Research Spotlight

Brill, J. V., J. A. Ashmore, M. L. Brengman, D. E. Buffington, S. D. Feldshon, K. E. Friedman, P. S. Margolis, D. Markus, L. Narramore, A. Rastogi, A. A. Starpoli, K. Strople, J. V. White and S. E. Streett (2017). “White paper aga: An episode-of-care framework for the management of obesity: Moving towards high value, high quality care: A report from the american gastroenterological association institute obesity episode of care and bundle initiative work group.” Clin Gastroenterol Hepatol: 2017 Feb [Epub ahead of print].

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In 2015–2016, the AGA convened a series of workgroups to address the coordinated management of patients with obesity. This was in recognition of the significant role that obesity plays in the development of gastrointestinal disorders, gastroenterology fellowship training in nutritional disorders, and that gastroenterologists are uniquely trained to treat obesity as endoscopists who specialize in digestive and nutritional diseases. The Practice Guide on Obesity and Weight Management, Education and Resources (POWER) program was developed by the AGA to guide gastroenterologists in how to play a pivotal role in the multidisciplinary care of patients with obesity.3 The AGA established the Obesity Episode of Care and Bundle Initiative Work Group to develop an episode framework to support value-based management of patients with obesity, focusing on the provision of nonsurgical and endoscopic services. This paper presents the recommendations of the workgroup.

Blazkova, J., S. Gupta, Y. Liu, B. Gaudilliere, E. A. Ganio, C. R. Bolen, R. Saar-Dover, G. K. Fragiadakis, M. S. Angst, S. Hasni, N. Aghaeepour, D. Stevenson, N. Baldwin, E. Anguiano, D. Chaussabel, M. C. Altman, M. J. Kaplan, M. M. Davis and D. Furman (2017). “Multicenter systems analysis of human blood reveals immature neutrophils in males and during pregnancy.” J Immunol 198(6): 2479-2488.

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Despite clear differences in immune system responses and in the prevalence of autoimmune diseases between males and females, there is little understanding of the processes involved…Using mass cytometry, we find increased frequencies of immature forms of neutrophils in the blood of women during late pregnancy. Thus, our findings show novel sex differences in innate immunity and identify a common neutrophil signature in males and in pregnant women.

Cedars, A., L. Benjamin, S. V. Burns, E. Novak and A. Amin (2017). “Clinical predictors of length of stay in adults with congenital heart disease.” Heart: 2017 Feb [Epub ahead of print].

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OBJECTIVE: Length of stay (LOS) is a major driver of inpatient care costs. To date, few studies have investigated risk factors associated with increased LOS in patients with adult congenital heart disease (ACHD). In the present work, we sought to address this knowledge gap. METHODS: We conducted an analysis of the State Inpatient Databases from Arkansas, California, Florida, Hawaii, Nebraska and New York. We analysed data on admissions in patients with ACHD and constructed a series of hierarchical regression models to identify the clinical factors having the greatest effects on LOS. RESULTS: We identified 99 103 inpatient hospitalisations meeting criteria for inclusion. Diagnoses associated with the longest LOS were septicaemia (LOS=14.2 days in patients atrial septal defect, and 11.7 days among all other ACHD) and pericarditis, endocarditis and myocarditis (LOS=13.6 days and 10.0 days, respectively). When separated by underlying anatomy, the variables most consistently associated with longer LOS were bacterial infection, complications of surgeries or medical care, acute renal disease and anaemia. CONCLUSIONS: In the present study, we identified risk factors associated with longer LOS in ACHD. These data may be used to identify at-risk patients for targeted intervention to decrease LOS and thereby cost.

Zurawski, G., X. Shen, S. Zurawski, G. D. Tomaras, D. C. Montefiori, M. Roederer, G. Ferrari, C. Lacabaratz, P. Klucar, Z. Wang, K. E. Foulds, S. F. Kao, X. Yu, A. Sato, N. L. Yates, C. LaBranche, S. Stanfield-Oakley, K. Kibler, B. Jacobs, A. Salazar, S. Self, J. Fulp, R. Gottardo, L. Galmin, D. Weiss, A. Cristillo, G. Pantaleo and Y. Levy (2017). “Superiority in rhesus macaques of targeting hiv-1 env gp140 to cd40 versus lox-1 in combination with replication competent nyvac-kc for induction of env-specific antibody and t cell responses.” J Virol: 2017 Feb [Epub ahead of print].

