key: cord-0876394-pg9rzbep authors: Gutiérrez-Abejón, Eduardo; Herrera-Gómez, Francisco; Martín-García, Débora; Tamayo, Eduardo; Álvarez, Francisco Javier title: A Population-Based Registry Analysis on Hospitalized COVID-19 Patients with Previous Cardiovascular Disease: Clinical Profile, Treatment, and Predictors of Death date: 2021-11-29 journal: J Cardiovasc Dev Dis DOI: 10.3390/jcdd8120167 sha: cf0eb51adfffb882882469f8cbf2fcb1d02ad6c2 doc_id: 876394 cord_uid: pg9rzbep A high percentage of patients with COVID-19 (coronavirus disease 2019) have previous cardiovascular disease (CVD). The findings presented here came from an epidemiological population-based registry study (real-world data) that enrolled all in-hospital COVID-19 patients with previous CVD from 1 March to 31 May 2020. Death, other comorbidities, hospital stay variables, ventilation type, and main clinical outcomes were evaluated. In Castile and Leon, 35.83% of the 7307 in-hospital COVID-19 patients who participated in this study had previous CVD, particularly arrhythmias (48.97%), cerebrovascular disease (25.02%), ischemic heart disease (22.8%), and chronic heart failure (20.82%). Of the patients, 21.36% were men and more than 90% were over 65 years of age, and the mortality rate achieved 32.93%. The most used medicines were antibiotics (91.41%), antimalarials (73.3%), steroids (46.64%), and antivirals (43.16%). The main predictors of death were age over 65 years (OR: 5), ventilation needs (OR: 2.81), treatment with anti-SIRS (systemic inflammatory response syndrome) medicines (OR: 1.97), antivirals (OR: 1.74) or steroids (OR: 1.68), SIRS (OR: 5.75), SARS (severe acute respiratory syndrome) (OR: 2.44), or AKI (acute kidney injury) (OR: 1.63) occurrence. Chronic heart failure and cerebrovascular disease were associated with a worse clinical course of COVID-19, especially in men older than 65 years with diabetes who developed SIRS, SARS, or AKI. Since the beginning of the COVID-19 (coronavirus disease 2019) pandemic in China in December 2019, a significant prevalence of previous cardiovascular diseases (CVDs) among SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infected patients has been observed [1] [2] [3] [4] [5] . In addition, these patients with underlying CVD have shown a worse The main study outcome was in-hospital patient death. Hospital stay variables were considered such as hospitalization period (in days) and length of stay in the intensive care unit (ICU) (in days). Furthermore, ventilation type data were obtained: oxygenation, non-invasive positive pressure ventilation (NIPPV), and invasive ventilation (IV). Finally, the following clinical outcomes were evaluated: severe acute respiratory syndrome (SARS), acute kidney injury (AKI), systemic inflammatory response syndrome (SIRS), acute heart failure, bacterial and fungal superinfection, and DIC. For medicine selections, the national recommendations [28, 29] were followed and grouped according to the Anatomical Therapeutic Chemical Code (ATC): antibiotics, antimalarials, steroids, antivirals, tocilizumab, and other anti-SIRS medicines (Supplementary Materials Table S1 ). For all analyses, the gender and age distribution of the population were considered, establishing two groups with a cut-off age of 65 years. The findings related to the prevalence of previous CVD, comorbidities, pharmacological treatment, and clinical outcomes are expressed in frequencies (percentage) with their corresponding 95% confidence intervals (95% CI) and as means accompanied by their standard deviations (SDs) or as medians accompanied by their interquartile range (IQR). For comparisons between groups, the Student's t-test or the Mann-Whitney U test for continuous variables and Pearson's chi-square test or Fisher's exact test for categorical variables were used, as appropriate. The normal data distribution was evaluated using the Kolmogorov-Smirnov and Shapiro-Wilk tests. To identify the predictors of in-hospital patients' death with previous CVD, a multivariate logistic regression with a forward selection approach was performed. The results are expressed in terms of adjusted odds ratio (OR) and 95% CI, and the following variables were included in the model: age (≥65), gender, ventilation, type of previous CVD (aneurysms, arrhythmias, atherosclerosis, heart dysfunction, cerebrovascular disease, ischemic heart disease, chronic heart failure, cardiomyopathy, and thrombosis-thrombophlebitis), other comorbidities (hypertension, diabetes, chronic kidney diseases, obesity, chronic respiratory disease, neoplasia, and autoimmune disease), obesity, medication use (antibiotics, anti-malarials, steroids, antivirals, tocilizumab, and anti-SIRS), and clinical outcomes (SARS, SIRS, DIC, acute heart failure, and bacterial and fungal superinfections). The level of significance was set at p ≤ 0.05. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS version 24.0., SPSS Inc., Chicago, IL, USA). In Castile and Leon, 7307 patients were hospitalized for COVID-19 between 1 March 2020 and 31 May 2020, 2618 (35.83%) of whom had previous CVD. Among patients with COVID-19 and previous CVD, more male than female (59.63% vs. 40.37%; p = 0.001) and approximately 90% of the patients were older than 65 years with a mortality rate of 32.93%. With respect to previous CVD, arrhythmias (48.97%), cerebrovascular disease (25.02%), ischemic heart disease (22.8%), and chronic heart failure (20.82%) were observed. Regarding the rest of the comorbidities, the following were representative: hypertension (66%), diabetes mellitus (29.56%), chronic respiratory disease (19.86%), neoplasia (14.21%), and chronic kidney disease (12.03%). SARS (15.51%), AKI (14.86%), and SIRS (4.05%) occurred among the participants ( Table 1 ). The percentage of obesity was higher in patients with previous CVD (25.62% vs. 15.14%; p = 0.001), being higher in female than in male (27.82% vs. 24.08%; p = 0.001). Medians for hospitalization and ICU length of stay were 10 (6-16) days and 14 (7-30) days, respectively. The most used ventilation mode was IV (3.13%), being almost four times higher in male than in female (4.61% vs. 0.95%; p = 0.001). On the other hand, the most used medicines were antibiotics (91.41%), antimalarials (73.3%), steroids (46.64%), and antivirals (43.16%) ( Table 1) . The mortality rate has decreased from 1 March 2020 and 15 March 2020, (69.05%) to 15 May 2020 and 31 May 2020 (16.55%). The hospital and ICU length of stay also decreased throughout the study period, from a median of 19.5 to 9 days and 26.5 to 8 days, respectively ( Figure 1 ). (aneurysms, arrhythmias, atherosclerosis, heart dysfunction, cerebrovascular disease, ischemic heart disease, chronic heart failure, cardiomyopathy, and thrombosis-thrombophlebitis), other comorbidities (hypertension, diabetes, chronic kidney diseases, obesity, chronic respiratory disease, neoplasia, and autoimmune disease), obesity, medication use (antibiotics, antimalarials, steroids, antivirals, tocilizumab, and anti-SIRS), and clinical outcomes (SARS, SIRS, DIC, acute heart failure, and bacterial and fungal superinfections). The level of significance was set at p ≤ 0.05. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS version 24.0., SPSS Inc., Chicago, IL, USA). In Castile and Leon, 7307 patients were hospitalized for COVID-19 between 1 March 2020 and 31 May 2020, 2618 (35.83%) of whom had previous CVD. Among patients with COVID-19 and previous CVD, more male than female (59.63% vs. 40.37%; p = 0.001) and approximately 90% of the patients were older than 65 years with a mortality rate of 32.93%. With respect to previous CVD, arrhythmias (48.97%), cerebrovascular disease (25.02%), ischemic heart disease (22.8%), and chronic heart failure (20.82%) were observed. Regarding the rest of the comorbidities, the following were representative: hypertension (66%), diabetes mellitus (29.56%), chronic respiratory disease (19.86%), neoplasia (14.21%), and chronic kidney disease (12.03%). SARS (15.51%), AKI (14.86%), and SIRS (4.05%) occurred among the participants ( Table 1 ). The percentage of obesity was higher in patients with previous CVD (25.62% vs. 15.14%; p = 0.001), being higher in female than in male (27.82% vs. 24.08%; p = 0.001). Medians for hospitalization and ICU length of stay were 10 (6-16) days and 14 (7-30) days, respectively. The most used ventilation mode was IV (3.13%), being almost four times higher in male than in female (4.61% vs. 0.95%; p = 0.001). On the other hand, the most used medicines were antibiotics (91.41%), antimalarials (73.3%), steroids (46.64%), and antivirals (43.16%) ( Table 1) . The mortality rate has decreased from March 1st and 15th, 2020, (69.05%) to 15 May 2020 and 31 May 2020 (16.55%). The hospital and ICU length