particularly variable in terms of both over-hydroxylation of Pro in the X-position and under-hydroxylation of Pro in the Y-position. In contrast, only a few unexpected PTMs in collagens type I and type III from human placenta were observed. Some observations are not reproducible between different sequencing efforts of the same sample, presumably due to a low population and/or the unpredictable nature of the ionization process. Additionally, despite the heterogeneous preparation and sourcing, collagen samples from commercial sources do not show elevated variations in PTMs compared to samples prepared from a single tissue and/or organism. These findings will contribute to the growing body of information regarding the PTMs of collagen by MS technology, and culminate to a more comprehensive understanding of the extent and the functional roles of the PTMs of collagen., Competing Interests: The authors have declared that no competing interests exist.

Background: To assess the efficacy and safety of restrictive versus liberal red blood cell transfusion thresholds in very low birth weight infants., Methods: We searched MEDLINE, EMBASE, and Cochrane database without any language restrictions. The last search was conducted in August 15, 2020. All randomized controlled trials comparing the use of restrictive versus liberal red blood cell transfusion thresholds in very low birth weight (VLBW) infants were selected. Pooled risk ratio (RR) for dichotomous variable with 95% confidence intervals were assessed by a random-effects model. The primary outcome was all-cause mortality., Results: Overall, this meta-analysis included 6 randomized controlled trials comprising 3,483 participants. Restrictive transfusion does not increase the risk of all-cause mortality (RR, 0.99; 95% CI, 0.84 to 1.17; I2 = 0%; high-quality evidence), and does not increase the composite outcome of death or neurodevelopmental impairment (RR, 1.01, 95% CI, 0.93-1.09; I2 = 7%; high-quality evidence) or other serious adverse events. Results were similar in subgroup analyses of all-cause mortality by weight of infants, gestational age, male infants, and transfusion volume., Conclusions: In very low birth weight infants, a restrictive threshold for red blood cell transfusion was not associated with increased risk of all-cause mortality, in either short term or long term., Competing Interests: The authors have declared that no competing interests exist.

Heterotaxy (HTX), a condition characterized by internal organs not being arranged as expected relative to each other and to the left-right axis, is often accompanied with congenital heart disease (CHD). The purpose was to detect the pathogenic variants in a Chinese family with HTX and CHD. A non-consanguineous Han Chinese family with HTX and CHD, and 200 unrelated healthy subjects were enlisted. Exome sequencing and Sanger sequencing were applied to identify the genetic basis of the HTX family. Compound heterozygous variants, c.3426-1G>A and c.4306C>T (p.(Arg1436Trp)), in the dynein axonemal heavy chain 11 gene (DNAH11) were identified in the proband via exome sequencing and further confirmed by Sanger sequencing. Neither c.3426-1G>A nor c.4306C>T variant in the DNAH11 gene was detected in 200 healthy controls. The DNAH11 c.3426-1G>A variant was predicted as altering the acceptor splice site and most likely affecting splicing. The DNAH11 c.4306C>T variant was predicted to be damaging, which may reduce the phenotype severity. The compound heterozygous variants, c.3426-1G>A and c.4306C>T, in the DNAH11 gene might be the pathogenic alterations resulting in HTX and CHD in this family. These findings broaden the variant spectrum of the DNAH11 gene and increase knowledge used in genetic counseling for the HTX family., Competing Interests: The authors have declared that no competing interests exist.

This is an epidemiological study on the gastrointestinal nematode (GIN) and Eimeria coccidia infections in Kazakh sheep and the F1 and F2 generations of Kazakh × Texel sheep crosses. A total of 7599 sheep fecal samples were collected from the Zhaosu County and Nilka County in Ili Kazakh Autonomous Prefecture in the four seasons-spring, summer, autumn, and winter of 2019. The parasite causing the infection was identified by the saturated saline floating method, and the infection intensity was calculated by the modified McMaster method. SPSS19.0 was used to evaluate the differences in the fecal egg count (FEC) of for GIN and the fecal oocyst count (FOC) value of for coccidia per sample. The results showed that there were nine types of sheep GIN infections and Eimeria coccidia in these two counties of Ililocations, with the dominant parasite species of Haemonchus contortus, Trichostrongylus spp., and Ostertagia spp as the predominant parasites in the sheep. Most of the GIN and coccidia infections in these two regions were mild and moderate. The mean log (FEC) of GIN infection in the Zhaosu area was significantly higher than that in the Nilka area, whereas the mean log (FOC) of coccidia infection in Zhaosu was significantly lower than that of Nilka. The mean log (FEC) of GIN infection in the four seasons was the highest in spring, followed by in summer, then in autumn, and the lowest in winter. The mean log (FOC) of coccidia infection was the highest in spring, followed by in autumn, and was the lowest in summer and winter. The mean log (FEC) of GIN infection and log (FOC) of coccidia infection of Kazakh sheep was significantly higher than the F1 generation, which was then significantly higher than the F2 generation of summer. A positive correlation was found between the EPG and OPG levels in the sheep. These results showed that the GIN and coccidia infection intensities of the F1 generation sheep of Kazakh ×Texel crosses were significantly lower than that of Kazakh sheep paving the way for marker-based resistance selection., Competing Interests: The authors have declared that no competing interests exist.

