Rapid growth of a left atrial myxoma was demonstrated in a patient who showed no echocardiographic evidence of the tumour when she was admitted for an atrial fibrillation catheter ablation. Eighteen months later, she presented with temporary visual disturbance, and transthoracic echocardiography showed a 35 x 25 x 20 mm left atrial myxoma. This was excised en-bloc and the histopathology confirmed the diagnosis of benign myxoma.

BACKGROUND:Tryptase, a mast cell protease, has been identified as a potential therapeutic target in managing patients with refractory asthma. We assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of MTPS9579A, an anti-tryptase antibody, in a phase 2a randomized trial for patients with uncontrolled asthma and a phase 1c trial to understand activity within the lower respiratory tract. METHODS:Phase 2a patients (n = 134) received 1800 mg MTPS9579A or placebo intravenously every 4 weeks for 48 weeks. The primary endpoint was time to the first composite exacerbation event. Phase 1c patients (n = 27) received one intravenous dose of 300 or 1800 mg MTPS9579A or placebo. Both trials measured MTPS9579A concentrations and effects on tryptase in serum and nasal lining fluid; phase 1c also analyzed bronchial lining fluid. RESULTS:MTPS9579A did not meet the primary endpoint (hazard ratio = 0.90; 95% CI: 0.55-1.47; p = 0.6835); exacerbation rates in the placebo group were low. Serum and nasal MTPS9579A pharmacokinetics and tryptase levels were consistent with data from healthy volunteers. However, in phase 1c patients, compared to nasal levels, MTPS9579A bronchial concentrations were 6.8-fold lower, and bronchial active and total tryptase levels were higher (119-fold and 30-fold, respectively). Pharmacokinetic/pharmacodynamic modeling predicted intravenous doses of 3800 mg every 4 weeks would be necessary to achieve 95% active tryptase inhibition from baseline. CONCLUSIONS:The MTPS9579A dose tested in the phase 2a study was insufficient to inhibit tryptase in bronchial lining fluid, likely contributing to the observed lack of efficacy.

The pharmacokinetic (PK) characteristics of omalizumab and its pharmacodynamic (PD) effect in patients has yet to be fully characterized in chronic spontaneous urticaria, which could elucidate its pathogenesis and treatment response. This study has two objectives; (1) characterize the population PK of omalizumab and its PD effect on IgE, and (2) develop a drug effect model of omalizumab in urticaria (via change in weekly itch severity score). The target-mediated population of PK/PD model incorporating omalizumab-IgE binding and turnover adequately described PK and PD of omalizumab. The effect compartment model and linear drug effect and additive placebo response adequately described placebo and treatment effects of omalizumab. Several baseline covariates were identified for PK/PD and drug effect models. The developed model has the potential to aid in understanding variability in PK/PD as well as response to omalizumab treatment.

