Normal Cardiac Anatomy and Clinical Evaluation.

The heart is positioned in the middle, superior, and posterior regions of the mediastinum. Although it is a midline structure, the apex of the heart is typically situated to the left of the midline (Fig. 4.1).

Clinical Presentation and Therapy of Atrioventricular Septal Defect.

Atrioventricular septal defects (AVSDs) consist of a number of cardiac malformations that result from abnormal development of the endocardial cushions. AVSDs occur in 0.19 of 1000 live births and constitute 4-5 % of congenital heart defects. AVSDs can be categorized as incomplete (or partial) or complete, and intermediate or transitional.

Clinical Presentation and Therapy of Anomalies of the Situs.

Situs abnormalities may occur in many and most often more complex congenital cardiac malformations. These conditions are collectively referred to as heterotaxy syndromes, derived from the Greek words "heteros" meaning different and "taxos" meaning orientation or arrangement. Clinically, heterotaxy spectrum encompasses defects in the left-right laterality and arrangement of visceral organs. "Situs" is derived from Latin and is the place where something exists or originates. In human anatomy, situs can be solitus (derived from Latin, meaning "normal"), inversus, or ambiguus. Heterotaxy syndrome represents an intermediate arrangement of internal organs between situs solitus and situs inversus, also known as "situs ambiguous." Situs ambiguus describes an abnormal distribution of major visceral organs within the chest and abdomen. The determination of situs as normal, inversus, or ambiguus is primarily based on the location of unpaired organs such as the spleen, liver, stomach, and intestines. Diagnosis is made by clinical examination, echocardiography, a chest X-ray (position of the heart, stomach, and liver), and ultrasound of the abdominal organs. Situs is considered solitus if the left atrium, spleen, stomach, and the trilobed lung are on the left side and the liver and bilobed lung are on the right side. Situs ambiguus is present if the location of unpaired structures is random or indeterminate even after detailed and appropriate imaging. Situs inversus results when the arrangement of the thoracic and abdominal organs is mirrored. Individuals with situs inversus or situs solitus do not experience fatal dysfunction of their organ systems, as general anatomy and morphology of the abdominothoracic organ-vessel systems are conserved.

Clinical Presentation and Therapy of Tricuspid Atresia and Univentricular Heart.

Although the terms "single ventricle" and "univentricular heart" are frequently used to describe a variety of complex congenital heart defects, in fact, nearly all hearts have two ventricles, although one of the two may be too small to be functional. A better term for these hearts would therefore be "functional single ventricle."

Clinical Presentation and Therapy of Truncus Arteriosus.

Truncus arteriosus (TA, also known as common arterial trunk) consists of only one great artery ("the truncus") with a semilunar valve (truncus valve) arising from the heart and an additional ventricular septal defect and (Fig. 50.1). This great artery is positioned above the ventricular septal defect and gives rise to the coronary arteries, the pulmonary arteries, and the aortic arch. Historically, TA has been classified by Collet and Edwards in three types, where in type I there was a common pulmonary artery truncus, in type II the left and right PA arise separately but close to each other, in type III both PA arise independently; in addition, there was a type IV that was later characterized as pulmonary atresia with VSD and major aortopulmonary collateral arteries arising from the descending aorta.

Clinical Presentation and Therapy of Hypoplastic Left Heart Syndrome.

Hypoplastic left heart syndrome (HLHS) is a complex congenital heart defect characterized by several abnormalities that result in a significantly underdeveloped left ventricle and severe hypoplasia of the ascending aorta, often leading to retrograde perfusion. These abnormalities include aortic valve atresia or severe stenosis, accompanied by a severely hypoplastic aortic valve annulus (Fig. 59.1). Mitral valve atresia, hypoplasia, and/or stenosis with a hypoplastic valve annulus with or without a ventricular septal defect can also contribute to the development of HLHS. Endocardial fibroelastosis and sinusoids may be present as well. The interatrial septum can either be closed or the foramen ovale severely stenotic. Other malformations, such as anomalous pulmonary venous drainage or variations of the systemic veins, may coexist. It is also common to observe a coarctation of the aorta in these cases.

Clinical Presentation and Therapy of Cardiomyopathies.

