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Abstract Stomach adenocarcinoma (STAD) is a prevalent malignancy that is highly aggressive and heterogeneous. Intratumor heterogeneity (ITH) showed strong link to tumor progression and metastasis. High ITH may promote tumor evolution. An ITH-related signature (IRS) was created using as integrative technique including 10 machine learning methods based on TCGA, GSE15459, GSE26253, GSE62254 and GSE84437 datasets. The relevance of IRS in predicting the advantages of immunotherapy was assessed using a number of prediction scores and three immunotherapy datasets (GSE78220, IMvigor210 and GSE91061). Vitro experiments were performed to verify the biological functions of AKR1B1. The RSF + Enet (alpha = 0.1) projected model was proposed as the ideal IRS because it had the highest average C-index. The IRS demonstrated a strong performance in serving as an independent risk factor for the clinical outcome of STAD patients. It performed exceptionally well in predicting the overall survival rate of STAD patients, as seen by the TCGA cohort’s AUC of 1-, 3-, and 5-year ROC curves, which were 0.689, 0.683, and 0.669, respectively. A low IRS score demonstrated a superior response to immunotherapy, as seen by a lower TIDE score, lower immune escape score, greater TMB score, higher PD1&CTLA4 immunophenoscore, higher response rate, and improved prognosis. Common chemotherapeutic and targeted treatment regimens had lower IC50 values in the group with higher IRS scores. Vitro experiment showed that AKR1B1 was upregulated in STAD and knockdown of AKR1B1 obviously suppressed tumor cell proliferation and migration. The present investigation produced the best IRS for STAD, which may be applied to prognostication, risk stratification, and therapy planning for STAD patients.

Abstract Improving fattening efficiency is an important goal of breeding commercial pigs, especially for the large-scale pig farms. Fattening efficiency index (FEI) can be used to evaluate the fattening efficiency. The aim of this study was to identify the factors affecting the fattening efficiency of commercial pigs in large-scale pig farms and further study the impact of these factors on the production performance of commercial pig batches at different production levels. The data of 9,570 batches was mainly consisted of four parts (farm facilities, general information of piglets, production performance of nursery pigs and finishing pigs). A total of 28 variables were evaluated by the multi-variable linear regression models. The differences in production factors significantly correlated with FEI at piglets-finishing stage were compared among high-performing (HP), moderate-performing (MP), and low-performing (LP) batches of commercial pigs during the nursery and finishing stage. Among the 28 variables, 18 were significantly correlated with fattening efficiency (P

Abstract Hepatitis B virus (HBV) infection is highly prevalent in Guangzhou, China. This study aimed to examine the long-term trend of HB incidence from 2008 to 2022 and the independent impacts of age, period, and cohort on the trends. HBV data were collected from the China Information System for Disease Control and Prevention. Joinpoint regression was utilized to examine temporal trends, and an age-period-cohort model was employed to estimate the effects of age, period, and cohort. A total of 327,585 HBV cases were included in this study. The incidence of chronic and acute HB showed a decreasing trend in Guangzhou over the past 15 years, with an average annual percent change of − 4.31% and − 16.87%, respectively. Age, period, and cohort all exerted significant effects. The incidence of HB was higher in males than in females and non-central areas compared to central areas. Age groups of 0–4 years and 15–24 years were identified as high-risk groups. The period relative risks for chronic HB incidence decreased initially and then stabilized. Cohorts born later had lower risks. Chronic HB incidences remain high in Guangzhou, especially among males, younger individuals, and residents of non-central areas. More efforts are still needed to achieve hepatitis elimination targets.

ObjectiveThis study focuses on assessing the cost-effectiveness of incorporating toripalimab alongside chemotherapy for the treatment of patients diagnosed with metastatic triple-negative breast cancer from the perspective of the Chinese healthcare system.MethodsA partitioned survival model was constructed to simulate the costs and health outcomes over the lifetime of patients with mTNBC. Clinical data regarding overall survival, progression-free survival, and treatment-related adverse events were derived from the TORCHLIGHT clinical trials. Incremental cost-effectiveness ratio (ICER) were calculated based on the gains in quality-adjusted life-year (QALY). The willingness-to-pay (WTP) threshold was defined as $39,855.79 per QALY. Additionally, sensitivity analyses were conducted to examine the robustness of the model.ResultsThe total cost incurred by the group receiving toripalimab was $38,040.62, while the placebo plus chemotherapy was $26,102.07. The utilization of the toripalimab regimen resulted in an increase of 0.74 QALYs and an incremental cost of $11,938.55 compared to the placebo plus chemotherapy group. The ICER was $16,133.18/QALY, indicating that toripalimab plus chemotherapy is a cost-effective strategy according to the WTP threshold. Sensitivity analyses confirmed the robustness of the results.ConclusionThis study suggests that the addition of toripalimab to chemotherapy for the treatment of mTNBC is a cost-effective strategy. The findings provide valuable evidence to guide decision-making regarding treatment selection for patients with mTNBC in China.

BackgroundThis study aims to systematically analyze the cost-effectiveness of the combination therapy comprising sugemalimab and chemotherapy in the management of advanced ESCC from the Chinese healthcare system perspective.MethodsAn advanced ESCC patient simulation partitioned survival approach model was developed to mimic the disease progression of patients undergoing treatment with sugemalimab in combination with chemotherapy versus chemotherapy alone. To ensure accuracy and precision, clinical data, treatment costs, and utility values were collected from comprehensive clinical trials and reliable economic databases. The cost-effectiveness analysis was conducted by assessing the incremental cost-effectiveness ratio in relation to the established willingness-to-pay threshold. One-way and probabilistic sensitivity analyses were performed to assess the robustness of the model.ResultsThe cumulative expenditure for the group of patients administered with sugemalimab amounted to US$ 41734.87, whereas the placebo group was associated with a total cost of US$ 22926.25. By evaluating the ICER, which quantifies the additional cost incurred per QALY gained, a value of US$ 61066.96 per QALY was determined. It is imperative to note that this ICER value surpasses the predetermined threshold for WTP in China, set at US$ 39,855.79 per QALY. Sensitivity analyses demonstrated that the results were sensitive to the cost of sugemalimab, progression-free survival, and utility values. These fluctuations did not result in a reversal of the study findings.ConclusionThe combination of sugemalimab with chemotherapy for the treatment of ESCC in China is currently not considered a cost-effective therapeutic approach. However, it is suggested that additional reductions in price may facilitate the potential for achieving cost-effectiveness.

ObjectiveThe goal of this study is to compare the cost-effectiveness of tislelizumab and sorafenib as first-line treatment for advanced hepatocellular carcinoma in China.MethodsA comprehensive cost-effectiveness analysis was undertaken within the framework of a partitioned survival model to accurately gage the incremental cost-effectiveness ratio (ICER) of tislelizumab compared to sorafenib. The model incorporated relevant clinical data and all survival rates were from RATIONALE-301 trials. The stability of the partitioned survival model was assessed by performing one-way and two-way sensitivity analyses.ResultsThe total cost incurred for the tislelizumab treatment was $16181.24, whereas the sorafenib was $14306.87. The tislelizumab regimen resulted in a significant increase of 0.18 quality-adjusted life years (QALYs) and an extra cost of $1874.37 as compared to chemotherapy. The ICER was $10413.17 per QALY, which was found to be below the willingness-to-pay (WTP) threshold of $37304.34/QALY. The results of the sensitivity analysis found that no fluctuations in any of the factors affected our results, even when these parameters fluctuated.ConclusionTislelizumab appears to be a cost-effective first-line treatment for advanced hepatocellular carcinoma when compared to sorafenib in China. These findings can inform decision-making processes regarding the selection of the most cost-effective treatment option for advanced hepatocellular carcinoma.

