Low-dose rectal inoculation of rhesus macaques by SIVsmE660 or SIVmac251 recapitulates human mucosal infection by HIV-1

We recently developed a novel strategy to identify transmitted HIV-1 genomes in acutely infected humans using single-genome amplification and a model of random virus evolution. Here, we used this approach to determine the molecular features of simian immunodeficiency virus (SIV) transmission in 18 experimentally infected Indian rhesus macaques. Animals were inoculated intrarectally (i.r.) or intravenously (i.v.) with stocks of SIVmac251 or SIVsmE660 that exhibited sequence diversity typical of early-chronic HIV-1 infection. 987 full-length SIV env sequences (median of 48 per animal) were determined from plasma virion RNA 1–5 wk after infection. i.r. inoculation was followed by productive infection by one or a few viruses (median 1; range 1–5) that diversified randomly with near starlike phylogeny and a Poisson distribution of mutations. Consensus viral sequences from ramp-up and peak viremia were identical to viruses found in the inocula or differed from them by only one or a few nucleotides, providing direct evidence that early plasma viral sequences coalesce to transmitted/founder viruses. i.v. infection was >2,000-fold more efficient than i.r. infection, and viruses transmitted by either route represented the full genetic spectra of the inocula. These findings identify key similarities in mucosal transmission and early diversification between SIV and HIV-1, and thus validate the SIV–macaque mucosal infection model for HIV-1 vaccine and microbicide research

ACC/AHA Guidelines for Coronary Artery Bypass Graft Surgery: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1991 Guidelines for Coronary Artery Bypass Graft Surgery)

The ACC/AHA Task Force on Practice Guidelines was formed to make recommendations regarding the appropriate use of diagnostic tests and therapies for patients with known or suspected cardiovascular disease. Coronary artery bypass graft (CABG) surgery is among the most common operations performed in the world and accounts for more resources expended in cardiovascular medicine than any other single procedure. Since the initial guidelines for CABG surgery were published in 1991, there has been considerable evolution in the surgical approach to coronary disease while at the same time there have been significant advances in preventive, medical, and percutaneous catheter approaches to therapy

Anesthesia advanced circulatory life support

The constellation of advanced cardiac life support (ACLS) events, such as gas embolism, local anesthetic overdose, and spinal bradycardia, in the perioperative setting differs from events in the pre-hospital arena. As a result, modification of traditional ACLS protocols allows for more specific etiology-based resuscitation. Perioperative arrests are both uncommon and heterogeneous and have not been described or studied to the same extent as cardiac arrest in the community. These crises are usually witnessed, frequently anticipated, and involve a rescuer physician with knowledge of the patient's comorbidities and coexisting anesthetic or surgically related pathophysiology. When the health care provider identifies the probable cause of arrest, the practitioner has the ability to initiate medical management rapidly. Recommendations for management must be predicated on expert opinion and physiological understanding rather than on the standards currently being used in the generation of ACLS protocols in the community. Adapting ACLS algorithms and considering the differential diagnoses of these perioperative events may prevent cardiac arrest

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Identification of variables needed to risk adjust outcomes of coronary interventions: evidence-based guidelines for efficient data collection

Objectives. Our objectives were to identify and define a minimum set of variables for interventional cardiology that carried the most statistical weight for predicting adverse outcomes. Though “gaming” cannot be completely avoided, variables were to be as objective as possible and reproducible and had to be predictive of outcome in current databases. Background. Outcomes of percutaneous coronary interventions depend on patient risk characteristics and disease severity and acuity. Comparing results of interventions has been difficult because definitions of similar variables differ in databases, and variables are not uniformly tracked. Identifying the best predictor variables and standardizing their definitions are a first step in developing a universal stratification instrument. Methods. A list of empirically derived variables was first tested in eight cardiac databases (158,273 cases). Three end points (in-hospital death, in-hospital coronary artery bypass graft surgery, Q wave myocardial infarction) were chosen for analysis. Univariate and multivariate regression models were used to quantify the predictive value of the variable in each database. The variables were then defined by consensus by a panel of experts. Results. In all databases patient demographics were similar, but disease severity varied greatly. The most powerful predictors of adverse outcome were measures of hemodynamic instability, disease severity, demographics and comorbid conditions in both univariate and multivariate analyses. Conclusions. Our analysis identified 29 variables that have the strongest statistical association with adverse outcomes after coronary interventions. These variables were also objectively defined. Incorporation of these variables into every cardiac dataset will provide uniform standards for data collected. Comparisons of outcomes among physicians, institutions and databases will therefore be more meaningful

Does Tight Glucose Control Prevent Myocardial Injury and Inflammation?

