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Background: Risk assessment in pulmonary arterial hypertension (PAH) is fundamental to guiding treatment and improved outcomes. Clinical models are excellent at identifying high-risk patients, but leave uncertainty amongst moderate-risk patients., Research Question: Can a multiple blood biomarker model of PAH, using previously described biomarkers, improve risk discrimination over current models?, Study Design and Methods: Using a multiplex enzyme-linked immunosorbent assay, we measured N-terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP), soluble suppressor of tumorigenicity, IL-6, endostatin, galectin 3, HDGF, and insulin-like growth factor binding proteins (IGFBP1-7) in training (n = 1,623), test (n = 696), and validation (n = 237) cohorts. Clinical variables and biomarkers were evaluated by principal component analysis. NT-proBNP was not included to develop a model independent of NT-proBNP. Unsupervised k-means clustering classified participants into clusters. Transplant-free survival by cluster was examined using Kaplan-Meier and Cox proportional hazard regressions. Hazard by cluster was compared with NT-proBNP, Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL), and European Society of Cardiology (ESC) and European Respiratory Society (ERS) risk models alone and combined clinical and biomarker models., Results: The algorithm generated 5 clusters with good risk discrimination using 6 biomarkers, weight, height, and age at PAH diagnosis. In the test and validation cohorts, the biomarker model alone performed equivalent to REVEAL (area under the receiver operating characteristic curve, 0.74). Adding the biomarker model to the ESC and ERS score and REVEAL score improved the ESC and ERS score and REVEAL score. The best overall model was the biomarker model adjusted for NT-proBNP with the best C statistic, Akaike information criterion, and calibration for the adjusted model compared with either the biomarker or NT-proBNP model alone., Interpretation: A multibiomarker model alone was equivalent to current PAH clinical mortality risk prediction models and improved performance when combined and added to NT-proBNP. Clinical risk scores offer excellent predictive models, but require multiple tests; adding blood biomarkers to models can improve prediction or can enable more frequent, noninvasive monitoring of risk in PAH to support therapeutic decision-making., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Pulmonary hypertension (PH) is a significant health problem that contributes to high morbidity and mortality in diverse cardiac, pulmonary, and systemic diseases in children. Evidence-based advances in PH care have been challenged by a paucity of quality endpoints for assessing clinical course and the lack of robust clinical trial data to guide pharmacologic therapies in children. While the landmark adult AMBITION trial demonstrated the benefit of up-front combination PH therapy with ambrisentan and tadalafil, it remains unknown whether upfront combination therapy leads to more rapid and sustained clinical benefits in children with various categories of PH. In this article, we describe the inception of the Kids Mod PAH Trial, a multicenter Phase III trial, to address whether upfront combination therapy (sildenafil and bosentan vs. sildenafil alone) improves PH outcomes in children, recognizing that marked differences between the etiology and therapeutic response between adults and children exist. The primary endpoint of this study is WHO functional class (FC) 12 months after initiation of study drug therapy. In addition to the primary outcome, secondary endpoints are being assessed, including a composite measure of time to clinical worsening, WHO FC at 24 months, echocardiographic assessment of PH and quantitative assessment of right ventricular function, 6-min walk distance, and NT-proBNP levels. Exploratory endpoints include selected biomarkers, actigraphy, and assessments of quality of life. This study is designed to pave the way for additional clinical trials by establishing a robust infrastructure through the development of a PPHNet Clinical Trials Network., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.)

