Rapid chromatin repression by Aire provides precise control of immune tolerance.

Aire mediates the expression of tissue-specific antigens in thymic epithelial cells to promote tolerance against self-reactive T lymphocytes. However, the mechanism that allows expression of tissue-specific genes at levels that prevent harm is unknown. Here we show that Brg1 generates accessibility at tissue-specific loci to impose central tolerance. We found that Aire has an intrinsic repressive function that restricts chromatin accessibility and opposes Brg1 across the genome. Aire exerted this repressive influence within minutes after recruitment to chromatin and restrained the amplitude of active transcription. Disease-causing mutations that impair Aire-induced activation also impair the protein's repressive function, which indicates dual roles for Aire. Together, Brg1 and Aire fine-tune the expression of tissue-specific genes at levels that prevent toxicity yet promote immune tolerance.

Epigenomics of human CD8 T cell differentiation and aging.

The efficacy of the adaptive immune response declines dramatically with age, but the cell-intrinsic mechanisms driving immune aging in humans remain poorly understood. Immune aging is characterized by a loss of self-renewing naïve cells and the accumulation of differentiated but dysfunctional cells within the CD8 T cell compartment. Using ATAC-seq, we inferred the transcription factor binding activities correlated with naive and central and effector memory CD8 T cell states in young adults. Integrating our results with RNA-seq, we identified transcription networks associated with CD8 T cell differentiation, with prominent roles implicated for BATF, ETS1, Eomes, and Sp1. Extending our analysis to aged humans, we found that the differences between the memory and naive subsets were largely preserved across age, but that naive and central memory cells from older individuals exhibited a shift toward more differentiated patterns of chromatin openness. Additionally, aged naive cells displayed a loss in chromatin accessibility at gene promoters, largely associated with a decrease in NRF1 binding. This shift was implicated in a marked drop-off in the ability of the aged naive cells to transcribe respiratory chain genes, which may explain the reduced capacity of oxidative phosphorylation in older naïve cells. Our findings identify BATF- and NRF1-driven gene regulation as potential targets for delaying CD8 T cell aging and restoring function.

Therapeutic Interchange of Clevidipine For Sodium Nitroprusside in Cardiac Surgery.

BACKGROUND: Generic price inflation has resulted in rising acquisition costs for sodium nitroprusside (SNP), an agent historically described as the drug of choice for the treatment of perioperative hypertension in cardiac surgery. PURPOSE: To describe the implementation and cost avoidance achieved by utilizing clevidipine as an alternative to SNP in cardiac surgery patients at a 520-bed community teaching hospital that performs more than 300 cardiac surgeries each year. METHODS: A multidisciplinary team inclusive of anesthesiologists, intensivists, pharmacists, and surgeons collaborated to develop a therapeutic interchange for SNP in cardiac surgery patients. Consistent with current guidelines for therapeutic interchange, the goal was to encourage a less expensive alternative that was demonstrated to be at least therapeutically equivalent to SNP based on data derived from clinical trials published in peer-reviewed literature. A comprehensive literature review identified clevidipine as an alternative to SNP for perioperative hypertension in cardiac surgery. Nicardipine was considered as well, but was not chosen as a substitute due to lack of strong evidence and comparative data with SNP. RESULTS: Clevidipine was implemented successfully in our cardiac surgery patients and will result in a net cost avoidance of approximately $300,000 in 2016. This is thought to be driven largely by the difference in acquisition cost between clevidipine and SNP. The operating room in our institution no longer keeps SNP stocked in anesthesia trays as a result of the success of our interchange. No requests have been made to return to the SNP standard. CONCLUSION: Through effective communication and multidisciplinary collaboration, our institution was able to develop an evidence-based and effective therapeutic interchange program for SNP.

Discovery of novel non-synonymous SNP variants in 988 candidate genes from 6 centenarians by target capture and next-generation sequencing.

Despite evidence of a substantial genetic component, the genetic factors that underlie longevity in humans remain to be identified. Previous genome-wide linkage and association studies have not found strong evidence for the contribution of common variants besides the APOE gene, suggesting the role of rare variants in human longevity. To discover rare variants that might contribute to longevity, we selected 988 candidate genes and performed a pilot study to identify novel non-synonymous variants in 6 Ashkenazi Jewish centenarians older than 105. Our candidate genes act in pathways implicated in aging and longevity, including neurodegeneration, cognitive function, lipid metabolism, DNA repair, and genome maintenance. By implementing custom-designed Agilent SureSelect target capture and next-generation sequencing, we discovered a total of 89 novel non-synonymous SNPs (nsSNPs) and validated 51 nsSNPs by iPLEX MassArray assays. Genotyping analysis of these novel SNPs in 410 Ashkenazi Jewish controls and 390 centenarians showed significant enrichment (5.3 fold, p = 0.02) of the p.Y318C variant in PMS2 and significant depletion (7.5 fold, p = 0.04) of the p.V465A variant in GABRR3 in centenarians compared to controls. Our study presents the potential of targeted next-generation sequencing for discovery of rare but functional genetic variation which may lead to exceptional longevity in humans.

