bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive Analysis of Quantitative Proteomics With DIA Mass Spectrometry and ceRNA Network in Intrahepatic Cholestasis of Pregnancy
Authors: Fang Dajun , Fang Yan , Zhang Weiqiang , Xiang Yun , Cheng Xi , Liang Mingfeng , Xia Huimin
Published: July 2022

Background: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific complication characterized by pruritus without skin damage and jaundice. The poor perinatal outcomes include fetal distress, preterm birth, and unexpected intrauterine death. However, the mechanism of ICP leading to poor prognosis is still unclear.

Methods: We analyzed 10 ICP and 10 normal placental specimens through quantitative proteomics of data-independent acquisition (DIA) to screen and identify differentially expressed proteins. GO, KEGG, COG/KOG, StringDB, InterProScan, Metascape, BioGPS, and NetworkAnalyst databases were used in this study. PITA, miRanda, TargetScan, starBase, and LncBase Predicted v.2 were used for constructing a competing endogenous RNA (ceRNA) network. Cytoscape was used for drawing regulatory networks, and cytoHubba was used for screening core nodes. The ICP rat models were used to validate the pathological mechanism.

Results: GO, KEGG, and COG/KOG functional enrichment analysis results showed the differentially expressed proteins participated in autophagy, autophagosome formation, cofactor binding, JAK-STAT signaling pathway, and coenzyme transport and metabolism. DisGeNET analysis showed that these differentially expressed proteins were associated with red blood cell disorder and slow progression. We further analyzed first 12 proteins in the upregulated and downregulated differentially expressed proteins and incorporated clinicopathologic parameters. Our results showed HBG1, SPI1, HBG2, HBE1, FOXK1, KRT72, SLC13A3, MBD2, SP9, GPLD1, MYH7, and BLOC1S1 were associated with ICP development. ceRNA network analysis showed that MBD2, SPI1, FOXK1, and SLC13A3 were regulated by multiple miRNAs and lncRNAs.

Conclusion: ICP was associated with autophagy. The ceRNA network of MBD2, SPI1, FOXK1, and SLC13A3 was involved in ICP progression, and these core proteins might be potential target.
Artificial Intelligence Model for Antiinterference Cataract Automatic Diagnosis: A Diagnostic Accuracy Study
Authors: Wu Xing , Xu Di , Ma Tong , Li Zhao Hui , Ye Zi , Wang Fei , Gao Xiang Yang , Wang Bin , Chen Yu Zhong , Wang Zhao Hui , Chen Ji Li , Hu Yun Tao , Ge Zong Yuan , Wang Da Jiang , Zeng Qiang
Published: July 2022

Background: Cataract is the leading cause of blindness worldwide. In order to achieve large-scale cataract screening and remarkable performance, several studies have applied artificial intelligence (AI) to cataract detection based on fundus images. However, the fundus images they used are original from normal optical circumstances, which is less impractical due to the existence of poor-quality fundus images for inappropriate optical conditions in actual scenarios. Furthermore, these poor-quality images are easily mistaken as cataracts because both show fuzzy imaging characteristics, which may decline the performance of cataract detection. Therefore, we aimed to develop and validate an antiinterference AI model for rapid and efficient diagnosis based on fundus images.

Materials and Methods: The datasets (including both cataract and noncataract labels) were derived from the Chinese PLA general hospital. The antiinterference AI model consisted of two AI submodules, a quality recognition model for cataract labeling and a convolutional neural networks-based model for cataract classification. The quality recognition model was performed to distinguish poor-quality images from normal-quality images and further generate the pseudo labels related to image quality for noncataract. Through this, the original binary-class label (cataract and noncataract) was adjusted to three categories (cataract, noncataract with normal-quality images, and noncataract with poor-quality images), which could be used to guide the model to distinguish cataract from suspected cataract fundus images. In the cataract classification stage, the convolutional-neural-network-based model was proposed to classify cataracts based on the label of the previous stage. The performance of the model was internally validated and externally tested in real-world settings, and the evaluation indicators included area under the receiver operating curve (AUC), accuracy (ACC), sensitivity (SEN), and specificity (SPE).

Results: In the internal and external validation, the antiinterference AI model showed robust performance in cataract diagnosis (three classifications with AUCs >91%, ACCs >84%, SENs >71%, and SPEs >89%). Compared with the model that was trained on the binary-class label, the antiinterference cataract model improved its performance by 10%.

Conclusion: We proposed an efficient antiinterference AI model for cataract diagnosis, which could achieve accurate cataract screening even with the interference of poor-quality images and help the government formulate a more accurate aid policy.
To Identify Adenomatous Polyposis Coli Gene Mutation as a Predictive Marker of Endometrial Cancer Immunotherapy
Authors: Song Yunfeng , Huang Jian , Wang Kai , Li Yiran
Published: July 2022

