Effect of dual pulmonary vasodilator therapy in pulmonary arterial hypertension associated with congenital heart disease: a retrospective analysis

Background: Patients with pulmonary arterial hypertension (PAH) are managed according to evidence-based treatment guidelines. Methods and results: In this single-centre retrospective analysis, we examined outcomes of patients with PAH caused by congenital heart disease (PAH-CHD) with respect to exercise capacity and survival of adults treated with either bosentan or sildenafil monotherapy or bosentan-sildenafil dual therapy between January 2007 and January 2014. Of the 82 patients analysed, 29 had Down syndrome; 54 (65.8%) received bosentan monotherapy, 16 (19.5%) sildenafil monotherapy and 12 (14.6%) dual therapy. Mean treatment duration was 2.5 years for all patients and 4.1 years for 38 patients treated for ≥2 years. Pooled patient and treatment data showed initial improvement followed by stabilisation in mean 6 min walk distance (6MWD). For Down and non-Down patients, mean 6MWD increased and then stabilised on bosentan monotherapy. Mean 6MWD of patients on dual therapy at the time of analysis was 246.3 m before PAH-specific therapy initiation, 211.9 m immediately prior to addition of a second therapy and 214.4 m at last visit while on dual therapy. 1, 2 and 3- year survival rates for all patients from time of treatment initiation were 96%, 87% and 80%, respectively. Conclusions: For the majority of patients, monotherapy with a PAH-specific medication provided improved and sustained exercise benefits. For the small percentage of patients who required it, add-on therapy appeared to prevent further deterioration in exercise capacity but did not improve 6MWD

Immersion mode heterogeneous ice nucleation by an illite rich powder representative of atmospheric mineral dust

Atmospheric dust rich in illite is transported globally from arid regions and impacts cloud properties through the nucleation of ice. We present measurements of ice nucleation in water droplets containing known quantities of an illite rich powder under atmospherically relevant conditions. The illite rich powder used here, NX illite, has a similar mineralogical composition to atmospheric mineral dust sampled in remote locations, i.e. dust which has been subject to long range transport, cloud processing and sedimentation. Arizona Test Dust, which is used in other ice nucleation studies as a model atmospheric dust, has a significantly different mineralogical composition and we suggest that NX illite is a better surrogate of natural atmospheric dust. Using optical microscopy, heterogeneous nucleation in the immersion mode by NX illite was observed to occur dominantly between 246 K and the homogeneous freezing limit. In general, higher freezing temperatures were observed when larger surface areas of NX illite were present within the drops. Homogenous nucleation was observed to occur in droplets containing low surface areas of NX illite. We show that NX illite exhibits strong particle to particle variability in terms of ice nucleating ability, with ~1 in 105 particles dominating ice nucleation when high surface areas were present. In fact, this work suggests that the bulk of atmospheric mineral dust particles may be less efficient at nucleating ice than assumed in current model parameterisations. For droplets containing ≤2 × 10−6 cm2 of NX illite, freezing temperatures did not noticeably change when the cooling rate was varied by an order of magnitude. The data obtained during cooling experiments (surface area ≤2 × 10−6 cm2) is shown to be inconsistent with the single component stochastic model, but is well described by the singular model (ns(236.2 K ≤ T ≤ 247.5 K) = exp(6.53043 × 104− 8.2153088 × 102T + 3.446885376T2 − 4.822268 × 10−3T3). However, droplets continued to freeze when the temperature was held constant, which is inconsistent with the time independent singular model. We show that this apparent discrepancy can be resolved using a multiple component stochastic model in which it is assumed that there are many types of nucleation sites, each with a unique temperature dependent nucleation coefficient. Cooling rate independence can be achieved with this time dependent model if the nucleation rate coefficients increase very rapidly with decreasing temperature, thus reconciling our measurement of nucleation at constant temperature with the cooling rate independence

Incidence and recognition of acute respiratory distress syndrome in a UK intensive care unit.

The reported incidence of ARDS is highly variable (2.5%-19% of intensive care unit (ICU) patients) and varies depending on study patient population used. We undertook a 6-month, prospective study to determine the incidence and outcome of ARDS in a UK adult University Hospital ICU. 344 patients were admitted during the study period, of these 43 (12.5%) were determined to have ARDS. Patients with ARDS had increased mortality at 28 days and 2 years post-diagnosis, and there was under-recognition of ARDS in both medical records and death certificattion. Our findings have implications for critical care resource planning.This is the final version of the article. It first appeared from BMJ Thorax via ://dx.doi.org/10.1136/thoraxjnl-2016-20840

Severe pulmonary hypertension associated with lung disease is characterised by a loss of small pulmonary vessels on quantitative computed tomography

