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Abstract Introduction Improving healthcare for people with multiple chronic or ongoing conditions is receiving increased attention, particularly due to the growing number of people experiencing multimorbidity (MM) and concerns about the sustainability of the healthcare system. Primary care has been promoted as an important resource for supporting people with MM to live well with their conditions and to prevent unnecessary use of health care services. However, traditional primary care has been criticized for not centring the needs and preferences of people with MM themselves. Our aim was to conduct a review that centred on the perspective of people with MM in multiple ways, including having patient partners co‐lead the design, conduct and reporting of findings, and focusing on literature that reported the perspective of people with MM, irrespective of it being experimental or nonexperimental. Methods We searched for published literature in CINAHL with Full Text (EBSCOhost) and MEDLINE All (Ovid). Findings from experimental and nonexperimental studies were integrated into collaboration with patient partners. Results Twenty‐nine articles were included in the review. Findings are described in five categories: (1) Care that is tailored to my unique situation; (2) meaningful inclusion in the team; (3) a healthcare team that is ready and able to address my complex needs; (4) supportive relationships and (5) access when and where I need it. Conclusion This review supports a reorientation of primary care systems to better reflect the experiences and perspectives of people with MM. This can be accomplished by involving patient partners in the design and evaluation of primary care services and incentivizing collaboration among health and social supports and services for people with MM. Patient or Public Contribution Patient partners were involved in the design and conduct of this review, and in the preparation of the manuscript. Their involvement is further elucidated in the manuscript text.

Abstract Establishing wetlands for nutrient capture and biodiversity support may introduce trade‐offs between environmentally beneficial functions and detrimental greenhouse gas emissions. Investigating the interaction of nutrient capture, primary production, greenhouse gas production and biodiversity support is imperative to understanding the overall function of wetlands and determining possible beneficial synergistic effects and trade‐offs. Here, we present temporally replicated data from 17 wetlands in hemi‐boreal Sweden. We explored the relationship between nutrient load, primary producing algae, production of methane and nitrous oxide, and emergence rates of chironomids to determine what factors affected each and how they related to each other. Chironomid emergence rates correlated positively with methane production and negatively with nitrous oxide production, where water temperature was the main driving factor. Increasing nutrient loads reduced methanogenesis through elevated nitrogen concentrations, while simultaneously enhancing nitrous oxide production. Nutrient loads only indirectly increased chironomid emergence rates through increased chlorophyll‐a concentration, via increased phosphorus concentrations, with certain taxa and food preference functional groups benefitting from increased chlorophyll‐a concentrations. However, water temperature seemed to be the main driving factor for chironomid emergence rates, community composition and diversity, as well as for greenhouse gas production. These findings increase our understanding of the governing relationships between biodiversity support and greenhouse gas production, and should inform future management when constructing wetlands.

Abstract The current extinction crisis requires effective assessment and monitoring tools. Genetic approaches are appealing given the relative ease of field sampling required to estimate genetic diversity characteristics assumed related to population size, evolutionary potential, and extinction risk, and to evaluate hybridization with non‐native species simultaneously. However, linkages between population genetic metrics of diversity from survey‐style field collections and demographic estimates of population size and extinction risk are still in need of empirical examples, especially for remotely distributed species of conservation concern where the approach might be most beneficial. We capitalized on an exceptional opportunity to evaluate congruence between genetic diversity metrics and demographic‐based estimates of abundance and extinction risk from a comprehensive Multiple Population Viability Analysis (MPVA) in a threatened fish, the Lahontan cutthroat trout (LCT). We sequenced non‐native trout reference samples and recently collected and archived tissue samples of most remaining populations of LCT (N = 60) and estimated common genetic assessment metrics, predicting minimal hybridization with non‐native trout, low diversity, and declining diversity over time. We further hypothesized genetic metrics would correlate positively with MPVA‐estimated abundance and negatively with extinction probability. We uncovered several instances of hybridization that pointed to immediate management needs. After removing hybridized individuals, cautious interpretation of low effective population sizes (2–63) suggested reduced evolutionary potential for many LCT populations. Other genetic metrics did not decline over time nor correlate with MPVA‐based estimates of harmonic mean abundance or 30‐year extinction probability. Our results demonstrate benefits of genetic monitoring for efficiently detecting hybridization and, though genetic results were disconnected from demographic assessment of conservation status, they suggest reduced evolutionary potential and likely a higher conservation risk than currently recognized for this threatened fish. We emphasize that genetic information provides essential complementary insight, in addition to demographic information, for evaluating species status.

