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Tetracycline (TC) is one of the most important therapeutic drugs that is widely used in hospitals. However, its harmful effects on human health and various ecosystems cannot be ignored. Owing to its poor metabolic activity and low biodegradability, TC commonly discharges as the parent compound and accumulates readily in sludges and soils by precipitation from wastewater, which can induce the evolution of antibiotic-resistant bacteria; therefore, it has been listed as one of the new pollutants with potential ecotoxicological risk. The control measures and environmental management of TC pollutants in environmental water samples require precise determination of TC pollutant concentrations. Carbon dots (CDs) are an emerging type of fluorescent material with numerous advantages such as easy preparation, low cost, low toxicity, and good biocompatibility. Consequently, they have attracted widespread attention in the field of TC detection. Herein, we synthesized TE-CDs with good blue-fluorescence performance via flow-assisted melt polymerization using tricarboxylic acid and ethylenediamine as raw precursors. The morphology and structure of the prepared TE-CDs were characterized. The transmission electron microscopy (TEM) results showed that the prepared TE-CDs were well dispersed, with an average diameter of (2.43±0.48) nm. The X-ray diffraction (XRD) results showed that the TE-CDs had an amorphous carbon structure. Infrared spectroscopy and X-ray photoelectron spectroscopy (XPS) characterizations showed that the surface of the TE-CDs was rich in hydrophilic groups, such as amino, hydroxyl, and carboxyl groups, which indicated that TE-CDs had good water solubility and were advantageous for detecting TC in medical wastewater. Subsequently, the optical properties of the TE-CDs were investigated. The fluorescence emission spectra of the TE-CDs were recorded at various excitation wavelengths. The emission spectra of the TE-CDs exhibited excitation wavelength dependence and when the excitation wavelength changes from 300 nm to 400 nm, their fluorescence intensity decreased to varying degrees. The TE-CDs exhibited optimal fluorescence intensity at an excitation wavelength of 368 nm, while the emission wavelength was 448 nm. TC could effectively quench the blue fluorescence of the CDs, and by utilizing this property, the detection of TC concentration could be achieved. After the addition of TC, the fluorescence of the system immediately reached an extreme value, and no significant change was observed within 10 min. An incubation time of 20 s was selected to obtain precise results. Additionally, the TE-CDs exhibited stable fluorescence intensity over a wide pH range. The fluorescence stability of the TE-CDs was investigated, and no significant change in fluorescence intensity was observed after standing for 10 d, indicating that the prepared TE-CDs had excellent fluorescence stability. The fluorescence intensity of the TE-CDs decreased to varying degrees within the range of 2-200 mg/L TC until complete quenching occurred. TC mass concentration in the range of 4-20 mg/L showed a good linear relationship ( R 2 =0.9978) with the fluorescence quenching intensity of the TE-CDs. The limit of detection was 0.2 mg/L. A preliminary investigation was undertaken to explore the quenching mechanism of the TE-CDs fluorescence by TC. Upon addition of TC, a significant reduction in the fluorescence lifetime of the TE-CDs was observed. During the quenching process, no new substances were observed by UV absorption spectroscopy. Additionally, no significant changes in the 1 H NMR spectra of the TE-CDs were noted before and after the addition of TC, indicating the absence of an interaction between the TE-CDs and TC. Therefore, the quenching mechanism may involve dynamic quenching. The selectivity and anti-interference ability of the developed method were evaluated; in the presence of interfering substances, TC quenched the fluorescence of the TE-CDs, indicating that the TE-CDs had good selectivity and anti-interference performance towards TC. The method was applied to the quantitative detection of TC in medical wastewater, with recoveries of 96.5%-119.8% and relative standard deviations of 0.8%-2.6%. In conclusion, the analytical performance of the proposed method is comparable with that of previously reported detection methods; moreover, the method has the advantages of low operational cost, simple preparation process, time-saving, and good repeatability. Therefore, the TE-CDs can be used as chemical sensors for the detection of TC in medical wastewater and have good practical applications.

The inversion of substrate size specificity is an evolutionary roadblock for proteins. The Duf4243 dioxygenases GedK and BTG13 are known to catalyze the aromatic cleavage of bulky tricyclic hydroquinone. In this study, we discover a Duf4243 dioxygenase PaD that favors small monocyclic hydroquinones from the penicillic-acid biosynthetic pathway. Sequence alignments between PaD and GedK and BTG13 suggest PaD has three additional motifs, namely motifs 1-3, distributed at different positions in the protein sequence. X-ray crystal structures of PaD with the substrate at high resolution show motifs 1-3 determine three loops (loops 1-3). Most intriguing, loops 1-3 stack together at the top of the pocket, creating a lid-like tertiary structure with a narrow channel and a clearly constricted opening. This drastically changes the substrate specificity by determining the entry and binding of much smaller substrates. Further genome mining suggests Duf4243 dioxygenases with motifs 1-3 belong to an evolutionary branch that is extensively involved in the biosynthesis of natural products and has the ability to degrade diverse monocyclic hydroquinone pollutants. This study showcases how natural enzymes alter the substrate specificity fundamentally by incorporating new small motifs, with a fixed overall scaffold-architecture. It will also offer a theoretical foundation for the engineering of substrate specificity in enzymes and act as a guide for the identification of aromatic dioxygenases with distinct substrate specificities., (© 2024. The Author(s).)

Ovarian cancer is a common malignant tumor in women, with a high mortality rate ranking first among gynecological tumors. Currently, there is insufficient understanding of the causes, pathogenesis, recurrence and metastasis of ovarian cancer, and early diagnosis and treatment still face great challenges. The sensitivity and specificity of existing ovarian cancer screening methods are still unsatisfactory. Centromere protein O (CENP-O) is a recently discovered structural centromere protein that is involved in cell death and is essential for spindle assembly, chromosome separation, and checkpoint signaling during mitosis. The abnormal high expression of CENP-O was detected in various tumors such as bladder cancer and gastric cancer, and it participates in the regulation of tumor cell proliferation. In this study, we detect the expression abundance of CENP-O mRNA in different ovarian cancer cells ( ES-2, A2780, Caov-3, OVCAR-3 and SK-OV-3). The biological function changes of cell proliferation and apoptosis were detected and the role of CENP-O in ovarian cancer cell proliferation and apoptosis was explored by knocking down the expression of CENP-O gene. The results showed that CENP-O gene was significantly expressed in 5 types of ovarian cancer cell lines. After knocking down the CENP-O gene, the proliferation and cloning ability of ovarian cancer cells decreased, and the apoptosis increased. This study indicates that CENP-O has the potential to be a molecular therapeutic target, and downregulating the expression of CENP-O gene can break the unlimited proliferation ability of cancer cells and promote their apoptosis, providing a foundation and new ideas for subsequent molecular mechanism research and targeted therapy., (© 2024. The Author(s).)

The influence of RG-I domains on high methoxyl pectin (HMP) sugar-acid gel properties has rarely been reported. In our work, HMP was modified by enzymatic de-esterification and degradation of RG-I domains to compare and analyze the relationship between the structure and final sugar-acid gel properties. The results showed that the degree of esterification (DE) of REP (pectin degraded by rhamnosidase) and GEP (pectin debranched by galactosidase) was the same as that of untreated HMP, whereas the DE of PMEP (pectin de-esterified by pectin methyl esterase) decreased from 59.63 % to 54.69 %. The monosaccharide composition suggested no significant changes in the HG and RG-I structural domains of PMEP. In contrast, the percentage of RG-I structural domains of REP and GEP dropped from 37 % to about 28 %, accompanied by a reduction in the proportion of the RG-I backbones and side chains. The rheological characterization of sugar-acid gels demonstrated an enhanced gel grade for PMEP and a weakened one for REP and GEP. Moreover, we constructed a correlation relationship between the fine structure of pectin and the properties of the sugar-acid gels, confirming the critical contribution of the RG-I region (especially the neutral sugar side chains) to the HMP sugar-acid gels., Competing Interests: Declaration of competing interest We declare that no known competing financial interests or personal relationships could have appeared to influence the work reported in this paper. We declare that this manuscript or part of its content is not submitted elsewhere, nor is it under consideration for submission elsewhere., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Metabolomics has emerged as a powerful tool in biomedical research to understand the pathophysiological processes and metabolic biomarkers of diseases. Nevertheless, it is a significant challenge in metabolomics to identify the reliable core metabolites that are closely associated with the occurrence or progression of diseases. Here, we proposed a new research framework by integrating detection-based metabolomics with computational network biology for function-guided and network-based identification of core metabolites, namely, FNICM. The proposed FNICM methodology is successfully utilized to uncover ulcerative colitis (UC)-related core metabolites based on the significantly perturbed metabolic subnetwork. First, seed metabolites were screened out using prior biological knowledge and targeted metabolomics. Second, by leveraging network topology, the perturbations of the detected seed metabolites were propagated to other undetected ones. Ultimately, 35 core metabolites were identified by controllability analysis and were further hierarchized into six levels based on confidence level and their potential significance. The specificity and generalizability of the discovered core metabolites, used as UC's diagnostic markers, were further validated using published data sets of UC patients. More importantly, we demonstrated the broad applicability and practicality of the FNICM framework in different contexts by applying it to multiple clinical data sets, including inflammatory bowel disease, colorectal cancer, and acute coronary syndrome. In addition, FNICM was also demonstrated as a practicality methodology to identify core metabolites correlated with the therapeutic effects of Clematis saponins. Overall, the FNICM methodology is a new framework for identifying reliable core metabolites for disease diagnosis and drug treatment from a systemic and a holistic perspective.

