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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 multiplex ELISA, we measured NT-proBNP, ST2, IL-6, Endostatin, Galectin-3, HDGF, and IGF binding proteins (IGFBP1-7) in train (n=1623), test (n=696) and validation (n=237) cohorts. Clinical variables, biomarkers were evaluated by principal component analysis. NT-proBNP was not included to develop an NT-proBNP independent model. Unsupervised k-means clustering classified subjects into clusters. Transplant-free survival by cluster was examined using Kaplan-Meier and Cox proportional hazard regressions. Hazard by cluster was compared to NT-proBNP, REVEAL, and ESC/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 (AUC 0.74). Adding the biomarker model to the ESC/ERS, and REVEAL scores improved the ESC/ERS and REVEAL scores. The best overall model was the biomarker model adjusted for NT-proBNP with the best C-statistic, AIC, and calibration for the adjusted model compared to either the biomarker or NT-proBNP model alone. INTERPRETATION: A multi-biomarker 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 enable more frequent, non-invasive monitoring of risk in PAH to support therapeutic decision making.

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Pulmonary arterial hypertension (PAH) is a poorly understood disease of the small pulmonary arteries. Pulmonary vascular remodeling and progressively rising pulmonary vascular resistance are hallmarks of the disease that ultimately result in right heart failure. Several genetic mutations, most notably in bone morphogenetic protein receptor type 2, have a causal association with heritable forms of PAH. Mutations in neurogenic locus notch homolog protein 3 (NOTCH3) have been reported in adults and children with PAH, but whether NOTCH3 is causally associated with PAH is debated. With this case report, we describe the clinical characteristics, comorbidities, and exposure history of an adult patient with PAH and multiple sclerosis who was found to have a NOTCH3 missense mutation and exposure to leflunomide.

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Numerous studies have demonstrated that endostatin (ES), a potent angiostatic peptide derived from collagen type XVIII α 1 chain and encoded by COL18A1, is elevated in pulmonary arterial hypertension (PAH). It is important to note that elevated ES has consistently been associated with altered hemodynamics, poor functional status, and adverse outcomes in adult and pediatric PAH. This study used serum samples from patients with Group I PAH and plasma and tissue samples derived from the Sugen/hypoxia rat pulmonary hypertension model to define associations between COL18A1/ES and disease development, including hemodynamics, right ventricle (RV) remodeling, and RV dysfunction. Using cardiac magnetic resonance imaging and advanced hemodynamic assessments with pressure-volume loops in patients with PAH to assess RV-pulmonary arterial coupling, we observed a strong relationship between circulating ES levels and metrics of RV structure and function. Specifically, RV mass and the ventricular mass index were positively associated with ES, whereas RV ejection fraction and RV-pulmonary arterial coupling were inversely associated with ES levels. Our animal data demonstrate that the development of pulmonary hypertension is associated with increased COL18A1/ES in the heart as well as the lungs. Disease-associated increases in COL18A1 mRNA and protein were most pronounced in the RV compared with the left ventricle and lung. COL18A1 expression in the RV was strongly associated with disease-associated changes in RV mass, fibrosis, and myocardial capillary density. These findings indicate that COL18A1/ES increases early in disease development in the RV and implicates COL18A1/ES in pathologic RV dysfunction in PAH.

