Strategies of preserving genetic diversity while maximizing genetic response from implementing genomic selection in pulse breeding programs.

KEY MESSAGE: Genomic selection maximizes genetic gain by recycling parents to germplasm pool earlier and preserves genetic diversity by restricting the number of fixed alleles and the relationship in pulse breeding programs. Using a stochastic computer simulation, we investigated the benefit of optimization strategies in the context of genomic selection (GS) for pulse breeding programs. We simulated GS for moderately complex to highly complex traits such as disease resistance, grain weight and grain yield in multiple environments with a high level of genotype-by-environment interaction for grain yield. GS led to higher genetic gain per unit of time and higher genetic diversity loss than phenotypic selection by shortening the breeding cycle time. The genetic gain obtained from selecting the segregating parents early in the breeding cycle (at F1 or F2 stages) was substantially higher than selecting at later stages even though prediction accuracy was moderate. Increasing the number of F1 intercross (F1i) families and keeping the total number of progeny of F1i families constant, we observed a decrease in genetic gain and increase in genetic diversity, whereas increasing the number of progeny per F1i family while keeping a constant number of F1i families increased the rate of genetic gain and had higher genetic diversity loss per unit of time. Adding 50 F2 family phenotypes to the training population increased the accuracy of genomic breeding values (GEBVs) and genetic gain per year and decreased the rate of genetic diversity loss. Genetic diversity could be preserved by applying a strategy that restricted both the percentage of alleles fixed and the average relationship of the group of selected parents to preserve long-term genetic improvement in the pulse breeding program.

Tight Glycemic Control in Critically Ill Children.

BACKGROUND: In multicenter studies, tight glycemic control targeting a normal blood glucose level has not been shown to improve outcomes in critically ill adults or children after cardiac surgery. Studies involving critically ill children who have not undergone cardiac surgery are lacking. METHODS: In a 35-center trial, we randomly assigned critically ill children with confirmed hyperglycemia (excluding patients who had undergone cardiac surgery) to one of two ranges of glycemic control: 80 to 110 mg per deciliter (4.4 to 6.1 mmol per liter; lower-target group) or 150 to 180 mg per deciliter (8.3 to 10.0 mmol per liter; higher-target group). Clinicians were guided by continuous glucose monitoring and explicit methods for insulin adjustment. The primary outcome was the number of intensive care unit (ICU)-free days to day 28. RESULTS: The trial was stopped early, on the recommendation of the data and safety monitoring board, owing to a low likelihood of benefit and evidence of the possibility of harm. Of 713 patients, 360 were randomly assigned to the lower-target group and 353 to the higher-target group. In the intention-to-treat analysis, the median number of ICU-free days did not differ significantly between the lower-target group and the higher-target group (19.4 days [interquartile range {IQR}, 0 to 24.2] and 19.4 days [IQR, 6.7 to 23.9], respectively; P=0.58). In per-protocol analyses, the median time-weighted average glucose level was significantly lower in the lower-target group (109 mg per deciliter [IQR, 102 to 118]; 6.1 mmol per liter [IQR, 5.7 to 6.6]) than in the higher-target group (123 mg per deciliter [IQR, 108 to 142]; 6.8 mmol per liter [IQR, 6.0 to 7.9]; P<0.001). Patients in the lower-target group also had higher rates of health care-associated infections than those in the higher-target group (12 of 349 patients [3.4%] vs. 4 of 349 [1.1%], P=0.04), as well as higher rates of severe hypoglycemia, defined as a blood glucose level below 40 mg per deciliter (2.2 mmol per liter) (18 patients [5.2%] vs. 7 [2.0%], P=0.03). No significant differences were observed in mortality, severity of organ dysfunction, or the number of ventilator-free days. CONCLUSIONS: Critically ill children with hyperglycemia did not benefit from tight glycemic control targeted to a blood glucose level of 80 to 110 mg per deciliter, as compared with a level of 150 to 180 mg per deciliter. (Funded by the National Heart, Lung, and Blood Institute and others; HALF-PINT ClinicalTrials.gov number, NCT01565941 .).

