Rectifying METTL4-Mediated N6-Methyladenine Excess in Mitochondrial DNA Alleviates Heart Failure.

BACKGROUND: Myocardial mitochondrial dysfunction underpins the pathogenesis of heart failure (HF), yet therapeutic options to restore myocardial mitochondrial function are scarce. Epigenetic modifications of mitochondrial DNA (mtDNA), such as methylation, play a pivotal role in modulating mitochondrial homeostasis. However, their involvement in HF remains unclear. METHODS: Experimental HF models were established through continuous angiotensin II and phenylephrine (AngII/PE) infusion or prolonged myocardial ischemia/reperfusion injury. The landscape of N6-methyladenine (6mA) methylation within failing cardiomyocyte mtDNA was characterized using high-resolution mass spectrometry and methylated DNA immunoprecipitation sequencing. A tamoxifen-inducible cardiomyocyte-specific Mettl4 knockout mouse model and adeno-associated virus vectors designed for cardiomyocyte-targeted manipulation of METTL4 (methyltransferase-like protein 4) expression were used to ascertain the role of mtDNA 6mA and its methyltransferase METTL4 in HF. RESULTS: METTL4 was predominantly localized within adult cardiomyocyte mitochondria. 6mA modifications were significantly more abundant in mtDNA than in nuclear DNA. Postnatal cardiomyocyte maturation presented with a reduction in 6mA levels within mtDNA, coinciding with a decrease in METTL4 expression. However, an increase in both mtDNA 6mA level and METTL4 expression was observed in failing adult cardiomyocytes, suggesting a shift toward a neonatal-like state. METTL4 preferentially targeted mtDNA promoter regions, which resulted in interference with transcription initiation complex assembly, mtDNA transcriptional stalling, and ultimately mitochondrial dysfunction. Amplifying cardiomyocyte mtDNA 6mA through METTL4 overexpression led to spontaneous mitochondrial dysfunction and HF phenotypes. The transcription factor p53 was identified as a direct regulator of METTL4 transcription in response to HF-provoking stress, thereby revealing a stress-responsive mechanism that controls METTL4 expression and mtDNA 6mA. Cardiomyocyte-specific deletion of the Mettl4 gene eliminated mtDNA 6mA excess, preserved mitochondrial function, and mitigated the development of HF upon continuous infusion of AngII/PE. In addition, specific silencing of METTL4 in cardiomyocytes restored mitochondrial function and offered therapeutic relief in mice with preexisting HF, irrespective of whether the condition was induced by AngII/PE infusion or myocardial ischemia/reperfusion injury. CONCLUSIONS: Our findings identify a pivotal role of cardiomyocyte mtDNA 6mA and the corresponding methyltransferase, METTL4, in the pathogenesis of mitochondrial dysfunction and HF. Targeted suppression of METTL4 to rectify mtDNA 6mA excess emerges as a promising strategy for developing mitochondria-focused HF interventions.

Small Extracellular Vesicles From Brown Adipose Tissue Mediate Exercise Cardioprotection.

RATIONALE: Long-term exercise provides reliable cardioprotection via mechanisms still incompletely understood. Although traditionally considered a thermogenic tissue, brown adipose tissue (BAT) communicates with remote organs (eg, the heart) through its endocrine function. BAT expands in response to exercise, but its involvement in exercise cardioprotection remains undefined. OBJECTIVE: This study investigated whether small extracellular vesicles (sEVs) secreted by BAT and their contained microRNAs (miRNAs) regulate cardiomyocyte survival and participate in exercise cardioprotection in the context of myocardial ischemia/reperfusion (MI/R) injury. METHODS AND RESULTS: Four weeks of exercise resulted in a significant BAT expansion in mice. Surgical BAT ablation before MI/R weakened the salutary effects of exercise. Adeno-associated virus 9 vectors carrying short hairpin RNA targeting Rab27a (a GTPase required for sEV secretion) or control viruses were injected in situ into the interscapular BAT. Exercise-mediated protection against MI/R injury was greatly attenuated in mice whose BAT sEV secretion was suppressed by Rab27a silencing. Intramyocardial injection of the BAT sEVs ameliorated MI/R injury, revealing the cardioprotective potential of BAT sEVs. Discovery-driven experiments identified miR-125b-5p, miR-128-3p, and miR-30d-5p (referred to as the BAT miRNAs) as essential BAT sEV components for mediating cardioprotection. BAT-specific inhibition of the BAT miRNAs prevented their upregulation in plasma sEVs and hearts of exercised mice and attenuated exercise cardioprotection. Mechanistically, the BAT miRNAs cooperatively suppressed the proapoptotic MAPK (mitogen-associated protein kinase) pathway by targeting a series of molecules (eg, Map3k5, Map2k7, and Map2k4) in the signaling cascade. Delivery of BAT sEVs into hearts or cardiomyocytes suppressed MI/R-related MAPK pathway activation, an effect that disappeared with the combined use of the BAT miRNA inhibitors. CONCLUSIONS: The sEVs secreted by BAT participate in exercise cardioprotection via delivering the cardioprotective miRNAs into the heart. These results provide novel insights into the mechanisms underlying the BAT-cardiomyocyte interaction and highlight BAT sEVs and their contained miRNAs as alternative candidates for exercise cardioprotection.

Case-mix adjustment of patient-reported experience measures in National Regional Center for Pediatric.

BACKGROUND: The aim of the study was to identify case-mix adjusters for the Chinese version of the Child Hospital Consumer Assessment of Healthcare Providers and Systems (Child-HCAHPS) and assess the impact of case-mix adjustment on patient experience measures in China. METHODS: This study analyzed data collected from six National Regional Center for Pediatric across China retrospectively. Participants were children aged ≤17 years and their guardians who completed the survey. The Chinese Child-HCAHPS was used to measure pediatric inpatient care experience. Candidate case-mix adjusters were assessed using a summary measure of explanatory power. Changes in scores and rankings of the six centers were quantified to assess the impact of adjustment. RESULTS: A total of 2708 respondents completed the survey from January to March 2021, with a response rate of 7-15%. The child's global health status and the respondent being the child's mother were identified as case-mix adjusters, and case-mix adjustment models for 18 patient experience items were constructed. Kendall's τ correlation of hospital rankings before and after adjustment ranged from 0.73 to 1.00. CONCLUSIONS: Although the impact of case-mix adjustment may appear modest in our sample, it demonstrated the feasibility, necessity, and methodology for further development of case-mix adjustment models in pediatric healthcare facilities in China. IMPACT: Case-mix adjustment models adjust for factors that are unamendable by healthcare providers that may affect patient experience ratings, thereby improving the comparability of institutional-level ratings. Standardized case-mix adjustment protocols for quality measures need to be modified in different settings. This is the first study to identify adjustment variables and the possible impact of case-mix adjustment on pediatric inpatients' experience measures in a Chinese population. This study provided evidence on the feasibility and necessity for further development of case-mix adjustment models for pediatric healthcare facilities in China.

Chemoproteomic and Transcriptomic Analysis Reveals that O-GlcNAc Regulates Mouse Embryonic Stem Cell Fate through the Pluripotency Network.

Self-renewal and differentiation of embryonic stem cells (ESCs) are influenced by protein O-linked ß-N-acetylglucosamine (O-GlcNAc) modification, but the underlying mechanism remains incompletely understood. Herein, we report the identification of 979 O-GlcNAcylated proteins and 1340 modification sites in mouse ESCs (mESCs) by using a chemoproteomics method. In addition to OCT4 and SOX2, the third core pluripotency transcription factor (PTF) NANOG was found to be modified and functionally regulated by O-GlcNAc. Upon differentiation along the neuronal lineage, the O-GlcNAc stoichiometry at 123 sites of 83 proteins-several of which were PTFs-was found to decline. Transcriptomic profiling reveals 2456 differentially expressed genes responsive to OGT inhibition during differentiation, of which 901 are target genes of core PTFs. By acting on the core PTF network, suppression of O-GlcNAcylation upregulates neuron-related genes, thus contributing to mESC fate determination.

Recent Development of Moisture-Enabled-Electric Nanogenerators.

Power generation by converting energy from the ambient environment has been considered a promising strategy for developing decentralized electrification systems to complement the electricity supply for daily use. Wet gases, such as water evaporation or moisture in the atmosphere, can be utilized as a tremendous source of electricity by emerging power generation devices, that is, moisture-enabled-electric nanogenerators (MEENGs). As a promising technology, MEENGs provided a novel manner to generate electricity by harvesting energy from moisture, originating from the interactions between water molecules and hydrophilic functional groups. Though the remarkable progress of MEENGs has been achieved, a systematic review in this specific area is urgently needed to summarize previous works and provide sharp points to further develop low-cost and high-performing MEENGs through overcoming current limitations. Herein, the working mechanisms of MEENGs reported so far are comprehensively compared. Subsequently, a systematic summary of the materials selection and fabrication methods for currently reported MEENG construction is presented. Then, the improvement strategies and development directions of MEENG are provided. At last, the demonstrations of the applications assembled with MEENGs are extracted. This work aims to pave the way for the further MEENGs to break through the performance limitations and promote the popularization of future micron electronic self-powered equipment.

FNDC5/Irisin attenuates diabetic cardiomyopathy in a type 2 diabetes mouse model by activation of integrin αV/ß5-AKT signaling and reduction of oxidative/nitrosative stress.

Irisin, the cleaved form of the fibronectin type III domain containing 5 (FNDC5) protein, is involved in metabolism and inflammation. Recent findings indicated that irisin participated in cardiovascular physiology and pathology. In this study, we investigated the effects of FNDC5/irisin on diabetic cardiomyopathy (DCM) in type 2 diabetic db/db mice. Downregulation of myocardial FNDC5/irisin protein expression and plasma irisin levels was observed in db/db mice compared to db/+ controls. Moreover, echocardiography revealed that db/db mice exhibited normal cardiac systolic function and impaired diastolic function. Adverse structural remodeling, including cardiomyocyte apoptosis, myocardial fibrosis, and cardiac hypertrophy were observed in the hearts of db/db mice. Sixteen-week-old db/db mice were intramyocardially injected with adenovirus encoding FNDC5 or treated with recombinant human irisin via a peritoneal implant osmotic pump for 4 weeks. Both overexpression of myocardial FNDC5 and exogenous irisin administration attenuated diastolic dysfunction and cardiac structural remodeling in db/db mice. Results from in vitro studies revealed that FNDC5/irisin protein expression was decreased in high glucose (HG)/high fat (HF)-treated cardiomyocytes. Increased levels of inducible nitric oxide synthase (iNOS), NADPH oxidase 2 (NOX2), 3-nitrotyrosine (3-NT), reactive oxygen species (ROS), and peroxynitrite (ONOO-) in HG/HF-treated H9C2 cells provided evidence of oxidative/nitrosative stress, which was alleviated by treatment with FNDC5/irisin. Moreover, the mitochondria membrane potential (ΔΨm) was decreased and cytochrome C was released from mitochondria with increased levels of cleaved caspase-3 in HG/HF-treated H9C2 cells, indicating the presence of mitochondria-dependent apoptosis, which was partially reversed by FNDC5/irisin treatment. Mechanistic studies showed that activation of integrin αVß5-AKT signaling and attenuation of oxidative/nitrosative stress were responsible for the cardioprotective effects of FNDC5/irisin. Therefore, FNDC5/irisin mediates cardioprotection in DCM by inhibiting myocardial apoptosis, myocardial fibrosis, and cardiac hypertrophy. These findings implicate that FNDC5/irisin as a potential therapeutic intervention for DCM, especially in type 2 diabetes mellitus (T2DM).

Influence of patient and hospital characteristics on inpatient satisfaction in China's tertiary hospitals: A cross-sectional study.

BACKGROUND: Patient satisfaction has been seen as a key criterion when evaluating hospitals and is one of the main focuses of the current health-care reform in China. This paper aimed to explore patient- and hospital-level factors associated with inpatient satisfaction, which can provide policy implications for the evaluation and development of a patient-oriented health-care system. METHODS: The paper analyses data from the 2017 China National Patient Survey which includes 20 300 inpatients from 131 tertiary hospitals across 31 provinces. Descriptive analysis and multivariable logistic regressions are conducted to identify key factors related to satisfaction. RESULTS: Patient sociodemographic characteristics, including gender, age, income and insurance type, are found to be strongly associated with their satisfaction of inpatient experience. In terms of institutional characteristics, hospital type, size, staffing and financial performance are also significantly correlated with inpatient satisfaction. Patients are more satisfied with specialist hospitals and large hospitals measured by the number of beds and surgeries. Hospitals with higher nurse-to-bed ratio also receive more satisfaction. The financial performance of hospitals, however, is negatively associated with satisfaction. CONCLUSION: Patient satisfaction contains unique information on service quality and thus should be incorporated into the matrix of hospital evaluation. Meanwhile, differences in patient composition must be adjusted to make fair comparisons across hospitals. Moreover, future reform needs to put greater efforts in the design of comprehensive public insurance scheme, efficient hospital structure and an overall well-functioning health-care delivery system in order to better serve patients in China.

Information Disclosure During the COVID-19 Epidemic in China: City-Level Observational Study.

BACKGROUND: Information disclosure is a top priority for official responses to the COVID-19 pandemic. The timely and standardized information published by authorities as a response to the crisis can better inform the public and enable better preparations for the pandemic; however, there is limited evidence of any systematic analyses of the disclosed epidemic information. This in turn has important implications for risk communication. OBJECTIVE: This study aimed to describe and compare the officially released content regarding local epidemic situations as well as analyze the characteristics of information disclosure through local communication in major cities in China. METHODS: The 31 capital cities in mainland China were included in this city-level observational study. Data were retrieved from local municipalities and health commission websites as of March 18, 2020. A checklist was employed as a rapid qualitative assessment tool to analyze the information disclosure performance of each city. Descriptive analyses and data visualizations were produced to present and compare the comparative performances of the cities. RESULTS: In total, 29 of 31 cities (93.5%) established specific COVID-19 webpages to disclose information. Among them, 12 of the city webpages were added to their corresponding municipal websites. A majority of the cities (21/31, 67.7%) published their first cases of infection in a timely manner on the actual day of confirmation. Regarding the information disclosures highlighted on the websites, news updates from local media or press briefings were the most prevalent (28/29, 96.6%), followed by epidemic surveillance (25/29, 86.2%), and advice for the public (25/29, 86.2%). Clarifications of misinformation and frequently asked questions were largely overlooked as only 2 cities provided this valuable information. The median daily update frequency of epidemic surveillance summaries was 1.2 times per day (IQR 1.0-1.3 times), and the majority of these summaries (18/25, 72.0%) also provided detailed information regarding confirmed cases. The reporting of key indicators in the epidemic surveillance summaries, as well as critical facts included in the confirmed case reports, varied substantially between cities. In general, the best performance in terms of timely reporting and the transparency of information disclosures were observed in the municipalities directly administered by the central government compared to the other cities. CONCLUSIONS: Timely and effective efforts to disclose information related to the COVID-19 epidemic have been made in major cities in China. Continued improvements to local authority reporting will contribute to more effective public communication and efficient public health research responses. The development of protocols and the standardization of epidemic message templates-as well as the use of uniform operating procedures to provide regular information updates-should be prioritized to ensure a coordinated national response.

Earlier changes in mice after D-galactose treatment were improved by mitochondria derived small peptide MOTS-c.

MOTS-c, as a mitochondria derived peptide, exerts benefits for insulin resistance in HFD mice and against various stresses in an AMPK dependent way. Here, in the D-galactose chronic injection models, exogenous MOTS-c was given to determine its direct anti-aging effects. The body weight, insulin sensitivity and blood glucose were determined with mild differences. Tissue morphology analyses disclosed that liver, visceral fat and dermal skin, all displayed aberrant lipid depositions in the D-galactose mice. MOTS-c treatment largely alleviated the lipid accumulations, corresponding with positive changes in mitochondria dynamics, observed in liver transmission electron microscopy and in altered mRNA levels of Drp1 and mitofusins. Notably, the aging phenotypes of small intestine tract were more obvious, including histological defects and lower Ki67 levels, plus with the higher levels of DNA stress, such as P21 and P16, as well as mitochondria dynamics. Collectively, these data provided the direct evidence to support that exogenous givings of MOTS-c prevented abnormal fat accumulations in D-gal mice, putatively via improvement of mitochondria dynamic related pathways.

A Tactile Sensor Decoupling Process.

An improved hybrid homotopy method is proposed to decouple the multi-input model of tactile sensors. The time-embedded homotopy algorithm is proved to be very suitable for solving the problem. Three tracking factors that control the efficiency of the algorithm are studied: tracking operator, stepsize, and accuracy. Trust region methods are applied to track the zero paths instead of the traditional differential algorithm, and a periodic sampling method is proposed to improve the efficiency of the algorithm. Numerical experiments show that both the robustness and accuracy have received a huge boost after the hybrid algorithm is applied.

Consumer satisfaction with tertiary healthcare in China: findings from the 2015 China National Patient Survey.

OBJECTIVE: This study aims to develop understanding of Chinese patient satisfaction with tertiary hospitals. DESIGN: The study draws on data collected from the 2015 China National Patient Survey. A Likert five-point scale was used to formulate the questionnaires. Descriptive analysis and logistic regression analysis were conducted. SETTING: A structured questionnaire was used by 1432 interviewers to interview 27 475 outpatients and 19 938 inpatients in 136 tertiary hospitals from 31 provinces. PARTICIPANTS: Outpatients in the dispensing area and inpatients in the discharging area were randomly interviewed. MAIN OUTCOME MEASURE(S): Key domains of the questionnaire include the layout of service functions, environment maintenance, process management, quality of care, humane care and the patient-doctor relationship. Within each domain, several indicators were set, and each indicator was given a statement. RESULTS: The overall satisfaction scores are 4.42 ± 0.68 and 4.67 ± 0.62 for outpatient and inpatient, respectively. The domains with highest satisfaction are 'diagnosis and treatment' for outpatient and 'nursing care' for inpatient. Outpatients were least satisfied with long waiting time, while inpatients were least satisfied with the food. The strongest predictor of overall satisfaction appears to be 'patient-doctor relationship' for both outpatients (OR = 3.53, 95% CI: 3.17-3.92) and inpatients (OR = 7.34, 95% CI: 5.55-9.70). CONCLUSIONS: Chinese hospitals need to pay more attention to offering more humane care to patients, hospital environment and process management improvement, reducing waiting times for seeing doctors and outpatient testing, and improving amenity services such as better food in the wards.

Welfare, wellness, and job satisfaction of Chinese physicians: A national survey of public tertiary hospitals in China.

Little national data are available on Chinese physicians' welfare, wellness, and job satisfaction. We conducted a self-administered smartphone-based national survey in early 2016 of 17 945 physicians from 136 tertiary hospitals across 31 provinces in China. In addition to collecting the physicians' basic information, we also measured 5 domains (the ethical and working environments, welfare, wellness, and job satisfaction). Half of the physicians reported a hospital-based annual income of less than RMB 72 000 ($10 300), and 60.31% of them did not think that the current medical pricing system reflects physicians' value. More than half (58.64%) of them did not have or did not know about medical malpractice insurance. These physicians worked long hours (an average of 10 h) and slept short hours (average 6 h). Only 35.78% of them thought that they were in good health, and 51.03% were in good mental health. Approximately, a quarter of them had helped to pay medical bills for patients who could not afford care, and 1 in 7 has been penalised for seeing patients who generated bad debts. Only 33.42% of them thought that their occupation receives social recognition and respect, and 70.98% would not encourage their children to pursue a medical career. The top 3 factors that may influence physician job satisfaction as chosen by the physicians were as follows: (1) the income distribution policy (45.92%), (2) working environment safety (25.86%), and (3) public trust and respect for their job (16.10%). In conclusion, we found that Chinese physicians bear heavy physical, mental, and financial stress, and many of them lack confidence that they receive trust and respect from society.

[Cost analysis of the colorectal neoplasm screen program in Beijing].

OBJECTIVE: To conduct with a cost analysis of the colorectal neoplasm screening program in Beijing, and provide data evidence for decision making. METHODS: Based on stratified cluster sampling method, we carried out a 2-stage colorectal neoplasm screening program within 6 districts, Dongcheng, Xicheng, Chaoyang, Haidian, Fengtai and Shijingshan, of Beijing city between October, 2012 to May. 2013. The first stage of the program was to conducting a cancer risk level evaluation for community residents who were forty years older and the second stage's task was to providing clinical exam for those high risk people who were selected from the first stage. There were about 12 953 residents were involved in this program. We calculated the main cost of the colorectal neoplasm screen program in Beijing. Then estimate the cost of detecting one Colorectal Neoplasm patient of this program and compare it with the total treatment cost for a patient. RESULT: 2 487 high risk residents were selected by the first stage and 1 055 of them made appointment for the colonoscopy exam but only 375 accepted the exam, participate rate was 35.5%. 9 neoplasm cancer patients and 71 pre-cancer patient were found at the second stage, the detection rate were 69.2/100 000 and 546/100 000, respectively. The direct input for this neoplasm screening program was 227 100 CNY and the transport expense was 4 200 CNY in the calculations. The cost for detecting one cancer patient was about 19 900 CNY. Comparing with the total medical care cost of a cancer patient (1 282 800 CNY), especially for those have been diagnosed as middle to end stage cancer, the screening program (cost 842 800 CNY) might help to reduce the total health expenditure about 128 700 CNY, based on 12 953 local residents age above 40 years old. CONCLUSION: An colonoscopy based colorectal neoplasm screening program showed its function on medical expenditure saving and might have advantage on health social labor creating.

Extracellular Vesicles in Cardiovascular Pathophysiology: Communications, Biomarkers, and Therapeutic Potential.

Extracellular vesicles (EVs) are diverse, membrane-bound vesicles released from cells into the extracellular environment. They originate from either endosomes or the cell membrane and typically include exosomes and microvesicles. These EVs serve as crucial mediators of intercellular communication, carrying a variety of contents such as nucleic acids, proteins, and lipids, which regulate the physiological and pathological processes of target cells. Moreover, the molecular cargo of EVs can reflect critical information about the originating cells, making them potential biomarkers for the diagnosis and prognosis of diseases. Over the past decade, the role of EVs as key communicators between cell types in cardiovascular physiology and pathology has gained increasing recognition. EVs from different cellular sources, or from the same source under different cellular conditions, can have distinct impacts on the management, diagnosis, and prognosis of cardiovascular diseases. Furthermore, it is essential to consider the influence of cardiovascular-derived EVs on the metabolism of peripheral organs. This review aims to summarize recent advancements in the field of cardiovascular research with respect to the roles and implications of EVs. Our goal is to provide new insights and directions for the early prevention and treatment of cardiovascular diseases, with an emphasis on the therapeutic potential and diagnostic value of EVs.

Cost-effectiveness and cost-utility analyses of three different gargles in the treatment of chronic periodontitis.

OBJECTIVE: This study aimed to investigate the economics of three different gargles in the treatment of chronic periodontitis. METHODS: A total of 108 patients with periodontitis received one of the following three gargles: xipayi, compound chlorhexidine, or Kangfuxin gargle. The basic information of the patients, the costs of the gargles, the periodontal indexes before and after treatment, and the scores of the 3-level version of the EuroQol Five Dimensions Questionnaire were collected. The cost-effectiveness and cost-utility of the various gargles were determined. RESULTS: The cost-effectiveness ratios (CER) of the three groups after treatment were 1828.75, 1573.34, and 1876.92 RMB, respectively. The utility values before treatment were 0.92, 0.90, and 0.91, respectively, and the utility values after treatment were 0.98, 0.98, and 0.97, respectively. The cost-utility ratios (CURs) were 213.43, 195.61, and 301.53 RMB, respectively. CONCLUSIONS: For each increase in effective rate and quality-adjusted life years, the treatment cost of periodontitis patients was lower than the gross domestic product per capita of Jiangsu Province, indicating that the treatment cost is completely worth it. The CER and CUR results were the same, and the compound chlorhexidine group was the lowest, demonstrating that when the same therapeutic effect was achieved, it cost the least.

Simultaneously Predicting the Pharmacokinetics of CES1-Metabolized Drugs and Their Metabolites Using Physiologically Based Pharmacokinetic Model in Cirrhosis Subjects.

Hepatic carboxylesterase 1 (CES1) metabolizes numerous prodrugs into active ingredients or direct-acting drugs into inactive metabolites. We aimed to develop a semi-physiologically based pharmacokinetic (semi-PBPK) model to simultaneously predict the pharmacokinetics of CES1 substrates and their active metabolites in liver cirrhosis (LC) patients. Six prodrugs (enalapril, benazepril, cilazapril, temocapril, perindopril and oseltamivir) and three direct-acting drugs (flumazenil, pethidine and remimazolam) were selected. Parameters such as organ blood flows, plasma-binding protein concentrations, functional liver volume, hepatic enzymatic activity, glomerular filtration rate (GFR) and gastrointestinal transit rate were integrated into the simulation. The pharmacokinetic profiles of these drugs and their active metabolites were simulated for 1000 virtual individuals. The developed semi-PBPK model, after validation in healthy individuals, was extrapolated to LC patients. Most of the observations fell within the 5th and 95th percentiles of simulations from 1000 virtual patients. The estimated AUC and Cmax were within 0.5-2-fold of the observed values. The sensitivity analysis showed that the decreased plasma exposure of active metabolites due to the decreased CES1 was partly attenuated by the decreased GFR. Conclusion: The developed PBPK model successfully predicted the pharmacokinetics of CES1 substrates and their metabolites in healthy individuals and LC patients, facilitating tailored dosing of CES1 substrates in LC patients.

Associations between parental adherence to healthy lifestyles and cognitive performance in offspring: A prospective cohort study in China.

BACKGROUND: Previous studies have reported associations of specific maternal and paternal lifestyle factors with offspring's cognitive development during early childhood. This study aimed to investigate the prospective associations between overall parental lifestyle and offspring's cognitive performance during adolescence and young adulthood in China. METHODS: We included 2531 adolescents aged 10-15 years at baseline in 2010 from the China Family Panel Studies. A healthy parental lifestyle score (ranged 0-5) was constructed based on the following five modifiable lifestyle factors: Smoking, drinking, exercise, sleep, and diet. Generalized estimating equation models were used to examine the association between baseline parental healthy lifestyle scores and offspring's fluid and crystallized intelligence in subsequent years (2012, 2014, 2016, and 2018). RESULTS: Offspring in the top tertile of parental healthy lifestyle scores performed better in overall fluid intelligence (multivariable-adjusted ß = 0.53, 95% confidence interval [CI]: 0.29-0.77) and overall crystallized intelligence (multivariable-adjusted ß = 0.35, 95% CI: 0.16-0.54) than those in the bottom tertile of parental healthy lifestyle scores. The results were similar after further adjustment for the offspring's healthy lifestyle scores and persisted across the subgroups of parental socioeconomic status. Additionally, maternal and paternal healthy lifestyle scores were independently associated with better offspring's cognitive performance, with significant contribution observed for paternal never-smoking, weekly exercise, and diversified diet. When both parents and offspring adhered to a healthier lifestyle, we observed the highest level of the offspring's overall crystallized intelligence. CONCLUSIONS: Our study indicates that parental adherence to a healthier lifestyle is associated with significantly better offspring's cognitive performance during adolescence and early adulthood, regardless of socioeconomic status. These findings highlight the potential cognitive benefits of promoting healthy lifestyles among parents of adolescents.

Cardiomyocyte ßII spectrin plays a critical role in maintaining cardiac function by regulating mitochondrial respiratory function.

AIMS: ßII spectrin is a cytoskeletal protein known to be tightly linked to heart development and cardiovascular electrophysiology. However, the roles of ßII spectrin in cardiac contractile function and pathological post-myocardial infarction remodeling remain unclear. Here, we investigated whether and how ßII spectrin, the most common isoform of non-erythrocytic spectrin in cardiomyocytes, is involved in cardiac contractile function and ischemia/reperfusion (I/R) injury. METHODS AND RESULTS: We observed that the levels of serum ßII spectrin breakdown products (ßII SBDPs) were significantly increased in patients with acute myocardial infarction (AMI). Concordantly, ßII spectrin was degraded into ßII SBDPs by calpain in mouse hearts after I/R injury. Using tamoxifen-inducible cardiac-specific ßII spectrin knockout mice, we found that deletion of ßII spectrin in the adult heart resulted in spontaneous development of cardiac contractile dysfunction, cardiac hypertrophy and fibrosis at 5 weeks after tamoxifen treatment. Moreover, at 1 week after tamoxifen treatment, although spontaneous cardiac dysfunction in cardiac-specific ßII spectrin knockout mice had not developed, deletion of ßII spectrin in the heart exacerbated I/R-induced cardiomyocyte death and heart failure. Furthermore, restoration of ßII spectrin expression via adenoviral small activating RNA (saRNA) delivery into the heart reduced I/R injury. Immunoprecipitation coupled with mass spectrometry (IP-LC-MS/MS) analyses and functional studies revealed that ßII spectrin is indispensable for mitochondrial complex I activity and respiratory function. Mechanistically, ßII spectrin promotes translocation of NADH:ubiquinone oxidoreductase 75 kDa Fe-S protein 1 (NDUFS1) from the cytosol to mitochondria by crosslinking with actin filaments (F-actin) to maintain F-actin stability. CONCLUSION: ßII spectrin is an essential cytoskeletal element for preserving mitochondrial homeostasis and cardiac function. Defects in ßII spectrin exacerbate cardiac I/R injury.

Compressive Properties and Energy Absorption Behavior of 316L Steel Foam Prepared by Space Holder Technique.

The effect of porosity and pore size on the quasi-static compression properties and energy absorption characteristics of the steel foam was investigated in this paper. The 316L steel foams were prepared through powder metallurgy using urea as the space holder. The macrostructure of steel foam and microstructure of the pore walls were characterized, and the quasi-static compression experiments were conducted on the specimens in the axial direction at a strain rate of 10-3 s-1. The results show that the increase in porosity decreases the yield strength and plastic modulus of the steel foam but increases the densification strain of the steel foam. The yield strength of the steel foam decreases significantly when the pore size is 2.37 mm. However, the pore size has little effect on the plastic modulus. Moreover, the energy absorption per volume of the steel foam decreases with increasing porosity at the same strain. The effect of porosity on energy absorption efficiency is greater than that of pore size.

Comparative analysis of prevention and control measures toward COVID-19 epidemic between Shanghai and Beijing.

Purpose: By serving and providing a guide for other regional places, this study aims to advance and guide the epidemic prevention and control methods, and practices and strengthen people's ability to respond to COVID-19 and other future potential public health risks. Design/methodology/approach: A comparative analysis was conducted that the COVID-19 epidemic development trend and prevention and control effects both in Beijing and Shanghai. In fact, regarding the COVID-19 policy and strategic areas, the differences between governmental, social, and professional management were discussed and explored. To prevent and be ready for potential pandemics, experience and knowledge were used and summarized. Findings: The strong attack of the Omicron variant in early 2022 has posed challenges to epidemic prevention and control practices in many Chinese cities. Shanghai, which had achieved relatively good performance in the fight against the epidemic, has exposed limitations in its epidemic prevention and control system in the face of Omicron. In fact, the city of Beijing has undertaken prompt and severe lockdown measures and achieved rather good results in epidemic prevention and control because of learning from Shanghai's experience and lessons; adhering to the overall concept of "dynamic clearing," implementing precise prevention and monitoring, enhancing community control, and making emergency plans and preparations. All these actions and measures are still essential in the shift from pandemic response to pandemic control. Research limitations/implications: Different places have introduced different urgent policies to control the spread of the pandemic. Strategies to control COVID-19 have often been based on preliminary and limited data and have tended to be slow to evolve as new evidence emerges. Hence, the effects of these anti-epidemic policies need to be further tested.