Australian National Standards of Care for Childhood-onset Heart Disease (CoHD Standards). 1st Edition.

These first Australian National Standards of Care for Childhood-onset Heart Disease (CoHD Standards) have been developed to inform the healthcare requirements for CoHD services and enable all Australian patients, families and carers impacted by CoHD (paediatric CoHD and adult congenital heart disease [ACHD]) to live their best and healthiest lives. The CoHD Standards are designed to provide the clarity and certainty required for healthcare services to deliver excellent, comprehensive, inclusive, and equitable CoHD care across Australia for patients, families and carers, and offer an iterative roadmap to the future of these services. The CoHD Standards provide a framework for excellent CoHD care, encompassing key requirements and expectations for whole-of-life, holistic and connected healthcare service delivery. The CoHD Standards should be implemented in health services in conjunction with the National Safety and Quality Health Service Standards developed by the Australian Commission on Safety and Quality in Health Care. All healthcare services should comply with the CoHD Standards, as well as working to their organisation's or jurisdiction's agreed clinical governance framework, to guide the implementation of structures and processes that support safe care.

A Review of Cardiac Surgical Procedures and Their Outcomes for Paediatric Rheumatic Heart Disease in Western Australia.

INTRODUCTION: Surgical intervention is an important treatment modality for advanced rheumatic heart disease (RHD). This study aimed to describe patient characteristics and outcomes from cardiac surgery for RHD in patients referred to the only tertiary paediatric hospital in Western Australia. METHODS: An analysis of patient characteristics and cardiac surgery outcomes in patients with RHD was undertaken, using data from clinical cardiac databases, medical notes, and correspondence from rural outreach clinics. RESULTS: 29 patients (59% female, 97% Aboriginal, Maori or Pacific Islander) underwent 41 valve interventions over 34 cardiac surgeries for RHD between 2000-2018. Median age at first surgery was 12.2 (range 4-16) years. Severe mitral regurgitation (MR) was the most common indication for primary surgery (62%), followed by mixed mitral regurgitation/aortic regurgitation (21%) and severe aortic regurgitation (17%). Mitral valve repair was the most common valve intervention (56%). Two patients had mitral valve replacement (MVR) at first operation, two patients had MVR at second operation and two had MVR at third operation. There was no early mortality. One patient required early (<30 days) reoperation for aortic valve repair failure. Two patients had late reoperations at 3.3 and 6.1 months after the first procedure for MR. Four (14%) patients experienced documented ARF recurrences. Late mortality occurred in 3 (10%) patients, all due to cardiac causes. On last follow-up echocardiogram 5 patients (17%) had moderate MR and none had severe MR. CONCLUSIONS: This is the first study to describe characteristics and outcomes in WA paediatric patients having surgery for RHD. Outcomes are comparable to similar studies, with favourable long-term survival.

Left ventricular remodelling in rheumatic heart disease - trends over time and implications for follow-up in childhood.

BACKGROUND: Rheumatic heart disease (RHD) is the most common form of acquired heart disease worldwide. In RHD, volume loading from mitral regurgitation leads to left ventricular (LV) dilatation, increased wall stress, and ultimately LV dysfunction. Improved understanding of LV dynamics may contribute to refined timing of intervention. We aimed to characterize and compare left ventricular remodelling between rheumatic heart disease (RHD) severity groups by way of serial echocardiographic assessment of volumes and function in children. METHODS: Children with RHD referred to Perth Children's Hospital (formally Princess Margaret Hospital) (1987-2020) were reviewed. Patients with longitudinal pre-operative echocardiograms at diagnosis, approximately 12 months and at most recent follow-up, were included and stratified into RHD severity groups. Left ventricular (LV) echocardiographic parameters were assessed. Adjusted linear mixed effect models were used to compare interval changes. RESULTS: 146 patients (median age 10 years, IQR 6-14 years) with available longitudinal echocardiograms were analysed. Eighty-five (58.2%) patients had mild, 33 (22.6%) moderate and 28 (19.2%) severe RHD at diagnosis. Mean duration of follow-up was 4.6 years from the initial diagnosis. Severe RHD patients had significantly increased end-systolic volumes (ESV) and end-diastolic volumes (EDV) compared to mild/moderate groups at diagnosis (severe versus mild EDV mean difference 27.05 ml/m2, p < 0.001, severe versus moderate EDV mean difference 14.95 ml/m2, p = 0.006). Mild and moderate groups experienced no significant progression of changes in volume measures. In severe RHD, LV dilatation worsened over time. All groups had preserved cardiac function. CONCLUSIONS: In mild and moderate RHD, the lack of progression of valvular regurgitation and ventricular dimensions suggest a stable longer-term course. Significant LV remodelling occurred at baseline in severe RHD with progression of LV dilatation over time. LV function was preserved across all groups. Our findings may guide clinicians in deciding the frequency and timing of follow-up and may be of clinical utility during further reiterations of the Australia and New Zealand RHD Guidelines.

