Comparing adolescent- and adult-onset unexplained cardiac arrest: Results from the Dutch Idiopathic VF Registry.

BACKGROUND: Current cohorts of patients with idiopathic ventricular fibrillation (IVF) primarily include adult-onset patients. Underlying causes of sudden cardiac arrest vary with age; therefore, underlying causes and disease course may differ for adolescent-onset vs adult-onset patients. OBJECTIVE: The purpose of this study was to compare adolescent-onset with adult-onset patients having an initially unexplained cause of VF. METHODS: The study included 39 patients with an index event aged ≤19 years (adolescent-onset) and 417 adult-onset patients from the Dutch Idiopathic VF Registry. Data on event circumstances, clinical characteristics, change in diagnosis, and arrhythmia recurrences were collected and compared between the 2 groups. RESULTS: In total, 42 patients received an underlying diagnosis during follow-up (median 7 [2-12] years), with similar yields (15% adolescent-onset vs 9% adult-onset; P = .16). Among the remaining unexplained patients, adolescent-onset patients (n = 33) had their index event at a median age of 17 [16-18] years, and 72% were male. The youngest patient was aged 13 years. In comparison with adults (n = 381), adolescent-onset patients more often had their index event during exercise (P <.01). Adolescent-onset patients experienced more appropriate implantable cardioverter-defibrillator (ICD) therapy during follow-up compared with adults (44% vs 26%; P = .03). Inappropriate ICD therapy (26% vs 17%; P = .19), ICD complications (19% vs 14%; P = .41), and deaths (3% vs 4%; P = 1) did not significantly differ between adolescent-onset and adult-onset patients. CONCLUSION: IVF may occur during adolescence. Adolescent-onset patients more often present during exercise compared with adults. Furthermore, they are more vulnerable to ventricular arrhythmias as reflected by a higher incidence of appropriate ICD therapy.

Pufendorf and Leibniz on duties of esteem in diplomatic relations.

The striving for self-worth is recognized as a driving force in international relations; but if self-worth is understood as a function of status in a power hierarchy, this striving often is a source of anxiety and conflict over status. The quasi-international relations within the early modern German Empire have prompted seventeenth-century natural law theorists such as Samuel Pufendorf and Gottfried Wilhelm Leibniz to reflect about this problem. In his De statu imperii Germanici (1667), Pufendorf regards the power differences and dependencies between the Reichsstände to be an expression of the deficits of constitutional structure of the Empire-a structure that, in his view, causes internal division because it leads to distorted practices of esteem between the estates. Against Pufendorf, Leibniz argues De jure suprematus ac legationis (1671) that political actors such as the German princes who are not Electors could fulfill functions under the law of nations such as forming confederations and peace keeping. Incoherently, however, Leibniz excludes less powerful estates such as the Imperial cities and the Hanseatic cities from the ensuing duties of esteem. This shortcoming, in turn, is arguably remedied in Pufendorf's later considerations concerning duties of esteem in diplomatic relations.

Clinical Characteristics and Follow-Up of Pediatric-Onset Arrhythmogenic Right Ventricular Cardiomyopathy.

OBJECTIVES: The goal of this study was to describe characteristics, cascade screening results, and predictors of adverse outcome in pediatric-onset arrhythmogenic right ventricular cardiomyopathy (ARVC). BACKGROUND: Although ARVC is increasingly recognized in children, pediatric ARVC cohorts remain underrepresented in the literature. METHODS: This study included 12 probands with pediatric-onset ARVC (aged <18 years at diagnosis) and 68 pediatric relatives (aged <18 years at first evaluation) referred for cascade screening. ARVC diagnosis was based on 2010 Task Force Criteria. Clinical presentation, diagnostic testing, and outcomes (sustained ventricular tachycardia [VT]; heart failure) were ascertained. Predictors of adverse outcome were determined by using univariable logistic regression. RESULTS: Pediatric-onset ARVC was diagnosed in 12 probands and 12 (18%) relatives at a median age of 16.6 years (interquartile range: 13.8-17.4 years), whereas 12 (18%) relatives reached ARVC diagnosis as adults (median age, 22.0 years; interquartile range: 20.0-26.7 years). Sudden cardiac death/arrest was the first disease manifestation in 3 (25%) probands and 3 (4%) relatives. In patients without ARVC diagnosis at presentation (n = 61), electrocardiogram and Holter monitoring abnormalities occurred before development of imaging Task Force Criteria (7.3 ± 5.0 years vs 8.4 ± 5.0 years). Clinical course was characterized by sustained VT (91%) and heart failure (36%) in probands, which were rare in relatives (2% and 0%, respectively). Male sex (P < 0.01), T-wave inversion V1-V3 (P < 0.01), premature ventricular complexes/runs (P ≤ 0.01), and decrease in biventricular ejection fraction (P ≤ 0.01) were associated with VT occurrence. CONCLUSIONS: Pediatric ARVC carries high arrhythmic risk, especially in probands. Disease progression is particularly observed on electrocardiogram or Holter monitoring. Arrhythmic events are associated with male sex, T-wave inversions, premature ventricular complexes/runs, and reduced biventricular ejection fraction.

