Randomized trial of influence of vitamin D on the prevention and improvement of symptomatic COVID-19.

We aimed to investigate the preventive effect of vitamin D2 on COVID-19 and the improvement of symptoms after COVID-19 infection. The study recruited 228 health care workers who tested negative PCR or antigen for COVID-19. Subjects were randomly allocated to vitamin D2 or non-intervention at a ratio 1:1. Subjects recorded PCR or antigen tests and the symptoms of COVID-19 twice a week during the follow-up visit. The concentration of serum 25-hydroxyvitamin D (25(OH)D), C-reaction protein (CRP), complement component C1q and inflammatory cytokines were measured. The rates of COVID-19 infection were 50.5% in the vitamin D2 group and 52.4% in the non-intervention group (P = 0.785). There was no difference in the COVID-19 symptoms between the two groups. The mean 25(OH)D level significantly increased from 14.1 to 31.1 ng/mL after administration (P < 0.001). The difference between the two groups was not significant for the concentrations of CRP, C1q and inflammatory cytokines on the thirtieth day of the trial. According to the second level of vitamin D, there was a 14.3% difference in positive infection rates between the vitamin D adequate (> 30 ng/mL) and deficient groups (< 20 ng/mL). Adequate vitamin D had a tendency to prevent COVID-19.Trial registration: ClinicalTrials.gov NCT05673980, dated: 12/2022.

Aquaporin 1 is renoprotective in septic acute kidney injury by attenuating inflammation, apoptosis and fibrosis through inhibition of P53 expression.

Sepsis associated Acute kidney injury (AKI) is a common clinical syndrome characterized by suddenly decreased in renal function and urinary volume. This study was designed to investigate the role of Aquaporin 1 (AQP1) and P53 in the development of sepsis-induced AKI and their potential regulatory mechanisms. Firstly, transcriptome sequencing analysis of mice kidney showed AQP1 expression was reduced and P53 expression was elevated in Cecal ligation and puncture (CLP)-induced AKI compared with controls. Bioinformatics confirmed that AQP1 expression was remarkably decreased and P53 expression was obviously elevated in renal tissues or peripheral blood of septic AKI patients. Moreover, we found in vivo experiments that AQP1 mRNA levels were dramatically decreased and P53 mRNA significantly increased following the increased expression of inflammation, apoptosis, fibrosis, NGAL and KIM-1 at various periods in septic AKI. Meanwhile, AQP1 and P53 protein levels increased significantly first and then decreased gradually in kidney tissue and serum of rats in different stages of septic AKI. Most importantly, in vivo and vitro experiments demonstrated that silencing of AQP1 greatly exacerbates renal or cellular injury by up-regulating P53 expression promoting inflammatory response, apoptosis and fibrosis. Overexpression of AQP1 prevented the elevation of inflammation, apoptosis and fibrosis by down-regulating P53 expression in Lipopolysaccharide (LPS)-induced AKI or HK-2 cells. Therefore, our results suggested that AQP1 plays a protective role in modulating AKI and can attenuate inflammatory response, apoptosis and fibrosis via downregulating P53 in septic AKI or LPS-induced HK-2cells. The pharmacological targeting of AQP1 mediated P53 expression might be identified as potential targets for the early treatment of septic AKI.

Zeta class glutathione S-transferase is involved in phoxim tolerance and is potentially regulated by the transcription factor CncC in Agrotis ipsilon (Lepidoptera: Noctuidae).

