A tryptophan metabolite made by a gut microbiome eukaryote induces pro-inflammatory T cells.

The large intestine harbors microorganisms playing unique roles in host physiology. The beneficial or detrimental outcome of host-microbiome coexistence depends largely on the balance between regulators and responder intestinal CD4+ T cells. We found that ulcerative colitis-like changes in the large intestine after infection with the protist Blastocystis ST7 in a mouse model are associated with reduction of anti-inflammatory Treg cells and simultaneous expansion of pro-inflammatory Th17 responders. These alterations in CD4+ T cells depended on the tryptophan metabolite indole-3-acetaldehyde (I3AA) produced by this single-cell eukaryote. I3AA reduced the Treg subset in vivo and iTreg development in vitro by modifying their sensing of TGFß, concomitantly affecting recognition of self-flora antigens by conventional CD4+ T cells. Parasite-derived I3AA also induces over-exuberant TCR signaling, manifested by increased CD69 expression and downregulation of co-inhibitor PD-1. We have thus identified a new mechanism dictating CD4+ fate decisions. The findings thus shine a new light on the ability of the protist microbiome and tryptophan metabolites, derived from them or other sources, to modulate the adaptive immune compartment, particularly in the context of gut inflammatory disorders.

Caspase-8 Collaborates with Caspase-11 to Drive Tissue Damage and Execution of Endotoxic Shock.

The execution of shock following high dose E. coli lipopolysaccharide (LPS) or bacterial sepsis in mice required pro-apoptotic caspase-8 in addition to pro-pyroptotic caspase-11 and gasdermin D. Hematopoietic cells produced MyD88- and TRIF-dependent inflammatory cytokines sufficient to initiate shock without any contribution from caspase-8 or caspase-11. Both proteases had to be present to support tumor necrosis factor- and interferon-ß-dependent tissue injury first observed in the small intestine and later in spleen and thymus. Caspase-11 enhanced the activation of caspase-8 and extrinsic cell death machinery within the lower small intestine. Neither caspase-8 nor caspase-11 was individually sufficient for shock. Both caspases collaborated to amplify inflammatory signals associated with tissue damage. Therefore, combined pyroptotic and apoptotic signaling mediated endotoxemia independently of RIPK1 kinase activity and RIPK3 function. These observations bring to light the relevance of tissue compartmentalization to disease processes in vivo where cytokines act in parallel to execute diverse cell death pathways.

Claudin-2 upregulation enhances intestinal permeability, immune activation, dysbiosis, and mortality in sepsis.

Intestinal epithelial expression of the tight junction protein claudin-2, which forms paracellular cation and water channels, is precisely regulated during development and in disease. Here, we show that small intestinal epithelial claudin-2 expression is selectively upregulated in septic patients. Similar changes occurred in septic mice, where claudin-2 upregulation coincided with increased flux across the paracellular pore pathway. In order to define the significance of these changes, sepsis was induced in claudin-2 knockout (KO) and wild-type (WT) mice. Sepsis-induced increases in pore pathway permeability were prevented by claudin-2 KO. Moreover, claudin-2 deletion reduced interleukin-17 production and T cell activation and limited intestinal damage. These effects were associated with reduced numbers of neutrophils, macrophages, dendritic cells, and bacteria within the peritoneal fluid of septic claudin-2 KO mice. Most strikingly, claudin-2 deletion dramatically enhanced survival in sepsis. Finally, the microbial changes induced by sepsis were less pathogenic in claudin-2 KO mice as survival of healthy WT mice injected with cecal slurry collected from WT mice 24 h after sepsis was far worse than that of healthy WT mice injected with cecal slurry collected from claudin-2 KO mice 24 h after sepsis. Claudin-2 upregulation and increased pore pathway permeability are, therefore, key intermediates that contribute to development of dysbiosis, intestinal damage, inflammation, ineffective pathogen control, and increased mortality in sepsis. The striking impact of claudin-2 deletion on progression of the lethal cascade activated during sepsis suggests that claudin-2 may be an attractive therapeutic target in septic patients.

