Thirty-Day Cardiovascular Readmissions Following Discharge with COVID-19: A US Nationwide Readmission Database Analysis from the Pandemic Year 2020.

BACKGROUND: COVID-19 is known to be associated with a myriad of cardiovascular (CV) complications during acute illness, but the rates of readmissions for CV complications after COVID-19 infection are less well established. METHODS: The U.S Nationwide Readmission Database was utilized to identify COVID-19 admissions from April 1st to November 30th, 2020 using ICD-10-CM administrative claims. RESULTS: A total of 521,351 admissions for COVID-19 were identified. The all-cause 30-day readmission rate was 11.6% (n=60,262). The incidence of CV readmissions was 5.1% (n=26,725), accounting for 44.3% of all-cause 30-day readmissions. Both CV and non-CV readmissions occurred at a median of 7 days. Patients readmitted with CV causes had a higher comorbidity burden with Charlson comorbidity median score of 6. The most common CV cause of readmission was acute heart failure (HF) (8.5%) followed by acute myocardial infarction (MI) (5.2%). Venous thromboembolism and stroke during 30-day readmission occurred at a rate of 4.6% and 3.6%, respectively. Stress cardiomyopathy and acute myocarditis were less frequent with an incidence of 0.1% and 0.2%, respectively. CV readmissions were associated with higher mortality compared with non-CV readmissions (16.5% vs. 7.5%, p<0.01). Each 30-day CV readmission was associated with greater cost of care than each non-CV readmission ($13,803 vs. $10,310, p=<0.01). CONCLUSIONS: Among survivors of index COVID-19 admission, 44.7% of all 30-day readmissions were attributed to CV causes. Acute HF remains the most common cause of readmission after COVID-19, followed closely by acute MI. CV causes of readmissions remain a significant source of mortality, morbidity, and resource utilization.

Heart Disease and Stroke Statistics-2023 Update: A Report From the American Heart Association.

BACKGROUND: The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). METHODS: The American Heart Association, through its Epidemiology and Prevention Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update with review of published literature through the year before writing. The 2023 Statistical Update is the product of a full year's worth of effort in 2022 by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. The American Heart Association strives to further understand and help heal health problems inflicted by structural racism, a public health crisis that can significantly damage physical and mental health and perpetuate disparities in access to health care, education, income, housing, and several other factors vital to healthy lives. This year's edition includes additional COVID-19 (coronavirus disease 2019) publications, as well as data on the monitoring and benefits of cardiovascular health in the population, with an enhanced focus on health equity across several key domains. RESULTS: Each of the chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. CONCLUSIONS: The Statistical Update represents a critical resource for the lay public, policymakers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.

International consensus statement on challenges for women in cardiovascular practice and research in the COVID-19 era.

The challenges to academic and professional development and career advancement of women in cardiology (WIC), imposed by the pandemic, not only impinge the female cardiologists' "leaky pipeline" but also make the "leakiness" more obvious. This consensus document aims to highlight the pandemic challenges WIC face, raise awareness of the gender equity gap, and propose mitigating actionable solutions derived from the data and experiences of an international group of female cardiovascular clinicians and researchers. This changing landscape has led to the need for highly specialized cardiologists who may have additional training in critical care, imaging, advanced heart failure, or interventional cardiology. Although women account for most medical school graduates, the number of WIC, particularly in mentioned sub-specialties, remains low. Moreover, women have been more affected by systemic issues within these challenging work environments, limiting their professional progression, career advancement, and economic potential. Therefore, it is imperative that tangible action points be noted and undertaken to ensure the representation of women in leadership, advocacy, and decision-making, and increase diversity in academia. Strategies to mitigate the negative impacts of the pandemic need to be taken during this COVID-19 pandemic to ensure WIC have a place in the field of Cardiology.

Influenza Vaccination for Cardiovascular Prevention: Further Insights from the IAMI Trial and an Updated Meta-analysis.