The impact of blood conservation on outcomes in cardiac surgery: is it safe and effective?

BACKGROUND: Increasing evidence shows that perioperative blood transfusion in cardiac surgery is associated with increased postoperative morbidity and mortality and decreased long-term survival. Tolerance of "permissive anemia" is an important element of perioperative blood conservation strategy. The safety of tolerating perioperative anemia has been a significant deterrent for widespread application of blood conservation. This study examines whether blood conservation is equally safe or superior to the common practice of transfusion in cardiac surgery. METHODS: The total study population consisted of 32,449 patients who underwent isolated coronary artery bypass surgery from June 2000 until December 2004 with complete data from 17 institutions in the State of New Jersey. Englewood Hospital and Medical Center (EH) has a well-established blood conservation program. Five hundred eighty-six EH patients (blood conservation cohort) were compared with a propensity score-matched cohort of 586 patients from the other New Jersey institutions (OH-M) representing the common practice of transfusion. Outcomes were classified as very serious complications, serious complications, or neither (no very serious complication or serious complication). Analysis consisted of McNemar tests and multiple logistic regression. RESULTS: Fewer patients were transfused at EH compared with OH-M (10.6% versus 42.5%; p < 0.0001). Englewood Hospital had 5 (0.8%) deaths versus 15 (2.5%) in the OH-M group (p = 0.02). Of the EH patients, 11.1% experienced a very serious complication or serious complication versus 18.7% in the OH-M cohort (p = 0.0002). Transfusion was associated with an increased risk of an adverse outcome in both cohorts (EH: odds ratio, 7.3; 95% confidence interval, 3.7 to 14.4 versus OH-M: odds ratio, 4.6; 95% confidence interval, 2.8 to 7.7). CONCLUSIONS: Blood conservation is safe and effective in reducing transfusions. Tolerance of perioperative anemia, which is one of the main components of blood conservation, does not increase the risk of complications or death in cardiac surgery. Avoidance of transfusion reduces the risk of complications. This study further solidifies the relationship between transfusion and adverse outcome in cardiac surgery.

Blood conservation in practice: an overview.

Allogeneic blood transfusions are associated with risks and unfavourable outcomes. Blood conservation provides an alternative, with potential to improve patient care with limited or no blood transfusion. Many approaches are available, but the most essential ones are simple and cost free.

Postoperative blood loss and transfusion associated with use of Hextend in cardiac surgery patients at a blood conservation center.

BACKGROUND: Hydroxyethyl starch (HES) solutions are readily available colloids, but their widespread use is shadowed by controversies surrounding their effects on bleeding. This retrospective study was conducted to evaluate the relationship between Hextend (HEX; Hospira, Inc.) doses of 1 to 20 mL/kg and allogeneic transfusion and 24-hour chest tube drainage (CTD) in cardiac surgeries at a blood conservation center. STUDY DESIGN AND METHODS: After institutional review board approval, data on 748 patients undergoing coronary artery bypass grafting (CABG), valve, or combined CABG and valve surgeries were collected. Cases not receiving HEX (due to contraindications, e.g., renal failure, bleeding diathesis) or receiving more than 20 mL per kg HEX, not accepting transfusions, or requiring more extensive surgery were excluded, and the remaining 621 cases were analyzed. RESULTS: Overall transfusion rate and mean CTD were 12.7 percent and 460.4 mL, respectively. Patients who received transfusions received more HEX (10.8 mL/kg vs. 9.8 mL/kg; p = 0.043) but HEX per kg was not associated with higher transfusion rates in multivariate analysis (p = 0.077). HEX per kg was associated with CTD in both uni- and multivariate analyzes (p < 0.001) with 1.66 percent increase in CTD for every 1 mL per kg increase in HEX. CONCLUSIONS: Although HEX was associated with transfusion in univariate analysis and with CTD in uni- and multivariate analysis, the former was no longer significant when adjusted for other predictors of transfusion in our selected patient population at a blood conservation center. The clinical significance of the observed increase in CTD remains undetermined. To minimize transfusion and bleeding in these patients, it is recommended that HEX be used in amounts of not more than 20 mL per kg together with point-of-care coagulation tests and other blood conservation strategies.

Anesthetic consideration for descending thoracic aortic aneurysm repair.