The black cutworm, Agrotis ipsilon (Lepidoptera: Noctuidae), is an important agricultural pest. Phoxim is an organophosphate insecticide that has been widely used to control A. ipsilon. The extensive application of phoxim has resulted in a reduction in phoxim susceptibility in A. ipsilon. However, the molecular mechanisms underlying phoxim tolerance in A. ipsilon remain unclear. In this work, we report the involvement of AiGSTz1, a zeta class glutathione S-transferase, in phoxim tolerance in A. ipsilon. Exposure to a sublethal concentration (LC50) of phoxim dramatically upregulated the transcription level of the AiGSTz1 gene in A. ipsilon larvae, and this upregulation might be caused by phoxim-induced oxidative stress. The recombinant AiGSTz1 protein expressed in Escherichia coli was able to metabolize phoxim. Furthermore, AiGSTz1 displayed antioxidant activity to protect against oxidative stress. Knockdown of AiGSTz1 by RNA interference significantly increased the mortality rate of A. ipsilon larvae in response to phoxim. In addition, the transcription factor AiCncC can bind to the cap 'n' collar isoform C: muscle aponeurosis fibromatosis (CncC:Maf) binding site in the putative promoter of the AiGSTz1 gene. Silencing of AiCncC resulted in a dramatic downregulation of AiGSTz1. These results indicated that AiGSTz1 is involved in phoxim tolerance and is potentially regulated by AiCncC. These findings provide valuable insights into the defense mechanisms used by A. ipsilon against phoxim.

Divergent roles of ADP-ribosylation factor GTPase-activating proteins in lignocellulose utilization of Trichoderma guizhouense NJAU4742.

BACKGROUND: The ability of lignocellulose degradation for filamentous fungi is always attributed to their efficient CAZymes system with broader applications in bioenergy development. ADP-ribosylation factor GTPase-activating proteins (Arf-GAPs), pivotal in fungal morphogenesis, lack comprehensive studies on their regulatory mechanisms in lignocellulose utilization. RESULTS: Here, the orthologs (TgGlo3 and TgGcs1) of Arf-GAPs in S. cerevisiae were characterized in Trichoderma guizhouense NJAU4742. The results indicated that overexpression of Tggcs1 (OE-Tggcs1) enhanced the lignocellulose utilization, whereas increased expression of Tgglo3 (OE-Tgglo3) elicited antithetical responses. On the fourth day of fermentation with rice straw as the sole carbon source, the activities of endoglucanase, cellobiohydrolase, xylanase, and filter paper of the wild-type strain (WT) reached 8.20 U mL-1, 4.42 U mL-1, 14.10 U mL-1, and 3.56 U mL-1, respectively. Compared to WT, the four enzymes activities of OE-Tggcs1 increased by 7.93%, 6.11%, 9.08%, and 12.92%, respectively, while those decreased to varying degrees of OE-Tgglo3. During the nutritional growth, OE-Tgglo3 resulted in the hyphal morphology characterized by sparsity and constriction, while OE-Tggcs1 led to a notable increase in vacuole volume. In addition, OE-Tggcs1 exhibited higher transport efficiencies for glucose and cellobiose thereby sustaining robust cellular metabolic rates. Further investigations revealed that Tgglo3 and Tggcs1 differentially regulated the transcription level of a dynamin-like GTPase gene (Tggtp), eliciting distinct redox states and apoptotic reaction, thus orchestrating the cellular response to lignocellulose utilization. CONCLUSIONS: Overall, these findings underscored the significance of TgArf-GAPs as pivotal regulators in lignocellulose utilization and provided initial insights into their differential modulation of downstream targets.

In situ chemoproteomic profiling reveals itaconate inhibits de novo purine biosynthesis in pathogens.

Itaconate serves as an immune-specific metabolite that regulates gene transcription and metabolism in both host and pathogens. S-itaconation is a post-translational modification that regulates immune response; however, its antimicrobial mechanism under the physiological condition remains unclear. Here, we apply a bioorthogonal itaconate probe to perform global profiling of S-itaconation in living pathogens, including S. Typhimurium, S. aureus, and P. aeruginosa. Some functional enzymes are covalently modified by itaconate, including those involved in the de novo purine biosynthesis pathway. Further biochemical studies demonstrate that itaconate suppresses this specific pathway to limit Salmonella growth by inhibiting the initiator purF to lower de novo purine biosynthesis and simultaneously targeting the guaABC cluster to block the salvage route. Our chemoproteomic study provides a global portrait of S-itaconation in multiple pathogens and offers a valuable resource for finding susceptible targets to combat drug-resistant pathogens in the future.