PURPOSE OF REVIEW: Influenza infection is a significant, well-established cause of cardiovascular disease (CVD) and CV mortality. Influenza vaccination has been shown to reduce major adverse cardiovascular events (MACE) and CV mortality. Therefore, major society guidelines have given a strong recommendation for its use in patients with established CVD or high risk for CVD. Nevertheless, influenza vaccination remains underutilized. Historically, influenza vaccination is administered to stable outpatients. Until recently, the safety and efficacy of influenza vaccination among patients with acute myocardial infarction (MI) had not been established. RECENT FINDINGS: The recently published Influenza Vaccination after Myocardial Infarction (IAMI) trial showed that influenza vaccination within 72 h of hospitalization for MI led to a significant 28% reduction in MACE and a 41% reduction in CV mortality, without any excess in serious adverse events. Additionally, we newly performed an updated meta-analysis of randomized clinical trials (RCTs) including IAMI and the recent Influenza Vaccine to Prevent Adverse Vascular Events (IVVE) trial. In pooled analysis of 8 RCTs with a total of 14,420 patients, influenza vaccine, as compared with control/placebo, was associated with significantly lower risk of MACE at follow-up [RR 0.75 (95%CI 0.57-0.97), I2 56%]. The recent IAMI trial showed that influenza vaccination in patients with recent MI is safe and efficacious at reducing CV morbidity and mortality. Our updated meta-analysis confirms a 25% reduction in MACE. The influenza vaccine should be strongly encouraged in all patients with CVD and incorporated as an essential facet of post-MI care and secondary CVD prevention.

Improving risk prediction for pulmonary embolism in COVID-19 patients using echocardiography.

SARS-CoV-2 infection is associated with increased risk for pulmonary embolism (PE), a fatal complication that can cause right ventricular (RV) dysfunction. Serum D-dimer levels are a sensitive test to suggest PE, however lacks specificity in COVID-19 patients. The goal of this study was to identify a model that better predicts PE diagnosis in hospitalized COVID-19 patients using clinical, laboratory, and echocardiographic imaging predictors. We performed a cross-sectional study of 302 adult patients admitted to the Johns Hopkins Hospital (March 2020-February 2021) for COVID-19 infection who underwent transthoracic echocardiography and D-dimer testing; 204 patients had CT angiography. Clinical, laboratory and imaging predictors including, but not limited to, D-dimer and RV dysfunction were used to build prediction models for PE using logistic regression. Model discrimination was assessed using area under the receiver operator curve (AUC) and calibration using Hosmer-Lemeshow χ 2 statistic. Internal validation was performed. The prevalence of PE was 7.6%. The model with positive D-dimer above 5 mg/L, RV dysfunction on echocardiography, and troponin had an AUC of 0.77, and cross-validated AUC of 0.74. D-dimer (>5 mg/L) had a positive association with PE (adj odds ratio = 4.40; 95% confidence interval: [1.80, 10.78]). We identified a model including clinical, imaging and laboratory variables that predicted PE in hospitalized COVID-19 patients. Positive D-dimer >5, RV dysfunction on echocardiography, and troponin were important predictors for calculating likelihood of PE diagnosis. This approach may be useful to aid in clinical decision-making related to diagnostic imaging and treatment. Prospective studies are needed to evaluate impact on patient outcomes.

Cardiovascular Disease Prevention During the COVID-19 Pandemic: Lessons Learned and Future Opportunities.

The coronavirus disease 2019 (COVID-19) pandemic has been the defining healthcare issue since its outbreak, consuming healthcare systems and disrupting all aspects of human life throughout 2020 and continuing through 2021. When reviewing cardiovascular disease (CVD) prevention throughout the COVID-19 pandemic, the first tendency may be to focus on the negative disruption. Months of quarantine, isolation, and missed healthcare visits or delayed care may have exacerbated the epidemic of CVD in the United States. Looking back, however, perhaps it wasn't a lost year as much as a health crisis that better prepared us for the battle to improve cardiovascular health. The pandemic brought new platforms for interacting with patients eager to engage, presenting a unique opportunity to reset how we approach preventive care. In this review, we discuss what the pandemic has taught us about caring for those vulnerable patients who were most afflicted-older adults, persons of color, and people facing adverse socioeconomic circumstances-and who continue to be impacted by CVD. We also identify opportunities for enhanced CVD prevention now boosted by the overnight adoption of telemedicine and other innovative cardiac care models. Lastly, we discuss how the COVID-19 pandemic has motivated physicians and patients alike to prioritize our health above all else, if only transiently, and how we can leverage this increased health awareness and investment into long-term, meaningful disease prevention.

