Implementation of Cholesterol-Lowering Therapy to Reduce Cardiovascular Risk in Persons Living with HIV.

The widespread availability of highly effective antiretroviral therapies has reduced mortality from opportunistic infections in persons living with HIV (PLHIV), resulting in an increase in atherosclerotic cardiovascular disease (ASCVD) and other chronic illnesses (Samji et al. 2013). Although there has been a decline in morbidity and mortality from ASCVD in the past several decades, contemporary studies continue to report higher rates of cardiovascular events (Rosenson et al. 2020). HIV has been identified as a risk enhancer for ASCVD by multiple professional guideline writing committees (Grundy Scott et al. 2019, Mach et al. 2020); however, the utilization of cholesterol-lowering therapies in PLHIV remains low (Rosenson et al. 2018). Moreover, the use of statin therapy in PLHIV is complicated by drug-drug interactions that may either elevate or lower the blood statin concentrations resulting in increased toxicity or reduced efficacy respectively. Other comorbidities commonly associated with HIV present other challenges for the use of cholesterol-lowering therapies. This review will summarize the data on lipoprotein-associated ASCVD risk in PLHIV and discuss the challenges with effective treatment. Finally, we present a clinical algorithm to optimize cardiovascular risk reduction in this high-risk population.

Coronary anatomy and comorbidities impact on elective PCI outcomes in left main and multivessel coronary artery disease.

INTRODUCTION: The effects of coronary anatomy, lesion complexity, and comorbidities on outcomes of elective percutaneous coronary intervention (PCI) in high-risk patients with left main (LM) and/or multivessel coronary artery disease (CAD) are not well studied, as these patients are typically underrepresented in the clinical trials. METHODS: This cohort study involved 33,568 consecutive elective PCI cases, excluding patients with prior coronary artery bypass graft, acute coronary syndrome within 24 hr of index PCI, or shock. All data were obtained from the New York State's PCI Reporting System from the calendar year 2015. In-hospital mortality was the primary outcome of study. Logistic regression models were built to calculate odds ratios (OR) with 95% confidence intervals (CI) for in-hospital mortality after adjustment for coronary anatomy and significant clinical comorbidities. RESULTS: In this cohort of elective PCI cases all cause in-hospital mortality was low (0.3%), with a clear mortality gradient according to the extent of CAD: 0.1% in 1 vessel disease, 0.4% in 2 vessel, 0.5% in 3 vessel disease, and 3.2% in patients with LM CAD (p < .001). Mortality was also significantly increased in patients with multiple comorbidities: 0.1% in patients with 1 comorbidity, 0.7% with 2, 2.5% with 3, and 7.4% with 4 or more studied comorbidities (p < .0001). When adjusted for coronary anatomy and lesion complexity, having any 4 or more comorbidities was associated with significantly increased odds of dying after elective PCI (OR 25.9, 95% CI 8.152-82.063, p < .0001). Furthermore, when compared to patients with 3-vessel CAD, and accounted for comorbidities, the patients with LM disease still had significantly increased (OR 5.254, 95% CI 3.104-8.891, p < .0001) odds of dying after elective PCI. CONCLUSIONS: In patients undergoing elective PCI, multivessel CAD and particularly LM disease are associated with significantly increased all-cause mortality. Furthermore, when adjusted for the extent of CAD and lesion complexity, comorbidity burden remains an important predictor of mortality.

Oral Anticoagulation for Atrial Fibrillation Thromboembolism Prophylaxis in the Chronic Kidney Disease Population: the State of the Art in 2019.

Atrial fibrillation (AF) is the most common cardiac rhythm disturbance and is associated with increased risk of thromboembolism. Oral anticoagulants are effective at reducing rates of thromboembolism in patients with AF in the general population. Patients with AF and concurrent chronic kidney disease (CKD) have higher risk of thromboembolism and bleeding compared with patients with normal renal function. Among moderate CKD and end-stage renal disease (ESRD) patients on chronic dialysis, the use of oral anticoagulants is controversial. Use of warfarin, while beneficial in non-CKD patients, raises a number of concerns such as increased bleeding risk, labile anticoagulant effect, and calciphylaxis, especially in the ESRD population. The newer direct oral anticoagulant (DOAC) agents have demonstrated comparable efficacy and improved safety profiles compared with coumadin but are not as well studied in the CKD population. This review highlights the efficacy and safety of coumadin and the DOACs for thromboembolism prophylaxis in non-valvular AF patients with CKD.

