Identification of NR3C2 as a functional diagnostic and prognostic biomarker and potential therapeutic target in non-small cell lung cancer.

Background: Non-small cell lung cancer (NSCLC), including the lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) subtypes, is a malignant tumor type with a poor 5-year survival rate. The identification of new powerful diagnostic biomarkers, prognostic biomarkers, and potential therapeutic targets in NSCLC is urgently required. Methods: The UCSC Xena, UALCAN, and GEO databases were used to screen and analyze differentially expressed genes, regulatory modes, and genetic/epigenetic alterations in NSCLC. The UCSC Xena database, GEO database, tissue microarray, and immunohistochemistry staining analyses were used to evaluate the diagnostic and prognostic values. Gain-of-function assays were performed to examine the roles. The ESTIMATE, TIMER, Linked Omics, STRING, and DAVID algorithms were used to analyze potential molecular mechanisms. Results: NR3C2 was identified as a potentially important molecule in NSCLC. NR3C2 is expressed at low levels in NSCLC, LUAD, and LUSC tissues, which is significantly related to the clinical indexes of these patients. Receiver operating characteristic curve analysis suggests that the altered NR3C2 expression patterns have diagnostic value in NSCLC, LUAD, and especially LUSC patients. Decreased NR3C2 expression levels can help predict poor prognosis in NSCLC and LUAD patients but not in LUSC patients. These results have been confirmed both with database analysis and real-world clinical samples on a tissue microarray. Copy number variation contributes to low NR3C2 expression levels in NSCLC and LUAD, while promoter DNA methylation is involved in its downregulation in LUSC. Two NR3C2 promoter methylation sites have high sensitivity and specificity for LUSC diagnosis with clinical application potential. NR3C2 may be a key participant in NSCLC development and progression and is closely associated with the tumor microenvironment and immune cell infiltration. NR3C2 co-expressed genes are involved in many cancer-related signaling pathways, further supporting a potentially significant role of NR3C2 in NSCLC. Conclusions: NR3C2 is a novel potential diagnostic and prognostic biomarker and therapeutic target in NSCLC.

Assessing the modification impact of vaccination on the relationship of the Discomfort Index with hand, foot, and mouth disease in Guizhou: A multicounty study.

BACKGROUND: Hand, foot, and mouth disease (HFMD) is a major public health issue in China while temperature and humidity are well-documented predictors. However, evidence on the combined effect of temperature and humidity is still limited. It also remains unclear whether such an effect could be modified by the enterovirus 71 (EV71) vaccination. METHODS: Based on 320,042 reported HFMD cases during the summer months between 2012 and 2019, we conducted a study utilizing Distributed Lag Non-Linear Models (DLNM) and time-varying DLNM to examine how China's HFMD EV71 vaccine strategy would affect the correlation between meteorological conditions and HFMD risk. RESULTS: The incidence of HFMD changed with the Discomfort Index in an arm-shaped form. The 14-day cumulative risk of HFMD exhibited a statistically significant increase during the period of 2017-2019 (following the implementation of the EV71 vaccine policy) compared to 2012-2016 (prior to the vaccine implementation). For the total population, the range of relative risk (RR) values for HFMD at the 75th, 90th, and 99th percentiles increased from 1.082-1.303 in 2012-2016 to 1.836-2.022 in 2017-2019. In the stratified analyses, Han Chinese areas show stronger relative growth, with RR values at the 75th, 90th, and 99th percentiles increased by 14.3%, 39.1%, and 134.4% post-vaccination, compared to increases of 22.7%, 41.6%, and 38.8% in minority areas. Similarly, boys showed greater increases (24.4%, 47.7%, 121.5%) compared to girls (8.1%, 28.1%, 58.3%). Additionally, the central Guizhou urban agglomeration displayed a tendency for stronger relative growth compared to other counties. CONCLUSIONS: Although the EV71 vaccine policy has been implemented, it hasn't effectively controlled the overall risk of HFMD. There's been a shift in the main viral subtypes, potentially altering population susceptibility and influencing HFMD occurrences. The modulating effects of vaccine intervention may also be influenced by factors such as race, sex, and economic level.

