Structure-Guided Design of Potent Coronavirus Inhibitors with a 2-Pyrrolidone Scaffold: Biochemical, Crystallographic, and Virological Studies.

Zoonotic coronaviruses are known to produce severe infections in humans and have been the cause of significant morbidity and mortality worldwide. SARS-CoV-2 was the largest and latest contributor of fatal cases, even though MERS-CoV has the highest case-fatality ratio among zoonotic coronaviruses. These infections pose a high risk to public health worldwide warranting efforts for the expeditious discovery of antivirals. Hence, we hereby describe a novel series of inhibitors of coronavirus 3CLpro embodying an N-substituted 2-pyrrolidone scaffold envisaged to exploit favorable interactions with the S3-S4 subsites and connected to an invariant Leu-Gln P2-P1 recognition element. Several inhibitors showed nanomolar antiviral activity in enzyme and cell-based assays, with no significant cytotoxicity. High-resolution crystal structures of inhibitors bound to the 3CLpro were determined to probe and identify the molecular determinants associated with binding, to inform the structure-guided optimization of the inhibitors, and to confirm the mechanism of action of the inhibitors.

CDKL3 is a targetable regulator of cell cycle progression in cancers.

Cell cycle regulation is largely abnormal in cancers. Molecular understanding and therapeutic targeting of the aberrant cell cycle are essentially meaningful. Here, we identified an under-appreciated Serine/Threonine kinase, CDKL3 (Cyclin-dependent kinase like 3), crucially drives the rapid cell cycle progression and cell growth in cancers. Mechanism-wise, CDKL3 localizes in the nucleus and associates with specific cyclin to directly phosphorylate Retinoblastoma (Rb) for quiescence exit. In parallel, CDKL3 prevents the ubiquitin-proteasomal degradation of CDK4 by direct phosphorylation on T172 to sustain G1 phase advancement. The crucial function of CDKL3 in cancers was demonstrated both in vitro and in vivo. We also designed, synthesized and characterized a first-in-class CDKL3-specific inhibitor, HZ1. HZ1 exhibits greater potency than CDK4/6 (Cyclin-dependent kinase 4/6) inhibitor in pan-cancer treatment by causing cell cycle arrest and overcomes the acquired resistance of the latter. In particular, CDKL3 has significant clinical relevance in colon cancer, and the effectiveness of HZ1 was demonstrated by murine and patient-derived cancer models. Collectively, this work presented an integrated paradigm of cancer cell cycle regulation and suggested CDKL3-targeting as a feasible approach in cancer treatment.

Farmland's silent threat: Comprehensive multimedia assessment of micropollutants through non-targeted screening and targeted analysis in agricultural systems.

Intricate agricultural ecosystems markedly influence the dynamics of organic micropollutants, posing substantial threats to aquatic organisms and human health. This study examined the occurrence and distribution of organic micropollutants across soils, ditch sediment, and water within highly intensified farming setups. Using a non-targeted screening method, we identified 405 micropollutants across 10 sampling sites, which mainly included pesticides, pharmaceuticals, industrial chemicals, and personal care products. This inventory comprised emerging contaminants, banned pesticides, and controlled pharmaceuticals that had eluded detection via conventional monitoring. Targeted analysis showed concentrations of 3.99-1021 ng/g in soils, 4.67-2488 ng/g in sediment, and 12.5-9373 ng/L in water, respectively, for Σ40pesticides, Σ8pharmaceuticals, and Σ3industrial chemicals, indicating notable spatial variability. Soil organic carbon content and wastewater discharge were likely responsible for their spatial distribution. Principal component analysis and correlation analysis revealed a potential transfer of micropollutants across the three media. Particularly, a heightened correlation was decerned between soil and sediment micropollutant levels, highlighting the role of sorption processes. Risk quotients surpassed the threshold of 1 for 13-23 micropollutants across the three media, indicating high environmental risks. This study highlights the importance of employing non-targeted and targeted screening in assessing and managing environmental risks associated with micropollutants.