Background: Although fetoscopic endoluminal tracheal occlusion (FETO) was recently shown to improve survival in a multicenter, randomized trial of severe congenital diaphragmatic hernia (CDH), morbidity outcomes remain essentially unknown. The purpose of this study was to assess long-term outcomes in children with severe CDH who underwent FETO., Methods: We conducted a prospective study of severe CDH patients undergoing FETO at an experienced North American center from 2015-2021 (NCT02710968). This group was compared to a cohort of non-FETO CDH patients with severe disease as defined by liver herniation, large defect size, and/or ECMO use. Clinical data were collected through a multidisciplinary CDH clinic. Statistics were performed with t-tests and Chi-squared analyses (p≤0.05)., Results: There were 18 FETO and 17 non-FETO patients. ECMO utilization was 56% in the FETO cohort. Despite significantly lower median observed/expected lung-to-head ratio (O/E LHR) in the FETO group, [FETO: 23% (IQR:18-25) vs. non-FETO: 36% (IQR: 28-41), p<0.001], there were comparable survival rates at discharge (FETO: 78% vs. non-FETO: 59%, p = 0.23) and at 5-years (FETO: 67% vs. non-FETO: 59%, p = 0.53) between the two cohorts. At a median follow up of 5.8 years, metrics of pulmonary hypertension, pulmonary morbidity, and gastroesophageal reflux disease improved among patients after FETO. However, most FETO patients remained on bronchodilators/inhaled corticosteroids (58%) and were feeding tube dependent (67%)., Conclusions: These North American data show that prenatal tracheal occlusion, in conjunction with a long-term multidisciplinary CDH clinic, is associated with acceptable long-term survival and morbidity in children after FETO., Level of Evidence: Level III., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Variation around the COL18A1 gene, which encodes the angiostatic peptide endostatin, may influence disease heterogeneity in pulmonary arterial hypertension https://bit.ly/3shXrNR., Competing Interests: Conflict of interest: C.E. Simpson reports support for the present manuscript received from NIH/NHLBI grants. Conflict of interest: M. Griffiths reports support for the present manuscript received from NIH/NHLBI grants. Conflict of interest: J. Yang has nothing to disclose. Conflict of interest: M.K. Nies has nothing to disclose. Conflict of interest: D. Vaidya reports receiving grants or contacts outside the submitted work from National Institutes of Health. Conflict of interest: S. Brandal has nothing to disclose. Conflict of interest: L.J. Martin reports support for the present manuscript received from NIH/NHLBI grants. Conflict of interest: M.W. Pauciulo has nothing to disclose. Conflict of interest: K.A. Lutz has nothing to disclose. Conflict of interest: A.W. Coleman has nothing to disclose. Conflict of interest: E.D. Austin reports support for the present manuscript received from NIH/NHLBI grants; and grants or contracts received from CMREF, outside the submitted work. Conflict of interest: D.D. Ivy reports support for the present manuscript received from NIH/NHLBI grants; and consulting fees received from The University of Colorado contracts with Actelion, Altavant, Bayer, and Gossamer Bio, outside the submitted work. Conflict of interest: W.C. Nichols reports support for the present manuscript received from NIH/NHLBI grants. Conflict of interest: A.D. Everett reports support for the present manuscript received from NIH/NHLBI grants. Conflict of interest: P.M. Hassoun reports receiving grants or contacts outside the submitted work from NIH/NHLBI; and he serves on a scientific Advisory Board for MSD, unrelated to the current work. Conflict of interest: R.L. Damico reports support for the present manuscript received from NIH/NHLBI grants., (Copyright ©The authors 2022.)