Incremental role of resting myocardial computed tomography perfusion for predicting physiologically significant coronary artery disease: A machine learning approach.

BACKGROUND: Evaluation of resting myocardial computed tomography perfusion (CTP) by coronary CT angiography (CCTA) might serve as a useful addition for determining coronary artery disease. We aimed to evaluate the incremental benefit of resting CTP over coronary stenosis for predicting ischemia using a computational algorithm trained by machine learning methods. METHODS: 252 patients underwent CCTA and invasive fractional flow reserve (FFR). CT stenosis was classified as 0%, 1-30%, 31-49%, 50-70%, and >70% maximal stenosis. Significant ischemia was defined as invasive FFR < 0.80. Resting CTP analysis was performed using a gradient boosting classifier for supervised machine learning. RESULTS: On a per-patient basis, accuracy, sensitivity, specificity, positive predictive, and negative predictive values according to resting CTP when added to CT stenosis (>70%) for predicting ischemia were 68.3%, 52.7%, 84.6%, 78.2%, and 63.0%, respectively. Compared with CT stenosis [area under the receiver operating characteristic curve (AUC): 0.68, 95% confidence interval (CI) 0.62-0.74], the addition of resting CTP appeared to improve discrimination (AUC: 0.75, 95% CI 0.69-0.81, P value .001) and reclassification (net reclassification improvement: 0.52, P value < .001) of ischemia. CONCLUSIONS: The addition of resting CTP analysis acquired from machine learning techniques may improve the predictive utility of significant ischemia over coronary stenosis.

Recent Insights into Pharmacologic Cardiovascular Risk Reduction in Type 2 Diabetes Mellitus.

Diabetes mellitus (DM) affects nearly 30 million Americans and carries an increased risk of macrovascular complications of myocardial infarction, stroke, and cardiovascular death. While aggressive cardiovascular risk factor reduction has long been advocated in patients with diabetes, clinical trials have only recently demonstrated that such reductions result in improved outcomes. This review discusses recent evidence for risk reduction strategies and therapies with a focus on the management of glycemia, dyslipidemia, and hypertension. Although the degree to which aggressive glycated hemoglobin reduction decreases the risk of macrovascular outcomes remains unclear, the use of specific agents, such as the newer sodium glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) agonists, may reduce cardiovascular events in patients with diabetes, irrespective of glycated hemoglobin reduction. Statins have been the mainstay of dyslipidemia management, with recent guidelines recommending statin use in all patients aged 40-75 years with diabetes. There is an emerging role for the recently developed proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in diabetes, as these agents further reduce serum cholesterol and clinical cardiovascular events beyond the maximum tolerated statin therapy. Lastly, most evidence suggests that aggressive blood pressure lowering in diabetic patients with hypertension reduces macrovascular events. Recent studies have re-affirmed a goal blood pressure of 140/90, and a lower pressure is likely prudent in most patients with diabetes. Specifically, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) may reduce cardiovascular risk in patients with diabetes beyond their blood pressure-lowering effect. In conclusion, there is a growing literature which shows that the risk of cardiovascular outcomes can be reduced in most patients with diabetes, as outlined in this review.

Chelation Therapy as a Cardiovascular Therapeutic Strategy: the Rationale and the Data in Review.

Chelation therapy, typically used to remove heavy metal toxins, has also been controversially used as a treatment for coronary artery disease. The first Trial to Assess Chelation Therapy (TACT) aimed to provide evidence on chelation therapy's potential for benefit or harm. Although TACT had some significant results, the trial does not provide enough evidence to recommend routine chelation therapy and has limitations. The second TACT was recently funded reigniting a discussion about the value of chelation therapy, its efficacy, and allocation of research resources. Despite limited evidence, patients continue to pursue chelation therapy as a treatment for coronary artery disease. As the medical community has a responsibility to understand all treatments patients pursue, it is important to comprehensively appraise chelation therapy for cardiovascular disease. Understanding the background of heavy metal toxicity, the putative target of chelation therapy, on the cardiovascular system is important to contextualize the role of chelation therapy in cardiovascular disease prevention. We review the clinical evidence of heavy metal toxicity and cardiovascular disease, and available clinical trial data on use of chelation therapy to minimize the cardiovascular burden of heavy metal toxicity.