CRISPR screens reveal convergent targeting strategies against evolutionarily distinct chemoresistance in cancer.

Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance.

Crystal structures of NAD(P)H nitroreductases from Klebsiella pneumoniae.

Klebsiella pneumoniae (Kp) is an infectious disease pathogen that poses a significant global health threat due to its potential to cause severe infections and its tendency to exhibit multidrug resistance. Understanding the enzymatic mechanisms of the oxygen-insensitive nitroreductases (Kp-NRs) from Kp is crucial for the development of effective nitrofuran drugs, such as nitrofurantoin, that can be activated as antibiotics. In this paper, three crystal structures of two Kp-NRs (PDB entries 7tmf/7tmg and 8dor) are presented, and an analysis of their crystal structures and their flavin mononucleotide (FMN)-binding mode is provided. The structures with PDB codes 7tmf (Kp-NR1a), 7tmg (Kp-NR1b) and 8dor (Kp-NR2) were determined at resolutions of 1.97, 1.90 and 1.35 Å, respectively. The Kp-NR1a and Kp-NR1b structures adopt an αß fold, in which four-stranded antiparallel ß-sheets are surrounded by five helices. With domain swapping, the ß-sheet was expanded with a ß-strand from the other molecule of the dimer. The difference between the structures lies in the loop spanning Leu173-Ala185: in Kp-NR1a the loop is disordered, whereas the loop adopts multiple conformations in Kp-NR1b. The FMN interactions within Kp-NR1/NR2 involve hydrogen-bond and π-stacking interactions. Kp-NR2 contains four-stranded antiparallel ß-sheets surrounded by eight helices with two short helices and one ß-sheet. Structural and sequence alignments show that Kp-NR1a/b and Kp-NR2 are homologs of the Escherichia coli oxygen-insensitive NRs YdjA and NfnB and of Enterobacter cloacae NR, respectively. By homology inference from E. coli, Kp-NR1a/b and Kp-NR2 may detoxify polynitroaromatic compounds and Kp-NR2 may activate nitrofuran drugs to cause bactericidal activity through a ping-pong bi-bi mechanism, respectively.

Discovery of a terpene synthase synthesizing a nearly non-flexible eunicellane reveals the basis of flexibility.

Eunicellane diterpenoids, containing a typical 6,10-bicycle, are bioactive compounds widely present in marine corals, but rarely found in bacteria and plants. The intrinsic macrocycle exhibits innate structural flexibility resulting in dynamic conformational changes. However, the mechanisms controlling flexibility remain unknown. The discovery of a terpene synthase, MicA, that is responsible for the biosynthesis of a nearly non-flexible eunicellane skeleton, enable us to propose a feasible theory about the flexibility in eunicellane structures. Parallel studies of all eunicellane synthases in nature discovered to date, including 2Z-geranylgeranyl diphosphate incubations and density functional theory-based Boltzmann population computations, reveale that a trans-fused bicycle with a 2Z-configuration alkene restricts conformational flexibility resulting in a nearly non-flexible eunicellane skeleton. The catalytic route and the enzymatic mechanism of MicA are also elucidated by labeling experiments, density functional theory calculations, structural analysis of the artificial intelligence-based MicA model, and mutational studies.

Methyl-Sensitive Amplification Polymorphism (MSAP) Analysis Provides Insights into the DNA Methylation Changes Underlying Adaptation to Low Temperature of Brassica rapa L.