In this study, ultra-performance liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS~E) was used to analyze the plasma components of Danzhi Xiaoyao Formula after oral administration. Forty-nine plasma components were found in the serum of rats by comparing the compound extract, drug-containing serum, and blank serum. Components, such as 6-hydroxycoumarin, poricoic acid F, deoxoglabrolide, 30-norhederagenin, kanzonol R, 3',6'-di-O-galloylpaeoniflorin, 16α-hydroxytrametenolic acid, 16-deoxyporicoic acid B, 3-O-acetyl-16α-hydroxytrametenolic acid, and 16α,25-dihydroxydehydroeburiconic acid, were first found in rat serum. Behavioral tests, including the tail suspension test, novel object recognition test, and novelty-suppressed feeding test, were conducted for behavioral analysis. It was confirmed that this formula had therapeutic effects on perimenopausal depression. Furthermore, in combination with the network pharmacology method, 53 core targets including MAPK1, HRAS, AKT1, EGFR, and ESR1 were screened, and these targets participated in 165 signaling pathways, including PI3K-AKT, AMPK, VEGFA, MAPK, and HIF-1. In summary, the potential effects of Danzhi Xiaoyao Formula in treating perimenopausal depression are associated with mechanisms in accelerating inflammation repair, improving neuroplasticity, affecting neurotransmitters, regulating estrogen levels, and promoting new blood vessel formation.

Objective: Osteogenesis is vitally important for bone defect repair, and Zuo Gui Wan (ZGW) is a classic prescription in traditional Chinese medicine (TCM) for strengthening bones. However, the specific mechanism by which ZGW regulates osteogenesis is still unclear. The current study is based on a network pharmacology analysis to explore the potential mechanism of ZGW in promoting osteogenesis., Methods: A network pharmacology analysis followed by experimental validation was applied to explore the potential mechanisms of ZGW in promoting the osteogenesis of bone marrow mesenchymal stem cells (BMSCs)., Results: In total, 487 no-repeat targets corresponding to the bioactive components of ZGW were screened, and 175 target genes in the intersection of ZGW and osteogenesis were obtained. And 28 core target genes were then obtained from a PPI network analysis. A GO functional enrichment analysis showed that the relevant biological processes mainly involve the cellular response to chemical stress, metal ions, and lipopolysaccharide. Additionally, KEGG pathway enrichment analysis revealed that multiple signaling pathways, including the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) signaling pathway, were associated with ZGW-promoted osteogensis. Further experimental validation showed that ZGW could increase alkaline phosphatase (ALP) activity as well as the mRNA and protein levels of ALP, osteocalcin (OCN), and runt related transcription factor 2 (Runx 2). What's more, Western blot analysis results showed that ZGW significantly increased the protein levels of p-PI3K and p-AKT, and the increases of these protein levels significantly receded after the addition of the PI3K inhibitor LY294002. Finally, the upregulated osteogenic-related indicators were also suppressed by the addition of LY294002., Conclusion: ZGW promotes the osteogenesis of BMSCs via PI3K/AKT signaling pathway., (© 2023. Huazhong University of Science and Technology.)

Background: Semen Aesculi, a traditional Chinese herbal medicine, has a long history of use for treating chest and abdominal pain with distension. In addition, the horse chestnut (Aesculus hippocastanum L.) is another species of Aesculus in Europe and has notable clinical significance in alleviating chronic venous insufficiency, hemorrhoids, and postoperative edema. Thus, highlighting the comparative study of Semen Aesculi and horse chestnut may broaden clinical applications., Objectives: To conduct a comprehensive comparative analysis on the chemical profiling of these two varieties and determine whether they have equivalent clinical efficacy by integrating plant metabolomics and multivariate statistical methods., Methods: Initially, a comprehensive characterisation was performed using ultra-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UPLC-QTOF-MS/MS) platform, and in total 44 active ingredients were identified. Then, untargeted metabolomics combined with principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) was applied for the discrimination of a German species and three official Chinese species. Next, 24 marker compounds responsible for the discrimination of different species were screened out and used to predict the species of unknown samples by genetic algorithm-optimised support vector machine (GA-SVM) with a high prediction accuracy. Finally, a heatmap visualisation was employed for clarifying the distribution of the identified active ingredients., Results: The three species of Chinese Semen Aesculi showed distinct separation from each other, while European horse chestnut and Aesculus chinensis Bunge were similar in chemical composition., Conclusions: This work provided experimental evidence for further expanding the clinical application of Chinese Semen Aesculi and promoted the species identification and quality control of Semen Aesculi., (© 2023 John Wiley & Sons Ltd.)

Hypocalcaemia following thyroid surgery can occur in up to 38% of patients. With over 7100 thyroid surgeries performed in 2018 in the UK, this is a common postoperative complication. Undertreated hypocalcaemia can result in cardiac arrhythmias and death. Preventing adverse events from hypocalcaemia requires preoperative identification and treatment of at-risk patients with vitamin D deficiency, timely recognition of postoperative hypocalcaemia and prompt appropriate treatment with calcium supplementation. This project aimed to design and implement a perioperative protocol for prevention, detection and management of post-thyroidectomy hypocalcaemia. A retrospective audit of thyroid surgeries (n=67; October 2017 to June 2018) was undertaken to establish baseline practice of (1) preoperative vitamin D levels assessment, (2) postoperative calcium checks and incidence of postoperative hypocalcaemia and (3) management of postoperative hypocalcaemia. A multidisciplinary team approach following quality improvement principles was then used to design a perioperative management protocol with all relevant stakeholders involved. After dissemination and implementation, the above measures were reassessed prospectively (n=23; April-July 2019). The percentage of patients having their preoperative vitamin D measured increased from 40.3% to 65.2%. Postoperative day-of-surgery calcium checks increased from 76.1% to 87.0%. Hypocalcaemia was detected in 26.8% of patients before and 30.43% of patients after protocol implementation. The postoperative component of the protocol was followed in 78.3% of patients. Limitations include low number of patients which precluded from analysis of the impact of the protocol on length of stay. Our protocol provides a foundation for preoperative risk stratification and prevention, early detection and subsequent management of hypocalcaemia in thyroidectomy patients. This aligns with enhanced recovery protocols. Moreover, we offer suggestions for others to build on this quality improvement project with the aim to further advance the perioperative care of thyroidectomy patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

To address the fierce competition for corporate innovation in the digital economy, this study introduces knowledge integration capability as a mediating variable in light of social information processing theory, and explores the mechanism of team learning climate on innovation performance. Data were collected from a sample of 184 team members for statistical analysis, and Statistical methods such as descriptive statistical analysis, correlation analysis, and regression analysis were used to verify the study hypotheses through SPSS and Amos software, and the results showed that: (1) Team learning climate has a significant positive effect on knowledge integration capability. (2) Team learning climate has a significant positive effect on innovation performance. (3) Knowledge integration capability has a significant positive effect on innovation performance. (4) Knowledge integration capability partially mediates the role between team learning climate and innovation performance. The results proved the perspective of knowledge integration capability for the mechanism of team learning climate on innovation performance from the perspective of knowledge integration capability, and provided theoretical references for creating a learning climate in companies to promote members' knowledge learning and enhance innovation performance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Li, Li, Liu and Deng.)

