Research Goes Red: Early Experience With a Participant-Centric Registry.

RATIONALE: Cardiovascular disease remains the leading cause of death in women. To address its determinants including persisting cardiovascular risk factors amplified by sex and race inequities, novel personalized approaches are needed grounded in the engagement of participants in research and prevention. OBJECTIVE: To report on a participant-centric and personalized dynamic registry designed to address persistent gaps in understanding and managing cardiovascular disease in women. METHODS AND RESULTS: The American Heart Association and Verily launched the Research Goes Red registry (RGR) in 2019, as an online research platform available to consenting individuals over the age of 18 years in the United States. RGR aims to bring participants and researchers together to expand knowledge by collecting data and providing an open-source longitudinal dynamic registry for conducting research studies. As of July 2021, 15 350 individuals have engaged with RGR. Mean age of participants was 48.0 48.0±0.2 years with a majority identifying as female and either non-Hispanic White (75.7%) or Black (10.5%). In addition to 6 targeted health surveys, RGR has deployed 2 American Heart Association-sponsored prospective clinical studies based on participants' areas of interest. The first study focuses on perimenopausal weight gain, developed in response to a health concerns survey. The second study is designed to test the use of social media campaigns to increase awareness and participation in cardiovascular disease research among underrepresented millennial women. CONCLUSIONS: RGR is a novel online participant-centric platform that has successfully engaged women and provided critical data on women's heart health to guide research. Priorities for the growth of RGR are centered on increasing reach and diversity of participants, and engaging researchers to work within their communities to leverage the platform to address knowledge gaps and improve women's health.

Managing Ischemic Heart Disease in Women: Role of a Women's Heart Center.

PURPOSE OF REVIEW: Heart centers for women (HCW) were developed due to the rising cardiovascular morbidity and mortality in women in the United States in the early 1990s. Our review encompasses the epidemiology, risk factors, diagnostic strategies, treatments, and the role of HCW in managing women with ischemic heart disease (IHD). RECENT FINDINGS: HCW use a multidisciplinary team to manage women with IHD. Due to the paucity of randomized controlled trials investigating various manifestations of IHD, some treatments are not evidence-based such as those for coronary microvascular dysfunction and spontaneous coronary artery dissection. Sex-specific risk factors have been identified and multimodality cardiac imaging is improving in diagnosing IHD in women. Treatments are being studied to help improve symptoms and outcomes in women with IHD. There has been progress in the care of women with IHD. HCW can be instrumental in treating women with IHD, doing research, and being a source of research study participants.

Atherosclerotic Cardiovascular Disease in South Asians in the United States: Epidemiology, Risk Factors, and Treatments: A Scientific Statement From the American Heart Association.

South Asians (from Bangladesh, Bhutan, India, the Maldives, Nepal, Pakistan, and Sri Lanka) make up one quarter of the world's population and are one of the fastest-growing ethnic groups in the United States. Although native South Asians share genetic and cultural risk factors with South Asians abroad, South Asians in the United States can differ in socioeconomic status, education, healthcare behaviors, attitudes, and health insurance, which can affect their risk and the treatment and outcomes of atherosclerotic cardiovascular disease (ASCVD). South Asians have higher proportional mortality rates from ASCVD compared with other Asian groups and non-Hispanic whites, in contrast to the finding that Asian Americans (Asian Indian, Chinese, Filipino, Japanese, Korean, and Vietnamese) aggregated as a group are at lower risk of ASCVD, largely because of the lower risk observed in East Asian populations. Literature relevant to South Asian populations regarding demographics and risk factors, health behaviors, and interventions, including physical activity, diet, medications, and community strategies, is summarized. The evidence to date is that the biology of ASCVD is complex but is no different in South Asians than in any other racial/ethnic group. A majority of the risk in South Asians can be explained by the increased prevalence of known risk factors, especially those related to insulin resistance, and no unique risk factors in this population have been found. This scientific statement focuses on how ASCVD risk factors affect the South Asian population in order to make recommendations for clinical strategies to reduce disease and for directions for future research to reduce ASCVD in this population.

Hypertensive Disorders of Pregnancy.