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by sustained elevations of pulmonary artery pressure. To date, we lack circulating, diagnostic, and prognostic markers that correlate to clinical and functional parameters. In this study, we performed mass spectrometry-based proteomics analysis to identify circulating biomarkers of PAH. Plasma samples from patients with idiopathic pulmonary arterial hypertension (IPAH, N  = 9) and matched normal controls ( N  = 9) were digested with trypsin and analyzed using data-dependent acquisition on an Orbitrap mass spectrometer. A total of 826 (false discovery rate [FDR] 0.047) and 461 (FDR 0.087) proteins were identified across all plasma samples obtained from IPAH and control subjects, respectively. Of these, 153 proteins showed >2 folds change ( p  < 0.05) between groups. Circulating levels of carbonic anhydrase 2 (CA2), plasma kallikrein (KLKB1), and the insulin-like growth factor binding proteins (IGFBP1-7) were quantified by immunoassay in an independent verification cohort ( N  = 36 PAH and N  = 35 controls). CA2 and KLKB1 were significantly different in PAH versus control but were not associated with any functional or hemodynamic measurements. Whereas, IGFBP1 and 2 were associated with higher pulmonary vascular resistance, IGFBP2, 4, and 7 with decreased 6-min walk distance (6MWD), and IGFBP1, 2, 4, and 7 with worse survival. This plasma proteomic discovery analysis suggests the IGF axis may serve as important new biomarkers for PAH and play an important role in PAH pathogenesis., Competing Interests: The authors declare that there are no conflict of interests., (© 2022 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Background Endostatin, an angiogenic inhibitor, is associated with worse pulmonary arterial hypertension (PAH) outcomes in adults and poor lung growth in children. This study sought to assess whether endostatin is associated with disease severity and outcomes in pediatric PAH. Methods and Results Serum endostatin was measured in cross-sectional (N=160) and longitudinal cohorts (N=64) of pediatric subjects with PAH, healthy pediatric controls and pediatric controls with congenital heart disease (CHD) (N=54, N=15), and adults with CHD associated PAH (APAH-CHD, N=185). Outcomes, assessed by regression and Kaplan-Meier analysis, included hemodynamics, change in endostatin over time, and transplant-free survival. Endostatin secretion was evaluated in pulmonary artery endothelial and smooth muscle cells. Endostatin was higher in those with PAH compared with healthy controls and controls with CHD and was highest in those with APAH-CHD. In APAH-CHD, endostatin was associated with a shorter 6-minute walk distance and increased mean right atrial pressure. Over time, endostatin was associated with higher pulmonary artery pressure and pulmonary vascular resistance index, right ventricular dilation, and dysfunction. Endostatin decreased with improved hemodynamics over time. Endostatin was associated with worse transplant-free survival. Addition of endostatin to an NT-proBNP (N-terminal pro-B-type natriuretic peptide) based survival analysis improved risk stratification, reclassifying subjects with adverse outcomes. Endostatin was secreted primarily by pulmonary artery endothelial cells. Conclusions Endostatin is associated with disease severity, disease improvement, and worse survival in APAH-CHD. Endostatin with NT-proBNP improves risk stratification, better predicting adverse outcomes. The association of elevated endostatin with shunt lesions suggests that endostatin could be driven by both pulmonary artery flow and pressure. Endostatin could be studied as a noninvasive prognostic marker, particularly in APAH-CHD.

