Lithium-thermal double indicator dilution: a new method of extravascular lung water measurement in the critically ill?

MD (Res)There is evidence to suggest that therapy targeted at normalising extravascular lung water volume (EVLW) can improve outcomes from critical illness. Indocyanine green-thermal double indicator dilution (ICG-thermal) is considered the clinical reference standard of EVLW volume measurement but is no longer commercially available. The accuracy and reliability of the only clinically available technology (single-thermal indicator dilution) has been questioned in several studies. This thesis incorporates two clinical studies and one laboratory study designed to assess the measurement of EVLW and intrathoracic blood volumes using a prototype lithium-thermal double indicator dilution technique. The proof of concept study suggested our hypothesis that intrathoracic blood volume (ITBV), which is required for the calculation of EVLW volume, could be determined using lithium indicator dilution, was valid. Peri-operative trends and absolute values of ITBV were consistent with those obtained using ICG-thermal in a similar patient study group. The median absolute value of ITBV measured at baseline using indocyanine green (1417 [±208] ml) was similar to that obtained using lithium indicator dilution 1542 (±601) ml. EVLW volume measured by three indicator dilution techniques was then compared to postmortem gravimetry in porcine models of acute lung injury. Sepsis and acute lung injury were associated with increased EVLW volume, (9.2 [±3.0] ml kg-1), compared to sham operated animals (6.6 [±0.45] ml kg-1) in keeping with previous studies. The Li-thermal (Bias-1.8 [±13.1] ml kg-1) and ICG-thermal (Bias-1.0 [±6.6] ml kg-1) techniques demonstrated acceptable accuracy, but wide limits of agreement suggested poor reliability. 4 The single-thermal technique systematically over-estimated EVLW, with unacceptably wide limits of agreement (Bias +8.5 [±14.5] ml kg-1). In this laboratory investigation, the double indicator methods appeared more reliable than the single-thermal technique. However none could be considered ideal. Results of the final clinical study suggested EVLW volume measurement in man with the Li-thermal method was clearly erroneous (Bias -7.6 [±7.4] ml kg-1) and compared poorly to simultaneous measurements made using the ICG-thermal method (Bias +13.2 [±14.4] ml kg-1). A considerable over-estimation of mean transit time (MTT) when compared to the ICG-thermal technique (Bias 12.8 [±13] sec) was observed, a likely consequence of using an external lithium ion electrode instead of an intra-arterial catheter. Manual analysis of the dilution curves suggested considerable variability when compared to the automated analysis. The poor accuracy of MTT, and consequently ITBV measurements in the clinical study, may partly be due to software analysis of the lithium dilution curves. Thoracic blood volumes derived from measurement of ICG transit time are reliable. However, EVLW calculations based on the thermal indicator transit time are likely to be inaccurate. The findings of these clinical and laboratory investigations demonstrate poor agreement between both the prototype Li-thermal and the single thermal measurements of EVLW volume and the ICG-thermal method. Trans-pulmonary lithium indicator dilution measurements of ITBV and EVLW volume using an external lithium ion electrode are not sufficiently accurate to safely guide clinical interventions in individual patients. Consequently we decided not to further develop the lithium-thermal technique of EVLW volume measurement

New estimates of the elasticity of marginal utility for the UK

This paper provides novel empirical evidence on the value of the elasticity of marginal utility, η, for the United Kingdom. η is a crucial component of the social discount rate (SDR), which determines the inter-temporal trade-offs that are acceptable to society. Using contemporaneous and historical data, new estimates are obtained using four revealed-preference techniques: the equal-sacrifice income tax approach, the Euler-equation approach, the Frisch additive-preferences approach and risk aversion in insurance markets. A meta-analysis indicates parameter homogeneity across approaches, and a central estimate of 1.5 for η. The confidence interval excludes unity, the value used in official guidance by the UK government. The term structure of the SDR is then estimated. The result is a short-run SDR of 4.5% declining to 4.2% in the very long-run. This is higher and flatter than the UK official guidance. The difference stems from incorrect calibration of social welfare and estimation of the diffusion of growth. Other things equal, the results suggest that current UK guidance might need to be updated

The use of maxLength in the RPKI

This document recommends that operators avoid using the maxLength attribute when issuing Route Origin Authorizations (ROAs) in the Resource Public Key Infrastructure (RPKI). These recommendations complement those in [RFC7115].https://datatracker.ietf.org/doc/draft-yossigi-rpkimaxlen/First author draf

Highly sensitive detection of small ruminant bovine spongiform encephalopathy within transmissible spongiform encephalopathy mixes by serial protein misfolding cyclic amplification

It is assumed that sheep and goats consumed the same bovine spongiform encephalopathy (BSE)-contaminated meat and bone meal that was fed to cattle and precipitated the BSE epidemic in the United Kingdom that peaked more than 20 years ago. De- spite intensive surveillance for cases of BSE within the small ruminant populations of the United Kingdom and European Union, no instances of BSE have been detected in sheep, and in only two instances has BSE been discovered in goats. If BSE is present within the small ruminant populations, it may be at subclinical levels, may manifest as scrapie, or may be masked by coinfection with scrapie. To determine whether BSE is potentially circulating at low levels within the European small ruminant populations, highly sensitive assays that can specifically detect BSE, even within the presence of scrapie prion protein, are required. Here, we present a novel assay based on the specific amplification of BSE PrPSc using the serial protein misfolding cyclic amplification as- say (sPMCA), which specifically amplified small amounts of ovine and caprine BSE agent which had been mixed into a range of scrapie-positive brain homogenates. We detected the BSE prion protein within a large excess of classical, atypical, and CH1641 scrapie isolates. In a blind trial, this sPMCA-based assay specifically amplified BSE PrPSc within brain mixes with 100% specific- ity and 97% sensitivity when BSE agent was diluted into scrapie-infected brain homogenates at 1% (vol/vol)

