Journal of clinical lipidology最新文献

{"title":"Enhancing lipoprotein(a) association studies: A complementary approach to principal component analysis.","authors":"Souichi Oka, Nobuko Inoue, Yoshiyasu Takefuji","doi":"10.1016/j.jacl.2025.08.021","DOIUrl":"https://doi.org/10.1016/j.jacl.2025.08.021","url":null,"abstract":"","PeriodicalId":15392,"journal":{"name":"Journal of clinical lipidology","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Greater alterations in atherogenic lipids and inflammatory markers in women during type 2 diabetes development and risk of coronary heart disease-findings from two population-based studies.","authors":"Yilin Yoshida, Danting Li, Xiang Li, Anand Rohatgi, Lydia Bazzano, Vivian A Fonseca, Lu Qi, Franck Mauvais-Jarvis","doi":"10.1016/j.jacl.2025.08.010","DOIUrl":"10.1016/j.jacl.2025.08.010","url":null,"abstract":"<p><strong>Background: </strong>Diabetes confers a greater risk of coronary heart disease (CHD) in women than in men, potentially due to women's antecedent of metabolic risk factors. We examined circulating metabolites and their associations with CHD risk in men and women across glycemic statuses.</p><p><strong>Methods: </strong>We analyzed data from 97,271 CHD-free UK Biobank participants. Metabolomic profiling was performed by nuclear magnetic resonance (NMR) spectroscopy of baseline plasma samples. We used linear regression models to examine the association between sex and log-transformed metabolites in newly diagnosed type 2 diabetes (T2D), prediabetes, and euglycemia, adjusting for age, race/ethnicity, Townsend deprivation index, income, smoking, alcohol consumption, physical activity, body mass index, medication use (for diabetes, lipid-lowering, and hypertension). Cox regression models were used to evaluate associations between metabolites and CHD risk (fatal or nonfatal myocardial infarction) stratified by sex and adjusted for the same covariates. We further considered menopausal status, and all analyses were adjusted for false discovery rate. The analyses were replicated in 6,199 participants of the Multi-Ethnic Study of Atherosclerosis (MESA) with NMR data.</p><p><strong>Results: </strong>With worsening glycemic status, women exhibited significantly higher atherogenic lipid/lipoprotein markers, fatty acids, and glycoprotein acetyls (GlycA) than men, as well as lower albumin and lactate (all P-values <.0001). Sex differences persisted regardless of menopausal status. In adjusted Cox regressions, 1 SD increase in triglyceride (TG), saturated fatty acids (SFA), and GlycA was associated with a greater risk of CHD in women with T2D than men over a 10-year follow-up (hazard ratios 1.2-1.5 in women and 0.9-1.04 in men, P-interaction <.05).</p><p><strong>Conclusions: </strong>With worsening glycemic status, women exhibit higher levels of atherogenic lipid and inflammatory markers. TG, GlycA, and SFA are more strongly associated with CHD risk in women with T2D than in men.</p>","PeriodicalId":15392,"journal":{"name":"Journal of clinical lipidology","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-HDL and LDL cholesterol, but not calculated remnant cholesterol, are associated with subclinical atherosclerosis.","authors":"Malin Mickelsson, Per Liv, Kristina Stefansson, Kim Ekblom, Anders Själander, Emma Nyman, Christer Grönlund, Ulf Näslund, Johan Hultdin","doi":"10.1016/j.jacl.2025.08.014","DOIUrl":"https://doi.org/10.1016/j.jacl.2025.08.014","url":null,"abstract":"<p><strong>Background: </strong>Elevated low-density lipoprotein (LDL) cholesterol levels represent a significant modifiable risk factor for atherosclerotic cardiovascular disease. However, a residual risk persists, possibly attributed to other atherogenic lipoproteins such as non-high-density lipoprotein (non-HDL) and remnant cholesterol. Nevertheless, few studies have explored the independent associations between these lipid biomarkers and early atherosclerotic disease.</p><p><strong>Objective: </strong>To evaluate the relative contributions of LDL, non-HDL, and remnant cholesterol to subclinical atherosclerosis, assessed by carotid ultrasonography.</p><p><strong>Method: </strong>In this cross-sectional study, we included 1929 previously healthy individuals from the pragmatic VIPVIZA trial who had available lipid levels and carotid ultrasonography results to assess subclinical disease. Non-HDL, LDL, and remnant cholesterol were calculated from a standard lipid profile. Subclinical atherosclerosis was assessed by carotid intima-media thickness (cIMT) and the presence of carotid plaques.