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Mycobacterium abscessus (M. abscessus) is a multidrug-resistant nontuberculous mycobacterium (NTM) that is responsible for a wide spectrum of infections in humans. The lack of effective bactericidal drugs and the formation of biofilm make its clinical treatment very difficult. The FDA-approved drug library containing 3048 marketed and pharmacopeial drugs or compounds was screened at 20 μM against M. abscessus type strain 19977 in 7H9 medium, and 62 hits with potential antimicrobial activity against M. abscessus were identified. Among them, bithionol, a clinically approved antiparasitic agent, showed excellent antibacterial activity and inhibited the growth of three different subtypes of M. abscessus from 0.625 μM to 2.5 μM. We confirmed the bactericidal activity of bithionol by the MBC/MIC ratio being ≤4 and the time–kill curve study and also electron microscopy study. Interestingly, it was found that at 128 μg/mL, bithionol could completely eliminate biofilms after 48h, demonstrating an outstanding antibiofilm capability compared to commonly used antibiotics. Additionally, bithionol could eliminate 99.9% of biofilm bacteria at 64 μg/mL, 99% at 32 μg/mL, and 90% at 16 μg/mL. Therefore, bithionol may be a potential candidate for the treatment of M. abscessus infections due to its significant antimicrobial and antibiofilm activities.

Background and Aims: Low-grade squamous intraepithelial lesion (LSIL) is one of two categories of cervical intraepithelial lesions. Given that controversy exists regarding its management, this comparative study aimed to evaluate the effect of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) in treating LSIL of the high-risk human papillomavirus (HR-HPV)-infected cervix. Methods: A total of 218 patients (25–45 years old) with cervical LSIL associated with HR-HPV who underwent ALA-PDT, loop electrosurgical excision procedure (LEEP), or observation only were included. The clearance rates of cervical LSIL and HR-HPV between the ALA-PDT, LEEP, and observation groups were compared at 6 and 12 months follow-up. Adverse reactions were also compared. The factors affecting the clearance on ALA-PDT of cervical LSIL were evaluated. Results: There were no statistically significant differences in lesion and HR-HPV clearance rates between the ALA-PDT and LEEP groups at 6 and 12 months. However, the lesion and HR-HPV clearance rates were significantly higher in the ALA-PDT group than that in the observation group. The adverse reaction rate was significantly lower in the ALA-PDT group than in the LEEP group. Conclusion: For patients with cervical LSIL, the lesion and HR-HPV clearance rates after ALA-PDT were close to those after LEEP and significantly higher than in the observation group. Moreover, the adverse reaction rate for ALA-PDT was much lower than that for LEEP. Therefore, ALA-PDT provides a new option for the minimally invasive treatment of cervical LSIL.

Background: This study aims to investigate the short-term changes in relatively normal retinal vessels following anti-vascular endothelial growth factor (anti-VEGF) therapy in nAMD patients, an area that currently represents a research gap. Methods: In this prospective study, we enrolled patients newly diagnosed with neovascular age-related macular degeneration (nAMD) and received standardized monthly anti-VEGF therapy for three months. Follow-ups were conducted at baseline and 1-week, 1-month, 2-months and 3-months post first injection. Assessment indicators included radial peripapillary capillary vascular density (RPC-VD) and retinal nerve fiber layer (RNFL) thickness in different optic disk regions using optical coherence tomography angiography, as well as intraocular pressure (IOP). Results: 68 nAMD patients (68 eyes) were included in this study. Significant reductions of RPC-VD and increases of RNFL thickness primarily in the nasal regions were observed 1-week post anti-VEGF (adjusted P < 0.05). Significant negative correlations were found between 1-week changes in RPC-VD and RNFL thickness in the nasal sectors (P < 0.05). From 1 to 3 months post-injection, RPC-VD and RNFL thickness essentially returned to baseline levels. Throughout the follow-up periods, IOP remained stable (P > 0.05). Conclusion: Anti-VEGF treatments transiently influence the relatively normal retinal vessels, which might lead to nerve fiber edema, predominantly on the nasal side of the optic disk.

Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at an advanced stage, presenting limited therapeutic options and a grim prognosis due to its aggressive nature. Despite ongoing exploration of various combination therapies, a standardized treatment approach after the first-line treatment progress remains elusive. This report details the cases of two patients with unresectable advanced PDAC who underwent distinct conversion treatment regimens involving immune checkpoint inhibitors (ICIs). Remarkably, both patients became eligible for surgery following different anti-PD-1 antibody-based conversion therapies, ultimately achieving R0 resection. In essence, our findings highlight the efficacy of the anti-PD-1 antibody combined with a tyrosine kinase inhibitor (TKI) regimen and chemotherapy alongside anti-PD-1 antibody as viable conversion therapies for preoperative advanced PDAC. Tumor immune microenvironment (TIME) analysis underscores the intratumoral and intertumoral heterogeneity observed in the postoperative immune landscape of surgical specimens. This insight contributes to a deeper understanding of the potential benefits of these conversion therapies in addressing the challenging landscape of advanced PDAC.

Fecal DNA test has emerged as a non-invasive alternative for colorectal cancer (CRC) screening in average-risk population. However, there is currently insufficient evidence in China to demonstrate the effectiveness of population-based CRC screening using fecal DNA based test. Here, a large-scale real-world study for CRC screening was implemented in Wuhan, Hubei province, China. A total of 98,683 subjects aged between 45 and 60 years were screened by a fecal DNA test (ColoTect®) which detected methylation status of SDC2, ADHFE1, and PPP2R5C. Participants who tested positive were advised to receive diagnostic colonoscopy. 4449 (4.5%) subjects tested positive for fecal DNA test, and 3200 (71.9%) underwent colonoscopy. Among these, 2347 (73.3%) had abnormal colonoscopy findings, of which 1330 (56.7%) subjects received pathological diagnosis. Detection rates for CRC and advanced precancerous lesions were 1.3% and 2.3%, respectively. Detection rates for nonadvanced adenomas and polyps were 14.0% and 21.6%, respectively. 28.0% of all colonoscopies showed colorectal neoplasm but lack pathological diagnosis. 6.1% showed other abnormalities such as enteritis. In conclusion, preliminary real-world evidence suggested that fecal DNA tests had promising diagnostic yield in population-based CRC screening.Clinical trial registrationhttps://www.chictr.org.cn/showproj.html?proj=192838, identifier ChiCTR2300070520.