Review and new insights into the catalytic structural domains of the Fe(ll) and 2-Oxoglutarate families.

Histone lysine demethylase (KDM), AlkB homolog (ALKBH), and Ten-Eleven Translocation (TET) proteins are members of the 2-Oxoglutarate (2OG) and ferrous iron-dependent oxygenases, each of which harbors a catalytic domain centered on a double-stranded ß-helix whose topology restricts the regions directly involved in substrate binding. However, they have different catalytic functions, and the deeply structural biological reasons are not yet clear. In this review, the catalytic domain features of the three protein families are summarized from both sequence and structural perspectives. The construction of the phylogenetic tree and comparison of the structure show ten relatively conserved ß-sheets and three key regions with substantial structural differences. We summarize the relationship between three key regions of remarkable differences and the substrate compatibility of the three protein families. This review facilitates research into substrate-selective inhibition and bioengineering by providing new insights into the catalytic domains of KDM, ALKBH, and TET proteins.

Chinese medicine Linggui Zhugan formula protects against diabetic kidney disease in close association with inhibition of proteinase 3-mediated podocyte apoptosis in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Linggui-Zhugan (LGZG) comprises four herbs and is a classic formula in traditional Chinese medicine. There is strong clinical evidence of its pleiotropic effects in the prevention of diabetes and its related complications. Although several classes of drugs are currently available for clinical management of diabetic kidney disease (DKD), tight glycemic and/or hypertension control may not prevent disease progression. This study evaluated the therapeutic effect of the ethnopharmacological agent LGZG on DKD. AIM OF THE STUDY: This study aimed to investigate the effects of LGZG formula with standard quality control on experimental DKD and its related metabolic disorders in animal model. Meanwhile, the present study aimed to investigate regulatory effects of LGZG on renal proteinase 3 (PR3) to reveal mechanisms underlying renoprotective benefits of LGZG. MATERIALS AND METHODS: LGZG decoction was fingerprinted by high-performance liquid chromatography for quality control. An experimental model of DKD was induced in C57 BL/6J mice by a combination of high-fat diet feeding, uninephrectomy, and intraperitoneal injection of streptozocin. The LGZG decoction was administrated by daily oral gavage. RESULTS: Treatment with LGZG formula significantly attenuated DKD-like traits (including severe albuminuria, mesangial matrix expansion, and podocyte loss) and metabolic dysfunction (disordered body composition and dyslipidemia) in mice. RNA sequencing data revealed a close association of LGZG treatment with marked modulation of signaling pathways related to podocyte injury and cell apoptosis. Mechanistically, LGZG suppressed the DKD-triggered increase in renal PR3 and podocyte apoptosis. In-vitro incubation of mouse immortalized podocytes with LGZG-medicated serum attenuated PR3-mediated apoptosis. CONCLUSION: Our data demonstrated that the LGZG formula protected against DKD in mice and was closely associated with its inhibitory effects on PR3-mediated podocyte apoptosis.

Aging-Related CYP3A Functional Changes in Chinese Older Patients: New Findings from Model-Based Assessment of Amlodipine.

Aging-related alterations in hepatic enzyme activity, particularly of the CYP3A, significantly impact drug efficacy and safety in older adults, making it essential to understand how aging affects CYP function for optimal drug therapy. The exogenous probe substrate method, a minimally invasive approach to assess liver metabolic enzyme activity in vivo, is effective in studying these changes. Amlodipine being extensively metabolized (> 90%) in the liver, primarily via cytochrome P450 enzyme CYP3A was selected as a probe to investigate and quantify the factors affecting the aging-related changes of CYP3A in the Chinese older population. Amlodipine concentration data were collected from an ongoing noninterventional clinical study conducted at Peking University Third Hospital. A physiologically-based pharmacokinetic modeling approach, grounded in population pharmacokinetic (PPK) analysis, was employed to physiologically quantify the aging-related changes in CYP3A function. A total of 132 amlodipine concentrations from 69 patients were obtained from the clinical study. PPK analysis shows that frailty phenotype but not age is a significant influence and frail patients have 37% greater plasma amlodipine exposure than nonfrail patients. This difference in CYP3A function may be attributed to a 63.2% lower CYP3A relative abundance in the frail patients, compared with that in the nonfrail patients. In the context of dose selection for older adults, focusing on frailty rather than chronological age should be recognized as a more relevant approach, because frailty might more accurately reflect the individual's biological age. Our study suggested a need to shift the research focus from chronological age to biological age.