High-value laboratory testing for hospitalized COVID-19 patients: a review.

We present here an evidence-based review of the utility, timing, and indications for laboratory test use in the domains of inflammation, cardiology, hematology, nephrology and co-infection for clinicians managing the care of hospitalized COVID-19 patients. Levels of IL-6, CRP, absolute lymphocyte count, neutrophils and neutrophil-to-lymphocyte ratio obtained upon admission may help predict the severity of COVID-19. Elevated LDH, ferritin, AST, and d-dimer are associated with severe illness and mortality. Elevated cardiac troponin at hospital admission can alert clinicians to patients at risk for cardiac complications. Elevated proBNP may help distinguish a cardiac complication from noncardiac etiologies. Evaluation for co-infection is typically unnecessary in nonsevere cases but is essential in severe COVID-19, intensive care unit patients, and immunocompromised patients.

Clinical Characteristics and Outcomes of Adults With a History of Heart Failure Hospitalized for COVID-19.

BACKGROUND: It is important to understand the risk for in-hospital mortality of adults hospitalized with acute coronavirus disease 2019 (COVID-19) infection with a history of heart failure (HF). METHODS: We examined patients hospitalized with COVID-19 infection from January 1, 2020 to July 22, 2020, from 88 centers across the US participating in the American Heart Association's COVID-19 Cardiovascular Disease registry. The primary exposure was history of HF and the primary outcome was in-hospital mortality. To examine the association between history of HF and in-hospital mortality, we conducted multivariable modified Poisson regression models that included sociodemographics and comorbid conditions. We also examined HF subtypes based on left ventricular ejection fraction in the prior year, when available. RESULTS: Among 8920 patients hospitalized with COVID-19, mean age was 61.4±17.5 years and 55.5% were men. History of HF was present in 979 (11%) patients. In-hospital mortality occurred in 31.6% of patients with history of HF, and 16.9% in patients without a history of HF. In a fully adjusted model, history of HF was associated with increased risk for in-hospital mortality (relative risk: 1.16 [95% CI, 1.03-1.30]). Among 335 patients with left ventricular ejection fraction, heart failure with reduced ejection fraction was significantly associated with in-hospital mortality in a fully adjusted model (heart failure with reduced ejection fraction relative risk: 1.40 [95% CI, 1.10-1.79]; heart failure with mid-range ejection fraction relative risk: 1.06 [95% CI, 0.65-1.73]; heart failure with preserved ejection fraction relative risk, 1.06 [95% CI, 0.84-1.33]). CONCLUSIONS: Risk for in-hospital mortality was substantial among adults with history of HF, in large part due to age and comorbid conditions. History of heart failure with reduced ejection fraction may confer especially elevated risk. This population thus merits prioritization for the COVID-19 vaccine.

Myocardial Work Efficiency, A Novel Measure of Myocardial Dysfunction, Is Reduced in COVID-19 Patients and Associated With In-Hospital Mortality.

Background: Although troponin elevation is common in COVID-19, the extent of myocardial dysfunction and its contributors to dysfunction are less well-characterized. We aimed to determine the prevalence of subclinical myocardial dysfunction and its association with mortality using speckle tracking echocardiography (STE), specifically global longitudinal strain (GLS) and myocardial work efficiency (MWE). We also tested the hypothesis that reduced myocardial function was associated with increased systemic inflammation in COVID-19. Methods and Results: We conducted a retrospective study of hospitalized COVID-19 patients undergoing echocardiography (n = 136), of whom 83 and 75 had GLS (abnormal >-16%) and MWE (abnormal <95%) assessed, respectively. We performed adjusted logistic regression to examine associations of GLS and MWE with in-hospital mortality. Patients were mean 62 ± 14 years old (58% men). While 81% had normal left ventricular ejection fraction (LVEF), prevalence of myocardial dysfunction was high by STE; [39/83 (47%) had abnormal GLS; 59/75 (79%) had abnormal MWE]. Higher MWE was associated with lower in-hospital mortality in unadjusted [OR 0.92 (95% CI 0.85-0.99); p = 0.048] and adjusted models [aOR 0.87 (95% CI 0.78-0.97); p = 0.009]. In addition, increased systemic inflammation measured by interleukin-6 level was associated with reduced MWE. Conclusions: Subclinical myocardial dysfunction is common in COVID-19 patients with clinical echocardiograms, even in those with normal LVEF. Reduced MWE is associated with higher interleukin-6 levels and increased in-hospital mortality. Non-invasive STE represents a readily available method to rapidly evaluate myocardial dysfunction in COVID-19 patients and can play an important role in risk stratification.

