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Combined modality clinical trials for favorable B-cell neoplasms: lonidamine plus whole body hyperthermia and/or total body irradiation.

Favorable B-cell neoplasms provide an excellent clinical model to evaluate the use of systemic multimodality therapy as an approach to the problem of tumor cell heterogeneity. Inherent in this concept is the use of multiple antineoplastic agents to produce supra-additive cytotoxicity without sacrificing therapeutic index. The results of three completed clinical studies and complementary laboratory investigations are reviewed to illustrate an innovative approach to the nodular lymphomas and chronic lymphocytic leukemia. The clinical trials summarized include: A) the combination of 41.8 degrees C whole body hyperthermia (WBH) and the chemotherapeutic drug lonidamine; B) the use of total body irradiation (TBI) (12.5 cGy twice a week, every other week--total planned dose 150 cGy) and daily oral lonidamine; C) the juxtapositioning of TBI (with the same fraction schema) and 41.8 degrees C WBH x 75 min--initiated 10 min after TBI. Also presented is the laboratory rationale and early clinical results for combining lonidamine, TBI, and WBH.

Animals↗

The Sex Offender Treatment and Evaluation Project: California's new outcome study.

The Sex Offender Treatment and Evaluation Project is a six-year clinical research program specifically mandated by the California State Legislature. Objectives of the project are: (a) to operate an innovative state hospital unit for sex offenders who volunteer for treatment during the last two years of their prison terms, and (b) to evaluate the effectiveness of the methods used in the experimental program. The treatment model is Relapse Prevention, a prescriptive and multimodal approach designed to train offenders to interrupt and control the chain of events leading to relapse (recidivism). Treatment effectiveness will be measured by comparing the 5-year recidivism rate for treated subjects with the rates for two control groups: (a) matched volunteers who were randomly assigned to a no-treatment group; and (b) a matched group of inmates who qualified for the program but did not volunteer. At this time, 44 sex offenders (34 child molesters and 10 rapists) are in the experimental treatment program. A majority of this first group of subjects will be released from the hospital in 1987.

Adult↗

Reported anatomical variability naturally leads to multimodal distributions of Denavit-Hartenberg parameters for the human thumb.

A realistic biomechanical thumb model would elucidate the functional consequences of orthopedic and neurological diseases and their treatments. We investigated whether a single parametric kinematic model can represent all thumbs, or whether different kinematic model structures are needed to represent different thumbs. We used Monte Carlo simulations to convert the anatomical variability in the kinematic model parameters into distributions of Denavit-Hartenberg parameters amenable for robotics-based models. Upon convergence (3550 simulations, where mean and coefficient of variance changed < 1% for the last 20 + % simulations) the distributions of Denavit-Hartenberg parameters appeared multimodal, in contrast to the reported unimodal distributions of the anatomy-based parameters. Cluster analysis and one-way analysis of variance confirmed four types of kinematic models (p < 0.0001) differentiated primarily by the biomechanically relevant order of MCP joint axes (in 65.2% of models, the flexion-extension axis was distal to the adduction-abduction axis); and secondarily by a detail specifying the direction of a common normal between successive axes of rotation. Importantly, this stochastic analysis of anatomical variability redefines the debate on whether a single generic biomechanical model can represent the entire population, or if subject-specific models are necessary. We suggest a practical third alternative: that anatomical and functional variability can be captured by a finite set of model-types.

Biomechanical Phenomena↗

Generative AI Models in Time-Varying Biomedical Data: Scoping Review.

BACKGROUND: Trajectory modeling is a long-standing challenge in the application of computational methods to health care. In the age of big data, traditional statistical and machine learning methods do not achieve satisfactory results as they often fail to capture the complex underlying distributions of multimodal health data and long-term dependencies throughout medical histories. Recent advances in generative artificial intelligence (AI) have provided powerful tools to represent complex distributions and patterns with minimal underlying assumptions, with major impact in fields such as finance and environmental sciences, prompting researchers to apply these methods for disease modeling in health care. OBJECTIVE: While AI methods have proven powerful, their application in clinical practice remains limited due to their highly complex nature. The proliferation of AI algorithms also poses a significant challenge for nondevelopers to track and incorporate these advances into clinical research and application. In this paper, we introduce basic concepts in generative AI and discuss current algorithms and how they can be applied to health care for practitioners with little background in computer science. METHODS: We surveyed peer-reviewed papers on generative AI models with specific applications to time-series health data. Our search included single- and multimodal generative AI models that operated over structured and unstructured data, physiological waveforms, medical imaging, and multi-omics data. We introduce current generative AI methods, review their applications, and discuss their limitations and future directions in each data modality. RESULTS: We followed the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines and reviewed 155 articles on generative AI applications to time-series health care data across modalities. Furthermore, we offer a systematic framework for clinicians to easily identify suitable AI methods for their data and task at hand. CONCLUSIONS: We reviewed and critiqued existing applications of generative AI to time-series health data with the aim of bridging the gap between computational methods and clinical application. We also identified the shortcomings of existing approaches and highlighted recent advances in generative AI that represent promising directions for health care modeling.

