Clinical manifestations and approach to the management of patients with common variable immunodeficiency and liver disease.

Purpose: The clinical spectrum of common variable immunodeficiency (CVID) includes predisposition to infections, autoimmune/inflammatory complications and malignancy. Liver disease is developed by a proportion of patients with CVID, but limited evidence is available about its prevalence, pathogenesis and prognostic outcome. This lack of evidence leads to the absence of guidelines in clinical practice. In this study, we aimed at defining the characteristics, course and management of this CVID complication in Spain. Methods: Spanish reference centers were invited to complete a cross-sectional survey. Thirty-eight patients with CVID-related liver disease from different hospitals were evaluated by a retrospective clinical course review. Results: In this cohort, abnormal liver function and thrombocytopenia were found in most of the patients (95% and 79% respectively), in keeping with the higher incidence of abnormal liver imaging and splenomegaly. The most common histological findings included nodular regenerative hyperplasia (NRH) and lymphocytic infiltration, which have been associated with portal hypertension (PHTN) leading to a poorer prognosis. Autoimmune/inflammatory complications occurred in 82% of the CVID patients that developed liver disease and 52% of the patients treated with immunomodulators showed a reduction in the liver function tests' abnormalities during treatment. Among the experts that conducted the survey, there was 80% or more consensus that the workup of CVID-related liver disease requires liver profile, abdominal ultrasound and transient elastography. The majority agreed that liver biopsy should be essential for diagnosis. There was 94% consensus that endoscopic studies should be performed in the presence of PHTN. However, there was 89% consensus that there is insufficient evidence on the management of these patients. Conclusion: Liver disease varies in severity and may contribute substantially to morbidity and mortality in patients with CVID. Hence the importance of close follow-up and screening of this CVID complication to prompt early targeted intervention. Further research is needed to evaluate the pathophysiology of liver disease in patients with CVID to identify personalized treatment options. This study emphasizes the urgent need to develop international guidelines for the diagnosis and management of this CVID complication.

Molecular Clustering Analysis of Blood Biomarkers in World Trade Center Exposed Community Members with Persistent Lower Respiratory Symptoms.

The destruction of the World Trade Center (WTC) on September 11, 2001 (9/11) released large amounts of toxic dusts and fumes into the air that exposed many community members who lived and/or worked in the local area. Many community members, defined as WTC survivors by the federal government, developed lower respiratory symptoms (LRS). We previously reported the persistence of these symptoms in patients with normal spirometry despite treatment with inhaled corticosteroids and/or long-acting bronchodilators. This report expands upon our study of this group with the goal to identify molecular markers associated with exposure and heterogeneity in WTC survivors with LRS using a selected plasma biomarker approach. Samples from WTC survivors with LRS (n = 73, WTCS) and samples from healthy control participants of the NYU Bellevue Asthma Registry (NYUBAR, n = 55) were compared. WTCS provided information regarding WTC dust exposure intensity. Hierarchical clustering of the linear biomarker data identified two clusters within WTCS and two clusters within NYUBAR controls. Comparison of the WTCS clusters showed that one cluster had significantly increased levels of circulating matrix metalloproteinases (MMP1, 2, 3, 8, 12, 13), soluble inflammatory receptors (receptor for advanced glycation end-products-RAGE, Interleukin-1 receptor antagonist (IL-1RA), suppression of tumorigenicity (ST)2, triggering receptor expressed on myeloid cells (TREM)1, IL-6Ra, tumor necrosis factor (TNF)RI, TNFRII), and chemokines (IL-8, CC chemokine ligand- CCL17). Furthermore, this WTCS cluster was associated with WTC exposure variables, ash at work, and the participant category workers; but not with the exposure variable WTC dust cloud at 9/11. A comparison of WTC exposure categorial variables identified that chemokines (CCL17, CCL11), circulating receptors (RAGE, TREM1), MMPs (MMP3, MMP12), and vascular markers (Angiogenin, vascular cell adhesion molecule-VCAM1) significantly increased in the more exposed groups. Circulating biomarkers of remodeling and inflammation identified clusters within WTCS and were associated with WTC exposure.

Accuracy of Deep Learning Echocardiographic View Classification in Patients with Congenital or Structural Heart Disease: Importance of Specific Datasets.

INTRODUCTION: Automated echocardiography image interpretation has the potential to transform clinical practice. However, neural networks developed in general cohorts may underperform in the setting of altered cardiac anatomy. METHODS: Consecutive echocardiographic studies of patients with congenital or structural heart disease (C/SHD) were used to validate an existing convolutional neural network trained on 14,035 echocardiograms for automated view classification. In addition, a new convolutional neural network for view classification was trained and tested specifically in patients with C/SHD. RESULTS: Overall, 9793 imaging files from 262 patients with C/SHD (mean age 49 years, 60% male) and 62 normal controls (mean age 45 years, 50.0% male) were included. Congenital diagnoses included among others, tetralogy of Fallot (30), Ebstein anomaly (18) and transposition of the great arteries (TGA, 48). Assessing correct view classification based on 284,250 individual frames revealed that the non-congenital model had an overall accuracy of 48.3% for correct view classification in patients with C/SHD compared to 66.7% in patients without cardiac disease. Our newly trained convolutional network for echocardiographic view detection based on over 139,910 frames and tested on 35,614 frames from C/SHD patients achieved an accuracy of 76.1% in detecting the correct echocardiographic view. CONCLUSIONS: The current study is the first to validate view classification by neural networks in C/SHD patients. While generic models have acceptable accuracy in general cardiology patients, the quality of image classification is only modest in patients with C/SHD. In contrast, our model trained in C/SHD achieved a considerably increased accuracy in this particular cohort.

