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PubMed2026

scRNA-seq and bulk RNA-seq reveal the characteristics of macrophage copper metabolism and establish a risk signature in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a prevalent malignancy with an urgent need for improved prognostic stratification and treatment-response prediction. This study aimed to explore a macrophage copper metabolism-associated prognostic model and to investigate the relationship between this risk model and the tumor immune microenvironment. METHODS: The FindClusters function was used to analyze cell clusters, and CellChat and CellPhoneDB/LIANA were employed for cell-cell communication analysis. Copper metabolism-related genes were sourced from the MSigDB database. A prognostic risk model was established using least absolute shrinkage and selection operator (LASSO) analysis and multivariate Cox regression analysis, and a nomogram was constructed by integrating the prognostic model with clinicopathological factors. Additional analyses were performed to map the seven model genes in single-cell data, assess model uncertainty and robustness, evaluate macrophage/copper/cuproptosis-related transcriptional programs, and examine the correlations between risk score, immune infiltration and predicted drug sensitivity. RESULTS: Using single-cell RNA sequencing (scRNA-seq) data, we identified four macrophage subpopulations. Macrophages with high SPP1 expression showed close interaction with T cell populations and were associated with copper ion metabolism. By incorporating 141 copper metabolism-related genes and using The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort, we constructed a seven-gene risk prediction model. Additional single-cell mapping showed that the model genes were detectable in the HCC single-cell dataset and showed a macrophage-associated expression pattern. The model showed moderate prognostic discrimination in TCGA-LIHC, whereas its external performance was heterogeneous and remained evaluable across external cohorts, with performance varying among datasets. Immune and mechanism-related analyses suggested that the risk signature was associated with macrophage-related infiltration, copper metabolism and cuproptosis-related transcriptional programs. Drug sensitivity analysis nominated Daporinad as a computationally predicted candidate compound, supporting Daporinad as a pharmacogenomic candidate for follow-up investigation. CONCLUSIONS: By integrating scRNA-seq and bulk RNA sequencing (RNA-seq) data, we constructed a macrophage copper metabolism-associated prognostic signature for HCC. The risk score was associated with survival, immune microenvironment features and predicted drug response, providing a transcriptomic framework for risk stratification and therapeutic hypothesis generation.

Hepatocellular carcinoma (HCC)↗

PubMedDate not supplied

Retrospective pharmacoeconomic evaluation of dosing vecuronium by peripheral nerve stimulation versus standard clinical assessment in critically ill patients.

Adjusting the dosage of vecuronium by peripheral nerve stimulation versus standard clinical dosing in critically ill patients reduces drug requirements to maintain a desired depth of paralysis and, on average, produces faster recovery of neuromuscular function. We retrospectively analyzed the health and economic outcomes of using train-of-four (TOF) end points by peripheral nerve stimulation in dosing neuromuscular blocking agents during continuous infusion in a medical intensive care unit (ICU). A decision-analytic model was used to calculate outcomes and costs of treatment using and not using TOF end points of dosing vecuronium. Data from our TOF trial provided the difference in neuromuscular and functional recovery time. Charges billed by the Patient Financial Services Department were used to determine hourly costs of ICU stay for recovery from neuromuscular blockade using costs:charges ratios estimated from a sample of 20 patients. The cost of vecuronium was determined using the hospital acquisition cost and the actual number of milligrams of drug given to each patient in the TOF trial. The cost of performing one TOF event was determined by timing six events performed by six pharmacists, and randomly selecting 60% of these to calculate a mean time/TOF event. The economic impact of dosing by TOF was determined by calculating the cost savings/patient dosed by TOF compared with those who had doses individualized by standard clinical assessment. One-way and multiway sensitivity analyses were performed to assess model uncertainty. The mean drug cost was $286 in the TOF group versus $580 in the standard dosing group. With a mean time/TOF assessment of 5.8 +/- 1.6 minutes, each episode cost $2.92 for a total TOF cost/patient of $23. At $54/hour of recovery time in the ICU, the estimated cost of ICU care for the TOF group was $34,214 versus $118,681 for the standard group. The estimated costs/patient were $459 and $1197, respectively, for a total cost savings/patient of $738. Sensitivity analyses showed the model to be robust. Estimated annual savings of $146,103 are projected by using TOF to individualize vecuronium doses in patients in the ICU. Individualizing vecuronium doses to TOF end points has both therapeutic and economic advantages. When considering costs of drug, TOF monitoring, and ICU, the total cost/patient was 40% of that in the control group.