Indirubin is a bisindole compound for the treatment of chronic myelocytic leukemia. Here, we presented a structure-guided method to improve the activity of a flavin-containing monooxygenase (bFMO) for the efficient production of indirubin in Escherichia coli. A flexible loop interlocked with the active pocket through a helix and the substrate tunnel rather than the active pocket in bFMO were identified to be two reconfigurable structures to improve its activity, resulting in K223R and N291T mutants with enhanced catalytic activity by 2.5- and 2.0-fold, respectively. A combined modification at the two regions (K223R/D317S) achieved a 6.6-fold improvement in catalytic efficiency (k cat /K m ) due to enhancing π-π stacking interactions stabilization. Finally, an engineered E. coli strain was constructed by metabolic engineering, which could produce 860.7 mg/L (18 mg/L/h) indirubin, the highest yield ever reported. This work provides new insight into the redesign of FMOs to boost their activities and an efficient approach to produce indirubin., (© 2022. The Author(s).)

Across the world, people living with schizophrenia (PLS) are often cared for by family caregivers. This is especially true in China where community-based systems of care for PLS are underdeveloped. Thus, family caregivers of PLS may experience emotional distress and burden in the absence of community-based services. Pearlin (1990) proposed a highly influential model for understanding the stress process and its relationship to health and wellbeing. Although the model has been examined worldwide, it has yet to be studied in China for caregivers of PLS. In the present study, we use Pearlin's stress process model to examine the mediating effect of perceived caregiver burden, family functioning, and caregivers' positive feelings about caregiving on PLS global functioning and caregiver depressive symptoms. We also examine whether the model differs for parent and spouse caregivers. A total of 327 primary family caregivers of PLS in Hunan province, China, were assessed cross-sectionally using culturally-validated measures. Bootstrap methods with Hayes's PROCESS Macro were used to test multiple mediation models of global functioning scores of PLS and caregiver depressive symptoms. In this first study of the stress process model of family caregivers of PLS in China, the results generally support the model. Caregiver perceived burden, family functioning, and positive caregiver feelings about caregiving all mediate the relationship between PLS global functioning and caregiver depression, with perceived caregiver burden having the strongest indirect effect. Analyses also show that the stress process differs between parent and spouse caregivers, with perceived caregiver burden a mediator for both groups but family functioning only a mediator for parent depressive symptoms. We discuss implications of these findings for extending the stress process model cross-culturally; suggest hypotheses for future research to examine parent and spouse differences; and discuss fruitful directions for intervention., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Severe fever with thrombocytopenia syndrome virus (SFTSV) is a novel tick-borne phlebovirus, which is listed in the most dangerous pathogens by the World Health Organization, and has 12-30% fatality rates. SFTSV antibodies were reported in minks that experienced abortion or reproductive failure. The aim of this study was to determine whether SFTSV infection causes an adverse pregnancy outcome in the fetus using a pregnant mouse model., Methodology/principal Findings: We found SFTSV in the fetus after infection in pregnant mice, and some dams showed adverse pregnancy outcomes after infection with SFTSV including placental damage, fetal reabsorption, and fetal intrauterine growth restriction (IUGR). SFTSV had obvious tropism characteristics in the placenta, especially in the labyrinth. In early-gestation, pregnant mice infected with SFTSV had fetal IUGR and a high viral load in the fetus. The virus widely spread in infected fetuses, including the hindbrain, thymus, heart, spinal cord, and liver., Conclusions: Our study demonstrated that SFTSV was vertically transmitted to the fetus through the placental barrier of immunocompetent mice, and resulted in adverse pregnancy outcomes., Competing Interests: The authors have declared that no competing interests exist.

Purpose: The Family Burden Interview Schedule (FBIS-24) and the Zarit Caregiver Burden Interview (ZBI-22) are among the most widely used measures for assessing caregiving burden, but their psychometric performances have not been compared in the same study of caregivers of people living with schizophrenia (PLS). This is important because the measures assess overlapping constructs- the FBIS-24 assesses objective burden (e.g., completion of manual tasks) and the ZBI-22 assesses subjective burden (e.g., perceived distress, stigma). This study seeks to fill this gap by comparing the reliability and validity of the FBIS-24 and the ZBI-22 in a Chinese community sample of caregivers of PLS., Methods: A Cross-sectional stud was conducted in a community-based mental health service program in Central South part of China. A total of 327 primary family caregivers of PLS completed face-to-face interviews of the FBIS-24, the ZBI-22, the Patient Health Questionnaire (PHQ-9), the Generalized Anxiety Disorder Scale (GAD-7), and the Family Adaptation, Partnership, Growth, Affection and Resolve Index scale (APGAR), and PLS were assessed using the Global Assessment of Function scale (GAF)., Results: Our findings show that both the FBIS-24 and ZBI-22 have comparable psychometric performance in terms of the internal consistency, convergent validity and known group's validity., Conclusion: Both the FBIS-24 and the ZBI-22 are psychometrically sound measures of caregiving burden but the choice of which measure to use will depend on the research question.

Obstructive sleep apnea (OSA) is a common chronic condition that has a significant impact on the biopsychosocial aspects of the patient's life. There is currently no psychometrically validated patient-reported outcome measure to assess the impact of this condition on the health-related quality of life. We designed a novel instrument based on common patient statements, prioritized by patient preference. Sixty-three patients with OSA and 33 participants with no symptoms of sleep-disordered breathing were asked to complete a 20-item initial questionnaire. The acceptability, reliability and validity of the instrument were assessed using known psychometric techniques. The instrument had strong acceptability and was completed within 180 s with no missing data. Five items were removed as they had a high ceiling factor. A further three items were removed as they did not represent the central construct uniquely. The final 12-item instrument had high internal consistency (Cronbach's alpha 0.91), strong test-retest reliability (p = .83) and high discriminant validity when comparing mean total scores of controls (6.88; 95% confidence interval [CI], 4.67-9.08) and those with OSA (31.39; 95% CI, 27.94-34.84) (p < .001). Further studies are planned to help validate this instrument for clinical use., (© 2019 European Sleep Research Society.)

Sexual behavior is highly species-specific. Although rodents have slightly different sexual behaviors, mice and rats have a similar sexual behavioral pattern. The purpose of this article is to describe the hormone-induced estrus ovariectomized female model and the experimental procedure for the assessment of sexual behavior of male mice. The most important sexual behavioral elements are demonstrated in the video and illustrations. The critical steps, advantages, and limitations of the sexual behavior test are explained as well. Finally, the behavior parameters are presented, and mounting, intromission, and ejaculation processes in mating are distinguished. Behavioral parameters are assessed in terms of the occurred duration and counts during the test period.

The radioprotective effect of amitriptyline, an inhibitor of acid sphingomyelinase (ASMase), on radiation-induced impairment of hippocampal neurogenesis, loss of interneuron, and animal weight changes was investigated in BALB/c mice by immunostaining of biomarkers for cell division (Ki67), immature neurons (doublecortin or DCX), and interneurons (parvalbumin or PV) in the dentate gyrus (DG) of hippocampus. The results indicated that preirradiation (with 10 mg/kg, 2 times per day, for 7 consecutive days) or postirradiation (with 10 mg/kg, 2 times per day, for 14 consecutive days) treatment (pretreatment or posttreatment) with intraperitoneal injection of amitriptyline prevented the loss of newly generated neurons, proliferating cells, and interneurons in the subgranular zone of the DG. At the molecular level, pretreatment or posttreatment inhibited the expression of sphingomyelin phosphodiesterase 1 ( SMPD1 ) gene which codes for ASMase. The pretreatment for 7 days also prevented radiation-induced weight loss from 2 to 3 weeks, but not within 1 week after irradiation. On the other hand, the posttreatment with amitriptyline for 14 days could improve animal weight gain from 4 to 6 weeks after irradiation. The present study suggests that amitriptyline may be a promising candidate radio-neuroprotective drug to improve radiation-induced impairment of hippocampal neurogenesis and relevant neurological and neuropsychological disorders., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2019.)

