scholarly journals Haemodynamic assessment of right ventricular overload in pulmonary hypertension: old parameters still fit better than new ones

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Pereira ◽  
J.G Santos ◽  
M.J Loureiro ◽  
F Ferreira ◽  
A.R Almeida ◽  
...  

Abstract Introduction Right ventricular (RV) adaptation to the increased pulmonary load is a key determinant of outcomes in pulmonary hypertension (PH). Pulmonary vascular resistance (PVR) is widely recognized as haemodynamic measure of RV overload. Cardiac filling pressure (CFP), RV stroke work (RVSW), pulmonary artery (PA) compliance and PA pulsatility index (PAPi) are emerging as new haemodynamic parameters to assess RV function. Aims To assess the predictive value of CFP, RVSW, PA compliance and PAPi in PH and to compare it with standard haemodynamic parameters. Methods Retrospective study including all consecutive right heart catheterizations performed from April/2009 to October/2019 in a PH referral centre. Procedures presenting PH were selected [mean pulmonary arterial pressure (mPAP) >20 mmHg, according to the new definition of the 6st World Symposium on PH]. CFP was calculated as [right atrial pressure (RAP) − pulmonary capillary wedge pressure], value >0.63 associated with RV failure; RVSW as CO / [(heart rate × (mPAP-RAP) × 0.0136], value <15; PA compliance [SV / pulmonary arterial systolic pressure (PASP) − pulmonary arterial diastolic pressure (PADP)], value <2.5]; PAPi [(PSAP − PDAP) / RAP, value <1.85]. Multivariate logistic regression was used to identify predictors of all-cause mortality. Receiver operating characteristic (ROC) curves and area under curve (AUC) were used to assess discrimination power. Results From a total of 569 procedures, 470 fulfilled PH criteria: mean age 57.9±16.0 years, 67.7% female, 35.5% performed under pulmonary vasodilator therapy. Pre-capillary PH was diagnosed in 71.9% of cases. Chronic thromboembolic PH was the most common subtype (34.4%). Concerning standard haemodynamic parameters: mPAP was 39.0±12.0 mmHg, mean RAP 8.0±5.0 mmHg, mean RVP 7.5±5.0 uWood and CI 2.5±0.8 L/min/m2. Median value of CFP was 0.6 (IQR 0.4–0.8), RVSW 15.2 (IQR 9.7–25.0), PA compliance 2.1 (IQR 0.9–2.9) and PAPi 5.3 (IQR 3.2–8.5). All-cause mortality rate was 22.8%. Patients experiencing adverse events had lower values of cardiac index (2.3±0.6 vs 2.6±0.8 L/min/m2, p<0.01), RVSW (11.2 vs 16.7, p<0.01) and PA compliance (2.2 vs 2.9, p<0.01) and higher values of PVR (10.0±5.5 versus 6.8±4.6 uWood, p<0.01) and mean RAP (9.9±6.1 versus 7.4±4.5, p<0.01). Multivariate logistic regression identified 2 independent predictors of adverse events: mean RAP (OR 1.08, 95% CI 1.02–1.13, p<0.01) and PVR (OR 1.11, 95% CI 1.06–1.17, p<0.01). According to the ROC curves, new haemodynamic parameters did not have acceptable discrimination power to adverse events occurrence (figure). Conclusions In this study, new haemodynamic parameters to assess RV overload in PH were not independent predictors of adverse events as opposite to standard haemodynamic parameters. Further studies are needed to clarify their predictive value, as it has major implications for understanding the arterial load in diseases of the pulmonary circulation. Funding Acknowledgement Type of funding source: None

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Pereira ◽  
J.G Santos ◽  
M.J Loureiro ◽  
F Ferreira ◽  
A.R Almeida ◽  
...  

