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Point: It's never too soon.

A multidisciplinary approach to prostate cancer has become the rule and not the exception. Involving the entire team, which includes a medical oncologist, from the time of initial diagnosis is optimal. This facilitates maximal patient education regarding treatment options and enhances informed decision making. A coordinated approach also promotes enrollment on clinical trials, which are often, multimodality, especially in high-risk early stage prostate cancer. Integrated therapeutic strategies throughout the patient's disease course can improve both patient care and satisfaction

Humans↗

Biological parametric mapping: A statistical toolbox for multimodality brain image analysis.

In recent years, multiple brain MR imaging modalities have emerged; however, analysis methodologies have mainly remained modality-specific. In addition, when comparing across imaging modalities, most researchers have been forced to rely on simple region-of-interest type analyses, which do not allow the voxel-by-voxel comparisons necessary to answer more sophisticated neuroscience questions. To overcome these limitations, we developed a toolbox for multimodal image analysis called biological parametric mapping (BPM), based on a voxel-wise use of the general linear model. The BPM toolbox incorporates information obtained from other modalities as regressors in a voxel-wise analysis, thereby permitting investigation of more sophisticated hypotheses. The BPM toolbox has been developed in Matlab with a user-friendly interface for performing analyses, including voxel-wise multimodal correlation, ANCOVA, and multiple regression. It has a high degree of integration with the SPM (statistical parametric mapping) software relying on it for visualization and statistical inference. Furthermore, statistical inference for a correlation field, rather than a widely used T-field, has been implemented in the correlation analysis for more accurate results. An example with in vivo data is presented, demonstrating the potential of the BPM methodology as a tool for multimodal image analysis.

Brain↗

Multimodality treatment of cancer.

Different and effective modalities are available for various cancers. However, early consideration is necessary to allow optimal integration. Failure to do this may compromise the cure potential for some tumours. The differing biology of tumours and the efficacy of various modalities dictates specific approaches for each. The principles of multimodality therapy can be considered together with the biological factors affecting the success and failure of each therapy tupe and this allows a multimodality approach to be based on careful planning. For many tumours, where effective systemic therapy exists, there are good reasons for commencing with a multimodality approach at the onset with adjuvant chemotherapy. Practical considerations dictate that surgeons must play a key role in the care of cancer patients. This in turn requires that they maintain a sound knowledge of multimodality therapy for the cancers that they treat.

Antineoplastic Agents↗

Advanced multimodal visualisation of clinical gait and fluoroscopy analyses in the assessment of total knee replacement.

Traditional gait and fluoroscopy analysis of human movement are largely utilised but are still limited in registration, integration, synchronisation and visualisation capabilities. The present work exploits the features of a recently developed software tool based on multimodal display (Data Manager developed within the EU-funded project 'Multimod') in an exemplary clinical case. Standard lower limb gait analysis, comprising segment position, ground reaction force and EMG data collection, and three-dimensional fluoroscopy analysis at the replaced joint were performed in a total knee replacement patient while ascending stairs. Clinical information such as X-rays and standard scores were also available. Data Manager was able to import all this variety of data and to structure these in an original hierarchical tree. Bone and prosthesis component models were registered to corresponding marker position data for effective three-dimensional animations. These were also synchronised with corresponding standard video sequences. Animations, video, time-histories of collected and also processed data were shown in various combinations, according to specific interests of the bioengineering and medical professionals expected to observe and to interpret this large amount of data. This software tool demonstrated to be a valuable means to enhance representation and interpretation of measurements coming from human motion analysis. In a single software, a thorough and effective clinical and biomechanical analysis of human motion was performed.

Arthroplasty, Replacement, Knee↗

Multimodal computational framework resolves B cell maturation in autoimmunity and ageing.

