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Background: Insulin-like growth factors (IGFs), and their binding proteins (IGFBPs), play a significant role in cardiovascular function and may influence the pathobiology of PAH. We determined the diagnostic and prognostic value of IGF1 and IGFBP2 in pediatric PAH., Methods: Serum was analyzed by ELISA for IGF1 and IGFBP2 in pediatric PAH subjects from the NHLBI PAH Biobank (PAHB, n = 175) and a cohort of asthmatic subjects (n = 46, age 0-21 years) as a chronic pediatric pulmonary disease control. Biomarkers were analyzed with demographic and clinical variables for PAH severity., Results: Serum IGF1 was significantly lower in PAH compared to controls, while IGFBP2 was elevated in PAH subjects compared to controls. In the PAHB, IGF1 was negatively associated with mPAP and PVR, while IGFBP2 was positively associated with PVR and negatively associated with cardiac output and 6-min walk distance. Higher IGFBP2 levels were associated with use of prostacyclin therapy. IGFBP2 was associated with death, transplant, or palliative shunt with a Cox proportional hazard ratio of 8.8 (p < 0.001) but not IGF1 (p = 0.13)., Conclusions: Circulating IGFBP2 is a novel marker for pediatric PAH, which is associated with worse functional status, and survival. IGF axis dysregulation may be an important mechanistic target in pediatric pulmonary arterial hypertension., Impact: Pediatric pulmonary hypertension is a severe disease, with poorly understood pathobiology. There are few studies looking at the pathobiology of pulmonary hypertension only in children. The IGF axis is dysregulated in pediatric pulmonary arterial hypertension. IGF axis dysregulation, with increased IGFBP2, is associated with worse clinical outcomes in pediatric pulmonary artery hypertension. IGF axis dysregulation gives new insight into the disease process and may be a mechanistic or therapeutic target.

Rabies is a viral zoonosis transmitted by vampire bats across Latin America. Substantial public health and agricultural burdens remain, despite decades of bats culls and livestock vaccinations. Virally vectored vaccines that spread autonomously through bat populations are a theoretically appealing solution to managing rabies in its reservoir host. We investigate the biological and epidemiological suitability of a vampire bat betaherpesvirus (DrBHV) to act as a vaccine vector. In 25 sites across Peru with serological and/or molecular evidence of rabies circulation, DrBHV infects 80-100% of bats, suggesting potential for high population-level vaccine coverage. Phylogenetic analysis reveals host specificity within neotropical bats, limiting risks to non-target species. Finally, deep sequencing illustrates DrBHV super-infections in individual bats, implying that DrBHV-vectored vaccines might invade despite the highly prevalent wild-type virus. These results indicate DrBHV as a promising candidate vector for a transmissible rabies vaccine, and provide a framework to discover and evaluate candidate viral vectors for vaccines against bat-borne zoonoses.

Introduction: Pulmonary hypertension (PH) is a common comorbidity of cardiopulmonary disease. Endostatin, an inhibitor of angiogenesis, is elevated in neonates with lung disease. ST2 is a heart failure biomarker correlated with PH in adults. We hypothesized that these biomarkers may be useful in diagnosing PH and categorizing its severity in infants., Methods: Endostatin, ST2, and NT-proBNP plasma concentrations from 26 infants with PH and 21 control infants without PH were correlated with echocardiographic and clinical features using regression models over time., Results: Endostatin, ST2, and NT-proBNP concentrations were elevated in PH participants versus controls (p < 0.0001). Endostatin was associated with right ventricular dysfunction (p = 0.014), septal flattening (p = 0.047), and pericardial effusion (p < 0.0001). ST2 concentrations predicted right to left patent ductus arteriosus flow (p = 0.009). NT-proBNP was not associated with PH features., Conclusions: Endostatin and ST2 concentrations were associated with echocardiographic markers of worse PH in infants and may be better predictors than existing clinical standards.

Background: Pulmonary arterial hypertension (PAH) is a fatal disease that results from cardio-pulmonary dysfunction with the pathology largely unknown. Insulin-like growth factor binding protein 2 (IGFBP2) is an important member of the insulin-like growth factor family, with evidence suggesting elevation in PAH patients. We investigated the diagnostic and prognostic value of serum IGFBP2 in PAH to determine if it could discriminate PAH from healthy controls and if it was associated with disease severity and survival., Methods: Serum IGFBP2 levels, as well as IGF1/2 levels, were measured in two independent PAH cohorts, the Johns Hopkins Pulmonary Hypertension program (JHPH, N = 127), NHLBI PAHBiobank (PAHB, N = 203), and a healthy control cohort (N = 128). The protein levels in lung tissues were determined by western blot. The IGFBP2 mRNA expression levels in pulmonary artery smooth muscle cells (PASMC) and endothelial cells (PAEC) were assessed by RNA-seq, secreted protein levels by ELISA. Association of biomarkers with clinical variables was evaluated using adjusted linear or logistic regression and Kaplan-Meier analysis., Results: In both PAH cohorts, serum IGFBP2 levels were significantly elevated (p < 0.0001) compared to controls and discriminated PAH from controls with an AUC of 0.76 (p < 0.0001). A higher IGFBP2 level was associated with a shorter 6-min walk distance (6MWD) in both cohorts after adjustment for age and sex (coefficient - 50.235 and - 57.336 respectively). Cox multivariable analysis demonstrated that higher serum IGFBP2 was a significant independent predictor of mortality in PAHB cohort only (HR, 3.92; 95% CI, 1.37-11.21). IGF1 levels were significantly increased only in the PAHB cohort; however, neither IGF1 nor IGF2 had equivalent levels of associations with clinical variables compared with IGFBP2. Western blotting shown that IGFBP2 protein was significantly increased in the PAH vs control lung tissues. Finally, IGFBP2 mRNA expression and secreted protein levels were significantly higher in PASMC than in PAEC., Conclusions: IGFBP2 protein expression was increased in the PAH lung, and secreted by PASMC. Elevated circulating IGFBP2 was associated with PAH severity and mortality and is a potentially valuable prognostic marker in PAH.

