Baylor Research Institute

Alaoui, L., G. Palomino, S. Zurawski, G. Zurawski, S. Coindre, N. Dereuddre-Bosquet, C. Lecuroux, C. Goujard, B. Vaslin, C. Bourgeois, P. Roques, R. Le Grand, O. Lambotte and B. Favier (2017). “Early siv and hiv infection promotes the lilrb2/mhc-i inhibitory axis in cdcs.” Cell Mol Life Sci: 2017 Nov [Epub ahead of print].

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Classical dendritic cells (cDCs) play a pivotal role in the early events that tip the immune response toward persistence or viral control. In vitro studies indicate that HIV infection induces the dysregulation of cDCs through binding of the LILRB2 inhibitory receptor to its MHC-I ligands and the strength of this interaction was proposed to drive disease progression. However, the dynamics of the LILRB2/MHC-I inhibitory axis in cDCs during early immune responses against HIV are yet unknown. Here, we show that early HIV-1 infection induces a strong and simultaneous increase of LILRB2 and MHC-I expression on the surface of blood cDCs. We further characterized the early dynamics of LILRB2 and MHC-I expression by showing that SIVmac251 infection of macaques promotes coordinated up-regulation of LILRB2 and MHC-I on cDCs and monocytes/macrophages, from blood and lymph nodes. Orientation towards the LILRB2/MHC-I inhibitory axis starts from the first days of infection and is transiently induced in the entire cDC population in acute phase. Analysis of the factors involved indicates that HIV-1 replication, TLR7/8 triggering, and treatment by IL-10 or type I IFNs increase LILRB2 expression. Finally, enhancement of the LILRB2/MHC-I inhibitory axis is specific to HIV-1 and SIVmac251 infections, as expression of LILRB2 on cDCs decreased in naturally controlled chikungunya virus infection of macaques. Altogether, our data reveal a unique up-regulation of LILRB2 and its MHC-I ligands on cDCs in the early phase of SIV/HIV infection, which may account for immune dysregulation at a critical stage of the anti-viral response.

Bapat, V., V. Rajagopal, C. Meduri, R. S. Farivar, A. Walton, S. J. Duffy, R. Gooley, A. Almeida, M. J. Reardon, N. S. Kleiman, K. Spargias, S. Pattakos, M. K. Ng, M. Wilson, D. H. Adams, M. Leon, M. J. Mack, S. Chenoweth and P. Sorajja (2017). “Early experience with new transcatheter mitral valve replacement.” J Am Coll Cardiol: 2017 Oct [Epub ahead of print].

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BACKGROUND: Transcatheter mitral valve replacement (TMVR) is a potential therapy for patients with symptomatic, severe mitral regurgitation (MR). The feasibility of this therapy remains to be defined. OBJECTIVE: We report our early experience with TMVR using a new valve system. METHODS: The valve is a self-expanding, nitinol valve with bovine pericardial leaflets that is placed using a transapical delivery system. Patients with symptomatic MR who were deemed high or extreme risk by the local heart teams were enrolled in a global pilot study at 14 sites (U.S., Australia, and Europe). RESULTS: 50 consecutively enrolled patients (mean age, 73+/-9 years; 58.0% men; 84% secondary MR) underwent TMVR with the valve. The mean STS score was 6.4+/-5.5%; 86% of patient were NYHA class III or IV, and the mean left ventricular ejection fraction was 43+/-12%. Device implant was successful in 48 patients with a median deployment time of 14 (IQR, 12, 17) minutes. The 30-day mortality was 14%, with no disabling strokes, or repeat interventions. Median follow-up was 173 (IQR, 54, 342) days. At latest follow-up, echocardiography confirmed mild or no residual MR in all implanted patients. Improvements in symptom class (79% in NYHA I or II at follow-up; p<0.0001 vs. baseline), and Minnesota heart failure questionnaire scores (56.2+/-26.8 vs. 31.7+/-22.1; p=0.011) were observed. CONCLUSIONS: TMVR with the valve was feasible in a population at high-or extreme-risk for conventional mitral valve replacement. These results inform trial design of TMVR in lower-risk patients with severe mitral valve regurgitation.

Cheng, L., Z. Zhang, G. Li, F. Li, L. Wang, L. Zhang, S. M. Zurawski, G. Zurawski, Y. Levy and L. Su (2017). “Human innate responses and adjuvant activity of tlr ligands in vivo in mice reconstituted with a human immune system.” Vaccine 35(45): 6143-6153.

