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Urban green spaces provide many benefits, including to human wellbeing, ecosystem services, and urban wildlife. Thus, there are many reasons to green up urban spaces, especially by using native species. Furthermore, urban green spaces are suited to enhancing biodiversity without negatively impacting food or fiber production. Municipalities and private landowners invest substantially in landscaping and its maintenance. However, much of that outlay supports non-native plants that may be less adapted to local conditions such as rainfall patterns and temperature ranges, thus having greater resource requirements, as well as being less supportive of native wildlife and possessing a greater potential of becoming invasive. Here, we explore ways to increase the use of native plant species in urban settings to reduce the need for watering or chemical application, enhance the support of native species, and reduce the risk of invasion to urban and ex-urban habitats. We identify three main impediments: the perception of native species as less aesthetically pleasing, the availability of native plants in the nursery industry, and the willingness of policymakers to take supportive measures. We propose methods to address all three, providing successful examples from a number of US localities and a case study that demonstrates what drivers might exist and what actions remain to be taken. [ABSTRACT FROM AUTHOR]

Due to the unique mental and physical health challenges military service members (MSVMs) often face as a result of their service, MSVMs are a key demographic of interest. Interaction with natural environments may play a positive role in MSVMs' overall health. Although previous research has been conducted on various population preferences and emotional responses to different types of gardens, there is a lack of data focused specifically on the garden preferences and emotional responses of MSVMs. To address this deficiency, an online survey was conducted featuring a series of questions with images related to landscape types and flower colors. The survey was disseminated via social media and military organizations to both civilians and military personnel (N = 366, with a 90.6% completion rate). Emotional responses were measured using a semantic differential scale. Most respondents were male, White, and between 25 and 35 years of age. MSVM respondents were primarily in the army and were either on active duty or honorably discharged. MSVMs and civilians showed similar garden and flower color preferences, each favoring wild landscape types and warm flower colors. However, the semantic differential analysis revealed MSVMs had significantly more negative emotional responses towards landscape types and flower colors compared to civilians. This indicates that the findings offer valuable insights into the unique emotional challenges faced by MSVMs, emphasizing the need for targeted interventions. Among military respondents, tropical landscapes were perceived more negatively. While it is crucial to incorporate preferred landscape elements into a design, understanding the emotional perceptions of these preferences is likely to aid garden designers in the creation of an environment that enhances overall well-being in an urban environment. [ABSTRACT FROM AUTHOR]

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. Can a multiple blood biomarker model of PAH, using previously described biomarkers, improve risk discrimination over current models? Using a multiplex enzyme-linked immunosorbent assay, we measured N-terminal pro-B-type natriuretic peptide (NT-proBNP), soluble suppressor of tumorigenicity, IL-6, endostatin, galectin 3, hepatoma derived growth factor, 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 and European Respiratory Society risk models alone and combined clinical and biomarker models. The algorithm generated five clusters with good risk discrimination using six 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 European Society of Cardiology and European Respiratory Society score and REVEAL score improved the European Society of Cardiology and European Respiratory Society 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. In this study, 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Children and adolescents' physical inactivity is a global problem. Financial incentives are increasingly utilised to support children's participation in sport, with programs introduced in multiple jurisdictions globally, however few programs have comprehensive evaluations. This study used a Delphi methodology to develop evaluation recommendations for an existing population-wide financial incentive program based in South Australia. Methods: A three-round Delphi study was conducted from October 2022 to April 2023. A diverse range of stakeholders including end-users, government representatives, academics/researchers, and Non-Government Organisation representatives participated in the Delphi panel. Round 1 focussed on the perceived importance of various evaluation components, including reach, process, and effectiveness. Round 2 focussed on identifying evaluation approaches and tools, while Round 3 determined methodological priorities and timeframes. A consensus level of ≥ 70% was set a priori (rating 6 or 7 on 7-point scale). Round 3 results were used to formulate evaluation recommendations. Results: Sixty-seven stakeholders agreed to participate, with an average response rate of 76% (87%; 73% and 67% for each round, respectively). All evaluation components gained consensus in Round 1. In Round 2, consensus was gained on 14 evaluation measures, including measuring the cost of sport, awareness of the program amongst eligible families, and reasons for non-participation, with evaluation methods generated for each measure. Round 3 results determined participants' preferred methods of evaluation and informed the development of evaluation recommendations. Recommended evaluation methods included mixed method approaches for provider and user process evaluations and measuring program awareness using an epidemiological survey. Conclusion: This Delphi study sought the views and opinions from diverse stakeholders to create evaluation recommendations for a population-wide sports voucher program. Results suggested that a comprehensive evaluation strategy is needed to understand the reach, effectiveness, and impact of the program. Additionally, there was a consensus on reallocating program funds for this evaluation. [ABSTRACT FROM AUTHOR]

