Showing papers by "Theo Heller published in 2020"

Healthcare recommendations for Joubert syndrome

Abstract: Joubert syndrome (JS) is a recessive neurodevelopmental disorder defined by a characteristic cerebellar and brainstem malformation recognizable on axial brain magnetic resonance imaging as the "Molar Tooth Sign". Although defined by the neurological features, JS is associated with clinical features affecting many other organ systems, particularly progressive involvement of the retina, kidney, and liver. JS is a rare condition; therefore, many affected individuals may not have easy access to subspecialty providers familiar with JS (e.g., geneticists, neurologists, developmental pediatricians, ophthalmologists, nephrologists, hepatologists, psychiatrists, therapists, and educators). Expert recommendations can enable practitioners of all types to provide quality care to individuals with JS and know when to refer for subspecialty care. This need will only increase as precision treatments targeting specific genetic causes of JS emerge. The goal of these recommendations is to provide a resource for general practitioners, subspecialists, and families to maximize the health of individuals with JS throughout the lifespan.

Vibration-controlled transient elastography for the detection of cirrhosis in chronic hepatitis D infection.

Abstract: Noninvasive detection of cirrhosis via vibration-controlled transient elastography (VCTE) has revolutionized the management of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. However, VCTE has not been studied in chronic hepatitis D virus (HDV) infection and accuracy remains in question due to the significant hepatic inflammation associated with this infection. Consecutive HBV, HCV and HDV patients who underwent VCTE (2006-2019) were evaluated. Diagnosis of cirrhosis was made via liver biopsy or clinical findings. VCTE was compared with other noninvasive serum fibrosis tests using AUROC curves. The performance of VCTE in HBV/HCV/HDV was also compared. We evaluated 319 patients (HBV-112; HCV-132; HDV-75), 278(87%) patients had histology for evaluation. HDV patients had evidence of higher hepatic inflammation as evidence by aspartate aminotransferase, alanine aminotransferase and histology activity index. Cirrhotic HDV patients had higher mean liver stiffness measurements compared with noncirrhotic patients (29.0 vs 8.3 kPa, P < .0001). VCTE demonstrated excellent diagnostic accuracy for the detection of cirrhosis with an AUROC of 0.90 compared with APRI (0.83), FIB-4 (0.88), AAR (0.73) and RPR (0.85). Performance of VCTE in HDV was comparable with HBV (0.93) and HCV (0.94). At the optimized cut-off value of ≥14.0 kPa for determining cirrhosis in HDV, VCTE had a sensitivity of 0.78, specificity of 0.86, NPV of 0.93 and PPV of 0.64. Hence, VCTE is a useful noninvasive test in HDV for determining cirrhosis despite the presence of significant hepatic inflammation.

Elevated Serum α-Fetoprotein is Associated with Abbreviated Survival for Patients with Fibrolamellar Hepatocellular Carcinoma Who Undergo a Curative Resection

Abstract: Fibrolamellar hepatocellular carcinoma (FLC) is a rare variant of hepatocellular carcinoma (HCC), with most clinical data stemming from single-institution series. The variability in the literature lends support for analysis using a large national dataset. In doing so, we sought to (1) define the characteristics and outcomes of patients with FLC; (2) determine factors associated with survival in patients undergoing resection; and (3) compare the overall survival (OS) of patients with FLC with a matched group of patients with HCC. The National Cancer Database was queried for patients with FLC, and their clinicopathologic features were recorded. Univariate and multivariate analyses were performed to delineate factors associated with survival. Between 2004 and 2015, 496 patients were diagnosed with FLC, 229 of whom underwent a curative resection. The median OS for patients with FLC undergoing curative resection was 78.5 months. Factors associated with abbreviated OS in this surgical cohort include multiple tumors [hazard ratio (HR) 3.15, p = 0.025], positive regional lymph nodes (HR 2.83, p = 0.023), and elevated serum α-fetoprotein (AFP; HR 2.81, p = 0.034). When the OS of patients with FLC was compared with a matched group of patients with HCC, no difference was detected (p = 0.748); however, patients with FLC and elevated AFP had abbreviated OS compared with patients with HCC and elevated AFP (43 vs. 82 months, p ≤ 0.001). Elevations in serum AFP occur more frequently than previously documented for patients with FLC and are associated with abbreviated OS. AFP levels may help guide the decision for operative intervention in patients with FLC.