Abstract Introduction Thermodilution (TD) and indirect Fick (IF) methods are widely used to measure cardiac output (CO). They are often used interchangeably to make critical clinical decisions, yet few studies have compared these approaches concerning agreement and comparative prognostic value as applied in medical practice. Purpose To assess agreement between TD and IF methods and to compare how well these methods predict mortality. Methods Retrospective cohort study including all consecutive right heart catheterizations performed in a referral pulmonary hypertension (PH) centre from 2010 to 2018. Cardiac index (CI) was calculated by indexed CO to body surface area. PH was classified according to the new definition of the 6st World Symposium on Pulmonary Hypertension 2018 [mean pulmonary arterial pressure (mPAP) >20 mmHg]. Patients with cardiac or extra-cardiac shunts or significant (moderate to severe or severe) tricuspid regurgitation were excluded. All-cause mortality over 1 year after right heart catheterization was recorded. Logistic regression was used to identify predictors of the adverse event. Results From a total of 569 procedures, 424 fulfilled the inclusion criteria: mean age 56.7±15.4 years, 67.3% female. Haemodynamic parameters were diagnosed of PH in 86.2% of cases: mPAP 35.3±15.3 mmHg, 83.6% pre-capillary subtype, 42.9% belonging to group 4 (chronic thromboembolic pulmonary hypertension) and 26.6% to group 1 (pulmonary arterial hypertension). Mean values of CO and CI were, respectively, 4.5±2.8 L/min and 2.5±0.8 L/min/m2 measured by TD and 4.6±2.4 L/min and 2.6±1.3 L/min/m2 measured by IF method. There was a median difference (IF minus TD) of - 0.03 / min to CO and - 0.05 L/min/m2 to CI but both meausres correlated only modestly (r=0.6 to TD and r=0.5 to IF). One-year all-cause mortality rate was 5.4% (median time to death was 50.5 days). Lower values of CO and CI assessed by TD were significantly associated with all-cause mortality occurrence (CO TD: 4.5±1.3 L/min versus 3.6±1.0 L/min, p<0.01; CI TD: 2.6±0.7 L/min/m2 versus 2.1±0.4 L/min/m2, p<0.01). No association was observed between CO (p=0.31) and CI (p=0.42) measured by IF method and the adverse event. Logistic regression identified 2 independent predictors of all-cause mortality: TD CO (OR 0.55, 95% CI 0.38–0.79, p<0.01) and TD CI (OR 0.34, 95% CI 0.17–0.67, p<0.01). Similar results were obtained when patients diagnosed with PH were independently analyzed. Conclusions There is only modest agreement between TD and IF CO and CI estimates. Despite being more time-consuming, TD measurements were predictors of all-cause mortality and present a highest prognostic value. These findings favored their used over IF in clinical practice. Funding Acknowledgement Type of funding source: None


Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Aaron Douen ◽  
Jeremy Oh ◽  
Wesley Romney ◽  
Ryan Panetti ◽  
Prakash Ramdass ◽  
...  

Introduction: Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are well known for upregulating ACE2 receptors. SARS-Cov-2 (COVID-19) infection utilizes the ACE2 receptor for proliferation and infection of host cells. Hypothesis: We hypothesize that the use of ACEI/ARBs will lead to a higher mortality and hospitalization rate among COVID-19 infected patients. Methods: The electronic health database at a public hospital in New York City was queried retrospectively for patients 18 years and older with a positive test for COVID-19 between 3/1/2020 - 4/1/2021. We examined baseline characteristics including comorbidities and whether they were prescribed ACEI/ARBs versus other medications including beta-blockers, calcium channel blockers, thiazides, or hydralazine. We categorized patients based on ACEI/ARB. The primary outcomes were all-cause mortality and hospitalization. The secondary outcomes were acute kidney injury, ventricular arrhythmia, myocardial infarction, heart failure, and intubation. We adjusted for comorbidities using multivariate logistic regression. Results: We identified 23,068 patients positive for SARS-CoV-2; 1,385 on ACEI/ARBs and 21,683 not on ACE/ARBs. The mean age in years was 65.90 +- 14.35 (SEM 0.386) and 44.01+-16.76, (SEM 0.114) for ACEI/ARB and non-ACEI/ARB respectively (p<0.001). The incidence of all cause mortality and hospitalization rate were significantly greater in the ACEI/ARB group. However, when adjusted for comorbidities using multivariate logistic regression, OR for mortality was 0.41 (CI 0.32-0.52, p<0.001) and for hospitalization was 4.12 (CI 3.49-4.86 p<0.001). For the secondary outcomes, non-ACEI/ARB patients had significantly increased unadjusted odds of all outcomes (p<0.001), except for ventricular tachycardia (p<0.618) and intubation (p< 0.214). Conclusion: Patients in the ACEI/ARB group demonstrated significantly lower mortality and increased hospitalization rates. Increased hospitalization may be due to more comorbidities. These results highlight the importance of continuing the use of ACEI and ARBs in COVID-19 patients for treatment of comorbidities and cardioprotective effects.


