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Cervical cancer, among the deadliest cancers affecting women globally, primarily arises from persistent infection with high-risk human papillomavirus (HPV). To effectively combat persistent infection and prevent the progression of precancerous lesions into malignancy, a therapeutic HPV vaccine is under development. This study utilized an immunoinformatics approach to predict epitopes of cytotoxic T lymphocytes (CTLs) and helper T lymphocytes (HTLs) using the E6 and E7 oncoproteins of the HPV16 strain as target antigens. Subsequently, through meticulous selection of T-cell epitopes and other necessary elements, a multi-epitope vaccine was constructed, exhibiting good immunogenic, physicochemical, and structural characteristics. Furthermore, in silico simulations showed that the vaccine not only interacted well with toll-like receptors (TLR2/TLR3/TLR4), but also induced a strong innate and adaptive immune response characterized by elevated Th1-type cytokines, such as interferon-gamma (IFN-γ) and interleukin-2 (IL2). Additionally, our study investigated the effects of different immunization intervals on immune responses, aiming to optimize a time-efficient immunization program. In animal model experiments, the vaccine exhibited robust immunogenic, therapeutic, and prophylactic effects. Administered thrice, it consistently induced the expansion of specific CD4 and CD8 T cells, resulting in substantial cytokines release and increased proliferation of memory T cell subsets in splenic cells. Overall, our findings support the potential of this multi-epitope vaccine in combating HPV16 infection and signify its candidacy for future HPV vaccine development.

Grafting lignin extracted from pulping black liquor onto hydrogel not only endows hydrogel with strong adsorption capacity, but also realizes the high value utilization of lignin, thereby alleviating the environmental pressure caused by the exhaust gas generated by direct combustion of black liquor. However, those lignin fragments have lost generous active functional groups as the high temperature polycondensation during industrial production, restricting the improvement of lignin-based hydrogel adsorption capacity. Herein, we propose a strategy combining amination and oxidation to prepare lignin derivatives with low molecular weight and high activity groups. The introduced amino groups promote the C α -C β cleavage of β-O-4 unit and the oxidation treatment converts S-unit hydroxyl to carboxyl. The hydrogel obtained by grafting aminated-oxidized-lignin shows satisfactory adsorption performance with a methylene blue adsorption capacity of 697.47 mg/g (vs. 195.12 mg/g for pristine hydrogel). The retention ability has also been greatly improved that only 0.43 % of the adsorbed methylene blue is released even after 96 h (vs. 5 % within just 12 h for pristine hydrogel). This work not only provides a new strategy for the high-value utilization of biomass resources, but also offers a new idea for the preparation of hydrogels with high adsorption performance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Secondary hyperparathyroidism (SHPT) is a prevalent chronic complication in patients undergoing hemodialysis. Parathyroidectomy (PTX) is crucial for reducing mortality and improving the prognosis in the treatment of refractory hyperparathyroidism. However, it is often associated with a number of postoperative complications such as postoperative hypotension, hyperkalemia, and hungry bone syndrome. A previous study demonstrated that low blood pressure influences the patency of autogenous arteriovenous fistulas (AVF). Few studies have examined AVF dysfunction following PTX. This study aimed to identify and describe the risk variables associated with AVF dysfunction after PTX., Methods: Cases of AVF dysfunction after PTX between 2015 and 2021 were studied. Four controls were identified for each patient and were matched for sex and age. Biochemical parameters and blood pressure of the patients before and after PTX were recorded. Risk factors for AVF dysfunction after PTX were identified using conditional logistic regression analysis., Results: Sixteen patients and 64 controls were included in this study. Baseline demographic and laboratory data were compared. Patients in the AVF dysfunction group had lower levels of postoperative calcium than the controls. After surgery, calcium levels decreased more in patients with AVF dysfunction than in the control group. The decrease in systolic blood pressure (ΔSBP) after PTX was greater in the AVF dysfunction group than that in the control group. For each 1 mmHg increment in ΔSBP, the risk of AVF dysfunction after surgery increased by 11.6% (OR = 1.116, 95% CI, 1.005-1.239, p  = .040). The likelihood of developing AVF dysfunction after surgery was twelvefold higher in diabetic patients than in non-diabetic patients (OR = 12.506, 95% CI, 1.113-140.492, p  = .041). Among patients with ΔSBP > 5.8 mmHg after PTX, the AVF failure rate was significantly greater in patients with diabetes than in those without diabetes. Patients with a history of AVF failure had a nine-fold higher risk of developing AVF dysfunction (OR = 9.143, 95% CI, 1.151-72.627, p  = .036). Serum albumin, hemoglobin, ΔiPTH, and age were not independent predictors of AVF dysfunction. The cutoff value for SBP was 5.8 mmHg, as determined by the Youden index of the receiver operating characteristic curve., Conclusion: Decreased systolic blood pressure (ΔSBP) after PTX, diabetes, and AVF failure history were risk factors for AVF dysfunction following PTX in patients with SHPT. Diabetes patients with ΔSBP > 5.8 mmHg were more prone to AVF dysfunction after PTX.

Abnormal N6-methyladenosine (m6A) methylation in RNA plays a pivotal role in the pathogenesis of many types of tumors by influencing mRNA metabolism, alternative splicing, translocation, stability and translation. However, the specific regulators and underlying mechanisms of m6A modification in the progression of lung adenocarcinoma are not well understood. In this study, we analyzed the RNA-seq transcriptome data downloaded from The Cancer Genome Atlas (TCGA) database, and identified "m6A writer" RNA binding motif protein 15 (RBM15) expression was significantly elevated in lung adenocarcinoma (LUAD) biopsies, and the higher RBM15 levels were correlated with the poorer overall survival (OS) of LUAD patients. Further study confirmed RBM15 was prominently expressed in LUAD tissues and cell lines. Moreover, silencing RBM15 in PC9 and H1299 cells reduced cell proliferation both in vitro and in vivo, while overexpression of RBM15 in A549 cells promoted cell growth. Mechanistically, lactate dehydrogenase A (LDHA) acted as a downstream target of RBM15. RBM15-mediated m6A modification of LDHA mRNA enhanced its stability to exert an oncogenic role in LUAD. Taken together, our findings suggest that the RBM15/LDHA axis might be a novel and promising therapeutic target for LUAD., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Eutrophication is one of the most important factors for the increasing production of organic carbon in inland waters. Variations in primary productivity across lakes due to eutrophication complicate predictions regarding future carbon burial and management of carbon sequestration in lakes. Phosphorus, an essential nutrient for plants and notorious for eutrophication, often limits primary productivity in lakes. It is crucial to normalize organic carbon burial to the content of total phosphorus (TP) in the water column to compare the inherent carbon burial capacity across lakes. However, the absence of long-term observational data of TP in lake water columns has hindered the ability to do so. In this study, we first verified that TP in sediments of Chinese lakes could substitute for that in the water column to reflect the annual primary productivity of lakes. Then we defined the inherent carbon burial potential of lakes as the total organic carbon to TP atomic ratio (TOC/TP) in the sediments. We quantified the inherent carbon burial potential of 90 lakes across China, exploring its spatial distribution, temporal trends, and potential controlling factors. The inherent carbon burial potential, based on surface sediments, decreased from western to eastern China, ranging from 466.1 to 24.3 with a mean of 137.0 ± 87.4. Mean annual precipitation was negatively related, while mean lake depth was positively related to the inherent carbon burial potential of the lakes across China. Analysis of sediment cores revealed that the mean inherent carbon burial potential of the lakes across China increased from 75.1 to 122.9 since the 1950s. Inherent carbon burial potential of the lakes in southwestern and eastern China, however, decreased since the 1990s. Changes in the extent of cultivated land in the watersheds were positively related to variations in the inherent carbon burial potential of Chinese lakes in the past few decades., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Podocyte injury plays an important role in the occurrence and progression of diabetic kidney disease (DKD), which leads to albuminuria. Cytoskeletal remodeling is an early manifestation of podocyte injury in DKD. However, the underlying mechanism of cytoskeletal remodeling has not been clarified. Histone deacetylase sirtuin6 (Sirt6) has been found to play a key role in DKD progression, and the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) pathway directly regulates the cytoskeletal structure of podocytes. Whereas, the relationship between Sirt6, the PI3K/AKT pathway and DKD progression remains unclear., Methods: Renal injury of db/db mice was observed by PAS staining and transmission electron microscope. Expression of Sirt6 in the glomeruli of db/db mice was detected by immunofluorescence. UBCS039, a Sirt6 activator, was used to explore the renal effects of Sirt6 activation on diabetic mouse kidneys. We also downregulating Sirt6 expression in podocytes using the Sirt6 inhibitor, OSS_128167, and induced upregulation of Sirt6 using a recombinant plasmid, after which the effects of Sirt6 on high glucose (HG)-induced podocyte damage were assessed in vitro . Podocyte cytoskeletal structures were observed by phalloidin staining. The podocyte apoptotic rate was assessed by flow cytometry, and PI3K/AKT signaling activation was measured by Western blotting., Results: Db/db mice exhibited renal damage including elevated urine albumin-to-creatinine ratio (ACR), increased mesangial matrix, fused podocyte foot processes, and thickened glomerular basement membrane. The expression of Sirt6 and PI3K/AKT pathway components was decreased in db/db mice. UBCS039 increased the expressions of Sirt6 and PI3K/AKT pathway components and ameliorated renal damage in db/db mice. We also observed consistent Sirt6 expression was in HG-induced podocytes in vitro . Activation of the PI3K/AKT pathway via a Sirt6 recombinant plasmid ameliorated podocyte cytoskeletal remodeling and apoptosis in HG-treated immortalized human podocytes in vitro , whereas Sirt6 inhibition by OSS_128167 accelerated HG-induced podocyte damage in vitro ., Conclusions: Sirt6 protects podocytes against HG-induced cytoskeletal remodeling and apoptosis through activation of the PI3K/AKT signaling pathway. These findings provide evidence supporting the potential efficacy of Sirt6 activation as a promising therapeutic strategy for addressing podocyte injury in DKD.

