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OBJECTIVEThe T1GER (A Study of SIMPONI to Arrest β-Cell Loss in Type 1 Diabetes) study showed many metabolic benefits of the tumor necrosis factor-α blocker golimumab in children and young adults with type 1 diabetes (T1D). Off-therapy effects are reported.RESEARCH DESIGNS AND METHODST1GER was a phase 2, placebo-controlled, randomized trial in which golimumab or placebo was administered for 52 weeks to participants 6–21 years old diagnosed with T1D within 100 days of randomization. Assessments occurred during the 52-week on-therapy and 52-week off-therapy periods.RESULTSAfter treatment was stopped, C-peptide area under the curve (AUC) remained greater in the treatment versus control group. At weeks 78 and 104, the golimumab group had lower reductions in the 4-h C-peptide AUC baseline than the placebo group, where specifically the golimumab group had reductions of 0.31 and 0.41 nmol/L, and the placebo group had reductions of 0.64 and 0.74 nmol/L. There were also trends in less insulin use, higher peak C-peptide levels and those in partial remission, and higher peak C-peptide levels in the golimumab group. Golimumab responders, defined as having an increase or minimal loss of C-peptide AUC and/or being in partial remission at week 52, showed even greater improvements in most metabolic parameters on and off therapy and had less hypoglycemia during the off-therapy period versus placebo. Adverse events, including infections, were similar between the groups during all time periods of the study.CONCLUSIONSIn children and young adults with new-onset T1D, golimumab preserved endogenous β-cell function and resulted in other favorable metabolic parameters on and off therapy. A subpopulation had disease stabilization while on therapy, with improved metabolic parameters off therapy.

Type 1 diabetes is an autoimmune disease characterized by progressive loss of pancreatic beta cells. Golimumab is a human monoclonal antibody specific for tumor necrosis factorIn this phase 2, multicenter, placebo-controlled, double-blind, parallel-group trial, we randomly assigned, in a 2:1 ratio, children and young adults (age range, 6 to 21 years) with newly diagnosed overt type 1 diabetes to receive subcutaneous golimumab or placebo for 52 weeks. The primary end point was endogenous insulin production, as assessed according to the area under the concentration-time curve for C-peptide level in response to a 4-hour mixed-meal tolerance test (4-hour C-peptide AUC) at week 52. Secondary and additional end points included insulin use, the glycated hemoglobin level, the number of hypoglycemic events, the ratio of fasting proinsulin to C-peptide over time, and response profile.A total of 84 participants underwent randomization - 56 were assigned to the golimumab group and 28 to the placebo group. The mean (±SD) 4-hour C-peptide AUC at week 52 differed significantly between the golimumab group and the placebo group (0.64±0.42 pmol per milliliter vs. 0.43±0.39 pmol per milliliter, P0.001). A treat-to-target approach led to good glycemic control in both groups, and there was no significant difference between the groups in glycated hemoglobin level. Insulin use was lower with golimumab than with placebo. A partial-remission response (defined as an insulin dose-adjusted glycated hemoglobin level score [calculated as the glycated hemoglobin level plus 4 times the insulin dose] of ≤9) was observed in 43% of participants in the golimumab group and in 7% of those in the placebo group (difference, 36 percentage points; 95% CI, 22 to 55). The mean number of hypoglycemic events did not differ between the trial groups. Hypoglycemic events that were recorded as adverse events at the discretion of investigators were reported in 13 participants (23%) in the golimumab group and in 2 (7%) of those in the placebo group. Antibodies to golimumab were detected in 30 participants who received the drug; 29 had antibody titers lower than 1:1000, of whom 12 had positive results for neutralizing antibodies.Among children and young adults with newly diagnosed overt type 1 diabetes, golimumab resulted in better endogenous insulin production and less exogenous insulin use than placebo. (Funded by Janssen Research and Development; T1GER ClinicalTrials.gov number, NCT02846545.).

T1D is an autoimmune disease characterized by progressive loss of pancreatic β cells. GLM is a human IgG1κ monoclonal antibody specific for tumor necrosis factor α. This study assessed whether GLM preserves β-cell function in children and young adults with newly diagnosed stage 3 T1D. This Phase 2a, double-blind, placebo (PBO)-controlled study randomized participants aged 6-21 yrs with newly diagnosed stage 3 T1D to receive subcutaneous GLM (BSA-based dose if 84 participants were enrolled (GLM, n = 56; PBO, n = 28). The study was positive as mean (SD) 4-hour C-peptide AUC at Week 52 was 0.64 (0.423) and 0.43 (0.388) pmol/mL with GLM and PBO, respectively (P In this study, golimumab demonstrated the ability to preserve endogenous insulin production and improve clinical and metabolic parameters in children and young adults with newly diagnosed stage 3 T1D. Disclosure T. Quattrin: Consultant; Self; Janssen Pharmaceuticals, Inc. Research Support; Self; Janssen Pharmaceuticals, Inc., Provention Bio, Inc. M.J. Haller: Advisory Panel; Self; SAB Biotherapeutics, Inc. A. Steck: None. E. Felner: None. Y. Li: Employee; Self; Janssen Research & Development, LLC. K. Xia: Employee; Self; Janssen Research & Development, LLC. J. Leu: Employee; Self; Janssen Research & Development, LLC. M. Rigby: None. R. Zoka: Employee; Self; Janssen Research & Development, LLC. J. Hedrick: Employee; Self; Janssen Pharmaceuticals, Inc. F. Vercruysse: Employee; Self; Janssen Pharmaceuticals, Inc. Stock/Shareholder; Self; Johnson & Johnson. Funding Janssen Research & Development, LLC