Short-Term Adverse Outcomes Associated With Hypoglycemia in Critically Ill Children.

OBJECTIVES: Previous studies report worse short-term outcomes with hypoglycemia in critically ill children. These studies relied on intermittent blood glucose measurements, which may have introduced detection bias. We analyzed data from the Heart And Lung Failure-Pediatric INsulin Titration trial to determine the association of hypoglycemia with adverse short-term outcomes in critically ill children. DESIGN: Nested case-control study. SETTING: Thirty-five PICUs. A computerized algorithm that guided the timing of blood glucose measurements and titration of insulin infusion, continuous glucose monitors, and standardized glucose infusion rates were used to minimize hypoglycemia. PATIENTS: Nondiabetic children with cardiovascular and/or respiratory failure and hyperglycemia. Cases were children with any hypoglycemia (blood glucose < 60 mg/dL), whereas controls were children without hypoglycemia. Each case was matched with up to four unique controls according to age group, study day, and severity of illness. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 112 (16.0%) of 698 children who received the Heart And Lung Failure-Pediatric INsulin Titration protocol developed hypoglycemia, including 25 (3.6%) who developed severe hypoglycemia (blood glucose < 40 mg/dL). Of these, 110 cases were matched to 427 controls. Hypoglycemia was associated with fewer ICU-free days (median, 15.3 vs 20.2 d; p = 0.04) and fewer hospital-free days (0 vs 7 d; p = 0.01) through day 28. Ventilator-free days through day 28 and mortality at 28 and 90 days did not differ between groups. More children with insulin-induced versus noninsulin-induced hypoglycemia had zero ICU-free days (35.8% vs 20.9%; p = 0.008). Outcomes did not differ between children with severe versus nonsevere hypoglycemia or those with recurrent versus isolated hypoglycemia. CONCLUSIONS: When a computerized algorithm, continuous glucose monitors and standardized glucose infusion rates were used to manage hyperglycemia in critically ill children with cardiovascular and/or respiratory failure, severe hypoglycemia (blood glucose < 40 mg/dL) was uncommon, but any hypoglycemia (blood glucose < 60 mg/dL) remained common and was associated with worse short-term outcomes.

Penis Transplantation: First US Experience.

OBJECTIVE: We describe the first successful penis transplant in the United States in a patient with a history of subtotal penectomy for penile cancer. BACKGROUND: Penis transplantation represents a new paradigm in restoring anatomic appearance, urine conduit, and sexual function after genitourinary tissue loss. To date, only 2 penis transplants have been performed worldwide. METHODS: After institutional review board approval, extensive medical, surgical, and radiological evaluations of the patient were performed. His candidacy was reviewed by a multidisciplinary team of surgeons, physicians, psychiatrists, social workers, and nurse coordinators. After appropriate donor identification and recipient induction with antithymocyte globulin, allograft procurement and recipient preparation took place concurrently. Anastomoses of the urethra, corpora, cavernosal and dorsal arteries, dorsal vein, and dorsal nerves were performed, and also inclusion of a donor skin pedicle as the composite allograft. Maintenance immunosuppression consisted of mycophenolate mofetil, tacrolimus, and methylprednisolone. RESULTS: Intraoperative, the allograft had excellent capillary refill and strong Doppler signals after revascularization. Operative reinterventions on postoperative days (PODs) 2 and 13 were required for hematoma evacuation and skin eschar debridement. At 3 weeks, no anastomotic leaks were detected on urethrogram, and the catheter was removed. Steroid resistant-rejection developed on POD 28 (Banff I), progressed by POD 32 (Banff III), and required a repeat course of methylprednisolone and antithymocyte globulin. At 7 months, the patient has recovered partial sensation of the penile shaft and has spontaneous penile tumescence. Our patient reports increased overall health satisfaction, dramatic improvement of self-image, and optimism for the future. CONCLUSIONS: We have shown that it is feasible to perform penile transplantation with excellent results. Furthermore, this experience demonstrates that penile transplantation can be successfully performed with conventional immunosuppression. We propose that our successful penile transplantation pilot experience represents a proof of concept for an evolution in reconstructive transplantation.

