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PubMed1991

Nonlinear dynamic behavior of the human knee joint--Part II: Time-domain analyses: effects of structural damage in postmortem experiments.

A description is given of the results obtained for step excitation for two human knee joint specimens using a time-domain analysis technique. As was expected from the results of a previous study, the magnitude of the dynamic load applied has a marked influence upon the stiffness and damping values for the two observed vibration modes. Deliberate damaging of selected joint elements also yields a well observable change in the dynamic behavior of the joint although these changes are difficult to interpret. Here the use of a nonlinear dynamic numerical model of the knee joint seems indispensable. An important observation is, however, that the experimental method discussed here enables to quantify the behavior of the joint and therefore may provide a valuable tool for validation of such a model.

Anterior Cruciate Ligament↗

PubMed1991

Nonlinear dynamic behavior of the human knee joint--Part I: Postmortem frequency domain analyses.

Characteristics results of postmortem experiments on five knee-joint specimens are reported. The experiments were performed to investigate the applicability of a local linearization technique that would make it possible to describe the dynamic behavior of the joint in terms of transfer functions. The results indicate that the stiffness of the bracing wires, attached to muscle tendons to create a static equilibrium position, can be accounted for when determining the stiffness of the joint. Besides the static equilibrium configuration, the magnitude of the dynamic load and the type of dynamic load applied to the joint can be shown to have their influence. As the influence of the dynamic load is significant, it has to be concluded that in essence the knee joint has to be regarded as a nonlinear system, making application of a Local Linearization Technique questionable. However, when the magnitude of the dynamic load is included as an additional measurement parameter, an indication can be obtained about the behavior of the joint and the degree of nonlinearity.

Biomechanical Phenomena↗

PubMed2026

Human-Centered Workspace Optimization: A 2 × 2 Factorial Study of Adjustable Furniture and Indoor Environmental Quality.

Small workspaces function as integrated systems, yet ergonomic furniture and indoor environmental conditions are usually evaluated separately. A six-site, assessor-blinded, randomized 2 × 2 factorial controlled study was conducted of two multicomponent packages-adjustable furniture and optimized indoor environmental quality (IEQ)-among 240 office workers for four weeks. Each group included 60 participants. Overall comfort in week 4 was highest for both packages (5.62 ± 0.53 versus 3.99 ± 0.60 with fixed furniture and basic IEQ). In a site-adjusted factorial model with HC3 robust standard errors, the adjustable-furniture effect was 0.86 points (95% confidence interval [CI], 0.62-1.09), the optimized-IEQ effect was 0.34 points (95% CI, 0.12-0.55), and their interaction was 0.44 points (95% CI, 0.14-0.74). Adjustable furniture improved postural comfort and reduced neck and lower back discomfort; optimized IEQ improved environmental comfort; both packages improved perceived productivity, satisfaction, and fatigue. The task-accuracy interaction did not remain significant after false-discovery-rate adjustment, and exploratory mediation and spline analyses did not support indirect or nonlinear effects. These results support coordinated ergonomic and environmental implementation while preserving distinct outcome pathways.

Interior Design and Furnishings↗

PubMed1991

Effects of perfusate buffer capacity on capillary CO2-HCO3(-)-H+ reactions: theory.

The importance of perfusate nonbicarbonate buffer capacity (beta nonHCO3) to intracapillary CO2-HCO3(-)-H+ reactions was assessed by theoretical analysis of CO2 exchange in saline-perfused pulmonary capillaries. Time courses for perfusate PCO2, [HCO3-], and [H+] were computed for capillaries containing different activities of luminal vascular carbonic anhydrase and different amounts of perfusate nonbicarbonate buffers. Mobilization of perfusate HCO3- toward CO2 during capillary transit is determined by the availability of HCO3- and H+. A supply of protons from the nonbicarbonate buffer pool is necessary to maintain a high rate of HCO3- dehydration. The analyses indicate that beta nonHCO3 has marked nonlinear effects on transcapillary CO2 exchange and intravascular pH equilibration. These nonlinear effects differ from those previously computed for CO2 reactions in an open system because the present model system consists of a sequential combination of open (within capillary proper) and closed (within postcapillary vasculature) systems. The role of luminal vascular carbonic anhydrase in capillary CO2 reactions is strongly dependent on beta nonHCO3. Perfusate nonbicarbonate buffer capacity must be considered when the results of experimental studies of transcapillary CO2 exchange and/or intravascular pH equilibration are interpreted.

