Developing an international concept-based curriculum for pharmacology education: The promise of core concepts and concept inventories.

Over recent years, studies have shown that science and health profession graduates demonstrate gaps in their fundamental pharmacology knowledge and ability to apply pharmacology concepts in practice. This article reviews the current challenges faced by pharmacology educators, including the exponential growth in discipline knowledge and competition for curricular time. We then argue that pharmacology education should focus on essential concepts that enable students to develop beyond 'know' towards 'know how to'. A concept-based approach will help educators prioritize and benchmark their pharmacology curriculum, facilitate integration of pharmacology with other disciplines in the curriculum, create alignment between universities and improve application of pharmacology knowledge to professional contexts such as safe prescribing practices. To achieve this, core concepts first need to be identified and unpacked, and methods for teaching and assessment using concept inventories developed. The International Society for Basic and Clinical Pharmacology Education Section (IUPHAR-Ed) Core Concepts of Pharmacology (CCP) initiative involves over 300 educators from the global pharmacology community. CCP has identified and defined the core concepts of pharmacology, together with key underpinning sub-concepts. To realize these benefits, pharmacology educators must develop methods to teach and assess core concepts. Work to develop concept inventories is ongoing, including identifying student misconceptions of the core concepts and creating a bank of multiple-choice questions to assess student understanding. Future work aims to develop and validate materials and methods to help educators embed core concepts within curricula. Potential strategies that educators can use to overcome factors that inhibit adoption of core concepts are presented.

Natriuretic Peptides as Biomarkers: Narrative Review and Considerations in Cardiovascular and Respiratory Dysfunctions.

Natriuretic peptides (NPs) encompass a family of structurally related hormone/paracrine factors acting through the natriuretic peptide system regulating cell proliferation, vessel tone, inflammatory processes, neurohumoral pathways, fluids, and electrolyte balance. The three most studied peptides are atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-Type natriuretic peptide (CNP). ANP and BNP are the most relevant NPs as biomarkers for the diagnosis and prognosis of heart failure and underlying cardiovascular diseases, such as cardiac valvular dysfunction, hypertension, coronary artery disease, myocardial infarction, persistent arrhythmias, and cardiomyopathies. Cardiac dysfunctions related to cardiomyocytes stretching in the atria and ventricles are primary elicitors of ANP and BNP release, respectively. ANP and BNP would serve as biomarkers for differentiating cardiac versus noncardiac causes of dyspnea and as a tool for measuring the prognosis of patients with heart failure; nevertheless, BNP has been shown with the highest predictive value, particularly related to pulmonary disorders. Plasma BNP has been reported to help differentiate cardiac from pulmonary etiologies of dyspnea in adults and neonates. Studies have shown that COVID-19 infection also increases serum levels of N-terminal pro b-type natriuretic peptide (NT-proBNP) and BNP. This narrative review assesses aspects of ANP and BNP on their physiology, and predictive values as biomarkers. We present an overview of the NPs' synthesis, structure, storage, and release, as well as receptors and physiological roles. Following, considerations focus on ANP versus BNP, comparing their relevance in settings and diseases associated with respiratory dysfunctions. Finally, we compiled data from guidelines for using BNP as a biomarker in dyspneic patients with cardiac dysfunction, including its considerations in COVID-19.

Resveratrol Supplants Captopril's Protective Effect on Cardiac Remodeling in a Hypertension Model Elicited by Renal Artery Stenosis.