Background: Enterovirus 71 (EV71) is the main pathogen that causes severe hand, foot, and mouth disease with fatal neurological complications. However, its neurovirulence mechanism is still unclear. Candidate virulence sites were screened out at structural protein VP1, but the function of these candidate virulence sites remains unclear. Several studies have shown that autophagy is associated with viral replication. However, the relationship between VP1 and autophagy in human neurons has not been studied., Methods: A recombinant virus-SDLY107-VP1, obtained by replacing the VP1 full-length gene of the SDLY107 strain with the VP1 full-length gene of the attenuated strain SDJN2015-01-was constructed and tested for replication and virulence. We then tested the effect of the recombinant virus on autophagy in nerve cells. The effect of autophagy on virus replication was detected by western blot and plaque test. Finally, the changes of mTOR signaling molecules during EV71 infection and the effect of mTOR on virus replication at the RNA level were detected., Results: Viral recombination triggered virulence attenuation. The replication ability of recombinant virus SDLY107-VP1 was significantly weaker than that of the parent strain SDLY107. The SDLY107 strain could inhibit autophagic flux and led to accumulation of autophagosomes, while the SDLY107-VP1 strain could not cause autophagosome accumulation. The synthesis of EV71 RNA was inhibited by inhibiting mTOR., Conclusions: Replacement of VP1 weakened the replication ability of virulent strains and reduced the level of autophagy in nerve cells. This autophagy facilitates the replication of virulent strains in nerve cells. VP1 is an important neurovirulence determinant of EV71, which affects virus replication by regulating cell autophagy. mTOR is a key molecule in this type of autophagy.

Studies on the willingness to receive institutional eldercare among the rural elderly are scarce. This study aims to explore factors associated with the willingness to receive institutional eldercare and community-based eldercare among the rural elderly. A cross-sectional study was conducted in three rural villages of Changde City, Hunan Province, China. A total of 517 elderly were recruited through multistage sampling from these villages. The dependent variable is the willingness to receive eldercare from family (as reference), institution, and community. The independent variables includes sociodemographic characteristics: having physical disease, depression, anxiety, and daily living activities, and concerns toward home-based, institutional, and community-based care, respectively. Results show that 78.3% of the elderly are willing to receive home-based eldercare, 10.8% institutional eldercare, and 8.5% community-based eldercare. The factors associated with the willingness to receive institutional eldercare are having concerns toward home-based (OR = 4.85, P<0.001) and institutional eldercare (OR = 5.51, P<0.001). The factors associated with community-based care is living alone (OR = 2.18, P = 0.034). Finally, the major concerns toward home-based eldercare are lack of care ability and separation of family members, whereas those toward institutional eldercare are unaffordable services and fear of being abandoned by the children. The major concerns toward community-based eldercare includes affordability and lack of necessary services. In summary, elderly having concerns toward home-based care and having no concerns about institutional care are willing to accept institutional eldercare. Elderly who are living alone is tend to accept community-based care. Unaffordable services and loss of contact with family members are the major concerns of institutional eldercare. Aside from the cost, the lack of necessary care services is also a serious concern of community-based eldercare., Competing Interests: The authors have declared that no competing interests exist.

Background: The purpose of the present study was to determine a statistically valid cutoff score for the Zarit Burden Interview (ZBI) in order to identify family caregivers at risk for depression and anxiety to guide for further assessment and future intervention., Methods: The ZBI, the Patient Health Questionnaire (PHQ), and the Generalized Anxiety Disorder Scale (GAD) were administered to a representative community sample of 327 family caregivers of schizophrenia individuals. A ZBI cutoff score was determined using three different statistical methods: tree-based modeling, K-means clustering technique and linear regression, followed by contingency analysis and receiver operating characteristic (ROC) curve to compare between depression and anxiety scale scores with the ZBI cutoff., Results: Findings suggest that a cutoff score of 48 in ZBI has significant predictive validity for identifying caregivers at risk for both depression and anxiety. A ZBI cutoff of 48 showed sensitivity of 73% for PHQ and 70% for GAD, specificity of 80% for PHQ and 79% for GAD, PPV (positive predictive value) of 75% for PHQ and 73% for GAD, NPV (negative predictive value) of 78% for PHQ and 76% for GAD., Conclusions: This cutoff score would enable health care providers to assess family caregivers at risk and provide necessary interventions to improve their quality of life in this important role.

Background: While it is widely acknowledged that family burden can be ameliorated with effective psycho-social interventions, how to measure family burden and define a valid cutoff to identify family caregivers in need of such interventions remains a key question. The purpose of the present study was to determine a statistically valid cutoff score for the Family Burden Interview Schedule (FBIS), using the cutoff scores of the Patient Health Questionnaire (PHQ-9) and the Generalized Anxiety Disorder Scale (GAD-7) as the reference., Methods: The FBIS, PHQ-9, and GAD-7 were administered to a representative community sample of 327 family caregivers of schizophrenia patients. A FBIS cutoff score was determined using three different statistical methods: tree-based modeling, K-means clustering technique and linear regression. Contingency analysis was conducted to compare the FBIS cutoff with depression and anxiety scale scores., Results: Findings proposed a cutoff score of 23 for the FBIS, with sensitivity being 76% for PHQ-9 and 74% for GAD-7, specificity being 68% for PHQ-9 and 67% for GAD-7., Conclusion: This cutoff score would enable health care providers to assess family caregivers at risk and provide necessary interventions to improve their quality of life.

Enterovirus A71 (EV-A71) is known for its manifestation as hand foot and mouth disease (HFMD), which has caused countless large-scale epidemic outbreaks throughout the world. However, the molecular pathogenesis of EV-A71 infection is still elusive. Previous studies found that the biological characteristics of a mild EV-A71 strain (SDLY1) and a severe EV-A71 strain (SDLY107) are significantly different, and sequence analysis showed that there are several differences in nucleotide sites of UTRs (88 nt, 123 nt, 143 nt, 154 nt, 187 nt, 241 nt, 243 nt, 253 nt, 291 nt, 438 nt, 440 nt, 571 nt, 579 nt, 602 nt, 658 nt, 664 nt, 690 nt, 696 nt, 7328 nt, 7335 nt, 7367 nt, and 7395 nt). The aim of this study was to determine whether these amino sites in UTRs are associated with the pathogenesis of EV-A71 and are responsible for different clinical manifestations. Based on the reverse genetics technology, we rescued two chimeric viruses SDLY107(1-5'UTR) and SDLY107(1-3'UTR) by replacing 5'UTR/3'UTR gene fragments of an infectious cDNA clone. Replication kinetics and cytotoxicity assays showed that the virulence of the two chimeric strains significantly changed in vitro. The viral loads of the two chimeric strains in infected ICR mice were reduced and pathological damage in the brains, lungs, intestinal tissues, and muscles were lightened. Our findings suggest that some nucleotide sites in UTRs may have a function in the pathogenicity and virulence of EV-A71., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: A key challenge in thyroid carcinoma is preoperatively diagnosing malignant thyroid nodules. The purpose of this study was to compare the classification performance of linear and nonlinear machine-learning algorithms for the evaluation of thyroid nodules using pathological reports as reference standard., Methods: Ethical approval was obtained for this retrospective analysis, and the informed consent requirement was waived. A total of 1179 thyroid nodules (training cohort, n = 700; validation cohort, n = 479) were confirmed by pathological reports or fine-needle aspiration (FNA) biopsy. The following ultrasonography (US) featu res were measured for each nodule: size (maximum diameter), margins, shape, aspect ratio, capsule, hypoechoic halo, composition, echogenicity, calcification pattern, vascularity, and cervical lymph node status. We analyzed five nonlinear and three linear machine-learning algorithms. The diagnostic performance of each algorithm was compared by using the area under the curve (AUC) of the receiver operating characteristic curve. We repeated this process 1000 times to obtain the mean AUC and 95% confidence interval (CI)., Results: Overall, nonlinear machine-learning algorithms demonstrated similar AUCs compared with linear algorithms. The Random Forest and Kernel Support Vector Machines algorithms achieved slightly greater AUCs in the validation cohort (0.954, 95% CI: 0.939-0.969; 0.954 95%CI: 0.939-0.969, respectively) than other algorithms., Conclusions: Overall, nonlinear machine-learning algorithms share similar performance compared with linear algorithms for the evaluation the malignancy risk of thyroid nodules., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: The aim of this study was to develop an ultrasound-based nomogram to improve the diagnostic accuracy of the identification of malignant thyroid nodules., Methods: A total of 1675 histologically proven thyroid nodules (1169 benign, 506 malignant) were included in this study. The nodules were grouped into the training dataset (n = 700), internal validation dataset (n = 479), or external validation dataset (n = 496). The grayscale ultrasound features included the nodule size, shape, aspect ratio, echogenicity, margins, and calcification pattern. We applied least absolute shrinkage and selection operator (lasso) regression to select the strongest features for the nomogram. Nomogram discrimination (area under the receiver operating characteristic curve, AUC) and calibration were assessed. The nomogram was subjected to bootstrapping validation (1000 bootstrap resamples) to calculate a mean AUC and 95% confidence interval (CI)., Results: The nomogram showed good discrimination in the training dataset, with an AUC of 0.936 (95% CI: 0.918-0.953) and good calibration. Application of the nomogram to the internal validation dataset also resulted in good discrimination (AUC: 0.935; 95% CI, 0.915-0.954) and good calibration. The model tested in an external validation dataset demonstrated a lower AUC of 0.782 (95% CI: 0.776-0.789)., Conclusions: This ultrasound-based nomogram can be used to quantify the probability of malignant thyroid nodules., Key Points: • Ultrasound examination is helpful in the differential diagnosis of malignant and benign thyroid nodules. • However, ultrasound accuracy relies heavily on examiner experience. • A less subjective diagnostic model is desired, and the developed nomogram for thyroid nodules showed good discrimination and good calibration.

