Self-Reported Reactogenicity After Different COVID-19 Vaccination Regimens.

BACKGROUND: In Rhineland-Palatinate, most COVID-19 vaccinations are centrally registered by the Rhineland-Palatinate Division of Vaccine Documentation, which includes self-reported vaccination reactions (SRVR) and their level of perceived intensity. We analyzed the occurrence of SRVR reported between 12/2020 and 12/2021 in relation to the different vaccination regimens involving BioNTech/Pfizer (BNT) and Moderna (m1273) mRNA vaccines and AstraZeneca (ChAd) and Johnson & Johnson (Ad26) viral vector vaccines. METHODS: Using sex-specific logistic regression models, we analyzed the occurrence of all local and systemic SRVR, as well as the occurrence of local and systemic SRVR that were self-rated as "severe" by the vaccinated persons, in relation to the vaccine of the first vaccination and the vaccination regimen of the second vaccination (BNT/BNT, ChAd/ChAd, m1273/m1273, ChAd/ BNT, ChAd/m1273). Vaccination with BNT or the BNT/BNT regimen formed the reference category for the estimated odds ratios (OR) with respective 95% confidence intervals. RESULTS: Of all those vaccinated, 40.7% provided valid information on SRVR after the first vaccination and 33.8% after the second vaccination. As a result, 887 052 individuals were included in the analyses. Their median age was 60 years, and 58% were women. The most common vaccination regimen was BNT/BNT (67.3%). The most common SRVR were pain at the injection site and fatigue. Self-reported reactogenicity after the first vaccination was lowest for BNT. Self-reported systemic reactogenicity was notably higher after vaccination with a vector vaccine. After the second vaccination, self-reported reactogenicity was lowest after a ChAd/ChAd regimen and highest after an m1273 second vaccination. CONCLUSION: With overall acceptable tolerability, differences in self-reported reactogenicity were evident depending on the particular COVID-19 vaccines and vaccination regimens in question.

Environmental assessment of interventions to restrain the impact of industrial pollution using a quasi-experimental design: limitations of the interventions and recommendations for public health policy.

BACKGROUND: In an industrial area, the asymmetry between the weights of the economic interests compared to the public-health needs can determine which interests are represented in decision-making processes. This might lead to partial interventions, whose impacts are not always evaluated. This study focuses on two interventions implemented in Taranto, Italy, a city hosting one of the largest steel plants in Europe. The first intervention deals with measures industrial plants must implement by law to reduce emissions during so called "wind days" in order to reduce PM10 and benzo [a] pyrene concentrations. The second one is a warning to the population with recommendations to aerate indoor spaces from 12 pm to 6 pm, when pollutant concentrations are believed to be lower. METHODS: To analyse the impact of the first intervention, we analysed monthly PM10 data in the period 2009-2016 from two monitoring stations and conducted an interrupted-time-series analysis. Coefficients of time-based covariates are estimated in the regression model. To minimise potential confounding, monthly concentrations of PM10 in a neighbourhood 13 km away from the steel plant were used as a control series. To evaluate the second intervention, hourly concentrations of PM10, SO2 and polycyclic-aromatic-hydrocarbons (PAHs) were analysed. RESULTS: PM10 concentrations in the intervention neighbourhood showed a peak just a few months before the introduction of the law. When compared to the control series, PM10 concentrations were constantly higher throughout the entire study period. After the intervention, there was a reduction in the difference between the two time-series (- 25.6%). During "wind days" results suggested no reduction in concentrations of air pollutants from 12 pm to 18 pm. CONCLUSION: Results of our study suggest revising the warning to the population. Furthermore, they evidence that in complex highly industrialised areas, air quality interventions cannot focus on only a single pollutant, but rather should consider the complex relationships between the different contaminants. Environmental interventions should be reviewed periodically, particularly when they have implications for social constraints. While the results of our study can be related only to the specific situation reported in the article, the methodology applied might be useful for the environmental management in industrial areas with similar features.

Gender specific excess mortality in Italy during the COVID-19 pandemic accounting for age.