Background: Renovascular hypertension elicits cardiac damage and remodeling. Two-kidney, one-clip (2K1C) is an experimental model used to study hypertension pathophysiology. In this model, the renin-angiotensin-system (RAS) is overactive due to renal artery stenosis, leading to cardiac remodeling. Redox mechanisms underlying RAS activation mediate hypertension-induced cardiovascular damage. Preclinical studies and clinical trials demonstrated resveratrol's protective effects in cardiovascular diseases, mainly attributed to its antioxidant properties. We hypothesized resveratrol alone or in combination with an angiotensin-converting enzyme (ACE) inhibitor would be beneficial against cardiac damage caused by renovascular hypertension. Objective: We investigated the benefits of resveratrol against cardiac remodeling in 2K1C rats compared with captopril. Methods: Male Wistar rats underwent unilateral renal stenosis - 2K1C Goldblatt model of hypertension. Systolic Blood Pressure (SBP) was measured before and 6 weeks after surgery. Hypertensive 2K1C rats presented SBP≥160 mmHg. From the 6th week after the surgery, the animals received oral resveratrol (20 mg/kg), captopril (12 mg/kg), or their combination for 3 times per week for 3 weeks. Whole heart hypertrophy was evaluated. Histological assays assessed left ventricle hypertrophy and fibrosis. Results: Renovascular hypertension caused cardiac hypertrophy, accompanied by increased myocyte diameter and collagen deposition. Resveratrol reduced 2K1C rats' SBP and whole heart hypertrophy, independently of captopril. Resveratrol caused a higher reduction in ventricular hypertrophy than captopril. Collagen deposition was greater reduced by 2K1C treated only with resveratrol than with captopril alone or combined with resveratrol. Conclusion: Independent of captopril, resveratrol prompts cardioprotective effects on cardiomyocyte remodeling and fibrosis resulting from renovascular hypertension in 2K1C rats.

Vascular reactivity stimulated by TMA and TMAO: Are perivascular adipose tissue and endothelium involved?

Trimethylamine (TMA), formed by intestinal microbiota, and its Flavin-Monooxygenase 3 (FMO3) product Trimethylamine-N-Oxide (TMAO), are potential modulators of host cardiometabolic phenotypes. High circulating levels of TMAO are associated with increased risk for cardiovascular diseases. We hypothesized that TMA/TMAO could directly change the vascular tone. Perivascular adipose tissue (PVAT) helps to regulate vascular homeostasis and may also possess FMO3. Thoracic aorta with(+) or without(-) PVAT, also + or - the endothelium (E), of male Sprague Dawley rats were isolated for measurement of isometric tone in response to TMA/TMAO (1nM-0.5 M). Immunohistochemistry (IHC) studies were done to identify the presence of FMO3. TMA and TMAO elicited concentration-dependent arterial contraction. However, at a maximally achievable concentration (0.2 M), contraction stimulated by TMA was of a greater magnitude (141.5 ± 16% of maximum phenylephrine contraction) than that elicited by TMAO (19.1 ± 4.03%) with PVAT and endothelium intact. When PVAT was preserved, TMAO-induced contraction was extensively reduced the presence (19.1 ± 4.03%) versus absence of E (147.2 ± 20.5%), indicating that the endothelium plays a protective role against TMAO-induced contraction. FMO3 enzyme was present in aortic PVAT, but the FMO3 inhibitor methimazole did not affect contraction stimulated by TMA in aorta + PVAT. However, the l-type calcium channel blocker nifedipine reduced TMA-induced contraction by ∼50% compared to the vehicle. Though a high concentration of these compounds was needed to achieve contraction, the findings that TMA-induced contraction was independent of PVAT and E and mediated by nifedipine-sensitive calcium channels suggest metabolite-induced contraction may be physiologically important.

Students' perception of animal or virtual laboratory in physiology practical classes in PBL medical hybrid curriculum.

Over the years, much criticism against animal use for physiology teaching has been made. Hence, replacement by suitable alternatives has increased in several pedagogical approaches. This study examined students' perceptions of animal versus virtual (video/computer) laboratory classes in physiological sciences associated with the effectiveness of the problem-based learning (PBL) hybrid curriculum. Three cohorts of medical students from the University of Ribeirão Preto, who participated in animal or virtual physiology classes or both, were asked to fill out a 5-point Likert questionnaire about knowledge acquisition/motivation, importance to PBL learning goals, skills acquired, need for animal use, academic formation, learning impairment, and alternative methods. We also assessed their grades in the final exam. A total of 350 students were included, in which 108 participated only in virtual classes, 120 only in practical animal laboratory classes, and 122 in both approaches. The majority agreed that the two methods improved their knowledge acquisition/motivation and helped to reinforce tutorial goals and to acquire skills. However, the cohort who experienced both approaches favored animal laboratory. Students believe animal use is needed and did not impair their learning. Conversely, their opinion about academic formation without animal laboratory classes was divided, as was whether this approach inspired them to seek alternative methods. Despite the different perceptions, there was no difference among the groups' final grades (7.3 ± 1 vs. 7.2 ± 1 vs. 7.2 ± 2 for virtual or practical animal laboratory classes or both, respectively). Therefore, virtual activities are not as effective as animal use in the opinions of the students, but they are successful strategies in physiology learning that can be used in practical classes in a hybrid PBL curriculum.

