105 research outputs found
MAPS - a computerized management analysis and planning system
Program lists work structure of projects at all levels. System integrates work item, its schedule, its status against the schedule, responsible personnel, and explanatory comments. structure of MAPS promotes natural organization of project work elements, project features and uses are given
Sequestration of Voriconazole and Vancomycin Into Contemporary Extracorporeal Membrane Oxygenation Circuits: Anin vitroStudy
Background: Bacterial and fungal infections are common and often contribute to death
in patients undergoing extracorporeal membrane oxygenation (ECMO). Drug disposition
is altered during ECMO, and adsorption in the circuit is an established causative factor.
Vancomycin and voriconazole are widely used, despite the lack of evidence-based
prescription guidelines.
Objective: The objective of this study was to determine the extraction of voriconazole
and vancomycin by the Xenios/Novalung ECMO circuits.
Methods: We have set up nine closed-loop ECMO circuits, consisting of four different
iLAActivve® kits for neonatal, pediatric, and adult support: three iLA-ActivveMiniLung®
petite kits, two iLA-ActivveMiniLung® kits, two iLA-ActivveiLA® kits, and two iLA-Activve
X-lung® kits. The circuits were primed with whole blood and maintained at physiologic
conditions for 24 h. Voriconazole and vancomycin were injected as a single-bolus
age-related dose into the circuits. Pre-membrane (P2) blood samples were obtained at
baseline and after drug injection at 2, 10, 30, 180, 360 min, and 24 h. A control sample
at 2 min was collected for spontaneous drug degradation testing at 24 h.
Results: Seventy-two samples were analyzed in triplicate. The mean percentage of drug
recovery at 24 h was 20% for voriconazole and 62% for vancomycin.
Conclusions: The extraction of voriconazole and vancomycin by contemporary ECMO
circuits is clinically relevant across all age-related circuit sizes and may result in reduced
drug exposure in vivo
Cyclic nucleotide-dependent relaxation in human umbilical vessels
Umbilical vessels have a low sensitivity to dilate, and this property is speculated to have physiological implications. We aimed to investigate the different relaxing responses of human umbilical arteries (HUAs) and veins (HUVs) to agonists acting through the cAMP and cGMP pathways. Vascular rings were suspended in organ baths for isometric force measurement. Following precontraction with the thromboxane prostanoid (TP) receptor agonist U44069, concentration-response curves to the nitric oxide (NO) donor sodium nitroprusside (SNP), the soluble guanylate cyclase (sGC) stimulator BAY 41-2272, the adenylate cyclase (AC) activator forskolin, the \u3b2-adrenergic receptor agonists isoproterenol (ADRB1), salmeterol (ADRB2), and BRL37344 (ADRB3), and the phosphodiesterase (PDE) inhibitors milrinone (PDE3), rolipram (PDE4), and sildenafil (PDE5) were performed. None of the tested drugs induced a relaxation higher than 30% of the U44069-induced tone. Rings from HUAs and HUVs showed a similar relaxation to forskolin, SNP, PDE inhibitors, and ADRB agonists. BAY 41-2272 was significantly more efficient in relaxing veins than arteries. ADRB agonists evoked weak relaxations (< 20%), which were impaired in endothelium-removed vessels or in the presence of the NO synthase inhibitor L-NAME, sGC inhibitor ODQ. PKA and PKG inhibitors impaired ADBR1-mediated relaxation but did not affect ADRB2-mediated relaxation. ADRB3-mediated relaxation was impaired by PKG inhibition in HUAs and by PKA inhibition in HUVs. Although HUA and HUV rings were relaxed by BRL37344, immunohistochemistry and RT-qPCR analysis showed that, compared to ADRB1 and ADRB2, ADRB3 receptors are weakly or not expressed in umbilical vessels. In conclusion, our study confirmed the low relaxing capacity of HUAs and HUVs from term infants. ADRB-induced relaxation is partially mediated by endothelium-derived NO pathway in human umbilical vessels
Drug Disposition and Pharmacotherapy in Neonatal ECMO: From Fragmented Data to Integrated Knowledge
Extracorporeal membrane oxygenation (ECMO) is a lifesaving support technology for
potentially reversible neonatal cardiac and/or respiratory failure. As the survival and the
overall outcome of patients rely on the treatment and reversal of the underlying disease,
effective and preferentially evidence-based pharmacotherapy is crucial to target recovery.
