scholarly journals Hyperuricemia as a prognostic marker for long-term outcomes in patients with myocardial infarction with nonobstructive coronary arteries

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Wenjian Ma ◽  
Side Gao ◽  
Sizhuang Huang ◽  
Jiansong Yuan ◽  
Mengyue Yu

Abstract Background Hyperuricemia (HUA) has been proved as a predictor of worse outcomes in patients with coronary artery disease. Here, we investigated the prognostic value of HUA in a distinct population with myocardial infarction with nonobstructive coronary arteries (MINOCA). Methods A total of 1179 MINOCA patients were enrolled and divided into HUA and non-HUA groups. HUA was defined as a serum uric acid level ≥ 420 μmol/L in men or ≥ 357 μmol/L in women. The primary study endpoint was a composite of major adverse cardiovascular events (MACE), including all-cause death, nonfatal MI, nonfatal stroke, revascularization, and hospitalization for unstable angina or heart failure. Kaplan–Meier, Cox regression, and receiver-operating characteristic analyses were performed. Results Patients with HUA (prevalence of 23.5%) had a significantly higher incidence of MACE (18.7% vs. 12.8%; p = 0.015) than patients without during the median follow-up of 41.7 months. HUA was closely associated with an increased risk of MACE even after multivariable adjustment (hazard ratio 1.498, 95% confidence interval: 1.080 to 2.077; p = 0.016). HUA remained a robust risk factor of MACE after propensity score matching analysis. Moreover, HUA showed an area under the curve (AUC) of 0.59 for predicting MACE. Incorporation of HUA to the thrombolysis in myocardial infarction (TIMI) score yielded a significant improvement in discrimination for MACE. Conclusions HUA was independently associated with poor prognosis after MINOCA. Routine assessment of HUA may facilitate risk stratification in this specific population.

2021 ◽  
Vol 12 ◽  
Author(s):  
Side Gao ◽  
Wenjian Ma ◽  
Sizhuang Huang ◽  
Xuze Lin ◽  
Mengyue Yu

BackgroundThyroid function is closely involved in cardiovascular diseases. The free triiodothyronine (fT3) to free thyroxine (fT4) ratio has been reported as a risk factor for coronary artery disease, but its prognostic value in euthyroid patients with myocardial infarction with nonobstructive coronary arteries (MINOCA) remains unclear.MethodsA total of 1162 euthyroid patients with MINOCA were enrolled and divided according to decreased tertiles of fT3/fT4 ratio. The study endpoint was major adverse cardiovascular events (MACE), including all-cause death, nonfatal MI, nonfatal stroke, revascularization, and hospitalization for unstable angina or heart failure. Kaplan-Meier, Cox regression, and receiver-operating characteristic analyses were performed.ResultsPatients with lower fT3/fT4 tertile levels had a significantly higher incidence of MACE (10.0%, 13.9%, 18.2%; p=0.005) over the median follow-up of 41.7 months. The risk of MACE increased with the decreasing fT3/fT4 tertiles even after multivariate adjustment (tertile1 as reference, tertile2: HR 1.58, 95% CI: 1.05-2.39, p=0.030; tertile3: HR 2.06, 95% CI: 1.17-3.11, p=0.006). Lower level of fT3/fT4 ratio remained a robust predictor of MACE in overall (HR 1.64, 95% CI: 1.18-2.29, p=0.003) and in subgroups. When adding fT3/fT4 ratio [area under the curve (AUC) 0.61] into the thrombolysis in myocardial infarction (TIMI) risk score (AUC 0.69), the combined model (AUC 0.74) yielded a significant improvement in discrimination for MACE (ΔAUC 0.05, p=0.023).ConclusionsLow level of fT3/fT4 ratio was strongly associated with a poor prognosis in euthyroid patients with MINOCA. Routine assessment of fT3/fT4 ratio may facilitate risk stratification in this specific population.