Counter-regulatory effects played by the ACE - Ang II - AT1 and ACE2 - Ang-(1-7) - Mas axes on the reactive oxygen species-mediated control of vascular function: perspectives to pharmacological approaches in controlling vascular complications.

The Renin-Angiotensin system plays an important role in the regulation of systemic blood pressure as well as in fluid and electrolyte balance. It is divided into two described axes, the ACE - Ang II - AT1 receptor, with Ang II as the main mediator, and the ACE2 - Ang-(1-7) - Mas receptor, with Ang-(1-7) responsible for the main effects. The main vascular effect induced by Ang II is contraction, while Ang-(1-7) includes relaxation in several vascular beds. Ang II also activates several cytokines that are important in the genesis of vascular inflammation and hypertrophy. In this context, Ang-(1-7) seems to have a protective role. Both AT1 and Mas receptors modulate, in different ways, the generation of, which are involved in the control of vascular tone and the genesis of vascular dysfunction triggered by several diseases, including diabetes mellitus, arterial hypertension and atherosclerosis. Thereby, this review presents an overview of the modulation played by the whole Renin-Angiotensin system on the reactive oxygen species-mediated control of vascular tone and the oxidative stress-elicited vascular dysfunction.

The Effect of Tranexamic Acid With or Without Tourniquet on Blood Loss in Total Knee Arthroplasty at a Community Hospital.

Tourniquets have long been used in total knee arthroplasty due to the theoretical improvement of bleeding control, integration of cement-bone interface, visibility, and efficiency of the overall surgery. However, this has become increasingly disputed. Comparative studies in total knee arthroplasty employing chemical prophylaxis, i.e., tranexamic acid, have been conducted. This retrospective cohort study evaluated the effect of tranexamic with or without a tourniquet on mean blood loss, hemoglobin, and length of stay in total knee arthroplasty patients. A total of 153 patients' records met the inclusion criteria, 95 patients (62%) were in the tranexamic acid-only group while 58 patients (38%) were in the tranexamic acid plus tourniquet group. Based on mean blood loss in mL (827.5 without vs. 810.1 with the tourniquet, p=0.805), hemoglobin counts in g/dL (12.6 without vs. 12.5 with the tourniquet, p=0.598), and length of stay in days (1.0 days without vs. 1.1 with the tourniquet, p=0.204), there was no statistical difference between the tranexamic alone vs. tranexamic plus tourniquet groups. There were no statistical differences in the mean BMI between groups (32.3 without vs. 32.4 with tourniquets, p=0.901). The patient population had more women (64.1%) than men (35.9%) (p=0.001), but no significant difference in gender based on tourniquet use (p=0.521). The tourniquet group averaged three years younger than the tranexamic alone group (age mean 68.2 without vs 65.3 with tranexamic, p=0.029). This study found no identifiable difference in the three observed variables, indicating that tourniquet provides limited to no additional benefit in reducing blood loss over tranexamic alone in total knee arthroplasty, while tranexamic alone has no deleterious decrease in mean hemoglobin or increase in length of stay.

Striae distensae as a diagnostic indicator for eating disorder pathologies.

OBJECTIVE: This manuscript provides a review of the relationship between patients with an underlying eating disorder (ED) and the presence of striae distensae (SD). Researchers and clinicians have recognized many different skin manifestations associated with EDs. According to the Diagnostic and Statistical Manual of Mental Disorders, EDs include, but are not limited to, anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED). The presence of specific skin findings often helps clinicians conclude whether or not a patient may have an underlying ED and require further evaluation. One skin finding associated with an ED with little current literature focus is SD. SD arises from a combination of hormonal imbalances and stretching of the dermis, triggering a local inflammatory response. The presence of SD leaves patients with diminished quality of life. There is no single guideline treatment for SD; however, topical and/or light and laser therapies can be utilized. METHOD: Using online medical literature databases and the PRISMA guidelines, 11 out of 574 articles met the acceptable criteria to be analyzed, emphasizing the lack of current literature on this subject. RESULTS: Anxiety and depression were comorbidities demonstrated to be strongly related to AN and obesity, secondary to BED, in patients who developed SD. Higher degrees of suicidal ideation and insomnia, along with lower self-esteem levels, were more likely to be present in these patients. CONCLUSION: Altogether, this review highlights the importance of continued evaluation of SD and its overall impact on patient's mental health, emphasizing an underlying ED.