Procedural Pain during Insertion of a Continuous Glucose Monitoring Device in Preterm Infants.

Procedural pain was compared between the insertion of a continuous glucose monitoring sensor and heel stick using the Premature Infant Pain Profile in a single-blinded controlled trial in preterm infants (≤32 weeks of gestation or birth weight ≤1500 g) (ClinicalTrials.govNCT02583776). Continuous glucose monitoring insertion was associated with lower pain scores compared with the heel stick.

Adjusting Insulin Delivery to Activity (AIDA) clinical trial: Effects of activity-based insulin profiles on glucose control in children with type 1 diabetes.

BACKGROUND: Increased daytime activity in children with type I diabetes mellitus (T1DM) is associated with increased risk of hypoglycemia. OBJECTIVE: To determine whether an automated weekly review of accelerometer, continuous glucose monitoring (CGM), and insulin pump data, could be used to identify children with increased risk of nighttime hypoglycemia and preemptively adjust the nighttime basal insulin profile according to daytime activity. RESEARCH AND DESIGN METHODS: Clinical trial of children with T1DM on insulin pump and CGM therapy. Subjects at risk of nighttime hypoglycemia were identified from regression analysis of daytime step count vs nighttime nadir glucose. If the regression slope was significantly different from zero (P < 0.05) subjects were managed with different algorithm derived nighttime basal insulin profiles following high and low activity days. RESULTS: Twenty children (median age: 12; range: 7-17 years) were enrolled. Regression slopes were significant in 10 children. In these children, baseline nighttime nadir glucose level was lower following high activity days (120 [110-139] vs 152 [130-162] mg/dL, P = 0.004). Use of activity-based nighttime basal profiles produced similar nighttime nadir glucose levels following high and low activity days (136 [123-175] vs 140 [108-180] mg/dL, P = 0.73) with fewer nighttime interventions to correct hypoglycemia (0 [0-0.16] vs 0.15 [0.13-0.22] per night, P = 0.008). CONCLUSION: Children with lower nighttime glucose levels following high daytime activity can be identified using step count data obtained from readily available accelerometers and the nighttime glucose control improved using different activity-based basal profiles.

Effective antigen presentation to helper T cells by human eosinophils.

Although eosinophils are inflammatory cells, there is increasing attention on their immunomodulatory roles. For example, murine eosinophils can present antigen to CD4+ T helper (Th) cells, but it remains unclear whether human eosinophils also have this ability. This study determined whether human eosinophils present a range of antigens, including allergens, to activate Th cells, and characterized their expression of MHC class II and co-stimulatory molecules required for effective presentation. Human peripheral blood eosinophils purified from non-allergic donors were pulsed with the antigens house dust mite extract (HDM), Timothy Grass extract (TG) or Mycobacterium tuberculosis purified protein derivative (PPD), before co-culture with autologous CD4+ Th cells. Proliferative and cytokine responses were measured, with eosinophil expression of HLA-DR/DP/DQ and the co-stimulatory molecules CD40, CD80 and CD86 determined by flow cytometry. Eosinophils pulsed with HDM, TG or PPD drove Th cell proliferation, with the response strength dependent on antigen concentration. The cytokine responses varied with donor and antigen, and were not biased towards any particular Th subset, often including combinations of pro- and anti-inflammatory cytokines. Eosinophils up-regulated surface expression of HLA-DR/DP/DQ, CD80, CD86 and CD40 in culture, increases that were sustained over 5 days when incubated with antigens, including HDM, or the major allergens it contains, Der p I or Der p II. Human eosinophils can, therefore, act as effective antigen-presenting cells to stimulate varied Th cell responses against a panel of antigens including HDM, TG or PPD, an ability that may help to determine the development of allergic disease.