The Olfactory Receptor Olfr25 Mediates Sperm Dysfunction Induced by Low-Dose Bisphenol A through the CatSper-Ca2+ Signaling Pathway.

Bisphenol A (BPA), a typical endocrine disruptor, is known to have various adverse effects on the male reproductive system. However, the toxic effects and mechanisms of low-dose BPA have not yet been fully explored. In this study, male Kunming mice were orally administered low-dose BPA (0.03, 0.3 and 3 mg/kg/d) for ten consecutive weeks. Pathological sections of testicular tissue showed no significant morphological differences after BPA exposure. An analysis of the functional parameters of sperm revealed that exposure to low-dose BPA significantly decreased sperm motility, chemotaxis, and the acrosome reaction. An in vitro BPA exposure model combined with an omics data analysis showed that the olfactory receptor-related pathway was significantly enriched after BPA treatment. Subsequent experiments verified the reduced mRNA level of a novel olfactory receptor gene, Olfr25, in vivo and in vitro exposure models. Meanwhile, exposure to low-dose BPA reduced the intracellular calcium ion concentration and the mRNA levels of pore-forming subunits of the CatSper channel in sperm. Importantly, the knockdown of Olfr25 inhibited calcium ion levels and CatSper subunit expression in GC-2 cells. Olfr25 overexpression attenuated the BPA-induced downregulation of CatSper subunit expression in GC-2 cells. These findings indicate that Olfr25 might participate in low-dose BPA-induced sperm dysfunction by affecting the CatSper-Ca2+ signaling pathway. This study reveals a new mechanism underlying the effects of low-dose BPA on sperm function and provides a reference for assessing the safety of low-dose BPA exposure.

Exploration for the Priority of HIV Intervention: Modelling Health Impact and Cost-Effectiveness - Six Cities, Eastern China, 2019-2028.

Introduction: In order to enhance the effectiveness of resource allocation, regions must tailor their responses to their specific epidemiological and economic situations. Methods: Utilizing Spectrum software, we projected the cost-effectiveness of 10 chosen HIV interventions in six cities in eastern China from 2019 to 2028. We assessed three scenarios - Base, Achievable, and Idealized - for each city. The analysis included the projected number of HIV infections and deaths averted, as well as the incremental cost-effectiveness ratios for each intervention in the six cities. Results: In Shijiazhuang, Wuxi, Yantai, and Zhenjiang, cities with initially low antiretroviral therapy (ART) coverage, ART showed significant effectiveness, especially for males. Conversely, in Foshan and Ningbo, where ART coverage was notably high, oral pre-exposure prophylaxis (PrEP) for men who have sex with men (MSM) proved effective in the Idealized scenario. MSM outreach, ART for males, and ART for females demonstrated cost-effectiveness across all six cities in both Achievable and Idealized scenarios at the predefined thresholds for each city. Discussion: Maintaining an appropriate coverage rate for outreach to MSM can lead to cost-effectiveness. In cities with low ART coverage, scaling up ART remains a crucial intervention. In regions with high ART coverage, consideration may be given to the utilization of oral PrEP for MSM individuals, requiring budget allocation.

Rsad2 mediates Bisphenol A-induced actin cytoskeletal disruption in mouse spermatocytes.

Bisphenol A (BPA) is widely exposed in populations worldwide and has negative effects on spermatogenesis both in animals and humans. The homeostasis of the actin cytoskeleton in the spermatogenic epithelium is crucial for spermatogenesis. Actin cytoskeleton destruction in the seminiferous epithelium is one of the important reasons for BPA-induced spermatogenesis disorder. However, the underlying molecular mechanisms remain largely unexplored. Herein, we explored the role and mechanism of Rsad2, an interferon-stimulated gene in BPA-induced actin cytoskeleton disorder in mouse GC-2 spermatocyte cell lines. After BPA exposure, the actin cytoskeleton was dramatically disrupted and the cell morphology was markedly altered accompanied by a significant increase in Rsad2 expression both in mRNA and protein levels in GC-2 cells. Furthermore, the phalloidin intensities and cell morphology were restored obviously when interfering with the expression of Rsad2 in BPA-treated GC-2 cells. In addition, we observed a significant decrease in intracellular ATP levels after BPA treatment, while the ATP level was obviously upregulated when knocking down the expression of Rsad2 in BPA-treated cells compared to cells treated with BPA alone. Moreover, Rsad2 relocated to mitochondria after BPA exposure in GC-2 cells. BPA promoted Rsad2 expression by activating type I IFN-signaling in GC-2 cells. In summary, Rsad2 mediated BPA-induced actin cytoskeletal disruption in GC-2 cells, which provided data to reveal the mechanism of BPA-induced male reproductive toxicity.

