The influence of perfusion solution on renal graft viability assessment

BACKGROUND: Kidneys from donors after cardiac or circulatory death are exposed to extended periods of both warm ischemia and intra-arterial cooling before organ recovery. Marshall’s hypertonic citrate (HOC) and Bretschneider’s histidine-tryptophan-ketoglutarate (HTK) preservation solutions are cheap, low viscosity preservation solutions used clinically for organ flushing. The aim of the present study was to evaluate the effects of these two solutions both on parameters used in clinical practice to assess organ viability prior to transplantation and histological evidence of ischemic injury after reperfusion. METHODS: Rodent kidneys were exposed to post-mortem warm ischemia, extended intra-arterial cooling (IAC) (up to 2 h) with preservation solution and reperfusion with either Krebs-Hensleit or whole blood in a transplant model. Control kidneys were either reperfused directly after retrieval or stored in 0.9% saline. Biochemical, immunological and histological parameters were assessed using glutathione-S-transferase (GST) enzymatic assays, polymerase chain reaction and mitochondrial electron microscopy respectively. Vascular function was assessed by supplementing the Krebs-Hensleit perfusion solution with phenylephrine to stimulate smooth muscle contraction followed by acetylcholine to trigger endothelial dependent relaxation. RESULTS: When compared with kidneys reperfused directly post mortem, 2 h of IAC significantly reduced smooth muscle contractile function, endothelial function and upregulated vascular cellular adhesion molecule type 1 (VCAM-1) independent of the preservation solution. However, GST release, vascular resistance, weight gain and histological mitochondrial injury were dependent on the preservation solution used. CONCLUSIONS: We conclude that initial machine perfusion viability tests, including ischemic vascular resistance and GST, are dependent on the perfusion solution used during in situ cooling. HTK-perfused kidneys will be heavier, have higher GST readings and yet reduced mitochondrial ischemic injury when compared with HOC-perfused kidneys. Clinicians should be aware of this when deciding which kidneys to transplant or discard

Code-Sharing in Cost-of-Illness Calculations: An Application to Antibiotic-Resistant Bloodstream Infections

Data Availability Statement: The linked JANIS-DPC dataset analyzed for this study is not fully available due to patient identifiable data being present. However, JANIS does provide surveillance data in its open report available. Requests to access the datasets should be directed to https://janis.mhlw.go.jp/english/about/index.html.Copyright © 2020 Naylor, Yamashita, Iwami, Kunisawa, Mizuno, Castro-Sánchez, Imanaka, Ahmad and Holmes. Background: More data-driven evidence is needed on the cost of antibiotic resistance. Both Japan and England have large surveillance and administrative datasets. Code sharing of costing models enables reduced duplication of effort in research. Objective: To estimate the burden of antibiotic-resistant Staphylococcus aureus bloodstream infections (BSIs) in Japan, utilizing code that was written to estimate the hospital burden of antibiotic-resistant Escherichia coli BSIs in England. Additionally, the process in which the code-sharing and application was performed is detailed, to aid future such use of code-sharing in health economics. Methods: National administrative data sources were linked with voluntary surveillance data within the Japan case study. R software code, which created multistate models to estimate the excess length of stay associated with different exposures of interest, was adapted from previous use and run on this dataset. Unit costs were applied to estimate healthcare system burden in 2017 international dollars (I$). Results: Clear supporting documentation alongside open-access code, licensing, and formal communication channels, helped the re-application of costing code from the English setting within the Japanese setting. From the Japanese healthcare system perspective, it was estimated that there was an excess cost of I$6,392 per S. aureus BSI, whilst oxacillin resistance was associated with an additional I$8,155. Conclusions: S. aureus resistance profiles other than methicillin may substantially impact hospital costs. The sharing of costing models within the field of antibiotic resistance is a feasible way to increase burden evidence efficiently, allowing for decision makers (with appropriate data available) to gain rapid cost-of-illness estimates.HPRU-2012-1004