PURPOSE OF REVIEW: Although pregnancy-related deaths are rare in the USA, they are on the rise and have more than doubled in the last 20 years. A substantial portion of these deaths are related to cardiovascular disease, specifically hypertensive disorders of pregnancy (HDP). In this review, we will discuss the definitions and proposed pathophysiology of HDP as well as its potential role in cardiovascular morbidity and mortality. RECENT FINDINGS: Placental hypoperfusion may lead to an imbalance in proangiogenic and antiangiogenic factors, notably an increase in soluble fms-like tyrosine kinsase-1 (sFlt-1), thereby leading to endothelial dysfunction. Progress has been made in terms of determining the factors which lead to preeclampsia. Potential novel biomarkers for predicting preeclampsia risk have been identified through this research. Preeclampsia not only has important implications for the health during pregnancy but also for future cardiovascular risk. However, the exact mechanism by which it increases cardiovascular risk and the degree of risk it portends are yet to be elucidated.

Reproductive Experiences and Cardiovascular Disease Care in Pregnancy-Capable and Postmenopausal Individuals: Insights From the American Heart Association Research Goes Red Registry.

To evaluate preconception health and adverse pregnancy outcome (APO) awareness in a large population-based registry. We examined data from the Fertility and Pregnancy Survey of the American Heart Association Research Goes Red Registry to questions regarding prenatal health care experiences, postpartum health, and awareness of the association of APOs with cardiovascular disease (CVD) risk. Among postmenopausal individuals, 37% were unaware that APOs were associated with long-term CVD risk, significantly varying by race-ethnicity. Fifty-nine percent of participants were not educated regarding this association by their providers, and 37% reported providers not assessing pregnancy history during current visits, significantly varying by race-ethnicity, income, and access to care. Only 37.1% of respondents were aware that CVD was the leading cause of maternal mortality. There is an urgent, ongoing need for more education on APOs and CVD risk, to improve the health-care experiences and postpartum health outcomes of pregnant individuals.

Reproductive Experiences and Cardiovascular Disease Care in Pregnancy Capable and Post-Menopausal Individuals: Insights from the American Heart Association Research Goes Red Registry.

Background: Information on reproductive experiences and awareness of adverse pregnancy outcomes (APOs) and cardiovascular disease (CVD) risk among pregnancy-capable and post-menopausal individuals has not been well described. We sought to evaluate preconception health and APO awareness in a large population-based registry. Methods: Data from the Fertility and Pregnancy Survey of the American Heart Association Research Goes Red Registry (AHA-RGR) were used. Responses to questions pertaining to prenatal health care experiences, postpartum health, and awareness of the association of APOs with CVD risk were used. We summarized responses using proportions for the overall sample and by stratifications, and we tested differences using the Chi-squared test. Results: Of 4,651individuals in the AHA-RGR registry, 3,176 were of reproductive age, and 1,475 were postmenopausal. Among postmenopausal individuals, 37% were unaware that APOs were associated with long-term CVD risk. This varied by different racial/ethnic groups (non-Hispanic White: 38%, non-Hispanic Black: 29%, Asian: 18%, Hispanic: 41%, Other: 46%; P = 0.03). Fifty-nine percent of the participants were not educated regarding the association of APOs with long-term CVD risk by their providers. Thirty percent of the participants reported that their providers did not assess pregnancy history during current visits; this varied by race-ethnicity ( P = 0.02), income ( P = 0.01), and access to care ( P = 0.02). Only 37.1% of the respondents were aware that CVD was the leading cause of maternal mortality. Conclusions: Considerable knowledge gaps exist in the association of APOs with CVD risk, with disparities by race/ethnicity, and most patients are not educated on this association by their health care professionals. There is an urgent and ongoing need for more education on APOs and CVD risk, to improve the health-care experiences and postpartum health outcomes of pregnant individuals.

Adequate enrollment of women in cardiovascular drug trials and the need for sex-specific assessment and reporting.

