Management of preterm labor: atosiban or nifedipine?

Preterm birth is strongly associated with neonatal death and long-term neurological morbidity. The purpose of tocolytic drug administration is to postpone threatening preterm delivery for 48 hours to allow maximal effect of antenatal corticosteroids and maternal transportation to a center with specialized neonatal care facilities. There is uncertainty about the value of atosiban (oxytocin receptor antagonist) and nifedipine (calcium channel blocker) as first-line tocolytic drugs in the management of preterm labor. For nifedipine, concerns have been raised about unproven safety, lack of placebo-controlled trials, and its off-label use. The tocolytic efficacy of atosiban has also been questioned because of a lack of reduction in neonatal morbidity. This review discusses the available evidence, the pros and cons of either drug and aims to provide information to support a balanced choice of first-line tocolytic drug: atosiban or nifedipine

Turbulent Dispersion in Cloudy Boundary Layers

Compared to dry boundary layers, dispersion in cloud-topped boundary layers has received less attention. In this LES based numerical study we investigate the dispersion of a passive tracer in the form of Lagrangian particles for four kinds of atmospheric boundary layers: 1) a dry convective boundary layer (for reference), 2) a smoke cloud boundary layer in which the turbulence is driven by radiative cooling, 3) a stratocumulus topped boundary layer and 4) a shallow cumulus topped boundary layer. We show that the dispersion characteristics of the smoke cloud boundary layer as well as the stratocumulus situation can be well understood by borrowing concepts from previous studies of dispersion in the dry convective boundary layer. A general result is that the presence of clouds enhances mixing and dispersion – a notion that is not always reflected well in traditional parameterization models, in which clouds usually suppress dispersion by diminishing solar irradiance. The dispersion characteristics of a cumulus cloud layer turn out to be markedly different from the other three cases and the results can not be explained by only considering the well-known top-hat velocity distribution. To understand the surprising characteristics in the shallow cumulus layer, this case has been examined in more detail by 1) determining the velocity distribution conditioned on the distance to the nearest cloud and 2) accounting for the wavelike behaviour associated with the stratified dry environment

Post-migration stressors and their association with symptom reduction and non-completion during treatment for traumatic grief in refugees

Background: Resettled refugees exposed to trauma and loss are at risk to develop mental disorders such as posttraumatic stress disorder (PTSD) and persistent complex bereavement disorder (PCBD). Post-migration stressors have been linked to poor mental health and smaller treatment effects. Aim: Our aim was to evaluate reductions in PTSD and PCBD symptoms and to explore the presence of post-migration stressors and their associations with symptom change and non-completion in a traumatic grief focused treatment in a cohort of refugees. Methods: Paired sample t-tests were used to test the significance of the symptom reductions in PTSD and PCBD symptoms during treatment. The presence of post-migration stressors was derived from a qualitative analysis of the patient files. Associations between post-migration stressors and symptom reductions as well as non-completion were calculated. Results: In this uncontrolled study, 81 files of consecutive patients were included. Significant reductions in both PCBD and PTSD symptomatology with medium effect sizes were found. Patients experienced a mean of three different post-migration stressors during the treatment. Undocumented asylum seekers were more likely to be non-completers. Ongoing conflict in the country of origin was associated with smaller PTSD symptom reductions and the total number of post-migration stressors was associated with smaller PCBD symptom reductions. Conclusions: Treatment for resettled refugees for traumatic grief coincides with alleviations in both PCBD and PTSD symptomatology. Specific post-migration stressors were associated with reduced treatment effects and increased non-completion. This is a first step towards well-informed improvements of mental health interventions for resettled refugees

Live long and PROSPERO: A comment on Chiu and coworkers

The a priori registration of systematic reviews provides a way to describe the methods for a meta-analysis before Review Paper selection commences. Chiu and coworkers report a systematic review of blood pressure variability, deviating from the protocol registered on PROSPERO (CRD42020190429)

Phase I and pharmacokinetic study of DE-310 in patients with advanced solid tumors