Currently available noninvasive markers for assessing disease severity and mortality risk in pulmonary arterial hypertension (PAH) are unrelated to fundamental disease biology. Endostatin, an angiostatic peptide known to inhibit pulmonary artery endothelial cell migration, proliferation and survival in vitro , has been linked to adverse haemodynamics and shortened survival in small PAH cohorts. This observational cohort study sought to assess: 1) the prognostic performance of circulating endostatin levels in a large, multicentre PAH cohort; and 2) the added value gained by incorporating endostatin into existing PAH risk prediction models. Endostatin ELISAs were performed on enrolment samples collected from 2017 PAH subjects with detailed clinical data, including survival times. Endostatin associations with clinical variables, including survival, were examined using multivariable regression and Cox proportional hazards models. Extended survival models including endostatin were compared to null models based on the REVEAL risk prediction tool and European Society of Cardiology/European Respiratory Society (ESC/ERS) low-risk criteria using likelihood ratio tests, Akaike and Bayesian information criteria and C-statistics. Higher endostatin was associated with higher right atrial pressure, mean pulmonary arterial pressure and pulmonary vascular resistance, and with shorter 6-min walk distance (p<0.01). Mortality risk doubled for each log higher endostatin (hazard ratio 2.3, 95% CI 1.6-3.4, p<0.001). Endostatin remained an independent predictor of survival when incorporated into existing risk prediction models. Adding endostatin to REVEAL-based and ESC/ERS criteria-based risk assessment strategies improved mortality risk prediction. Endostatin is a robust, independent predictor of mortality in PAH. Adding endostatin to existing PAH risk prediction strategies improves PAH risk assessment., Competing Interests: Conflict of interest: C.E. Simpson has nothing to disclose. Conflict of interest: M. Griffiths has nothing to disclose. Conflict of interest: J. Yang has nothing to disclose. Conflict of interest: M.K. Nies has nothing to disclose. Conflict of interest: R.D. Vaidya has nothing to disclose. Conflict of interest: S. Brandal has nothing to disclose. Conflict of interest: L.J. Martin reports grants from the NIH during the conduct of the study. Conflict of interest: M.W. Pauciulo has nothing to disclose. Conflict of interest: K.A. Lutz has nothing to disclose. Conflict of interest: A.W. Coleman has nothing to disclose. Conflict of interest: E.D. Austin reports grants from the NIH/NHLBI during the conduct of the study. Conflict of interest: The University of Colorado has contracts with Actelion, Bayer, GSK, Lilly, Liquidia and United Therapeutics for D.D. Ivy to be a consultant and to perform clinical trials. D.D. Ivy has received money for travel and lodging from Bayer, and food and beverages from United Therapeutics. Conflict of interest: W.C. Nichols has nothing to disclose. Conflict of interest: A.D. Everett has a patent (Biomarkers of Pulmonary Hypertension) pending. Conflict of interest: P.M. Hassoun served on a scientific advisory board for Merck & Co. Conflict of interest: R.L. Damico has nothing to disclose., (Copyright ©The authors 2021.)

Objective: Congenital diaphragmatic hernia (CDH) is a congenital defect associated with significant mortality and morbidity. We sought to assess the health-related quality of life (HRQoL) for caregivers of infants/children with CDH and determine risk factors for poorer HRQoL., Methods: Families were recruited from a CDH-specific outpatient clinic and HRQoL was assessed by a validated HRQoL instrument (PedsQLTM Family Impact Module) at several time points. Mixed models were used to identify demographic and clinical factors associated with worse HRQoL for caregivers., Results: A total of 29 subjects were recruited at a mean age of 2.4 ± 2.3 years. In terms of defect size, 6.9% had a Type A, 37.9% a Type B, 31.0% a Type C, and 24.1% a Type D. The mean HRQoL score at the first encounter was 67.6 ± 18.3; scores are reported from 0 to 100 with higher scores representing the higher reported quality of life. Lower median household incomes (p = .021) and use of extracorporeal membrane oxygenation (p = .013) were associated with poorer HRQoL scores. The presence of respiratory symptoms decreased HRQoL for caregivers, including daytime symptoms (p < .001) and nighttime symptoms (p < .001). While emergency department visits were not associated with a decrease in HRQoL, hospital admissions (p = .002), and reoperations for CDH (p < .001) were., Conclusion: Our study found a reduced quality of life associated with socioeconomic factors and severity of ongoing disease. Further study is needed to confirm these findings and identify strategies for aiding families cope with the chronicity of this congenital disease., (© 2021 Wiley Periodicals LLC.)

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.)