The adenomatous polyposis coli (APC) gene is the chromatin-remodeling-related gene and a typical tumor suppressor. Patients with a high expression of programmed death-ligand 1 (PD-L1) or a high level of tumor mutational burden (TMB) may benefit from immunotherapy in endometrial cancer (EC). This study aimed to demonstrate the role of APC in the diagnosis and immunotherapy treatment of EC. We performed an integrative analysis of a commercial panel including 520 cancer-related genes on 99 tumors from an endometrial cancer cohort in China and DNA-seq data from The Cancer Genome Atlas (TCGA) to identify new gene mutations as endometrial cancer immunotherapy markers. We found that the significant mutant genes that correlated with the PD-L1 expression and TMB were related to the chromatin state and generated a discovery set having 12 mutated genes, including the APC gene, which was identified as a new marker for immunotherapy. Further analysis revealed that tumors with the APC mutation had high TMB, increased expression of PD-L1, and increased lymphocytic infiltration. Next, we verified that APC has an inactive mutation in EC, which may affect the immune response, including PD-L1 expression, microsatellite instability, and lymphocytic infiltrate. Furthermore, patients with the APC mutation had longer overall survival. Our study demonstrates that APC could play an important role in enhancing the response to endometrial cancer treatment, particularly immunotherapy.
Mitochondrial sirtuin 3 and various cell death modalities
Authors: Yapryntseva Maria A. , Maximchik Polina V. , Zhivotovsky Boris , Gogvadze Vladimir
Published: July 2022

Sirtuin 3, a member of the mammalian sirtuin family of proteins, is involved in the regulation of multiple processes in cells. It is a major mitochondrial NAD+-dependent deacetylase with a broad range of functions, such as regulation of oxidative stress, reprogramming of tumor cell energy pathways, and metabolic homeostasis. One of the intriguing functions of sirtuin 3 is the regulation of mitochondrial outer membrane permeabilization, a key step in apoptosis initiation/progression. Moreover, sirtuin 3 is involved in the execution of various cell death modalities, which makes sirtuin 3 a possible regulator of crosstalk between them. This review is focused on the role of sirtuin 3 as a target for tumor cell elimination and how mitochondria and reactive oxygen species (ROS) are implicated in this process.
Addressing the contribution of agricultural systems to the phosphorus pollution challenge: a multi-dimensional perspective
Authors: Martín-Hernández Edgar , Taifouris Manuel , Martín Mariano
Published: July 2022

The intensification of agricultural systems has increased the food production efficiency, increasing the productivity while the production costs are reduced. Although these factors are key to global food security in a context of continued human population growth, the use of intensive agricultural techniques results in different environmental issues. Mitigating these negative impacts is a requirement for adopting sustainable food production systems. Notably, nutrient pollution is one of the main environmental issues associated with both livestock and crop production. These activities result in different point and non-point source releases of phosphorus, which eventually reach surface and ground waterbodies. This might result in the accumulation of phosphorus over time, contributing to the eutrophication of water ecosystems, and the development of harmful algal bloom (HABs) episodes. The releases of nutrients from agricultural activities can be abated through different management strategies, including the implementation of nutrient recovery techniques at livestock facilities, embracing precision fertilization methods, and developing integrated crop-livestock systems for achieving circular food production systems. In this work, we describe opportunities for Process System Engineering (PSE) to address the development of phosphorus management techniques for mitigating phosphorus pollution from agricultural systems balancing trade-offs between recovery cost and environmental impact mitigation. These techniques integrate the spatial analysis of nutrient pollution from agriculture using geographical information systems (GIS) with the assessment and the selection of phosphorus management techniques combining techno-economic analysis (TEA) and environmental metrics through multi-criteria decision analysis (MCDA) frameworks, and use mathematical programming for the conceptual design of integrated crop-livestock systems.
New strategies for a sustainable 99mTc supply to meet increasing medical demands: Promising solutions for current problems
Authors: Nawar Mohamed F. , Türler A.
Published: July 2022

The continuing rapid expansion of99mTc diagnostic agents always calls for scaling up99mTc production to cover increasing clinical demand. Nevertheless,99mTc availability depends mainly on the fission-produced99Mo supply. This supply is seriously influenced during renewed emergency periods, such as the past99Mo production crisis or the current COVID-19 pandemic. Consequently, these interruptions have promoted the need for99mTc production through alternative strategies capable of providing clinical-grade99mTc with high purity. In the light of this context, this review illustrates diverse production routes that either have commercially been used or new strategies that offer potential solutions to promote a rapid production growth of99mTc. These techniques have been selected, highlighted, and evaluated to imply their impact on developing99mTc production. Furthermore, their advantages and limitations, current situation, and long-term perspective were also discussed. It appears that, on the one hand, careful attention needs to be devoted to enhancing the99Mo economy. It can be achieved by utilizing98Mo neutron activation in commercial nuclear power reactors and using accelerator-based99Mo production, especially the photonuclear transmutation strategy. On the other hand, more research efforts should be devoted to widening the utility of99Mo/99mTc generators, which incorporate nanomaterial-based sorbents and promote their development, validation, and full automization in the near future. These strategies are expected to play a vital role in providing sufficient clinical-grade99mTc, resulting in a reasonable cost per patient dose.
Ecological Risk Assessment and Influencing Factors of Heavy-Metal Leaching From Coal-Based Solid Waste Fly Ash
Authors: Zhang Zhiguo , Cai Weiqing , Hu Youbiao , Yang Ke , Zheng Yonghong , Fang Chao , Ma Chengnan , Tan Yuning
Published: July 2022