Since the beginning of the COVID-19 pandemic, data have been accumulated to examine excess mortality in the first half of 2020. Mortality in the preceding year or years is used to calculate the expected number of deaths, which is then compared with the actual number of deaths in 2020. We calculated weekly age- and sex-specific mortality rates for 93.1% of the Italian municipalities for the years 2015-2019 and for the first 26 weeks in 2020. We assumed the mortality experience during 2015-2019 as the reference period to calculate standardised mortality ratios. Furthermore, in order to compare the mortality experience of males and females, we calculated sex- and age- specific weekly direct standardised mortality rates and differences between the observed and expected number of deaths. We observed considerable changes in the demographics in the Italian population between the years 2015 and 2020, particularly among people 60 years and older and among males. The population is aging and the proportion of elderly males has increased, which was not reflected adequately in previous estimates of excess mortality. Standardized excess mortality results show that in Italy between the 8th and 26th weeks in 2020, there were 33,035 excess deaths, which is only 643 fewer deaths than the official COVID-19 death toll for this time period. A comparative increase in the mortality rates was observed in March among both sexes, but particularly for males. Comparisons with recently published data show considerably higher excess deaths, but these data were either not covering the complete country or did not account for age and sex. Neglecting the demographic changes in a region, even over a short time span, can result in biased estimates.

Southern Italy: How the Availability of Radiation Therapy, Patient Outcomes, and Risk to Health Care Providers Have Changed During the Coronavirus Disease 2019 Pandemic.

The first actions and provisions in a Southern Italy Department of Radiation Oncology are described at the inception of the COVID-19 pandemic.

Methods for Evaluating Causality in Observational Studies.

BACKGROUND: In clinical medical research, causality is demonstrated b controlled trials (RCTs). Often, however, an RCT cannot be conducted for ethical reasons, and sometimes for practical reasons as well. In such cases, knowledge can be derived from an observational study instead. In this article, we present two methods that have not been widely used in medical research to date. METHODS: The methods of assessing causal inferences in observational studies are described on the basis of publications retrieved by a selective literature search. RESULTS: Two relatively new approaches-regression-discontinuity methods and interrupted time series-can be used to demonstrate a causal relationship under certain circumstances. The regression-discontinuity design is a quasi-experimental approach that can be applied if a continuous assignment variable is used with a threshold value. Patients are assigned to different treatment schemes on the basis of the threshold value. For assignment variables that are subject to random measurement error, it is assumed that, in a small interval around a threshold value, e.g., cholesterol values of 160 mg/dL, subjects are assigned essentially at random to one of two treatment groups. If patients with a value above the threshold are given a certain treatment, those with values below the threshold can serve as control group. Interrupted time series are a special type of regression-discontinuity design in which time is the assignment variable, and the threshold is a cutoff point. This is often an external event, such as the imposition of a smoking ban. A before-and-after comparison can be used to determine the effect of the intervention (e.g., the smoking ban) on health parameters such as the frequency of cardiovascular disease. CONCLUSION: The approaches described here can be used to derive causal inferences ies. They should only be applied after the prerequisites for their use have been carefully checked.

Ionising radiation and lens opacities in interventional physicians: results of a German pilot study.

We assessed the feasibility of an epidemiological study on the risk of radiation-related lens opacities among interventional physicians in Germany. In a regional multi-centre pilot study associated with a European project, we tested the recruitment strategy, a European questionnaire on work history for the latter dosimetry calculation and the endpoint assessment. 263 interventional physicians and 129 non-exposed colleagues were invited. Questionnaires assessed eligibility criteria, risk factors for cataract, and work history relating to occupational exposure to ionising radiation, including details on type and amount of procedures performed, radiation sources, and use of protective equipment. Eye examinations included regular inspection by an ophthalmologist, digital slit lamp images graded according to the lens opacities classification system, and Scheimpflug camera measurements. 46 interventional (17.5%) and 30 non-exposed physicians (23.3%) agreed to participate, of which 42 and 19, respectively, met the inclusion criteria. Table shields and ceiling suspended shields were used as protective equipment by 85% and 78% of the interventional cardiologists, respectively. However, 68% of them never used lead glasses. More, although minor, opacifications were diagnosed among the 17 interventional cardiologists participating in the eye examinations than among the 18 non-exposed (59% versus 28%), mainly nuclear cataracts in interventional cardiologists and cortical cataracts in the non-exposed. Opacification scores calculated from Scheimpflug measurements were higher among the interventional cardiologists, especially in the left eye (56% versus 28%). Challenges of the approach studied include the dissuading time investment related to pupil dilatation for the eye examinations, the reliance on a retrospective work history questionnaire to gather exposure-relevant information for dose reconstructions and its length, resulting in a low participation rate. Dosimetry data are bound to get better when the prospective lens dose monitoring as foreseen by 2013 European Directives is implemented and doses are recorded.