Background: Observational studies suggest that low 25-hydroxyvitamin D status is common and has been associated with higher mortality in critically ill patients. This study aim to investigate whether vitamin D supplementation is associated with lower mortality in critically ill patients., Method: We searched Medline, Embase, and Cochrane databases from inception to January 12, 2020, without language restrictions, for randomized controlled trials comparing the effect of vitamin D supplementation with placebo in critically ill patients. Two authors independently performed data extraction and assessed study quality. The primary outcome was all-cause mortality at the longest follow-up., Result: We identified nine trials with a total of 2066 patients. Vitamin D supplementation was not associated with reduced all-cause mortality at the longest follow-up (RR 0.90, 95% CI 0.74 to 1.09, I2 = 20%), at 30 days (RR 0.81, 95% CI 0.56 to 1.15), at 90 days (RR 1.15, 95% CI 0.92 to 1.44), and at 180 days (RR 0.82, 95% CI 0.65 to 1.03). Results were similar in the sensitivity analysis. The sample size met the optimum size in trial sequential analysis. Similarly, supplemental vitamin D was not associated with length of ICU stay, hospital stay, or mechanical ventilation., Conclusion: Vitamin D supplement was not associated with reduced all-cause mortality in critically ill patients., Systematic Review Registration: Open Science Framework https://osf.io/bgsjq., Competing Interests: The authors have declared that no competing interests exist.

Electromagnetic radiation has been proposed to non-aqueously stimulate shale formations, which can generate fractures and enhance the porosity of the matrix. The proposed method consumes electricity and thereby possesses significant advantages for sustainable and environmental hydrocarbon production. In this study, we investigate the pore structure variations of marine shale during electromagnetic radiation. First, the prepared marine shale samples are exposed to electromagnetic radiation for different times; an infrared thermometer monitors the temperatures. Then, the nitrogen adsorption/desorption technique is applied to examine the evolutions of the pore structure. Next, a scanning electron microscope is adopted to reveal the morphology and identify newly developed pores. Lastly, fractal analyses are performed to quantify pore structure variations. The sample exhibits quick temperature rises, whose temperature reaches about 300 °C after 5 min of electromagnetic radiation. The elevated temperature causes clay dehydration, thermal expansion, and organic matter decomposition, leading to significant changes in pore structures. The nitrogen adsorption/desorption characteristics demonstrate enhancements in pore spaces, including volume, size, and surface area. Fractal analyses show that the pores become rougher and exhibit less heterogeneity after electromagnetic radiation. The obtained results demonstrate a great potential of using electromagnetic radiation to enhance the porosity of shale rocks., Competing Interests: The authors have declared that no competing interests exist.

Drug repurposing is an attractive and pragmatic way offering reduced risks and development time in the complicated process of drug discovery. In the past, drug repurposing has been largely accidental and serendipitous. The most successful examples so far have not involved a systematic approach. Nowadays, remarkable advances in drugs, diseases and bioinformatic knowledge are offering great opportunities for designing novel drug repurposing approach through comprehensive understanding of drug information. In this study, we introduced a novel drug repurposing approach based on transcriptomic data and chemical structures using deep learning. One strong candidate for repurposing has been identified. Pimozide is an anti-dyskinesia agent that is used for the suppression of motor and phonic tics in patients with Tourette's Disorder. However, our pipeline proposed it as a strong candidate for treating non-small cell lung cancer. The cytotoxicity of pimozide against A549 cell lines has been validated., Competing Interests: The authors of this paper have read the journal’s policy and have the following All authors are paid employees of Beijing Deep Intelligent Pharma Technologies Co., Ltd. (https://www.dip-ai.com/). There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Our research aimed to explore the correlation between mid-upper arm circumference (MUAC) and central obesity and insulin resistance (IR) in Chinese subjects with type 2 diabetes., Materials: A total of 103 participants (60 men) were recruited in our study. MUAC was measured around the mid-arm between the shoulder and elbow. Waist circumference (WC) was obtained as central obesity parameter, and the IR parameter of Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) was calculated. The subjects were divided into three groups according to the tertiles cut-points of MUAC level., Results: Body mass index (BMI), WC, the percentages of central obesity and HOMA-IR were significantly higher in the groups with higher MUAC than those in the group with lower MUAC (all P < 0.05). Pearson analysis showed that MUAC was correlated with BMI, WC, waist-to-hip ratio (WHR), logHOMA-IR, low density lipoprotein cholesterol (LDL-C), uric acid (UA) and high density lipoprotein cholesterol (HDL-C) in all subjects. Multivariate linear regression analysis revealed that MUAC was independently associated with logHOMA-IR (β = 0.036, P<0.001) after adjusting for age, gender, WHR, UA, TG, LDL-C and HDL-C. Binary logistic regression analysis revealed that MUAC was an independent predictor of central obesity (OR: 2.129, 95%CI: 1.311-3.457, P = 0.002). Furthermore, MUAC≥30.9cm for male and ≥30.0cm for female were the optimal cutoff values for identifying central obesity., Conclusions: Our study indicated that among Chinese subjects with type 2 diabetes, MUAC is a simple and effective tool for the determination of central obesity and IR. Additionally, the larger MUAC is proved to be more associated with metabolic risk factors of higher UA and LDL-C and lowever HDL-C., Competing Interests: The authors have declared that no competing interests exist.

