Standards of care for CFTR variant-specific therapy (including modulators) for people with cystic fibrosis

Cystic fibrosis (CF) has entered the era of variant-specific therapy, tailored to the genetic variants in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. CFTR modulators, the first variant-specific therapy available, have transformed the management of CF.The latest standards of care from the European CF Society (2018) did not include guidance on variant-specific therapy, as CFTR modulators were becoming established as a novel therapy. We have produced interim standards to guide healthcare professionals in the provision of variant-specific therapy for people with CF.Here we provide evidence-based guidance covering the spectrum of care, established using evidence from systematic reviews and expert opinion. Statements were reviewed by key stakeholders using Delphi methodology, with agreement (≥80%) achieved for all statements after one round of consultation. Issues around accessibility are discussed and there is clear consensus that all eligible people with CF should have access to variant-specific therapy

The Greenhouse - Icehouse Transition : a dinoflagellate perspective

Through the analysis of the stratigraphic and spatial distribution of organic walled dinoflagellate cysts (dinocysts) from climatologically and oceanographically key sites, this project aims to contribute to a better understanding of the Eocene-Oligocene (E/O) environmental changes and their timing. A central issue is to identify the global environmental changes which are responsible for the Eocene cooling and its underlying mechanisms with the focus on the Oligocene isotope-1 (Oi-1) event, thought to mark the onset of major Antarctic glaciation. Two low-latitude sites were selected, Blake Nose (western North Atlantic) and Massignano (central Italy). For the first time a coherent taxonomy and biostratigraphy of dinocysts was established for the late Eocene at these latitudes. A high resolution correlation was established between the Massignano E/O Stratotype Section and the stratigraphically more extended ‘Massicore’. The composite section was used to analyse sea surface temperature (SST) change across the greenhouse-icehouse transition by means of dinocyst distribution. At Massignano, the Oi-1 event was recognised both qualitatively and quantitatively. In the power spectrum of the SSTdino the ~100 and ~400 kyr eccentricity cycles may be distinguished and correlated with La04. When orbitally tuned, the E/O GSSP dates ~100 kyr older than the Oi-1 event. The boundary’s age could either be ~33.75 or ~34.1 Ma, both differ significantly from the ~33.9 Ma age in the GTS 2004. Furthermore, when the data from the low-latitude sites were combined with extensive datasets from the Proto North Atlantic and adjacent regions, a suite of species sensitive to changes in SST was recognised. Their first and last occurrences reflect seven distinct phases of decreasing SSTs during the Middle Eocene to earliest Oligocene. These results clearly indicate that atmospheric cooling together with higher frequency orbital forcing played a key role in the transition from the Greenhouse to the Icehouse world

(Table T1) Dinoflagellate cyst abundance in ODP Hole 171B-1053A sediments

Site 1053 is located at the top of an escarpment cut into the upper part of Blake Nose (29°59.5385'N, 76°31.4135'W). The total core recovery was 189.5 m of upper middle to upper Eocene deposits. An exceptionally thick upper Eocene section was recovered, consisting mainly of siliceous nannofossil ooze (Norris, Kroon, Klaus, et al., 1998, doi:10.2973/odp.proc.ir.171B.1998). These Eocene sediments are unconsolidated as they were not buried by younger deposits. This chapter discusses the distribution of organic walled dinoflagellate cysts (dinocysts) at Hole 1053A. Bio(chrono)stratigraphic divisions cited here follow the initial assignment by the Leg 171B Shipboard Scientific Party (Norris, Kroon, Klaus, et al., 1998, doi:10.2973/odp.proc.ir.171B.1998)

Applicability of passive sampling to bioanalytical screening of bioaccumulative chemicals in marine wildlife

Quantification of bioaccumulative contaminants in biota is time and cost-intensive and the required extensive cleanup steps make it selective toward targeted chemical groups. Therefore tissue extracts prepared for chemical analysis are not amenable to assess the combined effects of unresolved complex mixtures. Passive equilibrium sampling with polydimethylsiloxane (PDMS) has the potential for unbiased sampling of mixtures, and the PDMS extracts can be directly dosed into cell-based bioassays. The passive sampling approach was tested by exposing PDMS to lipid-rich tissue (dugong blubber; 85% lipid) spiked with a known mixture of hydrophobic contaminants (five congeners of tetra- to octachloro-dibenzo-p-dioxins). The equilibrium was attained within 24 h. Lipid-PDMS partition coefficients (Klip-PDMS) ranged from 20 to 38, were independent of hydrophobicity, and within the range of those previously measured for organochlorine compounds. To test if passive sampling can be combined with bioanalysis without the need for chemical cleanup, spiked blubber-PDMS extracts were dosed into the CAFLUX bioassay, which specifically targets dioxin-like chemicals. Small quantities of lipids coextracted by the PDMS were found to affect the kinetics in the regularly applied 24-h bioassay; however, this effect was eliminated by a longer exposure period (72 h). The validated method was applied to 11 unspiked dugong blubber samples with known (native) dioxin concentrations. These results provide the first proof of concept for linking passive sampling of lipid-rich tissue with cell-based bioassays, and could be further extended to other lipid rich species and a wider range of bioanalytical end points

Chlorinated paraffins in the environment: a review on their production, fate, levels and trends between 2010 and 2015