Soilless production systems (i.e hydroponics, aeroponics, aquaponics) have become commonplace in urban settings and controlled environments. They are efficient nutrient recyclers, space savers, and water conservers. However, they lack high levels of biological richness in the root microbiome when compared to soil production systems, which may affect plant health and nutrient uptake. To address this issue and incorporate more sustainable practices, beneficial microorganisms (i.e. Trichoderma spp., Bacillus sp.) can be added in the form of biofertilizers. However, many factors affect impacts of microorganisms and their interactions with plants. In this experiment, Black Summer Pac Choi (Brassica rapa var. Chinensis) was grown for two trials in a Deep-Water system (DWS) or a Nutrient Film Technique system (NFT) with commercial biofertilizers containing Trichoderma spp., Bacillus amyloliquefaciens , a combination of both, and a control. Plant physiology, nutrient composition, and nutrient uptake efficiency (NUE) were generally negatively affected by Trichoderma spp. both growing systems, indicating that Trichoderma may not be recommended for hydroponic production. However, Bacillus amyloliquefaciens showed promise as an effective biofertilizer in the NFT systems and had a positive influence on NUE in DWS. [ABSTRACT FROM AUTHOR]

Agronomic biofortification of vitamin C is a promising strategy to address vitamin C deficiencies in populations that lack access to diverse and nutritious diets. Different application methods can improve the vitamin C content in various crops; however, foliar application of ascorbic acid (AA) solutions has been under-explored. To determine if spray concentration, number of applications, and day of harvest would affect vitamin C in arugula leafy greens, foliar sprays consisting of 100 ppm and 200 ppm of AA and deionized (DI) water control were applied. Treatment application was initiated during the baby-leaf stage and subjected to a total of three sprays over the course of the experiment, followed by harvest at two days and four days after spraying (DAS). The harvested plants were measured for fresh and dry biomass and analyzed for vitamin C content, mineral composition, chlorophyll levels, and carotenoid content. The results of this study demonstrated a notably elevated total vitamin C concentration (p = 0.0002) and AA content (p = 0.02) in arugula leaves treated with a 200 ppm AA spray following the third application and harvested at 4 DAS. Additionally, the AA application improved the fresh and dry weight of leafy greens but did not exhibit any significant variances regarding the mineral composition of P, K, Ca, Mg, S, B, Zn, Mn, and Fe. Alternatively, AA foliar sprays reduced Cu content in leaves suggesting that AA reduced Cu accumulation in arugula leafy greens. In summary, the findings of this study establish that the foliar application of 200 ppm AA is an effective approach for increasing the vitamin C content in arugula leafy greens while improving the plant's biomass, mineral composition, and stress responses. These biofortified arugula leafy greens exhibit the potential to offer plant protection against environmental stresses and a more consistent supply of vitamin C to humans upon consumption. [ABSTRACT FROM AUTHOR]

Soilless production systems (i.e hydroponics, aeroponics, aquaponics) have become commonplace in urban settings and controlled environments. They are efficient nutrient recyclers, space savers, and water conservers. However, they lack high levels of biological richness in the root microbiome when compared to soil production systems, which may affect plant health and nutrient uptake. To address this issue and incorporate more sustainable practices, beneficial microorganisms (i.e. Trichoderma spp., Bacillus sp.) can be added in the form of biofertilizers. However, many factors affect impacts of microorganisms and their interactions with plants. In this experiment, Black Summer Pac Choi (Brassica rapa var. Chinensis) was grown for two trials in a Deep-Water system (DWS) or a Nutrient Film Technique system (NFT) with commercial biofertilizers containing Trichoderma spp., Bacillus amyloliquefaciens, a combination of both, and a control. Plant physiology, nutrient composition, and nutrient uptake efficiency (NUE) were generally negatively affected by Trichoderma spp. both growing systems, indicating that Trichoderma may not be recommended for hydroponic production. However, Bacillus amyloliquefaciens showed promise as an effective biofertilizer in the NFT systems and had a positive influence on NUE in DWS. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Continuously secreted by all cell types, extracellular vesicles (EVs) are small membrane‐bound structures which shuttle bioactive cargo between cells across their external environment. Their central role as natural molecular messengers and ability to cross biological barriers has garnered significant attention in the use of EVs as therapeutic delivery vehicles. Still, harnessing the potential of EVs is faced with many obstacles. A cell line engineering approach can be used to exploit EVs to encapsulate a bespoke cargo of interest. However, full details regarding native EV‐loading mechanisms remain under debate, making this a challenge. While Chinese hamster ovary (CHO) cells are well known to be the preferred host for recombinant therapeutic protein production, their application as an EV producer cell host has been largely overlooked. In this study, we engineered CHO DG44 cells to produce custom EVs with bespoke cargo. To this end, genetic constructs employing split green fluorescent protein technology were designed for tagging both CD81 and protein cargoes to enable EV loading via self‐assembling activity. To demonstrate this, NanoLuc and mCherry were used as model reporter cargoes to validate engineered loading into EVs. Experimental findings indicated that our custom EV approach produced vesicles with up to 15‐fold greater cargo compared with commonly used passive loading strategies. When applied to recipient cells, we observed a dose‐dependent increase in cargo activity, suggesting successful delivery of engineered cargo via our custom CHO EVs. [ABSTRACT FROM AUTHOR]

