Pharmacological aspects of neonatal antidepressant withdrawal

Depression is common in reproductive age women, and continued pharmacologic treatment of depression during pregnancy may be necessary to prevent relapse, which could be harmful for both the fetus and the mother. Although data on drug safety are imperfect and incomplete, the benefits of antidepressant therapy during pregnancy generally outweigh the risks. Neonates who are exposed to antidepressant medications during gestation are at increased risk to have neonatal withdrawal syndrome, although the exact incidence of this complication is unknown because the definition of the syndrome is not clear and withdrawal reactions are probably underreported. Tricyclic antidepressant withdrawal syndrome is most likely related to muscarinergic activity and individual drug half-lives, and selective serotonin reuptake inhibitor withdrawal may be due to a decrease in available synaptic serotonin in the face of down-regulated serotonin receptors, the secondary effects of other neurotransmitters, and biological or cognitive sensitivity. Other factors that influence neonatal toxicity or withdrawal include the normal physiologic changes of pregnancy, the altered activity of CYP450 enzymes during pregnancy, drug-drug transporter (PgP and OCT3) interaction, and the presence of genetic polymorphisms in genes influencing drug metabolism. Further research is necessary

Time-resolved optical shadowgraphy of solid hydrogen jets as a testbed to benchmark particle-in-cell simulations

Particle-in-cell (PIC) simulations are a superior tool to model kinetics-dominated plasmas in relativistic and ultrarelativistic laser-solid interactions (dimensionless vectorpotential $a_0 > 1$). The transition from relativistic to subrelativistic laser intensities ($a_0 \lesssim 1$), where correlated and collisional plasma physics become relevant, is reaching the limits of available modeling capabilities. This calls for theoretical and experimental benchmarks and the establishment of standardized testbeds. In this work, we develop such a suitable testbed to experimentally benchmark PIC simulations using a laser-irradiated micron-sized cryogenic hydrogen-jet target. Time-resolved optical shadowgraphy of the expanding plasma density, complemented by hydrodynamics and ray-tracing simulations, is used to determine the bulk-electron temperature evolution after laser irradiation. As a showcase, a study of isochoric heating of solid hydrogen induced by laser pulses with a dimensionless vectorpotential of $a_0 \approx 1$ is presented. The comparison of the bulk-electron temperature of the experiment with systematic scans of PIC simulations demostrates that, due to an interplay of vacuum heating and resonance heating of electrons, the initial surface-density gradient of the target is decisive to reach quantitative agreement at \SI{1}{\ps} after the interaction. The showcase demostrates the readiness of the testbed for controlled parameter scans at all laser intensities of $a_0 \lesssim 1$

Recombinant human activated protein C in the treatment of acute respiratory distress syndrome

Rationale: Pulmonary coagulopathy may play a pathogenetic role in acute respiratory distress syndrome (ARDS), by contributing to alveolocapillary inflammation and increased permeability. Recombinant human activated protein C (rh-APC) may inhibit this process and thereby improve patient outcome. Methods: A prospective randomized, saline-controlled, single-blinded clinical trial was performed in the intensive care units of two university hospitals, and patients with ARDS were included within 24 h after meeting inclusion criteria. Intervention: A 4-day course of intravenous rh-APC (24 mcg/kg/h) (n = 33) versus saline (n = 38). Outcomes: The primary outcome parameter was the pulmonary leak index (PLI) of 67Gallium-transferrin as a measure of alveolocapillary permeability and secondary outcomes were disease severity scores and ventilator-free days, among others. Results: Baseline characteristics were similar; in 87% of patients the PLI was above normal and in 90% mechanical or noninvasive ventilation was instituted at a median lung injury score of 2.5. There was no evidence that Rh-APC treatment affected the PLI or attenuated lung injury and sequential organ failure assessment scores. Mean ventilator-free days amounted to 14 (rh-APC) and 12 days (saline, P = 0.35). 28-day mortality was 6% in rh-APC- and 18% in saline-treated patients (P = 0.12). There was no difference in bleeding events. The study was prematurely discontinued because rh-APC was withdrawn from the market. Conclusion: There is no evidence that treatment with intravenous rh-APC during 4 days for infectious or inflammatory ARDS ameliorates increased alveolocapillary permeability or the clinical course of ARDS patients. We cannot exclude underpowering. Trial Registration: Nederlands Trial Registe