BACKGROUND: DNA methylation can change rapidly to regulate the expression of stress-responsive genes. Previous studies have shown that there are significant differences in the cold resistance of winter rapeseed (Brassica rapa L.) after being domesticated in different selection environments; however, little is known about the epigenetic regulatory mechanisms of its cold resistance formation. METHODS: Four winter rapeseed materials ('CT-2360', 'MXW-1', '2018-FJT', and 'DT-7') domesticated in different environments were selected to analyze the DNA methylation level and pattern changes under low temperature using methylation-sensitive amplified polymorphism technology with 60 primer pairs. RESULTS: A total of 18 pairs of primers with good polymorphism were screened, and 1426 clear bands were amplified, with 594 methylation sites, accounting for 41.65% of the total amplified bands. The total methylation ratios of the four materials were reduced after low-temperature treatment, in which the DNA methylation level of 'CT-2360' was higher than that of the other three materials; the analysis of methylation patterns revealed that the degree of demethylation was higher than that of methylation in 'MXW-1', '2018-FJT', and 'DT-7', which were 22.99%, 19.77%, and 24.35%, respectively, and that the methylation events in 'CT-2360' were predominantly dominant at 22.95%. Fifty-three polymorphic methylated DNA fragments were randomly selected and further analyzed, and twenty-nine of the cloned fragments were homologous to genes with known functions. The candidate genes VQ22 and LOC103871127 verified the existence of different expressive patterns before and after low-temperature treatment. CONCLUSIONS: Our work implies the critical role of DNA methylation in the formation of cold resistance in winter rapeseed. These results provide a comprehensive insight into the adaptation epigenetic regulatory mechanism of Brassica rapa L. to low temperature, and the identified differentially methylated genes can also be used as important genetic resources for the multilateral breeding of winter-resistant varieties.

The transcription factor PagLBD4 represses cell differentiation and secondary cell wall biosynthesis in Populus.

LBD (LATERAL ORGAN BOUNDARIES DOMAIN) transcription factors are key regulators of plant growth and development. In this study, we functionally characterized the PagLBD4 gene in Populus (Populus alba × Populus glandulosa). Overexpression of PagLBD4 (PagLBD4OE) significantly repressed secondary xylem differentiation and secondary cell wall (SCW) deposition, while CRISPR/Cas9-mediated PagLBD4 knockout (PagLBD4KO) significantly increased secondary xylem differentiation and SCW deposition. Consistent with the functional analysis, gene expression analysis revealed that SCW biosynthesis pathways were significantly down-regulated in PagLBD4OE plants but up-regulated in PagLBD4KO plants. We also performed DNA affinity purification followed by sequencing (DAP-seq) to identify genes bound by PagLBD4. Integration of RNA sequencing (RNA-seq) and DAP-seq data identified 263 putative direct target genes (DTGs) of PagLBD4, including important regulatory genes for SCW biosynthesis, such as PagMYB103 and PagIRX12. Together, our results demonstrated that PagLBD4 is a repressor of secondary xylem differentiation and SCW biosynthesis in Populus, which possibly lead to the dramatic growth repression in PagLBD4OE plants.

Rare variations within the serine/arginine-rich splicing factor PtoRSZ21 modulate stomatal size to determine drought tolerance in Populus.

Rare variants contribute significantly to the 'missing heritability' of quantitative traits. The genome-wide characteristics of rare variants and their roles in environmental adaptation of woody plants remain unexplored. Utilizing genome-wide rare variant association study (RVAS), expression quantitative trait loci (eQTL) mapping, genetic transformation, and molecular experiments, we explored the impact of rare variants on stomatal morphology and drought adaptation in Populus. Through comparative analysis of five world-wide Populus species, we observed the influence of mutational bias and adaptive selection on the distribution of rare variants. RVAS identified 75 candidate genes correlated with stomatal size (SS)/stomatal density (SD), and a rare haplotype in the promoter of serine/arginine-rich splicing factor PtoRSZ21 emerged as the foremost association signal governing SS. As a positive regulator of drought tolerance, PtoRSZ21 can recruit the core splicing factor PtoU1-70K to regulate alternative splicing (AS) of PtoATG2b (autophagy-related 2). The rare haplotype PtoRSZ21hap2 weakens binding affinity to PtoMYB61, consequently affecting PtoRSZ21 expression and SS, ultimately resulting in differential distribution of Populus accessions in arid and humid climates. This study enhances the understanding of regulatory mechanisms that underlie AS induced by rare variants and might provide targets for drought-tolerant varieties breeding in Populus.