Anesthesia for surgery of the aorta poses some of the most difficult challenges for anesthesiologists. Major hemodynamic and physiologic stresses and sophisticated techniques of extracorporeal support are superimposed on patients with complex medical disease states. In this review, etiologies, natural history, and surgical techniques of thoracic aortic aneurysm are presented. Anesthetic considerations are discussed in detail, including the management of distal perfusion using partial cardiopulmonary bypass. Considerations of spinal cord protection, including management of proximal hypertension, cerebral spinal fluid drainage, and pharmacological therapies, are presented.

Use of the Hemobag for modified ultrafiltration in a Jehovah's Witness patient undergoing cardiac surgery.

Modified ultrafiltration is an important technique to concentrate the patient's circulating blood volume and the residual whole blood in the extracorporeal circuit post-cardiopulmonary bypass. The Hemobag system is a device cleared by the US Food and Drug Administration and represents a novel and safe modification of traditional modified ultrafiltration systems. It is quick and easy to operate by the perfusionist during the hemoconcentration process. Hemoconcentration is accomplished by having the Hemobag "recovery loop" circuit separate from the extracorporeal circuit. This allows the surgeons to continue with surgery, decannulate, and administer protamine simultaneously while the Hemobag is in use. The successful use of the Hemobag in a Jehovah's Witness patient has not been previously described in the literature. This case report describes how to set up and operate the Hemobag in a Jehovah's Witness patient undergoing cardiac surgery that requires an extracorporeal circuit.

Geographic regional differences in rocuronium bromide dose-response relation and time course of action: an overlooked factor in determining recommended dosage.

BACKGROUND: Geographic location is not acknowledged as a stratifying factor that can directly affect drug potency, because drugs are still licensed with the same recommended dose for different geographic regions. The aim of the current study was to compare the potency and duration of action of rocuronium bromide in 54 patients in three countries with different life habits, diet, and ambient conditions, namely white Austrians, white North Americans, and Han Chinese in China. METHODS: Neuromuscular block of six consecutive 50-microg/kg rocuronium incremental doses followed by 300 microg/kg was evaluated using the Relaxometer mechanomyograph (Groningen University, Groningen, Holland). Dose-response curves were created using log-dose-probit transformation. The authors compared rocuronium bromide ED50, ED90, and ED95 (effective doses required for 50%, 90%, and 95% first twitch depression, respectively) as well as Dur25 and Dur0.8 (times from last incremental dose administration until 25% first twitch and 0.8 train-of-four ratio recovery, respectively) in patients of the three countries. RESULTS: Rocuronium ED50, ED90, and ED95 were significantly higher in Austrian patients (258 +/- 68, 530 +/- 159, and 598 +/- 189 microg/kg) and Chinese patients (201 +/- 59, 413 +/- 107, and 475 +/- 155 microg/kg) compared with American patients (148 +/- 48, 316 +/- 116, and 362 +/- 149 microg/kg, respectively). Dur25 and Dur0.8 were significantly shorter in Austrian patients (22.3 +/- 5.5 and 36.9 +/- 12.8 min) and Chinese patients (30.4 +/- 7.5 and 45.7 +/- 15.9 min) compared with American patients (36.7 +/- 8.5 and 56.2 +/- 16.7 min, respectively). CONCLUSIONS: The authors demonstrated a significant difference in rocuronium potency and duration of action among patients in the three countries. Larger studies are required for determining dosage recommendations for different geographic regions.

Predictors of transfusion requirements for cardiac surgical procedures at a blood conservation center.

BACKGROUND: Previous studies defining perioperative risk factors for allogeneic transfusion requirements in cardiac surgery were limited to highly selected cardiac surgery populations or were associated with high transfusion rates. The purpose of this study was to determine perioperative risk factors and create a formula to predict transfusion requirements for major cardiac surgical procedures in a center that practices a multimodality approach to blood conservation. METHODS: We performed an observational study on 307 consecutive patients undergoing coronary artery bypass grafting, valve, and combined (coronary artery bypass grafting and valve) procedures. An equation was derived to estimate the risk of transfusion based on preoperative risk factors using multivariate analysis. In patients with a calculated probability of transfusion of at least 5%, intraoperative predictors of transfusion were identified by multivariate analysis. RESULTS: Thirty-five patients (11%) required intraoperative or postoperative allogeneic transfusions. Preoperative factors as independent predictors for transfusions included red blood cell mass, type of operation, urgency of operation, number of diseased vessels, serum creatinine of at least 1.3 mg/dL, and preoperative prothrombin time. Intraoperative factors included cardiopulmonary bypass time, three or fewer bypass grafts, lesser volume of acute normovolemic hemodilution removed, and total crystalloid infusion of at least 2,500 mL. The derived formula was applied to a validation cohort of 246 patients, and the observed transfusion rates conformed well to the predicted risks. CONCLUSIONS: A multimodality approach to blood conservation in cardiac surgery resulted in a low transfusion rate. Identifying patients' risks for transfusion should alter patient management perioperatively to decrease their transfusion rate and make more efficient use of blood resources.