Costs and Cost Analysis↗

PubMed2003

Comparative modeling of GABA(A) receptors: limits, insights, future developments.

GABA(A) receptors are chloride ion channels that mediate fast synaptic transmission and belong to a superfamily of pentameric ligand-gated ion channels. The recently published crystal structure of the acetylcholine binding protein can be used as a template for comparative modeling of the extracellular domain of GABA(A) receptors. In this commentary, difficulties with comparative modeling at low sequence identity are discussed, the degree of structural conservation to be expected within the superfamily is analyzed and numerical estimates of model uncertainties in functional regions are provided. Topography of the binding sites at subunit-interfaces is examined and possible targets for rational mutagenesis studies are suggested. Allosteric motions are considered and a mechanism for mediation of positive cooperativity at the benzodiazepine site is proposed.

Animals↗

PubMed2006

Time-scaling of trajectories for point-to-point robotic tasks.

In order to improve the tracking performance in the practical robot task of time-optimal point-to-point motion when torque limits and model uncertainty are present, in this paper is introduced an algorithm for on-line time-scaling of the desired trajectories, which is used along with a conventional trajectory tracking controller. Numerical examples for a two-degrees-of-freedom arm are provided, which illustrate the tracking accuracy of the proposed method.

Algorithms↗

PubMed2005

Scientific issues in the design of metrics for inclusion of oxides of nitrogen in global climate agreements.

The Kyoto Protocol seeks to limit emissions of various greenhouse gases but excludes short-lived species and their precursors even though they cause a significant climate forcing. We explore the difficulties that are faced when designing metrics to compare the climate impact of emissions of oxides of nitrogen (NO(x)) with other emissions. There are two dimensions to this difficulty. The first concerns the definition of a metric that satisfactorily accounts for its climate impact. NO(x) emissions increase tropospheric ozone, but this increase and the resulting climate forcing depend strongly on the location of the emissions, with low-latitude emissions having a larger impact. NO(x) emissions also decrease methane concentrations, causing a global-mean radiative forcing similar in size but opposite in sign to the ozone forcing. The second dimension of difficulty concerns the intermodel differences in the values of computed metrics. We explore the use of indicators that could lead to metrics that, instead of using global-mean inputs, are computed locally and then averaged globally. These local metrics may depend less on cancellation in the global mean; the possibilities presented here seem more robust to model uncertainty, although their applicability depends on the poorly known relationship between local climate change and its societal/ecological impact. If it becomes a political imperative to include NO(x) emissions in future climate agreements, policy makers will be faced with difficult choices in selecting an appropriate metric.

Climate↗

PubMed2001

Control of arterial partial pressure of oxygen in patients with respiratory abnormalities using an adaptive observer.

A system for controlling the arterial partial pressure of oxygen in patients on long-term oxygen therapy is proposed. After performing a parameter estimation of the model of pulmonary system, an adaptive observer is applied to perform the control task. The observer considers the model uncertainties as disturbances and rejects their impact on the system. As a result of this, the quality of the control can be drastically improved. The presented simulation and experimental results show the effectiveness of the proposed scheme. The proposed control scheme is applicable without preliminary adjustment of the control parameters.

Blood Gas Analysis↗

PubMed2005

Nonlinear control for algae growth models in the chemostat.

This paper deals with output feedback control of phytoplanktonic algae growth models in the chemostat. The considered class of model is of variable yield type, meaning that the ratio between the environmental nutrient absorption rate and the cells' growth rate varies, which is different from classical bioprocesses assumptions. On the basis of weak qualitative hypotheses on the analytical expressions of the involved biological phenomena (which guarantee robustness of the procedure toward modeling uncertainties) we propose a nonlinear controller and prove its ability to globally stabilize such processes. Finally, we illustrate our approach with numerical simulations and show its benefits for biological laboratory experiments, especially for ensuring persistence of the culture facing classical experimental problems.

Algorithms↗

PubMed2005

PID controller design for output PDFs of stochastic systems using linear matrix inequalities.

This paper presents a pseudo proportional-integral-derivative (PID) tracking control strategy for general non-Gaussian stochastic systems based on a linear B-spline model for the output probability density functions (PDFs). The objective is to control the conditional PDFs of the system output to follow a given target function. Different from existing methods, the control structure (i.e., the PID) is imposed before the output PDF controller design. Following the linear B-spline approximation on the measured output PDFs, the concerned problem is transferred into the tracking of given weights which correspond to the desired PDF. For systems with or without model uncertainties, it is shown that the solvability can be casted into a group of matrix inequalities. Furthermore, an improved controller design procedure based on the convex optimization is proposed which can guarantee the required tracking convergence with an enhanced robustness. Simulations are given to demonstrate the efficiency of the proposed approach and encouraging results have been obtained.

Algorithms↗

PubMed2004

Enhanced blood boron concentration estimation for BPA-F mediated BNCT.

The blood boron concentration regulates directly the BNCT irradiation time in which the prescribed dose to the patient is delivered. Therefore a proper estimation of the blood boron concentration for the treatment field based on the measured blood samples before irradiation is required. The bi-exponential model fit using Levenberg-Marquardt method was implemented for this purpose to provide the blood boron concentration estimates directly to the treatment data flow during the BNCT procedure. The harmonic mean bi-exponential decay half-lives of the studied patient data (n=28) were 15+/-8 and 320+/-70 min for the faster and slower half-life. The model uncertainty (n=28) was reasonably low, 0.7+/-0.1 microg/g (about 5%). The implemented algorithm provides a robust method for temporal blood boron concentration estimation for BPA-F mediated BNCT. Utilization of the infusion data improves the reliability of the estimate. The overall data flow during the treatment fulfills the practical requirements concerning the BNCT procedure.

Algorithms↗

PubMed2006

Incorporating diverse data and realistic complexity into demographic estimation procedures for sea otters.

Reliable information on historical and current population dynamics is central to understanding patterns of growth and decline in animal populations. We developed a maximum likelihood-based analysis to estimate spatial and temporal trends in age/sex-specific survival rates for the threatened southern sea otter (Enhydra lutris nereis), using annual population censuses and the age structure of salvaged carcass collections. We evaluated a wide range of possible spatial and temporal effects and used model averaging to incorporate model uncertainty into the resulting estimates of key vital rates and their variances. We compared these results to current demographic parameters estimated in a telemetry-based study conducted between 2001 and 2004. These results show that survival has decreased substantially from the early 1990s to the present and is generally lowest in the north-central portion of the population's range. The greatest temporal decrease in survival was for adult females, and variation in the survival of this age/sex class is primarily responsible for regulating population growth and driving population trends. Our results can be used to focus future research on southern sea otters by highlighting the life history stages and mortality factors most relevant to conservation. More broadly, we have illustrated how the powerful and relatively straightforward tools of information-theoretic-based model fitting can be used to sort through and parameterize quite complex demographic modeling frameworks.

Age Factors↗

PubMed2004

Nonlinear control for a class of hydraulic servo system.

The dynamics of hydraulic systems are highly nonlinear and the system may be subjected to non-smooth and discontinuous nonlinearities due to directional change of valve opening, friction, etc. Aside from the nonlinear nature of hydraulic dynamics, hydraulic servo systems also have large extent of model uncertainties. To address these challenging issues, a robust state-feedback controller is designed by employing backstepping design technique such that the system output tracks a given signal arbitrarily well, and all signals in the closed-loop system remain bounded. Moreover, a relevant disturbance attenuation inequality is satisfied by the closed-loop signals. Compared with previously proposed robust controllers, this paper's robust controller based on backstepping recursive design method is easier to design, and is more suitable for implementation.

Algorithms↗

PubMed2005

Economic analysis of on-demand maintenance therapy with proton pump inhibitors in patients with non-erosive reflux disease.

AIM: To evaluate the costs and effectiveness of on-demand maintenance therapy with oral esomeprazole, lansoprazole, omeprazole, pantoprazole or rabeprazole in patients with endoscopy-confirmed non-erosive reflux disease (NERD) in the UK. METHODS: A probabilistic model was developed to compare the costs and effectiveness of five proton pump inhibitors (PPIs) in endoscopy-negative, symptomatic NERD patients who had complete resolution of heartburn symptoms following 4 weeks of open-label acute PPI treatment. The total annual expected costs (euro, 2003 values) and utilities gained per patient were measured over a 1-year horizon from the perspective of the UK NHS. Model uncertainty was addressed by sensitivity analyses. RESULTS: The base-case annual median costs and utilities gained with on-demand PPI therapy were: 123 euro and 0.89 for rabeprazole 10mg; 176 euro and 0.90 for pantoprazole 20mg; 190 euro and 0.89 for esomeprazole 20mg; 195 euro and 0.91 for lansoprazole 15mg; 201 euro and 0.90 for omeprazole 20mg; and 210 euro and 0.91 for omeprazole 10mg. Differences in costs, but not in outcomes, were statistically significant. The results were robust to sensitivity analyses. CONCLUSIONS: In this analysis, on-demand use of rabeprazole for the management of NERD incurred the least cost in comparison with the other PPIs evaluated. Utility gains were comparable for all on-demand PPIs. The place of on-demand PPIs in therapy, however, requires further evaluation.

Anti-Ulcer Agents↗

PubMed1994

A commentary on the NRC report "Science and judgment in risk assessment".

This article provides a brief overview of the report "Science and Judgment in Risk Assessment," prepared by a Committee of the National Research Council/National Academy of Science in response to a U.S. Environmental Protection Agency request mandated by the Clean Air Act Amendments of 1990 (CAAA-1990). The report critiques EPA's current approaches for characterizing human cancer risks from exposure to chemicals and offers recommendations for the conduct of future cancer risk assessments, especially those required in implementing the CAAA-1990 provisions which are concerned with hazardous air pollutants. The report offers specific recommendations that address the role of default options, data needs, methods and models, uncertainty, variability, and the aggregation of data. A cross-cutting theme of the report is the use of an iterative approach in which screening assessments with limited data and, of necessity, default options used in the absence of specific scientific data may be performed initially followed by subsequent assessments, as needed, in which increasing amounts of data are developed and incorporated. In some instances, the specific data on a given chemical or pollutant source will replace conservative default options used in earlier assignments. The report includes two authored appendices that address issues related to the use of default options and their replacement by specific scientific information. One appendix by Finkel advocates a principle of "plausible conservatism" for choosing and altering default options and in making cancer risk estimates. A second appendix by McClellan and North advocates the full use of scientific information in the risk assessment process. This article gives major attention to the key aspects of the NRC/NAS report, especially those dealing with the use and replacement of default options. The default options and the extent to which the options are replaced with specific science have major impact on the final quantitation of cancer risk for exposure to chemicals.

Air Pollution↗

PubMed2004

A statistical evaluation of toxicity study designs for the estimation of the benchmark dose in continuous endpoints.

The benchmark approach is gaining attention as an alternative to the No-Observed-Adverse-Effect-Level (NOAEL) approach. However, current guidelines for the design of toxicity tests are based on assessing a NOAEL. It has been suggested that the current study design may not be optimal for assessing a Benchmark Dose (BMD). To further investigate this we performed three simulation studies in which a large number of designs were compared, focusing on continuous endpoints. Four fictitious endpoints were considered, their underlying dose-response curves having a linear, sublinear, supralinear, or sigmoidal shape. In each simulation run the BMD was derived from a model fitted to the generated data, where the selection of the model was based on that particular data set (according to a formal likelihood ratio test procedure). Thus, the model used for deriving the BMD in a single generated data set may not be the same as the one used for generating the data. In this way, model uncertainty is taken into account as well. The results show that the performance of a design is, first of all, determined by the total number of animals used. Distributing them over more dose groups does not result in a poorer performance of the study, despite the smaller number of animals per dose group. Dose placement is another crucial factor, and to minimize the risk of inadequate dose placement, the use of multiple dose studies is favorable. As a concomitant advantage, the use of multiple doses mitigates the disturbing effect of potential systematic errors in single dose groups. However, for endpoints with large residual variation (CV > or = 18%) there is a substantial probability of not detecting the overall dose-response, and this probability increases in designs with increasing number of dose groups. In such situations, six dose groups may be used as a compromise. Designs with high dose levels (i.e., associated with relatively high effects) are helpful in estimating doses with smaller effects (such as the benchmark dose), and it appears bad practice to omit higher dose groups to improve the fit at lower doses. The typical 28-day study design of four dose groups with five animals (per sex) may not be adequate to assess endpoints with large residual variation (CV > or = 18%), both in assessing a benchmark dose and in assessing a NOAEL.

Animals↗

PubMed2004

Prolonged enoxaparin therapy to prevent venous thromboembolism after primary hip or knee replacement. A cost-utility analysis.

BACKGROUND: Among patients undergoing elective total hip or knee replacement, prolonged prophylaxis with low-molecular-weight heparin significantly reduces the risk of symptomatic venous thromboembolism. Whether implementing routine prolonged prophylaxis is cost-effective remains uncertain. METHODS: We performed an economic modeling study to compare the costs and health outcomes of standard (12 days) with prolonged (42 days) enoxaparin prophylaxis against venous thromboembolism after elective total hip and knee replacement. The primary economic perspective was that of a societal healthcare payer, taking Belgium as a case country. We used cost-utility analysis, a form of cost effectiveness analysis in which costs are reported in monetary terms (euros) and health outcomes are converted into quality-adjusted life years (QALYs) gained, thereby incorporating a measure of quality of life (utility) into the health outcomes. Costs for diagnosis and treatment of proximal and distal deep vein thrombosis, pulmonary embolism, postphlebitic syndrome, and major bleeding were obtained from a Delphi panel (orthopaedic surgeons) and the official reimbursement rates (Federal Ministry of Health). QALYs for these health outcomes were based on utility scores as reported in the literature. The main outcome measure was the incremental cost-utility ratio, reported as the incremental cost per quality-adjusted life year gained (euros/QALY). The incremental cost-utility ratio refers to the amount of money needed to produce one additional QALY. We also performed sensitivity analyses on clinical and economic parameters to identify important model uncertainties. RESULTS: In the base-case analysis, incremental costs of prolonged prophylaxis amounted to 58 euros and 114 euros per patient, with an additional gain in QALY of 0.0083 and 0.0018 after total hip and knee replacement, respectively. Thus, a strategy of prolonged enoxaparin prophylaxis was associated with a cost-utility ratio of 6,964 euros/QALY and 64,907 euros/QALY after total hip and knee replacement, respectively. This tenfold difference in incremental cost-utility ratios between hip and knee replacement might have important practical implications. According to recent European guidelines, an intervention costing less than 20,000 euros per QALY is said to exhibit strong evidence for adoption, whereas one costing 20,000-100,000 euros exhibits moderate evidence for adoption. By current European guidelines, the cost of 6,964 euros and 64,907 euros per QALY gained would give strong evidence for adoption of prolonged enoxaparin prophylaxis among total hip replacement patients, but moderate evidence for adoption among total knee replacement patients. Sensitivity analyses using 20% changes from the base-case analysis showed this outcome to be robust. CONCLUSIONS: Our findings indicate that, among patients undergoing elective total hip or knee replacement, prolonged enoxaparin prophylaxis leads to increased health benefits at increased cost. Given the additional costs that healthcare decision makers in Europe are usually prepared to pay for a gain in utility, prolonged prophylaxis with enoxaparin is cost-effective after elective total hip replacement, and our data provide strong evidence for adoption of prolonged enoxaparin prophylaxis after elective total hip replacement.

Anticoagulants↗

PubMed1987

Facilitation and masking of briefly presented gratings: time-course and contrast dependence.

We measured two-alternative forced-choice contrast thresholds for briefly presented sinusoidal gratings in the presence of superimposed masking gratings of various contrasts, and at a range of onset asynchronies. Facilitation (lower thresholds) occurred when the mask was simultaneous, in-phase, and near-threshold, but was abolished at asynchronies of 50 msec or more and by presenting the test grating as a brief contrast reversal instead of a pulse. We argue that facilitation requires temporal summation of responses within the same neural channels, but our results do not distinguish between transducer and uncertainty models. Masking (threshold elevation) occurred over a broader range of asynchronies, and was not abolished by test contrast reversal. Masking and facilitation probably depend on different processes with different time-courses. The occurrence of masking at asynchronies outside the range of temporal summation suggests that a static, compressive transducer does not, in general, account for masking. Brief masking and prolonged contrast adaptation are very similar in magnitude, and as a function of contrast and relative spatial frequency. Masking and adaptation may have a common origin, but differ in speed of recovery.

Adaptation, Ocular↗

PubMed2006

Temporal representation and reasoning in medicine: Research directions and challenges.

OBJECTIVE: The main aim of this paper is to propose and discuss promising directions of research in the field of temporal representation and reasoning in medicine, taking into account the recent scientific literature and challenging issues of current interest as viewed from the different research perspectives of the authors of the paper. BACKGROUND: Temporal representation and reasoning in medicine is a well-known field of research in the medical as well as computer science community. It encompasses several topics, such as summarizing data from temporal clinical databases, reasoning on temporal clinical data for therapeutic assessments, and modeling uncertainty in clinical knowledge and data. It is also related to several medical tasks, such as monitoring intensive care patients, providing treatments for chronic patients, as well as planning and scheduling clinical routine activities within complex healthcare organizations. METHODOLOGY: The authors jointly identified significant research areas based on their importance as for temporal representation and reasoning issues; the subjects were considered to be promising topics of future activity. Every subject was addressed in detail by one or two authors and then discussed with the entire team to achieve a consensus about future fields of research. RESULTS: We identified and focused on four research areas, namely (i) fuzzy logic, time, and medicine, (ii) temporal reasoning and data mining, (iii) health information systems, business processes, and time, and (iv) temporal clinical databases. For every area, we first highlighted a few basic notions that would permit any reader--including those who are unfamiliar with the topic--to understand the main goals. We then discuss interesting and promising directions of research, taking into account the recent literature and underlining the yet unresolved medical/clinical issues that deserve further scientific investigation. The considered research areas are by no means disjointed, because they share common theoretical and methodological features. Moreover, subjects of imminent interest in medicine are represented in many of the fields considered. CONCLUSIONS: We propose and discuss promising subjects of future research that deserve investigation to develop software systems that will properly manage the multifaceted temporal aspects of information and knowledge encountered by physicians during their clinical work. As the subjects of research have resulted from merging the different perspectives of the authors involved in this study, we hope the paper will succeed in stimulating discussion and multidisciplinary work in the described fields of research.

Artificial Intelligence↗

PubMed2005

Potential human health benefits of antibiotics used in food animals: a case study of virginiamycin.

Risk management of food-animal antibiotics has reached a crucial juncture for public health officials worldwide. While withdrawals of animal antibiotics previously used to control animal bacterial illnesses are being encouraged in many countries, the human health impacts of such withdrawals are only starting to be understood. Increases in animal and human bacterial illness rates and antibiotic resistance levels in humans in Europe despite bans on animal antibiotics there have raised questions about how animal antibiotic use affects human health. This paper presents a quantitative human health risk and benefits assessment for virginiamycin (VM), a streptogramin antibiotic recommended for withdrawal from use in food animals in several countries. It applies a new quantitative Rapid Risk Rating Technique (RRRT) that estimates and multiplies data-driven exposure, dose-response, and consequence factors, as suggested by WHO (2003) to estimate human health impacts from withdrawing virginiamycin. Increased human health risks from more pathogens reaching consumers if VM use is terminated (6660 estimated excess campylobacteriosis cases per year in the base case) are predicted to far outweigh benefits from reduced streptogramin-resistant vancomycin-resistant Enterococcus faecium (VREF) infections in human patients (0.27 estimated excess cases per year in the base case). While lack of information about impacts of VM withdrawal on average human illnesses-per-serving of food animal meat precludes a deterministic conclusion, it appears very probable that such a withdrawal would cause many times more human illnesses than it would prevent. This qualitative conclusion appears to be robust to several scientific and modeling uncertainties.

Animal Husbandry↗