Ovine recombinant PrP as an inhibitor of ruminant prion propagation in vitro

Prion diseases are fatal and incurable neurodegenerative diseases of humans and animals. Despite years of research, no therapeutic agents have been developed that can effectively manage or reverse disease progression. Recently it has been identified that recombinant prion proteins (rPrP) expressed in bacteria can act as inhibitors of prion replication within the in vitro prion replication system Protein Misfolding Cyclic Amplification (PMCA). Here, within PMCA reactions amplifying a range of ruminant prions including distinct Prnp genotypes/host species and distinct prion strains, recombinant ovine VRQ PrP displayed consistent inhibition of prion replication and produced IC50 values of 122 and 171 nM for ovine scrapie and bovine BSE replication, respectively. These findings illustrate the therapeutic potential of rPrPs with distinct TSE diseases

Clinical updates on the effects of high intensity interval training (HIIT) exercise in people diagnosed with cancer. A systematic review and meta-analysis.

This study is to provide an updated critical evaluation on the effectiveness of high intensity interval training (HIIT) on health outcomes among cancer survivors. A systematic search was conducted using databases CINAHL and Medline (via EBSCOhost platform), Scopus, Web of Science Core Collection, and the Cochrane Central Register of Controlled Trials. Randomised, controlled, exercise trials involving cancer survivors were eligible. Data on the effects of HIIT among individuals diagnosed with cancer at any stage were included. Risk of bias was assessed with the Mixed Methods Appraisal Tool (MMAT). Standardised mean differences (SMD) were calculated to compare differences between exercise and usual care. Meta-analyses (including subgroup analyses) were undertaken on the primary outcome of interest, which was aerobic fitness. Secondary outcomes were fatigue, quality of life, physical function, muscle strength, pain, anxiety, depression, upper-body strength, lower-body strength, systolic and diastolic blood pressure. Thirty-five trials from forty-seven publications were included, with intervention durations ranging between four to 18 weeks. Breast cancer participants were represented in the highest number of trials (n=13, 37%). Significant effects in favour of HIIT exercise for improving aerobic fitness, quality of life, pain and diastolic blood pressure were observed (SMD range: 0.25–0.58, all p<0.01). Participation in HIIT exercise was associated with higher retention and improvements in aerobic fitness, quality of life, pain and diastolic blood pressure. The present results provide updated contemporary evidence for clinicians (e.g., exercise physiologists and physiotherapists) to prescribe HIIT exercise for cancer survivors to improve health before, during and following treatment

Methods for differentiating prion types in food-producing animals

Prions are an enigma amongst infectious disease agents as they lack a genome yet confer specific pathologies thought to be dictated mainly, if not solely, by the conformation of the disease form of the prion protein (PrPSc). Prion diseases affect humans and animals, the latter including the food-producing ruminant species cattle, sheep, goats and deer. Importantly, it has been shown that the disease agent of bovine spongiform encephalopathy (BSE) is zoonotic, causing variant Creutzfeldt Jakob disease (vCJD) in humans. Current diagnostic tests can distinguish different prion types and in food- producing animals these focus on the differentiation of BSE from the non-zoonotic agents. Whilst BSE cases are now rare, atypical forms of both scrapie and BSE have been reported, as well as two types of chronic wasting disease (CWD) in cervids. Typing of animal prion isolates remains an important aspect of prion diagnosis and is now becoming more focused on identifying the range of prion types that are present in food-producing animals and also developing tests that can screen for emerging, novel prion diseases. Here, we review prion typing methodologies in light of current and emerging prion types in food-producing animals

Persistence of scrapie infectivity within a farm environment after cleaning and decontamination

Scrapie of sheep/goats and Chronic Wasting Disease (CWD) of deer/elk are contagious prion diseases where environmental reservoirs are directly implicated in the transmission of disease. In this study the effectiveness of recommended scrapie farm decontamination regimes was evaluated by a sheep bioassay using buildings naturally contaminated with scrapie. Pens within a farm building were treated with either 20,000ppm free chorine solution for one hour, or were treated to same but were followed with painting and full re-galvanisation or replacement of metalwork within the pen. Scrapie susceptible lambs of the PRNP genotype VRQ/VRQ were reared within these pens and their scrapie status was monitored by RAMALT. All animals became infected over an 18-month period, even in the pen that had been subject to the most stringent decontamination process. This data suggests that recommended current guidelines for the decontamination of farm buildings following outbreaks of scrapie do little to reduce the titre of infectious scrapie material and that environmental re-contamination could also be an issue associated with these premises

A sensitive 301V BSE serial PMCA assay

The prion strain 301V, is a mouse passaged form of bovine spongiform encephalopathy (BSE). It has been used as a model of BSE for more than 20 years, in particular in the investigation of tissue distribution of infectivity, the molecular phenotype and transmission properties of BSE, strain typing assays and prion inactivation studies. Most 301V experiments have required murine bioassay as a method for the quantitation of infectivity. To date this model strain has not been studied with the protein misfolding cyclic amplification assay (PMCA) which detects prion-associated PrPSc protein. The detection of BSE PrPSc by PMCA can be more sensitive than mouse bioassay and is carried out in a much shorter time frame of days as opposed to months/years. Here, we describe the development of a new highly sensitive and specific PMCA assay for murine 301V and assess the sensitivity of the assay in direct comparison with murine bioassay of the same material. This in vitro assay detected, in a few days, 301V at a brain dilution of at least 1x10-9, compared to bioassay of the same material in VM mice that could detect down to a 1x10-8 dilution and took >180 days. The 301V PMCA may therefore offer a faster and more sensitive alternative to live animal bioassay when studying the BSE agent in VM mice