Multidisciplinary management of a Jehovah's Witness patient for the removal of a renal cell carcinoma extending into the right atrium.

PURPOSE: To highlight the management of a Jehovah's witness surgical patient presenting for cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest. CLINICAL FEATURES: A 47-yr-old male, Jehovah's Witness, with renal cell carcinoma was admitted for left radical nephrectomy and excision of tumour thrombus extending into the junction of the inferior vena cava (IVC) and right atrium (RA). The preoperative goals were to maximize red blood cell mass, delineate the extent of tumour extension and develop a surgical plan incorporating blood conservation strategies to minimize blood loss. A midline abdominal incision was made to optimize removal of the non-caval portion of the tumour from the intra-abdominal region. CPB and deep hypothermic circulatory arrest were instituted to aid in removing the tumour from the IVC and RA. Intraoperative blood conservation strategies included the use of acute normovolemic hemodilution, antifibrinolytics, cell salvage, point-of-care monitoring of heparin and protamine blood concentrations, leukocyte-depleting filter, and meticulous surgical techniques. The patient was successfully weaned from CPB and was transported to the cardiothoracic intensive care unit without complication. The patient was discharged home one week after the operation with a hemoglobin of 10.2 g x dL(-1) and a hematocrit of 31.2%. CONCLUSION: Multiple blood conservation techniques were employed to manage this Jehovah's Witness patient through complex cardiac surgery, which was previously denied to him at other institutions. The successful outcome of this patient, while respecting the right to refuse allogeneic blood products, is a result of a multidisciplinary collaboration as well as the application of established blood conservation techniques.

Comparison of arterial systolic pressure variation with other clinical parameters to predict the response to fluid challenges during cardiac surgery.

Prophylactic optimization of stroke volume during surgery has been thought by some to reduce complications following surgery. Mechanical ventilation has been shown to induce variations in systolic systemic arterial blood pressure. Measuring such variations in systolic pressure (SPV) might serve as an attractive method for guiding fluid therapy intraoperatively. It is unknown if variations in systolic pressure following the rapid intravenous administration of a specific volume of fluid would lead to changes in pressure measurements obtained from a pulmonary artery with sufficient sensitivity to predict or guide the need for expansion of the intravascular volume to optimize stroke volume as an index of cardiac function. The purpose of this study was to determine if such measurements of changes in systolic pressures would be useful in optimizing stroke volume. Nineteen patients undergoing cardiac surgery were enrolled in a prospective cohort study. Following induction of general anesthesia, one or more 250 mL boluses of 6% hetastarch were administered. Stroke volume was calculated from the cardiac output obtained by thermodilution using a pulmonary artery catheter. If the patient s stroke volume increased by less than 10% as a result of a given fluid challenge, the patient was classified as a non-responder. However, if the stroke volume increased by more than 10%, the patient was classified as a responder. The variations in systolic pressure and echocardiographic indices were simultaneously measured before and after the administration of each 250 mL fluid bolus. Pulmonary artery occlusion pressure (PAOP) values were significantly lower in patients who responded to fluid boluses (p=0.0085) than in those who did not. Similarly SPV and SPVdown values (defined as the decrease in systolic pressure with ventilation) were significantly greater in the responders (p<0.05). No significant intergroup differences were observed in SPVup (increase in systolic pressure with ventilation) or echocardiographic-derived left ventricular end diastolic area. A PAOP value less than 10 mm Hg predicted a response (sensitivity 68%, specificity 79%). Although significant intergroup differences in the extent of systolic pressure variations were observed, no appropriate threshold values could be determined that would accurately predict the response to a fluid bolus. There is a relationship between SPV and SPVdown values and intravascular volume status. SPV and echocardiographic-derived values did not predict the response to a fluid bolus as well as values obtained from the pulmonary artery catheter.

Anesthetic considerations for endovascular aortic repair.

Endovascular aortic repair is a new alternative to conventional surgical techniques. A variety of devices available for endovascular aortic repair are discussed and the outcomes after repair are reviewed. Anesthetic considerations during endovascular repair are dictated by the device being used, as well as the site of device deployment. Requirements for the optimization of hemodynamic states during proximal graft deployment are described, as well as the available options for induction of ventricular asystole. Since arterial rupture is always a risk when using this procedure, appropriate facilities must be present for resuscitation. Patients undergoing repair of thoracic aortic pathology may be candidates for perioperative transesophageal echocardiographic monitoring. Since a subgroup of these patients may be at risk for postoperative paraplegia, aggressive spinal cord protection should be considered. Patients with large aneurysms may be at risk for "post-implantation syndrome," which is characterized by hyperpyrexia, hypotension, and coagulopathy.