2018 ◽  
Vol 12 (5) ◽  
pp. E226-30 ◽  
Author(s):  
Dylan Hoare ◽  
Howard Evans ◽  
Heidi Richards ◽  
Rahim Samji

Introduction: Once used primarily in the identification of renal metastasis and lymphomas, various urological bodies are now adopting an expanded role for the renal biopsy. We sought to evaluate the role of the renal biopsy in a Canadian context, focusing on associated adverse events, radiographic burden, and diagnostic accuracy.Methods: This retrospective review incorporated all patients undergoing ultrasound (US)/computed tomography (CT)-guided biopsies for T1 and T2 renal masses. There were no age or lesion size limitations. The primary outcome of interest was the correlation between initial biopsy and final surgical pathology. A binomial logistic regression analysis was conducted to determine any confounding factors. Secondary outcomes included the accuracy of tumour cell typing, grading, the safety profile, and radiographic burden associated with these patients.Results: A total of 148 patients satisfied inclusion criteria for this study. Mean age and lesions size at detection were 60.9 years (±12.4) and 3.6 cm (±2.0), respectively. Most renal masses were identified with US (52.7%) or CT (44.6%). Three patients (2.0%) experienced adverse events of note. Eighty-six patients (58.1%) proceeded to radical/partial nephrectomy. Our biopsies held a diagnostic accuracy of 90.7% (sensitivity 96.2%, specificity 87.5%, positive predictive value 98.7%, negative predictive value 70.0%, kappa 0.752, p<0.0005). Binomial logistic regression revealed that age, lesion size, number of radiographic tests, time to biopsy, and modality of biopsy (US/CT) had no influence on the diagnostic accuracy of biopsies.Conclusions: Renal biopsies are safe, feasible, and diagnostic. Their role should be expanded in the routine evaluation of T1 and T2 renal masses.


2017 ◽  
Vol 8 (1) ◽  
pp. 204589321774805 ◽  
Author(s):  
Barbara L. LeVarge ◽  
Anica C. Law ◽  
Blanche Murphy

Infection, thrombosis, and catheter dislodgment are well-recognized potential complications of chronic intravenous prostanoid therapy for pulmonary arterial hypertension. As long-term outcomes of pulmonary hypertension patients improve, novel adverse events are likely to arise. We describe the sudden development of unexplained hypotension and lightheadedness in a patient receiving intravenous epoprostenol for several years, ultimately determined to be due to an unusual catheter complication, not previously described in this population.


2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Shuran Shao ◽  
Chunyan Luo ◽  
Kaiyu Zhou ◽  
Yimin Hua ◽  
Mei Wu ◽  
...  

Abstract Background Intravenous immunoglobulin (IVIG) resistance prediction is one pivotal topic of interests in Kawasaki disease (KD) since those patients with KD resistant to IVIG might improve of an early-intensified therapy. Data regarding predictive value of procalcitonin (PCT) for IVIG resistance, particularly for repeated IVIG resistance in KD was limited. This study aimed to testify the predictive validity of PCT for both initial and repeated IVIG resistance in KD. Methods A total of 530 KD patients were prospectively recruited between January 2015 and March 2019. The clinical and laboratory data were compared between IVIG-responsive and IVIG-resistant groups. Multivariate logistic regression analysis was applied to determine the association between PCT and IVIG resistance. Receiver operating characteristic (ROC) curves analysis was further performed to assess the validity of PCT in predicting both initial and repeated IVIG resistance. Results The serum PCT level was significantly higher in initial IVIG-resistance group compared with IVIG-response group (p = 0.009), as well as between repeated IVIG responders and nonresponders (p = 0.017). The best PCT cutoff value for initial and repeated IVIG resistance prediction was 1.48 ng/ml and 2.88 ng/ml, respectively. The corresponding sensitivity was 53.9 and 51.4%, while the specificity were 71.8 and 73.2%, respectively. Multivariate logistic regression analysis failed to identify serum PCT level as an independent predictive factor for both initial and repeated IVIG resistance in KD. Conclusions Serum PCT levels were significantly higher in IVIG nonresponders, but PCT may not be suitable as a single marker to accurately predict both initial and repeated IVIG resistance in KD.