Background: Pulmonary hypertension (PH) in patients with chronic lung disease (CLD) predicts reduced functional status, clinical worsening and increased mortality, with patients with severe PH-CLD (≥35 mmHg) having a significantly worse prognosis than mild to moderate PH-CLD (21-34 mmHg). The aim of this cross-sectional study was to assess the association between computed tomography (CT)-derived quantitative pulmonary vessel volume, PH severity and disease aetiology in CLD. Methods: Treatment-naïve patients with CLD who underwent CT pulmonary angiography, lung function testing and right heart catheterisation were identified from the ASPIRE registry between October 2012 and July 2018. Quantitative assessments of total pulmonary vessel and small pulmonary vessel volume were performed. Results: 90 patients had PH-CLD including 44 associated with COPD/emphysema and 46 with interstitial lung disease (ILD). Patients with severe PH-CLD (n=40) had lower small pulmonary vessel volume compared to patients with mild to moderate PH-CLD (n=50). Patients with PH-ILD had significantly reduced small pulmonary blood vessel volume, compared to PH-COPD/emphysema. Higher mortality was identified in patients with lower small pulmonary vessel volume. Conclusion: Patients with severe PH-CLD, regardless of aetiology, have lower small pulmonary vessel volume compared to patients with mild-moderate PH-CLD, and this is associated with a higher mortality. Whether pulmonary vessel changes quantified by CT are a marker of remodelling of the distal pulmonary vasculature requires further study

Functional Redundancy of Class I Phosphoinositide 3-Kinase (PI3K) Isoforms in Signaling Growth Factor-Mediated Human Neutrophil Survival

We have investigated the contribution of individual phosphoinositide 3-kinase (PI3K) Class I isoforms to the regulation of neutrophil survival using (i) a panel of commercially available small molecule isoform-selective PI3K Class I inhibitors, (ii) novel inhibitors, which target single or multiple Class I isoforms (PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ), and (iii) transgenic mice lacking functional PI3K isoforms (p110δKOγKO or p110γKO). Our data suggest that there is considerable functional redundancy amongst Class I PI3Ks (both Class IA and Class IB) with regard to GM-CSF-mediated suppression of neutrophil apoptosis. Hence pharmacological inhibition of any 3 or more PI3K isoforms was required to block the GM-CSF survival response in human neutrophils, with inhibition of individual or any two isoforms having little or no effect. Likewise, isolated blood neutrophils derived from double knockout PI3K p110δKOγKO mice underwent normal time-dependent constitutive apoptosis and displayed identical GM-CSF mediated survival to wild type cells, but were sensitized to pharmacological inhibition of the remaining PI3K isoforms. Surprisingly, the pro-survival neutrophil phenotype observed in patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD) was resilient to inactivation of the PI3K pathway

Elevated DNA methylation across a 48-kb region spanning the HOXA gene cluster is associated with Alzheimer's disease neuropathology

Introduction Alzheimer's disease is a neurodegenerative disorder that is hypothesized to involve epigenetic dysregulation of gene expression in the brain. Methods We performed an epigenome-wide association study to identify differential DNA methylation associated with neuropathology in prefrontal cortex and superior temporal gyrus samples from 147 individuals, replicating our findings in two independent data sets (N = 117 and 740). Results We identify elevated DNA methylation associated with neuropathology across a 48-kb region spanning 208 CpG sites within the HOXA gene cluster. A meta-analysis of the top-ranked probe within the HOXA3 gene (cg22962123) highlighted significant hypermethylation across all three cohorts (P = 3.11 × 10−18). Discussion We present robust evidence for elevated DNA methylation associated with Alzheimer's disease neuropathology spanning the HOXA gene cluster on chromosome 7. These data add to the growing evidence highlighting a role for epigenetic variation in Alzheimer's disease, implicating the HOX gene family as a target for future investigation

The use of Macitentan in Fontan circulation: a case report.

BACKGROUND: The Fontan circulation, a result of a palliative procedure in patients with single systemic ventricles, is defined by chronically elevated pulmonary vascular resistance. When traditional heart failure therapies fail, pharmacological agents that reduce pulmonary artery pressures may be used. These include endothelial-receptor antagonists, prostanoids and phosphodiesterase type 5 inhibitors. We report the first use of macitentan, an endothelin-receptor antagonist, in a patient with a Fontan circulation. CASE PRESENTATION: We describe the case of a 50 year old female with tricuspid atresia and transposition of the great arteries. Following complex surgery as a child, she subsequently underwent a fenestrated modified atrial pulmonary Fontan operation which was later converted to a total cavopulmonary anastomosis Fontan circulation. Due to failure of various medications to relieve her worsening symptoms, she was commenced on macitentan in April 2016. Few months later, she demonstrated a significant symptomatic improvement and associated increase in her incremental shuttle walking test distance. CONCLUSIONS: Macitentan has slower receptor dissociation kinetics compared to other endothelin-receptor antagonists, leading to enhanced pharmacological activity with promising effects in patients with pulmonary arterial hypertension. The patient we report has shown considerable improvement in exercise capacity following introduction of this medication and thus we suggest further randomised trials to establish the role of different endothelin-receptor antagonists in the management of the Fontan circulation

British Lung Foundation/United Kingdom primary immunodeficiency network consensus statement on the definition, diagnosis, and management of granulomatous-lymphocytic interstitial lung disease in common variable immunodeficiency disorders