Impact of mitral regurgitation on left ventricular remodeling and function in children with rheumatic heart disease.

The impact of mitral regurgitation (MR) from pediatric rheumatic heart disease (RHD) and its effect on left ventricular (LV) remodeling and function following surgical intervention is uncertain. The objective is to explore the impact of mitral valve (MV) surgeries on myocardial mechanics, remodeling and function and identify pre-operative predictors of post-operative dysfunction which may contribute to the optimal timing of intervention. A retrospective review of echocardiographic data was performed of eighteen pediatric patients with RHD (median 9yrs, IQR 6-12) who underwent MV surgery. Echocardiograms pre-operatively and a median of 13.5 months (IQR 10.2-15) following intervention were compared to controls. Pre-operative LV end-diastolic indexed volumes (LVEDVi) were significantly increased compared to controls and remained persistently larger post-operatively. LV ejection fraction (LVEF) (pre 62.6% ± 6.1, post 51.7% ± 9.7, p = 0.002), and global longitudinal strain (GLS) (pre - 24.3 ± 4.1, post - 18.2 ± 2.6, p < 0.001) decreased post-operatively at mid-term follow-up. Pre-operative LVEDVi was a significant predictor of post-operative LVEF, with a cut-off of ≥ 102 ml/m2 associated with LV dysfunction (LVEF < 55%; sensitivity 70%, specificity 75%). Pre-operative LVEDVi also negatively correlated with GLS (r = - 0.58, p = 0.01). LV dimensions and volumes remain persistently larger than controls while LV function decreases post-surgical alleviation of MR in paediatric RHD. Pre-operative LVEDVi predicted post-operative LV dysfunction and utilising LV indexed volumes in directing timing of surgical planning should be considered. Further studies are required to investigate whether timely alleviation of MR before significant LV dilatation and remodeling occur may substantially prevent LV dysfunction and improve outcomes.

Maternal blood pressure trajectories and associations with gestational age at birth: a functional data analytic approach.

BACKGROUND: Research has revealed group-level differences in maternal blood pressure trajectories across pregnancy. These trajectories are typically constructed using clinical blood pressure data and multivariate statistical methods that are prone to bias and ignore the functional, dynamic process underlying a single blood pressure observation. The aim of this study was to use functional data analysis to explore blood pressure variation across pregnancy, and multivariate methods to examine whether trajectories are related to gestational age at birth. METHODS: Clinical blood pressure observations were available from 370 women who participated in a longitudinal pregnancy cohort study conducted in Montreal, Quebec, Canada. Functional data analysis was used to smooth blood pressure data and then to conduct a functional principal component analysis to examine predominant modes of variation. RESULTS: Three eigenfunctions explained greater than 95% of the total variance in blood pressure. The first accounted for approximately 80% of the variance and was characterized by a prolonged-decrease trajectory in blood pressure; the second explained 10% of the variance and captured a late-increase trajectory; and the third accounted for approximately 7% of the variance and captured a mid-decrease trajectory. The prolonged-decrease trajectory of blood pressure was associated with older, and late-increase with younger gestational age at birth. CONCLUSION: Functional data analysis is a useful method to model repeated maternal blood pressure observations and many other time-related cardiovascular processes. Results add to previous research investigating blood pressure trajectories across pregnancy through identification of additional, potentially clinically important modes of variation that are associated with gestational age at birth.

Intraoperative Management of Adult Patients on Extracorporeal Membrane Oxygenation: an Expert Consensus Statement From the Society of Cardiovascular Anesthesiologists-Part I, Technical Aspects of Extracorporeal Membrane Oxygenation.