Wolff on duties of esteem in the law of peoples.

The role that the desire for self-worth plays in international relations has become a prominent topic in contemporary political theory. Contemporary accounts are based on the notion of national self-worth as a function of status; therefore, the desire for national self-worth is seen as a source of anxiety and conflict over status. By contrast, according to Christian Wolff, there exists a duty to take care that both one's own and other political communities deserve to be esteemed. In his view, this duty is grounded in the duty of self-perfection because the qualities for which communities deserve to be esteemed are those that promote the self-perfection of individuals. From this perspective, he argues that duties of esteem toward political communities should not be seen as an outcome of power relations but rather as an outcome of the fulfillment of functions of the law of peoples. Wolff's line of argument draws attention to the possibility that anger over a violation of the desire for honor could be mistaken for an expression of specific culture-specific sensitivities, while what really may be expressed is a diverging interpretation of the implications of dependence in international relations.

Helvétius's challenge: Moral luck, political constitutions, and the economy of esteem.

This article explores a historical challenge for contemporary accounts of the role that the desire of being esteemed can play in exercising social control. According to Geoffrey Brennan and Philip Pettit, the economy of esteem normally has two aspects: it is supportive of virtuous action and it occurs spontaneously. The analysis of esteem presented by the 18th-century materialist Claude-Adrien Helvétius challenges the intuition that these two aspects go together unproblematically. This is so because, in Helvétius's view, the desire for esteem is always triggered by sensible interest. In the frequent situations where sensible interest diverges from the demands of virtue, the economy of esteem thus can be spontaneous but will not be supportive of virtue. Helvétius allows for cases of moral luck where sensible interest coincides with the demands of virtue but regards these cases as rare occurrences. This is why he believes that a functioning economy of esteem crucially depends on political constitutions-in which case the economy of esteem can be supportive of virtue but will not be spontaneous.

Side-by-side comparability of batch and continuous downstream for the production of monoclonal antibodies.

Continuous processing is the future production method for monoclonal antibodies (mAbs). A fully continuous, fully automated downstream process based on disposable equipment was developed and implemented inside the MoBiDiK pilot plant. However, a study evaluating the comparability between batch and continuous processing based on product quality attributes was not conducted before. The work presented fills this gap comparing both process modes experimentally by purifying the same harvest material (side-by-side comparability). Samples were drawn at different time points and positions in the process for batch and continuous mode. Product quality attributes, product-related impurities, as well as process-related impurities were determined. The resulting polished material was processed to drug substance and further evaluated regarding storage stability and degradation behavior. The in-process control data from the continuous process showed the high degree of accuracy in providing relevant process parameters such as pH, conductivity, and protein concentration during the entire process duration. Minor differences between batch and continuous samples are expected as different processing conditions are unavoidable due to the different nature of batch and continuous processing. All tests revealed no significant differences in the intermediates and comparability in the drug substance between the samples of both process modes. The stability study of the final product also showed no differences in the stability profile during storage and forced degradation. Finally, online data analysis is presented as a powerful tool for online-monitoring of chromatography columns during continuous processing.

Value, Justice, and Presumption in the Late Scholastic Controversy over Price Regulation.

In the sixteenth and early seventeenth centuries, theories of price regulation were developed in order to analyze the demands of justice in situations where markets cease to function-be it through natural conditions, wars, or artificially induced shortages in supply. This article investigates the relevance of the methodological notion of presumption for the legally binding power of laws concerning price regulation. In particular, the relation between presumptions (assumptions that are taken to be true unless and until proven false), the cost-and-labor theory of value, and the question of the morally binding power of laws concerning legal prices are explored.