Characterization of Stripe Rust Resistance Genes in the Wheat Cultivar Chuanmai45.

The objective of this research was to characterize the high level of resistance to stripe that has been observed in the released wheat cultivar, Chuanmai45. A combination of classic genetic analysis, molecular and cytogenetic methods were used to characterize resistance in an F2 population derived from Chuanmai45 and the susceptible Chuanmai42. Inheritance of resistance was shown to be conferred by two genes in Chuanmai45. Fluorescence in situ hybridization (FISH) was used along with segregation studies to show that one gene was located on a 1RS.1BL translocation. Molecular markers were employed to show that the other locus was located on chromosome 4B. The defeated gene, Yr24/26, on chromosome 1BL was present in the susceptible parent and lines that recombined this gene with the 1RS.1BL translocation were identified. The germplasm, loci, and associated markers identified in this study will be useful for application in breeding programs utilizing marker-assisted selection.

Tight glycemic control after pediatric cardiac surgery in high-risk patient populations: a secondary analysis of the safe pediatric euglycemia after cardiac surgery trial.

BACKGROUND: Our previous randomized, clinical trial showed that postoperative tight glycemic control (TGC) for children undergoing cardiac surgery did not reduce the rate of health care-associated infections compared with standard care (STD). Heterogeneity of treatment effect may exist within this population. METHODS AND RESULTS: We performed a post hoc exploratory analysis of 980 children from birth to 36 months of age at the time of cardiac surgery who were randomized to postoperative TGC or STD in the intensive care unit. Significant interactions were observed between treatment group and both neonate (age ≤30 days; P=0.03) and intraoperative glucocorticoid exposure (P=0.03) on the risk of infection. The rate and incidence of infections in subjects ≤60 days old were significantly increased in the TGC compared with the STD group (rate: 13.5 versus 3.7 infections per 1000 cardiac intensive care unit days, P=0.01; incidence: 13% versus 4%, P=0.02), whereas infections among those >60 days of age were significantly reduced in the TGC compared with the STD group (rate: 5.0 versus 14.1 infections per 1000 cardiac intensive care unit days, P=0.02; incidence: 2% versus 5%, P=0.03); the interaction of treatment group by age subgroup was highly significant (P=0.001). Multivariable logistic regression controlling for the main effects revealed that previous cardiac surgery, chromosomal anomaly, and delayed sternal closure were independently associated with increased risk of infection. CONCLUSIONS: This exploratory analysis demonstrated that TGC may lower the risk of infection in children >60 days of age at the time of cardiac surgery compared with children receiving STD. Meta-analyses of past and ongoing clinical trials are necessary to confirm these findings before clinical practice is altered. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00443599.

Standardized evaluation of algorithms for computer-aided diagnosis of dementia based on structural MRI: the CADDementia challenge.

Algorithms for computer-aided diagnosis of dementia based on structural MRI have demonstrated high performance in the literature, but are difficult to compare as different data sets and methodology were used for evaluation. In addition, it is unclear how the algorithms would perform on previously unseen data, and thus, how they would perform in clinical practice when there is no real opportunity to adapt the algorithm to the data at hand. To address these comparability, generalizability and clinical applicability issues, we organized a grand challenge that aimed to objectively compare algorithms based on a clinically representative multi-center data set. Using clinical practice as the starting point, the goal was to reproduce the clinical diagnosis. Therefore, we evaluated algorithms for multi-class classification of three diagnostic groups: patients with probable Alzheimer's disease, patients with mild cognitive impairment and healthy controls. The diagnosis based on clinical criteria was used as reference standard, as it was the best available reference despite its known limitations. For evaluation, a previously unseen test set was used consisting of 354 T1-weighted MRI scans with the diagnoses blinded. Fifteen research teams participated with a total of 29 algorithms. The algorithms were trained on a small training set (n=30) and optionally on data from other sources (e.g., the Alzheimer's Disease Neuroimaging Initiative, the Australian Imaging Biomarkers and Lifestyle flagship study of aging). The best performing algorithm yielded an accuracy of 63.0% and an area under the receiver-operating-characteristic curve (AUC) of 78.8%. In general, the best performances were achieved using feature extraction based on voxel-based morphometry or a combination of features that included volume, cortical thickness, shape and intensity. The challenge is open for new submissions via the web-based framework: http://caddementia.grand-challenge.org.