The impact of mild and moderate COVID-19 infection on the progression of kidney dysfunction in patients with IgA nephropathy.

Background: Previous research indicates that coronavirus disease 2019 (COVID-19) infection may have a role in triggering immunoglobulin A (IgA) nephropathy. However, limited research has explored the clinical implications of COVID-19 infection in individuals already diagnosed with IgA nephropathy. This study aimed to determine whether COVID-19 infection independently affects the subsequent trajectory of kidney function in IgA nephropathy patients. Methods: This was a single-center cohort study. The study included 199 patients diagnosed with IgA nephropathy. The COVID-19 infection status was determined using a combined method: a questionnaire and the Health Code application, both administered at the end of 2022 in northern China. Kidney function trajectory was assessed by the estimated glomerular filtration rate (eGFR), calculated based on serum creatinine levels measured during follow-up outpatient visits. The primary endpoint of interest was the eGFR trajectory. Results: Out of the 199 participants, 75% (n = 181) reported a confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, determined through antigen or polymerase chain reaction tests, accounting for 79% (n = 143) of the infected patients. A significant majority (98%) experienced mild to moderate symptoms. Over a median follow-up period of 10.7 months post-COVID-19 infection, notable clinical events included gross hematuria in 30 patients (16.6%), which normalized within an average of 3 days. Additionally, a 2-fold increase in proteinuria or progression to the nephrotic range was observed in 10 individuals (5.5%). No cases of acute kidney injury were noted. COVID-19 exposure was associated with an absolute change in eGFR of 2.98 mL/min/1.73 m2 per month (95% confidence interval 0.46 to 5.50). However, in a fully adjusted model, the estimated changes in eGFR slope post-COVID-19 were -0.39 mL/min/1.73 m2 per month (95% confidence interval -0.83 to 0.06, P = .088) which included the possibility of no significant effect. Notably, a higher rate of kidney function decline was primarily observed in patients with a baseline eGFR <45 mL/min/1.73 m2 [-0.56 mL/min/1.73 m2 (-1.11 to -0.01), P = .048]. In the cohort, there were few instances of severe COVID-19 cases. The absence of long-term follow-up outcomes was observed. Conclusions: Overall, mild to moderate COVID-19 infection does not appear to significantly exacerbate the subsequent decline in kidney function among IgA nephropathy patients, particularly in those with preserved baseline kidney function.

Prevalence and related factors of nephrolithiasis among medical staff in Qingdao, China: a retrospective cross-sectional study.

BACKGROUND: Certain occupations may predispose individuals to urolithiasis, a multi-factorial disease. The study aimed to evaluate the prevalence and related factors of nephrolithiasis in medical staff in Qingdao, China. METHODS: Physical examination results of 5115 in-service medical staff aged 22-60 years old were retrospectively analyzed. Multivariable logistic regression analysis and stratified analyses by age and gender were applied to explore the related factors of nephrolithiasis in these medical staff. RESULTS: The overall nephrolithiasis prevalence in medical staff in Qingdao, China was 4.65%. Doctors were more prone to nephrolithiasis than nurses (5.63% vs. 3.96%, P = 0.013) and the peak prevalence (6.69%) was observed in medical staff working in the emergency department (ED). Male gender (OR = 1.615, 95% CI = 1.123-2.323, P = 0.010), overweight or obesity (OR = 1.674, 95% CI = 1.266-2.214, P < 0.001), work seniority ≥ 10 years (OR = 2.489, 95%CI = 1.675-3.699, P < 0.001) and working in the ED (OR = 1.815, 95% CI = 1.202-2.742, P = 0.005) were independent predictors for nephrolithiasis in medical staff based on the results of multivariate logistic regression analysis. The associations between overweight or obesity and nephrolithiasis risk as well as between work seniority ≥ 10 years and nephrolithiasis risk in medical staff were independent of age or gender in stratified analysis. CONCLUSIONS: Nephrolithiasis prevalence in medical staff in Qingdao, China seemed not to be higher than that in the general population. Medical staff with work seniority ≥ 10 years and working in the ED should pay abundant attention to take measures to modify their nephrolithiasis risk.