of stay also decreased throughout the study period, from a median of 19.5 to 9 days and 26.5 to 8 days, respectively ( Figure 1 ). Table 2 shows the most used medicines grouped by type: ceftriaxone (70.24%) and azithromycin (67.49%) (antibiotics), hydroxychloroquine (69.14%) (antimalarials), methylprednisolone (43.32%) (steroids), lopinavir-ritonavir (43.12%) (antivirals), and interferon beta (6.38%) (other anti-SIRS). Among non-deceased patients, antimalarials were used more frequently, specifically hydroxychloroquine (p = 0.005), while among deceased patients, steroids, such as methylprednisolone (p = 0.001), and other anti-SIRS (p = 0.001) were used more frequently (Table 2) . Between 1 March 2020 and 31 May 2020, the use of antibiotics and steroids remained stable. On the other hand, a decrease in the use of antimalarials (61.9-25.9%), antivirals (50-9.35%), tocilizumab (9.52-1.44%), and other anti-SIRS, especially interferon beta (26.19-1.44%) was observed (Supplementary Materials Table S2 and Figure 2 ). The multiple logistic regression analysis for all in-hospital COVID-19 patients showed that previous CVD impact on death (OR: 1.57; 95% CI: 1.39-1.79). Furthermore, in patients with previous CVD, the presence of comorbidities, such as diabetes mellitus, was associated with a higher probability of death compared to those patients with previous CVD without comorbidities (OR: 1.27, 1.05-1.55). In patients with previous CVD, it was observed that patients with chronic heart failure (OR: 1.27, 1.02-1.58) and with cerebrovascular disease (OR: 1.35, 1.09-1.66) were most likely to die than those who had other types of previous CVD. In addition, among in-hospital COVID-19 patients, death was more likely to occur in those over 65 years of age (OR: 5, 3. The multiple logistic regression analysis for all in-hospital COVID-19 patients showed that previous CVD impact on death (OR: 1.57; 95% CI: 1.39-1.79). Furthermore, in patients with previous CVD, the presence of comorbidities, such as diabetes mellitus, was associated with a higher probability of death compared to those patients with previous CVD without comorbidities (OR: 1.27, 1.05-1.55). In patients with previous CVD, it was observed that patients with chronic heart failure (OR: 1.27, 1.02-1.58) and with cerebrovascular disease (OR: 1.35, 1.09-1.66) were most likely to die than those who had other types of previous CVD. In addition, among in-hospital COVID-19 patients, death was more likely to occur in those over 65 years of age ( Approximately one out of three in-hospital COVID-19 patients had previous CVD, mainly arrhythmias, cerebrovascular disease, ischemic heart disease, and chronic heart failure. The mortality rate of these patients was the third highest, after those who developed AKI (46.1%) and SARS (42.53%). As in other studies conducted by our team [32, 33] , the use of antibiotics and steroids remained stable, while the use of antimalarials, antivirals, tocilizumab, and other anti-SIRS decreased between 1 March 2020 and 31 May 2020. Our results show that males with previous CVD, especially chronic heart failure or cerebrovascular diseases, older than 65 years, who needed some type of ventilation, and who developed SIRS, SARS, and AKI had a higher risk of death. In addition, the use of anti-SIRS medicines, antivirals, and steroids was related to a worse prognosis of the disease. At this point, it is convenient to clarify the dual role of ACE2. First, COVID-19 symptoms were more severe in patients with CVD, which might be associated with increased secretion of ACE2 in these patients compared with healthy individuals [3] . Second, the Approximately one out of three in-hospital COVID-19 patients had previous CVD, mainly arrhythmias, cerebrovascular disease, ischemic heart disease, and chronic heart failure. The mortality rate of these patients was the third highest, after those who developed AKI (46.1%) and SARS (42.53%). As in other studies conducted by our team [32, 33] , the use of antibiotics and steroids remained stable, while the use of antimalarials, antivirals, tocilizumab, and other anti-SIRS decreased between 1 March 2020 and 31 May 2020. Our results show that males with previous CVD, especially chronic heart failure or cerebrovascular diseases, older than 65 years, who needed some type of ventilation, and who developed SIRS, SARS, and AKI had a higher risk of