Abstract Extracellular vesicles (EVs) have the potential to provide new insights into skeletal muscle (SM) physiology and pathophysiology. However, current isolation protocols often do not eliminate co‐isolated components such as lipoproteins and RNA binding proteins that could confound outcomes and hinder downstream clinical translation. In this study, we validated an EV isolation protocol that combined size‐exclusion chromatography (SEC) with ultrafiltration (UF) to increase sample throughput, scalability and purity, while providing the very first analysis of the effects of UF column choice and fraction window on EV recovery. C2C12 myotube conditioned medium was pre‐concentrated using either Amicon® Ultra 15 or Vivaspin®20 100 KDa UF columns and processed by SEC (IZON, qEV 70 nm). The resulting thirty fractions obtained were individually analysed to identify an optimal fraction window for EV recovery. The EV marker TSG101 could be detected from fractions 5 to 14, while CD9 and Annexin A2 only up to fraction 6. ApoA1+ lipoprotein co‐isolates were detected from fraction 6 onwards for both protocols. Strikingly, Amicon and Vivaspin UF concentration protocols led to qualitative and quantitative variations in EV marker profiles and purity. Eliminating lipoprotein co‐isolation by reducing the SEC fraction window resulted in a net loss of particles, but increased measures of sample purity and had only a negligible impact on the presence of EV marker proteins. In conclusion, our study developed an effective UF+SEC protocol for the isolation of EVs based on sample purity (fractions 1–5) and total EV abundance (fractions 2–10). We provide evidence to demonstrate that the choice of UF column can affect the composition of the resulting EV preparation and needs to be considered when being applied in EV isolation studies in SM. The resulting protocols will be valuable in isolating highly pure EV preparations for applications in a range of therapeutic and diagnostic studies.

Abstract Background Although some emergency department risk stratification tools consider non‐specific ECG findings as an aid in disposition decisions, their clinical value in patients with an initially low high‐sensitivity cardiac troponin I (hsTnI) is unclear. Objective Our purpose was to determine if non‐specific ECG (ns‐ECG) findings are associated with 30‐day major adverse cardiac events (MACE) in ED patients presenting with suspected acute coronary syndromes (ACS) who have a low initial hsTnI. Methods Using the prospective Siemens Atellica hsTnI Food and Drug Administration submission observational database, we conducted a retrospective cohort study of the association between ns‐ECG findings (defined as left bundle branch block [LBBB], ST depression [STD], or T‐wave inversions [TWI]) and 30‐day MACE (death, myocardial infarction, heart failure hospitalization, or coronary revascularization). Eligible patients presented with suspected ACS to one of 29 US EDs from April 2015 to April 2016, had stable vital signs, a blood sample for hsTnI (Siemen's Atellica, Siemens Healthineers, Inc, Malvern, PA) obtained at 1, 3, and 6 hours after ED presentation, and were followed for 30 days. The relationship between 30‐day outcome, initial hsTnI, and ns‐ECG was evaluated using chi‐square testing. Results Of 2676 enrolled, 1313 patients met the inclusion criteria and are included in the analysis. Median (interquartile range) age was 62 years (54, 72), 54% were male, with 56% white, and 39% African American. Median (interquartile range) times from symptom onset to presentation and presentation to specimen collection were 92 (0, 216) and 146 (117, 177) minutes, respectively. The most common presenting symptoms were chest pain (84%), followed by dyspnea (9%). ECG findings were categorized as T‐wave inversion or non‐specific T wave changes (42%), ST depression ns‐ECG ST changes (16%), or LBBB (2%). Thirty‐day MACE occurred in 72 (5.5%) patients, with coronary revascularization (35 patients, 2.7%) and heart failure (25 patients, 1.9%) being the most frequent outcomes. In patients with an initial hsTnI below the limit of quantitation (LOQ) of 2.5 ng/L (n = 449), there was no association between ns‐ECG changes and 30‐day MACE (P = 0.42). If the hsTnI was ≥LOQ (2.5 ng/L), there were increased rates of 30‐day MACE and ns‐ECG findings (P = 0.01). Conclusion In ED suspected ACS patients without unstable vital signs, and an initial hsTnI less than the LOQ (2.5 ng/L), ns‐ECG findings are not associated with 30‐day major adverse cardiac events. The use of ns‐ECG findings in ACS disposition should be considered in the context of hsTnI levels.

