A clinical and cost-effectiveness analysis of the HeartMate 3 left ventricular assist device for transplant-ineligible patients: a United Kingdom perspective

Background: The clinical and cost-effectiveness of left ventricular assist device (LVAD) therapy for patients with advanced heart failure (HF) who are ineligible for heart transplantation is debated in the UK. This study develops an indirect comparison between the fully magnetically levitated HeartMate 3 (HM 3) LVAD and medical therapy (MT) to evaluate expected clinical and cost-effectiveness in the UK National Health Service (NHS) context. Methods: We performed an economic analysis comparing the HM3 pump against the HeartMate II LVAD (MOMENTUM 3), and then another analysis comparing MT with the first- and second-generation HeartMate XVE pump LVAD and HeartMate II LVAD for the same patient population (REMATCH and ROADMAP, respectively). By bridging those 2 analyses, an indirect comparison between HM3 and MT in the form of a network meta-analysis was developed. A literature search was performed to select the most appropriate pair of studies for this purpose. Outcomes were adjusted to produce Kaplan-Meier curves for the cost-effectiveness evaluation by using a decision-analytic model. Data were extrapolated linearly over a 5-year time horizon. Uncertainty and additional scenarios were addressed by one-way and probabilistic sensitivity analysis. Local costs and health utility were used from England, thereby representing the UK context. Results: The incremental cost-effectiveness ratio (ICER) for LVAD vs MT in transplant ineligible patients with advanced HF was estimated to be £47,361 per quality-adjusted life year gained, with a 97.1% probability of being cost-effective at £50,000. In a subgroup of patients who are inotropic therapy dependent (INTERMACS 1-3 severity profile), the ICER was £45,616, while for a population with less-ill ambulatory HF (INTERMACS profile 4-7) the ICER changed to £64,051. Conclusions: This study provides evidence that HM3 LVAD therapy in advanced HF patients ineligible for heart transplantation may be cost-effective compared to MT in the NHS UK-England context. The ICER is lowest for patients dependent on inotropic support, but exceeds the willingness to pay threshold of £50,000 in ambulatory noninotropic therapy dependent advanced HF patients

Effects of Electricity and Altered Conductivity on Rainbow Trout Embryos: A Study to Determine Efficacy of Electricity for Eradication of Invasive Salmonids

Electricity has been an applied means of facilitating capture and removal of invasive fishes for many years. Current methods involve use of electrodes to establish a current through which passing fish will be susceptible to a brief shock to stun. This method, however, only affects free swimming individuals and is not inclusive of early life history stages such as embryos within spawning substrate. This study evaluates the susceptibility of embryonic and larval stage rainbow trout (Oncorhynchus mykiss) to direct DC current between 2-20v/cm in varying conductive waters to determine lethality for invasive salmonid eradication efforts. Rainbow trout embryos (n = 10 embryos/exposure) were initially exposed to homogeneous electric fields for 5 sec with a water conductivity of 220uS/cm from 1 day post fertilization (DPF)/ 27 temperature units (TU) to 15 DPF/405TU. Mortality was assessed 24 hours post exposure and the LV50 (lethal voltage) at 220uS/cm was determined for each TU. Embryos from six periods of development were then exposed to their respective LV50 voltages in varying conductive waters (20-600uS/cm). Susceptibility to direct DC voltages increased with voltage but overall susceptibility decreased with development. Susceptibility to a constant voltage increased with increasing conductivity and was consistent throughout early development (81TU-292TU), but the effects of increased conductivity were not enhanced in eyed embryos after 364TU. Results indicate that direct DC current applied prior to eyed embryonic stages, the period of greatest trout embryo susceptibility, is an effective means of eradicating invasive and nuisance salmonids

COVID-19: Time for precision epidemiology

The global COVID-19 (SARS-CoV2, COVID-19) tsunami caused by SARSCoV2 is inundating and often-overwhelming health care systems in most countries and regions..

Employer Policies and Practices to Manage and Prevent Disability: Foreword to the Special Issue

Purpose Employer policies and practices have been shown to impact workplace disability, but research in this area has waned in recent years despite an aging workforce, a growing prevalence of chronic health conditions, and a larger proportion of working-age adults on permanent work disability in many jurisdictions. The purpose of this article is to describe the background rationale and methodology for an invited conference designed to improve research of employer strategies to curtail work disability. Methods A multidisciplinary team of 26 international researchers with published research in employer-based disability management or related fields were invited to attend a 3-day conference in Hopkinton, Massachusetts, USA. The overall goal was to review the status of current research of workplace disability management and prevention, examine its relevance for employer decision-making, compare conceptual frameworks or theoretical perspectives, and recommend future research directions. Working groups were organized and draft manuscripts were prepared in advance. Conference activities included working group presentations and critiques, discussions with a panel of industry consultants and advisors, group interaction and debate, generation of final recommendations, and manuscript revision. Results/Conclusion Six principal domains were established with respect to future research: (a) further elucidation of the key workplace factors that buffer the disabling effects of injury and illness; (b) more innovative and feasible options for workplace intervention; (c) measurement of workplace-relevant disability outcomes; (d) a stronger theoretical framework for understanding the factors behind employer uptake and implementation; (e) a focus on special clinical populations and occupations where disability risk is most troubling; and (f) better representation of workers and employers that reflect the diverse and changing nature of work. Final comments and recommendations of the working groups are presented in the following six articles in this special issue of the Journal of Occupational Rehabilitation. Conference attendees recommended changes in methodology, collaboration strategies, and theoretical perspectives to improve the practical and scientific impact of future research of employer practices

The human platelet: strong transcriptome correlations among individuals associate weakly with the platelet proteome.