Background: Three biomarkers, soluble suppression of tumorigenicity 2 (ST2), galectin 3 (Gal3), and N-terminal brain natriuretic peptide prohormone (NT-proBNP), are approved for noninvasive risk assessment in left-sided heart failure, and small observational studies have shown their prognostic usefulness in heterogeneous pulmonary hypertension cohorts. We examined associations between these biomarkers and disease severity and survival in a large cohort of patients with pulmonary arterial hypertension (PAH) (ie, group 1 pulmonary hypertension). We hypothesized that additive use of biomarkers in combination would improve the prognostic value of survival models., Methods: Biomarker measurements and clinical data were obtained from 2,017 adults with group 1 PAH. Associations among biomarker levels and clinical variables, including survival times, were examined with multivariable regression models. Likelihood ratio tests and the Akaike information criterion were used to compare survival models., Results: Higher ST2 and NT-proBNP were associated with higher pulmonary pressures and vascular resistance and lower 6-min walk distance. Higher ST2 and NT-proBNP levels were associated with increased risk of death (hazard ratios: 2.79; 95% CI, 2.21-3.53; P < .001 and 1.84; 95% CI, 1.62-2.10; P < .001, respectively). The addition of ST2 to survival models composed of other predictors of survival, including NT-proBNP, significantly improved model fit and predictive capacity., Conclusions: ST2 and NT-proBNP are strong, noninvasive prognostic biomarkers in PAH. Despite its prognostic value in left-sided heart failure, Gal3 was not predictive in PAH. Adding ST2 to survival models significantly improves model predictive capacity. Future studies are needed to develop multimarker assays that improve noninvasive risk stratification in PAH., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Although widely used in cardiology, relation of heart failure biomarkers to cardiac haemodynamics in patients with CHD (and in particular with pulmonary insufficiency undergoing pulmonary valve replacement) remains unclear. We hypothesised that the cardiac function biomarkers N-terminal pro-brain natriuretic peptide (NT-proBNP), soluble suppressor of tumorigenicity 2, and galectin-3 would have significant associations to right ventricular haemodynamic derangements., Methods: Consecutive patients ( n = 16) undergoing cardiac catheterisation for transcatheter pulmonary valve replacement were studied. NT-proBNP, soluble suppressor of tumorigenicity 2, and galectin-3 levels were measured using a multiplex enzyme-linked immunosorbent assay from a pre-intervention blood sample obtained after sheath placement. Spearman correlation was used to identify significant correlations (p ≤ 0.05) of biomarkers with baseline cardiac haemodynamics. Cardiac MRI data (indexed right ventricular and left ventricular end-diastolic volumes and ejection fraction) prior to device placement were also compared to biomarker levels., Results: NT-proBNP and soluble suppressor of tumorigenicity 2 were significantly correlated (p < 0.01) with baseline mean right atrial pressure and right ventricular end-diastolic pressure. Only NT-proBNP was significantly correlated with age. Galectin-3 did not have significant associations in this cohort. Cardiac MRI measures of right ventricular function and volume were not correlated to biomarker levels or right heart haemodynamics., Conclusions: NT-proBNP and soluble suppressor of tumorigenicity 2, biomarkers of myocardial strain, significantly correlated to invasive pressure haemodynamics in transcatheter pulmonary valve replacement patients. Serial determination of soluble suppressor of tumorigenicity 2, as it was not associated with age, may be superior to serial measurement of NT-proBNP as an indicator for timing of pulmonary valve replacement.

Rationale: Pulmonary arterial hypertension (PAH) is a fatal disease, and pulmonary microvascular remodeling is an important contributor to PAH development. Therefore, we hypothesized that a circulating angiogenic factor could predict disease severity and survival., Objectives: We sought to assess the relationship of serum hepatoma-derived growth factor (HDGF) with PAH disease severity and survival., Methods: Using a newly developed enzyme-linked immunosorbent assay, we evaluated circulating HDGF levels in two independent PAH cohorts and two different characterized control cohorts. Clinical and laboratory data were also used to assess the value of HDGF as a PAH prognostic biomarker., Measurements and Main Results: Serum HDGF levels were significantly elevated in two independent PAH cohorts. Importantly, serum HDGF levels were not elevated in a noncardiac chronic disease cohort. Further, patients with elevated HDGF had significantly lower exercise tolerance, worse New York Heart Association functional class, and higher levels of N-terminal pro-brain natriuretic peptide. HDGF was a strong predictor of mortality, with an unadjusted hazard ratio of 4.5 (95% confidence interval, 1.9-10.3; P = 0.003 by log-rank test). In multivariable Cox proportional hazards models, elevated HDGF levels predicted decreased survival after being adjusted for age, PAH subtype, invasive hemodynamics, and N-terminal pro-brain natriuretic peptide., Conclusions: Elevated HDGF was associated with worse functional class, exertional intolerance, and increased mortality in PAH, suggesting HDGF as a potential biomarker for predicting mortality and as having possible diagnostic value for distinguishing PAH from non-PAH. HDGF may add additional value in PAH risk stratification in clinical trials and may represent a potential target for future PAH drug development.

