Research Spotlight

Posted October 15th 2018

Updated International Consensus Diagnostic Criteria for Eosinophilic Esophagitis: Proceedings of the AGREE Conference.

Stuart Spechler M.D.

Stuart Spechler M.D.

Dellon, E. S., C. A. Liacouras, J. Molina-Infante, G. T. Furuta, J. M. Spergel, N. Zevit, S. J. Spechler, S. E. Attwood, A. Straumann, S. S. Aceves, J. A. Alexander, D. Atkins, N. C. Arva, C. Blanchard, P. A. Bonis, W. M. Book, K. E. Capocelli, M. Chehade, E. Cheng, M. H. Collins, C. M. Davis, J. A. Dias, C. . . . et al., and A. J. Bredenoord (2018). “Updated International Consensus Diagnostic Criteria for Eosinophilic Esophagitis: Proceedings of the AGREE Conference.” Gastroenterology Sep 6. [Epub ahead of print].

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BACKGROUND & AIMS: Over the last decade, clinical experiences and research studies raised concerns regarding use of proton pump inhibitors (PPIs) as part of the diagnostic strategy for eosinophilic esophagitis (EoE). We aimed to clarify the use of PPIs in the evaluation and treatment of children and adults with suspected EoE to develop updated international consensus criteria for EoE diagnosis. METHODS: A consensus conference was convened to address the issue of PPI use for esophageal eosinophilia using a process consistent with standards described in the Appraisal of Guidelines for Research and Evaluation II. Pediatric and adult physicians and researchers from gastroenterology, allergy, and pathology subspecialties representing 14 countries used online communications, teleconferences, and a face-to-face meeting to review the literature and clinical experiences. RESULTS: Substantial evidence documented that PPIs reduce esophageal eosinophilia in children, adolescents, and adults, with several mechanisms potentially explaining the treatment effect. Based on these findings, an updated diagnostic algorithm for EoE was developed, with removal of the PPI trial requirement. CONCLUSIONS: EoE should be diagnosed when there are symptoms of esophageal dysfunction and at least 15 eosinophils per high-power field (or approximately 60 eosinophils per mm(2)) on esophageal biopsy and after a comprehensive assessment of non-EoE disorders that could cause or potentially contribute to esophageal eosinophilia. The evidence suggests that PPIs are better classified as a treatment for esophageal eosinophilia that may be due to EoE than as a diagnostic criterion, and we have developed updated consensus criteria for EoE that reflect this change.


Posted October 15th 2018

Metabolic syndrome and hip fracture: Epidemiology and perioperative outcomes.

Shawna L. Watson M.D.

Shawna L. Watson M.D.

Cichos, K. H., J. L. Churchill, S. G. Phillips, S. L. Watson, G. McGwin, Jr., E. S. Ghanem and B. A. Ponce (2018). “Metabolic syndrome and hip fracture: Epidemiology and perioperative outcomes.” Injury Sep 8. [Epub ahead of print].

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INTRODUCTION: Hip fractures and metabolic syndrome (MetS) are becoming major global healthcare burdens as populations age. This study sought to determine the impact of MetS in hip fracture patients on perioperative outcomes following operative fixation or arthroplasty. METHODS: Data from the 2004-2014 Nationwide Inpatient Sample was used to select 3,348,207 discharges with hip fracture. MetS patients were identified by having at least 3 of 4 component comorbidities: hypertension, dyslipidemia, obesity, and diabetes. Logistic regression was used to estimate odds ratios for the association between MetS and perioperative outcomes adjusted for age, gender, race, payer status, and comorbidities. RESULTS: Overall, 32% of hip fracture patients were treated with open reduction internal fixation (ORIF), 28% hemiarthroplasty (HA), 18% closed reduction with internal fixation (CRPP), and 3% primary total hip arthroplasty (THA). The remaining 19% of cases were either treated via unspecified procedure of hip repair (9%), managed non-operatively (2%), underwent multiple procedures during the hospital stay (6%), or the surgical procedure data was missing (2%) and were excluded from procedural analyses. The prevalence of MetS was 7.9% and increased among minorities, patients treated at urban hospitals, with comorbidities (heart failure, kidney disease, peripheral vascular disease), and with Medicare coverage. MetS was associated with increased odds of any adverse event (p < 0.0001), specifically: acute renal failure, myocardial infarction, acute posthemorrhagic anemia. MetS was also associated with increased LOS (p < 0.0001) and increased total charges (p < 0.0001). However, MetS was associated with reduced odds of postoperative pneumonia, deep vein thrombosis and pulmonary embolism, surgical site infection, septicemia, and in-hospital mortality (p < 0.0001). The above associations were maintained for MetS patients stratified according to their treatment groups: HA, CRPP, and ORIF. CONCLUSIONS: MetS is associated with increased odds of complications in hip fracture patients but decreased odds of in-hospital mortality. This may be related to patients' nutritional status and catabolic states in the perioperative period.


Posted October 15th 2018

TLR3 agonist and CD40-targeting vaccination induces immune responses and reduces HIV-1 reservoirs.

Gerard Zurawski Ph.D.

Gerard Zurawski Ph.D.

Cheng, L., Q. Wang, G. Li, R. Banga, J. Ma, H. Yu, F. Yasui, Z. Zhang, G. Pantaleo, M. Perreau, S. Zurawski, G. Zurawski, Y. Levy and L. Su (2018). “TLR3 agonist and CD40-targeting vaccination induces immune responses and reduces HIV-1 reservoirs.” J Clin Invest 128(10): 4387-4396.

