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Aims: The aim of the SCIENCE trial was to investigate whether a single treatment with direct intramyocardial injections of adipose tissue‐derived mesenchymal stromal cells (CSCC_ASCs) was safe and improved cardiac function in patients with chronic ischaemic heart failure with reduced ejection fraction (HFrEF). Methods and results: The study was a European multicentre, double‐blind, placebo‐controlled phase II trial using allogeneic CSCC_ASCs from healthy donors or placebo (2:1 randomization). Main inclusion criteria were New York Heart Association (NYHA) class II–III, left ventricular ejection fraction (LVEF) <45%, and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) levels >300 pg/ml. CSCC_ASCs or placebo (isotonic saline) were injected directly into viable myocardium. The primary endpoint was change in left ventricular end‐systolic volume (LVESV) at 6‐month follow‐up measured by echocardiography. A total of 133 symptomatic HFrEF patients were included. The treatment was safe without any drug‐related severe adverse events or difference in cardiac‐related adverse events during a 3‐year follow‐up period. There were no significant differences between groups during follow‐up in LVESV (0.3 ± 5.0 ml, p = 0.945), nor in secondary endpoints of left ventricular end‐diastolic volume (−2.0 ± 6.0 ml, p = 0.736) and LVEF (−1.6 ± 1.0%, p = 0.119). The NYHA class improved slightly within the first year in both groups without any difference between groups. There were no changes in 6‐min walk test, NT‐proBNP, C‐reactive protein or quality of life the first year in any groups. Conclusion: The SCIENCE trial demonstrated safety of intramyocardial allogeneic CSCC_ASC therapy in patients with chronic HFrEF. However, it was not possible to improve the pre‐defined endpoints and induce restoration of cardiac function or clinical symptoms. [ABSTRACT FROM AUTHOR]

Uncertainty about market developments and their implications characterize financial markets. Increasingly, machine learning is deployed as a tool to absorb this uncertainty and transform it into manageable risk. This article analyses machine‐learning‐based uncertainty absorption in financial markets by drawing on 182 interviews in the finance industry, including 45 interviews with informants who were actively applying machine‐learning techniques to investment management, trading, or risk management problems. We argue that while machine‐learning models are deployed to absorb financial uncertainty, they also introduce a new and more profound type of uncertainty, which we call critical model uncertainty. Critical model uncertainty refers to the inability to explain how and why the machine‐learning models (particularly neural networks) arrive at their predictions and decisions—their uncertainty‐absorbing accomplishments. We suggest that the dialectical relation between machine‐learning models' uncertainty absorption and multiplication calls for further research in the field of finance and beyond. [ABSTRACT FROM AUTHOR]

Copyright of Tropical Medicine & International Health is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Since the beginning of the 21st century, electronic monitoring (EM) has emerged as a cost‐efficient supplement to existing catch monitoring programmes in fisheries. An EM system consists of various activity sensors and cameras positioned on vessels to remotely record fishing activity and catches. The first objective of this review was to describe the state of play of EM in fisheries worldwide and to present the insights gained on this technology based on 100 EM trials and 12 fully implemented programmes. Despite its advantages, and its global use for monitoring, progresses in implementation in some important fishing regions are slow. Within this context, the second objective was to discuss more specifically the European experiences gained through 16 trials. Findings show that the three major benefits of EM were as follows: (a) cost‐efficiency, (b) the potential to provide more representative coverage of the fleet than any observer programme and (c) the enhanced registration of fishing activity and location. Electronic monitoring can incentivize better compliance and discard reduction, but the fishing managers and industry are often reluctant to its uptake. Improved understanding of the fisher's concerns, for example intrusion of privacy, liability and costs, and better exploration of EM benefits, for example increased traceability, sustainability claims and market access, may enhance implementation on a larger scale. In conclusion, EM as a monitoring tool embodies various solid strengths that are not diminished by its weaknesses. Electronic monitoring has the opportunity to be a powerful tool in the future monitoring of fisheries, particularly when integrated within existing monitoring programmes. [ABSTRACT FROM AUTHOR]

