Genetic regulation and targeted reversal of lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension.

Vascular inflammation critically regulates endothelial cell (EC) pathophenotypes, particularly in pulmonary arterial hypertension (PAH). Dysregulation of lysosomal activity and cholesterol metabolism have known inflammatory roles in disease, but their relevance to PAH is unclear. In human pulmonary arterial ECs and in PAH, we found that inflammatory cytokine induction of the nuclear receptor coactivator 7 (NCOA7) both preserved lysosomal acidification and served as a homeostatic brake to constrain EC immunoactivation. Conversely, NCOA7 deficiency promoted lysosomal dysfunction and proinflammatory oxysterol/bile acid generation that, in turn, contributed to EC pathophenotypes. In vivo, mice deficient for Ncoa7 or exposed to the inflammatory bile acid 7α-hydroxy-3-oxo-4-cholestenoic acid (7HOCA) displayed worsened PAH. Emphasizing this mechanism in human PAH, an unbiased, metabolome-wide association study (N=2,756) identified a plasma signature of the same NCOA7-dependent oxysterols/bile acids associated with PAH mortality (P<1.1x10-6). Supporting a genetic predisposition to NCOA7 deficiency, in genome-edited, stem cell-derived ECs, the common variant intronic SNP rs11154337 in NCOA7 regulated NCOA7 expression, lysosomal activity, oxysterol/bile acid production, and EC immunoactivation. Correspondingly, SNP rs11154337 was associated with PAH severity via six-minute walk distance and mortality in discovery (N=93, P=0.0250; HR=0.44, 95% CI [0.21-0.90]) and validation (N=630, P=2x10-4; HR=0.49, 95% CI [0.34-0.71]) cohorts. Finally, utilizing computational modeling of small molecule binding to NCOA7, we predicted and synthesized a novel activator of NCOA7 that prevented EC immunoactivation and reversed indices of rodent PAH. In summary, we have established a genetic and metabolic paradigm and a novel therapeutic agent that links lysosomal biology as well as oxysterol and bile acid processes to EC inflammation and PAH pathobiology. This paradigm carries broad implications for diagnostic and therapeutic development in PAH and in other conditions dependent upon acquired and innate immune regulation of vascular disease.

Pulmonary primary oxysterol and bile acid synthesis as a predictor of outcomes in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare and fatal vascular disease with heterogeneous clinical manifestations. To date, molecular determinants underlying the development of PAH and related outcomes remain poorly understood. Herein, we identify pulmonary primary oxysterol and bile acid synthesis (PPOBAS) as a previously unrecognized pathway central to PAH pathophysiology. Mass spectrometry analysis of 2,756 individuals across five independent studies revealed 51 distinct circulating metabolites that predicted PAH-related mortality and were enriched within the PPOBAS pathway. Across independent single-center PAH studies, PPOBAS pathway metabolites were also associated with multiple cardiopulmonary measures of PAH-specific pathophysiology. Furthermore, PPOBAS metabolites were found to be increased in human and rodent PAH lung tissue and specifically produced by pulmonary endothelial cells, consistent with pulmonary origin. Finally, a poly-metabolite risk score comprising 13 PPOBAS molecules was found to not only predict PAH-related mortality but also outperform current clinical risk scores. This work identifies PPOBAS as specifically altered within PAH and establishes needed prognostic biomarkers for guiding therapy in PAH.

Exploring the experiences of parents of Autistic children when attending the diagnostic imaging department for an X-ray examination.