Impact of COVID-19 on Medical Education: A Narrative Review of Reports from Selected Countries.

The COVID-19 pandemic presented unprecedented challenges to medical training worldwide. Many studies examining barriers, such as student safety concerns and technological issues for adaptability to a virtual learning mode, were conducted during social distancing and described the pandemic's impact on medical education. This narrative sought to review how medical schools adapted to the pandemic and to provide a unique analysis of the challenges faced in delivering medical curricula worldwide. A search of the medical education literature yielded articles describing methods employed by medical colleges from locations worldwide. All articles that met search parameters were archived on PubMed. Of 109 manuscripts, 12 describe strategies adopted by 10 countries. They support the discussion of teaching and learning at the pre-clerkship and clerkship levels during the COVID-19 pandemic. Online learning became the method adopted by medical schools worldwide to address hurdles during the pandemic. Access to technology, the internet, and appropriate infrastructure, resulted in solid indicators of medical education success. From the student's perspective, the most significant advantage of this strategy was flexibility. The compiled reports are representative approaches used during the pandemic and may serve as guidelines for medical colleges when strategic change is needed during pre-clerkship and clerkship education. Strategies based on information technology proved successful; however, more equitable access is necessary. It is crucial to consider the complexities of syndemic conditions when adjusting the curriculum in challenging situations such as a pandemic.

Identifying the core concepts of pharmacology education: A global initiative.

BACKGROUND AND PURPOSE: In recent decades, a focus on the most critical and fundamental concepts has proven highly advantageous to students and educators in many science disciplines. Pharmacology, unlike microbiology, biochemistry, or physiology, lacks a consensus list of such core concepts. EXPERIMENTAL APPROACH: We sought to develop a research-based, globally relevant list of core concepts that all students completing a foundational pharmacology course should master. This two-part project consisted of exploratory and refinement phases. The exploratory phase involved empirical data mining of the introductory sections of five key textbooks, in parallel with an online survey of over 200 pharmacology educators from 17 countries across six continents. The refinement phase involved three Delphi rounds involving 24 experts from 15 countries across six continents. KEY RESULTS: The exploratory phase resulted in a consolidated list of 74 candidate core concepts. In the refinement phase, the expert group produced a consensus list of 25 core concepts of pharmacology. CONCLUSION AND IMPLICATIONS: This list will allow pharmacology educators everywhere to focus their efforts on the conceptual knowledge perceived to matter most by experts within the discipline. Next steps for this project include defining and unpacking each core concept and developing resources to help pharmacology educators globally teach and assess these concepts within their educational contexts.

Assessing Root Causes of First Case On-time Start (FCOTS) Delay in the Orthopedic Department at a Busy Level II Community Teaching Hospital.

INTRODUCTION: Due to the high cost of operating room time, hospitals have been under increasing pressure to optimize operating room (OR) efficiency. One parameter that has been used to predict OR efficiency is First Case On-Time Start (FCOTS). In this brief report, the authors describe results from a quality improvement project designed to identify the rates and primary causes of first case delay for elective procedures within the orthopedic department at their suburban community hospital. METHODS: This was a retrospective, quality improvement project. The authors reviewed information from their anesthesia group to identify the rate and causes for delayed FCOTS, as well as observations and employee interviews to map contributing factors of delay. RESULTS: Surgery data on 159 days reviewed indicated that 107 (67.3%) days had first case delays. Of the 398 total first cases during this period, 156 (39.2%) were found to be delayed. The authors identified surgeon practices, with 74 (56.5%) as the main contributor to delay, followed by pre-operative processes, with 24 (18.3%), and room-related causes, 17 (13.0%). The anesthesia department and the patient were minor causes of delay, with 9 (6.9%) and 7 (5.3%) of case delays respectively. DISCUSSION: Results were similar to other studies, indicating surgeons and pre-operative as main cause for delay. A fishbone diagram revealed patient factors, inefficiency in the pre-operative process, and staff tardiness as some of the causes. CONCLUSIONS: During this project, surgeon practices and preoperative processes were the main factors contributing to OR inefficiency within the community-based hospital. Future strategies to improve daily OR flow within similar institutions should target surgeon on-time arrival and streamlining of the pre-operative process to effectively reduce FCOTS delays.