Ultrasound B-lines for detection of late lung fibrosis in breast cancer patients after radiation therapy.

BACKGROUND AND PURPOSE: Radiation therapy (RT) for breast cancer after conservative surgery can be life-saving but remains associated with significant late side effects, including lung fibrosis, detected by chest CT. Aim of this study was to assess whether lung ultrasound (LUS) may detect late lung fibrosis through the biomarker of B-lines. MATERIALS AND METHODS: We evaluated 30 women (median age 67 years, range 46-80 years) about 3-8 years after RT (follow up 38-101 months, median 58 months) for left (n = 12) or right (n = 18) breast cancer (stage 1, n = 24; stage 2, n = 6), treated with total dose 40.5 - 50.00 Gy with/without boost dose). In all, both treated and contralateral hemithorax were evaluated. LUS was performed and B-lines evaluated with a 28-region antero-lateral scan, from second to fifth intercostal spaces, along the mid-axillary, anterior axillary, mid-clavicular, and parasternal lines. In each space, the B-lines were counted from 0 = black lung to 10 = white lung. The sum of B-lines in all spaces generated the B-line score of each hemithorax. RESULTS: Median B-line score was higher in the irradiated site than in the contralateral control hemithorax (9, 1st-3rd quartiles: 2-23 vs 3, 1st-3rd quartiles: 1-4; P < 0.05). In the treated hemithorax, higher mean lung doses ( > median value of 2.7 Gy) were associated with more B-lines when compared to lower doses (< 2.7 Gy): 9 vs 5, p <0.001. CONCLUSION: RT in female breast cancer survivors is associated with increase in B-lines in the targeted hemithorax, likely due to lung fibrosis, and related to the lung mean dose. LUS can provide a simple "echo-marker" of lung fibrosis.

The Potential Role of Lung Ultrasound B-Lines for Detection of Lung Radio-Induced Toxicity in Breast Cancer Patients after Radiation Therapy.

BACKGROUND AND PURPOSE: Breast cancer patients exposed to doses of radiation after radiotherapy could develop toxicity to lung. Lung ultrasound (LUS) is able to detect interstitial lung disease by the evaluation of B-lines. The aim of our study was to assess the number of B-lines to diagnose lung involvement after chest radiotherapy. MATERIALS AND METHODS: We measured LUS B-lines in the treated and contralateral lung of 20 breast cancer patients, 1-3 months after the end of radiotherapy and 1 year after previous LUS. The sum of the B-lines number in the 72 sites on anterior and posterior chest yielded a global B-lines score. RESULTS: B-lines were more numerous in treated (median: 21; 1st-3rd quartiles: 11-31) versus untreated hemithorax (median: 3; 1st-3rd quartiles: 1-5) in both examination at T1-3 months (Kolmogorov-Smirnov test P < 0.001) and T1 year (median: 21; 1st-3rd quartiles: 12-28 vs. median: 4; 1st-3rd quartiles: 1-10; Kolmogorov-Smirnov test P < 0.01). Within the treated hemithorax, B-lines were more frequent in the anterior than in the posterior chest in both examination at T1-3 months (Kolmogorov-Smirnov test: P < 0.0001) and T1 year (Kolmogorov-Smirnov test: P < 0.01). Abnormal scores (B-lines>5) were present in 17/20 treated versus 7/20 untreated hemithoraxes (85.0 vs. 35.0%, P < 0.01) in the first LUS and likewise in 16/17 treated versus 7/17 in untreated hemithorax (94.1% vs. 41.2%, P < 0.01) after 1-year follow-up. CONCLUSION: Among women receiving radiotherapy after breast cancer, B-lines are present predominantly in the irradiated lung. These data suggest that B-lines by LUS could provide, at a subclinical stage, a radiation-free biomarker of radiotherapy-induced lung damage.

Kinetics of B-type natriuretic peptide plasma levels in patients with left-sided breast cancer treated with radiation therapy: Results after one-year follow-up.