Tight glycemic control versus standard care after pediatric cardiac surgery.

BACKGROUND: In some studies, tight glycemic control with insulin improved outcomes in adults undergoing cardiac surgery, but these benefits are unproven in critically ill children at risk for hyperinsulinemic hypoglycemia. We tested the hypothesis that tight glycemic control reduces morbidity after pediatric cardiac surgery. METHODS: In this two-center, prospective, randomized trial, we enrolled 980 children, 0 to 36 months of age, undergoing surgery with cardiopulmonary bypass. Patients were randomly assigned to either tight glycemic control (with the use of an insulin-dosing algorithm targeting a blood glucose level of 80 to 110 mg per deciliter [4.4 to 6.1 mmol per liter]) or standard care in the cardiac intensive care unit (ICU). Continuous glucose monitoring was used to guide the frequency of blood glucose measurement and to detect impending hypoglycemia. The primary outcome was the rate of health care-associated infections in the cardiac ICU. Secondary outcomes included mortality, length of stay, organ failure, and hypoglycemia. RESULTS: A total of 444 of the 490 children assigned to tight glycemic control (91%) received insulin versus 9 of 490 children assigned to standard care (2%). Although normoglycemia was achieved earlier with tight glycemic control than with standard care (6 hours vs. 16 hours, P<0.001) and was maintained for a greater proportion of the critical illness period (50% vs. 33%, P<0.001), tight glycemic control was not associated with a significantly decreased rate of health care-associated infections (8.6 vs. 9.9 per 1000 patient-days, P=0.67). Secondary outcomes did not differ significantly between groups, and tight glycemic control did not benefit high-risk subgroups. Only 3% of the patients assigned to tight glycemic control had severe hypoglycemia (blood glucose <40 mg per deciliter [2.2 mmol per liter]). CONCLUSIONS: Tight glycemic control can be achieved with a low hypoglycemia rate after cardiac surgery in children, but it does not significantly change the infection rate, mortality, length of stay, or measures of organ failure, as compared with standard care. (Funded by the National Heart, Lung, and Blood Institute and others; SPECS ClinicalTrials.gov number, NCT00443599.).

Anti-IL-4/-13 based therapy in asthma.

It is recognised that airway inflammation is key to asthma pathogenesis. Biopharmaceutical approaches have identified new therapies that target key cells and mediators that drive the inflammatory responses in the asthmatic lung. Such an approach resulted in the development of biologics targeted at inhibition of IL-4, IL-5 and IL-13. However, early clinical trials with these biologics in patients with asthma were for the most part disappointing even though they were highly effective in animal models of asthma. It is becoming apparent that significant clinical effects with anti-cytokine-based biologic therapies are more likely in carefully selected patient populations that take asthma phenotypes into account. The development of discriminatory biomarkers and genetic profiling may aid identification of such patients with asthma. This review is an update of the evidence demonstrating the effectiveness or otherwise of the targeting of the TH2 cytokines IL-4 and IL-13 with biologics in patients with asthma.

Tight glycemic control in the ICU - is the earth flat?

Tight glycemic control in the ICU has been shown to reduce mortality in some but not all prospective randomized control trials. Confounding the interpretation of these studies are differences in how the control was achieved and underlying incidence of hypoglycemia, which can be expected to be affected by the introduction of continuous glucose monitoring (CGM). In this issue of Critical Care, a consensus panel provides a list of the research priorities they believe are needed for CGM to become routine practice in the ICU. We reflect on these recommendations and consider the implications for using CGM today.

Cardiac output assessed by non-invasive monitoring is associated with ECG changes in children with critical asthma.