Identification of the origin of pathogenic immune cells is crucial for therapeutic interventions and diagnosis but pseudotime methods struggle to trace immune cells accurately. Current trajectory inference methods for B cell development and response in health and disease either ignore or underutilize antigen receptor sequence information, limiting their ability to resolve developmental pathways, particularly for pathogenic populations. Widely used methods such as Monocle 3 reconstruct developmental paths from transcriptomic similarity alone, discarding the features from immune receptors. Dandelion has combined the immune receptor features with transcriptomics but it struggles to simulate the trajectory path of B cells. Here we present ClonoTrace, a computational framework that integrates BCR sequence features with transcriptomic trajectory inference through gated fusion of multimodal embeddings. In fetal B cell development and germinal centre development, ClonoTrace demonstrates closer concordance with the canonical reference ordering than Monocle 3 and Dandelion. Applied to systemic lupus erythematosus, ClonoTrace indicates a memory B cell extrafollicular maturation route alongside the naïve B cell route, accompanied by induction of ZEB2 with a concomitant decline of BACH2 along the trajectory, as a candidate alternative route to pathogenic double negative 2 B cells (DN2) in systemic lupus erythematosus (SLE) patients. In healthy ageing, ClonoTrace resolved three candidate age-related B cell maturation routes, from naïve, IgM+ memory and switched-memory B cells, each passing through a DN2-associated transcriptional state that is ordered before age-associated B cells along the inferred trajectory. ClonoTrace's fate probability algorithm indicated that IgM+ memory B cell to ABC transition as the leading candidate age-associated transition, which may be distinct from SLE DN2 maturation. ClonoTrace provides a generalizable framework for receptor-informed trajectory inference, describing candidate developmental routes of pathogenic B cell populations in autoimmunity and ageing.

Humans↗

Mast cells in rat dermis and jejunal lamina propria show a five-fold difference in unit granule volume.

The cytoplasmic granules of mast cells have a periodic multimodal size distribution in which the volumes of individual granules are integral multiples of the intermodal distance, a volume defined as the "unit granule" or v1. In this study, we used two 3-month-old male rats to analyze two classical mast cell subpopulations, dermal "connective tissue-type mast cells" and jejunal lamina propria "mucosal mast cells", for the morphometric characteristics of their cytoplasmic granules. Both v1 and the mean volume of individual cytoplasmic granules were much smaller in dermal than in jejunal mast cells (ratios of 1:5.5 and 1:4.2, respectively), but dermal mast cells contained 150% more granules per cell than did jejunal mast cells. The two types of mast cells did not differ significantly in total cell volume, nucleus volume, aggregate volume of cytoplasmic granules per cell or numbers of unit granules comprising a granule of mean volume. These findings add unit granule volume to the list of phenotypic characteristics which express significant variation in anatomically distinct populations of mast cells.

Animals↗

MRI-based surface-assisted parcellation of human cerebellar cortex: an anatomically specified method with estimate of reliability.

We revisit here a surface assisted parcellation (SAP) system of the human cerebellar cortex originally described in Makris, N., Hodge, S.M., Haselgrove, C., Kennedy, D.N., Dale, A., Fischl, B., Rosen, B.R., Harris, G., Caviness, V.S., Jr., Schmahmann, J.D., 2003. Human cerebellum: surface-assisted cortical parcellation and volumetry with magnetic resonance imaging. J Cogn Neurosci 15, 584-599. This system preserves the topographic and morphologic uniqueness of the individual cerebellum and allows for volumetric analysis and representation of multimodal structural and functional data on the cerebellar cortex. This methodology integrates features of automated routines of the program FreeSurfer as well as semi-automated and manual procedures of the program Cardviews to create 64 cerebellar parcellation units based on fissure information and anatomical landmarks of the cerebellar surface. Using this technique, we undertook the parcellation of ten cerebella by two independent raters. The reliability of the resulting parcellation units (64 total) was high, with an average Intraclass Correlation Coefficient (ICC) of 0.724 in the vermis and 0.853 in the hemispheres. Clusters of parcellation units were then created, based on lobar and connectivity data and functional hypotheses. These 36 clusters, when treated as anatomical units, had an average ICC of 0.933. Whereas the individual units provide a high level of detail and anatomical specificity, the clusters add flexibility to the analysis by providing higher reliability.