death. In addition, the use of anti-SIRS medicines, antivirals, and steroids was related to a worse prognosis of the disease. At this point, it is convenient to clarify the dual role of ACE2. First, COVID-19 symptoms were more severe in patients with CVD, which might be associated with increased secretion of ACE2 in these patients compared with healthy individuals [3] . Second, the inhibition of ACE2 may be another factor of lung injury as well as the cause of the systemic inflammation following cytokine release, which can result in acute respiratory distress syndrome (ARDS) and multiorgan dysfunction [16] [17] [18] . The prevalence of in-hospital COVID-19 patients with previous CVD is higher than other Spanish [34, 35] , European [36] , and Chinese [1] cohorts, while it is lower compared to another US cohort [37] . This finding is possible in relation to the predominance of the elderly in Castile and Leon, which is demonstrated by the elevated median age observed (83 years). As in other national [34, 35] and international cohorts [38] [39] [40] [41] , our findings showed a higher prevalence in males than in females. A meta-analysis carried out by Ortolan et al. [42] showed that males are 61% more likely to die from COVID-19 infection than females. This higher predisposition in males appears to be related to differences in innate immunity, steroid hormones, and factors related to sex chromosomes. In this sense, the double copy of the X chromosome in females is essential against viral infections. However, it is observed that female are at a higher risk of COVID-19 clinical manifestations in the long term than males [43] . Surprisingly, in our cohort, hospital death was not influenced by the obesity factor as was the case in other studies [44, 45] . One possible explanation is that the obesity rate of our patients was lower than in other cohorts [46] . Although primarily a respiratory disease, COVID-19 also causes important systemic effects, especially on the cardiovascular and immune systems. For this reason, in patients with previous CVD, mortality rates of 5-10 times higher are observed [8] . Our findings showed that the increase in mortality was not so pronounced among patients without previous CVD (19.68%) compared to patients with previous CVD (32.93%). As in other published studies [38, 40, 41, [47] [48] [49] , hypertension and diabetes were the most observed comorbidities, followed by chronic respiratory disease and some type of neoplasia, increasing the thrombotic event risk, which is associated with a mortality increase [50] . The pharmacological treatments used for COVID-19 have significant cardiovascular toxicities and side effects. However, data on side effects come from chronic treatments for other clinical conditions such as autoimmune diseases (hydroxychloroquine, chloroquine, and tocilizumab), hepatitis (interferon), or HIV (lopinavir-ritonavir) [26] . Azithromycin was consumed mainly by patients who did not die (69.36%), although it is known that this antibiotic in combination with hydroxychloroquine prolongs the QT interval [51] . Antimalarial drugs (i.e., hydroxychloroquine and chloroquine) were used in three out of four patients. It is known that these drugs at high doses mainly cause cardiac conduction disorders, in addition to ventricular hypertrophy, hypokinesia, heart failure, pulmonary arterial hypertension, and valve dysfunction [52] . Steroids were used in half of deceased patients (51.51%) and a positive OR was observed (1.68). This may be since in the case of methylprednisolone, which was the most frequently used steroid, it has been associated with electrolyte derangements, fluid retention, and hypertension [53] . The percentage of patients treated with antivirals (43.16%) was lower than in other studies [54] , but it has been related to a higher probability of death (OR: 1.74). The combination of lopinavir-ritonavir must be used with caution, since it can interact with cardiovascular medicines metabolized by cytochrome P450-3A4 such as antiarrhythmics, antiplatelets, and anticoagulants [55] , in addition to causing QT and PR segment prolongation [56] . In the case of remdesevir, no associated cardiovascular adverse effects have been reported [25] . The use of tocilizumab (8.33%) has demonstrated cardiovascular safety in patients with rheumatoid arthritis, although it is not currently confirmed in