Hyperreflective Material Boundary Remodeling in Neovascular Age-Related Macular Degeneration: A Post Hoc Analysis of the AVENUE Trial.

OBJECTIVE: To describe the spatial and temporal characteristics of hyperreflective material (HRM) on spectral-domain OCT (SD-OCT) in neovascular age-related macular degeneration (nAMD) during antiangiogenic treatment and explore associations with best-corrected visual acuity (BCVA) and macular atrophy (MA). DESIGN: Retrospective regrading of SD-OCT-images from the multicenter, randomized controlled AVENUE trial (NCT02484690, conducted from August 2015 to September 2017). PARTICIPANTS: Treatment-naive nAMD patients enrolled from 50 sites in the US. METHODS: Retrospective regrading and secondary analysis. MAIN OUTCOME MEASURES: Spectral-domain OCT images from 207 study eyes that fit criteria for the present analysis were graded for HRM features, its evolution, and associated hypertransmission into choroid (HTC), a proxy for MA. The appearance of a well-defined hyperreflective inner boundary that separated persistent HRM from the neurosensory retina continuous with the adjacent retinal pigment epithelium layer was defined as hyperreflective material boundary remodeling (HRM-BR). Patterns of HRM composition/evolution were defined as follows: (1) no subretinal HRM at baseline, (2) fully resolved, (3) persistent with complete HRM-BR, or (4) partial/absent HRM-BR. Associations of HRM patterns with BCVA and HTC were analyzed. Predictive factors for complete HRM-BR were explored. RESULTS: Of 207 included eyes, subretinal HRM was present in 159 (76.8%) at baseline and persisted until month 9 in 118 (57.0%) eyes. Of these 118 eyes, 44.9% developed complete HRM-BR and had similar BCVA outcomes by month 9 compared with no/fully resolved subretinal HRM. Partial/absent HRM-BR had a strong negative association with BCVA outcome (-6.1 ETDRS letters; P = 0.016) and a higher frequency of intralesional HTC (69.2%) compared with eyes with complete HRM-BR (20.8%) at month 9. Older age (odds ratio [OR], 0.96; P = 0.054) and presence of intralesional HTC (OR, 0.06; P = 0.010) at baseline were associated with lower odds of complete HRM-BR at month 9. CONCLUSIONS: In nAMD eyes under antiangiogenic treatment, complete HRM-BR occurred frequently and was associated with better BCVA than when HRM-BR was only partial/absent. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Angiopoietin 2 and hsCRP are associated with pulmonary hemodynamics and long-term mortality respectively in CTEPH-Results from a prospective discovery and validation biomarker study.

INTRODUCTION: Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed disease of uncertain etiology. Altered endothelial homeostasis, defective angiogenesis and inflammation are implicated. Angiopoietin 2 (Ang2) impairs acute thrombus resolution and is associated with vasculopathy in idiopathic pulmonary arterial hypertension. METHODS: We assessed circulating proteins associated with these processes in serum from patients with CTEPH (n = 71) before and after pulmonary endarterectomy (PEA), chronic thromboembolic pulmonary disease without pulmonary hypertension (CTEPD, n = 9) and healthy controls (n = 20) using Luminex multiplex arrays. Comparisons between groups were made using multivariable rank regression models. Ang2 and high-sensitivity C-reactive protein (hsCRP) were measured in a larger validation dataset (CTEPH = 277, CTEPD = 26). Cox proportional hazards models were used to identify markers predictive of survival. RESULTS: In CTEPH patients, Ang2, interleukin (IL) 8, tumor necrosis factor α, and hsCRP were elevated compared to controls, while vascular endothelial growth factor (VEGF) c was lower (p < 0.05). Ang2 fell post-PEA (p < 0.05) and was associated with both pre- and post-PEA pulmonary hemodynamic variables and functional assessments (p < 0.05). In the validation dataset, Ang2 was significantly higher in CTEPH compared to CTEPD. Pre-operative hsCRP was an independent predictor of mortality. CONCLUSIONS: We hypothesize that CTEPH patients have significant distal micro-vasculopathy and consequently high circulating Ang2. Patients with CTEPD without pulmonary hypertension have no discernible distal micro-vasculopathy and therefore have low circulating Ang2. This suggests Ang2 may be critical to CTEPH disease pathogenesis (impaired thrombus organization and disease severity).

Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension.

BACKGROUND: Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension (PAH). Compelling preclinical data supports the therapeutic blockade of interleukin-6 (IL-6) signalling. METHODS: We conducted a phase 2 open-label study of intravenous tocilizumab (8 mg·kg-1) over 6 months in patients with group 1 PAH. Co-primary end-points were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a mendelian randomisation study was undertaken on 11 744 individuals with European ancestry including 2085 patients with idiopathic/heritable disease for the IL-6 receptor (IL6R) variant (rs7529229), known to associate with circulating IL-6R levels. RESULTS: We recruited 29 patients (male/female 10/19; mean±sd age 54.9±11.4 years). Of these, 19 had heritable/idiopathic PAH and 10 had connective tissue disease-associated PAH. Six were withdrawn prior to drug administration; 23 patients received at least one dose of tocilizumab. Tocilizumab was discontinued in four patients owing to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma IL-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the lead IL6R variant on risk of PAH (OR 0.99, p=0.88). CONCLUSION: Adverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.

Mid-term follow-up after aortic valve replacement with the Carpentier Edwards Magna Ease prosthesis.

BACKGROUND: Approximately 250,000 heart valve operations are performed annually worldwide. An intensive research and development effort has led to progressively more advanced heart valve prostheses. The Carpentier-Edwards Perimount Magna Ease (CEPME) prosthesis represents the latest iteration of the Edwards Perimount series of aortic tissue valves. The current study aims to evaluate the midterm performance of this bioprosthesis. METHODS: Five hundred and eighteen patients with aortic stenosis underwent aortic valve replacement with the CEPME valve at Papworth Hospital between August 2008 and November 2011. After a minimum of 3 years from the index operation, eligible patients were retrospectively and consecutively recruited to participate. Recruitment was closed after 100 eligible patients had completed all study assessments. Investigations at follow-up included echocardiography, and NYHA status. Primary endpoints included valve performance measures. RESULTS: The mean age was 72 years, 64% were male and median follow-up was 5.1 years. NYHA status had improved in 66% of patients. The average postoperative peak and mean pressure gradients decreased by 51.2 mmHg (64.5%) and 31.8 mmHg (59.4%), with a significant improvement in NYHA status. The frequency of moderate aortic regurgitation was 3%. There was no evidence for structural valve deterioration. CONCLUSIONS: The CEPME has excellent mid-term durability. Its use effectively improves haemodynamics and functional capacity.

Early Outcomes After Mitral Valve Repair versus Replacement in the Elderly: A Propensity Matched Analysis.

BACKGROUND: To compare early outcomes of mitral valve repair versus replacement in elderly patients with degenerative mitral valve disease. METHODS: A retrospective review of prospectively collected clinical data of patients over 75 years of age, who underwent mitral valve surgery for degenerative disease, between 2010 and 2013, was carried out. Those undergoing mitral valve repair and replacement were propensity matched to adjust for baseline clinical differences. RESULTS: A total 260 patients were identified: mitral valve repair was undertaken in 145 and replacement in 115 patients. After propensity matching, 78 patients were included in each group. In the entire, unmatched population, in-hospital mortality was significantly higher in those undergoing replacement compared with those undergoing repair (9.6% vs 1.4%, p=0.003). In-hospital death occurred in six (7.7%) of the propensity matched replacement group and none in the repair group (p=0.012). Amongst the propensity matched groups, probability of survival at 1, 2 and 3 years were 0.94, 0.90 and 0.86 respectively for the repair group and 0.85, 0.77 and 0.69 for the replacement group: the HR for death between replacement and repair is 2.5 (1.2-5.4), p=0.012. CONCLUSIONS: Within the limitations imposed by retrospective analyses, our study demonstrates that, in elderly patients with degenerative disease of the mitral valve, repair is associated with improved short-term and mid-term outcomes compared with mitral valve replacement.

