Reproductive isolation is an intrinsic aspect of species formation. For that reason, the identification of the precise isolating traits, and the rates at which they evolve, is crucial to understanding how species originate and persist. Previous work has measured the rates of evolution of prezygotic and postzygotic barriers to gene flow, yet no systematic analysis has studied the rates of evolution of postmating-prezygotic (PMPZ) barriers. We measured the magnitude of two barriers to gene flow that act after mating occurs but before fertilization. We also measured the magnitude of a premating barrier (female mating rate in nonchoice experiments) and two postzygotic barriers (hybrid inviability and hybrid sterility) for all pairwise crosses of all nine known extant species within the melanogaster subgroup. Our results indicate that PMPZ isolation evolves faster than hybrid inviability but slower than premating isolation. Next, we partition postzygotic isolation into different components and find that, as expected, hybrid sterility evolves faster than hybrid inviability. These results lend support for the hypothesis that, in Drosophila, reproductive isolation mechanisms (RIMs) that act early in reproduction (or in development) tend to evolve faster than those that act later in the reproductive cycle. Finally, we tested whether there was evidence for reinforcing selection at any RIM. We found no evidence for generalized evolution of reproductive isolation via reinforcement which indicates that there is no pervasive evidence of this evolutionary process. Our results indicate that PMPZ RIMs might have important evolutionary consequences in initiating speciation and in the persistence of new species.

Advances have been made in identifying genetic etiologies of congenital heart defects. Through this knowledge, preventive strategies have been designed and instituted, and prospective parents are counseled regarding their risk of having an affected child. Great strides have been made in genetic variant identification, and genetic susceptibility to environmental exposures has been hypothesized as an etiology for congenital heart defects. Unfortunately, similar advances in understanding have not been made regarding strategies to prevent nongenetic risk factors. Less information is available regarding the potential adverse effect of modifiable risk factors on the fetal heart. This review summarizes the available literature on these modifiable exposures that may alter the risk for congenital heart disease. Information regarding paternal characteristics and conditions, maternal therapeutic drug exposures, parental nontherapeutic drug exposures, and parental environmental exposures are presented. Factors are presented in terms of risk for congenital heart defects as a group. These factors also are broken down by specific defect type. Although additional investigations are needed in this area, many of the discussed risk factors present an opportunity for prevention of potential disease.

Background Through ventricular interdependence, pulmonary hypertension (PH) induces left ventricular (LV) dysfunction. We hypothesized that pediatric PH patients have LV diastolic dysfunction, related to adverse pulmonary hemodynamics, leftward septal shift, and prolonged right ventricular (RV) systole. Methods and Results Echocardiography was prospectively performed at two institutions in 54 pediatric PH patients during cardiac catheterization, and in 54 matched controls. Diastolic LV measures including myocardial deformation were assessed by echocardiography. PH patients had evidence of LV diastolic dysfunction, most consistent with impaired LV relaxation, though some features of reduced ventricular compliance were present. PH patients demonstrated the following: reduced mitral E velocity and inflow duration, mitral E’ and E’/A’, septal E’ and A’, pulmonary vein S and D wave velocities, and LV basal global early diastolic circumferential strain rate; and increased mitral E deceleration time, LV isovolumic relaxation time, mitral E/E’, and pulmonary vein A wave duration. PH patients demonstrated leftward septal shift and prolonged RV systole, both known to affect LV diastole. These changes were exacerbated in severe PH. There were no statistically significant differences in diastolic measures between patients with and without a shunt, and minimal differences between patients with and without congenital heart disease. Multiple echocardiographic LV diastolic parameters demonstrated weak to moderate correlations with invasively-determined PH severity, leftward septal shift, and prolonged RV systole. Conclusions Pediatric PH patients exhibit LV diastolic dysfunction most consistent with impaired relaxation and reduced myocardial deformation, related to invasive hemodynamics, leftward septal shift, and prolonged RV systole.