INTRODUCTION: Autism is a neuro-developmental condition which affects the social-emotional skills, behaviour, language, communication skills and flexibility of thoughts of an individual and their sensory processing. This can result in Autistic service users finding it difficult to navigate current healthcare provision and cope with the unpredictable environment. This paper explores the experiences of parents of Autistic children when attending the diagnostic imaging department for an X-ray examination. METHODS: A cross sectional, mixed methods approach was adopted and the initial phase consisting of an online survey for parents to complete is the subject of this paper. The quantitative data was analysed using descriptive statistics and cross comparison between questions was also completed. Thematic analysis was taken to analyse the data from the two open questions at the end of the survey. RESULTS: The online survey results are presented in this paper under four key themes; waiting times and environment, forms of communication, lack of understanding of staff regarding Autism and preparation for the X-ray examination. CONCLUSION: The overall rating of the parents' experience whilst in the X-ray/diagnostic imaging department was positive, however there are several areas which received low scores which need further attention. These were waiting areas, waiting times, staff development and patient preparation. IMPLICATIONS FOR PRACTICE: The development of more inclusive waiting areas is needed, more effective lines of communication between staff to expedite the patient journey where possible, staff development of both radiographers and also support staff and the review of design of more accessible and inclusive patient information.

Toward Autism-Friendly Magnetic Resonance Imaging: Exploring Autistic Individuals' Experiences of Magnetic Resonance Imaging Scans in the United Kingdom, a Cross-Sectional Survey.

Background: Autistic individuals might undergo a magnetic resonance imaging (MRI) examination for clinical concerns or research. Increased sensory stimulation, lack of appropriate environmental adjustments, or lack of streamlined communication in the MRI suite may pose challenges to autistic patients and render MRI scans inaccessible. This study aimed at (i) exploring the MRI scan experiences of autistic adults in the United Kingdom; (ii) identifying barriers and enablers toward successful and safe MRI examinations; (iii) assessing autistic individuals' satisfaction with MRI service; and (iv) informing future recommendations for practice improvement. Methods: We distributed an online survey to the autistic community on social media, using snowball sampling. Inclusion criteria were: being older than 16, have an autism diagnosis or self-diagnosis, self-reported capacity to consent, and having had an MRI scan in the United Kingdom. We used descriptive statistics for demographics, inferential statistics for group comparisons/correlations, and content analysis for qualitative data. Results: We received 112 responses. A total of 29.6% of the respondents reported not being sent any information before the scan. Most participants (68%) confirmed that radiographers provided detailed information on the day of the examination, but only 17.1% reported that radiographers offered some reasonable environmental adjustments. Only 23.2% of them confirmed they disclosed their autistic identity when booking MRI scanning. We found that quality of communication, physical environment, patient emotions, staff training, and confounding societal factors impacted their MRI experiences. Autistic individuals rated their overall MRI experience as neutral and reported high levels of claustrophobia (44.8%). Conclusion: This study highlighted a lack of effective communication and coordination of care, either between health care services or between patients and radiographers, and lack of reasonable adjustments as vital for more accessible and person-centered MRI scanning for autistic individuals. Enablers of successful scans included effective communication, adjusted MRI environment, scans tailored to individuals' needs/preferences, and well-trained staff.

Why is this an important issue?: Magnetic resonance imaging (MRI) is an examination that shows human anatomy and may explain the causes of symptoms. Autistic people may need MRI scans for various reasons, such as low back pain, headaches, accidents, or epilepsy. They have known sensitivities to sound, light, smell, or touch and increased anxiety, so the narrow, loud, isolating, unfamiliar MRI environment may be overwhelming to them. If MRI scans are, for these reasons, inaccessible, many autistic people will have to live with long-standing conditions, pain, or other symptoms, or have delayed treatment, with impact on their quality of life, and life expectancy. What was the purpose of this study?: We tried to understand how autistic people perceive MRI examinations, things that work, and the challenges they face. We also asked for their suggestions to improve practice and accessibility. What did we do?: We distributed an online questionnaire to autistic adults through social media. We analyzed the data using appropriate statistical and text analysis methods. What were the results of the study?: We received 112 responses. Autistic people rated their overall MRI experience as average. Nearly a third (29.6%) reported they were not sent any information before MRI, and only 17.1% reported that radiographers offered some reasonable environmental adjustments. Most participants (68%) reported that radiographers provided detailed information on the day of the scan. Only 23.2% of them disclosed their autistic identity when booking MRIs. We found that quality of communication, physical environment, patient emotions, staff training, stigma, and timely autism diagnosis impacted their MRI experiences. What do these findings add to what was already known?: Autistic people MRI scan experiences are at the heart of this project. Our project shows that MRI for common symptoms is often inaccessible by autistic people. We should improve the MRI environment, adjust communication format/content for them, and deliver person-centered care in MRI. Health care professionals should receive relevant training, to understand the challenges autistic people might face and better support them in MRI scanning. What are potential weaknesses in the study?: The pandemic has impacted participant recruitment; therefore, the results of this sample may not reflect the full impact on the wider autistic population or adequately represent the autistic community, due to small size and including only people who could consent.These results come from different centers, so there is a lot of variation in the use of MRI equipment. How will these findings help autistic adults now or in the future?: We outline the main challenges associated with MRI, so autistic adults and their families/carers understand more of what they could expect in future examinations; hopefully, researchers and scanner manufacturers will try to tackle these challenges to make MRI scans truly accessible for autistic people.We shared this knowledge with stakeholders to develop guidelines and started using it in training. We want to ensure that MRI is person-centered and more accessible for autistic patients.