Bicarbonates↗

PubMed2026

Association of time-averaged systemic immune-inflammation indices with in-hospital mortality after intracerebral hemorrhage: a retrospective study.

BACKGROUND: Systemic inflammation plays a central role in secondary brain injury following intracerebral hemorrhage (ICH). Although inflammatory indices such as the neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and systemic inflammation response index (SIRI) are linked to poor outcomes, their associations with mortality are commonly assumed to be linear, potentially overlooking nonlinear patterns where mortality risk rises steeply at higher levels. METHODS: We conducted a retrospective study using the MIMIC-IV database, including 440 patients with non-traumatic ICH who were alive and remained in the ICU for at least 72 h after admission. Mean NLR, SII, and SIRI were calculated from measurements obtained during this period. Multivariable logistic regression and restricted cubic spline (RCS) analyses were applied to assess their independent and nonlinear associations with in-hospital mortality. Model discrimination and calibration were internally validated using 1,000 bootstrap resamples. RESULTS: The in-hospital mortality rate was 26.1%. After multivariable adjustment, NLR and SIRI remained independently associated with mortality. Patients in the highest SIRI quartile had the highest risk of death (aOR = 5.12; 95% CI: 2.57-12.24; p < 0.001). RCS analysis revealed a significant nonlinear association between SIRI and mortality (p-nonlinearity < 0.05), showing a steep risk increase at higher SIRI levels. Adding SIRI to the base model provided a modest improvement in discrimination (AUC 0.762 to 0.785, p = 0.045) and significantly improved risk reclassification (cNRI = 0.4778, p < 0.001; IDI = 0.0240, p = 0.0151). CONCLUSIONS: Among patients with ICH who met the 72-hour eligibility criterion, higher 72-hour average SIRI was independently associated with in-hospital mortality. As a time-averaged measure, SIRI should be interpreted as a dynamic marker integrating the initial inflammatory state and the early clinical course rather than as a purely baseline prognostic factor. Although adding SIRI to the base model modestly improved discrimination and risk reclassification, it should be considered a candidate prognostic marker requiring external validation before clinical application.

Humans↗

PubMed1992

Determination of sensitivity to metocurine in exercised horses.

On the basis of results in dogs, conditioning exercise may increase sensitivity to nondepolarizing muscle relaxants. Five Thoroughbreds were exercised/conditioned 3 times weekly on a treadmill for 8 months. Increasing maximal rate of O2 consumption verified that the horses were responding to exercise conditioning. Six nonexercised Thoroughbreds served as the control group. Studies were done with horses under general anesthesia by use of halothane during partial paralysis by a brief constant-rate infusion with the muscle relaxant, metocurine iodide. Quantification of degree of paralysis of the hoof twitch (eg, digital extensor) occurred with simultaneous quantification of blood values of metocurine. Pharmacokinetic and pharmacodynamic analyses of the data were done by a nonlinear regression program, using the Hill equation. There were no differences in findings between exercised and nonexercised horses. The mean blood concentration for the 50% paralyzing dose of metocurine was 0.44 +/- 0.11 (SD) microgram/ml in exercised horses, and 0.58 +/- 0.22 microgram/ml in nonexercised horses. Despite evidence for a response to conditioning, a significant change in the sensitivity of the neuromuscular junction to metocurine was not found.

Animals↗

PubMed1975

Developmental change in the apparent kinetic properties of drug-oxidizing enzymes in the human liver.

When analyzing the effect of substrate concentration on the reaction rate of aminopyrine N-demethylation, aniline p-hydroxylation, and 3,4-benzpyrene hydroxylation by human fetal and adult liver samples we found that Lineweaver-Burk and Eadie-Hofstee analyses yielded mostly linear lines with fetal liver, but nonlinear lines with adult livermthis may be taken to indicate that a qualitative change in drug-oxidizing enzymes of the human liver occurs during ontogenetic development, of the human liver occurs during ontogenetic development, possibly so that during the fetal period liver contains one ana during the adult period two enzymes metabolizing aminopyrine, anilinw, and 3,4-benzpyrene.