Summary: Background: Essential thrombocythemia (ET), a myeloproliferative neoplasm (MPN), has a substantial risk of evolving into post-essential thrombocythemia myelofibrosis (post-ET MF). This study aims to establish a prediction nomogram for early prediction of post-ET MF in ET patients. Methods: The training cohort comprised 558 patients from 8 haematology centres between January 1, 2010, and May 1, 2023, while the external validation cohort consisted of 165 patients from 6 additional haematology centres between January 1, 2010, and May 1, 2023. Univariable and multivariable Cox regression analysis was performed to identified independent risk factors and establish a nomogram to predict the post-ET MF free survival. Both bias-corrected area under the curve (AUC), calibration curves and concordance index (C-index) were employed to assess the predictive accuracy of the nomogram. Findings: Multivariate Cox regression demonstrated that elevated red blood cell distribution width (RDW), elevated levels of lactate dehydrogenase (LDH) and the level of haemoglobin (Hb), a history of smoking and the presence of splenomegaly were independent risk factors for post-ET MF. The C-index displayed of the training and validation cohorts were 0.877 and 0.853. The 5 years, 10 years AUC values in training and external validation cohorts were 0.948, 0.769 and 0.978, 0.804 respectively. Bias-corrected curve is close to the ideal curve and revealed a strong consistency between actual observation and prediction. Interpretation: We developed a nomogram capable of predicting the post-ET MF free survival probability at 5 years and 10 years in ET patients. This tool helps doctors identify patients who need close monitoring and appropriate counselling. Funding: This research was funded by the Key R&D Program of Zhejiang (No. 2022C03137); the Public Technology Application Research Program of Zhejiang, China (No. LGF21H080003); and the Zhejiang Medical Association Clinical Medical Research special fund project (No. 2022ZYC-D09).

BackgroundPrevious cross-sectional studies have identified multiple potential risk factors for functional dyspepsia (FD). However, the causal associations between these factors and FD remain elusive. Here we aimed to fully examine the causal relationships between these factors and FD utilizing a two-sample MR framework.MethodsA total of 53 potential FD-related modifiable factors, including those associated with hormones, metabolism, disease, medication, sociology, psychology, lifestyle and others were obtained through a comprehensive literature review. Independent genetic variants closely linked to these factors were screened as instrumental variables from genome-wide association studies (GWASs). A total of 8875 FD cases and 320387 controls were available for the analysis. The inverse variance weighted (IVW) method was employed as the primary analytical approach to assess the relationship between genetic variants of risk factors and the FD risk. Sensitivity analyses were performed to evaluate the consistency of the findings using the weighted median model, MR-Egger and MR-PRESSO methods.ResultsGenetically predicted depression (OR 1.515, 95% confidence interval (CI) 1.231 to 1.865, p = 0.000088), gastroesophageal reflux disease (OR 1.320, 95%CI 1.153 to 1.511, p = 0.000057) and years of education (OR 0.926, 95%CI 0.894 to 0.958, p = 0.00001) were associated with risk for FD in univariate MR analyses. Multiple medications, alcohol consumption, poultry intake, bipolar disorder, mood swings, type 1 diabetes, elevated systolic blood pressure and lower overall health rating showed to be suggestive risk factors for FD (all pConclusionsOur comprehensive MR study demonstrated that depression and lower educational attainment were causal factors for FD at the genetic level.

Abstract Both the hippocampus and amygdala are involved in working memory (WM) processing. However, their specific role in WM is still an open question. Here, we simultaneously recorded intracranial EEG from the amygdala and hippocampus of epilepsy patients while performing a WM task, and compared their representation patterns during the encoding and maintenance periods. By combining multivariate representational analysis and connectivity analyses with machine learning methods, our results revealed a functional specialization of the amygdala-hippocampal circuit: The mnemonic representations in the amygdala were highly distinct and decreased from encoding to maintenance. The hippocampal representations, however, were more similar across different items but remained stable in the absence of the stimulus. WM encoding and maintenance were associated with bidirectional information flow between the amygdala and the hippocampus in low-frequency bands (1–40 Hz). Furthermore, the decoding accuracy on WM load was higher by using representational features in the amygdala during encoding and in the hippocampus during maintenance, and by using information flow from the amygdala during encoding and that from the hippocampus during maintenance, respectively. Taken together, our study reveals that WM processing is associated with functional specialization and interaction within the amygdala-hippocampus circuit.

Abstract Background The purpose of this study was to evaluate the accuracy of automatic cephalometric landmark localization and measurements using cephalometric analysis via artificial intelligence (AI) compared with computer-assisted manual analysis. Methods Reconstructed lateral cephalograms (RLCs) from cone-beam computed tomography (CBCT) in 85 patients were selected. Computer-assisted manual analysis (Dolphin Imaging 11.9) and AI automatic analysis (Planmeca Romexis 6.2) were used to locate 19 landmarks and obtain 23 measurements. Mean radial error (MRE) and successful detection rate (SDR) values were calculated to assess the accuracy of automatic landmark digitization. Paired t tests and Bland‒Altman plots were used to compare the differences and consistencies in cephalometric measurements between manual and automatic analysis programs. Results The MRE for 19 cephalometric landmarks was 2.07 ± 1.35 mm with the automatic program. The average SDR within 1 mm, 2 mm, 2.5 mm, 3 and 4 mm were 18.82%, 58.58%, 71.70%, 82.04% and 91.39%, respectively. Soft tissue landmarks (1.54 ± 0.85 mm) had the most consistency, while dental landmarks (2.37 ± 1.55 mm) had the most variation. In total, 15 out of 23 measurements were within the clinically acceptable level of accuracy, 2 mm or 2°. The rates of consistency within the 95% limits of agreement were all above 90% for all measurement parameters. Conclusion Automatic analysis software collects cephalometric measurements almost effectively enough to be acceptable in clinical work. Nevertheless, automatic cephalometry is not capable of completely replacing manual tracing. Additional manual supervision and adjustment for automatic programs can increase accuracy and efficiency.

In this present paper, the optimization of microwave extraction (ME) of Cremastra appendiculata (D. Don) Makino was performed using the single factor design and response surface methodology. The ME extraction yield along with the contents of three major components of C. appendiculata Makino, including militarine, dactylorhin A, and colchicine was selected as the comprehensive indicators to evaluate the extraction process. Subsequently, the HPLC fingerprint of the above three components from 13 batches of C. appendiculata Makino was investigated. Finally, the anti-fungal activity of C. appendiculata Makino extract was evaluated by conducting a disk-diffusion method. The results demonstrated that the optimal ME technologies of C. appendiculata Makino were the ethanol concentration of 55%, the solid-liquid ratio of 1:30 g/mL, and the extraction time of 17 min. Under the above conditions, the extract yield was 12.83%. HPLC fingerprint analysis results showed that the contents of three major components displayed a consistent trend in all 13 tested samples. Militarine was found existed in 13 batches of C. appendiculata Makino, while dactylorhin A and colchicine were not detected in one sample. The results indicated a content difference in three active ingredients in C. appendiculata Makino from different areas. The anti-phytopathogenic activity results showed that the C. appendiculata Makino extract did not shown inhibitory activity against Colletotrichum gloeosporioides, Phytophthora capsica, Botrytis cinerea, Alternaria solani, Pseudomonas fluorescens, Xanthomnas oryzae, and Fusarium graminearum with their inhibition zones were less than 6 mm. However, the C. appendiculata Makino extract exhibited inhibitory activity toward to Ralstonia solanacearum with the diameter of the inhibition zone was 8.5 mm, showed antibacterial selectivity. In this study, the optimal ME technologies of C. appendiculata Makino was determined, and the established method the contents of three major components of C. appendiculata Makino was stable and feasible.These results can provide the basis for the quality control and comprehen-sive utilization of C. appendiculata Makinos.