In order to promote and broaden the utilization of fly ash as a resource, the fly ash from a 2,660-MW coal-fired power plant in Huainan (China) was investigated. The physical and chemical properties of fly ash were characterized by scanning electron microscopy, energy spectrum analysis, and XRD. The content and different forms of the heavy metals Cd, Cr, Cu, Co, and Ni were determined by acid digestion, oscillation leaching, and Tessier five-step extraction. The effect of pH, temperature, and particle size on the leached amount of heavy metals was studied. Finally, the ecological risk index was calculated for each heavy metal via the risk assessment coding (RAC) method and Hakanson ecological risk assessment method, allowing the ecological risk of fly ash to be determined under different environmental conditions. Results showed that the average concentrations of Cd, Cr, Co, and Ni were all below the risk screening values reported for environmental pollutants (pH > 7.5). Under varying pH, temperature, and particle size conditions, the leached amounts (oscillation leaching) were below the soil risk screening values for agricultural land in China. An RAC-Cd value of >50% indicates a high ecological risk, while the RAC values of Co and Ni were between 10 and 30%, indicating a medium ecological risk, and the RAC values of Cr and Cu were <10%, indicating a low ecological risk. With increasing pH, the potential ecological risk index (RI) decreased, with a maximum RI of 59.62 observed at pH 2.8. With increasing temperature, the potential ecological RI increased initially to a maximum of 27.69 at 25°C and then decreased thereafter. With increasing particle size, the ecological RI decreased, with the highest RI of 4.06 occurring at <0.075 mm. The Hakanson ecological RI value was below 150, indicating a slight ecological risk. Therefore, fly ash can be considered as a soil additive and conditioner that is suitable for use in the improvement of reclamation soil in coal mining subsidence areas.
Palladium-catalyzed allylic etherification of phenols with vinyl ethylene carbonate
Authors: Lin Shibo , Zhao Xiaotian , He Lihui , Li Xuanhao , Jiang Qian , Xiang Lan , Ye Yongqin , Gan Xiaohong
Published: July 2022

The palladium-catalyzed decarboxylative reactions of phenols and vinyl ethylene carbonate to produce allylic aryl ethers under mild conditions have been established. Adopting an inexpensive PdCl2(dppf) catalyst promotes the efficient conversion of phenols to the corresponding allylic aryl ethers via the formation of a new C-O bond in good isolated yields with complete regioselectivities, acceptable functional group tolerance and operational simplicity. The robust procedure could be completed smoothly by conducting a scaled-up reaction with comparable efficiency to afford the target product.
Effect of Nanoscale Zero-Valent Iron on Arsenic Bioaccessibility and Bioavailability in Soil
Authors: Chen Shuo , Han Lei , Wang Qiu , Liu Chenglang , Liu Yuzhen , Li Jie
Published: July 2022

Hand-to-mouth activity is considered to be the main way for children to come into contact with contaminated soil, and bioavailability is an important factor affecting their health risk. To reduce soil As risk to humans by oral exposure, nanoscale zero-valent iron (nZVI) has been extensively studied for immobilizing As-contaminated soil, but its efficiency has not been investigated using in vitro assay and its influence on As-RBA. In this study, two contaminated soil samples (A and B) were amended with 1% and 2% (w/w) nZVI for 56 days to study its effect on As fraction by sequence extraction, As bioaccessibility by SBRC assay, and As relative bioavailability (RBA) by the mouse liver and kidney model. Based on the sequence extraction, the As associated with the E1 (exchangeable fraction) and C2 (carbonate fraction) fractions were decreased from 3.00% to 1.68% for soil A and from 21.6% to 7.86% for soil B after being treated with 2% nZVI for 56 days. When assessing As bioaccessibility in all soils treated with nZVI by SBRC assay, it was found that As bioaccessibility was significantly higher in the gastric phase (GP) and lower in the intestinal phase (IP) (p < 0.05), and the bioaccessible Fe concentration decreased significantly from the gastric to intestinal phase at the same time. Based on the mouse liver–kidney model, the As-RBA in soil A increased from 21.6% to 22.3% and 39.9%, but in soil B decreased from 73.0% to 55.3% and 68.9%, respectively. In addition, there was a significant difference between As bioaccessibility based on GP or IP of SBRC assay and As-RBA in two soils after being treated with nZVI for 56 days. To more accurately assess the effects of nZVI human arsenic exposure, As-RBA should be considered in concert with secondary evidence provided through fraction and bioaccessibility assessments. In addition, it is necessary to develop a suitable in vitro assay to predict As-RBA in nZVI-amended soils.
Apigenin-Mn(II) loaded hyaluronic acid nanoparticles for ulcerative colitis therapy in mice
Authors: Lv Feng , Zhang Yuchen , Peng Qiao , Zhao Xinxin , Hu Datao , Wen Jinpeng , Liu Kailai , Li Ruilin , Wang Ke , Sun Jinyao
Published: July 2022

Ulcerative colitis (UC) is a chronic idiopathic inflammatory bowel disease characterized by rapid progression and frequent comorbidities that make its treatment challenging. Nanomaterial-based strategies have been extensively studied to target the GI mucosal immune system in recent years. Herein, we propose a novel apigenin-Mn(II) loaded sodium hyaluronate nanoparticles where apigenin (API) was incorporated in the Mn2+ ramework, coated with hyaluronic acid. The apigenin-Mn(II) loaded sodium hyaluronate nanoparticles (API-Mn(II)@HA NPs) exhibited a diameter of 200 nm and were effective against UC. The preparation of the API-Mn(II) complex was relatively simple, and the mechanism underlying its therapeutic effect on UC induced by sodium dextran sulfate (DSS) was studied in detail. We found that API-Mn(II)@HA nanoparticles could effectively repair the intestinal barrier and significantly improve the damaged colon tissue by mediating inflammatory factors. This study provides novel insights on a new kind of active targeted nanoparticle for improving the efficacy of drugs for UC treatment.
Discovery of novel natural products as dual MNK/PIM inhibitors for acute myeloid leukemia treatment: Pharmacophore modeling, molecular docking, and molecular dynamics studies
Authors: Mohamed Linda M. , Eltigani Maha M. , Abdallah Marwa H. , Ghaboosh Hiba , Bin Jardan Yousef A. , Yusuf Osman , Elsaman Tilal , Mohamed Magdi A. , Alzain Abdulrahim A.
Published: July 2022