Re-exposure to beta cell autoantigens and its relevance in the presence of donor-specific antibodies (DSA) in pancreatic allograft recipients is not well known. Thirty-three patients requiring a pancreas transplant were enrolled in an IRB approved study. They underwent prospective monitoring for DSA and beta cell autoantibody (BCAA) levels to GAD65, insulinoma-associated antigen 2 (IA-2), insulin (micro-IAA [mIAA]), and islet-specific zinc transporter isoform-8 (ZnT8). Twenty-five (75.7%) had pre-transplant BCAA. Twenty had a single antibody (mIAA n = 15, GAD65 n = 5); five had two or more BCAA (GAD65 + mIAA n = 2, GAD65 + mIAA+IA-2 n = 2, GA65 + mIAA+IA-2 + ZnT8 = 1). No changes in GAD65 (p > 0.29), IA-2 (>0.16), and ZnT8 (p > 0.07) were observed between pre-transplant and post-transplant at 6 or 12 months. A decrease in mIAA from pre- to post-6 months (p < 0.0001), 12 months (p < 0.0001), and from post-6 to post-12 months (p = 0.0002) was seen. No new BCAA was observed at one yr. Seven (21.0%) developed de novo DSA. The incidence of DSA was 24% in patients with BCAA vs. 25% in patients without BCAA (p = 0.69). Pancreatic allograft function of patients with vs. without BCAA, and with and without BCAA + DSA was comparable until last follow-up (three yr). Re-exposure to beta cell autoantigens by pancreas transplant may not lead to increased levels or development of new BCAA or pancreatic allograft dysfunction.

Our aim is to determine indicators of survival in children with severe hypoxic respiratory failure (HRF) after transition to high-frequency oscillatory ventilation (HFOV). Single-center retrospective examination of children with HRF transitioned to HFOV. Blood gases and ventilator settings 24 hours prior to and 48 hours after HFOV in survivors and nonsurvivors were evaluated. Sixty-two children with mean age of 7 years and mean weight of 26 kg were included with an observed mortality of 29%. Mean airway pressures (Paw), oxygenation index (OI), arterial oxygen partial pressure (PaO(2))/fraction of inspired oxygen (FiO(2)) (P/F) ratio, pH, bicarbonate, and arterial carbon dioxide partial pressure were similar prior to HFOV in survivors and nonsurvivors. During HFOV, mean OI and P/F ratio improved in both groups with an average Paw increase of ∼10 cm H(2)O. Survivors had lower OI than nonsurvivors (21 ± 0.9 vs. 26.5 ± 2.2; p 200. Survivors had higher pH than nonsurvivors at 36 hours (7.40 ± 0.01 vs. 7.32 ± 0.02; p

Although insulin is lifesaving and sustaining for those with type 1 diabetes (T1D), curing the disease will be much more complex than simple replacement of this hormone. T1D is an autoimmune disease orchestrated by T cells, and includes many arms of the immune response. Tremendous effort has gone into understanding its underlying immune, genetic, and environmental causes, and this progress has led to immunologically based clinical trials in T1D. This review will focus primarily on the clinical trials of the past decade that have attempted to translate these fundamental findings.It is known that powerful, nonspecific immune suppressants can temporarily slow the course of newly diagnosed T1D, yet are too toxic for long-term use, especially in children. Recent clinical trials to reverse T1D have used newly developed therapies that target specific components of the immune process believed to be involved with T1D. Although well justified and designed, no recent approach has resulted in clinical remission and few have had any effect on disease course.Advances in our fundamental understanding of how the human diabetes immune response is activated and regulated coupled with lessons that have been learnt from the most recent era of completed trials are guiding us toward the development of more effective, multipronged therapies to ablate diabetes autoimmunity, restore immune tolerance, preserve β cells, and, ultimately, improve the lives of patients with T1D.

Mixed-meal tolerance tests (MMTTs) are used in clinical trials to evaluate β-cell function in patients with new-onset type 1 diabetes (1,2). Some trials use a 4-h MMTT, whereas others use an abbreviated (2-h) protocol to reduce investigator and subject burden. In the T1DAL (Inducing Remission in Type 1 Diabetes With Alefacept) trial of patients with new-onset type 1 diabetes, the primary analysis using the 2-h test failed to reach statistical significance ( P = 0.065), but a 4-h test did ( P = 0.019) (3). We investigated the effect of abbreviating the test using data from 186 patients participating in three clinical trials conducted by the Immune Tolerance Network (3–5). Trials were approved by institutional review boards at the participating institutions. Written informed consent or assent was obtained. Each patient contributed up to three 4-h MMTTs, conducted yearly, for a total of 506 paired 2- and 4-h observations. For this analysis, the 4-h assessment, which captures more of the complete hormonal response, was selected as the reference. The percent of the total 4-h C-peptide area under the curve (AUC) captured in the first 2 h ranged from 28% to 72%. Mean AUCs (mAUCs) were computed as 2- or 4-h AUCs divided by duration, 120 or 240 min, respectively. The correlation between the 2- and 4-h mAUCs was 0.98. Generally, the variability of the 2-h test was greater than that of the 4-h test (Fig. 1 A ). After adjusting for baseline, however, the variability was similar. Figure 1 Analysis of 2- and 4-h C-peptide AUCs during MMTTs. The C-peptide …

