Resistin predicts disease severity and survival in patients with pulmonary arterial hypertension.

BACKGROUND: Abnormal remodeling of distal pulmonary arteries in patients with pulmonary arterial hypertension (PAH) leads to progressively increased pulmonary vascular resistance, followed by right ventricular hypertrophy and failure. Despite considerable advancements in PAH treatment prognosis remains poor. We aim to evaluate the potential for using the cytokine resistin as a genetic and biological marker for disease severity and survival in a large cohort of patients with PAH. METHODS: Biospecimens, clinical, and genetic data for 1121 adults with PAH, including 808 with idiopathic PAH (IPAH) and 313 with scleroderma-associated PAH (SSc-PAH), were obtained from a national repository. Serum resistin levels were measured by ELISA, and associations between resistin levels, clinical variables, and single nucleotide polymorphism genotypes were examined with multivariable regression models. Machine-learning (ML) algorithms were applied to develop and compare risk models for mortality prediction. RESULTS: Resistin levels were significantly higher in all PAH samples and PAH subtype (IPAH and SSc-PAH) samples than in controls (P < .0001) and had significant discriminative abilities (AUCs of 0.84, 0.82, and 0.91, respectively; P < .001). High resistin levels (above 4.54 ng/mL) in PAH patients were associated with older age (P = .001), shorter 6-min walk distance (P = .001), and reduced cardiac performance (cardiac index, P = .016). Interestingly, mutant carriers of either rs3219175 or rs3745367 had higher resistin levels (adjusted P = .0001). High resistin levels in PAH patients were also associated with increased risk of death (hazard ratio: 2.6; 95% CI: 1.27-5.33; P < .0087). Comparisons of ML-derived survival models confirmed satisfactory prognostic value of the random forest model (AUC = 0.70, 95% CI: 0.62-0.79) for PAH. CONCLUSIONS: This work establishes the importance of resistin in the pathobiology of human PAH. In line with its function in rodent models, serum resistin represents a novel biomarker for PAH prognostication and may indicate a new therapeutic avenue. ML-derived survival models highlighted the importance of including resistin levels to improve performance. Future studies are needed to develop multi-marker assays that improve noninvasive risk stratification.

Developing transmissible vaccines for animal infections.

Intrinsically safe designs and a staged transparent development process will be essential.

Advances in understanding bat infection dynamics across biological scales.

Over the past two decades, research on bat-associated microbes such as viruses, bacteria and fungi has dramatically increased. Here, we synthesize themes from a conference symposium focused on advances in the research of bats and their microbes, including physiological, immunological, ecological and epidemiological research that has improved our understanding of bat infection dynamics at multiple biological scales. We first present metrics for measuring individual bat responses to infection and challenges associated with using these metrics. We next discuss infection dynamics within bat populations of the same species, before introducing complexities that arise in multi-species communities of bats, humans and/or livestock. Finally, we outline critical gaps and opportunities for future interdisciplinary work on topics involving bats and their microbes.

Recombinant transmissible vaccines will be intrinsically contained despite the ability to superinfect.

INTRODUCTION: Transmissible vaccines offer a novel approach to suppressing viruses in wildlife populations, with possible applications against viruses that infect humans as zoonoses - Lassa, Ebola, rabies. To ensure safety, current designs propose a recombinant vector platform in which the vector is isolated from the target wildlife population. Because using an endemic vector creates the potential for preexisting immunity to block vaccine transmission, these designs focus on vector viruses capable of superinfection, spreading throughout the host population following vaccination of few individuals. AREAS COVERED: We present original theoretical arguments that, regardless of its R0 value, a recombinant vaccine using a superinfecting vector is not expected to expand its active infection coverage when released into a wildlife population that already carries the vector. However, if superinfection occurs at a high rate such that individuals are repeatedly infected throughout their lives, the immunity footprint in the population can be high despite a low incidence of active vaccine infections. Yet we provide reasons that the above expectation is optimistic. EXPERT OPINION: High vaccine coverage will typically require repeated releases or release into a population lacking the vector, but careful attention to vector choice and vaccine engineering should also help improve transmissible vaccine utility.

Management of paediatric sleep-disordered breathing.