Accurate phenotypic and endotypic characterization of asthma is critical to inform treatment decisions, particularly for patients with eosinophilic or type-2 (T2) high asthma who are more responsive to inhaled corticosteroids and are candidates for biologic therapies targeting T2 inflammation.1 Current biomarkers of T2 inflammation, including blood and sputum eosinophilia, and fractional exhaled nitric oxide (FENO), have limitations. Thus there is an unmet need for additional, more accurate biomarkers and to understand the relationship between such biomarkers and airway immunopathology.1 Periostin, a matrix protein secreted by epithelial and stromal cells and a biomarker of T2 inflammation in clinical research, can be measured in sputum and has been associated with the T2-high endotype and persistent airflow obstruction in patients with severe asthma.2 The relationship of sputum periostin to airway dysfunction in the form of airway hyperresponsiveness (AHR) and airway inflammation was examined in individuals with mild-to-moderate asthma who were not using controller therapies. In this cross-sectional assessment, individuals with and without asthma were recruited based on rigorous diagnostic testing, with further characterization of participants for endogenous AHR in the form of exercise-induced bronchoconstriction (EIB).3, 4 Briefly, individuals underwent methacholine challenge testing, dry air exercise challenge, induced sputum collection and research bronchoscopy. Periostin levels in induced sputum supernatant were measured at a 1:2 dilution using a sandwich ELISA assay (Genentech, Inc., South San Francisco, CA; lower limit of quantitation [LLOQ]: 37 pg/mL).5 We assessed induced sputum cell differentials and expression of selected genes (IL4, IL5, IL13, ARG2, INFG, TPSAB1, CMA1, and CPA3) by qPCR. Individuals were categorized for T2 inflammation using the sputum Type-2 Gene Mean (T2GM), with T2-high asthma defined by a T2GM ≥2 standard deviations above that of healthy controls within the study population.3, 4, 6 Endobronchial biopsies were assessed by immunohistochemistry and quantified by design-based stereology, to precisely quantify the numerical density of mast cells and eosinophils per reference volume within different compartments of the airway wall.3, 4 Nonparametric statistics were used. Correlations between continuous variables were assessed using Spearman's rho (r). Forty-three study participants had sputum periostin measured, and all but two had periostin levels above the LLOQ including 10 healthy controls (median age [IQR], 24.5 [23–34.3]; % females, 80%) and 33 individuals with asthma (median [IQR] for age, 23 [21–28.5]; FEV1% predicted, 92 [83–95] and FEV1/FVC ratio, 0.77 [0.71–0.84]; % females, 72.7%). There was no difference in sputum periostin concentration between healthy controls and subjects with asthma (median [IQR], 0.30 [0.09–0.69] vs. 0.18 [0.06–0.45]; p = 0.51) and there was no significant association between sputum periostin levels and baseline lung function or the severity of AHR to methacholine (Table 1). There was also no association between sputum periostin concentration and baseline lung function amongst individuals with asthma (Table 1). Amongst individuals with asthma, 20 (60.6%) had a positive exercise challenge test (EIB+). Sputum periostin concentration was similar between EIB− and EIB+ asthmatics (median [IQR], 0.14 [0.06 to 0.23] vs. 0.20 [0.12 to 0.74]; p = 0.16) and did not correlate with the severity of endogenous AHR (Table 1). Airway T2 gene expression was available from 31 individuals, with 14/31 classified as T2-high according to their T2GM. Our prior analysis of this cohort found that the T2GM and individual T2 cytokines correlate with the severity of AHR.3, 4 Here, sputum periostin was non-significantly higher amongst T2-high individuals, across the full study population (median [IQR], 0.36 [0.18–0.68] vs. 0.19 [0.06–0.59], p = 0.14) and after restricting analysis to individuals with asthma (median [IQR], 0.36 [0.18–0.68] vs. 0.15 [0.05–0.38], p = 0.08). Further correlation analyses revealed a significant association between sputum periostin and the sputum T2GM (Table 1). Of the genes included in the T2GM, sputum periostin was most strongly correlated with the expression of IL4 and IL5, and to a lesser extent with IL13 in induced sputum cells (Table 1). Conversely, neither the expression of ARG2 nor INFG in sputum correlated with sputum periostin concentration (Table 1). Subjects with ‘eosinophilic asthma’, defined by sputum eosinophil percentage ≥3%, had a higher sputum periostin concentration compared to non-eosinophilic asthma (median [IQR], 0.50 [0.20–1.09] vs. 0.16 [0.06–0.37], p = 0.03). Sputum periostin differentiated eosinophilic from non-eosinophilic asthma with an area under the ROC curve of 0.8 (95% CI, 0.63–0.97; p = 0.04). Across the full study population and amongst the individuals with asthma, sputum periostin correlated significantly with sputum eosinophil concentration (Table 1). We also further refined the relationship between sputum periostin and the precise location of eosinophils in the airway wall, revealing that sputum periostin concentration correlated with the density of subepithelial eosinophils, but not intraepithelial eosinophils (Table 1). Prior analysis of this cohort revealed that intraepithelial mast cell density and the expression of TPSAB1 and CPA3 in induced sputum were associated with the severity of EIB.4 No association was identified between sputum periostin and the density of mast cells in different compartments of the airway wall. However, expression of genes encoding key mast cell proteases implicated in T2 inflammation (TPSAB1, CPA3) correlated with sputum periostin concentration across the full study population (Table 1). From this pilot assessment, we show that sputum periostin is positively correlated with airway T2 gene expression and airway eosinophilia, but did not differ between individuals with and without asthma and was not associated with reduced lung function or with non-specific AHR to methacholine challenge. As the precise location of eosinophils and mast cells in the airway wall was characterized in this cohort, we demonstrated that sputum periostin correlated with the overall eosinophil density in the airway wall and eosinophils in the subepithelial compartment, the eosinophil location that is most closely associated with T2 airway inflammation.3 However, sputum periostin was not related to mast cells or eosinophils within the epithelial compartment, which are increased in subjects with asthma and tightly associated with airway dysfunction in the form of endogenous AHR, the most specific form of AHR in asthma.3, 4 Periostin has been proposed as a potential biomarker for asthma and for identifying individuals with T2 inflammation. However, serum periostin levels do not reliably differentiate adults with asthma from healthy controls7 but are consistently associated with classic peripheral T2 biomarkers2 and may predict responsiveness to T2-directed biologic therapies.1 Studies evaluating airway periostin levels in induced sputum have been limited with mixed results. One study found similar levels between individuals with mild-to-moderate asthma and healthy controls8 and another identified significantly higher sputum periostin levels in individuals with severe asthma.9 No prior studies have evaluated the details of the components of airway dysfunction with airway periostin levels, but serum periostin levels have been associated with AHR in children, particularly endogenous AHR.10 In children, asthma tends to be T2 predominant, so there may be less discordance between T2 inflammation and AHR, and periostin levels vary widely with age in children.11 We used a direct assessment of T2 gene expression in the airways (rather than peripheral biomarkers such as blood eosinophils or FENO) to demonstrate an association between the level of periostin in induced sputum and the T2 endotype in a well-defined cohort of individuals with mild-to-moderate asthma who were not using controller therapy at the time of assessment. We present evidence that sputum periostin is more closely associated with the T2 endotype and less of a marker of asthma or airway dysfunction, with additional details shown about the relationship of periostin to the precise location of mast cells and eosinophils in the airway wall. As few studies have characterized airway physiology and tissue infiltration with immune cells in relation to airway levels of periostin amongst individuals with asthma, these results add to the growing body of evidence of discordance between T2 biomarkers and airway dysfunction in the form of AHR in asthma. Taha Al-Shaikhly: Data curation (equal); formal analysis (lead); investigation (equal); writing – original draft (lead); writing – review and editing (equal). Ryan C. Murphy: Data curation (equal); formal analysis (equal); validation (equal); writing – original draft (equal); writing – review and editing (equal). Ying Lai: Investigation (equal); writing – review and editing (equal). Charles W. Frevert: Conceptualization (equal); formal analysis (equal); investigation (equal); methodology (equal); writing – review and editing (equal). Jason S. Debley: Formal analysis (equal); investigation (equal); validation (equal); writing – review and editing (equal). Steven F. Ziegler: Funding acquisition (equal); writing – review and editing (equal). Kit Wong: Formal analysis (equal); writing – review and editing (equal). Guiquan Jia: Formal analysis (equal); investigation (equal); writing – review and editing (equal). Cecile T. J. Holweg: Formal analysis (equal); writing – review and editing (equal). Michael C. Peters: Formal analysis (equal); investigation (equal); writing – review and editing (equal). Teal S. Hallstrand: Conceptualization (lead); data curation (equal); formal analysis (equal); funding acquisition (lead); investigation (lead); methodology (lead); project administration (lead); resources (lead); supervision (lead); validation (lead); writing – original draft (equal); writing – review and editing (equal). The work was supported by the National Institutes of Health (grant numbers: U19AI125378, K24AI130263 and R01HL153979). Taha Al-Shaikhly has a patent MicroRNAs as Predictors of Response to Anti-IgE Therapies in Chronic Spontaneous Urticaria pending. Charles W. Frevert, Jason S. Debley, Steven F. Ziegler, and Teal S. Hallstrand report grants from the National Institute of Health during the conduct of the study. Michael C. Peters reports grants from National Institute of Health-NHLBI, Boeringer-Ingelheim, Astrazeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Sanofi-Genzyme-Regeneron, and Teva, outside the submitted work. Kit Wong, Guiquan Jia, and Cecile T. J. Holweg are employees of Genentech. All other authors declared no conflict of interest. This study was performed in accordance with the Declaration of Helsinki. This human study was approved by Institutional Review Board at the University of Washington (Seattle, Washington). All adult participants provided written informed consent to participate in this study. Data available on request from the authors. Visual Abstract Sputum periostin is a biomarker of type 2 inflammation but not airway dysfunction in asthma Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Cardiac surgery performed on patients in cardiogenic shock is associated with a high mortality and morbidity. Preoperative Extra Corporeal Membrane Oxygenation (ECMO) in cardiogenic shock gives critically-ill patients a chance for surgical intervention and is associated with better surgical outcomes. We present a 29-year-old male who had a ventricular septal defect closure as a child and presented with multi-organ injuries following polytrauma. He was in cardiogenic shock despite maximal inotropic support. Transesophageal echocardiography demonstrated torrential tricuspid regurgitation (TR) from a flail tricuspid valve (TV) leaflet as the cause of cardiogenic shock. He was stabilized on Veno-Arterial ECMO and underwent reoperative cardiac surgery. Intra-operatively, the anterior leaflet of his TV and its papillary muscle was detached from the right ventricle. He had a successful tissue TV replacement. Early surgery was indicated to treat right ventricular failure due to torrential TR, but due to his restricting non-cardiac injuries, ECMO was successfully used as a short-term support strategy and as a bridge to definitive surgery.