Objective: To evaluate clinical, pathological and gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (Gd-EOB-DTPA-enhanced MRI) findings of hepatocellular carcinoma (HCC) in non-cirrhotic livers and compare with HCC in cirrhotic livers., Methods: This retrospective study included patients with pathologically confirmed HCC who underwent preoperative Gd-EOB-DTPA-enhanced MRI between January 2015 and October 2021. Propensity scores were utilized to match non-cirrhotic HCCs (NCHCCs) patients with cirrhotic HCCs (CHCCs) patients. The clinical, pathological and MR imaging features of NCHCCs were compared with CHCCs. Correlation between these features and the presence of NCHCCs were analyzed by logistic regression analysis. The predictive efficacy was evaluated using receiver operating characteristic (ROC) analysis. The area under the receiver operating characteristic curve (AUC) was used to compare performance, and the Delong test was used to compare AUCs., Results: After propensity score matching (1:3), a total of 144 patients with HCCs (36 NCHCCs and 108 CHCCs) were included. NCHCCs were larger in tumor size than CHCCs (P < 0.001, Cohen's d = 0.737). NCHCCs were more common in patients who have hepatitis C (5.6 % vs 1.9 %, P > 0.05) or have no known liver disease (11.1 % vs 0.9 %, P = 0.004), while hepatitis B was more common in CHCC patients (83.3 % vs 97.2 %, P = 0.003). Compared with CHCCs, NCHCCs more frequently demonstrated non-smooth tumor margin (P = 0.001, Cramer's V = 0.273), peri-tumoral hyperintensity (P < 0.05, Cramer's V = 0.185), hyperintense and heterogeneous signals in hepatobiliary phase (HBP) (P < 0.05). CHCCs were more likely to have satellite nodules compared to NCHCCs (33.3 % vs 57.4 %, P < 0.05, Cramer's V = 0.209). Based on the univariate and multivariate logistic regression analysis, the tumor size, non-smooth tumor margin, heterogeneous intensity in HBP and satellite nodule were significantly correlated to NCHCCs (P all <0.05). ROC curve analysis demonstrated that tumor size and non-smooth tumor margin were potential imaging predictors for the diagnosis of NCHCC, with AUC values of 0.715 and 0.639, respectively. The combination of the two imaging features for identifying NCHCC achieved an AUC value of 0.761, with a sensitivity of 0.889 and a specificity of 0.630., Conclusion: NCHCCs were more likely to show larger tumor size, non-smooth tumor margin, peri-tumoral hyperintensity, as well as hyperintense and heterogeneous signals in HBP at Gd-EOB-DTPA-enhanced MR imaging compared with NCHCCs. Tumor size and non-smooth tumor margin in HBP may help to discriminate NCHCCs., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Sulfate is the second most common nonmetallic ion in modern oceans, as its concentration dramatically increased alongside tectonic activity and atmospheric oxidation in the Proterozoic. Microbial sulfate/sulfite metabolism, involving organic carbon or hydrogen oxidation, is linked to sulfur and carbon biogeochemical cycles. However, the coevolution of microbial sulfate/sulfite metabolism and Earth's history remains unclear. Here, we conducted a comprehensive phylogenetic analysis to explore the evolutionary history of the dissimilatory sulfite reduction (Dsr) pathway. The phylogenies of the Dsr-related genes presented similar branching patterns but also some incongruencies, indicating the complex origin and evolution of Dsr. Among these genes, dsrAB is the hallmark of sulfur-metabolizing prokaryotes. Our detailed analyses suggested that the evolution of dsrAB was shaped by vertical inheritance and multiple horizontal gene transfer events and that selection pressure varied across distinct lineages. Dated phylogenetic trees indicated that key evolutionary events of dissimilatory sulfur-metabolizing prokaryotes were related to the Great Oxygenation Event (2.4-2.0 Ga) and several geological events in the "Boring Billion" (1.8-0.8 Ga), including the fragmentation of the Columbia supercontinent (approximately 1.6 Ga), the rapid increase in marine sulfate (1.3-1.2 Ga), and the Neoproterozoic glaciation event (approximately 1.0 Ga). We also proposed that the voluminous iron formations (approximately 1.88 Ga) might have induced the metabolic innovation of iron reduction. In summary, our study provides new insights into Dsr evolution and a systematic view of the coevolution of dissimilatory sulfur-metabolizing prokaryotes and the Earth's environment., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The purpose of this study was to investigate the relationship between childhood chronic stress(CCS), Protein kinase C beta (PRKCB) methylation and adolescent major depressive disorder (MDD). After recruiting 100 adolescents with MDD and 50 healthy controls (HCs), we evaluated the severity of CCS. PRKCB methylation was assessed by pyrosequencing using whole blood-derived DNA. To explore the relationship between CCS, PRKCB and adolescent MDD, we conducted correlation analysis and regression analysis, and constructed multiplicative interaction models and generalized linear models. PRKCB methylation and CCS were both found to be associated with MDD, and CCS was associated with PRKCB methylation. No significant CCS-PRKCB methylation interactions were observed. However, we found the interaction of CCS and MDD on PRKCB methylation. Our results found that PRKCB methylation was influenced by CCS and the disease itself, and PRKCB methylation was significantly positively associated with MDD severity, suggesting that PRKCB methylation may be a potential biomarker for adolescent MDD. This study is a cross-sectional observational study, which cannot draw the conclusion of causality. Prospective cohort studies are needed to further examine the relationship between CCS, adolescent MDD, and PRKCB methylation.

Transgenic glyphosate-resistant maize has emerged as a way to expand the use of glyphosate for weed control. Studying the microbiome in the tissues and rhizosphere soil of transgenic plants is vital for understanding the glyphosate-resistant mechanism and optimizing the transgenic design of crops. In our study, the expression of a mutant cp4epsps gene in transgenic maize, which confers tolerance to glyphosate, was performed using the maize variety Xianyu 335 as the genetically modified acceptor line. This transgenic modification did not affect the initial bacterial community in the leaf, stem, or root of maize, but promoted a differential bacterial community in the rhizosphere soil. Under glyphosate application, the abundance of beneficial bacteria involved in N fixation and P solubilization in plant tissues and the rhizosphere soil of glyphosate-resistance maize were higher than those in the glyphosate-sensitive maize. In contrast, the abundance of pathogens had the opposite trend, suggesting that the enhanced health of transgenic maize prevented microbiome deterioration under glyphosate. The re-inoculation of bacterial strains isolated from glyphosate-resistance maize into the leaf and rhizosphere soil of glyphosate-sensitive maize resulted in an enhanced photosynthetic capacity in response to glyphosate, demonstrating the vital role of specific bacteria for glyphosate resistance. Our study provides important evidence of how transgenic maize tolerance to herbicides affects the bacterial communities across the maize niches under glyphosate toxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The impact of nitrogen (N) and phosphorus (P) on the physiological and biochemical processes crucial for tree seedling growth is substantial. Although the study of plant hydraulic traits in response to N and P is growing, comprehensive research on their combined effects remains limited. Malus sieversii, a key ancestral species of modern apples and a dominant species in Xinjiang's Tianshan wild fruit forest, is witnessing a decline due to climate change, pests and diseases, compounded by challenges in seedling regeneration. Addressing this, a 4-year study was conducted to determine the optimal fertilisation method for it. The experiment explored varying levels of N (N10, N20 and N40) and P (P2, P4 and P8), and their combined effects (N20Px: N20P2, N20P4, N20P8; NxP4: N10P4, N20P4 and N40P4), assessing their impact on gas exchange, hydraulic traits, and the interplay among functional traits in Tianshan Mountains' M. sieversii seedlings. Our study revealed that All N-inclusive fertilisers slightly promoted the net photosynthetic rate. N10 significantly increasing leaf hydraulic conductivity. All P-inclusive fertilisers adversely affected hydraulic conductivity. P8, N20P4 and N20P8 notably increased seedlings' vulnerability to embolism. Seedlings can adaptively adjust multiple functional traits in response to nutrient changes. The research suggests N10 and N20 as the most effective fertilisation treatments for M. sieversii seedlings in this region, while fertilisation involving phosphorus is less suitable. This study contributes valuable insights into the specific nutrient needs of it, vital for conservation and cultivation efforts in the Tianshan region., (© 2024 John Wiley & Sons Ltd.)