Effectiveness of integrase strand transfer inhibitors among treatment-naive people living with HIV/AIDS in Guangdong, China: A real-world, retrospective cohort study.

Integrase strand transfer inhibitors (INSTIs) in anti-retroviral therapy (ART) have been recommended by the World Health Organization for their higher efficacy, favorable safety and tolerability. However, the clinical evidence supporting switching to INSTI-containing regimens in low-and-middle-income countries (LMICs) is limited, as few patients have access to these regimens. We aimed to assess the effectiveness of INSTI-containing regimens in real-world settings in China compared to government-provided free ART. We compared the short-term (first 4 mo following ART initiation) and long-term (1 year after ART initiation) effectiveness between INSTI-containing regimens and free ART drugs provided by the Chinese government in 4 dimensions: viral suppression status, immune response, liver and kidney function, and AIDS-related diseases. We obtained data from electronic medical records in the National Infectious Disease Surveillance System. To control baseline confounders, we used propensity score matching (PSM), calculated using logistic regression including socio-demographic and baseline factors. Among 12,836 patients from 2012 to 2019, 673 (5.2%) used INSTI-containing regimens. Patients with INSTI-containing regimens were matched to those with free drugs (644 vs 644). For short-term effectiveness, patients initiating INSTI-containing regimens were more likely to achieve viral suppression (81.4% vs 52.0%; P < .001). The differences in immune response, liver and kidney function and AIDS-related diseases were not significant between the 2 groups. For long-term effectiveness, viral suppression rates were similar (87.96% vs 84.59%; P = .135), with no significant differences in immune response, liver and kidney function, or AIDS-related diseases. Our study suggests that patients initiating ART with INSTI-containing regimens have worse physical status at baseline than patients starting with free ART drugs. Furthermore, we found better virological performances of INSTI-containing regimens in the short-term but not in the long-term due to a high rate of drug changes. Our findings have clinical implications and provide new evidence regarding the effectiveness of INSTI-containing regimens in LMICs.

Progress in clinical diagnosis and treatment of colorectal cancer with rare genetic variants.

Targeted therapy is crucial for advanced colorectal cancer (CRC) positive for genetic drivers. With advances in deep sequencing technology and new targeted drugs, existing standard molecular pathological detection systems and therapeutic strategies can no longer meet the requirements for careful management of patients with advanced CRC. Thus, rare genetic variations require diagnosis and targeted therapy in clinical practice. Rare gene mutations, amplifications, and rearrangements are usually associated with poor prognosis and poor response to conventional therapy. This review summarizes the clinical diagnosis and treatment of rare genetic variations, in genes including erb-b2 receptor tyrosine kinase 2 (ERBB2), B-Raf proto-oncogene, serine/threonine kinase (BRAF), ALK receptor tyrosine kinase/ROS proto-oncogene 1, receptor tyrosine kinase (ALK/ROS1), neurotrophic receptor tyrosine kinases (NTRKs), ret proto-oncogene (RET), fibroblast growth factor receptor 2 (FGFR2), and epidermal growth factor receptor (EGFR), to enhance understanding and identify more accurate personalized treatments for patients with rare genetic variations.

Mining the Carbon Intermediates in Plastic Waste Upcycling for Constructing C-S Bond.