AIMS The most common pathogen to cause postoperative infections in Denmark is Staphylococcus aureus. Despite using prophylactic antibiotics, infections are still seen. Whether the tissue concentration is above the minimal inhibitory concentration (MIC) for the pathogen is unknown. Thus, the concentration of dicloxacillin in muscle and adipose tissue was measured after intravenous administration, in healthy men. METHODS MIC for dicloxacillin against S. aureus was determined using the broth macrodilution method. A microdialysis (MD) catheter was placed in the subcutaneous tissue of the abdomen and in the lateral vastus muscle of the thigh of six healthymale volunteers. They were given 2 g dicloxacillin intravenously. Samples from blood and MD fluid were collected. The unbound dicloxacillin was isolated from plasma. Samples were analysed with high performance liquid chromatography (HPLC). RESULTS The maximum concentration was reached in muscle tissue after 0.5 h and in adipose tissue after 0.8 h. AUC0–6h for the dicloxacillin concentration in adipose tissue was significantly lower when compared to the unbound dicloxacillin concentration in plasma. The dicloxacillin concentration was above theMIC for sensitive S. aureus for a minimum of 2.3 h and a median of 4.1 h in muscle tissue and a minimum of 1.8 h and a median of 3.2 h in adipose tissue. CONCLUSIONS The unbound dicloxacillin concentration in adipose and muscle tissue remained above the MIC for sensitive S. aureus, for a period sufficient for many orthopaedic procedures. Whether this is true in patients with compromised circulation remains to be investigated. [ABSTRACT FROM AUTHOR]

Copyright of Tropical Medicine & International Health is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Tropical Medicine & International Health is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Colorectal cancer (CRC) is one of the leading causes of cancer deaths in Western countries. A significant number of CRC patients undergoing curatively intended surgery subsequently develop recurrence and die from the disease. MicroRNAs (miRNAs) are aberrantly expressed in cancers and appear to have both diagnostic and prognostic significance. In this study, we identified novel miRNAs associated with recurrence of CRC, and their possible mechanism of action. TaqMan® Human MicroRNA Array Set v2.0 was used to profile the expression of 667 miRNAs in 14 normal colon mucosas and 46 microsatellite stable CRC tumors. Four miRNAs (miR-362-3p, miR-570, miR-148 a* and miR-944) were expressed at a higher level in tumors from patients with no recurrence ( p<0.015), compared with tumors from patients with recurrence. A significant association with increased disease free survival was confirmed for miR-362-3p in a second independent cohort of 43 CRC patients, using single TaqMan® microRNA assays. In vitro functional analysis showed that over-expression of miR-362-3p in colon cancer cell lines reduced cell viability, and proliferation mainly due to cell cycle arrest. E2F1, USF2 and PTPN1 were identified as potential miR-362-3p targets by mRNA profiling of HCT116 cells over-expressing miR-362-3p. Subsequently, these genes were confirmed as direct targets by Luciferase reporter assays and their knockdown in vitro phenocopied the effects of miR-362-3p over-expression. We conclude that miR-362-3p may be a novel prognostic marker in CRC, and hypothesize that the positive effects of augmented miR-362-3p expression may in part be mediated through the targets E2F1, USF2 and PTPN1. [ABSTRACT FROM AUTHOR]