MNK-2 and PIM-2 kinases play an indispensable role in cell proliferation signaling pathways linked to tyrosine kinase inhibitors resistance. In this study, pharmacophore modeling studies have been conducted on the co-crystalized ligands of MNK-2 and PIM-2 enzyme crystal structures to determine the essential features required for the identification of potential dual inhibitors. The obtained pharmacophore features were then screened against a library of 270,540 natural products from the ZINC database. The matched natural molecules were docked into the binding sites of MNK-2 and PIM-2 enzymes. The compounds with high docking scores with the two enzymes were further subjected to MM-GBSA calculations and ADME prediction. This led to the identification of compound 1 (ZINC000085569211), compound 2 (ZINC000085569178), and compound 3 (ZINC000085569190), with better docking scores compared to the reference co-crystallized ligands of MNK-2 and PIM-2. Moreover, compounds 1‒3 displayed better MM-GBSA binding free energies compared to the reference ligands. Finally, molecular dynamics (MD) study was used to assess the interaction stability of the compounds with MNK-2. To this end, compounds 1 and 3 bound strongly to the target during the whole period of MD simulation. The findings of the current study may further help the researchers in the discovery of novel molecules against MNK-2 and PIM-2.
The giant E3 ligase HUWE1 is linked to tumorigenesis, spermatogenesis, intellectual disability, and inflammatory diseases
Authors: Qi Lu , Xu Xiaoqing , Qi Xiaopeng
Published: July 2022

E3 ubiquitin ligases determine the substrate specificity and catalyze the ubiquitination of lysine residues. HUWE1 is a catalytic HECT domain-containing giant E3 ligase that contains a substrate-binding ring structure, and mediates the ubiquitination of more than 40 diverse substrates. HUWE1 serves as a central node in cellular stress responses, cell growth and death, signal transduction, etc. The expanding atlas of HUWE1 substrates presents a major challenge for the potential therapeutic application of HUWE1 in a particular disease. In addition, HUWE1 has been demonstrated to play contradictory roles in certain aspects of tumor progression in either an oncogenic or a tumor-suppressive manner. We recently defined novel roles of HUWE1 in promoting the activation of multiple inflammasomes. Inflammasome activation-mediated immune responses might lead to multifunctional effects on tumor therapy, inflammation, and autoimmune diseases. In this review, we summarize the known substrates and pleiotropic functions of HUWE1 in different types of cells and models, including its involvement in development, cancer, neuronal disorder and infectious disease. We also discuss the advances in cryo-EM-structural analysis for a functional-mechanistic understanding of HUWE1 in modulating the multitudinous diverse substrates, and introduce the possibility of revisiting the comprehensive roles of HUWE1 in multiple aspects within one microenvironment, which will shed light on the potential therapeutic application of targeting giant E3 ligases like HUWE1.
Role of Gut Microbiome in Autism Spectrum Disorder and Its Therapeutic Regulation
Authors: Taniya Masuma Afrin , Chung Hea-Jong , Al Mamun Abdullah , Alam Safaet , Aziz Md. Abdul , Emon Nazim Uddin , Islam Md. Minarul , Hong Seong-T shool , Podder Bristy Rani , Ara Mimi Anjuman , Aktar Suchi Suzia , Xiao Jian
Published: July 2022

Autism spectrum disorder (ASD) is a neurological disorder that affects normal brain development. The recent finding of the microbiota–gut–brain axis indicates the bidirectional connection between our gut and brain, demonstrating that gut microbiota can influence many neurological disorders such as autism. Most autistic patients suffer from gastrointestinal (GI) symptoms. Many studies have shown that early colonization, mode of delivery, and antibiotic usage significantly affect the gut microbiome and the onset of autism. Microbial fermentation of plant-based fiber can produce different types of short-chain fatty acid (SCFA) that may have a beneficial or detrimental effect on the gut and neurological development of autistic patients. Several comprehensive studies of the gut microbiome and microbiota–gut–brain axis help to understand the mechanism that leads to the onset of neurological disorders and find possible treatments for autism. This review integrates the findings of recent years on the gut microbiota and ASD association, mainly focusing on the characterization of specific microbiota that leads to ASD and addressing potential therapeutic interventions to restore a healthy balance of gut microbiome composition that can treat autism-associated symptoms.
Development of a nested PCR assay for specific detection of Metschnikowia bicuspidata infecting Eriocheir sinensis
Authors: Bao Jie , Chen Ye , Xing Yuenan , Feng Chengcheng , Hu Qingbiao , Li Xiaodong , Jiang Hongbo
Published: July 2022

In recent years, the “milky disease” caused by Metschnikowia bicuspidata has seriously affected the Eriocheir sinensis culture industry. Discovering and blocking the transmission route has become the key to controlling this disease. The existing polymerase chain reaction (PCR) detection technology for M. bicuspidata uses the ribosomal DNA (rDNA) sequence, but low sensitivity and specificity lead to frequent false detections. We developed a highly specific and sensitive nested PCR method to detect M. bicuspidata, by targeting the hyphally regulated cell wall protein (HYR) gene. This nested HYR-PCR produced a single clear band, showed no cross-reaction with other pathogens, and was superior to rDNA-PCR in specificity and sensitivity. The sensitivity of nested HYR-PCR (6.10 × 101 copies/μL) was greater than those of the large subunit ribosomal RNA gene (LSU rRNA; 6.03 × 104 copies/μL) and internal transcribed spacer (ITS; 6.74 × 105 copies/μL) PCRs. The nested HYR-PCR also showed a higher positivity rate (71.1%) than those obtained with LSU rRNA (16.7%) and ITS rDNA (24.4%). In conclusion, we developed a new nested HYR-PCR method for the specific and sensitive detection of M. bicuspidata infection. This will help to elucidate the transmission route of M. bicuspidata and to design effective management and control measures for M. bicuspidata disease.
Magnolol as a potent antifungal agent inhibits Candida albicans virulence factors via the PKC and Cek1 MAPK signaling pathways
Authors: Xie Yufei , Hua Hong , Zhou Peiru
Published: July 2022