2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Side Gao ◽  
Wenjian Ma ◽  
Sizhuang Huang ◽  
Xuze Lin ◽  
Mengyue Yu

Abstract Background Abnormal glucose metabolism including diabetes (DM) and prediabetes (pre-DM) have been reported as predictors of poorer outcomes after acute myocardial infarction (AMI). However, the prognostic value of pre-DM in patients with myocardial infarction with nonobstructive coronary arteries (MINOCA) remains unclear. Methods A total of 1179 MINOCA patients were prospectively recruited and divided into normoglycemia (NG), pre-DM, and DM groups according to glycated hemoglobin (HbA1c) levels or past history. The primary endpoint was a composite of major adverse cardiovascular events (MACE), including all-cause death, nonfatal MI, nonfatal stroke, revascularization and hospitalization for unstable angina or heart failure. Kaplan–Meier and Cox regression analyses were performed. Results Patients with pre-DM and DM had a significantly higher incidence of MACE compared with NG group (10.8%, 16.1%, 19.4%; p = 0.003) over the median follow-up of 41.7 months. After multivariate adjustment, both pre-DM and DM were significantly associated with an increased risk of MACE (NG as reference; pre-DM: 1.45, 95% CI 1.03–2.09, p = 0.042; DM: HR 1.79, 95% CI 1.20–2.66, p = 0.005). At subgroup analysis, pre-DM remained a robust risk factor of MACE compared to NG. In addition, pre-DM had a similar impact as DM on long-term prognosis in patients with MINOCA. Conclusions Pre-DM defined as raised HbA1c was associated with a poor prognosis in patients with MINOCA. Routine assessment of HbA1c enables an early recognition of pre-DM and thus may facilitate risk stratification in this specific population.


2021 ◽  
Vol 8 ◽  
Author(s):  
Side Gao ◽  
Wenjian Ma ◽  
Sizhuang Huang ◽  
Xuze Lin ◽  
Mengyue Yu

Background: Sex differences in clinical profiles and prognosis after acute myocardial infarction have been addressed for decades. However, the sex-based disparities among patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) remain largely unreported. Here, we investigated sex-specific characteristics and long-term outcomes in MINOCA population.Methods: A total of 1,179 MINOCA patients were enrolled, including 867 men and 312 women. The mean follow-up was 41.7 months. The primary endpoint was a composite of major adverse cardiovascular events (MACE), including all-cause death, non-fatal reinfarction, revascularization, non-fatal stroke, and hospitalization for unstable angina or heart failure. Baseline data and outcomes were compared. Kaplan-Meier curves and Cox regression analyses were used to identify association between sex and prognosis.Results: Female patients with MINOCA had more risk profiles with regard to older age and higher prevalence of hypertension and diabetes compared with men. The evidence-based medical treatment was similar in men and women. The incidence of MACE (men vs. women: 13.8 vs. 15.3%, p = 0.504) did not differ significantly between the sexes. The Kaplan-Meier analysis also indicated that women had a similar incidence of MACE compared to men (log rank p = 0.385). After multivariate adjustment, female sex was not associated with the risk of MACE in overall (adjusted hazard ratio 1.02, 95% confidence interval: 0.72–1.44, p = 0.916) and in subgroups of MINOCA patients.Conclusion: The long-term outcomes were similar for men and women presenting with MINOCA despite older age and more comorbidities in women. Future research should aim to improve in-hospital and post-discharge care for both sexes with MINOCA.


2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
B Izquierdo ◽  
R Olsen ◽  
R Abad ◽  
D Nieto ◽  
C Perela ◽  
...  