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TLR ligands (TLR-Ls) represent a class of novel vaccine adjuvants. However, their immunologic effects in humans remain poorly defined in vivo. Using a humanized mouse model with a functional human immune system, we investigated how different TLR-Ls stimulated human innate immune response in vivo and their applications as vaccine adjuvants for enhancing human cellular immune response. We found that splenocytes from humanized mice showed identical responses to various TLR-Ls as human PBMCs in vitro. To our surprise, various TLR-Ls stimulated human cytokines and chemokines differently in vivo compared to that in vitro. For example, CpG-A was most efficient to induce IFN-alpha production in vitro. In contrast, CpG-B, R848 and Poly I:C stimulated much more IFN-alpha than CpG-A in vivo. Importantly, the human innate immune response to specific TLR-Ls in humanized mice was different from that reported in C57BL/6 mice, but similar to that reported in nonhuman primates. Furthermore, we found that different TLR-Ls distinctively activated and mobilized human plasmacytoid dendritic cells (pDCs), myeloid DCs (mDCs) and monocytes in different organs. Finally, we showed that, as adjuvants, CpG-B, R848 and Poly I:C can all enhance antigen specific CD4+ T cell response, while only R848 and Poly I:C induced CD8+ cytotoxic T cells response to a CD40-targeting HIV vaccine in humanized mice, correlated with their ability to activate human mDCs but not pDCs. We conclude that humanized mice serve as a highly relevant model to evaluate and rank the human immunologic effects of novel adjuvants in vivo prior to testing in humans.

Tolia, V. N., K. Murthy, M. M. Bennett, E. S. Miller, D. K. Benjamin, P. B. Smith and R. H. Clark (2017). “Antenatal methadone vs buprenorphine exposure and length of hospital stay in infants admitted to the intensive care unit with neonatal abstinence syndrome.” J Perinatol: 2017 Oct [Epub ahead of print].

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OBJECTIVE: Antenatal exposure to methadone or buprenorphine often causes neonatal abstinence syndrome (NAS) in newborns. However, comparative effects on affected infants’ hospital courses are inconclusive. We sought to estimate the relationship of antenatal exposure with methadone or buprenorphine and infants’ length of stay among hospitalized infants with NAS. STUDY DESIGN: This was a retrospective cohort study of hospitalized infants with NAS with either maternal exposure. Eligible infants were singleton infants born 36 weeks’ gestation and diagnosed with NAS<7 days of age between 2011 and 2014 in the Pediatrix Clinical Data Warehouse. Infant with congenital anomalies and those of multiple gestation were excluded. RESULTS: Of 3364 eligible infants, 2202 (65%) were exposed to methadone and 1162 (34%) to buprenorphine. Infants exposed to buprenorphine had a lower rate of pharmacologic treatment for NAS (88 vs 91%, P<0.001). Median length of hospital stay was shorter among infants exposed to buprenorphine (21 days (inter-quartile range; 13-31) vs methadone (24 days (15-38), P<0.0001)). On multivariable Cox proportional hazard analyses, buprenorphine was associated with a shorter length of stay (hazard ratio (HR)=1.47 (95% confidence interval (CI): 1.32-1.62, P<0.001) after controlling for maternal age, parity, race or ethnicity, prenatal care, smoking status, use of antidepressants, use of benzodiazepines, and infant gestational age, small for gestational age status, cesarean delivery, sex, out born status, type of pharmacotherapy, breast milk use, year and center. We observed similar results in model using infants matched 1:1 with propensity scores for antenatal medication exposure (HR 1.39 for buprenorphine, CI 1.32-1.62, P<0.001). CONCLUSION: Among infants born 36 weeks' gestation with NAS, antenatal buprenorphine exposure was associated with a decreased length of stay relative to antenatal methadone exposure.

Roden-Foreman, J. W., M. M. Bennett, E. E. Rainey, J. S. Garrett, M. B. Powers and A. M. Warren (2017). “Secondary traumatic stress in emergency medicine clinicians.” Cogn Behav Ther 46(6): 522-532.

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Previously called Secondary Traumatic Stress (STS), secondary exposure to trauma is now considered a valid DSM-5 Criterion A stressor for posttraumatic stress disorder (PTSD). Previous studies have found high rates of STS in clinicians who treat traumatically injured patients. However, little research has examined STS among Emergency Medicine (EM) physicians and advanced practice providers (APPs). The current study enrolled EM providers (N = 118) working in one of 10 hospitals to examine risk factors, protective factors, and the prevalence of STS in this understudied population. Most of the participants were physicians (72.9%), Caucasian (85.6%), and male (70.3%) with mean age of 39.7 (SD = 8.9). Overall, 12.7% of the sample screened positive for STS with clinical levels of intrusion, arousal, and avoidance symptom clusters, and 33.9% had at least one symptom cluster at clinical levels. Low resilience and a history of personal trauma were positively associated with positive STS screens and STS severity scores. Borderline significance suggested that female gender and spending >/=10% of one’s time with trauma patients could be additional risk factors. Findings suggest that resilience-building interventions may be beneficial.