Biomarker Predictors of Clinical Efficacy of the Anti-IgE Biologic, Omalizumab, in Severe Asthma in Adults: Results of the SoMOSA Study.

BACKGROUND: The anti-IgE monoclonal, omalizumab, is widely used for severe asthma. This study aimed to identify biomarkers that predict clinical improvement during one year of omalizumab treatment. METHODS: 1-year, open-label, Study of Mechanisms of action of Omalizumab in Severe Asthma (SoMOSA) involving 216 severe (GINA step 4/5) uncontrolled atopic asthmatics (≥2 severe exacerbations in previous year) on high-dose inhaled corticosteroids, long-acting ß-agonists, ± mOCS. It had two phases: 0-16 weeks, to assess early clinical improvement by Global Evaluation of Therapeutic Effectiveness (GETE), and 16-52 weeks, to assess late responses by ≥50% reduction in exacerbations or dose of maintenance oral corticosteroids (mOCS). All participants provided samples (exhaled breath, blood, sputum, urine) before and after 16 weeks of omalizumab treatment. RESULTS: 191 patients completed phase 1; 63% had early improvement. Of 173 who completed phase 2, 69% had reduced exacerbations by ≥50%, while 57% (37/65) on mOCS reduced their dose by ≥50%. The primary outcome 2, 3-dinor-11-ß-PGF2α, GETE and standard clinical biomarkers (blood and sputum eosinophils, exhaled nitric oxide, serum IgE) did not predict either clinical response. Five breathomics (GC-MS) and 5 plasma lipid biomarkers strongly predicted the ≥50% reduction in exacerbations (receiver operating characteristic area under the curve (AUC): 0.780 and 0.922, respectively) and early responses (AUC:0.835 and 0.949, respectively). In independent cohorts, the GC-MS biomarkers differentiated between severe and mild asthma. Conclusions This is the first discovery of omics biomarkers that predict improvement to a biologic for asthma. Their prospective validation and development for clinical use is justified. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

Examining the impact of pulmonary hypertension on nonprofessional caregivers: A mixed-methods systematic review.

Pulmonary hypertension (PH) is a heterogeneous condition, associated with a high symptom burden and high rates of disability. While nonprofessional caregivers are essential in helping patients live better, little is known about the impact on caregivers and support that is currently available. This review has synthesised evidence examining experiences of caregivers of adults with PH. Web of Science, PubMed, PsycINFO, and Cochrane Library were searched for all types of study design. Articles were evaluated and analysed using a Joanna Briggs Institute approach. Eight articles primarily focussed on pulmonary arterial hypertension and chronic thromboembolic PH were identified investigating 456 caregivers from at least 10 countries. Four categories were identified describing caregiver demographics, responsibilities, impact, and support. Four integrated themes emerged identifying possible unmet needs and therapeutic targets: (1) Change, reflecting the various demands caring had on people as they attempted to balance the needs of the patient and their own; (2) Preparedness, discussing how caregivers could feel uncertain and unskilled for their duties and unsupported; (3) Isolation, with caregivers often encountering challenges to gaining information on PH turning to PH organisations and others affected for support and connection; and (4) Physical and mental demands, reflecting the multifaceted impact of caring. Findings add to the evidence demonstrating that PH can have a considerable impact on patients' support network. Providing support for caregivers of people with PH is an unmet need and may have a positive impact on patients and is an area that requires further research.

Elective lower limb orthopedic arthroplasty surgery in patients with pulmonary hypertension.

Patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (PH) are at increased risk when undergoing anesthesia and major surgery. Data on outcomes for elective orthopedic surgery in patients with PH are limited. A patient pathway was established to provide access to elective lower limb arthroplasty. This included assessment of orthopedic needs, fitness for anesthesia, preoperative optimization, and intra- and postoperative management. Patient data were retrospectively retrieved using patient's hospital records. Between 2012 and 2020, 29 operations (21 total hip replacements [THRs], 7 total knee replacements [TKRs], 1 total hip revision) were performed in 25 patients (mean age: 67 years). Perioperatively, 72% were treated with low-dose intravenous prostanoid. All had arterial lines, and central access and perioperative lithium dilution cardiac output monitoring was used in 86% of cases. Four patients underwent GA, 21 spinal anesthesia, and 4 CSE anesthesia. Supplemental nerve blocks were performed in all patients undergoing general, and 12 of 21 undergoing spinal anesthesia. All were managed in high dependency postoperatively. Hospital length of stay and complication rates were higher than reported in non-PH patients. Perioperative complications included hypotension requiring vasopressors (n = 10), blood transfusion (n = 7), nonorthopedic infection (n = 4), and decompensated right heart failure (n = 1). There was no associated mortality. All implants were functioning well at 6 weeks and subsequent follow-up. EmPHasis-10 quality of score decreased by 5.5 (±2.1) (p = 0.04). A dedicated multiprofessional pathway can be used to safely select and manage patients with PH through elective lower limb arthroplasty.

Enhanced neutrophil extracellular trap formation in COVID-19 is inhibited by the protein kinase C inhibitor ruboxistaurin.

Background: Neutrophil extracellular traps (NETs) are web-like DNA and protein lattices which are expelled by neutrophils to trap and kill pathogens, but which cause significant damage to the host tissue. NETs have emerged as critical mediators of lung damage, inflammation and thrombosis in coronavirus disease 2019 (COVID-19) and other diseases, but there are no therapeutics to prevent or reduce NETs that are available to patients. Methods: Neutrophils were isolated from healthy volunteers (n=9) and hospitalised patients with COVID-19 at the acute stage (n=39) and again at 3-4 months post-acute sampling (n=7). NETosis was measured by SYTOX green assays. Results: Here, we show that neutrophils isolated from hospitalised patients with COVID-19 produce significantly more NETs in response to lipopolysaccharide (LPS) compared to cells from healthy control subjects. A subset of patients was captured at follow-up clinics (3-4 months post-acute sampling), and while LPS-induced NET formation is significantly lower at this time point, it remains elevated compared to healthy controls. LPS- and phorbol myristate acetate (PMA)-induced NETs were significantly inhibited by the protein kinase C (PKC) inhibitor ruboxistaurin. Ruboxistaurin-mediated inhibition of NETs in healthy neutrophils reduces NET-induced epithelial cell death. Conclusion: Our findings suggest ruboxistaurin could reduce proinflammatory and tissue-damaging consequences of neutrophils during disease, and since it has completed phase III trials for other indications without safety concerns, it is a promising and novel therapeutic strategy for COVID-19.

Lung MRI with hyperpolarised gases: current & future clinical perspectives.

The use of pulmonary MRI in a clinical setting has historically been limited. Whilst CT remains the gold-standard for structural lung imaging in many clinical indications, technical developments in ultrashort and zero echo time MRI techniques are beginning to help realise non-ionising structural imaging in certain lung disorders. In this invited review, we discuss a complementary technique - hyperpolarised (HP) gas MRI with inhaled 3He and 129Xe - a method for functional and microstructural imaging of the lung that has great potential as a clinical tool for early detection and improved understanding of pathophysiology in many lung diseases. HP gas MRI now has the potential to make an impact on clinical management by enabling safe, sensitive monitoring of disease progression and response to therapy. With reference to the significant evidence base gathered over the last two decades, we review HP gas MRI studies in patients with a range of pulmonary disorders, including COPD/emphysema, asthma, cystic fibrosis, and interstitial lung disease. We provide several examples of our experience in Sheffield of using these techniques in a diagnostic clinical setting in challenging adult and paediatric lung diseases.

Xenon ventilation MRI in difficult asthma: initial experience in a clinical setting.