2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
R H Boeger ◽  
P Siques ◽  
J Brito ◽  
E Schwedhelm ◽  
E Pena ◽  
...  

Abstract Prolonged exposure to altitude-associated chronic hypoxia (CH) may cause high altitude pulmonary hypertension (HAPH). Chronic intermittent hypobaric hypoxia (CIH) occurs in individuals who commute between sea level and high altitude. CIH is associated with repetitive acute hypoxic acclimatization and conveys the long-term risk of HAPH. As nitric oxide (NO) is an important regulator of systemic and pulmonary vascular tone and asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis that increases in hypoxia, we aimed to investigate whether ADMA predicts the incidence of HAPH among Chilean frontiers personnel exposed to six months of CIH. We performed a prospective study of 123 healthy male subjects who were subjected to CIH (5 days at appr. 3,550 m, followed by 2 days at sea level) for six months. ADMA, SDMA, L-arginine, arterial oxygen saturation, systemic arterial blood pressure, and haematocrit were measured at baseline and at months 1, 4, and 6 at high altitude. Acclimatization to high altitude was determined using the Lake Louise Score and the presence of acute mountain sickness (AMS). Echocardiography was performed after six months of CIH in a subgroup of 43 individuals with either good (n=23) or poor (n=20) aclimatization to altitude, respectively. Logistic regression was used to assess the association of biomarkers with HAPH. 100 study participants aged 18.3±1.3 years with complete data sets were included in the final analysis. Arterial oxygen saturation decreased upon the first ascent to altitude and plateaued at about 90% during the further course of the study. Haematocrit increased to about 47% after one month and remained stable thereafter. ADMA continuously increased and SDMA decreased during the study course, whilst L-arginine levels showed no distinct pattern. The incidence of AMS and the Lake Louise Score were high after the first ascent (53 and 3.1±2.4, respectively) and at one month of CIH (47 and 3.0±2.6, respectively), but decreased to 20 and 1.4±2.0 at month 6, respectively (both p<0.001 for trend). In echocardiography, 18 participants (42%) showed a mean pulmonary arterial pressure (mPAP) greater than 25 mm Hg (mean ± SD, 30.4±3.9 mm Hg), out of which 9 (21%) were classified as HAPH (mPAP ≥30 mm Hg; mean ± SD, 33.9±2.2 mm Hg). Baseline ADMA, but not SDMA, was significantly associated with mPAP at month 6 in univariate logistic regression analysis (R = 0.413; p=0.007). In ROC analysis, a cut-off for baseline ADMA of 0.665 μmol/l was determined as the optimal cut-off level to predict HAPH (mPAP >30 mm Hg) with a sensitivity of 100% and a specificity of 63.6%. ADMA concentration increases during long-term CIH. It is an independent predictive biomarker for the incidence of HAPH. SDMA concentration decreases during CIH and shows no association with HAPH. Our data support a role of impaired NO-mediated pulmonary vasodilation in the pathogenesis of high altitude pulmonary hypertension. Acknowledgement/Funding CONICYT/FONDEF/FONIS Sa 09I20007; FIC Tarapaca BIP 30477541-0; BMBF grant 01DN17046 (DECIPHER); Georg & Jürgen Rickertsen Foundation, Hamburg


2017 ◽  
Vol 41 (3) ◽  
pp. 865-874 ◽  
Author(s):  
Junjie Xiao ◽  
Rongrong Gao ◽  
Yihua Bei ◽  
Qiulian Zhou ◽  
Yanli Zhou ◽  
...  