N6-Methyladenine DNA Modification in the Human Genome.

DNA N6-methyladenine (6mA) modification is the most prevalent DNA modification in prokaryotes, but whether it exists in human cells and whether it plays a role in human diseases remain enigmatic. Here, we showed that 6mA is extensively present in the human genome, and we cataloged 881,240 6mA sites accounting for ∼0.051% of the total adenines. [G/C]AGG[C/T] was the most significantly associated motif with 6mA modification. 6mA sites were enriched in the coding regions and mark actively transcribed genes in human cells. DNA 6mA and N6-demethyladenine modification in the human genome were mediated by methyltransferase N6AMT1 and demethylase ALKBH1, respectively. The abundance of 6mA was significantly lower in cancers, accompanied by decreased N6AMT1 and increased ALKBH1 levels, and downregulation of 6mA modification levels promoted tumorigenesis. Collectively, our results demonstrate that DNA 6mA modification is extensively present in human cells and the decrease of genomic DNA 6mA promotes human tumorigenesis.

Time required for commitment to T cell proliferation depends on TCR affinity and cytokine response.

T cell activation and effector functions are determined by the affinity of the interaction between T cell receptor (TCR) and its antigenic peptide MHC (pMHC) ligand. A better understanding of the quantitative aspects of TCR-pMHC affinity-dependent T cell activation is critical for the development of new immunotherapeutic strategies. However, the role of TCR-pMHC affinity in regulating the kinetics of CD8+ T cell commitment to proliferation and differentiation is unknown. Here, we show that the stronger the TCR-pMHC affinity, the shorter the time of T cell-APC co-culture required to commit CD8+ T cells to proliferation. The time threshold for T cell cytokine production is much lower than that for cell proliferation. There is a strong correlation between affinity-dependent differences in AKT phosphorylation and T cell proliferation. The cytokine IL-15 increases the poor proliferation of T cells stimulated with low affinity pMHC, suggesting that pro-inflammatory cytokines can override the affinity-dependent features of T cell proliferation.

Dynamic N6 -methyladenosine RNA modification regulates peanut resistance to bacterial wilt.

N6 -methyladenosine (m6 A) is the most abundant mRNA modification in eukaryotes and is an important regulator of gene expression as well as many other critical biological processes. However, the characteristics and functions of m6 A in peanut (Arachis hypogea L.) resistance to bacterial wilt (BW) remain unknown. Here, we analyzed the dynamic of m6 A during infection of resistant (H108) and susceptible (H107) peanut accessions with Ralstonia solanacearum (R. solanacearum), the causative agent of BW. Throughout the transcriptome, we identified 'URUAY' as a highly conserved motif for m6 A in peanut. The majority of differential m6 A located within the 3' untranslated region (UTR) of the transcript, with fewer in the exons. Integrative analysis of RNA-Seq and m6 A methylomes suggests the correlation between m6 A and gene expression in peanut R. solanacearum infection, and functional analysis reveals that m6 A-associated genes were related to plant-pathogen interaction. Our experimental analysis suggests that AhALKBH15 is an m6 A demethylase in peanut, leading to decreased m6 A levels and upregulation of the resistance gene AhCQ2G6Y. The upregulation of AhCQ2G6Y expression appears to promote BW resistance in the H108 accession.

The RIPK3 Scaffold Regulates Lung Inflammation During Pseudomonas Aeruginosa Pneumonia.