COVID and Cardiovascular Disease: What We Know in 2021.

PURPOSE OF REVIEW: Coronavirus disease 2019 (COVID-19) has been the cause of significant global morbidity and mortality. Here, we review the literature to date of the short-term and long-term consequences of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection on the heart. RECENT FINDINGS: Early case reports described a spectrum of cardiovascular manifestations of COVID-19, including myocarditis, stress cardiomyopathy, myocardial infarction, and arrhythmia. However, in most cases, myocardial injury in COVID-19 appears to be predominantly mediated by the severity of critical illness rather than direct injury to myocardium from viral particles. While cardiac magnetic resonance imaging remains a powerful tool for diagnosing acute myocarditis, it should be used judiciously in light of low baseline prevalence of myocarditis. Guiding an athletic patient through return to play (RTP) after COVID-19 infection is a challenging process. More recent data show RTP has been a safe endeavor using a screening protocol. "Long COVID" or post-acute sequelae of SARS-CoV-2 infection has also been described. The reported symptoms span a large breadth of cardiopulmonary and neurologic complaints including fatigue, palpitations, chest pain, breathlessness, brain fog, and dysautonomia including postural tachycardia syndrome (POTS). Management of POTS/dysautonomia primarily centers on education, exercise, and salt and fluid repletion. Our understanding of the impact of COVID-19 on the cardiovascular system is constantly evolving. As we enter a new age of survivorship, additional research is needed to catalogue the burden of persistent cardiopulmonary symptoms. Research is also needed to learn how acute management may alter the likelihood and prevalence of this chronic syndrome.

The role of sex and inflammation in cardiovascular outcomes and mortality in COVID-19.

OBJECTIVE: Higher mortality in COVID-19 in men compared to women is recognized, but sex differences in cardiovascular events are less well established. We aimed to determine the independent contribution of sex to stroke, myocardial infarction and death in the setting of COVID-19 infection. METHODS: We performed a retrospective cohort study of hospitalized COVID-19 patients in a racially/ethnically diverse population. Clinical features, laboratory markers and clinical events were initially abstracted from medical records, with subsequent clinician adjudication. RESULTS: Of 2060 patients, myocardial injury (32% vs 23%, p = 0.019), acute myocardial infarction (2.7% vs 1.6%, p = 0.114), and ischemic stroke (1.8% vs 0.7%, p = 0.007) were more common in men vs women. In-hospital death occurred in 160 men (15%) vs 117 women (12%, p = 0.091). Men had higher odds of myocardial injury (odds ratio (OR) 2.04 [95% CI 1.43-2.91], p < 0.001), myocardial infarction (1.72 [95% CI 0.93-3.20], p = 0.085) and ischemic stroke (2.76 [95% CI 1.29-5.92], p = 0.009). Despite adjustment for demographics and cardiovascular risk factors, male sex predicted mortality (HR 1.33; 95% CI:1.01-1.74; p = 0.041). While men had significantly higher markers of inflammation, in sex-stratified analyses, increase in interleukin-6, C-reactive protein, ferritin and d-dimer were predictive of mortality and myocardial injury similarly in both sexes. CONCLUSIONS: Adjusted odds of myocardial injury, ischemic stroke and all-cause mortality, but not myocardial infarction, are significantly higher in men compared to women with COVID-19. Higher inflammatory markers are present in men but associated similarly with risk in both men and women. These data suggest that adverse cardiovascular outcomes in men vs. women are independent of cardiovascular comorbidities.