Magnolol, a lignin compound extracted from Magnolia officinalis Cortex, has been found to have prominent antifungal effects against Candida albicans. However, the specific mechanism still remains unclear. Therefore, this study aimed to further explore the inhibition mechanism of magnolol against Candida albicans virulence factors and the related signaling pathways. By an XTT reduction assay, a hyphal formation assay, confocal laser scanning microscopy, transmission electron microscopy, a calcofluor white staining assay, and a cell wall β-glucan quantitative detection assay, we evaluated the inhibitory effects of magnolol against the adhesion, hyphal formation, biofilm viability, biofilm spatial structure, and cell wall ultrastructure of Candida albicans. Moreover, by RNA sequencing and qRT-PCR, we confirmed the effects of magnolol in inhibiting the gene expression of Candida albicans virulence factors and the related signaling pathways. The results revealed that the adhesion and hyphal formation of Candida albicans were inhibited significantly by magnolol. The viability and spatial structures of Candida albicans biofilms were further weakened. Candida albicans ultrastructure showed partial thinning of cell walls and even rupture, with cytoplasmic leakage. The cell wall intergrity and β-glucan content were also radically reduced. Moreover, magnolol caused significant inhibition of the expression of Candida albicans adhesion, invasion, hyphal formation, biofilm formation, β-1,3-glucan synthesis, and hydrolase secretion-related genes, including ALS1, ALS3, EFG1, EAP1, FKS1, FKS2, PLB2, and SAP2. Furthermore, the PKC pathway-related genes (RHO1, PKC1, BCK1, MKK2, MKC1) and Cek1 pathway-related genes (CDC42, CST20, STE11, HST7, CEK1) were also significantly downregulated, indicating that the inhibition of magnolol against Candida albicans virulence factors might be related to PKC and Cek1 MAPK signaling pathways. In conclusion, the findings of this study confirmed the inhibition mechanism of magnolol against Candida albicans virulence factors, which might be related to PKC and Cek1 MAPK pathways, thus laying the theoretical foundation for its clinical antifungal applications.
Early Versus Delayed Enteral Feeding in Predicted Severe Acute Gallstone Pancreatitis: A Retrospective Study
Authors: Jin Zheng , Wei Yaping , Hu Shanshan , Sun Minhui , Fang Mengdie , Shen Hongzhang , Yang Jianfeng , Zhang Xiaofeng , Jin Hangbin
Published: July 2022

Background

The optimal timing of enteral nutrition (EN) initiation in predicted severe acute gallstone pancreatitis (SAGP) and its influence on disease outcomes are not well known.

Methods

We conducted a retrospective study of patients with predicted SAGP treated with endoscopic retrograde cholangiopancreatography and EN. The patients were classified into two groups according to the timing of EN initiation after admission: within 48 h, and more than 48 h. The primary outcome was in-hospital mortality. The secondary outcomes were length of hospital stay, need for intensive care admission, need for surgical intervention, improvements in blood test results after 7-10 days of EN, incidence of pancreatic necrosis and infection, and hospital care costs. The microbiological profiles of infectious complications were also evaluated.

Results

Of the 98 patients, 31 and 67 started EN within 48 h, and more than 48 h after admission, respectively. Early EN was associated with a decrease in in-hospital mortality (0 vs. 11.9%; p=0.045), length of hospital stay (median:18 vs. 27 days; p=0.001), need for intensive care admission (3.2% vs. 20.9%; p=0.032), and hospital care costs (median:9,289 vs. 13,518 US$; p=0.007), compared to delayed EN. Moreover, early EN for 7-10 days had more beneficial effects on blood test results than delayed EN, including total protein (p=0.03) and CRP (p=0.006) levels. However, the need for surgical intervention and incidence of pancreatic necrosis did not differ between the two groups. In our study, Gram-negative bacteria were the main responsible pathogens (50.5%). Infection with multidrug-resistant organisms (MDRO) was found in 19.4% of the patients. The most common MDRO was MDR Enterococcus faecium. Early EN was not superior in reducing incidence of infected pancreatic necrosis, bacteremia, polymicrobial infection, or MDROs.