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BACKGROUND: Pulmonary arterial hypertension (PAH) is characterised by poor exercise tolerance. The contribution of right ventricular (RV) diastolic function to the augmentation of cardiac output during exercise is not known. This study leverages pressure-volume (P-V) loop analysis to characterise the impact of RV diastology on poor flow augmentation during exercise in PAH. METHODS: RV P-V loops were measured in 41 PAH patients at rest and during supine bike exercise. Patients were stratified by median change in cardiac index (CI) during exercise into two groups: high and low CI reserve. Indices of diastolic function (end-diastolic elastance (E ed)) and ventricular interdependence (left ventricular transmural pressure (LVTMP)) were compared at matched exercise stages. RESULTS: Compared to patients with high CI reserve, those with low reserve exhibited lower exercise stroke volume (36 versus 49 mL·m-2; p=0.0001), with higher associated exercise afterload (effective arterial elastance (E a) 1.76 versus 0.90 mmHg·mL-1; p<0.0001), RV stiffness (E ed 0.68 versus 0.26 mmHg·mL-1; p=0.003) and right-sided pressures (right atrial pressure 14 versus 8 mmHg; p=0.002). Higher right-sided pressures led to significantly lower LV filling among the low CI reserve subjects (LVTMP -4.6 versus 3.2 mmHg; p=0.0001). Interestingly, low exercise flow reserve correlated significantly with high afterload and RV stiffness, but not with RV contractility nor RV-PA coupling. CONCLUSIONS: Patients with poor exercise CI reserve exhibit poor exercise RV afterload, stiffness and right-sided filling pressures that depress LV filling and stroke work. High afterload and RV stiffness were the best correlates to low flow reserve in PAH. Exercise unmasked significant pathophysiological PAH differences unapparent at rest.

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We sought to investigate differential metabolism in patients with systemic sclerosis (SSc) who develop pulmonary arterial hypertension (PAH) versus those who do not, as a method of identifying potential disease biomarkers. In a nested case-control design, serum metabolites were assayed in SSc subjects who developed right heart catheterization-confirmed PAH (n = 22) while under surveillance in a longitudinal cohort from Johns Hopkins, then compared with metabolites assayed in matched SSc patients who did not develop PAH (n = 22). Serum samples were collected at "proximate" (within 12 months) and "distant" (within 1-5 yr) time points relative to PAH diagnosis. Metabolites were identified using liquid chromatography-mass spectroscopy (LC-MS). An LC-MS dataset from SSc subjects with either mildly elevated pulmonary pressures or overt PAH from the University of Michigan was compared. Differentially abundant metabolites were tested as predictors of PAH in two additional validation SSc cohorts. Long-chain fatty acid metabolism (LCFA) consistently differed in SSc-PAH versus SSc without PH. LCFA metabolites discriminated SSc-PAH patients with mildly elevated pressures in the Michigan cohort and predicted SSc-PAH up to 2 yr before clinical diagnosis in the Hopkins cohort. Acylcholines containing LCFA residues and linoleic acid metabolites were most important for discriminating SSc-PAH. Combinations of acylcholines and linoleic acid metabolites provided good discrimination of SSc-PAH across cohorts. Aberrant lipid metabolism is observed throughout the evolution of PAH in SSc. Lipidomic signatures of abnormal LCFA metabolism distinguish SSc-PAH patients from those without PH, including before clinical diagnosis and in mild disease.NEW & NOTEWORTHY Abnormal lipid metabolism is evident across time in the development of SSc-PAH, and dysregulated long-chain fatty acid metabolism predicts overt PAH.

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Physical inactivity is a global health problem. Childhood is an opportune time to establish healthy physical activity behaviors, including the participation in organized physical activity, such as sports. We hypothesize that financial incentives can improve young people's participation in physical activity and sports. The design of the incentive and the context in which it operates are crucial to its success.

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In recent years, metabolomics, the systematic study of small-molecule metabolites in biological samples, has yielded fresh insights into the molecular determinants of pulmonary diseases and critical illness. The purpose of this article is to orient the reader to this emerging field by discussing the fundamental tenets underlying metabolomics research, the tools and techniques that serve as foundational methodologies, and the various statistical approaches to analysis of metabolomics datasets. We present several examples of metabolomics applied to pulmonary and critical care medicine to illustrate the potential of this avenue of research to deepen our understanding of pathophysiology. We conclude by reviewing recent advances in the field and future research directions that stand to further the goal of personalizing medicine to improve patient care.

