Continuous Glucose Monitoring (CGM) systems could improve glycemic control in critically ill patients. We aimed to identify the evidence on the clinical benefits and accuracy of CGM systems in these ...patients. For this, we performed a systematic search in Ovid MEDLINE, from inception to 26 July 2016. Outcomes were efficacy, accuracy, safety, workload and costs. Our search retrieved 356 articles, of which 37 were included. Randomized controlled trials on efficacy were scarce (
= 5) and show methodological limitations. CGM with automated insulin infusion improved time in target and mean glucose in one trial and two trials showed a decrease in hypoglycemic episodes and time in hypoglycemia. Thirty-two articles assessed accuracy, which was overall moderate to good, the latter mainly with intravascular devices. Accuracy in critically ill children seemed lower than in adults. Adverse events were rare. One study investigated the effect on workload and cost, and showed a significant reduction in both. In conclusion, studies on the efficacy and accuracy were heterogeneous and difficult to compare. There was no consistent clinical benefit in the small number of studies available. Overall accuracy was moderate to good with some intravascular devices. CGM systems seemed however safe, and might positively affect workload and costs.
Depatuxizumab mafodotin (depatux-m, ABT-414) is a tumor-selective antibody drug conjugate (ADC) comprised of the anti-EGFR antibody ABT-806 and the monomethyl auristatin F (MMAF) warhead. Depatux-m ...has demonstrated promising clinical activity in glioblastoma multiforme (GBM) patients and is currently being evaluated in clinical trials in first-line and recurrent GBM disease settings. Depatux-m responses have been restricted to patients with amplified EGFR, highlighting the need for therapies with activity against tumors with nonamplified EGFR overexpression. In addition, depatux-m dosing has been limited by corneal side effects common to MMAF conjugates. We hypothesized that a monomethyl auristatin E (MMAE) ADC utilizing an EGFR-targeting antibody with increased affinity may have broader utility against tumors with more modest EGFR overexpression while mitigating the risk of corneal side effects. We describe here preclinical characterization of ABBV-221, an EGFR-targeting ADC comprised of an affinity-matured ABT-806 conjugated to MMAE. ABBV-221 binds to a similar EGFR epitope as depatux-m and retains tumor selectivity with increased binding to EGFR-positive tumor cells and greater
potency. ABBV-221 displays increased tumor uptake and antitumor activity against wild-type EGFR-positive xenografts with a greatly reduced incidence of corneal side effects relative to depatux-m. ABBV-221 has similar activity as depatux-m against an EGFR-amplified GBM patient derived xenograft (PDX) model and is highly effective alone and in combination with standard-of-care temozolomide in an EGFRvIII-positive GBM xenograft model. Based on these results, ABBV-221 has advanced to a phase I clinical trial in patients with advanced solid tumors associated with elevated levels of EGFR.
Glucose measurement in intensive care medicine is performed intermittently with the risk of undetected hypoglycemia. The workload for the ICU nursing staff is substantial. Subcutaneous continuous ...glucose monitoring (CGM) systems are available and may be able to solve some of these issues in critically ill patients.
In a randomized controlled design in a mixed ICU in a teaching hospital we compared the use of subcutaneous CGM with frequent point of care (POC) to guide insulin treatment. Adult critically ill patients with an expected stay of more than 24 hours and in need of insulin therapy were included. All patients received subcutaneous CGM. CGM data were blinded in the control group, whereas in the intervention group these data were used to feed a computerized glucose regulation algorithm. The same algorithm was used in the control group fed by intermittent POC glucose measurements. Safety was assessed with the incidence of severe hypoglycemia (<2.2 mmol/L), efficacy with the percentage time in target range (5.0 to 9.0 mmol/L). In addition, we assessed nursing workload and costs.
In this study, 87 patients were randomized to the intervention and 90 to the control group. CGM device failure resulted in 78 and 78 patients for analysis. The incidence of severe glycemia and percentage of time within target range was similar in both groups. A significant reduction in daily nursing workload for glucose control was found in the intervention group (17 versus 36 minutes; P <0.001). Mean daily costs per patient were significantly reduced with EUR 12 (95% CI -32 to -18, P = 0.02) in the intervention group.
Subcutaneous CGM to guide insulin treatment in critically ill patients is as safe and effective as intermittent point-of-care measurements and reduces nursing workload and daily costs. A new algorithm designed for frequent measurements may lead to improved performance and should precede clinical implementation.
Clinicaltrials.gov, NCT01526044. Registered 1 February 2012.