Conclusions

In patients with predicted SAGP, early EN is associated with a decrease in in-hospital mortality, length of hospital stay, need of intensive care admission, and hospital care costs, compared to delayed EN. There are no significant benefits of early EN in reducing the rate of infection-related complications. Further studies with larger sample sizes are warranted.
The role of the Pseudomonas aeruginosa hypermutator phenotype on the shift from acute to chronic virulence during respiratory infection
Authors: Hall Kalen M. , Pursell Zachary F. , Morici Lisa A.
Published: July 2022

Chronic respiratory infection (CRI) with Pseudomonas aeruginosa (Pa) presents many unique challenges that complicate treatment. One notable challenge is the hypermutator phenotype which is present in up to 60% of sampled CRI patient isolates. Hypermutation can be caused by deactivating mutations in DNA mismatch repair (MMR) genes including mutS, mutL, and uvrD. In vitro and in vivo studies have demonstrated hypermutator strains to be less virulent than wild-type Pa. However, patients colonized with hypermutators display poorer lung function and a higher incidence of treatment failure. Hypermutation and MMR-deficiency create increased genetic diversity and population heterogeneity due to elevated mutation rates. MMR-deficient strains demonstrate higher rates of mucoidy, a hallmark virulence determinant of Pa during CRI in cystic fibrosis patients. The mucoid phenotype results from simple sequence repeat mutations in the mucA gene made in the absence of functional MMR. Mutations in Pa are further increased in the absence of MMR, leading to microcolony biofilm formation, further lineage diversification, and population heterogeneity which enhance bacterial persistence and host immune evasion. Hypermutation facilitates the adaptation to the lung microenvironment, enabling survival among nutritional complexity and microaerobic or anaerobic conditions. Mutations in key acute-to-chronic virulence “switch” genes, such as retS, bfmS, and ampR, are also catalyzed by hypermutation. Consequently, strong positive selection for many loss-of-function pathoadaptive mutations is seen in hypermutators and enriched in genes such as lasR. This results in the characteristic loss of Pa acute infection virulence factors, including quorum sensing, flagellar motility, and type III secretion. Further study of the role of hypermutation on Pa chronic infection is needed to better inform treatment regimens against CRI with hypermutator strains.
Live attenuated influenza A virus vaccines with modified NS1 proteins for veterinary use
Authors: Nogales Aitor , DeDiego Marta L. , Martínez-Sobrido Luis
Published: July 2022

Influenza A viruses (IAV) spread rapidly and can infect a broad range of avian or mammalian species, having a tremendous impact in human and animal health and the global economy. IAV have evolved to develop efficient mechanisms to counteract innate immune responses, the first host mechanism that restricts IAV infection and replication. One key player in this fight against host-induced innate immune responses is the IAV non-structural 1 (NS1) protein that modulates antiviral responses and virus pathogenicity during infection. In the last decades, the implementation of reverse genetics approaches has allowed to modify the viral genome to design recombinant IAV, providing researchers a powerful platform to develop effective vaccine strategies. Among them, different levels of truncation or deletion of the NS1 protein of multiple IAV strains has resulted in attenuated viruses able to induce robust innate and adaptive immune responses, and high levels of protection against wild-type (WT) forms of IAV in multiple animal species and humans. Moreover, this strategy allows the development of novel assays to distinguish between vaccinated and/or infected animals, also known as Differentiating Infected from Vaccinated Animals (DIVA) strategy. In this review, we briefly discuss the potential of NS1 deficient or truncated IAV as safe, immunogenic and protective live-attenuated influenza vaccines (LAIV) to prevent disease caused by this important animal and human pathogen.
Contact pathway in surgical and transcatheter aortic valve replacement
Authors: de la Morena-Barrio María Eugenia , Corral Javier , López-García Cecilia , Jiménez-Díaz Víctor Alonso , Miñano Antonia , Juan-Salvadores Pablo , Esteve-Pastor María Asunción , Baz-Alonso José Antonio , Rubio Ana María , Sarabia-Tirado Francisco , García-Navarro Miguel , García-Lara Juan , Marín Francisco , Vicente Vicente , Pinar Eduardo , Cánovas Sergio José , de la Morena Gonzalo
Published: July 2022

Background

Aortic valve replacement is the gold standard treatment for severe symptomatic aortic stenosis, but thrombosis of bioprosthetic valves (PVT) remains a concern.

Objective

To analyze the factors involved in the contact pathway during aortic valve replacement and to assess their impact on the development of thromboembolic complications.

Methods

The study was conducted in 232 consecutive patients who underwent: transcatheter aortic valve replacement (TAVR, N = 155), and surgical valve replacement (SAVR, N = 77) (MUVITAVI project). Demographic and clinical data, outcomes including a combined end point (CEP) of thrombotic events, and imaging controls were recruited. Samples were collected 24 h before and 48 h after valve replacement. FXII, FXI and (pre)kallikrein were evaluated by Western Blot and specific ELISA with nanobodies.

Results

The CEP of thrombotic events was reached by 19 patients: 13 patients presented systemic embolic events and 6 patients subclinical PVT. Valve replacement did not cause FXII activation or generation of kallikrein. There was a significant reduction of FXI levels associated with the procedure, which was statistically more pronounced in SAVR than in TAVR. Cases with reductions of FXI below 80% of basal values had a lower incidence of embolic events during the procedure than patients in whom FXI increased above 150%: 2.7 vs. 16.7%; p: 0.04.