Cardiovascular disease (CVD) is the leading cause of death for women in the United States and globally. There is an abundance of evidence-based trials evaluating the efficacy of drug therapies to reduce morbidity and mortality in CVD. Additionally, there are well-established influences of sex, through a variety of mechanisms, on pharmacologic treatments in CVD. Despite this, the majority of drug trials are not powered to evaluate sex-specific outcomes, and much of the data that exists is gathered post hoc and through meta-analysis. The FDA established a committee in 1993 to increase the enrollment of women in clinical trials to improve this situation. Several authors, reviewing committees, and professional societies have highlighted the importance of sex-specific analysis and reporting. Despite these statements, there has not been a major improvement in representation or reporting. There are ongoing efforts to assess trial design, female representation on steering committees, and clinical trial processes to improve the representation of women. This review will describe the pharmacologic basis for the need for sex-specific assessment of cardiovascular drug therapies. It will also review the sex-specific reporting of landmark drug trials in hypertension, coronary artery disease (CAD), hyperlipidemia, and heart failure (HF). In reporting enrollment of women, several therapeutic areas like antihypertensives and newer anticoagulation trials fare better than therapeutics for HF and acute coronary syndromes. Further, drug trials and cardiometabolic or lifestyle intervention trials had a higher percentage of female participants than the device or procedural trials.

Association of Neighborhood Income with Clinical Outcomes Among Pregnant Patients with Cardiac Disease.

Cardiovascular disease is the leading cause of pregnancy mortality. Socioeconomic and racial disparities in pregnancy are well established. Despite this, little is known about the impact of social determinants of health in pregnant patients with heart disease. This study aims to determine whether pregnant patients with heart disease living in lower income neighborhoods and managed at cardio-obstetrics programs have higher rates of cardiac events or preterm deliveries compared with those living in higher income neighborhoods. This is a retrospective cohort study of 206 patients between 2010 and 2020 at a quaternary care hospital in Northern California. The exposure was household income level based on neighborhood defined by the US Census data. Patients in lower income neighborhoods (N = 103) were 45% Hispanic, 34% White, and 14% Asian versus upper income neighborhoods (N = 103), which were 48% White, 31% Asian, and 12% Hispanic (p < 0.001). There was no significant difference in the rates of intrapartum cardiac events (10% vs. 4%; p = 0.16), postpartum cardiac events (14% vs. 17%; p = 0.7), and preterm delivery (24% vs. 17%; p = 0.23). The rates of antepartum hospitalization were higher for lower income neighborhoods (42% vs 22%; p = 0.004). While there is no significant difference in cardiac events and preterm delivery rates between patients from low versus high income neighborhoods, patients from lower income neighborhoods have higher antepartum hospitalization rates. Earlier identification of clinical deterioration provided by a cardio-obstetrics team may contribute to increased hospitalizations, which might mitigate socioeconomic disparities in outcomes for these pregnant patients with heart disease.

Clinical factors associated with a positive postpartum depression screen in people with cardiac disease during pregnancy.

Background: While people with cardiac disease are known to be at increased lifetime risk of depression, little is known about postpartum depression rates in this population. Describing rates of positive postpartum depression screens and identifying risk factors that are unique to cardiac patients may help inform risk reduction strategies. Methods: This retrospective cohort study included pregnant patients with congenital and/or acquired cardiac disease who delivered at a single institution between 2014 and 2020. The primary outcome was a positive postpartum depression screen, defined as Edinburgh Postpartum Depression Score (EPDS) ≥10. Potential exposures were selected a priori and compared between patients with and without a positive postpartum depression screen using Wilcoxon rank-sum and Fisher's exact tests. Secondary outcomes were responses to a longitudinal follow-up survey sent to English-speaking patients evaluating cardiac status, mental health, and infant development. Results: Of 126 eligible cardiac patients, 23 (18.3%) had a positive postpartum depression screen. Patients with a positive postpartum depression screen were more likely to have had antepartum anticoagulation with heparin or enoxaparin (56.5% versus 26.2%, p=0.007), blood transfusion during delivery (8.7% versus 0%, p=0.032), and maternal-infant separation postpartum (52.2% versus 28.2%, p=0.047) compared to patients with a negative screen. Among 29 patients with a positive screen who responded to the follow up survey, 50% reported being formally diagnosed with anxiety or depression and 33.3% reported child development problems. Conclusions: Our results highlight the importance of screening for postpartum depression in patients with cardiac disease, especially those requiring antepartum anticoagulation or maternal-infant separation postpartum.

Addressing postpartum contraception practices utilizing a multidisciplinary Pregnancy Heart Team approach.