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Pulmonary arterial hypertension (PAH) is a morbid disease characterized by significant lung endothelial cell (EC) dysfunction. Prior work has shown that microvascular endothelial cells (MVECs) isolated from animals with experimental PAH and patients with PAH exhibit significant abnormalities in metabolism and calcium signaling. With regards to metabolism, we and others have shown evidence of increased aerobic glycolysis and evidence of increased utilization of alternate fuel sources (such as fatty acids) in PAH EC. In the realm of calcium signaling, our prior work linked increased activity of the transient receptor potential vanilloid-4 (TRPV4) channel to increased proliferation of MVECs isolated from the Sugen/Hypoxia rat model of PAH (SuHx-MVECs). However, the relationship between metabolic shifts and calcium abnormalities was not clear. Specifically, whether shifts in metabolism were responsible for increasing TRPV4 channel activity in SuHx-MVECs was not known. In this study, using human data, serum samples from SuHx rats, and SuHx-MVECs, we describe the consequences of increased MVEC fatty acid oxidation in PAH. In human samples, we observed an increase in long-chain fatty acid levels that was associated with PAH severity. Next, using SuHx rats and SuHx-MVECs, we observed increased intracellular levels of lipids. We also show that increasing intracellular lipid content increases TRPV4 activity, whereas inhibiting fatty acid oxidation normalizes basal calcium levels in SuHx-MVECs. By exploring the fate of fatty acid-derived carbons, we observed that the metabolite linking increased intracellular lipids to TRPV4 activity was ß-hydroxybutyrate (BOHB), a product of fatty acid oxidation. Finally, we show that BOHB supplementation alone is sufficient to sensitize the TRPV4 channel in rat and mouse MVECs. Returning to humans, we observe a transpulmonary BOHB gradient in human patients with PAH. Thus, we establish a link between fatty acid oxidation, BOHB production, and TRPV4 activity in MVECs in PAH. These data provide new insight into metabolic regulation of calcium signaling in lung MVECs in PAH.NEW & NOTEWORTHY In this paper, we explore the link between metabolism and intracellular calcium levels in microvascular endothelial cells (MVECs) in pulmonary arterial hypertension (PAH). We show that fatty acid oxidation promotes sensitivity of the transient receptor potential vanilloid-4 (TRPV4) calcium channel in MVECs isolated from a rodent model of PAH.

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Understanding metabolic evolution underlying pulmonary arterial hypertension (PAH) development may clarify pathobiology and reveal disease-specific biomarkers. Patients with systemic sclerosis (SSc) are regularly surveilled for PAH, presenting an opportunity to examine metabolic change as disease develops in an at-risk cohort. We performed mass spectrometry-based metabolomics on longitudinal serum samples collected before and near SSc-PAH diagnosis, compared with time-matched SSc subjects without PAH, in a SSc surveillance cohort. We validated metabolic differences in a second cohort and determined metabolite-phenotype relationships. In parallel, we performed serial metabolomic and hemodynamic assessments as the disease developed in a preclinical model. For differentially expressed metabolites, we investigated corresponding gene expression in human and rodent PAH lungs. Kynurenine and its ratio to tryptophan (kyn/trp) increased over the surveillance period in patients with SSc who developed PAH. Higher kyn/trp measured two years before diagnostic right heart catheterization increased the odds of SSc-PAH diagnosis (OR 1.57, 95% CI 1.05-2.36, P = 0.028). The slope of kyn/trp rise during SSc surveillance predicted PAH development and mortality. In both clinical and experimental PAH, higher kynurenine pathway metabolites correlated with adverse pulmonary vascular and RV measurements. In human and rodent PAH lungs, expression of TDO2, which encodes tryptophan 2,3 dioxygenase (TDO), a protein that catalyzes tryptophan conversion to kynurenine, was significantly upregulated and tightly correlated with pulmonary hypertensive features. Upregulated kynurenine pathway metabolism occurs early in PAH, localizes to the lung, and may be modulated by TDO2. Kynurenine pathway metabolites may be candidate PAH biomarkers and TDO warrants exploration as a potential novel therapeutic target.NEW & NOTEWORTHY Our study shows an early increase in kynurenine pathway metabolism in at-risk subjects with systemic sclerosis who develop pulmonary arterial hypertension (PAH). We show that kynurenine pathway upregulation precedes clinical diagnosis and that this metabolic shift is associated with increased disease severity and shorter survival times. We also show that gene expression of TDO2, an enzyme that generates kynurenine from tryptophan, rises with PAH development.