Identification of host gene regulation and resistance pathway dynamics at diverse infection stages of Rhizoctonia solani AG3-TB.

Rhizoctonia solani is a fungal pathogen that causes significant losses in agricultural production. Because of its rapid transmission and broad host range, the exploration of genes involved in defense responses to the infection of R. solani has become an important task. Here, we performed a time-course RNA-Seq experiment to explore crucial genes or pathways involved in host responses to R. solani AG3-TB infection at 6, 12, 24, 36, 48, and 72 hours post inoculation (hpi). GO and KEGG enrichment analysis revealed that most DEGs were enriched in the basal metabolism pathways, including carbohydrate metabolic processes and the biosynthesis of amino acids. Moreover, catalase (CAT) and superoxide dismutase (SOD) were up-regulated, and transcription factors (TFs) such as WRKY, AP2, and MYB were increased significantly compared to the control (0 hpi). Silencing of WRKY70 and catalase-3 exhibited elevated susceptibility to the fungal infection. To summarize, the TFs WRKY70 and WRKY75, genes involved in jasmonic acid (JA), salicylic acid (SA), and brassinosteroids (BR) signaling pathways, and defense-related enzymes may play crucial roles in the host responses to R. solani AG3-TB infection.

Efficacy and safety of minodronate in the treatment of postmenopausal osteoporosis with low back pain: a single-centre, randomized and open-label controlled trial.

BACKGROUND: Low back pain is one of the most common symptoms of osteoporosis. The pain can seriously affect patients' mood and quality of life; it can also further aggravate bone loss, causing a serious social burden. Minodronate is an oral bisphosphonate that needs to be administered daily. It significantly reduces levels of bone turnover markers (BTMs) and rapidly improves symptoms of low back pain in patients with osteoporosis. Osteoporosis requires long-term treatment, and daily dosing reduces patient compliance. Minodronate has a better safety profile than other bisphosphonates. The objective of the trial is to explore the efficacy and safety of minodronate in the treatment of low back pain in postmenopausal osteoporosis patients. METHODS: This is a single-centre, randomized, open-label controlled trial with a 24-week duration. Seventy-two eligible patients will be randomly divided into 4 groups. Subjects will be randomized at a 1:1 ratio to receive either minodronate (1 mg/day) or alendronate (10 mg/day) every day; senior women (≥ 75 years old) and older women (< 75 years old) will be at a ratio of 1:2. The primary outcome is the time required for the visual analogue scale (VAS) score to decline by ≥ 10 from baseline. The secondary outcome is the changes in VAS scores from baseline, the frequency and dosage of rescue medication, BTMs, bone mineral density (BMD), and variations in upper gastrointestinal (GI) symptom scores from baseline (including heartburn, pain, and bloating). DISCUSSION: This study will provide objective evidence for the efficiency and safety of minodronate. Furthermore, it will be helpful to evaluate the quantitative relationship between BTMs and BMD in patients with osteoporosis under different ages. TRIAL REGISTRATION: This study protocol has been registered with ClinicalTrials.gov ID NCT05645289 ( https://clinicaltrials.gov/search?term=NCT05645289 ) on December 8, 2022. The registry name is Peking University Third Hospital. This study protocol was reviewed and approved by the Peking University Third Hospital Medical Science Research Ethics Committee (M2022465, 2022.08.09, V2.0). The results will be published in scientific peer-reviewed journals. TRIAL STATUS: The protocol was registered at ClinicalTrials.gov (registration number: NCT05645289). Recruitment has started in January 2023 and is still ongoing.