Objectives: The Three Delays model is a well‐established global public health framework for the utilization of obstetric services where each delay represents a series of factors affecting utilization: (1) Delay #1—Deciding to seek care, (2) Delay #2—Reaching an appropriate facility and (3) Delay #3—Receiving adequate care. The aim of this qualitative study was to explore the application of the Three Delays model to dental service utilization and describe factors attributed to delayed utilization within this framework. Methods: This study utilized a framework analysis, underpinned by the Three Delays model, to examine delays in dental care utilization. A criterion purposive sample of English‐speaking adults (18+ years) in Massachusetts and Florida, USA with limited dental care access was recruited. Data were collected via semi‐structured interviews conducted in two phases: 17 individual interviews, followed by interviews with a subset of five participants over 3 months (a total of 18 interviews). The analysis involved inductive thematic coding and systematic organization within the framework. Results: Major themes and subthemes were constructed from the participants' narratives, identified and categorized as factors in the Three Delays framework. Each of the delays was interrelated to the other two, and Delay #1 was the most common delay based on the participants' interviews. The themes and subthemes contributing to one or more delays included interpersonal communication, prior dental experience, financial considerations, childcare costs, social connection, technology literacy, time constraints, competing priorities, stressors such as eviction and immigration status and microaggressions including racism and stigma. Conclusion: The Three Delays model was applicable to the study of dental care utilization and factors that impact the decision to seek dental care, reaching an appropriate dental facility and receiving adequate dental care in this study context. [ABSTRACT FROM AUTHOR]

Poor youth mental health is an area of global concern. Summer holiday programs may provide environments that support mental health when the structures and supports of school are not available. The aim of this review was to determine the effectiveness of summer holiday programs in improving the mental health, social–emotional well-being, and cognitive (non-academic) outcomes of children and adolescents. Studies of summer holiday programs for school-aged children (5–18 years) were included if they measured any mental, socio-emotional or cognitive (non-academic) outcome. Studies were excluded if they were published prior to 2000, targeted clinical populations or lasted less than five days. Six databases were searched (April 2023). Risk of bias was assessed using the PEDro tool. Study outcomes were grouped according to three main constructs: mental health (psychological well-being, anxiety, depression, distress, and self-perception including self-esteem, self-worth, self-concept, confidence, and competence); social–emotional well-being (behavior and social skills, e.g., communication, bullying, conflict resolution, empathy, and social skills); and cognitive function (memory, selective attention, and executive function). A fourth "other" group captured substance use, personality traits, character skills, and values. Effect sizes were calculated as the standardized mean difference between pre- and post-intervention scores. The synthesis involved a random-effects meta-analysis (presented in forest plots), where possible, with the remaining outcomes narratively synthesized. Twenty-six studies (n = 6812 participants) were included. The results of the meta-analysis suggested that summer programs showed a statistically non-significant trend toward reducing symptoms of anxiety and depression (k = 2 studies, SMD = −0.17, 95% CI −2.94, 2.60), psychological distress (k = 2 studies, SMD −0.46, 95% CI –1.71, 0.79), and no effect on self-esteem (k = 6 studies, SMD = 0.02, 95% CI −0.02, 0.06) or self-worth (k = 3 studies, SMD = 0.05, 95% CI 0.00, 0.11). Narrative syntheses indicated a pattern toward improvements in general mental health, self-perception, social–emotional outcomes, and cognition. Studies were generally small, with a high risk of bias. Summer holiday programs for children and adolescents show trends toward improving mental, social, emotional, and cognitive outcomes. Programs targeting disadvantaged children showed stronger patterns of improvement related to mental health and self-perception than programs targeting the general population. While effect sizes are small to negligible, they consistently indicate improvements. Summer programs present a promising avenue to promote mental health in children; however, further rigorously designed, clearly reported control-group studies are required to more fully understand their effects. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 ¼ 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 ¼ 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. Longchain fatty acid metabolism (LCFA) consistently differed in SSc-PAH versus SSc without PH. LCFA metabolites discriminated SScPAH 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. [ABSTRACT FROM AUTHOR]

Military service members (MSVMs) suffer from mental and physical health ailments upon returning home from enlistment. Due to the enormity of these different and complex ailments, many unique therapeutic methods, like therapeutic gardens, have been utilized on MSVM populations to improve their overall wellbeing. Therapeutic gardens are built following a set of guidelines meant to serve general populations instead of target populations. There has been little research on the preferences of landscape design elements in therapeutic gardens by MSVMs. To determine if landscape design elements can be optimized for therapeutic gardens that serve MSVMs, a series of questions with pictures pertaining to preferences were created in an online survey that was released to civilians on social media and MSVMs through U.S. military organizations (N = 366, 90.6% completed). The average respondents were male, Caucasian, and 25–35 years old. The majority of MSVM respondents were or had enlisted in the Army branch, and were currently active duty, or honorably discharged. MSVMs and civilians had overall similar preferences of utilities and garden elements. While commonalities were found among the two respondent groups, with a preference for clear walkways, lighting wild and natural views, there were differences. In contrast to civilians, MSVMs also overwhelmingly preferred fences and gates, and the creation of privacy and prospect views instead of refuge views. Results indicate that an increased line-of-sight in fenced-in areas may make MSVMs more comfortable in therapeutic garden settings. These differences may assist urban planners and landscapers in the building of green spaces tailored to target populations like MSVMs and to illustrate the importance of building inclusive spaces for populations of concern. [ABSTRACT FROM AUTHOR]