This review provides an update on information regarding the production volumes, regulations, as well as the environmental levels, trends, fate and human exposure to chlorinated paraffin mixtures (CPs). CPs encompas thousands congeners with varying properties and environmental fate. Based on their carbon chain lengths, CPs are divided into short- (SCCPs; C), medium- (MCCPs; C) and long- (LCCPs; C ) chained groups. They are high production volume and persistent chemicals, and their cumulative global production already surpasses that of other persistent anthropogenic chemicals (e.g. PCBs). However, international regulations are still curbed by insufficient information on their levels and fate, including bioaccumulation and toxicity potential. An increasing number of studies since 2010 demonstrate that CPs are detected in almost every compartment in the environment, including remote areas. Consensus on the long range transport and high bioaccumulation potential (BCF > 5000 & TMF > 1) has recently been reached for SCCPs, fulfilling criteria under the Stockholm Convention for designation as a persistent organic pollutant; information on their levels is, however, still sparse for many countries. M/LCCPs have received comparatively little attention in the past, but as replacement chemicals for SCCPs, MCCPs are now considered in an increasing number of studies. The limited data to date suggests MCCPs are widely used. Although data on their bioaccumulation and toxicity are still inconclusive, MCCPs and LCCPs with C may also have a bioaccumulation potential. Considering this and their high production volumes, use, and ubiquitous occurrence in the environment, a better understanding on the levels and fate of all CPs is needed

Recent developments in capabilities for analysing chlorinated paraffins in environmental matrices: a review

Concems about the high production volumes, persistency, bioaccumulation potential and toxicity of chlorinated paraffin (CP) mixtures, especially short-chain CPs (SCCPs), are rising. However, information on their levels and fate in the environment is still insufficient, impeding international classifications and regulations. This knowledge gap is mainly due to the difficulties that arise with CP analysis, in particular the chromatographic separation within CPs and between CPs and other compounds. No fully validated routine analytical method is available yet and only semi-quantitative analysis is possible, although the number of studies reporting new and improved methods have rapidly increased since 2010. Better cleanup procedures that remove interfering compounds, and new instrumental techniques, which distinguish between medium-chain CPs (MCCPs) and SCCPs, have been developed. While gas chromatography coupled to an electron capture negative ionisation mass spectrometry (GC/ECNI-MS) remains the most commonly applied technique, novel and promising use of high resolution time of flight MS (TOF-MS) has also been reported. We expect that recent developments in high resolution TOF-MS and Orbitrap technologies will further improve the detection of CPs, including long-chain CPs (LCCPs), and the group separation and quantification of CP homologues. Also, new CP quantification methods have emerged, including the use of mathematical algorithms, multiple linear regression and principal component analysis. These quantification advancements are also reflected in considerably improved interlaboratory agreements since 2010. Analysis of lower chlorinated paraffins

Applicability of Passive Sampling to Bioanalytical Screening of Bioaccumulative Chemicals in Marine Wildlife

Quantification of bioaccumulative contaminants in biota is time and cost-intensive and the required extensive cleanup steps make it selective toward targeted chemical groups. Therefore tissue extracts prepared for chemical analysis are not amenable to assess the combined effects of unresolved complex mixtures. Passive equilibrium sampling with polydimethylsiloxane (PDMS) has the potential for unbiased sampling of mixtures, and the PDMS extracts can be directly dosed into cell-based bioassays. The passive sampling approach was tested by exposing PDMS to lipid-rich tissue (dugong blubber; 85% lipid) spiked with a known mixture of hydrophobic contaminants (five congeners of tetra- to octachloro-dibenzo-<i>p</i>-dioxins). The equilibrium was attained within 24 h. Lipid-PDMS partition coefficients (<i>K</i>_lip‑PDMS) ranged from 20 to 38, were independent of hydrophobicity, and within the range of those previously measured for organochlorine compounds. To test if passive sampling can be combined with bioanalysis without the need for chemical cleanup, spiked blubber-PDMS extracts were dosed into the CAFLUX bioassay, which specifically targets dioxin-like chemicals. Small quantities of lipids coextracted by the PDMS were found to affect the kinetics in the regularly applied 24-h bioassay; however, this effect was eliminated by a longer exposure period (72 h). The validated method was applied to 11 unspiked dugong blubber samples with known (native) dioxin concentrations. These results provide the first proof of concept for linking passive sampling of lipid-rich tissue with cell-based bioassays, and could be further extended to other lipid rich species and a wider range of bioanalytical end points

Determination of chlorinated paraffins (CPs): Analytical conundrums and the pressing need for reliable and relevant standards

The determination of chlorinated paraffins (CPs) has posed an intractable challenge in analytical chemistry for over three decades. The combination of an as yet unspecifiable number (tens - hundreds of thousands) of individual congeners in mass produced commercial CP mixtures and the steric interactions between them, contrive to defy efforts to characterise their residual occurrences in environmental compartments, food and human tissues. However, recent advances in instrumentation (mass spectrometric detectors and nuclear magnetic resonance), combined with interlaboratory studies, have allowed a better insight into the nature of the conundrums. These include the variability of results, even between experienced laboratories when there is insufficient matching between analytical standards and occurrence profiles, the poor (or no) response of some instrumentation to some CP congener configurations (multiple terminal chlorines or < four chlorines) and the occurrence of chlorinated olefins in commercial mixtures. The findings illustrate some limitations in the existing set of commercially available standards. These include cross-contamination of some standards (complex CP mixtures), an insufficient number of single chain standards (existing ones do not fully reflect food/biota occurrences), lack of homologue group standards and unsuitability of some configurationally defined CP congeners/labelled standards (poor instrument response and a smaller likelihood of occurrence in commercial mixtures). They also indicate an underestimation in reported occurrences arising from those CPs that are unresponsive during measurement. A more extensive set of standards is suggested and while this might not be a panacea for accurate CP determination, it would reduce the layers of complexity inherent in the analysis