Soils are important sources of sediment and phosphorus in rural catchments, necessitating the development of mathematical models for impact assessment. In this paper, multiple empirical models are ...tested on an event basis at four nested locations in an intensively managed grassland headwater catchment while accounting for parameter and data uncertainties using extended Generalized Likelihood Uncertainty Estimation (GLUE). The study provides the first template of model comparison under data uncertainty in soil erosion and phosphorus transfer modelling as well as hypotheses of soil and water processes in the study catchment. A fodder field, yielding large sediment and phosphorus concentrations in runoff, is characterized by inter‐event variation in sediment‐discharge relationship, mild intra‐event hysteretic behaviour and seemingly random erosion incidents. Sediment‐discharge variation is partly formalized by parameter variation as a function of antecedent soil moisture, indicative of a gradual shift from transport‐ to source‐limited behaviour, decreasing soil erodibility and/or decreasing initial flow erosivity and transport capacity with increasing antecedent wetness. The catchment outlet appears to be source‐limited while converging flows with different sediment concentrations, variable erosion processes and/or sporadic entrainment of near‐ or in‐stream sediments gain importance. Phosphorus dynamics are strongly linked to those of sediment. Non‐linearities can be explained by preferential transfer of phosphorus‐rich organic matter at small flows while there is no significant evidence of preferential transfer of phosphorus‐rich mineral fines. Iterating between collecting data, constraining uncertainties and rejecting and improving models is suggested as a consistent framework for understanding soil erosion and phosphorus movement.
MicroRNAs that are overexpressed in cystic fibrosis (CF) bronchial epithelial cells (BEC) negatively regulate CFTR and nullify the beneficial effects of CFTR modulators. We hypothesized that it is ...possible to reverse microRNA-mediated inhibition of CFTR using CFTR-specific target site blockers (TSBs) and to develop a drug-device combination inhalation therapy for CF. Lead microRNA expression was quantified in a series of human CF and non-CF samples and in vitro models. A panel of CFTR 3′ untranslated region (UTR)-specific locked nucleic acid antisense oligonucleotide TSBs was assessed for their ability to increase CFTR expression. Their effects on CFTR activity alone or in combination with CFTR modulators were measured in CF BEC models. TSB encapsulation in poly-lactic-co-glycolic acid (PLGA) nanoparticles was assessed as a proof of principle of delivery into CF BECs. TSBs targeting the CFTR 3′ UTR 298–305:miR-145-5p or 166–173:miR-223-3p sites increased CFTR expression and anion channel activity and enhanced the effects of ivacaftor/lumacaftor or ivacaftor/tezacaftor in CF BECs. Biocompatible PLGA-TSB nanoparticles promoted CFTR expression in primary BECs and retained desirable biophysical characteristics following nebulization. Alone or in combination with CFTR modulators, aerosolized CFTR-targeting TSBs encapsulated in PLGA nanoparticles could represent a promising drug-device combination therapy for the treatment for CFTR dysfunction in the lung.
Precise targeting of specific miR-145-5p or miR-223-3p binding sites with target site blockers encapsulated in biocompatible nanoparticles restores CFTR activity and enhances CFTR modulator action in p.Phe508del/p.Phe508del CF bronchial epithelial cells.
Fluid Stewardship of Maintenance Intravenous Fluids Carr, John R.; Hawkins, W. Anthony; Newsome, Andrea Sikora ...
Journal of Pharmacy Practice,
10/2022, Letnik:
35, Številka:
5
Book Review, Journal Article
Recenzirano
Odprti dostop
Despite the frequent use of maintenance intravenous fluids (mIVF) in critically ill patients, limited guidance is available. Notably, fluid overload secondary to mIVF mismanagement is associated with ...significant adverse patient outcomes. The Four Rights (right drug, right dose, right duration, right patient) construct of fluid stewardship has been proposed for the safe evaluation and use of fluids. The purpose of this evidence-based review is to offer practical insights for the clinician regarding mIVF selection, dosing, and duration in line with the Four Rights of Fluid Stewardship.
1 Veterinary Laboratories Agency, Woodham Lane, New Haw, Addlestone, Surrey KT15 3NB, UK
2 FARA, Oak Farm, Harpsden Bottom, Henley-on-Thames, Oxon RG9 4HY, UK
3 NSPAC, DEFRA, Whittington Road, ...Worcester WR5 2SU, UK
4 SARDAS, 27 Laverockdale Park, Edinburgh EH13 0QE, UK
Correspondence Gerald Wells g.a.h.wells{at}vla.defra.gsi.gov.uk
Studies to test the transmissibility of the bovine spongiform encephalopathy (BSE) agent to pigs began in 1989. Parenteral inoculation of the agent by three routes simultaneously (intracranially, intravenously and intraperitoneally) produced disease with an incubation period range of 69150 weeks. Pre-clinical pathological changes were detected in two pigs killed electively at 105 and 106 weeks post-inoculation. Infectivity was detected by bioassay in inbred mice in the CNS of those pigs that developed spongiform encephalopathy. Infectivity was also found in the stomach, jejunum, distal ileum and pancreas of terminally affected pigs. These findings show that pigs are susceptible to BSE. In contrast, disease failed to occur in pigs retained for 7 years after exposure by feeding BSE-affected brain on three separate days, at 12 week intervals. The amounts fed each day were equivalent to the maximum daily intake of meat and bone meal in rations for pigs aged 8 weeks. No infectivity was found in tissues assayed from the pigs exposed orally. This included tissues of the alimentary tract. It is suggested that these pigs did not become infected. The relatively high oral exposure used in these experiments compared with feed-borne exposure in the field may explain the absence of an epidemic of spongiform encephalopathy in domestic pigs concurrent with the BSE epidemic in the UK.
