Implementing glucose control in intensive care: a multicenter trial using statistical process control

Glucose control (GC) with insulin decreases morbidity and mortality of critically ill patients. In this study we investigated GC performance over time during implementation of GC strategies within three intensive care units (ICUs) and in routine clinical practice. All adult critically ill patients who stayed for >24 h between 1999 and 2007 were included. Effects of implementing local GC guidelines and guideline revisions on effectiveness/efficiency-related indicators, safety-related indicators, and protocol-related indicators were measured. Data of 17,111 patient admissions were evaluated, with 714,141 available blood glucose levels (BGL) measurements. Mean BGL, time to reach target, hyperglycemia index, sampling frequency, percentage of hyperglycemia events, and in-range measurements statistically changed after introducing GC in all ICUs. The introduction of simple rules on GC had the largest effect. Subsequent changes in the protocol had a smaller effect than the introduction of the protocol itself. As soon as the protocol was introduced, in all ICUs the percentage of hypoglycemia events increased. Various revisions were implemented to reduce hypoglycemia events, but levels never returned to those from pre-implementation. More intensive implementation strategies including the use of a decision support system resulted in better control of the process. There are various strategies to achieve GC in routine clinical practice but with variable success. All of them were associated with an increase in hypoglycemia events, but GC was never stopped. Instead, these events have been accepted and managed. Statistical process control is a useful tool for monitoring phenomena over time and captures within-institution change

Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase Modulates Oscillations of Pancreatic Islet Metabolism

Pulses of insulin from pancreatic beta-cells help maintain blood glucose in a narrow range, although the source of these pulses is unclear. It has been proposed that a positive feedback circuit exists within the glycolytic pathway, the autocatalytic activation of phosphofructokinase-1 (PFK1), which endows pancreatic beta-cells with the ability to generate oscillations in metabolism. Flux through PFK1 is controlled by the bifunctional enzyme PFK2/FBPase2 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase) in two ways: via (1) production/degradation of fructose-2,6-bisphosphate (Fru2,6-BP), a potent allosteric activator of PFK1, as well as (2) direct activation of glucokinase due to a protein-protein interaction. In this study, we used a combination of live-cell imaging and mathematical modeling to examine the effects of inducibly-expressed PFK2/FBPase2 mutants on glucose-induced Ca2+ pulsatility in mouse islets. Irrespective of the ability to bind glucokinase, mutants of PFK2/FBPase2 that increased the kinase:phosphatase ratio reduced the period and amplitude of Ca2+ oscillations. Mutants which reduced the kinase:phosphatase ratio had the opposite effect. These results indicate that the main effect of the bifunctional enzyme on islet pulsatility is due to Fru2,6-BP alteration of the threshold for autocatalytic activation of PFK1 by Fru1,6-BP. Using computational models based on PFK1-generated islet oscillations, we then illustrated how moderate elevation of Fru-2,6-BP can increase the frequency of glycolytic oscillations while reducing their amplitude, with sufficiently high activation resulting in termination of slow oscillations. The concordance we observed between PFK2/FBPase2-induced modulation of islet oscillations and the models of PFK1-driven oscillations furthermore suggests that metabolic oscillations, like those found in yeast and skeletal muscle, are shaped early in glycolysis

Prediction of Outcome and Endovascular Treatment Benefit

Background and purposeBenefit of early endovascular treatment (EVT) for ischemic stroke varies considerably among patients. The MR PREDICTS decision tool, derived from MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), predicts outcome and treatment benefit based on baseline characteristics. Our aim was to externally validate and update MR PREDICTS with data from international trials and daily clinical practice.MethodsWe used individual patient data from 6 randomized controlled trials within the HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) collaboration to validate the original model. Then, we updated the model and performed a second validation with data from the observational MR CLEAN Registry. Primary outcome was functional independence (defined as modified Rankin Scale score 0–2) 3 months after stroke. Treatment benefit was defined as the difference between the probability of functional independence with and without EVT. Discriminative performance was evaluated using a concordance (C) statistic.ResultsWe included 1242 patients from HERMES (633 assigned to EVT, 609 assigned to control) and 3156 patients from the MR CLEAN Registry (all of whom underwent EVT within 6.5 hours). The C-statistic for functional independence was 0.74 (95% CI, 0.72–0.77) in HERMES and, after model updating, 0.80 (0.78–0.82) in the Registry. Median predicted treatment benefit of routinely treated patients (Registry) was 10.3% (interquartile range, 5.8%–14.4%). Patients with low (<1%) predicted treatment benefit (n=135/3156 [4.3%]) had low rates of functional independence, irrespective of reperfusion status, suggesting potential absence of treatment benefit. The updated model was made available online for clinicians and researchers at www.mrpredicts.com.ConclusionsBecause of the substantial treatment effect and small potential harm of EVT, most patients arriving within 6 hours at an endovascular-capable center should be treated regardless of their clinical characteristics. MR PREDICTS can be used to support clinical judgement when there is uncertainty about the treatment indication, when resources are limited, or before a patient is to be transferred to an endovascular-capable center