Abstract Background The regimen of nivolumab plus ipilimumab (NI) has been recommended by the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology-Malignant Pleural Mesothelioma (Version 1.2022) and Chinese Guidelines for the Clinical Diagnosis and Treatment of Malignant Pleural Mesothelioma (2021 edition) as the first-line treatment for Malignant Pleural Mesothelioma (MPM). But whether immunotherapy has a financial advantage over conventional chemotherapy (pemetrexed plus cisplatin/carboplatin, C) is uncertain. Methods Based on survival and safety data from the CheckMate 743 clinical trial (NCT02899299), a partitioned survival model was constructed using TreeAge Pro2022 software. The model cycle was set to 1 month and the study period was 10 years. The output indicators included total cost, quality-adjusted life year (QALY) and incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses were used to assess the robustness of the results, considering only direct medical costs. Results and discussion The ICER for group NI versus Group C was $375,656/QALY in all randomized patients, $327,943/QALY in patients with epithelioid histology, and $115,495/QALY in patients with non-epithelioid histology. The ICERs of all three different populations all exceeded the willingness-to-pay threshold (three times the per capita gross domestic product of China in 2021). The results of univariate sensitivity analysis showed that the price of pemetrexed and nivolumab had great influence on the analysis results. The results of the probabilistic sensitivity analysis show that the probability of the NI scheme being more economical in all three different populations was 0. What is new and conclusion From the perspective of the Chinese healthcare system, in patients with unresectable MPM, NI has no economic advantage over C.

Abstract Objective The objective of this study is to evaluate the cost-effectiveness of adding pembrolizumab to the standard first-line therapy of advanced biliary tract cancer (BTC) with gemcitabine and cisplatin from the perspective of the Chinese healthcare system. Methods The partitioned survival model developed from clinical data obtained in The KEYNOTE-966 trial served as the basis for a simulation in the TreeAge Pro 2011 software. The objective of the research was to estimate the 10-year life expectancy and total healthcare costs of patients with BTC, utilizing primary outcomes that evaluated costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). To establish the willingness-to-pay (WTP) threshold, the 2022 Chinese per capita gross domestic product (GDP) of $37304.346/QALY was adopted. Furthermore, sensitivity analysis was conducted to ascertain the study’s results under varying levels of uncertainty. Results Compared to chemotherapy alone, the addition of pembrolizumab to chemotherapy has been shown to yield an incremental gain of 0.184 quality-adjusted life years (QALY) at an additional cost of $103940.706. This translates into an incremental cost-effectiveness ratio (ICER) of $564895.141/QALY, which exceeds the willingness-to-pay (WTP) threshold in China. One-way sensitivity analyses performed on the model recognize the utility of PD, subsequent cost, and the cost of Pembrolizumab 100 mg had a major influence on the outcomes. However, no parameter elicited an ICER lower than the willingness-to-pay (WTP) threshold. Conclusions Based on the perspective of the Chinese healthcare system, the utilization of pembrolizumab in combination with chemotherapy as an first-line treatment option for BTC does not appear to be a cost-effective approach compared to chemotherapy as a standalone therapy.

This study aimed to evaluate the therapeutic potential of inhibiting protein arginine methyltransferase 5 (PRMT5) in cisplatin-induced hearing loss. The effects of PRMT5 inhibition on cisplatin-induced auditory injury were determined using immunohistochemistry, apoptosis assays, and auditory brainstem response. The mechanism of PRMT5 inhibition on hair cell survival was assessed using RNA-seq and Cleavage Under Targets and Tagment-quantitative polymerase chain reaction (CUT&Tag-qPCR) analyses in the HEI-OC1 cell line. Pharmacological inhibition of PRMT5 significantly alleviated cisplatin-induced damage to hair cells and spiral ganglion neurons in the cochlea and decreased apoptosis by protecting mitochondrial function and preventing the accumulation of reactive oxygen species. CUT&Tag-qPCR analysis demonstrated that inhibition of PRMT5 in HEI-OC1 cells reduced the accumulation of H4R3me2s/H3R8me2s marks at the promoter region of the Pik3ca gene, thus activating the expression of Pik3ca. These findings suggest that PRMT5 inhibitors have strong potential as agents against cisplatin-induced ototoxicity and can lay the foundation for further research on treatment strategies of hearing loss.

BackgroundSerplulimab has shown promising results in the treatment of extensive-stage small cell lung cancer (ES-SCLC). This study aimed to evaluate the cost-effectiveness of serplulimab combination therapy compared to chemotherapy alone in patients with ES-SCLC from the Chinese healthcare system perspective.MethodsA partitioned survival model was developed to simulate the costs and outcomes of patients receiving serplulimab combination therapy or chemotherapy alone over a time horizon of 10 years. Data on overall survival, progression-free survival, and adverse events were obtained from the ASTRUM-005 randomized clinical trial. Costs were estimated from a healthcare system perspective and included drug acquisition, administration, monitoring, and management of adverse events. One-way and probabilistic sensitivity analyses were conducted to assess the impact of uncertainty on the results.ResultsThe base-case analysis showed that the combination of serplulimab and chemotherapy has demonstrated a significant increase in QALYs of 0.626 compared to chemotherapy alone. This improved outcome is accompanied by an additional cost of $10893.995. The ICER for incorporating serplulimab into the treatment regimen is $17402.548 per QALY gained. One-way sensitivity analysis confirmed the robustness of the findings. Probabilistic sensitivity analysis demonstrated that serplulimab combination therapy had a 97.40% high probability of being cost-effective compared to chemotherapy alone at the WTP thresholds.ConclusionIn contrast to chemotherapy as a standalone treatment, the addition of serplulimab to chemotherapy is believed to offer potential cost-effectiveness as a preferred initial therapeutic approach for patients with ES-SCLC in China.

Objective The objective of this study was to evaluate the cost-effectiveness of durvalumab in combination with chemotherapy compared with chemotherapy alone as first-line therapy for metastatic non-small-cell lung cancer (NSCLC) from the perspective of the US payer.Methods Based on the POSEIDON clinical trial, a partition survival model was developed to compare the cost-effectiveness of durvalumab in combination with chemotherapy versus chemotherapy alone for the first-line treatment of metastatic NSCLC. The model’s primary outcomes were costs, life years (LYs), quality-adjusted LYs (QALYs) and the incremental cost-effectiveness ratio (ICER). The analysis only considered direct medical costs, and health utility value was determined using published literature. The robustness of the model was tested by probabilistic sensitivity analyses.Results The combination therapy of durvalumab and chemotherapy improved survival by 0.713 QALYs at an incremental cost of $64 104.638 compared with chemotherapy alone, resulting in an ICER of $89 908.328 per QALY gained from the US payer perspective. The combination therapy had a 92.3% probability of being cost-effective at a willingness-to-pay threshold of $150 000 per QALY based on incremental net health benefits. Sensitivity analyses confirmed the model’s consistency, and none of the parameters significantly influenced the findings.Conclusion Durvalumab in combination with chemotherapy represents a more cost-effective strategy for first-line therapy in patients with metastatic NSCLC in the USA compared with chemotherapy alone.