BACKGROUND: Cardiovascular disease has emerged as the leading cause of maternal morbidity and mortality, making planned pregnancy, and thereby reliable contraception among people with cardiovascular disease, vital. OBJECTIVE: This study aimed to compare postpartum contraceptive practices among people with cardiovascular disease (cardiac cohort) cared for by a Pregnancy Heart Team to people with other chronic comorbidities (high-risk cohort), and people without comorbidities (low-risk cohort). We hypothesized that the Pregnancy Heart Team influenced baseline contraception counseling and practices among those with cardiovascular disease. STUDY DESIGN: This was a retrospective cohort study comparing postpartum contraceptive practices between a cardiac cohort who received care by a multidisciplinary team between 2012 and 2020 and high-risk and low-risk cohorts delivering at a single academic center between 2016 and 2019. We investigated presence of a contraceptive plan (at birthing admission, discharge, and postpartum visit) and uptake of reliable contraception by 8 weeks postpartum. RESULTS: We included 1464 people: 189 with cardiovascular disease, 197 with other chronic comorbidities, and 1078 low-risk people. At birth hospitalization admission, reliable contraception was planned among 42% of the cardiac cohort, 40% of the high-risk cohort, and 31% of the low-risk cohort, with similar distributions at the time of discharge and at 8 weeks postpartum. Compared with the cardiac cohort, by 8 weeks postpartum, the high-risk cohort had similar odds of using highly reliable forms of contraception (39% vs 36%; adjusted odds ratio, 0.78; 95% confidence interval, 0.50-1.21) and similar odds of having a plan to use the most reliable forms of contraception (intrauterine device, implant, bilateral tubal ligation) at the time of birthing admission (42% vs 40%; adjusted odds ratio, 0.78; 95% confidence interval, 0.50-1.22), discharge (47% vs 45%; adjusted odds ratio, 0.95; 95% confidence interval, 0.61-1.48), and postpartum visit (35% vs 29%; adjusted odds ratio, 0.76; 95% confidence interval, 0.49-1.17). The low-risk cohort had lower odds of using a reliable form of contraception (39% vs 27%; adjusted odds ratio, 0.53; 95% confidence interval, 0.37-0.75) and was less likely to have a plan for reliable contraception at the time of birthing admission (42% vs 31%; adjusted odds ratio, 0.54; 95% confidence interval, 0.38-0.76), discharge (47% vs 33%; adjusted odds ratio, 0.58; 95% confidence interval, 0.4-0.82), and postpartum visit (35% vs 21%; adjusted odds ratio, 0.50; 95% confidence interval, 0.35-0.71). CONCLUSION: People with cardiovascular disease cared for by a Pregnancy Heart Team had higher odds of reliable postpartum contraception planning and uptake compared with a low-risk cohort and similar odds compared with a high-risk cohort. Pregnancy could serve as a critical period for contraception counseling and family planning among people with cardiovascular disease. A multidisciplinary team should be used to address postpartum contraception as a modifiable risk factor to reduce maternal morbidity and mortality among those with cardiovascular disease.

Development and validation of a risk prediction index for severe maternal morbidity based on preconception comorbidities among infertile patients.

OBJECTIVE: To develop and validate a preconception risk prediction index for severe maternal morbidity (SMM), defined by the Centers for Disease Control and Prevention as indicators of a life-threatening complication, among infertile patients. DESIGN: Retrospective analysis of live births and stillbirths from 2007 to 2017 among infertile women. SETTING: National commercial claims database. PATIENT(S): Infertile women identified on the basis of diagnosis, testing, or treatment codes. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The primary outcome was SMM, identified as any indicator from the Centers for Disease Control and Prevention Index except blood transfusion alone, which was found to overestimate cases. Twenty preconception comorbidities associated with a risk of SMM were selected from prior literature. Targeted ensemble learning methods were used to rank the importance of comorbidities as potential risk factors for SMM. The independent strength of the association between each comorbidity and SMM was then used to define each comorbidity's risk score. RESULT(S): Among 94,097 infertile women with a delivery, 2.3% (n = 2,181) experienced an SMM event. The highest risk of SMM was conferred by pulmonary hypertension, hematologic disorders, renal disease, and cardiac disease. Associated significant risks were lowest for substance abuse disorders, prior cesarean section, age ≥40 years, gastrointestinal disease, anemia, mental health disorders, and asthma. The receiver operating characteristic area under the curve for the developed comorbidity score was 0.66. Calibration plots showed good concordance between the predicted and actual risk of SMM. CONCLUSION(S): We developed and validated an index to predict the probability of SMM on the basis of preconception comorbidities in patients with infertility. This tool may inform preconception counseling of infertile women and support maternal health research initiatives.