AIMS:Chronic degenerative mitral regurgitation leads to volume overload causing left ventricular (LV) enlargement and eventually LV impairment. Current guidelines determining thresholds for intervention are based on LV diameters and ejection fraction (LVEF). There are sparse data examining the value of LV volumes and newer markers of LV performance on outcomes of surgery in mitral valve prolapse. The aim of this study is to identify the best marker of LV impairment after mitral valve surgery.METHODS AND RESULTS:Prospective, observational study of patients with mitral valve prolapse undergoing mitral valve surgery. Pre-operative LV diameters, volumes, LVEF, global longitudinal strain (GLS), and myocardial work measured. Post-operative LV impairment defined as LVEF < 50% at 1 year post-surgery. Eighty-seven patients included. Thirteen percent developed post-operative LV impairment. Patients with post-operative LV dysfunction showed significantly larger indexed LV end-systolic diameters, indexed LV end-systolic volumes (LVESVi), lower LVEF, and more abnormal GLS than patients without post-operative LV dysfunction. In multivariate analysis, LVESVi [odds ratio 1.11 (95% CI 1.01-1.23), P = 0.039] and GLS [odds ratio 1.46 (95% CI 1.00-2.14), P = 0.054] were the only independent predictors of post-operative LV dysfunction. The optimal cut-off of 36.3 mL/m2 for LVESVi had a sensitivity of 82% and specificity of 78% for detection of post-operative LV impairment.CONCLUSION:Post-operative LV impairment is common. Indexed LV volumes (36.3 mL/m2) provided the best marker of post-operative LV impairment.