Objective To rank health problems contributing most to the burden of disease in Zimbabwe using disability-adjusted life years as the population health measure. Methods Epidemiological information was derived from multiple sources. Population size and total number of deaths by age and sex for the year 1997 were taken from a nationwide census. The cause of death pattern was determined based on data from the Vital Registration System, which was adjusted for under-reporting of human immunodeficiency virus (HIV) and reallocation of ill-defined causes. Non-fatal disease figures were estimated based on local disease registers, surveys and routine health service data supplemented by estimates from epidemiological studies from other settings if no Zimbabwean sources were available. Disease and public health experts were consulted about the identification of the best possible sources of information, the quality of these sources and data adjustments made. Results From the information collected, HIV infection emerged as the single most serious public health problem in Zimbabwe responsible for 49% of the total disease burden. A quarter of the total burden of disease was attributed to morbidity rather than premature mortality. The share of the disease burden was similar in females and males. Conclusion Using local sources of information to a large extent, it was possible to develop plausible estimates of the size and the relative significance of the major health problems in Zimbabwe. The disease pattern of Zimbabwe differed substantially from regional estimates for sub-Saharan Africa justifying the need for countries to develop their own burden of disease estimates. [ABSTRACT FROM AUTHOR]

Quality-adjusted life year (QALY) models are widely used for economic evaluation in the health care sector. In the first part of the paper, we establish an overview of QALY models where health varies over time and provide a theoretical analysis of model identification and parameter estimation from time trade-off (TTO) and standard gamble (SG) scores. We investigate deterministic and probabilistic models and consider five different families of discounting functions in all. The second part of the paper discusses four issues recurrently debated in the literature. This discussion includes questioning the SG method as the gold standard for estimation of the health state index, re-examining the role of the constant-proportional trade-off condition, revisiting the problem of double discounting of QALYs, and suggesting that it is not a matter of choosing between TTO and SG procedures as the combination of these two can be used to disentangle risk aversion from discounting. We find that caution must be taken when drawing conclusions from models with chronic health states to situations where health varies over time. One notable difference is that in the former case, risk aversion may be indistinguishable from discounting. [ABSTRACT FROM AUTHOR]

Copyright of International Wound Journal is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Aims To identify the principal human cytochrome P450 (CYP) enzyme(s) responsible for the human in vitro biotransformation of repaglinide. Previous experiments have identified CYP3A4 as being mainly responsible for the in vitro metabolism of repaglinide, but the results of clinical investigations have suggested that more than one enzyme may be involved in repaglinide biotransformation. Methods [14 C]-Repaglinide was incubated with recombinant CYP and with human liver microsomes (HLM) from individual donors in the presence of inhibitory antibodies specific for individual CYP enzymes. Metabolites, measured by high-performance liquid chromatography (HPLC) with on-line radiochemical detection, were identified by liquid chromatography-mass spectrophotometry (LC-MS) and LC-MS coupled on-line to a nuclear magnetic resonance spectrometer (LC-MS-NMR). Results CYP3A4 and CYP2C8 were found to be responsible for the conversion of repaglinide into its two primary metabolites, M4 (resulting from hydroxylation on the piperidine ring system) and M1 (an aromatic amine). Specific inhibitory monoclonal antibodies against CYP3A4 and CYP2C8 significantly inhibited (> 71%) formation of M4 and M1 in HLM. In a panel of HLM from 12 individual donors formation of M4 and M1 varied from approximately 160–880 pmol min-1 mg-1 protein and from 100–1110 pmol min-1 mg-1 protein, respectively. The major metabolite generated by CYP2C8 was found to be M4. The rate of formation of this metabolite in HLM correlated significantly with paclitaxel 6α-hydroxylation (r s = 0.80; P = 0.0029). Two other minor metabolites were also detected. One of them was M1 and the other was repaglinide hydroxylated on the isopropyl moiety (M0-OH). The rate of formation of M4 in CYP2C8 SupersomesTM was 2.5 pmol min-1 pmol-1 CYP enzyme and only about 0.1 pmol min-1 pmol-1 CYP enzyme in CYP3A4 SupersomesTM . The major metabolite generated by CYP3A4 was M1. The rate of formation of this metabolite in HLM correlated significantly with testosterone 6β-hydroxylation (r s = 0.90; P = 0.0002). Three other metabolites were identified, namely, M0-OH, M2 (a dicarboxylic acid formed by oxidative opening of the piperidine ring) and M5. The rate of M1 formation in CYP3A4 SupersomesTM was 1.6 pmol min-1 pmol-1 CYP enzyme but in CYP2C8 Super-somesTM it was only approximately 0.4 pmol min-1 pmol-1 CYP enzyme. Conclusions The results confirm an important role for both CYP3A4 and CYP2C8 in the human in vitro biotransformation of repaglinide. This dual CYP biotransformation may have consequences for the clinical pharmacokinetics and drug-drug interactions involving repaglinide if one CYP pathway has sufficient capacity to compensate if the other is inhibited. [ABSTRACT FROM AUTHOR]