The primary aim of this study was to determine changes in CI and SI, if any, in children hospitalized with status asthmatics during the course of treatment as measured by non-invasive EC monitoring. The secondary aim was to determine if there is an association between Abnormal CI (defined as <5 or >95 % tile adjusted for age) and Abnormal ECG (defined as ST waves changes) Non-invasive cardiac output (CO) recordings were obtained daily from admission (Initial) to discharge (Final). Changes in CI and SI measurements were compared using paired t tests or 1-way ANOVA. The association between Abnormal CI on Initial CO recording and Abnormal ECG was analyzed by Fischer's exact test. Data are presented as mean ± SEM with mean differences reported with 95 % confidence interval; p < 0.05 was considered significant. Thirty-five children with critical asthma were analyzed. CI decreased from 6.2 ± 0.2 to 4.5 ± 0.1 [-1.6 (-0.04 to -0.37)] L/min/m(2) during hospitalization. There was no change in SI. There was a significant association between Abnormal Initial CI and Abnormal ECG (p = 0.02). In 11 children requiring prolonged hospitalization CI significantly decreased from 7.2 ± 0.5 to 4.0 ± 0.2 [-3.2 (-4.0 to -2.3)] L/min/m(2) and SI decreased from 51.2 ± 3.8 to 40.3 ± 2.0 [-11.0 (-17.6 to -4.4)] ml/beat/m(2) There was a significant decrease in CI in all children treated for critical asthma. In children that required a prolonged course of treatment, there was also a significant decrease in SI. Abnormal CI at Initial CO recording was associated with ST waves changes on ECG during hospitalization. Future studies are required to determine whether non-invasive CO monitoring can predict which patients are at risk for developing abnormal ECG.

T-cell receptor-optimized peptide skewing of the T-cell repertoire can enhance antigen targeting.

Altered peptide antigens that enhance T-cell immunogenicity have been used to improve peptide-based vaccination for a range of diseases. Although this strategy can prime T-cell responses of greater magnitude, the efficacy of constituent T-cell clonotypes within the primed population can be poor. To overcome this limitation, we isolated a CD8(+) T-cell clone (MEL5) with an enhanced ability to recognize the HLA A*0201-Melan A(27-35) (HLA A*0201-AAGIGILTV) antigen expressed on the surface of malignant melanoma cells. We used combinatorial peptide library screening to design an optimal peptide sequence that enhanced functional activation of the MEL5 clone, but not other CD8(+) T-cell clones that recognized HLA A*0201-AAGIGILTV poorly. Structural analysis revealed the potential for new contacts between the MEL5 T-cell receptor and the optimized peptide. Furthermore, the optimized peptide was able to prime CD8(+) T-cell populations in peripheral blood mononuclear cell isolates from multiple HLA A*0201(+) individuals that were capable of efficient HLA A*0201(+) melanoma cell destruction. This proof-of-concept study demonstrates that it is possible to design altered peptide antigens for the selection of superior T-cell clonotypes with enhanced antigen recognition properties.

Increasing use of hypertonic saline over mannitol in the treatment of symptomatic cerebral edema in pediatric diabetic ketoacidosis: an 11-year retrospective analysis of mortality*.