Currently limited data exist to support the clinicians in their every-day intensive care
prescribing practice with the contemporary ECMO technology. Indeed, drug dosing to
optimize pharmacotherapy during neonatal ECMO is a major challenge. The impact
of the maturational changes of the organ function on both pharmacokinetics (PK) and
pharmacodynamics (PD) has been widely established over the last decades. Next to the
developmental pharmacology, additional non-maturational factors have been recognized
as key-determinants of PK/PD variability. The dynamically changing state of critical illness
during the ECMO course impairs the achievement of optimal drug exposure, as a result
of single or multi-organ failure, capillary leak, altered protein binding, and sometimes a
hyperdynamic state, with a variable effect on both the volume of distribution (Vd) and
the clearance (Cl) of drugs. Extracorporeal membrane oxygenation introduces further
PK/PD perturbation due to drug sequestration and hemodilution, thus increasing the
Vd and clearance (sequestration). Drug disposition depends on the characteristics of
the compounds (hydrophilic vs. lipophilic, protein binding), patients (age, comorbidities,
surgery, co-medications, genetic variations), and circuits (roller vs. centrifugal-based
systems; silicone vs. hollow-fiber oxygenators; renal replacement therapy). Based on the
potential combination of the above-mentioned drug PK/PD determinants, an integrated
approach in clinical drug prescription is pivotal to limit the risks of over- and under-dosing.
The understanding of the dose-exposure-response relationship in critically-ill neonates on
ECMO will enable the optimization of dosing strategies to ensure safety and efficacy for
the individual patient. Next to in vitro and clinical PK data collection, physiologically-based
pharmacokinetic modeling (PBPK) are emerging as alternative approaches to provide bedside dosing guidance. This article provides an overview of the available
evidence in the field of neonatal pharmacology during ECMO. We will identify the main
determinants of altered PK and PD, elaborate on evidence-based recommendations on
pharmacotherapy and highlight areas for further research
A maChine and deep Learning Approach to predict pulmoNary hyperteNsIon in newbornS with congenital diaphragmatic Hernia (CLANNISH): Protocol for a retrospective study
Introduction Outcome predictions of patients with congenital diaphragmatic hernia (CDH) still have some limitations in the prenatal estimate of postnatal pulmonary hypertension (PH). We propose applying Machine Learning (ML), and Deep Learning (DL) approaches to fetuses and newborns with CDH to develop forecasting models in prenatal epoch, based on the integrated analysis of clinical data, to provide neonatal PH as the first outcome and, possibly: Favorable response to fetal endoscopic tracheal occlusion (FETO), need for Extracorporeal Membrane Oxygenation (ECMO), survival to ECMO, and death. Moreover, we plan to produce a (semi)automatic fetus lung segmentation system in Magnetic Resonance Imaging (MRI), which will be useful during project implementation but will also be an important tool itself to standardize lung volume measures for CDH fetuses. Methods and analytics Patients with isolated CDH from singleton pregnancies will be enrolled, whose prenatal checks were performed at the Fetal Surgery Unit of the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (Milan, Italy) from the 30th week of gestation. A retrospective data collection of clinical and radiological variables from newborns' and mothers' clinical records will be performed for eligible patients born between 01/01/2012 and 31/12/2020. The native sequences from fetal magnetic resonance imaging (MRI) will be collected. Data from different sources will be integrated and analyzed using ML and DL, and forecasting algorithms will be developed for each outcome. Methods of data augmentation and dimensionality reduction (feature selection and extraction) will be employed to increase sample size and avoid overfitting. A software system for automatic fetal lung volume segmentation in MRI based on the DL 3D U-NET approach will also be developed. Ethics and dissemination This retrospective study received approval from the local ethics committee (Milan Area 2, Italy). The development of predictive models in CDH outcomes will provide a key contribution in disease prediction, early targeted interventions, and personalized management, with an overall improvement in care quality, resource allocation, healthcare, and family savings. Our findings will be validated in a future prospective multicenter cohort study