RIPK3 (receptor-interacting protein kinase 3) activity triggers cell death via necroptosis, whereas scaffold function supports protein binding and cytokine production. To determine if RIPK3 kinase or scaffold domains mediate pathology during Pseudomonas aeruginosa infection, control mice and those with deletion or mutation of RIPK3 and associated signaling partners were subjected to Pseudomonas pneumonia and followed for survival or killed for biologic assays. Murine immune cells were studied in vitro for Pseudomonas-induced cytokine production and cell death, and RIPK3 binding interactions were blocked with the viral inhibitor M45. Human tissue effects were assayed by infecting airway epithelial cells with Pseudomonas and measuring cytokine production after siRNA inhibition of RIPK3. Deletion of RIPK3 reduced inflammation and decreased animal mortality after Pseudomonas pneumonia. RIPK3 kinase inactivation did neither. In cell culture, RIPK3 was dispensable for cell killing by Pseudomonas and instead drove cytokine production that required the RIPK3 scaffold domain but not kinase activity. Blocking the RIP homotypic interaction motif (RHIM) with M45 reduced the inflammatory response to infection in vitro. Similarly, siRNA knockdown of RIPK3 decreased infection-triggered inflammation in human airway epithelial cells. Thus, the RIPK3 scaffold drives deleterious pulmonary inflammation and mortality in a relevant clinical model of Pseudomonas pneumonia. This process is distinct from kinase-mediated necroptosis, requiring only the RIPK3 RHIM. Inhibition of RHIM signaling is a potential strategy to reduce lung inflammation during infection.

TOP1α, UPF1, and TTG2 regulate seed size in a parental dosage-dependent manner.

Cues of maternal and paternal origins interact to control seed development, and the underlying molecular mechanisms are still far from clear. Here, we show that TOPOISOMERASE Iα (TOP1α), UP-FRAMESHIFT SUPPRESSOR 1 (UPF1), and TRANSPARENT TESTA GLABRA2 (TTG2) gametophytically, biparentally regulate seed size in Arabidopsis. TOP1α and UPF1 are mainly expressed in antipodal cells, and loss of their function leads to ectopic TTG2 expression in these female gametophytic cells. We further demonstrate that TOP1α and UPF1 directly repress TTG2 expression through affecting its chromatin status and determine its relative expression in antipodal cells versus sperm cells, which controls seed size in a dosage-dependent and parent-of-origin-dependent manner. The molecular interplay among these three genes explains their biparental gametophytic effect during diploidy and interploidy reciprocal crosses. Taken together, our findings reveal a molecular framework of parental interaction for seed size control.

Self-helped detection of obstructive sleep apnea based on automated facial recognition and machine learning.

PURPOSE: The diagnosis of obstructive sleep apnea (OSA) relies on time-consuming and complicated procedures which are not always readily available and may delay diagnosis. With the widespread use of artificial intelligence, we presumed that the combination of simple clinical information and imaging recognition based on facial photos may be a useful tool to screen for OSA. METHODS: We recruited consecutive subjects suspected of OSA who had received sleep examination and photographing. Sixty-eight points from 2-dimensional facial photos were labelled by automated identification. An optimized model with facial features and basic clinical information was established and tenfold cross-validation was performed. Area under the receiver operating characteristic curve (AUC) indicated the model's performance using sleep monitoring as the reference standard. RESULTS: A total of 653 subjects (77.2% males, 55.3% OSA) were analyzed. CATBOOST was the most suitable algorithm for OSA classification with a sensitivity, specificity, accuracy, and AUC of 0.75, 0.66, 0.71, and 0.76 respectively (P < 0.05), which was better than STOP-Bang questionnaire, NoSAS scores, and Epworth scale. Witnessed apnea by sleep partner was the most powerful variable, followed by body mass index, neck circumference, facial parameters, and hypertension. The model's performance became more robust with a sensitivity of 0.94, for patients with frequent supine sleep apnea. CONCLUSION: The findings suggest that craniofacial features extracted from 2-dimensional frontal photos, especially in the mandibular segment, have the potential to become predictors of OSA in the Chinese population. Machine learning-derived automatic recognition may facilitate the self-help screening for OSA in a quick, radiation-free, and repeatable manner.

Chromatin accessibility illuminates single-cell regulatory dynamics of rice root tips.