Homocysteine (Hcy) is a metabolic intermediate product derived from methionine. Hyperhomocysteinemia is a condition associated with various diseases. Hcy is recognized as a risk factor for cardiovascular disease (CVD). Ferroptosis, a novel form of cell death, is primarily characterized by substantial iron accumulation and lipid peroxidation. Recent research indicates a close association between ferroptosis and the pathophysiological processes of tumors, neurological diseases, CVD, and other ailments. However, limited research has been conducted on the impact of Hcy on ferroptosis. Therefore, this paper aimed to investigate the potential roles and mechanisms of homocysteine and ferroptosis in the context of cardiovascular disease. By conducting comprehensive literature research and analysis, we aimed to summarize recent advancements in understanding the effects of homocysteine on ferroptosis in cardiovascular diseases. This research contributes to a profound understanding of this critical domain., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Immunotherapy through the activation of the stimulator of interferon genes (STING) signaling pathway is increasingly recognized for its robust anti-tumor efficacy. However, the effectiveness of STING activation is often compromised by inadequate anti-tumor immunity and a scarcity of primed immune cells in the tumor microenvironment. Herein, we design and fabricate a co-axial 3D-printed scaffold integrating a non-nucleotide STING agonist, SR-717, and an AKT inhibitor, MK-2206, in its respective shell and core layers, to synergistically enhance STING activation, thereby suppressing tumor recurrence and growth. SR-717 initiates the STING activation to enhance the phosphorylation of the factors along the STING pathway, while MK-2206 concurrently inhibits the AKT phosphorylation to facilitate the TBK1 phosphorylation of the STING pathway. The sequential and sustained release of SR-717 and MK-2206 from the scaffold results in a synergistic STING activation, demonstrating substantial anti-tumor efficacy across multiple tumor models. Furthermore, the scaffold promotes the recruitment and enrichment of activated dendritic cells and M1 macrophages, subsequently stimulating anti-tumor T cell activity, thereby amplifying the immunotherapeutic effect. This precise and synergistic activation of STING by the scaffold offers promising potential in tumor immunotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The functionality of activated sludge in wastewater treatment processes depends largely on the structural and microbial composition of its flocs, which are complex assemblages of microorganisms and their secretions. However, monitoring these flocs in real-time and consistently has been challenging due to the lack of suitable technologies and analytical methods. Here we present a laboratory setup capable of capturing instantaneous microscopic images of activated sludge, along with algorithms to interpret these images. To improve floc identification, an advanced Mask R-CNN-based segmentation that integrates a Dual Attention Network (DANet) with an enhanced Feature Pyramid Network (FPN) was used to enhance feature extraction and segmentation accuracy. Additionally, our novel PointRend module meticulously refines the contours of boundaries, significantly minimising pixel inaccuracies. Impressively, our approach achieved a floc detection accuracy of >95%. This development marks a significant advancement in real-time sludge monitoring, offering essential insights for optimising wastewater treatment operations proactively., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Objective: Preeclampsia (PE) increases the risk of many adverse maternal and fetal outcomes. This study was to investigate the correlation between epicardial adipose tissue (EAT) thickness and PE and birth weight., Methods: This was a single-center retrospective study, 221 patients with PE were selected, and 81 women without hypertension and proteinuria were selected as a comparison. Echocardiogram was performed in their first prenatal examinations at 11-13 gestational weeks, and the thickness of EAT was measured. At the subsequent follow-up, the birth weight was recorded., Results: EAT thickness was significantly elevated (6.60 ± 1.34 vs. 5.71 ± 1.79 mm, p  < 0.001) in severe PE compared to mild PE. In the multivariate analysis, EAT thickness (OR 5.671, 95% CI, 1.991-16.150, p  = 0.001), and C reactive protein (OR 4.097, 95% CI, 2.323-7.224, p  < 0.001) were found as significant independent predictors of severe PE after adjusting for other risk factors. Linear regression analysis showed that hs-CRP, EAT thickness, and severe PE significantly negatively affected birth weight., Conclusion: EAT thickness can be used to identify pregnant women with severe PE risks and low birth weight. It is an independent risk factor for severe PE but is not a valuable sign of mild PE.

Objective: This study aimed to investigate the impact of serum androgen levels on metabolic profiles in patients with polycystic ovary syndrome (PCOS)., Methods: We included 216 patients with PCOS and 216 healthy individuals selected as the control group. According to the measured serum androgen levels, patients with PCOS were divided into the hyperandrogenism group and non-hyperandrogenism group. Clinical metabolic indicators were assessed and compared between the two groups. Additionally, we assessed the correlation between androgen levels and clinical metabolic indicators., Results: The body mass index, waist-to-hip ratio, mF-G score, and acne score, as well as T, LH, LSH/FSH, FPG, Cr, UA, TG, TC, and LDL-C levels were significantly higher in the PCOS group than in the control group. The incidence of hyperandrogenism and clinical hyperandrogenism in the PCOS group was significantly higher than that in the control group. Regarding clinical hyperandrogenism, hirsutism, acne, and acanthosis nigricans were significantly more common in the PCOS group than in the control group. Serum androgen levels were significantly correlated with the mF-G score, acne score, FSH, glucose concentration at 30 min, glucose concentration at 60 min, glucose concentration at 120 min, FINS, N120, HOMA-IR, HbA1c, AUCG, UA, TG, and hHDL-Clevels., Conclusion: Elevated serum androgen levels are commonly observed in patients with PCOS and are associated with multiple metabolic abnormalities. Therefore, it is recommended to regularly monitor glucose and lipid metabolism-related indicators in patients with PCOS who have elevated androgen levels.

Antibody-drug conjugates (ADCs) have emerged as a novel class of targeted cancer therapies and been successfully applied in the treatment of breast cancer (BC). Discoidin domain receptor 1 (DDR1) is a single transmembrane receptor tyrosine kinase and has been identified as a possible target for cancer. In this study, we explored the potential of an anti-DDR1 ADC, named T 4 H 11 -DM4, for the treatment of DDR1-positive BC. We demonstrated that high protein expression and RNA expression of DDR1 in BC tissues. In vitro , T 4 H 11 -DM4 was potently cytotoxic to DDR1-expressing BC cells, with IC50 in the nanomolar range. In mice BC xenograft models, T 4 H 11 -DM4 dramatically eliminated BC tumours, without observable toxicity. Taken together, our findings demonstrated that DDR1 can serve as a promising therapeutic target for BC.

Basic standard samples are integral for ensuring consistency and quality control of tea. Understanding the real reasons behind the hierarchical system of Shuixian tea grades in the Chinese national standard is crucial to the scientific development of tea standardization. In this investigation, different grade samples of Shuixian tea strictly conformed to the Chinese national standard, serving as the research objects. Sensory evaluation, SEM and HS-SPME-GC-MS were employed to comprehensively analyze the aroma characteristics. The odor profiles of special grade samples predominantly featured floral and fruity aromas, which attributed to compounds such as geraniol, indole, phenylethyl alcohol. Additionally, hexanal, (E)-3-hexen-1-ol and other compounds contributed to fruity and sweet aroma in first grade. Notably, the predominant roasted and sweet aromas of second grade were attributed to compounds including pyridine, 2,5-dimethyl-pyrazine. This study lays a solid foundation for the scientific development of Chinese national standards and international standard system., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The innate immune system serves as the body's initial defense, swiftly detecting danger via pattern recognition receptors (PRRs). Among these, nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing proteins (NLRPs) are pivotal in recognizing pathogen-associated and damage-associated molecular patterns, thereby triggering immune responses. NLRPs, the most extensively studied subset within the NLR family, form inflammasomes that regulate inflammation, essential for innate immunity activation. Recent research highlights NLRPs' significant impact on various human diseases, including cancer. With differential expression across organs, NLRPs influence cancer progression by modulating immune reactions, cell fate, and proliferation. Their clinical significance in cancer makes them promising therapeutic targets. This review provides a comprehensive overview of the structure, function, activation mechanism of the NLRPs family and its potential role in cancer progression. In addition, we particularly focused on the concept of NLRP as a therapeutic target and its potential value in combination with immune checkpoint inhibitors., Competing Interests: Declaration of competing interest All of the authors have indicated that they have no competing interests in the content of the article. This manuscript has been read and approved by all authors and is not under consideration for publication elsewhere., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Developing approaches to induce noncentrosymmetric (NCS) frameworks through atomic-scale structural optimizations is crucial due to the growing need for new ultraviolet (UV) nonlinear optical (NLO) materials. Herein, the first two new NCS pyridine carboxylates, ZnBr(C 6 H 3.5 FNO 2 ) 2 ( 1 ) and Cd(C 6 H 3 FNO 2 ) 2 (H 2 O) 2 ( 2 ), were successfully synthesized using centrosymmetric (CS) templates and rational structural reconstructions induced by different ionic radius. Both compounds crystallize in the orthorhombic system and feature metal-centered zero-dimensional (0D) isolated clusters. Substituting the [ZnO 2 N 2 O] pyramid in the CS pyridine carboxylate with the [ZnO 2 N 2 Br] pyramid in compound 1 breaks the centrality, leading to an NCS framework with a second harmonic generation (SHG) response of 1.7 × KH 2 PO 4 (KDP). Introducing a larger Cd 2+ cation results in a trans -to- cis transition of the [MO 4 N 2 ] (M = Zn, Co, and Ni in CS templates, Cd in 2 ) octahedra, forming a wing-shaped asymmetric 0D cluster with an SHG response of 2.1 × KDP. These findings indicate an approach that can effectively induce NCS structures of 0D organic-inorganic hybrid materials.