Preferences and Attitudes of Cardiologists in Management of Patients with Cancer.

Background: With recent improvements in survival of cancer patients and common use of high-value care at end of life, the management of cardiovascular disease (CVD) in patients with cancer is increasingly important. To our knowledge, there are no current U.S. data examining how the presence and extent of cancer influence cardiologists' decision making for common cardiovascular conditions. Methods: An anonymous online vignette-based survey of cardiologists was conducted at five U.S. institutions investigating how the extent of gastrointestinal and thoracic malignancies (prior/localized, metastatic) would influence treatment recommendations for atrial fibrillation (AF), aortic stenosis, unstable angina (UA), and obstructive coronary artery disease (CAD). Results: Thirty-three percent (86/259) of cardiologists completed the survey between September and November 2019. Participants were 67% male, 51% below age 40, and 58% had five or more years of clinical experience. Majority of cardiologists practiced at teaching hospitals (72%) and were noninterventional (63%). Cardiologists were more likely to recommend procedural interventions for patients with localized cancer than for those with metastatic disease: AF (left atrial appendage occlusion: 20% vs. 8%), atrial stenosis (aortic valve repair: 83% vs. 11%), UA (left heart catheter: 70% vs. 27%), and obstructive CAD (percutaneous coronary intervention: 81% vs. 38%). In patients with metastatic cancer, most cardiologists sought an oncology (82%) or a palliative care (69%) consultation. However, a persistent trend of undertreatment in patients with localized cancers and overtreatment in patients with end-of-life disease was apparent. Conclusions: Cardiologists were less likely to recommend invasive cardiovascular therapies to patients with metastatic cancer. This preference pattern likely reflects the influence of comorbidities and quality of life expectation on cardiologists' treatment recommendations but may also be related to the stigma of advanced cancer. Better communication between cardiologists and oncologists is necessary to provide a personalized care of patients with cancer and CVD that would maximize treatment benefit with least morbidity.

Sex Differences Remain Under-Reported in Cardiovascular Publications.

Background: For the past two decades, there has been increased interest from medical journals and calls to action from various organizations such as the National Institutes of Health to study sex differences in cardiovascular (CV) disease. It is unknown whether this emphasis has translated to a growth in publications addressing sex differences in CV disease. Materials and Methods: We performed a bibliometric analysis of all CV publications from 2006 to 2015. The National Library of Medicine's PubMed database was searched for articles containing the phrases "cardiac," "cardiovascular" or "cardiology," in the first author affiliation field. This was followed by a subsequent search for publications containing any of the following phrases in the title and/or abstract: "woman," "women," "female," "females," "gender," or "sex." The presence of such terms defined the publication as sex-specific. Trends over time were analyzed for specified subgroups, including publication category and funding source. Results: A total of 189,543 CV publications were identified, out of which there were 24,615 (12.99%) sex-specific publications. For the 10-year period, there were no significant changes in the relative proportion of sex-specific publications. When specific publication categories were analyzed, there were significant proportional increase of sex-specific publications in general articles category, but not for reviews, clinical trials, meta-analysis, or letters. Conclusion: Despite calls for greater attention, only a small fraction of publications for the past decade have reported on sex differences. There was no significant proportional growth of sex-specific publications for a recent 10-year period, except for the general research articles.

Pre-hospital ECG for acute coronary syndrome in urban India: a cost-effectiveness analysis.