Vitamin C is crucial for physical well-being, and its deficiency can lead to severe health consequences. Biofortification has been used to address this deficiency by enhancing vitamin C in plants. Additionally, soilless agriculture has been used to conserve and optimize water use in comparison to conventional agriculture. While hydrogels have been shown to improve water conservation and are used for biofortification in crops, their application has only been explored in soil-based and hydroponic farming. The aeroponics system is a plant-growing method that has shown potential for increasing yields and biomass while conserving water and nutrients. In this paper, we have developed an aeroponic-compatible medium to grow romaine lettuce (Lactuca sativa L.) with eggshell powder (ESP) mixed with calcium-alginate hydrogel as a substrate and nutrient source aiming to conserve water and incorporate vitamin C through biofortification. Herein, lower water spray time and higher intervals, with varied gel types and ESP concentrations, resulted in healthy lettuce growth. Plants treated with 0.5% ascorbic acid-absorbed ESP-mixed alginate hydrogel for biofortification showed higher levels of vitamin C compared to the traditional method. This study suggests using an alginate hydrogel–ESP-based substrate in aeroponics to reduce water usage and enhance plant biofortification of vitamin C. [ABSTRACT FROM AUTHOR]

Plant growth and physiology can be affected by environmental and chemical factors that have the potential to influence yields. Among the factors that influence plant growth, neonicotinoid seed treatments have shown significant effects on plant growth, particularly in cotton. The dual benefits seen from neonicotinoids on plant growth and insect control show promise in improving cotton yields but little is known about how different seed treatments affect seedling physiology. A greenhouse experiment was undertaken to investigate how three neonicotinoid seed treatments (clothianidin, thiamethoxam, and imidacloprid) affect the physiology and growth of cotton seedlings in controlled environmental conditions. A randomized complete block design was used to examine seed treatments and an untreated control. Cotton seeds were treated, grown, and evaluated for physiological changes until the fifth true leaf-stage and measurements were taken at each of these stages. Data were collected on plant height, shoot fresh weight, leaf area, root length, and root biomass. In addition, chlorophyll pigments and nutrient analysis were performed on cotton seedlings. The seedlings of imidacloprid treated seeds had greater height, shoot fresh mass, leaf area, and relative growth rate by the fifth true leaf stage compared to other treated plants; however, clothianidin showed comparative performance at earlier stages in plant development that equilibrated over time. While all neonicotinoid seed treatments showed positive effects, imidacloprid showed the most potential as a bioactivator on plant growth. [ABSTRACT FROM AUTHOR]

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 b-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. [ABSTRACT FROM AUTHOR]

Background: Effective therapeutics given early to high-risk ambulatory patients with coronavirus disease 2019 (COVID-19) could improve outcomes and reduce overall healthcare burden. However, conducting site visits in non-hospitalised patients, who should remain isolated, is problematic. Aim: To evaluate the feasibility of a purely remote (virtual) study in non-hospitalised patients with COVID-19; and the efficacy and safety of nebulised recombinant interferon-β1a (SNG001) in this setting. Design & setting: Randomised, double-blind, parallel-group study, which was conducted remotely. Method: Eligible patients aged ≥65 years (or ≥50 years with risk factors) with COVID-19 and not requiring hospital admission were recruited remotely. They were randomised to SNG001 or placebo once-daily via nebuliser for 14 days. The main outcomes were assessments of feasibility and safety, which were all conducted remotely. Results: Of 114 patients treated, 111 (97.4%) completed 28 days of follow-up. Overall compliance to study medication was high, with ≥13 doses taken by 89.7% and 92.9% of treated patients in the placebo and SNG001 groups, respectively. Over the course of the study, only two patients were hospitalised, both in the placebo group; otherwise there were no notable differences between treatments for the efficacy parameters. No patients withdrew owing to an adverse event, and a similar proportion of patients experienced on-treatment adverse events in the two treatment groups (64.3% and 67.2% with SNG001 and placebo, respectively); most were mild or moderate and not treatment-related. Conclusion: This study demonstrated that it is feasible to conduct a purely virtual study in community-based patients with COVID-19, when the study included detailed daily assessments and with medication administered via nebuliser. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Although many acute exacerbations of COPD (AECOPD) are triggered by non-bacterial causes, they are often treated with antibiotics. Preliminary research suggests that the Chinese herbal medicine “Shufeng Jiedu” (SFJD), may improve recovery and therefore reduce antibiotic use in patients with AECOPD. Aims: To assess the feasibility of conducting a randomised placebo-controlled clinical trial of SFJD for AECOPD in UK primary care. Methods: GPs opportunistically recruited patients experiencing an AECOPD. Participants were randomised 1:1 to usual care plus SFJD or placebo for 14 days. Participants, GPs and research nurses were blinded to treatment allocation. GPs could prescribe immediate, delayed or no antibiotics, with delayed prescribing encouraged where appropriate. Participants were asked to complete a participant diary, including EXACT-PRO and CAT™ questionnaires for up to 4 weeks. Outcomes included recruitment rate and other measures of study feasibility described using only descriptive statistics and with no formal comparisons between groups. We also conducted qualitative interviews with recruited and non-recruited COPD patients and clinicians, analysed using framework analysis. Results: Over 6 months, 19 participants (6 SFJD, 13 placebo) were recruited. Sixteen (84%) participants returned diaries or provided a diary by recall. Overall, 1.3 participants were recruited per 1,000 patients on the COPD register per month open. Median duration of treatment was 9.8 days in the intervention group vs 13.3 days in the placebo group. The main reason for discontinuation in both groups was perceived side-effects. in both groups. Point estimates for both the EXACT-PRO and CAT™ outcomes suggested possible small benefits of SFJD. Most patients and clinicians were happy to try SFJD as an alternative to antibiotics for AECOPD. Recruitment was lower than expected because of the short recruitment period, the lower incidence of AECOPD during the COVID-19 pandemic, patients starting antibiotics from “rescue packs” before seeing their GP, and workforce challenges in primary care. Conclusion: Recruitment was impaired by the COVID-19 pandemic. Nevertheless, we were able to demonstrate the feasibility of recruiting and randomising participants and identified approaches to address recruitment challenges such as including the trial medication in COPD patients’ “rescue packs” and delegating recruitment to a central trials team. [ABSTRACT FROM AUTHOR]