The current guidelines recommend intervention in severe degenerative mitral regurgitation (MR) in symptomatic patients or asymptomatic patients with left ventricular dilatation or dysfunction. The insidious onset of symptoms may mean that patients do not report their symptoms. The role of systematic exercise testing for symptoms in MR is not clearly defined. A total of 97 patients with moderate to severe asymptomatic MR underwent exercise echocardiography combined with cardiopulmonary exercise testing. The predictors of exercise-induced dyspnea, symptom-free survival, and mitral valve intervention were identified. A total of 18 patients (19%) developed limiting dyspnea on exercise. Spontaneous symptom-free survival at 24 months was significantly higher in those without exercise-induced symptoms than those with exercise-induced symptoms, p <0.0001. The only independent predictors of spontaneous symptoms at 2 years were effective regurgitant orifice area (odds ratio 27.45, 95% confidence interval [CI] 1.43 to 528.40, p = 0.03) and exercise-induced symptoms (odds ratio 11.56, 95% CI 1.71 to 78.09, p = 0.01). The only independent predictor of surgery was indexed left ventricular systolic volumes (odds ratio 1.17, 95% CI 1.04 to 1.30, p = 0.006). Where only the patients who underwent surgery due to symptoms were included, the only independent predictor was exercise-induced symptoms (odds ratio 13.94, 95% CI 1.39 to 140.27, p = 0.025). In conclusion, in patients with primary asymptomatic degenerative MR, 1/5 develop revealed symptoms during exercise. This predicts a subsequent development of spontaneous symptoms and mitral valve intervention due to symptoms.