</p><p><strong>Results: </strong>We found that all lipid variables (LDL, non-HDL, and remnant cholesterol) were associated with subclinical atherosclerosis in univariable models (P < .01 across all models for cIMT and P < .001, P < .001, P = .003 respectively for carotid plaques). In multivariable-adjusted models, increasing LDL and non-HDL cholesterol levels were still significantly associated with increased odds of having carotid plaques (P < .001 for both) and increased cIMT (P < .001 for both). However, no independent association between remnant cholesterol and subclinical atherosclerosis was observed in the model adjusted for LDL cholesterol levels (P = .073 for cIMT and = .818 for plaque).</p><p><strong>Conclusion: </strong>Increasing LDL and non-HDL cholesterol levels, but not remnant cholesterol, seem to contribute to carotid subclinical atherosclerosis.</p>","PeriodicalId":15392,"journal":{"name":"Journal of clinical lipidology","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Statin use in transthyretin amyloid cardiomyopathy: Assessing tolerability and drug interaction risks with tafamidis.","authors":"Azita H Talasaz, Margaret O Cuomo, Mathew S Maurer","doi":"10.1016/j.jacl.2025.08.015","DOIUrl":"https://doi.org/10.1016/j.jacl.2025.08.015","url":null,"abstract":"<p><strong>Background: </strong>Transthyretin cardiac amyloidosis (ATTR-CM) is a progressive cardiomyopathy treated with tafamidis, a transthyretin stabilizer that improves survival and quality of life. Tafamidis inhibits the breast cancer resistance protein (BCRP), raising concern for drug-drug interactions, particularly with rosuvastatin.</p><p><strong>Objective: </strong>To evaluate the potential interaction between tafamidis and statins in patients with ATTR-CM.</p><p><strong>Methods: </strong>We conducted a retrospective study of 103 patients with confirmed ATTR-CM receiving both tafamidis and statin therapy at Columbia University Irving Medical Center.</p><p><strong>Results: </strong>The most commonly prescribed statins were atorvastatin (61%) and rosuvastatin (30%). Fourteen patients (12%) experienced changes in their statin regimen, with 7 involving rosuvastatin and 6 with atorvastatin due to adverse effects or proactive adjustments. Myalgias and elevated liver enzymes were the most frequent adverse events. One case of rhabdomyolysis was reported with atorvastatin 80 mg. Risk factors for statin intolerance-including advanced age, and use of amiodarone contributed to statin change.</p><p><strong>Conclusions: </strong>Our findings highlight the need for individualized statin selection in ATTR-CM patients treated with tafamidis, favoring statins with lower dependency on BCRP and efflux transporters with cautious dosing. Patients should be monitored for muscle-related symptoms and alternative lipid-lowering agents should be considered when appropriate to optimize safety and treatment efficacy.</p>","PeriodicalId":15392,"journal":{"name":"Journal of clinical lipidology","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Simulation model to estimate pretreatment (baseline) low-density lipoprotein cholesterol levels in people living with homozygous familial hypercholesterolemia.","authors":"Jing Gu, Robert J Sanchez, Alexandra Koumas, Sandeep Tripathi, Harshit Dixit, Adam Amer, Laurence Sperling, Christie M Ballantyne","doi":"10.1016/j.jacl.2025.08.011","DOIUrl":"https://doi.org/10.1016/j.jacl.2025.08.011","url":null,"abstract":"<p><strong>Introduction: </strong>Pretreatment levels of low-density lipoprotein cholesterol (LDL-C) are a primary consideration for the clinical diagnosis of homozygous familial hypercholesterolemia (HoFH). However, determination of pretreatment LDL-C can be challenging in this population because many individuals begin lipid-lowering therapy (LLT) early in life before diagnosis of HoFH.</p><p><strong>Methods: </strong>A previously developed simulation model was adapted to estimate pretreatment LDL-C in people living with HoFH, based on their treated LDL-C value and current LLT (statin, ezetimibe, alirocumab, evolocumab, and/or lipoprotein apheresis).</p><p><strong>Results: </strong>The tool includes an interface for users to provide relevant details for estimating non-clinical pretreatment LDL-C, specifically for patients suspected of having HoFH.</p><p><strong>Conclusion: </strong>This HoFH-specific calculator is provided as a supplemental tool to facilitate education about and awareness of the potential of having HoFH, which may lead to reduced time to appropriate treatments for people living with HoFH and, ultimately, optimize their outcomes.</p>","PeriodicalId":15392,"journal":{"name":"Journal of clinical lipidology","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extreme lipoprotein(a) is a cardiovascular risk equivalent in heterozygous familial hypercholesterolemia.","authors":"Martine Paquette, Bertrand Cariou, Simon-Pierre Guay, Antonio Gallo, Liam R Brunham, Sophie Béliard, Alexis Baass","doi":"10.1016/j.jacl.2025.08.009","DOIUrl":"https://doi.org/10.1016/j.jacl.2025.08.009","url":null,"abstract":"<p><strong>Background: </strong>Extreme elevations in lipoprotein(a) [Lp(a)] and familial hypercholesterolemia (FH) are both monogenic diseases associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). The identification of high Lp(a) risk thresholds would help to improve risk assessment in subjects with heterozygous FH (HeFH).