BACKGROUND: Patients with acute coronary syndrome (ACS) in India have increased pre-hospital delay and low rates of thrombolytic reperfusion. Use of ECG could reduce pre-hospital delay among patients who first present to a general practitioner (GP). We assessed whether performing ECG on patients with acute chest pain would improve long-term outcomes and be cost-effective. METHODS: We created a Markov model of urban Indian patients presenting to a GP with acute chest pain to compare a GP's performing an ECG versus not performing one. Variables describing the accuracy of a GP's referral decision in chest pain and ACS, ACS treatment patterns, the effectiveness of thrombolytic reperfusion, and costs were derived from Indian data where available and other developed world studies. The model was used to estimate the incremental cost-effectiveness ratio (ICER) of the intervention in 2007 US dollars per quality adjusted life years (QALY) gained. RESULTS: Under baseline assumptions, the ECG strategy cost an additional $12.65 per QALY gained compared to no ECG. Sensitivity analyses around the cost of the ECG, cost of thrombolytic, and referral accuracy of the GP yielded ICERs for the ECG strategy ranging between cost-saving and $1124/QALY. All results indicated the intervention is cost-effective under current World Health Organization recommendations. CONCLUSIONS: While direct presentation to the hospital with acute chest pain is preferable, in urban Indian patients presenting first to a GP, an ECG performed by the GP is a cost-effective strategy to reduce disability and mortality. This strategy should be clinically studied and considered until improved emergency transport services are available.

Cryptococcal meningitis initially presenting with ST elevations and elevated cardiac biomarkers.

Acute neurological events are a common cause of ECG abnormalities and transient elevations in cardiac biomarkers. This case describes an uncommon presentation of cryptococcal meningitis in a non-immunosuppressed patient, presenting with altered sensorium and derangements in cardiac profile. Delay in diagnosing meningitis was avoided by paying close attention to the patient's presenting symptoms and by pursuing non-cardiac causes of ECG changes and elevations in cardiac troponin. Expeditious treatment and involvement of the infectious disease consultant resulted in excellent clinical response without permanent neurological sequelae.

Coronary Revascularization in High-Risk Stable Patients With Significant Comorbidities: Challenges in Decision-Making.

PURPOSE OF REVIEW: There is a growing cohort of complex high-risk patients with stable ischemic heart disease (SIHD) who present for coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI). These patients are older, have complex coronary disease, and a substantial comorbidity burden including frailty. The procedural risks and outcomes of CABG and PCI in these patients are more difficult to assess based on the available literature, which has generally studied a younger population with a lower comorbidity burden. RECENT FINDINGS: There have been initiatives to recalibrate and expand risk models derived from procedural registries to inform the care of complex higher-risk patients, including patients "turned down" for CABG. There is greater recognition of the need for improved assessment of risk, quality, and benefits of coronary revascularization in higher-risk SIHD patients with a substantial comorbidity burden. Clinicians and patients should be aware that there are significant evidence gaps regarding revascularization in complex high-risk patients. The limitations of procedural-derived risk scores should be understood when presenting treatment options. Future randomized controlled trials and expanded registries are greatly desired and should be achievable. Meanwhile, a multidisciplinary heart team approach should be employed for proper decision-making.

An acutely occluded Cabrol graft presenting as an acute coronary syndrome.

The Cabrol technique employs a synthetic graft to connect the coronary arteries to an aortic graft in patients with complex disease of the ascending aorta. Acute Cabrol graft thrombosis is a life-threatening situation that presents as acute coronary syndrome, as it leads to acute coronary hypoperfusion. We present a patient with unstable anginal symptoms who had undergone aortic surgery 6 months prior to presentation. Cardiac catheterisation was concerning for aortic dissection yet was later revealed to be acute occlusion of a Cabrol graft. The patient ultimately died of cardiogenic shock. We review the Cabrol technique, complications and management of acute graft thrombosis.

Hyperkalemia Is Associated With Increased Mortality Among Unselected Cardiac Intensive Care Unit Patients.