Abstract Background Insomnia can either be a primary problem or it may be associated with other psychological conditions, ranging from anxiety to depression. Some studies have reported that pts with MINOCA (myocardial infarction with non-obstructive coronary arteries) have more emotional disorders than the rest of pts with myocardial infarction (MI). However, a relationship with insomnia has not been yet described. The aim of this study is to compare insomnia levels between patients with MINOCA and the rest of MI patients using a validated scale: Insomnia Severity Index (ISI) (Figure 1). Methods We performed an analytical and observational study in which all consecutive MI pts from July 2017 to December 2020 were recruited. We used the latest definitions of MINOCA according to the 2020 ESC Guidelines. A group of experts reviewed all MINOCA cases in order to exclude those who did not fulfil criteria. Therefore, takotsubo syndrome and pts with myocarditis were excluded. ISI questionnaire was completed by each patient during admission. Total score ranges from 0 to 28 points. Depending on the final score, pts could have no clinically significant insomnia (0–7 points), subthreshold insomnia (8–14 points), clinical insomnia of moderate severity (15–21 points) and severe clinical insomnia (22–28 points). Follow up analysis included major adverse cardiovascular events (MACE: cardiovascular readmission, myocardial reinfarction, stroke and death from any cause). Survival analysis is based on Cox regression. Median follow-up was 25±23 months. Results From a total of 413 consecutive MI pts, 244 (59%) completed the questionnaire. Of them, 32 (13%) were MINOCA pts. There were no statistically significant differences in insomnia levels between both groups (Table 1). Even in absolute terms, both groups presented same mean levels: MINOCA mean value 7.6±6 points vs rest of MI 7.7±6 points, p=0.8. When separated by sex, women in the MI group had higher punctuation levels than men (24% of moderate clinical insomnia in women vs 8.9% of men, p=0.03). Punctuation in ISI questionnaire showed no significant differences in MACE in MINOCA pts (HR 0.9, CI 95% (0.7–1.2)), nor in the rest of MI pts (HR 0.9, CI 95% (0.9–1.03)). Conclusions Levels of insomnia were similar in MINOCA pts than in the rest of MI pts. Follow up showed no differences in MACE between both groups regarding insomnia according to ISI. Women had higher punctuation levels than men, with more clinical insomnia in a moderate grade. Subjective emotions could lead to mistaken findings, making it necessary to use ISI questionnaire or other objective validated scales to correctly study some disorders and their distribution in different populations. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Spanish Society of Cardiology Table 1. Insomnia severity index Figure 1. ISI Questionnaire


2021 ◽  
Vol 8 ◽  
Author(s):  
Side Gao ◽  
Haobo Xu ◽  
Sizhuang Huang ◽  
Jiansong Yuan ◽  
Mengyue Yu

Background: Current guidelines recommend ticagrelor as the preferred P2Y12 inhibitor on top of aspirin in patients after an acute coronary syndrome. Yet, the efficacy and safety of ticagrelor vs. clopidogrel in patients with myocardial infarction with nonobstructive coronary arteries (MINOCA) remain uncertain.Methods: A total of 1,091 patients with MINOCA who received dual antiplatelet therapy were enrolled and divided into the clopidogrel (n = 878) and ticagrelor (n = 213) groups. The primary efficacy endpoint was a composite of major adverse cardiovascular events (MACE), including all-cause death, nonfatal MI, stroke, revascularization, and hospitalization for unstable angina or heart failure. The safety endpoint referred to bleeding events. The Kaplan-Meier, propensity score matching (PSM), and Cox regression analyses were performed.Results: The incidence of MACE was similar for clopidogrel- and ticagrelor-treated patients over the median follow-up of 41.7 months (14.3 vs. 15.0%; p = 0.802). The use of ticagrelor was not associated with a reduced risk of MACE compared with clopidogrel after multivariable adjustment in overall (HR = 1.25, 95% CI: 0.84–1.86, p = 0.262) and in subgroups of MINOCA patients. Further, there was no significant difference in the risk of bleeding between two groups (HR = 1.67, 95% CI: 0.83–3.36, p = 0.149). After PSM, 206 matched pairs were identified, and the differences between clopidogrel and ticagrelor for ischemic endpoints and bleeding events remained nonsignificant (all p > 0.05).Conclusions: In this observational analysis of MINOCA patients, ticagrelor was not superior to clopidogrel in reducing ischemic events and did not cause a significant increase in bleeding, indicating a similar efficacy and safety between clopidogrel and ticagrelor. A randomized study of ticagrelor vs. clopidogrel in this specific population is needed.


2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
J Lopez Pais ◽  
M J Espinosa Pascual ◽  
B Izquierdo Coronel ◽  
D Galan Gil ◽  
B Alcon Duran ◽  
...  