Understanding the carbon cycling process and assessing the carbon sequestration potential in freshwater lakes relies heavily on their source-sink relationship. However, human activity and climate change have obscured the clarity of this relationship and its driving mechanisms, particularly in northern grassland lakes. This study focused on Hulun Lake, the largest grassland lake in northern China, to quantitatively analyze the carbon dioxide exchange flux (FCO2) at the water-air interface from 1963 to 2023. The analysis revealed significant seasonal, interannual, and decadal variations in the FCO2. Over the past 60 years, FCO2 varying significant in seasons and years has notably decreased, averaging 0.324 ± 0.106 gC·m -2 ·d -1 . Notably, there was a qualitative change in FCO2 from "sink" (0.161 ± 0.109 gC·m -2 ·d -1 ) to "source" (-0.130 ± 0.087 gC·m -2 ·d -1 )between 2019 and 2020. From 1963 to 2019, the lake acted as a CO 2 source, releasing an average flux of 0.438 ± 0.111 gC·m -2 ·d -1 . During this period, FCO2 was the highest in spring, followed by summer, and the lowest in autumn and winter when the lake was covered by ice. In 2020, the lake transitioned into a CO 2 sink with an average FCO2 of -0.248 ± 0.042 gCm -2 ·d -1 from 2020 to 2023. During this period, FCO2 peaked in autumn, followed by summer and spring, and was lowest in winter when the lake was ice covered. A structural model equation (SEM) was employed to analyze the effects of various factors, including physical, chemical, and biological aspects, on FCO2 and the source-sink pattern of Hulun Lake. This study suggested that lake eutrophication, compounded by global warming, may be the primary driving force behind these changes. Rising temperatures and eutrophication enhanced the primary productivity of the lake. The amount of CO 2 fixed through photosynthesis surpassed that emitted by respiration. Consequently, the eutrophication may alter the CO 2 exchange pattern in Hulun Lake, shifting it from a "source" to a "sink"., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: This study aimed to evaluate the acceptability and effects of internet-based cognitive behavioral therapy (iCBT) or CBT-oriented interventions compared with control groups on depressive symptoms, remission of depression, and quality of life (QOL) in adolescents., Methods: We searched English and Chinese databases for randomized controlled trials up to October 10, 2024 that investigated the effects of iCBT compared with controls in adolescents exhibiting elevated depressive symptoms or diagnosed with depression. Standardized mean differences (SMDs), relative risks (RRs), and 95% confidence intervals were applied to evaluate the pooled effects of outcomes., Results: A total of 19 RCTs involving 3574 cases were included in this study. We found small effects on depressive symptoms severity at different time points (posttest: SMD = -0.49 [-0.66, -0.33]; 3-month follow-up [FU3]: SMD = -0.21 [-0.30, -0.11]; FU6: SMD = -0.18 [-0.35, -0.02]; FU12: SMD = -0.38 [-0.56, -0.20]). We also found a significant effect in depression remission rate at the posttest (RR = 1.74 [1.36, 2.21]) and a significant effect in QOL at the posttest (SMD = 0.30 [0.07, 0.54]). However, the result regarding acceptability was nonsignificant (RR = 1.22 [0.76, 1.97]). No significant publication bias was found in these results., Conclusion: iCBT or internet-based CBT-oriented interventions can effectively reduce depressive symptom severity and improve depression remission rate and QOL in depressed adolescents. These results are preliminary and require further validation through future systematic reviews., (© 2024 Chinese Cochrane Center, West China Hospital of Sichuan University and John Wiley & Sons Australia, Ltd.)

Gain-of-function (GOF) variants, which introduce new or amplify protein functions, are essential for understanding disease mechanisms. Despite advances in genomics and functional research, identifying and analyzing pathogenic GOF variants remains challenging owing to fragmented data and database limitations, underscoring the difficulty in accessing critical genetic information. To address this challenge, we manually reviewed the literature, pinpointing 3089 single-nucleotide variants and 72 insertions and deletions in 579 genes associated with 1299 diseases from 2069 studies, and integrated these with the 3.5 million predicted GOF variants. Our approach is complemented by a proprietary scoring system that prioritizes GOF variants on the basis of the evidence supporting their GOF effects and provides predictive scores for variants that lack existing documentation. We then developed a database named GoFCards for general geneticists and clinicians to easily obtain GOF variants in humans (http://www.genemed.tech/gofcards). This database also contains data from >150 sources and offers comprehensive variant-level and gene-level annotations, with the aim of providing users with convenient access to detailed and relevant genetic information. Furthermore, GoFCards empowers users with limited bioinformatic skills to analyze and annotate genetic data, and prioritize GOF variants. GoFCards offers an efficient platform for interpreting GOF variants and thereby advancing genetic research., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Sepsis is a severe systemic inflammatory syndrome triggered by infection and is a leading cause of morbidity and mortality in intensive care units (ICUs). Immune dysfunction is a hallmark of sepsis. In this study, the authors investigated cell-cell communication among lymphoid-derived leucocytes using single-cell RNA sequencing (scRNA-seq) to gain a deeper understanding of the underlying mechanisms in late-stage sepsis. The authors' findings revealed that both the number and strength of cellular interactions were elevated in septic patients compared to healthy individuals, with several pathways showing significant alterations, particularly in conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs). Notably, pathways such as CD6-ALCAM were more activated in sepsis, potentially due to T cell suppression. This study offers new insights into the mechanisms of immunosuppression and provides potential avenues for clinical intervention in sepsis., (© 2024 The Author(s). IET Systems Biology published by John Wiley & Sons Ltd on behalf of The Institution of Engineering and Technology.)

Inappropriate CD4 + T helper (T H ) cell differentiation leads to progression of inflammatory and autoimmune diseases, yet the regulatory mechanisms governing stability and activity of transcription factors controlling T H cell differentiation remain elusive. Here, we describe how pseudokinase serine threonine kinase 40 (STK40) facilitates T H 1/T H 17 differentiation under pathological conditions. STK40 in T cells is dispensable for immune homeostasis in resting mice. However, mice with T cell-specific deletion of STK40 exhibit attenuated symptoms of experimental autoimmune encephalomyelitis and colitis, accompanied by diminished T H 1 and T H 17 cell differentiation. Mechanistically, STK40 facilitates K48-linked polyubiquitination and proteasomal degradation of FOXO1/4 through promoting their interaction with E3 ligase COP1. Inhibition of FOXO4 or FOXO1, respectively, restores differentiation potential of STK40-deficient T H 1/T H 17 cells. Together, our data suggest a crucial role of STK40 in T H 1 and T H 17 cell differentiation, thereby enabling better understanding of the molecular regulatory network of CD4 + T cell differentiation and providing effective targets for the treatment of autoimmune diseases.

Background: Pulmonary hemorrhage (PH) in respiratory distress syndrome (RDS) in extremely preterm infants exhibits a high mortality rate and poor long-term outcomes. The aim of the present study was to develop a machine learning (ML) predictive model for RDS with PH in extremely preterm infants., Methods: We performed a retrospective analysis of extremely preterm infants with RDS at the Children's Hospital of Soochow University between January 2015 and January 2021. We applied three ML algorithms-logistic regression (LR), random forest (RF), and extreme gradient boosting (XGBoost)-to evaluate the performance of each model using the area under the curve (AUC), and developed a predictive model based on the optimal model. We calculated SHapley Additive exPlanations (SHAP) values to determine variables importance and show visualization results, and constructed a nomogram for individualized prediction., Results: A total of 309 patients with RDS were enrolled, including 48 (15.5%) with PH. A total of 29 variables were collected, including demographic and clinical characteristics, laboratory data, and image classification. According to the AUC values, the RF model performed best (AUC = 0.868). Based on the SHAP values, the top five important variables in the RF model were gestational age, PaO 2 /FiO 2 , birth weight, mean platelet volume, and Apgar score at 5 min., Conclusions: Our study showed that the RF model could be used to predict the risk of PH in RDS in extremely preterm infants. The nomogram provides clinicians with an effective tool for early warning and timely management., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Ethics Committee of the Children’s Hospital of Soochow University (no. 2015010512), which waived the informed consent requirement because of the retrospective nature of the study and minimal risk to participants. All methods were carried out in accordance with relevant guidelines and regulations. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Graphene has been widely studied as an ideal material for the adsorption and separation. In this work, we used molecular dynamics simulations to investigate the evolution of diffusion and local structure of CH 4 , CO 2 , SO 2 , and H 2 O mixtures into double-layers graphene under seven different interlayer spacings and four different CO 2 concentrations. The results showed that the adsorption of CH 4 and CO 2 molecules on the graphene surface weakened with increased interlayer spacing. The diffusion capacities of CH 4 and CO 2 in the mixed system were significantly improved by increasing the interlayer spacing. In interlayer spacings ranging from 5 to 10 nm, the diffusion capacities of each component varied significantly in the order CH 4 > CO 2 ≫ H 2 O > SO 2 . Compared with CH 4 and CO 2 , the local structures of SO 2 and H 2 O were more affected by the interlayer spacing. Larger interlayer spacings or higher CO 2 concentrations were advantageous for the formation of stronger hydrogen bond structures between H 2 O molecules. When the CO 2 concentrations were between 10% and 20% and the interlayer spacing of graphene was 8 nm, the graphene structure exhibited the best adsorption and separation effects on CH 4 and other components.