Frataxin deficiency disrupts mitochondrial respiration and pulmonary endothelial cell function.

Deficiency of iron­sulfur (FeS) clusters promotes metabolic rewiring of the endothelium and the development of pulmonary hypertension (PH) in vivo. Joining a growing number of FeS biogenesis proteins critical to pulmonary endothelial function, recent data highlighted that frataxin (FXN) reduction drives Fe-S-dependent genotoxic stress and senescence across multiple types of pulmonary vascular disease. Trinucleotide repeat mutations in the FXN gene cause Friedreich's ataxia, a disease characterized by cardiomyopathy and neurodegeneration. These tissue-specific phenotypes have historically been attributed to mitochondrial reprogramming and oxidative stress. Whether FXN coordinates both nuclear and mitochondrial processes in the endothelium is unknown. Here, we aim to identify the mitochondria-specific effects of FXN deficiency in the endothelium that predispose to pulmonary hypertension. Our data highlight an Fe-S-driven metabolic shift separate from previously described replication stress whereby FXN knockdown diminished mitochondrial respiration and increased glycolysis and oxidative species production. In turn, FXN-deficient endothelial cells had increased vasoconstrictor production (EDN1) and decreased nitric oxide synthase expression (NOS3). These data were observed in primary pulmonary endothelial cells after pharmacologic inhibition of FXN, mice carrying a genetic endothelial deletion of FXN, and inducible pluripotent stem cell-derived endothelial cells from patients with FXN mutations. Altogether, this study indicates FXN is an upstream driver of pathologic aberrations in metabolism and genomic stability. Moreover, our study highlights FXN-specific vasoconstriction in vivo, prompting future studies to investigate available and novel PH therapies in contexts of FXN deficiency.

Learning from patient experiences of projection imaging through the use of online feedback platforms.

INTRODUCTION & BACKGROUND: Projection radiography remains a well-used diagnostic tool in healthcare, and its use is continually increasing. The volume of feedback collected from patients has grown exponentially but is rarely analysed within the service to meaningfully underpin change. Professions such as nursing currently make use of patient feedback during training yet there is comparatively little use in diagnostic radiography. Research exists into the use of social media during radiotherapy treatment, highlighting how it could be embraced in future research. However, there remains a sparsity of publications discussing the experiences of patients with projection radiography despite its prominence within diagnostic imaging. Online platforms for feedback are available to most industries and readily embraced and used. They are also becoming increasingly available to healthcare providers. This study aimed to assess and analyse the patient experience of projection radiography using the stories of patients via an online platform. METHODOLOGY: Recognising that humans do not experience healthcare in a binary way, the authors selected a narrative method as the most appropriate qualitative methodology to analyse and understand 181 patient stories relating to projection radiography from the Care Opinion UK website. Each story was read three times to establish codes and themes and to ensure author familiarity with the patient's words & descriptions. This resulted in 30 empirical codes with the most frequently used being split into three major themes for discussion RESULTS & CONCLUSION: The three major themes considered the radiography experience, the encounter with professionals and service provision. Online sources of feedback provide valuable data for health researchers and provide access to insights which might otherwise go unconsidered. Patients instinctively perceive radiological examinations to result in delays to their care and report surprise when discovering examinations are delivered swiftly, though it remains that innovations such as radiographer-led discharge could be better utilised to enhance the patient experience. In addition, it is evident that administrative functions in diagnostic radiology departments are considered poor and from the descriptions given in the study by patients, the administrative side of the service does not meet their needs. Patient stories demonstrate that radiography is not perceived as vital to patient care and is frequently devalued through the notion that health professions are limited to medical doctor and nurse. The work of radiographers is not valueless to the patient evidenced by their desire to thank staff for their work, but its value is poorly understood and could be further enhanced by embracing online feedback as part of continuing professional and service development.