Paediatric sleep-disordered breathing is a common condition which varies in severity from snoring to obstructive sleep apnoea. Paediatric sleep-disordered breathing is usually diagnosed clinically, with investigations such as polysomnography reserved for more complex cases. Management can involve watching and waiting, medical or adjunct treatments and adenotonsillectomy. National working groups have sought to standardise the pathway for surgery and improve the management of surgical and anaesthetic complications. Current guidelines use age, weight and comorbidities to stratify risk for these surgical cases. This article summarises these recommendations and outlines the important factors that indicate cases that may be more suitable for management in secondary and tertiary units. Appropriate case selection will reduce pressure on tertiary units while maintaining training opportunities in district general hospitals.

Kynurenine pathway metabolism evolves with development of preclinical and scleroderma-associated pulmonary arterial hypertension.

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.

Low-affinity insulin-like growth factor binding protein 7 and its association with pulmonary arterial hypertension severity and survival.

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.

Exercise training and resting blood pressure: a large-scale pairwise and network meta-analysis of randomised controlled trials.

OBJECTIVE: To perform a large-scale pairwise and network meta-analysis on the effects of all relevant exercise training modes on resting blood pressure to establish optimal antihypertensive exercise prescription practices. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: PubMed (Medline), the Cochrane library and Web of Science were systematically searched. ELIGIBILITY CRITERIA: Randomised controlled trials published between 1990 and February 2023. All relevant work reporting reductions in systolic blood pressure (SBP) and/or diastolic blood pressure (DBP) following an exercise intervention of ≥2 weeks, with an eligible non-intervention control group, were included. RESULTS: 270 randomised controlled trials were ultimately included in the final analysis, with a pooled sample size of 15 827 participants. Pairwise analyses demonstrated significant reductions in resting SBP and DBP following aerobic exercise training (-4.49/-2.53 mm Hg, p<0.001), dynamic resistance training (-4.55/-3.04 mm Hg, p<0.001), combined training (-6.04/-2.54 mm Hg, p<0.001), high-intensity interval training (-4.08/-2.50 mm Hg, p<0.001) and isometric exercise training (-8.24/-4.00 mm Hg, p<0.001). As shown in the network meta-analysis, the rank order of effectiveness based on the surface under the cumulative ranking curve (SUCRA) values for SBP were isometric exercise training (SUCRA: 98.3%), combined training (75.7%), dynamic resistance training (46.1%), aerobic exercise training (40.5%) and high-intensity interval training (39.4%). Secondary network meta-analyses revealed isometric wall squat and running as the most effective submodes for reducing SBP (90.4%) and DBP (91.3%), respectively. CONCLUSION: Various exercise training modes improve resting blood pressure, particularly isometric exercise. The results of this analysis should inform future exercise guideline recommendations for the prevention and treatment of arterial hypertension.

Metabolomic Differences in Connective Tissue Disease-Associated Versus Idiopathic Pulmonary Arterial Hypertension in the PVDOMICS Cohort.

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.

Intravenous prostacyclins for right ventricular failure following left ventricular assist device in paediatric heart failure.

Right ventricular failure after placement of left ventricular assist device in paediatric heart failure is associated with increased mortality. We report successful use of intravenous prostacyclin for right ventricular support and pulmonary hypertension after initiation of left ventricular assist device support. This suggests that intravenous prostacyclins may be an important therapy in right ventricular failure following ventricular assist device implantation.

Insulin-like growth factor binding Protein-4: A novel indicator of pulmonary arterial hypertension severity and survival.

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.

High-Intensity Interval Training and Cardiometabolic Health in the General Population: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