patients with previous CVD [57] . The anti-SIRS medicines are associated with a greater probability of death (OR: 1.97), probably because the patients are in a more advanced and more severe phase of the disease; therefore, the probability of death is higher. Regarding thromboprophylaxis strategies, according to different studies [58, 59] , initial treatment with heparin improves the prognosis of COVID-19 by increasing survival until hospital discharge compared to routine thromboprophylaxis, especially in non-critical patients. Lastly, this study has several limitations that must be mentioned. Occasionally, the diagnosis of COVID-19 was made according to clinical and radiological criteria without microbiological confirmation. Another possible limitation was the unavailability of other variables, such as earlier lifestyle factors, physical activity level, or sleep, which can influence the results of the logistic regression model regarding the prediction of hospital death in patients with previous CVD. Regarding pharmacological treatment, only the Spanish guidelines [28, 29] indicators were considered, and other possible treatments used may have been ignored. On the other hand, cardiovascular pharmacological treatments during patient admission were not available, which may be a limitation. Almost one out of three in-hospital COVID-19 patients had a previous CVD, of which half had arrhythmias history. In addition, these patients had a worse disease prognosis with higher mortality than the global patient average [32] . According to our findings, men older than 65 years with diabetes who developed SIRS, SARS, or AKI had a higher probability of hospital death. Among previous CVDs, chronic heart failure and cerebrovascular disease were associated with a worse clinical course of the disease, and a greater probability of associated death was observed. Regarding pharmacological treatment, antivirals and antimalarials, especially, have shown long-term cardiovascular toxicity, but it is too early to analyze their short-term effects. The medicines used for COVID-19 treatment were modified throughout the study period according to the availability and the national guideline recommendations [28, 29] . Definitely, previous CVDs are related to a worse prognosis of COVID-19; therefore, "special attention" to these patients must be paid, especially after steroid, antiviral, and anti-SIRS administration, which are associated with a higher probability of death. Supplementary Materials: The following are available online at https://www.mdpi.com/article/1 0.3390/jcdd8120167/s1, Table S1 : List of medicines used in the COVID-19 treatment according to Spanish guidelines; Table S2 : Treatment and clinical outcome evolution of in-hospital COVID-19 patients with previous cardiovascular diseases. Informed Consent Statement: Patient consent was waived due to the fact that this was a retrospective observational study, and anonymized databases provided by the health authorities were used. Restrictions apply to the availability of these data. Data were obtained from regional health authorities (Gerencia Regional de Salud (GRS)) and may be requested from sdinvestigacion@saludcastillayleon.es (GRS). Prevalence and Impact of Cardiovascular Metabolic Diseases on COVID-19 in China The COVID-19 Pandemic and Its Impact on the Cardio-Oncology Population COVID-19 and the Cardiovascular System COVID-19 and Cardiovascular Disease: From Basic Mechanisms to Clinical Perspectives A Current Review of COVID-19 for the Cardiovascular Specialist Clinical Features of Patients Infected with 2019 Novel Coronavirus in Clinical Predictors of Mortality Due to COVID-19 Based on an Analysis of Data of 150 Patients from Wuhan, China The Science Underlying COVID-19: Implications for the Cardiovascular System A History of Heart Failure Is an Independent Risk Factor for Death in Patients Admitted with Coronavirus 19 Disease Clinical Insights and Vascular Mechanisms Cardiovascular Complications in COVID-19 Tissue Distribution of ACE2 Protein, the Functional Receptor for SARS Coronavirus. A First Step in Understanding SARS Pathogenesis SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor Single-Cell RNA-Seq Data Analysis on the Receptor ACE2 Expression Reveals the Potential Risk of Different Human Organs Vulnerable to 2019-NCoV Infection. Front Hypothesis: Sex-Related Differences in ACE2 