Myocardial Injury in Severe COVID-19 Compared With Non-COVID-19 Acute Respiratory Distress Syndrome.

BACKGROUND: Knowledge gaps remain in the epidemiology and clinical implications of myocardial injury in coronavirus disease 2019 (COVID-19). We aimed to determine the prevalence and outcomes of myocardial injury in severe COVID-19 compared with acute respiratory distress syndrome (ARDS) unrelated to COVID-19. METHODS: We included intubated patients with COVID-19 from 5 hospitals between March 15 and June 11, 2020, with troponin levels assessed. We compared them with patients from a cohort study of myocardial injury in ARDS and performed survival analysis with primary outcome of in-hospital death associated with myocardial injury. In addition, we performed linear regression to identify clinical factors associated with myocardial injury in COVID-19. RESULTS: Of 243 intubated patients with COVID-19, 51% had troponin levels above the upper limit of normal. Chronic kidney disease, lactate, ferritin, and fibrinogen were associated with myocardial injury. Mortality was 22.7% among patients with COVID-19 with troponin under the upper limit of normal and 61.5% for those with troponin levels >10 times the upper limit of normal (P<0.001). The association of myocardial injury with mortality was not statistically significant after adjusting for age, sex, and multisystem organ dysfunction. Compared with patients with ARDS without COVID-19, patients with COVID-19 were older and had higher creatinine levels and less favorable vital signs. After adjustment, COVID-19-related ARDS was associated with lower odds of myocardial injury compared with non-COVID-19-related ARDS (odds ratio, 0.55 [95% CI, 0.36-0.84]; P=0.005). CONCLUSIONS: Myocardial injury in severe COVID-19 is a function of baseline comorbidities, advanced age, and multisystem organ dysfunction, similar to traditional ARDS. The adverse prognosis of myocardial injury in COVID-19 relates largely to multisystem organ involvement and critical illness.

Multimodality Imaging for Cardiac Evaluation in Patients with COVID-19.

PURPOSE OF REVIEW: A growing number of cardiovascular manifestations resulting from the novel SARS-CoV-2 coronavirus (COVID-19) have been described since the beginning of this global pandemic. Acute myocardial injury is common in this population and is associated with higher rates of morbidity and mortality. The focus of this review centers on the recent applications of multimodality imaging in the diagnosis and management of COVID-19-related cardiovascular conditions. RECENT FINDINGS: In addition to standard cardiac imaging techniques such as transthoracic echocardiography, other modalities including computed tomography and cardiac magnetic resonance imaging have emerged as useful adjuncts in select patients with COVID-19 infection, particularly those with suspected ischemic and nonischemic myocardial injury. Data have also emerged suggesting lasting COVID-19 subclinical cardiac effects, which may have long-term prognostic implications. With the spectrum of COVID-19 cardiovascular manifestations observed thus far, it is important for clinicians to recognize the role, strengths, and limitations of multimodality imaging techniques in this patient population.

Gender Differences in Publication Authorship During COVID-19: A Bibliometric Analysis of High-Impact Cardiology Journals.

Background The purpose of this study was to examine gender differences in authorship of manuscripts in select high-impact cardiology journals during the early coronavirus disease 2019 (COVID-19) pandemic. Methods and Results All manuscripts published between March 1, 2019 to June 1, 2019 and March 1, 2020 to June 1, 2020 in 4 high-impact cardiology journals (Journal of the American College of Cardiology, Circulation, JAMA Cardiology, and European Heart Journal) were identified using bibliometric data. Authors' genders were determined by matching first name with predicted gender using a validated multinational database (Genderize.io) and manual adjudication. Proportions of women and men first, co-first, senior, and co-senior authors, manuscript types, and whether the manuscript was COVID-19 related were recorded. In 2019, women were first authors of 176 (22.3%) manuscripts and senior authors of 99 (15.0%) manuscripts. In 2020, women first authored 230 (27.4%) manuscripts and senior authored 138 (19.3%) manuscripts. Proportions of woman first and senior authors were significantly higher in 2020 compared with 2019. Women were more likely to be first authors if the manuscript's senior author was a woman (33.8% for woman first/woman senior versus 23.4% for woman first/man senior; P<0.001). Women were less likely to be first authors of COVID-19-related original research manuscripts (P=0.04). Conclusions Representation of women as key authors of manuscripts published in major cardiovascular journals increased during the early COVID-19 pandemic compared with similar months in 2019. However, women were significantly less likely to be first authors of COVID-19-related original research manuscripts. Future investigation into the gender-disparate impacts of COVID-19 on academic careers is critical.