Objective: No study has comprehensively evaluated the effect of postweaning isolation on the social and sexual behaviors of a certain strain of rodents in ethology. The present study aims to explore how and to what extent isolation rearing after postweaning affects the social and sexual behaviors of male CD-1 mice in adulthood systematically. Methods: Male CD-1 mice were randomly assigned to two groups: isolation reared (IS, one mouse per cage, n = 30) and group housed (GH, five mice per cage, n = 15). The mice underwent isolation rearing from postnatal day 23 to day 93. Then, social affiliation, recognition and memory were measured through selection task experiments. Social interaction under a home cage and novel environment were measured via resident-intruder and social interaction test, respectively. Furthermore, sexual preference, homosexual and heterosexual behaviors were measured. Results: Our study found that postweaning isolation increased the social affiliation for conspecifics ( p = 0.001), reduced social recognition ( p = 0.042) and impaired social memory. As for social interaction, isolated mice showed a remarkably increased aggression toward the intruder male in a home cage or novelty environment. For instance, isolated mice presented a short attack latency ( p < 0.001), high attack frequency ( p < 0.001) and long attack duration ( p < 0.001). In addition, isolated mice exhibited further social avoidance. Contrastingly, isolated mice displayed a reduced sexual preference for female (IS: 61.47 ± 13.80%, GH: 70.33 ± 10.06%, p = 0.038). As for heterosexual behavior, isolated mice have a short mating duration ( p = 0.002), long mounting latency ( p = 0.002), and long intromission latency ( p = 0.015). However, no association was observed between postweaning isolation and homosexual behavior in male CD-1 mouse. Conclusion: Postweaning isolation increased the social affiliation, impaired the social cognition and considerably increased the aggression in social interaction of adult male CD-1 mice. Postweaning isolation induced a decreased sexual preference for female in adulthood. Postweaning isolation extended the latency to mate, thereby reducing mating behavior. No association was observed between isolation and homosexual behavior.

The effect of acute X-ray irradiation with 2 Gy or fractionated exposure with 0.2 Gy continuously for 10 days (0.2 Gy × 10 = 2 Gy) was evaluated in the postnatal day 21 (P21) BALB/c mouse model. Both acute and fractionated irradiation induced impairment of cell proliferation and neurogenesis in the subgranular zone of the dentate gyrus labeled by Ki67 and doublecortin, respectively. Parvalbumin immunopositive interneurons in the subgranular zone were also reduced significantly. However, the 2 patterns of irradiation did not affect animal weight gain when measured at ages of P90 and P180 or 69 and 159 days after irradiation. Behavioral tests indicated that neither acute nor fractionated irradiation with a total dose of 2 Gy induced deficits in the contextual fear or spatial memory and memory for novel object recognition. Animal motor activity was also not affected in the open-field test. The disparity of the impairment of neurogenesis and unaffected cognition suggests that the severity of impairment of neurogenesis induced by acute or fractionated irradiation with a total dose of 2 Gy at P21 may not be worse enough to induce the deficit of cognition., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The present study aimed to investigate differences in family burden and caregiver distress in a population of caregivers for schizophrenia, by separating patient gender and caregiver gender., Methods: A sample of 327 primary family caregivers was recruited from a Chinese rural community through a one-stage cluster-sampling method. A cross-sectional design was employed, using validated measures to assess both family burden and primary caregivers' depression and anxiety., Results: Significant differences by gender were detected in family burden and caregiver distress. Family burden was significantly higher for male patients on the domains of effect on physical and mental health of others, and significantly higher for female caregivers on the domains of financial burden and effect on physical and mental health of others. Caregivers of male patients were more likely to suffer from anxiety than caregivers of female patients (52.7% vs 38.1%, P =0.012); female caregivers were more likely to suffer from depression (51.2% vs 38.6%, P = 0.031) and anxiety (51.6% vs 38.1%, P =0.020) than male caregivers., Conclusion: The results reinforced the expected differences in caregiving experiences of a schizophrenia population by gender, which has implications for the future design of gender-specific interventions to alleviate family burden and caregiver distress., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Objective: Although various short forms of Zarit Burden Interview (ZBI) have been developed, there is a lack of standard psychometric testing and comparison among them. The study aims to examine the psychometric properties of ten short versions of the most frequently used ZBI among a sample of schizophrenia caregivers and to find the one with the best performance. Methods: Cross-sectional door-to-door survey of ZBI-22 and a series of validated instrument data from 327 family caregivers of schizophrenia patients in a Chinese rural community were conducted from October 2015 to January 2016. Reliability was assessed using McDonald's omega coefficient (ω). Validity including concurrent validity, known group's validity, and criterion validity were assessed by Spearman correlations and Mann-Whitney U tests. Overall discrimination ability was evaluated using the area under the receiver operating characteristic curve (AUC). Results: Reliability was generally good for all short forms (ω = 0.69-0.84), except for the Gort ZBI-4 (ω = 0.58), which is acceptable considering its small item numbers. Concurrent validity was good across all various ZBI forms with significant negative correlations with patient's function ( r = -0.34 to -0.48, p < 0.01), as well as significant positive correlations with caregiver's depression ( r = 0.49-0.65, p < 0.01), and anxiety symptoms ( r = 0.45-0.58, p < 0.01). Known groups' validity (carers with disease vs. without disease; carers being parents vs. spouse vs. others) showed inconsistent results among various short forms. Criterion validity was generally good for all short forms with significant positive correlations with Family Burden Interview Schedule ( r = 0.67-0.75, p < 0.01), except for the Higginson ZBI-1( r = 0.57, p < 0.01). Discriminative ability was also good for all short forms (AUC range: 0.85-0.99), with various cutpoints proposed. Among all ten short forms, the Ballesteros ZBI-12 and the Gort ZBI-7 outperformed others with almost equally good performance in comprehensive psychometric testing. Conclusions: This study provides support for the reliability, validity, and discriminative ability of the ten various short forms of ZBI for use among schizophrenia family caregivers, with the Ballesteros ZBI-12 and the Gort ZBI-7 endorsed as the best ones.

Objective: The present study aims to provide a comprehensive profile of the primary family caregivers of schizophrenia individuals in rural China., Method: A cross-sectional study was conducted with a sample of 327 primary family caregivers of schizophrenia individuals recruited through a one-stage cluster sampling in Ningxiang County of Hunan province, China. The social demographic and psychological profiles of primary caregivers were measured using standard scales and self-designed scales., Results: The typical caregiver profile consists of a 58-year old married first degree relative (mostly parents or spouses) with a low socio-economic position. Most of them have been caregiving for over 10 years (74.3%) and have some physical illness (67.0%). The major caregiving activities were medicine management (71.6%) and hospital visit (69.4%), yet there is still 17.1% primary caregivers involved with neither of the care. Most (84%) of caregivers reported some kind of burden, with anxiety in 45.9% of caregivers and depression in 45.4%. Family caregivers also reported positive aspects of caregiving including a well-functional family (51.0%) and rewarding feelings (58.3%)., Conclusion: The findings of the present study have brought attention to a special group of family caregivers for schizophrenia, with implications for intervention on them in the future., (Copyright © 2018. Published by Elsevier Inc.)