Effect of ranolazine on symptom and quality of life in patients with angina in the absence of obstructive coronary artery disease: A case control study.

BACKGROUND: More than 20% of patients presenting to the catheterization lab have no significant obstructive coronary artery disease (CAD) despite having angina. Several occult coronary abnormalities, including endothelial dysfunction, microvascular dysfunction (MVD), and/or a myocardial bridge (MB), may explain their symptoms. We studied the effect of ranolazine on symptoms and quality of life (QOL) in these patients. METHODS: We retrospectively studied 53 patients prescribed with ranolazine, matched on sex and age, with 106 patients on standard of care who underwent comprehensive invasive testing. Endothelial dysfunction was defined as a decrease in luminal diameter of >20% after intracoronary acetylcholine, MVD as an index of microvascular resistance ≥25, and a MB as an echolucent half-moon sign and/or ≥10% systolic compression on intravascular ultrasound. A Seattle Angina Questionnaire (SAQ) and SF-12 questionnaire were completed at baseline and follow-up. RESULTS: Median follow-up was 1.9 (1.7-2.2) years. Endothelial dysfunction was present in 109 (69%), MVD in 36 (23%), and an MB in 86 (54%). Both groups had significant improvement in all dimensions of the SF-12 and SAQ with the exception of treatment satisfaction. We found no significant difference in change in SAQ and SF-12 scores between the groups, although the ranolazine group had significantly lower baseline SAQ scores. CONCLUSION: In patients with angina and no obstructive CAD, ranolazine is no different than standard of care in symptomatic and QOL improvement. Further randomized trials are warrented to confirm our findings and identify novel medical therapies in this patient population.

Bicuspid Aortic Valve and Ascending Aortic Aneurysm in a Twin Pregnancy.

Bicuspid aortic valve with ascending aortic aneurysm is a common condition encountered in pregnancy. There are limited data on how to manage these patients. To our knowledge, we report the only case of a bicuspid aortic valve and aortic aneurysm with twin gestations. (Level of Difficulty: Intermediate.).

Physcomitrella patens: mosses enter the genomic age.

The sequenced genome of the moss Physcomitrella patens provides a powerful tool for comparative analyses of land plant genomes. In parallel, several tools for studying gene function have been developed in P. patens, including RNA interference, inducible promoters and gene targeting, a unique attribute of this plant system. The results of these initiatives are now being realized. For example, transcriptomic analyses illustrate commonalities among plant lineages in gene content, structure, and regulation. Transgenic studies show that the regulatory factors ABSCISIC ACID INSENSITIVE3 (ABI3) and LEAFY (LFY) have molecular functions that are conserved between moss and angiosperms, in spite of the fact that they function in non-homologous tissues. Future work in P. patens will contribute to our understanding of the molecular basis of plant development and evolution.

Psychological Distress Among Female Cardiac Patients Presenting to a Women's Heart Health Clinic.

Female cardiac patients are at greater risk for mental health disorders than their male counterparts, and these mental health disorders have been associated with increased cardiac morbidity and mortality. However, few studies have closely examined the mental health disorders found among the female cardiac population. The primary aim of this study was to examine the prevalence of psychological distress in a sample of female cardiac outpatients at an academic medical center. A secondary aim was to determine whether different demographic variables, cardiac risk factors, or cardiac diagnoses were associated with different levels of emotional distress. A survey, including demographic information, medical status, and standardized symptom measures was completed by 117 female patients scheduled for medical visits at an outpatient women's heart health clinic over a 4-month period. Using standardized self-report questionnaires, 38% scored in the moderate-to-severe range for at least 1 mental disorder and 50% endorsed current insomnia. Symptoms of clinical depression (20%) and anxiety (42)% were endorsed at higher rates than predominantly male or mixed comparison samples. Although there was no apparent relation between the severity of cardiac problems and the degree of psychological distress, women with diagnoses of hyperlipidemia, prediabetes, and diabetes reported greater psychological distress than those without these problems. Women with lower income also reported more psychological distress. In conclusion, our findings suggest an unmet need for integrated mental health services for female cardiac patients.