Adult↗

PubMed2026

Comparison of classic statistical methods and machine learning approaches to classify readiness.

MOTIVATION: Predicting physical and cognitive readiness in warfighters is critical for mission success. These predictions can be improved by identifying key biomarkers using multiple omics modalities. The MASTR-E study conducted by McKetney and colleagues is one of the most comprehensive multi-omics studies of saliva samples collected from warfighters, which also applied classic linear statistical (CLS) techniques to discover key biomarkers of readiness. Aligning with McKetney et al.'s assumptions, we operationalize readiness as a binary proxy, where pre-mission samples are labeled as "ready" to reflect a rested, unstressed physiological baseline, while post-mission samples are labeled "not ready" to reflect cumulative physical and cognitive load from the mission. As such, readiness here is not a direct biological or physiological construct, but an inferred state likely dominated by stress-related physiological changes. This assumption and definition is discussed further in the Introduction and Limitations sections. Here, we apply machine learning (ML) analyses to better assess generalizability, consider hidden interactions, and identify nonlinear patterns in the data. We investigated whether ML approaches could predict readiness and identify relevant biomarkers. ML models were trained on proteomics-only or metabolomics-only datasets to classify participants as ready or not ready and important model features were considered as putative biomarkers. Training and testing datasets were curated for two objectives: (i) recognize biomolecular signatures indicative of readiness within the same donor and (ii) assess generalizability across warfighters by withholding donors for testing. RESULTS: Proteomics-based models achieved AUCs of 0.907 ± 0.034 and 0.860 ± 0.063 for Objectives 1 and 2, respectively. Metabolomics-based models achieved Objective 1 AUC of 0.994 ± 0.007 and Objective 2 AUC of 0.993 ± 0.010. Comparative analysis with existing literature validates the model's feature importances, but the identified putative biomarkers significantly differ from those discovered through CLS analyses, as only one ML-identified biomarker overlapping with those identified through CLS methods. We show that these ML models and identified features are more robust to noise and generalizable across participants than those identified using CLS methods. AVAILABILITY: The analysis pipelines are provided as Jupyter notebooks, including all code and documentation, and are available publicly on GitHub at {https://github.com/netrias/ReadinessClassification}.

Machine Learning↗

PubMed1976

Response of unmyelinated (C) polymodal nociceptors to thermal stimuli applied to monkey's face.

1. The response of C polymodal nociceptors to thermal and mechanical stimuli applied to the monkey's face was recorded extracellulary in the trigeminal ganglion in rhesus monkeys anesthetized with sodium pentobarbital. Conduction velocities, determined from electrical stimulation of receptive fields (RFs), were in the range for unmyelinated C fibers (mean=0.82 m/s, n=20; SD=+/-0.17). With two exceptions cutaneous RFs were single spots (median=2 mm2; n=37) and usually were identical for thermal and mechanical stimuli. The median force threshold for the sample of units was 1.2 g (von Frey technique; n = 39; range = 0.07-8.5 g). 2. Discharges to thermal stimuli were investigated with a feedback-controlled contact thermode which permitted temperature changes less than or equal 12.0 degrees C/s. Thermal thresholds ranged from 38 degree to 49 degree C (median=46 degrees C; n=37), and maximum discharge frequencies were obtained in the noxious heat range (45-55 degrees C). For a graded series of 5 s duration stimuli from an adapting temperature of 35 degrees C, the number of impulses increased as a monotonic function of stimulus intensity over the range from threshold temperature to 50-53 degrees C. Many stimulus-response functions were positively accelerated, and linear regression analyses showed that most units examined were best fit by nonlinear functions. 3. The typical pattern of activity to 5 s duration temperature shifts into the noxious heat range was a short accelerating burst of impulses followed by deceleration to a lower rate of discharge prior to termination of the stimulus. The temporal profile of the discharge of impulses was virtually identical at different adapting temperatures. In units tested with 30 s duration stimuli at 2-6 degrees C above threshold, the mean frequency of discharge during the final 25 s was 1.46 impulses/s (n=6; SD=+/-0.89). 4. Application of noxious heat stimuli a few degrees above threshold temperature typically sensitized or enhanced the response of the unit to subsequent application of heat stimuli. The signs of sensitization consisted of a decrease in threshold temperature, increased frequency of discharge, decreased latency to the first impulse, and afterdischarges. Units failed to respond throughout the duration of 30 s stimuli if the final temperature exceeded 50 degrees C. Depressed responses were sometimes produced by application of intense (greater than or equal 55 degrees C) stimuli, presumably as a result of partial inactivation of the receptor. 5. In a correlative analysis, the latency and pattern of discharge in a sample of units were compared with escape responses in two monkeys to temperature shifts into the noxious heat range (49 and 51 degrees C). The analysis revealed that the discharge of C polymodal nociceptors alone cannot account for fast escape responses, but the discharge may contribute to escape responses which occur more than 3.5 s after the onset of stimulation.