Algorithms↗

Quantitative and qualitative perceptual analysis of cold dysesthesia and hyperalgesia in fibromyalgia.

Somatosensory perception thresholds, perceived intensity, and quality of perceptions were assessed in 20 women with fibromyalgia syndrome (FMS) and in 20 healthy age-matched female controls. All patients and controls scaled perceived intensity and described perceived quality of randomized thermal (Thermotest) and tactile (von Frey filaments) stimulation. Perceived intensity was scaled by free-number magnitude estimation and interindividual comparability was accomplished by Master Scaling. Perceived quality was assessed by choosing verbal descriptors from a list. Thenar was used as a reference for each modality tested. All patients were able to reliably scale perceived intensity at thenar, as well as in pain-affected body areas. Perception thresholds for cold pain, heat pain, cold-pain tolerance and heat-pain tolerance were significantly lower in patients than controls. For cold and tactile stimulation, the master scaled perceived intensities were significantly higher in patients' pain-affected areas, whereas for warmth/heat stimulation, the intensities were significantly lower. In the qualitative perceptual analysis the most striking and significant finding was the aberration of cold-evoked perceptions in all patients: most stimuli in the range of 30-10 degrees C were reported as heat or other paresthetic or dysesthetic perceptions. The perceptual quality of warmth, and of touch, did not differ from the controls. Another aberration was observed in the nociceptive range of thermal and of tactile stimulation as significantly more frequent pain-related descriptors than in controls. This indicates a general nociceptive facilitation in addition to the lower thermal pain thresholds. The combination of cold hyperesthesia, cold dysesthesia, and multimodal hyperalgesia suggests a selective pathophysiology at a particular level of integration, possibly in the insular cortex. It is suggested that the aberrations revealed by the supraliminal sensory evaluation may be generic for FMS. Particularly, the aberrations established in all patients for perceived quality and intensity in the cold sensory channel may be an additional diagnostic criterion.

Adult↗

Subthalamic nucleus stimulation for advanced Parkinson's disease: how to find a far medial STN.

In a patient with advanced Parkinson's disease, an anatomically deviant far medial subthalamic nucleus (STN) posed problems in the placement of DBS electrodes for chronic high frequency (HF) stimulation despite the use of multimodal targeting with 1) statistical atlas data, 2) T (2)-weighted (T (2)W) magnetic resonance imaging (MRI), 3) microelectrode recording, and 4) clinical testing with macro stimulation. Diagnostic T (2)W MRI suggested that the patient's STN was in a typical location and seemed to confirm the statistical atlas-based planning. Intraoperatively, cell activity recording (MER) with five parallel electrodes could not reveal any STN typical activity profile and electrical stimulation was not able to disclose a medial or lateral displacement of the electrodes. The operation was discontinued and postoperative stereotactic CT confirmed that the correct target area had been approached during the operation. Postoperative T (2)W MRI now disclosed a left STN which was 2 mm medial of the initial target and lead to a further medial target definition and finally to a successful DBS placement. In conclusion, finding a deep seated DBS target like the STN can be difficult in cases with an extremely deviant anatomy even if reiterative sophisticated multimodal planning is used. In the presented case we applied the integrated information from intraoperative MER, macrostimulation and postoperative imaging work-up and were able to complete DBS implantation successfully.

Brain Mapping↗

The role of movement and object in action memory: a comparative study between blind, blindfolded and sighted subjects.

Two experiments systematically compared four SPT conditions involving real/imaginary movement and real/imaginary object with one VT condition involving no enactment and no object. To test the effect of visual information on SPT memory, sighted subjects were compared with blindfolded subjects (in Experiment 1) and blind subjects (in Experiment 2). All subjects learned all SPTs and VTs. Free recall data showed no difference between the SPT conditions and between the groups of subjects; only blind subjects were found to be limited in the use of visualization strategy. All SPTs were recalled better than VTs, indicating that the enactment effect is not determined by either movement or object alone, rather both have an effective role and are equally involved for obtaining the enactment effect. The results provide no support for the motor encoding and multimodality views of SPTs, but are in line with the episodic integration view which assumes that neither movement nor object are of special importance, rather both have contribution in the enactment effect.