Summary Background Type 1 diabetes results from autoimmune targeting of the pancreatic β cells, likely mediated by effector memory T (Tem) cells. CD2, a T cell surface protein highly expressed on Tem cells, is targeted by the fusion protein alefacept, depleting Tem cells and central memory T (Tcm) cells. We postulated that alefacept would arrest autoimmunity and preserve residual β cells in patients newly diagnosed with type 1 diabetes. Methods The T1DAL study is a phase 2, double-blind, placebo-controlled trial in patients with type 1 diabetes, aged 12–35 years who, within 100 days of diagnosis, were enrolled at 14 US sites. Patients were randomly assigned (2:1) to receive alefacept (two 12-week courses of 15 mg intramuscularly per week, separated by a 12-week pause) or a placebo. Randomisation was stratified by site, and was computer-generated with permuted blocks of three patients per block. All participants and site personnel were masked to treatment assignment. The primary endpoint was the change from baseline in mean 2 h C-peptide area under the curve (AUC) at 12 months. Secondary endpoints at 12 months were the change from baseline in the 4 h C-peptide AUC, insulin use, major hypoglycaemic events, and HbA 1c concentrations. This trial is registered with ClinicalTrials.gov, number NCT00965458. Findings Of 73 patients assessed for eligibility, 33 were randomly assigned to receive alefacept and 16 to receive placebo. The mean 2 h C-peptide AUC at 12 months increased by 0·015 nmol/L (95% CI −0·080 to 0·110) in the alefacept group and decreased by 0·115 nmol/L (–0·278 to 0·047) in the placebo group, and the difference between groups was not significant (p=0·065). However, key secondary endpoints were met: the mean 4 h C-peptide AUC was significantly higher (mean increase of 0·015 nmol/L [95% CI −0·076 to 0·106] vs decrease of −0·156 nmol/L [–0·305 to −0·006]; p=0·019), and daily insulin use (0·48 units per kg per day for placebo vs 0·36 units per kg per day for alefacept; p=0·02) and the rate of hypoglycaemic events (mean of 10·9 events per person per year for alefacept vs 17·3 events for placebo; p 1c concentrations at week 52 were not different between treatment groups (p=0·75). So far, no serious adverse events were reported and all patients had at least one adverse event. In the alefacept group, 29 (88%) participants had an adverse event related to study drug versus 15 (94%) participants in the placebo group. In the alefacept group, 14 (42%) participants had grade 3 or 4 adverse events compared with nine (56%) participants in the placebo group; no deaths occurred. Interpretation Although the primary outcome was not met, at 12 months, alefacept preserved the 4 h C-peptide AUC, lowered insulin use, and reduced hypoglycaemic events, suggesting efficacy. Safety and tolerability were similar in the alefacept and placebo groups. Alefacept could be useful to preserve β-cell function in patients with new-onset type 1 diabetes. Funding US National Institutes of Health and the Juvenile Diabetes Research Foundation.

Background: Type 1 diabetes results from T-cell-mediated destruction of β cells. Findings from preclinical studies and pilot clinical trials suggest that antithymocyte globulin (ATG) might be effective for reducing this autoimmune response. We assessed the safety and efficacy of rabbit ATG in preserving islet function in participants with recent-onset type 1 diabetes, and report here our 12-month results. Methods: For this phase 2, randomised, placebo-controlled, clinical trial, we enrolled patients with recent-onset type 1 diabetes, aged 12-35 years, and with a peak C-peptide of 0·;4 nM or greater on mixed meal tolerance test from 11 sites in the USA. We used a computer generated randomisation sequence to randomly assign patients (2:1, with permuted-blocks of size three or six and stratified by study site) to receive either 6·;5 mg/kg ATG or placebo over a course of four days. All participants were masked and initially managed by an unmasked drug management team, which managed all aspects of the study until month 3. Thereafter, to maintain masking for diabetes management throughout the remainder of the study, participants received diabetes management from an independent, masked study physician and nurse educator. The primary endpoint was the baseline-adjusted change in 2-h area under the curve C-peptide response to mixed meal tolerance test from baseline to 12 months. Analyses were by intention to treat. This is a planned interim analysis of an on-going trial that will run for 24 months of follow-up. This study is registered with ClinicalTrials.gov, number NCT00515099. Findings: Between Sept 10, 2007, and June 1, 2011, we screened 154 individuals, randomly allocating 38 to ATG and 20 to placebo. We recorded no between-group difference in the primary endpoint: participants in the ATG group had a mean change in C-peptide area under the curve of -0·;195 pmol/mL (95% CI -0·;292 to -0·;098) and those in the placebo group had a mean change of -0·;239 pmol/mL (-0·;361 to -0·;118) in the placebo group (p=0·;591). All except one participant in the ATG group had both cytokine release syndrome and serum sickness, which was associated with a transient rise in interleukin-6 and acute-phase proteins. Acute T cell depletion occurred in the ATG group, with slow reconstitution over 12 months. However, effector memory T cells were not depleted, and the ratio of regulatory to effector memory T cells declined in the first 6 months and stabilised thereafter. ATG-treated patients had 159 grade 3-4 adverse events, many associated with T-cell depletion, compared with 13 in the placebo group, but we detected no between-group difference in incidence of infectious diseases. Interpretation: Our findings suggest that a brief course of ATG does not result in preservation of β-cell function 12 months later in patients with new-onset type 1 diabetes. Generalised T-cell depletion in the absence of specific depletion of effector memory T cells and preservation of regulatory T cells seems to be an ineffective treatment for type 1 diabetes. Funding: US National Institutes of Health and the Juvenile Diabetes Research Foundation. © 2013 Elsevier Ltd.

Objective: To evaluate the literature and identify important aspects of insulin therapy that facilitate safe and effective infusion therapy for a defined glycemic end point. Methods: Where available, the literature was evaluated using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology to assess the impact of insulin infusions on outcome for general intensive care unit patients and those in specific subsets of neurologic injury, traumatic injury, and cardiovascular surgery. Elements that contribute to safe and effective insulin infusion therapy were determined through literature review and expert opinion. The majority of the literature supporting the use of insulin infusion therapy for critically ill patients lacks adequate strength to support more than weak recommendations, termed suggestions, such that the difference between desirable and undesirable effect of a given intervention is not always clear. Recommendations: The article is focused on a suggested glycemic control end point such that a blood glucose ≥150 mg/dL triggers interventions to maintain blood glucose below that level and absolutely

Type 1 diabetes mellitus (T1DM) is a T cell-mediated autoimmune disease resulting in islet β cell destruction, hypoinsulinemia, and severely altered glucose homeostasis. T1DM has classically been attributed to the pathogenic actions of auto-reactive effector T cells (Teffs) on the β cell. Recent literature now suggests that a failure of a second T cell subtype, known as regulatory T cells (Tregs), plays a critical role in the development of T1DM. During immune homeostasis, Tregs counterbalance the actions of autoreactive Teff cells, thereby participating in peripheral tolerance. An imbalance in the activity between Teff and Tregs may be crucial in the breakdown of peripheral tolerance, leading to the development of T1DM. In this review, we summarize our current understanding of Treg function in health and in T1DM, and examine the effect of experimental therapies for T1DM on Treg cell number and function in both mice and humans.