An evolutionary variable neighbourhood search for the unrelated parallel machine scheduling problem

This article addresses a challenging industrial problem known as the unrelated parallel machine scheduling problem (UPMSP) with sequence-dependent setup times. In UPMSP, we have a set of machines and a group of jobs. The goal is to find the optimal way to schedule jobs for execution by one of the several available machines. UPMSP has been classified as an NP-hard optimisation problem and, thus, cannot be solved by exact methods. Meta-heuristic algorithms are commonly used to find sub-optimal solutions. However, large-scale UPMSP instances pose a significant challenge to meta-heuristic algorithms. To effectively solve a large-scale UPMSP, this article introduces a two-stage evolutionary variable neighbourhood search (EVNS) methodology. The proposed EVNS integrates a variable neighbourhood search algorithm and an evolutionary descent framework in an adaptive manner. The proposed evolutionary framework is employed in the first stage. It uses a mix of crossover and mutation operators to generate diverse solutions. In the second stage, we propose an adaptive variable neighbourhood search to exploit the area around the solutions generated in the first stage. A dynamic strategy is developed to determine the switching time between these two stages. To guide the search towards promising areas, a diversity-based fitness function is proposed to explore different locations in the search landscape. We demonstrate the competitiveness of the proposed EVNS by presenting the computational results and comparisons on the 1640 UPMSP benchmark instances, which have been commonly used in the literature. The experiment results show that our EVNS obtains better results than the compared algorithms on several UPMSP instances

Why has positive inotropy failed in chronic heart failure? Lessons from prior inotrope trials.

Current pharmacological therapies for heart failure with reduced ejection fraction are largely either repurposed anti-hypertensives that blunt overactivation of the neurohormonal system or diuretics that decrease congestion. However, they do not address the symptoms of heart failure that result from reductions in cardiac output and reserve. Over the last few decades, numerous attempts have been made to develop and test positive cardiac inotropes that improve cardiac haemodynamics. However, definitive clinical trials have failed to show a survival benefit. As a result, no positive inotrope is currently approved for long-term use in heart failure. The focus of this state-of-the-art review is to revisit prior clinical trials and to understand the causes for their findings. Using the learnings from those experiences, we propose a framework for future trials of such agents that maximizes their potential for success. This includes enriching the trials with patients who are most likely to derive benefit, using biomarkers and imaging in trial design and execution, evaluating efficacy based on a wider range of intermediate phenotypes, and collecting detailed data on functional status and quality of life. With a rapidly growing population of patients with advanced heart failure, the epidemiologic insignificance of heart transplantation as a therapeutic intervention, and both the cost and morbidity associated with ventricular assist devices, there is an enormous potential for positive inotropic therapies to impact the outcomes that matter most to patients

Outcomes of Multi-Drug Resistant Tuberculosis (MDR-TB) among a Cohort of South African Patients with High HIV Prevalence

Multidrug-resistant tuberculosis (MDR-TB) is a major clinical challenge, particularly in patients with human immunodeficiency virus (HIV) co-infection. MDR-TB treatment is increasingly available, but outcomes have not been well characterized. South Africa has provided MDR-TB treatment for a decade, and we evaluated outcomes by HIV status for patients enrolled between 2000 and 2004 prior to anti-retroviral access.We assessed treatment outcomes in a prospective cohort of patients with MDR-TB from eight provincial programs providing second line drugs. World Health Organization definitions were used. Results were stratified by HIV status.Seven hundred fifty seven patients with known HIV status were included in the final analysis, and HIV infection was documented in 287 (38%). Overall, 348 patients (46.0%) were successfully treated, 74 (9.8%) failed therapy, 177 (23.4%) died and 158 (20.9%) defaulted. Patients with HIV were slightly younger and less likely to be male compared to HIV negative patients. Patients with HIV were less likely to have a successful treatment outcome (40.0 vs. 49.6; P<0.05) and more likely to die (35.2 vs. 16.2; P<0.0001). In a competing risk survival analysis, patients with HIV had a higher hazard of death (HR: 2.33, P<0.0001). Low baseline weight (less than 45 kg and less than 60 kg) was also associated with a higher hazard of death (HR: 2.52, P<0.0001; and HR: 1.50, P<0.0001, respectively, compared to weight greater than 60 kg). Weight less than 45 kg had higher risk of failure (HR: 3.58, P<0.01). Any change in treatment regimen was associated with a higher hazard of default (HR: 2.86; 95% CI 1.55-5.29, P<0.001) and a lower hazard of death (HR: 0.63, P<0.05).In this MDR-TB treatment program patients with HIV infection and low weight had higher hazards of death. Overall treatment outcomes were poor. Efforts to improve treatment for MDR-TB are urgently needed