Abstract Background Despite all the recent publications, including new guidelines, myocardial infarction with non-obstructive coronary arteries (MINOCA) is still a controversy “working diagnosis”. MINOCA patients have a characteristic risk profile, with a lower prevalence of classical risk factors (CVRF). The aim of this study is to analyze the relationship between known proinflammatory conditions and MINOCA. Methods Analytical and observational study developed in a University Hospital, which covers 220.000 individuals. We analyzed data of 109 consecutive MINOCA patients admitted to our center during a 3 years period (2016–2018). We used the definitions and the clinical management of the 2016 European Society of Cardiology Working Group Position Paper on MINOCA. The composite of proinflammatory conditions (PIC) includes vasculitis and other autoimmune pathologies; connective tissue diseases, the presence of active cancer and the fact of presenting the myocardial infarction as a complication during admission for a non-cardiovascular pathology. Follow up analysis included death from any cause and major adverse cardiovascular events (MACE). Survival analysis is based on Cox regression and represented by Kaplan Meier curves. Median follow up was 17 months. Results Around one-third of the MINOCA patients had PIC (34.8%). They tended to be older (67.9±14 vs 62.8±15, p 0.08), with no differences in rate of female sex (55.3 vs 49.3%, p 0.55) neither in traditional CVRF: Tobacco (40.5 vs 42.6%), diabetes (18.4 vs 26.8%), dyslipidaemia (39.5 vs 48.6%) or hypertension (55.3 vs 64.8%). Patients with PIC had a higher proportion of ischemic ECG at presentation (75.7 vs 53.5%, p 0.03), a tendency to worse ejection fraction (45.9 vs 28.2%, p 0.07) and higher in-hospital mortality (2.6 vs 0.0%, p 0.17). Levels of troponin were similar (4.0±6.0 vs 6.6±10.4, p 0.2) During follow-up (Figure 1), PIC was related to a higher all-cause-mortality (16.2 vs 1.5%, Hazard Ratio (HR) 10.7 (95% Confidence Interval [CI]: 1.3–89.0, p 0.03). Patients with PIC also showed a non-significant higher cardiovascular mortality (5.3 vs 1.4%, HR 3.5 [CI: 0.3–38.5], p 0.3) and higher rate of MACE (13.5 vs 9.2%, HR 1.6 [CI: 0.5–5.1], p 0.4). Conclusion In this study, MINOCA patients had a high prevalence of PIC, being present in more than one-third of them. They are linked to worse prognosis, with higher all-cause mortality and a non-significant increase in cardiovascular mortality and MACE, which could be significant with the appropriate number of patients.


2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
J Lopez Pais ◽  
L Alvarez Rodriguez ◽  
B Izquierdo Coronel ◽  
M Pedreira Perez ◽  
R Agra Bermejo ◽  
...  

Abstract Background Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA) remains a challenge in cardiology clinical practice. 2016 European Society of Cardiology Working Group position paper (ESC-WGPP) recommend to treat them as the rest of myocardial infarctions, mainly with dual antiplatelet therapy (DAT), beta blockers, Angiotensin Converter Enzyme Inhibitors (ACEI), and statins. The aim of this study is to analyse the use of optimal medical treatment (OMT) of ischemic heart disease (IHD) treatment on this group of patients and its implication in their prognosis. Methods Analytical and observational study based on a retrospective cohort of MINOCA (according to the definitions of ESC-WGPP) extracted from the myocardial infarction registries of three University Hospitals during the period from 2003–2018 (N: 9371). We analysed data about the treatment of all consecutive MINOCA. Treatment prescribed was the one considered by their responsible doctors. We recorded specific information about treatment prescribed after hospitalization. Follow up analysis based on Cox regression included death from any cause and major adverse cardiovascular events ([MACE], a composite of a recurrence of myocardial infarction, stroke or transient ischemic attack or death from any cardiovascular cause) Median follow up was 52.6±32.5 months. Results Of 9371 patients initially admitted for acute myocardial infarction, 620 were classified as MINOCA (incidence 6.6%). Median age was 64.2 years old, and 40.7% were women. Regarding cardiovascular risk factors, 25.1% were smokers, 19.0% had diabetes, 42.3 had dyslipidemia and 57.7% hypertension. At discharge, 18.2% had ventricular dysfunction. DAT was prescribed in 32.4% of MINOCA patients, beta blockers in 59.5%, ACEI in 54.8% and statins in 71.9%. Statins showed impact on MINOCAs prognosis, with a significant reduction in total mortality Hazard Ratio (HR): 0.60 (95%Confidence Interval [CI]: 0.38–0.94) p 0.03. DAT had a non-significant reduction in total mortality (HR 0.64 [CI: 0.37–1.13] p 0.12). The rest of the OMT of IHD showed no significant impact on total mortality: beta blockers (HR 0.84 [CI: 0.54–1.31] p 0.45) and ACEI (1.30 [CI: 0.83–2.03] p 0.25) None of the OMT had impact on MACE after MINOCA: DAT (HR 0.97 [CI: 0.70–1.35] p 0.87), beta blockers (HR 0.92 [CI: 0.69–1.23] p 0.57), ACEI (1.13 [CI: 0.85–1.51] p 0.40) and statins (0.94 [CI: 0.69–1.30] p 0.74). Figure 1 Conclusion This study suggests that statins may be liked with a better prognosis in MINOCA, whereas the rest of conventional IHD treatments showed no difference in the course of the illness. This could be due to the heterogeneity of physiopathological mechanisms underlying the working diagnosis of MINOCA. So, following the 2016 ESC-WGPP on MINOCA recommendations, a deep diagnostic study must be performed in order to individualize the treatment.