Abstract Anthropogenic disturbances associated with urban ecosystems can create favorable conditions for populations of some invasive plant species. Light pollution is one of these disturbances, but how it affects the growth and establishment of invasive plant populations is unknown. Cheatgrass (Bromus tectorum) is a problematic invasive species where it has displaced native grassland communities in the United States, but to our knowledge, there have been no studies of the ecological factors that affect cheatgrass presence in urban ecosystems. We conducted field surveys in urban alleys in Denver, Colorado, to compare the presence of cheatgrass at sites with and without artificial light at night (hereafter artificial light) from streetlights. These streetlights are mounted on utility poles, which cause ground disturbance when installed in alleys; we were able to test the independent effect of poles on cheatgrass establishment because not all poles have streetlights on them. We found that cheatgrass was positively associated with the presence of streetlights and to a lesser extent poles. In addition to cheatgrass, we also found that other plants were positively associated with the presence of both poles and streetlights. Our results suggest that artificial light may benefit the occurrence of cheatgrass and other plant species in urban settings. While invasive populations of cheatgrass in wild habitats attract the most attention from managers, we suggest more consideration for this grass in urban environments where its growth and establishment benefit from anthropogenic changes.

Abstract Civilization is dependent upon plants for survival. Plants permeate our every moment and our relationship with them will dictate how we will manage the threats of climate change and ecological collapse defining the Anthropocene. Yet, despite the significance of plants and the critical role they have played in shaping ecosystems, civilizations, and human cultures, many people are now disconnected from the botanical world. Students are presented with little plant content, particularly identification, compared with animal content. Consequently, we are producing few plant scientists and educating fewer scientists about plants. This drives a self‐accelerating cycle we term the extinction of botanical education. A process of knowledge erosion, that in this instance contributes to our separation from the natural world, makes us blind to the biodiversity crisis and inhibits our ability to restore it. We argue that neglecting the importance of plants within education threatens the foundations of industries and professions that rely on this knowledge. Furthermore, this extinction of botanical education creates an existential threat: Without the skills to fully comprehend the scale of and solutions to human‐induced global change, how do we as a society combat it? We present key research agendas that will enable us to reverse the extinction of botanical education and highlight the critical role plants play on the global stage.

Abstract Aims Concentrations of insulin‐like growth factor binding protein‐7 (IGFBP7) have been linked to abnormal cardiac structure and function in patients with chronic heart failure (HF), but cardiovascular correlates of the biomarker in patients with more acute presentations are lacking. We aimed to determine the relationship between IGFBP7 concentrations and cardiac structure and to evaluate the impact of IGFBP7 on the diagnosis of acute HF among patients with acute dyspnoea. Methods and results In this pre‐specified subgroup analysis of the International Collaborative of N‐terminal pro‐B‐type Natriuretic Peptide Re‐evaluation of Acute Diagnostic Cut‐Offs in the Emergency Department (ICON‐RELOADED) study, we included 271 patients with and without acute HF. All patients presented to an emergency department with acute dyspnoea, had blood samples for IGFBP7 measurement, and detailed echocardiographic evaluation. Higher IGFBP7 concentrations were associated with numerous cardiac abnormalities, including increased left atrial volume index (LAVi; r = 0.49, P