Melatonin (MT) has many important functions in plants. In this study, different concentrations of MT (0, 50, 100, 150, and 200 μmol/L) were sprayed on grape seedlings, and its effects on plant growth and sucrose metabolism were determined. The results show that there was a mutual influence and promotional relationship between growth and sugar metabolism in grape seedlings. The MT treatments promoted the development and growth of grape seedlings by increasing their biomass and promoting the photosynthetic performance of leaves. This resulted in increased nutrient absorption and a greater ability to compete for resources. The increase in photosynthesis resulted in greater sucrose production. The MT treatments increased the activities of enzymes related to sucrose metabolism, so that a large amount of sucrose was hydrolysed into glucose and fructose to meet the rapid growth requirements of grape seedlings. The increased total soluble sugars contents and increased activities of antioxidant enzymes resulted in greater resistance of grape seedlings, and greater adaptability to environmental changes. In general, MT treatments had beneficial effects on grape seedling growth, glucose metabolism, and resistance. Under these conditions, foliar spraying with MT at 150 μmol/L had the best effects., Competing Interests: The authors have declared that no competing interests exist.

Intensive care data are valuable for improvement of health care, policy making and many other purposes. Vast amount of such data are stored in different locations, on many different devices and in different data silos. Sharing data among different sources is a big challenge due to regulatory, operational and security reasons. One potential solution is federated machine learning, which is a method that sends machine learning algorithms simultaneously to all data sources, trains models in each source and aggregates the learned models. This strategy allows utilization of valuable data without moving them. One challenge in applying federated machine learning is the possibly different distributions of data from diverse sources. To tackle this problem, we proposed an adaptive boosting method named LoAdaBoost that increases the efficiency of federated machine learning. Using intensive care unit data from hospitals, we investigated the performance of learning in IID and non-IID data distribution scenarios, and showed that the proposed LoAdaBoost method achieved higher predictive accuracy with lower computational complexity than the baseline method., Competing Interests: The authors have declared that no competing interests exist.

Dysfunctional mitochondria have been implicated in aging and age-related disorders such as Parkinson's diseases (PD). We previously showed that pink1 and parkin, two familial PD genes, function in a linear pathway to maintain mitochondrial integrity and function. Studies of mammalian cell lines also suggest that these genes regulate mitochondrial autophagy(mitophagy). Overexpressing Parkin promotes proteostasis and function of aged muscles both in fruit flies and mice, and recent studies also indicated that mitochondrial ubiquitination are accumulated in aged muscles. However, the underlying mechanisms for pink1 and parkin mediated mitophagy on longevity is not fully understood. Here, we found that mitochondrial ubiquitination increased in indirect flight muscles (IFMs) in an age-dependent manner. Overexpression of pink1 or parkin in IFMs can abolish mitochondrial ubiquitination, restore ATP level and extend lifespan, while blocking autophagy via ATG1 knock-down suppress these effects in aged IFMs. Taken together, these results show that pink1/parkin promotes mitophagy of mitochondrial ubiquitination in aged muscles and extend lifespan in an Atg1-dependent manner. Our study provides physiological evidence that mitophagy of mitochondrial ubiquitination mediated by PINK1/ Parkin is crucial for muscle function and highlights the role of mitophagy in the pathogenesis of chronic diseases like PD., Competing Interests: The authors have declared that no competing interests exist.

To accurately study the risk assessment of landslide disasters, firstly, the environmental conditions of induced landslide disasters are regarded as a fuzzy system, and the landslide risk factors in the multi-level analysis system are constructed to build a multi-level fuzzy evaluation index system. Then, the cloud model theory is introduced to improve the importance scale and membership degree involved in the evaluation process, and the multi-level fuzzy comprehensive evaluation method of landslide risk improved by a cloud model is proposed. Thus, a multi-level fuzzy evaluation cloud model for evaluating landslide risk is established. Finally, using the improved cloud model method, a multistage fuzzy comprehensive evaluation of landslide risk is conducted for the K112+210~K112 +630 section of the Long Chuan to Huaiji Highway Project in Guangdong Province. The results show that the improved cloud model can solve the problem of uncertainty in the process of landslide preparation and occurrence, greatly improve the effectiveness of landslide evaluation results, and provide an effective reference for landslide disaster prevention., Competing Interests: The authors have declared that no competing interests exist.

Although many studies have confirmed that antimicrobial peptides (AMPs: PBD-mI and LUC-n) can be used as feed additives, there are few reports of their use in ruminants. The present study aimed to investigate the impact of AMPs on ameliorating rumen fermentation function and rumen microorganisms in goats. Eighteen 4-month-old Chuanzhong black goats were used in a 60-day experiment (6 goats per group). Group I was used as the control and was fed a basal diet, the group II were fed the basal diet supplemented with 2 g of AMPs [per goat/day] and group III were fed the basal diet supplemented 3 g of AMPs [per goat/day], respectively. Rumen fluid samples were collected at 0, 20 and 60 days. Bacterial 16S rRNA genes and ciliate protozoal 18S rRNA genes were amplified by PCR from DNA extracted from rumen samples. The amplicons were sequenced by Illumina MiSeq. Rumen fermentation parameters and digestive enzyme activities were also examined. Our results showed that dietary supplementation with AMPs increased the levels of the bacterial genera Fibrobacter, Anaerovibrio and Succiniclasticum and also increased the ciliates genus Ophryoscolex, but reduced the levels of the bacterial genera Selenomonas, Succinivibrio and Treponema, and the ciliate genera Polyplastron, Entodinium, Enoploplastron and Isotricha. Supplementation with AMPs increased the activities of xylanase, pectinase and lipase in the rumen, and also increased the concentrations of acetic acid, propionic acid and total volatile fatty acids. These changes were associated with improved growth performance in the goats. The results revealed that the goats fed AMPs showed improved rumen microbiota structures, altered ruminal fermentation, and improved efficiency regarding the utilization of feed; thereby indicating that AMPs can improve growth performance. AMPs are therefore suitable as feed additives in juvenile goats., Competing Interests: The authors have declared that no competing interests exist.