Distributed Computing Grid Experiences in CMS

The CMS experiment is currently developing a computing system capable of serving, processing and archiving the large number of events that will be generated when the CMS detector starts taking data. During 2004 CMS undertook a large scale data challenge to demonstrate the ability of the CMS computing system to cope with a sustained data-taking rate equivalent to 25% of startup rate. Its goals were: to run CMS event reconstruction at CERN for a sustained period at 25 Hz input rate; to distribute the data to several regional centers; and enable data access at those centers for analysis. Grid middleware was utilized to help complete all aspects of the challenge. To continue to provide scalable access from anywhere in the world to the data, CMS is developing a layer of software that uses Grid tools to gain access to data and resources, and that aims to provide physicists with a user friendly interface for submitting their analysis jobs. This paper describes the data challenge experience with Grid infrastructure and the current development of the CMS analysis system

Dynamics of the bacterial gut microbiota in preterm and term infants after intravenous amoxicillin/ceftazidime treatment

BACKGROUND: It is important to understand the consequences of pre-emptive antibiotic treatment in neonates, as disturbances in microbiota development during this key developmental time window might affect early and later life health outcomes. Despite increasing knowledge regarding the detrimental effect of antibiotics on the gut microbiota, limited research focussed on antibiotic treatment duration. We determined the effect of short and long amoxicillin/ceftazidime administration on gut microbiota development during the immediate postnatal life of preterm and term infants. METHODS: Faeces was collected from 63 (pre) term infants at postnatal weeks one, two, three, four and six. Infants received either no (control), short-term (ST) or long-term (LT) postpartum amoxicillin/ceftazidime treatment. RESULTS: Compared to control infants, ST and LT infants' microbiota contained significantly higher abundance of Enterococcus during the first two postnatal weeks at the expense of Bifidobacterium and Streptococcus. Short and long antibiotic treatment both allowed for microbiota restoration within the first six postnatal weeks. However, Enterococcus and Bifidobacterium abundances were affected in fewer ST than LT infants. CONCLUSIONS: Intravenous amoxicillin/ceftazidime administration affects intestinal microbiota composition by decreasing the relative abundance of Escherichia-Shigella and Streptococcus, while increasing the relative abundance of Enterococcus and Lactobacillus species during the first two postnatal weeks. Thriving of enterococci at the expense of bifidobacteria and streptococci should be considered as aspect of the cost-benefit determination for antibiotic prescription.</p

The transcriptional profile of coronary arteritis in Kawasaki disease

BackgroundKawasaki Disease (KD) can cause potentially life-threatening coronary arteritis in young children, and has a likely infectious etiology. Transcriptome profiling is a powerful approach to investigate gene expression in diseased tissues. RNA sequencing of KD coronary arteries could elucidate the etiology and the host response, with the potential to improve KD diagnosis and/or treatment.MethodsDeep RNA sequencing was performed on KD (n = 8) and childhood control (n = 7) coronary artery tissues, revealing 1074 differentially expressed mRNAs. Non-human RNA sequences were subjected to a microbial discovery bioinformatics platform, and microbial sequences were analyzed by Metastats for association with KD.ResultsT lymphocyte activation, antigen presentation, immunoglobulin production, and type I interferon response were significantly upregulated in KD arteritis, while the tumor necrosis factor α pathway was not differentially expressed. Transcripts from known infectious agents were not specifically associated with KD coronary arteritis.ConclusionsThe immune transcriptional profile in KD coronary artery tissues has features of an antiviral immune response such as activated cytotoxic T lymphocyte and type I interferon-induced gene upregulation. These results provide new insights into the pathogenesis of KD arteritis that can guide selection of new immunomodulatory therapies for high-risk KD patients, and provide direction for future etiologic studies

Paracetamol serum concentrations in preterm infants treated with paracetamol intravenously: a case series