Abstract Background Immune checkpoint inhibitor (ICI) combined with chemotherapy has exhibited promising results in small sample studies of pancreatic cancer patients. The efficacy of toripalimab, a programmed cell death protein 1 (PD-1) monoclonal antibody has been explored in the previous studies and it was established that immune-related adverse events (irAEs) associated with administration of this drug deserve proper attention and adequate management. Case presentation A 43-year-old female patient with advanced pancreatic ductal adenocarcinoma (PDAC) was treated with toripalimab in combination with gemcitabine and nab-paclitaxel (T-GA) as the first-line treatment. She developed immune-related encephalopathy with stuttering as the main clinical symptom and Magnetic resonance imaging (MRI) showed multiple cerebral white matter demyelination changes, concomitant with asymptomatic cardiac enzyme elevation and hypothyroidism. The symptoms resolved after the discontinuation of toripalimab and corticosteroid treatment. Conclusions Stuttering might be an early sign of neurotoxicity which can be easily neglected during the treatment. These findings provide guidance for the identification of these rare and occult neurological irAEs (n-irAEs) in the clinical practice.

Background The association between the serum free light chain (sFLC) ratio and the prognosis of multiple myeloma (MM) patients is controversial.Aim The purpose of this study is to explore the relationship between the sFLC ratio and the prognosis of MM patients through meta-analysis.Methods Online public databases were searched to find relevant studies. The retrieval time is limited from the establishment of the database to July 2021. The overall survival (OS) and progression-free survival (PFS) rates were compared. The results were described using hazard ratio (HR) and a 95% confidence interval (CI). Qualitative studies were also included.Results A total of 9 studies involving 2864 participants were included. A pooled analysis based on four studies including newly-diagnosed MM patients, demonstrated that an abnormal sFLC ratio was associated with poor outcomes of OS (HR = 1.82, 95% CI: 1.15–2.90) and PFS (HR = 1.87, 95% CI: 1.20–2.90). Three qualitative studies showed that an abnormal sFLC ratio was related with poor outcomes of OS (studies all included newly diagnosed MM patients) and PFS (two studies included newly-diagnosed MM patients and one study included non-newly-diagnosed MM patients). Two studies stated that the sFLC ratio is not associated with OS (both studies included non-newly-diagnosed MM patients) and one study reported that the sFLC ratio is not associated with PFS (study included non-newly-diagnosed MM patients).Conclusion sFLC ratio could be used to predict adverse outcomes in newly-diagnosed MM patients, but is not suitable for non-newly-diagnosed MM patients.

Pancreatic cancer is one of the leading causes of cancer-related mortality in both developed and developing countries. The incidence of pancreatic cancer in China accounts for about a quater of the global incidence, and the epidemiological characteristics and therapeutic strategies differ due to social, economic, cultural, environmental, and public health factors. Non-domestic guidelines do not reflect the clinicopathologic characteristics and treatment patterns of Chinese patients. Thus, in 2018, the Chinese Society of Clinical Oncology (CSCO) organized a panel of senior experts from all sub-specialties within the field of pancreatic oncology to compile the Chinese guidelines for the diagnosis and treatment of pancreatic cancer. The guidelines were made based on both the Western and Eastern clinical evidence and updated every one or two years. The experts made consensus judgments and classified evidence-based recommendations into various grades according to the regional differences, the accessibility of diagnostic and treatment resources, and health economic indexes in China. Here we present the latest version of the guidelines, which covers the diagnosis, treatment, and follow-up of pancreatic cancer. The guidelines might standardize the diagnosis and treatment of pancreatic cancer in China and will encourage oncologists to design and conduct more clinical trials about pancreatic cancer.

ObjectivesThe aim of this study was to evaluate the performance of a new double-antigen sandwich test that is based on the light-initiated chemiluminescent assay (LiCA®) for detecting anti-hepatitis C virus antibodies (anti-HCV) in comparison to Architect®.MethodsAnalytical characteristics and diagnostic performance were tested using seroconversion panels and large pools of clinical samples. Positive results were validated by the strip immunoblot assay (RIBA) and HCV RNA.ResultsRepeatability and within-lab imprecision of LiCA® anti-HCV were 1.31%–3.27%. The C5–C95 interval was −5.44%–5.03% away from C50. LiCA® detected seroconversion in an average of 28.9 days and showed a mean of 3.7 (p = 0.0056) days earlier than Architect®. In a pool of 239 samples with known HCV genotypes 1 to 6, both assays correctly detected all subjects. In 16,305 clinical patient sera, LiCA® detected 4 false-negative (0.25‰) and 14 false-positive (0.86‰) anti-HCV cases, while Architect® recorded 6 false-negative (0.37‰) and 138 false-positive (8.46‰) subjects, respectively. Compared to Architect®, LiCA® presented a significantly better performance in specificity (99.91% vs. 99.14%, n = 16,018, p < 0.0001), positive predictive value (95.29% vs. 67.06%, n = 419, p < 0.0001), and overall accuracy (99.89% vs. 99.12%, n = 16,305, p < 0.0001), while no significant difference in sensitivity (98.61% vs. 97.91%, n = 287, p = 0.5217) and negative predictive value (99.98% vs. 99.96%, n = 15,886, p = 0.3021) was seen. An S/Co value of 3.28 was predicted to be the threshold with a positivity ≥95% for the LiCA® anti-HCV assay.ConclusionLiCA® anti-HCV is a precise and fully automatic chemiluminescent assay with superior sensitivity and specificity. The assay can be used as a valuable tool to supplement the diagnosis of HCV infection.

ABSTRACT Providencia rettgeri is a clinically significant opportunistic pathogen that is involved in urinary tract infections. Due to the resolution limitations of identification, distinguishing P. rettgeri from closely related species is challenging by commercial biochemical test systems. Here, we first reported a novel species, Providencia hangzhouensis, which had been misidentified as P. rettgeri. Exhibiting ≤91.97% average nucleotide identity (ANI) and ≤46.10% in silico DNA-DNA hybridization values with all known Providencia species, P. hangzhouensis falls well beneath the established species-defining thresholds. We conducted a population genomics analysis of P. hangzhouensis isolates worldwide. Our study revealed that P. hangzhouensis has emerged in many countries and has formed several transmission clusters. We found that P. hangzhouensis shared the highest ANI values (91.54% and 91.97%) with P. rettgeri and P. huaxiensis, respectively. The pan-genome analysis revealed that these three species possessed a similar component of pan-genomes. Two genes associated with metabolism, folE2 and ccmM, were identified to be specific to P. hangzhouensis. Furthermore, we also observed that carbapenem-resistance genes frequently occur in P. hangzhouensis with the bla IMP-27 being the most prevalent (46.15%; 36/78). The emergence of P. hangzhouensis is often accompanied by extended-spectrum β-lactamase and carbapenem-resistance genes, and calls for tailored surveillance of this species as a clinically relevant species in the future. IMPORTANCE Our study has identified and characterized a novel species, Providencia hangzhouensis, which is associated with urinary tract infections and was previously misidentified as Providencia rettgeri. Through this study, we have identified specific genes unique to P. hangzhouensis, which could serve as marker genes for rapid PCR identification. Additionally, our findings suggest that the emergence of P. hangzhouensis is often accompanied by extended-spectrum β-lactamase and carbapenem-resistance genes, emphasizing the need for attention to clinical management and the importance of accurate species identification and proper drug use.