Study Objective: Anesthesiologists at our hospital commonly administer spinal anesthesia for routine lumbar spine surgeries. Anecdotal impressions suggested that patients received fewer anesthesia-administered intravenous medications, including vasopressors, during spinal versus general anesthesia. We hypothesized that data review would confirm these impressions. The objective was to test this hypothesis by comparing specific elements of spinal versus general anesthesia for 1-2 level open lumbar spine procedures., Design: Retrospective single institutional study., Setting: Academic medical center, operating rooms., Patients: Consecutive patients (144 spinal and 619 general anesthesia) identified by automatic structured query of our electronic anesthesia record undergoing lumbar decompression, foraminotomy or microdiscectomy by one surgeon under general or spinal anesthesia., Interventions: Spinal or general anesthesia., Measurements: Numbers of medications administered during the case., Main Results: Anesthesiologists administered in the operating room a total of 10 ± 2 intravenous medications for general anesthetics and 5 ± 2 medications for spinal anesthetics (-5, 95% CI -5 to -4, p<0.001, univariate analysis). Multivariable analysis supported this finding (spinal versus general anesthesia: -4, 95% CI -5 to -4, p<0.001). Spinal anesthesia patients were less likely to receive ephedrine, or phenylephrine (by bolus or by infusion) (all p<0.001, Chi-squared test). Spinal anesthesia patients were also less likely to receive labetolol or esmolol (both p = 0.002, Fishers' Exact test). No neurologic injuries were attributed to, or masked by, spinal anesthesia. Three spinal anesthetics failed., Conclusions: For routine lumbar surgery in our cohort, spinal compared to general anesthesia was associated with significantly fewer drugs administered during a case and less frequent use of vasoactive agents. Safety implications include greater hemodynamic stability with spinal anesthesia along with reduced risks for medication error and transmission of pathogens associated with medication administration., Competing Interests: The authors have declared that no competing interests exist.

Large-scale breeding environments often lead to oxidative stress. Macrophages play an important role in the immune system and are vulnerable to reactive oxygen species (ROS), which result in macrophage death. Curcumin is the main active component of turmeric and exerts antioxidant effects. Here, we measured the activity of some antioxidant enzymes and chose the Nrf2-Keap1 signaling pathway to study the protective effects of curcumin on macrophages under oxidative stress in vitro. We used RAW264.7 cells as a research model, and oxidative damage was induced by hydrogen peroxide (H2O2). Cell viability was measured by an MTT assay. Flow cytometry was used to measure cellular ROS and apoptosis. The effect of curcumin on Nrf2-Keap1 signaling pathway-related genes was analyzed by qRT-PCR. Furthermore, the translocation of Nrf2 protein was also investigated by Western blot analysis of total and nuclear proteins. All curcumin-treated groups exhibited increased activity of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX). Low- and middle-dose curcumin decreased malondialdehyde (MDA) and ROS levels, but high-dose curcumin increased MDA and ROS production. We found that low-dose curcumin protected cells from apoptosis, while apoptosis in the middle- and high-dose curcumin-treated groups were stagnant in the early stage. Furthermore, middle-dose curcumin upregulated Nrf2 expression after H2O2 treatment for 4 h. Low- and middle-dose curcumin could activate Nrf2 and promote it to migrate into nuclei. The translocation of Nrf2 to the nucleus to upregulate the expression of haemoxygenase-1 (HO-1) was promoted in the low- and middle-dose curcumin-treated groups. The middle-dose curcumin-treated group also exhibited enhanced expression of glutamate-cysteine ligase, a modifier subunit (GLCM), but inhibited transcription of glutamate-cysteine ligase, a catalytic subunit (GCLC). Curcumin resisted oxidants by increasing the activity of antioxidant enzymes and activating the Nrf2-Keap1 pathway, which could potentially promote cell survival., Competing Interests: The authors have declared that no competing interests exist.

In the Netherlands, toxoplasmosis ranks second in disease burden among foodborne pathogens with an estimated health loss of 1,900 Disability Adjusted Life Years and a cost-of-illness estimated at €45 million annually. Therefore, effective and preferably cost-effective preventive interventions are warranted. Freezing meat intended for raw or undercooked consumption and improving biosecurity in pig farms are promising interventions to prevent Toxoplasma gondii infections in humans. Putting these interventions into practice would expectedly reduce the number of infections; however, the net benefits for society are unknown. Stakeholders bearing the costs for these interventions will not necessary coincide with the ones having the benefits. We performed a Social Cost-Benefit Analysis to evaluate the net value of two potential interventions for the Dutch society. We assessed the costs and benefits of the two interventions and compared them with the current practice of education, especially during pregnancy. A 'minimum scenario' and a 'maximum scenario' was assumed, using input parameters with least benefits to society and input parameters with most benefits to society, respectively. For both interventions, we performed different scenario analyses. The freezing meat intervention was far more effective than the biosecurity intervention. Despite high freezing costs, freezing two meat products: steak tartare and mutton leg yielded net social benefits in both the minimum and maximum scenario, ranging from €10.6 million to €31 million for steak tartare and €0.6 million to €1.5 million for mutton leg. The biosecurity intervention would result in net costs in all scenarios ranging from €1 million to €2.5 million, due to high intervention costs and limited benefits. From a public health perspective (i.e. reducing the burden of toxoplasmosis) and the societal perspective (i.e. a net benefit for the Dutch society) freezing steak tartare and leg of mutton is to be considered., Competing Interests: The authors have declared that no competing interests exist.