Abstract Understanding how patient‐reported quality of life (QoL) and socioeconomic status (SES) relate to survival of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) may improve prognostic information sharing. This study explores associations among QoL, SES, and survival through administration of the Euro‐QoL 5‐Dimension, 3‐level and Functional Assessment of Cancer Therapy‐Leukemia and financial impact questionnaires to 138 adult participants with newly diagnosed AML or MDS in a longitudinal, pan‐Canadian study. Cox regression and lasso variable selection models were used to explore associations among QoL, SES, and established predictors of survival. Secondary outcomes were changes in QoL, performance of the QoL instruments, and lost income. We found that higher QoL and SES were positively associated with survival. The Lasso model selected the visual analog scale of the EQ‐5D‐3L as the most important predictor among all other variables (P = .03; 92% selection). Patients with AML report improved QoL after treatment, despite higher mean out‐of‐pocket expenditures compared with MDS (up to $599 CDN/month for AML vs $239 for MDS; P = .05), greater loss of productivity‐related income (reaching $1786/month for AML vs $709 for MDS; P

Abstract Background Prior data has demonstrated increased mortality in hospitalized patients with acute heart failure (AHF) and troponin elevation. No data has specifically examined the prognostic significance of troponin elevation in patients with AHF discharged after emergency department (ED) management. Objective Evaluate the relationship between troponin elevation and outcomes in patients with AHF who are treated and released from the ED. Methods This was a secondary analysis of the Get with the Guidelines to Reduce Disparities in AHF Patients Discharged from the ED (GUIDED‐HF) trial, a randomized, controlled trial of ED patients with AHF who were discharged. Patients with elevated conventional troponin not due to acute coronary syndrome (ACS) were included. Our primary outcome was a composite endpoint: time to 30‐day cardiovascular death and/or heart failure‐related events. Results Of the 491 subjects included in the GUIDED‐HF trial, 418 had troponin measured during the ED evaluation and 66 (16%) had troponin values above the 99th percentile. Median age was 63 years (interquartile range, 54‐70), 62% (n = 261) were male, 63% (n = 265) were Black, and 16% (n = 67) experienced our primary outcome. There were no differences in our primary outcome between those with and without troponin elevation (12/66, 18.1% vs 55/352, 15.6%; P = 0.60). This effect was maintained regardless of assignment to usual care or the intervention arm. In multivariable regression analysis, there was no association between our primary outcome and elevated troponin (hazard ratio, 1.00; 95% confidence interval, 0.49–2.01, P = 0.994) Conclusion If confirmed in a larger cohort, these findings may facilitate safe ED discharge for a group of patients with AHF without ACS when an elevated troponin is the primary reason for admission.

Abstract We employ an automatic earthquake detection algorithm to seismic waveforms recorded between the years 2000 and 2020 in southwest British Columbia. 32,121 events which possess at least three paired P‐ and S‐wave arrival times are located, compared to 21,538 seismic events in the existing Geologic Survey of Canada catalog. This augmented catalog is employed for double‐difference seismic tomography across Vancouver Island, with particular focus on the Nootka Fault zone (NFZ). The NFZ is a transform boundary that separates the Juan de Fuca and Explorer plates in a zone of distributed left‐lateral strike‐slip faulting. Tomographic results indicate that a double seismic zone exists within the NFZ that parallels Vp/Vs structure typically observed in subduction zones. Specifically, a dipping high Vp/Vs layer is underlain by reduced Vp/Vs material. Structural complexities are revealed by three Mw > 6 events and their aftershocks. The 2004 Mw 6.3 and 2011 Mw 6.4 events are interpreted to reside southeast of the NFZ within the Juan de Fuca plate at depths as shallow as 20 km, and the 2014 Mw 6.6 event is interpreted to reside within oceanic lithosphere of the NFZ at depths >35 km. Vp/Vs structure further indicates that underthrust oceanic lithosphere of the Explorer plate extends to 20 km depth beneath Brooks Peninsula. Our results support the hypothesis that the NFZ represents a structurally independent slice of oceanic lithosphere that exhibits (a) a more northerly trajectory than typically depicted, and (b) increased plate curvature when compared to either the Juan de Fuca or Explorer plates.