Extracorporeal membrane oxygenation (ECMO) is used to support patients with refractory cardiopulmonary failure. Given ECMO's increased use in adults and the fact that many ECMO patients are cared for by anesthesiologists, the Society of Cardiovascular Anesthesiologists ECMO working group created an expert consensus statement that is intended to help anesthesiologists manage adult ECMO patients who are cared for in the operating room. In the first part of this 2-part series, technical aspects of ECMO are discussed, and related expert consensus statements are provided.

Intraoperative Management of Adult Patients on Extracorporeal Membrane Oxygenation: An Expert Consensus Statement From the Society of Cardiovascular Anesthesiologists-Part I, Technical Aspects of Extracorporeal Membrane Oxygenation.

Extracorporeal membrane oxygenation (ECMO) is used to support patients with refractory cardiopulmonary failure. Given ECMO's increased use in adults and the fact that many ECMO patients are cared for by anesthesiologists, the Society of Cardiovascular Anesthesiologists ECMO working group created an expert consensus statement that is intended to help anesthesiologists manage adult ECMO patients who are cared for in the operating room. In the first part of this 2-part series, technical aspects of ECMO are discussed, and related expert consensus statements are provided.

Intraoperative Management of Adult Patients on Extracorporeal Membrane Oxygenation: An Expert Consensus Statement From the Society of Cardiovascular Anesthesiologists-Part II, Intraoperative Management and Troubleshooting.

In the second part of the Society of Cardiovascular Anesthesiologists Extracorporeal Membrane Oxygenation (ECMO) working group expert consensus statement, venoarterial (VA) and venovenous (VV) ECMO management and troubleshooting in the operating room are discussed. Expert consensus statements are provided about intraoperative monitoring, anesthetic drug dosing, and management of intraoperative problems in VA and VV ECMO patients.

Birth prevalence of congenital heart defects in Western Australia, 1990-2016.

AIM: To describe the birth prevalence and characteristics of congenital heart defects in a geographically defined Australian population. METHODS: This descriptive, population-based study examined congenital heart defects in live births, stillbirths and pregnancy terminations ascertained by the Western Australian Register of Developmental Anomalies, 1990-2016. Birth prevalence (per 1000 births) was stratified by severity, known cause, maternal and birth characteristics, and primary diagnosis; and prevalence ratios were calculated for Aboriginal versus non-Aboriginal births. Temporal trends in prevalence, diagnosis age and infant mortality were examined. RESULTS: For births 1990-2010 (allowing 6 years for complete case ascertainment by 2016), 6419 cases were identified; prevalence was 11.5 per 1000 births (95% confidence interval (CI), 11.2-11.8). Severe defects were ascertained in 2.5 per 1000 births (95% CI 2.4-2.7). Most cases were liveborn (5842, 91.0%), and 28.9% had other birth defects. Prevalence was slightly higher in Aboriginal births (prevalence ratio 1.1; 95% CI 1.0-1.2); and the infant mortality rate more than doubled (13.4% vs. 5.8%, P < 0.001). Prenatal diagnosis increased over time but, in remote areas, was significantly lower for Aboriginal versus non-Aboriginal cases (3.1% vs. 9.3%; P = 0.008). A cause was identified in 920 cases (14.3%), more often for severe defects (347, 24.4%); 63% of known causes were rare diseases. Congenital heart defects associated with fetal alcohol spectrum disorder were much more common in Aboriginal births (prevalence ratio 82; 95% CI 28-239). CONCLUSIONS: Earlier detection of congenital heart defects and improved survival has occurred over time, although discrepancies between ethnic groups and regions warrant further investigation and strategic action.

Future directions for risk communications at EFSA.

This editorial proposes directions for the European Food Safety Authority (EFSA) to meet its current and future obligations as a source of public information and communication on food-related risks in the EU. These directions are intended to guide EFSA's communications through changes driven by new legal obligations, a new organisational strategy cycle and social and technological evolution. This editorial summarises the rationales for shifts in some cases already underway towards embedding audience analysis throughout our risk communication practices, rolling out partnership approaches for producing and delivering public information and greater digital prowess and social media integration. It describes the main audience clusters for EU food safety risk communication, related content strategies and the technical and professional skills required to pursue them.

Sentience and transcendence: personal reflections on physical and mental adaptation from a near-death event and life-limiting surgery.