BACKGROUND: High-intensity interval training (HIIT) remains a promising exercise mode in managing cardiometabolic health. Large-scale analyses are necessary to understand its magnitude of effect on important cardiometabolic risk factors and inform guideline recommendations. OBJECTIVE: We aimed to perform a novel large-scale meta-analysis on the effects of HIIT on cardiometabolic health in the general population. METHODS: PubMed (MEDLINE), the Cochrane library and Web of Science were systematically searched. Randomised controlled trials (RCTs) published between 1990 and March 2023 were eligible. Research trials reporting the effects of a HIIT intervention on at least one cardiometabolic health parameter with a non-intervention control group were considered. RESULTS: This meta-analysis included 97 RCTs with a pooled sample size of 3399 participants. HIIT produced significant improvements in 14 clinically relevant cardiometabolic health parameters, including peak aerobic capacity (VO2) [weighted mean difference (WMD): 3.895 ml min-1 kg-1, P < 0.001), left ventricular ejection fraction (WMD: 3.505%, P < 0.001), systolic (WMD: - 3.203 mmHg, P < 0.001) and diastolic (WMD: - 2.409 mmHg, P < 0.001) blood pressure, resting heart rate (WMD: - 3.902 bpm, P < 0.001) and stroke volume (WMD: 9.516 mL, P < 0.001). Body composition also significantly improved through reductions in body mass index (WMD: - 0.565 kg m-2, P < 0.001), waist circumference (WMD: - 2.843 cm, P < 0.001) and percentage body fat (WMD: - 0.972%, P < 0.001). Furthermore, there were significant reductions in fasting insulin (WMD: - 13.684 pmol L-1, P = 0.004), high-sensitivity C-reactive protein (WMD: - 0.445 mg dL-1, P = 0.043), triglycerides (WMD: - 0.090 mmol L-1, P = 0.011) and low-density lipoprotein (WMD: - 0.063 mmol L-1, P = 0.050), concurrent to a significant increase in high-density lipoprotein (WMD: 0.036 mmol L-1, P = 0.046). CONCLUSION: These results provide further support for HIIT in the clinical management of important cardiometabolic health risk factors, which may have implications for physical activity guideline recommendations.

Inferring the disruption of rabies circulation in vampire bat populations using a betaherpesvirus-vectored transmissible vaccine.

Transmissible vaccines are an emerging biotechnology that hold prospects to eliminate pathogens from wildlife populations. Such vaccines would genetically modify naturally occurring, nonpathogenic viruses ("viral vectors") to express pathogen antigens while retaining their capacity to transmit. The epidemiology of candidate viral vectors within the target wildlife population has been notoriously challenging to resolve but underpins the selection of effective vectors prior to major investments in vaccine development. Here, we used spatiotemporally replicated deep sequencing to parameterize competing epidemiological mechanistic models of Desmodus rotundus betaherpesvirus (DrBHV), a proposed vector for a transmissible vaccine targeting vampire bat-transmitted rabies. Using 36 strain- and location-specific time series of prevalence collected over 6 y, we found that lifelong infections with cycles of latency and reactivation, combined with a high R0 (6.9; CI: 4.39 to 7.85), are necessary to explain patterns of DrBHV infection observed in wild bats. These epidemiological properties suggest that DrBHV may be suited to vector a lifelong, self-boosting, and transmissible vaccine. Simulations showed that inoculating a single bat with a DrBHV-vectored rabies vaccine could immunize >80% of a bat population, reducing the size, frequency, and duration of rabies outbreaks by 50 to 95%. Gradual loss of infectious vaccine from vaccinated individuals is expected but can be countered by inoculating larger but practically achievable proportions of bat populations. Parameterizing epidemiological models using accessible genomic data brings transmissible vaccines one step closer to implementation.

Improved closed test setup for biodegradation testing of slightly volatile substances in water-sediment systems (OECD 308).

Standardized biodegradation testing methods, like the OECD 308 Aerobic and Anaerobic Transformation in Aquatic Sediment Systems, generate data on biodegradation required during environmental risk and hazard assessment of chemicals under different European and international regulations. However, difficulties arise when applying the OECD 308 guideline for testing hydrophobic volatile chemicals. Especially the use of a co-solvent (like acetone) as a measure to facilitate the application of the test chemical in combination with a closed setup to reduce losses due to volatilization tend to deplete/restrict the amount of oxygen in the test system. The result is a low oxygen or even anoxic water column in the water-sediment system. Thus, the degradation half-lives of the chemical generated from such tests are not directly comparable to the regulatory half-life values for Persistence assessment of the test chemical. The aim of this work was to further develop the closed setup to improve and maintain aerobic conditions in the water phase of the water-sediment systems for testing slightly volatile hydrophobic test chemicals. This improvement was attained by optimizing the test system geometry and agitation technique to maintain aerobic conditions in the water phase in a closed test setup, investigating appropriate co-solvent application strategy, and trialing the resulting test setup. This study shows that when using a closed test setup for OECD 308 tests, agitation of the water phase overlaying the sediment and the test item application using low co-solvent volume is critical for maintaining an aerobic water layer.