Background: Calcimimetics have been shown to be effective and safe therapies for the treatment of secondary hyperparathyroidism (sHPT), a serious complication of disordered mineral metabolism associated with dialysis-dependent chronic kidney disease. Etelcalcetide, a recently approved intravenous calcimimetic, reduces serum parathyroid hormone (PTH), calcium, phosphorus, and fibroblast growth factor-23 concentrations. Here we report the first integrated safety profile of etelcalcetide using pooled data from five pivotal clinical trials., Methods: This analysis included data from patients receiving hemodialysis with moderate to severe sHPT enrolled in two randomized, placebo-controlled trials; a randomized active-controlled (with cinacalcet) trial; and two single-arm, open-label extension trials. Patients initially received etelcalcetide intravenously 5 mg three times weekly (TIW) after hemodialysis; with potential dose increases of 2.5 or 5 mg at 4-week intervals to a maximum dose of 15 mg TIW, depending on serum PTH and calcium levels. The nature, frequency, and severity of treatment-emergent adverse events (AEs) and changes in laboratory parameters were assessed., Results: Overall, we evaluated 1023 patients from the placebo-controlled trials, 683 from the active-controlled trial, and 1299 from open-label extensions. The frequency and nature of common treatment-emergent AEs reported for the etelcalcetide arm were consistent among the placebo-controlled and active-controlled trials. The most common AEs were those related to mineral metabolism (decreased blood calcium, hypophosphatemia, muscle spasms) or gastrointestinal abnormalities (diarrhea, nausea, vomiting). Hypocalcemia leading to discontinuation of either calcimimetic was experienced in ≤ 1% of patients., Conclusions: This integrated safety assessment of etelcalcetide across placebo- and active-controlled trials showed an overall favorable risk/benefit profile, with safety similar to that of cinacalcet. Consistent with its mechanism of action, the most important risks associated with etelcalcetide were serum calcium reductions and hypocalcemia-related AEs; no new safety findings were identified in the pooled long-term extension trials., Competing Interests: G. Block has been a consultant for Amgen Inc., Ardelyx, Keryx, AstraZeneca, Celgene, ZS, Relypsa, Akebia, Daiichi-Sankyo, Sanifit, and OPKO; has ownership interest in Ardelyx and Nephroceuticals; has received research funding from Keryx and NIH; received honoraria from Amgen Inc., Sanofi, Keryx, AstraZeneca, Celgene, Akebia, Daiichi-Sankyo, ONO, and OPKO; has been a scientific advisor for Amgen Inc., Akebia, Celgene, and AstraZeneca; has participated in speakers bureau with OPKO; and is a Medical Director with DaVita. G. Chertow has been a consultant for Akebia, AMAG, Amgen Inc., Ardelyx, AstraZeneca, Durect, Gilead, and Keryx; has ownership interest in Ardelyx, Durect, Outset, PuraCath, and Physiowave; and has received research funding from Amgen and Janssen. J. Sullivan holds stock in Nektar Therapeutics, NantHealth, Sage Therapeutics, and Marinus Pharmaceuticals; and is an employee and stockholder of Amgen Inc. O. Mather is an employee and stockholder of Amgen Inc. H. Deng was an employee at the time these trials were completed and is a stockholder of Amgen Inc. H. Tomlin and M. Serenko were employees and stockholders of Amgen Inc. at the time these trials were completed. M. Serenko holds stock in Editas, Ionis, Juno, Intelia, Bioverativ Inc., Celgene, and WAVE Life Sciences.

Dengue virus (DENV), a single-stranded RNA virus and Flaviviridae family member, is transmitted by Aedes aegypti and Aedes albopictus mosquitoes. DENV causes dengue fever, which may progress to severe dengue. Hospital-based surveillance was performed in two Chinese regions, Guangzhou and Xishuangbanna, during the dengue epidemics in 2014 and 2015, respectively. Acute-phase serum was obtained from 133 patients with suspected dengue infections during the peak season for dengue cases. Viremia levels, virus sero-positivity, serotype distribution, infection type, clinical manifestations and virus phylogenetics were investigated. Of the 112 DENV-confirmed cases, 92(82.14%) were IgM antibody-positive for DENV, and 69(51.88%) were positive for DENV RNA. From these cases, 47(41.96%) were classified as primary infections, 39(34.82%) as secondary infections and 26 (23.21%) as undetermined infections. The viremia levels were negatively correlated with IgM presence, but had no relationship with the infection type. DENV-1 genotype V dominated in Guangzhou, whereas the DENV-2 Cosmopolitan genotype dominated in Xishuangbanna, where fewer DENV-1 genotype I cases occurred. DENV-2 is associated with severe dengue illness with more serious clinical issues. The strains isolated during 2014-2015 are closely related to the isolates obtained from other Chinese regions and to those isolated recently in Southeast Asian countries. Our results indicate that DENV is no longer an imported virus and is now endemic in China. An extensive seroepidemiological study of DENV and the implementation of vector control measures against it are now warranted in China., Competing Interests: The authors have declared that no competing interests exist.