Incidence of atrial fibrillation following transcatheter closure of atrial septal defects in adults.

Transcatheter closure of secundum atrial septal defect (ASD) and patent foramen ovale (PFO) has become a routine procedure. Little is known about the effect of atrial septal device implantation on the occurrence of atrial fibrillation (AF). We evaluated the frequency of AF occurring after transcatheter PFO and ASD closure in a large population. From 1994 until 2007 a total of 1,062 patients underwent transcatheter closure of an interatrial communication. New-onset AF was defined by 12-lead electrocardiogram or Holter monitoring in patients without a history of AF at baseline. Of the 1,062 patients, 822 had a PFO and 240 had an ASD. During a median follow up of 20 months, new-onset AF was documented in 8% of patients. New-onset AF occurred in 7% of patients after PFO closure and in 12% of patients with underlying ASD. The annual incidence of new-onset AF was 2.5% and 4.1% in patients with PFO and ASD, respectively. Generally, patients with new-onset AF were older than those without AF. Device type or size did not influence the occurrence of AF. In the group of patients with PFO, residual shunt was more common in patients with AF compared with the non-AF group. In conclusion, AF is more common after PFO and ASD closure compared with the general population; although device type or size did not impact the occurrence of AF, residual shunt may influence the occurrence of AF after intervention in patients with underlying PFO.

Recurrent events following patent foramen ovale closure in patients above 55 years of age with presumed paradoxical embolism.

OBJECTIVES: The aim of this article is to summarize our experience of patent foramen ovale (PFO) closure in patients above the age of 55 years. BACKGROUND: PFO is associated with cryptogenic thromboembolic events (TEs) in patients younger than 55 years. Little is known about the recurrence rate of TE in patients above the age of 55 years undergoing PFO closure for presumed paradoxical embolism. METHODS: PFO closure was performed in 1,055 patients, 423 of whom were above 55 years of age. Implantation of the device was guided by fluoroscopy and transesophageal or intracardiac echocardiography. RESULTS: A PFO occluding device was implanted successfully in all patients. Residual shunt was documented in 10% of patients above 55 years of age and in 8.4% of patients aged 55 years or younger (P = 0.325). During a median follow-up period of 18 months (range, 0-162 months) the annual incidence of recurrent TE in patients above 55 years was 1.8% while patients aged 55 or below had an annual incidence of recurrent TE of 1.3%. TE-free survival was similar in patients above 55 years of age compared with those aged 55 years and below. CONCLUSIONS: PFO closure in older patients is as efficient and seems comparable to those under the age of 55. Although traditional cardiovascular risk factors may be more frequent in the older age group compared with those younger than 55 years, PFO closure should not be withheld as a possible therapeutic option in this age group.

Percutaneous mechanical thrombectomy for massive pulmonary embolism using a conservative treatment strategy.

INTRODUCTION: Percutaneous mechanical thrombectomy (PMT) for treatment of massive pulmonary embolism (PE) has been shown to be technically feasible, although the complication rate of the procedure appears relatively high. Whether a conservative treatment approach defined by an early termination of the PMT procedure once hemodynamic and clinical parameters of the patient have improved is associated with lower complication rates is unknown. We report our experience of PMT in patients with massive PE using the Angiojet system following a conservative treatment strategy. METHODS: From April 2003 until November 2007, 13 patients underwent PMT with the Angiojet system. Indications for PMT were massive PE and either failed thrombolysis or contraindications to thrombolytic therapy. All patients were deemed high risk for surgical thrombectomy. RESULTS: Technical success was achieved in 12 patients (92%). Mean systemic arterial pressure increased from 87 to 106 mmHg following PMT (P = 0.011), while the heart rate decreased from 119 to 97 beats per minute (P = 0.041). In-hospital mortality was 15% (2 of 13 patients). No complications occurred which were attributable to the PMT procedure. Right ventricular size and function improved in the majority of patients following the PMT procedure. CONCLUSION: Using a conservative treatment approach of PMT for the treatment of massive PE carries a low periprocedural complication rate. The low morbidity was achieved without compromising clinical outcome, documented by an in-hospital mortality of 15%. PMT using a conservative treatment approach may result in comparable mortality, but lower morbidity than PMT using more aggressive, angiographically guided treatment strategies.