Critical care nursing workforce in crisis: A discussion paper examining contributing factors, the impact of the COVID-19 pandemic and potential solutions.

AIMS AND OBJECTIVES: The critical care nursing workforce is in crisis, with one-third of critical care nurses worldwide intending to leave their roles. This paper aimed to examine the problem from a wellbeing perspective, offering implications for research, and potential solutions for organisations. DESIGN: Discursive/Position paper. METHOD: The discussion is based on the nursing and wellbeing literature. It is guided by the authors' collaborative expertise as both clinicians and researchers. Data were drawn from nursing and wellbeing peer-reviewed literature, such as reviews and empirical studies, national surveys and government and thinktank publications/reports. RESULTS: Critical care nurses have been disproportionately affected by the COVID-19 pandemic with studies consistently showing critical care nurses to have the worst psychological outcomes on wellbeing measures, including depression, burnout and post-traumatic stress disorder (PTSD). These findings are not only concerning for the mental wellbeing of critical care nurses, they also raise significant issues for healthcare systems/organisations: poor wellbeing, increased burnout and PTSD are directly linked with critical care nurses intending to leave the profession. Thus, the wellbeing of critical care nurses must urgently be supported. Resilience has been identified as a protective mechanism against the development of PTSD and burnout, thus offering evidence-based interventions that address resilience and turnover have much to offer in tackling the workforce crisis. However, turnover data must be collected by studies evaluating resilience interventions, to further support their evidence base. Organisations cannot solely rely on the efficacy of these interventions to address their workforce crisis but must concomitantly engage in organisational change. CONCLUSIONS: We conclude that critical care nurses are in urgent need of preventative, evidence-based wellbeing interventions, and make suggestions for research and practice.

Cardiac Dysfunction Biomarkers Are Associated With Potential for Successful Separation From Extracorporeal Membrane Oxygenation in Children.

Biomarkers of cardiac dysfunction may aid in decision making about organ recovery and optimal timing of separation from extracorporeal membrane oxygenation (ECMO). We conducted a prospective observational study of children from 0 to <18 years who underwent ECMO between 7/2010 and 6/2015 in a single center. In this pilot study, we aimed to determine whether Suppression of tumorigenicity 2 (ST2), N -terminal pro-B-type natriuretic peptide (NT-proBNP), galectin-3, and endostatin were associated with ability to separate from ECMO. Fifty neonatal and pediatric participants supported on venoarterial ECMO were included (median age 13 days, 50% male). Twelve (24%) participants were unable to separate from extracorporeal support. Plasma ST2 concentrations at cannulation were higher in children who were ultimately unable to separate versus those who successfully separated from ECMO (median 395.3 ng/mL vs. 207.4 ng/mL, p = 0.012). ST2 and NT-proBNP concentrations decreased significantly from the first to the last ECMO day in patients successfully separated from ECMO ( p < 0.0001 and p = 0.017, respectively). Endostatin concentrations increased significantly from the first to the last ECMO day in both groups. Galectin-3 concentrations were not associated with the ability to separate from ECMO. Cardiac dysfunction biomarkers, particularly ST2, may aid in decannulation decision-making in pediatric ECMO patients. These results should be validated with a larger study.

A monograph of the African and Madagascan species of Cyperus sect. Incurvi (Cyperaceae).

Cyperus sect. Incurvi (Cyperaceae) contains 31 species worldwide, with important continental radiations in Australasia, Tropical Africa and Madagascar, and the Neotropics. Here, a monograph of the African and Madagascan species of Cyperus sect. Incurvi is presented, including descriptions, illustrations, synonymy, notes on habitat and ecology, geographic distribution ranges and conservation assessments. Our results identify eight species of Cyperus sect. Incurvi endemic to Madagascar, and a further three species native to Tropical Africa. Seven species of Cyperus sect. Incurvi have been typified herein. Six rare Madagascan endemics are assessed as threatened with extinction.

COL18A1 genotypic associations with endostatin levels and clinical features in pulmonary arterial hypertension: a quantitative trait association study.

Variation around the COL18A1 gene, which encodes the angiostatic peptide endostatin, may influence disease heterogeneity in pulmonary arterial hypertension https://bit.ly/3shXrNR.

Proteomics discovery of pulmonary hypertension biomarkers: Insulin-like growth factor binding proteins are associated with disease severity.

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.