Cloud Computing (CC) is the most prevalent paradigm under which services are provided over the Internet. The most relevant feature for its success is its capability to promptly scale service based on ...user demand. When scaling, the main objective is to maximize as much as possible service performance. Moreover, resources in the Cloud are usually so abundant, that they can be assumed infinite from the service point of view: an application provider can have as many servers it wills, as long it pays for it. This model has some limitations. First, energy efficiency is not among the first criteria for scaling decisions, which has raised concerns about the environmental effects of today's wild computations in the Cloud. Moreover, it is not viable for Edge Computing (EC), a paradigm in which computational resources are distributed up to the very edge of the network, i.e., co-located with base stations or access points. In edge nodes, resources are limited, which imposes different parsimonious scaling strategies to be adopted. In this work, we design a scaling strategy aimed to instantiate, parsimoniously, a number of microservices sufficient to guarantee a certain Quality of Service (QoS) target. We implement such a strategy in a Kubernetes/Docker environment. The strategy is based on a simple Proportional-Integrative-Derivative (PID) controller. In this paper we describe the system design and a preliminary performance evaluation.
The study objective was to compare clinical outcomes in a dedicated adult cardiac surgery intensive care unit before and after the implementation of 24-hour intensivist coverage.
Between 2008 and ...2016, 16,454 consecutive adult patients were admitted to the cardiac surgery intensive care unit after cardiac surgery. During this period, postoperative patients in the cardiac surgery intensive care unit were managed by intensivists during the day (group A); in July 2010, the nighttime coverage was transferred from the hands of residents and fellows to intensivists (group B). Postoperative outcomes before and after this change using 1-to-1 propensity score matching were examined. Patients were stratified a priori into low- and high-risk (<5% and ≥5% predicted mortality) based on the European System for Cardiac Operative Risk Evaluation II.
Matched patients in group A had significantly higher cardiac surgery intensive care unit (2.1% vs 1.4%, P = .01) and in-hospital (2.7% vs 1.8%, P = .008) mortality. This higher mortality was only observed among high-risk group A patients who had significantly higher rates of cardiac surgery intensive care unit mortality (6.8% vs 4.1%, P = .01) and in-hospital mortality (8.5% vs 5.3%, P = .01) compared with the high-risk group B. The median duration of mechanical ventilation (5.8 vs 4.3 hours, P < .0001) and the risk of prolonged ventilation greater than 48 hours (5.3% vs 4%, P = .008) were significantly higher among group A patients; this higher rate of respiratory adverse events was observed in all strata of preoperative risk.
In this large cohort of patients admitted to a dedicated adult cardiac surgery intensive care unit, 24-hour intensivist coverage was associated with reduced mortality among patients with an expected operative mortality 5% or greater. These data suggest that preoperative risk stratification and adaptive cardiac surgery intensive care unit physician staffing may result in improved clinical outcomes and optimized hospital resource use.
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SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in ...the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator, controlling SHP2 activity is of high therapeutic interest. As part of our comprehensive program targeting SHP2, we identified multiple allosteric binding modes of inhibition and optimized numerous chemical scaffolds in parallel. In this drug annotation report, we detail the identification and optimization of the pyrazine class of allosteric SHP2 inhibitors. Structure and property based drug design enabled the identification of protein–ligand interactions, potent cellular inhibition, control of physicochemical, pharmaceutical and selectivity properties, and potent in vivo antitumor activity. These studies culminated in the discovery of TNO155, (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro4.5decan-4-amine (1), a highly potent, selective, orally efficacious, and first-in-class SHP2 inhibitor currently in clinical trials for cancer.