Adaptation, Physiological↗

PubMed1992

Physical aspects of the EEG in schizophrenics.

Physical and dynamic aspects of the electroencephalogram (EEG) were evaluated in 12 schizophrenic patients and 12 matched healthy control subjects by means of two descriptive measures proposed by Hjorth (complexity and mobility) and by a nonlinear measure, dimensional complexity. These measures were compared to power spectra analyses. EEG was recorded from frontal, central, and parietal leads under resting conditions (eyes open and eyes closed) for 12 epochs each of 25 sec. Patients showed the expected increased activity in the 1-7 Hz band and, furthermore, a scalp distribution of dimensional complexity and Hjorth complexity opposite to the distribution in controls: in patients dimensional complexity yielded higher values at frontal (Fz) than central (Cz) leads, whereas the resemblance to sinusoidal waveshape (Hjorth complexity) was larger at Fz than Cz. Results indicate more dynamic complexity or variables determining the dynamics of brain processes in frontal areas in patients.

Adult↗

PubMed1992

Analysis of machine-dependent and object-induced geometric distortion in 2DFT MR imaging.

Geometric distortion in MR imaging predominantly arises from the inhomogeneity of the static field and the nonlinearity of the gradients. It is the purpose of this paper to analyse the object and machine related contributions to geometric distortion in order to determine which corrections are necessary for attaining a specified precision. System related imperfections were measured by systematic variation of the strength, direction, and polarity of the read-out gradient in imaging experiments on a grid of cylindrical sample tubes. For the 1.5-T system used in this study, static field related errors up to 7 mm and gradient related errors up to 4 mm were observed (midcoronal plane, FOV 400-mm, G-read between 0.5 and 3.0 mT/m). Field related errors were shown to be inversely proportional to gradient strength, whereas gradient related errors turned out to be virtually independent of gradient strength. It therefore seems recommendable to always apply the strongest available selection and read-out gradients when geometric fidelity is given preference to signal-to-noise considerations. Correction of system related geometric distortions in MR images can readily be performed by table lookup. Object-induced distortions of the gradient fields were studied by experiments on a grid of sample tubes immersed into a cylindrical water bath of variable saline concentration. These experiments revealed a negligible influence of the object on the gradient error distribution, and lead to the conclusion that correction for the nonlinearity of the gradients only requires the application of system dependent correction factors. Object-related distortions of B0 were studied by conventional SE and fat-suppressed IR experiments on phantoms and human subjects. In these experiments the polarity of the read-out gradient was reversed. Subtraction images showed significant object-induced inhomogeneities of the static field at tissue-air interfaces and in the immediate vicinity of the object being imaged. A first attempt to correct for object related B0 inhomogeneities was made by contour analysis of the source images. At present this correction still has to be done manually.

Fourier Analysis↗

PubMed1992

PKRD: a pharmacokinetic program for least-squares and bayesian analysis of repeated-dose pharmacokinetic curves.

A microcomputer program is presented which analyses multiple-dose pharmacokinetic curves using either a least-squares nonlinear analysis or a bayesian fit. The least-squares subroutine is designed to fit retrospective pharmacokinetic curves and can generate the so-called population pharmacokinetic parameters using the Standard Two-Stage method. The bayesian subroutine can instead be used prospectively to individualise the dosage regimen of a patient based on the concentrations measured in the initial phases of the drug treatment. All the pharmacokinetic subroutines of the program use the one-compartment model with either constant-rate intravenous infusion or oral route with zero-order absorption. The program was tested in a series of ten bone marrow transplantation patients treated with cyclosporine. The least-squares estimates of the one-compartment parameters, calculated by the program, were compared with those generated by the SIMKIN program.