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Activation of HIV-1 reservoirs and induction of anti-HIV-1 T cells are critical to control HIV-1 rebound after combined antiretroviral therapy (cART). Here we evaluated in humanized mice (hu-mice) with persistent HIV-1 infection the therapeutic effect of TLR3 agonist and a CD40-targeting HIV-1 vaccine, which consists of a string of 5 highly conserved CD4+ and CD8+ T cell epitope-rich regions of HIV-1 Gag, Nef, and Pol fused to the C-terminus of a recombinant anti-human CD40 antibody (alphaCD40.HIV5pep). We show that alphaCD40.HIV5pep vaccination coadministered with poly(I:C) adjuvant induced HIV-1-specific human CD8+ and CD4+ T cell responses in hu-mice. Interestingly, poly(I:C) treatment also reactivated HIV-1 reservoirs. When administrated in therapeutic settings in HIV-1-infected hu-mice under effective cART, alphaCD40.HIV5pep with poly(I:C) vaccination induced HIV-1-specific CD8+ T cells and reduced the level of cell-associated HIV-1 DNA (or HIV-1 reservoirs) in lymphoid tissues. Most strikingly, the vaccination significantly delayed HIV-1 rebound after cART cessation. In summary, the alphaCD40.HIV5pep with poly(I:C) vaccination approach both activates replication of HIV-1 reservoirs and enhances the anti-HIV-1 T cell response, leading to a reduced level of cell-associated HIV-1 DNA or reservoirs. Our proof-of-concept study has significant implication for the development of CD40-targeting HIV-1 vaccine to enhance anti-HIV-1 immunity and reduce HIV-1 reservoirs in patients with suppressive cART.


Posted October 15th 2018

The epicardial adipose inflammatory triad: coronary atherosclerosis, atrial fibrillation, and heart failure with a preserved ejection fraction.

Milton Packer M.D.

Milton Packer M.D.

Packer, M. (2018). “The epicardial adipose inflammatory triad: coronary atherosclerosis, atrial fibrillation, and heart failure with a preserved ejection fraction.” Eur J Heart Fail Sep 17. [Epub ahead of print].

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Effect of epicardial adipose inflammation on coronary arteries: Classically, coronary atherosclerosis has been viewed as an inflammatory response to the transit of lipoproteins from the bloodstream across the endothelium and into the vessel wall. However, accelerated coronary atherosclerosis is also a prominent feature of many systemic inflammatory disorders, in a manner that is independent of circulating lipoproteins. How can systemic inflammation promote the development of obstructive coronary artery disease? Systemic inflammation leads to the accumulation and deranged biology of epicardial adipocytes. The resulting transmission of pro‐inflammatory cytokines and mesenchymal cells from the perivascular adipose tissue across the vascular adventitia can lead to plaque formation within the coronary vessels. In chronic inflammatory states, the accumulation of epicardial adipose tissue is closely associated with the presence, severity and progression of coronary artery disease, in a manner that is independent of circulating lipids or adiposity. Focal obstructive lesions reside in the coronary arterial segments that are immediately adjacent to areas of epicardial fat with the greatest thickness, and experimental resection of the epicardium ameliorates coronary atherosclerosis. These observations support the hypothesis that the accumulation of epicardial adipose tissue (and inflammation of perivascular fat) can act in a paracrine manner to adversely influence the structure and function of the coronary arteries. (Excerpt from text, p. 2; no abstract available.)


Posted October 15th 2018

Growth differentiation factor-15 is not modified by sacubitril/valsartan and is an independent marker of risk in patients with heart failure and reduced ejection fraction: the PARADIGM-HF trial.

Milton Packer M.D.

Milton Packer M.D.

Bouabdallaoui, N., B. Claggett, M. R. Zile, J. J. V. McMurray, E. O’Meara, M. Packer, M. F. Prescott, K. Swedberg, S. D. Solomon and J. L. Rouleau (2018). “Growth differentiation factor-15 is not modified by sacubitril/valsartan and is an independent marker of risk in patients with heart failure and reduced ejection fraction: the PARADIGM-HF trial.” Eur J Heart Fail Sep 11. [Epub ahead of print].

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AIMS: Growth differentiation factor-15 (GDF-15) is associated with adverse prognosis in cardiovascular (CV) and non-CV diseases. We evaluated the association of GDF-15 with CV and non-CV outcomes in the PARADIGM-HF trial. METHODS AND RESULTS: In 1935 patients with heart failure and reduced ejection fraction (HFrEF) in PARADIGM-HF, median GDF-15 values were elevated and similar in sacubitril/valsartan and enalapril patients (1626 ng/L and 1690 ng/L, respectively). Diabetes, age, creatinine, high-sensitive troponin T, N-terminal pro-B-type natriuretic peptide, and New York Heart Association class III/IV were most strongly associated with elevated GDF-15 values (all P < 0.001) (adjusted R(2) = 0.3857). Baseline GDF-15 and changes in GDF-15 at both 1 month and 8 months (log-transformed) were associated with subsequent mortality and CV events. Each 20% increment in baseline GDF-15 value was associated with a higher risk of mortality [adjusted hazard ratio (HR) 1.13, 95% confidence interval (CI) 1.08-1.18, P < 0.001], the combined endpoint of CV death or hospitalization for heart failure (adjusted HR 1.09, 95% CI 1.05-1.14, P < 0.001) and heart failure death (adjusted HR 1.16, 95% CI 1.05-1.28, P < 0.001). Changes in GDF-15 were not influenced by assigned therapy (all P-values >/= 0.1). CONCLUSION: In patients with ambulatory HFrEF, GDF-15 is not modified by sacubitril/valsartan and is strongly associated with mortality and CV outcomes, suggesting that GDF-15 is a marker of poor outcomes in these patients. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01035255.