Conclusion

TAVR or SAVR did not significantly activate the contact pathway. A significant reduction of FXI, was observed, particularly in SAVR, associated with lower incidence of thrombotic events. These results encourage evaluating the usefulness and safety of FXI-directed antithrombotic treatments in these patients.
Real-World and Regulatory Perspectives of Artificial Intelligence in Cardiovascular Imaging
Authors: Wellnhofer Ernst
Published: July 2022

Recent progress in digital health data recording, advances in computing power, and methodological approaches that extract information from data as artificial intelligence are expected to have a disruptive impact on technology in medicine. One of the potential benefits is the ability to extract new and essential insights from the vast amount of data generated during health care delivery every day. Cardiovascular imaging is boosted by new intelligent automatic methods to manage, process, segment, and analyze petabytes of image data exceeding historical manual capacities. Algorithms that learn from data raise new challenges for regulatory bodies. Partially autonomous behavior and adaptive modifications and a lack of transparency in deriving evidence from complex data pose considerable problems. Controlling new technologies requires new controlling techniques and ongoing regulatory research. All stakeholders must participate in the quest to find a fair balance between innovation and regulation. The regulatory approach to artificial intelligence must be risk-based and resilient. A focus on unknown emerging risks demands continuous surveillance and clinical evaluation during the total product life cycle. Since learning algorithms are data-driven, high-quality data is fundamental for good machine learning practice. Mining, processing, validation, governance, and data control must account for bias, error, inappropriate use, drifts, and shifts, particularly in real-world data. Regulators worldwide are tackling twenty-first century challenges raised by “learning” medical devices. Ethical concerns and regulatory approaches are presented. The paper concludes with a discussion on the future of responsible artificial intelligence.
Identifying novel subgroups in heart failure patients with unsupervised machine learning: A scoping review
Authors: Sun Jin , Guo Hua , Wang Wenjun , Wang Xiao , Ding Junyu , He Kunlun , Guan Xizhou
Published: July 2022

Background

Heart failure is currently divided into three main forms, HFrEF, HFpEF, and HFmrEF, but its etiology is diverse and highly heterogeneous. Many studies reported a variety of novel subgroups in heart failure patients, with unsupervised machine learning methods. The aim of this scoping review is to provide insights into how these techniques can diagnose and manage HF faster and better, thus providing direction for future research and facilitating its routine use in clinical practice.

Methods

The review was performed following PRISMA-SCR guideline. We searched the PubMed database for eligible publications. Studies were included if they defined new subgroups in HF patients using clustering analysis methods, and excluded if they are (1) Reviews, commentary, or editorials, (2) Studies not about defining new sub-types, or (3) Studies not using unsupervised algorithms. All study screening and data extraction were conducted independently by two investigators and narrative integration of data extracted from included studies was performed.

Results

Of the 498 studies identified, 47 were included in the analysis. Most studies (61.7%) were published in 2020 and later. The largest number of studies (46.8%) coming from the United States, and most of the studies were authored and included in the same country. The most commonly used machine learning method was hierarchical cluster analysis (46.8%), the most commonly used cluster variable type was comorbidity (61.7%), and the least used cluster variable type was genomics (12.8%). Most of the studies used data sets of less than 500 patients (48.9%), and the sample size had negative correlation with the number of clustering variables. The majority of studies (85.1%) assessed the association between cluster grouping and at least one outcomes, with death and hospitalization being the most commonly used outcome measures.

Conclusion

This scoping review provides an overview of recent studies proposing novel HF subgroups based on clustering analysis. Differences were found in study design, study population, clustering methods and variables, and outcomes of interests, and we provided insights into how these studies were conducted and identify the knowledge gaps to guide future research.
Holter-determined arrhythmias in young elite athletes with suspected risk: Insights from a 20-year experience
Authors: Boraita Araceli , Heras María-Eugenia , Valenzuela Pedro L. , Diaz-Gonzalez Leonel , Morales-Acuna Francisco , Alcocer-Ayuga María , Bartolomé-Mateos Sonia , Santos-Lozano Alejandro , Lucia Alejandro
Published: July 2022

Purpose

We assessed the occurrence of rhythm alterations in elite athletes with suspected risk using Holter monitoring, and the association of Holter-determined rhythm alterations with echocardiographic findings.

Methods

A large cohort of Spanish elite athletes (N = 6,579, 34% female) underwent in-depth cardiological examination (including echocardiographic evaluation, and resting and exercise electrocardiogram [ECG]) between 01/02/1998 and 12/31/2018. Holter monitoring was performed in those reporting cardiovascular symptoms, with suspicion of cardiac structural abnormalities potentially associated with dangerous arrhythmias, or with resting/exercise ECG features prompting a closer examination. We assessed the occurrence of cardiac rhythm alterations, as well as the association between echocardiography-determined conditions and rhythm alterations.

Results

Most athletes (N = 5925) did not show any sign/symptom related to arrhythmia (including normal resting and exercise/post-exercise ECG results) whereas 9.9% (N = 654; 28% female; median age, 24 years [interquartile range 19–28]; competition experience [mean ± SD] 10±6 years) met the criteria to undergo Holter monitoring. Among the latter, sinus bradycardia was the most common finding (present in 96% of cases), yet with a relatively low proportion of severe (<30 bpm) bradycardia (12% of endurance athletes during night-time). Premature atrial and ventricular beats were also common (61.9 and 39.4%, respectively) but sinus pauses ≥3 s, high-grade atrioventricular blocks, and atrial fibrillation/flutter were rare (<1%). Polymorphic premature ventricular contractions (PVC, 1.4%) and idioventricular rhythm (0.005%) were also rare. PVC couplets were relatively prevalent (10.7%), but complex ventricular arrhythmias were not frequent (PVC triplets: 1.8%; sustained ventricular tachycardia: 0.0%; and nonsustained ventricular tachycardia: 1.5%). On the other hand, no associations were found between arrhythmias (including their different morphologies) and major cardiac structural alterations (including mitral prolapse). However, an association was found between mild mitral regurgitation and supraventricular (odds ratio 2.61; 95% confidence interval 1.08–6.32) and ventricular (2.80; 1.15–6.78; p = 0.02) arrhythmias, as well as between mild or moderate mitral regurgitation and ventricular arrhythmias (2.49; 1.03–6.01).