Abstract The Sulphide Queen carbonatite deposit at Mountain Pass in southeast California is a world class rare earth element (REE) resource. This study images electrical resistivity structure of the REE deposit and surrounding area to characterize resources under cover. An east‐west elongated grid (35 × 15 km) of 65 wideband magnetotelluric stations spanning from eastern Shadow Valley to eastern Ivanpah Valley were collected and modeled in three‐dimensions (3‐D). Gravity, aeromagnetic, and geologic data are used to inform interpretation of structures in the resistivity model, including the following observations. Shadow Valley is filled with conductive sediment that locally dips southward to a depth of 1 km. The Kingston Range‐Halloran Hills detachment fault dips westward at ∼15 degrees. The REE deposit is a moderate low resistivity zone dipping southwest to a possible depth of ∼1 km, and is bounded by the North and South faults and bisected by the Middle fault. Ivanpah Dry Lake is underlain by a north striking southward dipping sedimentary basin. Two possible zones of mineralization are observed in Ivanpah Valley, one along the western edge of Ivanpah Dry Lake and one on the western edge of valley along a new inferred fault. The brittle‐ductile transition is imaged at ∼10 km below mean sea level. No deep electrically conductive structures are imaged to be related to the REE deposit likely due to the complex geologic history of the Mojave terrane. Future studies should regional target Proterozoic rocks and search within for geophysical signatures similar to Mountain Pass.

Abstract Hyperkalemia is a common electrolyte abnormality identified in the emergency department (ED) and potentially fatal. However, there is no consensus over the potassium threshold that warrants intervention or its treatment algorithm. Commonly used medications are at best temporizing measures, and the roles of binders are unclear in the emergent setting. As the prevalence of comorbid conditions altering potassium homeostasis rises, hyperkalemia becomes more common, and hence there is a need to standardize management. A panel was assembled to synthesize the available evidence and identify gaps in knowledge in hyperkalemia treatment in the ED. The panel was composed of 7 medical practitioners, including 5 physicians, a nurse, and a clinical pharmacist with collective expertise in the areas of emergency medicine, nephrology, and hospital medicine. This panel was sponsored by the American College of Emergency Physicians with a goal to create a consensus document for managing acute hyperkalemia. The panel evaluated the evidence on calcium for myocyte stabilization and potassium shifting and excretion. This article summarizes information on available therapies for hyperkalemia and proposes a hyperkalemia treatment algorithm for the ED practitioner based on the currently available literature and highlights diagnostic pitfalls and evidence gaps.

Abstract Serpentinization of ultramafic rocks is fundamental to modern plate tectonics and for volatile (re‐)cycling into the mantle and magmatic arcs. Serpentinites are also highly reactive with CO2 such that they are prime targets for carbon sequestration. Serpentinization and carbonation of ultramafic rocks results in changes in their physical properties such that they should be detectable using geophysical surveys; this could provide constraint on the reactivity of rocks without extensive sample characterization. We constrain the physio‐chemical relationships in altered ophiolitic ultramafic rocks using petrographic observations, major‐element chemistry, quantitative X‐ray diffraction, and physical properties on a suite of >400 samples from the Canadian Cordillera. Serpentinization results in a systematic decrease in density that reflects the increase in serpentine abundance and carbonation results in an increase in density, mostly reflecting the formation of magnesite; based on these data, we present two formulations for determining extent of serpentinization: one based on major‐element chemistry and the other on density. Magnetic susceptibility is variable during serpentinization; most harzburgitic samples show a 100‐fold increase in magnetic susceptibility, whereas most dunitic samples and a minor proportion of harzburgitic samples show very little change in magnetic susceptibility. We use quantitative mineralogy and physical properties of the samples to constrain a model for using density and magnetic susceptibility to approximate the mineralogy of ultramafic rock. Although further work is required to understand the role of remanence in applying these models to geophysical data, this presents an advancement and opportunity to prospect for the most reactive ultramafic rocks for carbon sequestration.