21 22Reproductive isolation (RI) is an intrinsic aspect of species, as described in the Biological 23 Species Concept. For that reason, the identification of the precise traits and mechanisms 24 of RI, and the rates at which they evolve, is crucial to understanding how species 25 originate and persist. Nonetheless, precise measurements of the magnitude of 26 reproductive isolation are rare. Previous work has measured the rates of evolution of 27 prezygotic and postzygotic barriers to gene flow, yet no systematic analysis has carried 28 out the study of the rates of evolution of postmating-prezygotic (PMPZ) barriers. We 29 systematically measured the magnitude of two barriers to gene flow that act after mating 30 occurs but before zygotic fertilization and also measured a premating (female mating rate 31 in nonchoice experiments) and two postzygotic barriers (hybrid inviability and hybrid 32 sterility) for all pairwise crosses of species within the Drosophila melanogaster 33 subgroup. Our results indicate that PMPZ isolation evolves faster than hybrid inviability 34 but slower than premating isolation. We also describe seven new interspecific hybrids in 35 the group. Our findings open up a large repertoire of tools that will enable researchers to 36 manipulate hybrids and explore the genetic basis of interspecific differentiation, 37 reproductive isolation, and speciation.

Background Through ventricular interdependence, pulmonary hypertension (PH) induces left ventricular (LV) dysfunction. We hypothesized that LV strain/strain rate, surrogate measures of myocardial contractility, are reduced in pediatric PH and relate to invasive hemodynamics, right ventricular (RV) strain, and functional measures of PH. Methods and Results At two institutions, echocardiography was prospectively performed in 54 pediatric PH patients during cardiac catheterization, and in 54 matched controls. PH patients had reduced LV global longitudinal strain (LS) (-18.8 [-17.3 - -20.4]% vs. -20.2 [-19.0 - -20.9]%, P=0.0046) predominantly due to reduced basal (-12.9 [-10.8 - -16.3]% vs. -17.9 [-14.5 - -20.7]%, P<0.0001) and mid (-17.5 [-15.5 - -19.0]% vs. -21.1 [-19.1 - -23.0]%, P<0.0001) septal strain. Basal global circumferential strain (CS) was reduced (-18.7 [-15.7 - -22.1]% vs. -20.6 [-19.0 - -22.5]%, P=0.0098), as were septal and free-wall segments. Mid CS was reduced within the free-wall. Strain rates were reduced in similar patterns. “Basal septum” LS, the combined average LS of basal and mid interventricular septal segments, correlated strongly with degree of PH (r=0.66, P<0.0001), pulmonary vascular resistance (r=0.60, P<0.0001), and RV free-wall LS (r=0.64, P<0.0001). Brain natriuretic peptide levels correlated moderately with septal LS (r=0.48, P=0.0038). PH functional class correlated moderately with LV free-wall LS (r=-0.48, P=0.0051). The septum, shared between ventricles and affected by septal shift, was the most affected LV region in PH. Conclusions Pediatric PH patients demonstrate reduced LV strain/strain rate, predominantly within the septum, with relationships to invasive hemodynamics, RV strain, and functional PH measures.

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Background Ventricular septal flattening, frequently present in pulmonary hypertension (PH), can be quantified using eccentricity index (EI). EI has not been evaluated by concurrent echocardiography and cardiac catheterization and traditionally does not account for postsystolic septal flattening, often seen in PH. We evaluated left ventricular shape, including a novel measure of maximal EI to account for postsystolic septal flattening, to establish the relationship with concurrent invasive hemodynamics. Methods Echocardiography was performed at 2 institutions in 78 pediatric PH patients during cardiac catheterization and in 78 matched controls. From midpapillary parasternal short-axis views, EI and right-to-left ventricular diameter ratio were assessed. Results EI and right-to-left ventricular measures were significantly increased in PH compared with controls. Shape measures correlated with invasive hemodynamics and PH outcome measures (PH-related hospitalization, functional class, medical therapy escalation, and BNP [brain natriuretic peptide]). End-systolic EI of 1.16 best identified the presence of PH, whereas a maximal EI of 1.42 and 1.94 best identified half-systemic and systemic PH, respectively. A maximal EI of 1.27 was associated with an odds ratio of 16.16 (95% CI, 6.62–39.46) for PH-related hospitalization or escalation of therapy. Conclusions Using simultaneous echocardiography and catheterization in the largest study population to date, we demonstrate that EI and right-to-left ventricular ratio correlate with invasive hemodynamics and outcomes measures, and EI can accurately define those with clinically important PH. These measures strengthen the ability of echocardiography to identify and follow pediatric PH patients, especially in the absence of methods to quantify right ventricular systolic pressures.