Objective: Cemiplimab combined with chemotherapy has emerged as a promising treatment option for advanced non-small cell lung cancer (NSCLC). Accordingly, this study has been conducted to evaluate the cost-effectiveness of this combination therapy in comparison to chemotherapy alone from the perspective of the United States healthcare system. Methods: The present study is based on a partitioned survival model developed from clinical data obtained during the 2-year follow-up of the phase III EMPOWER-Lung 3 part 2 trial. The purpose of this investigation is to estimate the 10-year life expectancy and total healthcare costs of patients with advanced NSCLC by leveraging primary outcomes that evaluated costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER).To establish the willingness-to-pay (WTP) threshold for the analysis, a value of $150,000/QALY was adopted. Sensitivity analysis was performed to determine the impact of varying levels of uncertainty on the results of this study. Results: When compared to chemotherapy alone, the addition of cemiplimab to chemotherapy has been demonstrated to result in an incremental gain of 1.593 QALY at an additional cost of $109351.298. This equates to an incremental cost-effectiveness ratio (ICER) of $68644.883/QALY. One-way sensitivity analyses were conducted on the model, which acknowledged the influence of several parameters, such as subsequent costs, the utility of progressive disease, the cost of best supportive care, the cost of cemiplimab per mg, and the utility of progression-free survival on the outcomes. Nonetheless, none of these parameters yielded an ICER lower than the WTP threshold. Conclusions: From the perspective of the United States healthcare system, the utilization of cemiplimab in combination with chemotherapy as a first-line treatment option for NSCLC appears to be a cost-effective approach as compared to using chemotherapy as a standalone therapy.

ObjectivesIn order to control the first longitudinal vibration mode of propulsion shafting systems, a dynamic vibration absorber with disc spring negative stiffness is proposed and its experimental verification carried out. MethodsA test bench is established for the propulsion shafting system containing a dynamic vibration absorber with negative stiffness. According to the first longitudinal vibration mode of the shafting, a dynamic vibration absorber with negative stiffness integrated into the thrust bearing is developed. Vibration transmission tests under different rotational speeds, static thrusts and negative stiffness are then carried out, and acceleration response data on the thrust bearing foundation and shafting is obtained. ResultsThe results show that the developed dynamic vibration absorber with negative stiffness can achieve vibration suppression of 7.8 dB for the thrust bearing foundation in the first longitudinal mode of the propulsion shafting with a mass ratio of 1.6%, and the vibration control effect of the negative stiffness dynamic vibration absorber is maintained at 3.3 dB when the natural frequency changes by 5% and the thrust changes by 40%. The vibration response on the thrust bearing foundation and shafting do not deteriorate even at non-optimal negative stiffness. ConclusionsThis study shows that a dynamic vibration absorber with negative stiffness can effectively suppress vibration transmission at the first longitudinal mode of a shafting under different rotational speeds.

In recent years, several cross-cultural studies reported that Westerners focus more on central aspects of a scene (e.g., an object) relative to peripheral aspects (e.g., the background), whereas Easterners more evenly allocate attention to central and peripheral aspects. In memory tasks, Easterners exhibit worse recognition for the central object when peripheral aspects are changed, whereas Westerners are less affected by peripheral changes. However, most of these studies rely on hit rates without correcting for response bias, whereas studies accounting for response bias failed to replicate cultural differences in memory tasks. In this event-related potential (ERP) study, we investigated item and source memory for semantically unrelated object-scene pairs in German and Chinese young adults using memory measures corrected for response bias (i.e., the discrimination index Pr). Both groups completed study-test cycles with either item memory tests or source memory tests. In item memory blocks, participants completed an old/new recognition test for the central object. Source memory blocks entailed an associative recognition test for the association between object and background. Item and source memory were better for intact than for recombined pairs. However, as verified with frequentist and Bayesian analyzes, this context effect was not modulated by culture. The ERP results revealed an old/new effect for the item memory task in both groups which was again not modulated by culture. Our findings suggest that cultural differences in young adults do not manifest in intentional memory tasks probing memory for object-scene pairs without semantic relations when using bias-corrected memory measures.

ABSTRACT Plasmid-mediated quinolone resistance (PMQR) determinants, such as qnrVC genes, have been widely reported in Vibrio spp. while other types of PMQR genes were rarely reported in these bacteria. This study characterized the phenotypic and genotypic features of foodborne Vibrio spp. carrying qnrS, a key PMQR gene in Enterobacteriaceae. Among a total of 1,811 foodborne Vibrio isolates tested, 34 (1.88%) were found to harbor the qnrS gene. The allele qnrS2 was the most prevalent, but coexistence with other qnr alleles was common. Missense mutations in the quinolone resistance-determining region (QRDR) of the gyrA and parC genes were only found in 11 of the 34 qnrS-bearing isolates. Antimicrobial susceptibility tests showed that all 34 qnrS-bearing isolates were resistant to ampicillin and that a high percentage also exhibited resistance to cefotaxime, ceftriaxone, and trimethoprim-sulfamethoxazole. Genetic analysis showed that these phenotypes were attributed to a diverse range of resistance elements that the qnrS-bearing isolates harbored. The qnrS2 gene could be found in both the chromosome and plasmids; the plasmid-borne qnrS2 genes could be found on both conjugative and nonconjugative plasmids. pAQU-type qnrS2-bearing conjugative plasmids were able to mediate expression of phenotypic resistance to both ciprofloxacin and cephalosporins. Transmission of this plasmid among Vibrio spp. would speed up the emergence of multidrug-resistant (MDR) pathogens that are resistant to the most important antibiotics used in treatment of Vibrio infections, suggesting that close monitoring of emergence and dissemination of MDR Vibrio spp. in both food samples and clinical settings is necessary. IMPORTANCE Vibrio spp. used to be very susceptible to antibiotics. However, resistance to clinically important antibiotics, such as cephalosporins and fluoroquinolones, among clinically isolated Vibrio strains is increasingly common. In this study, we found that plasmid-mediated quinolone resistance (PMQR) genes, such as qnrS, that have not been previously reported in Vibrio spp. can now be detected in food isolates. The qnrS2 gene alone could mediate expression of ciprofloxacin resistance in Vibrio spp.; importantly, this gene could be found in both the chromosome and plasmids. The plasmids that harbor the qnrS2 gene could be both conjugative and nonconjugative, among which the pAQU-type qnrS2-bearing conjugative plasmids were able to mediate expression of resistance to both ciprofloxacin and cephalosporins. Transmission of this plasmid among Vibrio spp. would accelerate the emergence of multidrug-resistant pathogens.