Abstract Background Evidence showed possible benefits of a less gestational weight gain (GWG) than the US Institute of Medicine (IOM) recommendation in gestational diabetes mellitus (GDM) pregnancy. Here, we aimed to explore an appropriate GWG range in GDM women according to adverse pregnancy outcomes. Methods We enrolled all the singleton GDM pregnant women (n = 14,213) from January 2015 to December 2018 in Xi'an, Northwest China. According to the pre-pregnancy body mass index (BMI), they were classified into the Underweight (

Epstein-Barr virus-associated lymphoepithelioma-like intrahepatic cholangiocarcinoma (EBVa LEL-ICC) is a rare tumor, characterized by a rich tumor immune microenvironment (TIME). While this tumor is reportedly sensitive to immunotherapy, its response has been inconsistent. This decreased sensitivity was associated with reduced TIME abundance. We report the case of a 53-year-old woman with EBVa LEL-ICC having reduced TIME abundance. The patient presented with a liver lesion, which was detected using ultrasound. Initially, the tumor was sensitive to immunotherapy and chemotherapy (IC), but resistance developed after a short interval. Subsequently, stereotactic ablative radiotherapy (SABR) was added to the patient’s treatment, which now consisted of ICSABR. Successful tumor shrinkage was achieved with the combination therapy regimen. Thus, surgery and ICSABR are effective adjuncts to the first-line IC therapy in improving the survival rate of patients with EBVa LEL-ICC. The results of this study support multidisciplinary treatment as a viable treatment strategy for EBVa LEL-ICC.

ObjectivesThe aim of this study was to understand the impact of multimorbidity on catastrophic health expenditures for people with hypertension.MethodsData were obtained from the China Health and Retirement Longitudinal Study (CHARLS) in 2018, 8,342 adults were included in our analysis. Propensity score matching method was used to compare the risk of catastrophic health expenditures between the hypertension patients (treatment group) and those without any chronic disease (control group) in middle-aged and older adults. Patients with hypertension were also divided into two groups: only hypertension and multimorbidity.ResultsHypertension increased the likelihood of CHE by 11.3% in older adults. Further analysis showed that hypertension alone does not increase the risk of CHE, and the risk of CHE in hypertension patients with multimorbidity was 12.9% higher than those without chronic disease.ConclusionOur study highlights the importance of healthy management of patients with only hypertension and preventing them from developing multimorbidity.

Abstract Background Health inequality, including physical and mental health inequality, is an important issue. What role social capital plays in mental health inequality is still ambiguous, especially in developing countries. The aim of this study is to explore the relationship between social capital and mental health inequality in China. Method Both family-level and community-/village-level social capitals are included in our analysis. Data is mainly extracted from the China Family Panel Studies in 2018, and lagged term of social capital in CFPS 2016 was used to link with other variables in 2018. Depressive symptoms and subjective well-being are set as indicators of mental health. A series of OLS regression models were conducted to estimate the effects of social capital on mental health and mental health inequality. Results Higher levels of social capital and income are related to a lower level of depressive symptoms and a higher level of subjective well-being. The positive coefficient of interaction term of family-level social capital and income level in the urban area indicates that the inhibiting effect of social capital on depressive symptoms is pro-poor. The negative coefficient of interaction term of village-level social capital and income level in the rural area suggests that the promoting effect of social capital on subjective well-being is pro-poor, too. Conclusion The results show that severe mental health inequality exists in China; family-level social capital can buffer depressive symptom inequality, and village-level social capital can buffer SWB inequality. Although the amount of social capital of the poor is less than the rich, the poor can better use social capital to improve their mental health. Our study advocates enhancing social participation and communication for the poor to reduce mental health inequality.

The human placenta is a unique temporary organ with a mysterious immune tolerance. The formation of trophoblast organoids has advanced the study of placental development. HLA-G is uniquely expressed in the extravillous trophoblast (EVT) and has been linked to placental disorders. With older experimental methodologies, the role of HLA-G in trophoblast function beyond immunomodulation is still contested, as is its role during trophoblast differentiation. Organoid models incorporating CRISPR/Cas9 technology were used to examine the role of HLA-G in trophoblast function and differentiation. JEG-3 trophoblast organoids (JEG-3-ORGs) were established that highly expressed trophoblast representative markers and had the capacity to differentiate into EVT. CRISPR/Cas9 based on HLA-G knockout (KO) significantly altered the trophoblast immunomodulatory effect on the cytotoxicity of natural killer cells, as well as the trophoblast regulatory effect on HUVEC angiogenesis, but had no effect on the proliferation and invasion of JEG-3 cells and the formation of TB-ORGs. RNA-sequencing analysis further demonstrated that JEG-3 KO cells followed similar biological pathways as their wild-type counterparts during the formation of TB-ORGs. In addition, neither HLA-G KO nor the exogenous addition of HLA-G protein during EVT differentiation from JEG-3-ORGs altered the temporal expression of the known EVT marker genes. Based on the JEG-3 KO (disruption of exons 2 and 3) cell line and the TB-ORGs model, it was determined that HLA-G has a negligible effect on trophoblast invasion and differentiation. Despite this, JEG-3-ORG remains a valuable model for studying trophoblast differentiation.

BackgroundPrevious studies have explored the relationship between the geriatric nutritional risk index (GNRI) and survival outcomes of diffuse large B-cell lymphoma (DLBCL) cases, but the results were inconsistent. Consequently, the present meta-analysis was conducted to investigate how GNRI affects DLBCL and its function in terms of prognosis.MethodsThe Web of Science, PubMed, Embase, and Cochrane Library databases were thoroughly searched until January 18, 2023. We calculated combined hazard ratios (HRs) and 95% confidence intervals (CIs) to estimate the relationship between the GNRI and survival outcomes of patients with DLBCL.ResultsThis meta-analysis included seven articles involving 2,353 cases. A lower level of GNRI predicted dismal overall survival (HR=1.40, 95% CI=1.25–1.56, p

AIM: To explore the effects of laser-activated remote phosphors (LARP) on visual function in guinea pigs. METHODS: Electroretinogram (ERG) of guinea pigs were observed after LARP irradiation at different frequencies and irradiation times. We evaluated the expression of rhodopsin, β-catenin, connexin36, calretinin, and calbindin in the retina of guinea pigs and measured the density of photoreceptor cells after high-frequency LARP irradiation. RESULTS: After LARP irradiation, the ERG results showed that the amplitude of the dark-adapted 3.0 b-wave of the model eye was lower than that of the control eye after high-frequency irradiation (P