BACKGROUND: Hyperpolarised gas magnetic resonance imaging (MRI) can be used to assess ventilation patterns. Previous studies have shown the image-derived metric of ventilation defect per cent (VDP) to correlate with forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and FEV1 in asthma. OBJECTIVES: The aim of this study was to explore the utility of hyperpolarised xenon-129 (129Xe) ventilation MRI in clinical care and examine its relationship with spirometry and other clinical metrics in people seen in a severe asthma service. METHODS: 26 people referred from a severe asthma clinic for MRI scanning were assessed by contemporaneous 129Xe MRI and spirometry. A subgroup of 18 patients also underwent reversibility testing with spirometry and MRI. Quantitative MRI measures of ventilation were calculated, VDP and the ventilation heterogeneity index (VHI), and compared to spirometry, Asthma Control Questionnaire 7 (ACQ7) and blood eosinophil count. Images were reviewed by a multidisciplinary team. RESULTS: VDP and VHI correlated with FEV1, FEV1/FVC and forced expiratory flow between 25% and 75% of FVC but not with ACQ7 or blood eosinophil count. Discordance of MRI imaging and symptoms and/or pulmonary function tests also occurred, prompting diagnostic re-evaluation in some cases. CONCLUSION: Hyperpolarised gas MRI provides a complementary method of assessment in people with difficult to manage asthma in a clinical setting. When used as a tool supporting clinical care in a severe asthma service, occurrences of discordance between symptoms, spirometry and MRI scanning indicate how MRI scanning may add to a management pathway.

A Bittersweet Response to Infection in Diabetes; Targeting Neutrophils to Modify Inflammation and Improve Host Immunity.

Chronic and recurrent infections occur commonly in both type 1 and type 2 diabetes (T1D, T2D) and increase patient morbidity and mortality. Neutrophils are professional phagocytes of the innate immune system that are critical in pathogen handling. Neutrophil responses to infection are dysregulated in diabetes, predominantly mediated by persistent hyperglycaemia; the chief biochemical abnormality in T1D and T2D. Therapeutically enhancing host immunity in diabetes to improve infection resolution is an expanding area of research. Individuals with diabetes are also at an increased risk of severe coronavirus disease 2019 (COVID-19), highlighting the need for re-invigorated and urgent focus on this field. The aim of this review is to explore the breadth of previous literature investigating neutrophil function in both T1D and T2D, in order to understand the complex neutrophil phenotype present in this disease and also to focus on the development of new therapies to improve aberrant neutrophil function in diabetes. Existing literature illustrates a dual neutrophil dysfunction in diabetes. Key pathogen handling mechanisms of neutrophil recruitment, chemotaxis, phagocytosis and intracellular reactive oxygen species (ROS) production are decreased in diabetes, weakening the immune response to infection. However, pro-inflammatory neutrophil pathways, mainly neutrophil extracellular trap (NET) formation, extracellular ROS generation and pro-inflammatory cytokine generation, are significantly upregulated, causing damage to the host and perpetuating inflammation. Reducing these proinflammatory outputs therapeutically is emerging as a credible strategy to improve infection resolution in diabetes, and also more recently COVID-19. Future research needs to drive forward the exploration of novel treatments to improve infection resolution in T1D and T2D to improve patient morbidity and mortality.

Critical care outcomes in patients with pre-existing pulmonary hypertension: insights from the ASPIRE registry.

Pulmonary hypertension (PH) is a life-shortening condition characterised by episodes of decompensation precipitated by factors such as disease progression, arrhythmias and sepsis. Surgery and pregnancy also place additional strain on the right ventricle. Data on critical care management in patients with pre-existing PH are scarce. We conducted a retrospective observational study of a large cohort of patients admitted to the critical care unit of a national referral centre between 2000-2017 to establish acute mortality, evaluate predictors of in-hospital mortality and establish longer term outcomes in survivors to hospital discharge. 242 critical care admissions involving 206 patients were identified. Hospital survival was 59.3%, 94% and 92% for patients admitted for medical, surgical or obstetric reasons, respectively. Medical patients had more severe physiological and laboratory perturbations than patients admitted following surgical or obstetric interventions. Higher APACHE II (Acute Physiology and Chronic Health Evaluation) score, age and lactate, and lower oxygen saturation measure by pulse oximetry/inspiratory oxygen fraction (S pO2 /F iO2 ) ratio, platelet count and sodium level were identified as independent predictors of hospital mortality. An exploratory risk score, OPALS (oxygen (S pO2 /F iO2 ) ≤185; platelets ≤196×109·L-1; age ≥37.5 years; lactate ≥2.45 mmol·L-1; sodium ≤130.5 mmol·L-1), identified medical patients at increasing risk of hospital mortality. One (11%) out of nine patients who were invasively ventilated for medical decompensation and 50% of patients receiving renal replacement therapy left hospital alive. There was no significant difference in exercise capacity or functional class between follow-up and pre-admission in patients who survived to discharge. These data have clinical utility in guiding critical care management of patients with known PH. The exploratory OPALS score requires validation.