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Insulin-like growth factor (IGF) binding proteins (IGFBPs) are a family of growth factor modifiers, some of which are known to be independently associated with pulmonary arterial hypertension (PAH) survival. IGF factor binding protein 7 (IGFBP7) is a unique low-affinity IGFBP that, independent of IGF, stimulates prostacyclin production. This study proposed to establish associations between IGFBP7 and PAH severity and survival, using enrollment and longitudinal samples. Serum IGFBP7 levels were significantly elevated in patients with PAH compared to controls. After adjusting for age and sex, logarithmic increases in IGFBP7 were associated with a 20 m shorter six-minute walk distance (6MWD; p < 0.001), a 2-3 mmHg higher mean right atrial pressure (p < 0.001 and 0.02), and a higher likelihood of a greater REVEAL 2.0 risk category placement (p < 0.001). Kaplan-Meier analysis demonstrated significantly decreased survival with IGFBP7 above the median and Cox multivariable analysis adjusted for age and sex, demonstrated higher serum IGFBP7 was an independent predictor of survival. Though the exact mechanism is still unknown, given IGFBP7's role as a prostacyclin stimulant, it has potential use as a therapeutic target for disease modulation.

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BACKGROUND: Around 40% of Australian children do not participate in sport. Cost is a major barrier to participation, particularly for children from low socioeconomic backgrounds. This study aimed to evaluate the uptake of a population-level children's sports subsidy scheme, including sociodemographic differences in uptake. METHODS: A state-wide cross-sectional analysis comparing sports voucher claimants (primary school-aged children with a valid Medicare or Australian visa number) from the 2019 financial year with population census data from South Australia. Chi-square was used to examine whether the percentage of eligible children who claimed a voucher differed based on age, sex, socioeconomic status (SES), and geographical remoteness. Subgroup analyses were conducted for the lowest 2 socioeconomic disadvantage deciles, split by gender. Scatterplots were used to compare sports between high and low SES children. RESULTS: A total of 74,668 children claimed sports vouchers (45.5% of eligible children). Children who were relatively younger, female, from low socioeconomic backgrounds, and from major cities were least likely to claim the voucher. The 5 most common sports were Australian rules football (30.2%), netball (13.6%), soccer (13.1%), gymnastics (10.4%), and basketball (5.7%), with the popular sports similar for high and low SES children. CONCLUSIONS: Future work is needed to understand how Sports Voucher, and sport participation rates have changed over time, and to improve voucher uptake among girls, city dwellers, and low SES children.

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Although PAH is partially attributed to disordered metabolism, previous human studies have mostly examined circulating metabolites at a single time point, potentially overlooking crucial disease biology. Current knowledge gaps include an understanding of temporal changes that occur within and across relevant tissues, and whether observed metabolic changes might contribute to disease pathobiology. We utilized targeted tissue metabolomics in the Sugen hypoxia (SuHx) rodent model to investigate tissue-specific metabolic relationships with pulmonary hypertensive features over time using regression modeling and time-series analysis. Our hypotheses were that some metabolic changes would precede phenotypic changes, and that examining metabolic interactions across heart, lung, and liver tissues would yield insight into interconnected metabolic mechanisms. To support the relevance of our findings, we sought to establish links between SuHx tissue metabolomics and human PAH -omics data using bioinformatic predictions. Metabolic differences between and within tissue types were evident by Day 7 postinduction, demonstrating distinct tissue-specific metabolism in experimental pulmonary hypertension. Various metabolites demonstrated significant tissue-specific associations with hemodynamics and RV remodeling. Individual metabolite profiles were dynamic, and some metabolic shifts temporally preceded the emergence of overt pulmonary hypertension and RV remodeling. Metabolic interactions were observed such that abundance of several liver metabolites modulated lung and RV metabolite-phenotype relationships. Taken all together, regression analyses, pathway analyses and time-series analyses implicated aspartate and glutamate signaling and transport, glycine homeostasis, lung nucleotide abundance, and oxidative stress as relevant to early PAH pathobiology. These findings offer valuable insights into potential targets for early intervention in PAH.