BACKGROUND: Root development and function have central roles in plant adaptation to the environment. The modification of root traits has additionally been a major driver of crop performance since the green revolution; however, the molecular underpinnings and the regulatory programmes defining root development and response to environmental stress remain largely unknown. Single-cell reconstruction of gene regulatory programmes provides an important tool to understand the cellular phenotypic variation in complex tissues and their response to endogenous and environmental stimuli. While single-cell transcriptomes of several plant organs have been elucidated, the underlying chromatin landscapes associated with cell type-specific gene expression remain largely unexplored. RESULTS: To comprehensively delineate chromatin accessibility during root development of an important crop, we applied single-cell ATAC-seq (scATAC-seq) to 46,758 cells from rice root tips under normal and heat stress conditions. Our data revealed cell type-specific accessibility variance across most of the major cell types and allowed us to identify sets of transcription factors which associate with accessible chromatin regions (ACRs). Using root hair differentiation as a model, we demonstrate that chromatin and gene expression dynamics during cell type differentiation correlate in pseudotime analyses. In addition to developmental trajectories, we describe chromatin responses to heat and identify cell type-specific accessibility changes to this key environmental stimulus. CONCLUSIONS: We report chromatin landscapes during rice root development at single-cell resolution. Our work provides a framework for the integrative analysis of regulatory dynamics in this important crop organ at single-cell resolution.

Design of Hollow Porous P-NiCo2O4@Co3O4 Nanoarray and Its Alkaline Aqueous Zinc-Ion Battery Performance.

Alkaline aqueous zinc-ion batteries possess a wider potential window than those in mildly acidic systems; they can achieve high energy density and are expected to become the next generation of energy storage devices. In this paper, a hollow porous P-NiCo2O4@Co3O4 nanoarray is obtained by ion etching and the calcination and phosphating of ZiF-67, which is directly grown on foam nickel substrate, as a precursor. It exhibits excellent performance as a cathode material for alkaline aqueous zinc-ion batteries. A high discharge specific capacity of 225.3 mAh g-1 is obtained at 1 A g-1 current density, and it remains 81.9% when the current density is increased to 10 A g-1. After one thousand cycles of charging and discharging at 3 A g-1 current density, the capacity retention rate is 88.8%. Even at an excellent power density of 25.5 kW kg-1, it maintains a high energy density of 304.5 Wh kg-1. It is a vital, promising high-power energy storage device for large-scale applications.

Single-cell RNA-seq of Lotus japonicus provide insights into identification and function of root cell types of legume.

The roots of legume plant play a crucial role in nitrogen fixation. However, the transcriptomes of different cell types of legume root and their functions remain largely unknown. Here, we performed single-cell RNA sequencing and profiled more than 22,000 single cells from root tips of Lotus japonicus, a model species of legume. We identified seven clusters corresponding to seven major cell types, which were validated by in situ hybridization. Further analysis revealed regulatory programs including phytohormone and nodulation associated with specific cell types, and revealed conserved and diverged features for the cell types. Our results represent the first single-cell resolution transcriptome for legume root tips and a valuable resource for studying the developmental and physiological functions of various cell types in legumes.

A reduction in metabolism explains the tradeoffs associated with the long-term adaptation of phytoplankton to high CO2 concentrations.

Phytoplankton are responsible for nearly half of global primary productivity and play crucial roles in the Earth's biogeochemical cycles. However, the long-term adaptive responses of phytoplankton to rising CO2 remains unknown. Here we examine the physiological and proteomics responses of a marine diatom, Phaeodactylum tricornutum, following long-term (c. 900 generations) selection to high CO2 conditions. Our results show that this diatom responds to long-term high CO2 selection by downregulating proteins involved in energy production (Calvin cycle, tricarboxylic acid cycle, glycolysis, oxidative pentose phosphate pathway), with a subsequent decrease in photosynthesis and respiration. Nearly similar extents of downregulation of photosynthesis and respiration allow the high CO2 -adapted populations to allocate the same fraction of carbon to growth, thereby maintaining their fitness during the long-term high CO2 selection. These results indicate an important role of metabolism reduction under high CO2 and shed new light on the adaptive mechanisms of phytoplankton in response to climate change.