Purpose of review In a relatively short time, advances in both basic science and clinical medicine have revolutionized the way we understand disease processes and suggested novel approaches that may be able to be used to treat or cure some of the most relevant human afflictions. In type 1 diabetes, one unintended consequence of this has been the polarization of the investigational groups (i.e., immunologists and endocrinologists) interested in developing novel therapies for this condition. This review will examine how and why such polarization exists, and why past and current approaches to develop critically needed translational investigators may be falling short. Recent findings Despite significant efforts to increase the number of individuals trained in both basic science and clinical medicine, the number of academic physician–scientists is on the decline. Increased demands from academic institutions coupled with severe difficultly in securing extramural funding are probably playing important roles in this concerning trend. Summary Type 1 diabetes will continue to be a significant strain on individuals, their families and society until a cure is found. More than ever, there is a critical need to support appropriately trained translational investigators who can best facilitate bringing the promise of basic research to clinical reality.

Objective To determine which children are susceptible to critical illness hyperglycemia (CIH) and whether CIH severity and duration correlate with diagnosis or illness severity. Study design We developed a standard approach to identify and treat CIH in our medical/surgical pediatric intensive care unit. We define CIH as persistent blood glucose (BG) >140 mg/dL and titrate infused insulin to maintain BG 80 to 140 mg/dL. We conducted a retrospective analysis of patients with hyperglycemia from June 2006 through May 2007. Main outcomes were risk of development of CIH in different patient subgroups and CIH severity and duration. Results Average peak BG, CIH duration, and peak insulin requirements were 199 mg/dL, 6.3 days, and 0.09 units/kg/h, respectively, in patients with CIH. CIH severity and duration were highest in neurosurgical and patients with sepsis, those requiring mechanical ventilation and vasopressors, extracorporeal support, and those with highest illness severity scores. Conclusions CIH severity and duration correlate with diagnosis and illness severity. Certain "risk factors" may be predictive of who develops CIH.

Background. Despite advances in the field of lung transplantation, the median survival after lung transplant remains below 5 years. Early rejection is a risk factor for the development of chronic rejection. In animal models of transplant tolerance, regulatory T cells (Tregs) can prevent the establishment of rejection. Methods. This study was designed to explore the dynamics of Tregs focally and systemically in lung transplant recipients. Sequential surveillance bronchoscopy results were available in 51 patients with at least four sequential samples recovered from each patient at defined times posttransplant. In 36 individuals, a complete year of follow-up data for BAL was analyzed. In 33 of these individuals had a complete year of follow-up data for peripheral blood monocyte cell specimens were also analyzed. Lung lavage cells were recovered from each bronchoscopy and corresponding blood draw and subjected to polychromatic flow cytometry. The percentage of CD4 lymphocytes, which expressed the intracellular transcription factor FoxP3 was recorded at each point. At each time point, lung biopsy specimens were scored for rejection. Results. Lung Treg frequency was significantly more variable than blood Treg frequency. Treg frequency in the lung was increased in the aftermath of acute rejection. In contrast, lung Treg frequency declined sequentially in patients demonstrating continued quiescence. Mean BAL Treg level integrated over the first transplant year correlated inversely with the degree of acute cellular rejection. In contrast, blood Treg levels demonstrated no correlation with lung pathology. Conclusions. Lung Tregs increase in the setting of acute cellular rejection, whereas declining levels of BAL Tregs correlates with immunologic quiescence.

To evaluate the success and dosing requirements of propofol in children for prolonged procedural sedation by a nonanesthesiology-based sedation service.The pediatric sedation service at this institution uses propofol as its preferred sedative, and the local guideline suggests using 3 mg/kg for induction and 5 mg kg(-1) h(-1) for maintenance sedation. Doses can be adjusted as needed to individualize successful sedation. A retrospective analysis of patients sedated for 30 minutes or longer was conducted. Patients were stratified into 4 cohorts based on age (1 year [n = 16], 1-2 years [n = 85], 3-7 years [n = 54], and7 years [n = 55]) and dosing patterns, success, and adverse effects were investigated.Two hundred forty-nine patients met the inclusion criteria. Mean age was 4.8 years (SD, 4.1). The mean induction dose was 3.2 mg/kg (range, 0.9-9.7), and the mean maintenance infusion was 5.2 mg kg(-1) h(-1) (range, 0.14-21.3). No differences were seen in the induction doses in the different age cohorts, yet the SD was largest in the youngest cohort compared to any other. Although no differences were seen in maintenance rates by age, the greatest SD for dosing was seen in the oldest cohort. For all ages, all sedations were successful (100%) and unanticipated adverse effects rare (1%).Although it seems that the mean dosing of propofol does not vary significantly with age, there is greater variability in induction dosage for those younger than 1 year and in maintenance dosing for those 7 years or older. The results and general dosing parameters may assist pediatric subspecialists in using propofol for prolonged procedural sedation.

To determine whether ultrasound (US) increases successful central venous catheter (CVC) placement, decreases site attempts, and decreases CVC placement complications.A prospective observational cohort study evaluating a transition by the Pediatric Critical Care Medicine service to US-guided CVC placement. Medical and surgical patients in a 21-bed quaternary multidisciplinary pediatric intensive care unit had CVCs placed by attendings, fellows, residents, and a nurse practitioner.Ninety-three patients were prospectively enrolled into the landmark (LM) group and 119 into the US group.: After collection of prospective LM data, training with US guidance was provided. CVCs were subsequently placed with US guidance.Operator information, disease process, emergent/routine, sites attempted, and complications were recorded. Procedure time was from initial skin puncture to guidewire placement. There was no difference overall in success rates (88.2% LM vs. 90.8% US, p = 0.54) or time to successful placement (median seconds 269 LM vs. 150 US, p = 0.14) between the two groups. Median number of attempts were fewer with US for all CVCs attempted (3 vs. 1, p0.001) as were attempts at1 anatomical site (20.7% LM vs. 5.9% US, p = 0.001). Use of US was associated with fewer inadvertent artery punctures (8.5% vs. 19.4%, p = 0.03). Time to successful placement by residents was decreased with US (median 919 seconds vs. 405 seconds, p = 0.02). More internal jugular CVCs were placed during the US period than during the LM period (13.4% vs. 2.1%).US-guided CVC placement in children is associated with decreased number of anatomical sites attempted and decreased number of attempts to gain placement. Time to placement by residents was decreased with US, but not the time to placement by other operators. US guidance increased the use of internal jugular catheter placement and decreased artery punctures. US guidance did not improve success rates.

