Golimumab and Beta-Cell Function in Youth with New-Onset Type 1 Diabetes.

BACKGROUND: 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 factor α that has already been approved for the treatment of several autoimmune conditions in adults and children. Whether golimumab could preserve beta-cell function in youth with newly diagnosed overt (stage 3) type 1 diabetes is unknown. METHODS: In 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. RESULTS: 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, P<0.001). 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. CONCLUSIONS: 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.).

Voltage-Gated Potassium Channels Ensure Action Potential Shape Fidelity in Distal Axons.

The initiation and propagation of the action potential (AP) along an axon allows neurons to convey information rapidly and across distant sites. Although AP properties have typically been characterized at the soma and proximal axon, knowledge of the propagation of APs toward distal axonal domains of mammalian CNS neurons remains limited. We used genetically encoded voltage indicators (GEVIs) to image APs with submillisecond temporal resolution simultaneously at different locations along the long axons of dissociated hippocampal neurons from rat embryos of either sex. We found that APs became sharper and showed remarkable fidelity as they traveled toward distal axons, even during a high-frequency train. Blocking voltage-gated potassium channels (Kv) with 4-AP resulted in an increase in AP width in all compartments, which was stronger at distal locations and exacerbated during AP trains. We conclude that the higher levels of Kv channel activity in distal axons serve to sustain AP fidelity, conveying a reliable digital signal to presynaptic boutons.SIGNIFICANCE STATEMENT The AP represents the electrical signal carried along axons toward distant presynaptic boutons where it culminates in the release of neurotransmitters. The nonlinearities involved in this process are such that small changes in AP shape can result in large changes in neurotransmitter release. Since axons are remarkably long structures, any distortions that APs suffer along the way have the potential to translate into a significant modulation of synaptic transmission, particularly in distal domains. To avoid these issues, distal axons have ensured that signals are kept remarkably constant and insensitive to modulation during a train, despite the long distances traveled. Here, we uncover the mechanisms that allow distal axonal domains to provide a reliable and faithful digital signal to presynaptic terminals.

Distance-dependent gradient in NMDAR-driven spine calcium signals along tapering dendrites.

Neurons receive a multitude of synaptic inputs along their dendritic arbor, but how this highly heterogeneous population of synaptic compartments is spatially organized remains unclear. By measuring N-methyl-d-aspartic acid receptor (NMDAR)-driven calcium responses in single spines, we provide a spatial map of synaptic calcium signals along dendritic arbors of hippocampal neurons and relate this to measures of synapse structure. We find that quantal NMDAR calcium signals increase in amplitude as they approach a thinning dendritic tip end. Based on a compartmental model of spine calcium dynamics, we propose that this biased distribution in calcium signals is governed by a gradual, distance-dependent decline in spine size, which we visualized using serial block-face scanning electron microscopy. Our data describe a cell-autonomous feature of principal neurons, where tapering dendrites show an inverse distribution of spine size and NMDAR-driven calcium signals along dendritic trees, with important implications for synaptic plasticity rules and spine function.

Transmembrane AMPAR regulatory protein γ-2 is required for the modulation of GABA release by presynaptic AMPARs.

Presynaptic ionotropic glutamate receptors (iGluRs) play important roles in the control of synaptogenesis and neurotransmitter release, yet their regulation is poorly understood. In particular, the contribution of transmembrane auxiliary proteins, which profoundly shape the trafficking and gating of somatodendritic iGluRs, is unknown. Here we examined the influence of transmembrane AMPAR regulatory proteins (TARPs) on presynaptic AMPARs in cerebellar molecular layer interneurons (MLIs). 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a partial agonist at TARP-associated AMPARs, enhanced spontaneous GABA release in wild-type mice but not in stargazer mice that lack the prototypical TARP stargazin (γ-2). These findings were replicated in mechanically dissociated Purkinje cells with functional adherent synaptic boutons, demonstrating the presynaptic locus of modulation. In dissociated Purkinje cells from stargazer mice, AMPA was able to enhance mIPSC frequency, but only in the presence of the positive allosteric modulator cyclothiazide. Thus, ordinarily, presynaptic AMPARs are unable to enhance spontaneous release without γ-2, which is required predominantly for its effects on channel gating. Presynaptic AMPARs are known to reduce action potential-driven GABA release from MLIs. Although a G-protein-dependent non-ionotropic mechanism has been suggested to underlie this inhibition, paradoxically we found that γ-2, and thus AMPAR gating, was required. Following glutamate spillover from climbing fibers or application of CNQX, evoked GABA release was reduced; in stargazer mice such effects were markedly attenuated in acute slices and abolished in the dissociated Purkinje cell-nerve bouton preparation. We suggest that γ-2 association, by increasing charge transfer, allows presynaptic AMPARs to depolarize the bouton membrane sufficiently to modulate both phasic and spontaneous release.