Abstract Background Postpartum urinary retention (PUR) may lead to bladder neuromuscular damage and subsequently voiding dysfunction. However, the literature regarding the incidence of and risk factors for PUR remains unclear. Moreover, previously reported studies are limited to small sample sizes. Thus, this study aimed to assess the incidence of and risk factors for overt PUR after vaginal delivery. Methods This retrospective case-control study included all primiparas who delivered vaginally between July 1, 2017, and June 30, 2019, at our institution. The case group comprised 677 women diagnosed with overt PUR who required catheterisation after delivery. The control group comprised 677 women without overt PUR randomly selected in a 1:1 ratio matched for date of delivery and who delivered immediately after each woman with overt PUR to minimise the impact of variations over time in obstetric practice. Univariate and multivariate logistic regression analyses were performed to investigate the factors associated with overt PUR. Results Of the 12,609 women included in our study, 677 were diagnosed with overt PUR (incidence 5.37%). Univariate analysis identified epidural analgesia, episiotomy, perineal tears, instrument-assisted delivery, duration of labour stage, intrauterine operation, and vulvar oedema as risk factors for PUR. Multivariate logistic regression identified epidural analgesia (odds ratio [OR] = 1.41, 95% confidence interval [CI]: 1.11–1.79, P = 0.005), vulvar oedema (OR = 6.92, 95% CI: 4.65–10.31, P

Abstract Glioblastoma (GBM) is a type of brain cancer with high morbidity and mortality worldwide. The clinical significance, biological roles, and underlying molecular mechanisms of DNA poly ε-B subunit (POLE2) in GBM were investigated in the study. Firstly, the Cancer Genome Atlas (TCGA) database found that POLE2 was highly expressed in GBM. Immunohistochemistry (IHC) results further confirmed that POLE2 was abnormally elevated in GBM. In addition, loss-of-function assays revealed that POLE2 knockdown could inhibit the malignant behaviors of GBM, especially reduce cell viability, weaken cell clone formation, enhance the sensitivity of apoptosis, restrain migration and inhibit epithelial-mesenchymal transition (EMT) in vitro. In vivo experiments further clarified the suppressive effects of reduced POLE2 expression on tumors. Mechanically, POLE2 knockdown promoted the ubiquitination as well as reduced the stability of Forkhead transcription factor (FOXM1), which is a known tumor promotor in GBM, through Aurora kinase A (AURKA). Moreover, the knockdown of FOXM1 could weaken the promoting effects of POLE2 on malignant behaviors of GBM. In conclusion, our study revealed crucial roles and a novel mechanism of POLE2 involved in GBM through AURKA-mediated stability of FOXM1 and may provide the theoretical basis of molecular therapy for GBM.

BackgroundAn increasing number of innovations have been discovered for treating hepatocellular carcinoma (HCC or commonly called HCC) therapy, Ferroptosis and mitochondrial metabolism are essential mechanisms of cell death. These pathways may act as functional molecular biomarkers that could have important clinical significance for determining individual differences and the prognosis of HCC. The aim of this study was to construct a stable and reliable comprehensive model of genetic features and clinical factors associated with HCC prognosis.MethodsIn this study, we used RNA-sequencing (fragments per kilobase of exon model per million reads mapped value) data from the Cancer Genome Atlas (TCGA) database to establish a prognostic model. We enrolled 104 patients for further validation. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes enrichment analyses (KEGG) analysis were used for the functional study of differentially expressed genes. Pan-cancer analysis was performed to evaluate the function of the Differentially Expressed Genes (DEGs). Thirteen genes were identified by univariate and least absolute contraction and selection operation (LASSO) Cox regression analysis. The prognostic model was visualized using a nomogram.ResultsWe found that eight genes, namely EZH2, GRPEL2, PIGU, PPM1G, SF3B4, TUBG1, TXNRD1 and NDRG1, were hub genes for HCC and differentially expressed in most types of cancer. EZH2, GRPEL2 and NDRG1 may indicate a poor prognosis of HCC as verified by tissue samples. Furthermore, a gene set variation analysis algorithm was created to analyze the relationship between these eight genes and oxidative phosphorylation, mitophagy, and FeS-containing proteins, and it showed that ferroptosis might affect inflammatory-related pathways in HCC.ConclusionEZH2, GRPEL2, NDRG1, and the clinical factor of tumor size, were included in a nomogram for visualizing a prognostic model of HCC. This nomogram based on a functional study and verification by clinical samples, shows a reliable performance of patients with HCC.

Background: The study concerning the influence of Conbercept, which is an anti-Vascular endothelial growth factor (VEGF) agent, in intraocular pressure (IOP) spike is limited and warrants further investigation. The current study aimed to investigate the changes of intraocular pressure after intravitreal injection (IVI) of Conbercept and evaluate the risk factors associated with intraocular pressure spikes.Methods: Patients with diabetic macular edema receiving intravitreal injection of 0.05 ml (0.5 mg) Conbercept were involved in the study. All patients underwent slit lamp examination to determine the status of phakia/pseudophakia. The axial length was measured using IOL Master 500 before intravitreal injection. Patients underwent a Conbercept intravitreal injection with a 30-gauge needle in a standard fashion. The intraocular pressure was measured 2 min before injection, and 2, 10, 30 min, 1, 2, 5, 24 h after injection using a rebound tonometer. The changes of intraocular pressure and the relevant risk factors were evaluated. Patients were subdivided into phakic group and pseudophakic group to analyze the effect of lens status on intraocular pressure changes.Results: Forty patients with a mean age of 62.48 ± 12.22 years were included in the study. The mean intraocular pressure values at baseline and 2, 10, 30 min, 1, 2, 5, 24 h after injection were 14.81 ± 3.13 mmHg, 26.80 ± 9.43 mmHg, 18.76 ± 6.16 mmHg, 16.54 ± 5.94 mmHg, 15.64 ± 3.75 mmHg, 14.46 ± 3.03 mmHg, 14.10 ± 1.88 mmHg, 14.23 ± 2.71 mmHg respectively. The intraocular pressure after injection for 2, 10 min was significantly higher than baseline (p < 0.001, p = 0.001, respectively). The intraocular pressure between baseline and post-injection for 30 min or beyond were comparable (all p > 0.05). No significant difference was found between the phakic group and pseudophakic group (p = 0.422). The changes of intraocular pressure were positively correlated with age (r = 0.329, p = 0.038), but negatively with axial length (r = −0.472, p = 0.002).Conclusion: intravitreal injection of Conbercept may cause rapid spike of intraocular pressure, but is safe with respect to short-term changes. The intraocular pressure in patients with older age and shorter axial length is more likely to be higher after intravitreal injection.