Interprofessional practice in the Intensive Treatment Unit during the Covid-19 pandemic; the reflections of an Advanced Practitioner Radiographer.

Background: The onset of the Covid-19 pandemic in March 2020 posed significant challenges to the National Health Service (NHS) in the United Kingdom (UK). Existing workforce shortages were further exacerbated with staff absence, and the need to redeploy staff into frontline clinical areas became a necessity. Purpose: The exploration of the experiences of an Advanced Practitioner Radiographer volunteering in the Intensive Treatment Unit (ITU) during the Covid-19 pandemic. Method: Interview using Microsoft Teams© involving one participant facilitated by two researchers using a semi-structured interview schedule. Discussion: Redeployment to ITU has allowed individuals to work outside of their normal scope of practice. The non-hierarchical structure within teams, focussed minds and demonstrated interprofessional collaboration at its best, ensuring the best patient care was delivered to those critically affected by the virus. Conclusion: The interprofessional practice demonstrated in ITU during the pandemic should be applied to future learning and training opportunities, to develop individuals and prepare for future pandemics.

Paediatric magnetic resonance imaging adaptations without the use of sedation or anaesthesia: A narrative review.

Magnetic Resonance Imaging (MRI) produces images with high soft tissue contrast without the use of ionising radiation, making it a valuable tool for scanning paediatrics. However, it can be difficult to scan children when they are awake, resulting often in poor image quality scans and necessitating the use of sedation and general anaesthesia (GA). The aim of sedation and anaesthesia is to reduce anxiety and movement during image acquisition, thereby improving compliance and image quality. However, there are adverse risks and costs to their use, leading to the need to consider alternative imaging adaptation methods. This research discussed potential methods of reducing anxiety and improving paediatric compliance during MRI examinations, by assessing their feasibility for use in the clinical setting. The literature suggests that adaption strategies and modification of radiographer techniques were mostly effective in reducing the requirement of sedation/GA.

Autism-friendly MRI: Improving radiography practice in the UK, a survey of radiographer practitioners.

INTRODUCTION: Autistic individuals undergoing magnetic resonance imaging (MRI) examinations may face significant challenges, mainly due to sensory overload and MRI environment-related limitations. This study aimed to explore radiographers' perspectives and experiences regarding MRI scanning of autistic individuals. METHODS: Data collection was achieved using a specifically designed mixed methods questionnaire on Qualtrics. The snowball technique was used. This UK-wide survey was electronically distributed by three main recruitment agencies between December 2020 and February 2021. RESULTS: 130 valid responses were received. A lack of relevant training and knowledge related to autism was noted. Effective communication, optimisation and customisation of the MRI examination, and MRI environment adjustments facilitated the completion of a safe and effective MRI examination. Poor patient-radiographer communication, unavailability of Special Educational Needs (SEN) experts, lack of specialised radiographer training and lack of specific guidelines were identified as the main barriers to successful MRI examinations. CONCLUSION: Although routine MRI safety and patient care rules will apply, MRI scanning of autistic individuals requires customisation and reasonable adjustments in communication, environment, and training of clinical teams. In addition, guidelines should be established to be used as a reference point to improve clinical practice. The adjustments proposed by radiographers were all consistent with the interventions in the wider literature. IMPLICATIONS FOR PRACTICE: MRI practice for personalised care of autistic individuals should be aligned with current evidence, to customise communication and offer workflow and environmental adjustments. Formal training related to autism, integrated within radiography academic curricula and better co-ordination and communication of interdisciplinary teams would provide the necessary skill mix to deliver safe, high quality MRI scans with optimal experience for autistic service users and their carer(s).