Instrumental causes and the natural origin of souls in Antonio Ponce Santacruz's theory of animal generation.

This article studies the theory of animal seeds as purely material entities in the early seventeenth-century medical writings of Antonio Ponce Santacruz, royal physician to the Spanish king Philipp IV. Santacruz adopts the theory of the eduction of substantial forms from the potentiality of matter, according to which new kinds of causal powers can arise out of material composites of a certain complexity. Santacruz stands out among the late Aristotelian defenders of eduction theory because he applies the concept of an instrument of direction developed by the medieval Avicenna commentator Gentile da Foligno and gives a novel turn to this concept by interpreting animal seeds as separate instruments. The article situates Santacruz's theory in the context of early modern debates about the concept of the eduction of forms, as well as in the context of early modern debates about the concept of separate instruments. Particular attention is paid to Santacruz's responses to the biological views of Julius Caesar Scaliger and Thomas Feyens. Santacruz's response to Scaliger turns out to be central for his explication of the eduction relation, and Santacruz's response to Feyens turns out to be central for his explication of the nature of instrumental causation.

Linking the heart and the brain: Neurodevelopmental disorders in patients with catecholaminergic polymorphic ventricular tachycardia.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an uncommon inherited arrhythmia disorder characterized by adrenergically evoked ventricular arrhythmias. Mutations in the cardiac calcium release channel/ryanodine receptor gene (RYR2) are identified in the majority of patients with CPVT. RyR2 is also the major RyR isoform expressed in the brain. OBJECTIVE: The purpose of this study was to estimate the prevalence of intellectual disability (ID) and other neurodevelopmental disorders (NDDs) in RYR2-associated CPVT (CPVT1) and to study the characteristics of these patients. METHODS: We reviewed the medical records of all CPVT1 patients from 12 international centers and analyzed the characteristics of all CPVT1 patients with concomitant NDDs. We functionally characterized the mutations to assess their response to caffeine activation. We did not correct for potential confounders. RESULTS: Among 421 CPVT1 patients, we identified 34 patients with ID (8%; 95% confidence interval 6%-11%). Median age at diagnosis was 9.3 years (interquartile range 7.0-14.5). Parents for 24 of 34 patients were available for genetic testing, and 13 of 24 (54%) had a de novo mutation. Severity of ID ranged from mild to severe and was accompanied by other NDDs in 9 patients (26%). Functionally, the ID-associated mutations showed a markedly enhanced response of RyR2 to activation by caffeine. Seventeen patients (50%) also had supraventricular arrhythmias. During median follow-up of 8.4 years (interquartile range 1.8-12.4), 15 patients (45%) experienced an arrhythmic event despite adequate therapy. CONCLUSION: Our study indicates that ID is more prevalent among CPVT1 patients (8%) than in the general population (1%-3%). This subgroup of CPVT1 patients reveals a malignant cardiac phenotype with marked supraventricular and ventricular arrhythmias.

Long-term outcome of transvenous pacemaker implantation in infants: a retrospective cohort study.

AIM: Evaluation of long-term outcome of transvenous pacemaker (PM) implantation in infants. METHODS AND RESULTS: A retrospective analysis of all transvenous PM implantations in infants <10 kg between September 1997 and October 2001 was made. Indications for PM implantation, age at implantation, and determinants of long-term outcome including cardiac function, PM function, and PM (system) complications were noted. Seven patients underwent transvenous VVI(R) PM implantation. Median age at implantation was 3 days (range: 1 day to 14 months), median weight 3.5 kg (range: 2.3-8.7 kg), and median follow-up 14 years (range: 12.3-16.3 years). Pacemaker indications were congenital complete atrioventricular block (n = 4), long QT syndrome with heart block (n = 2), and post-operative complete atrioventricular block with sinus node dysfunction (n = 1). No procedural complications were noted. Today all patients are alive and symptom free with good PM and cardiac function. Two patients underwent PM generator relocation for imminent skin necrosis and skin traction. Two patients suffered from asymptomatic left subclavian vein occlusion and developed thrombosis on the PM electrode. Three patients were converted to an epicardial PM system, due to atrial perforation after upgrading procedure (n = 1), syncope with need for implantable cardioverter defibrillator implantation (n = 1), and systolic dysfunction with development of dilated cardiomyopathy, which normalized under cardiac resynchronization therapy pacing (n = 1). Two patients needed atrioventricular (AV) valve repair for severe insufficiency. Two patients underwent repositioning of dysfunctional PM leads. In five patients, transvenous leads were removed. Indications were elective lead replacement (n = 1), atrial perforation (n = 1), and switch to an epicardial system (n = 3). CONCLUSION: Transvenous PM implantation in infants (<10 kg) is associated with a high incidence of vascular occlusion, thrombosis, and severe atrioventricular valve regurgitation during long-term follow-up. We advocate an epicardial approach for PM implantation in small children.