Postconsumer plastics are generally perceived as valueless with only a small portion of plastic waste being closed-loop recycled into similar products while most of them are discarded in landfills. Depositing plastic waste in landfills not only harms the environment but also signifies a substantial economic loss. Alternatively, constructing value-added chemical feedstocks via mining the waste-derived intermediate species as a carbon (C) source under mild electrochemical conditions is a sustainable strategy to realize the circular economy. This proof-of-concept work provides an attractive "turning trash to treasure" strategy by integrating electrocatalytic polyethylene terephthalate (PET) plastic upcycling with a chemical C-S coupling reaction to synthesize organosulfur compounds, hydroxymethanesulfonate (HMS). HMS can be produced efficiently (Faradaic efficiency, FE of ∼70%) via deliberately capturing electrophilic intermediates generated in the PET monomer (ethylene glycol, EG) upcycling process, followed by coupling them with nucleophilic sulfur (S) species (i.e., SO32- and HSO3-). Unlike many previous studies conducted under alkaline conditions, PET upcycling was performed over an amorphous MnO2 catalyst under near-neutral conditions, allowing for the stabilization of electrophilic intermediates. The compatibility of this strategy was further investigated by employing biomass-derived compounds as substrates. Moreover, comparable HMS yields can be achieved with real-world PET plastics, showing its enormous potential in practical application. Lastly, Density function theory (DFT) calculation reveals that the C-C cleavage step of EG is the rate-determining step (RDS), and amorphous MnO2 significantly decreases the energy barriers for both RDS and C-S coupling when compared to the crystalline counterpart.

Advances in Small-Molecule Dual Inhibitors Targeting EGFR and HER2 Receptors as Anti-Cancer Agents.

As members of the protein tyrosine kinase family, the Epidermal Growth Factor Receptor (EGFR) and Human Epidermal Growth Factor Receptor 2 (HER2) play essential roles in cellular signal transduction pathways. Overexpression or abnormal activation of EGFR and HER2 can lead to the development of various solid tumors. Therefore, they have been confirmed as biological targets for the development of anticancer drugs. Due to the fact that many cancers are highly susceptible to developing resistance to single-target EGFR inhibitors in clinical practice, dual inhibitors that target both EGFR and HER2 have been developed to increase efficacy, reduce drug resistance and interactions, and improve patient compliance. Currently, a variety of EGFR/HER2 dual inhibitors have been developed, with several drugs already approved for marketing or in clinical trials. In this review, we summarize recent advancements in small-molecule EGFR/HER2 dual inhibitors by focusing on structure-activity relationships and share novel insights into developing anticancer agents.

Global Burden and Trends of Primary Liver Cancer Attributable to Comorbid Type 2 Diabetes Mellitus Among People Living with Hepatitis B: An Observational Trend Study from 1990 to 2019.

BACKGROUND: Type 2 diabetes mellitus (T2DM) increases the risk of liver cancer among people living with hepatitis B virus (HBV). Our study aimed to estimate the global burden and trends of liver cancer attributable to comorbid T2DM among people living with HBV from 1990 to 2019. METHODS: We calculated the population attributable fractions (PAFs) of liver cancer attributable to comorbid T2DM among the burden of HBV-related liver cancer. We applied the PAFs to the burden of HBV-related liver cancer derived from the Global Burden of Disease (GBD) 2019 database to obtain the burden of liver cancer attributable to HBV-T2DM comorbidity. The prevalence, disability-adjusted life year (DALY), and deaths of liver cancer attributable to the comorbidity were assessed at the global, regional, and country levels and then stratified by the sociodemographic index (SDI), sex, and age group. Estimated annual percentage changes (EAPCs) were calculated to quantify the temporal trends. RESULTS: In 2019, the global age-standardized prevalence and DALY rates of liver cancer attributable to HBV-T2DM comorbidity were 9.9 (8.4-11.5) and 182.4 (154.9-212.7) per 10,000,000 individuals, respectively. High-income Asia Pacific and East Asia had the highest age-standardized prevalence and DALY rates of liver cancer attributable to HBV-T2DM comorbidity, respectively. From 1990 to 2019, age-standardized prevalence and DALY rates increased in 16 out of 21 GBD regions. High-income North America had the largest annual increases in both age-standardized prevalence rates (EAPC = 6.07; 95% UI, 5.59 to 6.56) and DALY rates (EAPC = 4.77; 95% UI, 4.35 to 5.20), followed by Australasia and Central Asia. Across all SDI regions, the high SDI region exhibited the most rapid increase in age-standardized prevalence and DALY rates from 1990 to 2019. Additionally, men had consistently higher disease burdens than women across all age groups. The patterns of mortality burden and trends are similar to those of DALYs. CONCLUSIONS: The burden of liver cancer attributable to comorbid T2DM among people living with HBV has exhibited an increasing trend across most regions over the last three decades. Tailored prevention strategies targeting T2DM should be implemented among individuals living with HBV.