Cardiomyopathies are a group of diseases that primarily affect the heart muscle, leading to mechanical or electrical dysfunction of the heart. They can be categorized into primary and secondary forms. Primary cardiomyopathies can be further classified as congenital, acquired, or mixed. In terms of the heart muscle itself, there are five distinct types of cardiomyopathies: hypertrophic cardiomyopathy, dilated or congestive cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic (right ventricular) dysplasia, and noncompaction cardiomyopathy. While cardiomyopathies primarily affect the heart, they can also have systemic manifestations, impacting other organs and potentially causing progressive debilitation, heart failure, or even death.

Clinical Presentation and Therapy of Total Anomalous Pulmonary Venous Return.

Total anomalous pulmonary venous return (TAPVR) is rare (accounting for about 1% of all CHD) and can occur as a single lesion or in combination with other types of CHD (such as heterotaxy or HLHS). TAPVR is defined as an abnormal connection where all pulmonary veins do not drain into the left atrium but into the right atrium either directly or through a vein that is connected to the right atrium. TAPVR can be divided into four anatomic groups (Fig. 32.1): (1) supracardiac (about 55%), (2) cardiac (about 30%), (3) infracardiac (about 13%), and (4) mixed (very rare). In addition, it can be divided into two physiological types: nonobstructed and obstructed. Embryologically, all pulmonary veins usually connect to a pulmonary venous confluence that connects to the left atrium. If this connection does not occur, the pulmonary venous confluence connects to a systemic vein instead.

The PREVENT dementia programme: baseline demographic, lifestyle, imaging and cognitive data from a midlife cohort study investigating risk factors for dementia.

PREVENT is a multi-centre prospective cohort study in the UK and Ireland that aims to examine midlife risk factors for dementia and identify and describe the earliest indices of disease development. The PREVENT dementia programme is one of the original epidemiological initiatives targeting midlife as a critical window for intervention in neurodegenerative conditions. This paper provides an overview of the study protocol and presents the first summary results from the initial baseline data to describe the cohort. Participants in the PREVENT cohort provide demographic data, biological samples (blood, saliva, urine and optional cerebrospinal fluid), lifestyle and psychological questionnaires, undergo a comprehensive cognitive test battery and are imaged using multi-modal 3-T MRI scanning, with both structural and functional sequences. The PREVENT cohort governance structure is described, which includes a steering committee, a scientific advisory board and core patient and public involvement groups. A number of sub-studies that supplement the main PREVENT cohort are also described. The PREVENT cohort baseline data include 700 participants recruited between 2014 and 2020 across five sites in the UK and Ireland (Cambridge, Dublin, Edinburgh, London and Oxford). At baseline, participants had a mean age of 51.2 years (range 40-59, SD ± 5.47), with the majority female (n = 433, 61.9%). There was a near equal distribution of participants with and without a parental history of dementia (51.4% versus 48.6%) and a relatively high prevalence of APOEɛ4 carriers (n = 264, 38.0%). Participants were highly educated (16.7 ± 3.44 years of education), were mainly of European Ancestry (n = 672, 95.9%) and were cognitively healthy as measured by the Addenbrookes Cognitive Examination-III (total score 95.6 ± 4.06). Mean white matter hyperintensity volume at recruitment was 2.26 ± 2.77 ml (median = 1.39 ml), with hippocampal volume being 8.15 ± 0.79 ml. There was good representation of known dementia risk factors in the cohort. The PREVENT cohort offers a novel data set to explore midlife risk factors and early signs of neurodegenerative disease. Data are available open access at no cost via the Alzheimer's Disease Data Initiative platform and Dementia Platforms UK platform pending approval of the data access request from the PREVENT steering group committee.

Clinical Presentation and Therapy of Atrial Septal Defect.

Atrial septal defects (ASDs) occur in 1 of 1500 live births and constitute 6-10% of congenital heart defects. There is a female-to-male predominance of 2 to 1. According to their embryological origins, we can differentiate five different types of ASDs (see Fig. 23.1).

Clinical Presentation and Therapy of Ventricular Septal Defect.

Ventricular septal defects (VSDs) occur in 1.5-3.5 of 1000 live births and constitutes 20 % of congenital cardiac defects. There is no gender predominance.

Clinical Presentation and Therapy of Tetralogy of Fallot and Double-Outlet Right Ventricle.