Usefulness of the STOP-Bang Questionnaire in a Cardiac Surgical Population.

OBJECTIVE: The aim of this study was to assess the predictive accuracy of the STOP-Bang questionnaire in relation to obstructive sleep apnea (OSA) detected by nocturnal oximetry, as well as postoperative outcomes, in a population undergoing cardiac surgery. DESIGN: A prospective observational cohort study. SETTING: The specialist cardiothoracic center at the Royal Papworth Hospital, Cambridge University Health Partners, United Kingdom. PARTICIPANTS: All adult patients, undergoing elective coronary artery bypass grafting with or without cardiac valve surgery between March 2013 and July 2014 were included. The authors excluded patients participating in other interventional studies, those who had a tracheostomy before surgery, and those who required emergency surgery or were due to be admitted on the day of surgery. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Cardiac surgical patients were screened for the risk of OSA with the use of STOP-Bang questionnaire. The presence of OSA prior to surgery was assessed with overnight oximetry. The predictive performance of the STOP-Bang questionnaire was assessed by calculating sensitivity, specificity, positive predictive value, negative predictive value, and area under the curve (AUC)-receiver operating characteristic curve (ROC). Multiple-logistic regression models were used to assess for associations between the STOP-Bang scores and postoperative outcomes. The STOP-Bang questionnaire discriminated poorly between mild OSA (AUC-ROC 0.57 [95% confidence interval (CI) 0.47-0.67]) and moderate/severe OSA (AUC-ROC 0.82 (95% CI 0.69-0.95)]. Accuracy was increased by modifying the cut-off value to 6 or greater, with sensitivity and specificity of 75% and 77%, respectively. A STOP-Bang score indicating the possibility of OSA was not significantly associated with prolonged intensive care unit lengths of stay (hazard ratio [HR] 1.1; 95% CI 0.99-1.19; p = 0.08) or postoperative complications (odds ratio [OR] 1.0; 95% CI 0.59-1.72; p = 0.98). CONCLUSIONS: In the study population, a STOP-Bang questionnaire score of 3 or greater had limited predictive value for identifying cardiac surgical patients at high risk of OSA. STOP-Bang scores were not significantly associated with worse postoperative outcomes. A STOP-Bang score of 6 or greater could help identify patients in need of a sleep study to confirm the presence of OSA as such patients may be at increased risk of postoperative complications.

Effects of Patent Foramen Ovale Closure on Obstructive Sleep Apnea Syndrome: PCOSA Study.

BACKGROUND: Previous studies have shown a higher prevalence of patent foramen ovale (PFO) in patients with obstructive sleep apnea syndrome (OSAS). Right to left shunting through a PFO may be encouraged by the respiratory physiology of OSAS, contributing to the disease pathophysiology. We assessed whether PFO closure would improve respiratory polygraphy parameters compared with baseline measurements in patients with OSAS. METHODS: Twenty-six patients with newly diagnosed OSAS and a moderate-large PFO (prevalence, 18% of 143 patients screened) were referred for PFO closure. The oxygen desaturation index (ODI), apnea-hypopnea index (AHI), Epworth Sleepiness Scale (ESS), 6-minute walk test (6MWT), and Sleep Apnea Quality of Life Index (SAQLI) results were compared in these patients at baseline (before continuous positive pressure ventilation [CPAP]) and at 6-month follow-up (after interrupting CPAP for 1 week). RESULTS: All PFOs were safely sealed at 6 months, as confirmed by repeated transthoracic echocardiography. The ODI (44.8 [interquartile range (IQR), 31.2-63.5) vs 42.3 [IQR, 34.0-60.8]; P = 0.89) and AHI (47.9 [IQR, 31.5-65.2] vs 42.3 [IQR, 32.1-63]; P = 0.99) did not change after PFO closure nor did the 6MWT, although the ESS (13.0 [IQR, 12.0-16.8] vs 6.0 [IQR, 4.0-8.8]; P < 0.001) and the SAQLI (3.4 [IQR, 2.8-4.3] vs 4.4 [IQR, 3.9-5.3]; P < 0.001) did improve. CONCLUSIONS: The prevalence of PFO in OSAS appears to be no higher than that in the general population. Although PFO closure is safe and effective, it did not improve respiratory polygraphy measures of OSAS severity. The improvement in the ESS and SAQLI likely reflect residual benefits from CPAP.