New sexually transmitted HIV infections from 2016 to 2050 in Guangdong Province, China: a study based on a dynamic compartmental model.

BACKGROUND: In Guangdong Province, China, there is lack of information on the HIV epidemic among high-risk groups and the general population, particularly in relation to sexual transmission, which is a predominant route. The new HIV infections each year is also uncertain owing to HIV transmission from men who have sex with men (MSM) to women, as a substantial proportion of MSM also have female sexual partnerships to comply with social demands in China. METHODS: A deterministic compartmental model was developed to predict new HIV infections in four risk groups, including heterosexual men and women and low- and high-risk MSM, in Guangdong Province from 2016 to 2050, considering HIV transmission from MSM to women. The new HIV infections and its 95% credible interval (CrI) were predicted. An adaptive sequential Monte Carlo method for approximate Bayesian computation (ABC-SMC) was used to estimate the unknown parameter, a mixing index. We calibrated our results based on new HIV diagnoses and proportions of late diagnoses. The Morris and Sobol methods were applied in the sensitivity analysis. RESULTS: New HIV infections increased during and 2 years after the COVID-19 pandemic, then declined until 2050. New infections rose from 8,828 [95% credible interval (CrI): 6,435-10,451] in 2016 to 9,652 (95% CrI: 7,027-11,434) in 2019, peaking at 11,152 (95% CrI: 8,337-13,062) in 2024 before declining to 7,084 (95% CrI: 5,165-8,385) in 2035 and 4,849 (95% CrI: 3,524-5,747) in 2050. Women accounted for approximately 25.0% of new HIV infections, MSM accounted for 40.0% (approximately 55.0% of men), and high-risk MSM accounted for approximately 25.0% of the total. The ABC-SMC mixing index was 0.504 (95% CrI: 0.239-0.894). CONCLUSIONS: Given that new HIV infections and the proportion of women were relatively high in our calibrated model, to some extent, the HIV epidemic in Guangdong Province remains serious, and services for HIV prevention and control are urgently needed to return to the levels before the COVID-19 epidemic, especially in promoting condom-based safe sex and increasing awareness of HIV prevention to general population.

Trends in Intention to Take the Second Booster COVID-19 Vaccination and Associated Factors in China: Serial Cross-Sectional Surveys.

BACKGROUND: The escalating complexity of the COVID-19 epidemic underscores the need for heightened attention to booster vaccinations. This study aims to examine the changing trend in the public's intention to receive the second COVID-19 booster vaccination over time and the associated factors following the COVID-19 policy optimization in China. METHOD: Eight cross-sectional surveys utilizing SMS questionnaire links were conducted in Guangzhou, China, from December 2022 to April 2023. The Mann-Kendall test was employed to analyze the trend in intentions to receive the second booster vaccination across the survey time. Adjusted and multivariate logistic analyses were used to analyze the factors associated with vaccination intention. Parallel analyses were performed for two subgroups with different COVID-19 infection statuses. RESULTS: A total of 9860 respondents were surveyed in the eight rounds, of which 8048 completed the first booster vaccination and were included in the analysis. The overall COVID-19 infection rate was 60.0% (4832/8048), while the overall vaccination intention was 72.2% (5810/8048) among respondents. The vaccination intention exhibited a significant declining trend over time, decreasing from 81.5% in December 2022 to 52.2% in April 2023. An adjusted logistic regression analysis revealed that anxiety and depression were negatively associated with an intention to receive the second booster vaccination, while COVID-19-related preventive behaviors and a high engagement in COVID-19-related information were positively associated with an intention to receive the second booster vaccination. A subgroup analysis revealed that the association between psychological and behavioral characteristics and vaccination intention remained relatively stable among individuals with different histories of COVID-19 infections. CONCLUSION: There was a significant decline in the intention to receive the second booster vaccination following the optimization of the COVID policy in China. Our findings emphasize the urgency of the second booster vaccination and provide a foundation for the development of tailored interventions to enhance and sustain vaccination intention among the public.