Assessing the trend in sustainable remediation: A questionnaire survey of remediation professionals in various countries.

Over the past decade, sustainable remediation has grown from an emerging concept into a widely accepted new institutional norm. Scholar literature increased exponentially from nearly none in late 1990s to over 400 publications per year in 2014. The present study used a questionnaire survey conducted in 2012 and 2014 to assess the global trend in the awareness and practice of sustainable remediation. A total of 373 responses were received from survey participants located in 22 countries. The survey found that the US and the UK similarly had the highest level of awareness and adoption rate of sustainable remediation. Asia and other developing countries had much lower awareness levels and/or adoption rates. For all regions, the adoption rates were significantly lower than awareness levels, indicating a large gap between awareness and practice. One specific example is regarding minimizing greenhouse gas emission, which is a focal point in sustainable remediation literature, but with very low adoption rate according to this survey. This study also found that the adoption rates of a few sustainable remediation considerations, such as "minimizing local scale secondary impact", "minimizing national to global scale secondary impact", and "bringing prosperity to disadvantaged community", had decreased between 2012 and 2014. On the other hand, the survey also suggests the remediation community has rendered more expertise, training, and resources in sustainable remediation between 2012 and 2014. The mixed results suggest that in order to enhance sustainable remediation adoption, it is imperative to employ continued effort to enhance the understanding of sustainable remediation by practitioners and to link self-interest and public interest with sustainable remediation considerations.

Targeting memory T cells in type 1 diabetes.

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.

Re-exposure to beta cell autoantigens in pancreatic allograft recipients with preexisting beta cell autoantibodies.

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.

Inconsistencies in care of the pediatric hematopoietic stem cell transplant recipient with respiratory failure: opportunity for standardization and improved outcome.

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.

Vasovagal syncope and severe bradycardia following intranasal dexmedetomidine for pediatric procedural sedation.

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.

Successful use of intravenous dexmedetomidine for magnetic resonance imaging sedation in autistic children.

OBJECTIVES: Autism and autism spectrum disorders (A/ASD) represent a family of neurodevelopmental conditions that are associated with overactive, difficult-to-control behaviors. Sedating these patients for magnetic resonance imaging (MRI) poses challenges. Children with A/ASD were examined against clinical controls to determine the effectiveness and safety of intravenous (IV) dexmedetomidine for deep sedation. METHODS: The quality assurance data on all of the children who received IV dexmedetomidine sedation for MRI between July 2007 and December 2012 were reviewed. Patients in both groups were sedated by an intensivist-based team with a standard plan of 2 µg/kg IV dexmedetomidine administered for 10 minutes followed by an infusion of 1 µg · kg(-1)· hour(-1). The amount of IV dexmedetomidine was titrated to the deep level of sedation. A total of 56 patients in the A/ASD group and 107 in the control group were sedated with no reported sedation failures. Sedation parameters were compared between the A/ASD and control groups using analysis of covariance models, controlling for age, sex, and weight. RESULTS: Children in the A/ASD group were predominantly male (73%) and older (6.1 ± 0.3 years) than children in the control group (56%; 5.0 ± 0.2 years; P < 0.05 for both). Procedure time was significantly shorter for patients in the A/ASD group than in control patients (34.6 ± 2.4 vs 44.3 ± 1.6 minutes; P < 0.05). The A/ASD and control groups required a similar IV bolus of dexmedetomidine (2.6 µg/kg ± 0.1 vs 2.4 µg/kg ± 0.10; P = 0.29), with a significantly lower infusion dose in the A/ASD group (0.74 µg/kg ± 0.05 vs 0.89 µg/kg ± 0.03; P < 0.05). Heart rates were similar in the A/ASD group and the control group (67.0 beats per minute ± 1.6 vs 69.3 ± 1.1 beats per minute; P = 0.250). There were no complications. Recovery time was approximately 7 minutes longer in the A/ASD group than in the control group, but this was nonsignificant (101.2 ± 3.5 minutes vs 94.2 ± 2.4 minutes; P = 0.12). Analyses were performed using analysis of covariance methods and generalized linear models to control for age, sex, and weight. CONCLUSIONS: Children with A/ASD can be successfully sedated for MRIs with IV dexmedetomidine without complications.