Persistent infection with high-risk human papillomavirus (HPV) is a major risk factor for cervical cancer. Greater than 90% of these cancers originate in the cervical transformation zone (TZ), a narrow region of metaplastic squamous epithelium that develops at the squamocolumnar junction between the ectocervix and endocervix. It is unclear why the TZ has high susceptibility to malignant transformation and few studies have specifically examined cells from this region. We hypothesized that cells cultured from TZ are more susceptible to cellular immortalization, an alteration that contributes to malignant development. We cultured primary epithelial cells from each region of human cervix (ectocervix, endocervix and TZ) and measured susceptibility to immortalization after transfection with the complete HPV-16 genome or infection of HPV16 E6/E7 retroviruses. Cells cultured from each cervical region expressed keratin markers (keratin 14 and 18) that confirmed their region of origin. In contrast to our prediction, cells from TZ were equally susceptible to immortalization as cells from ectocervix or endocervix. Thus, increased susceptibility of the TZ to cervical carcinogenesis is not due to increased frequency of immortalization by HPV-16. We developed a series of HPV16-immortalized cell lines from ectocervix, endocervix and TZ that will enable comparisons of how these cells respond to factors that promote cervical carcinogenesis., Competing Interests: This work was funded by an award from the National Cancer Institute 1R15CA173703-1 (CDW) and an award from US Biomax, Inc. (CDW). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Panicle traits in rice impact yield and quality. The OsGRF4 gene encodes a growth-regulating factor controlling panicle traits, and was recently cloned. Gene expression profiling analysis can be used to study the molecular mechanisms underlying OsGRF4 regulation. Use of near-isogenic lines (NILs) reduces genetic background noise in omics studies. We compared transcriptome profiling of 7 cm long young panicles of NIL-Osgrf4 and NIL-OsGRF4 using RNAs sequence analyses. Eighty differentially expressed genes (DEGs) were identified. Our target gene OsGRF4 was up-regulated in NIL-OsGRF4 plants, which is consistent with a previous qPCR analysis. Hierarchical cluster analysis showed OsGRF4 is tightly clustered with the up-regulated DEG LOC&#95;Os02g47320. Gene Ontology (GO) and KEGG analysis suggested that DEGs were primarily involved in somatic embryogenesis and chitinase activity. Two up-regulated DEGs, LOC&#95;Os04g41680 and LOC&#95;Os04g41620, were significantly enriched in the top 8 GO terms, and were over&#95;represented in term of seed development, and may play key roles in grain shape regulation. The transcription factor Osmyb1 also exhibited differential expression between NILs, and may be is an important regulator of panicle traits. By searching reported functions of DEGs and by co-localization with previous identified quantitative trait loci (QTL), we determined that the pleiotropic gene OsGRF4 may also be involve in abiotic stress resistance. This study provides new candidates genes for further understanding the molecular mechanisms underlying rice panicle trait regulation., Competing Interests: The authors have declared that no competing interests exist.

Background: Behcet's disease (BD) is a chronic, multisystem-involved vasculitis and its pathogenesis remains elusive. No specific serological markers for BD diagnosis have been established. Identification of novel diagnostic biomarkers will be helpful in timely diagnostic and treatment for Behcet's disease., Objective: To screen novel autoantigens or autoantibodies with potential diagnostic value in circulating immune complexes (CICs) from BD patients., Methods: A proteomic strategy for immune complexome analysis was developed, in which CICs were separated from serum sample of 10 BD patients and 10 healthy controls and then subjected to Orbitrap mass spectrometry for autoantigen profiling. Anti-tubulin-α-1c antibody levels were further determined by enzyme-linked immunosorbent assay (ELISA) in sera of patients with BD, systemic lupus erythematosus (SLE), recurrent aphthous ulcers (RAU), ANCA associated systemic vasculitis (AASV), Takayasu's arteritis (TA) and 59 healthy controls., Result: A total of 17 potential antigens were identified in CICs from BD patients, but not in HC. The autoantibody to one of the identified antigens, tubulin-α-1c, was significantly increased in BD patients compared with that in healthy and disease controls. The sensitivity and specificity of tubulin-α-1c antibody in the diagnosis of BD in this study were 61.36% and 88.4%, respectively. Further analysis demonstrated that anti-tubulin-α-1c was associated with complications of deep venous thrombosis and erythema nodosum in BD. The levels of anti-tubulin-α-1c were also significantly correlated with the BD inflammation and disease activity markers ESR, CRP and BVAS., Conclusion: Anti-tubulin-α-1c antibody is a promising biomarker in diagnosis and severity evaluation of BD and in indicating the risk of deep venous thrombosis and erythema nodosum. The immune complexome analysis by proteomic CIC autoantigen screening is a feasible way of identifying novel biomarkers in BD., Competing Interests: The authors have declared that no competing interests exist.

Relative expression levels of twenty-four amylase genes in Shiraia sp. SUPER-H168 were investigated by real-time quantitative PCR when various carbohydrates, including glucose, sucrose, maltose, amylose, amylopectin and corn flour, were used as carbon source. Genes, including an α-glucosidase gene Amy33 (2997 bp), an α-amylase gene Amy365-1 (1749 bp) and a glycogen debranching enzyme gene Amy130 (2487 bp), were overexpressed, and four overexpression transformants were constructed, respectively. When Amy365-1 and Amy130 were co-overexpressed, relative expression levels of seven hypocrellin biosynthesis genes and four related genes in central carbon catabolism were all increased. Expression of Amy33 was also increased along with increase of Amy365-1 and Amy130. Under liquid state fermentation, biomasses and hypocrellin productions were both gradually increased in four overexpression strains than those of wild type strain. Under SSF, hypocrellin production of Amy365-1 and Amy130 co-expression strain reached 71.85 mg/gds, which was 2.83 fold than that of wild type strain, and residual sugar was decreased from 35.47% to 16.68%. These results can provide a practical approach for other secondary metabolites by filamentous fungi under SSF when raw starch material is used as carbon source.