Research Note: Poria cocos polysaccharide alleviates lipopolysaccharide-induced intestinal inflammation and barrier damage in broiler chickens.

This study aimed to explore the impact of dietary supplementation of Poria cocos polysaccharide (PCP) on the lipopolysaccharide(LPS)-induced intestinal inflammation, morphology, and barrier damage in broilers. A total of 240 1-day-old male Arbor Acre broilers were randomly divided into 4 groups in a 2 × 2 factorial design comprising PCP supplementation (0 or 2 g/kg PCP from d 1 to 23) and LPS challenge (intraperitoneal injection of 1.5 mg/kg body weight of LPS or the same volume of sterile saline at d 22). Our results showed that compared to the non-LPS-treated groups, the treated birds showed a decrease in the ADG, VH, V/C, and the expression of ZO-1, occludin, claudin 1, and mucin2 in the duodenum and jejunum (P < 0.05). However, dietary PCP supplementation significantly mitigated these effects (P < 0.05) except for mucin2 in the duodenum. Furthermore, LPS treatment increased the levels of sIgA and upregulated the mRNA abundances of IL-1ß, IL-6, TNF-α, IFN-γ, TLR-4, and MyD88 both in the duodenal and jejunal mucosa (P < 0.05). Whereas, PCP supplementation significantly reversed the LPS-induced effects on these genes (P < 0.05) except for the TLR-4 and MyD88. However, LPS did not impact the expression of anti-inflammatory IL-10 in the duodenal and jejunal mucosa (P > 0.05). Briefly, this study implied that dietary PCP supplementation could ameliorate intestinal inflammation and mucosal damage of LPS-challenged broilers, improving broiler performance.

Combined transcriptomic and metabolomic analysis revealed that pH changes affected the expression of carbohydrate and ribosome biogenesis-related genes in Aspergillus niger SICU-33.

The process of carbohydrate metabolism and genetic information transfer is an important part of the study on the effects of the external environment on microbial growth and development. As one of the most significant environmental parameters, pH has an important effect on mycelial growth. In this study, the effects of environmental pH on the growth and nutrient composition of Aspergillus niger (A. niger) filaments were determined. The pH values of the medium were 5, 7, and 9, respectively, and the molecular mechanism was further investigated by transcriptomics and metabolomics methods. The results showed that pH 5 and 9 significantly inhibited filament growth and polysaccharide accumulation of A. niger. Further, the mycelium biomass of A. niger and the crude polysaccharide content was higher when the medium's pH was 7. The DEGs related to ribosome biogenesis were the most abundant, and the downregulated expression of genes encoding XRN1, RRM, and RIO1 affected protein translation, modification, and carbohydrate metabolism in fungi. The dynamic changes of pargyline and choline were in response to the oxidative metabolism of A. niger SICU-33. The ribophorin_I enzymes and DL-lactate may be important substances related to pH changes during carbohydrate metabolism of A.niger SICU-33. The results of this study provide useful transcriptomic and metabolomic information for further analyzing the bioinformatic characteristics of A. niger and improving the application in ecological agricultural fermentation.

Model-informed drug development of envafolimab, a subcutaneously injectable PD-L1 antibody, in patients with advanced solid tumors.