Evaluation of Confocal Laser Endomicroscopy for Detection of Occult Gastric Carcinoma in CDH1 Variant Carriers

Abstract: Background & Aims Hereditary diffuse gastric cancer, attributed to inactivating germline CDH1 variants, is characterized by signet ring cell (SRC) morphology. We sought to evaluate the occult cancer detection rate using probe-based confocal laser endomicroscopy (pCLE) during endoscopic surveillance. Methods A prospective, single-institution study was conducted in asymptomatic adults with pathogenic or likely pathogenic (P/LP) CDH1 variants. Subjects received endoscopic gastric surveillance using pCLE in conjunction with the consensus Cambridge method (CM) of non-targeted mucosal biopsies. Systematic examination was performed with white light endoscopy (WLE) and pCLE. Abnormalities visualized by pCLE were biopsied, followed by non-targeted mucosal biopsies according to the CM. Pathologists were blinded to clinical and endomicroscopic findings. Primary endpoint was to determine pCLE sensitivity for detection of occult SRC carcinoma compared to CM. Results Thirty-six patients with P/LP CDH1 variants underwent endoscopy using pCLE and CM. Majority were female (75%) with median age 47 years. Median procedure time was 52.5 minutes, without serious adverse events. Targeted biopsies of focal abnormalities on WLE were negative for carcinoma. Overall, 19.4% (7/36) patients had SRC detected on ≥1 biopsy. Non-targeted CM biopsies revealed SRC in 11.1% (4/36), whereas pCLE revealed SRC in 16.7% (6/36). Fifteen patients, 5 of whom had SRC at endoscopy, underwent total gastrectomy; all 15 explants contained occult carcinoma. In those 15 patients, the false-negative SRC detection rates for pCLE and CM were 67% and 87%, respectively. Conclusions Confocal endomicroscopy alone has low sensitivity for occult cancer detection in CDH1 variant carriers. Reliable endoscopic surveillance is lacking as an alternative to prophylactic surgery in this high-risk population. (http://ClinicalTrials.gov, Number: NCT03648879).

Modeling Challenges of Ebola Virus-Host Dynamics during Infection and Treatment

Abstract: Mathematical modeling of Ebola virus (EBOV)–host dynamics during infection and treatment in vivo is in its infancy due to few studies with frequent viral kinetic data, lack of approved antiviral therapies, and limited insight into the timing of EBOV infection of cells and tissues throughout the body. Current in-host mathematical models simplify EBOV infection by assuming a single homogeneous compartment of infection. In particular, a recent modeling study assumed the liver as the largest solid organ targeted by EBOV infection and predicted that nearly all cells become refractory to infection within seven days of initial infection without antiviral treatment. We compared our observations of EBOV kinetics in multiple anatomic compartments and hepatocellular injury in a critically ill patient with Ebola virus disease (EVD) with this model’s predictions. We also explored the model’s predictions, with and without antiviral therapy, by recapitulating the model using published inputs and assumptions. Our findings highlight the challenges of modeling EBOV–host dynamics and therapeutic efficacy and emphasize the need for iterative interdisciplinary efforts to refine mathematical models that might advance understanding of EVD pathogenesis and treatment.

Circulating TNF-like protein 1A (TL1A) is elevated early in rheumatoid arthritis and depends on TNF

Abstract: The tumor necrosis factor (TNF) superfamily cytokine TNF-like protein 1A (TL1A) and its receptor DR3 are essential for diverse animal models of autoimmune disease and may be pathogenic in rheumatoid arthritis (RA). However, the relationship of TL1A to disease duration, activity, and response to anti-TNF and other therapies in RA is not clear. We measured soluble TL1A in synovial fluid (SF), serum, or plasma from RA first-degree relatives (FDRs) and in early RA and established disease. We measured the effects of anti-TNF and methotrexate (MTX) therapy on circulating TL1A from multiple independent RA treatment trials. We also determined the ability of a blocking anti-TL1A antibody to inhibit clinical disease and articular bone destruction in the murine collagen-induced arthritis (CIA) model of human RA. Soluble TL1A was specifically elevated in the blood and SF of patients with RA compared to patients with other diseases and was elevated early in disease and in at-risk anti-cyclic citrullinated peptide (CCP) (+) first-degree relatives (FDRs). Therapeutic TNF inhibition reduced serum TL1A in both responders and non-responders, whereas TL1A declined following MTX treatment only in responders. In murine CIA, TL1A blockade was clinically efficacious and reduced bone erosions. TL1A is specifically elevated in RA from early in the disease course and in at-risk FDRs. The decline in TL1A after TNF blockade suggests that TL1A levels may be a useful biomarker for TNF activity in RA. These results support the further investigation of the relationship between TL1A and TNF and TL1A blockade as a potential therapeutic strategy in RA.

Management of healthcare personnel living with hepatitis B, hepatitis C, or human immunodeficiency virus in US healthcare institutions.