Characterization of Persistent Uncontrolled Asthma Symptoms in Community Members Exposed to World Trade Center Dust and Fumes.

The destruction of the World Trade Center (WTC) towers on the 11th of September, 2001 released a vast amount of aerosolized dust and smoke resulting in acute and chronic exposures to community members as well as responders. The WTC Environmental Health Center (WTC EHC) is a surveillance and treatment program for a diverse population of community members, including local residents and local workers with WTC dust exposure. Many of these patients have reported persistent lower respiratory symptoms (LRS) despite treatment for presumed asthma. Our goal was to identify conditions associated with persistent uncontrolled LRS despite standard asthma management. We recruited 60 patients who were uncontrolled at enrollment and, after a three-month run-in period on high-dose inhaled corticosteroid and long acting bronchodilator, reassessed their status as Uncontrolled or Controlled based on a score from the Asthma Control Test (ACT). Despite this treatment, only 11 participants (18%) gained Controlled status as defined by the ACT. We compared conditions associated with Uncontrolled and Controlled status. Those with Uncontrolled symptoms had higher rates of upper airway symptoms. Many patients had persistent bronchial hyper-reactivity (BHR) and upper airway hyper-reactivity as measured by paradoxical vocal fold movement (PVFM). We found a significant increasing trend in the percentage of Controlled with respect to the presence of BHR and PVFM. We were unable to identify significant differences in lung function or inflammatory markers in this small group. Our findings suggest persistent upper and lower airway hyper-reactivity that may respond to standard asthma treatment, whereas others with persistent LRS necessitate additional diagnostic evaluation, including a focus on the upper airway.

Altered Underlying Renal Tubular Function in Patients With Chronic Hepatitis B Receiving Nucleos(t)ide Analogs in a Real-World Setting: The MENTE Study.

BACKGROUND: Cases of renal tubular dysfunction have been reported in patients with hepatitis B and in patients with human immunodeficiency virus who are undergoing tenofovir treatment. However, little is known about the impact on tubular function in patients with chronic hepatitis B (CHB) under long-term use of entecavir (ETV) and tenofovir disoproxil fumarate (TDF). We evaluated markers of renal tubular function and bone turnover in patients with CHB treated with ETV or TDF. PATIENTS AND METHODS: A multicenter, cross-sectional study was performed on markers of renal tubular function and bone turnover in hepatitis B virus-monoinfected patients on long-term treatment with Entecavir or Tenofovir (the MENTE study). The analyzed parameters were: retinol-binding protein/creatinine, neutrophil gelatinase-associated lipocalin/creatinine, excretion of phosphates, uric acid excretion, glomerular filtrate, protein/creatinine, albumin/creatinine, serum creatinine, phosphate, CTX, P1NP, vitamin D, and parathormone. RESULTS: A total of 280 patients (ETV: 89, TDF: 69, control: 122) were included in this study. The TDF group was associated with altered levels of retinol-binding protein (RBP)/creatinine (TDF 25% vs. 7% ETV and control; P<0.001). Protein/creatinine, uric acid excretion, P1NP1, and parathormone were higher in the TDF group. The proportion of patients with serum phosphate <2.5 mg/dL was higher in both the ETV and the TDF groups compared with the control. The multivariate analysis showed that the use of TDF was independently associated with a higher risk of altered excretion of RBP/creatinine (4.4; interquartile range: 1.4 to 14; P=0.013). CONCLUSIONS: We found an independent association between TDF use and altered RBP excretion. This finding indicates subclinical tubular damage. Because tubular dysfunction can precede the decline of renal function, close monitoring of RBP levels in patients with CHB on nucleos(t)ide analog treatment must be performed for early detection of TDF-related renal toxicity. In this study, these differences in tubular function were not associated with concomitant changes in markers of bone turnover.

Structural characteristics of a lipid peroxidation product, trans-2-nonenal, that favour inhibition of membrane-associated phosphotyrosine phosphatase activity.

Protein-tyrosine phosphatases (PTPs) are very susceptible to oxidation by reactive oxygen species (ROS), which induce the oxidation of catalytic cysteines, thereby inactivating these PTPs. PTPs are also inactivated by treatment with different aldehydes (such as trans-2-nonenal), produced after tissue damage by ROS. However, the molecular mechanisms behind such aldehyde-due inactivation remain unknown. Using commercially available compounds, we examined the structural characteristics of trans-2-nonenal that allow the inhibition of platelet membrane-associated PTP activity, as well as how these compounds affect the dynamics of SH-, CO- and NH2- protein groups on the membranes. PTP was effectively inhibited by physiological amounts of trans-2-nonenal (1-10 microM). Incubation with trans-2-nonene (10 microM) also decreased PTP activity, although to a lower extent. Treatment with nonyl aldehyde almost eliminated PTP inhibition. Decreases in protein thiols were visible after trans-2-nonenal and trans-2-nonene treatments. Both the latter compounds also increased protein carbonyls (although trans-2-nonenal was more effective) and decreased protein amino groups to an equal extent. Collectively, our data indicate that alpha,beta unsaturation (and not a double bond in another position) is the most important structural determinant for PTP inhibition, the alkenal with 9-carbon atoms being the most effective in eliciting such inhibition. The data allow us to predict the modification of sulfhydryls and/or the formation of addition products with lysyl or histidyl residues, and hence the kind of specific antibodies that it would be necessary to generate in order to test such modifications directly.