When treating acute respiratory failure, both hypoxemia and hyperoxemia should be avoided. SpO2 should be monitored closely and O2 flows adjusted accordingly. Achieving this goal might be easier with ...automated O2 titration compared with manual titration of fixed-flow O2. We evaluated the feasibility of using an automated O2 titration device in subjects treated for acute hypoxemic respiratory failure in a tertiary care hospital.BACKGROUNDWhen treating acute respiratory failure, both hypoxemia and hyperoxemia should be avoided. SpO2 should be monitored closely and O2 flows adjusted accordingly. Achieving this goal might be easier with automated O2 titration compared with manual titration of fixed-flow O2. We evaluated the feasibility of using an automated O2 titration device in subjects treated for acute hypoxemic respiratory failure in a tertiary care hospital.Health-care workers received education and training about oxygen therapy, and were familiarized with an automated O2 titration device (FreeO2,). A coordinator was available from 8:00 am to 5:00 pm during weekdays to provide technical assistance. The ability of the device to maintain SpO2 within the prescribed therapeutic window was recorded. Basic clinical information was recorded.METHODSHealth-care workers received education and training about oxygen therapy, and were familiarized with an automated O2 titration device (FreeO2,). A coordinator was available from 8:00 am to 5:00 pm during weekdays to provide technical assistance. The ability of the device to maintain SpO2 within the prescribed therapeutic window was recorded. Basic clinical information was recorded.Subjects were enrolled from November 2020 to August 2022. We trained 508 health-care workers on the use of automated O2 titration, which was finally used on 872 occasions in 763 subjects, distributed on the respiratory, COVID-19, and thoracic surgery wards, and in the emergency department. Clinical information could be retrieved for 609 subjects (80%) who were on the system for a median (interquartile range) of 3 (2-6) d, which represented 2,567 subject-days of clinical experience with the device. In the 82 subjects (14%) for whom this information was available, the system maintained SpO2 within the prescribed targets 89% of the time. Ninety-six subjects experienced clinical deterioration as defined by the need to be transferred to the ICU and/or requirement of high flow nasal oxygen but none of these events were judged to be related to the O2 device.RESULTSSubjects were enrolled from November 2020 to August 2022. We trained 508 health-care workers on the use of automated O2 titration, which was finally used on 872 occasions in 763 subjects, distributed on the respiratory, COVID-19, and thoracic surgery wards, and in the emergency department. Clinical information could be retrieved for 609 subjects (80%) who were on the system for a median (interquartile range) of 3 (2-6) d, which represented 2,567 subject-days of clinical experience with the device. In the 82 subjects (14%) for whom this information was available, the system maintained SpO2 within the prescribed targets 89% of the time. Ninety-six subjects experienced clinical deterioration as defined by the need to be transferred to the ICU and/or requirement of high flow nasal oxygen but none of these events were judged to be related to the O2 device.Automated O2 titration could be successfully implemented in hospitalized subjects with hypoxemic respiratory failure from various causes. This experience should foster further improvement of the device and recommendations for an optimized utilization.CONCLUSIONSAutomated O2 titration could be successfully implemented in hospitalized subjects with hypoxemic respiratory failure from various causes. This experience should foster further improvement of the device and recommendations for an optimized utilization.
HR-pQCT based micro finite element (μFE) analyses are considered as “gold standard” for virtual biomechanical analyses of peripheral bone sites such as the distal segment of radius and tibia. An ...attractive alternative for clinical use is a homogenized finite element method (hFE) based on constitutive models, because of its much shorter evaluation times and modest computational resource requirements. Such hFE models have been experimentally validated for the distal segment of the radius, but neither for the distal segments of the tibia nor for both measurement sites together. Accordingly, the aim of the present study was to refine and experimentally validate an hFE processing pipeline for in vivo prediction of bone strength and stiffness at the distal segments of the radius and the tibia, using only one unified set of material properties.
An existing hFE analysis procedure was refined in several aspects: 1) to include a faster evaluation of material orientation based on the mean surface length (MSL) method, 2) to distinguish cortical and trabecular bone compartments with distinct material properties and 3) to directly superimpose material properties in mixed phase elements instead of densities. Based on an existing dataset of the distal segment of fresh-frozen radii (double sections 20.4 mm, n = 21) and a newly established dataset of the distal segment of fresh-frozen tibiae (triple sections, 30.6 mm, n = 25), a single set of material properties was calibrated on the radius dataset and validated on the tibia dataset by comparing hFE stiffness and ultimate load with respective experimental results, obtained by compressing the samples on a servo-hydraulic testing machine at a monotonic and quasi-static displacement rate up to failure.