Camellia oleifera is a vital economic crop of southern China. Accurate mapping and monitoring of Camellia oleifera plantations are essential for promoting sustainable operations within the Camellia oleifera industry. However, traditional remote sensing interpretation methods are no longer feasible for the large-scale extraction of plantation areas. This study proposes a novel deep learning-based method that utilizes GF-2 remote sensing imagery to achieve precise mapping and efficient monitoring of Camellia oleifera plantations. First, we conducted a comparative analysis of the performance of various semantic segmentation models using a self-compiled dataset of Camellia oleifera plantations. Subsequently, we proceeded to validate the prediction results obtained from the most effective deep-learning network model for Camellia oleifera plantations in Hengyang City. Finally, we incorporated DEM data to analyze the spatial distribution patterns. The findings indicate that the U-Net++ network model outperforms other semantic segmentation methods when applied to our self-generated dataset of Camellia oleifera plantations. It achieves a recall rate of 0.89, a precision rate of 0.92, and an mIOU of 0.83, demonstrating the effectiveness of the proposed method in identifying and monitoring Camellia oleifera plantations. By combining the predicted results with the data from DEM, we discovered that these plantations are typically situated at elevations ranging from 50 to 200 m, with slopes below 25°, and facing south or southeast. Moreover, a significant positive spatial correlation and clustering phenomenon are observed among the townships in Hengyang City. The method proposed in this study facilitates rapid and precise identification and monitoring of Camellia oleifera plantations, offering significant theoretical support and a scientific foundation for the management and ecological conservation of Camellia oleifera plantations.

Anadequate selenium (Se) intake can enhance human immunity and prevent diseases development. About one billion people in the world have varying degrees of Se deficiency in the world. Organic Se from tea infusion is the most easily absorbed and utilized Se form by the human body. Therefore the production of tea plants rich in Se is an effective way to increase Se dietary intake, but there are few studies on the involvement and functions of miRNAs in the responses of tea plants after Se treatment. MicroRNAs (miRNAs) are endogenous (non-coding) single-stranded RNAs that play crucial roles in regulating plant nutrient element acquisition and accumulation. Physiological analysis discovered that the total Se content in tea plant roots markedly increased under 0.05 mmol·L−1 selenite treatment, with no toxicity symptoms in the leaves and roots. To screen the miRNAs responsive to Se treatment in tea plants, miRNA libraries were constructed from the tea cultivar “Echa 1”. Using high-throughput sequencing, 455 known miRNAs and 203 novel miRNAs were identified in this study. In total, 13 miRNAs were selected that were differentially expressed in tea plants’ roots under 0.05 mmol·L−1 selenite treatments. Gene Ontology enrichment analysis revealed that the target genes of the differentially expressed miRNAs mainly belonged to the metabolic process, membrane, and catalytic activity ontologies. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis suggested that beta-alanine, taurine, hypotaurine, and sulfur metabolism were the most enriched pathways among the differentially expressed miRNAs, implying their involvement in Se accumulation and tolerance in tea plants. Further characterization of the data revealed that the number of novel miRNAs was comparable to that of known miRNAs, indicating that novel miRNAs significantly contributed to the regulation of Se accumulation in tea plant roots. Thisstudy lays the foundation for further research on the regulatory mechanisms underlying Se accumulation and tolerance in tea plants, providing targets to molecular breeding strategies for improving tea nutritional properties.

Solute carrier family 31 member 1 (SLC31A1) encodes a protein that functions as a homotrimer for the uptake of dietary copper. As a vital member of the cuproptosis gene family, it plays an essential role in both normal tissues and tumors. In this study, we analyzed SLC31A1 across human cancer types to gain a better understanding of SLC31A1’s role in cancer development. We searched for information using online databases to analyze, systematically and comprehensively, the role of SLC31A1 in tumors. Amongst nine cancer types, the expression of SLC31A1 was significantly different between tumors and normal tissues. According to further analysis, pancreatic cancer had the highest mutation rate of the SLC31A1 gene, and the methylation levels of the gene were significantly reduced in seven tumors. The expression of SLC31A1 is also linked to the infiltration of tumors by immune cells, the expression of immune checkpoint genes, and immunotherapy markers (TMB and MSI), suggesting that SLC31A1 may be of particular relevance in immunotherapy. This thorough analysis of SLC31A1 across different types of cancer gives us a clear and comprehensive insight into its role in causing cancer on a systemic level.

Abstract Background China’s government launched a large-scale healthcare reform from 2009. One of the main targets of this round reform was to improve the primary health care system. Major reforms for primary healthcare institutions include increasing government investment. However, there are insufficient empirical studies based on large sample to catch long-term effect of increased government subsidy and lack of sufficient incentives on township healthcare centers (THCs), therefore, this study aims to provide additional empirical evidence on the concern by conducting an empirical analysis of THCs in Shaanxi province in China. Methods We collected nine years (2009 to 2017) data of THCs from the Health Finance Annual Report System (HFARS) that was acquired from the Health Commission of Shaanxi Province. We applied two-way fixed effect model and continue difference-in-difference (DID) model to estimate the effect of percentage of government subsidy on medical provision. Results A clear jump of the average percentage of government subsidy to total revenue of THCs can be found in Shaanxi province in 2011, and the average percentage has been more than 60% after 2011. Continue DID models indicate every 1% percentage of government subsidy to total revenue increase after 2011 resulted in a decrease of 1.1 to 3.5% in THCs healthcare provision (1.9% in medical revenue, 1.2% in outpatient visit, 3.5% in total occupy beds of inpatient, 1.1% in surgery revenue, 2.1% in sickbed utilization rate). The results show that the THCs with high government subsidy reduce the number of medical services after 2011. Conclusions We think that it is no doubt that the government should take more responsibility for the financing of primary healthcare institutions, the problem is when government plays a central role in the financing and delivery of primary health care services, more effective incentives should be developed.

Abstract Background Caring for grandchildren is regarded as one of the principle roles of middle- and old-aged adults, especially among rural Chinese grandparents. This study aims to examine the gender differences in depressive symptoms of rural Chinese grandparents caring for grandchildren, based on the gender differences in grandparental role engagement and the theories of role strain and role enhancement. Methods A total of 4833 rural citizens with one or more grandchildren were selected from the China Health and Retirement Longitudinal Study (CHARLS) conducted in 2015. Grandchild care was measured by continuous variable (duration) and categorical variable (no care, low intensity, moderate intensity, high intensity). Depressive symptoms were assessed by the Center for Epidemiologic Studies Depression Scale (CES-D). We used coarsened exact matching (CEM) to balance the covariates of caregivers and non-caregivers. Following CEM, 1975 non-caregivers and 2212 caregivers were identified (N = 4187). Multilevel linear regression was employed to examine the gender differences in depressive symptoms. We also tested for the moderating role of gender on the association between grandchild care and depressive symptoms. Results Grandmothers were more likely to provide grandchild care (54.42% vs 51.43%) at high intensity (61.46% vs 51.01%), with longer duration (39.24 h vs 33.15 h) than that given by grandfathers. Grandmothers suffered more from depressive symptoms than grandfathers, and such gap increased when grandparents were involved in high-intensity care. Grandmothers providing grandchild care, particularly at moderate intensity, were associated with fewer depressive symptoms (Coef. = − 0.087, 95%CI: − 0.163, − 0.010; Coef. = − 0.291, 95%CI: − 0.435, − 0.147), compared with non-caregivers. Grandmothers giving moderate intensity of grandchild care were also associated with fewer depressive symptoms (Coef. = − 0.171, 95% CI: − 0.313, − 0.029), compared with those with low-intensity care. However, such associations were not significant among grandfathers. Conclusions Our findings highlight the gender differences in depressive symptoms of rural Chinese grandparents caring for grandchildren. Grandparents should be encouraged to engage in grandchild care, but at moderate intensity. The health status of middle- and old-aged adults, particularly females, should be monitored closely. Humanistic care, preventive care and curative treatment strategies focusing on such populations should be developed and refined.