For many regenerative electrochemical energy-conversion systems, hybrid electrocatalysts comprising transition metal (TM) oxides and heteroatom-doped (e.g., nitrogen-doped) carbonaceous materials are promising bifunctional oxygen reduction reaction/oxygen evolution reaction electrocatalysts, whose enhanced electrocatalytic activities are attributed to the synergistic effect originated from the TM-N-C active sites. However, it is still ambiguous which configuration of nitrogen dopants, either pyridinic or pyrrolic N, when bonded to the TM in oxides, predominately contributes to the synergistic effect. Herein, an innovative strategy based on laser irradiation is described to controllably tune the relative concentrations of pyridinic and pyrrolic nitrogen dopants in the hybrid catalyst, i.e., NiCo 2 O 4 NPs/N-doped mesoporous graphene. Comparative studies reveal the dominant role of pyridinic-NCo bonding, instead of pyrrolic-N bonding, in synergistically promoting reversible oxygen electrocatalysis. Moreover, density functional theory calculations provide deep insights into the corresponding synergistic mechanism. The optimized hybrid, NiCo/NLG-270, manifests outstanding reversible oxygen electrocatalytic activities, leading to an overpotential different ΔE among the lowest value for highly efficient bifunctional catalysts. In a practical reversible Zn-air battery, NiCo/NLG-270 exhibits superior charge/discharge performance and long-term durability compared to the noble metal electrocatalysts., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Most of the risk models for predicting contrast-induced acute kidney injury (CI-AKI) are available for postcontrast exposure prediction, thus have limited values in practice. We aimed to develop a novel nomogram based on preprocedural features for early prediction of CI-AKI in patients after coronary angiography (CAG) or percutaneous coronary intervention (PCI). A total of 245 patients were retrospectively reviewed from January 2015 to January 2017. Least absolute shrinkage and selection operator (Lasso) regression model was applied to select most strong predictors for CI-AKI. The CI-AKI risk score was calculated for each patient as a linear combination of selected predictors that were weighted by their respective coefficients. The discrimination of nomogram was assessed by C-statistic. The occurrence of CI-AKI was 13.9% (34 out of 245). We identified ten predictors including sex, diabetes mellitus, lactate dehydrogenase level, C-reactive protein, years since drinking, chronic kidney disease (CKD), stage of CKD, stroke, acute myocardial infarction, and systolic blood pressure. The CI-AKI prediction nomogram obtained good discrimination (C-statistic, 0.718, 95%CI: 0.637-0.800, p = 7.23 × 10 -5 ). The cutoff value of CI-AKI risk score was -1.953. Accordingly, the novel nomogram we developed is a simple and accurate tool for preprocedural prediction of CI-AKI in patients undergoing CAG or PCI., Competing Interests: CONFLICTS OF INTEREST The authors have declared that no conflicts of interest exists.

We aim to assess the level of family burden of schizophrenia patients and identify its predicting factors in a rural community sample of China. A sample of 327 primary caregivers was recruited through a one-stage cluster sampling in Ningxiang County of Hunan province, China. Family burden was assessed using the Family Burden Interview Schedule (FBIS) of Pai and Kapur. Our results showed that the mean score of FBIS was 23.62±9.76 (range, 0-48), with over half (52%) caregivers reported their family burden being moderate and severe. Among the six domains of family burden, financial burden (76%) was the commonest burden, while disruption of family interactions (37%) was the least mentioned. A multivariate analysis of family burden revealed that patient being admitted for over 3 times, caregiver being female, having a middle school education, and with additional dependents, as well as higher care network function were positive predictors of family burden, while higher patient function and family function, and increasing patient age were negative predictors of family burden. Intervention to decrease family burden may be best served by improving family function and exploring alternative care model instead of hospitalization.

The British Thyroid Association recommended in new guidelines on thyroid cancer treatment [Kwak et al. (Korean J Radiol 14:110-117, 2013)] that ultrasound grading of thyroid nodules should be incorporated into MDT management. A retrospective study was carried out to determine that the impact of US grading has had on MDT decision making in practice. The design used in the study is a retrospective review of case notes. The study was carried out in the hub hospital for thyroid cancer in the North west London Cancer network. We included consecutive patients referred to the regional thyroid multidisciplinary meeting between August 2014 and May 2015 for investigation of thyroid nodules. Data were collected on patient demographics, co-morbidity, thy grading, ultrasound grading, surgery, post-operative histology, and radioactive iodine treatment details. Accuracy of cytology and ultrasound in diagnosing malignancy was correlated to definitive histology. 99 patients with thyroid nodules were included in the study. 97% of patients had at least one fine needle aspiration and 75% had ultrasound grading. Thy3f (Bethesda IV) nodules were more likely to be carcinoma if associated with a U4 grade rather than U3 (67 vs 18%, p = 0.028). Ultrasound grading has recently been introduced to the standard practice in investigation of thyroid nodules. Further assessment of the accuracy of ultrasound grading in clinical practice may allow us to risk-stratify thy3a/thy3f (Bethesda III/IV) lesions and personalise treatment.

Manganese-based oxides have exhibited high promise as noncoinage alternatives to Pt/C for catalyzing oxygen reduction reaction (ORR) in basic solution and a mix of Mn 3+/4+ valence is believed to be vital in achieving optimum ORR performance. Here, it is proposed that, distinct from the most studied perovskites and spinels, Mn-based mullites with equivalent molar ratio of Mn 3+ and Mn 4+ provide a unique platform to maximize the role of Mn valence in facile ORR kinetics by introducing modest content of oxygen deficiency, which is also beneficial to enhanced catalytic activity. Accordingly, amorphous mullite SmMn 2 O 5- δ nanoparticles with finely tuned concentration of oxygen vacancies are synthesized via a versatile top-down approach and the modest oxygen-defective sample with an Mn 3+ /Mn 4+ ratio of 1.78, i.e., Mn valence of 3.36 gives rise to a superior overall ORR activity among the highest reported for the family of Mn-based oxides, comparable to that of Pt/C. Altogether, this study opens up great opportunities for mullite-based catalysts to be a cost-effective alternative to Pt/C in diverse electrochemical energy storage and conversion systems., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: Asymmetrical hearing thresholds are common in people claiming compensation for noise-induced hearing loss (NIHL). When present and otherwise unexplained, there is some controversy as to whether such asymmetry can be attributed to occupational noise exposure. In this review, our main objectives were to collate the overall prevalence of this finding in subjects with NIHL, and further, to provide a balanced argument regarding causality., Data Sources: MEDLINE, CINAHL, EMBASE, Cochrane, Google Scholar. No date or language restrictions., Study Selection and Data Extraction: A systematic review of the literature was performed and data on noise exposure, pure tone audiometry, and lateralized hearing outcomes were reviewed. Newcastle-Ottawa (N-O) criteria were employed to assess quality of studies where applicable., Data Synthesis: N/A CONCLUSION:: Six studies met the inclusion criteria giving a total of 4,735 individual cases with NIHL. Asymmetrical hearing loss accounted for between 2.4% and 22.6% of NIHL cases (L-R difference >15 dB for any frequency 0.5-8 kHz). However, the overwhelming majority of subjects in this review have symmetrical hearing loss when adjusted for other significant variables, e.g., age, sex, and binaural hearing deterioration. Subjects considered for noise exposure remuneration were men (94.3% SE ± 2.7), aged 52.9 years (inter-quartile range, 46.1-58.4), and from a broad range of industrial backgrounds. Future research will be needed to establish the influence of other factors such as smoking status, exposure to chemical agents, specific drugs, or genetic predisposition.

Background: Under-utilization of mental health services is a global health issue. Recognition of mental disorders, as the first step to seeking help from professional sources, has been well studied in developed countries, yet little is known about the situation in rural areas of developing countries like China. The purpose of the study is to understand the recognition of depression, anxiety, and alcohol abuse and its predictive factors in a Chinese rural sample, Methods: Face-to-face interviews were conducted on a representative rural adult sample in a cross-sectional study in China (N = 2052). Respondents were presented with three vignettes depicting depression, anxiety and alcohol abuse and asked to label the disorder and its cause to assess their recognition of the three mental disorders. They also completed the Patient Health Questionnaire (PHQ-9), the Generalized Anxiety Disorder Scale (GAD-7), and the Alcohol Use Disorders Identification Test (AUDIT) to assess their current mental health status., Results: The alcohol abuse vignette was more frequently attributed as a mental problem than the depression vignette and anxiety vignette. The correct labeling rate was 16.1 % in the depression vignette, 15.5 % in the anxiety vignette, and 58.2 % in the alcohol vignette. Higher education is the common and also strongest factor positively predicting the recognition of all three vignettes. Beyond that, being female is an independent predictor of correct recognition of alcohol abuse, while recognition of depression and anxiety were positively predicted by younger age., Conclusions: Lower recognition of depression and anxiety as compared to alcohol abuse confirms the importance and need to increase the public's awareness and knowledge about common mental disorders. Recognition of common mental disorders could be improved through general public campaign and education, while paying attention to the unique predictive factors for each specific disorder and implement targeted intervention.