Safe and effective use of a glycemic control protocol for neonates in a cardiac ICU.

OBJECTIVE: 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. DESIGN: A retrospective review. SETTING: A pediatric cardiac ICU in a tertiary academic center. INTERVENTIONS: 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. MEASUREMENTS: 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. MAIN RESULTS: 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. CONCLUSIONS: 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.

Two-Year Follow-up From the T1GER Study: Continued Off-Therapy Metabolic Improvements in Children and Young Adults With New-Onset T1D Treated With Golimumab and Characterization of Responders.

OBJECTIVE: The T1GER (A Study of SIMPONI to Arrest ß-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 METHODS: T1GER 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. RESULTS: After 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. CONCLUSIONS: In children and young adults with new-onset T1D, golimumab preserved endogenous ß-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.

C-peptide and metabolic outcomes in trials of disease modifying therapy in new-onset type 1 diabetes: an individual participant meta-analysis.

BACKGROUND: Metabolic outcomes in type 1 diabetes remain suboptimal. Disease modifying therapy to prevent ß-cell loss presents an alternative treatment framework but the effect on metabolic outcomes is unclear. We, therefore, aimed to define the relationship between insulin C-peptide as a marker of ß-cell function and metabolic outcomes in new-onset type 1 diabetes. METHODS: 21 trials of disease-modifying interventions within 100 days of type 1 diabetes diagnosis comprising 1315 adults (ie, those 18 years and older) and 1396 children (ie, those younger than 18 years) were combined. Endpoints assessed were stimulated area under the curve C-peptide, HbA1c, insulin use, hypoglycaemic events, and composite scores (such as insulin dose adjusted A1c, total daily insulin, U/kg per day, and BETA-2 score). Positive studies were defined as those meeting their primary endpoint. Differences in outcomes between active and control groups were assessed using the Wilcoxon rank test. FINDINGS: 6 months after treatment, a 24·8% greater C-peptide preservation in positive studies was associated with a 0·55% lower HbA1c (p<0·0001), with differences being detectable as early as 3 months. Cross-sectional analysis, combining positive and negative studies, was consistent with this proportionality: a 55% improvement in C-peptide preservation was associated with 0·64% lower HbA1c (p<0·0001). Higher initial C-peptide levels and greater preservation were associated with greater improvement in HbA1c. For HbA1c, IDAAC, and BETA-2 score, sample size predictions indicated that 2-3 times as many participants per group would be required to show a difference at 6 months as compared with C-peptide. Detecting a reduction in hypoglycaemia was affected by reporting methods. INTERPRETATION: Interventions that preserve ß-cell function are effective at improving metabolic outcomes in new-onset type 1 diabetes, confirming their potential as adjuncts to insulin. We have shown that improvements in HbA1c are directly proportional to the degree of C-peptide preservation, quantifying this relationship, and supporting the use of C-peptides as a surrogate endpoint in clinical trials. FUNDING: JDRF and Diabetes UK.

Multi-synaptic boutons are a feature of CA1 hippocampal connections in the stratum oriens.

Excitatory synapses are typically described as single synaptic boutons (SSBs), where one presynaptic bouton contacts a single postsynaptic spine. Using serial section block-face scanning electron microscopy, we found that this textbook definition of the synapse does not fully apply to the CA1 region of the hippocampus. Roughly half of all excitatory synapses in the stratum oriens involved multi-synaptic boutons (MSBs), where a single presynaptic bouton containing multiple active zones contacted many postsynaptic spines (from 2 to 7) on the basal dendrites of different cells. The fraction of MSBs increased during development (from postnatal day 22 [P22] to P100) and decreased with distance from the soma. Curiously, synaptic properties such as active zone (AZ) or postsynaptic density (PSD) size exhibited less within-MSB variation when compared with neighboring SSBs, features that were confirmed by super-resolution light microscopy. Computer simulations suggest that these properties favor synchronous activity in CA1 networks.

Guidelines for the use of an insulin infusion for the management of hyperglycemia in critically ill patients.