Combined Genetic Association and Differed Expression Analysis of UBE2L3 Uncovers a Genetic Regulatory Role of (Immuno)proteasome in IgA Nephropathy.

Introduction: IgA nephropathy (IgAN) is a leading cause of end-stage renal disease. The exact pathogenesis of IgAN is not well defined, but some genetic studies have led to a novel discovery that the (immuno)proteasome probably plays an important role in IgAN. Methods: We firstly analyzed the association of variants in the UBE2L3 region with susceptibility to IgAN in 3,495 patients and 9,101 controls, and then analyzed the association between lead variant and clinical phenotypes in 1,803 patients with regular follow-up data. The blood mRNA levels of members of the ubiquitin-proteasome system including UBE2L3 were analyzed in peripheral blood mononuclear cells from 53 patients and 28 healthy controls. The associations between UBE2L3 and the expression levels of genes involved in Gd-IgA1 production were also explored. Results: The rs131654 showed the most significant association signal in UBE2L3 region (OR: 1.10, 95% CI: 1.04-1.16, p = 2.29 × 10-3), whose genotypes were also associated with the levels of Gd-IgA1 (p = 0.04). The rs131654 was observed to exert cis-eQTL effects on UBE2L3 in various tissues and cell types, particularly in immune cell types in multiple databases. The UBE2L3, LUBAC, and proteasome subunits were highly expressed in patients compared with healthy controls. High expression levels of UBE2L3 were not only associated with higher proteinuria (r = 0.34, p = 0.01) and lower eGFR (r = -0.28, p = 0.04), but also positively correlated with the gene expression of LUBAC and other proteasome subunits. Additionally, mRNA expression levels of UBE2L3 were also positively correlated with IL-6 and RELA, but negatively correlated with the expression levels of the key enzyme in the process of glycosylation including C1GALT1 and C1GALT1C1. Conclusion: In conclusion, by combined genetic association and differed expression analysis of UBE2L3, our data support a role of genetically conferred dysregulation of the (immuno)proteasome in regulating galactose-deficient IgA1 in the development of IgAN.

Analysis of risk factors for difficult implant removal in children with slipped capital femoral epiphysis treated by cannulated screws.

Introduction: Cannulated screws are widely used in the treatment of slipped capital femoral epiphysis, which can be removed after physeal closure on patient's request. This study aimed to analysis the potential risk factors for difficult removal in children with slipped capital femoral epiphysis treated by cannulated screws. Patients and methods: This study enrolled 32 hips that had undergone removal of cannulated screws after treatment of slipped capital femoral epiphysis at our department. The primary outcomes were the difficult screw removal. The secondary outcomes were functional outcome assessed by using a modified Harris Hip Score and complications of fractures and surgical site infection. Related risk factors for difficult removal were recorded and analyzed by multivariable logistic regression. Results: In total, 32 hips were evaluated, with a mean age of 14.9 ± 1.3 years old (range, 13-19 years). Six (18.8%) hips presented with difficult removal, including 4 cases of screws' slip and 2 breakages. The average implantation time in the difficult removal group (5.7 ± 1.0) was also significantly longer than that in the easily removed group (3.8 ± 0.9, p = 0.001). The mean surgical time in patients with difficult removal was 66.3 ± 11.6 min, which was also significantly longer than that (54.8 ± 8.3) in the other patients (p = 0.008). The duration of screw implantation was an independent risk factor for difficult removal. Conclusions: Prolonged screw duration was a predictor for difficult removal in children with slipped capital femoral epiphysis treated by cannulated screws. An early surgery after physeal closure might benefit those with a request for screw removal.