Experiences of diagnostic radiographers through the Covid-19 pandemic.

INTRODUCTION: Diagnostic Radiography plays a major role in the diagnosis and management of patients with Covid-19. This has seen an increase in the demand for imaging services, putting pressure on the workforce. Diagnostic radiographers, as with many other healthcare professions, have been on the frontline, dealing with an unprecedented situation. This research aimed to explore the experience of diagnostic radiographers working clinically during the Covid-19 pandemic. METHODS: Influenced by interpretative phenomenology, this study explored the experiences of diagnostic radiographers using virtual focus group interviews as a method of data collection. RESULTS: Data were analysed independently by four researchers and five themes emerged from the data. Adapting to new ways of working, feelings and emotions, support mechanisms, self-protection and resilience, and professional recognition. CONCLUSION: The adaptability of radiographers came across strongly in this study. Anxieties attributed to the provision of personal protective equipment (PPE), fear of contracting the virus and spreading it to family members were evident. The resilience of radiographers working throughout this pandemic came across strongly throughout this study. A significant factor for coping has been peer support from colleagues within the workplace. The study highlighted the lack of understanding of the role of the radiographer and how the profession is perceived by other health care professionals. IMPLICATIONS FOR PRACTICE: This study highlights the importance of interprofessional working and that further work is required in the promotion of the profession.

A systematic review of person-centred adjustments to facilitate magnetic resonance imaging for autistic patients without the use of sedation or anaesthesia.

LAY ABSTRACT: Autistic patients often undergo magnetic resonance imaging examinations. Within this environment, it is usual to feel anxious and overwhelmed by noises, lights or other people. The narrow scanners, the loud noises and the long examination time can easily cause panic attacks. This review aims to identify any adaptations for autistic individuals to have a magnetic resonance imaging scan without sedation or anaesthesia. Out of 4442 articles screened, 53 more relevant were evaluated and 21 were finally included in this study. Customising communication, different techniques to improve the environment, using technology for familiarisation and distraction have been used in previous studies. The results of this study can be used to make suggestions on how to improve magnetic resonance imaging practice and the autistic patient experience. They can also be used to create training for the healthcare professionals using the magnetic resonance imaging scanners.

Simultaneous Pharmacologic Inhibition of Yes-Associated Protein 1 and Glutaminase 1 via Inhaled Poly(Lactic-co-Glycolic) Acid-Encapsulated Microparticles Improves Pulmonary Hypertension.