<p>Abstract</p> <p>Introduction</p> <p>Until now, studies on paracetamol given intravenously have mainly been performed with the pro-drug propacetamol or with paracetamol in preterm babies above 32 weeks of gestation. Studies in these babies indicate that intravenous paracetamol is tolerated well, however studies on the efficacy of intravenous paracetamol are lacking. There are no pharmacokinetic data on the administration of multiple doses of paracetamol in preterm babies with a gestational age below 32 weeks.</p> <p>Case presentation</p> <p>We present a case series of nine Caucasian preterm babies, six boys and three girls, with a mean gestational age of 28.6 weeks (range 25.9 to 31.6 weeks). Case one, a girl with a gestational age of 25 weeks and six days, presented with necrotizing enterocolitis. In the second case, a female baby with a gestational age of 26 weeks and two days presented with hematoma. In case three, a female baby with a gestation of 26 weeks and one day developed intraventricular hemorrhage. In case four, a male baby with a gestational age of 31 weeks and four days presented with pain after vacuum delivery. Case five, a female baby born after a gestation of 29 weeks and six days presented with hematoma. In case six, a male baby with a gestation of 30 weeks and six days presented with hematoma. In case seven, a male baby, born with a gestational age of 30 weeks and six days, presented with caput succedaneum and hematoma. In case eight, a male baby, born after a gestation of 28 weeks and four days, developed abdominal distention. Case nine, a female baby, born with a gestational age of 27 weeks and three days presented with hematoma. These babies were treated with intravenous paracetamol 15 mg/kg every six hours. Serum concentrations and aspartate transaminase were determined after prolonged administration. Pain scores were assessed using the Premature Infant Pain Profile.</p> <p>Conclusion</p> <p>Paracetamol serum concentrations ranged from 8 to 64 mg/L after eight to 12 doses of intravenous paracetamol. Adequate analgesia was obtained in seven babies. During paracetamol therapy the median serum level of aspartate transaminase was 20 U/L (range 12 to 186 U/L). This case series indicates that prolonged intravenous administration of paracetamol in preterm babies with a gestational age of less than 32 weeks is tolerated well in the first days after birth. However, in the absence of proper pharmacokinetic data in this age group we cannot advocate the use of paracetamol intravenously.</p

Integrated care for older multimorbid heart failure patients:protocol for the ESCAPE randomized trial and cohort study

ESCAPE Evaluation of a patient-centred biopsychosocial blended collaborative care pathway for the treatment of multimorbid elderly patients. Therapeutic Area Healthcare interventions for the management of older patients with multiple morbidities. Aims Multi-morbidity treatment is an increasing challenge for healthcare systems in ageing societies. This comprehensive cohort study with embedded randomized controlled trial tests an integrated biopsychosocial care model for multimorbid elderly patients. Hypothesis A holistic, patient-centred pro-active 9-month intervention based on the blended collaborative care (BCC) approach and enhanced by information and communication technologies can improve health-related quality of life (HRQoL) and disease outcomes as compared with usual care at 9 months. Methods Across six European countries, ESCAPE is recruiting patients with heart failure, mental distress/disorder plus ≥2 medical co-morbidities into an observational cohort study. Within the cohort study, 300 patients will be included in a randomized controlled assessor-blinded two-arm parallel group interventional clinical trial (RCT). In the intervention, trained care managers (CMs) regularly support patients and informal carers in managing their multiple health problems. Supervised by a clinical specialist team, CMs remotely support patients in implementing the treatment plan—customized to the patients' individual needs and preferences—into their daily lives and liaise with patients' healthcare providers. An eHealth platform with an integrated patient registry guides the intervention and helps to empower patients and informal carers. HRQoL measured with the EQ-5D-5L as primary endpoint, and secondary outcomes, that is, medical and patient-reported outcomes, healthcare costs, cost-effectiveness, and informal carer burden, will be assessed at 9 and ≥18 months. Conclusions If proven effective, the ESCAPE BCC intervention can be implemented in routine care for older patients with multiple morbidities across the participating countries and beyond

The bilirubin albumin ratio in the management of hyperbilirubinemia in preterm infants to improve neurodevelopmental outcome: A randomized controlled trial - BARTrial

Background and Objective: High bilirubin/albumin (B/A) ratios increase the risk of bilirubin neurotoxicity. The B/A ratio may be a valuable measure, in addition to the total serum bilirubin (TSB), in the management of hyperbilirubinemia. We aimed to assess whether the additional use of B/A ratios in the management of hyperbilirubinemia in preterm infants improved neurodevelopmental outcome. Methods: In a prospective, randomized controlled trial, 615 preterm infants of 32 weeks' gestation or less were randomly assigned to treatment based on either B/A ratio and TSB thresholds (consensus-based), whichever threshold was crossed first, or on the TSB thresholds only. The primary outcome was neurodevelopment at 18 to 24 months' corrected age as assessed with the Bayley Scales of Infant Development III by investigators unaware of treatment allocation. Secondary outcomes included complications of preterm birth and death. Results: Composite motor (100±13 vs. 101±12) and cognitive (101±12 vs. 101±11) scores did not differ between the B/A ratio and TSB groups. Demographic characteristics, maximal TSB levels, B/A ratios, and other secondary outcomes were similar. The rates of death and/or severe neurodevelopmental impairment for th