Hydrogel-forming microneedle (MN) arrays are minimally-invasive devices that can penetrate the stratum corneum, the main barrier to topical drug application, without causing pain. However, drug delivery using hydrogel-forming MN arrays tends to be relatively slow compared to rapid drug delivery using conventional needles and syringes. Therefore, in this work, for the first time, different physical and chemical delivery enhancement methods were employed in combination with PVA-based hydrogel-forming MN arrays. Using a model drug, ibuprofen (IBU) sodium, the designed systems were assessed in terms of the extent of transdermal delivery. Iontophoresis (ITP) and heat-assisted drug delivery technology were investigated as physical permeation enhancement techniques. Ex vivo studies demonstrated that the ITP (0.5 mA/cm 2 )-mediated combination strategy significantly enhanced the transdermal permeation of IBU sodium over the first 6 h (~ 5.11 mg) when compared to MN alone (~ 1.63 mg) (p < 0.05). In contrast, heat-assisted technology showed almost no promoting effect on transdermal delivery. Furthermore, IBU sodium-containing rapidly dissolving lyophilised and effervescent reservoirs, classified as chemical modification methods, were prepared. Both strategies achieved rapid and effective ex vivo IBU sodium permeation, equating to ~ 78% (30.66 mg) and ~ 71% (28.43 mg) from lyophilised and effervescent reservoirs, respectively. Moreover, in vivo pharmacokinetic studies showed that the IBU sodium plasma concentration within lyophilised and effervescent groups reached a maximum concentration (C max ) at 4 h (~ 282.15 µg/mL) and 6 h (~ 140.81 µg/mL), respectively. These strategies not only provided rapid achievement of therapeutic levels (10-15 µg/ml), but also resulted in sustained release of IBU sodium for at least 48 h, which could effectively reduce the frequency of administration, thereby improving patient compliance and reducing side effects of IBU sodium., Competing Interests: Declarations. Ethics approval and consent to participate:  All institutional and national guidelines for the care and use of laboratory animals were followed.  Consent for publication : All authors have approved the final version of the manuscript.  Competing interest:  Ryan Donnelly is an inventor of patents that have been licensed to companies developing microneedle-based products and is a paid advisor to companies developing microneedle-based products. The resulting potential conflict of interest has been disclosed and is managed by Queen’s University Belfast. The companies had no role in the design of the manuscript, in the collection, analyses, or interpretation of the various studies reviewed, in the writing of the manuscript, or in the decision to publish.  All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024. The Author(s).)

Background: The present study aimed to investigate changes in intranetwork functional connectivity (FC) and internetwork FC in middle-aged and elderly individuals with normal cognition (NC) and varying degrees of periodontitis to determine the effects of periodontitis on brain function., Methods: Periodontal findings and resting-state functional magnetic resonance imaging data were acquired from 51 subjects with NC. Independent component analysis and correlation analysis were used for the statistical analysis of the data., Results: Differences in intranetwork FC were observed among groups in the anterior default-mode network (aDMN), dorsal attention network and dorsal sensorimotor network (dSMN). Compared with the nonperiodontitis (NP) group or the mild-periodontitis group, the analysis of internetwork FC showed increased FC between the auditory network and the ventral attention network (VAN), between the aDMN and the salience network (SN), and between the SN and the VAN and decreased FC between the posterior default-mode network and the right frontoparietal network in the moderate-to-severe periodontitis group. Additionally, internetwork FC between the dSMN and the VAN was also increased in the moderate-to-severe periodontitis group compared to the NP group. The altered intra- and internetwork FC were significantly correlated with the periodontal clinical index., Conclusion: Our results confirmed that periodontitis was associated with both intra- and internetwork FC changes even in NC. The present study indicates that periodontitis might be a potential risk factor for brain damage and provides a theoretical clue and a new treatment target for the early prevention of Alzheimer disease., Plain Language Summary: Recent research has proposed that periodontitis is a potential risk factor for Alzheimer disease (AD). However, the relationship between periodontitis and the brain function of middle-aged and elderly individuals with normal cognition (NC) remains unclear. Analyzing the effect of periodontitis on brain function in the NC stage can provide clues to AD development and help achieve early prevention of dementia. The present study aimed to investigate changes in brain functional connectivity (FC) in NC with different severity of periodontitis to determine the effects of periodontitis on brain function. Both changed intranetwork FC and internetwork FC were found in the moderate-to-severe periodontitis group, and periodontitis was associated with brain network function impairment in NC. The present study indicates that periodontitis might be a potential risk factor for brain damage even in NC stage, and provides a theoretical clue and a new treatment target for the early prevention of AD., (© 2024 American Academy of Periodontology.)

The peptide-drug conjugate (PDC) has emerged as one of the new approaches for cancer therapy, which has the advantages of improved drug target ability and reduced adverse effects compared with the traditional chemotherapy. CD133 is a surface antigen specific to cancer stem cells, which are thought to be responsible for the self-renewal, proliferation, metastasis, and chemoresistance of cancer cells. A PDC for CD133 was designed by us, and it consists of CD133 targeting peptide LS-7 (amino acid sequence LQNAPRS), a pH-sensitive linker (succinyl), and a cytotoxic payload, the cytotoxic molecule camptothecin (CPT) with potent toxicity in vivo and in vitro. An antitumor study exhibited that the conjugate LS-7-CPT has not only improved its cytotoxicity in tumor cells but also retained its anticancer effect in vivo. In addition, the acute toxicity in mice of LS-7-CPT has been improved and the maximum tolerated dose has been increased by at least 56.2-fold. Pull-down and in vivo fluorescent imaging results indicated that LS-7-CPT was enriched in mice tumors by targeting CD133 protein. As far as we know, this is the first report for a PDC molecule designed for CD133, which is important for the study of CPT drug development.