</p><p><strong>Objective: </strong>To find the Lp(a) value at which the observed 10-year ASCVD risk corresponds to a cardiovascular risk equivalent in a cohort of HeFH patients in primary cardiovascular prevention.</p><p><strong>Methods: </strong>This multinational observational study used data from 3 prospective cohorts from France, UK, and Canada. A total of 2979 adult patients with HeFH in primary prevention diagnosed using genetic or clinical criteria (Dutch Lipid Clinic Network score ≥6) and 10,521 non-FH control participants in secondary cardiovascular prevention were included in the study. The 10-year risk of incident ASCVD was assessed using Kaplan-Meier estimates, whereas the relative risk was estimated using Cox proportional hazards regression models.</p><p><strong>Results: </strong>The 90th percentile of Lp(a) in the group of FH subjects in primary prevention corresponds to ≥100 mg/dL (≥250 nmol/L). The observed 10-year risk of ASCVD associated with an Lp(a) ≥100 mg/dL (≥250 nmol/L) vs <100 mg/dL (<250 nmol/L) was 28.7% and 11.0%, respectively, compared to 34.9% in non-FH individuals in secondary cardiovascular prevention.</p><p><strong>Conclusion: </strong>This study showed that 10% of HeFH in primary cardiovascular prevention have an extreme cardiovascular risk associated with the presence of a double monogenic dyslipidemia. These individuals should be treated more aggressively to prevent ASCVD and may greatly benefit from novel therapeutics targeting Lp(a).</p>","PeriodicalId":15392,"journal":{"name":"Journal of clinical lipidology","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145053779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human monocyte inflammation in patients with Lp(a) or atherosclerotic cardiovascular disease is not accompanied by changes in chromatin accessibility in circulating classical monocytes.","authors":"Rosalie W M Kempkes, Jordan M Kraaijenhof, Bram W van Os, Yannick Kaiser, Nick S Nurmohamed, Guillermo R Griffith, Esther Lutgens, Erik S G Stroes, Koen H M Prange, Menno P J de Winther, Jeffrey Kroon, Annette E Neele","doi":"10.1016/j.jacl.2025.08.003","DOIUrl":"https://doi.org/10.1016/j.jacl.2025.08.003","url":null,"abstract":"<p><strong>Background and aims: </strong>High plasma lipoprotein(a) [Lp(a)] levels are associated with accelerated atherosclerosis and subsequent atherosclerotic cardiovascular disease (ASCVD), potentially through enhanced inflammatory signaling of monocytes. Given that monocytes are major players in ASCVD risk and the role of epigenetic changes in regulating their responsiveness, we propose that investigating changes in chromatin accessibility could reveal the underlying mechanisms of enhanced monocyte inflammation.</p><p><strong>Methods: </strong>In this observational case-control study, we collected blood from subjects with low (<25 nmol/L) and elevated (>350 nmol/L) plasma Lp(a) with and without a history of ASCVD, matched for age and sex. A total of 60 subjects were included in the study, comprising 60% males and a mean age of 62.8 ± 7.8 years. We assessed gene expression and chromatin accessibility of fluorescence-activated cell sorting (FACS)-sorted classical monocytes using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and bulk assay for transposase-accessible chromatin (ATAC)-sequencing and analyzed plasma cytokine levels.</p><p><strong>Results: </strong>Subjects with high plasma Lp(a) showed significantly increased gene expression of IFIT3. At the plasma level, subjects with high Lp(a) without ASCVD were distinguished by higher concentrations of chemokine C-X-C motif ligand 10 (CXCL10). While these results are consistent with previous research demonstrating increased interferon-γ signaling in monocytes of individuals with elevated Lp(a), we did not detect differences in chromatin accessibility of monocytes between subjects with high or low Lp(a), irrespective of ASCVD status.</p><p><strong>Conclusion: </strong>While subjects with high Lp(a) levels showed enhanced monocyte inflammation, no differences in chromatin accessibility were detected. This suggests that the pro-inflammatory signature of Lp(a) and ASCVD on monocytes is regulated at a level other than chromatin accessibility.