Objective: To assess whether circulating interleukin-6 (IL-6) is associated with measures of disease severity and clinical worsening in pediatric pulmonary arterial hypertension (PAH)., Study Design: IL-6 was measured by enzyme-linked immunosorbent assay in serum samples from a cross-sectional cohort from the National Heart, Lung, and Blood Institute Pulmonary Arterial Hypertension Biobank (n = 175) and a longitudinal cohort from Children's Hospital Colorado (CHC) (n = 61). Associations between IL-6, disease severity, and outcomes were studied with regression and Kaplan-Meier analysis., Results: In analyses adjusted for age and sex, each log-unit greater IL-6 was significantly associated in the Pulmonary Arterial Hypertension Biobank cohort with greater pulmonary vascular resistance indices, lower odds of having idiopathic PAH or treatment with prostacyclin, and greater odds of having PAH associated with a repaired congenital shunt. In the CHC cohort, each log-unit greater IL-6 was significantly associated with greater mean pulmonary arterial pressure over time. Kaplan-Meier analysis in the CHC cohort revealed that IL-6 was significantly associated with clinical worsening (a composite score of mortality, transplant, or palliative surgery) (P = .037)., Conclusions: IL-6 was significantly associated with worse hemodynamics at baseline and over time and may be associated with clinical worsening. IL-6 may provide a less-invasive method for disease monitoring and prognosis in pediatric PAH as well as a potential therapeutic target., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: To determine if children with congenital heart disease (CHD) have lower newborn T-cell receptor excision circles (TREC) levels than the general population and to evaluate if low TREC levels in newborns with CHD are associated with clinical complications such as hospitalization for infection., Study Design: The Connecticut Newborn Screening Program reported TREC levels for newborns with CHD delivered between October 2011 and September 2016 at 2 major Connecticut children's hospitals. TREC levels for children with CHD were compared with the general population. TREC levels and outcome measures, including hospitalization for infection, were compared., Results: We enrolled 575 participants with CHD in the study. The median TREC level for newborns with CHD was lower than the general population (180.1 copies/μL vs 312.5 copies/μL; P < .01). patients with CHD requiring hospitalization for infection had lower median TREC levels than their counterparts (143.0 copies/μL vs 186.7 copies/μL; P < .01). The combination of prematurity and low TREC level had a strong relationship to hospitalization for infection (area under the receiver operative characteristic curve of 0.89). There was no association between TREC level and CHD severity., Conclusions: Newborns with CHD demonstrated lower TREC levels than the general population. Low TREC levels were associated with hospitalization for infection in preterm children with CHD. Study limitations include that this was a retrospective chart review. These findings may help to identify newborns with CHD at highest risk for infection, allowing for potential opportunities for intervention., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Host specificity has been investigated for centuries in mistletoes, viruses, insects, parasitoids, lice and flukes, yet it is poorly understood. Reviewing the numerous studies on mistletoe host specificity may contribute to our understanding of these plants and put into context the dynamics at work in root parasitic plants and animal parasites. The mechanisms that determine host specificity in mistletoes are not as well documented and understood as those in other groups of parasites. To rectify this, we synthesized the available literature and analyzed data compiled from herbaria, published monographs and our own field studies in South Africa. As for other groups of parasites, multiple factors influence mistletoe host specificity. Initially, pollination affects gene flow. Subsequently, seed dispersal vectors (birds and marsupials), host abundance and compatibility (genetic, morphological, physiological and chemical), history and environmental conditions affect the interaction of mistletoes and their hosts and determine host specificity. Mistletoe-host network analyses and a geographic mosaic approach combined with long-term monitoring of reciprocal transplant experiments, genetic analyses of confined mistletoe populations and comparative phylogenetic studies could provide further insights to our understanding of host specificity. Some of these approaches have been used to study animal-plant interactions and could be adopted to test and evaluate host specificity in mistletoes at local and larger geographic scales., (© The Authors 2016. Published by Oxford University Press on behalf of the Annals of Botany Company.)

Background and Methodology: Information is presented on the management of women referred to a sexual health service during a 1-year period for management of a non-palpable contraceptive implant or of a palpable implant considered unsuitable for routine removal., Results: Fifty-two women were referred. Thirty-four implants were non-palpable and their depth on ultrasound ranged from 2.7 to 12mm. Seventeen were fully or partly palpable and their depth ranged from 3mm or less (16 cases) to 5.6&emsp14;mm (one case). Nine had had previous failed attempts at removal, including three with two previous failed attempts. Three implants were located at sites other than the medial aspect of the arm, and were associated with long localisation times. Forty-seven implants were removed at a one-stop clinic appointment through a 2-3mm incision using ring forceps. The mean time for removal from making the incision to complete extraction was 4.8&emsp14;minutes. Three cases judged to be of higher risk were removed under local anaesthesia in theatre through a 15mm incision. These included the only case where removal was attempted unsuccessfully in the outpatient clinic. Seven of the implants were Nexplanon(®), including four cases seen during the last month of data collection., Conclusions: Removal with the technique described is rapid, with an average time of 4-5 minutes, and less than 10minutes in >90% of cases. Preliminary indications suggest that the introduction of Nexplanon has not resolved the problem of deep implant insertion. Based on our experience we suggest criteria for centres providing removal of deep implants.