Adolescent↗

PubMed1992

Reassessing benzene cancer risks using internal doses.

Human cancer risks from benzene exposure have previously been estimated by regulatory agencies based primarily on epidemiological data, with supporting evidence provided by animal bioassay data. This paper reexamines the animal-based risk assessments for benzene using physiologically-based pharmacokinetic (PBPK) models of benzene metabolism in animals and humans. It demonstrates that internal doses (interpreted as total benzene metabolites formed) from oral gavage experiments in mice are well predicted by a PBPK model developed by Travis et al. Both the data and the model outputs can also be accurately described by the simple nonlinear regression model total metabolites = 76.4x/(80.75 + x), where x = administered dose in mg/kg/day. Thus, PBPK modeling validates the use of such nonlinear regression models, previously used by Bailer and Hoel. An important finding is that refitting the linearized multistage (LMS) model family to internal doses and observed responses changes the maximum-likelihood estimate (MLE) dose-response curve for mice from linear-quadratic to cubic, leading to low-dose risk estimates smaller than in previous risk assessments. This is consistent with the conclusion for mice from the Bailer and Hoel analysis. An innovation in this paper is estimation of internal doses for humans based on a PBPK model (and the regression model approximating it) rather than on interspecies dose conversions. Estimates of human risks at low doses are reduced by the use of internal dose estimates when the estimates are obtained from a PBPK model, in contrast to Bailer and Hoel's findings based on interspecies dose conversion. Sensitivity analyses and comparisons with epidemiological data and risk models suggest that our finding of a nonlinear MLE dose-response curve at low doses is robust to changes in assumptions and more consistent with epidemiological data than earlier risk models.

Animals↗

PubMed1992

The population dynamics of nematode infections of ruminants: the effect of seasonality in the free-living stages.

A previously published differential equation model for the dynamics of nematode infections of ruminants is modified to allow for time-dependent development and loss rates in the free-living stages. This converts the nonlinear autonomous system to one with periodic coefficients. Fourier transform methods are used to analyse the response of the modified system to these forced oscillations. For biologically reasonable parameter values, the annual pattern of parasitism is determined for the nonautonomous system, and compared with that for the autonomous system with periodic perturbations, and a system incorporating both effects. It is found that, whereas periodic perturbations due to management intervention determine the qualitative annual patterns of larval abundance and host infection, the seasonal dynamics of the larval stages change the magnitude of the adult worm burden.

Animals↗

PubMed2026

Beyond predictive performance: A systematic review and critical methodological appraisal of AI/ML and conventional modelling strategies in breast, colorectal, and pancreatic Cancer.

BACKGROUND: Predictive modelling for cancer risk, treatment-related complications, and survival is central to precision oncology. Conventional logistic regression (LR) and Cox proportional hazards (CoxPH) regression remain widely used but are limited when modelling nonlinear interactions, high-dimensional imaging features, and multimodal clinical-metabolic predictors. Artificial intelligence (AI) and machine learning (ML) methods offer expanded capability through automated feature extraction, ensemble learning, and flexible survival modelling, but the evidence on when AI/ML adds value over conventional models across cancer sites and predictive tasks remains fragmented. OBJECTIVE: To systematically evaluate the methodological performance, validation strategies, and translational limitations of AI/ML models compared with conventional statistical models in published predictive-modelling studies for breast, colorectal, or pancreatic cancer. METHODS: PubMed, Scopus, and Web of Science were searched for studies published between January 2019 and March 2025. Two reviewers independently conducted title-and-abstract screening, full-text eligibility assessment, and PROBAST risk-of-bias assessment. Sixty-five studies (n = 907,567 participants) were narratively synthesised by cancer site, predictive task, model family, comparator, validation strategy, predictor modality, and calibration or explainability reporting. RESULTS: The 65 studies comprised breast cancer (n = 35), colorectal cancer (n = 21), and pancreatic cancer (n = 9). AI/ML superiority over LR and CoxPH was task- and data-dependent. CNN- and U-Net-based models predominated in imaging and body-composition tasks, tree-based ensembles consistently outperformed LR for tabular perioperative complication prediction, and CoxPH remained competitive, and in the largest pancreatic risk study, superior to XGBoost (C-index 0.802 vs 0.723) in well-structured datasets. PROBAST analysis-domain risk was moderate in 54 of 65 studies (83%), driven by limited external validation, sparse calibration reporting (11/65), and few decision-curve analyses (7/65). CONCLUSION: AI/ML adds the most methodological value in imaging-derived feature extraction and nonlinear perioperative prediction, while conventional regression remains preferable in large, structured datasets with linear predictors. Clinical translation requires standardised body-composition definitions, external validation, calibration assessment, decision-curve analysis, and explainability, in line with TRIPOD+AI and CLAIM standards.