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We compared the HIV-1-specific immune responses generated by targeting HIV-1 envelope protein (Env gp140) to either CD40 or LOX-1, two endocytic receptors on dendritic cells (DCs), in Rhesus macaques primed with a poxvirus vector (NYVAC-KC) expressing Env gp140. The DC-targeting vaccines, humanized recombinant monoclonal antibodies fused to Env gp140, were administered as a boost with poly ICLC adjuvant either alone or co-administered with the NYVAC-KC vector. All the DC-targeting vaccine administrations with poly ICLC increased the low-level serum anti-Env IgG responses elicited by NYVAC-KC priming significantly more (up to P =0.01) than a group without poly ICLC. The responses were robust, cross-reactive, and contained antibodies specific to multiple epitopes within gp140 including the C1, C2, V1-3, C4, C5, and gp41 immuno-dominant regions. The DC-targeting vaccines also elicited modest serum Env-specific IgA responses. All groups gave serum neutralization activity limited to Tier 1 viruses and antibody dependent cytotoxicity responses (ADCC) after DC-targeting boosts. Furthermore, CD4+ and CD8+ T cell responses specific to multiple Env epitopes were strongly boosted by the DC-targeting vaccines + poly ICLC. Together, these results indicate that prime/boost immunization via NYVAC-KC and either alphaCD40.Env gp140/poly ICLC or alphaLOX-1.Env gp140/poly ICLC induced balanced antibody and T cell responses against HIV-1 Env. Co-administration of NYVAC-KC with the DC-targeting vaccines increased T cell responses, but had minimal effects on antibody responses except for suppressing serum IgA responses. Overall, compared to LOX-1, targeting Env to CD40 gave more robust T cell and serum antibody responses with broader epitope representation and greater durability.IMPORTANCE An effective vaccine to prevent HIV-1 infection does not yet exist. An approach to elicit strong protective antibody development is to direct virus protein antigens specifically to dendritic cells, which are now known to be the key cell type for controlling immunity. Here we have tested in non-human primates two prototype vaccines engineered to direct the HIV-1 coat protein Env to dendritic cells. These vaccines bind to either CD40 or LOX-1, two dendritic cell surface receptors with different functions and tissue distributions. We tested the vaccines described above in combination with attenuated virus vectors that express Env. Both vaccines, but especially that delivered via CD40, raised robust immunity against HIV-1 as measured by monitoring potentially protective antibody and T cell responses in the blood. The safety and efficacy of the CD40-targeted vaccine justifies further development for future human clinical trials.

Chen, Y. B., T. Wang, M. T. Hemmer, C. Brady, D. R. Couriel, A. Alousi, J. Pidala, A. Urbano-Ispizua, S. W. Choi, T. Nishihori, T. Teshima, Y. Inamoto, B. Wirk, D. I. Marks, H. Abdel-Azim, L. Lehmann, L. Yu, M. Bitan, M. S. Cairo, M. Qayed, R. Salit, R. P. Gale, R. Martino, S. Jaglowski, A. Bajel, B. Savani, H. Frangoul, I. D. Lewis, J. Storek, M. Askar, M. A. Kharfan-Dabaja, M. Aljurf, O. Ringden, R. Reshef, R. F. Olsson, S. Hashmi, S. Seo, T. R. Spitzer, M. L. MacMillan, A. Lazaryan, S. R. Spellman, M. Arora and C. S. Cutler (2017). “Gvhd after umbilical cord blood transplantation for acute leukemia: An analysis of risk factors and effect on outcomes.” Bone Marrow Transplant 52(3): 400-408.

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Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, we analyzed 1404 umbilical cord blood transplantation (UCBT) patients (single (<18 years)=810, double (18 years)=594) with acute leukemia to define the incidence of acute GvHD (aGvHD) and chronic GvHD (cGvHD), analyze clinical risk factors and investigate outcomes. After single UCBT, 100-day incidence of grade II-IV aGvHD was 39% (95% confidence interval (CI), 36-43%), grade III-IV aGvHD was 18% (95% CI, 15-20%) and 1-year cGvHD was 27% (95% CI, 24-30%). After double UCBT, 100-day incidence of grade II-IV aGvHD was 45% (95% CI, 41-49%), grade III-IV aGvHD was 22% (95% CI, 19-26%) and 1-year cGvHD was 26% (95% CI, 22-29%). For single UCBT, multivariate analysis showed that absence of antithymocyte globulin (ATG) was associated with aGvHD, whereas prior aGvHD was associated with cGvHD. For double UCBT, absence of ATG and myeloablative conditioning were associated with aGvHD, whereas prior aGvHD predicted for cGvHD. Grade III-IV aGvHD led to worse survival, whereas cGvHD had no significant effect on disease-free or overall survival. GvHD is prevalent after UCBT with severe aGvHD leading to higher mortality. Future research in UCBT should prioritize prevention of GvHD.