PURPOSE: To analyze temporal changes of B-type natriuretic peptide (BNP) used as index of heart remodeling in left-sided breast cancer patients after radiotherapy (RT) and its relationship with dosimetric parameters. METHODS AND MATERIALS: BNP and dose-volume parameters for heart and ventricle were collected in 59 patients (median age 58.0 years) during a 1-year follow-up. Biochemical measurements were performed before the RT treatment (T0), at 15 days during RT (T(15day)), at the end of RT (T(endRT)), and then at 1, 3, 6, 9, 12 months (T1, T3, T6, T9 and T12). A logistical regression analysis was performed to identify demographic characteristics, dosimetric variables and risk factors associated with increased values of BNP. RESULTS: The ratio between the BNP value at T12 and the BNP value at T0 (BNP(T12)/BNP(T0)) increased significantly (p < 0.01). A significant association was found between the variation of BNP values after 1 year and the isodose received by 50% of the volume (D50% [Gy]) both to the heart (p = 0.03) and ventricle (p = 0.04). CONCLUSIONS: BNP plasma levels could provide additional information about subclinical RT-induced cardiotoxicity earlier than traditional ecocardiographic data.

Mortality analysis by neighbourhood in a city with high levels of industrial air pollution.

OBJECTIVES: Taranto, a city in south-eastern Italy, suffers serious environmental pollution from industrial sources. A previous cohort analysis found mortality excesses among neighbourhoods closest to industrial areas. Aim of this study was to investigate whether mortality also increased in other neighbourhoods compared to Apulia region. METHODS: Standardized mortality ratios were computed. Number of deaths and of person-years at risk by neighbourhood came from the previous cohort study for 1998-2008 period. Reference population was Apulia region excluding Taranto province. A meta-analysis was conducted across less close neighbourhoods computing summary SMR estimates and evaluating heterogeneity. RESULTS: For the entire city higher mortality values are confirmed for all causes, all malignant neoplasms and several specific sites, neurological, cardiac, respiratory and digestive diseases. High mortality values are not confined to neighbourhoods closest to industrial areas for lung cancer, cardiac, respiratory and digestive diseases, in both sexes, and among women for all malignant neoplasms and pancreatic cancer. CONCLUSIONS: Increased mortality risks can also be observed in Taranto neighbourhoods not directly adjacent to industrial areas. Spatial trend, impact of socio-economic factors and duration of residence should be further explored.

A vinyl chloride-exposed worker with an adrenal gland angiosarcoma: a case report.

Adrenal epithelioidangiosarcoma (AEA) is a rare neoplasm that accounts for less than 1% of sarcomas. Due to its rarity, it can easily be misdiagnosed, both by the clinician and the pathologist. Data on the patient's occupational history was collected and analyzed. The bibliographic data was found on the PUBMED bibliographic search site after entering the word "extrahepaticangiosarcoma". We report a case of adrenal epithelioidangiosarcoma (AEA) in a 68 yr-old Caucasian male factory worker exposed to Vinyl Chloride (VC) for 15 yr. He underwent surgery, chemotherapy and radiotherapy. Hepatic angiosarcoma is a known consequence of VC exposure, but occupational causality of extra-hepatic angiosarcoma is controversial. Extra-hepatic angiosarcomas have been reported in VC workers, but never AEA. Cancerogenic effects of VC involve all endothelial areas of the body and extra-hepatic endothelial tumors may also be caused by this substance. This is the first published report of AEA diagnosed in a worker exposed to VC.

Spatial variability of air pollutants in the city of Taranto, Italy and its potential impact on exposure assessment.

Epidemiological studies typically use monitored air pollution data from a single station or as averaged data from several stations to estimate population exposure. In industrialized urban areas, this approach may present critical issues due to the spatial complexities of air pollutants which are emitted by different sources. This study focused on the city of Taranto, which is one of the most highly industrialized cities in southern Italy. Epidemiological studies have revealed several critical situations in this area, in terms of mortality excess and short-term health effects of air pollution. The aims of this paper are to study the variability of air pollutants in the city of Taranto and to interpret the results in relation to the applicability of the data in assessing population exposure. Meteorological and pollution data (SO2, NO2, PM10), measured simultaneously and continuously during the period 2006-2010 in five air quality stations, were analyzed. Relative and absolute spatial concentration variations were investigated by means of statistical indexes. Results show significant differences among stations. The highest correlation between stations was observed for PM10 concentrations, while critical values were found for NO2. The worst values were observed for the SO2 series. The high values of 90th percentile of differences between pairs of monitoring sites for the three pollutants index suggest that mean concentrations differ by large amounts from site to site. The overall analysis supports the hypothesis that various parts of the city are differently affected by the different emission sources, depending on meteorological conditions. In particular, analysis revealed that the influence of the industrial site may be primarily identified with the series of SO2 data which exhibit higher mean concentration values and positive correlations with wind intensity when the monitoring station is downwind from the industrial site. Results suggest evaluating the population exposure to air pollutants in industrialized cities by taking into account the possible zones of influence of different emission sources. More research is needed to identify an indicator, which ought to be a synthesis of several pollutants, and take into account the meteorological variables.