Pseudomonas aeruginosa gene PA4880 encodes a Dps-like protein with a Dps fold, bacterioferritin-type ferroxidase centers, and endonuclease activity.

We report the biochemical, structural, and functional characterization of the protein coded by gene PA4880 in the P. aeruginosa PAO1 genome. The PA4880 gene had been annotated as coding a probable bacterioferritin. Our structural work shows that the product of gene PA4880 is a protein that adopts the Dps subunit fold, which oligomerizes into a 12-mer quaternary structure. Unlike Dps, however, the ferroxidase di-iron centers and iron coordinating ligands are buried within each subunit, in a manner identical to that observed in the ferroxidase center of P. aeruginosa bacterioferritin. Since these structural characteristics correspond to Dps-like proteins, we term the protein as P. aeruginosa Dps-like, or Pa DpsL. The ferroxidase centers in Pa DpsL catalyze the oxidation of Fe2+ utilizing O2 or H2O2 as oxidant, and the resultant Fe3+ is compartmentalized in the interior cavity. Interestingly, incubating Pa DpsL with plasmid DNA results in efficient nicking of the DNA and at higher concentrations of Pa DpsL the DNA is linearized and eventually degraded. The nickase and endonuclease activities suggest that Pa DpsL, in addition to participating in the defense of P. aeruginosa cells against iron-induced toxicity, may also participate in the innate immune mechanisms consisting of restriction endonucleases and cognate methyl transferases.

Prevention of cyclophosphamide-induced immune suppression by polysaccharides from Apocynum venetum flowers via enhancing immune response, reducing oxidative stress, and regulating gut microbiota in mice.

Introduction: Emerging proof suggests that Apocynum venetum flowers polysaccharide (AVFP) has immunomodulatory effects in vitro. However, the action mechanism of AVFA is still unclear in vivo. The purpose of this study is to probe into the potential mechanism of AVFA in immunosuppressed mice by investigating organ index, cytokine levels, anti-oxidative stress capacity, transcriptomics, and gut microbiota. Methods: Immunocompromised mice induced by cyclophosphamide (CTX) were divided into six groups. The enzyme-labeled method, hematoxylin and eosin, transcriptomics, and high-throughput sequencing were used to detect the regulatory effects of AVFP on immunocompromised mice and the function of AVFP on the concentration of short-chain fatty acids (SCFAs) by high-performance liquid chromatography (HPLC) analysis. The Spearman correlation analysis was used to analyze the correlation between the intestinal microbiota and biochemical indexes. Results: The experimental results illustrated that AVFP has protective effects against CTX-induced immunosuppression in mice by prominently increasing the organ index and levels of anti-inflammatory factors in serum in addition to enhancing the antioxidant capacity of the liver. Meanwhile, it could also signally decrease the level of pro-inflammatory cytokines in serum, the activity of transaminase in serum, and the content of free radicals in the liver, and alleviate the spleen tissue damage induced by CTX. Transcriptomics results discovered that AVFP could play a role in immune regulation by participating in the NF-κB signaling pathway and regulating the immune-related genes Bcl3, Hp, Lbp, Cebpd, Gstp2, and Lcn2. Gut microbiota results illustrated that AVFP could increase the abundance of beneficial bacteria, reduce the abundance of harmful bacteria, and regulate the metabolic function of intestinal microorganisms while dramatically improving the content of SCFAs, modulating immune responses, and improving the host metabolism. The Spearman analysis further evaluated the association between intestinal microbiota and immune-related indicators. Conclusion: These findings demonstrated that AVFP could enhance the immune effects of the immunosuppressed mice and improve the body's ability to resist oxidative stress.