Background: Although subsequent breast cancer risk after primary lobular carcinoma in situ (LCIS) has been studied intensively, whether the risk of second breast cancer after first LCIS varies with hormone receptor (HR) status of primary tumor remains unclear., Methods: We identified 10,304 women with primary pure unilateral LCIS between 1998 and 2007 from the Surveillance, Epidemiology and End Results (SEER) 18 Registries. Kaplan-Meier estimates of 5 or 10-year probabilities of second ipsilateral breast cancers (IBCs) and contralateral breast cancers (CBCs) were calculated. Multivariable Cox proportional model was performed to identify impact of HR status of primary LCIS, and other demographic, clinicopathologic or treatment characteristics on risk of second IBCs or CBCs., Results: Of the 10,304 women with primary LCIS included in this study, 9949 (96.5%) patients had HR+ tumors, and 355 (3.5%) had HR- tumors. Multivariable-adjusted analyses showed that although there was no difference in risk of total second IBCs between women with HR+ and HR- LCIS (P = 0.152), patients with HR+ LCIS had a statistically lower risk of second invasive IBCs compared to those with HR- LCIS (hazard ratio 0.356, 95% CI 0.141-0.899, P = 0.029). Women with primary HR+ LCIS had lower risks of both second total and invasive CBCs compared to those with HR- LCIS (total CBCs: hazard ratio 0.340, 95% CI 0.228-0.509, P<0.001; invasive CBCs: hazard ratio 0.172, 95% CI 0.108-0.274, P<0.001). Additionally, black women had a 2-fold risk of developing subsequent total IBCs than white women (P = 0.028)., Conclusions: This population-based study demonstrated that the risk of second breast cancers was significantly increased in women with HR- first LCIS compared to those with HR+ LCIS. These findings warrant intensive surveillance for second breast cancers in HR- LCIS survivors.

Spiral waves are observed in the chemical, physical and biological systems, and the emergence of spiral waves in cardiac tissue is linked to some diseases such as heart ventricular fibrillation and epilepsy; thus it has importance in theoretical studies and potential medical applications. Noise is inevitable in neuronal systems and can change the electrical activities of neuron in different ways. Many previous theoretical studies about the impacts of noise on spiral waves focus an unbounded Gaussian noise and even colored noise. In this paper, the impacts of bounded noise and rewiring of network on the formation and instability of spiral waves are discussed in small-world (SW) network of Hodgkin-Huxley (HH) neurons through numerical simulations, and possible statistical analysis will be carried out. Firstly, we present SW network of HH neurons subjected to bounded noise. Then, it is numerically demonstrated that bounded noise with proper intensity σ, amplitude A, or frequency f can facilitate the formation of spiral waves when rewiring probability p is below certain thresholds. In other words, bounded noise-induced resonant behavior can occur in the SW network of neurons. In addition, rewiring probability p always impairs spiral waves, while spiral waves are confirmed to be robust for small p, thus shortcut-induced phase transition of spiral wave with the increase of p is induced. Furthermore, statistical factors of synchronization are calculated to discern the phase transition of spatial pattern, and it is confirmed that larger factor of synchronization is approached with increasing of rewiring probability p, and the stability of spiral wave is destroyed., Competing Interests: The authors have declared that no competing interests exist.

Aims: To summarize our experience of radiofrequency catheter ablation (RFCA) for recurrent drug-refractory ventricular tachycardias (VTs) due to arrhythmogenic right ventricular cardiomyopathy (ARVC) in our center over the past 11 years and its related factors., Methods and Results: We reviewed 48 adults (mean age 39.9 ± 12.9 years, range: 14 to 65) who met the present ARVC diagnostic criteria and accepted RFCA for VTs from December 2004 to April 2016. The patients received a total of 70 procedures using two ablation approaches, the endocardial approach in 52 RFCAs, and the combined epicardial and endocardial approach (the combined approach) in 18 RFCAs. Kaplan-Meier survival analysis showed that the combined approach achieved better acute procedural success (p = 0.003) and better long-term outcomes (p = 0.028) than the endocardial approach. Patients who obtained acute procedural success with non-inducibility had better long-term outcomes (p < 0.001). COX regression of multivariate analysis showed that procedural success was the only factor that benefited long-term outcome, irrespective of the endocardial or the combined approach (p = 0.001). The rate of sudden cardiac death (SCD) in patients without procedural success was significantly higher than that in patients with procedural success (p = 0.005). All patients without implantable cardioverter defibrillator (ICD) implantation who had successful final RFCA survived., Conclusions: The combined approach resulted in better procedural success and long-term VT-free survival compared with the endocardial approach in ARVC patients with recurrent VTs. Acute procedural success with non-inducibility was strongly related to better long-term VT-free survival and reduced SCD, irrespective of whether this was achieved by the endocardial approach or the combined approach., Competing Interests: The authors have declared that no competing interests exist.