High sensitivity and high quality-factor are crucial for achieving outstanding sensing performance in photonic biosensors. However, strong optical field confinement and high light-biomolecule interactions on photonic surfaces are usually contradictory and challenging to satisfy simultaneously. Here, a distinctive configuration for addressing this issue is reported: embedding a nanophotonic metasurface inside a micro vertical cavity as a meta-channel (metacavity) biosensor. The analyte solution serves as the cavity medium, thereby maximizing the light-analyte interaction. Simulation validation is conducted to optimize the metacavity with high structural robustness and remarkable optical and sensing properties. Large-scale low-cost metacavity biosensors are realized by combining anodic aluminum oxide template technique and wafer bonding. Experimentally, the metacavity biosensor demonstrates a notable quality-factor (maximum 4140) and high bulk refractometric sensitivity (450 nm RIU -1 ), resulting in an unprecedented figure-of-merit (1670 RIU -1 ). Moreover, the metacavity biosensor achieves high surface sensitivity, together with a detection-limit of 119 viral copies mL -1 for label-free severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudovirus sensing, revealing remarkable performance in both bulk and surface sensing., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Linear substituents, despite their simpler structures compared to heterocyclic ones, exhibit distinct chemical behaviors. Using sulfacetamide (SAM) and sulfaguanidine (SGD) as model compounds, we assessed the impact of these substituents on degradation efficiency, active species identification, reaction pathways, and intermediate toxicity during electrooxidation in water. Through density functional theory, we elucidated the mechanisms, focusing on electronic structural changes and interactions with active species. Notably, the acetyl group in SAM (0.1016) acquired more electrons than the guanidyl group in SGD (0.0281), resulting in SAM having a higher free energy change (ΔG=15.06kcal/mol) compared to SGD (ΔG=9.59kcal/mol). This difference makes SAM less likely to undergo direct electron transfer and less reactive towards hydroxyl radical addition, leading to slower degradation rates. The applied potential notably increased SAM's sensitivity to hydroxyl radicals. Both the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) were contributed by the parent fragment, facilitating electrophilic reactions mainly on the aniline part. Seventeen intermediate products and three major transformation pathways were identified, emphasizing aniline group destruction before discharge. This research enhances understanding of the degradation and environmental fate of sulfonamides, providing valuable insights for optimizing pollutant degradation and discharge reduction., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The relationship between nontraditional lipid profiles and type 2 diabetes mellitus (T2DM) remains ambiguous within the hypertension population. The objective of this study is to examine the association between nontraditional lipid profiles and T2DM in Chinese adults with hypertension. The current investigation encompassed 13 728 participants with hypertension from the China Hypertension Registry Study. Logistic regression analysis and smooth curve fitting were employed to evaluate the association between nontraditional lipid profiles and T2DM. The prevalence of T2DM was found to be 17.8%. In the fully adjusted model, atherogenic index of plasma (AIP) exhibited the highest odds ratios (ORs) for T2DM (OR: 2.71, 95% confidence interval [CI]: 2.26-3.26). Conversely, the fully adjusted ORs (95% CI) for total cholesterol (TC)/high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C)/HDL-C, and non-high-density lipoprotein cholesterol (Non-HDL-C) were 1.33 (1.25-1.41), 1.40 (1.29-1.51), and 1.41 (1.34-1.49), respectively. Additionally, the study demonstrated that AIP had a superior ability to identify T2DM. Subgroup analyses indicated that the relationship between AIP and Non-HDL-C with T2DM was more significant in the lighter weight population. In addition, the association of TC/HDL-C with LDL-C/HDL-C with T2DM was stronger in the lower homocysteine level population. Among the southern Chinese population with hypertension, all nontraditional lipid indices positively correlated with the risk of T2DM. Among these lipid indices, AIP exhibited superior discriminatory power in identifying T2DM compared to TC/HDL-C, LDL-C/HDL-C. Trial Registration: ChiCTR1800017274., (© 2024 The Author(s). The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Background: Nurses in dynamic healthcare environments face escalating challenges that impact their efficacy and well-being. These challenges arise from both the increasing complexity of medical procedures and the intense emotional demands of caregiving, often leading to compassion fatigue. A global prevalence of burnout at 30.0% was observed over the past decade. This study examines the relationship between structural empowerment, empathy (cognitive and affective), and compassion fatigue among Chinese nurses. Understanding these relationships is crucial for developing strategies to mitigate compassion fatigue. It also contributes to enhancing nurses' well-being., Methods: Conducted at a public hospital in Shanghai, this cross-sectional study surveyed 305 nurses, with 277 valid responses. Structural empowerment was measured using the Conditions for Work Effectiveness Questionnaire-II, empathy with the Kiersma-Chen Empathy Scale, and compassion fatigue with the Compassion Fatigue Short Scale. We performed correlation and mediation analyses to explore the direct and indirect effects of structural empowerment on compassion fatigue through empathy., Results: A significant negative direct effect of structural empowerment on compassion fatigue was evidenced by a coefficient of -0.165 (confidence interval: [-0.311, -0.013]). Further analysis revealed a negative indirect effect through cognitive empathy, indicated by an effect of -0.103 (confidence interval: [-0.220, -0.008]). Increased structural empowerment was linked to higher levels of cognitive empathy, which correlated with decreased compassion fatigue. Conversely, the mediation through affective empathy showed a positive indirect effect, indicated by an effect of 0.126 (confidence interval: [0.047, 0.229]). This suggests that higher structural empowerment was associated with increased affective empathy, leading to higher levels of compassion fatigue., Conclusion: The study illuminates the dual role of empathy within the framework of structural empowerment and its impact on compassion fatigue. Cognitive empathy serves as a protective factor, reducing susceptibility to compassion fatigue, while affective empathy appears to heighten vulnerability. These findings provide direct evidence supporting the dual processing pathways of empathy. It is recommended that healthcare policies integrate organizational support with targeted empathy training, such as cognitive reappraisal, emotion regulation, and peer support, to effectively counteract compassion fatigue among nurses. However, due to the cross-sectional nature and the single-hospital setting, the findings should be interpreted cautiously., Competing Interests: Declarations Ethics approval and consent to participate Ethics approval and consent to participate: Ethics approval was obtained from the institutional review board (IRB) of Shanghai Pudong New Area People’ s Hospital [Ref: 2021伦审K55号]. Informed consent was obtained from all subjects involved in the study. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Developing instant detection systems with disease diagnostic capabilities holds immense importance for remote or resource-limited areas. However, the task of creating these systems-which are simultaneously easy to operate, rapid in detection, and cost-effective-remains a challenge. In this study, we present a compact highly sensitive photothermal reverse transcriptase-loop-mediated isothermal amplification (RT-LAMP) chip (SPRC) designed for the detection of multiple diseases. The nucleic acid (NA) amplification on the chip is achieved through LAMP driven by either LED illumination or simple sunlight focusing. SPRC performs sample addition and amplification within a limited volume and autonomous enrichment of NA during the sample addition process, achieving a limit of detection (LOD) as low as 0.2 copies per microliter. Through 120 clinical samples, we achieved an accuracy of 95%, with a specificity exceeding 97.5%. Overall, SPRC has achieved promising progress in the application of point-of-care testing (POCT) by using light energy to simultaneously detect multiple diseases.

Hyperlipidemia and its associated cardiovascular complications are the major causes of mortality and disability worldwide. Simvastatin (SIM) is one of the most commonly prescribed lipid-lowering drugs for the treatment of hyperlipidemia by competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. However, the extensive first-pass metabolism leading to low oral bioavailability and frequent daily doses may lead to poor patient compliance and adverse effects caused by plasma fluctuations. To overcome these challenges, this work purposed two microneedle (MN) delivery strategies for the potential enhancement of SIM delivery. Firstly, nanocrystal (NC) formulations of SIM were investigated, followed by incorporation into a trilayer dissolving microneedle (DMN) design. Furthermore, a novel effervescent powder-carrying MN (EMN) design was developed to enhance intradermal delivery by incorporating the effervescent agents into the drug powder. Both MN approaches exhibited significantly improved permeation and in-skin deposition ability in the Franz cell study, with the ex vivo delivery efficiency of 64.33 ± 6.17 % and 40.11 ± 4.53 % for EMNs and DMNs, respectively. Most importantly, in vivo studies using a female Sprague-Dawley rat model confirmed the successful delivery of SIM from NCs-loaded DMNs (C max  = 287.39 ± 106.82 ng/mL) and EMNs (C max  = 203.05 ± 17.07 ng/mL) and maintain therapeutically relevant plasma concentrations for 15 days following a single application. The enhanced bioavailabilities of DMNs and EMNs were 24.28 % and 103.82 %, respectively, which were both significantly higher than that of conventional oral administration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

A 34-year-old man with no medical history presented to our hospital with a sore throat and difficult oral intake for two days before admission. He had various symptoms, including red eyes, ocular discharge, a fever, and intraoral ulcers, and he was admitted immediately. The polymerase chain reaction test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was positive, as was the adenovirus antigen test of the pharyngeal swab fluid, suggesting overlapping adenovirus and SARS-CoV-2 infections. The patient's condition improved with conservative treatment. This case of severe and varied symptoms caused by co-infection with adenovirus and SARS-CoV-2 has been previously reported.

Whether shellfish mariculture should be included in the blue carbon profile as a strategy to combat climate change has been controversial. It is highly demanding not only to provide calibration quantitation, but also to provide an ecosystem-based mechanism. In this study, we chose mussel farms as a case study to evaluate their contributions to carbon sinks and their responses to sedimentary carbon fixation and sequestration. First, we quantified the air-sea CO 2 flux in the mussel aquacultural zone and observed a weak carbon sink (-0.15 ± 0.07 mmol·m -2 ·d -1 ) during spring. Next, by analyzing the carbon composition in the sediment, we recorded a noticeable and unexpected increase in the sedimentary recalcitrant carbon (RC) content in the mussel farming case. To address this surprising sedimentary phenomenon, a long-term indoor experimental test was conducted to distinguish the consequences of mussel engagement with sedimentary RC. Our observational data support the idea that mussel engagement promotes accumulation of RC in sediments by 2.5-fold. Furthermore, the relative intensity of carboxylic-rich alicyclic molecule (CRAM)-like compounds (recalcitrant dissolved organic matter (RDOM)) increased by 451.4 % in the mussel-engaged sedimentary dissolved organic matter (DOM) in comparison to the initial state. Mussel engagement had a significantly positive effect on the abundance of sedimentary carbon-fixing genes. Therefore, we definitively conclude that mussel farming is blue carbon positive and propose a new alternative theory that mussel farming areas may have high carbon sequestration potential via an ecologically integrated "3 M" (microalgae-mussel-microbiota) consortium. The "mussel pump" accelerates carbon sequestration and enhances climate-related ecosystem services., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Dried roots of Peucedanum decursivum, a traditional Chinese medicine (TCM), has historically respiratory diseases such as cough, thick phlegm, headache, fever, and gynecological diseases, rheumatoid arthritis, and nasopharyngeal carcinoma., Aim of the Study: Made an endeavor to evaluate the research trajectory of P. decursivum, comprehensively discern its developmental status, and offer a guideline for future investigations., Materials and Methods: A meticulous search of literatures and books from 1955 to 2024 via databases like PubMed, Web of Science and CNKI was conducted, including topics and keywords of " P. decursivum" "Angelica decursivum" and "Zihua Qianhu"., Results: P. decursivum and its prescriptions have traditionally been used for treating phlegm-heat cough, wind-heat cough, gastrointestinal diseases, pain relief and so on. It contains 234 identified compounds, encompassing coumarins, terpenes, volatile oils, phenolic acids, fatty acids and derivatives. It exhibits diverse pharmacological activities, including anti-asthmatic, anti-inflammatory, antioxidant effects, anti-hypertensive, anti-diabetic, anti-Alzheimer, and anti-cancer properties, primarily attributed to coumarins. Microscopic identification, HPLC fingerprinting, and bioinformatics identification are the primary methods currently used for the quality control., Conclusion: P. decursivum demonstrates anti-asthmatic, anti-inflammatory, and antioxidant effects, aligning with its traditional use. However, experimental validation of its efficacy against phlegm and viruses is needed. Additionally, analgesic effects mentioned in historical texts lack modern pharmacological studies. Numerous isolated compounds exhibit highly valuable medicinal properties. Future research can delve into exploring these substances further. Rigorous of heavy metal contamination, particularly Cd and Pb, is necessary. Simultaneously, investigating its pharmacokinetics and toxicity in humans is crucial for the safety., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Lung cancer remains one of the most fatal cancers worldwide, with a high incidence of metastasis and a low 5-year survival rate. Histone deacetylase inhibitors (HDACis) have shown significant potential in lung cancer treatment, but their clinical use is often hindered by poor water solubility, rapid clearance, and systemic toxicity. In this study, we developed a novel therapeutic strategy by camouflaging black phosphorus (BP) with M1 macrophage membranes (MB) and loaded HDACi suberoylanilide hydroxamic acid (SAHA) onto the camouflaged black phosphorus (MB) for targeted lung cancer therapy. The M1 membrane coating enhanced the specificity of the SAHA-loaded black phosphorus toward lung cancer cells. Black phosphorus not only served as a carrier for HDACis but also facilitated photothermal therapy (PTT) through its photothermal conversion capabilities, establishing a highly efficient therapeutic platform. MBS demonstrated strong antitumor activity with minimal systemic toxicity. This multifunctional platform, inspired by biological systems, shows great promise for delivering a wide range of HDACis and offers synergistic therapeutic potential through the combination of photothermal therapy and chemotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Bacterial chemotaxis enhances bacterial adaptation to the environment and is important for biofilm formation. Biofilms play a key role in inducing larval settlement and metamorphosis in many marine invertebrates. However, the specific mechanisms by which bacterial chemotaxis influences larval settlement and metamorphosis in mussels remain unknown. The findings indicate that the absence of the chemotaxis gene cheW resulted in reduced motility of Pseudoalteromonas marina , accompanied by an increase in c-di-GMP content. The Δ cheW strain exhibited a higher capacity for biofilm formation compared to the wild-type strain. The extracellular protein content of the Δ cheW strain exhibited a significant 77% reduction, specifically in the flagellin content. The inducing activity of Δ cheW was reduced by 56% compared to the wild-type strain. This study highlights that the deficiency of the chemotaxis gene cheW inhibited larval settlement and metamorphosis in mussels through c-di-GMP regulation of extracellular protein production. It provides a novel ecological function of bacterial chemotaxis in regulating the larval settlement and metamorphosis of marine invertebrates.