NOX2 is the prototypical member of the NADPH oxidase NOX superfamily and produces superoxide (O2•-), a key reactive oxygen species (ROS) that is essential in innate and adaptive immunity. Mutations that lead to deficiency in NOX2 activity correlate with increased susceptibility to bacterial and fungal infections, resulting in chronic granulomatous disease. The core of NOX2 is formed by a heterodimeric transmembrane complex composed of NOX2 (formerly gp91) and p22, but a detailed description of its structural architecture is lacking. Here, we present the structure of the human NOX2 core complex bound to a selective anti-NOX2 antibody fragment. The core complex reveals an intricate extracellular topology of NOX2, a four-transmembrane fold of the p22 subunit, and an extensive transmembrane interface which provides insights into NOX2 assembly and activation. Functional assays uncover an inhibitory activity of the 7G5 antibody mediated by internalization-dependent and internalization-independent mechanisms. Overall, our results provide insights into the NOX2 core complex architecture, disease-causing mutations, and potential avenues for selective NOX2 pharmacological modulation.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) frequently remains uncontrolled despite maximal medical therapy and sinonasal surgery, presenting several unmet needs and challenges. Omalizumab previously demonstrated efficacy in CRSwNP in duplicate phase 3, randomized, placebo-controlled trials (POLYP 1, POLYP 2). Objective: This open-label extension evaluated the continued efficacy, safety, and durability of response of omalizumab in adults with CRSwNP who completed POLYP 1 or 2. Methods: After 24 weeks of omalizumab or placebo in POLYP 1 and 2, patients (n = 249) received open-label omalizumab plus background nasal mometasone therapy for 28 weeks and were subsequently followed for 24 weeks after omalizumab discontinuation. Efficacy end points assessed change from baseline for the coprimary end points, Nasal Polyp Score and Nasal Congestion Score, and the secondary end points of Sino-Nasal Outcome Test 22, Total Nasal Symptom Score and its components, and University of Pennsylvania Smell Identification Test scores. Safety objectives included incidence of adverse events and adverse events leading to omalizumab discontinuation. Results: Patients who continued omalizumab experienced further improvements across coprimary end points and secondary end points through 52 weeks. Patients who switched from placebo to omalizumab experienced favorable responses across end points through week 52 that were similar to POLYP 1 and 2 at week 24. After omalizumab discontinuation, scores gradually worsened over the 24-week follow-up, but remained improved from pretreatment levels for both groups. The safety profile was similar to previous reports. Conclusions: The efficacy and safety profile from this study supports extended omalizumab treatment up to 1 year for CRSwNP with inadequate response to nasal corticosteroids.

Immunoglobulin E (IgE) is a well-known key factor in allergic airway disease; however, its central role in non-allergic airway inflammation is often underestimated. In some airway diseases, IgE is produced as a result of allergic sensitization. However, in others, IgE production occurs despite the lack of a specific allergen. Although multiple pathways contribute to the production of IgE in airway disease, it is its activity in mediating the inflammatory response that is associated with disease. Therefore, an understanding of IgE as the unifying component of upper and lower airway diseases has important implications for both diagnosis and treatment. Understanding the role of IgE in each upper and lower airway disease highlights its potential utility as a diagnostic marker and therapeutic target. Further classification of these diseases by whether they are IgE mediated or non-IgE mediated, rather than by the existence of an underlying allergic component, accounts for both systemic and localized IgE activity. Improvements in diagnostic methodologies and standardization of clinical practices with this classification in mind can help identify patients with IgE-mediated diseases. In doing so, this group of patients can receive optimal care through targeted anti-IgE therapeutics, which have already demonstrated efficacy across numerous IgE-mediated upper and lower airway diseases.

BACKGROUND:Patients with acute severe aortic regurgitation (AR) due to infective endocarditis can progress rapidly from the hemodynamically stable patient to pulmonary edema and cardiogenic shock. We sought to identify patients at risk of decompensation where emergent surgery should be undertaken. METHODS:We identified 90 patients with acute severe AR from the echocardiography laboratory database. Baseline clinical, hemodynamic (heart rate (HR) and blood pressure (BP)), and echocardiographic data including mitral filling, premature mitral valve closure (PMVC), and diastolic mitral regurgitation (DMR) were identified. The primary endpoint was subsequent development of pulmonary edema or severe hemodynamic instability. RESULTS:Patients who met the primary endpoint had a higher HR (98.5 bpm vs 80.5 bpm), lower diastolic BP (54 mm Hg vs 61.5 mm Hg), higher mitral E-wave velocity (113 cm/s vs 83 cm/s), higher E/e' ratio (12.4 vs 8), higher proportion of DMR (27.8% vs 7.4%), and PMVC (25% vs 9.3%) than patients who did not meet the endpoint. The proportion of patients with the primary endpoint increased as HR increased ((≤81 bpm) 3/30 (10%), (81-94 bpm) 11/31 (35.5%), (≥94 bpm) 22/29 (75.9%), P < .0001) and as the diastolic BP reduced ((≤54 mm Hg) 19/31 (61.3%), (54-63 mm Hg) 12/31 (38.7%), (≥63 mm Hg) 5/28 (17.9%), P = .003). Independent predictors were a higher HR (OR 1.08 (95% CI 1.04-1.13) P = .0003) and DMR (OR 4.71 (95% CI 1.23-18.09), P = .02). CONCLUSION:Decompensation in acute severe AR is common. Independent predictors of decompensation are increasing HR(≥94 bpm) and the presence of DMR. Those with these adverse markers should be considered for emergent surgery.