BACKGROUND: For the anucleate platelet it has been unclear how well platelet transcriptomes correlate among different donors or across different RNA profiling platforms, and what the transcriptomes\u27 relationship is with the platelet proteome. We profiled the platelet transcriptome of 10 healthy young males (5 white and 5 black) with no notable clinical history using RNA sequencing and by Affymetrix microarray. RESULTS: We found that the abundance of platelet mRNA transcripts was highly correlated across the 10 individuals, independently of race and of the employed technology. Our RNA-seq data showed that these high inter-individual correlations extend beyond mRNAs to several categories of non-coding RNAs. Pseudogenes represented a notable exception by exhibiting a difference in expression by race. Comparison of our mRNA signatures to a publicly available quantitative platelet proteome showed that most (87.5%) identified platelet proteins had a detectable corresponding mRNA. However, a high number of mRNAs that were present in the transcriptomes of all 10 individuals had no representation in the proteome. Spearman correlations of the relative abundances for those genes represented by both an mRNA and a protein showed a weak (~0.3) connection. Further analysis of the overlapping and non-overlapping platelet mRNAs and proteins identified gene groups corresponding to distinct cellular processes. CONCLUSIONS: The results of our analyses provide novel insights for platelet biology, show only a weak connection between the platelet transcriptome and proteome, and indicate that it is feasible to assemble a platelet mRNA-ome that can serve as a reference for future platelet transcriptomic studies of human health and disease. REVIEWED BY: This article was reviewed by Dr Mikhail Dozmorov (nominated by Dr Yuri Gusev), Dr Neil Smalheiser and Dr Eugene Koonin

Diesel exhaust particulate induces pulmonary and systemic inflammation in rats without impairing endothelial function ex vivo or in vivo

<p>Abstract</p> <p>Background</p> <p>Inhalation of diesel exhaust impairs vascular function in man, by a mechanism that has yet to be fully established. We hypothesised that pulmonary exposure to diesel exhaust particles (DEP) would cause endothelial dysfunction in rats as a consequence of pulmonary and systemic inflammation.</p> <p>Methods</p> <p>Wistar rats were exposed to DEP (0.5 mg) or saline vehicle by intratracheal instillation and hind-limb blood flow, blood pressure and heart rate were monitored <it>in situ </it>6 or 24 h after exposure. Vascular function was tested by administration of the endothelium-dependent vasodilator acetylcholine (ACh) and the endothelium-independent vasodilator sodium nitroprusside (SNP) <it>in vivo </it>and <it>ex vivo </it>in isolated rings of thoracic aorta, femoral and mesenteric artery from DEP exposed rats. Bronchoalveolar lavage fluid (BALF) and blood plasma were collected to assess pulmonary (cell differentials, protein levels & interleukin-6 (IL-6)) and systemic (IL-6), tumour necrosis factor alpha (TNFα) and C-reactive protein (CRP)) inflammation, respectively.</p> <p>Results</p> <p>DEP instillation increased cell counts, total protein and IL-6 in BALF 6 h after exposure, while levels of IL-6 and TNFα were only raised in blood 24 h after DEP exposure. DEP had no effect on the increased hind-limb blood flow induced by ACh <it>in vivo </it>at 6 or 24 h. However, responses to SNP were impaired at both time points. In contrast, <it>ex vivo </it>responses to ACh and SNP were unaltered in arteries isolated from rats exposed to DEP.</p> <p>Conclusions</p> <p>Exposure of rats to DEP induces both pulmonary and systemic inflammation, but does not modify endothelium-dependent vasodilatation. Other mechanisms <it>in vivo </it>limit dilator responses to SNP and these require further investigation.</p

PROTEIN STRUCTURE REPORT Solution structure of the E3 ligase HOIL-1 Ubl domain

Abstract: The E3 ligases HOIL-1 and parkin are each comprised of an N-terminal ubiquitin-like (Ubl) domain followed by a zinc-binding region and C-terminal RING-In-between-RING-RING domains. These two proteins, involved in the ubiquitin-mediated degradation pathway, are the only two known E3 ligases to share this type of multidomain architecture. Further, the Ubl domain of both HOIL-1 and parkin has been shown to interact with the S5a subunit of the 26S proteasome. The solution structure of the HOIL-1 Ubl domain was solved using NMR spectroscopy to compare it with that of parkin to determine the structural elements responsible for S5a intermolecular interactions. The final ensemble of 20 structures had a b-grasp Ubl-fold with an overall backbone RMSD of 0.59 6 0.10 Å in the structured regions between I55 and L131. HOIL-1 had a unique extension of both b1 and b2 sheets compared to parkin and other Ubl domains, a result of a four-residue insertion in this region. A similar 15-residue hydrophobic core in the HOIL-1 Ubl domain resulted in a comparable stability to the parkin Ubl, but significantly lower than that observed for ubiquitin. A comparison with parkin and other Ubl domains indicates that HOIL-1 likely uses a conserved hydrophobic patch (W58, V102, Y127, Y129) found on the b1 face, the b3-b4 loop and b5, as well as a C-terminal basic residue (R134) to recruit the S5a subunit as part of the ubiquitin-mediated proteolysis pathway

