Pharmacokinetic modeling of intravenous sildenafil in newborns with congenital diaphragmatic hernia

Purpose: We developed a pharmacokinetic model of intravenous sildenafil in newborns with congenital diaphragmatic hernia (CDH) to achieve a target plasma concentration of over 50 μg/l. Methods: Twenty-three CDH newborns with pulmonary hypertension (64 blood samples) received intravenous sildenafil. Patients received a loading dose of 0.35 mg/kg (IQR 0.16 mg/kg) for 3 h, followed by a continuous infusion of 1.5 mg/kg/day (IQR 0.1 mg/kg/day). For model development, non-linear mixed modeling was used. Inter-individual variability (IIV) and inter-occasion variability were tested. Demographic and laboratory parameters were evaluated as covariates. Normalized prediction distribution errors (NPDE) and visual predictive check (VPC) were used for model validation. Results: A two-compartment disposition model of sildenafil and a one-compartment disposition model of desmethyl sildenafil (DMS) was observed with IIV in sildenafil and DMS clearance and volume of distribution of sildenafil. NPDE and VPC revealed adequate predictability. Only postnatal age increased sildenafil clearance. This was partly compensated by a higher DMS concentration, which also has a therapeutic effect. In this small group of patients, sildenafil was tolerated well. Conclusions: This model for sildenafil in CDH patients shows that concentration-targeted sildenafil dosing of 0.4 mg/kg in 3 h, followed by 1.6 mg/kg/day continuous infusion achieves appropriate sildenafil plasma levels

Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe: The CDH EURO Consortium Consensus - 2015 Update

In 2010, the congenital diaphragmatic hernia (CDH) EURO Consortium published a standardized neonatal treatment protocol. Five years later, the number of participating centers has been raised from 13 to 22. In this article the relevant literature is updated, and consensus has been reached between the members of the CDH EURO Consortium. Key updated recommendations are: (1) planned delivery after a gestational age of 39 weeks in a high-volume tertiary center; (2) neuromuscular blocking agents to be avoided during initial treatment in the delivery room; (3) adapt treatment to reach a preductal saturation of between 80 and 95% and postductal saturation >70%; (4) target PaCO2 to be between 50 and 70 mm Hg; (5) conventional mechanical ventilation to be the optimal initial ventilation strategy, and (6) intravenous sildenafil to be considered in CDH patients with severe pulmonary hypertension. This article represents the current opinion of all consortium members in Europe for the optimal neonatal treatment of CDH

The North American tree-ring fire-scar network

Fire regimes in North American forests are diverse and modern fire records are often too short to capture important patterns, trends, feedbacks, and drivers of variability. Tree-ring fire scars provide valuable perspectives on fire regimes, including centuries-long records of fire year, season, frequency, severity, and size. Here, we introduce the newly compiled North American tree-ring fire-scar network (NAFSN), which contains 2562 sites, >37,000 fire-scarred trees, and covers large parts of North America. We investigate the NAFSN in terms of geography, sample depth, vegetation, topography, climate, and human land use. Fire scars are found in most ecoregions, from boreal forests in northern Alaska and Canada to subtropical forests in southern Florida and Mexico. The network includes 91 tree species, but is dominated by gymnosperms in the genus Pinus. Fire scars are found from sea level to >4000-m elevation and across a range of topographic settings that vary by ecoregion. Multiple regions are densely sampled (e.g., >1000 fire-scarred trees), enabling new spatial analyses such as reconstructions of area burned. To demonstrate the potential of the network, we compared the climate space of the NAFSN to those of modern fires and forests; the NAFSN spans a climate space largely representative of the forested areas in North America, with notable gaps in warmer tropical climates. Modern fires are burning in similar climate spaces as historical fires, but disproportionately in warmer regions compared to the historical record, possibly related to under-sampling of warm subtropical forests or supporting observations of changing fire regimes. The historical influence of Indigenous and non-Indigenous human land use on fire regimes varies in space and time. A 20th century fire deficit associated with human activities is evident in many regions, yet fire regimes characterized by frequent surface fires are still active in some areas (e.g., Mexico and the southeastern United States). These analyses provide a foundation and framework for future studies using the hundreds of thousands of annually- to sub-annually-resolved tree-ring records of fire spanning centuries, which will further advance our understanding of the interactions among fire, climate, topography, vegetation, and humans across North America

Data Descriptor: A global multiproxy database for temperature reconstructions of the Common Era