Background Pulmonary hypertension (PH) is a deadly disease characterized by vascular stiffness and altered cellular metabolism. Current treatments focus on vasodilation and not other root causes of pathogenesis. Previously, it was demonstrated that glutamine metabolism, as catalyzed by GLS1 (glutaminase 1) activity, is mechanoactivated by matrix stiffening and the transcriptional coactivators YAP1 (yes-associated protein 1) and transcriptional coactivator with PDZ-binding motif (TAZ), resulting in pulmonary vascular proliferation and PH. Pharmacologic inhibition of YAP1 (by verteporfin) or glutaminase (by CB-839) improved PH in vivo. However, systemic delivery of these agents, particularly YAP1 inhibitors, may have adverse chronic effects. Furthermore, simultaneous use of pharmacologic blockers may offer additive or synergistic benefits. Therefore, a strategy that delivers these drugs in combination to local lung tissue, thus avoiding systemic toxicity and driving more robust improvement, was investigated. Methods and Results We used poly(lactic-co-glycolic) acid polymer-based microparticles for delivery of verteporfin and CB-839 simultaneously to the lungs of rats suffering from monocrotaline-induced PH. Microparticles released these drugs in a sustained fashion and delivered their payload in the lungs for 7 days. When given orotracheally to the rats weekly for 3 weeks, microparticles carrying this drug combination improved hemodynamic (right ventricular systolic pressure and right ventricle/left ventricle+septum mass ratio), histologic (vascular remodeling), and molecular markers (vascular proliferation and stiffening) of PH. Importantly, only the combination of drug delivery, but neither verteporfin nor CB-839 alone, displayed significant improvement across all indexes of PH. Conclusions Simultaneous, lung-specific, and controlled release of drugs targeting YAP1 and GLS1 improved PH in rats, addressing unmet needs for the treatment of this deadly disease.

Matrix stiffening induces a pathogenic QKI-miR-7-SRSF1 signaling axis in pulmonary arterial endothelial cells.

Pulmonary arterial hypertension (PAH) refers to a set of heterogeneous vascular diseases defined by elevation of pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR), leading to right ventricular (RV) remodeling and often death. Early increases in pulmonary artery stiffness in PAH drive pathogenic alterations of pulmonary arterial endothelial cells (PAECs), leading to vascular remodeling. Dysregulation of microRNAs can drive PAEC dysfunction. However, the role of vascular stiffness in regulating pathogenic microRNAs in PAH is incompletely understood. Here, we demonstrated that extracellular matrix (ECM) stiffening downregulated miR-7 levels in PAECs. The RNA-binding protein quaking (QKI) has been implicated in the biogenesis of miR-7. Correspondingly, we found that ECM stiffness upregulated QKI, and QKI knockdown led to increased miR-7. Downstream of the QKI-miR-7 axis, the serine and arginine-rich splicing factor 1 (SRSF1) was identified as a direct target of miR-7. Correspondingly, SRSF1 was reciprocally upregulated in PAECs exposed to stiff ECM and was negatively correlated with miR-7. Decreased miR-7 and increased QKI and SRSF1 were observed in lungs from patients with PAH and PAH rats exposed to SU5416/hypoxia. Lastly, miR-7 upregulation inhibited human PAEC migration, whereas forced SRSF1 expression reversed this phenotype, proving that miR-7 depended upon SRSF1 to control migration. In aggregate, these results define the QKI-miR-7-SRSF1 axis as a mechanosensitive mechanism linking pulmonary arterial vascular stiffness to pathogenic endothelial function. These findings emphasize implications relevant to PAH and suggest the potential benefit of developing therapies that target this miRNA-dependent axis in PAH.

Being a newly qualified diagnostic radiographer: Learning to fly in the face of reality.

INTRODUCTION: The phenomenon of role transition has been investigated by a range of differing professions over a range of time and utilising a range of different methodologies. It is acknowledged by all studies that the period of transition from student to practitioner is a challenging and at times a stressful experience, often culminating in the newly qualified practitioners experiencing the reality shock of practice. This paper explores one of the key subthemes 'reality hits' which was identified during a wider PhD study Being and Becoming a Diagnostic Radiographer. METHODS: A longitudinal study was utilised employing an interpretive phenomenological methodology, collating data from nine participants during their first year as a newly qualified diagnostic radiographer. Each participant was interviewed at three months, six months and twelve months. RESULTS: Six main themes were identified. This paper explores the subtheme 'reality hits' which strongly featured in the three and six month interviews. CONCLUSION: Eight of the nine participants found the first three to six months a stressful and emotional time. The experience of the graduates during this time raises issues which need to be used to inform future curriculum development, practice placement models and support strategies.

Evolving systems biology approaches to understanding non-coding RNAs in pulmonary hypertension.