OBJECTIVES: Cerebral edema in diabetic ketoacidosis is a devastating complication with significant morbidity and mortality. This entity has traditionally been treated with mannitol, but use of 3% hypertonic saline has become an accepted alternative. We sought to assess if changes in the use of hyperosmolar therapies for treatment of cerebral edema in diabetic ketoacidosis may have influenced mortality over the last decade. DESIGN: Retrospective cohort study. SETTING: Patients discharged between 1999 and 2009 from 41 children's hospitals that provided data to the Pediatric Health Information System database. PATIENTS: A total of 43,107 children (age < 19) with diagnosis codes related to diabetic ketoacidosis were identified and further classified as having cerebral edema if treated with mannitol and/or 3% hypertonic saline. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Billing for 3% hypertonic saline and mannitol was quantified, and mortality associated with both diabetic ketoacidosis and cerebral edema in diabetic ketoacidosis was examined. Overall mortality in diabetic ketoacidosis was 0.25% and significantly decreased (p < 0.001) over the study period, whereas the frequency of treatment with hyperosmolar agents (3.8%) was unchanged. Use of mannitol as a sole agent decreased from 98% to 49%, 3% hypertonic saline as a sole agent increased from 2% to 39%, and combined therapy increased from 0% to 10%. Use of 3% hypertonic saline alone was associated with a higher mortality than mannitol alone (adjusted odds ratio, 2.71 [95% CI, 1.01-7.26]) in patients treated for cerebral edema. Similar results were obtained after adjustment for the propensity to receive hypertonic saline (adjusted odds ratio, 2.33 [95% CI, 1.07-5.07]) and in the subset of subjects receiving mechanical ventilation (adjusted odds ratio, 3.27 [95% CI, 1.12-9.60]). CONCLUSION: Hypertonic saline has replaced mannitol as the most commonly used agent at many institutions for treatment of cerebral edema in diabetic ketoacidosis. In our analysis, however, use of hypertonic saline as a sole agent was associated with an increased risk of mortality. Recognizing the limitations of administrative data, we conclude that equipoise regarding choice of therapy for treatment of cerebral edema in diabetic ketoacidosis should be maintained until a more definitive study is performed to guide therapy of this potentially lethal complication.

Design and rationale of safe pediatric euglycemia after cardiac surgery: a randomized controlled trial of tight glycemic control after pediatric cardiac surgery.

OBJECTIVES: To describe the design of a clinical trial testing the hypothesis that children randomized to tight glycemic control with intensive insulin therapy after cardiac surgery will have improved clinical outcomes compared to children randomized to conventional blood glucose management. DESIGN: Two-center, randomized controlled trial. SETTING: Cardiac ICUs at two large academic pediatric centers. PATIENTS: Children from birth to those aged 36 months recovering in the cardiac ICU after surgery with cardiopulmonary bypass. INTERVENTIONS: Subjects in the tight glycemic control (intervention) group receive an intravenous insulin infusion titrated to achieve normoglycemia (target blood glucose range of 80-110 mg/dL; 4.4-6.1 mmol/L). The intervention begins at admission to the cardiac ICU from the operating room and terminates when the patient is ready for discharge from the ICU. Continuous glucose monitoring is performed during insulin infusion to minimize the risks of hypoglycemia. The standard care group has no target blood glucose range. MEASUREMENTS AND MAIN RESULTS: The primary outcome is the development of any nosocomial infection (bloodstream, urinary tract, and surgical site infection or nosocomial pneumonia). Secondary outcomes include mortality, measures of cardiorespiratory function and recovery, laboratory indices of nutritional balance, immunologic, endocrinologic, and neurologic function, cardiac ICU and hospital length of stay, and neurodevelopmental outcome at 1 and 3 yrs of age. A total of 980 subjects will be enrolled (490 in each treatment arm) for sufficient power to show a 50% reduction in the prevalence of the primary outcome. CONCLUSIONS: Pediatric cardiac surgery patients may recognize great benefit from tight glycemic control in the postoperative period, particularly with regard to reduction of nosocomial infections. The Safe Pediatric Euglycemia after Cardiac Surgery trial is designed to provide an unbiased answer to the question of whether this therapy is indeed beneficial and to define the associated risks of therapy.

Cardiac parameters in children recovered from acute illness as measured by electrical cardiometry and comparisons to the literature.