Effect of Age and Sex on the QTc Interval in Children and Adolescents With Type 1 and 2 Long-QT Syndrome.

BACKGROUND: In congenital long-QT syndrome, age, sex, and genotype have been associated with cardiac events, but their effect on the trend in QTc interval has never been established. We, therefore, aimed to assess the effect of age and sex on the QTc interval in children and adolescents with type 1 (LQT1) and type 2 (LQT2) long-QT syndrome. METHODS AND RESULTS: QTc intervals of 12-lead resting electrocardiograms were determined, and trends over time were analyzed using a linear mixed-effects model. The study included 278 patients with a median follow-up of 4 years (interquartile range, 1-9) and a median number of 6 (interquartile range, 2-10) electrocardiograms per patient. Both LQT1 and LQT2 male patients showed QTc interval shortening after the onset of puberty. In LQT2 male patients, this was preceded by a progressive QTc interval prolongation. In LQT1, after the age of 12 years, male patients had a significantly shorter QTc interval than female patients. In LQT2, during the first years of life and from 14 to 26 years, male patients had a significantly shorter QTc interval than female patients. On the contrary, between 5 and 14 years, LQT2 male patients had significantly longer QTc interval than LQT2 female patients. CONCLUSIONS: There is a significant effect of age and sex on the QTc interval in long-QT syndrome, with a unique pattern per genotype. The age of 12 to 14 years is an important transitional period. In the risk stratification and management of long-QT syndrome patients, clinicians should be aware of these age-, sex-, and genotype-related trends in QTc interval and especially the important role of the onset of puberty.

Nicolaus Taurellus on forms and elements.

This article examines the conception of elements in the natural philosophy of Nicolaus Taurellus (1547-1606) and explores the theological motivation that stands behind this conception. By some of his early modern readers, Taurellus may have been understood as a proponent of material atoms. By contrast, I argue that considerations concerning the substantiality of the ultimate constituents of composites led Taurellus to an immaterialist ontology, according to which elements are immaterial forms that possess active and passive potencies as well as motion and extension. In Taurellus's view, immaterialism about elements provides support for the theological doctrine of creation ex nihilo. As he argues, the ontology of immaterial forms helps to explicate a sense in which creatures are substances, not accidents of the divine substance. In particular, he maintains that immaterial forms stand in suitable relations of ontological dependence to God: creation dependence (since forms would not exist without the divine act of creation), but neither subsistence dependence (since forms continue to exist without continued divine agency) nor activity dependence (since forms are active without requiring divine concurrence).

Upgrading of a co-digestion plant by implementation of a hydrolysis stage.

An existing co-digestion plant needed to be rehabilitated after a 20 year operational period. This was planned to be done in sequence by halving the digester volume for a period of 1.5 years. The aim of the present study was to improve the performance of the halved co-digestion capacity by implementing an upstream thermal hydrolysis reactor or an ultrasonic pre-treatment of the substrates. The results of the ultrasonic bench-scale batch experiments showed that an ultrasonic pre-treatment of the co-substrates 'municipal bio-waste suspension and excess activated sludge led to disintegration efficiencies of up to 51%. However, treating kitchen-waste and primary sludge in the same manner was not promising as the disintegration yields were rather low. The results of the hydrolysis bench-scale batch experiments showed that the optimal boundary conditions for the hydrolysis reactor were a hydrolysis temperature of about 42 °C at a retention time of 24 h. The results of the continuous two-stage experiments showed that it was possible to reduce the retention time in the second stage to about 24% and to increase the biogas yield to about 12.8 %, and the methane yield to about 28% as a result of the implementation of the hydrolysis reactor in the existing system. After the rehabilitation of the existing digesters it was possible to raise the daily substrate input to the two existing digesters from 312 to 495 m³ day(-1) with an upstream hydrolysis reactor volume of only 474 m³.