In this article I reflect on my experience of adapting physically, mentally and spiritually to a medical trauma that had life-changing consequences. I consider how, over 7 years to the time of writing, mental difficulties were inseparable from the physical; and how, for me, both are aspects of a form of understanding knowable only as mystery. Writing from a position of religious faith, I try to convey my experiences in a way that will be of interest to others regardless of their views. At the end, I reflect on aspects of my care that might be particularly relevant for a holistic, person-centred therapeutic approach.

Suspected Lower Extremity Ischemia After End-to-Side Femoral Arterial Grafting for VA-ECMO.

Lower extremity ischemic complications are frequently encountered after femoral cannulation for venoarterial extracorporeal membrane oxygenation (VA-ECMO). Many are attributed to mechanical obstruction of distal arterial blood flow related to intraluminal positioning of the arterial cannula. Routine use of distal perfusion catheters is ineffective at eliminating the development of these serious complications. Side- arm grafting instead of direct arterial cannulation is suggested as an alternative. Here, the authors present a case wherein a patient developed suspected lower extremity ischemia from hyperperfusion after femoral VA-ECMO cannulation during use of an arterial side- arm graft, calling into question the benefits of this cannulation strategy.

Effects of a Clonidine Taper on Dexmedetomidine Use and Withdrawal in Adult Critically Ill Patients-A Pilot Study.

OBJECTIVES: Prolonged use of dexmedetomidine has become increasingly common due to its favorable sedative and anxiolytic properties. Hypersympathetic withdrawal symptoms have been reported with abrupt discontinuation of prolonged dexmedetomidine infusions. Clonidine has been used to transition patients off dexmedetomidine infusions for ICU sedation. The objective of this study was to compare the occurrence of dexmedetomidine withdrawal symptoms in ICU patients transitioning to a clonidine taper versus those weaned off dexmedetomidine alone after prolonged dexmedetomidine infusion. DESIGN: This was a single-center, prospective, double cohort observational study conducted from November 2017 to December 2018. SETTING: Medical-surgical, cardiothoracic, and neurosurgical ICUs in a tertiary care hospital. PATIENTS: We included adult ICU patients being weaned off dexmedetomidine after receiving continuous infusions for at least 3 days. INTERVENTIONS: Patients were either weaned off dexmedetomidine alone or with a clonidine taper at the discretion of the providers. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the incidence of at least two dexmedetomidine withdrawal symptoms during a single assessment within 24 hours of dexmedetomidine discontinuation. Time on dexmedetomidine after wean initiation and difference in medication cost were also evaluated. Forty-two patients were included in this study: 15 received clonidine (Group C) and 27 weaned off dexmedetomidine alone (Group D). There was no significant difference in the incidence of two or more withdrawal symptoms between groups (73% in Group C vs 59% in Group D; p = 0.51). Patients in Group C spent less time on dexmedetomidine after wean initiation compared with patients in Group D (19 vs 42 hr; p = 0.02). An average cost savings of $1,553.47 per patient who received clonidine was observed. No adverse effects were noted. CONCLUSIONS: Our study demonstrated that patients receiving clonidine were able to wean off dexmedetomidine more rapidly, with a considerable cost savings and no difference in dexmedetomidine withdrawal symptoms, compared with patients weaned off dexmedetomidine alone. Clonidine may be a safe, effective, and practical option to transition patients off prolonged dexmedetomidine infusions.

The scholarship of teaching and learning in emergency management and homeland security: Trends, gaps, barriers, and opportunities.

Underlying the nature of what is and is not a profession are education standards. Among the characteristics defining a profession's specialized boundaries are the education standards comprising its academic programs. The status of the Scholarship of Teaching and Learning (SoTL) is explored for both emergency management and homeland security (EM/HS) at this point in time. The aim of this article is to increase the conceptual understanding of SoTL by discussing what SoTL is, explaining why it is important, exploring our current state of knowledge in this area, and by identifying current barriers and opportunities for improvement. Several possible means of better integrating SoTL into the EM/HS discipines are highlighted: Making SoTL a higher priority, increasing exposure to existing research, advancing knowledge within our own disciplines, sharing knowledge through publications and conferences, and applying knowledge in our teaching. Conclusively, the vital nature of SoTL research can more deeply establish the professional boundaries for both disciplines.