EmPHasis-10 health-related quality of life score predicts outcomes in patients with idiopathic and connective tissue disease-associated pulmonary arterial hypertension: results from a UK multicentre study.

Health-related quality of life (HRQoL) scores assess symptom burden in pulmonary arterial hypertension (PAH) but data regarding their role in prognostication and risk stratification are limited. We assessed these relationships using the emPHasis-10 HRQoL measure.1745 patients with idiopathic PAH (IPAH), drug-induced PAH (DPAH), heritable PAH (HPAH) (collectively "(I/D/H)PAH"), or connective tissue disease-associated PAH (CTD-PAH), who had completed emPHasis-10 questionnaires at one of six UK referral centres between 2014 and 2017, were identified. Correlations with exercise capacity and World Health Organization (WHO) functional class were assessed, and exploratory risk stratification thresholds were tested.Moderate correlations were seen between emPHasis-10 scores and 6-min walk distance (r=-0.546), incremental shuttle walk distance (r=-0.504) and WHO functional class (r=0.497) (all p<0.0001). Distribution of emPHasis-10 score differed significantly between each WHO functional class (all p<0.0001). On multivariate analysis, emPHasis-10 score, but not WHO functional class, was an independent predictor of mortality. In a risk stratification approach, scores of 0-16, 17-33 and 34-50 identified incident patients with 1-year mortality of 5%, 10% and 23%, respectively. Survival of patients in WHO functional class III could be further stratified using an emPHasis-10 score ≥34 (p<0.01). At follow-up, patients with improved emPHasis-10 scores had improved exercise capacity (p<0.0001) and patients who transitioned between risk groups demonstrated similar survival to patients originally in those risk groups.The emPHasis-10 score is an independent prognostic marker in patients with (I/D/H)PAH or CTD-PAH. It has utility in risk stratification in addition to currently used parameters. Improvement in emPHasis-10 score is associated with improved exercise capacity.

Maximal Exercise Testing Using the Incremental Shuttle Walking Test Can Be Used to Risk-Stratify Patients with Pulmonary Arterial Hypertension.

Rationale: Exercise capacity predicts mortality in pulmonary arterial hypertension (PAH), but limited data exist on the routine use of maximal exercise testing.Objectives: This study evaluates a simple-to-perform maximal test (the incremental shuttle walking test) and its use in risk stratification in PAH.Methods: Consecutive patients with pulmonary hypertension were identified from the ASPIRE (Assessing the Spectrum of Pulmonary hypertension Identified at a REferral centre) registry (2001-2018). Thresholds for levels of risk were identified at baseline and tested at follow-up, and their incorporation into current risk stratification approaches was assessed.Results: Of 4,524 treatment-naive patients with pulmonary hypertension who underwent maximal exercise testing, 1,847 patients had PAH. A stepwise reduction in 1-year mortality was seen between levels 1 (≤30 m; 32% mortality) and 7 (340-420 m; 1% mortality) with no mortality for levels 8-12 (≥430 m) in idiopathic and connective tissue disease-related PAH. Thresholds derived at baseline of ≤180 m (>10%; high risk), 190-330 m (5-10%; intermediate risk), and ≥340 m (<5%; low risk of 1-yr mortality) were applied at follow-up and also accurately identified levels of risk. Thresholds were incorporated into the REVEAL (Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management) 2.0 risk score calculator and French low-risk approach to risk stratification, and distinct categories of risk remained.Conclusions: We have demonstrated that maximal exercise testing in PAH stratifies mortality risk at baseline and follow-up. This study highlights the potential value of the incremental shuttle walking test as an alternative to the 6-minute walking test, combining some of the advantages of maximal exercise testing and maintaining the simplicity of a simple-to-perform field test.