N-terminal pro-B-type natriuretic peptide plasma levels as a potential biomarker for cardiac damage after radiotherapy in patients with left-sided breast cancer.

PURPOSE: Adjuvant radiotherapy (RT) after breast-conserving surgery has been associated with increased cardiovascular mortality. Cardiac biomarkers may aid in identifying patients with radiation-mediated cardiac dysfunction. We evaluated the correlation between N-terminal pro-B­type natriuretic peptide (NT-proBNP) and troponin (TnI) and the dose of radiation to the heart in patients with left-sided breast cancer. METHODS AND MATERIALS: NT-proBNP and TnI plasma concentrations were measured in 30 left-sided breast cancer patients (median age, 55.0 years) 5 to 22 months after RT (Group I) and in 30 left-sided breast cancer patients (median age, 57.0 years) before RT as control group (Group II). Dosimetric and geometric parameters of heart and left ventricle were determined in all patients of Group I. Seventeen patients underwent complete two-dimensional echocardiography. RESULTS: NT-proBNP levels were significantly higher (p = 0.03) in Group I (median, 90.0 pg/ml; range, 16.7­333.1 pg/ml) than in Group II (median, 63.2 pg/ml; range, 11.0­172.5 pg/ml). TnI levels remained below the cutoff threshold of 0.07 ng/ml in both groups. In patients with NT-proBNP values above the upper limit of 125 pg/ml, there were significant correlations between plasma levels and V(3 Gy)(%) (p = 0.001), the ratios (p = 0.01), the ratios D(15 cm)(3)/D(50%) (Gy) (p = 0.008) for the heart and correlations between plasma levels and V(2 Gy) (%) (p = 0.002), the ratios (p = 0.03), and the ratios (p = 0.05) for the ventricle. CONCLUSIONS: Patients with left-sided breast cancer show higher values of NT-pro BNP after RT when compared with non­RT-treated matched patients, increasing in correlation with high doses in small volumes of heart and ventricle. The findings of this study show that the most important parameters are not the mean doses but instead the small percentage of organ volumes (heart or ventricle) receiving high dose levels, supporting the notion that the heart behaves as a serial organ.

Sixteen-year air quality data analysis of a high environmental risk area in Southern Italy.

The Brindisi area is characterized by the presence of industries with high environmental impact, located along its eastern border. Epidemiological studies have revealed several critical situations: two short-term (2003-2005) epidemiological studies have shown that PM(10) and NO(2) are adversely associated with daily hospital admissions: one of the two pointed to the associations with wind blowing from the southern, eastern and western sectors. This study aims to expand the time span of available air quality data in order to provide a more complete and extensive epidemiological study. Multi-year series (from 1992 to 2007) of SO(2), NO(2), and TSP concentration data are presented and analyzed. Data show a significant downward trend of SO(2) from 1992 to 2007, while for the TSP series, the downward trend is limited to the period 1992-1994. Marked seasonal trends are evident for all three pollutants, especially for NO(2) and TSP. The NO(2) series shows higher levels in winter. Inversely, the TSP series shows its maximum values during the summer months, associated with a moderate correlation with temperature and a poor correlation with other pollutants. Analysis of the series for wind sectors revealed the influence of the industrial site and of the harbor. The concentration series exhibit high concentration values and stronger correlations between them and with meteorology for wind blowing from the eastern sectors. Overall analysis supports the hypothesis of a different origin for TSP during the year and for different wind regimes and therefore possible size and chemical differences in TSP, which should be further investigated due to their health implications.