Exploring the relationship between illness perception, self-management and quality of life among HIV-positive men who have sex with men.

AIMS: This study aimed to explore the mediating effect of self-management (SM) on the relationship between illness perception and quality of life (QOL) among Human immunodeficiency virus (HIV)-positive men who have sex with men (MSM). DESIGN: A cross-sectional study. METHODS: We explored the effect of illness perception and self-management on QOL using the multiple regression model. Moreover, we conducted a simple mediation analysis to examine the role of SM in the relationship between illness perception and QOL. In addition, a parallel mediation analysis was performed to investigate the differences in domains of SM on the relationship between illness perception and QOL. RESULTS: Among 300 Chinese HIV-positive MSM, the mean score of SM was 39.9 ± 6.97, with a range of 14.0-54.0. The higher score in SM indicated a higher level of HIV SM. SM was negatively related to illness perception (r = -0.47) while positively related to QOL (r = 0.56). SM partially mediated the relationship between illness perception and QOL, accounting for 25.3% of the total effect. Specifically, both daily self-management health practices and the chronic nature of the self-management domain played a parallel role in mediating the relationship between illness perception and QOL. CONCLUSION: Our study demonstrated that SM was a significant factor influencing QOL among HIV-positive MSM. Focusing on daily self-management health practices and the chronic nature of self-management could be the potential key targets for enhancing HIV self-management strategies. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: This study emphasized the role of SM in the well-being of HIV-positive MSM and underscored the importance of developing interventions that integrate SM strategies to improve QOL in this population. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Discovery of new tricyclic spiroindole derivatives as potent P-glycoprotein inhibitors for reversing multidrug resistance enabled by a synthetic methodology-based library.

The discovery of novel and highly effective P-gp inhibitors is considered to be an effective strategy for overcoming tumor drug resistance. In this paper, a phenotypic screening via a self-constructed synthetic methodology-based library identified a new class of tricyclic spiroindole derivatives with excellent tumor multidrug resistance reversal activity. A stereospecific compound OY-103-B with the best reversal activity was obtained based on a detailed structure-activity relationship study, metabolic stability optimization and chiral resolution. For the VCR-resistant Eca109 cell line (Eca109/VCR), co-administration of 5.0 µM OY-103-B resulted in a reversal fold of up to 727.2, superior to the typical third-generation P-gp inhibitor tariquidar. Moreover, the compound inhibited the proliferation of Eca109/VCR cells in a concentration-dependent manner in plate cloning and flow cytometry. Furthermore, fluorescence substrate accumulation assay and chemotherapeutic drug reversal activity tests demonstrated that OY-103-B reversed tumor drug resistance via P-gp inhibition. In conclusion, this study provides a novel skeleton that inspires the design of new P-gp inhibitors, laying the foundation for the treatment of drug-resistant tumors.

A Microactuator Array Based on Ionic Electroactive Artificial Muscles for Cell Mechanical Stimulation.

Mechanical stimulation is prevalent within organisms, and appropriate regulation of such stimulation can significantly enhance cellular functions. Consequently, the in vitro construction and simulation of mechanical stimulation have emerged as a research hotspot in biomechanics. In recent years, a class of artificial muscles named electroactive polymers (EAPs), especially ionic EAPs, have shown promising applications in biomechanics. While several techniques utilizing ionic EAPs for cell mechanical stimulation have been reported, further research is needed to advance and enhance their practical applications. Here, we prepared a microactuator array based on ionic EAP artificial muscles for cell mechanical stimulation. As a preliminary effort, we created a 5 × 5 microactuator array on a supporting membrane by employing laser cutting. We evaluated the electro-actuation performance of the microactuators through experimental testing and numerical simulations, affirming the potential use of the microactuator array for cell mechanical stimulation. The devised approach could inspire innovative design concepts in the development of miniaturized intelligent electronic devices, not only in biomechanics and biomimetics but also in other related fields.