A population pharmacokinetic study of benzathine benzylpenicillin G administration in children and adolescents with rheumatic heart disease: new insights for improved secondary prophylaxis strategies.

BACKGROUND: Benzathine benzylpenicillin G (BPG) is recommended as secondary prophylaxis to prevent recurrence of acute rheumatic fever and subsequent rheumatic heart disease (RHD). Following intramuscular injection, BPG is hydrolysed to benzylpenicillin. Little is known of the pharmacokinetics of benzylpenicillin following BPG in populations at risk of RHD. METHODS: We conducted a longitudinal pharmacokinetic study of children and adolescents receiving secondary prophylaxis throughout six monthly cycles of BPG. Dried blood spot samples were assayed with LC-MS/MS. Benzylpenicillin concentrations were analysed using non-linear mixed-effects modelling with subsequent simulations based on published BMI-for-age and weight-for-age data. RESULTS: Eighteen participants contributed 256 concentrations for analysis. None had benzylpenicillin concentrations >0.02 mg/L for the full time between doses. The median duration above this target was 9.8 days for those with a lower BMI (<25 kg/m2), who also had lower weights, and 0 days for those with a higher BMI (≥25 kg/m2). Although fat-free mass was a key determinant of benzylpenicillin exposure after a standard dose of BPG, having a higher BMI influenced absorption and almost doubled (increase of 86%) the observed t½. CONCLUSIONS: Few children and adolescents receiving BPG as secondary prophylaxis will achieve concentrations >0.02 mg/L for the majority of the time between injections. The discordance of this observation with reported efficacy of BPG to prevent rheumatic fever implies a major knowledge gap relating to pharmacokinetic/pharmacodynamic relationships between benzylpenicillin exposure and clinical outcomes.

Long-term medical and psychosocial outcomes in congenital diaphragmatic hernia survivors.

OBJECTIVE: Survival rates for congenital diaphragmatic hernia (CDH) are increasing. The long-term outcomes of CDH survivors were compared with a healthy control group to assess the morbidity for guidance of antenatal counselling and long-term follow-up programmes. PARTICIPANTS AND DESIGN: Participants born with CDH in Western Australia 1993-2008 were eligible with matched controls from the general population. Participants had comprehensive lung function tests, echocardiogram, low-dose chest CT scan and completed a Strengths and Difficulties Questionnaire (SDQ) and quality of life (QOL) questionnaire. RESULTS: 34 matched case-control pairs were recruited. Demographic data between groups were similar. Cases were smaller at follow-up (weight Z-score of -0.2vs0.3; p=0.03; height Z-score of -0.3vs0.6; p=0.01). Cases had lower mean Z-scores for forced expiratory volume in 1 s (FEV1) (-1.49 vs -0.01; p=0.004), FEV1/forced vital capacity (-1.92 vs -1.2; p=0.009) and forced expiratory flow at 25-75% (FEF25-75) (-1.18vs0.23; p=0.007). Cases had significantly worse respiratory mechanics using forced oscillation technique. Subpleural triangles architectural distortion, linear opacities and scoliosis on chest CT were significantly higher in cases. Prosthetic patch requirement was associated with worse lung mechanics and peak cough flow. Cases had significantly higher rates of gastro-oesophageal reflux disease (GORD) and GORD medication usage. Developmental delay was significantly higher in cases. More cases had a total difficulties score in the high to very high range (25% vs 0%, p=0.03) on the SDQ and reported lower objective QOL scores (70.2 vs 79.8, p=0.02). CONCLUSION: Survivors of CDH may have significant adverse long-term medical and psychosocial issues that would be better recognised and managed in a multidisciplinary clinic.

Incidence of Dexmedetomidine Withdrawal in Adult Critically Ill Patients: A Pilot Study.