Using the identified set of material properties, the hFE-predicted stiffness and failure load were in excellent agreement with respective experimental results at both measurement sites (radius stiffness R2 = 0.93, slope = 1.00, intercept = 479 N/mm2/radius ultimate load: R2 = 0.97, slope = 1.00, intercept = 679 N; tibia stiffness R2 = 0.96, slope = 1.01, intercept = −1027 N/mm2/tibia ultimate load: R2 = 0.97, slope = 1.04, intercept = 394 N; combined dataset stiffness R2 = 0.95, slope = 1.01, intercept = −230 N/mm2/combined dataset ultimate load: R2 = 0.97, slope = 1.03, intercept = 495 N).
In conjunction with unified BV/TV calibration, the established hFE pipeline accurately predicts experimental stiffness and ultimate load of distal multi-sections at the radius and tibia. Processing time for non-linear analysis was substantially reduced compared to previous μFE and hFE methods but could be further minimized by estimating bone strength based on a fast and linear analysis like as is currently done with μ FE.
Structure–activity relationships around a novel series of B-RafV600E inhibitors are reported. The enzymatic and cellular potencies of inhibitors derived from two related hinge-binding groups were ...compared and3-methoxypyrazolopyridine proved to be superior. The 3-alkoxy group of lead B-RafV600E inhibitor 1 was extended and minimally affected potency. The propyl sulfonamide tail of compound 1, which occupies the small lipophilic pocket formed by an outward shift of the αC-helix, was expanded to a series of arylsulfonamides. X-ray crystallography revealed that this lipophilic pocket unexpectedly enlarges to accommodate the bulkier aryl group.
AKI after cardiac surgery remains strongly associated with mortality and lacks effective treatment or prevention. Preclinical studies suggest that cell-based interventions may influence functional ...recovery. We conducted a phase 2, randomized, double-blind, placebo-controlled trial in 27 centers across North America to determine the safety and efficacy of allogeneic human mesenchymal stem cells (MSCs) in reducing the time to recovery from AKI after cardiac surgery. We randomized 156 adult subjects undergoing cardiac surgery with evidence of early AKI to receive intra-aortic MSCs (AC607;
=67) or placebo (
=68). The primary outcome was the time to recovery of kidney function defined as return of postintervention creatinine level to baseline. The median time to recovery of kidney function was 15 days with AC607 and 12 days with placebo (25th, 75th percentile range, 10-29 versus 6-21, respectively; hazard ratio, 0.81; 95% confidence interval, 0.53 to 1.24;
=0.32). We did not detect a significant difference between groups in 30-day all-cause mortality (16.7% with AC607; 11.8% with placebo) or dialysis (10.6% with AC607; 7.4% with placebo). At follow-up, 12 patients who received AC607 and six patients who received placebo had died. Rates of other adverse events did not differ between groups. In these patients with AKI after cardiac surgery, administration of allogeneic MSCs did not decrease the time to recovery of kidney function. Our results contrast with those in preclinical studies and provide important information regarding the potential effects of MSCs in this setting.
To quantify the effects of acute oxygen supplementation on lower limb blood flow (QLEG), O2 delivery (QO2LEG), and O2 uptake (VO2LEG) during exercise and to determine whether the metabolic capacity ...of the lower limb is exhausted at peak exercise during room air breathing in patients with COPD.
Oxygen (FIO2 = 0.75) and air were randomly administered to 14 patients with COPD (FEV1: 35 +/- 2% pred, mean +/- SEM) during two symptom-limited incremental cycle exercise tests. Before exercise, a cannula was installed in a radial artery and a thermodilution catheter inserted in the right femoral vein. At each exercise step, five-breath averages of respiratory rate, tidal volume, and ventilation (VE), dyspnea and leg fatigue scores, arterial and venous blood gases, and QLEG were obtained. From these measurements, VO2LEG was calculated.