Objectives: This study aimed to explore cut-off scores of the 9-item Patient Health Questionnaire (PHQ-9) and 2-item Patient Health Questionnaire (PHQ-2) for depression screening in Chinese rural elderly., Methods: A cross-sectional study was conducted on 839 residents aged 60 years and above in rural areas of Liuyang County. PHQ-9 was adopted to evaluate depression. The Structured Clinical Interview for DSM Disorders (SCID-I) was adopted to diagnose major depressive disorder (MDD) as a golden standard. Sensitivity, specificity, positive and negative predictive value, positive and negative likelihood ratio, Youden's index and the receiver operating characteristic (ROC) curve were analyzed on PHQ-9 and PHQ-2., Results: The Cronbach's alphas of PHQ-9 and PHQ-2 were 0.82 and 0.76, respectively. The score of 8 of the PHQ-9 showed the highest Youden's index of 0.85, with a sensitivity of 0.97 and specificity of 0.89 respectively, and the area under the ROC curve (AUC) was 0.97 (95% CI: 0.96-0.98). The score of 3 of PHQ-2 showed the highest Youden's index of 0.79, with both sensitivity and specificity were 0.90 and the AUC was 0.94 (95% CI: 0.90-0.97)., Conclusions: Both PHQ-9 and PHQ-2 are valid screening instruments for depression in the rural elderly in China, with recommended cut-off scores of 8 and 3 respectively.

Objective: To explore the relationship between birth weight and fat mass- and obesity-associated (FTO) gene expression and promoter methylation status in the Chinese population., Methods: Seventy-five neonates and their mothers were recruited from Yuying Children's Hospital of Wenzhou Medical University. Subjects were divided into three groups by birth weight: low (< 3,500 g, n = 20), medium (3,500-3,999 g, n = 30) and high (≥ 4,000 g, n = 25). Placental FTO transcript levels and promoter methylation were determined by quantitative PCR and Sequenom MassARRAY®., Results: Placental FTO mRNA expression was significantly increased in the high- and medium-weight groups compared to the low-weight group (p = 0.023). Methylation rates of CpG11 sites were significantly decreased in high-birth weight newborns (p = 0.018). Multiple linear regressions showed placental FTO mRNA, maternal pre-pregnancy body mass index (BMI) and CpG11 methylation rate were independently associated with increased fetal birth weight. Additionally, FTO mRNA expression was negatively associated with CpG6.7.8.9 methylation in mothers that underwent C-section., Conclusions: High placental FTO expression is associated with increased birth weight in Chinese neonates, and FTO promoter methylation level at a specific CpG site is negatively associated with birth weight. Further work is needed to determine the functionality of this CpG site in placentas.

Background: Graves' disease is an autoimmune disease caused by the production of auto-antibodies against the thyroid-stimulating hormone receptor, which stimulates follicular cell production of thyroid hormone. It is the commonest cause of hyperthyroidism and may cause considerable morbidity with increased risk of cardiovascular and respiratory adverse events. Five per cent of people with Graves' disease develop moderate to severe Graves' ophthalmopathy. Thyroid surgery for Graves' disease commonly falls into one of three categories: 1) total thyroidectomy, which aims to achieve complete macroscopic removal of thyroid tissue; 2) bilateral subtotal thyroidectomy, in which bilateral thyroid remnants are left; and 3) unilateral total and contralateral subtotal thyroidectomy, or the Dunhill procedure. Recent American Thyroid Association guidelines on treatment of Graves' hyperthyroidism emphasised the role of surgery as one of the first-line treatments. Total thyroidectomy removes target tissue for the thyroid-stimulating hormone receptor antibody. It controls hyperthyroidism at the cost of lifelong thyroxine replacement. Subtotal thyroidectomy leaves a thyroid remnant and may be less likely to lead to complications, however a higher rate of recurrent hyperthyroidism is expected and revision surgery would be challenging. The choice of the thyroidectomy technique is currently largely a matter of surgeon preference, and a systematic review of the evidence base is required to determine which option offers the best outcomes for patients., Objectives: To assess the optimal surgical technique for Graves' disease and Graves' ophthalmopathy., Search Methods: We searched the Cochrane Library, MEDLINE and PubMed, EMBASE, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). The date of the last search was June 2015 for all databases. We did not apply any language restrictions., Selection Criteria: Only randomised controlled trials (RCTs) involving participants with a diagnosis of Graves' disease based on clinical features and biochemical findings of hyperthyroidism were eligible for inclusion. Trials had to directly compare at least two surgical techniques of thyroidectomy. There was no age limit to study inclusion., Data Collection and Analysis: Two review authors independently extracted and cross-checked the data for analysis, evaluation of risk of bias and establishment of 'Summary of findings' tables using the GRADE instrument. The senior review authors reviewed the data and reconciled disagreements., Main Results: We included five RCTs with a total of 886 participants; 172 were randomised to total thyroidectomy, 383 were randomised to bilateral subtotal thyroidectomy, 309 were randomised to the Dunhill procedure and 22 were randomised to either bilateral subtotal thyroidectomy or the Dunhill procedure. Follow-up ranged between six months and six years. One trial had three comparison arms. All five trials were conducted in university hospitals or tertiary referral centres for thyroid disease. All thyroidectomies were performed by experienced surgeons. The overall quality of the evidence ranged from low to moderate. In all trials, blinding procedures were insufficiently described. Outcome assessment for objective outcomes was blinded in one trial. Surgeons were not blinded in any of the trials. One trial blinded participants. Attrition bias was a substantial problem in one trial, with 35% losses to follow-up. In one trial the analysis was not carried out on an intention-to-treat basis.Total thyroidectomy was more effective than subtotal thyroidectomy techniques (both bilateral subtotal thyroidectomy and the Dunhill procedure) at preventing recurrent hyperthyroidism in 0/150 versus 11/200 participants (OR 0.14 (95% CI 0.04 to 0.46); P = 0.001; 2 trials; moderate quality evidence). Total thyroidectomy was also more effective than bilateral subtotal thyroidectomy at preventing recurrent hyperthyroidism in 0/150 versus 10/150 participants (odds ratio (OR) 0.13 (95% confidence interval (CI) 0.04 to 0.44); P = 0.001; 2 trials; moderate quality evidence). Compared to bilateral subtotal thyroidectomy, the Dunhill procedure was more likely to prevent recurrent hyperthyroidism in 20/283 versus 8/309 participants (OR 2.73 (95% CI 1.28 to 5.85); P = 0.01; 3 trials; low quality evidence). Total thyroidectomy compared with subtotal thyroidectomy conferred a greater risk of permanent hypocalcaemia/hypoparathyroidism in 8/172 versus 3/221 participants (OR 4.79 (95% CI 1.36 to 16.83); P = 0.01; 3 trials; low quality evidence). Effects of the various surgical techniques on permanent recurrent laryngeal nerve palsy and regression of Graves' ophthalmopathy were neutral. One death was reported in one study in year three of follow-up. No study investigated health-related quality of life or socioeconomic effects., Authors' Conclusions: Total thyroidectomy is more effective than subtotal thyroidectomy (both bilateral subtotal thyroidectomy and the Dunhill procedure) at preventing recurrent hyperthyroidism in Graves' disease. The type of surgery performed does not affect regression of Graves' ophthalmopathy. There was some evidence that total thyroidectomy compared with subtotal thyroidectomy conferred a greater risk of permanent hypocalcaemia/hypoparathyroidism, which however, was not seen in comparison with bilateral subtotal thyroidectomy. Permanent recurrent laryngeal nerve palsy did not seem to be affected by type of thyroidectomy. Health-related quality of life as a patient-important outcome measure should form a core determinant of any future trial on the effects of thyroid surgery for Graves' disease.

Purpose: We aimed to investigate mental health help-seeking intentions and preferences of rural Chinese adults and determine predictors of the intentions., Methods: A total of 2052 representative rural residents aged 18-60 completed a cross-sectional survey by face-to-face interviews. The survey included seven questions asking about respondents' help-seeking intentions and preferences, and a series of internationally validated instruments to assess self-perceived health status, depression, anxiety, alcohol abuse, mental health literacy, and attitudes towards mental illness., Results: Nearly 80% of respondents were willing to seek psychological help if needed, and 72.4% preferred to get help from medical organizations, yet only 12% knew of any hospitals or clinics providing such help. A multivariate analysis of help-seeking intention revealed that being female, having lower education, higher social health, higher mental health knowledge, and physical causal attribution for depression were positive predictors of help-seeking intention., Conclusion: A huge gap exists between the relatively higher intention for help-seeking and significantly lower knowledge of helpful resources. Predictors of help-seeking intention for mental problems in the current study are consistent with previous studies. Interventions to increase help-seeking for mental problems by Chinese rural adults may be best served by focusing on increasing public awareness of help sources, as well as improving residents' mental health literacy and social health, with special focus on males and those more educated.