Prognostic Value of Number and Site of Calcified Coronary Lesions Compared With the Total Score

ObjectivesThis study sought to evaluate the long-term prognostic value of the number and sites of calcified coronary lesions and to compare the accuracy of number of calcified lesions with the extent of total calcium score.BackgroundThere is a strong relationship between mortality and total coronary artery calcium (CAC) score. It is not known whether the number of calcified lesions or their location influences outcome.MethodsA total of 14,759 asymptomatic patients were referred for evaluation of CAC scanning using electron beam tomography. Univariable and multivariable Cox proportional hazards models were developed to estimate time to all-cause mortality at, on average, 6.8 years (n = 281).ResultsRisk-adjusted annual mortality was 0.19% (95% confidence interval 0.18% to 0.21%) for patients without any calcified lesions. For patients with >20 lesions, annual risk-adjusted mortality exceeded 2% per year. Mortality rates were significantly higher for left main lesions as compared to other coronary arteries with annual mortality rates of 1.3%, 2.1%, 9.2%, and 13.6% for 1 to 2, 3 to 5, and ≥6 lesions, respectively (p < 0.0001). For left main CAC scores of 0 to 10, 11 to 100, 101 to 399, and 400 to 999, annual risk-adjusted mortality was 0.33%, 0.81%, 1.73%, and 7.71%, respectively (p < 0.0001). All 4 patients with a CAC score of ≥1,000 in the left main died during follow-up. However, patients with more frequent calcified lesions also had higher CAC scores. Specifically, ≥81% of patients with >10 calcified lesions also had a CAC score ≥100. With exception, for patients with CAC scores ≥1,000, annual mortality was dramatically higher at 3.0% to 4.5% for those with 1 to 5 calcified lesions as compared with 1.1% to 2.0% for those with 6 or more lesions (p < 0.0001).ConclusionsWe report that mortality rates increased proportionally with the number of calcified lesions. Although predictive information is contained in the number of calcified lesions, its added statistical value is minimal. With exception, patients with frequent lesions in the left main or those with a few large calcified lesions have a particularly high mortality risk

The 1995 scientific assessment of the atmospheric effects of stratospheric aircraft

This report provides a scientific assessment of our knowledge concerning the impact of proposed high-speed civil transport (HSCT) aircraft on the atmosphere. It comes at the end of Phase 1 of the Atmospheric Effects of Stratospheric Aircraft element of the NASA High-Speed Research Program. The fundamental problem with stratospheric flight is that pollutant residence times are long because the stratosphere is a region of permanent temperature inversion with stable stratification. Using improved two-dimensional assessment models and detailed fleet emissions scenarios, the assessment examines the possible impact of the range of effluents from aircraft. Emphasis is placed on the effects of NO(x) and H2O on the atmospheric ozone content. Measurements in the plume of an in-flight Concorde supersonic transport indicated a large number of small particles. These measurements, coupled with model sensitivity studies, point out the importance of obtaining a more detailed understanding of the fate of sulfur in the HSCT exhaust. Uncertainties in the current understanding of the processes important for determining the overall effects of HSCT's on the atmosphere are discussed and partially quantified. Research directions are identified to improve the quantification of uncertainties and to reduce their magnitude

Polymer blends based on sulfonated poly(ether ketone ketone) and poly(ether sulfone) as proton exchange membranes for fuel cells,

Abstract The importance of the blend microstructure and its effect on conductivity and structural integrity of proton exchange membranes (PEM) were investigated. Sulfonated poly(ether ketone ketone) (SPEKK) was selected as the proton-conducting component in a blend with either poly(ether sulfone) (PES) or SPEKK with a different sulfonation level. The second component was added to improve the mechanical stability in the fuel cell environment. Membranes were cast from solution using N-methyl-2-pyrrolidone (NMP) and dimethylacetamide (DMAc). Special attention was paid to the ternary solution behavior. Solution cast SPEKK/PES membranes are homogeneous for all studied compositions, 8/2 through 5/5 (w/w), and sulfonation levels, 1.7-3.5 mequiv./g. Although this polymer pair does not show evidence for intrinsic compatibility, the excellent solvent quality results in a frozen-in structure during solution casting. The morphology of SPEKK/SPEKK blends can be tailor-made by finding the right balance between composition, casting solvent and temperature. Co-continuous morphologies can be devised for an SPEKK blend with sulfonation levels of 1.2 and 2 mequiv./g. Both blends show lower swelling than the parent SPEKK. This results in better stability of PEMs during fuel cell testing