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 <180 mg/dL. There is a slight reduction in mortality with this treatment end point for general intensive care unit patients and reductions in morbidity for perioperative patients, postoperative cardiac surgery patients, post-traumatic injury patients, and neurologic injury patients. We suggest that the insulin regimen and monitoring system be designed to avoid and detect hypoglycemia (blood glucose ≤ 70 mg/dL) and to minimize glycemic variability.Important processes of care for insulin therapy include use of a reliable insulin infusion protocol, frequent blood glucose monitoring, and avoidance of finger-stick glucose testing through the use of arterial or venous glucose samples. The essential components of an insulin infusion system include use of a validated insulin titration program, availability of appropriate staffing resources, accurate monitoring technology, and standardized approaches to infusion preparation, provision of consistent carbohydrate calories and nutritional support, and dextrose replacement for hypoglycemia prevention and treatment. Quality improvement of glycemic management programs should include analysis of hypoglycemia rates, run charts of glucose values <150 and 180 mg/dL. The literature is inadequate to support recommendations regarding glycemic control in pediatric patients. CONCLUSIONS: While the benefits of tight glycemic control have not been definitive, there are patients who will receive insulin infusion therapy, and the suggestions in this article provide the structure for safe and effective use of this therapy.

Randomized phase I trial of antigen-specific tolerizing immunotherapy with peptide/calcitriol liposomes in ACPA+ rheumatoid arthritis.

BACKGROUNDAntigen-specific regulation of autoimmune disease is a major goal. In seropositive rheumatoid arthritis (RA), T cell help to autoreactive B cells matures the citrullinated (Cit) antigen-specific immune response, generating RA-specific V domain glycosylated anti-Cit protein antibodies (ACPA VDG) before arthritis onset. Low or escalating antigen administration under "sub-immunogenic" conditions favors tolerance. We explored safety, pharmacokinetics, and immunological and clinical effects of s.c. DEN-181, comprising liposomes encapsulating self-peptide collagen II259-273 (CII) and NF-κB inhibitor 1,25-dihydroxycholecalciferol.METHODSA double-blind, placebo-controlled, exploratory, single-ascending-dose, phase I trial assessed the impact of low, medium, and high DEN-181 doses on peripheral blood CII-specific and bystander Cit64vimentin59-71-specific (Cit-Vim-specific) autoreactive T cell responses, cytokines, and ACPA in 17 HLA-DRB1*04:01+ or *01:01+ ACPA+ RA patients on methotrexate.RESULTSDEN-181 was well tolerated. Relative to placebo and normalized to baseline values, Cit-Vim-specific T cells decreased in patients administered medium and high doses of DEN-181. Relative to placebo, percentage of CII-specific programmed cell death 1+ T cells increased within 28 days of DEN-181. Exploratory analysis in DEN-181-treated patients suggested improved RA disease activity was associated with expansion of CII-specific and Cit-Vim-specific T cells; reduction in ACPA VDG, memory B cells, and inflammatory myeloid populations; and enrichment in CCR7+ and naive T cells. Single-cell sequencing identified T cell transcripts associated with tolerogenic TCR signaling and exhaustion after low or medium doses of DEN-181.CONCLUSIONThe safety and immunomodulatory activity of low/medium DEN-181 doses provide rationale to further assess antigen-specific immunomodulatory therapy in ACPA+ RA.TRIAL REGISTRATIONAnzctr.org.au identifier ACTRN12617001482358, updated September 8, 2022.FUNDINGInnovative Medicines Initiative 2 Joint Undertaking (grant agreement 777357), supported by European Union's Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations; Arthritis Queensland; National Health and Medical Research Council (NHMRC) Senior Research Fellowship; and NHMRC grant 2008287.

Stiff-Person Syndrome: Seeing Past Comorbidities to Reach the Correct Diagnosis.