Objectives: The present study aims to assess mental health literacy (MHL) using a standardised multifaceted 20-item instrument called Mental Health Knowledge Questionnaire (MHKQ) developed by the Chinese Ministry of Health, among a rural Chinese population., Setting: Four villages in Liuyang county of Hunan province, China., Participants: This was a cross-sectional study. A multistage cluster-sampling method was adopted, leading to a final sampling frame of 2377 residents aged 18-60 years from four villages of Liuyang county. Included in the study were residents aged 18-60 years living in their village for at least half a year; excluded were those not living in the areas during the research period, those with difficulty in communication due to serious physical or mental illness and those who were cognitively impaired or actively psychotic. Finally, 2052 participants completed the survey., Primary and Secondary Outcome Measures: Primary outcome was correct response rate of the MHKQ; secondary outcome measures were association between sociodemographics and MHL, and association between MHL and health outcomes., Results: Correct response rates for the 20 MHKQ items ranged from 19% to 94%, with a mean rate of 58%. Younger age (r=-0.02, p<0.01), higher education (r: 1.38-2.69, p<0.01) and higher income (r=0.41, p<0.01), were independently associated with higher MHL. MHL was independently associated with self-rated general health (r=2.31, p<0.01), depression (r=-0.09, p<0.01) and anxiety (r=-0.07, p<0.05)., Conclusions: MHL in the rural areas of Liuyang is lower than that reported in urban areas of China. There is much room for improvement with regard to MHL promotion in rural areas of China. Younger age, higher education and higher income are the three robust factors related to higher MHL, so cohort-specific educational intervention efforts may be indicated., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: The main treatment for locally-advanced, unresectable non-small cell lung cancer (NSCLC) is radical radiotherapy, with or without chemotherapy. Numerous trials have been performed, the results of which often disagree. Despite publication of several systematic reviews, there is not a consensus on practice, and outcomes are poor. To address this problem, we have applied a recently published evidence aggregation method to update the Cochrane systematic review (CSR) of lung chemo-radiotherapy., Method: We extracted data on 28 trials consisting of 4352 patients treated using 54 different regimens. We aggregated trials involving heterogeneous outcomes (both effects and side-effects). Our method identifies the evidence for the "best" treatment using preference criteria over outcomes and criteria concerning evidence quality., Result: Concurrent, platinum-based, conventionally fractionated chemo-radiotherapy was the most strongly supported option. 60 Gy in 30 fractions with concurrent cisplatin and vinblastine was superior under all combinations of preference criteria and evidence quality criteria that were considered. There was evidence for the use of concurrent and consolidation chemotherapy with conventionally-fractionated radiotherapy, but the choice of individual regimen was highly dependent on the choices for preference criteria over outcomes and for the criteria concerning evidence quality., Discussion: Using evidence from the trials analysed in the CSR, together with some more recent studies, we identify a finer-grained recommendation than the CSR, though our findings are consistent with that of the CSR. Furthermore, we have identified individual regimens that may be optimal., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Iatrogenic complications associated with current treatment protocols for oropharyngeal squamous cell carcinoma are noted to cause high rates of acute and chronic morbidity. The aims of this study are to provide an overview of the current de-escalation trials for human papillomavirus positive (HPV+) oropharyngeal carcinoma and to evaluate the evidence supporting improved response to treatment of patients within this viral cohort. This study reviewed all completed or in progress randomised controlled trials (RCTs) assessing clinical interventions for human papillomavirus-associated locally advanced oropharyngeal squamous cell carcinoma. We utilised a validated 'risk of bias' tool to assess study quality. We identified nine RCTs that met the full inclusion criteria for this review (all of which are currently on-going and will report from 2015 onwards). Five RCTs performed a post hoc analysis by HPV status, which allowed meta-analysis of 1130 patients. The data reveal a significant difference in overall survival (hazard ratio (HR) 0.49 [95% confidence interval (CI) 0.35-0.69]), loco-regional failure (HR 0.43 [95% CI 0.17-1.11]) and disease specific survival (0.41 [95% 0.3-0.56]) in favour of the HPV+ category. In considering de-escalation treatment protocols, nine studies are currently ongoing. Our meta-analysis provides strong evidence for an improved prognosis in the viral associated cohort when treated by platinum based chemotherapy in combination with radiotherapy or primary radiotherapy. So far, one trial (with moderate to high risk of bias) suggests a reduced survival outcome for the HPV+ population when using the epidermal growth factor receptor (EGFR) inhibitor cetuximab., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: To assess the prevalence and severity of voice symptoms in individuals with a diagnosis of autoimmune disease., Study Design: Cross-sectional survey., Setting: Study participants were recruited from a rheumatology tertiary referral clinic at Norfolk and Norwich University Hospital., Subjects and Methods: A cross-sectional questionnaire analyzing 109 patients with autoimmune disease (rheumatoid arthritis, seronegative spondyloarthritis, connective tissue disease) and a control group of 41 patients with non-autoimmune disease (osteoarthritis/osteoporosis). Main outcome measures were the Voice Handicap Index-10 (VHI-10), xerostomia scale, acid reflux inquiry, and anxiety/depression scale., Results: Patients with autoimmune disease were more likely to experience voice symptoms as assessed by the VHI-10 questionnaire (P = .0035). Subgroup analysis showed autoimmune patients were more likely to report voice symptoms regardless of whether they were on a disease-modifying antirheumatic drug (DMARD; P = .0010) or non-DMARD (P = .017), suggesting autoimmune disease may be an independent risk factor from pharmacotherapy. Xerostomia was more common in an autoimmune population compared with the control group (P = .02). A positive correlation between xerostomia and VHI-10 scores was found for the DMARD group (Spearman rank coefficient = 0.49, P < .001). No significant difference in acid reflux inquiry (P = .44) or the anxiety/depression scale (P = .36) was found when comparing the autoimmune and control groups., Conclusion: Patients with autoimmune disease have increased likelihood of voice symptoms when compared with a control population with non-autoimmune disease. Further prospective studies to elucidate the cause of voice disorder would be valuable.

Background: Radiotherapy plus concomitant and adjuvant temozolomide (RCAT) is now standard treatment for grade IV glioblastoma (GBM). We report the results from our 7 years experience of using RCAT, and the potential role of a change in platelet count as a prognostic factor., Methods: We identified all patients with biopsy-proven GBM who received RCAT at the Royal Free Hospital between 2002 and 2009. We extracted data on demographic, tumour and treatment variables and overall survival and conducted univariate analyses on the association of the baseline factors with survival, and included those that were significant in a multivariate model. We then conducted exploratory analyses on the impact of changes in haematological parameters and overall survival., Results: A total of eighty-four patients were included in the final analysis. Median overall survival in our study was 17.6 months. Overall survival rate at 1 year and 2 years were 70 and 36 %, respectively. Platelet counts were seen to fall when measured from baseline to beginning of week 6. A decrease in platelet count from baseline to week 6 was associated with longer survival (p = 0.006), and this remains significant when adjusted for known prognostic factors., Conclusion: Our study shows the survival benefit seen in the phase III trial is reproducible in clinical practice. In addition, decreased platelet count during concurrent radiotherapy and temozolomide appears to correlate with prolonged survival, a finding that warrants further investigation.

The field of liver transplantation is limited by the availability of donor organs. The use of living donor and split cadaveric grafts is one potential method of expanding the donor pool. However, primary graft dysfunction can result from the use of partial livers despite the absence of other causes such as vascular obstruction or sepsis. This increasingly recognised phenomenon is termed "Small-for-size syndrome" (SFSS). Studies in animal models and humans have suggested portal hyperperfusion of the graft combined with poor venous outflow and reduced arterial flow might cause sinusoidal congestion and endothelial dysfunction. Graft related factors such as graft to recipient body weight ratio < 0.8, impaired venous outflow, steatosis > 30% and prolonged warm/cold ischemia time are positively predictive of SFSS. Donor related factors include deranged liver function tests and prolonged intensive care unit stay greater than five days. Child-Pugh grade C recipients are at relatively greater risk of developing SFSS. Surgical approaches to prevent SFSS fall into two categories: those targeting portal hyperperfusion by reducing inflow to the graft, including splenic artery modulation and portacaval shunts; and those aiming to relieve parenchymal congestion. This review aims to examine the controversial diagnosis of SFSS, including current strategies to predict and prevent its occurrence. We will also consider whether such interventions could jeopardize the graft by compromising regeneration.