BACKGROUND AND OBJECTIVES: Envafolimab is the first and only globally approved subcutaneously injectable PD-L1 antibody for the treatment of instability-high (MSI-H) or DNA mismatch repair deficient (dMMR) advanced solid tumors in adults, including those with advanced colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. The aim of this investigation was to examine the pharmacokinetic and exposure-response (E-R) profile of envafolimab in patients with solid tumors to support the approval of fixed and alternative dose regimens. METHODS: In this study, a population pharmacokinetic (PopPK) modeling approach will be employed to quantitatively evaluate intrinsic and extrinsic covariates. Additionally, PopPK-estimated exposure parameters were used to evaluate E-R relationship for safety and efficacy to provide a theoretical basis for recommending optimal treatment regimens. Simulations were performed on the dosing regimens of body weight-based regimen of 2.50 mg/kg QW, fixed dose 150 mg QW, and 300 mg Q2W for the selection of alternative dosing regimens. Data from 4 clinical studies (NCT02827968, NCT03101488, NCT03248843, and NCT03667170) were utilized. RESULTS: The PopPK dataset comprised 182 patients with 1810 evaluable envafolimab concentration records. Finally, a one-compartment model incorporating first-order absorption, first-order linear elimination, and time-dependent elimination according to an Emax function was found to accurately describe the concentration-time data of envafolimab in patients with advanced solid tumors. Creatinine clearance and country were identified as statistically significant factors affecting clearance, but had limited clinical significance. A relative flat exposure-response relationship was observed between early measures of safety and efficacy to verify that no dose adjustment is required. Simulation results indicated that 2.50 mg/kg QW, 150 mg QW, and 300 mg Q2W regimen yield similar steady-state exposure. CONCLUSIONS: No statistically significant difference was observed between weight-based and fixed dose regimens. Model-based simulation supports the adoption of a 150 mg weekly or 300 mg biweekly dosing regimen of envafolimab in the solid tumor population, as these schedules effectively balance survival benefits and safety risks.

SARS-CoV-2 spike protein acts as a ß-adrenergic receptor agonist: A potential mechanism for cardiac sequelae of long COVID.

BACKGROUND: Currently, pathophysiological mechanisms of post-acute sequelae of coronavirus disease-19-cardiovascular syndrome (PASC-CVS) remain unknown. METHODS AND RESULTS: Patients with PASC-CVS exhibited significantly higher circulating levels of severe acute respiratory syndrome-coronavirus-2 spike protein S1 than the non-PASC-CVS patients and healthy controls. Moreover, individuals with high plasma spike protein S1 concentrations exhibited elevated heart rates and normalized low frequency, suggesting cardiac ß-adrenergic receptor (ß-AR) hyperactivity. Microscale thermophoresis (MST) assay revealed that the spike protein bound to ß1- and ß2-AR, but not to D1-dopamine receptor. These interactions were blocked by ß1- and ß2-AR blockers. Molecular docking and MST assay of ß-AR mutants revealed that the spike protein interacted with the extracellular loop 2 of both ß-ARs. In cardiomyocytes, spike protein dose-dependently increased the cyclic adenosine monophosphate production with or without epinephrine, indicating its allosteric effects on ß-ARs. CONCLUSION: Severe acute respiratory syndrome-coronavirus-2 spike proteins act as an allosteric ß-AR agonist, leading to cardiac ß-AR hyperactivity, thus contributing to PASC-CVS.

Systematic Quantitative Analysis of Fetal Dexamethasone Exposure and Fetal Lung Maturation in Pregnant Animals: Model Informed Dexamethasone Precision Dose Study.

Dexamethasone (DEX) was applied in neonatal respiratory distress syndrome treatment of pregnant women. We established a pharmacokinetics (PK)/pharmacodynamics(PD)/end point model of pregnant animals based on published data and then extrapolated to simulate fetal exposure and lung maturation in pregnant women. We first established the PK/PD/end point model for DEX in pregnant sheep. We considered the competitive effect of cortisol (Cort) and DEX binding with glucocorticoid receptor and then used the indirect response model to describe disaturated-phosphatidylcholine (DSPC) dynamics. Based on that, we established a regression relationship between DSPC and fetal lung volume (V40). We then extrapolated the PD/end point model of pregnant sheep to pregnant monkeys by corrected stages of morphologic lung maturation in two species. Finally, we utilized the interspecies extrapolation strategy to simulate fetal exposure (AUC0-48h) and V40 relationship in pregnant women. The current model could well describe the maternal-fetal PK of DEX in pregnant animals. Simulated DEX AUC0-24h values of the umbilical venous to maternal plasma ratio in pregnant sheep and monkeys were 0.31 and 0.27, respectively. The simulated Cort curve and V40 in pregnant sheep closely matched the observed data within a 2-fold range. For pregnant monkeys, model-simulated V40 were well fitted with external verification data, which showed good interspecies extrapolation performance. Finally, we simulated fetal exposure-response relationship in pregnant women, which indicated that the fetal AUC0-48h of DEX should not be less than 300 and 100 ng/mL·hr at GW28 and GW34 to ensure fetal lung maturity. The current model preliminarily provided support for clinical DEX dose optimization.