Hyperglycemia is a risk factor for poor outcome in critically ill patients, and glycemic control may decrease morbidity and mortality in adults. There is limited information regarding hyperglycemia and its control in pediatric intensive care.To determine prevalence and risk factors for hyperglycemia and evaluate our approach to glycemic control in critically ill children. DESIGN, SETTING, PATIENTS, AND MAIN OUTCOMES: A pediatric-specific protocol to identify and manage hyperglycemia was developed and instituted as standard practice in our pediatric intensive care unit, and was applicable to patients6 months and5 kg, without end-stage liver disease or type 1 diabetes mellitus. Triggers for routine blood glucose assessment were based on supportive measures including mechanical ventilation, vasopressor/inotrope infusions, and antihypertensive infusions. Hyperglycemic patients, defined by two consecutive blood glucose readings of140 mg/dL (7.7 mmol/L), were treated with infused insulin to maintain blood glucose levels 80-140 mg/dL (4.4-7.7 mmol/L). We performed retrospective analysis 6 months after instituting this approach. Main outcomes were prevalence and risk factors for hyperglycemia, and effectiveness of our approach to achieve glycemic control.None.One hundred forty-five of 477 patients had blood glucose actively assessed, and 74 developed hyperglycemia and were managed with insulin. This approach to identify patients with hyperglycemia had a positive predictive value of 51% and negative predictive value of 94%. Hyperglycemia prevalence was 20%. Mechanical ventilation, vasopressor/inotropic infusion, continuous renal replacement therapy, high illness severity scores, and longer lengths of stay were associated with hyperglycemia. The average blood glucose of patients with hyperglycemia was 200 mg/dL (11 mmol/L), and on average, patients were treated with insulin for 6.3 days with 2.4 units/kg/day. Blood glucose levels were160 mg/dL (8.8 mmol/L) in 70% of insulin-treated days, 80-140 mg/dL (4.4-7.7 mmol/L) in 49% of insulin-treated days, and 4% of insulin-treated patients had any blood glucose measurements40 mg/dL (2.2 mmol/L).Hyperglycemia is prevalent in pediatric intensive care units and may be effectively identified and managed using a protocolized approach.

OBJECTIVE—Blocking T-cell signaling is an effective means to prevent autoimmunity and allograft rejection in many animal models, yet the clinical translation of many of these approaches has not resulted in the success witnessed in experimental systems. Improved understanding of these approaches may assist in developing safe and effective means to treat disorders such as autoimmune diabetes.RESEARCH DESIGN AND METHODS—We studied the effect of anti-CD154 and CTLA4-Ig on diabetes development, and the requirements to induce tolerance in nod.scid mice after transfer of transgenic β-cell reactive BDC2.5.NOD T-cells.RESULTS—Nod.scid recipients of diabetogenic BDC2.5.NOD cells were protected indefinitely from diabetes by a short course of combined costimulation blockade, despite the continued diabetogenic potential of their T-cells. The presence of pathogenic T-cells in the absence of disease indicates peripheral immune tolerance. T-cell maturation occurred in protected recipients, yet costimulation blockade temporarily blunted early T-cell proliferation in draining pancreatic nodes. Tolerance required preexisting regulatory T-cells (Tregs), and protected recipients had greater numbers of Tregs than diabetic recipients. Diabetes protection was successful in the presence of homeostatic expansion and high T-cell precursor frequency, both obstacles to tolerance induction in other models of antigen-specific immunity.CONCLUSIONS—Immunotherapies that selectively suppress effector T-cells while permitting the development of natural regulatory mechanisms may have a unique role in establishing targeted long-standing immune protection and peripheral tolerance. Understanding the mechanism of these approaches may assist in the design and use of therapies for human conditions, such as type 1 diabetes.

This article reviews selected issues of endocrine concerns in the pediatric intensive care unit, exclusive of diabetic ketoacidosis. The sympathoadrenergic arm of the neuroendocrine stress response is described, followed by discussions of two topics of particular current concern: critical illness hyperglycemia and relative adrenal insufficiency. A selected set of common scenarios encountered in the daily practice of intensive care follows.

In natural history studies, maintenance of higher levels of C-peptide secretion (a measure of endogenous insulin production) correlates with a lower incidence of major hypoglycemic events in patients with type 1 diabetes mellitus (T1D), but it is unclear whether this is also true for drug-induced C-peptide preservation.We analyzed hypoglycemic events and glycemic control data from the T1DAL (Inducing Remission in New-Onset T1D with Alefacept) study, a trial of alefacept in new-onset T1D, which found significant C-peptide preservation at 1 and 2 years. We performed a post hoc analysis using mixed models of the association between the meal-stimulated 4-hour C-peptide AUC (4-hour AUC) and rates of major hypoglycemia, measures of glycemic control (glycosylated hemoglobin [HbA1c]; mean glucometer readings), and variability (glucometer SDs; highest and lowest readings), and an index of partial remission (insulin dose-adjusted HbA1c[ IDAA1c]).Data from 49 participants (33 in the alefacept group and 16 in the placebo group) were analyzed at baseline and 12 and 24 months. We found that the 4-hour AUC at baseline and at 1 year was a significant predictor of the number of hypoglycemic events during the ensuing 12-month interval (p = 0.030). There was a strong association between the 4-hour AUC and glucometer SDs (P0.001), highest readings (p0.001), and lowest readings (p = 0.03), all measures of glycemic variability. There was a strong inverse correlation between the 4-hour AUC and 2 measures of glycemic control: HbA1c and mean glucometer readings (both p0.001). There was also a strong inverse correlation between the 4-hour AUC and IDAA1c values (p0.001), as well as a strong correlation between IDAA1c values and glucometer SDs (p0.001), suggesting that reduced glycemic variability is associated with a trend toward partial remission. None of these analyses found a significant difference between the alefacept and placebo groups.Measures of glycemic variability and control, including rates of hypoglycemia, are significantly correlated with preservation of C-peptide regardless of whether this is achieved by immune intervention with alefacept or natural variability in patients with new-onset T1D. Thus, preservation of endogenous insulin production by an immunomodulatory drug may confer clinical benefits similar to those seen in patients with higher C-peptide secretion due to slow disease progression.