Background Hyperkalemia has been associated with increased mortality in patients with myocardial infarction, but few data exist regarding hyperkalemia in cardiac intensive care unit ( CICU ) patients. We hypothesize that hyperkalemia is associated with increased mortality in unselected CICU patients. Methods and Results We retrospectively reviewed a historical cohort of 9681 CICU patients admitted from January 2007 to December 2015. Hyperkalemia was defined as admission potassium ≥5.0 mEq/L and hypokalemia as admission potassium <3.5 mEq/L. Multivariate logistic regression was used to determine predictors of in-hospital mortality. Postdischarge survival was assessed using Kaplan-Meier analysis and Cox proportional hazards models. The mean age of included patients was 67±15 years, with 36% females, and in-hospital mortality was 9%. Hyperkalemia occurred in 1187 (12.3%) and hypokalemia occurred in 719 (7.4%) patients. Both patients with hyperkalemia (unadjusted odds ratio, 2.85; 95% CI, 2.40-3.39; P<0.001) and patients with hypokalemia (unadjusted odds ratio, 2.31; 95% CI, 1.85-2.88; P<0.001) were at increased risk of unadjusted in-hospital mortality. After adjustment for illness severity and renal function, only patients with hyperkalemia demonstrated increased risk of in-hospital death (adjusted odds ratio, 1.44; 95% CI, 1.11-1.87; P=0.006). Among hospital survivors, only patients with hyperkalemia had lower postdischarge survival by Kaplan-Meier analysis ( P<0.001). After adjustment for illness severity and renal function, hospital survivors with admission hyperkalemia remained at increased risk for postdischarge mortality (adjusted hazard ratio, 1.20; 95% CI, 1.08-1.34; P<0.001). Conclusions Hyperkalemia on CICU admission is associated with higher in-hospital and postdischarge mortality, independent of renal function and illness severity. These findings emphasize the importance of potassium abnormalities as a risk predictor in patients admitted to the CICU .

A Comparison of the Updated Diamond-Forrester, CAD Consortium, and CONFIRM History-Based Risk Scores for Predicting Obstructive Coronary Artery Disease in Patients With Stable Chest Pain: The SCOT-HEART Coronary CTA Cohort.

OBJECTIVES: This study sought to compare the performance of history-based risk scores in predicting obstructive coronary artery disease (CAD) among patients with stable chest pain from the SCOT-HEART study. BACKGROUND: Risk scores for estimating pre-test probability of CAD are derived from referral-based populations with a high prevalence of disease. The generalizability of these scores to lower prevalence populations in the initial patient encounter for chest pain is uncertain. METHODS: We compared 3 scores among patients with suspected CAD in the coronary computed tomographic angiography (CTA) randomized arm of the SCOT-HEART study for the outcome of obstructive CAD by coronary CTA: the updated Diamond-Forrester score (UDF), CAD Consortium clinical score (CAD2), and CONFIRM risk score (CRS). We tested calibration with goodness-of-fit, discrimination with area under the receiver-operating curve (AUC), and reclassification with net reclassification improvement (NRI) to identify low-risk patients. RESULTS: In 1,738 patients (age 58 ± 10 years and 44.0% women), overall calibration was best for UDF, with underestimation by CRS and CAD2. Discrimination by AUC was highest for CAD2 at 0.79 (95% confidence interval [CI]: 0.77 to 0.81) than for UDF (0.77 [95% CI: 0.74 to 0.79]) or CRS (0.75 [95% CI: 0.73 to 0.77]) (p < 0.001 for both comparisons). Reclassification of low-risk patients at the 10% probability threshold was best for CAD2 (NRI 0.31, 95% CI: 0.27 to 0.35) followed by CRS (NRI 0.21, 95% CI: 0.17 to 0.25) compared with UDF (p < 0.001 for all comparisons), with a consistent trend at the 15% threshold. CONCLUSIONS: In this multicenter clinic-based cohort of patients with suspected CAD and uniform CAD evaluation by coronary CTA, CAD2 provided the best discrimination and classification, despite overestimation of obstructive CAD as evaluated by coronary CTA. CRS exhibited intermediate performance followed by UDF for discrimination and reclassification.

Colon cancer laterality is associated with atherosclerosis and coronary artery disease.

BACKGROUND: Primary right-sided colon cancer (RCC) is associated with a higher mortality than left-sided colon cancer (LCC), but the etiology of this phenomenon remains unclear. We sought to study whether cancer laterality is associated with the prevalence of clinical coronary artery disease, calcific atherosclerosis as measured by computed tomography (CT), and cardiovascular risk factors. METHODS: We conducted a single center retrospective study of 546 participants who had previously been diagnosed with colon cancer between January 2005 and December 2014. The presence of coronary and aortic calcifications was assessed by CT in 486 of these patients. We examined the prevalence of clinical cardiovascular disease (CAD) (prior myocardial infarction or revascularization), comorbidities, coronary and aortic calcification in patients with RCC (n=261) and LCC (n=285). Logistic regression analysis was performed to assess the likelihood of clinical CAD and calcific atherosclerosis by cancer laterality. RESULTS: Compared to patients with LCC, patients with RCC were more likely to have hypertension, hyperlipidemia, hypothyroidism and clinical CAD. In the patients with available CT scans, RCC was associated with higher prevalence of coronary, thoracic, and abdominal calcifications than LCC. On univariate and multivariate analyses, RCC was associated with higher likelihood of clinical CAD (adjusted risk ratio 2.15, 95% CI, 1.37-3.38, P=0.001) as well as radiological evidence of calcific atherosclerosis compared to LCC. CONCLUSIONS: we found that both clinical CAD and vascular calcifications are prevalent in patients with colon cancer, and are independently increased in patients with RCC compared to LCC.