Abstract Climate change is anticipated to exacerbate the extinction risk of species whose persistence is already compromised by habitat loss, invasive species, disease, or other stressors. In coastal areas of the southeastern United States (USA), many imperiled vertebrates are vulnerable to hurricanes, which climate models predict to become more severe in the 21st century. Despite this escalating threat, explicit adaptation strategies that address hurricane threats, in particular, and climate change more generally, are largely underrepresented in recovery planning and implementation. We provide a basis for stronger emphasis on strategic planning for imperiled species facing the increasing threat of catastrophic hurricanes. Our reasoning comes from observations of short‐term environmental and biological impacts of Hurricane Michael, which impacted the Gulf Coast of the southeastern USA in October 2018. During this storm, St. Marks National Wildlife Refuge, located along the northern Gulf of Mexico's coast in the panhandle region of Florida, received storm surge that was 3.0–3.6 m (NAVD88) above sea level. Storm surge pushed sea water into some ephemeral freshwater ponds used for breeding by the federally threatened frosted flatwoods salamander (Ambystoma cingulatum). After the storm, specific conductance across all ponds measured varied from 80 to 23,100 µS/cm, compared to 75 to 445 µS/cm in spring 2018. For 17 overwashed wetlands that were measured in both spring and fall 2018, posthurricane conductance observations were, on average, more than 90 times higher than in the previous spring, setting the stage for varying population responses across this coastal landscape. Importantly, we found live individual flatwoods salamanders at both overwashed and non‐overwashed sites, although we cannot yet assess the demographic consequences of this storm. We outline actions that could be incorporated into climate adaptation strategies and recovery planning for imperiled species, like A. cingulatum, that are associated with freshwater coastal wetlands in hurricane‐prone regions.

Abstract Objective Advanced machine learning technology provides an opportunity to improve clinical electrocardiogram (ECG) interpretation, allowing non‐cardiology clinicians to initiate care for atrial fibrillation (AF). The Lucia Atrial Fibrillation Application (Lucia App) photographs the ECG to determine rhythm detection, calculates CHA2DS2‐VASc and HAS‐BLED scores, and then provides guideline‐recommended anticoagulation. Our purpose was to determine the rate of accurate AF identification and appropriate anticoagulation recommendations in emergency department (ED) patients ultimately diagnosed with AF. Methods We performed a single‐center, observational retrospective chart review in an urban California ED, with an annual census of 70,000 patients. A convenience sample of hospitalized patients with AF as a primary or secondary discharge diagnosis were evaluated for accurate ED AF diagnosis and ED anticoagulation rates. This was done by comparing the Lucia App against a gold standard board‐certified cardiologist diagnosis and using the American College of Emergency Physicians AF anticoagulation guidelines. Results Two hundred and ninety seven patients were enrolled from January 2016 until December 2019. The median age was 79 years and 44.1% were female. Compared to the gold standard diagnosis, the Lucia App detected AF in 98.3% of the cases. Physicians recommended guideline‐consistent anticoagulation therapy in 78.5% versus 98.3% for the Lucia App. Of the patients with indications for anticoagulation and discharged from the ED, only 25.0% were started at discharge. Conclusion Use of a cloud‐based ECG identification tool can allow non‐cardiologists to achieve similar rates of AF identification as board‐certified cardiologists and achieve higher rates of guideline‐recommended anticoagulation therapy in the ED.

Abstract The measurement of physicochemical properties of polydisperse complex biological samples, for example, extracellular vesicles, is critical to assess their quality, for example, resulting from their production and isolation methods. The community is gradually becoming aware of the need to combine multiple orthogonal techniques to perform a robust characterization of complex biological samples. Three pillars of critical quality attribute characterization of EVs are sizing, concentration measurement and phenotyping. The repeatable measurement of vesicle concentration is one of the key‐challenges that requires further efforts, in order to obtain comparable results by using different techniques and assure reproducibility. In this study, the performance of measuring the concentration of particles in the size range of 50–300 nm with complementary techniques is thoroughly investigated in a step‐by step approach of incremental complexity. The six applied techniques include multi‐angle dynamic light scattering (MADLS), asymmetric flow field flow fractionation coupled with multi‐angle light scattering (AF4‐MALS), centrifugal liquid sedimentation (CLS), nanoparticle tracking analysis (NTA), tunable resistive pulse sensing (TRPS), and high‐sensitivity nano flow cytometry (nFCM). To achieve comparability, monomodal samples and complex polystyrene mixtures were used as particles of metrological interest, in order to check the suitability of each technique in the size and concentration range of interest, and to develop reliable post‐processing data protocols for the analysis. Subsequent complexity was introduced by testing liposomes as validation of the developed approaches with a known sample of physicochemical properties closer to EVs. Finally, the vesicles in EV containing plasma samples were analysed with all the tested techniques. The results presented here aim to shed some light into the requirements for the complex characterization of biological samples, as this is a critical need for quality assurance by the EV and regulatory community. Such efforts go with the view to contribute to both, set‐up reproducible and reliable characterization protocols, and comply with the Minimal Information for Studies of Extracellular Vesicles (MISEV) requirements.