PCSK9 Inhibitor Added to High-Intensity Statin Therapy to Prevent Cardiovascular Events in Patients with Acute Coronary Syndrome after Percutaneous Coronary Intervention: A Randomized, Double- Blind, Placebo-Controlled, Multicenter SHAWN Study.

BACKGROUND: It is currently uncertain whether the combination of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor and high-intensity statin treatment can effectively reduce cardiovascular events in patients with acute coronary syndrome (ACS) who have undergone percutaneous coronary intervention (PCI) for culprit lesions. METHODS: This study protocol describes a double-blind, randomized, placebo-controlled, multicenter study aiming to investigate the efficacy and safety of combining a PCSK9 inhibitor with high-intensity statin therapy in patients with ACS following PCI. A total of 1212 patients with ACS and multiple lesions will be enrolled and randomly assigned to receive either PCSK9 inhibitor plus high-intensity statin therapy or high-intensity statin monotherapy. The randomization process will be stratified by sites, diabetes, initial presentation and use of stable (≥4 weeks) statin treatment at presentation. PCSK 9 inhibitor or its placebo is injected within 4 hours after PCI for the culprit lesion. The primary endpoint is the composite of cardiovascular death, myocardial infarction, stroke, re-hospitalization due to ACS or heart failure, or any ischemia-driven coronary revascularization at one-year follow-up between two groups. Safety endpoints mean PCSK 9 inhibitor and statin intolerance. CONCLUSION: The SHAWN study has been specifically designed to evaluate the effectiveness and safety of adding a PCSK9 inhibitor to high-intensity statin therapy in patients who have experienced ACS following PCI. The primary objective of this study is to generate new evidence regarding the potential benefits of combining a PCSK9 inhibitor with high-intensity statin treatment in reducing cardiovascular events among these patients.

Quantity, Duration, Adherence, and Reasons for Dietary Supplement Use among Adults: Results from NHANES 2011-2018.

Dietary supplement use is common among US adults. We aimed to investigate the quantity, duration, adherence, and reasons for supplement use in individuals who take supplements. Data from 2011 to 2018 from the National Health and Nutrition Examination Survey (NHANES) dataset were analyzed. Four cycles of data were combined to estimate these outcomes. Results are presented as overall group and by subgroups. All analyses were weighted to be nationally representative. The Taylor Series Linearization approach was used to generate variance estimates. A total of 12,529 participants were included. Over 70% of these individuals reported taking more than one unit of dietary supplements daily. Notably, approximately 40% had been taking supplements for more than five years and about 67% were highly adherent to at least one supplement. However, only 26.9% of these supplements were taken following a doctor's recommendation. The primary reasons for dietary supplements intake included improving overall health (37.2%), maintaining health (34.7%), bone health (21.4%), and diet supplementation (20.3%). Our findings indicate that most participants proactively used multiple dietary supplements focused on self-managed health and prevention, with substantial dedication to long-term use and high adherence. Healthcare professionals should play a more active role in guiding such behaviors to optimize the health outcomes of dietary supplement users across the United States.

Environmental, economic, and social sustainability in aquaculture: the aquaculture performance indicators.

Aquaculture is a rapidly growing food production technology, but there are significant concerns related to its environmental impact and adverse social effects. We examine aquaculture outcomes in a three pillars of sustainability framework by analyzing data collected using the Aquaculture Performance Indicators. Using this approach, comparable data has been collected for 57 aquaculture systems worldwide on 88 metrics that measure social, economic, or environmental outcomes. We first examine the relationships among the three pillars of sustainability and then analyze performance in the three pillars by technology and species. The results show that economic, social, and environmental outcomes are, on average, mutually reinforced in global aquaculture systems. However, the analysis also shows significant variation in the degree of sustainability in different aquaculture systems, and weak performance of some production systems in some dimensions provides opportunity for innovative policy measures and investment to further align sustainability objectives.