Summary Background Although statin therapy reduces the risk of occlusive vascular events in people with diabetes mellitus, there is uncertainty about the effects on particular outcomes and whether ...such effects depend on the type of diabetes, lipid profile, or other factors. We undertook a prospective meta-analysis to help resolve these uncertainties. Methods We analysed data from 18 686 individuals with diabetes (1466 with type 1 and 17 220 with type 2) in the context of a further 71 370 without diabetes in 14 randomised trials of statin therapy. Weighted estimates were obtained of effects on clinical outcomes per 1·0 mmol/L reduction in LDL cholesterol. Findings During a mean follow-up of 4·3 years, there were 3247 major vascular events in people with diabetes. There was a 9% proportional reduction in all-cause mortality per mmol/L reduction in LDL cholesterol in participants with diabetes (rate ratio RR 0·91, 99% CI 0·82–1·01; p=0·02), which was similar to the 13% reduction in those without diabetes (0·87, 0·82–0·92; p<0·0001). This finding reflected a significant reduction in vascular mortality (0·87, 0·76–1·00; p=0·008) and no effect on non-vascular mortality (0·97, 0·82–1·16; p=0·7) in participants with diabetes. There was a significant 21% proportional reduction in major vascular events per mmol/L reduction in LDL cholesterol in people with diabetes (0·79, 0·72–0·86; p<0·0001), which was similar to the effect observed in those without diabetes (0·79, 0·76–0·82; p<0·0001). In diabetic participants there were reductions in myocardial infarction or coronary death (0·78, 0·69–0·87; p<0·0001), coronary revascularisation (0·75, 0·64–0·88; p<0·0001), and stroke (0·79, 0·67–0·93; p=0·0002). Among people with diabetes the proportional effects of statin therapy were similar irrespective of whether there was a prior history of vascular disease and irrespective of other baseline characteristics. After 5 years, 42 (95% CI 30–55) fewer people with diabetes had major vascular events per 1000 allocated statin therapy. Interpretation Statin therapy should be considered for all diabetic individuals who are at sufficiently high risk of vascular events.
Temozolomide (TMZ) has been the standard-of-care chemotherapy for glioblastoma (GBM) patients for more than a decade. Despite this long time in use, significant questions remain regarding how best to ...optimize TMZ therapy for individual patients. Understanding the relationship between TMZ response and factors such as number of adjuvant TMZ cycles, patient age, patient sex, and image-based tumor features, might help predict which GBM patients would benefit most from TMZ, particularly for those whose tumors lack O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation.
Using a cohort of 90 newly-diagnosed GBM patients treated according to the standard of care, we examined the relationships between several patient and tumor characteristics and volumetric and survival outcomes during adjuvant chemotherapy. Volumetric changes in MR imaging abnormalities during adjuvant therapy were used to assess TMZ response. T1Gd volumetric response is associated with younger patient age, increased number of TMZ cycles, longer time to nadir volume, and decreased tumor invasiveness. Moreover, increased adjuvant TMZ cycles corresponded with improved volumetric response only among more nodular tumors, and this volumetric response was associated with improved survival outcomes. Finally, in a subcohort of patients with known MGMT methylation status, methylated tumors were more diffusely invasive than unmethylated tumors, suggesting the improved response in nodular tumors is not driven by a preponderance of MGMT methylated tumors.
Our finding that less diffusely invasive tumors are associated with greater volumetric response to TMZ suggests patients with these tumors may benefit from additional adjuvant TMZ cycles, even for those without MGMT methylation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Nepenthes pitcher plants trap prey in specialized leaves formed into pitchers. Most lowland species live in open, sunny habitats and capture prey to obtain nutrients, principally nitrogen (N). ...Nepenthes ampullaria is commonly found under closed canopy forest and possesses morphological traits that indicate adaptation to trap leaf litter as a nutrient source. We tested this hypothesis by comparing foliar stable N isotope abundance (δ15N) between plants growing under forest canopy at 20 sites (litterfall present) and those growing in 20 open areas (no litterfall) in Borneo. Foliar δ15N values were significantly lower and total N concentrations were higher for the plants with access to litterfall. Using a mixing model, we estimated that N. ampullaria plants growing under forest canopy derived
\documentclass{aastex}
\usepackage{amsbsy}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{bm}
\usepackage{mathrsfs}
\usepackage{pifont}
\usepackage{stmaryrd}
\usepackage{textcomp}
\usepackage{portland,xspace}
\usepackage{amsmath,amsxtra}
\usepackageOT2,OT1{fontenc}
\newcommand\cyr{
\renewcommand\rmdefault{wncyr}
\renewcommand\sfdefault{wncyss}
\renewcommand\encodingdefault{OT2}
\normalfont
\selectfont}
\DeclareTextFontCommand{\textcyr}{\cyr}
\pagestyle{empty}
\DeclareMathSizes{10}{9}{7}{6}
\begin{document}
\landscape
$$35.7\% \pm 0.1\% $$
\end{document}
of their foliar N from leaf litter inputs.
PDF