2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
J Lopez Pais ◽  
B Izquierdo Coronel ◽  
D Galan Gil ◽  
B Alcon Duran ◽  
M J Espinosa Pascual ◽  
...  

Abstract Background There is controversy to whether Takotsubo Syndrome (TTS) should be classified as a Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA). The aim of this study is to compare the clinical profile and prognosis of TTS with non-TTS MINOCA patients. Methods Analytical and observational study developed in a University Hospital, which covers 220.000 individual. We analyzed the clinical data of all consecutive MINOCA patients admitted to our center during a 3 years period (2016–2018). We used the definitions and the clinical management of 2016 ESC Working Group Position Paper on MINOCA, which considers TTS as a MINOCA. Follow up analysis included death from any cause and major adverse cardiovascular events (MACE). Survival analysis is based on Cox regression. Median follow-up was 17 months. Results Twenty-six out of 109 patients (24%) classified as MINOCA where TTS. Patients with TTS were older (72.2±11.5 vs 62.3±14.9, p<0.01) and the female proportion was higher (72.0 vs 43.9%, p 0.01) than in the non-TTS MINOCA group. Regarding cardiovascular risk factors, there were no significant differences: Hypertension (56.0 vs 63.4%), Dyslipidemia (48.9 vs 45.7%), smoking rate (41.7 vs 41.8%) and diabetes (32.0 vs 22.0%,). The antecedent of atrial fibrillation tended to be higher in TTS group (4.0 vs 18.3%, p 0.08). TTS patients at admission referred angina as the main symptom in fewer cases (56.0 vs 78.0%, p 0.03), but they had an electrocardiogram suggesting ischemia more frequently (87.5 vs 53.7%, p<0.01). TTS presented more frequently with Killip class worse than II (24.9 vs 1.2%, p<0.01) and with more systolic dysfunction (92.0 vs 15.9%m p<0.01) than non-TTS MINOCA. There was no significant difference in the peak of troponin (5.7±9.7 vs 5.6±8.8). Levels of hemoglobin at the admission were lower in the TTS group (12.4±2.2 vs 13.8±2.0, p<0.01). The proportion of in-hospital complications (recovered cardiac arrest, shock, pulmonary edema, ictus, re-infarction) were higher in the TTS group (40.0 vs 6.1%, p<0.01). TTS was an intercurrent complication during admission for a non-cardiovascular pathology in more occasions than non-TTS MINOCA (16 vs 4.9%, p 0.06). During follow-up, TTS showed worse prognosis, with higher all-cause mortality: 16.0 vs 4.0%, Hazard Ratio (HR) 4.49 (Confidence Interval [CI] 1.01–20.10, p<0.05); a tendency to more cardiovascular mortality: 8.0 vs 1.2%, p 0.07, HR 6.7 (CI 0.61–74.35, p 0.12) and to an excess of MACE: 20.0 vs 8.0%, p 0.1, HR 3.1 (CI 0.92–9.98, p 0.07). Conclusion There are differences in the clinical profile and prognosis of TTS patients compared to the rest of non-TTS MINOCA, being TTS a more aggressive entity. We think these data are in line with the recently released 4th Universal Definition of Myocardial Infarction, where TTS should be considered apart from the rest causes of “myocardial injury” or “myocardial infarction”, being an entity with its own characteristics and prognosis.