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Importance: Low levels of physical activity during hospitalization are thought to contribute to a range of poor outcomes for patients. Using wearable activity trackers during hospitalization may help improve patient activity, sedentary behavior, and other outcomes. Objective: To evaluate the association of interventions that use wearable activity trackers during hospitalization with patient physical activity, sedentary behavior, clinical outcomes, and hospital efficiency outcomes. Data Sources: OVID MEDLINE, CINAHL, Embase, EmCare, PEDro, SportDiscuss, and Scopus databases were searched from inception to March 2022. The Cochrane Central Register for Controlled trials, ClinicalTrials.gov, and World Health Organization Clinical Trials Registry were also searched for registered protocols. No language restrictions were imposed. Study Selection: Randomized clinical trials and nonrandomized clinical trials of interventions that used wearable activity trackers to increase physical activity or reduce sedentary behavior in adults (aged 18 years or older) who were hospitalized were included. Data Extraction and Synthesis: Study selection, data extraction, and critical appraisal were conducted in duplicate. Data were pooled for meta-analysis using random-effects models. The Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was followed. Main Outcomes and Measures: The primary outcomes were objectively measured physical activity or sedentary behavior. Secondary outcomes included clinical outcomes (eg, physical function, pain, mental health), and hospital efficiency outcomes (eg, length of stay, readmission). Results: Fifteen studies with a total of 1911 participants were included, representing various surgical cohorts (4 studies), stroke rehabilitation (3 studies), orthopedic rehabilitation (3 studies), mixed rehabilitation (3 studies), and mixed medical (2 studies). All studies were included in meta-analyses. There was a significant association between wearable activity tracker interventions with higher overall physical activity (standardized mean difference, 0.35; 95% CI, 0.15 to 0.54; I2 = 72%; P < .002) and less sedentary behavior (mean difference, -35.46 min/d; 95% CI, -57.43 to -13.48 min/d; I2 = 0; P = .002), and a significant association between wearable activity tracker interventions with improvements in physical function (standardized mean difference, 0.27; 95% CI, 0.08 to 0.46; I2 = 0; P = .006) compared with usual care. There was no significant association between wearable activity tracker interventions with pain, mental health, length of stay, or readmission risk. Conclusions and Relevance: In this systematic review and meta-analysis, interventions that used wearable activity trackers with patients who are hospitalized were associated with higher physical activity levels, less sedentary behavior, and better physical functioning compared with usual care.

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Chatbots (also known as conversational agents and virtual assistants) offer the potential to deliver healthcare in an efficient, appealing and personalised manner. The purpose of this systematic review and meta-analysis was to evaluate the efficacy of chatbot interventions designed to improve physical activity, diet and sleep. Electronic databases were searched for randomised and non-randomised controlled trials, and pre-post trials that evaluated chatbot interventions targeting physical activity, diet and/or sleep, published before 1 September 2022. Outcomes were total physical activity, steps, moderate-to-vigorous physical activity (MVPA), fruit and vegetable consumption, sleep quality and sleep duration. Standardised mean differences (SMD) were calculated to compare intervention effects. Subgroup analyses were conducted to assess chatbot type, intervention type, duration, output and use of artificial intelligence. Risk of bias was assessed using the Effective Public Health Practice Project Quality Assessment tool. Nineteen trials were included. Sample sizes ranged between 25-958, and mean participant age ranged between 9-71 years. Most interventions (n = 15, 79%) targeted physical activity, and most trials had a low-quality rating (n = 14, 74%). Meta-analysis results showed significant effects (all p < 0.05) of chatbots for increasing total physical activity (SMD = 0.28 [95% CI = 0.16, 0.40]), daily steps (SMD = 0.28 [95% CI = 0.17, 0.39]), MVPA (SMD = 0.53 [95% CI = 0.24, 0.83]), fruit and vegetable consumption (SMD = 0.59 [95% CI = 0.25, 0.93]), sleep duration (SMD = 0.44 [95% CI = 0.32, 0.55]) and sleep quality (SMD = 0.50 [95% CI = 0.09, 0.90]). Subgroup analyses showed that text-based, and artificial intelligence chatbots were more efficacious than speech/voice chatbots for fruit and vegetable consumption, and multicomponent interventions were more efficacious than chatbot-only interventions for sleep duration and sleep quality (all p < 0.05). Findings from this systematic review and meta-analysis indicate that chatbot interventions are efficacious for increasing physical activity, fruit and vegetable consumption, sleep duration and sleep quality. Chatbot interventions were efficacious across a range of populations and age groups, with both short- and longer-term interventions, and chatbot only and multicomponent interventions being efficacious.