A Proteomics-Based Assessment of Inflammation Signatures in Endotoxemia.

We have previously shown that multimers of plasma pentraxin-3 (PTX3) were predictive of survival in patients with sepsis. To characterize the release kinetics and cellular source of plasma protein changes in sepsis, serial samples were obtained from healthy volunteers (n = 10; three time points) injected with low-dose endotoxin (lipopolysaccharide [LPS]) and analyzed using data-independent acquisition MS. The human plasma proteome response was compared with an LPS-induced endotoxemia model in mice. Proteomic analysis of human plasma revealed a rapid neutrophil degranulation signature, followed by a rise in acute phase proteins. Changes in circulating PTX3 correlated with increases in neutrophil-derived proteins following LPS injection. Time course analysis of the plasma proteome in mice showed a time-dependent increase in multimeric PTX3, alongside increases in neutrophil-derived myeloperoxidase (MPO) upon LPS treatment. The mechanisms of oxidation-induced multimerization of PTX3 were explored in two genetic mouse models: MPO global knock-out (KO) mice and LysM Cre Nox2 KO mice, in which NADPH oxidase 2 (Nox2) is only deficient in myeloid cells. Nox2 is the enzyme responsible for the oxidative burst in neutrophils. Increases in plasma multimeric PTX3 were not significantly different between wildtype and MPO or LysM Cre Nox2 KO mice. Thus, PTX3 may already be stored and released in a multimeric form. Through in vivo neutrophil depletion and multiplexed vascular proteomics, PTX3 multimer deposition within the aorta was confirmed to be neutrophil dependent. Proteomic analysis of aortas from LPS-injected mice returned PTX3 as the most upregulated protein, where multimeric PTX3 was deposited as early as 2 h post-LPS along with other neutrophil-derived proteins. In conclusion, the rise in multimeric PTX3 upon LPS injection correlates with neutrophil-related protein changes in plasma and aortas. MPO and myeloid Nox2 are not required for the multimerization of PTX3; instead, neutrophil extravasation is responsible for the LPS-induced deposition of multimeric PTX3 in the aorta.

Adults' experiences of living with pulmonary hypertension: a thematic synthesis of qualitative studies.

OBJECTIVES: Pulmonary hypertension is a life-shortening disease that has a considerable impact on quality of life. Improving our understanding of how individuals are affected and cope with the disease will help to improve services and outcomes. This review synthesises the published qualitative research that has listened to adults discuss their experiences of living with the disease. DESIGN: A comprehensive systematic search of four databases was conducted in May 2020: Web of Science, PubMed, PsycINFO and Cochrane Library. Suitable studies were evaluated using the Critical Appraisal Skills programme. Findings from the studies were extracted and subjected to a thematic synthesis. RESULTS: Nineteen articles were identified reflecting the experiences of over 1900 individuals impacted by pulmonary hypertension from Europe, North and South America and Asia. Ten studies did not report participant's WHO functional class of pulmonary hypertension, which resulted in comparing experiences between different severity difficult. All studies met the majority of the quality assessment items. Six descriptive themes emerged discussing participant's experiences of diagnosis, treatment, prognosis, healthcare professionals, impact and coping with pulmonary hypertension. Four higher order analytical themes were developed from the descriptive themes, reflecting: (i) uncertainties and anxiety that participants encountered related to pulmonary hypertension; (ii) lack of recognition of the impact of the condition; (iii) frustration at the paucity of awareness of pulmonary hypertension in society and healthcare settings and (iv) participant's accounts of transitioning through different stages of living with the disease. CONCLUSIONS: These findings form the first synthesis of experiences of life in individuals impacted by pulmonary hypertension and illustrate the multifaceted impact of the condition. The voices of numerous groups are missing from the literature highlighting the need for additional research. The results have implications for clinical practice emphasising the role of educational and psychological therapies to support those with the disease.