Artificial Intelligence↗

Statistical analysis of multimode weakly nonlinear Rayleigh-Taylor instability in the presence of surface tension.

A weakly nonlinear model is proposed for the Rayleigh-Taylor instability in the presence of surface tension. The dynamics of a multimode perturbation of the interface between two incompressible, inviscid, irrotational, and immiscible fluids is analyzed. The quadratic and cubic nonlinear effects are taken into account. They include the nonlinear corrections to the exponential growths of the fundamental modulations. The role of the initial modulation spectrum is discussed. A saturation criterion in terms of the product of a local rms and a particular wave number is exhibited. It gives theoretical foundations for numerical conjectures and allows one to analyze the effects of fundamental parameters of the problem such as the dimension or the Atwood number.

Journal Article↗

Clinical and pathophysiological observations in migraine and tension-type headache explained by integration of vascular, supraspinal and myofascial inputs.

A vascular-supraspinal-myogenic (VSM) model for pain in migraine based on our previous clinical and pathophysiological observations is proposed. According to the model, perceived pain (headache) intensity is determined by the sum of nociception from cephalic arteries and pericranial myofascial tissues converging upon the same neurons and integrated with supraspinal effects (usually facilitating). Vascular input predominates over myofascial input in migraine, whereas significance of supraspinal facilitation is difficult to estimate. The importance of these 3 effects may vary between patients and in the same individual with time. The model is in accordance with recent experimental studies showing convergence of somatovisceral afferents upon n. caudalis neurons. Also, long term potentiation due to nociceptive activation and sensitization of neurons to input from wider areas and non-nociceptive stimuli are relevant to our model. In tension-type headache, nociception is primarily myofascial, but vascular input cannot be disregarded. Supraspinal facilitation probably plays a large, sometimes dominant role (the MSV model). The model explains much of the complexity of the clinical picture of these disorders as well as their tendency to overlap and to change into one another. Also, a number of pathophysiological observations such as why muscles are tender during migraine, why trigger-point injection may cure migraine attacks and why chronic tension-type headache is often associated with episodes of pulsating pain, can be explained. The model gives a rational explanation of empirically developed, internationally accepted, multimodal treatment strategies for migraine and tension-type headache. It may thus serve a useful purpose in explaining the disorder to patients. Finally, the model points to several avenues of future research in animals and man.

Animals↗

Near-infrared fluorescence imaging of microcalcification in an animal model of breast cancer.

RATIONALE AND OBJECTIVES: At present, there is no animal model of breast cancer that forms reproducible microcalcification. The aim of this study was to develop a straightforward, reproducible model system that could be used to develop multimodality contrast agents for the identification of breast cancer microcalcification. METHODS: The R3230 mammary adenocarcinoma cell line was implanted in the mammary fat pad of female Fischer 344 rats (two rats with two implanted tumors and two rats with a single implanted tumor). After growth to 1-2 cm in diameter, tumors were implanted with 100 microm hydroxyapatite crystals (positive control) or calcium oxalate crystals (negative control). Twenty-four hours after crystal implantation, rats were injected intravenously with a previously described near-infrared fluorescent bisphosphonate derivative known as Pam78, and the tumors were imaged using a reflectance optical imaging system. RESULTS: Tumors implanted with hydroxyapatite displayed bright, focal, near-infrared fluorescence in the area of crystal implantation. Control tumors, grown in the same animal and implanted with calcium oxalate, did not display any near-infrared fluorescence, even along the needle track used for crystal implantation. CONCLUSIONS: A simple and rapid animal model of focal calcification in breast cancer tumors has been developed and validated. The model used Pam78, a near-infrared fluorescent contrast agent specific for hydroxyapatite. The potential usefulness of the model for developing similar contrast agents for magnetic resonance and other imaging modalities is discussed.

Animals↗

Expression of bone morphogenic protein 2/4, transforming growth factor-beta1, and bone matrix protein expression in healing area between vascular tibia grafts and irradiated bone-experimental model of osteonecrosis.