2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
J Lopez-Pais ◽  
B Izquierdo Coronel ◽  
S Raposeiras-Roubin ◽  
L Alvarez Rodriguez ◽  
O Vedia ◽  
...  

Abstract Aims Whether Takotsubo syndrome (TTS) should be classified within myocardial infarction with non-obstructive coronary arteries (MINOCA) is still controversial. The aim of this work is to evaluate main differences between TTS and non-TTS MINOCA. Methods and results A cohort study based on two prospective registries: TTS from the RETAKO registry (N:1055) and non-TTS MINOCA patients from contemporary records of acute myocardial infarction from 5 national centres (N:1080). Definitions and management recommended by the ESC were used. Survival analysis was based on Cox regression; propensity score matching was created to adjust prognostic variables. TTS were more often women (85.9% vs. 51.9%; p&lt;0.001) and older (69.4±12.5 vs. 64.5±14.1 years; p&lt;0.001). Atrial fibrillation was more frequent in non-TTS MINOCA (10.4% vs. 14.4%; p 0.007). Psychiatric disorders were more prevalent in TTS (15.5% vs. 10.2%, p&lt;0.001). In-hospital mortality and complications were higher in TTS: 3.4 vs 1.8%, (p 0.015) and 25.8% vs. 11.5%, (p&lt;0.001). Median follow-up was 32.4 months; TTS had less major adverse cardiovascular events (MACE): Hazard Ratio (HR) 0.59; 95% confidence interval (CI) 0.42 to 0.83. There were no differences in total mortality (HR 0.87; CI: 0.64 to 1.19), but TTS had lower cardiovascular mortality (HR 0.58; CI: 0.35 to 0.98). Conclusions TTS has a different patient's profile and a more aggressive acute phase than the rest of MINOCA. However, its long-term cardiovascular prognosis is better. These results support that TTS should be considered a distinct entity with unique characteristics and prognosis. Funding Acknowledgement Type of funding source: None


Author(s):  
Mustafa Umut Somuncu ◽  
Belma Kalayci ◽  
Ahmet Avci ◽  
Tunahan Akgun ◽  
Huseyin Karakurt ◽  
...  

AbstractBackgroundThe increase in soluble suppression of tumorigenicity 2 (sST2) both in the diagnosis and prognosis of heart failure is well established; however, existing data regarding sST2 values as the prognostic marker after myocardial infarction (MI) are limited and have been conflicting. This study aimed to assess the clinical significance of sST2 in predicting 1-year adverse cardiovascular (CV) events in MI patients.Materials and methodsIn this prospective study, 380 MI patients were included. Participants were grouped into low sST2 (n = 264, mean age: 60.0 ± 12.1 years) and high sST2 groups (n = 116, mean age: 60.5 ± 11.6 years), and all study populations were followed up for major adverse cardiovascular events (MACE) which are composed of CV mortality, target vessel revascularization (TVR), non-fatal reinfarction, stroke and heart failure.ResultsDuring a 12-month follow-up, 68 (17.8%) patients had MACE. CV mortality and heart failure were significantly higher in the high sST2 group compared to the low sST2 group (15.5% vs. 4.9%, p = 0.001 and 8.6% vs. 3.4% p = 0.032, respectively). Multivariate Cox regression analysis concluded that high serum sST2 independently predicted 1-year CV mortality [hazard ratio (HR) 2.263, 95% confidence interval (CI) 1.124–4.557, p = 0.022)]. Besides, older age, Killip class >1, left anterior descending (LAD) as the culprit artery and lower systolic blood pressure were the other independent risk factors for 1-year CV mortality.ConclusionsHigh sST2 levels are an important predictor of MACE, including CV mortality and heart failure in a 1-year follow-up period in MI patients.


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