To determine the incidence of dexmedetomidine withdrawal in adult critically ill patients. DESIGN: This was a prospective, observational study of patients from November 2017 to December 2018. SETTING: Medical-surgical, cardiothoracic, and neurosurgical ICUs in a tertiary care hospital. PATIENTS: Adult critically ill patients on dexmedetomidine infusions for at least 3 days. INTERVENTIONS: Indicators of withdrawal were assessed at baseline and at least daily during the dexmedetomidine wean period. Delirium was assessed using the Confusion Assessment Method for the ICU. Sedation was assessed using the Richmond Agitation-Sedation Scale. The Withdrawal Assessment Tool-1 was performed and vital signs were recorded during each assessment. Patients were considered positive for dexmedetomidine withdrawal if they had two or more of the following symptoms: positive Confusion Assessment Method for the ICU, Richmond Agitation-Sedation Scale greater than +1, positive Withdrawal Assessment Tool-1 assessment, tachycardia (heart rate > 90 beats/min), and hypertension (systolic blood pressure > 140 mm Hg or mean arterial pressure > 90). MEASUREMENTS AND MAIN RESULTS: Forty-two patients were included in the study, with 64% of patients experiencing signs of dexmedetomidine withdrawal. The median time on dexmedetomidine for all patients was 9.6 days (5.8-12.7 d), and the median dose of dexmedetomidine received was 0.8 µg/kg/hr (0.5-1 µg/kg/hr). Of the patients who were positive for withdrawal, the most prevalent withdrawal symptoms observed included delirium, hypertension, and agitation (93%, 48%, and 33%, respectively). We found no correlation between chronic opioid tolerance and incidence of withdrawal symptoms. Peak dexmedetomidine doses greater than 0.8 µg/kg/hr and cumulative daily doses of dexmedetomidine greater than 12.9 µg/kg/d were associated with a higher incidence of withdrawal. CONCLUSIONS: The majority of patients in our study demonstrated signs that may be indicative of dexmedetomidine withdrawal. Peak and cumulative daily dexmedetomidine dose, rather than duration of therapy, may be associated with a higher incidence of withdrawal signs. Regular screening of patients on prolonged dexmedetomidine infusions is recommended to ensure safe and effective use in critically ill patients.

Optimal Scores: An Alternative to Parametric Item Response Theory and Sum Scores.

The aim of this paper is to discuss nonparametric item response theory scores in terms of optimal scores as an alternative to parametric item response theory scores and sum scores. Optimal scores take advantage of the interaction between performance and item impact that is evident in most testing data. The theoretical arguments in favor of optimal scoring are supplemented with the results from simulation experiments, and the analysis of test data suggests that sum-scored tests would need to be longer than an optimally scored test in order to attain the same level of accuracy. Because optimal scoring is built on a nonparametric procedure, it also offers a flexible alternative for estimating item characteristic curves that can fit items that do not show good fit to item response theory models.

Long-Term Outcomes of Hypertrophic Cardiomyopathy Diagnosed During Childhood: Results From a National Population-Based Study.

BACKGROUND: Late survival and symptomatic status of children with hypertrophic cardiomyopathy have not been well defined. We examined long-term outcomes for pediatric hypertrophic cardiomyopathy. METHODS: The National Australian Childhood Cardiomyopathy Study is a longitudinal population-based cohort study of children (0-10 years of age) diagnosed with cardiomyopathy between 1987 and 1996. The primary study end point was time to death or cardiac transplantation. RESULTS: There were 80 patients with hypertrophic cardiomyopathy, with a median age at diagnosis of 0.48 (interquartile range, 0.1, 2.5) years. Freedom from death/transplantation was 86% (95% confidence interval [CI], 77.0-92.0) 1 year after presentation, 80% (95% CI, 69.0-87.0) at 10 years, and 78% (95% CI, 67.0-86.0) at 20 years. From multivariable analyses, risk factors for death/transplantation included symmetrical left ventricular hypertrophy at the time of diagnosis (hazard ratio, 4.20; 95% CI, 1.60-11.05; P=0.004), Noonan syndrome (hazard ratio, 2.88; 95% CI, 1.02-8.08; P=0.045), higher posterior wall thickness z score (hazard ratio, 1.45; 95% CI, 1.22-1.73; P<0.001), and lower fractional shortening z score (hazard ratio, 0.84; 95% CI, 0.74-0.95; P=0.005) during follow-up. Nineteen (23%) subjects underwent left ventricular myectomy. At a median of 15.7 years of follow-up, 27 (42%) of 63 survivors were treated with ß-blocker, and 13 (21%) had an implantable cardioverter-defibrillator. CONCLUSIONS: The highest risk of death or transplantation for children with hypertrophic cardiomyopathy is within 1 year after diagnosis, with low attrition rates thereafter. Many subjects receive medical, surgical, or device therapy.