The Utilization of Cultural Movements to Overcome Stigma in Narrative of Postnatal Depression.

Background: Despite affecting 15% of new mothers, experience of postnatal depression has often been hidden by stigma, cultural beliefs, and lack of medical understanding. We examined the barriers to women sharing their experience and gaining help, using their own words to illuminate the experiences of stigma and injustice. This study examines the narratives of women across the twentieth century, explores cultural movements that framed and contextualized their experiences, and marks how women became more empowered to speak of maternal distress. Methods: Narrative literature was identified via searches of literature catalogs. Narrative accounts provided a lens through which to analyze cultural understandings of postnatal depression according to historical method. Contemporary medical and sociological literature discussing postnatal depression was used to contextualize the social climate within which these narratives were written. This work combines historical analysis with philosophical framework to develop insight into patient experiences of mental ill-health and associated stigma. Results: This research identified three core cultural movements providing women with a framework in which to discuss their experiences of postnatal depression: the labor movement in the early twentieth century, the second-wave feminism movement in the mid-twentieth century (ca. 1960-1980), and the so-called "Prozac revolution" emerging at the end of the twentieth century. These movements provided distinct culturally acceptable etiologies around which women were able to frame their experience of postnatal depression. This provided women with space in which to share and process their experiences and aided them in overcoming contemporary stigma against mental illness by challenging disparaging stereotypes of the depressed mother. Conclusions: Despite the stigmatizing nature of mental illness, women have demonstrated resilience and ingenuity by utilizing acceptable cultural movements to reframe their experiences of postnatal depression, challenging traditional perceptions of motherhood and effectively earned recognition of their sufferings. During this period, concordance between patient perceptions of postnatal depression and clinical understandings of the condition has been variable. Highlighting the detriment to therapeutic relationship when discordance is present, the narrators have demonstrated the need to destigmatize illness and facilitate cooperation between physician and patient and remind clinicians of the importance of placing patient experience at the center of care.

UK consensus statement on the diagnosis of inducible laryngeal obstruction in light of the COVID-19 pandemic.

Prior to the COVID-19 pandemic, laryngoscopy was the mandatory gold standard for the accurate assessment and diagnosis of inducible laryngeal obstruction. However, upper airway endoscopy is considered an aerosol-generating procedure in professional guidelines, meaning routine procedures are highly challenging and the availability of laryngoscopy is reduced. In response, we have convened a multidisciplinary panel with broad experience in managing this disease and agreed a recommended strategy for presumptive diagnosis in patients who cannot have laryngoscopy performed due to pandemic restrictions. To maintain clinical standards whilst ensuring patient safety, we discuss the importance of triage, information gathering, symptom assessment and early review of response to treatment. The consensus recommendations will also be potentially relevant to other future situations where access to laryngoscopy is restricted, although we emphasize that this investigation remains the gold standard.

Pellino-1 Regulates the Responses of the Airway to Viral Infection.

Exposure to respiratory pathogens is a leading cause of exacerbations of airway diseases such as asthma and chronic obstructive pulmonary disease (COPD). Pellino-1 is an E3 ubiquitin ligase known to regulate virally-induced inflammation. We wished to determine the role of Pellino-1 in the host response to respiratory viruses in health and disease. Pellino-1 expression was examined in bronchial sections from patients with GOLD stage two COPD and healthy controls. Primary bronchial epithelial cells (PBECs) in which Pellino-1 expression had been knocked down were extracellularly challenged with the TLR3 agonist poly(I:C). C57BL/6 Peli1-/- mice and wild type littermates were subjected to intranasal infection with clinically-relevant respiratory viruses: rhinovirus (RV1B) and influenza A. We found that Pellino-1 is expressed in the airways of normal subjects and those with COPD, and that Pellino-1 regulates TLR3 signaling and responses to airways viruses. In particular we observed that knockout of Pellino-1 in the murine lung resulted in increased production of proinflammatory cytokines IL-6 and TNFα upon viral infection, accompanied by enhanced recruitment of immune cells to the airways, without any change in viral replication. Pellino-1 therefore regulates inflammatory airway responses without altering replication of respiratory viruses.