Key message: We found four indicative traits of innate immunity. Sorghum-resistant varieties had a greater trichome, stomatal and chloroplast density, and smaller mesophyll intercellular width than susceptible varieties. The sorghum aphid (SA), Melanaphis sorghi (Theobald), can severely reduce sorghum yield. The contribution of structural traits to SA resistance has not been extensively studied. Moreover, the current screening method for resistance is inherently subjective for resistance and requires infestation in plants. Quantifying the microanatomical basis of innate SA resistance is crucial for developing reliable screening tools requiring no infestation. The goal of this study was to identify structural traits linked to physical innate SA resistance in sorghum. We conducted controlled environment and field experiments under no SA infestation conditions, with two resistant (R. LBK1 and R. Tx2783) and two susceptible (R. Tx7000 and R. Tx430) varieties. Leaf tissues collected at the fifth leaf stage in the controlled environment experiment were analyzed for the epidermal and mesophyll traits using light and transmission electron microscopy. Leaf tissues collected at physiological maturity in the field experiment were analyzed for surface traits using scanning electron microscopy. Our results showed that stomatal density, trichome density, trichome length, and chloroplast density are key leaf structural traits indicative of physical innate SA resistance. We found that resistant varieties had a greater density of trichomes (39%), stomata (31%), and chloroplast (42%), and smaller mesophyll intercellular width (− 52%) than susceptible varieties. However, the chloroplast, mitochondria, and epidermal cell ultrastructural traits were ineffective indicators of SA resistance. Our findings provide the foundation for developing an objective high-throughput method for SA resistance screening. We suggest a follow-up validation experiment to confirm our outcomes under SA infestation conditions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Semiarid pasture management strategies can affect soil hydraulic and thermal properties that determine water fluxes and storage, and heat flow in unsaturated soils. We evaluated long-term (>10 years) perennial and annual semiarid pasture system effects on saturated hydraulic conductivity (ks), soil water retention curves (SWRCs), soil water thresholds (i.e., volumetric water content (θv) at saturation, field capacity (FC), and permanent wilting point (PWP); plant available water (PAW)), thermal conductivity (λ), and diffusivity (Dt) within the 0–20 cm soil depth. Forage systems included: Old World bluestem (Bothriochloa bladhii) + legumes (predominantly alfalfa (Medicago sativa)) (OWB-legume), native grass-mix (native), alfalfa + tall wheatgrass (Thinopyrum ponticum) (alfalfa-TW), and annual grass-mix (annual) pastures on a clay loam soil; and native, teff (Eragrostis tef), OWB-grazed, and OWB-ungrazed pastures on a sandy clay loam soil. The perennial OWB-legume and native pastures had increased soil organic matter (SOM) and reduced bulk density (ρb), improving ks, soil water thresholds, λ, and Dt, compared to annual teff and alfalfa-TW (P < 0.05). Soil λ, but not Dt, increased with increasing θv. Grazed pastures decreased ks and water retention compared to other treatments (P < 0.05), yet did not affect λ and Dt (P > 0.05), likely due to higher ρb and contact between particles. Greater λ and Dt at saturation and PWP in perennial versus annual pastures may be attributed to differing SOM and ρb, and some a priori differences in soil texture. Overall, our results suggest that perennial pasture systems are more beneficial than annual systems for soil water storage and heat movement in semiarid regions. [ABSTRACT FROM AUTHOR]

The consumption of plants plays an important role in human health. In addition to providing macro and micronutrients, plants are the sole sources of several phytonutrients that play a major role in disease prevention. However, in modern diets, increased consumption of cheaper, processed foods with poor nutritional value over fruits and vegetables leads to insufficient consumption of essential nutrients such as vitamin C. Taking supplements can address some of the insufficient nutrients in a diet. However, supplements are not as diverse or bioavailable as the nutrients in plants. Improving the abundance of nutrients in plants will reduce the amounts that need to be consumed, thereby reducing the price barrier and use of supplements. In this study, broccoli (Brassica oleracea var. italica) microgreens grown in a controlled environment were biofortified for increased vitamin C content. The microgreens grown on growing pads were treated with supplemental nutrient solutions. Treatments were applied four to five days after germination and included four different concentrations of ascorbic acid specifically, 0% (control), 0.05%, 0.1%, 0.25% and 0.5%, added to the nutrient solution. Microgreens with turgid cotyledons and appearance of tip of first true leaves were harvested about 14 days after germination and were analyzed for biomass, chlorophylls, carotenoids, vitamin C and other minerals content. The ascorbic acid improved the microgreens' fresh biomass, percent dry matter, chlorophylls, carotenoids, vitamin C, and potassium content. Moreover, this study also mapped out the correlation between ascorbic acid, phytochemicals, and broccoli microgreens' mineral composition. The total vitamin C was positively correlated to K and negatively correlated to chlorophylls, N, P, Mg, Ca, S, and B (p < 0.01). These relationships can be applied in future vitamin C biofortification research across different microgreens. In conclusion, vitamin C was increased up to 222% by supplemental ascorbic acid without being detrimental to plant health and mineral composition. [ABSTRACT FROM AUTHOR]