Introduction: The importance of identifying relevant indicators of antidepressant efficacy is highlighted by the low response rates to antidepressant treatment for depression. The ABC gene family, encoding ATP-dependent transport proteins facilitating the transport of psychotropic drugs, has drawn attention. This study delved into the relationship between antidepressant efficacy and seven single nucleotide polymorphisms of ABCB1 and ABCB6 genes., Methods: A total of 549 depressed patients participated in the study, and all completed a 6-week course of antidepressant treatment. Cognitive function was assessed at baseline and post-treatment. Patients were categorized based on post-treatment HAMD-17 scores (with HAMD≤7 indicating remission), and comparisons were made between different groups in terms of allelic gene frequencies and genotypes. Logistic regression was used to explore the interaction between cognitive function and genotype on efficacy. Dual-luciferase reporter assays were performed to compare the regulatory effects of rs1109866 allele variants on the ABCB6 promoter., Results: There were no notable differences in allelic gene frequencies and genotypes between the remission and non-remission groups. Nonetheless, a significant interaction was identified between the rs1109866 genotype and language fluency-related indicators concerning efficacy (p=0.029) before correction. The dual-luciferase reporter assays demonstrated markedly higher fluorescence intensity of rs1109866-C compared to that of rs1109866-T (p<0.001)., Discussion: Relying solely on genetic polymorphisms of ABC family genes as predictors of antidepressant treatment response may not be sufficient. However, the interaction between the rs1109866 and cognition plays a pivotal role. The potentially enhanced transcriptional activity of rs1109866-C might offer insight into its impact on antidepressant efficacy., Competing Interests: All the authors declare that they have no conflicts of interest., (Thieme. All rights reserved.)

Background: Dihydrolipoamide S-acetyltransferase ( DLAT ) is a subunit of the pyruvate dehydrogenase complex (PDC), a rate-limiting enzyme complex, that can participate in either glycolysis or the tricarboxylic acid cycle (TCA). However, the pathogenesis is not fully understood. We aimed to perform a more systematic and comprehensive analysis of DLAT in the occurrence and progression of tumors, and to investigate its function in patients' prognosis and immunotherapy., Methods: The differential expression, diagnosis, prognosis, genetic and epigenetic alterations, tumor microenvironment, stemness, immune infiltration cells, function enrichment, single-cell analysis, and drug response across cancers were conducted based on multiple computational tools. Additionally, we validated its carcinogenic effect and possible mechanism in glioma cells., Results: We exhibited that DLAT expression was increased in most tumors, especially in glioma, and affected the survival of tumor patients. DLAT was related to RNA modification genes, DNA methylation, immune infiltration, and immune infiltration cells, including CD4+ T cells, CD8+ T cells, Tregs, and cancer-associated fibroblasts. Single-cell analysis displayed that DLAT might regulate cancer by mediating angiogenesis, inflammation, and stemness. Enrichment analysis revealed that DLAT might take part in the cell cycle pathway. Increased expression of DLAT leads tumor cells to be more resistant to many kinds of compounds, including PI3Kβ inhibitors, PKC inhibitors, HSP90 inhibitors, and MEK inhibitors. In addition, glioma cells with DLAT silence inhibited proliferation, migration, and invasion ability, and promoted cell apoptosis., Conclusion: We conducted a comprehensive analysis of DLAT in the occurrence and progression of tumors, and its possible functions and mechanisms. DLAT is a potential diagnostic, prognostic, and immunotherapeutic biomarker for cancer patients., Competing Interests: The authors declare that they have no conflicts of interest to report regarding the present study., (© 2024 The Authors.)

Background: This meta-analysis aimed to determine the incidence and overall risk of major adverse cardiovascular events (MACEs) related to immune checkpoint inhibitors (ICIs)., Methods: We systematically searched all cohort studies, including the available MACE data in cancer patients receiving ICIs, in PubMed, Embase, and the Cochrane Library, from their inception to September 5, 2023. The primary outcome was the incidence of MACEs associated with ICI exposure, and the secondary outcome was the overall risk of MACEs associated with ICI exposure versus non-ICI exposure controls. Risk ratios with 95% confidence intervals were used in the random- or fixed-effects models., Results: Overall, 26 cohort studies met the inclusion criteria, involving 109,883 cancer patients. In the median follow-up period ranging from 3.3 to 55.2 months, the incidence of MACEs associated with ICI exposure was 8.22%, ranging from 0.55% to 3.98%, among the nine MACEs, including myocarditis, tachyarrhythmia, pericarditis, pericardial effusions, cardiovascular death, myocardial infarction, heart failure, stroke, and conduction disorder. The incidence of MACE associated with non-ICI exposure was 3.84%, ranging from 0.81% to 4.72%. The risks of all-grade MACEs and pericardial effusions were significantly higher in the ICI group than in the non-ICI controls. ICI treatment, age, male sex, and prior radiation therapy were significantly associated with MACEs., Conclusion: The risk of MACEs during ICI treatment in patients with cancer is more common than is currently recognized. ICI use is closely associated with an increased risk of MACEs. Patients at risk were older, male, and had a history of radiation therapy., (© 2024 The Association for the Publication of the Journal of Internal Medicine.)

Single-molecule localization super-resolution fluorescence imaging relies on the fluorescence ON/OFF switching of fluorescent probes to break the diffraction limit. However, the unreacted or nonspecifically bound probes cause non-targeted ON/OFF switching, resulting in substantial fluorescence background that significantly reduces localization precision and accuracy. Here, we report a blinkogenic probe HM-DS655-Halo that remains blinking OFF until it binds to HaloTag, thereby triggering its self-blinking activity and enabling its application in direct SMLM imaging in living cells without wash-out steps. We employed the ratio of the duty cycle before and after self-blinking activation, termed as the parameter "R DC " to characterize blinkogenicity. The covalent binding to HaloTag induces HM-DS655-Halo to transition from a fluorescent OFF state to a fluorescence blinking state. This transition also leads to a change in the R DC value, which is calculated to be 12, ensuring super blinkogenicity to effectively suppress background signals in living cells. HM-DS655-Halo was successfully applied in dynamic SMLM imaging of diverse intracellular sub-structures with minimal background noise, including mitochondrial fission and contact, cell migration, and pseudopod growth., (© 2024 Wiley-VCH GmbH.)

Background: Pulpotomy is a widely recommended treatment for deep caries and reversible pulpitis in primary teeth. However, there is a significant lack of large-scale clinical studies evaluating the long-term efficacy of pulpotomy in primary molars, especially in studies with follow-up periods extending beyond a two years., Aim: This study aimed to evaluate the long-term efficacy of mineral trioxide aggregate (MTA) and iRoot BP Plus for pulpotomy in primary molars performed under general anesthesia and to investigate factors influencing the success rate., Methods: In this retrospective study, a total of 942 primary molars from 422 children who met the inclusion criteria underwent pulpotomy. Propensity score matching method (PSM) was used to match the MTA and iRoot BP Plus groups in a 1:1 ratio based on covariates. Efficacy was assessed using the Zurn & Seale criteria. Kaplan-Meier survival analysis and Cox proportional hazards model were performed to analyze the outcomes., Results: PSM resulted in 266 pairs of matched teeth from 532 teeth of 291 children (mean age: 4.64 ± 1.07 years, ranging from 2 to 8 years). Long-term clinical and radiographic evaluations revealed higher success rates for iRoot BP Plus (24-month: 99.54%/97.25%; 36-month: 97.22%/95.83%) compared to MTA (24-month: 94.76%/95.29%; 36-month: 92.50%/91.25%). Survival analysis indicated a statistically significant difference between two groups ( P  = 0.0042). Age, gender, tooth position, and decayed tooth surface showed no significant impact on pulpotomy success, whereas the choice of pulp capping materials significantly influenced the outcome (HR [95% CI]=0.3745[0.1857-0.7552], P  = 0.006)., Conclusion: Clinical and radiographic evaluations support the use of iRoot BP Plus for pulpotomy in primary molars., Competing Interests: The authors declare there are no competing interests., (©2024 Zhao et al.)