Electrical cardiometry (EC) is a non-invasive cardiac output method that can assess cardiac index (CI) and stroke index (SI) but there are no reference values for children per se. The primary aim of this study was to develop reference values for clinical application. The secondary aim was to compare the EC measurements to published values. We performed a prospective observational study in patients (<21 years of age) without structural heart disease who had recovered from an acute illness. EC recordings in children that had normal heart rate and mean arterial blood pressure at discharge were eligible for analysis. The relationship of CI or SI and age in children was performed by regression analysis. Similar analysis was performed comparing measurements by EC to cardiac parameters values compiled from reference sources to assess bias in EC. Eighty-three children (2 weeks-21 years of age) were studied. There was a significant curvilinear relationship between CI or SI and age by EC (F-test, p < 0.05). Regression curves of cardiac parameters reported in the literature using 6 Fick's method, thermodilution, echocardiography and cardiac MRI were the same or higher than (0-19.6 %) values obtained with EC, with higher values being statistically significant (p < 0.05 all). There is a curvilinear relationship of CI or SI and age by EC in normal children. Cardiac parameters reported in the literature using alternative methods are different from those obtained with EC but are within acceptable ranges, with EC biased to underestimate CI. Adjustment of target value is required for EC goal-directed therapies.

Ultrasound-guided retrobulbar nerve block in horses: a cadaveric study.

OBJECTIVE: To develop an ultrasound-guided technique for retrobulbar nerve block in horses, and to compare the distribution of three different volumes of injected contrast medium (CM) (4, 8 and 12 mL), with the hypothesis that successful placement of the needle within the retractor bulbi muscle cone would lead to the most effective dispersal of CM towards the nerves leaving the orbital fissure. STUDY DESIGN: Prospective experimental cadaver study. ANIMALS: Twenty equine cadavers. METHODS: Ultrasound-guided retrobulbar injections were performed in 40 cadaver orbits. Ultrasound visualization of needle placement within the retractor bulbi muscle cone and spread of injected CM towards the orbital fissure were scored. Needle position and destination of CM were then assessed using computerized tomography (CT), and comparisons performed between ultrasonographic visualization of orbital structures and success rate of injections (intraconal needle placement, CM reaching the orbital fissure). RESULTS: Higher scores for ultrasound visualization resulted in a higher success rate for intraconal CM injection, as documented on the CT images. Successful intraconal placement of the needle (22/34 orbits) resulted in CM always reaching the orbital fissure. CM also reached the orbital fissure in six orbits where needle placement was extraconal. With 4, 8 and 12 mL CM, the orbital fissure was reached in 16/34, 23/34 and 28/34 injections, respectively. CONCLUSION AND CLINICAL RELEVANCE: The present study demonstrates the use of ultrasound for visualization of anatomical structures and needle placement during retrobulbar injections in equine orbits. However, this approach needs to be repeated in controlled clinical trials to assess practicability and effectiveness in clinical practice.

A randomized trial of population-based clinical decision support to manage health and resource use for Medicaid beneficiaries.

To determine whether a clinical decision support system can favorably impact the delivery of emergency department and hospital services. Randomized clinical trial of three clinical decision support delivery modalities: email messages to care managers (email), printed reports to clinic administrators (report) and letters to patients (letter) conducted among 20,180 Medicaid beneficiaries in Durham County, North Carolina with follow-up through 9 months. Patients in the email group had fewer low-severity emergency department encounters vs. controls (8.1 vs. 10.6/100 enrollees, p < 0.001) with no increase in outpatient encounters or medical costs. Patients in the letter group had more outpatient encounters and greater outpatient and total medical costs. There were no treatment-related differences for patients in the reports group. Among patients <18 years, those in the email group had fewer low severity (7.6 vs. 10.6/100 enrollees, p < 0.001) and total emergency department encounters (18.3 vs. 23.5/100 enrollees, p < 0.001), and lower emergency department ($63 vs. $89, p = 0.002) and total medical costs ($1,736 vs. $2,207, p = 0.009). Patients who were ≥18 years in the letter group had greater outpatient medical costs. There were no intervention-related differences in patient-reported assessments of quality of life and medical care received. The effectiveness of clinical decision support messaging depended upon the delivery modality and patient age. Health IT interventions must be carefully evaluated to ensure that the resultant outcomes are aligned with expectations as interventions can have differing effects on clinical and economic outcomes.