Background. Immature dendritic cells (DC) can promote long-term transplant survival in rodents. We assessed the impact of stably immature, donor-derived DC on alloimmune reactivity in rhesus macaques. Methods. CD14 + monocytes isolated from leukapheresis products of Macacca mulatta were cultured in granulocyte-macrophage colony stimulating factor plus interleukin (IL)-4 ± vitamin (vit) D3, and IL-10. Major histocompatibility complex class II and cosignaling molecule expression was determined on CD11c + cells by flow cytometry. T-cell allostimulatory capacity of the DC, including DC exposed to proinflammatory cytokines, was determined in mixed leukocyte reaction. To test their influence in vivo, purified DC were infused intravenously into allogeneic recipients, either alone or followed by CTLA4Ig, 24 hr later. Proliferative responses of recipient CFSE-labeled T cells to donor or third party DC, cytokine production by stimulated T cells, and circulating alloantibody levels were determined by flow cytometry, up to 100 days postinfusion. Results. VitD3/IL-10-conditioned, monocyte-derived DC were resistant to maturation and failed to induce allogeneic T cell proliferation in vitro. After their infusion, an increase in anti-donor and anti-third party T-cell reactivity was observed, that subsequently subsided to fall significantly below pretreatment levels (by day 56) only in animals also given CTLA4Ig. No increase in circulating immunoglobulin (Ig) M or IgG anti-donor alloantibody titers compared with pretreatment values was detected. With DC+CTLA4Ig infusion, alloreactive IL-10-producing T cells were prevalent in the circulation after day 28. Conclusions. Maturation-resistant rhesus DC infusion is well-tolerated. DC + CTLA4Ig infusion modulates allogeneic T-cell responses and results in hyporesponsiveness to donor and third party alloantigens.

A strategy for producing high-level hematopoietic chimerism after non-myeloablative conditioning has been established in the rhesus macaque. This strategy relies on hematopoietic stem cell transplantation after induction with a non-myeloablative dose of busulfan and blockade of the IL2-receptor in the setting of mTOR inhibition with sirolimus and combined CD28/CD154 costimulation blockade. Hematopoietic stem cells derived from bone marrow and leukopheresis products both were found to be successful in inducing high-level chimerism. Mean peripheral blood peak donor chimerism was 81% with a median chimerism duration of 145 days. Additional immune modulation strategies, such as pre-transplant CD8 depletion, donor-specific transfusion, recipient thymectomy or peritransplant deoxyspergualin treatment did not improve the level or durability of chimerism. Recipient immunologic assessment suggested that chimerism occurred amidst donor-specific down-regulation of alloreactive T cells, and the reappearance of vigorous T-mediated alloreactivity accompanied rejection of the transplants. Furthermore, viral reactivation constituted a significant transplant-related toxicity and may have negatively impacted the ability to achieve indefinite survival of transplanted stem cells. Nevertheless, this chimerism-induction regimen induced amongst the longest-lived stem cell chimerism reported to date for non-human primates and thus represents a platform upon which to evaluate emerging tolerance-induction strategies.

Type 1 diabetes (T1D) is a chronic autoimmune disease that leads to progressive destruction of pancreatic beta cells. Compared to healthy controls, a characteristic feature of patients with T1D is the presence of self-reactive T cells with a memory phenotype. These autoreactive memory T cells in both the CD4(+) and CD8(+) compartments are likely to be long-lived, strongly responsive to antigenic stimulation with less dependence on costimulation for activation and clonal expansion, and comparatively resistant to suppression by regulatory T cells (Tregs) or downregulation by immune-modulating agents. Persistence of autoreactive memory T cells likely contributes to the difficulty in preventing disease progression in new-onset T1D and maintaining allogeneic islet transplants by regular immunosuppressive regimens. The majority of immune interventions that have demonstrated some success in preserving beta cell function in the new-onset period have been shown to deplete or modulate memory T cells. Based on these and other considerations, preservation of residual beta cells early after diagnosis or restoration of beta cell mass by use of stem cell or transplantation technology will require a successful strategy to control the autoreactive memory T cell compartment, which could include depletion, inhibition of homeostatic cytokines, induction of hyporesponsiveness, or a combination of these approaches.

In September 2005, an National Institutes of Health-sponsored workshop was held in Atlanta, Georgia, which focused on non-human primate transplantation tolerance models. The aim of this workshop was an open exchange of techniques and assays applicable to this important translational transplantation model. A major focus of the workshop was the development of assays that are capable of monitoring immune status after transplant. These include mixed lymphocyte reaction assays (using both tritiated thymidine and carboxyfluorescein succinimidyl ester to assess T-cell proliferation), large-scale production of dendritic cells for immune analysis, the molecular analysis of graft rejection and acceptance using single-plex RNA analysis, and multiplex flow cytometric and gene array analysis, as well as sophisticated multi-color flow cytometric profiling of immunocyte subpopulations and cytokine expression patterns. This review will summarize the progress presented at the workshop toward the application of these techniques to immune analysis in non-human primates and discuss their relative contributions to ongoing evaluation of immune tolerance after transplantation.