Breast Cancer Therapeutics and Biomarkers: Past, Present, and Future Approaches.

Breast cancer (BC) is the leading cause of cancer death in women and the second-most common cancer. An estimated 281 550 new cases of invasive BC will be diagnosed in women in the United States, and about 43 600 will die during 2021. Continual research has shed light on all disease areas, including tumor classification and biomarkers for diagnosis/prognosis. As research investigations evolve, new classes of drugs are emerging with potential benefits in BC treatment that are covered in this manuscript. The initial sections present updated classification and terminology used for diagnosis and prognosis, which leads to the following topics, discussing the past and present treatments available for BC. Our review will generate interest in exploring the complexity of the cell cycle and its association with cancer biology as part of the plethora of target factors toward developing newer drugs and effective therapeutic management of BC.

Red flags for the differential diagnosis of granulomatous mastitis: a case report.

BACKGROUND: Granulomatous mastitis (GM) is a rare benign chronic inflammatory breast disease. GM presents as a heterogeneous illness with variable clinical presentations, and its diagnosis is usually made by exclusion. There are no guidelines for the treatment of GM. This manuscript describes the management of a patient with GM, initially unsuccessfully treated outside our clinic under a diagnosis of mastitis. The patient's history, physical examination, and needle biopsy flagged the patient's findings as nonmalignant; however, imaging studies indicated a tumor. Differential diagnosis became a critical element of her care. This case report represents a valuable resource to foster more assertive clinical practice in managing patients with GM. The case coordination and its course were led by a team from an outreach clinic that provides health care services to underserved communities in the state of Michigan. CASE PRESENTATION: A 41-year-old G1P1 Hispanic female immigrant from Central America presented with a rare breast disease, granulomatous mastitis. A similar presentation occurred 5 years before pregnancy when she had an episode of pain and swelling in the left breast, which resolved spontaneously. She sought our services after being diagnosed with mastitis that was unsuccessfully treated. Physical examination revealed a nodular mass in the outer quadrants of the left breast without regional lymphadenopathy. Needle biopsy showed fibrohistiocytic and florid inflammatory reactions, with no evidence of invasive carcinoma. However, this result was inconsistent with the degree of abnormality revealed by the mammogram (BI-RADS grade 5), ultrasound, and physical examination. Full incisional biopsy revealed cystic neutrophilic GM. The surgical procedure, antibiotics, and corticosteroids resulted in a successful combination to secure the stable control of the symptoms and progression of this rare benign breast disease to date. CONCLUSIONS: This patient's case highlights the importance of integrated communication among front-line primary care and other health care professionals to reduce the risk of invasive procedures and avoid institutional costs. GM is a rare disease. We raised the manifold red flags in which the multiple professional chains recruited to care for this patient were concerning for advanced breast cancer. The lack of experience and evidence-based medicine contributed to the contradictory interpretation of the findings on GM's diagnosis.

Abnormalities in electrocardiographic ventricular repolarization in patients with dengue virus infection.

INTRODUCTION: Dengue virus infection (DENV) is an arboviral disease that affects millions of people in many countries throughout the world every year. The disease is caused by the bite of a mosquito (Aedes aegypti and / or Aedes albopictus). The symptoms/signs observed in this arboviral disease are unspecific, and the blood count usually shows leukopenia and thrombocytopenia. Although ECG changes may be observed in DENV, little is known about parameters of ventricular repolarization in patients with this condition. Accordingly, the aim of this study was to evaluate the QTc and QT interval dispersion to detect ventricular repolarization changes in patients with DENV. METHODOLOGY: Ninety-three consecutive patients seen during DENV epidemics in a small town with non-complicated DENV were included; 93 normal individuals served as controls. Clinical data, blood count and the 12-lead ECG were obtained from each individual. RESULTS: The QTc duration was higher in patients with DENV in comparison to controls. Furthermore, 5% of DENV patients had abnormal lengthening of the QTc interval. No difference regarding QT interval dispersion was observed between DENV patients and controls. No DENV patient had increased lengthening of the QT interval dispersion. CONCLUSIONS: Myocardial repolarization changes do occur in patients with DENV. Having into account the potential impact of these changes on patients' outcome, and because 12-lead ECG is not routinely recommended in the setting of DENV in our country, we recommend that a 12-lead ECG be taken from each patient with this condition during DENV epidemics.