The depolymerization of lignin into valuable aromatic chemicals is one of the key goals towards establishing economically viable biorefineries. In this contribution we present a simple approach for ...converting lignin to aromatic monomers in high yields under mild reaction conditions. The methodology relies on the use of catalytic amounts of easy‐to‐handle metal triflates (M(OTf)x). Initially, we evaluated the reactivity of a broad range of metal triflates using simple lignin model compounds. More advanced lignin model compounds were also used to study the reactivity of different lignin linkages. The product aromatic monomers were either phenolic C2‐acetals obtained by stabilization of the aldehyde cleavage products by reaction with ethylene glycol or methyl aromatics obtained by catalytic decarbonylation. Notably, when the method was ultimately tested on lignin, especially Fe(OTf)3 proved very effective and the phenolic C2‐acetal products were obtained in an excellent, 19.3±3.2 wt % yield.
Nutty triflates: Metal triflates are introduced as an easy‐to‐handle alternative to triflic acid for the cleavage of lignin β‐O‐4 linkages in conjunction with stabilization of reactive intermediates. The reactivity of several model compounds and lignin is studied. In particular, iron(III) triflate proved effective, providing as much as 19.3±3.2 wt % yield of a set of three aromatic C2‐acetals from lignin.
Despite clinical efficacy, current approved agents targeting EGFR are associated with on-target toxicities as a consequence of disrupting normal EGFR function. MAb 806 is a novel EGFR antibody that ...selectively targets a tumor-selective epitope suggesting that a mAb 806-based therapeutic would retain antitumor activity without the on-target toxicities associated with EGFR inhibition. To enable clinical development, a humanized variant of mAb 806 designated ABT-806 was generated and is currently in phase 1 trials. We describe the characterization of binding and functional properties of ABT-806 compared with the clinically validated anti-EGFR antibody cetuximab. ABT-806 binds the mutant EGFRvIII with high affinity and, relative to cetuximab, exhibits increased potency against glioblastoma multiforme cell line and patient-derived xenografts expressing this form of the receptor. ABT-806 also inhibits the growth of squamous cell carcinoma xenograft models expressing high levels of wild-type EGFR, associated with inhibition of EGFR signaling, although higher doses of ABT-806 than cetuximab are required for similar activity. ABT-806 enhances in vivo potency of standard-of-care therapies used to treat glioblastoma multiforme and head and neck squamous cell carcinoma. An indium-labeled version of ABT-806, (111)In-ABT-806, used to investigate the relationship between dose and receptor occupancy, revealed greater receptor occupancy at lowers doses in an EGFRvIII-expressing model and significant uptake in an orthotopic model. Collectively, these results suggest that ABT-806 may have antitumor activity superior to cetuximab in EGFRvIII-expressing tumors, and similar activity to cetuximab in tumors highly overexpressing wild-type EGFR with reduced toxicity.
Background
We assessed the association of intravenous insulin and glucose infusion with intensive care unit (ICU) and hospital mortality.
Methods
For this retrospective association study, we used ...data from all patients admitted to a medical-surgical ICU between January 2012 and September 2017. We excluded patients admitted < 24 h, patients with a diabetic ketoacidosis, patients with a therapy restriction upon ICU admission and readmissions. Using multivariate logistic regression, we examined the relation between intravenous insulin and glucose infusion and ICU and hospital mortality for all patients. Additionally, we used the same model to analyze the outcomes for patients admitted > 72 h.
Results
Of 9507 eligible patients, 3966 were included. After correction for potential confounders, intravenous insulin was associated with ICU and hospital mortality in patients admitted > 24 h (
n
= 3966) (odds ratio (OR) 1.09 95% CI 1.05–1.13 and 1.09 95% CI 1.06–1.13 per 0.1 IU/kg added, respectively). Likewise, intravenous glucose was associated with ICU mortality (OR 1.01 95% CI 1.00–1.01) but not with hospital mortality and (OR 1.00 95% CI 1.00–1.01) per g/day added, respectively. In patients admitted > 72 h (
n
= 1550), insulin dose was associated with both ICU and hospital mortality (
p
= 0.002 and
p
< 0.001, respectively), but glucose infusion was not (
p
= 0.08 and
p
= 0.2, respectively).
Conclusions
Intravenous insulin administration is associated with an increased risk of ICU and hospital mortality, after correction for potential confounders. Parenteral glucose administration was limited in amount but was still associated with ICU mortality. However, based on these results, it is unknown whether this association is an epiphenomenon, or represents a true harm of insulin and glucose administration.
Rhinovirus (RV) C can cause asymptomatic infection and respiratory illnesses ranging from the common cold to severe wheezing.