Background: Existing literature suggests that endocrine measures, including the steroid hormones of cortisol and Dehydroepiandrosterone (DHEA), as well as the DHEA to cortisol ratio in the human hair can be used as promising biomarkers of chronic stress among humans. However, data are limited regarding the validity of these measures as biomarkers of chronic stress among people living with HIV (PLWH), whose endocrine system or hypothalamic pituitary adrenal (HPA) axis may be affected by HIV infection and/or antiretroviral therapy (ART) medications., Method: Using hair sample data and self-reported survey from 60 PLWH in China, we examined the validity of three endocrine measures among Chinese PLWH using a known-groups validation strategy. High-stress group (n = 30) and low-stress group (n = 30) of PLWH were recruited through individual assessment interviews by a local licensed psychologist. The endocrine measures in hair were extracted and assessed by LC-APCI-MS/MS method. Both bivariate and multivariate analyses were conducted to examine the associations between the endocrine measures and the stress level, and to investigate if the associations differ by ART status., Results: The levels of endocrine measures among Chinese PLWH were consistent with existing studies among PLWH. Generally, this pilot study confirmed the association between endocrine measures and chronic stress. The high stress group showed higher level hair cortisol and lower DHEA to cortisol ratio. The higher stress group also reported higher scores of stressful life events, perceived stress, anxiety and depression. Hair cortisol level was positively related to anxiety; DHEA was negatively associated with stressful life events; and the DHEA to cortisol ratio was positively related to stressful life events and perceived stress. ART did not affect the associations between the endocrine measures and stress level., Conclusions: Our findings suggest that hair cortisol and DHEA to cortisol ratio can be used as promising biomarkers of chronic stress among PLWH. Clarifying the role of steroid hormones in the psychoimmunology of PLWH may yield important implications for clinical practice and psychological intervention., Competing Interests: The authors have declared that no competing interests exist.

Protein translational machinery is an important component of the proteostasis network that maintains cellular proteostasis and regulates aging and other cellular processes. Ample evidence indicates that inhibition of translation initiation factor activities enhances stress resistance in model organisms. Eukaryotic translation initiation factor 5B (eIF5B) acts by joining the pre-40S subunit with the 60S ribosomal unit to form an 80S-like complex during protein translational initiation. Reduced eIF5B expression may disrupt proteostasis and trigger cellular processes associated with stress responses. In this study, the physiological effects of altered eIF5B expression were examined in 293T and HepG2 cells. Cells with eIF5B-knockdown (eIF5B-KN) grew more slowly than control cells, and had a lower level of intracellular reactive oxygen species (ROS), increased resistance to oxidative stress and enhanced autophagy. Proteomic analysis showed that eIF5B knockdown resulted in upregulation of 88 proteins and downregulation of 130 proteins compared with control cells. The differentially expressed proteins were associated with diverse cellular processes including amino acid metabolism, RNA processing and protein metabolism, and DNA synthesis. Autonomous downregulation of the mitogen-activated protein kinase (MAPK) signaling pathway was identified as confirmed by western blotting and qPCR. We proposed that deactivation of MAPK pathway modulated proteostasis and induced prolonged S-phase of the cell-cycle, contributing to the slow growth of eIF5B-KN cells. eIF5B silencing also inactivated the mTOR pathway, downregulated glutamine transporters, enhanced autophagy, and decreased 28S rRNA and 5.8S rRNA expression levels which were reversed by restoration of eIF5B expression. Taken together, these results suggest that eIF5B silencing provides a negative feedback to deactivate MAPK signaling, leading to reduced cell growth. These findings provide a useful resource to further biological exploration of the functions of protein synthesis in regulation of proteostasis and stress responses., Competing Interests: The authors have declared that no competing interests exist.

Background: Since the discovery of cell-free foetal DNA in the plasma of pregnant women, many non-invasive prenatal testing assays have been developed. In the area of skeletal dysplasia diagnosis, some PCR-based non-invasive prenatal testing assays have been developed to facilitate the ultrasound diagnosis of skeletal dysplasias that are caused by de novo mutations. However, skeletal dysplasias are a group of heterogeneous genetic diseases, the PCR-based method is hard to detect multiple gene or loci simultaneously, and the diagnosis rate is highly dependent on the accuracy of the ultrasound diagnosis. In this study, we investigated the feasibility of using targeted capture sequencing to detect foetal de novo pathogenic mutations responsible for skeletal dysplasia., Methodology/principal Findings: Three families whose foetuses were affected by skeletal dysplasia and two control families whose foetuses were affected by other single gene diseases were included in this study. Sixteen genes related to some common lethal skeletal dysplasias were selected for analysis, and probes were designed to capture the coding regions of these genes. Targeted capture sequencing was performed on the maternal plasma DNA, the maternal genomic DNA, and the paternal genomic DNA. The de novo pathogenic variants in the plasma DNA data were identified using a bioinformatical process developed for low frequency mutation detection and a strict variant interpretation strategy. The causal variants could be specifically identified in the plasma, and the results were identical to those obtained by sequencing amniotic fluid samples. Furthermore, a mean of 97% foetal specific alleles, which are alleles that are not shared by maternal genomic DNA and amniotic fluid DNA, were identified successfully in plasma samples., Conclusions/significance: Our study shows that capture sequencing of maternal plasma DNA can be used to non-invasive detection of de novo pathogenic variants. This method has the potential to be used to facilitate the prenatal diagnosis of skeletal dysplasia.

Recently, a new type of small interfering RNAs (qiRNAs) of typically 20~21 nucleotides was found in Neurospora crassa and rice and has been shown to regulate gene silencing in the DNA damage response. Identification of qiRNAs is fundamental for dissecting regulatory functions and molecular mechanisms. In contrast to other expensive and time-consuming experimental methods, the computational prediction of qiRNAs is a conveniently rapid method for gaining valuable information for a subsequent experimental verification. However, no tool existed to date for the prediction of qiRNAs. To this purpose, we developed the novel qiRNA prediction software package qiRNApredictor. This software demonstrates a promising sensitivity of 93.55% and a specificity of 71.61% from the leave-one-out validation. These studies might be beneficial for further experimental investigation. Furthermore, the local package of qiRNApredictor was implemented and made freely available to the academic community at Supplementary material.