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.

Association between severity of untreated sleep apnoea and postoperative complications following major cardiac surgery: a prospective observational cohort study.

OBJECTIVE: To examine whether untreated sleep apnoea is associated with prolonged Intensive Care Unit (ICU) stay and increased frequency of postoperative ICU complications, in patients undergoing major cardiac surgery. PATIENTS/METHODS: Adult patients, undergoing elective coronary artery bypass grafting with or without cardiac valve surgery, between March 2013 and July 2014, were considered. We excluded patients participating in other interventional studies, those who had a tracheostomy before surgery, required emergency surgery or were due to be admitted on the day of surgery. Patients underwent inpatient overnight oximetry on the night prior to their surgery to assess for the presence of sleep apnoea. Since oximetry alone cannot differentiate obstructive from central apnoea, the results are reported as sleep apnoea which was diagnosed in patients with an arterial oxygen desaturation index (ODI) ≥ 5/h. RESULTS: The primary outcome measure was length of stay (LoS) in ICU in days. The secondary outcome was a composite measure of postoperative complications in ICU. Multivariate models were developed to assess associations between ODI and the primary and secondary outcome measures, adjusting for preselected predictor variables, relative to primary and secondary outcomes. There was no significant association between ODI and ICU LoS, HR 1.0, 95% CI 0.99-1.02; p = 0.12. However we did find a significant association between ODI and postoperative complications in the ICU, OR = 1.1; 95% CI 1.02-1.17; p = 0.014. The probability of developing complications rose with higher ODI, reflecting sleep apnoea severity. CONCLUSIONS: Acknowledging the limitations of this prospective study, untreated sleep apnoea did not predict an increased length of stay in ICU but we do report an association with postoperative complications in patients undergoing major cardiac surgery.

Vaccination of koalas with a prototype chlamydial vaccine is safe, does not increase the incidence of lymphoma-related disease and maybe associated with increased lifespan in captive koalas.

OBJECTIVES: To assess the impact of Chlamydia vaccination on survival of captive koalas, and to compare the incidence of lymphomas and neoplasias between vaccinated and unvaccinated koalas. METHODS: Survival analysis using Cox and Weibull regressions on 54 vaccinated and 52 matched unvaccinated koalas, and chi-square contingency table for incidence of lymphomas/neoplasias. RESULTS: Vaccination was found to have a significant positive effect on koala lifespan (P=0.03), with vaccinated koalas having a median lifespan of 12.25 years compared to 8.8 years for unvaccinated ones. The effect of sex on lifespan was not significant (P=0.31). The risk ratio of unvaccinated over vaccinated koalas was 2.2 with both Cox and Weibull regressions. There was no association between the incidence of lymphoma/neoplasias and vaccination status (P=0.33). CONCLUSIONS: Koalas vaccinated with a prototype Chlamydia vaccine may live longer than unvaccinated ones. There was no known Chlamydia infection among koalas, so our interpretation is that vaccination may have boosted the innate and adaptive immune systems to protect against a wide spectrum of bacteria, fungi and parasites. Vaccinated koalas did not show negative physiological effects of the vaccine, for example, the frequency of deaths due to lymphomas/neoplasias was the same in both vaccinated and unvaccinated animals.