CD28 Agonism Improves Survival in Immunologically Experienced Septic Mice via IL-10 Released by Foxp3+ Regulatory T Cells.

Immune dysregulation during sepsis is mediated by an imbalance of T cell costimulatory and coinhibitory signaling. CD28 is downregulated during sepsis and is significantly altered on memory versus naive T cells. Thus, to study the role of CD28 during sepsis in a more physiologically relevant context, we developed a "memory mouse" model in which animals are subjected to pathogen infections to generate immunologic memory, followed by sepsis induction via cecal ligation and puncture. Using this system, we show that agonistic anti-CD28 treatment resulted in worsened survival in naive septic animals but conferred a significant survival advantage in immunologically experienced septic animals. Mechanistically, this differential response was driven by the ability of CD28 agonism to elicit IL-10 production from regulatory T cells uniquely in memory but not naive mice. Moreover, elevated IL-10 released by activated regulatory T cells in memory mice inhibited sepsis-induced T cell apoptosis via the antiapoptotic protein Bcl-xL. Together, these data demonstrate that immunologic experience is an important parameter that affects sepsis pathophysiology and can fundamentally change the outcome of modulating the CD28 pathway during sepsis. This study suggests that testing therapeutic strategies in immunologically experienced hosts may be one way to increase the physiologic relevance of rodent models in sepsis research.

Fast assessment of left ventricular systolic function in obstructive sleep apnea patients with automated function imaging: Comparison with mitral annular plane systolic excursion.

BACKGROUND: Early detection of left ventricular (LV) subclinical dysfunction is clinically relevant before developing irreversible impairment in obstructive sleep apnea (OSA) patients. Mitral annulus plane systolic excursion (MAPSE) is a fast tool for OSA due to high prevalent obesity; another quick but more comprehensive tool is LV global longitudinal stain (GLS) based on automated function imaging (AFI). We therefore aimed to compare the feasibility and reproducibility of AFI to MAPSE in OSA patients, as a good model in whom obesity is common. METHODS: A comprehensive echocardiographic examination was done in 186 consecutive patients having polysomnography for suspected OSA. MAPSE was measured by using M-mode to calculate excursion of mitral annulus. GLS was derived by offline analysis of three long-axis views that semi-automatically detects LV endocardial boundary, which is adjusted manually as necessary with AFI measurement. Variability of AFI and MAPSE were compared among the different subgroups. RESULTS: Despite a relatively high obesity rate (42.9%), the feasibility of AFI was 94% (175/186) and that of 100% in MAPSE. AFI showed excellent correlation (r = .882) superior to MAPSE (r = .819) between the Expert and Beginner. Intra- and inter- observer variability of AFI and MAPSE in Bland-Altman analysis were 5.5% and 6.5%; 6.2% and 8.8%, respectively. In repeated measurements, AFI showed higher intra-class correlation (ICC = .95) than MAPSE (ICC = .87) (p < 0.05). Furthermore, analysis showed that AFI was feasible even in more obese patients (BMI≥28 kg/m2 ). CONCLUSIONS: Even in obese patients with OSA, AFI-GLS is feasible and more reliable for less expert operators than MAPSE in detecting LV longitudinal dysfunction.

Pioglitazone combined with atorvastatin promotes plaque stabilization in a rabbit model.