Activity May Contribute to Higher Mortality in Men Versus Women With COVID-19 A Pneumonia Outbreak Associated with a New Coronavirus of Probable Bat Origin Isolation and Characterization of a Bat SARS-like Coronavirus That Uses the ACE2 Receptor Angiotensin-Converting Enzyme 2 (ACE2) as a SARS-CoV-2 Receptor: Molecular Mechanisms and Potential Therapeutic Target The Trinity of COVID-19: Immunity, Inflammation and Intervention Cytokine-Induced Modulation of Cardiac Function Bidirectional Relation between Inflammation and Coagulation The Cardiovascular Complications of Chimeric Antigen Receptor T Cell Therapy Cardiovascular Manifestations and Treatment Considerations in COVID-19 Acute Pulmonary Embolism and COVID-19 Pneumonia: A Random Association? First Approval. Drugs 2020 COVID-19 and the Cardiovascular System: Implications for Risk Assessment, Diagnosis, and Treatment Options Cardiovascular Considerations for Patients, Health Care Workers, and Health Systems During the COVID-19 Pandemic Spanish Ministry of Health Clinical Management of COVID-19 Spanish Agency for Medicine and Health Products Available Treatments for the Management of Respiratory Infection by SARS-CoV-2 RECORD Working Committee. The REporting of Studies Conducted Using Observational Routinely-Collected Health Data (RECORD) Statement The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for Reporting Observational Studies Clinical Profile, Treatment and Predictors during the First COVID-19 Wave: A Population-Based Registry Analysis from Castile and Leon Hospitals Clinical Profile, Pharmacological Treatment, and Predictors of Death Among Hospitalized COVID-19 Patients With Acute Kidney Injury: A Population-Based Registry Analysis Clinical Characteristics of Patients Hospitalized with COVID-19 in Spain: Results from the SEMI-COVID-19 Registry Characteristics and Predictors of Death among 4035 Consecutively Hospitalized Patients with COVID-19 in Spain Risk factors for in-hospital mortality in patients with acute myocardial infarction during the COVID-19 outbreak Epidemiology of COVID-19 in a Long-Term Care Facility Clinical Characteristics of Coronavirus Disease 2019 in China Clinical Characteristics of 113 Deceased Patients with Coronavirus Disease 2019: Retrospective Study Features of 20 133 UK Patients in Hospital with COVID-19 Using the ISARIC WHO Clinical Characterisation Protocol: Prospective Observational Cohort Study Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area Does Gender Influence Clinical Expression and Disease Outcomes in COVID-19? A Systematic Review and Meta-Analysis Sex and Gender Differences in COVID-19: More to Be Learned! Am COVID-19: Obesity, Deprivation and Death How Important Is Obesity as a Risk Factor for Respiratory Failure, Intensive Care Admission and Death in Hospitalised COVID-19 Patients? Results from a Single Italian Centre Factors Associated with Hospital Admission and Critical Illness among 5279 People with Coronavirus Disease Clinical Course and Risk Factors for Mortality of Adult Inpatients with COVID-19 in Wuhan, China: A Retrospective Cohort Study Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy A Cohort of Patients with COVID-19 in a Major Teaching Hospital in Europe Abnormal Coagulation Parameters Are Associated with Poor Prognosis in Patients with Novel Coronavirus Pneumonia QTc Interval Prolongation, Torsade de Pointes, and Regulatory Issues: A Narrative Review Based on the Study of Case Reports Cardiac Complications Attributed to Chloroquine and Hydroxychloroquine: A Systematic Review of the Literature Clinical and Biochemical Indexes from 2019-NCoV Infected Patients Linked to Viral Loads and Lung Injury Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Systematic Review of Treatment Effects KALETRA(R) Oral Film Coated Tablets, Oral Solution, Lopinavir Ritonavir Oral Film Coated Tablets, Oral Solution. Product Insert Cardiovascular Safety of Tocilizumab Versus Etanercept in Rheumatoid Arthritis: A Randomized Controlled Trial Thromboprophylaxis Strategies to Improve the Prognosis of COVID-19 ATTACC Investigators ACTIV-4a Investigators; REMAP-CAP Investigators Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with COVID-19 The authors thank the Gerencia Regional de Salud de Castilla and León for access to the JIMENA, MEDORA, and CONCYLIA databases. The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.