Curcumin is a natural medicine with a wide range of anti-tumour activities. However, due to β-diketone moiety, curcumin exhibits poor stability and pharmacokinetics which significantly limits its clinical applications. In this article, two types of dicarbonyl curcumin analogues with improved stability were designed through the calculation of molecular stability by density functional theory. Twenty compounds were synthesised, and their anti-tumour activity was screened. A plurality of analogues had significantly stronger activity than curcumin. In particular, compound B2 ((2E,2′E)-3,3′-(1,4-phenylene)bis(1-(2-chlorophenyl)prop-2-en-1-one)) exhibited excellent anti-lung cancer activity in vivo and in vitro. In addition, B2 could upregulate the level of reactive oxygen species in lung cancer cells, which in turn activated the endoplasmic reticulum stress and led to cell apoptosis and pyroptosis. Taken together, curcumin analogue B2 is expected to be a novel candidate for lung cancer treatment with improved chemical and biological characteristics.

IntroductionDetermination of pediatric Crohn's disease (CD) remains a major diagnostic challenge. However, the rapidly emerging field of artificial intelligence has demonstrated promise in developing diagnostic models for intractable diseases.MethodsWe propose an artificial neural network model of 8 gene markers identified by 4 classification algorithms based on Gene Expression Omnibus database for diagnostic of pediatric CD.ResultsThe model achieved over 85% accuracy and area under ROC curve value in both training set and testing set for diagnosing pediatric CD. Additionally, immune infiltration analysis was performed to address why these markers can be integrated to develop a diagnostic model.ConclusionThis study supports further clinical facilitation of precise disease diagnosis by integrating genomics and machine learning algorithms in open-access database.

Introduction: In the present paper, experiments for a contra-rotating axial fan have been conducted to investigate the influences of the fan parameters including axial distance, blade number, blade pattern and blade thickness on the performance and noise characteristics under variable rotational speed regulation.Methods: The characteristic curves and spectrum characteristics of the contra-rotating axial fan with different structural configurations are compared and analyzed. Moreover, the spectrum density of the velocity obtained from the experiment is compared with the classic turbulence models.Results: The results show the characteristic curves of the shaft power and the sound pressure level (SPL) are nearly identical, which indicates the axial distance and blade number are not sensible factors for the contra-rotating axial fan under variable rotational speed regulation. The blade profiles of the fan have an impact on the characteristic curves of the SPL and the shaft power curves of the fan decrease evidently with increase of the blade thickness, while the shaft power curves are very close with different blade patterns.Discussion: In general, the blade profiles are sensible factors for the contra-rotating axial fan under variable rotational speed regulation. Through the SPL spectrum analysis of the contra-rotating axial fan with different blade profile, it can be concluded that the blade profile of the rotors has an obvious impact on the broadband noise characteristics under moderate and high frequency range.

Cisplatin-related ototoxicity is a critical side effect of chemotherapy and can lead to irreversible hearing loss. This study aimed to assess the potential effect of the DNA methyltransferase (DNMT) inhibitor RG108 on cisplatin-induced ototoxicity. Immunohistochemistry, apoptosis assay, and auditory brainstem response (ABR) were employed to determine the impacts of RG108 on cisplatin-induced injury in murine hair cells (HCs) and spiral ganglion neurons (SGNs). Rhodamine 123 and TMRM were utilized for mitochondrial membrane potential (MMP) assessment. Reactive oxygen species (ROS) amounts were evaluated by Cellrox green and Mitosox-red probes. Mitochondrial respiratory function evaluation was performed by determining oxygen consumption rates (OCRs). The results showed that RG108 can markedly reduce cisplatin induced damage in HCs and SGNs, and alleviate apoptotic rate by protecting mitochondrial function through preventing ROS accumulation. Furthermore, RG108 upregulated BCL-2 and downregulated APAF1, BAX, and BAD in HEI-OC1 cells, and triggered the PI3K/AKT pathway. Decreased expression of low-density lipoprotein receptor-related protein 1 (LRP1) and high methylation of the LRP1 promoter were observed after cisplatin treatment. RG108 treatment can increase LRP1 expression and decrease LRP1 promoter methylation. In conclusion, RG108 might represent a new potential agent for preventing hearing loss induced by cisplatin via activating the LRP1-PI3K/AKT pathway.

Background: This study evaluated the cost-effectiveness of nivolumab plus chemotherapy (NC) or ipilimumab versus chemotherapy as a first-line treatment for advanced esophageal squamous cell carcinoma (ESCC) in the United States and China. Methods: A partitioned survival model was constructed from the perspective of the US third-party payers and Chinese healthcare system. Health states and transition probabilities were modeled based on the survival data from the CheckMate-648 clinical trial (NCT03143153). The time horizon for the model was 10 years. Only direct medical costs were considered. One-way and probabilistic sensitivity analyses were conducted to assess the robustness of the results. Results: In the United States, nivolumab plus ipilimumab (NI) led to an incremental cost-effectiveness ratio (ICER) of $155,159.82/quality-adjusted life year (QALY) and $104,297.07/QALY gained in the overall population and in patients with tumor cell programmed death-ligand 1 (PD-L1) expression of ⩾1% (subgroup), respectively. The ICER for the subgroup was between the willingness-to-pay (WTP) threshold values of $100,000/QALY and $150,000/QALY, and the other case was higher than $150,000/QALY. NC led to an ICER of $518,062.85/QALY and $193,169.49/QALY gained in the overall population and the subgroup, respectively. Both ICERs were significantly higher than the WTP threshold of $150,000/QALY. In China, the ICERs for patients treated with the addition of nivolumab were >$90,000/QALY in all cases, significantly exceeding the WTP threshold of $37,654/QALY. Conclusions: NI is more cost-effective than NC or chemotherapy alone for treating advanced ESCC with PD-L1 expression ⩾1% in the United States. Chemotherapy alone is the only cost-effective option in China.

Objective: Sugemalimab is approved in China as a first-line treatment in combination with chemotherapy for metastatic nonsquamous non-small cell lung cancer (NSCLC). This study aims to evaluate the cost-effectiveness of first-line additional sugemalimab in combination with chemotherapy vs. chemotherapy from the perspective of the Chinese healthcare system.Materials and methods: A three-state Markov model was designed to evaluate the costs and quality-adjusted life years (QALYs) of first-line sugemalimab combination with chemotherapy vs. chemotherapy over a 10-year period. Data on clinical outcomes were obtained from GEMSTONE-302 clinical trials. Costs and health utilities were collected from local databases and published literature. The uncertainty of the model parameters was explored through sensitivity analysis.Results: Compared to chemotherapy, sugemalimab treatment for NSCLC resulted in an extra 0.50 QALYs at an additional cost of $73627.99, with an incremental cost-effectiveness ratio (ICER) of 148354.07/QALY at the willingness-to-pay (WTP) threshold of $37663.26/QALY. One-way sensitivity analysis indicated that the primary motivator in this model was the cost of sugemalimab. However, none of the parameters significantly affected the model’s results.Conclusion: Sugemalimab combination therapy is not economically advantageous for the first-line management of metastatic non-squamous NSCLC, according to the Chinese healthcare system.