To identify how age and other individual-level factors are associated ...with susceptibility to RV-C illnesses.
Longitudinal data from the COAST (Childhood Origins of Asthma) birth cohort study were analyzed to determine relationships between age and RV-C infections. Neutralizing antibodies specific for RV-A and RV-C (three types each) were determined using a novel PCR-based assay. Data were pooled from 14 study cohorts in the United States, Finland, and Australia, and mixed-effects logistic regression was used to identify factors related to the proportion of RV-C versus RV-A detection.
In COAST, RV-A and RV-C infections were similarly common in infancy, whereas RV-C was detected much less often than RV-A during both respiratory illnesses and scheduled surveillance visits (
< 0.001, χ
) in older children. The prevalence of neutralizing antibodies to RV-A or RV-C types was low (5-27%) at the age of 2 years, but by the age of 16 years, RV-C seropositivity was more prevalent (78% vs. 18% for RV-A;
< 0.0001). In the pooled analysis, the RV-C to RV-A detection ratio during illnesses was significantly related to age (
< 0.0001),
genotype (
< 0.05), and wheezing illnesses (
< 0.05). Furthermore, certain RV types (e.g., C2, C11, A78, and A12) were consistently more virulent and prevalent over time.
Knowledge of prevalent RV types, antibody responses, and populations at risk based on age and genetics may guide the development of vaccines or other novel therapies against this important respiratory pathogen.
Lowering of hyperglycemia in the intensive care unit (ICU) is widely practiced. We investigated in which way glucose regulation, defined as mean glucose concentration during admission, is associated ...with ICU mortality in a medical and a surgical cohort.
Retrospective database cohort study including patients admitted between January 2004 and December 2007 in a 20-bed medical/surgical ICU in a teaching hospital. Hyperglycemia was treated using a computerized algorithm targeting for glucose levels of 4.0-7.0 mmol/l. Five thousand eight hundred twenty-eight patients were eligible for analyses, of whom 1,339 patients had a medical and 4,489 had a surgical admission diagnosis.
The cohorts were subdivided in quintiles of increasing mean glucose. We examined the relation between these mean glucose strata and mortality. In both cohorts we observed the highest mortality in the lowest and highest strata. Logistic regression analysis adjusted for age, sex, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, admission duration and occurrence of severe hypoglycemia showed that in the medical cohort mean glucose levels <6.7 mmol/l and >8.4 mmol/l and in the surgical cohort mean glucose levels < 7.0 mmol/l and >9.4 mmol/l were associated with significantly increased ICU mortality (OR 2.4-3.0 and 4.9-6.2, respectively). Limitations of the study were its retrospective design and possible incomplete correction for severity of disease.
Mean overall glucose during ICU admission is related to mortality by a U-shaped curve in medical and surgical patients. In this cohort of patients a 'safe range' of mean glucose regulation might be defined approximately between 7.0 and 9.0 mmol/l.
Background: The GluCath® intra-arterial continuous glucose monitoring (IA-CGM) system uses a novel quenched chemical fluorescence sensing mechanism to optically measure blood glucose when deployed in ...the radial artery. The aim of this study was to compare the accuracy of the IA-CGM and the FreeStyle Navigator® subcutaneous continuous glucose monitoring (SC-CGM) system with standard care. Methods: After admission to the intensive care unit (ICU), the IA-CGM was inserted via a 20 gauge radial arterial study catheter and the SC-CGM was placed at the abdominal wall of postoperative cardiac surgery patients with an expected ICU length of stay > 24 hours. Each device was calibrated according to manufacturer instructions. Glucose values of both CGM systems were blinded for the clinical staff. Reference blood glucose samples were collected from the study catheter every 1-2 hours for at least 24 hours and analyzed on a Radiometer ABL blood gas analyzer. Results: The IA-CGM and SC-CGM sensors were successfully inserted in 8 subjects. Accuracy assessment was performed with 183 paired points: 85.8% of the IA-CGM measurements and 84.2% of the SC-CGM measurements met ISO 15197:2003 glucometer criteria (within 20%) across a 79-248 mg/dl (4.4-13.8 mmol/L) glucose range. Overall ± SD mean absolute relative difference was 12.3 ± 11.3% for IA-CGM and 11.1 ± 8.3% for SC-CGM (difference −1.2%, 95% CI −3.3 to 0.8; P = .24). Conclusions: The IA-CGM system directly measured arterial blood glucose and did not interfere with clinical care. However, accuracy was similar to that of the less invasive SC-CGM device.
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