Observation of Two New Excited Ξb0 States Decaying to Λb0 K-π+

Two narrow resonant states are observed in the Λb0K-π+ mass spectrum using a data sample of proton-proton collisions at a center-of-mass energy of 13 TeV, collected by the LHCb experiment and corresponding to an integrated luminosity of 6 fb-1. The minimal quark content of the Λb0K-π+ system indicates that these are excited Ξb0 baryons. The masses of the Ξb(6327)0 and Ξb(6333)0 states are m[Ξb(6327)0]=6327.28-0.21+0.23±0.12±0.24 and m[Ξb(6333)0]=6332.69-0.18+0.17±0.03±0.22 MeV, respectively, with a mass splitting of Δm=5.41-0.27+0.26±0.12 MeV, where the uncertainties are statistical, systematic, and due to the Λb0 mass measurement. The measured natural widths of these states are consistent with zero, with upper limits of Γ[Ξb(6327)0]<2.20(2.56) and Γ[Ξb(6333)0]<1.60(1.92) MeV at a 90% (95%) credibility level. The significance of the two-peak hypothesis is larger than nine (five) Gaussian standard deviations compared to the no-peak (one-peak) hypothesis. The masses, widths, and resonant structure of the new states are in good agreement with the expectations for a doublet of 1D Ξb0 resonances

A search for rare B → Dμ+μ− decays

A search for rare B→Dμ+μ− decays is performed using proton-proton collision data collected by the LHCb experiment, corresponding to an integrated luminosity of 9 fb−1. No significant signals are observed in the non-resonant μ+μ− modes, and upper limits of B(B0→D ̄ ̄ ̄ ̄0μ+μ−)<5.1×10−8, B(B+→D+sμ+μ−)<3.2×10−8, B(B0s→D ̄ ̄ ̄ ̄0μ+μ−)<1.6×10−7 and fc/fu⋅B(B+c→D+sμ+μ−)<9.6×10−8 are set at the 95\% confidence level, where fc and fu are the fragmentation fractions of a B meson with a c and u quark respectively in proton-proton collisions. Each result is either the first such measurement or an improvement by three orders of magnitude on an existing limit. Separate upper limits are calculated when the muon pair originates from a J/ψ→μ+μ− decay. The branching fraction of B+c→D+sJ/ψ multiplied by the fragmentation-fraction ratio is measured to be fc/fu⋅B(B+c→D+sJ/ψ)=(1.63±0.15±0.13)×10−5, where the first uncertainty is statistical and the second systematic

Search for dark photons produced in 13 TeV pppp collisions

Searches are performed for both promptlike and long-lived dark photons, A 0 , produced in proton-proton collisions at a center-of-mass energy of 13 TeV, using A 0 → μ þ μ − decays and a data sample corresponding to an integrated luminosity of 1 . 6 fb − 1 collected with the LHCb detector. The promptlike A 0 search covers the mass range from near the dimuon threshold up to 70 GeV, while the long-lived A 0 search is restricted to the low-mass region 214 <m ð A 0 Þ < 350 MeV. No evidence for a signal is found, and 90% confidence level exclusion limits are placed on the γ – A 0 kinetic-mixing strength. The constraints placed on promptlike dark photons are the most stringent to date for the mass range 10 . 6 <m ð A 0 Þ < 70 GeV, and are comparable to the best existing limits for m ð A 0 Þ < 0 . 5 GeV. The search for long-lived dark photons is the first to achieve sensitivity using a displaced-vertex signature

Measurement of Λb0 , Λc+ , and Λ decay parameters using Λb0→Λc+h− decays

A comprehensive study of the angular distributions in the bottom-baryon decays Λ0 b → Λ c+h−(h = π, K), followed by Λþ c → Λhþ with Λ → pπ− or Λþ c → pK0 S decays, is performed using a data sample of proton-proton collisions corresponding to an integrated luminosity of 9 fb−1 collected by the LHCb experiment at center-of-mass energies of 7, 8, and 13 TeV. The decay parameters and the associated charge-parity (CP) asymmetries are measured, with no significant CP violation observed. For the first time, the Λ0 b → Λþ c h− decay parameters are measured. The most precise measurements of the decay parameters α, β, and γ are obtained for Λþ c decays and an independent measurement of the decay parameters for the strange-baryon Λ decay is provided. The results deepen our understanding of weak decay dynamics in baryon decays

Biosynthetic homeostasis and resilience of the complement system in health and infectious disease

BACKGROUND: The complement system is a central component of the innate immune system. Constitutive biosynthesis of complement proteins is essential for homeostasis. Dysregulation as a consequence of genetic or environmental cues can lead to inflammatory syndromes or increased susceptibility to infection. However, very little is known about steady state levels in children or its kinetics during infection. METHODS: With a newly developed multiplex mass spectrometry-based method we analyzed the levels of 32 complement proteins in healthy individuals and in a group of pediatric patients infected with bacterial or viral pathogens. FINDINGS: In plasma from young infants we found reduced levels of C4BP, ficolin-3, factor B, classical pathway components C1QA, C1QB, C1QC, C1R, and terminal pathway components C5, C8, C9, as compared to healthy adults; whereas the majority of complement regulating (inhibitory) proteins reach adult levels at very young age. Both viral and bacterial infections in children generally lead to a slight overall increase in complement levels, with some exceptions. The kinetics of complement levels during invasive bacterial infections only showed minor changes, except for a significant increase and decrease of CRP and clusterin, respectively. INTERPRETATION: The combination of lower levels of activating and higher levels of regulating complement proteins, would potentially raise the threshold of activation, which might lead to suppressed complement activation in the first phase of life. There is hardly any measurable complement consumption during bacterial or viral infection. Altogether, expression of the complement proteins appears surprisingly stable, which suggests that the system is continuously replenished. FUND: European Union's Horizon 2020, project PERFORM, grant agreement No. 668303