A proportion of people living with common variable immunodeficiency disorders develop granulomatous-lymphocytic interstitial lung disease (GLILD). We aimed to develop a consensus statement on the definition, diagnosis, and management of GLILD. All UK specialist centers were contacted and relevant physicians were invited to take part in a 3-round online Delphi process. Responses were graded as Strongly Agree, Tend to Agree, Neither Agree nor Disagree, Tend to Disagree, and Strongly Disagree, scored +1, +0.5, 0, −0.5, and −1, respectively. Agreement was defined as greater than or equal to 80% consensus. Scores are reported as mean ± SD. There was 100% agreement (score, 0.92 ± 0.19) for the following definition: “GLILD is a distinct clinico-radio-pathological ILD occurring in patients with [common variable immunodeficiency disorders], associated with a lymphocytic infiltrate and/or granuloma in the lung, and in whom other conditions have been considered and where possible excluded.” There was consensus that the workup of suspected GLILD requires chest computed tomography (CT) (0.98 ± 0.01), lung function tests (eg, gas transfer, 0.94 ± 0.17), bronchoscopy to exclude infection (0.63 ± 0.50), and lung biopsy (0.58 ± 0.40). There was no consensus on whether expectant management following optimization of immunoglobulin therapy was acceptable: 67% agreed, 25% disagreed, score 0.38 ± 0.59; 90% agreed that when treatment was required, first-line treatment should be with corticosteroids alone (score, 0.55 ± 0.51)

Identifying At-Risk Patients with Combined Pre- and Postcapillary Pulmonary Hypertension Using Interventricular Septal Angle at Cardiac MRI

Purpose To assess interventricular septal (IVS) angle in the identification of combined pre- and postcapillary pulmonary hypertension (Cpc-PH) in patients with pulmonary hypertension (PH) due to left-sided heart disease. Materials and Methods In this retrospective study, consecutive, incident patients suspected of having PH underwent same-day right-sided heart catheterization (RHC) and MRI at a PH referral center between April 2012 and April 2017. The diagnostic accuracy of the IVS angle to identify Cpc-PH in patients with pulmonary arterial wedge pressure (PAWP) greater than 15 mmHg was assessed by using receiver operator characteristic curves, sensitivity, specificity, and negative and positive predictive values. IVS angle also was assessed as a predictor of all-cause mortality by using Cox uni- and multivariable proportional hazards regression. Results A total of 708 patients underwent same-day MRI and RHC, and 171 patients had PAWP greater than 15 mmHg. Mean age was 70 years (range, 21-90 years) (women: mean age, 69 years; range, 21-88 years) (men: mean age, 71 years; range, 43-90 years). Systolic IVS angle correlated with diastolic pulmonary gradient (DPG) (r = 0.739, P < .001). Receiver operating characteristic curve analysis showed septal angle enabled identification of Cpc-PH (DPG ≥ 7), with an area under the receiver operating characteristic curve of 0.911 (P < .001). A 160° threshold, derived from the first half of patients with raised PAWP, enabled identification of a DPG of at least 7 mmHg with 67% sensitivity and 93% specificity (P < .001) in the second cohort of patients with raised PAWP. IVS angle was predictive of all-cause mortality (standardized univariable hazard ratio, 1.615; P < .01). Conclusion The systolic interventricular septal angle is elevated in patients with combined pre- and postcapillary pulmonary hypertension and enables one to predict those patients who have PH due to left-sided heart disease who have an increased risk of death. Online supplemental material is available for this article

In vivo imaging reveals increased eosinophil uptake in the lungs of obese asthmatic patients.

To The Editor: Eosinophils play an important pathogenic role in pulmonary and systemic conditions including eosinophilic asthma and eosinophilic granulomatosis with polyangiitis.1,2 While progress has been made in understanding the mechanisms responsible for the activation of these cells, existing biomarkers of eosinophilic inflammation are indirect and/or invasive and do not always correlate with tissue eosinophilia. Hence, there is a need to develop non-invasive biomarkers of tissue eosinophilia. We have previously demonstrated the capacity of SPECT (single photon emission computed tomography) to quantify neutrophil uptake into the lungs of COPD patients.3 We sought to determine whether this methodology could be used to quantify eosinophil kinetics and pulmonary uptake, which may differ amongst diseases characterized by eosinophilic inflammation. In particular, the role of the eosinophil in asthma with obesity, a distinct asthma endotype associated with increased severity,4 is controversial. We hypothesized that injection of radiolabeled eosinophils, coupled with SPECT/CT, would reveal changes in eosinophil kinetics in patients compared to healthy volunteers.This work was supported by Asthma UK [08/11], the Medical Research Council [grant number MR/J00345X/1], the Wellcome Trust [grant number 098351/Z/12/Z], Cambridge NIHR Biomedical Research Centre, Wellcome Trust Senior Fellowship (to CEB) [grant number WT082265], AirPROM 7th EU Framework grant and Leicester NIHR Biomedical Research Centre