Impact of the permanent ventricular pacing site on left ventricular function in children: a retrospective multicentre survey.

BACKGROUND: Chronic right ventricular (RV) pacing is associated with deleterious effects on cardiac function. OBJECTIVE: In an observational multicentre study in children with isolated atrioventricular (AV) block receiving chronic ventricular pacing, the importance of the ventricular pacing site on left ventricular (LV) function was investigated. METHODS: Demographics, maternal autoantibody status and echocardiographic measurements on LV end-diastolic and end-systolic dimensions and volumes at age <18 years were retrospectively collected from patients undergoing chronic ventricular pacing (>1 year) for isolated AV block. LV fractional shortening (LVFS) and, if possible LV ejection fraction (LVEF) were calculated. Linear regression analyses were adjusted for patient characteristics. RESULTS: From 27 centres, 297 children were included, in whom pacing was applied at the RV epicardium (RVepi, n = 147), RV endocardium (RVendo, n = 113) or LV epicardium (LVepi, n = 37). LVFS was significantly affected by pacing site (p = 0.001), and not by maternal autoantibody status (p = 0.266). LVFS in LVepi (39 ± 5%) was significantly higher than in RVendo (33 ± 7%, p < 0.001) and RVepi (35 ± 8%, p = 0.001; no significant difference between RV-paced groups, p = 0.275). Subnormal LVFS (LVFS < 28%) was seen in 16/113 (14%) RVendo-paced and 21/147 (14%) RVepi-paced children, while LVFS was normal (LVFS ≥ 28%) in all LVepi-paced children (p = 0.049). These results are supported by the findings for LVEF (n = 122): LVEF was <50% in 17/69 (25%) RVendo- and in 10/35 (29%) RVepi-paced patients, while LVEF was ≥ 50% in 17/18 (94%) LVepi-paced patients. CONCLUSION: In children with isolated AV block, permanent ventricular pacing site is an important determinant of LV function, with LVFS being significantly higher with LV pacing than with RV pacing.

Julius Caesar Scaliger on plant generation and the question of species constancy.

The sixteenth-century physician and philosopher Julius Caesar Scaliger combines the view that living beings are individuated by a single substantial form with the view that the constituents of the organic body retain their identity due to the continued existence and operation of their own substantial forms. This essay investigates the implications of Scaliger's account of subordinate and dominant substantial forms for the question of the constancy of biological species. According to Scaliger, biological mutability involves not only change on the ontological level of accidents but, in some cases, also change on the level of substantial forms. While he shares the received view that substantial forms themselves cannot undergo change, he maintains that relations of domination and subordination between substantial forms can undergo change. He uses his theory of how such changes can occur to explain cases of revertible plant degeneration. Moreover, in his view plants that belong to previously unknown biological species can emerge from changes in the relations between the many forms contained in plant seeds.

Material souls and imagination in late Aristotelian embryology.

This article explores some continuities between Late Aristotelian and Cartesian embryology. In particular, it argues that there is an interesting consilience between some accounts of the role of imagination in trait acquisition in Late Aristotelian and Cartesian embryology. Evidence for this thesis is presented using the extensive biological writings of the Padua-based philosopher and physician, Fortunio Liceti (1577-1657). Like the Cartesian physiologists, Liceti believed that animal souls are material beings and that acts of imagination result in material images that can be transmitted by means of medical spirits to the embryo. Moreover, while the Cartesian embryologists accepted such a view in a quite speculative way, one finds penetrating criticism of imagination theories of trait acquisition in the Late Aristotelian tradition. Evidence for this thesis is presented using the no less extensive biological writings of Liceti's contemporary, Emilio Parisano (1567-1643). In conclusion, the Late Aristotelian tradition itself provides the theoretical tools for excising immaterial formative forces from embryology and at the same time evinces a much more acute sense for the problems inherent in imagination theories of trait acquisition than the Cartesian tradition.