Our appreciation of the roles of non-coding RNAs, in particular microRNAs, in the manifestation of pulmonary hypertension (PH) has advanced considerably over the past decade. Comprised of small nucleotide sequences, microRNAs have demonstrated critical and broad regulatory roles in the pathogenesis of PH via the direct binding to messenger RNA transcripts for degradation or inhibition of translation, thereby exerting a profound influence on cellular activity. Yet, as inherently pleiotropic molecules, microRNAs have been difficult to study using traditional, reductionist approaches alone. With the advent of high-throughput -omics technologies and more advanced computational modelling, the study of microRNAs and their multi-faceted and complex functions in human disease serves as a fertile platform for the application of systems biology methodologies in combination with traditional experimental techniques. Here, we offer our viewpoint of past successes of systems biology in elucidating the otherwise hidden actions of microRNAs in PH, as well as areas for future development to integrate these strategies into the discovery of RNA pathobiology in this disease. We contend that such successful applications of systems biology in elucidating the functional architecture of microRNA regulation will further reveal the molecular mechanisms of disease, while simultaneously revealing potential diagnostic and therapeutic strategies in disease amelioration.

Embracing diversity in radiography: The role of service users.

This article outlines the importance of cultural competence for student radiographers. The UK population is becoming more diverse in terms of ethnicity, the population is also made up of a much wider age range, varying genders and people of different sexual orientation, physical abilities and faiths. Radiographers need to be able to communicate with and care for people of all backgrounds. Radiographers need to be able to build relationships with service users based on mutual respect to provide optimum care despite personal differences. In order to prepare for this, service user involvement in the radiography curriculum is key. This article discussed the way in which service users are involved at one university. All of the strategies used enable students to learn about the different people that they will encounter in their professional role and to develop cultural competence. It is vitally important that student radiographers feel comfortable to interact with and care for service users from different backgrounds and cultures and to be able to demonstrate an awareness of and sensitivity to the range of issues and individual needs of every service user they may encounter in their professional role.

Endothelial dysfunction in pulmonary arterial hypertension: an evolving landscape (2017 Grover Conference Series).

Endothelial dysfunction is a major player in the development and progression of vascular pathology in pulmonary arterial hypertension (PAH), a disease associated with small vessel loss and obstructive vasculopathy that leads to increased pulmonary vascular resistance, subsequent right heart failure, and premature death. Over the past ten years, there has been tremendous progress in our understanding of pulmonary endothelial biology as it pertains to the genetic and molecular mechanisms that orchestrate the endothelial response to direct or indirect injury, and how their dysregulation can contribute to the pathogenesis of PAH. As one of the major topics included in the 2017 Grover Conference Series, discussion centered on recent developments in four areas of pulmonary endothelial biology: (1) angiogenesis; (2) endothelial-mesenchymal transition (EndMT); (3) epigenetics; and (4) biology of voltage-gated ion channels. The present review will summarize the content of these discussions and provide a perspective on the most promising aspects of endothelial dysfunction that may be amenable for therapeutic development.

Emerging Metabolic Therapies in Pulmonary Arterial Hypertension.

Pulmonary hypertension (PH) is an enigmatic vascular disorder characterized by pulmonary vascular remodeling and increased pulmonary vascular resistance, ultimately resulting in pressure overload, dysfunction, and failure of the right ventricle. Current medications for PH do not reverse or prevent disease progression, and current diagnostic strategies are suboptimal for detecting early-stage disease. Thus, there is a substantial need to develop new diagnostics and therapies that target the molecular origins of PH. Emerging investigations have defined metabolic aberrations as fundamental and early components of disease manifestation in both pulmonary vasculature and the right ventricle. As such, the elucidation of metabolic dysregulation in pulmonary hypertension allows for greater therapeutic insight into preventing, halting, or even reversing disease progression. This review will aim to discuss (1) the reprogramming and dysregulation of metabolic pathways in pulmonary hypertension; (2) the emerging therapeutic interventions targeting these metabolic pathways; and (3) further innovation needed to overcome barriers in the treatment of this devastating disease.