Background/Aims: Identification of novel biomarkers to identify acute heart failure (AHF) patients at high risk of mortality is an area of unmet clinical need. Recently, we reported that the baseline level of circulating miR-30d was associated with left ventricular remodeling in response to cardiac resynchronization therapy in advanced chronic heart failure patients. However, the role of circulating miR-30d as a prognostic marker of survival in patients with AHF has not been explored. Methods: Patients clinically diagnosed with AHF were enrolled and followed up for 1 year. Quantitative reverse transcription polymerase chain reactions were used to determine serum miR-30d levels. The univariate logistic regression analysis and multivariate logistic regression analysis were used to determine the predictors for all-cause mortality in AHF patients. Kaplan–Meier survival analysis was used to analyze the role of miR-30d in prediction of survival. Results: A total of 96 AHF patients were enrolled and followed up for 1 year. Serum miR-30d was significantly lower in AHF patients who expired in the one year follow-up period compared to those who survived. Univariate logistic regression analysis yielded 18 variables that were associated with all-cause mortality in AHF patients, while the multivariate logistic regression analysis identified 4 variables including heart rate, hemoglobin, serum sodium, and serum miR-30d level associated with mortality. ROC curve analysis showed that hemoglobin, heart rate and serum sodium displayed poor prognostic value for AHF (AUCs not higher than 0.700) compared to miR-30d level (AUC = 0.806). Kaplan–Meier survival analysis confirmed that patients with higher serum miR-30d levels had significantly lower mortality (P=0.001). Conclusion: In conclusion, this study shows evidence for the predictive value of circulating miR-30d as 1-year all-cause mortality in AHF patients. Large multicentre studies are further needed to validate our findings and accelerate the transition to clinical utilization.


PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9068
Author(s):  
Houyong Zhu ◽  
Zhaodong Li ◽  
Xiaoqun Xu ◽  
Xiaojiang Fang ◽  
Tielong Chen ◽  
...  

Aim Inflammation-based Glasgow Prognostic Scores (GPS) have been reported to predict the prognosis of patients with acute ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). The goal of this study was to investigate whether three kinds of GPSs can effectively predict major cardiovascular adverse events (MACEs) in STEMI or non-ST-segment elevation myocardial infarction (NSTEMI) patients undergoing PPCI, elective PCI (EPCI) or conservative drug therapy during hospitalization. Methods In this retrospective cohort study, patients with acute myocardial infarction (AMI) were divided into 0, 1 or 2 score according to the GPSs. Logistic regression and receiver operating characteristic (ROC) curve analysis were performed to assess the predictive value of GPSs for MACE and all-cause mortality during hospitalization. Three kinds of GPSs, Inflammation-based Glasgow Prognostic Score (GPS), modified GPS (MGPS) and high-sensitivity CRP-modified GPS (HS-MGPS) and Global Registry of Acute Coronary Events (GRACE) score were applied in this study. Results A total of 188 patients were enrolled. The ROC curve with MACE showed that the AUC of GPS (0.820 (95% confidence interval (CI) [0.754–0.885]), P < 0.001) was larger than that of MGPS (0.789 (95% CI [0.715–0.863]), P < 0.001), HS-MGPS (0.787 (95% CI [0.717–0.856]), P < 0.001) and GRACE score (0.743 (95% CI [0.672–0.814]), P < 0.001). The ROC curve with all-cause mortality showed that the AUC of GPS (0.696 (95% CI [0.561–0.831]), P = 0.005) was similar to the HS-MGPS (0.698 (95% CI [0.569–0.826]), P = 0.005) and higher than the MGPS (0.668 (95% CI [0.525–0.812]), P = 0.016), but lower than the GRACE score (0.812 (95% CI [0.734–0.889]), P < 0.001). Multivariate logistic regression analysis showed that the GPS was an independent risk factor for the incidence of MACE during hospitalization. Compared with the odds ratio (OR) value for a GPS of 0, the OR for a GPS of 1 was 7.173 (95% CI [2.425–21.216]), P < 0.001), and that for a GPS of 2 was 18.636 (95% CI [5.813–59.746]), P < 0.001), but not an independent risk factor for all-cause mortality (P = 0.302). GRACE score was an independent risk factor for MACE (1.019 (95% CI [1.004–1.035]), P = 0.015) and all-cause mortality (1.040 (95% CI [1.017–1.064]), P = 0.001). In the subgroups classified according to the type of AMI, the presence of disease interference GPSs and the type of PCI, the ability of GPS to predict the occurrence of MACE seemed to be greater than that of MGPS and HS-MGPS. Conclusion The GPS has a good predictive value for the occurrence of MACE during hospitalization in patients with AMI, regardless of STEMI or NSTEMI, the choice of PCI mode and the presence or absence of diseases that interfere with GPS. However, GPS is less predictive of all-cause mortality during hospitalization than GRACE score, which may be due to the interference of patients with other diseases.