BACKGROUND Epicardial adipose tissue (EAT) directly overlies the myocardium, with changes in its morphology and volume associated with myriad cardiovascular and metabolic diseases. However, EAT’s immune structure and cellular characterization remain incompletely described. We aimed to define the immune phenotype of EAT in humans and compare such profiles across lean, obese, and diabetic patients.METHODS We recruited 152 patients undergoing open-chest coronary artery bypass grafting (CABG), valve repair/replacement (VR) surgery, or combined CABG/VR. Patients’ clinical and biochemical data and EAT, subcutaneous adipose tissue (SAT), and preoperative blood samples were collected. Immune cell profiling was evaluated by flow cytometry and complemented by gene expression studies of immune mediators. Bulk RNA-Seq was performed in EAT across metabolic profiles to assess whole-transcriptome changes observed in lean, obese, and diabetic groups.RESULTS Flow cytometry analysis demonstrated EAT was highly enriched in adaptive immune (T and B) cells. Although overweight/obese and diabetic patients had similar EAT cellular profiles to lean control patients, the EAT exhibited significantly (P ≤ 0.01) raised expression of immune mediators, including IL-1, IL-6, TNF-α, and IFN-γ. These changes were not observed in SAT or blood. Neither underlying coronary artery disease nor the presence of hypertension significantly altered the immune profiles observed. Bulk RNA-Seq demonstrated significant alterations in metabolic and inflammatory pathways in the EAT of overweight/obese patients compared with lean controls.CONCLUSION Adaptive immune cells are the predominant immune cell constituent in human EAT and SAT. The presence of underlying cardiometabolic conditions, specifically obesity and diabetes, rather than cardiac disease phenotype appears to alter the inflammatory profile of EAT. Obese states markedly alter EAT metabolic and inflammatory signaling genes, underlining the impact of obesity on the EAT transcriptome profile.FUNDING Barts Charity MGU0413, Abbott, Medical Research Council MR/T008059/1, and British Heart Foundation FS/13/49/30421 and PG/16/79/32419.

International guidance recognizes the shortcomings of the modified Duke Criteria (mDC) in diagnosing infective endocarditis (IE) when transoesophageal echocardiography (TOE) is equivocal. 18F-FDG PET/CT (PET) has proven benefit in prosthetic valve endocarditis (PVE), but is restricted to extracardiac manifestations in native disease (NVE). We investigated the incremental benefit of PET over the mDC in NVE. Dual-center retrospective study (2010-2018) of patients undergoing myocardial suppression PET for NVE and PVE. Cases were classified by mDC pre- and post-PET, and evaluated against discharge diagnosis. Receiver Operating Characteristic (ROC) analysis and net reclassification index (NRI) assessed diagnostic performance. Valve standardized uptake value (SUV) was recorded. 69/88 PET studies were evaluated across 668 patients. At discharge, 20/32 had confirmed NVE, 22/37 PVE, and 19/69 patients required surgery. PET accurately re-classified patients from possible, to definite or rejected (NRI: NVE 0.89; PVE 0.90), with significant incremental benefit in both NVE (AUC 0.883 vs 0.750) and PVE (0.877 vs 0.633). Sensitivity and specificity were 75% and 92% in NVE; 87% and 86% in PVE. Duration of antibiotics and C-reactive Protein level did not impact performance. No diagnostic SUV cut-off was identified. PET improves diagnostic certainty when combined with mDC in NVE and PVE.

Multiple guidelines exist for the diagnosis and management of mitral regurgitation (MR), the second most common valvular heart disease in high-income countries, with recommendations that do not always match. We systematically reviewed guidelines on diagnosis and management of MR, highlighting similarities and differences to guide clinical decision-making. We searched national and international guidelines in MEDLINE and EMBASE (1 June 2010 to 1 September 2021), the Guidelines International Network, National Guideline Clearinghouse, National Library for Health Guidelines Finder, Canadian Medical Association Clinical Practice Guidelines Infobase, and websites of relevant organizations. Two reviewers independently screened the abstracts and identified articles of interest. Guidelines that were rigorously developed (as assessed with the Appraisal of Guidelines for Research and Evaluation II instrument) were retained for analysis. Five guidelines were retained. There was consensus on a multidisciplinary approach from the heart team and for the definition and grading of severe primary MR. There was general agreement on the thresholds for intervention in symptomatic and asymptomatic primary MR; however, discrepancies were present. There was agreement on optimization of medical therapy in severe secondary MR and intervention in patients symptomatic despite optimal medical therapy, but no consensus on the choice of intervention (surgical repair/replacement vs. transcatheter approach). Cut-offs for high-risk intervention in MR, risk stratification of progressive MR, and guidance on mixed valvular disease were sparse.