Circulating MicroRNA Levels Indicate Platelet and Leukocyte Activation in Endotoxemia Despite Platelet P2Y12 Inhibition.

There is evidence for the effects of platelet inhibition on innate immune activation. Circulating microRNAs (miRNAs) have been implicated as markers of platelet and leukocyte activation. In the present study, we assessed the effects of P2Y12 inhibitors on platelet and leukocyte miRNAs during endotoxemia. Healthy volunteers were randomly assigned to receive oral ticagrelor (n = 10), clopidogrel (n = 8) or no drug (n = 8) for one week, followed by an intravenous bolus of 2 ng/kg endotoxin. Serum was collected at baseline, after one week of antiplatelet treatment and 6 and 24 h after endotoxin administration. MiRNAs were screened using LNA-based qPCR, followed by TaqMan-qPCR validation of candidates. Clinical validation was performed in 41 sepsis patients. Platelet-enriched miR-197, miR-223 and miR-223* were decreased in volunteers following antiplatelet therapy. Endotoxin increased platelet miRNAs, whilst the opposite effect was seen for leukocyte-enriched miR-150. Neither of these endotoxin-mediated effects were altered by P2Y12 inhibitors. Sepsis patients with fatal outcomes (n = 12) had reduced miR-150 levels compared with survivors (n = 29). In conclusion, we show that miR-150 is downregulated in experimental endotoxemia and can predict survival in sepsis but is unaffected by P2Y12 inhibition. While P2Y12 inhibition reduces platelet-associated miRNAs in healthy volunteers, it fails to attenuate the response of platelet miRNAs to endotoxemia.

Diagnostic accuracy of CT pulmonary angiography in suspected pulmonary hypertension.

OBJECTIVES: Computed tomography (CT) pulmonary angiography is widely used in patients with suspected pulmonary hypertension (PH). However, the diagnostic and prognostic significance remains unclear. The aim of this study was to (a) build a diagnostic CT model and (b) test its prognostic significance. METHODS: Consecutive patients with suspected PH undergoing routine CT pulmonary angiography and right heart catheterisation (RHC) were identified. Axial and reconstructed images were used to derive CT metrics. Multivariate regression analysis was performed in the derivation cohort to identify a diagnostic CT model to predict mPAP ≥ 25 mmHg (the existing ESC guideline definition of PH) and > 20 mmHg (the new threshold proposed at the 6th World Symposium on PH). In the validation cohort, sensitivity, specificity and compromise CT thresholds were identified with receiver operating characteristic (ROC) analysis. The prognostic value of the CT model was assessed using Kaplan-Meier analysis. RESULTS: Between 2012 and 2016, 491 patients were identified. In the derivation cohort (n = 247), a CT model was identified including pulmonary artery diameter, right ventricular outflow tract thickness, septal angle and left ventricular area. In the validation cohort (n = 244), the model was diagnostic, with an area under the ROC curve of 0.94/0.91 for mPAP ≥ 25/> 20 mmHg respectively. In the validation cohort, 93 patients died; mean follow-up was 42 months. The diagnostic thresholds for the CT model were prognostic, log rank, all p < 0.01. DISCUSSION: In suspected PH, a diagnostic CT model had diagnostic and prognostic utility. KEY POINTS: • Diagnostic CT models have high diagnostic accuracy in a tertiary referral population of with suspected PH. • Diagnostic CT models stratify patients by mortality in suspected PH.