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OBJECTIVE: Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) experience worse survival and derive less benefit from pulmonary vasodilator therapies than patients with idiopathic PAH (IPAH). We sought to identify differential metabolism in patients with CTD-PAH versus patients with IPAH that might underlie these observed clinical differences. METHODS: Adult participants with CTD-PAH (n = 141) and IPAH (n = 165) from the Pulmonary Vascular Disease Phenomics (PVDOMICS) study were included. Detailed clinical phenotyping was performed at cohort enrollment, including broad-based global metabolomic profiling of plasma samples. Participants were followed prospectively for ascertainment of outcomes. Supervised and unsupervised machine learning algorithms and regression models were used to compare CTD-PAH versus IPAH metabolomic profiles and to measure metabolite-phenotype associations and interactions. Gradients across the pulmonary circulation were assessed using paired mixed venous and wedged samples in a subset of 115 participants. RESULTS: Metabolomic profiles distinguished CTD-PAH from IPAH, with patients with CTD-PAH demonstrating aberrant lipid metabolism with lower circulating levels of sex steroid hormones and higher free fatty acids (FAs) and FA intermediates. Acylcholines were taken up by the right ventricular-pulmonary vascular (RV-PV) circulation, particularly in CTD-PAH, while free FAs and acylcarnitines were released. In both PAH subtypes, dysregulated lipid metabolites, among others, were associated with hemodynamic and RV measurements and with transplant-free survival. CONCLUSIONS: CTD-PAH is characterized by aberrant lipid metabolism that may signal shifted metabolic substrate utilization. Abnormalities in RV-PV FA metabolism may imply a reduced capacity for mitochondrial beta oxidation within the diseased pulmonary circulation.

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Proteomic analysis of patients with pulmonary arterial hypertension (PAH) has demonstrated significant abnormalities in the insulin-like growth factor axis (IGF). This study proposed to establish associations between a specific binding protein, insulin-like growth factor binding protein 4 (IGFBP4), and PAH severity as well as survival across varying study cohorts. In all cohorts studied, serum IGFBP4 levels were significantly elevated in PAH compared to controls (p < 0.0001). IGFBP4 concentration was also highest in the connective tissue-associated PAH (CTD-PAH) and idiopathic PAH subtypes (876 and 784 ng/mL, median, respectively). After adjustment for age and sex, IGFBP4 was significantly associated with worse PAH severity as defined by a decreased 6-min walk distance (6MWD), New York heart association functional class (NYHA-FC), REVEAL 2.0 score and higher right atrial pressures. In longitudinal analysis provided by one of the study cohorts, IGFBP4 was prospectively significantly associated with a shorter 6MWD, worse NYHA-FC classification, and decreased survival. Cox multivariable analysis demonstrated higher serum IGFBP4 as an independent predictor of survival in the overall PAHB cohort. Therefore, this study established that higher circulating IGFBP4 levels were significantly associated with worse PAH severity, decreased survival and disease progression. Dysregulation of IGF metabolism/growth axis may play a significant role in PAH cardio-pulmonary pathobiology.