2017 ◽  
Vol 42 (2) ◽  
pp. 615-622 ◽  
Author(s):  
Shutong Shen ◽  
Rongrong Gao ◽  
Yihua Bei ◽  
Jin Li ◽  
Haifeng Zhang ◽  
...  

Background/Aims: Irisin is a peptide hormone cleaved from a plasma membrane protein fibronectin type III domain containing protein 5 (FNDC5). Emerging studies have indicated association between serum irisin and many major chronic diseases including cardiovascular diseases. However, the role of serum irisin as a predictor for mortality risk in acute heart failure (AHF) patients is not clear. Methods: AHF patients were enrolled and serum was collected at the admission and all patients were followed up for 1 year. Enzyme-linked immunosorbent assay was used to measure serum irisin levels. To explore predictors for AHF mortality, the univariate and multivariate logistic regression analysis, and receiver-operator characteristic (ROC) curve analysis were used. To determine the role of serum irisin levels in predicting survival, Kaplan-Meier survival analysis was used. Results: In this study, 161 AHF patients were enrolled and serum irisin level was found to be significantly higher in patients deceased in 1-year follow-up. The univariate logistic regression analysis identified 18 variables associated with all-cause mortality in AHF patients, while the multivariate logistic regression analysis identified 2 variables namely blood urea nitrogen and serum irisin. ROC curve analysis indicated that blood urea nitrogen and the most commonly used biomarker, NT-pro-BNP, displayed poor prognostic value for AHF (AUCs ≤ 0.700) compared to serum irisin (AUC = 0.753). Kaplan-Meier survival analysis demonstrated that AHF patients with higher serum irisin had significantly higher mortality (P<0.001). Conclusion: Collectively, our study identified serum irisin as a predictive biomarker for 1-year all-cause mortality in AHF patients though large multicenter studies are highly needed.


2018 ◽  
Vol 16 ◽  
pp. 205873921877224
Author(s):  
Hongyue Wang ◽  
Xiangtuo Wang ◽  
Haichuan Dou ◽  
Chenhao Li ◽  
Mingji Cui ◽  
...  

The purpose of this study was to summarize the pathogens that cause peritoneal dialysis (PD)-associated peritonitis and to identify risk factors for PD-associated peritonitis. This retrospective study included 115 end-stage renal disease (ESRD) patients receiving PD therapy. Patients were categorized into two groups: peritonitis group (n = 41) and non-peritonitis group (n = 74). Clinical data and laboratory tests were collected from medical records. The multivariate logistic regression model was used to evaluate associations between PD-associated peritonitis and potential risk factors. PD-associated peritonitis occurred 54 times in 41 patients. The most frequently identified pathogen was Gram-positive cocci (57.78%). Multivariate logistic regression analysis showed that serum albumin (β = –0.208, P < 0.001), blood phosphorus concentration (β = –1.732, P = 0.001), gastrointestinal disorders (β = 1.624, P = 0.043), and use of calcitriol (β = –2.239, P = 0.048) were significantly correlated with PD-associated peritonitis. Receiver operating characteristic (ROC) curves showed that the areas under the curve were 0.832 for serum albumin and 0.700 for blood phosphorus concentration with optimal cut-off values of 29.1 g/L for serum albumin and 1.795 mmol/L for blood phosphorus concentration. Gram-positive coccus is the major pathogen responsible for PD-associated peritonitis. Serum albumin <29.1 g/L, blood phosphorus concentration <1.795 mmol/L, and intestinal disorders are risk factors for PD-associated peritonitis, whereas the use of calcitriol can reduce the risk of PD-associated peritonitis.


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