Edible flowers are a rich source of phytochemicals with potential health benefits. Yet, changes in production practices can influence the phytochemical composition of edible flowers. Practices such as the addition of biochar have been used to affect growing media properties as well as to conserve peat resources. However, there is little known about how biochar affects the phytochemical composition of edible flowers. To determine if biochar affects phytochemicals in Viola cornuta, four cultivars were subjected to different rates of biochar, with and without fertilizer. At the rate of 10% biochar and without fertilizer application, flower polyphenol and flavonoid concentrations were decreased by 10–20% in two cultivars. However, at 25% biochar, flower polyphenol concentrations varied widely. When fertilizer was added, no effects of biochar were seen. Phytochemical characterization of unfertilized plants further revealed that while increased rates of biochar reduced concentrations of certain antioxidant compounds, these compounds were increased when fertilizer was added. Overall, fertilization can counteract some of the negative effects of biochar on Viola cultivars, resulting in higher nutritional quality and an increase in bioactive compounds produced, providing an ability to replace the peat moss with biochar. [ABSTRACT FROM AUTHOR]

Rationale: To date, it remains unclear whether recent changes in the management of patients with systemic sclerosis-associated pulmonary hypertension (SSc-PH) have improved survival. Objectives: To describe a cohort of SSc-PH patients and compare their characteristics and survival between the last two decades. Methods: SSc-PH patients prospectively enrolled in the Johns Hopkins PH Center Registry were grouped into two cohorts based on the date of diagnostic right heart catheterization: cohort A included patients diagnosed between 1999 and 2010, and cohort B included those diagnosed between 2010 and 2021. Patients' characteristics were compared between the two cohorts. Measurements and Main Results: Of 504 SSc-PH patients distributed almost equally between the two cohorts, 308 (61%) had World Symposium on Pulmonary Hypertension (WSPH) Group 1, 43 (9%) had Group 2, and 151 (30%) had Group 3. Patients with Group 1 disease in cohort B had significantly better clinical and hemodynamic characteristics at diagnosis, were more likely to receive upfront combination pulmonary arterial hypertension therapy, and had a nearly 4-year increase in median transplant-free survival in univariable analysis compared to those in cohort A (P<0.01). Improved transplant-free survival was still observed after adjusting for patients' baseline characteristics. In contrast, for Group 2 or 3 SSc-PH patients, there were no differences in baseline clinical, hemodynamic, or survival characteristics between the two cohorts. Conclusions: This is the largest single-center study that compares clinical characteristics of SSc-PH patients between the last two decades. Transplant-free survival has improved significantly for those with Group 1 disease over the last decade, possibly secondary to earlier detection and better therapeutic management. Conversely, those with Group 2 or 3 disease continue to have dismal prognosis. [ABSTRACT FROM AUTHOR]

In pulmonary artery hypertension (PAH), emerging evidence suggests that metabolic abnormalities may be contributing to cellular dysfunction in PAH. Metabolic abnormalities such as glycolytic shift have been observed intracellularly in several cell types in PAH, including microvacular endothelial cells (MVECs). Concurrently, metabolomics of human PAH samples has also revealed a variety of metabolic abnormalities; however the relationship between the intracellular metabolic abnormalities and the serum metabolome in PAH remains under investigation. In this study, we utilize the sugen/hypoxia (SuHx) rodent model of PAH to examine the RV, LV and MVEC intracellular metabolome (using targeted metabolomics) in normoxic and SuHx rats. We additionally validate key findings from our metabolomics experiments with data obtained from cell culture of normoxic and SuHx MVECs, as well as metabolomics of human serum samples from two different PAH patient cohorts. Taken together, our data, spanning rat serum, human serum and primary isolated rat MVECs reveal that: (1) key classes of amino acids (specifically, branched chain amino acids—BCAA) are lower in the pre‐capillary (i.e., RV) serum of SuHx rats (and humans); (2) intracellular amino acid levels (in particular BCAAs) are increased in SuHx‐MVECs; (3) there may be secretion rather than utilization of amino acids across the pulmonary microvasculature in PAH and (4) an oxidized glutathione gradient is present across the pulmonary vasculature, suggesting a novel fate for increased glutamine uptake (i.e., as a source of glutathione). in MVECs in PAH. In summary, these data reveal new insight into the shifts in amino acid metabolism occurring across the pulmonary circulation in PAH. [ABSTRACT FROM AUTHOR]