Performance evaluation of typical flocculants for efficient harvesting of Chlorella sorokiniana under different carbon application modes.

In this study, the growth characteristics of microalgae cultured with different carbon sources were analyzed, and the flocculation characteristics under the influence of carbon sources were evaluated using three typical flocculants. The results showed that the organic carbon sources could significantly increase the content of extracellular proteins in microalgae. Specifically, the extracellular protein concentrations of microalgae cultured with pure BG-11, ethanol, sodium acetate and glucose were 18.2 29.2, 97.3, and 34.7 mg/g, respectively. During the flocculation process, microalgae cultured with sodium acetate exhibited a weak response to the flocculant because of excessive extracellular proteins inhibited flocculation. In addition, the flocculation efficiency was also less than 50.0% cultured with sodium acetate in all pH test ranges when alum and chitosan were used as flocculants. It could be inferred that the flocculant initially happened to charge neutralization with the negatively charged proteins in the solution and then bridged the charges with the microalgae. These findings provide insights into the effects of different carbon sources on microalgal flocculation, promising organic integration of microalgae wastewater treatment and harvesting.

Vaccination intentions of hypertensive Chinese individuals during the COVID-19 epidemic: a structural equation modeling study.

OBJECTIVE: Given the high prevalence of hypertension among Chinese adults, this population is at a significantly increased risk of severe COVID-19 complications. The purpose of this study is to assess the willingness of Chinese hypertensive adults to receive the COVID-19 vaccine and to identify the diverse factors that shape their vaccination decisions. METHODS: Sampling was conducted utilizing multistage stratified random sampling, and ultimately, a total of 886 adult hypertensive patients from Luzhou City in Southwest China were included in this study. The questionnaire design was based on the Theory of Planned Behaviour and was used to investigate their willingness to be vaccinated with COVID-19. Structural equation modeling was employed for data analysis. RESULTS: The results showed that 75.6% of hypertensive individuals were willing to receive COVID-19 vaccination. The structural equation modeling revealed that Subjective Norms (path coefficient = 0.361, CR = 8.049, P < 0.001) and Attitudes (path coefficient = 0.253, CR = 4.447, P < 0.001) had positive effects on vaccination willingness, while Perceived Behavioral Control (path coefficient=-0.004, CR=-0.127, P = 0.899) had no significant impact on Behavioral Attitudes. Mediation analysis indicated that Knowledge (indirect path coefficient = 0.032, LLCI = 0.014, ULCI = 0.058), Risk Perception (indirect path coefficient = 0.077, LLCI = 0.038, ULCI = 0.124), and Subjective Norms (indirect path coefficient = 0.044, LLCI = 0.019, ULCI = 0.087) significantly influenced vaccination willingness through Attitudes as a mediating factor. CONCLUSION: The willingness of hypertensive individuals to receive the COVID-19 vaccination is not satisfactory. The Theory of Planned Behavior provides valuable insights into understanding their vaccination intentions. Efforts should be concentrated on enhancing the subjective norms, attitudes, and knowledge about vaccination of hypertensive patients.

Oxidative stress and metabolic process responses of Chlorella pyrenoidosa to nanoplastic exposure: Insights from integrated analysis of transcriptomics and metabolomics.