Reproducible climate reconstructions of the Common Era (1 CE to present) are key to placing industrial-era warming into the context of natural climatic variability. Here we present a community-sourced database of temperature-sensitive proxy records from the PAGES2k initiative. The database gathers 692 records from 648 locations, including all continental regions and major ocean basins. The records are from trees, ice, sediment, corals, speleothems, documentary evidence, and other archives. They range in length from 50 to 2000 years, with a median of 547 years, while temporal resolution ranges from biweekly to centennial. Nearly half of the proxy time series are significantly correlated with HadCRUT4.2 surface temperature over the period 1850-2014. Global temperature composites show a remarkable degree of coherence between high-and low-resolution archives, with broadly similar patterns across archive types, terrestrial versus marine locations, and screening criteria. The database is suited to investigations of global and regional temperature variability over the Common Era, and is shared in the Linked Paleo Data (LiPD) format, including serializations in Matlab, R and Python.(TABLE)Since the pioneering work of D'Arrigo and Jacoby1-3, as well as Mann et al. 4,5, temperature reconstructions of the Common Era have become a key component of climate assessments6-9. Such reconstructions depend strongly on the composition of the underlying network of climate proxies10, and it is therefore critical for the climate community to have access to a community-vetted, quality-controlled database of temperature-sensitive records stored in a self-describing format. The Past Global Changes (PAGES) 2k consortium, a self-organized, international group of experts, recently assembled such a database, and used it to reconstruct surface temperature over continental-scale regions11 (hereafter, ` PAGES2k-2013').This data descriptor presents version 2.0.0 of the PAGES2k proxy temperature database (Data Citation 1). It augments the PAGES2k-2013 collection of terrestrial records with marine records assembled by the Ocean2k working group at centennial12 and annual13 time scales. In addition to these previously published data compilations, this version includes substantially more records, extensive new metadata, and validation. Furthermore, the selection criteria for records included in this version are applied more uniformly and transparently across regions, resulting in a more cohesive data product.This data descriptor describes the contents of the database, the criteria for inclusion, and quantifies the relation of each record with instrumental temperature. In addition, the paleotemperature time series are summarized as composites to highlight the most salient decadal-to centennial-scale behaviour of the dataset and check mutual consistency between paleoclimate archives. We provide extensive Matlab code to probe the database-processing, filtering and aggregating it in various ways to investigate temperature variability over the Common Era. The unique approach to data stewardship and code-sharing employed here is designed to enable an unprecedented scale of investigation of the temperature history of the Common Era, by the scientific community and citizen-scientists alike

An Assessment Of The Dendroclimatic Potential Of Three Conifer Species In Northern Minnesota

Ring-width chronologies from Pinus resinosa Ait., Pinus strobus L., and Thuja occidentalis L. were developed in two areas of the Boundary Waters Canoe Area Wilderness to assess their growth climate response and their potential for developing reconstructions of climate. New red pine chronologies were combined with existing chronologies to extend the ring-width record both into the past and into the present. Ring-width response to climate, assessed using correlation analysis and response functions, was broadly similar among all three species with relatively significant positive relationships with June–July precipitation and significant negative (but less consistent) associations with June–July temperatures (p < 0.05). White-cedar appeared to have a broader phenological window of response with a stronger spring influence when compared to other species included in this study. Comparisons with other nearby proxies showed relatively strong coherence overall but with some important regional differences. Overall, these species may be useful for placing current climatic patterns in the Boundary Waters within a longer term perspective but care should be taken with respect to identifying appropriate climatic records for calibration.This item is part of the Tree-Ring Research (formerly Tree-Ring Bulletin) archive. For more information about this peer-reviewed scholarly journal, please email the Editor of Tree-Ring Research at [email protected]

Tree rings detect earthworm invasions and their effects in northern hardwood forests

Invasions of European earthworms into the forests of northern North America are causing dramatic changes in forest floor structure, vegetation communities, biogeochemical cycling, and site hydrology. However, long-term studies on the effects of invasive earthworms are limited because little data exist on the timing and rate of earthworm invasion at specific sites. We successfully used tree rings to identify the timing of earthworm invasions and the effects of earthworm activity on the Acer saccharum overstory of two recently invaded sites in northern Minnesota, thereby establishing a method to date earthworm invasions at other sites. In addition to identifying a tree-ring signature related to earthworm invasion, we found trees growing in invaded conditions were more sensitive to drought than trees growing in earthworm-free conditions. Increased drought sensitivity by A. saccharum has important implications for possible range shifts under climate change scenarios that include increasing drought frequency and severity