Geometric and dosimetric approach to determine probability of late cardiac mortality in left tangential breast irradiation: comparison between wedged beams and field-in-field technique.

PURPOSE: To evaluate the probability of late cardiac mortality resulting from left breast irradiation planned with tangential fields and to compare this probability between the wedged beam and field-in-field (FIF) techniques and to investigate whether some geometric/dosimetric indicators can be determined to estimate the cardiac mortality probability before treatment begins. METHODS AND MATERIALS: For 30 patients, differential dose-volume histograms were calculated for the wedged beam and FIF plans, and the corresponding cardiac mortality probabilities were determined using the relative seriality model. As a comparative index of the dose distribution uniformity, the planning target volume (PTV) percentages involved in 97-103% of prescribed dose were determined for the two techniques. Three geometric parameters were measured for each patient: the maximal length, indicates how much the heart contours were displaced toward the PTV, the angle subtended at the center of the computed tomography slice by the PTV contour, and the thorax width/thickness ratio. RESULTS: Evaluating the differential dose-volume histograms showed that the gain in uniformity between the two techniques was about 1.5. With the FIF technique, the mean dose sparing for the heart, the left anterior descending coronary artery, and the lung was 15% (2.5 Gy vs. 2.2 Gy), 21% (11.3 Gy vs. 9.0 Gy), and 42% (8.0 Gy vs. 4.6 Gy) respectively, compared with the wedged beam technique. Also, the cardiac mortality probability decreased by 40% (from 0.9% to 0.5%). Three geometric parameters, the maximal length, angle subtended at the center of the computed tomography slice by the PTV contour, and thorax width/thickness ratio, were the determining factors (p = .06 for FIF, and p = .10 for wedged beam) for evaluating the cardiac mortality probability. CONCLUSION: The FIF technique seemed to yield a lower cardiac mortality probability than the conventional wedged beam technique. However, although our study demonstrated that FIF technique improved the dose coverage of the PTV, the restricted number of patients enrolled and the short follow-up did not allow us to evaluate and compare the breast cancer survival rates of the patients.

Ozone and cardiovascular injury.

Air pollution is increasingly recognized as an important and modifiable determinant of cardiovascular diseases in urban communities. The potential detrimental effects are both acute and chronic having a strong impact on morbidity and mortality. The acute exposure to pollutants has been linked to adverse cardiovascular events such as myocardial infarction, heart failure and life-threatening arrhythmias. The long-terms effects are related to the lifetime risk of death from cardiac causes. The WHO estimates that air pollution is responsible for 3 million premature deaths each year. The evidence supporting these data is very strong nonetheless, epidemiologic and observational data have the main limitation of imprecise measurements. Moreover, the lack of clinical experimental models makes it difficult to demonstrate the individual risk. The other limitation is related to the lack of a clear mechanism explaining the effects of pollution on cardiovascular mortality. In the present review we will explore the epidemiological, clinical and experimental evidence of the effects of ozone on cardiovascular diseases. The pathophysiologic consequences of air pollutant exposures have been extensively investigated in pulmonary systems, and it is clear that some of the major components of air pollution (e.g. ozone and particulate matter) can initiate and exacerbate lung disease in humans 1. It is possible that pulmonary oxidant stress mediated by particulate matter and/or ozone (O3) exposure can result in downstream perturbations in the cardiovasculature, as the pulmonary and cardiovascular systems are intricately associated, and it is well documented that specific environmental toxins (such as tobacco smoke 2) introduced through the lungs can initiate and/or accelerate cardiovascular disease development. Indeed, several epidemiologic studies have proved that there is an association between PM and O3 and the increased incidence of cardiovascular morbidity and mortality 3. Most of the evidence comes from studies of ambient particles concentrations. However, in Europe and elsewhere, the air pollution profile has gradually changed toward a more pronounced photochemical component. Ozone is one of the most toxic components of the photochemical air pollution mixture. Indeed, the biological basis for these observations has not been elucidated. In the present review, the role of ozone as chemical molecule will be firstly considered. Secondly, pathogenetic mechanisms connecting the atmospheric ozone level and cardiovascular pathology will be examined. Thirdly, the literature relating hospitalization frequency, morbidity and mortality due to cardiovascular causes and ozone concentration will be studied. The correlation between ozone level and occurrence of acute myocardial infarction will be eventually discussed.