Tetralogy of Fallot (TOF) is the most common cyanotic heart defect. TOF consists of the combination of four anomalies (Fig. 35.1): (1) a large malalignment ventricular septal defect, (2) an obstruction of the right ventricular outflow tract (usually infundibular and valvular pulmonary stenosis with a small pulmonary valve annulus and supravalvular stenosis, (3) an aorta that "overrides" the ventricular septal defect, and (4) right ventricular hypertrophy. TOF represents 4-8% of congenital heart defects. Specific variations of TOF include all forms of pulmonary atresia with VSD and absent pulmonary valve syndrome. In addition, the left and right main pulmonary arteries may be stenotic or hypoplastic. In these cases, there may be major aortopulmonary collateral arteries (MAPCAs) which are vessels arising from the aorta or the subclavian arteries that supply segments of the pulmonary arterial tree. Additional variations include an ASD (Pentalogy of Fallot), a right aortic arch, and coronary abnormalities.

Clinical Presentation and Therapy of d-Transposition of the Great Arteries.

d-Transposition of the great arteries (d-TGA) is the most common form of congenital heart disease that presents with cyanosis in a newborn. The aorta arises from the right ventricle and the pulmonary artery arises from the left ventricle. It constitutes 3-5% of all congenital heart defects. In a simple d-TGA (about two-thirds of patients), there is no other cardiac abnormality other than a patent foramen ovale (PFO) and a patent ductus arteriosus (PDA). In a complex d-TGA additional cardiac abnormalities such as VSD, pulmonary stenosis or coronary abnormalities are present. About one-third to 40% of patients with d-TGA have an associated ventricular septal defect. Among patients with d-TGA, 6% of those with intact ventricular septum and 31% of those with ventricular septal defect have associated pulmonary stenosis. Coronary abnormalities are of importance with regard to the complexity of surgical repair.

Clinical Presentation and Therapy of Semilunar Valve and Aortic Arch Anomalies.

The following semilunar valve defects and aortic arch anomalies are called simple defects because there is a single problem that can be well described. Based on the degree of malformation and hemodynamic consequence, these simple lesions can however be life threatening immediately after birth. They all affect either the left or right outflow tract or the aortic arch.

Clinical Presentation and Therapy of Coronary Artery Anomalies.

There are two major coronary arteries that arise normally directly above the aortic valve in the sinus. The left main coronary artery (LCA or LMCA) arises from the left coronary sinus and divides shortly after its origin into the left anterior descending and the circumflex coronary arteries (LCX). Branches of the left anterior descending (LAD) coronary artery include the left conus, septal, and diagonal arteries. Branches of the circumflex coronary artery may include the sinus node artery, Kugel's artery, marginal arteries, and the left atrial circumflex artery (Fig. 47.1). The LAD follows the interventricular septum to the apex, the LCX turns posterior, follows the atrioventricular groove between the left atrium and ventricle to the coronary sinus. Branches of the right coronary artery (RCX) include the conal branch, the sinus node artery, an atrial branch, the right ventricular muscle branches (including the acute marginal branch), the posterior descending coronary artery, the atrioventricular node artery, and septal branches (Fig. 47.2). The RCX follows the atrioventricular groove between the right atrium and ventricle. The "dominant coronary artery" is the one giving rise to the posterior descending coronary artery. It originates from the right coronary artery in 80% of people.

Clinical Presentation and Therapy of Ebstein Anomaly.

Ebstein anomaly is a rare congenital heart defect, accounting for less than 1% of cardiac malformations and occurring in approximately 1 out of 210,000 live births. It is characterized by an abnormality of the tricuspid valve, where the valve is positioned lower than normal in the right ventricle. Although primarily a tricuspid valve defect, the right ventricle itself is often structurally abnormal and weakened (myopathic).

Clinical Presentation and Therapy of Arrhythmias.

The electrocardiogram (ECG) is one of the cornerstones of diagnostic investigations in pediatric or adult cardiology. The standard ECG includes 12 leads; there are 6 leads that are derived from electrodes from the arms and legs (Einthoven and Goldberger leads) and 6 precordial leads (Wilson leads).

Poverty trajectories and child and mother well-being outcomes in Ireland: findings from an Irish prospective cohort.