Aims: This study aimed to evaluate the cost-effectiveness of lenvatinib plus pembrolizumab (LP) vs. chemotherapy for patients with previously treated mismatch repair proficient advanced endometrial cancer in China.Methods: A lifetime of partitioned survival Markov was used to evaluate the overall lifetime, total costs, quality adjusted life years (QALYs), and incremental cost effectiveness ratio (ICER) across a 10-years time horizon in the study 309–KEYNOTE-775 clinical trial. Direct costs and utility values were gathered from available literature. The willingness to pay (WTP) was defined at $37,663.26 per QALY. Sensitivity analyses were carried out to determine the model’s uncertainty.Results: According to the baseline analysis, the LP group gained 4.02 total life years and 3.13 QALYs for $93,496.69, whereas the chemotherapy group gained 2.86 total life years and 2.24 QALYs for $30,578.04. LP versus chemotherapy resulted in an incremental cost of $62,918.65, with an ICER of $70,962.09/QALY, which was higher than China’s WTP threshold ($37,663.26/QALY). The ICERs were most sensitive to the cost of pembrolizumab and the cycle of LP delivered, according to the sensitivity analysis. However, changing the range of those parameters has no influence on the model’s results.Conclusion: Our present analysis suggests that LP treatment is not cost-effective for patients with previously treated mismatch repair proficient advanced endometrial cancer. However, LP treatment may be a cost-effective treatment option if the price is reduced.

The aim of this study was to investigate the effect of LLY-283, a selective inhibitor of protein arginine methyltransferase 5 (PRMT5), on a noise-induced hearing loss (NIHL) mouse model and to identify a potential target for a therapeutic intervention against NIHL. Eight-week-old male C57BL/6 mice were used. The auditory brainstem response was measured 2 days after noise exposure. The apoptosis of hair cells (HCs) was detected by caspase-3/7 staining, whereas the accumulation of reactive oxygen species (ROS) was measured by 4-HNE staining. We demonstrated that the death of HCs and loss of cochlear synaptic ribbons induced by noise exposure could be significantly reduced by the presence of LLY-283. LLY-283 pretreatment before noise exposure notably decreased 4-HNE and caspase-3/7 levels in the cochlear HCs. We also noticed that the number of spiral ganglion neurons (SGNs) was notably increased after LLY-283 pretreatment. Furthermore, we showed that LLY-283 could increase the expression level of p-AKT in the SGNs. The underlying mechanism involves alleviation of ROS accumulation and activation of the PI3K/AKT pathway, indicating that LLY-283 might be a potential candidate for therapeutic intervention against NIHL.

Abstract Background Unprotected anal intercourse (UAI) within the context of concurrent sexual relationship are prevalent among men who have sex with men (MSM) who have regular male sex partners and it aggravates the risk of HIV infection among this community. The aim of this study was to assess the effect of intimate relationship characteristics on UAI among MSM couples at the dyadic level. Methods Two hundred four MSM couples were recruited from a HIV testing clinic from April 2017 to April 2018 in Guangzhou, China. The actor-partner interdependence model (APIM) was applied for dyadic analysis. Each MSM couple was divided into the insertive role and the receptive role according to their regular anal sex role. In this context, actor effect is the impact of an MSM’s intimate relationship characteristics on his own UAI, and partner effect is the impact of his partner’s intimate relationship characteristics on his UAI. Results Of the 408 participants, 58.82% had UAI with regular male sex partner (UAI-RP) and 8.09% had concurrent UAI. Intimate relationship characteristics were associated with concurrent UAI, but not associated with UAI-RP. For the receptive role, his relationship investment exerted significant actor and partner effects on concurrent UAI (AOR actor = 1.31, P

Carbapenem-resistant and hypervirulent Klebsiella pneumoniae strains are emerging. Here Xie et al. show that these phenotypes are carried on a plasmid formed from the fusion of a virulence plasmid with a conjugative plasmid.

BackgroundThis study aimed to analyze the economics of pembrolizumab plus chemotherapy as first-line treatment in patients with esophageal squamous cell carcinoma (ESCC) and programmed cell death-Ligand 1 (PD-L1) combined positive score (CPS) of 10 or more in China.MethodsBased on the advanced ESCC of the KEYNOTE-590 clinical trial data, a Markov model was performed to simulate the clinical course and evaluate the patient's total lifetime, total costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) for pembrolizumab plus chemotherapy (cisplatin and 5-fluorouracil) vs. chemotherapy alone in first-line treatment of ESCC and PD-L1 CPS of 10 or more. Utility values and direct costs related to the treatments were gathered from the published literature data. One-way and probabilistic sensitivity analyses were conducted to check the stability of the model.ResultsThe baseline analysis indicated that the incremental effectiveness and cost of pembrolizumab plus chemotherapy vs. chemotherapy alone added 1.23 QALYs and resulted in an incremental cost of $51,320.22, which had an ICER of $41,805.12/QALY, higher than the willingness-to-pay (WTP) threshold of China ($37,663.26/QALY). The sensitivity analysis demonstrated that the ICERs were most sensitive to the cycle of pembrolizumab used and the cost of pembrolizumab.ConclusionThe result of our present analysis suggests that the addition of pembrolizumab plus chemotherapy as first-line treatment might not be cost-effective for patients with ESCC and PD-L1 CPS of 10 or more in China.

Cingulin, a cytoplasmic element of tight junctions (TJs), is involved in maintenance of the integrity of epithelial and endothelial cells. However, the role of cingulin in the development of auditory organs remains unclear. Zebrafish is popular as a model organism for hearing research. Using the whole mount in situ hybridization (WISH) experiment, we detected the expression of cingulin b in the posterior lateral line system (PLLs) of zebrafish. We traced the early development progress of zebrafish PLLs from 36 hpf to 72 hpf, and found that inhibition of cingulin b by target morpholinos resulted in severe developmental obstruction, including decreased number of neuromasts, reduced proliferative cells in the primordium, and repressed hair cell differentiation in the neuromasts. To examine the potential mechanism of cingulin b in the development of zebrafish PLL neuromasts, we performed RNA-seq analysis to compare the differently expressed genes (DEGs) between cingulin b knockdown samples and the controls. The KEGG enrichment analysis revealed that MAPK signaling pathway and cellular senescence were the key pathways with most DEGs in cingulin b-MO morphants compared to the Control-MO embryos. Furthermore, quantitative RT-PCR analysis confirmed the findings by RNA-seq that the transcript levels of cell cycle negative regulators such as tp53 and cdkn1a, were remarkably upregulated after inhibition of cingulin b. Our results therefore indicated an important role of cingulin b in the development of auditory organs, and MAPK signaling pathway was inhibited while cellular senescence pathway was activated after downregulation of cingulin b. We bring forward new insights of cingulin by exploring its function in auditory system.