Abstract: David K. Henderson MD1, Louise-Marie Dembry MD, MS, MBA2, Costi D. Sifri MD34 , Tara N. Palmore MD5, E. Patchen Dellinger MD, Professor Emeritus6 , Deborah S. Yokoe MD, MPH7, Christine Grady PhD8 , Theo Heller MD9, David Weber MD, MPH10111213, Carlos del Rio MD141516 , Neil O. Fishman MD1718, Valerie M. Deloney MBA19 , Tammy Lundstrom MD, JD20 and Hilary M. Babcock MD, MPH21 1Clinical Center, National Institutes of Health, Bethesda, Maryland, 2Veterans Administration of Connecticut Healthcare System Hospital Epidemiology, West Haven, Connecticut, 3Office of Hospital Epidemiology, University of Virginia Health System, Charlottesville, Virginia, 4Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, Virginia, 5Clinical Center, National Institutes of Health, Bethesda, Maryland, 6University of Washington, Department of Surgery, Seattle, Washington, 7Division of Infectious Diseases, Department of Medicine, University of California–San Francisco, San Francisco, California, 8Bioethics Department Clinical Center, National Institutes of Health, Bethesda, Maryland, 9Translational Hepatology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, 10Division of Infectious Diseases, UNC School of Medicine, Chapel Hill, North Carolina, 11Gillings School of Global Public Health, Chapel Hill, North Carolina, 12UNC Hospitals Departments of Hospital Epidemiology, Chapel Hill, North Carolina, 13UNC Health Care, Chapel Hill, North Carolina, 14Emory Vaccine Center, Atlanta, Georgia, 15Hubert Department of Global Health, Rollins School of Public Health, Atlanta, Georgia, 16Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, 17University of Pennsylvania Health System, Philadelphia, Pennsylvania, 18Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, 19The Society for Healthcare Epidemiology of America, Arlington, Virginia, 20Trinity Health, Livonia, Michigan and 21Washington University School of Medicine, and Medical Director for the Infection Prevention and Epidemiology Consortium of BJC HealthCare, St Louis, Missouri

Exploring the Link Between Platelet Numbers and Vascular Homeostasis Across Early and Late Stages of Fibrosis in Hepatitis C.

Abstract: Thrombocytopenia is a hallmark of advanced liver disease. Platelets, growth factors (GFs), and vascular integrity are closely linked factors in disease pathogenesis, and their relationship, particularly in early disease stages, is not entirely understood. The aim was to compare circulating platelets, growth factors, and vascular injury markers (VIMs) in hepatitis C-infected (HCV) patients with early fibrosis and cirrhosis. Retrospective evaluation of serum GFs and VIMs by ELISA were evaluated from twenty-six HCV patients. Analytes from an earlier time-point were correlated with MELD at a later time-point. Platelets and GFs decreased, and VIMs increased with fibrosis. Platelets correlated positively with PDGF-AA, PDGF-BB, TGFB1, EGF, and P-selectin, and negatively with ICAM-3 and VCAM-1. P-selectin showed no correlations with VIMs but positively correlated with PDGF-AA, PDGF-BB, TGFB1, and EGF. Soluble VCAM-1 and ICAM-3 were linked to increasing fibrosis, liver enzymes, and synthetic dysfunction. Higher VCAM-1 and ICAM-3 and lower P-selectin at an earlier time-point were linked to higher MELD score at a later time-point. In chronic HCV, progressive decline in platelets and growth factors with fibrosis and their associations suggest that platelets are an important source of circulating GFs and influence GF decline with fibrosis. Enhanced markers of vascular injury in patients with early fibrosis suggest an earlier onset of endothelial dysfunction preceding cirrhosis. Associations of VIMs with platelets suggest a critical link between platelets and vascular homeostasis. Circulating markers of vascular injury may not only have prognostic importance but emphasize the role of vascular dysfunction in liver disease pathogenesis (NCT00001971).

Spontaneous Gastrointestinal Perforations in STAT3-Deficient Hyper-IgE Syndrome.

Abstract: To the Editor, Dominant negative mutations in signal transducer and activator of transcription 3 (STAT3) cause a rare primary immune deficiency, STAT3-deficient hyper-IgE syndrome (STAT3 LOF), characterized by recurrent skin and pulmonary infections, eczematous rashes, and mucocutaneous candidiasis, as well as connective tissue, skeletal, and vascular abnormalities such as scoliosis and craniosynostosis [1]. Gastrointestinal (GI) symptoms are common, with 60% of patients reporting at least one GI symptom in our cohort, most commonly gastroesophageal reflux disease, dysphagia, dysmotility, constipation, and diarrhea [1, 2]. Bowel perforations have been reported infrequently [2, 3]. Recent data has emerged suggesting an increased frequency of gastrointestinal perforation due to tocilizumab, a monoclonal antibody to the interleukin-6 (IL-6) receptor that is approved for use in rheumatoid arthritis and other rheumatologic conditions [4]. Given that IL-6 signals through STAT3 and intestinal perforations have been reported in STAT3 LOF patients, we sought to characterize the incidence and clinical presentations of intestinal perforations in our STAT3 LOF cohort. This cohort consists of patients followed on a National Institute of Allergy and Infectious Diseases (NIAID) institutional review board (IRB)-approved natural history study to which all patients, or their guardians, had provided informed consent. We reviewed 158 STAT3 LOF charts and found 10 patients who suffered from a gastrointestinal perforation, for an overall rate of 6.3%. Here, we present one case in detail with each case summarized in Table 1.