Humans↗

PubMed1979

A nonlinear model for studying oscillations in the blood pressure control system.

The idea that physiological systems sometimes include oscillations as part of their control function is a relatively new idea; the paper discusses the role of such oscillations in the regulation of arterial blood pressure and how they can be studied by modelling techniques. A nonlinear model is proposed which can be related directly to the physiology. This is seen as an important step because mainly previous studies of biological oscillations have used lumped equations, e.g. the Van der Pol equation, which do not possess the property. On the basis of the model, the oscillatory behaviour of the blood pressure control system is analysed by the application of the dual input describing function technique, a powerful analytical method which has wide application to the study of nonlinear oscillatory phenomena in physiology. The final section of the paper considers the digital simulation of the model by Z transform techniques and how the simulation can be used to study the interaction of respiratory and blood pressure control systems.

Blood Pressure↗

PubMed1976

Relationships between skeletal maturity and submaximal working capacity in boys 8 to 18 years.

Skeletal age (SA) height, weight, PWC130, Vo2 at 130 heart rate (Vo130) and cardiorespiratory adaptation to work at 3 kgm-sec-1 were measured in 237 boys ranging in age from 8 to 18 years. Correlations for the total population for the variables of the study are generally higher with SA than with chronological age (CA), although there is no significant difference between the two sets of correlations. Analysis of linear trend indicate that significant nonlinear components are more frequent in the relationships between the variables and SA than with CA.Multiple regression analyses for each variate as dependent variable indicate that height and body weight generally contribute more to the explained variance, while SA is the next best predictor. CA is the least significant of the four independent variables. The total variance explained between any of the submaximal working capacity related measures acting as dependent variable and CA, height and weight is not significantly affected by the presence or absence of SA. The present study thus indicates that SA is not a significant factor in explaining submaximal working capacity, beyond CA, height and weight, when considered over the 8 to 18 year age span. However, when considering shorter age spans, or when considering the adolescent period (12-16 years), SA correlates better with PWC130 (.320 less than r less than .675) and with Vo130 (.299 less than r less than .772).

Adolescent↗

PubMed2026

Assessing the comorbidity between asthma and depression through polygenic risk scoring and time-to-event models.

BACKGROUND: Patients with asthma have an increased risk of developing depression, affecting their quality of life. To date, the processes contributing to this comorbidity remain unclear. METHODS: We integrated two large genome-wide association studies (88,486 patients with asthma and 447,859 controls; 412,024 patients with depression and 1,587,577 controls) with cross-sectional and longitudinal information available from the All of Us Research Program (N = 87,167) through polygenic risk scoring (PRS), Cox proportional-hazards models, one-sample Mendelian randomization (MR), and gene-set and drug-repurposing analyses. RESULTS: We observed that depression PRS was associated with increased asthma risk (hazard ratio, HR = 1.13, 95% CI = 1.09-1.17), also when accounting for comorbidity status (HR = 1.08, 95% CI = 1.04-1.12). Conversely, the effect of asthma PRS was null after accounting for comorbidity status. One-sample MR analysis showed an effect of depression genetic liability on asthma, ranging from beta = 0.36 ± 0.03 when considering a linear relationship to beta = 3.21 ± 0.31 when considering possible nonlinear relationships. Conversely, the effect of asthma genetic risk on depression was null after accounting for potential confounders. The gene-set analyses showed that asthma and depression polygenic risks share biological processes, molecular functions, and cellular components related to the immune system and the lung-brain axis. CONCLUSIONS: Genetic predisposition contributes to asthma-depression comorbidity through direct effects and shared pathogenic processes. These findings highlight the potential to develop targeted interventions to prevent and treat the co-occurrence of respiratory and neuropsychiatric disorders.

Comorbidity↗