Background: Pulmonary hypertension (PH) is a significant cause of morbidity in preterm infants, but no screening guidelines exist. We sought to identify risk factors and clinical outcomes associated with PH in preterm infants to develop a PH risk score., Methods: Retrospective analysis of two separate populations of preterm infants (NICU cohort n = 230; Clinic registry n = 580)., Results: 8.3% of the NICU cohort had PH after 4 weeks of age, while 14.8% of the clinic registry had PH after 2 months of age. Lower birth weights and longer initial hospitalizations were associated with PH in both populations (p<0.001 for all tests). Using adjusted logistic regression, patent ductus arteriosus (PDA) requiring ligation was associated with PH in both the NICU cohort (OR: 3.19; p = 0.024) and the clinic registry (OR: 2.67; p<0.001). Risk factors (birth weight ≤780 grams, home supplemental oxygen use, and PDA ligation) identified in the clinic registry (training dataset) were validated in the NICU cohort with 0-1 factors present were associated with ≤1.5% probability of having PH, any 2 factors with a 25% probability, and all 3 factors with a 40% probability., Conclusions: Lower birth weight, PDA ligation, and respiratory support were associated with PH in both populations. A PH risk score based on clinical indicators from the training dataset predicted PH in the validation set. This risk score could help focus resources to preterm infants at higher risk for PH. Further work is needed to determine whether earlier or more aggressive management of ductal lesions could alter PH outcomes., Competing Interests: The authors have declared that no competing interests exist.

Background and Objectives: Pulmonary hypertension (PH) has been associated with substantial morbidity and mortality in children, but existing analyses of inpatient care are limited to small single-institution series or focused registries representative of selected patient subgroups. We examined US national data on pediatric PH hospitalizations to determine trends in volume, demographics, procedures performed during admission, and resource utilization., Methods: Retrospective cohort study using a national administrative database of pediatric hospital discharges: the Kids' Inpatient Database., Results: Children with PH accounted for 0.13% of the 43 million pediatric hospitalizations in the United States between 1997 and 2012, and discharges demonstrated an increasing trend over the study period (P < .0001). Cumulative, inflation-adjusted national hospital charges for PH hospitalizations rose (P = .0003) from $926 million in 1997 to $3.12 billion in 2012. Patients with PH without associated congenital heart disease (CHD) comprised an increasing and majority (56.4%) proportion over the study period (P < .0001), children without associated CHD admitted at urban teaching hospitals comprised the fastest-growing subgroup. In-hospital, all-cause mortality was high (5.9%) in children with PH, but demonstrated a decreasing trend (P < .0001)., Conclusions: Morbidity and mortality of pediatric PH continue to represent substantial and growing health care burdens. Shifts in case mix toward PH not associated with CHD, toward noncardiac procedures, and toward care in urban teaching hospitals will increase pressure to manage resource utilization in this small but growing patient group and to improve expertise and define excellence in PH care across a wide range of clinical settings., (Copyright © 2015 by the American Academy of Pediatrics.)