The anti-immunoglobulin E (IgE) antibody, omalizumab (Xolair), is approved in the United States for the treatment of allergic asthma and chronic spontaneous urticaria, and has recently been studied for the treatment of nasal polyposis following completion of the two replicate phase 3 studies (POLYP 1 and POLYP 2). The dosing of omalizumab used in the phase 3 studies is based on a combination of patients' pre-treatment IgE level and body weight, similar to the approach used in allergic asthma. The objectives of the current analyses were to evaluate whether the pharmacokinetics (PK) of omalizumab and its pharmacodynamic (PD) effect on free and total IgE level in chronic rhinosinusitis with nasal polyps (CRSwNP) are consistent with those in allergic asthma via population PK/PD modeling and simulation, and to graphically explore exposure-response relationships and free IgE-response relationships in CRSwNP. Omalizumab PK and PD effect of total and free IgE in CRSwNP are generally consistent with those in asthma. Observed post-treatment free IgE suppressions were generally within the target range of the baseline IgE- and body weight-based omalizumab dosing table, with 74.2% and 93.0% of patients achieving a serum free IgE level below 25 ng/mL and 50 ng/mL, respectively at Week 24. Exposureresponse analyses indicated that there was no clear correlation between omalizumab or free IgE concentration and key efficacy endpoints within the POLYP studies. Overall, these results indicate that the body weight and IgE-based dosing regimen of omalizumab was appropriate for use in CRSwNP patients.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by IgE hyperproduction and eosinophilic inflammation. The anti-IgE antibody, omalizumab, has demonstrated efficacy in patients with CRSwNP and comorbid asthma previously. Objective: Our aim was to determine omalizumab safety and efficacy in CRSwNP in phase 3 trials (POLYP 1 and POLYP 2). Methods: Adults with CRSwNP with inadequate response to intranasal corticosteroids were randomized (1:1) to omalizumab or placebo and intranasal mometasone for 24 weeks. Coprimary end points included change from baseline to week 24 in Nasal Polyp Score (NPS) and Nasal Congestion Score. Secondary end points included change from baseline to week 24 in Sino-Nasal Outcome Test-22 (SNOT-22) score, University of Pennsylvania Smell Identification Test, sense of smell, postnasal drip, runny nose, and adverse events. Results: Patients in POLYP 1 (n = 138) and POLYP 2 (n = 127) exhibited severe CRSwNP and substantial quality of life impairment evidenced by a mean NPS higher than 6 and SNOT-22 score of approximately 60. Both studies met both the coprimary end points. SNOT-22 score, University of Pennsylvania Smell Identification Test score, sense of smell, postnasal drip, and runny nose were also significantly improved for omalizumab versus placebo. In POLYP 1 and POLYP 2, the mean changes from baseline at week 24 for omalizumab versus placebo were as follows: NPS, -1.08 versus 0.06 (P < .0001) and - 0.90 versus -0.31 (P = .0140); Nasal Congestion Score, -0.89 versus -0.35 (P = .0004) and -0.70 versus -0.20 (P = .0017); and SNOT-22 score, -24.7 versus -8.6 (P < .0001) and -21.6 versus - 6.6 (P < .0001). Adverse events were similar between groups. Conclusion: Omalizumab significantly improved endoscopic, clinical, and patient-reported outcomes in severe CRSwNP with inadequate response to intranasal corticosteroids, and it was well tolerated.