Conclusions

Irrespective of the sports discipline, “dangerous” ventricular arrhythmias are overall infrequent even among young elite athletes who require Holter monitoring due to the presence of symptoms or abnormal echocardiographic/ECG findings, and do not seem to be associated with underlying serious cardiac structural pathologies.
Pathology-related changes in cardiac energy metabolites, inflammatory response and reperfusion injury following cardioplegic arrest in patients undergoing open-heart surgery
Authors: Skeffington Katie L. , Moscarelli Marco , Abdul-Ghani Safa , Fiorentino Francesca , Emanueli Costanza , Reeves Barnaby C. , Punjabi Prakash P. , Angelini Gianni D. , Suleiman M-Saadeh
Published: July 2022

Introduction

Changes in cardiac metabolites in adult patients undergoing open-heart surgery using ischemic cardioplegic arrest have largely been reported for non-ventricular tissue or diseased left ventricular tissue, with few studies attempting to assess such changes in both ventricular chambers. It is also unknown whether such changes are altered in different pathologies or linked to the degree of reperfusion injury and inflammatory response. The aim of the present work was to address these issues by monitoring myocardial metabolites in both ventricles and to establish whether these changes are linked to reperfusion injury and inflammatory/stress response in patients undergoing surgery using cold blood cardioplegia for either coronary artery bypass graft (CABG, n = 25) or aortic valve replacement (AVR, n = 16).

Methods

Ventricular biopsies from both left (LV) and right (RV) ventricles were collected before ischemic cardioplegic arrest and 20 min after reperfusion. The biopsies were processed for measuring selected metabolites (adenine nucleotides, purines, and amino acids) using HPLC. Blood markers of cardiac injury (Troponin I, cTnI), inflammation (IL- 6, IL-8, Il-10, and TNFα, measured using Multiplex) and oxidative stress (Myeloperoxidase, MPO) were measured pre- and up to 72 hours post-operatively.

Results

The CABG group had a significantly shorter ischemic cardioplegic arrest time (38.6 ± 2.3 min) compared to AVR group (63.0 ± 4.9 min, p = 2 x 10−6). Cardiac injury (cTnI release) was similar for both CABG and AVR groups. The inflammatory markers IL-6 and Il-8 were significantly higher in CABG patients compared to AVR patients. Metabolic markers of cardiac ischemic stress were relatively and significantly more altered in the LV of CABG patients. Comparing diabetic and non-diabetic CABG patients shows that only the RV of diabetic patients sustained major ischemic stress during reperfusion and that diabetic patients had a significantly higher inflammatory response.

Discussion

CABG patients sustain relatively more ischemic stress, systemic inflammatory response and similar injury and oxidative stress compared to AVR patients despite having significantly shorter cross-clamp time. The higher inflammatory response in CABG patients appears to be at least partly driven by a higher incidence of diabetes amongst CABG patients. In addition to pathology, the use of cold blood cardioplegic arrest may underlie these differences.
Effects of the Chinese herbal medicine Hong Huang decoction, on myocardial injury in breast cancer patients who underwent anthracycline-based chemotherapy
Authors: Cao Sihan , Xue Jingxian , Chen Lu , Hao Yun , Lu Meijuan , Feng Ming , Wang Huanhuan , Zhou Jun , Yao Chang
Published: July 2022

Objective

To assess the effects of Hong Huang Decoction (HHD), a Chinese herbal medicine, on myocardial injury in breast cancer patients who underwent anthracycline (ANT)-based chemotherapy.

Methods

A total of 51 patients with breast cancer who underwent an ANT-based chemotherapy program and met the inclusion/exclusion criteria were allocated to the treatment or placebo groups using a random number generation process. Patients in the treatment group received liquid HHD twice a day. Treatment was given from 1 day prior to chemotherapy up to the end of chemotherapy (after 6 months). Participants in the placebo group received a placebo over the same schedule. Left ventricular ejection fraction (LVEF), global longitudinal strain (GLS), diagnostic markers of acute myocardial infarction [e.g., lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), and B-type natriuretic peptide (BNP)], nitric oxide (NO), superoxide dismutase (SOD), as well as pro-inflammatory cytokines [e.g., tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and human C-reactive protein (CRP)], and anti-inflammatory cytokine interleukin-10 (IL-10), were outcome measures assessed before chemotherapy, 3 and 6 months after chemotherapy.

Results

Compared to the placebo group, the GLS value was significantly higher in the treatment group (19.95 ± 1.16 vs. 19.06 ± 1.64, P ≤ 0.001). Significant differences were also noted for levels of SOD (689.71 ± 203.60 vs. 807.88 ± 182.10, P < 0.05), IL-6 (58.04 ± 22.06 vs. 194.20 ± 40.14, P ≤ 0.001), IL-10 (237.90 ± 94.98 vs. 68.81 ± 32.92, P ≤ 0.001), NO (75.05 ± 26.39 vs. 55.83 ± 19.37, P ≤ 0.005), and TNF-α (301.80 ± 134.20 vs. 680.30 ± 199.60, P ≤ 0.001) in the patients before chemotherapy compared to 6 months after initiating chemotherapy.

Conclusion

HHD regulated the levels of IL-6, IL-10, SOD, NO, and TNF-α. The results demonstrated that GLS is a better indicator of early myocardial injury compared to LVEF, and HHD could modulate oxidative stress to protect against ANT cardio toxicity.

Clinical trial registration

Chinese Clinical Trial Registry, identifier ChiCTR1900022394. Date of registration: 2019-04-09.