Heptafluoropropylene oxide dimer acid (HFPO-DA), as an alternative to perfluorooctanoic acid (PFOA), has been shown to pose similar environmental and health risks as other perfluorinated compounds. The electrochemical-based advanced oxidation processes are promising techniques for the treatment of perfluorinated compounds, and the boron-doped diamond (BDD) anode could degrade HFPO-DA under mild conditions. However, the roles of radicals in the degradation and how to overcome the steric hindrance of the -CF 3 branch on the carboxyl group were not yet clear. In this study, we investigated the degradation mechanism of HFPO-DA on the BDD anode. Instead of other non-active anodes (PbO 2 and SnO 2 electrodes), HFPO-DA can be degradable on the BDD electrode with a rate constant logarithmic correlation to the applied current density. The hydroxyl radical (•OH) was one of the key factors in the degradation of HFPO-DA, accounting for almost 89% of the significant effect, and the direct electron transfer was the rate-limiting step in the degradation reaction. Physicochemical characterization including field emission scanning electron microscope (FE-SEM), X-ray photo-electron spectroscopy (XPS), water contact angle, and electrochemical property indicated that the BDD electrode was fluorinated after electrolysis, the electrode surface became more hydrophobic due to the bonding of -C x F y , leading to a decrease in the electrochemically active area. Moreover, degradation products (pentafluoropropionic acid, trifluoroacetic acid, and fluorine ion) were detected and the mass balance of carbon and fluorine was calculated during the degradation. Therefore, a degradation mechanism for HFPO-DA was proposed, which involved direct electron transfer, decarboxylation, radical reaction, decarboxylation, and decarboxylation. The de-CF 3 step initiated the fluorination of the BDD electrode, which was initiated by the defluorination process. This study contributes to the understanding of the electro-oxidative degradation of perfluoroalkyl ether carboxylic acids and provides guidance for the application of electrochemical advanced oxidation processes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Objective: The main objective of this study is to investigate whether there is a difference in the occurrence of MSAF between fever and nonfever-pregnant women during the COVID-19 pandemic. Study Design: We conducted a multicenter retrospective study including pregnant women during the COVID-19 pandemic. Among the 400 pregnant women included in the final data analysis, 238 had fever during delivery, while 162 nonfever-pregnant women met the inclusion and exclusion criteria and served as controls. We collected various obstetric and neonatal parameters for both groups of patients, compared, and statistically tested the significance of these parameters. For parameters with significant statistical differences and clinical significance, we performed logistic regression analysis to explore potential risk factors for MSAF. Result: In a sample of 400 parturients, a total of 69 individuals (17.25%) were discovered to have MSAF with the prevalence increasing to 21.85% in the fever population. A statistically significant association was observed between fever during pregnancy and MSAF, with a higher risk of development observed in fever-pregnant women compared to nonfever ones. Specifically, the odds of developing MSAF increased by a factor of 0.979 in fever-pregnant women compared to nonfever ones, as determined by a logistic regression model (OR = 1.979, 95% CI = 1.061∼3.693, p =0.032). Moreover, pregnant women with COVID-19 infection had a significantly higher risk of developing MSAF, with the odds increasing by a factor of 2.567 compared to uninfected pregnant women (OR = 3.567, 95% CI = 1.622∼7.845, p =0.002). In addition, the study also identified abnormal fetal heart monitoring ( p < 0.05) and gestational age ( p < 0.05) as independent risk factors for the occurrence of MSAF. Conclusion: For pregnant women infected with COVID-19, the rate of MSAF disturbance significantly increases, therefore, it is necessary to pay more attention to fetal heart changes and amniotic fluid conditions, and actively managing labor is beneficial for improving delivery outcomes., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Runrun Feng et al.)

Epigenetic regulation has emerged as a promising therapeutic strategy for lung cancer treatment, which can facilitate the antitumor responses by modulating epigenetic dysregulation of target proteins in lung cancer. The proteolysis-targeting chimera (PROTAC) reagent, dBET6 shows effective inhibition of bromodomain-containing protein 4 (BRD4) that exerts antitumor efficacy by degrading BRD4 via the ubiquitin-proteasome system. Nevertheless, the low tissue specificity and bioavailability impede its therapeutic effects and clinical translation on lung cancer treatment. Herein, we developed a type of dual targeting and bioresponsive nano-PROTAC (c R GD/L LC membrane/D S-P LGA/d B ET6, named RLDPB), which was constructed by using the pH and glutathione (GSH)-responsive polymer, disulfide bond-linked poly(lactic-co-glycolic acid) (PLGA-S-S-PLGA, DS-PLGA) to load the PROTAC agent dBET6, and further camouflaged with the homotypic LLC cell membranes, followed by the conjugation with cRGD ligand to the surface of the nanoparticles. Notably, RLDPB showed enhanced celluar uptake by lung cancer cells in vitro and accumulation in the tumors via the dual targeting structure including cRGD and LLC membrane. The pH/GSH responsiveness improved the release of dBET6 from the DS-PLGA-based nanoparticles within the cells. RLDPB was demonstrated to facilitate tumor regression by inducing the apoptosis of lung cancer cells with the degradation of BRD4. Thus, RLDPB can be considered a powerful tool to suppress lung cancer, which opens a new avenue to treat lung cancer by PROTAC., Competing Interests: Declarations Ethics approval and consent to participate Animal experiments were permitted by the Institutional Animal Care and Use Committee (No. S2023-770) and performed under the guidelines of the Animal Welfare Act of Guangzhou Medical University. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: To report on quality assurance (QA) and protocol adherence (PA) in a multicentre phase III trial for head and neck cancer, evaluate patterns of protocol deviations and investigate the effect of PA on study outcomes., Methods: All 221 patients from the ARTFORCE trial (NCT01504815) were included in this study. Pre- and per-treatment QA measures included protocol guidelines, a dummy run, early case reviews and trial meetings. FDG-PET-guided dose painting and scheduled adaptive radiotherapy were reviewed in patients in the experimental arm (eRT). Patient and disease characteristics, as well as institutes' accrual rate and timing were examined for correlation with PA. Cox regression was used to determine the impact of PA on outcome., Results: The dummy run was completed in all nine institutes and early case reviews were completed in five out of nine institutes that contributed 190 out of 221 patients. Among all patients randomized to eRT, 64 % had at least one deviation of the experimental trial components. Protocol deviations were significantly correlated with the institute patients were treated at (Cramer'sV 0.34-0.48). Despite early identification of institute-specific deviations in QA, these continued during the trial. No significant associations were seen between deviations and accrual timing or rate (P ≥ 0.26). Within eRT, no significant relation was observed between experimental PA and locoregional control (LRC), the primary endpoint of the trial (P≥.15)., Conclusions: Despite QA, protocol deviations persisted during the trial, which were mostly institute-specific. However, deviations of the experimental treatment strategy did not significantly impact LRC and therefore the trial conclusion., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Anna Liza M.P. de Leeuw; PhD-student at the Antoni van Leeuwenhoek hospital. Jordi Giralt; Radiation oncologist at the Vall d'Hebron Unniversity Hospital. Yungan Tao; Radiation oncologist at the Institut Gustave roussy. Sergi Benavente; Radiation oncologist at the Vall d'Hebron Unniversity Hospital. Thanh-Vân France Nguyen; Radiation oncologist at the Institut Gustave roussy. Frank J.P. Hoebers; Radiation oncologist at the Maastro Center. Ann Hoeben; Clinical oncologist at the Maastro Center. Chris H.J. Terhaard; retired radiation oncologist at the University Medical Center Utrecht. Lip Wai Lee; Radiation oncologist at the Christie NHS Foundation Trust. Signe Friesland; Radiation oncologist at the Karolinska Comprehensive Cancer Center. Roel J.H.M. Steenbakkers; Radiation oncologist at the University Medical Center Groningen. Lisa Tans; Radiation oncologist at the Erasmus Medical Center. Simon R. van Kranen; Postdoc at the Antoni van Leeuwenhoek hospital. Jeroen B van de Kamer; Medical physicist at the Antoni van Leeuwenhoek hospital. Harry Bartelink; retired radiation oncologist at the Antoni van Leeuwenhoek hospital. Coen R.N. Rasch; Professor at Leiden University; Radiation oncologist at the Leiden University Medical Center; Jan-Jakob Sonke; Professor by special appointment at University of Amsterdam; senior group leader at Antoni van Leeuwenhoek hospital; ownership of patent/license fees/copyright at Elekta AB; member of the international advisory board at Physics, medicine and biology; editorial board member of Physics & Imaging in Radiation Oncology. Olga Hamming-Vrieze; Radiation oncologist at Antoni van Leeuwenhoek hospital]., (Copyright © 2024. Published by Elsevier B.V.)