Rice husk biochar (RHB) is a low-cost and renewable resource that has been found to be highly effective for the remediation of water and soil environments. Its yield, structure, composition, and physicochemical properties can be modified by changing the parameters of the preparation process, such as the heating rate, pyrolysis temperature, and carrier gas flow rate. Additionally, its specific surface area and functional groups can be modified through physical, chemical, and biological means. Compared to biochar from other feedstocks, RHB performs poorly in solutions with coexisting metal, but can be modified for improved adsorption. In contaminated soils, RHB has been found to be effective in adsorbing heavy metals and organic matter, as well as reducing pollutant availability and enhancing crop growth by regulating soil properties and releasing beneficial elements. However, its effectiveness in complex environments remains uncertain, and further research is needed to fully understand its mechanisms and effectiveness in environmental remediation.

Bacterioplankton communities are closely related to river alterations and biogeochemical processes in freshwater reservoirs. Affected by reservoir regulation and hydrological variation, regulated rivers can create distinctive patterns in bacterioplankton communities. In this study, we conducted 16S rRNA V4 amplicon high-throughput sequencing to investigate compositional changes in the bacterioplankton community and its environmental responses to damming effects in the Pengxi River, the largest tributary on the northern bank of the Three Gorges Reservoir (TGR). The bacterial community was dominated by the phyla Proteobacteria and Actinobacteria, accounting for 51.0% and 13.1% of all sequences, respectively. Distinct differences in the bacterioplankton community composition were observed between the backwater and riverine areas, and the dominant taxa showed clear shifts at the class level between the upper stream and backwater area sites along the Pengxi River. Conductivity, transparency and temperature were considered the major environmental factors driving the bacterioplankton composition variation. Additionally, the functional profiles of the bacterioplankton community corresponded with compositional changes in reservoir regulation by TGR. Therefore, these results provide insights into dam effects on the bacterioplankton community in the Pengxi River, and further research should focus on the potential ecological processes of river regulation by dams or reservoirs.

BackgroundPrognostic nutritional index (PNI) is one of the most important factors related to prognosis in many types of cancer. This study aimed to evaluate the PNI on predicting the overall survival (OS) in resectable esophageal squamous cell carcinoma (ESCC).MethodsA total of 165 patients with resectable ESCC were included in our retrospective study. PNI values before surgery were calculated for each patient [PNI = 10 × albumin (gr/dL) + 0.005 × total lymphocyte count (mm3)]. PNI cutoff value was selected by drawing receiver operating characteristics (ROC) curve, which used OS time as the endpoint. The Kaplan-Meier method and the Cox regression model of multivariate analysis were used to analyze the prognostic relationship between PNI and OS.ResultsAmong the 165 patients, 34 (20.6%) were women and 131 (79.4%) were men. The mean age was 62.67 ± 7.95 years, with the age range from 44 to 85 years. The average PNI was 46.68 ± 8.66. ROC curve showed that the best cutoff value was 43.85. All patients were divided into two groups: 72 patients (43.6%) were in the low PNI group (

Abstract Background Genetic analysis of gene expression level is a promising approach for characterizing candidate genes that are involved in complex economic traits such as meat quality. In the present study, we conducted expression quantitative trait loci (eQTL) and allele-specific expression (ASE) analyses based on RNA-sequencing (RNAseq) data from the longissimus muscle of 189 Duroc × Luchuan crossed pigs in order to identify some candidate genes for meat quality traits. Results Using a genome-wide association study based on a mixed linear model, we identified 7192 cis-eQTL corresponding to 2098 cis-genes (p ≤ 1.33e-3, FDR ≤ 0.05) and 6400 trans-eQTL corresponding to 863 trans-genes (p ≤ 1.13e-6, FDR ≤ 0.05). ASE analysis using RNAseq SNPs identified 9815 significant ASE-SNPs in 2253 unique genes. Integrative analysis between the cis-eQTL and ASE target genes identified 540 common genes, including 33 genes with expression levels that were correlated with at least one meat quality trait. Among these 540 common genes, 63 have been reported previously as candidate genes for meat quality traits, such as PHKG1 (q-value = 1.67e-6 for the leading SNP in the cis-eQTL analysis), NUDT7 (q-value = 5.67e-13), FADS2 (q-value = 8.44e-5), and DGAT2 (q-value = 1.24e-3). Conclusions The present study confirmed several previously published candidate genes and identified some novel candidate genes for meat quality traits via eQTL and ASE analyses, which will be useful to prioritize candidate genes in further studies.

Abstract Background Mounting evidences have displayed that the dysregulation of miRNAs plays important roles in the pathogenesis of gastric cancer (GC). The purpose of this study was to explore the biological functions and potential mechanism of miR-489 in GC progression. Methods Quantitative real-time PCR (qRT-PCR) and western blot were performed to examine the mRNA expression and protein levels of miR-489 and HDAC7. The relationship between miR-489 and HDAC7 was analyzed by Spearman rank correlation. 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay and transwell assays were conducted for determining the effect of miR-489 and HDAC7 on GC cell viability, migration, and invasion. TargetScan and luciferase reporter assay were used to confirm the target gene of miR-489 in GC cells. Results The findings showed that miR-489 was dramatically decreased in GC tissues and GC cell lines (SGC-7901 and MKN45). Moreover, it was closely correlated with overall survival (OS) and progression-free survival (PFS) of GC patients. Downregulation of miR-489 significantly promoted GC cell proliferation, invasion, and migration. Additionally, HDAC7 was confirmed as the direct target of miR-489. Knockdown of HDAC7 exerted inhibited effect on GC progression and it markedly overturned miR-489 inhibitor-medicated effect on GC cells. More interestingly, via targeting HDAC7, miR-489 blocked the activation of PI3K/AKT pathway in GC cells. Conclusions Correctively, miR-489 played as a tumor suppressor in GC cell growth by targeting HDAC7, and miR-489 might function as a novel biomarker for diagnosis or therapeutic targets of human GC.

Two types of GaN vertical-cavity surface-emitting lasers (VCSELs), with and without lateral optical confinement (LOC) structure, were fabricated and their performances were compared. Compared with the VCSEL without LOC, the device with LOC showed a great improvement in threshold current, slope efficiency, output power and differential quantum efficiency, which was mainly due to the reduction of internal loss. Devices with LOC showed clear and multi-transversal mode structures. However, thermal dissipation became worse. The effects of such a design on thermal resistance and transverse modes were discussed.

Background: This study aimed to analyze the cost effectiveness of camrelizumab in the second-line treatment of advanced or metastatic esophageal squamous cell carcinoma in China.Methods: On the basis of the ESCORT clinical trial, a partitioned survival model was constructed to simulate the patient’s lifetime quality-adjusted life years (QALYs), lifetime costs, and incremental cost-effectiveness ratio (ICER). One-way sensitivity and probability sensitivity analyses were performed to test the stability of the model.Results: Treatment of esophageal squamous cell carcinoma with camrelizumab added 0.36 QALYs and resulted in an incremental cost of $1,439.64 compared with chemotherapy, which had an ICER of $3,999 per QALY gained. The ICER was far lower than the threshold of willingness to pay for one time the GDP per capita in China. Sensitivity analysis revealed that the ICERs were most sensitive to the cost of drugs, but the parameters did not have a major effect on the results of the model.Conclusion: Camrelizumab is likely to be a cost-effective option compared with chemotherapy for patients with advanced or metastatic esophageal squamous cell carcinoma. This informs patient selection and clinical path development.