</p>","PeriodicalId":15392,"journal":{"name":"Journal of clinical lipidology","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Triglyceride-glucose index and 28-day all-cause mortality in critically ill obese patients: A commentary on methodological considerations.","authors":"Songsong Luo","doi":"10.1016/j.jacl.2025.08.004","DOIUrl":"https://doi.org/10.1016/j.jacl.2025.08.004","url":null,"abstract":"","PeriodicalId":15392,"journal":{"name":"Journal of clinical lipidology","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enzyme replacement therapy in cholesteryl ester storage disease: A case report on lysosomal acid lipase deficiency management.","authors":"Marisol Ibarra-Ramírez, Leonor Hinojosa-Amaya, Idalia Cura-Esquivel, Ulises Torres-Flores, Laura E Martínez de Villarreal","doi":"10.1016/j.jacl.2025.08.005","DOIUrl":"https://doi.org/10.1016/j.jacl.2025.08.005","url":null,"abstract":"<p><strong>Background: </strong>Lysosomal acid lipase deficiency (LAL-D) is a rare autosomal recessive disorder caused by pathogenic variants in the LIPA gene. The clinical spectrum ranges from early-onset Wolman disease to later presentations in childhood and adulthood, formerly known as cholesteryl ester storage disease (CESD). Impaired lysosomal acid lipase (LAL) activity leads to the accumulation of cholesteryl esters and triglycerides, causing progressive hepatic and metabolic dysfunction.</p><p><strong>Case presentation: </strong>We describe a 17-year-old Mexican female diagnosed with CESD at age 13 after evaluation for short stature and severe hypercholesterolemia. Laboratory workup revealed markedly elevated liver enzymes and lipid levels, with severely reduced LAL activity. Molecular testing identified a homozygous LIPA(NM_000235.3):c.894G>A variant. Enzyme replacement therapy (ERT) with sebelipase alfa (1 mg/kg biweekly) was initiated, leading to progressive normalization of lipid and hepatic profiles. Over a 48-month follow-up, the patient exhibited catch-up growth (gain of 17 cm and 21 kg), pubertal development with the onset of menarche at age 16, and achievement of Tanner stage III.</p><p><strong>Conclusion: </strong>This case underscores the importance of early recognition of CESD in patients with unexplained dyslipidemia, elevated liver enzymes, and growth delay. Timely initiation of sebelipase alfa resulted in favorable biochemical and clinical outcomes. Comprehensive diagnostic evaluation-including enzymatic and genetic testing-is critical for accurate diagnosis and personalized management of LAL-D.</p>","PeriodicalId":15392,"journal":{"name":"Journal of clinical lipidology","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HDL remodeling and enrichment with apoCIII and apoE in Indigenous Australians.","authors":"Maaike Kockx, Jeffrey Wang, Natasha J Howard, Avinash Suryawanshi, Stephen J Nicholls, Alex Brown, Leonard Kritharides","doi":"10.1016/j.jacl.2025.08.006","DOIUrl":"https://doi.org/10.1016/j.jacl.2025.08.006","url":null,"abstract":"<p><strong>Background: </strong>Indigenous Australians have an increased risk of type 2 diabetes mellitus (T2DM) and premature cardiovascular disease. Subpopulations of high-density lipoprotein (HDL) have been associated with increased cardiovascular risk, but HDL composition, size, or function have not been studied in Indigenous Australians.</p><p><strong>Methods: </strong>The study consisted of 86 non-Indigenous participants, 43 of whom had T2DM, and 75 Indigenous participants, 36 of whom had T2DM. HDL lipid and apolipoprotein content were determined using enzymatic assays and enzyme-linked immunosorbent assays, respectively, and HDL size and distribution were investigated using nuclear magnetic resonance spectroscopy. Transporter-independent, ATP-binding cassette transporter-A1(ABCA1)- and ABCG1-specific cholesterol efflux capacity (CEC) were determined using cell lines stably expressing human ABCA1 or ABCG1.</p><p><strong>Results: </strong>Indigenous participants had significantly lower concentrations of large (10.3-12.0 nm), small (7.4-7.8 nm), and total HDL particles, which persisted after adjustment for serum triglyceride (TG), body mass index (BMI), and T2DM. HDL from Indigenous Australians was also highly enriched in TG, apolipoprotein (apo) E, and apoCIII (all P < .001). Transporter-independent and ABCG1-mediated CEC were not different between the populations. ABCA1-specific CEC per HDL particle was higher in Indigenous than in non-Indigenous subjects (P < .001), and persisted after adjustment for TG, BMI, and T2DM. Multivariable analysis identified that ABCA1-specific CEC was independently and positively associated with HDL-apoCIII and HDL-apoE levels.</p><p><strong>Conclusions: </strong>Indigenous Australians demonstrate significant compositional, size, and functional changes in circulating HDL, which is only partially explained by BMI, hypertriglyceridemia, or T2DM. Remodeled HDL may serve as a biomarker of increased cardiovascular risk in Indigenous Australians.</p>","PeriodicalId":15392,"journal":{"name":"Journal of clinical lipidology","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}