The object of this study was to analyze drug interactions between repaglinide, a short-acting insulin secretagogue, and five other drugs interacting with CYP3A4: ketoconazole, rifampicin, ethinyloestradiol/levonorgestrel (in an oral contraceptive), simvastatin, and nifedipine. In two open-label, two-period, randomized crossover studies, healthy subjects received repaglinide alone, repaglinide on day 5 of ketoconazole treatment, or repaglinide on day 7 of rifampicin treatment. In three open-label, three-period, randomized crossover studies, healthy subjects received 5 days of repaglinide alone; 5 days of ethinyloestradiol/levonorgestrel, simvastatin, or nifedipine alone; or 5 days of repaglinide concomitant with ethinyloestradiol/levonorgestrel, simvastatin, or nifedipine. Compared to administration of repaglinide alone, concomitant ketoconazole increased mean AUC0-∞for repaglinide by 15% and mean Cmaxby 7%. Concomitant rifampicin decreased mean AUC0-∞for repaglinide by 31% and mean Cmaxby 26%. Concomitant treatment with CYP3A4 substrates altered mean AUC0-5hand mean Cmaxfor repaglinide by 1% and 17% (ethinyloestradiol/levonorgestrel), 2% and 27% (simvastatin), or 11% and 3% (nifedipine). Profiles of blood glucose concentration following repaglinide dosing were altered by less than 8% by both ketoconazole and rifampicin. In all five studies, most adverse events were related to hypoglycemia, as expected in a normal population given a blood glucose regulator. The safety profile of repaglinide was not altered by pretreatment with ketoconazole or rifampicin or by coadministration with ethinyloestradiol/levonorgestrel. The incidence of adverse events increased with coadministration of simvastatin or nifedipine compared to either repaglinide or simvastatin/nifedipine treatment alone. No clinically relevant pharmacokinetic interactions occurred between repaglinide and the CYP3A4 substrates ethinyloestradiol/levonorgestrel, simvastatin, or nifedipine. The pharmacokinetic profile of repaglinide was altered by administration of potent inhibitors or inducers, such as ketoconazole or rifampicin, but to a lesser degree than expected. These results are probably explained by the metabolic pathway of repaglinide that involves other enzymes than CYP3A4, reflected to some extent by a small change in repaglinide pharmacodynamics. Thus, careful monitoring of blood glucose in repaglinide-treated patients receiving strong inhibitors or inducers of CYP3A4 is recommended, and an increase in repaglinide dose may be necessary. No safety concerns were observed, except a higher incidence in adverse events in patients receiving repaglinide and simvastatin or nifedipine. [ABSTRACT FROM PUBLISHER]

A series of optical experiments was designed to investigate several factors that may help to explain the Hering Illusion. In this illusion subjects are shown two vertical lines crossed by angular lines which stem from the point midway between them; subjects then report the straight pair of parallel lines as appearing curved in a bow-shaped manner. Findings indicate increased perceived curvature of the lines when the angles presented are greater in number or size. The illusion is further increased if the angles and lines are shown sequentially rather than simultaneously. Similar results occur on presentation of a circle cutting through the rays of a quadrangular star; the circle looks 'squarish'. When lines or circles are presented to one eye only while the other eye receives the angles or star, this illusion still holds. All perceived curvature shows anti-apical distortion, which appears due to neuro-cortical after-effects underlying visual perception. [ABSTRACT FROM AUTHOR]