Objectives: There are relatively few studies on mechanisms of cognitive deficits in late-life schizophrenia (LLS). Brain-derived neurotrophic factor (BDNF), as an important neuroplastic molecule, has been reported to be involved in neurocognitive impairment in schizophrenia. This study aimed to examine whether peripheral BDNF levels were associated with cognitive deficits in LLS, which has not been explored yet.Methods: Forty-eight LLS patients and 45 age-matched elderly controls were recruited. We measured all participants on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) for cognition and serum BDNF levels. Psychopathological symptoms in patients were assessed by the Positive and Negative Syndrome Scale (PANSS).Results: The levels of BDNF in LLS patients were significantly lower than those in healthy controls (8.80 ± 2.30 vs. 12.63 ± 5.08 ng/ml, p < 0.001). The cognitive performance of LLS patients was worse than that of the controls on RBANS total score and scores of immediate memory, attention, language, and delayed memory (all p ≤ 0.005). BDNF was positively associated with attention in LLS patients (r = 0.338, p = 0.019).Conclusion: Our findings suggest that older patients with schizophrenia exhibit lower BDNF levels and more cognitive deficits than older controls, supporting the accelerated aging hypothesis of schizophrenia. Moreover, decreased BDNF is related to attention deficits, indicating that BDNF might be a candidate biomarker of cognitive impairments in LLS patients.

Abstract Background At present, many laboratories and hospitals all over the world are attempting and exploring the clinical transformation of this tissue engineered bone graft (TEBG) strategy. Many successful cases of bone tissue engineering (BTE) repair were based on young individuals. But there are little studies about the effectiveness of TEBG strategy in physiological aged individuals. Methods In this research, we studied whether aging factor has influence on the skull repair effect of Fetal-TEBG, at the level of the large animal models. We used the fetal bone marrow stromal cells (Fetal-BMSCs) as the seed cells, combining the decalcified bone matrix (DBM) scaffolds, to repair the skull defects of the aged goats and the young goats. The repair effects on both aged goat and young goat were compared by Micro-CT and histology examination. Results The skull defects of the young goats could be repaired better than that of the aged goats after 6 months by Fetal-TEBG; In the aged goats, although not completely repaired, the defects repaired by Fetal-TEBG was better than that repaired by the Control DBM scaffold. Conclusions Aging factor has impact on the bone repair effect of Fetal-TEBG; and the BTE strategy is still efficacious even in the aged individuals. The improvement of the aged state may promote the repair effect of the BTE in the aged individuals.

Abstract Background Bone tissue engineering is not widely used in clinical treatment. Two main reasons hide behind this: (1) the seed cells are difficult to obtain and (2) the process of tissue engineering bone construction is too complex and its efficiency is still relatively low. It is foreseeable that in the near future, the problem of seed cell sources could be solved completely in tissue engineering bone repair. As for the complex process and low efficiency of tissue engineering bone construction, usually two strategies would be considered: (1) the construction strategy based on injectable bone tissue and (2) the construction strategy based on osteogenic cell sheets. However, the application of injectable bone tissue engineering (iBTE) strategy and osteogenic cell sheet strategy is limited and they could hardly be used directly in repairing defects of large segmental bone, especially load-bearing bone. Methods In this study, we built an osteogenic micro-tissue with simple construction but with a certain structure and composition. Based on this, we established a new iBTE repair strategy—osteogenic micro-tissue in situ repair strategy, mainly targeting at solving the problem of large segmental bone defect. The steps are as follows: (1) Build the biodegradable three-dimensional scaffold based on the size of the defect site with 3D printing rapid prototyping technology. (2) Implant the three-dimensional scaffold into the defect site. This scaffold is considered as the “steel framework” that could provide both mechanical support and space for bone tissue growth. (3) Inject the osteogenic micro-tissue (i.e., the “cell-extracellular matrix” complex), which could be considered as “concrete,” into the three-dimensional scaffold, to promote the bone tissue regeneration in situ. Meanwhile, the digested cells were injected as the compared group in this experiment. After 3 months, the effect of in situ bone defect repair of osteogenic micro-tissue and digested cells was compared. Results It is confirmed that osteogenic micro-tissue could achieve a higher efficiency on cell usage and has a better repair effect than the digested cells. Conclusions Osteogenic micro-tissue repairing strategy would be a more promising clinical strategy to solve the problem of large segmental bone defect.

Abstract Background Developing cartilage constructed with the appropriate matrix composition and persistent chondrogenesis remains an enduring challenge in cartilage defects. Cartilage progenitor cell (CPC)-based tissue engineering has attracted recent attention because of its strong chondrogenic differentiation capacity. However, due to the lack of a suitable chondrogenic niche, the clinical application of CPC-regenerated cartilage in the subcutaneous environment remains a challenge. In this study, exosomes derived from chondrocytes (CC-Exos) were used to provide the CPC constructs with a cartilage signal in subcutaneous environments for efficient ectopic cartilage regeneration. Methods Rabbit CPC-alginate constructs were prepared and implanted subcutaneously in nude mice. CC-Exos were injected into the constructs at the same dose (30 μg exosomes per 100 μL injection) after surgery and thereafter weekly for a period of 12 weeks. Exosomes derived from bone mesenchymal stem cells (BMSC-Exos) were used as the positive control. The mice in the negative control were administered with the same volume of PBS. At 4 and 12 weeks after implantation, the potential of CC-Exos and BMSC-Exos to promote chondrogenesis and stability of cartilage tissue in a subcutaneous environment were analyzed by histology, immunostaining, and protein analysis. The influences of BMSC-Exos and CC-Exos on chondrogenesis and angiogenic characteristics in vitro were assessed via coculturing with CPCs and human umbilical vein endothelial cells. Results The CC-Exos injection increased collagen deposition and minimized vascular ingrowth in engineered constructs, which efficiently and reproducibly developed into cartilage. The generated cartilage was phenotypically stable with minimal hypertrophy and vessel ingrowth up to 12 weeks, while the cartilage formed with BMSC-Exos was characterized by hypertrophic differentiation accompanied by vascular ingrowth. In vitro experiments indicated that CC-Exos stimulated CPCs proliferation and increased expression of chondrogenesis markers while inhibiting angiogenesis. Conclusions These findings suggest that the novel CC-Exos provides the preferable niche in directing stable ectopic chondrogenesis of CPCs. The use of CC-Exos may represent an off-the-shelf and cell-free therapeutic approach for promoting cartilage regeneration in the subcutaneous environment.

As a general sensory disorder, hearing loss was a major concern worldwide. Autophagy is a common cellular reaction to stress that degrades cytoplasmic waste through the lysosome pathway. Autophagy not only plays major roles in maintaining intracellular homeostasis but is also involved in the development and pathogenesis of many diseases. In the auditory system, several studies revealed the link between autophagy and hearing protection. In this review, we aimed to establish the correlation between autophagy and hair cells (HCs) from the aspects of ototoxic drugs, aging, and acoustic trauma and discussed whether autophagy could serve as a potential measure in the protection of HCs.