We report syncope and bradycardia in an 11-year-old girl following administration of intranasal dexmedetomidine for sedation for a voiding cystourethrogram. Following successful completion of VCUG and a 60-min recovery period, the patient's level of consciousness and vital signs returned to presedation levels. Upon leaving the sedation area, the patient collapsed, with no apparent inciting event. The patient quickly regained consciousness and no injury occurred. The primary abnormality found was persistent bradycardia, and she was admitted to the hospital for telemetric observation. The bradycardia lasted ~2 h, and further cardiac workup revealed no underlying abnormality. Unanticipated and previously unreported outcomes may be witnessed as we expand the use of certain sedatives to alternative routes of administration.

Objective Examine comparative dosing, efficacy, and safety of propofol alone or with an initial, subdissociative dose of ketamine approach for deep sedation. Background Propofol is a sedative-hypnotic agent used increasingly in children for deep sedation. As a nonanalgesic agent, use in procedures (e.g., bone marrow biopsies/aspirations, renal biopsies) is debated. Our intensivist procedural sedation team sedates using one of two protocols: propofol-only (P-O) approach or age-adjusted dose of 0.25 or 0.5 mg/kg intravenous ketamine (K + P) prior to propofol. With either approach, an initial induction dose of 1 mg/kg propofol is recommended and then intermittent dosing throughout the procedure to achieve adequate sedation to safely and effectively perform the procedure. Approach: Retrospective evaluation of 754 patients receiving either the P-O or K + P approach to sedation. Results A total of 372 P-O group patients and 382 K + P group. Mean age (7.3 ± 5.5 years for P-O; 7.3 ± 5.4 years for K + P) and weight (30.09 ± 23.18 kg for P-O; 30.14 ± 24.45 kg for K + P) were similar in both groups (p = NS). All patients successfully completed procedures with a 16% combined incidence of hypoxia (SPO2

Type 1 diabetes (T1D) results from destruction of pancreatic beta cells by autoreactive effector T cells. We hypothesized that a combination of targeted depletion and modulation of effector T cell activity by alefacept would result in prolonged preservation of endogenous insulin secretion in patients with newly diagnosed T1D. In a multicenter, randomized, double-blind, placebo-controlled trial we compared alefacept (two 12-week courses of 15 mg intramuscularly per week, separated by a 12-week pause) with placebo in patients with new-onset T1D. Endpoints assessed at 24 months included meal-stimulated C-peptide area under the curve (AUC), insulin use, hypoglycemic events, and immunologic responses.

Background: Evaluate patterns in existing cost data for patients with respiratory illness managed in a large academic Pediatric Intensive Care Unit (PICU), with the goal to identify targets for potential cost-management strategies. Methods: Retrospective, observational study of patients admitted to a 34-bed multidisciplinary PICU from October 2011 to September 2012. Study design: Variable direct costs (VDC) for each All Patient Refined Diagnosis Related Group (APR DRG) were obtained from the Decision Support Group and detailed analysis was performed for top respiratory APR DRGs. Results: During the study period, 1,999 patients were admitted to the PICU equating to 17,053 PICU days. Medical critical care patients accounted for 54% of all admissions and 46% PICU days. The top 5 respiratory-related APR DRGs accounted for almost 45% of all PICU medical admissions. Non-asthma respiratory-related APR DRGs accounted for 23% of medical admission and 18% of medical PICU days. Of the total VDC for this subgroup, 54% and 20% was attributed to nursing and respiratory care respectively, with a significant minority (

There is variability in critical care outcome of the HSCT recipient. One potential reason may be due to the inconsistent ventilation approaches. To quantitate this variability, we conducted a survey to assess self-reported use of ventilation and adjunctive strategies for the HSCT recipient. Electronic survey, open from June 2012 through January 201, distributed through the Pediatric Acute Lung Injury and Sepsis Investigators network electronic mailing list. Ninety-four individual responses were from 36 different institutions. The majority indicated that HSCT recipients requiring critical care were admitted to the general PICU. The vast majority (89%) endorsed routine practice of low-tidal-volume ventilation strategies. More than half stated that pressure-regulated volume control is the starting mode of choice. Eighty-three percent felt their group practiced early initiation of lung protective strategies. Eleven percent encouraged "early transition" to HFOV. Inhaled nitric oxide and milrinone were reported at the highest frequencies, but the majority used these empirically. Opinions regarding variables that affect outcomes of the HSCT were diverse. The estimated mortality of HSCT patients with respiratory was highly variable. Strategies for ventilation and oxygenation, use of HFOV, and adjunctive therapies are variable among pediatric intensivists.

RT6 is a glycosyl-phosphatidylinositol-linked surface molecule present on most mature rat T-cells. RT6+ T-cells can prevent the expression of autoimmune diabetes in the BB rat, but the mechanism is unknown. Because cross-linking of other glycosyl-phosphatidylinositol-linked T-cell proteins is known to activate T-cells, we investigated the signaling properties of RT6. Antibody cross-linking of RT6 enhanced expression of the α subunit of the interleukin-2 (IL-2) receptor and potentiated the proliferation of rat T-cells cultured in the presence of phorbol ester plus recombinant IL-2 (rIL-2) and/or rIL-4. RT6 was found to coimmunoprecipitate with five tyrosine phosphorylated proteins including p60fyn and p56lck, members of the src tyrosine kinase family. Pretreatment of T-cells with phorbol ester increased the phosphorylation of proteins that coimmunoprecipitated with RT6, altered the electrophoretic mobility of several of these coimmunoprecipitated phosphoproteins, and increased the amount of p60fyn and p56lck coimmunoprecipitated with RT6. These data indicate that RT6-mediated signaling events may prime T-cells to respond to exogenous cytokines, suggesting a possible mechanism by which surface RT6 may influence T-cell function.