PURPOSE: For the surgical treatment of osteoradionecrosis after multimodal therapy of head-and-neck cancers, free vascular bone grafts are used to reconstruct osseous structures in the previously irradiated graft bed. Reduced, or even absent osseous healing in the transition area between the vascular graft and the irradiated graft bed represents a clinical problem. Inflammatory changes and fibrosis lead to delayed healing, triggered by bone morphogentic protein 2/4 (BMP2/4) and transforming growth factor (TGF)-beta(1). Given the well-known fibrosis-inducing activity of TGF-beta(1), an osteoinductive effect has been reported for BMP2/4. However, the influence of irradiation (RT) on this cytokine expression remains elusive. Therefore, the aim of the present in vivo study was to analyze the expression of BMP2/4, TGF-beta(1), collagen I, and osteocalcin in the transition area between the bone graft and the graft bed after RT. METHODS AND MATERIALS: Twenty Wistar rats (male, weight 300-500 g) were used in this study. A free vascular tibia graft was removed in all rats and maintained pedicled in the groin region. Ten rats underwent RT with 5 x 10 Gy to the right tibia, the remainder served as controls. After 4 weeks, the previously removed tibia grafts were regrafted into the irradiated (Group 1) and nonirradiated (Group 2) graft beds. The interval between RT and grafting was 4 weeks. After a 4-week osseous healing period, the bone grafts were removed, and the transition area between the nonirradiated graft and the irradiated osseous graft bed was examined histomorphometrically (National Institutes of Health imaging program) and immunohistochemically (avidin-biotin-peroxidase complex) for the expression of BMP2/4, TGF-beta(1), collagen I, and osteocalcin. RESULTS: Absent or incomplete osseous healing of the graft was found in 9 of 10 rats after RT with 50 Gy and in 1 of 10 of the rats with nonirradiated osseous grafts. Histomorphometrically, the proportion of osseous healing in the transition area was 17% in Group 1 and 48% in Group 2 (p = 0.001). Compared with the nonirradiated rats, reduced enchondral and perichondral ossification was found in the healing area after RT, with a reduction of BMP2/4 and osteocalcin expression. TGF-beta(1) and collagen I expression in the transition area to the irradiated osseous graft bed was significantly increased compared with that in the nonirradiated osseous graft bed. CONCLUSION: After RT, osseous healing of vascular bone grafts is significantly reduced and may be a result of radiation-induced inhibition of BMP2/4 and osteocalcin expression. In addition, induction of TGF-beta(1) and collagen I expression occurs. Because the effects of the TGF-beta superfamily are manifold and partially unknown, additional research directions could be in the exogenous application of BMP2/4 and inhibition of TGF-beta(1) by antibody treatment to search for appropriate therapeutic approaches for improving osseous healing in the irradiated graft bed.

Animals↗

From brainstem to cortex: computational models of saccade generation circuitry.

The brain circuitry of saccadic eye movements, from brainstem to cortex, has been extensively studied during the last 30 years. The wealth of data gathered allowed the conception of numerous computational models. These models proposed descriptions of the putative mechanisms generating this data, and, in turn, made predictions and helped to plan new experiments. In this article, we review the computational models of the five main brain regions involved in saccade generation: reticular formation saccadic burst generators, superior colliculus, cerebellum, basal ganglia and premotor cortical areas. We present the various topics these models are concerned with: location of the feedback loop, multimodal saccades, long-term adaptation, on the fly trajectory correction, strategy and metrics selection, short-term spatial memory, transformations between retinocentric and craniocentric reference frames, sequence learning, to name the principle ones. Our objective is to provide a global view of the whole system. Indeed, narrowing too much the modelled areas while trying to explain too much data is a recurrent problem that should be avoided. Moreover, beyond the multiple research topics remaining to be solved locally, questions regarding the operation of the whole structure can now be addressed by building on the existing models.

Animals↗

The development of intersensory temporal perception: an epigenetic systems/limitations view.

Several theories have stressed the importance of intersensory integration for development but have not identified specific underlying integration mechanisms. The author reviews and synthesizes current knowledge about the development of intersensory temporal perception and offers a theoretical model based on epigenetic systems theory, proposing that responsiveness to 4 basic features of multimodal temporal experience--temporal synchrony, duration, temporal rate, and rhythm--emerges in a sequential, hierarchical fashion. The model postulates that initial developmental limitations make intersensory synchrony the basis for the integration of intersensory temporal relations and that the emergence of responsiveness to the other, increasingly more complex, temporal relations occurs in a hierarchical, sequential fashion by building on the previously acquired intersensory temporal processing skills.

Adult↗

Cancer of the anal canal. Model for preoperative adjuvant combined modality therapy.