Histone demethylase PHF8 is crucial for multiple developmental processes, and hence, the awareness of its function in developing auditory organs needs to be increased. Using in situ hybridization (ISH) labeling, the mRNA expression of PHF8 in the zebrafish lateral line system and otic vesicle was monitored. The knockdown of PHF8 by morpholino significantly disrupted the development of the posterior lateral line system, which impacted cell migration and decreased the number of lateral line neuromasts. The knockdown of PHF8 also resulted in severe malformation of the semicircular canal and otoliths in terms of size, quantity, and position during the inner ear development. The loss of function of PHF8 also induced a defective differentiation in sensory hair cells in both lateral line neuromasts and the inner ear. ISH analysis of embryos that lacked PHF8 showed alterations in the expression of many target genes of several signaling pathways concerning cell migration and deposition, including the Wnt and FGF pathways. In summary, the current findings established PHF8 as a novel epigenetic element in developing auditory organs, rendering it a potential candidate for hearing loss therapy.

This retrospective study investigated the effect of iron status on peritonitis by analyzing longitudinal iron parameters in peritoneal dialysis (PD) patients. Patients who received PD at our center from 1 January 2006 to 31 December 2015 were included and followed up until 31 December 2017. According to the joint quartiles of baseline transferrin saturation and ferritin, iron status was categorized as reference iron status (RIS), absolute iron deficiency (AID), functional iron deficiency (FID), and high iron status (HIS). Generalized estimating equations and Cox regression models with time-dependent covariates were used. A total of 1258 PD patients were included; 752 (59.8%) were male, with a mean (±standard deviation) age of 47.4 (±14.9) years. During a median follow-up period of 35.5 (interquartile range, 18.4–60.0) months, 450 (34.3%) patients had 650 episodes of peritonitis. By analyzing longitudinal data, patients with AID were independently positively associated with the occurrence (adjusted odds ratio (AOR) = 1.45) and treatment failure of peritonitis (adjusted hazard ratio (AHR) = 1.85). Patients with HIS were positively associated with the treatment failure of peritonitis (AHR = 2.70). Longitudinal AID and HIS were associated with the episodes and poor prognosis of peritonitis. Active clinical monitoring and correction of iron imbalance in patients with PD are needed.

Source memory is one of the cognitive abilities that are most vulnerable to aging. Luckily, the brain plasticity could be modulated to counteract the decline. The repetitive transcranial magnetic stimulation (rTMS), a relatively non-invasive neuro-modulatory technique, could directly modulate neural excitability in the targeted cortical areas. Here, we are interested in whether the application of rTMS could enhance the source memory performance in healthy older adults. In addition, event-related potentials (ERPs) were employed to explore the specific retrieval process that rTMS could affect. Subjects were randomly assigned to either the rTMS group or the sham group. The rTMS group received 10 sessions (20 min per session) of 10 Hz rTMS applying on the right dorsolateral prefrontal cortex (i.e., F4 site), and the sham group received 10 sessions of sham stimulation. Both groups performed source memory tests before and after the intervention while the electroencephalogram (EEG) was recorded during the retrieval process. Behavioral results showed that the source memory performance was significantly improved after rTMS compared with the sham stimulation; ERPs results showed that during the retrieval phase, the left parietal old/new effect, which reflected the process of recollection common to both young and old adults, increased in the rTMS group compared with the sham stimulation group, whereas the late reversed old/new effect specific to the source retrieval of older adults showed similar attenuation after intervention in both groups. The present results suggested that rTMS could be an effective intervention to improve source memory performance in healthy older adults and that it selectively facilitated the youth-like recollection process during retrieval. This study was registered in the Chinese Clinical Trial Registry (ChiCTR) with the identifier chictr-ire-15006371.

In this paper, the graphene-assisted Goos–Hänchen (GH) shift of the optical beam reflected from a planar multilayer configuration is investigated. The increased positive Goos–Hänchen shifts can be modulated by adjusting the Fermi energy due to graphene with unique optical properties in the visible light range. Moreover, the GH shift can be tuned by varying the layers of graphene, the thickness of the medium, incident wavelength, and so on. These results will be useful for designing the novel graphene-based optical sensing and switching.

Memory decline has become an issue of major importance in the aging society. Anodal transcranial direct current stimulation (atDCS) is a viable tool to counteract age-associated episodic memory deterioration. However, the underlying neural mechanisms are unclear. In this single-blind, sham-controlled study, we combined atDCS and functional magnetic resonance imaging to assess the behavioral and neural consequences of multiple-session atDCS in older adults. Forty-nine healthy older adults received either 10 sessions of anodal or sham stimulation over the left dorsolateral prefrontal cortex. Before and after stimulation, participants performed a source memory task in the MRI scanner. Compared to sham stimulation, atDCS significantly improved item memory performance. Additionally, atDCS significantly increased regional brain activity around the stimulation area in the prefrontal cortex and extended to the bilateral anterior cingulate cortex. Neural changes in the prefrontal cortex correlated with memory gains. Our findings therefore indicate that multiple-session offline atDCS may improve memory in older adults by inducing neural alterations.

In this paper, we theoretically investigated the reflected group delay from the graphene/hexagonal boron nitride (hBN) heterostructure in the infrared band. Since the significant Lorentz resonance characteristic of the dielectric constant of hBN in the bands of near 7.28 μm and 12.72 μm, the new graphene/hBN heterostructure is used to realize flexible switching of reflected group delay by the Lorentz resonance mechanism. It is shown that the reflected group delay can be effectively enhanced by tuning the Fermi energy or the number of graphene layers. Moreover, the reflected group delay can be tuned positive or negative depending on the hBN thickness or incident angle. These results will be useful for design of graphene-based optical delay devices in the infrared band. Keywords: Graphene, Hexagonal boron nitride (hBN), Group delay, Infrared band

In this paper, we have shown that tunable nonlinear group delay of reflected light beam at terahertz frequencies can be achieved by a modified Otto configuration with the insertion of monolayer graphene and nonlinear substrate. This large nonlinear reflected group delay originates from the excitation of surface plasmon resonance at the interface of two dielectrics with graphene. Graphene sheet with unique optical properties can enhance the surface plasmon resonance and modulate bistable behavior of the reflected group delay by suitably adjusting the Fermi energy of the graphene and the relaxation time. Moreover, the large negative and positive of reflected group delay is sensitive to the thicknesses of the air layer. We believe these intriguing phenomena are promising for some potential applications in graphene-based optical delay devices. Keywords: Group delay, Graphene, Nonlinear surface plasmon, Otto configuration

In this paper, a bimetallic sensor based on graphene-hexagonal boron nitride (hBN) heterostructure is theoretically studied. The sensitivity of the sensor can be improved by enhancing the Goos–Hänchen (GH) shift in the infrared band. The theoretical results show that adjusting the Fermi level, the number of graphene layers and the thickness of hBN, a GH shift of 182.09 λ can be obtained. Moreover, sensitivity of 2.02 × 105 λ/RIU can be achieved with monolayer graphene, the thickness of gold layer is 20 nm, silver layer is 15 nm, and the hBN thickness of 492 nm. This heterogeneous infrared sensor has the advantages of high sensitivity and strong stability. The research results will provide a theoretical basis for the design of a new high-sensitivity infrared band sensor.