Oxidative stress is a universal interpretation for the toxicity mechanism of nanoplastics to microalgae. However, there is a lack of deeper insight into the regulation mechanism in microalgae response to oxidative stress, thus affecting the prevention and control for nanoplastics hazard. The integrated analysis of transcriptomics and metabolomics was employed to investigate the mechanism for the oxidative stress response of Chlorella pyrenoidosa to nanoplastics and subsequently lock the according core pathways and driver genes induced. Results indicated that the linoleic acid metabolism, glycine (Gly)-serine (Ser)-threonine (Thr) metabolism, and arginine and proline metabolism pathways of C. pyrenoidosa were collectively involved in oxidative stress. The analysis of linoleic acid metabolism suggested that nanoplastics prompted algal cells to secrete more allelochemicals, thereby leading to destroy the immune system of cells. Gly-Ser-Thr metabolism and arginine and proline metabolism pathways were core pathways involved in algal regulation of cell membrane function and antioxidant system. Key genes, such as LOX2.3, SHM1, TRPA1, and proC1, are drivers of regulating the oxidative stress of algae cells. This investigation lays the foundation for future applications of gene editing technology to limit the hazards of nanoplastics on aquatic organism.

Application and Quality of Model-Based Meta-Analysis in Pharmaceutical Research: A Systematic Cross-Sectional Analysis and Practical Considerations.

Model-based meta-analysis (MBMA) can be used in assisting drug development and optimizing treatment in clinical practice, potentially reducing costs and accelerating drug approval. We aimed to assess the application and quality of MBMA studies. We searched multiple databases to identify MBMA in pharmaceutical research. Eligible MBMA should incorporate pharmacological concepts to construct mathematical models and quantitatively examine and/or predict drug effects. Relevant information was summarized to provide an overview of the application of MBMA. We used AMSTAR-2 and PRISMA 2020 checklists to evaluate the methodological and reporting quality of included MBMA, respectively. A total of 143 MBMA studies were identified. MBMA was increasingly used over time for one or more areas: drug discovery and translational research (n = 8, 5.6%), drug development decision making (n = 42, 29.4%), optimization of clinical trial design (n = 46, 32.2%), medication in special populations (n = 15, 10.5%), and rationality and safety of drug use (n = 71, 49.7%). The included MBMA covered 17 disease areas, with the top three being nervous system diseases (n = 19, 13.2%), endocrine/nutritional/metabolic diseases (n = 17, 11.8%), and neoplasms (n = 16, 11.1%). Of these MBMA studies, 138 (96.5%) were rated as very low quality. The average rate of compliance with PRISMA was only 51.4%. Our findings suggested that MBMA was mainly used to evaluate the efficacy and safety of drugs, with a focus on chronic diseases. The methodological and reporting quality of MBMA should be further improved. Given AMSTAR-2 and PRISMA checklists were not specifically designed for MBMA, adapted assessment checklists for MBMA should be warranted.

Concentration-QTc Modeling of the DPP-4 Inhibitor HSK7653 in a First-in-Human Study of Chinese Healthy Volunteers.

Cofrogliptin (HSK7653) is a long-acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus with a twice-monthly dosing regimen. This study included 62 participants (48 without food effect, 14 with food effect) receiving single doses of HSK7653 (5, 10, 25, 50, 100, and 150 mg) or placebo. Pharmacokinetic samples were collected over 24 hours postdosing and sampling times are aligned with 12-lead electrocardiograms (ECGs) which were derived from continuous ECG recordings. For the concentration-QT interval corrected for heart rate (C-QTc) analysis, we used linear mixed-effects modeling to characterize the correlation between plasma concentrations of HSK7653 and the change from baseline in the QT interval which was corrected by Fridericia's formula (ΔQTcF). The result showed that a placebo-corrected Fridericia corrected QT interval (ΔΔQTcF) prolongation higher than 10 milliseconds is unlikely at the mean maximum observed concentration (Cmax) (411 ng/mL) associated with the recommended therapeutic doses (25 mg twice-monthly), even at the highest supratherapeutic concentration (2425 ng/mL). Thus, HSK7653 does not significantly affect QT prolongation at either recommended doses or the highest supratherapeutic concentration.