BACKGROUND: Poverty is associated with poor outcomes, yet exposure to distinct poverty trajectories in early childhood is not well understood. OBJECTIVE: To understand the prevalence of different trajectories of household poverty and their association with mid-childhood and mother indicators of physical health and psychopathology in Ireland. METHODS: We used a nationally representative, prospective cohort (Growing Up in Ireland-Infant Cohort). Household poverty included lowest third income decile, subjective poverty and material deprivation when children were aged 9 months, and 3, 5, 9 years. We used group-based multitrajectory cluster modelling to classify trajectories of poverty. Using multivariable logistic regression, adjusted with separate child and mother confounders, we assessed the association of poverty trajectories from 9 months to 9 years with child outcomes (overweight, any longstanding illness and psychopathology) at age 9 years and the same poverty trajectories over the same 9-year period with mother outcomes (overweight, any longstanding illness and depression). RESULTS: Of 11 134 participants, 4 trajectories were identified: never in poverty (43.1%), material/subjective>monetary poverty (16.1%), monetary>material poverty (25.6%) and persistent poverty (15.2%). Children in persistent poverty compared with those in never in poverty experienced higher odds of being overweight at 9 years (adjusted OR (aOR) 1.70, 95% CI 1.34, 2.16), having a longstanding illness (aOR 1.51, 95% CI 1.20, 1.91), and psychopathology (aOR 2.06, 95% CI 1.42, 2.99). The outcomes for primary parents (99.7% were mothers) were as follows: having higher odds of being overweight (aOR 1.49, 95% CI 1.16, 1.92), having a longstanding illness (aOR 2.13, 95% CI 1.63, 2.79), and depression (aOR 3.54, 95% CI 2.54, 4.94). CONCLUSIONS: Any poverty trajectory was associated with poorer psychopathology and physical well-being in late childhood for children and their mothers in Ireland.

Antipsychotic prescribing: national findings of children and adolescents attending mental health services in Ireland.

Antipsychotic prescribing trends vary internationally, albeit off-label use remains high (i.e., target symptoms). We aim to describe antipsychotic use, target conditions, target symptoms and dosing regimens in children and adolescents in Ireland. We used a sampled cohort from a national audit of children and adolescents attending mental health services with predefined inclusion and exclusion criteria from Jul-2021 to Dec-2021 who were prescribed at least one psychotropic medication and up to and including 17-years of age (n = 3528). Each service provided anonymised data. We described the frequency of antipsychotic medication, medication type, target condition, target symptom and medication doses. We used multivariable logistic regression, adjusted with available co-variates to assess the association of being prescribed an antipsychotic medication. Twelve percentage (n = 437) were prescribed an antipsychotic and 16-17-years (n = 211, 48.3%) was the most common age category. The commonest reason for prescribing an antipsychotic was target symptoms (i.e., off-label use) (n = 329; 75.%) and of these symptoms, agitation (n = 77/329; 25%) and irritability (56/239; 25%) were the most common. Quetiapine (n = 127; 29%) was the most common antipsychotic, followed by risperidone (n = 125; 28.6%), aripiprazole (n = 107; 24.5%), and olanzapine (n = 66; 15.1%). In adjusted analysis, having a psychotic disorder ((adjusted-odds-ratio) aOR: 39.63, CI 95%, 13.40-117.22), bipolar disorder (aOR: 16.96, CI 95%, 3.60-80.00), autism spectrum disorder (aOR: 3.24, CI 95%, 2.45-4.28) or aggression symptoms (aOR: 16.75, CI 95%, 7.22-38.89) was associated with prescribing an antipsychotic medication. This is the first study in children and adolescents that describes the target conditions and target symptoms for antipsychotic use in Ireland. Our results show a high proportion of antipsychotic prescribing based on target symptoms rather than target condition or diagnosis.

Pharmaceutical Considerations and Metabolic Fate of Parenteral Lipid Nanoparticle Dosage Forms.

The physical stability of parenteral dispersions for delivery of drugs to patients is of particular clinical importance, given their general overall superior bioavailability compared to other routes of administration. Although official pharmacopeial methods for lipid injectable emulsions have been established for triglyceride oil-in-water dispersions (i.e., "mini-emulsions") through USP Chapter <729>, no pharmaceopeial guidance exists for lipid nanoparticle (LNP)-based "micro-emulsions". At present, there are several LNP-based drugs approved for clinical use, including mRNA vaccines. Moreover, the increased interest in using mRNA as a platform technology for an array of potential therapeutic drug candidates increases the importance of developing appropriate methods to ensure their physical stability, safety and efficacy. For all dispersions and by various detection mechanisms (e.g., electrical, mechanical, mathematical), the fusion or growth of droplets/particles in the large-diameter tails of the particle size distribution (PSD) signals the onset of instability. Consequently, the measurement for LNP dispersions will require the use of a modified optical detection design in order to extend the lower particle detection limit into the "relative" large-diameter tail of the PSD for both light extinction and light-scattering methods based on single-particle optical sensing techniques. Fortunately, the technology is currently available and capable of providing the requisite quantitative analysis.