An analysis of preoperative multimodality adjuvant therapy with 5-fluorouracil, mitomycin-C, and radiation therapy revealed that 38 of 45 patients (84 percent) treated were rendered free of cancer after chemotherapy/radiation therapy. No recurrence of tumor has been noted in those patients rendered free of disease by the preoperative treatment. Seven patients (15 percent) with residual macroscopic or microscopic cancer after preoperative therapy have had recurrence, all in distant sites. These seven patients have died from the disease. The prognosis for patients in this series depended on the success of the preoperative therapy in eradicating all tumor prior to surgery. Mitomycin-C and 5-fluorouracil are cytotoxic for local disease and for microscopic distant disease as well. Abdomino-perineal resection is unnecessary for patients whose primary tumor is eradicated by the preoperative therapy. The role of the relatively low dose of radiation therapy needs to be further defined.

Adult↗

Multimodal contrast agent for combined computed tomography and magnetic resonance imaging applications.

OBJECTIVE: The objective of this study was to examine the feasibility of a multimodal system to effectively induce and maintain contrast enhancement in both computed tomography (CT) and magnetic resonance (MR) for radiation therapy applications. MATERIALS AND METHODS: The physicochemical characteristics of a liposome-encapsulated iohexol and gadoteridol formulation were assessed in terms of agent loading efficiencies, size and morphology, in vitro stability, and release kinetics. The imaging properties of the liposome formulation were assessed based on T1 and T2 relaxivity measurements and in vitro CT and MR imaging in a phantom. A preliminary imaging-based evaluation of the in vivo stability of this multimodal contrast agent was also performed in a lupine model. RESULTS: The average agent loading levels achieved were 26.5+/-3.8 mg/mL for iodine and 6.6+/- 1.5 mg/mL for gadolinium. These concentrations correspond to approximately 10% of that found in the commercially available preparations of each of these agents. However, this liposome-based formulation is expected to have a smaller volume of distribution and prolonged circulation lifetime in vivo. This multimodal system was found to have high agent retention in vitro, which translated into maintained contrast enhancement (up to 3 days) and stability in vivo. CONCLUSIONS: This study demonstrated the feasibility of engineering a multimodal contrast agent with prolonged contrast enhancement in vivo for use in CT and MR. This contrast agent may serve as a valuable tool for cardiovascular imaging as well as image registration and guidance applications in radiation therapy.

Animals↗

Integration of single cell multiomics data by deep transfer hypergraph neural network.

Multi-omics characterization of individual cells offers remarkable potential for analyzing the dynamics and relationships of gene regulatory states across millions of cells. How to integrate multimodal data is an open problem, existing integration methods struggle with accuracy and modality-specific biological variation retention. In this paper, we present scHyper (scalable, interpretable machine learning for single cell integration), a low-code and data-efficient deep transfer model designed for integrating paired and unpaired single-cell multimodal data. We benchmark scHyper against datasets from different multimodal data. ScHyper learns a low-dimensional representation and aligns the covariance matrices of the measured modalities, achieving high accuracy even with large scale atlas-level datasets with low memory and computational time across different cell lines, shedding light on regulatory relationships between different types of omics. Altogether, we show that scHyper is a versatile and robust tool for cell-type label transfer and integration from multimodal single-cell datasets.

Single-Cell Analysis↗

Dyslexia: the possible benefit of multimodal integration of fMRI- and EEG-data.

Biological research about dyslexia has been conducted using various neuroimaging methods like functional Magnetic Resonance Imaging (fMRI) or Electroencephalography (EEG). Since language functions are characterized by both distributed network activities and speed of processing within milliseconds, high temporal as well as high spatial resolution of activation profiles are of interest: "where" can dyslexia specific activations be detected and "when" do language processes start to diverge between dyslexics and controls? Due to the network character of language processing, fMRI-constrained distributed source models based on EEG-data were computed for multimodal data integration. First single-case results show that this method could be a promising approach for the understanding of a repeatedly described experimental finding for dyslexia like that of an overactivation in inferior frontal language areas. Multimodal data analysis for the subjects presented here could probably demonstrate that inferior frontal overactivations are the consequence of a phonological deficit and could represent ongoing articulation processes used to solve phonologically challenging tasks.

Adolescent↗

Neuronal firing in anterior cingulate neurons changes modes across trials in single states of multitrial reward schedules.