Stiff-person syndrome (SPS) is a rare disorder seen in approximately one in one million people. Although it is rare, the symptoms and findings of a typical case should paint a clear clinical picture for those who are familiar with the disease. The primary findings in SPS include progressive axial muscle rigidity as well as muscle spasms. These symptoms most commonly occur in the setting of antibodies against Glutamic Acid Decarboxylase (GAD), the rate-limiting enzyme in the production of Gamma-Aminobutyric Acid (GABA), which is the primary inhibitory enzyme in the central nervous system. Here, we report the case of a 65-year-old African-American female with a past medical history of hypothyroidism, anxiety, and depression with psychotic features who presented with axial muscle rigidity and lactic acidosis. She had been symptomatic for several months and reported extensive workups performed at two previous hospitals without a definitive diagnosis. A complete neurological and musculoskeletal investigation yielded no positive findings except for the presence of GAD antibodies. The patient was treated with diazepam, tizanidine, and Intravenous Immunoglobulin (IVIG) with significant improvement, thus solidifying the diagnosis of SPS, a rare autoimmune and/or paraneoplastic syndrome.

A disparity between physician attitudes and practice regarding hyperglycemia in pediatric intensive care units in the United States: a survey on actual practice habits.

INTRODUCTION: Hyperglycemia is common in critically ill patients and is associated with increased morbidity and mortality. Strict glycemic control improves outcomes in some adult populations and may have similar effects in children. While glycemic control has become standard care in adults, little is known regarding hyperglycemia management strategies used by pediatric critical care practitioners. We sought to assess both the beliefs and practice habits regarding glycemic control in pediatric intensive care units (ICUs) in the United States (US). METHODS: We surveyed 30 US pediatric ICUs from January to May 2009. Surveys were conducted by phone between the investigators and participating centers and consisted of a 22-point questionnaire devised to assess physician perceptions and center-specific management strategies regarding glycemic control. RESULTS: ICUs included a cross section of centers throughout the US. Fourteen out of 30 centers believe all critically ill hyperglycemic adults should be treated, while 3/30 believe all critically ill children should be treated. Twenty-nine of 30 believe some subsets of adults with hyperglycemia should be treated, while 20/30 believe some subsets of children should receive glycemic control. A total of 70%, 73%, 80%, 27%, and 40% of centers believe hyperglycemia adversely affects outcomes in cardiac, trauma, traumatic brain injury, general medical, and general surgical pediatric patients, respectively. However, only six centers use a standard, uniform approach to treat hyperglycemia at their institution. Sixty percent of centers believe hypoglycemia is more dangerous than hyperglycemia. Seventy percent listed fear of management-induced hypoglycemia as a barrier to glycemic control at their center. CONCLUSIONS: Considerable disparity exists between physician beliefs and actual practice habits regarding glycemic control among pediatric practitioners, with few centers reporting the use of any consistent standard approach to screening and management. Physicians wishing to practice glycemic control in their critically ill pediatric patients may want to consider adopting center-wide uniform approaches to improve safety and efficacy of treatment.

Continuous glucose monitors prove highly accurate in critically ill children.

INTRODUCTION: Hyperglycemia is associated with increased morbidity and mortality in critically ill patients and strict glycemic control has become standard care for adults. Recent studies have questioned the optimal targets for such management and reported increased rates of iatrogenic hypoglycemia in both critically ill children and adults. The ability to provide accurate, real-time continuous glucose monitoring would improve the efficacy and safety of this practice in critically ill patients. The aim of our study is to determine if a continuous, interstitial glucose monitor will correlate with blood glucose values in critically ill children. METHODS: We evaluated 50 critically ill children age 6 weeks to 16 years old with a commercially available continuous glucose monitor (CGM; Medtronic Guardian®). CGM values and standard blood glucose (BG) values were compared. During the study, no changes in patient management were made based on CGM readings alone. RESULTS: Forty-seven patients had analyzable CGM data. A total of 1,555 CGM and routine BG measurements were compared using Clarke error grid and Bland-Altman analysis. For all readings, 97.9% were within clinically acceptable agreement. The mean absolute relative difference between CGM and BG readings was 15.3%. For the 1,555 paired CGM and BG measurements, there is a statistically significant linear relationship between CGM values and BG (P < .0001). A high degree of clinical agreement existed in three subpopulation analyses based on age, illness severity, and support measures. This included some of our smallest patients (that is, < 12 months old), those who required vasopressors, and those who were treated for critical illness hyperglycemia. CONCLUSIONS: In one of the largest studies to date, in a highly vulnerable ICU population, CGM values have a clinically acceptable correlation with the BG values now used diagnostically and therapeutically. Our data contest the theoretical concerns posed by some regarding CGM use in the ICU. The existing medical evidence may now support a role for CGM devices in the identification and management of hyperglycemia in diverse ICU settings.