PURPOSE: To assess the maximum-tolerated dose, toxicity, and pharmacokinetics of DE-310, a macromolecular prodrug of the topoisomerase I inhibitor exatecan (DX-8951f). in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients received DE-310 as a 3-hour infusion once every 2 weeks (dose, 1.0-2.0 mg/m(2)) or once every 6 weeks (dose, 6.0-9.0 mg/m(2)). Because pharmacokinetics revealed a drug terminal half-life exceeding the 2 weeks administration interval, the protocol was amended to a 6-week interval between administrations also based on available information from a parallel trial using an every 4 weeks schedule. Conjugated DX-8951 (the carrier-linked molecule), and the metabolites DX-8951 and glycyl-DX-8951 were assayed in various matrices up to 35 days post first and second dose. RESULTS: Twenty-seven patients were enrolled into the study and received a total of 86 administrations. Neutropenia and grade 3 thrombocytopenia, and grade 3 hepatotoxicity with veno-occlusive disease, were dose-limiting toxicities. Other hematologic and nonhematologic toxicities were mild to moderate and reversible. The apparent half-life of conjugated DX-8951, glycyl-DX-8951, and DX-8951 was 13 days. The area under the curve ratio for conjugated DX-8951 to DX-8951 was 600. No drug concentration was detectable in erythrocytes, skin, and saliva, although low levels of glycyl-DX-8951 and DX-8951 were detectable in tumor biopsies. One patient with metastatic adenocarcinoma of unknown primary achieved a histologically proven complete remission. One confirmed partial remission was observed in a patient with metastatic pancreatic cancer and disease stabilization was noted in 14 additional patients. CONCLUSIONS: The recommended phase II dose of DE-310 is 7.5 mg/m(2) given once every 6 weeks. The active moiety DX-8951 is released slowly from DE-310 and over an extended period, achieving the desired prolonged exposure to this topoisomerase I inhibitor

Bone health in children with Angelman syndrome at the ENCORE Expertise Center

Angelman syndrome (AS) is a rare genetic disorder due to lack of UBE3A function on chromosome 15q11.2q13 caused by a deletion, uniparental paternal disomy (UPD), imprinting center disorder (ICD), or pathological variant of the UBE3A gene. AS is characterized by developmental delay, epilepsy, and lack of speech. Although fractures are observed frequently in our clinical practice, there are few studies on bone health in AS. The aim of this study is to investigate bone health in children with AS. In this prospective cohort study, we describe bone health in 91 children with AS visiting the ENCORE Expertise Center for AS between April 2010 and December 2021. Bone health was assessed with the bone health index (BHI) in standard deviation score (SDS) measured by digital radiogrammetry of the left hand using BoneXpert software. Risk factors analyzed were age, sex, genetic subtype, epilepsy, anti-seizure medication use, mobility, body mass index (BMI), and onset of puberty. Children with AS had a mean BHI of −1.77 SDS (SD 1.4). A significantly lower BHI was found in children with a deletion (−2.24 SDS) versus non-deletion (−1.02 SDS). Other factors associated with reduced BHI-SDS were inability to walk and late onset of puberty. Children with a history of one or more fractures (22%) had a significantly lower BHI than children without fractures (−2.60 vs −1.56 SDS). Longitudinal analysis showed a significant decrease in BHI-SDS with age in all genetic subtypes. Conclusions: Children with AS have a reduced bone health. Risk factors are deletion genotype, no independent walking, and late onset of puberty. Bone health decreased significantly with age. What is Known: • Children with neurological disorders often have a low bone health and higher risk of fractures. • Little is known about bone health in children with Angelman syndrome (AS). What is New: • Children with AS showed a reduced bone health and this was significantly associated with having a deletion, not being able to walk independently, and late onset of puberty. • Longitudinal analysis showed a significant decrease in bone health as children got older.</p

Formulation of the Dutch Atmospheric Large-Eddy Simulation (DALES) and Overview of Its Applications

The current version of the Dutch Atmospheric Large-Eddy Simulation (DALES) is presented. DALES is a large-eddy simulation code designed for studies of the physics of the atmospheric boundary layer, including convective and stable boundary layers as well as cloudy boundary layers. In addition, DALES can be used for studies of more specific cases, such as flow over sloping or heterogeneous terrain, and dispersion of inert and chemically active species. This paper contains an extensive description of the physical and numerical formulation of the code, and gives an overview of its applications and accomplishments in recent years

Noise Minimization in Cell-Free Gene Expression

Biochemical reactions that involve small numbers of molecules are accompanied by a degree of inherent randomness that results in noisy reaction outcomes. In synthetic biology, the ability to minimize noise particularly during the reconstitution of future synthetic protocells is an outstanding challenge to secure robust and reproducible behavior. Here we show that by encapsulation of a bacterial cell-free gene expression system in water-in-oil droplets, in vitro-synthesized MazF reduces cell-free gene expression noise &gt;2-fold. With stochastic simulations we identify that this noise minimization acts through both increased degradation and the autoregulatory feedback of MazF. Specifically, we find that the expression of MazF enhances the degradation rate of mRNA up to 18-fold in a sequence-dependent manner. This sequence specificity of MazF would allow targeted noise control, making it ideal to integrate into synthetic gene networks. Therefore, including MazF production in synthetic biology can significantly minimize gene expression noise, impacting future design principles of more complex cell-free gene circuits.</p