Abstract Background There is an increasing trend on the practices of parental self-medication with antibiotics (PSMA) around world, accelerating the antibiotic abuse. This study aims to examine the nationality differences in the practices of PSMA and knowledge, attitudes and practices (KAP) toward antibiotic use, and understand the practices of PSMA among parents of various nationalities in China. Methods A cross-sectional study based on a structured questionnaire survey was conducted in Xi’an, Shaanxi Province, China, from September 2018 to October 2018. A total of 299 respondents participated in. The practices of PSMA (a dichotomous variable) and KAP toward antibiotic use (a continuous variable) served as dependent variables. Participant’s nationality was regarded as the independent variable. Binary logistic regression and ordinary least square regression were employed to examine the association between parent’s nationality and the practices of PSMA, and KAP toward antibiotic use, respectively. Results 121 (40.88%) Chinese, 100 (33.76%) other Asians and 75 (25.34%) Occidentals were included in final analysis, with a sample size of 296. Chinese were more likely to practice PSMA (OR = 7.070; 95% CI 1.315, 38.01), with worse knowledge (Coef. = − 0.549; 95% CI − 1.021, − 0.078), attitudes (Coef. = − 3.069; 95% CI − 4.182, − 1.956) and practices (Coef. = − 1.976; 95% CI − 3.162, − 0.790) toward antibiotic use, compared to their Occidental counterparts. The main reasons for the practices of PSMA were enough previous medication experience (80.49%) and same ailments with no need to see a doctor (39.02%), with common symptoms such as fever (60.98%) and cough (58.54%). Purchasing antibiotics at pharmacies (92.08%) and using leftover antibiotics (26.83%) were usual approaches. Conclusions The study highlights the gaps in the practices of PSMA and KAP toward antibiotic use among parents of different nationalities. The access to obtain antibiotics from pharmacies reflects the pharmacists’ unaware of laws on prescription of antibiotics, fierce competition in the pharmacy market, and the government’s lax supervision in China. It suggests the need to improve pharmacists’ training, enforce current legislations on pharmacy market regarding the sale of antibiotics, and provide practical and effective educational interventions for residents about antibiotic use.

Background It is 1 of the standard treatment options for metastasis pancreatic cancer to receive nab-paclitaxel (125 mg/m 2 ) plus gemcitabine (1000 mg/m 2 ) on days 1, 8 and 15 every 28 days. Some patients showed intolerance and inconvenience to this therapeutic regimen. Thus, we conducted this retrospective real-world study to determine the efficacy and tolerability of a modified 21-day nab-paclitaxel plus gemcitabine (nab-P/Gem) regimen for the first-line treatment of locally advanced or metastatic pancreatic cancer. Methods Patients with locally advanced and metastatic pancreatic cancer treated with nab-paclitaxel (125 mg/m 2 ) plus gemcitabine (1000 mg/m 2 ) on days 1 and 8 every 21-day at West China Hospital and Shang Jin Hospital of Sichuan University from Mar 2018 to Dec 2021 were reviewed retrospectively. Clinical characteristics of patients were collected. The progression-free survival, overall survival, objective response rate, disease control rate, and toxicity were evaluated. Results A total of 113 patients who received the modified regimen of 21-day nab-P/Gem chemotherapy were included. The median overall survival was 9.3 months and the median progression-free survival was 4.4 months. The objective response rate and disease control rate were 18.6% and 56.7%, respectively. The median relative dose intensity for this modified regimen was 65%. The adverse events were mild to moderate, and the most common grade 3 or 4 treatment-related adverse events were neutropenia (21%) and leukopenia (16%). Conclusions Our study showed that this modified regimen of 21-day nab-P/Gem for locally advanced and metastatic pancreatic cancer had comparable efficacy and tolerable toxicity. This treatment may provide a considerable option for pancreatic cancer patients who desire a modified schedule. The modified regimen of 21-day nab-P/Gem is also an option worth considering during the coronavirus disease 2019 pandemic for minimizing the number of visits and limiting the risk of exposure.

IntroductionThe disadvantaged socioeconomic status could have accumulated negative effects on individual. In the Chinese context, studying subjective and relative poverty is more important under the implementation of the Targeted Poverty Alleviation campaign. This study aims to provide evidence of the relationship between the duration of subjective poverty and both physical and mental health among Chinese adults, using nationally longitudinal data from 2010 to 2018.Materials and methodsData were extracted from a nationally representative survey database—the China Family Panel Study (CFPS). The total sample size contains 12,003 adults, with 3,532 in the urban area and 8,471 in the rural area. Self-rated health and depressive symptoms were set as indicators of physical health and mental health, respectively. The duration of subjective poverty was measured by self-rated income level in the local area from 2010 to 2016. A series of ordinary least square regression was adopted to measure the relationship between duration of subjective poverty and health.ResultsFor the urban residents, the average duration of subjective poverty is 1.99 time points, while 1.98 time points for the rural residents. Net of objective poverty, duration of subjective poverty has a significantly negative association with individual's self-rated health in the rural sample (Coef. = −0.10, p < 0.001). Compared with those who have not experienced subjective poverty, the self-rated health score of people who experienced four time points is likely to decrease by 0.54 in the rural area and 0.30 in the urban area. In terms of mental health, 1 unit increase in the duration of subjective poverty is related to 0.15 unit increase in Center for Epidemiologic Studies Depression Scale-8 (CES-D8) scores in the urban sample and 0.46 in the rural sample. Compared with those who have not experienced subjective poverty, the CES-D8 scores of people who experienced four time points are likely to increase by 1.47 in the rural area and 0.95 in the urban area.ConclusionA longer duration of subjective poverty has a cumulatively negative effect on Chinese residents' physical and mental health, especially in rural area. Our study advocates researchers and policymakers pay more attention to the cumulative effect of subjective poverty on health.