Background: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are a major reason for consultations in primary care, hospital admissions, deterioration in function, and mortality. Despite the majority of exacerbations not being caused by bacteria, as many as 70% of patients who present in UK primary care with AECOPD are prescribed antibiotics as part of standard care. However, finding effective non-antibiotic treatments for COPD exacerbations is a priority to reduce antibiotic use. The Chinese herbal medicine Shufeng Jiedu® (SFJD) has the potential to reduce treatment failure and duration of hospital stay. This study aims to determine the feasibility of conducting a fully powered randomised, double blind, placebo-controlled clinical trial on SFJD for AECOPD in UK primary care. Methods: This study is a phase III, two-arm individually double blind, randomised, placebo-controlled feasibility trial with nested qualitative study, coordinated by the Southampton Clinical Trial Unit (SCTU). Patients aged ≥ 40 years, with a current AECOPD, presenting with increased sputum purulence/volume, or breathlessness, and for whom the GP is considering use of antibiotics, will be eligible to participate. We aim to recruit seven eligible participants per month and randomise them to receive either the patent Chinese herbal medicine SFJD capsules or placebo for 14 consecutive days and to follow-up for 12 weeks. The primary outcomes include the feasibility of recruitment, study retention, and the percentage of diary completion. Discussion: If this trial demonstrates the feasibility of recruitment, delivery, and follow-up, we will seek funding for a fully powered placebo-controlled trial of SFJD for the treatment of AECOPD in primary care. Trial registration: This trial is registered via ISRCTN on 1 July 2021, identifier: ISRCTN26614726. [ABSTRACT FROM AUTHOR]

Purpose: Tuberculosis (TB) remains one of the most serious diseases caused by a single organism. Multiple (MDR) and extensively (XDR) drug resistant disease poses a threat to global health and requires new drugs and/or innovative approaches to treatment. A number of drugs have been proposed as inhaled therapy for TB, frequently prepared by spray drying. CPZEN-45 is a novel anti-tubercular drug that has poor oral bioavailability but has shown promise when administered via inhalation. Methods: Excipient-free CPZEN-45 HCl has been spray dried into a powder with physicochemical characteristics, aerodynamic particle size distribution, and delivered dose suitable for consideration as an inhaled product. Results: The mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of the powder delivered using a RS01 inhaler were 2.62 ± 0.04 μm and 1.76 ± 0.09, respectively. Additionally, the powder was physically and chemically stable after storage at ambient conditions for >1.5 years with particle size similar to freshly manufactured product. Overages in spray dried powder were recycled the powder and resprayed into drug product likewise resulting in negligible change in quality thus allowing for further preclinical characterization as necessary. CPZEN-45 was scaled up using pilot-scale manufacturing equipment where the density of the powder was increased to facilitate larger delivered doses without affecting the aerodynamic performance properties. Conclusion: The spray dried powders were suitable for pharmacokinetics, efficacy and preclinical toxicology studies. The final method of manufacture may be used directly for CGMP particle manufacture to support IND and Phase I clinical trials and beyond. [ABSTRACT FROM AUTHOR]

Vitamin C (Vit C) is an essential micronutrient and antioxidant for human health. Unfortunately, Vit C cannot be produced in humans and is ingested through diet while severe deficiencies can lead to scurvy. However, consumption is often inconsistent, and foods vary in Vit C concentrations. Biofortification, the practice of increasing micronutrient or mineral concentrations, can improve the nutritional quality of crops and allow for more consistent dietary levels of these nutrients. Of the three leading biofortification practices (i.e., conventional, transgenic, and agronomical), the least explored approach to increase Vit C in microgreens is agronomically, especially through the supplemental application of ascorbic acid. In this study, biofortification of Vit C in microgreens through supplemental ascorbic acid was attempted and proven achievable. Arugula (Eruca sativa 'Astro') microgreens were irrigated with four concentrations of ascorbic acid and a control. Total Vit C (T-AsA) and ascorbic acid increased in microgreens as supplementary concentrations increased. In conclusion, biofortification of Vit C in microgreens through supplemental ascorbic acid is achievable, and consumption of these bio-fortified microgreens could help fulfill the daily Vit C requirements for humans, thereby reducing the need for supplemental vitamins. [ABSTRACT FROM AUTHOR]

Background: Given the morbidity and mortality associated with pulmonary arterial hypertension (PAH), risk stratification approaches that guide therapeutic management have been previously employed. However, most patients remain in the intermediate-risk category despite initial therapy. Herein, we sought to determine whether echocardiographic parameters could improve the risk stratification of intermediate-risk patients. Methods: Prevalent PAH patients previously enrolled in observational studies at 3 pulmonary hypertension centers were included in this study. A validated PAH risk stratification approach was used to stratify patients into low-, intermediate-, and high-risk groups. Right ventricular echocardiographic parameters were used to further stratify intermediate-risk patients into intermediate-low- and intermediate-high-risk groups based on transplant-free survival. Results: From a total of 146 patients included in our study, 38 patients died over a median follow-up of 2.5 years. Patients with intermediate-/high-risk had worse echocardiographic parameters. Tricuspid annular plane systolic excursion (TAPSE) and the degree of tricuspid regurgitation (TR) were highly associated with survival (p < 0.01, p = 0.04, respectively) and were subsequently used to further stratify intermediate-risk patients. Among intermediate-risk patients, survival was worse for patients with TAPSE < 19 mm compared to those with TAPSE ≥ 19 mm (estimated one-year survival 74% vs. 96%, p < 0.01) and for patients with moderate/severe TR compared to those with no/trace/mild TR (estimated one-year survival 70% vs. 93%, p < 0.01). Furthermore, among intermediate-risk patients, those with both TAPSE < 19 mm and moderate/severe TR had an estimated one-year survival (56%) similar to that of high-risk patients (56%), and those with both TAPSE ≥ 19 mm and no/trace/mild TR had an estimated one-year survival (97%) similar to that of low-risk patients (95%). Conclusions: Echocardiography, a routinely performed, non-invasive imaging modality, plays a pivotal role in discriminating distinct survival phenotypes among prevalent intermediate-risk PAH patients using TAPSE and degree of TR. This can potentially help guide subsequent therapy. [ABSTRACT FROM AUTHOR]