Pulmonary arterial hypertension, group 1 of the pulmonary hypertension disease family, involves pulmonary vascular remodelling, right ventricular dysfunction and cardiac failure. Oxidative stress, through activation of mitogen-activated protein kinases is implicated in these changes. Inhibition of apoptosis signal-regulating kinase 1, an apical mitogen-activated protein kinase, prevented pulmonary arterial hypertension developing in rodent models. Here, we investigate apoptosis signal-regulating kinase 1 in pulmonary arterial hypertension by examining the impact that its inhibition has on the molecular and cellular signalling in established disease. Apoptosis signal-regulating kinase 1 inhibition was investigated in in vivo pulmonary arterial hypertension and in vitro pulmonary hypertension models. In the in vivo model, male Sprague Dawley rats received a single subcutaneous injection of Sugen SU5416 (20 mg/kg) prior to two weeks of hypobaric hypoxia (380 mmHg) followed by three weeks normoxia (Sugen/hypoxic), then animals were either maintained for three weeks on control chow or one containing apoptosis signal-regulating kinase 1 inhibitor (100 mg/kg/day). Cardiovascular measurements were carried out. In the in vitro model, primary cultures of rat pulmonary artery fibroblasts and rat pulmonary artery smooth muscle cells were maintained in hypoxia (5% O 2 ) and investigated for proliferation, migration and molecular signalling in the presence or absence of apoptosis signal-regulating kinase 1 inhibitor. Sugen/hypoxic animals displayed significant pulmonary arterial hypertension compared to normoxic controls at eight weeks. Apoptosis signal-regulating kinase 1 inhibitor decreased right ventricular systolic pressure to control levels and reduced muscularised vessels in lung tissue. Apoptosis signal-regulating kinase 1 inhibition was found to prevent hypoxia-induced proliferation, migration and cytokine release in rat pulmonary artery fibroblasts and also prevented rat pulmonary artery fibroblast-induced rat pulmonary artery smooth muscle cell migration and proliferation. Apoptosis signal-regulating kinase 1 inhibition reversed pulmonary arterial hypertension in the Sugen/hypoxic rat model. These effects may be a result of intrinsic changes in the signalling of adventitial fibroblast.