OBJECTIVE: It is not yet clear whether plaque inflammation and cardiovascular events are reduced further when pioglitazone and atorvastatin are combined. Our study aimed to determine whether pioglitazone combined with atorvastatin can restrain the progression of atherosclerosis and promote plaque stabilization in a rabbit model. METHOD AND RESULT: Thirty rabbits were randomly divided into an atherosclerosis group, an atorvastatin group, and an atorvastatin plus pioglitazone group. The atherosclerosis model was induced using balloon injury and feeding a high-fat diet. Plasma samples were then used to analyze glucose, triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), high-sensitivity C-reactive protein (hs-CRP), and matrix metalloproteinase-9 (MMP-9). The area percentage of atherosclerotic plaques was analyzed by hematoxylin-eosin staining. The relative reductions in TG and LDL-C and the increase in HDL-C levels were significantly greater in the combination therapy group than in the atorvastatin monotherapy group (TG: -33.60 ± 7.17% vs -24.16 ± 8.04%, p < 0.001; LDL-C: -42.89 ± 1.63% vs -37.13 ± 1.35%, p < 0.001; and HDL-C: 25.18 ± 5.53% vs 10.43 ± 6.31%, p < 0.001). The relative reductions in hs-CRP and MMP-9 levels were significantly greater in the combination therapy group than in the atorvastatin monotherapy group (-69.38 ± 1.06% vs-53.73 ± 1.92%, p < 0.001; -32.77 ± 2.49% vs -13.36 ± 1.66%, p < 0.001). The area percentage of atherosclerotic plaques was significantly smaller in the atorvastatin group (47.75%, p < 0.05) and in the atorvastatin plus pioglitazone group (22.57%, p < 0.05) than in the atherosclerosis group (84.08%, p < 0.05). CONCLUSION: We can thus conclude that the combination treatment of atorvastatin and pioglitazone provided additive benefits on inflammatory parameters and lipid metabolism. Pioglitazone combined with atorvastatin can further restrain the progression of atherosclerosis and promote plaque stabilization in a rabbit model.

Reorganization of the 3D chromatin architecture of rice genomes during heat stress.

BACKGROUND: The three-dimensional spatial organization of the genome plays important roles in chromatin accessibility and gene expression in multiple biological processes and has been reported to be altered in response to environmental stress. However, the functional changes in spatial genome organization during environmental changes in crop plants are poorly understood. RESULTS: Here we perform Hi-C, ATAC-seq, and RNA-seq in two agronomically important rice cultivars, Nipponbare (Nip; Japonica) and 93-11 (Indica), to report a comprehensive profile of nuclear dynamics during heat stress (HS). We show that heat stress affects different levels of chromosome organization, including A/B compartment transition, increase in the size of topologically associated domains, and loss of short-range interactions. The chromatin architectural changes were associated with chromatin accessibility and gene expression changes. Comparative analysis revealed that 93-11 exhibited more dynamic gene expression and chromatin accessibility changes, including HS-related genes, consistent with observed higher HS tolerance in this cultivar. CONCLUSIONS: Our data uncovered higher-order chromatin architecture as a new layer in understanding transcriptional regulation in response to heat stress in rice.

Glycemic Control Status and Long-Term Clinical Outcomes in Diabetic Chronic Total Occlusion Patients: An Observational Study.

BACKGROUND: Whether good glycemic control can result in clinical benefits for diabetic chronic total occlusion (CTO) patients is still a matter of debate. METHODS: We studied 1029 diabetic CTO patients. Based on one-year glycosylated hemoglobin A (HbA1c) levels, we assigned the patients into 2 groups: HbA1c<7% group (n = 448) and HbA1c ≥ 7% group (n = 581). We further subdivided the patients into the successful CTO revascularization (CTO-SR) and nonsuccessful CTO revascularization (CTO-NSR) groups. Kaplan-Meier analysis and Cox regression before and after propensity score matching were used to compare major adverse cardiovascular events (MACE) and other endpoints. RESULTS: There were no significant differences between the groups in terms of most endpoints in the overall patients. After propensity score-matched analysis, patients with HbA1c < 7.0 tended to be superior in terms of MACE, which was mainly attributed to repeat revascularization but the other endpoints. Furthermore, the benefit of the HbA1c < 7 group was more prominent among patients with CTO-NSR in terms of MACE, repeat revascularization, and target vessel revascularization (TVR); and the improvement of the HbAc1 < 7 group was more prominent among patients without chronic heart failure (CHF) (P=0.027). CONCLUSIONS: HbA1c < 7.0 was associated with a reduced incidence of MACE, which was mainly attributed to a reduction in repeat revascularization. Good glycemic control can improve diabetic CTO patients' clinical prognosis, especially in CTO-NSR patients.