Deciphering the Coevolutionary Dynamics of L2 ß-Lactamases via Deep Learning.

L2 ß-lactamases, serine-based class A ß-lactamases expressed by Stenotrophomonas maltophilia, play a pivotal role in antimicrobial resistance (AMR). However, limited studies have been conducted on these important enzymes. To understand the coevolutionary dynamics of L2 ß-lactamase, innovative computational methodologies, including adaptive sampling molecular dynamics simulations, and deep learning methods (convolutional variational autoencoders and BindSiteS-CNN) explored conformational changes and correlations within the L2 ß-lactamase family together with other representative class A enzymes including SME-1 and KPC-2. This work also investigated the potential role of hydrophobic nodes and binding site residues in facilitating the functional mechanisms. The convergence of analytical approaches utilized in this effort yielded comprehensive insights into the dynamic behavior of the ß-lactamases, specifically from an evolutionary standpoint. In addition, this analysis presents a promising approach for understanding how the class A ß-lactamases evolve in response to environmental pressure and establishes a theoretical foundation for forthcoming endeavors in drug development aimed at combating AMR.

Cu Promoted the Dynamic Evolution of Ni-Based Catalysts for Polyethylene Terephthalate Plastic Upcycling.

Upcycling plastic wastes into value-added chemicals is a promising approach to put end-of-life plastic wastes back into their ecocycle. As one of the polyesters that is used daily, polyethylene terephthalate (PET) plastic waste is employed here as the model substrate. Herein, a nickel (Ni)-based catalyst was prepared via electrochemically depositing copper (Cu) species on Ni foam (NiCu/NF). The NiCu/NF formed Cu/CuO and Ni/NiO/Ni(OH)2 core-shell structures before electrolysis and reconstructed into NiOOH and CuOOH/Cu(OH)2 active species during the ethylene glycol (EG) oxidation. After oxidation, the Cu and Ni species evolved into more reduced species. An indirect mechanism was identified as the main EG oxidation (EGOR) mechanism. In EGOR, NiCu60s/NF catalyst exhibited an optimal Faradaic efficiency (FE, 95.8%) and yield rate (0.70 mmol cm-2 h-1) for formate production. Also, over 80% FE of formate was achieved when a commercial PET plastic powder hydrolysate was applied. Furthermore, commercial PET plastic water bottle waste was employed as a substrate for electrocatalytic upcycling, and pure terephthalic acid (TPA) was recovered only after 1 h electrolysis. Lastly, density functional theory (DFT) calculation revealed that the key role of Cu was significantly reducing the Gibbs free-energy barrier (ΔG) of EGOR's rate-determining step (RDS), promoting catalysts' dynamic evolution, and facilitating the C-C bond cleavage.

Optimized reusable modular 3D-printed models of choledochal cyst to simulate laparoscopic and robotic bilioenteric anastomosis.

Laparoscopic and robotic surgery is a challenge to the surgeon's hand-eye coordination ability, which requires constant practice. Traditional mentor training is gradually shifting to simulation training based on various models. Laparoscopic and robotic bilioenteric anastomosis is an important and difficult operation in hepatobiliary surgery. We constructed and optimized the reusable modular 3D-printed models of choledochal cyst. The aim of this study was to verify the ability of this optimized model to distinguish between surgeons with different levels of proficiency and the benefits of repeated practice. A total of 12 surgeons with different levels participated in the study. Operation completion time and OSATS score were recorded. The model was validated by Likert scale. Surgeons were shown the steps and contents before performing laparoscopic or robotic bilioenteric anastomosis using the model. Surgeons with different levels of experience showed different levels when performing laparoscopic bilioenteric anastomosis on this model. Repeated training can significantly shorten the time of laparoscopic bilioenteric anastomosis and improve the operation scores of surgeons with different levels of experience. At the same time, preliminary results have shown that the performance of surgeons on the domestic robotic platform was basically consistent with their laparoscopic skills. This model may distinguish surgeons with different levels of experience and may improve surgical skills through repeated practice. It is worth noting that in order to draw more reliable conclusions, more subjects should be collected and more experiments should be done in the future.