To investigate the safety and efficacy of a hyperglycemia protocol in neonates with critical cardiac illness. Neonates are often regarded as high risk for hypoglycemia while receiving continuous insulin infusions and thus have been excluded from some clinical trials.A retrospective review.A pediatric cardiac ICU in a tertiary academic center.Neonates with critical cardiac illness who developed hyperglycemia were placed on an insulin-hyperglycemia protocol at the attending physician's discretion. Insulin infusions were titrated based on frequent blood glucose monitoring.Critical illness hyperglycemia was defined as a blood glucose less than 140 mg/dL. Hypoglycemia was defined as moderate (≤ 60 mg/dL) or severe (≤ 40 mg/dL). Initiating blood glucose, lowest blood glucose during insulin infusion, doses of insulin, duration of insulin, and time to blood glucose greater than 140 mg/dL were evaluated.A total of 44 patients were placed on the protocol between January 2009 and October 2011. The majority of insulin infusions were initiated in the early postoperative period (33 of 44, 75%). Moderate hypoglycemia occurred in two patients (4.5%), with blood glucose levels of 49 and 53 mg/dL. No episodes of severe hypoglycemia occurred. A total of 345 discrete blood glucose levels were analyzed; two of these being greater than 60 mg/dL (0.58%). Mean blood glucose prior to starting insulin was 252 ± 45 mg/dL and time until euglycemia was 6.1 ± 3.9 hours. The mean duration of insulin infusion was 24.6 ± 38.7 hours, mean peak dose was 0.10 ± 0.05 units/kg/hour, and mean insulin dose was 0.06 ± 0.02 units/kg/hour. For postoperative patients, mean time after bypass until onset of hyperglycemia was 2.2 ± 2.6 hours.A glycemic control protocol can safely and effectively be applied to neonates with critical cardiac disease. Neonates with critical cardiac illness should be included in clinical trials evaluating the benefits of glycemic control.

Using co stimulatory blockade to prevent activation and activity of beta cell specific effector T cells is a promising approach for preventing or reversing Type 1 diabetes (T1D). Regulatory T cells are likely critical for the maintenance of long-term tolerance. At present, it is unclear how co-stimulatory blocking agents affect the activity of regulatory T cells. To better understand the mechanism of costimulation blockade induced tolerance in murine autoimmune diabetes, we evaluated the effect of CD28 and CD154 blockade on both beta cell-specific effector and regulatory T cell responses. Diabetes transferred by lymphocytes isolated from BDC2.5.NOD mice could be prevented if cells were antigenactivated ex vivo in the presence of CTLA4Ig and anti- CD154. Following antigen-stimulation, both effector (Teffs; FoxP3-) and regulatory (Tregs; FoxP3+) CD4+ T cells upregulated CD25, divided and accumulated. Co-culture with CTLA4Ig and anti-CD154 dampened the quantitative and qualitative Teff response (i.e. cell cycling and CD25 expression), but there was little effect on the Treg response. Adding exogenous IL-2 to such cultures reversed the diabetes protective effect of CD28/CD154 blockade. These findings suggest that Tregs do not only respond vigorously to antigen, but they rely less on traditional costimulatory signals than Teffs. Understanding the different signaling requirements of Teff and Tregs may facilitate the development and investigation of rational therapeutic interventions in Type1 diabetes that will both quiet diabetogenic effector T cells and enhance regulatory pathways.

Mitogen-activated protein kinases (MAP kinases) are a group of closely related enzymes implicated in signal transduction pathways. We report the molecular cloning of four human proteins (p40mapk, p41mapk, p44mapk and p63mapk, with high homology to members of the MAP kinase family. Sequence analysis demonstrated that p44mapk and p63mapk were the products of distinct genes. However, the p40mapk and p41mapk were found to be related, and are likely to result from alternative processing of transcripts from a single gene. The heterogeneous expression of these human MAP kinase isoforms in different tissues may reflect the diversity of signal transduction pathways in differentiated cells.

This study aimed to determine the prevalence of hyperglycemia among pediatric postoperative cardiac patients, its impact on outcomes, and whether hyperglycemia can be controlled effectively in this population. A retrospective chart review of 100 postoperative patients admitted to the authors’ pediatric cardiac intensive care unit (ICU) was conducted. Patients were evaluated for incidence of hyperglycemia, defined as blood glucose (BG) level exceeding 7.7 mmol/l (140 mg/dl), and outcomes. The evaluation also included 20 different postoperative patients with a BG level exceeding 7.7 mmol/l (140 mg/dl) who received management with insulin via the authors’ pediatric-specific glycemic control protocol. The BG control and hypoglycemic rates in this cohort were assessed. The prevalence of hyperglycemia was 84%. The hyperglycemic patients had higher inotrope scores, longer hospital stays, more mechanical ventilation days, and higher mortality rates than those without hyperglycemia. For the patients with hyperglycemia managed via the authors’ pediatric-specific glycemic control protocol, 62% of all BG values were within the authors’ goal range, and less than 4% of BG values were less than 3.3 mmol/l (60 mg/dl). No patient had a BG level lower than 2.2 mmol/l (40 mg/dl) during glycemic management. Severe hyperglycemia is prevalent among postoperative pediatric cardiac patients and correlates with morbidity and mortality. Hyperglycemia may be controlled effectively in these patients using a pediatric-specific glycemic control protocol without increasing the incidence of hypoglycemia.

We have used a sensitive and specific in vivo killing assay to monitor the kinetics, anatomic location and mechanisms controlling NK-mediated rejection of Balb/c bone marrow by C57BL/6 natural killer (NK) cells. We find that NK killing of fully allogeneic bone marrow is a rapid, highly efficient process, leading to substantial rejection of transplanted marrow within 6 h of transplant and elimination of 85% of the transplanted cells within 2 days. NK-mediated rejection occurred predominantly in the spleen, with sparing of rejection in the bone marrow and lymph nodes. Rejection was dependent on Perforin gene function, but was independent of interferon-gamma. Finally, rejection of Balb/c bone marrow by B6 NK cells required signaling through the Ly49D receptor, but occurred despite blockade of NKG2D, which distinguishes these results from previous studies using semiallogeneic transplant pairs. These results identify NK cells as highly active mediators of bone marrow rejection, and suggest that inhibiting NK function early during transplantation may increase the efficiency of engraftment and allow successful engraftment of limiting doses of donor bone marrow.