BackgroundNADH: ubiquinone oxidoreductase subunit C1(NDUFC1) encodes a subunit of the Complex I, which may support the structural stability of Complex I and assist in its biogenesis. The expression and functional roles of NDUFC1 in hepatocellular carcinoma (HCC) remain unknown.ResultWe knocked down the expression of NDUFC1 in HCC cell lines to explore the effects of NDUFC1 downregulation on HCC in vitro. MTT assay determined that downregulation of NDUFC1 significantly inhibited cell proliferation. Flow cytometry with (propidium iodide) PI staining indicated silencing of NDUFC1 arrested cell cycle of BEL-7404 cells at G2 phase and SK-HEP-1 cells at S/G2 phase. Annexin V-PI double staining and flow cytometric analysis showed that the downregulation of NDUFC1 significantly increased the population of apoptotic cells. Wound-healing assay and transwell assay indicated that the downregulation of NDUFC1 suppressed the migration and invasion of HCC cells. According to the detection of complex1 activity, we found that the activity of NDUFC1 silenced group decreased, whereas the content of ROS increased. Furthermore, combined with bioinformatics analysis of senescence-related genes, we found that the silence of NDUFC1 in HCC could induce senescence and inhibit autophagy. In addition, NDUFC1 could correlate positively with cancer-related pathways, among which the p53 pathways and the PI3K/Akt/mTOR pathways. Finally, NDUFC1 is high expression in HCC specimens. High NDUFC1 expression was associated with poor prognosis and was an independent risk factor for reduced overall survival (OS).ConclusionsOur study indicated, for the first time, that NDUFC1 is an independent risk factor for the poor prognosis of HCC patients. NDUFC1 may promote tumor progression by inhibiting mitochondrial Complex I and up-regulating ROS through multiple cancer-related and senescence-related pathways of HCC, including p53 pathways and PI3K/Akt/mTOR pathways. We suppose that NDUFC1 might be a potential target for the mitochondrial metabolism therapy of HCC.

BackgroundGastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) is a group of rare but highly aggressive malignancies. The standard chemotherapy regimens composed of etoposide and cisplatin/carboplatin (EP/EC) are of limited efficacy. This prospective, multicenter, phase II study is conducted to explore the effectiveness and safety of first-line anti-PD-1 antibody (camrelizumab) combined with chemotherapy in advanced GEP-NEC patients.MethodsPatients with unresectable or metastatic GEP-NEC will receive camrelizumab combined with standard first-line chemotherapy every 3 weeks (camrelizumab 200 mg, administered intravenously on day 1; etoposide 100 mg/m2, administered intravenously on days 1–3; cisplatin 75 mg/m2, administered intravenously on day 1 or carboplatin area under the curve 5 mg/ml per min, administered intravenously on day 1). All patients were naïve to systemic therapy in the advanced setting. The primary endpoint is a 6-month progression-free survival (PFS) rate. The secondary endpoints are objective response rate, PFS, overall survival and adverse reactions.DiscussionThis is the first study to investigate the therapeutic potential of camrelizumab plus chemotherapy for advanced GEP-NEC. It is expected that this trial will propose a new and effective treatment strategy for GEP-NEC in the first-line setting.Clinical Trial RegistrationThis trial is registered at the Chinese Clinical Trial Registry http://www.chictr.org.cn, identifier ChiCTR2100047314.Date of RegistrationJune 12, 2021.

Abstract Background C. sinensis is an important economic crop with fluoride over-accumulation in its leaves, which poses a serious threat to human health due to its leaf consumption as tea. Recently, our study has indicated that cell wall proteins (CWPs) probably play a vital role in fluoride accumulation/detoxification in C. sinensis. However, there has been a lack in CWP identification and characterization up to now. This study is aimed to characterize cell wall proteome of C. sinensis leaves and to develop more CWPs related to stress response. A strategy of combined cell wall proteomics and N-glycoproteomics was employed to investigate CWPs. CWPs were extracted by sequential salt buffers, while N-glycoproteins were enriched by hydrophilic interaction chromatography method using C. sinensis leaves as a material. Afterwards all the proteins were subjected to UPLC-MS/MS analysis. Results A total of 501 CWPs and 195 CWPs were identified respectively by cell wall proteomics and N-glycoproteomics profiling with 118 CWPs in common. Notably, N-glycoproteomics is a feasible method for CWP identification, and it can enhance CWP coverage. Among identified CWPs, proteins acting on cell wall polysaccharides constitute the largest functional class, most of which might be involved in cell wall structure remodeling. The second largest functional class mainly encompass various proteases related to CWP turnover and maturation. Oxidoreductases represent the third largest functional class, most of which (especially Class III peroxidases) participate in defense response. As expected, identified CWPs are mainly related to plant cell wall formation and defense response. Conclusion This was the first large-scale investigation of CWPs in C. sinensis through cell wall proteomics and N-glycoproteomics. Our results not only provide a database for further research on CWPs, but also an insight into cell wall formation and defense response in C. sinensis.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with molecular heterogeneity, inducing differences in biological behavior, and therapeutic strategy. NGS profiles of pathogenic alterations in the Chinese PDAC population are limited. We conducted a retrospective study to investigate the predictive role of DNA damage repair (DDR) mutations in precision medicine. Methods The NGS profiles were performed on resected tissues from 195 Chinese PDAC patients. Baseline clinical or genetic characteristics and survival status were collected. The Kaplan–Meier survival analyses were performed by the R version 3.6.1. Results The main driver genes were KRAS, TP53, CDKN2A, and SMAD4. Advanced patients with KRAS mutation showed a worse OS than KRAS wild-type (p = 0.048). DDR pathogenic deficiency was identified in 30 (15.38%) of overall patients, mainly involving BRCA2 (n = 9, 4.62%), ATM (n = 8, 4.10%) and RAD50 genes (n = 3, 1.54%). No significance of OS between patients with or without DDR mutations (p = 0.88). But DDR mutation was an independent prognostic factor for survival analysis of advanced PDAC patients (p = 0.032). For DDR mutant patients, treatment with platinum-based chemotherapy (p = 0.0096) or olaparib (p = 0.018) respectively improved the overall survival. No statistical difference between tumor mutation burden (TMB) and DDR mutations was identified. Treatment of PD-1 blockades did not bring significantly improved OS to DDR-mutated patients than the naive DDR group (p = 0.14). Conclusions In this retrospective study, we showed the role of germline and somatic DDR mutation in predicting the efficacy of olaparib and platinum-based chemotherapy in Chinese patients. However, the value of DDR mutation in the prediction of hypermutation status and the sensitivity to the PD-1 blockade needed further investigation.

The Yellow River Delta is an important grain production base in China, and it is a typical Yellow River irrigated area. Chemical fertilizer overuse has seriously affected grain production safety, and understanding the fertilizer application situation is useful for scientific agronomy management. In this study, we collected the data of the N, P, K fertilizers for crop cultivation in Donging City from 2011 to 2020, and we collected 185 investigating questionnaires to gather information on the fertilizer application rate for small farmers. The results showed that the amount of total fertilizer used has decreased from the year 2015, but the macro element fertilizer rate for crop cultivation exceeded the recommended dosage. The application of compound fertilizer increased during the investigated 10 years, and its proportion in 2020 was 1.65 times higher than in 2011. For obtaining an ideal grain yield, the N and P2O5 had relative reduction rates of 67.8% and 69.6% for wheat planting. Furthermore, the relative reduction rates of N, P2O5, and K2O were 25.9%, 69.6%, and 59.7%, respectively, for maize cultivation when compared to the recommended dosage. During wheat growth, the potassium fertilizer was needed to increase the dosage, although the K element content in the soil was high. Furthermore, the medium and trace elements are all important nutrients for improving crop yield and quality which need to be studied. More scientific measurements should be conducted to match chemical fertilizer reduction to constructing healthy and sustainable agriculture in the Yellow River irrigated area.