Effect of cooling methods on dimensional accuracy and surface finish of a turned titanium part

In metal cutting, the choice of cooling method influences the deformation mechanism, which is related to the dimensional accuracy and surface finish of the parts. The deformation mechanism of titanium alloys under machining conditions is known to be very different from that of commonly used industrial materials. Therefore, the effect of cooling methods on dimensional accuracy and surface finish in machining titanium is of particular interest. This paper investigates experimentally and analytically the influence of cooling method and cutting parameters on two major dimensional accuracy characteristics of a turned titanium part—diameter error and circularity, and surface finish. Data were analyzed via three methods: traditional analysis, Pareto ANOVA, and Taguchi method. The findings indicate that the cooling method has significant effect on circularity error (contribution ratio 76.75 %), moderate effect on diameter error (contribution ratio 25.00 %), and negligible effect on surface finish (contribution ratio 0.16 %)

The Mechanism of Enhanced Insulin Amyloid Fibril Formation by NaCl Is Better Explained by a Conformational Change Model

The high propensity of insulin to fibrillate causes severe biomedical and biotechnological complications. Insulin fibrillation studies attain significant importance considering the prevalence of diabetes and the requirement of functional insulin in each dose. Although studied since the early years of the 20th century, elucidation of the mechanism of insulin fibrillation has not been understood completely. We have previously, through several studies, shown that insulin hexamer dissociates into monomer that undergoes partial unfolding before converting into mature fibrils. In this study we have established that NaCl enhances insulin fibrillation mainly due to subtle structural changes and is not a mere salt effect. We have carried out studies both in the presence and absence of urea and Gdn.HCl and compared the relationship between conformation of insulin induced by urea and Gdn.HCl with respect to NaCl at both pH 7.4 (hexamer) and pH 2 (monomer). Fibril formation was followed with a Thioflavin T assay and structural changes were monitored by circular dichroism and size-exclusion chromatography. The results show salt-insulin interactions are difficult to classify as commonly accepted Debye-Hückel or Hofmeister series interactions but instead a strong correlation between the association states and conformational states of insulin and their propensity to fibrillate is evident

Polar opposites? NGOs, left parties and the fight for social change in Nepal

In the early 1990s, when NGOs were rising to prominence as an ostensible force for social change in Nepal, the Maoists were also beginning to organise, and denounced NGOs as agents of imperialism. The Maoists came to prominence by fighting a People’s War launched in 1996, with the intention of improving life for the poor peasant and working-class majority. But after a decade-long struggle, the Maoists became incorporated into the parliamentary system. While Nepal’s first democratic revolution in 1990 met formal, popular political demands, which were consolidated in a subsequent revolution in 2006 overthrowing the monarchy and bringing the People’s War to an end, there was little socio-economic progress for the vast majority. The argument advanced in this article is that this lack of progress relied on the interplay of two phenomena: an anti-Maoist alliance consisting of the international community, the domestic ruling elite and NGOs, and a fundamental ambiguity at the heart of the Maoists’ political theory

The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure