Gradient-based optimization with B-splines on sparse grids for solving forward-dynamics simulations of three-dimensional, continuum-mechanical musculoskeletal system models.

Investigating the interplay between muscular activity and motion is the basis to improve our understanding of healthy or diseased musculoskeletal systems. To be able to analyze the musculoskeletal systems, computational models are used. Albeit some severe modeling assumptions, almost all existing musculoskeletal system simulations appeal to multibody simulation frameworks. Although continuum-mechanical musculoskeletal system models can compensate for some of these limitations, they are essentially not considered because of their computational complexity and cost. The proposed framework is the first activation-driven musculoskeletal system model, in which the exerted skeletal muscle forces are computed using 3-dimensional, continuum-mechanical skeletal muscle models and in which muscle activations are determined based on a constraint optimization problem. Numerical feasibility is achieved by computing sparse grid surrogates with hierarchical B-splines, and adaptive sparse grid refinement further reduces the computational effort. The choice of B-splines allows the use of all existing gradient-based optimization techniques without further numerical approximation. This paper demonstrates that the resulting surrogates have low relative errors (less than 0.76%) and can be used within forward simulations that are subject to constraint optimization. To demonstrate this, we set up several different test scenarios in which an upper limb model consisting of the elbow joint, the biceps and triceps brachii, and an external load is subjected to different optimization criteria. Even though this novel method has only been demonstrated for a 2-muscle system, it can easily be extended to musculoskeletal systems with 3 or more muscles.

A two-muscle, continuum-mechanical forward simulation of the upper limb.

By following the common definition of forward-dynamics simulations, i.e. predicting movement based on (neural) muscle activity, this work describes, for the first time, a forward-dynamics simulation framework of a musculoskeletal system, in which all components are represented as continuous, three-dimensional, volumetric objects. Within this framework, the mechanical behaviour of the entire muscle-tendon complex is modelled as a nonlinear hyperelastic material undergoing finite deformations. The feasibility and the full potential of the proposed forward-dynamics simulation framework is demonstrated on a two-muscle, three-dimensional, continuum-mechanical model of the upper limb. The musculoskeletal model consists of three bones, i.e. humerus, ulna, and radius, an one-degree-of-freedom elbow joint, and an antagonistic muscle pair, i.e. the biceps and triceps brachii, and takes into consideration the contact between the skeletal muscles and the humerus. Numerical studies have shown that the proposed upper limb model is capable of predicting realistic moment arms and muscle forces for the entire range of activation and motion. Within the limitations of the model, the presented simulations provide, for the first time, insights into existing contact forces and their influence on the muscle fibre stretch. Based on the presented simulations, the overall change in fibre stretch is typically less than 3%, despite the fact that the contact forces reach up to 71% of the exerted muscle force. Movement-predicting simulations are achieved by minimising a nonlinear moment equilibrium equation. Based on the forward-dynamics simulation approach, an iterative solution procedures for position-driven (inverse dynamics) and force-driven scenarios have been proposed accordingly. Applying these methodologies to time-dependent scenarios demonstrates that the proposed methods can be linked to state-of-the-art control algorithms predicting time-dependent muscle activation levels based on principles of forward dynamics.

Dehydration indicators for broiler chickens at slaughter.

Freedom of (prolonged) thirst is considered to be of paramount importance for animal welfare. This emotion normally results from dehydration, which can be measured using physiological indicators. Because no reliable physiological indicator for thirst was available for broilers, we aimed to identify such a measure in this study. This indicator would ideally be integrated into quality control systems in commercial slaughter plants. In the first experiment, water deprivation was manipulated systematically by withdrawing water for different durations (total water withdrawal for 0 (control), 24, 36, or 48 h, or a 10-d period with restricted access to water for 2 times 10 min per day). A significant decrease in drained blood content and BW occurred from 36 h of total water deprivation onward (both P = 0.03), whereas long-term restricted access tended to decrease drained blood content (P = 0.05). No effect of water deprivation or restriction on skin turgor was found. In the second experiment, water was withdrawn for 0 (control), 6, 12, 24, or 48 h. Plasma chloride concentration was increased after 6 h of water withdrawal, but did not rise further with longer withdrawal. If assessed at slaughter, chloride will thus mainly reflect the catching-to-slaughter interval. In contrast, plasma creatinine and hematocrit levels showed a numerical decrease after 6 h of water withdrawal, but rose again after prolonged withdrawal. Plasma creatinine values were significantly higher in 24-h-deprived birds than in 6-h-deprived birds (P < 0.01), allowing for discernment between water withdrawal during catching and transport from dehydration that had occurred on the farm. Blood sodium concentrations and plasma osmolality showed a steady increment between 0 and 24 h of water deprivation (P < 0.001 and P < 0.001 for both), and may thus be used to assess the combined effects of water deprivation on farm and during the catching-to-slaughter interval. These findings may form the basis of an on-farm or at-slaughter test that could be included in integrated animal welfare assessment schemes.

Influence of procalcitonin on decision to start antibiotic treatment in patients with a lower respiratory tract infection: insight from the observational multicentric ProREAL surveillance.

Procalcitonin (PCT)-guided antibiotic stewardship is a successful strategy to decrease antibiotic use. We assessed if clinical judgement affected compliance with a PCT-algorithm for antibiotic prescribing in a multicenter surveillance of patients with lower respiratory tract infections (LRTI). Initiation and duration of antibiotic therapy, adherence to a PCT algorithm and outcome were monitored in consecutive adults with LRTI who were enrolled in a prospective observational quality control. We correlated initial clinical judgment of the treating physician with algorithm compliance and assessed the influence of PCT on the final decision to initiate antibiotic therapy. PCT levels correlated with physicians' estimates of the likelihood of bacterial infection (p for trend <0.02). PCT influenced the post-test probability of antibiotic initiation with a greater effect in patients with non-pneumonia LRTI (e.g., for bronchitis: -23 % if PCT ≤ 0.25 µg/L and +31 % if PCT > 0.25 µg/L), in European centers (e.g., in France -22 % if PCT ≤ 0.25 µg/L and +13 % if PCT > 0.25 µg/L) and in centers, which had previous experience with the PCT-algorithm (-16 % if PCT ≤ 0.25 µg/L and +19 % if PCT > 0.25 µg/L). Algorithm non-compliance, i.e. antibiotic prescribing despite low PCT-levels, was independently predicted by the likelihood of a bacterial infection as judged by the treating physician. Compliance was significantly associated with identification of a bacterial etiology (p = 0.01). Compliance with PCT-guided antibiotic stewardship was affected by geographically and culturally-influenced subjective clinical judgment. Initiation of antibiotic therapy was altered by PCT levels. Differential compliance with antibiotic stewardship efforts contributes to geographical differences in antibiotic prescribing habits and potentially influences antibiotic resistance rates.

Automated assessment of footpad dermatitis in broiler chickens at the slaughter-line: evaluation and correspondence with human expert scores.

Footpad dermatitis is increasingly used as an indicator of decreased broiler welfare, and automation of dermatitis monitoring potentially reduces the effort needed to monitor commercial flocks. In this study we evaluated a prototype system for the automatic assessment of footpad dermatitis in broiler chickens by comparing the automatic assessment with a human expert assessment. The expert aimed at selecting 2 times (different period) 20 broilers per footpad dermatitis category (5 categories in total), from 2 different flocks of 38-d-old broilers on an experimental farm. Two days later these broilers were transported to the slaughterhouse, where footpad dermatitis was assessed by the automatic system. Subsequently the footpads were reassessed by the same expert that had selected the birds. Automatic scores were only weakly correlated with scores given by the expert on-farm (r = 0.54) and at the slaughterhouse (r = 0.59). Manual evaluation of the photographs on which the automatic system based its scores revealed several errors. For 41.1% of the birds, the automatic system assessed only one of the footpads, whereas for 15.2% neither footpad was assessed. For 49.4% of the birds, scores were based on partially incorrectly identified areas. When data from such incomplete and obviously incorrect assessments were discarded, stronger correlations between automatic and expert scores were found (r = 0.68 and r = 0.74 for expert scores given on-farm and at-slaughter, respectively). Footpads that were missed by the automatic system were more likely to receive a high expert score at slaughter (P = 0.02). However, average flock scores did not differ greatly between automatic and expert scores. The prototype system for automatic dermatitis assessment needs to be improved on several points if it is to replace expert assessment of footpad dermatitis.

Skipping meals or carbohydrate-free meals in order to determine Basal insulin requirements in subjects with type 1 diabetes mellitus?

INTRODUCTION: Basal insulin dose requirements in patients with type 1 diabetes may be derived from the course of glucose concentrations in the fasting state; i. e. by skipping meals. The present study examined whether fasting tests could be replaced by carbohydrate-free meals. MATERIAL AND METHODS: 16 adult patients with type 1 diabetes (10 male) on intensive insulin therapy participated in this prospective intervention study. Mean age (+/-SD) was 44+/-12 years, BMI 24+/-3 kg/m (2), mean HbA1c was 7.5+/-0.6% and duration of diabetes 15+/-12 years. All participants skipped dinner and plasma glucose concentrations were hourly monitored from 7 p.m. to 11 p.m. This blood glucose profile was compared with three test meals given at 7 p.m. at day 2-4, consumed either in the hospital (meal 1) or at home (meal 2 and 3). No insulin injection (except to basal insulin) was allowed. Test meals consisted of 2.5 g carbohydrate, 32.4 g protein, 52.0 g fat (according to 612 kcal). RESULTS: During 16 fasting tests plasma glucose concentration remained stable between 7.2+/-2.4 mmol/l at 7 p.m. and 6.8+/-2.8 mmol/l at 11 p.m. (p=0.461). Following the intake of near carbohydrate-free meals (48 tests), plasma glucose concentrations rose within 4 h from 6.7+/-2.0 at 7 p.m. to 9.8+/-3.4 mmol/l at 11 p.m. (p<0.0001). The increase in plasma glucose concentrations was similar in all three different meals tested. CONCLUSION: Plasma glucose concentrations significantly increase in patients with type 1 diabetes following the intake of carbohydrate-free meals. Carbohydrate-free meal-tests cannot replace skipping meal tests to determine the basal insulin requirement in patients with type 1 diabetes.

Identification and climatology of cut-off lows near the tropopause.

Cut-off low pressure systems (COLs) are defined as closed lows in the upper troposphere that have become completely detached from the main westerly current. These slow-moving systems often affect the weather conditions at the earth's surface and also work as a mechanism of mass transfer between the stratosphere and the troposphere, playing a significant role in the net flow of tropospheric ozone. In the first part of this work we provide a comprehensive summary of results obtained in previous studies of COLs. Following this, we present three long-term climatologies of COLs. The first two climatologies are based on the conceptual model of a COL, using European Centre for Medium-range Weather Forecasts (ECMWF) analyses (1958-2002) and National Centers for Environmental Prediction-National Center for Atmospheric Research (1948-2006) reanalysis data sets. The third climatology uses a different method of detection, which is based on using potential vorticity as the physical parameter of diagnosis. This approach was applied only to the ECMWF reanalysis data. The final part of the paper is devoted to comparing results obtained by these different climatologies in terms of areas of preferential occurrence, life span, and seasonal cycle. Despite some key differences, the three climatologies agree in terms of the main areas of COL occurrence, namely (1) southwestern Europe, (2) the eastern north Pacific coast, and (3) the north China-Siberian region. However, it is also shown that the detection of these areas of main COL occurrence, as obtained using the potential vorticity approach, depends on the level of isentropic analysis used.

The ABC-Pyramid Atmospheric Research Observatory in Himalaya for aerosol, ozone and halocarbon measurements.

In this work we present the new ABC-Pyramid Atmospheric Research Observatory (Nepal, 27.95 N, 86.82 E) located in the Himalayas, specifically in the Khumbu valley at 5079 m a.s.l. This measurement station has been set-up with the aim of investigating natural and human-induced environmental changes at different scales (local, regional and global). After an accurate instrumental set-up at ISAC-CNR in Bologna (Italy) in autumn 2005, the ABC-Pyramid Observatory for aerosol (physical, chemical and optical properties) and trace gas measurements (ozone and climate altering halocarbons) was installed in the high Khumbu valley in February 2006. Since March 2006, continuous measurements of aerosol particles (optical and physical properties), ozone (O3) and meteorological parameters as well as weekly samplings of particulate matter (for chemical analyses) and grab air samples for the determination of 27 halocarbons, have been carried out. These measurements provide data on the typical atmospheric composition of the Himalayan area between India and China and make investigations of the principal differences and similarities between the monsoon and pre-monsoon seasons possible. The study is carried out within the framework of the Ev-K2-CNR "SHARE-Asia" (Stations at High Altitude for Research on the Environment in Asia) and UNEP-"ABC" (Atmospheric Brown Clouds) projects. With the name of "Nepal Climate Observatory-Pyramid" the station is now part of the Observatory program of the ABC project.

[Pharmaco-economic evaluations of new drugs: potential key to a more efficient allocation of the health care budget]. / Farmaco-economische evaluaties van nieuwe geneesmiddelen: mogelijk de sleutel tot een doelmatiger verdeling van het gezondheidszorgbudget.

In the light of rising expenditure on drugs and health care, a transparent, rational and careful decision-making process is required for the reimbursement of drugs. In the Netherlands, the Ministry of Health intends using pharmaco-economics in this process, i.e., new drugs will not only be judged on their clinical efficacy but also on their cost-effectiveness. Guidelines for pharmaco-economic research in the Netherlands have been published. According to these guidelines, a pharmaco-economic study must contain a cost-effectiveness analysis and/or a cost-utility analysis. In addition, a budgetary impact analysis is required. By 2005, all new drugs with therapeutic added value must supply a pharmaco-economic evaluation in order to apply for reimbursement. It will be the Minister of Health who decides whether a new drug will be reimbursed.

Genetic predisposition in patients undergoing cardiopulmonary bypass surgery is associated with an increase of inflammatory cytokines.

OBJECTIVE: Cardiopulmonary bypass (CPB) surgery induces a transient rise in pro-inflammatory cytokines typically released by activated monocytes. The E4 variant of apolipoprotein E is a recognized risk factor for atherosclerosis. It has recently been shown that apolipoprotein E affects monocyte functions in vitro and leads to higher levels of median lipoprotein (a) in humans. The aim of the study is to investigate if the E4 genetic variant of apolipoprotein E affects cytokine release after CPB surgery. METHODS: 22 patients were operated on with standard coronary artery bypass grafting. Concentrations of interleukin 8 (IL-8) and tumor necrosis factor (TNF-alpha) were measured by automated Immulite immunoassay at regular intervals within 48 h after surgery. Total apparent cytokine outputs were calculated as area under the curve. Results are expressed as mean+/-standard deviation and compared by unpaired t-test. RESULTS: In the presented patient population 6 (27%) carried the E4 allele. Sixteen (63%) showed no E4 allele. Mean cross clamp time (CCT) was 56.2+/-13.5 min versus 55.7+/-12.1 min and CPB time was 91.8+/-17.5 versus 93.5+/-15.7 min. No statistical difference between E4-carriers and E4 non-carriers regarding CCT and CPB was observed. The total amount of IL-8 and TNF-alpha was higher in patients carrying the E4 genetic variant of apolipoprotein E in comparison to E4 non-carriers (P<0.08, P<0.039). CONCLUSION: The presence of the E4 allele is associated with increased release of IL-8 and TNF-alpha after CBP surgery. The preoperative determination of E4 in patients undergoing cardiac surgery may lead to additional perioperative measures for the treatment of an increased systemic inflammatory response.