Increasing costs and environmental issues regarding excessive use of peat moss is impacting the horticultural industry. Biochar is a valuable substrate additive that has the potential to reduce the use of peatmoss in greenhouse production. However, its varying effects on ornamentals requires that individual species and cultivars of crops must be evaluated to determine the threshold for benefits. Viola cornuta is a high value ornamental crop; however, information on how different rates of biochar rates affect productivity and physiology of Viola cultivars in container production is not known. To determine if biochar rates could increase the productivity of Viola, we mixed a peat-based substrate with 10, 25, and 50% (w:w) hardwood biochar in two studies on four cultivars. Without fertilizers, 10 and 25% biochar improved plant biomass, growth, root length, and flowering, but 50% biochar was found to have negative effects on plant growth and flowering. Cultivars varied in their response to biochar rates. When fertilizer was applied in the second experiment, biochar rates did not impact growth parameters or flowering. These results suggest that up to 25% biochar can be used in Viola production without detrimental impacts. However, 50% biochar can be used with the addition of fertilizer without negatively affecting plant growth. Biochar can have a short-term impact on the growth characteristics of Viola plants in container production, but fertilization and growing period of Viola may influence these effects. These results indicate that biochar could be the suitable replacement for peat moss, with up to 50% biochar rate in Viola production reducing the environmental and economic burden for peat moss. [ABSTRACT FROM AUTHOR]

Cardiac magnetic resonance (CMR) measures of right ventricular (RV) mass, volumes, and function have diagnostic and prognostic value in pulmonary arterial hypertension (PAH). We hypothesized that RV mass‐based metrics would discriminate incident PAH as redefined by the lower mean pulmonary arterial pressure (mPAP) threshold of >20 mmHg at the Sixth World Symposium on Pulmonary Hypertension (6th WSPH). Eighty‐nine subjects with suspected PAH underwent CMR imaging, including 64 subjects with systemic sclerosis (SSc). CMR metrics, including RV and left ventricular (LV) mass, were measured. All subjects underwent right heart catheterization (RHC) for assessment of hemodynamics within 48 h of CMR. Using generalized linear models, associations between CMR metrics and PAH were assessed, the best subset of CMR variables for predicting PAH were identified, and relationships between mass‐based metrics, hemodynamics, and other predictive CMR metrics were examined. Fifty‐nine subjects met 6th WSPH criteria for PAH. RV mass metrics, including ventricular mass index (VMI), demonstrated the greatest magnitude difference between subjects with versus without PAH. Overall and in SSc, VMI and RV mass measured by CMR were among the most predictive variables discriminating PAH at RHC, with areas under the receiver operating characteristic curve 0.86 and 0.83. respectively. VMI increased linearly with pulmonary vascular resistance and with mPAP in PAH, including in lower ranges of mPAP associated with mild PAH. VMI ≥ 0.37 yielded a positive predictive value of 90% for discriminating PAH. RV mass metrics measured by CMR, including VMI, discriminate incident, treatment‐naïve PAH as defined by 6th WSPH criteria. [ABSTRACT FROM AUTHOR]

Introduction and aims Biologics targeting the tumour necrosis factor (TNF) and the interleukin (IL)-17/23 axis are highly effective treatments for psoriasis but can result in cutaneous adverse events. The pathogenesis of paradoxical eczema, an atopic dermatitis (AD) phenotype occurring after biologic initiation in people with psoriasis, is unknown. This study explored the systemic disease signature of paradoxical eczema. Methods We used single-cell RNA-Seq on peripheral blood mononuclear cells (PBMCs) from three patients with psoriasis with paradoxical eczema, and three matched, biologic-treated controls who had psoriasis. Differential gene expression, gene network expression and cell–cell interaction (using MultiNicheNet) analyses allowed comparison of cases and controls. We assessed overlap between paradoxical eczema and AD using six AD transcriptome datasets. Results Overall, 32 827 PBMCs (14 521 from cases, 18 306 from controls) were included and categorized into 27 clusters. Between cases and controls, there were 727 differentially expressed genes (DEGs) (log fold-change > 0.25, adjusted P  < 0.05). A total of 94 of the top 100 DEGs were from monocytes. Significant DEG networks (P < 0.05) mostly mapped to T-cell and monocyte clusters, with commonly enriched pathways in cases including interferon (IFN)-γ, IFN-α, TNF, IL-2/signal transducer and activator of transcription 5 and T-cell differentiation pathways. Cell–cell interaction analysis revealed that the most prioritized interactions in controls, based on differential expression data and known ligand-receptor interactions, included immune regulatory interactions (including ligands such as transforming growth factor β1 and lymphocyte-activation gene 3). In cases, functions of prioritized interactions included chemotaxis, leucocyte activation, T-cell priming and IFN-γ signalling. There was significant enrichment of concordance in the direction of effect of DEGs (65%, P = 5.39 × 10−6) and enriched pathways (85%, P = 3.62 × 10−13) between AD and paradoxical eczema. Conclusions Patients with paradoxical eczema have reduced immune regulatory mechanisms and evidence of monocyte and T-cell activation systemically, with increased production IFN-γ, IFN-α and TNF. There is a significant overlap with the AD transcriptome. [ABSTRACT FROM AUTHOR]