Remdesivir for the treatment of COVID-19: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The nucleotide analogue prodrug remdesivir was among the first antiviral therapies to be tested in randomized controlled trials (RCTs) for COVID-19. We performed a meta-analysis to understand efficacy and safety. METHODS: We searched PubMed, EMBASE, Cochrane library, and ClinicalTrials.gov databases (from January 1, 2020 to November 5, 2020). We included RCTs comparing the efficacy and safety of remdesivir to control/placebo in COVID-19. Two independent investigators abstracted data, assessed the quality of evidence, and rated the certainty of evidence. RESULTS: A total of 4 RCTs with 7334 patients with COVID-19 were included. At a follow-up of 28-29 days from randomization, very low certainty evidence showed that use of remdesivir compared with control group (placebo and/or standard of care) was not associated with a significant decrease in time to clinical improvement (standardized mean difference -0.80 day; [CI, -2.12, 0.53]). However, moderate certainty of evidence showed that remdesivir was associated with higher rates of recovered patients (risk difference [RD] 0.07 [0.05, 0.08]) and discharged patients (RD 0.07 [0.03, 0.11]) and lower rates of developing serious adverse events (RD -0.05 [-0.10, -0.01]) compared with control. Moderate and very low certainty of evidence showed there was no significant difference in deaths at 28-29 days follow-up (RD -0.01 [-0.03, 0.01]) and developing any adverse events (RD 0.01 [-0.17, 0.19]) between both groups, respectively. CONCLUSION: Patients given remdesivir are more likely to demonstrate recovery and were associated with higher rates of hospital discharge, but not with significant reduction in mean time to clinical improvement or mortality.

Cardiovascular implications of COVID-19 versus influenza infection: a review.

BACKGROUND: Due to the overlapping clinical features of coronavirus disease 2019 (COVID-19) and influenza, parallels are often drawn between the two diseases. Patients with pre-existing cardiovascular diseases (CVD) are at a higher risk for severe manifestations of both illnesses. Considering the high transmission rate of COVID-19 and with the seasonal influenza approaching in late 2020, the dual epidemics of COVID-19 and influenza pose serious cardiovascular implications. This review highlights the similarities and differences between influenza and COVID-19 and the potential risks associated with coincident pandemics. MAIN BODY: COVID-19 has a higher mortality compared to influenza with case fatality rate almost 15 times more than that of influenza. Additionally, a significantly increased risk of adverse outcomes has been noted in patients with CVD, with ~ 15 to 70% of COVID-19 related deaths having an underlying CVD. The critical care need have ranged from 5 to 79% of patients hospitalized due to COVID-19, a proportion substantially higher than with influenza. Similarly, the frequency of vascular thrombosis including deep venous thrombosis and pulmonary embolism is markedly higher in COVID-19 patients compared with influenza in which vascular complications are rarely seen. Unexpectedly, while peak influenza season is associated with increased cardiovascular hospitalizations, a decrease of ~ 50% in cardiovascular hospitalizations has been observed since the first diagnosed case of COVID-19, owing in part to deferred care. CONCLUSION: In the coming months, increasing efforts towards evaluating new interventions will be vital to curb COVID-19, especially as peak influenza season approaches. Currently, not enough data exist regarding co-infection of COVID-19 with influenza or how it would progress clinically, though it may cause a significant burden on an already struggling health care system. Until an effective COVID-19 vaccination is available, high coverage of influenza vaccination should be of utmost priority.