Peak exercise capacity increased from 46 +/- 3 W in room air to 59 +/- 5 W when supplemental oxygen was used (P < 0.001). QLEG, QO2LEG, and VO2LEG were greater at peak exercise with O2 than with air (P < 0.05). During submaximal exercise, dyspnea score and VE were significantly reduced with O2 (P < 0.05), whereas QLEG, VO2LEG, and leg fatigue were similar under both experimental conditions. The improvement in peak exercise work rate correlated with the increase in peak QO2LEG (r = 0.66, P < 0.01), peak VO2LEG (r = 0.53, P < 0.05), and reduction in dyspnea at iso-exercise intensity (r = 0.56, P < 0.05).
The improvement in peak exercise capacity with oxygen supplementation could be explained by the reduction in dyspnea at submaximal exercise and the increases in QO2LEG and VO2LEG, which enabled the exercising muscles to perform more external work. These data indicate that the metabolic capacity of the lower limb muscles was not exhausted at peak exercise during room air breathing in these patients with COPD.
The discovery of 2 (GDC-0980), a class I PI3K and mTOR kinase inhibitor for oncology indications, is described. mTOR inhibition was added to the class I PI3K inhibitor 1 (GDC-0941) scaffold primarily ...through the substitution of the indazole in 1 for a 2-aminopyrimidine. This substitution also increased the microsomal stability and the free fraction of compounds as evidenced through a pairwise comparison of molecules that were otherwise identical. Highlighted in detail are analogues of an advanced compound 4 that were designed to improve solubility, resulting in 2. This compound, is potent across PI3K class I isoforms with IC50s of 5, 27, 7, and 14 nM for PI3Kα, β, δ, and γ, respectively, inhibits mTOR with a K i of 17 nM yet is highly selective versus a large panel of kinases including others in the PIKK family. On the basis of the cell potency, low clearance in mouse, and high free fraction, 2 demonstrated significant efficacy in mouse xenografts when dosed as low as 1 mg/kg orally and is currently in phase I clinical trials for cancer.
A majority of patients with idiopathic pulmonary arterial hypertension (IPAH) display persistent exercise intolerance despite new specific therapies. Whether patients with IPAH exhibit peripheral ...muscle dysfunction that may contribute to this limitation remains unknown. The hypothesis that the muscles of patients with IPAH are weaker and display morphological changes compared with those of control subjects and that those changes partly correlate with their exercise capacity was tested.
To characterise quadriceps function, morphology and the enzymatic profile of patients with IPAH.
Exercise capacity, limb muscle cross-sectional area by CT scan, quadriceps strength by maximal voluntary contraction and non-volitional magnetic stimulation of the femoral nerve (quadriceps twitch; TWq), and muscle morphology and enzymatic profile by quadriceps biopsy of 10 patients with IPAH were compared with those of 10 matched controls subjects.
Patients with IPAH displayed a lower proportion of type I muscle fibres (p=0.05), a lower maximal voluntary contraction (p=0.05) and TWq (p=0.01), and an increased muscular phosphofructokinase/3-hydroxyacyl-CoA-dehydrogenase ratio (p=0.05). They also tended to have lower thigh muscle cross-sectional area (p=0.15). Maximal oxygen uptake correlated with quadriceps strength (R(2)=0.42, p=0.04), and oxygen uptake at anaerobic threshold correlated with muscle oxidative capacity assessed by oxidative enzyme level for citrate synthase (R(2)=0.45, p=0.05) and 3-hydroxyacyl-CoA-dehydrogenase (R(2)=0.86, p<0.01), and type I fibre capillarity (R(2)=0.57, p=0.02).
Patients with IPAH present significant peripheral muscle changes that partly correlated with their exercise capacity.
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