Formative assessment scores in tutorial sessions correlates with OSCE and progress testing scores in a PBL medical curriculum.

BACKGROUND: Effective assessments programs are a challenge in problem-based learning (PBL). One of the main principles of this educational setting is the Formative Assessment (FA). We hypothesized that students' performance assessed by FA in tutorial sessions in a PBL curriculum is related to other summative assessments. OBJECTIVE: To investigate the correlation among FA in tutorial sessions with grades obtained in Objective Structured Clinical Evaluation (OSCE) and Progress Testing (PT) to better understand the assessment process in PBL medical teaching approach and to predict student's future performance. DESIGN: An observational cross-sectional study was conducted comparing FA, OSCE and PT scores from 4th to 8th semester medical students. Correlation analyses were performed using pooled and separate data from the 4th and 8th semesters. RESULTS: From the 5th to 8th semester, OSCE scores were smaller compared to the FA, while PT scores were lower in all stages. In the pooled data, the correlation analysis showed a significant positive relationship between grades on FA and OSCE, FA and PT and OSCE and PT. A significant correlation among the three assessments strategies was also detected in the 8th semester, but not in the 4th semester. CONCLUSIONS: Assessment strategies in PBL approach, including FA, OSCE and PT, have positive correlations, which increases as the medical course becomes more complex.

Renal perivascular adipose tissue: Form and function.

Renal sympathetic activity affects blood pressure in part by increasing renovascular resistance via release of norepinephrine (NE) from sympathetic nerves onto renal arteries. Here we test the idea that adipose tissue adjacent to renal blood vessels, i.e. renal perivascular adipose tissue (RPVAT), contains a pool of NE which can be released to alter renal vascular function. RPVAT was obtained from around the main renal artery/vein of the male Sprague Dawley rats. Thoracic aortic PVAT and mesenteric PVAT also were studied as brown-like and white fat comparators respectively. RPVAT was identified as a mix of white and brown adipocytes, because of expression of both brown-like (e.g. uncoupling protein 1) and white adipogenic genes. All PVATs contained NE (ng/g tissue, RPVAT:524 ±â€¯68, TAPVAT:740 ±â€¯16, MPVAT:96 ±â€¯24). NE was visualized specifically in RPVAT adipocytes by immunohistochemistry. The presence of RPVAT (+RPVAT) did not alter the response of isolated renal arteries to NE compared to responses of arteries without RPVAT (-RPVAT). By contrast, the maximum contraction to the sympathomimetic tyramine was ~2× greater in the renal artery +PVAT versus -PVAT. Tyramine-induced contraction in +RPVAT renal arteries was reduced by the α1-adrenoceptor antagonist prazosin and the NE transporter inhibitor nisoxetine. These results suggest that tyramine caused release of NE from RPVAT. Renal denervation significantly (>50%) reduced NE content of RPVAT but did not modify tyramine-induced contraction of +RPVAT renal arteries. Collectively, these data support the existence of a releasable pool of NE in RPVAT that is independent of renal sympathetic innervation and has the potential to change renal arterial function.

Nitric Oxide and Related Aspects Underlying Angina.

Increased number of patients affected by metabolic syndrome (MS) has prompted the necessity of better understanding what is involved in such syndrome. Nevertheless, the establishment of promising therapies depends on the knowledge about the interaction of molecules within MS. In such context, Nitric Oxide (NO) emerges from a bulk of works relating its roles on aspects of MS, including cardiovascular diseases, their symptoms and comorbidities, which are thought to be triggered by similar sources. NO, nitric oxide synthase and enzymatic chains are keys for those disease and symptoms processes. NO has been separately described as part of hypertensive, ischemic and pain signaling. Although there are similar pathways likely shared for generating cardiovascular symptoms such angina, they are barely associated to NO in literature. The present review aims to clarify the patterns of NO alteration in metabolic syndrome directly concerned to cardiovascular symptoms, especially angina.