Cardiogenic Shock: Recent Developments and Significant Knowledge Gaps.

PURPOSE OF REVIEW: Patients with cardiogenic shock (CS) continue to have high rates of morbidity and mortality. We aimed to describe current principles in the management of CS including coronary revascularization, medical management, mechanical circulatory support, and supportive care. RECENT FINDINGS: Revascularization is still recommended, but trials have not found a benefit in the revascularization of nonculprit artery lesions. New mechanical circulatory support options are available, but optimal use remains uncertain. Overall improvement in outcomes appears to have plateaued. There remain substantial knowledge gaps about the management of CS. The ideal timing and selection criteria for mechanical support remain under-developed. There has been little systematic study to inform medical management or supportive care of this patient population. A more expansive research focus is necessary to improve the care of CS.

Successful percutaneous coronary intervention significantly improves coronary sinus blood flow as assessed by transthoracic echocardiography.

BACKGROUND: Transthoracic echocardiography (TTE) has been used to assess coronary sinus blood flow (CSBF), which reflects total coronary arterial blood flow. Successful angioplasty is expected to improve coronary arterial blood flow. Changes in CSBF after percutaneous coronary intervention (PCI), as assessed by TTE, have not been systematically evaluated. HYPOTHESIS: TTE can be utilized to reflect increased CSBF after a successful, clinically indicated PCI. METHODS: The study cohort included 31 patients (18 females, 62 ± 11 years old) referred for diagnostic cardiac catheterization for suspected coronary artery disease and possible PCI, when clinically indicated. All performed PCIs were successful, with good angiographic outcome. CSBF per cardiac cycle (mL/beat) was measured using transthoracic two-dimensional and Doppler flow imaging as the product of coronary sinus (CS) area and CS flow time-velocity integral. CSBF per minute (mL/min) was calculated as the product of heart rate and CSBF per cardiac cycle. In each patient, CSBF was assessed prospectively, before and after cardiac catheterization with and without clinically indicated PCI. Within- and between-group differences in CSBF before and after PCI were assessed using repeated measures analysis of variance. RESULTS: Technically adequate CSBF measurements were obtained in 24 patients (77%). In patients who did not undergo PCI, there was no significant change in CSBF (278.1 ± 344.1 versus 342.7 ± 248.5, p = 0.36). By contrast, among patients who underwent PCI, CSBF increased significantly (254.3 ± 194.7 versus 618.3 ± 358.5 mL/min, p < 0.01, p-interaction = 0.03). Other hemodynamic and echocardiographic parameters did not change significantly before and after cardiac catheterization in either treatment group. CONCLUSIONS: Transthoracic echocardiographic assessment can be employed to document CSBF changes after angioplasty. Future studies are needed to explore the clinical utility of this noninvasive metric.

Solitary cardiac metastasis from primary oral squamous cell carcinoma presenting as ST-elevation MI.

Cardiac metastases from oral squamous cell carcinoma (SCC) are rare, especially in the absence of systemic metastasis. We describe a case of a patient presenting with chest pain and ECG abnormalities concerning for ST-elevation myocardial infarction that eventually was found to have an incidental right ventricular mass on chest CT angiogram. Ultimately, she had an intracardiac echocardiography-assisted biopsy diagnosis of isolated cardiac metastasis from primary oral SCC. The extent of the disease precluded any surgical intervention, and the patient subsequently transitioned to hospice care. Most cardiac metastases remain clinically silent until widespread systemic disease leads to death. Thus, cardiac metastasis should be considered in a patient with SCC who develops new cardiovascular symptoms or conduction abnormalities.