Analysis of the human proteome has become increasingly sophisticated, and offers invaluable potential insight into the pathophysiology of human disease. The increasing standardization of methods, speed, and sophistication of mass spectrometric analysis, availability of reliable antibodies, and dissemination of information among the scientific community has allowed for exponential growth of our knowledge base. The continued effort to provide a molecular explanation for future medical applications based on biomarker discovery is epitomized by the outstanding efforts of the human proteome project, whose goal is to generate a map of the human proteome. However, proteomic analysis is underrepresented in pediatric illness; given the unique challenges of research in the pediatric population, proteomic analysis represents enormous untapped potential, especially in the further elucidation of the pathophysiology of rare diseases such as pulmonary hypertension (PH). In this article, we will describe the unique challenge of pediatric research, the importance of alternative avenues such as proteomics for in-depth analysis of pediatric pathobiology at the cellular level, the specific need for proteomic investigation of pediatric PH, the current status of PH proteomics, and future directions., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Pulmonary hypertension (PH) is an increasingly recognized complication of premature birth and bronchopulmonary dysplasia (BPD), and is associated with increased morbidity and mortality. Extreme phenotypic variability exists among preterm infants of similar gestational ages, making it difficult to predict which infants are at increased risk for developing PH. Intrauterine growth retardation or drug exposures, postnatal therapy with prolonged positive pressure ventilation, cardiovascular shunts, poor postnatal lung and somatic growth, and genetic or epigenetic factors may all contribute to the development of PH in preterm infants with BPD. In addition to the variability of severity of PH, there is also qualitative variability seen in PH, such as the variable responses to vasoactive medications. To reduce the morbidity and mortality associated with PH, a multi-pronged approach is needed. First, improved screening for and increased recognition of PH may allow for earlier treatment and better clinical outcomes. Second, identification of both prenatal and postnatal risk factors for the development of PH may allow targeting of therapy and resources for those at highest risk. Third, understanding the pathophysiology of the preterm pulmonary vascular bed may help improve outcomes through recognizing pathways that are dysregulated in PH, identifying novel biomarkers, and testing novel treatments. Finally, the recognition of conditions and exposures that may exacerbate or lead to recurrent PH is needed to help with developing treatment guidelines and preventative strategies that can be used to reduce the burden of disease., (Copyright © 2012 Wiley Periodicals, Inc.)

Context: Plasma cell myelomas (PCMs) are traditionally diagnosed by the percentage (%) of plasma cells (PCs) in the bone marrow aspirate differential combined with clinical parameters and radiographic findings. PCs are most reliably quantitated in bone marrow (BM) tissues by CD138 immunohistochemistry (IHC). However, there are no correlations of % CD138+ cells with clinical parameters or overall survival (OS). The presence of cyclin D1 has correlated with worst prognosis, but cyclin D1 has not been correlated with routine cytogenetics. CD56+, although not significantly reported in reactive plasmacytoses, monoclonal gammopathy of undetermined significance (MGUS), nor in lymphoplasmacytic lymphomas (LPLs), has not been evaluated in borderline diagnostic (borderline) cases., Objectives: It includes: (1) correlating the percentages of PCs by CD138 IHC, cyclin D1 status, and CD56 expression with clinical parameters and OS in PCMs, (2) correlating cyclin D1 status with routine cytogenetics in PCMs, borderline cases, and MGUSs, and (3) analyzing CD56 expression in PCMs, borderline cases, MGUSs, and LPLs., Design: Bone marrow aspirates, BM touch preparations, and BM clot and/or biopsy sections with CD138/kappa/lambda IHC (44-PCMs, 9-MGUSs, 17-borderline cases, 3-LPLs, and 3-reactive plasmacytoses) were reviewed and stained with CD56 and cyclin D1., Results/conclusions: Increased CD138+ cells did not correlate significantly with clinical parameters or OS. Cyclin D1+ did not correlate with the presence of a t(11;14) by routine cytogenetics [although detected in all t(11;14)+ cases], clinical parameters, nor OS. CD56 expression was identified in PCMs, MGUSs, and LPL but not in reactive plasmacytoses. CD56+ did not distinguish PCMs, MGUS, and LPLs, and did not correlate with clinical parameters or OS. CD56 and cyclin D1 IHC were better evaluated in BM clot than biopsy sections.