Atorvastatin Promotes Macrocalcification, But Not Microcalcification in Atherosclerotic Rabbits: An 18F-NaF PET/CT Study.

INTRODUCTION: Our study aimed to investigate the effect of atorvastatin on plaque calcification by matching the results obtained by 18F-sodium fluoride (18F-NaF) positron emission tomography (PET)/computed tomography (CT) with data from histologic sections. METHODS AND RESULTS: The rabbits were divided into 2 groups as follows: an atherosclerosis group (n = 10) and an atorvastatin group (n = 10). All rabbits underwent an abdominal aortic operation and were fed a high-fat diet to induce atherosclerosis. Plasma samples were used to analyze serum inflammation markers and blood lipid levels. 18F-NaF PET/CT scans were performed twice. The plaque area, macrophage number and calcification were measured, and the data from the pathological sections were matched with the 18F-NaF PET/CT scan results. The mean standardized uptake value (0.725 ± 0.126 vs. 0.603 ± 0.071, P < 0.001) and maximum standardized uptake value (1.024 ± 0.116 vs. 0.854 ± 0.091, P < 0.001) significantly increased in the atherosclerosis group, but only slightly increased in the atorvastatin group (0.616 ± 0.103 vs. 0.613 ± 0.094, P = 0.384; 0.853 ± 0.099 vs.0.837 ± 0.089, P < 0.001, respectively). The total calcium density was significantly increased in rabbits treated with atorvastatin compared with rabbits not treated with atorvastatin (1.64 ± 0.90 vs. 0.49 ± 0.35, P < 0.001), but the microcalcification level was significantly lower. There were more microcalcification deposits in the areas with increased radioactive uptake of 18F-NaF. CONCLUSIONS: Our study suggests that the anti-inflammatory activity of atorvastatin may promote macrocalcification but not microcalcification within atherosclerotic plaques. 18F-NaF PET/CT can detect plaque microcalcifications.

Cost-Effectiveness of Evolocumab Therapy for Myocardial Infarction: The Chinese Healthcare Perspective.

PURPOSE: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are an indispensable lipid-lowering treatment option, but their cost-effectiveness has been questioned. This study aimed to perform a health economic evaluation of evolocumab versus placebo in patients with myocardial infarction (MI) in China. METHODS: A Markov cohort state-transition model was developed in decision analysis software to estimate the incremental cost-effectiveness ratio (ICER), defined as cost per quality-adjusted life-year (QALY) saved. The simulation subjects could undergo non-fatal MI and/or stroke, or vascular or non-vascular death event. We integrated the Chinese population-specific demographics and event rates with the risk reduction of evolocumab based on the FOURIER trial and/or lowering of low-density lipoprotein cholesterol (LDL-C). Age-related change, event costs and utilities were included from published sources. RESULTS: At its current list price [33,748 Chinese yuan (CNY) annually per person], the ICER for evolocumab therapy was 927,713 CNY per QALY gained when integrating the FOURIER trial with absolute reduction of LDL-C. The probability of cost-effectiveness of evolocumab versus placebo was 1.96%, with a generally accepted threshold of 212,676 CNY per QALY gained. A reduction in acquisition price by approximately 70% (to less than 10,255 CNY annually) was needed to be cost-effective. Alternative scenario analyses of therapeutic benefit showed that the ICER for evolocumab in MI patients with uncontrolled familial hypercholesterolemia (FH) was 187,736 CNY per QALY gained. CONCLUSION: Evolocumab in patients with MI was not cost-effective based on the price in 2019 in China; however, treatment with evolocumab was more favorable in MI patients with FH.