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Right ventricular (RV) adaptation is the principal determinant of outcomes in pulmonary arterial hypertension (PAH), however, RV function is challenging to assess. RV responses to hemodynamic stressors are particularly difficult to interrogate without invasive testing. This study sought to identify metabolomic markers of in vivo right ventricular function and exercise performance in PAH. Consecutive subjects with PAH (n = 23) underwent rest and exercise right heart catheterization with multibeat pressure volume loop analysis. Pulmonary arterial blood was collected at rest and during exercise. Mass spectrometry-based targeted metabolomics were performed, and metabolic associations with hemodynamics and comprehensive measures of RV function were determined using sparse partial least squares regression. Metabolite profiles were compared with N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) measurements for accuracy in modeling ventriculo-arterial parameters. Thirteen metabolites changed in abundance with exercise, including metabolites reflecting increased arginine bioavailability, precursors of catecholamine and nucleotide synthesis, and branched-chain amino acids. Higher resting arginine bioavailability predicted more favorable exercise hemodynamics and pressure-flow relationships. Subjects with more severe PAH augmented arginine bioavailability with exercise to a greater extent than subjects with less severe PAH. We identified relationships between kynurenine pathway metabolism and impaired ventriculo-arterial coupling, worse RV diastolic function, lower RV contractility, diminished RV contractility with exercise, and RV dilation with exercise. Metabolite profiles outperformed NT-proBNP in modeling RV contractility, diastolic function, and exercise performance. Specific metabolite profiles correspond to RV functional measurements only obtainable via invasive pressure-volume loop analysis and predict RV responses to exercise. Metabolic profiling may inform discovery of RV functional biomarkers.NEW & NOTEWORTHY In this cohort of patients with pulmonary arterial hypertension (PAH), we investigate metabolomic associations with comprehensive right ventricular (RV) functional measurements derived from multibeat RV pressure-volume loop analysis. Our results show that tryptophan metabolism, particularly the kynurenine pathway, is linked to intrinsic RV function and PAH pathobiology. Findings also highlight the importance of arginine bioavailability in the cardiopulmonary system's response to exercise stress. Metabolite profiles selected via unbiased analysis outperformed N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) in predicting load-independent measures of RV function at rest and cardiopulmonary system performance under stress. Overall, this work suggests the potential for select metabolites to function as disease-specific biomarkers, offers insights into PAH pathobiology, and informs discovery of potentially targetable RV-centric pathways.

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OBJECTIVE: The objective of this study was to investigate the impact of daily screening for medical readiness to participate in early mobilisation in the paediatric intensive care unit (PICU), on reducing time to mobilisation and to explore the safety-, feasibility-, and patient-level barriers to the practice. METHODS: An interventional study with a historical control group was conducted in a PICU in a tertiary teaching hospital in Australia. The Early Mobilisation Screening Checklist was applied at 24-48 h of PICU stay with the aim to reduce time to commencing mobilisation. All patients aged term to 18 years admitted to the PICU for >48 h were included in this study. Data on time to mobilisation and patient characteristics were collected by an unblinded case note audit of children admitted to the PICU over 5 months in 2018 for the baseline group and over a corresponding period in 2019 for the intervention group. MEASUREMENTS AND MAIN RESULTS: A total of 71 children were enrolled. Survival analysis was used to compare time to mobilisation between groups, and a cox regression model found that children in the intervention group were 1.26 times more likely to participate in mobility, but this was not statistically significant (P = 0.391, log rank test for equality of survival functions). Early mobilisation was safe, with no adverse events reported in 177 participant mobilisation days. Feasibility was demonstrated by 62% of participants mobilising within 72 h of admission. Mechanical ventilation during stay (P = 0.043) and days receiving sedation infusion (% of days) (P = 0.042) were associated with a decreased likelihood of participating in mobility. CONCLUSIONS: Implementation of routine screening alone does not significantly reduce time to commencing mobility in the PICU. Early mobilisation in the PICU is safe and feasible and resulted in no adverse events during mobilisation. Patient characteristics influencing participation in mobility warrant further exploration.

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