Hyperglycemia has been postulated to be cardiotoxic. We addressed the hypothesis that uncontrolled blood glucose induces myocardial damage in diabetic patients undergoing isolated coronary artery bypass graft surgery receiving continuous insulin infusion in the immediate postoperative period. Our primary aim was to assess the degree of tight glycemic control for each patient and to link the degree of glycemic control to intermediate outcome of myocardial damage. We prospectively enrolled 199 consecutive patients with diabetes undergoing isolated coronary artery bypass graft surgery from October 2003 through August 2005. Preoperative hemoglobin A1c and glucose measures were collected from the surgical admission. We measured biomarkers of myocardial damage (cardiac troponin I) and metabolic dysfunction (blood glucose and hemoglobin A1c) to identify a difference among patients under tight (90–100% of glucose measures ≤150 mg/dL) or loose (<90%) glycemic control. All patients received continuous insulin infusion in the immediate postoperative period. We discovered 45.6% of the patients were in tight control. We found tight glycemic control resulted in no significant difference in troponin I release. Mean cardiac troponin I for tight and loose control was 4.9 and 8.5 (ng/mL), p value .3. We discovered patients varied with their degree of control, even with established protocols to maintain glucose levels within the normal range. We were unable to verify tight glycemic control compared to loose control was significantly associated with decreased cardiac troponin I release. Future studies are needed to evaluate the cardiotoxic mechanisms of hyperglycemia postulated in this study

Using Biomarkers to Improve the Preoperative Prediction of Death in Coronary Artery Bypass Graft Patients

The current risk prediction models for mortality following coronary artery bypass graft (CABG) surgery have been developed on patient and disease characteristics alone. Improvements to these models potentially may be made through the analysis of biomarkers of unmeasured risk. We hypothesize that preoperative biomarkers reflecting myocardial damage, inflammation, and metabolic dysfunction are associated with an increased risk of mortality following CABG surgery and the use of biomarkers associated with these injuries will improve the Northern New England (NNE) CABG mortality risk prediction model. We prospectively followed 1731 isolated CABG patients with preoperative blood collection at eight medical centers in Northern New England for a nested case-control study from 2003–2007. Preoperative blood samples were drawn at the center and then stored at a central facility. Frozen serum was analyzed at a central laboratory on an Elecsys 2010, at the same time for Cardiac Troponin T, N-Terminal pro-Brain Natriuretic Peptide, high sensitivity C-Reactive Protein, and blood glucose. We compared the strength of the prediction model for mortality using multivariable logistic regression, goodness of fit and tested the equality of the receiving operating characteristic curve (ROC) area. There were 33 cases (dead at discharge) and 66 randomly matched controls (alive at discharge). The ROC for the preoperative mortality model was improved from .83 (95% confidence interval: .74–.92) to .87 (95% confidence interval: .80–.94) with biomarkers (p-value for equality of ROC areas .09). The addition of biomarkers to the NNE preoperative risk prediction model did not significantly improve the prediction of mortality over patient and disease characteristics alone. The added measurement of multiple biomarkers outside of preoperative risk factors may be an unnecessary use of health care resources with little added benefit for predicting in-hospital mortality

Evidence of Previous Infection with Mycobacterium avium-Mycobacterium intracellulare Complex among Healthy Subjects: An International Study of Dominant Mycobacterial Skin Test Reactions

Skin tests with 0.1 mL of intermediate-strength Mycobacterium tuberculosis purified protein derivative (PPD) and 0.1 mL of Mycobacterium avium sensitin were conducted on 484 healthy subjects from diverse geographic sites. Reactions of ⩾5 mm to one antigen that exceeded the reaction to the other by ⩾3 mm were considered M. avium- or PPD-dominant. PPD-dominant reactions were more frequent at sites where routine Bacille Calmette-Guérin immunization is done or where there are high rates of tuberculosis: New Hampshire, 2%; Boston, 7%; Finland, 14%; Trinidad, 26%; and Kenya, 28%. However, rates of M. avium-dominant reactions ranged from 7% to 12% at all sites. Analysis of dominant reactions based on a more stringent 10-mm minimum reaction size showed similar trends. These data suggest that exposure to MAC is similar in developed and developing countries but that broad mycobacterial immunity is greater in developing countries and may contribute to the lower rates of disseminated MAC infections in AIDS in these areas