The recorded responses of single neurons often vary considerably in the numbers of spikes emitted across repeats of a single experimental condition. Because of this irregularity and for theoretical convenience the responses are often approximated using a Poisson process. However, it has been frequently pointed out that many details of the responses, including the distribution of spike counts across similar trials, are not consistent with a Poisson process, even an inhomogeneous one. Wiener and Richmond (2003, J Neurosci 23:2394-2406) showed that the spike count distributions could usually be fitted nicely by mixtures of a few (1-3) Poisson distributions, a step they regarded as a computational convenience. Now, we find that a substantial proportion (47%) of the neuronal responses from anterior cingulate cortex, which we conceptualize as part of a system related to the balance between work and reward, have responses with multimodal firing rate distributions. When these distributions are modeled as mixtures of Poisson distributions, the proportions of the different Poisson distributions are related to behavioral state, and might be related to cognitive factors. This suggests that the neurons undergo behaviorally-related mode changes.

Action Potentials↗

Phase mutual information as a similarity measure for registration.

This article describes a new method for non-rigid alignment of multimodal images. Multimodal image registration is most often accomplished by modelling, in some sense, an intensity mapping between the images. Here, the alternative strategy of modelling a relationship between local image phase is introduced. This method is intrinsically image feature based, and searches for relationships between feature appearances, rather than tissue class intensity. This enables registration of modalities for which image intensity is not a simple function of tissue class, for example ultrasound. It is also demonstrated that this method performs comparably to an intensity method even when the images are related by a simple intensity transform, but that the phase method is significantly more robust to image artifacts which corrupt the ideal intensity mapping.

Algorithms↗

The emergence of a shared action ontology: building blocks for a theory.

To have an ontology is to interpret a world. In this paper we argue that the brain, viewed as a representational system aimed at interpreting our world, possesses an ontology too. It creates primitives and makes existence assumptions. It decomposes target space in a way that exhibits a certain invariance, which in turn is functionally significant. We will investigate which are the functional regularities guiding this decomposition process, by answering to the following questions: What are the explicit and implicit assumptions about the structure of reality, which at the same time shape the causal profile of the brain's motor output and its representational deep structure, in particular of the conscious mind arising from it (its "phenomenal output")? How do they constrain high-level phenomena like conscious experience, the emergence of a first-person perspective, or social cognition? By reviewing a series of neuroscientific results and integrating them with a wider philosophical perspective, we will emphasize the contribution the motor system makes to this process. As it will be shown, the motor system constructs goals, actions, and intending selves as basic constituents of the world it interprets. It does so by assigning a single, unified causal role to them. Empirical evidence demonstrates that the brain models movements and action goals in terms of multimodal representations of organism-object-relations. Under a representationalist analysis, this process can be conceived of as an internal, dynamic representation of the intentionality-relation itself. We will show how such a complex form of representational content, once it is in place, can later function as a functional building block for social cognition and for a more complex, consciously experienced representation of the first-person perspective as well.

Animals↗

Multimodality diagnosis of liver tumors: feature analysis with CT, liver-specific and contrast-enhanced MR, and a computer model.

RATIONALE AND OBJECTIVES: The purpose of this study was to measure and to clarify the diagnostic contributions of image-based features in differentiating benign from malignant and hepatocyte-containing from non-hepatocyte-containing liver lesions. MATERIALS AND METHODS: Six experienced abdominal radiologists each read images from 146 cases (including a contrast material-enhanced computed tomographic [CT] scan and contrast-enhanced and unenhanced magnetic resonance [MR] images) following a checklist-questionnaire requiring them to rate quantitatively each of as many as 131 image features and then reported on each of the two differentiations. The diagnostic value of each feature was assessed, and linear discriminant analysis was used to develop statistical prediction rules (SPRs) for merging feature data into computerized "second opinions." For the two differentiations, accuracy (area under the receiver operating characteristic curve [Az]) was then determined for the radiologists' readings by themselves and for each of three SPRs. RESULTS: Thirty-seven candidate features had diagnostic value for each of the two differentiations (a slightly different feature set for each). Radiologists' performance at both differentiations was excellent (Az = 0.929 [benign vs malignant] and 0.926 [hepatocyte-containing vs non-hepatocyte-containing]). Performance of the SPR that operated on the features from all modalities together was better than that of radiologists (Az = 0.936 [benign vs malignant] and 0.951 [hepatocyte-containing vs non-hepatocyte-containing]), but this difference was of marginal statistical significance (P = .11). Contrast-enhanced MR imaging and contrast-enhanced CT each made significant adjunctive contributions to accuracy compared with unenhanced MR imaging alone. CONCLUSION: Many CT- and MR imaging-based features have diagnostic value in differentiating benign from malignant and hepatocyte-containing from non-hepatocyte-containing liver lesions. Radiologists could also benefit from the fully informed SPR's "second opinions."

Adult↗