BackgroundThe anti–interleukin 13 (IL‐13) monoclonal antibody lebrikizumab improves lung function in patients with moderate‐severe uncontrolled asthma, but its effects on airway inflammation and remodeling are unknown. CLAVIER was designed to assess lebrikizumab’s effect on eosinophilic inflammation and remodeling.MethodsWe performed bronchoscopy on patients with uncontrolled asthma before and after 12 weeks of randomised double‐masked treatment with lebrikizumab (n=31) or placebo (n=33). The primary endpoint was relative change in airway subepithelial eosinophils per mm2 of basement membrane (cells/mm2). Pre‐specified secondary and exploratory outcomes included change in IL‐13–associated biomarkers and measures of airway remodeling.FindingsThere was a baseline imbalance in tissue eosinophils and high variability between treatment groups. There was no discernible change in adjusted mean subepithelial eosinophils/mm2 in response to lebrikizumab (95% CI, −82·5%, 97·5%). As previously observed, FEV1 increased after lebrikizumab treatment. Moreover, subepithelial collagen thickness decreased 21·5% after lebrikizumab treatment (95% CI, −32·9%, −10·2%), while fractional exhaled nitric oxide, CCL26, and SERPINB2 mRNA expression in bronchial tissues also diminished. Lebrikizumab was well tolerated, with a safety profile consistent with other lebrikizumab asthma studies.InterpretationWe did not observe reduced tissue eosinophil numbers in association with lebrikizumab treatment. However, in pre‐specified secondary analyses, lebrikizumab treatment was associated with diminished degree of subepithelial fibrosis, a feature of airway remodeling, as well as improved lung function and reduced key pharmacodynamic biomarkers in bronchial tissues. These results reinforce the importance of IL‐13 in airway pathobiology and suggest that neutralization of IL‐13 may reduce asthmatic airway remodeling.Clinical trial registrationNCT02099656Support or Funding InformationThe study was sponsored by F. Hoffmann‐La Roche Ltd.

Chronic rhinosinusitis with nasal polyposis (CRSwNP) and asthma frequently coexist. Although the anti-IgE monoclonal antibody, omalizumab, has demonstrated efficacy in patients with CRSwNP with comorbid asthma, whether there is a difference in patients with or without comorbid asthma is an important remaining question. We performed a subgroup analysis of pooled data from phase III, placebo-controlled, 24-week, omalizumab trials, POLYP1 and POLYP2, which enrolled adult patients with corticosteroid-refractory CRSwNP. Patients remained on intranasal mometasone furoate for the study duration. Placebo-adjusted effects were calculated from baseline at Week 24 for nasal polyps score (NPS), nasal congestion score (NCS), and sino-nasal outcome test (SNOT-22) among patients with (n=151) and without (n=114) comorbid asthma. 57.0% of patients in the pooled population had asthma. Physician-assessed asthma severity was typically mild (35.1%) or moderate (58.3%); severe asthma was present in 6.6% of patients. Improvements from baseline at Week 24 were significantly greater for omalizumab- vs placebo-treated patients across all three endpoints. For asthma and non-asthma patients, improvements were similar across endpoints with placebo-adjusted effects of -0.98 (P<0.0001) and -0.72 (P=0.0054) for NPS, -0.52 (P=0.0003) and -0.56 (P=0.0007) for NCS, and -14.82 (P<0.0001) and -16.14 (P<0.0001) for SNOT-22. Adverse events were generally similar between study arms. Among patients with CRSwNP, omalizumab improved NPS, NCS and SNOT-22 scores in those with and without comorbid asthma, and there were no marked differences in response between groups. As most patients had mild-to-moderate asthma, it is unclear whether these results extend to the more severe asthma population.

Background: During this SARS-CoV-2 pandemic, there has been unprecedented stress on health care systems, resulting in a change to how services are carried out. The most prominent question for healthcare professionals specialising in cardiac surgery is, should we operate during this pandemic, and to what extent ? Methods: As one of the biggest, specialised cardiac surgery centres in the UK, we researched the available published evidence surrounding this question, to formulate an answer. During this process we considered the potential risks of cardiac surgery during a pandemic on the patients, staff, the healthcare system, and the community. We also considered the immunological aspect of cardiac surgery patients and the risk it entails on them. Results We have discussed the available evidence and consequences of our findings, and we found Patients are subjected to greater risk of catching Covid-19 whilst being in hospital. Patient’s immunity is disrupted for up to 3 months post CPB, which makes them more vulnerable to catch the Covid-19 infection during admission and after discharge. Plus the burden on the whole healthcare system, by using the precious resources and occupying the necessary staff and hospital beds needed during the pandemic surge. Conclusion: Try and minimise cardiac surgery operations down to emergencies or unstable patients who have no other options apart from surgery, particularly during the surge stage of the pandemic. Strictly following structured pathways and protocols, updating relevant protocols with emerging new evidence.