Propranolol 0.2% eye micro-drops for retinopathy of prematurity : a prospective phase IIb study
Background: Oral propranolol reduces retinopathy of prematurity (ROP) progression, although not safely. Propranolol 0.1% eye micro-drops administered to newborns with stage 2 ROP are well-tolerated, but not sufficiently effective. Methods: A multi-center open-label trial was conducted to assess the safety and efficacy of propranolol 0.2% eye micro-drops in newborns with stage 1 ROP. The progression of the disease was evaluated with serial ophthalmologic examinations. Hemodynamic, respiratory, biochemical parameters, and propranolol plasma levels were monitored. Demographic and perinatal characteristics, co-morbidities and co-intervention incidences, together with ROP progression, were compared with a historical control group in the same centers participating in the trial. Results: Ninety-eight newborns were enrolled and compared with the historical control group. Populations were not perfectly homogeneous (as demonstrated by the differences in the Apgar score and the different incidence rate in surfactant administration and oxygen exposure). The progression to ROP stage 2 or 3 plus was significantly lower than the incidence expected on the basis of historical data (Risk Ratio 0.521, 95% CI 0.297- 0.916). No adverse effects related to propranolol were observed and the mean propranolol plasma level was significantly lower than the safety cutoff of 20 ng/mL. Unexpectedly, three newborns treated with oral propranolol before the appearance of ROP, showed a ROP that was unresponsive to propranolol eye micro-drops and required laser photocoagulation treatment. Conclusion: Propranolol 0.2% eye micro-drops were well-tolerated and appeared to reduce the ROP progression expected on the basis of a comparison with a historical control group. Propranolol administered too early appears to favor a more aggressive ROP, suggesting that a \u3b2-adrenoreceptor blockade is only useful during the proliferative phase. Further randomized placebo-controlled trials are required to confirm the current results
The CoDiNOS trial protocol: an international randomised controlled trial of intravenous sildenafil versus inhaled nitric oxide for the treatment of pulmonary hypertension in neonates with congenital diaphragmatic hernia
INTRODUCTION: Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that impairs normal lung development, causing pulmonary hypertension (PH). PH in CDH newborns is the main determinant for morbidity and mortality. Different therapies are still mainly based on 'trial and error'. Inhaled nitric oxide (iNO) is often the drug of first choice. However, iNO does not seem to improve mortality. Intravenous sildenafil has reduced mortality in newborns with PH without CDH, but prospective data in CDH patients are lacking. METHODS AND ANALYSIS: In an open label, multicentre, international randomised controlled trial in Europe, Canada and Australia, 330 newborns with CDH and PH are recruited over a 4-year period (2018-2022). Patients are randomised for intravenous sildenafil or iNO. Sildenafil is given in a loading dose of 0.4 mg/kg in 3 hours; followed by continuous infusion of 1.6 mg/kg/day, iNO is dosed at 20 ppm. Primary outcome is absence of PH on day 14 without pulmonary vasodilator therapy and/or absence of death within the first 28 days of life. Secondary outcome measures include clinical and echocardiographic markers of PH in the first year of life. We hypothesise that sildenafil gives a 25% reduction in the primary outcome from 68% to 48% on day 14, for which a sample size of 330 patients is needed. An intention-to-treat analysis will be performed. A p-value (two-sided) <0.05 is considered significant in all analyses. ETHICS AND DISSEMINATION: Ethics approval has been granted by the ethics committee in Rotterdam (MEC-2017-324) and the central Committee on Research Involving Human Subjects (NL60229.078.17) in the Netherlands. The principles of the Declaration of Helsinki, the Medical Research Involving Human Subjects Act and the national rules and regulations on personal data protection will be used. Parental informed consent will be obtained. TRIAL REGISTRATION NUMBER: NTR6982; Pre-results
Pain in the cancer patient : different pain characteristics CHANGE pharmacological treatment requirements
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Prevalencia y estacionalidad de la Pediculosis capitis en la poblaciĂłn infante-juvenil de la region sanitaria, Buenos Aires, Argentina
The Potential Role of an Extended-Release, Abuse-Deterrent Oxycodone/Acetaminophen Fixed-Dose Combination Product for the Treatment of Acute Pain
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