Patients classified as idiopathic pulmonary arterial hypertension (defined as Group 1 on European Respiratory Society (ERS)/European Cardiac Society (ESC) criteria) may have evidence of minor co-existing lung disease on thoracic computed tomography. We hypothesised that these idiopathic pulmonary arterial hypertension patients ( IPAH lung disease ) are a separate subgroup of idiopathic pulmonary arterial hypertension with different phenotype and outcome compared with idiopathic pulmonary arterial hypertension patients without co-existing lung disease ( IPAH no lung disease ). Patients with ‘ IPAH lung disease ’ have been eligible for all clinical trials of Group 1 patients because they have normal clinical examination and normal spirometry but we wondered whether they responded to treatment and had similar survival to patients with ‘ IPAH no lung disease ’. We described the outcome of the cohort of patients with ‘ IPAH no lung disease ’ in a previous paper. Here, we have compared incident ‘ IPAH lung disease ’ patients with ‘ IPAH no lung disease ’ patients diagnosed concurrently in all eight Pulmonary Hypertension centres in the UK and Ireland between 2001–2009. Compared with ‘ IPAH no lung disease ’ ( n = 355), ‘ IPAH lung disease ’ patients ( n = 137) were older, less obese, predominantly male, more likely to be current/ex-smokers and had lower six-minute walk distance, lower % predicted diffusion capacity for carbon monoxide, lower mean pulmonary arterial pressure and lower pulmonary vascular resistance index. After three months of pulmonary hypertension-targeted treatment, six-minute walk distance improved equally in ‘ IPAH lung disease ’ and ‘ IPAH no lung disease ’. However, survival of ‘ IPAH lung disease ’ was lower than ‘ IPAH no lung disease ’ (one year survival: 72% compared with 93%). This survival was significantly worse in ‘ IPAH lung disease ’ even after adjusting for age, gender, smoking history, comorbidities and haemodynamics. ‘ IPAH lung disease ’ patients had similar short-term improvement in six-minute walk distance with anti-pulmonary arterial hypertension therapy but worse survival compared with ‘ IPAH no lung disease ’ patients. This suggests that ‘ IPAH lung disease ’ are a separate phenotype and should not be lumped with ‘ IPAH no lung disease ’ in clinical trials of Group 1 pulmonary arterial hypertension.

Cardiac magnetic resonance-derived ventricular variables are predictive of mortality in pulmonary arterial hypertension. Rodent models which emphasize ventricular function, allowing serial monitoring, are needed to identify pathophysiological features and novel therapies for pulmonary arterial hypertension. We investigated longitudinal changes in the Sugen–hypoxia model during disease progression. Sprague Dawley rats ( n = 32) were divided into two groups. (1) Sugen–hypoxia: a dose of subcutaneous Sugen-5416 and placed in hypobaric hypoxia for two weeks followed by normoxia for three weeks. (2) Normoxia: maintained at normal pressure for five weeks. Rats were examined at five or eight weeks with right-heart catheter, cardiac magnetic resonance, and autopsy. Compared to normoxic controls (23.9 ± 4.1 mmHg), right ventricular systolic pressure was elevated in Sugen–hypoxia rats at five and eight weeks (40.9 ± 15.5 mmHg, p = 0.026; 48.9 ± 9.6 mmHg, p = 0.002). Right ventricular end-systolic volume index was increased in eight weeks Sugen–hypoxia (0.28 ± 0.04 µlcm –2 , p = 0.003) compared to normoxic controls (0.18 ±0.03 mlcm –2 ). There was progressive dilatation of the right ventricular at eight weeks Sugen–hypoxia compared to normoxic controls (0.75 ± 0.13 µlcm –2 vs 0.56 ± 0.1 µlcm –2 p = 0.02). Ventricle mass index by cardiac magnetic resonance at five weeks (0.34 ± 0.06, p = 0.003) and eight weeks Sugen–hypoxia (0.34 ± 0.06, p = 0.002) were higher than normoxic controls (0.21 ± 0.04). Stroke volume, right ventricular ejection fraction, and left ventricular variables were preserved in Sugen–hypoxia. Ventricular changes during the course of illness in a pulmonary arterial hypertension rodent model can be examined by cardiac magnetic resonance. These changes including right ventricular hypertrophy and subsequent dilatation are similar to those seen in pulmonary arterial hypertension patients. Despite the persisting pulmonary hypertension, there are features of adaptive cardiac remodeling through the study duration.

Pulmonary hypertension (PH) is highly heterogeneous and despite treatment advances it remains a life-shortening condition. There have been significant advances in imaging technologies, but despite evidence of their potential clinical utility, practice remains variable, dependent in part on imaging availability and expertise. This statement summarizes current and emerging imaging modalities and their potential role in the diagnosis and assessment of suspected PH. It also includes a review of commonly encountered clinical and radiological scenarios, and imaging and modeling-based biomarkers. An expert panel was formed including clinicians, radiologists, imaging scientists, and computational modelers. Section editors generated a series of summary statements based on a review of the literature and professional experience and, following consensus review, a diagnostic algorithm and 55 statements were agreed. The diagnostic algorithm and summary statements emphasize the key role and added value of imaging in the diagnosis and assessment of PH and highlight areas requiring further research.