A machine-learning algorithm using claims data to identify patients with homozygous familial hypercholesterolemia.

Homozygous familial hypercholesterolemia (HoFH) is an underdiagnosed and undertreated ultra-rare disease. We utilized claims data from the Komodo Healthcare Map database to develop a machine-learning model to identify potential HoFH patients. We tokenized patients enrolled in MyRARE (patient support program for those prescribed evinacumab-dgnb in the United States) and linked them with their Komodo claims. A true positive HoFH cohort (n = 331) was formed by including patients from MyRARE and patients with prescriptions for evinacumab-dgnb or lomitapide. The negative cohort (n = 1423) comprised patients with or at risk for cardiovascular disease. We divided the cohort into an 80% training and 20% testing set. Overall, 10,616 candidate features were investigated; 87 were selected due to clinical relevance and importance on prediction performance. Different machine-learning algorithms were explored, with fast interpretable greedy-tree sums selected as the final machine-learning tool. This selection was based on its satisfactory performance and its easily interpretable nature. The model identified four useful features and yielded precision (positive predicted value) of 0.98, recall (sensitivity) of 0.88, area under the receiver operating characteristic curve of 0.98, and accuracy of 0.97. The model performed well in identifying HoFH patients in the testing set, providing a useful tool to facilitate HoFH screening and diagnosis via healthcare claims data.

Current treatments for the management of homozygous familial hypercholesterolemia: a systematic review and commentary.

AIMS: Homozygous familial hypercholesterolemia (HoFH) is a rare disorder characterized by markedly elevated circulating low-density lipoprotein cholesterol (LDL-C) from birth. This review aimed to critically evaluate treatments for HoFH with respect to their efficacy, safety, accessibility, overall context and position within the treatment pathway. METHODS: A mixed-methods review was undertaken to systematically identify and characterize primary interventional studies on HoFH, with a focus on LDL-C reduction as the primary outcome. Interventions assessed were ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), lomitapide, evinacumab, with or without LDL apheresis. RESULTS: Twenty-six seminal studies reporting unique patient data were identified. Four studies were randomized controlled trials (RCTs) with the remainder being single-arm trials or observational registries. Data extracted were heterogeneous and not suitable for meta-analyses. Two RCTs, assessed at being low risk of bias, demonstrated PCSK9i were safe and moderately effective. An RCT demonstrated evinacumab was safe and effective in all HoFH subgroups. Lomitapide was reported to be efficacious in a single-arm trial, but issues with adverse events, tolerability, and adherence were identified. An RCT on ezetimibe showed it was moderately effective when combined with a statin. LDL apheresis was reported as effective, but its evidence base was at very high risk of bias. All interventions lowered LDL-C, but the magnitude of this, and certainty in the supporting evidence, varied. CONCLUSION: In practice, multiple treatments are required to treat HoFH. The sequencing of these should be made on an individualized basis, with consideration made to the benefits of each intervention.

Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disorder that results in elevated cholesterol levels, which can cause premature cardiovascular events such as heart attacks and stroke. We performed a literature review to systematically identify and analyse studies reporting on newer treatments for HoFH which lower cholesterol levels, focussing on the overall advantages and disadvantages of each treatment. We identified 26 studies, including clinical trials and observational research, reporting on the interventions ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), lomitapide, evinacumab, and LDL apheresis. While all treatments showed promise in reducing cholesterol levels, none were sufficient to effectively treat HoFH on their own, and often the confidence in the results were limited by the methodological weaknesses of the studies. The evidence suggests that management of HoFH requires an individualized approach, with consideration given to the efficacy, safety, tolerability and accessibility of each treatment.