Adult↗

Multimodality image fusion in dose escalation studies of brain tumors.

This article examines the utility of integrating images from computed tomography (CT), magnetic resonance imaging (MRI), and single photon emission computed tomography (SPECT) for radiation treatment planning of brain tumors for dose escalation studies. The information obtained from these imaging modalities is complementary to each other and could provide anatomic (through CT and MRI) and metabolic (through SPECT) information of the target. This anato-metabolic target localization could be expected to facilitate precise radiation therapy planning for brain tumors by delineating the boundary between the tumor, edema, and the normal brain parenchyma and identify the viable tumor nidus with greater degree of certainty. This could in turn lead to minimize dose to the normal tissue and permit dose escalation to the region of interest. The utility of these anato-metabolic imaging modalities for defining the clinical target volumes along with planning target volumes for different phases of the radiation therapy is illustrated.

Adult↗

Toward a systems- and control-oriented agent framework.

This paper develops a systems- and control-oriented intelligent agent framework called the hybrid intelligent control agent (HICA), as well as its composition into specific kinds of multiagent systems. HICA is essentially developed around a hybrid control system core so that knowledge-based planning and coordination can be integrated with verified hybrid control primitives to achieve the coordinated control of multiple multimode dynamical systems. The scheme is applied to the control of teams of unmanned air and ground vehicles engaged in a pursuit-evasion war game. Results are demonstrated in simulation.

Algorithms↗

Contribution of pedunculopontine tegmental nucleus neurons to performance of visually guided saccade tasks in monkeys.

The cholinergic pedunculopontine tegmental nucleus (PPTN) is one of the major ascending arousal systems in the brain stem and is linked to motor, limbic, and sensory systems. Based on previous studies, we hypothesized that PPTN would be related to the integrative control of movement, reinforcement, and performance of tasks in behaving animals. To investigate how PPTN contributes to the behavioral control, we analyzed the activity of PPTN neurons during visually guided saccade tasks in three monkeys in relation to saccade preparation, execution, reward, and performance of the task. During visually guided saccades, we observed saccade-related burst (26/70) and pause neurons (19/70), indicating that a subset of PPTN neurons are related to both saccade execution and fixation. Burst neurons exhibited greater selectivity for saccade direction than pause neurons. The preferred directions for both burst and pause neurons were not aligned with either horizontal or vertical axes, nor biased strongly in either the ipsilateral or the contralateral direction. The spatial representation of the saccade-related activity of PPTN neurons is different from other brain stem saccade systems and may therefore relay saccade-related activity from different areas. Increasing discharges were observed around reward onset in a subset of neurons (22/70). These neurons responded to the freely delivered rewards within ~140 ms. However, during the saccade task, the latencies of the responses around reward onset ranged between 100 ms before and 200 ms after the reward onset. These results suggest that the activity observed after appropriate saccade during the task may include response associated with reward. We found that the reaction time to the appearance of the fixation point (FP) was longer when the animal tended to fail in the ensuring task. This reaction time to FP appearance (RTFP) served as an index of motivation. The RTFP could be predicted by the neuronal activity of a subset of PPTN neurons (13/70) that varied their activity levels with task performance, discharging at a higher rate in successful versus error trials. A combination of responses related to saccade execution, reward delivery, and task performance was observed in PPTN neurons. We conclude from the multimodality of responses in PPTN neurons that PPTN may serve as an integrative interface between the various signals required for performing purposive behaviors.

Animals↗

Analysis of the probability distribution of small random samples by nonlinear fitting of integrated probabilities.

Small random samples of biochemical and biological data are often representative of complex distribution functions and are difficult to analyze in detail by conventional means. The common approaches reduce the data to a few representative parameters (such as their moments) or combine the data into a histogram plot. Both approaches reduce the information content of the data. By fitting the empirical cumulative distribution function itself with models of integrated probability distributions, the information content of the raw data can be fully utilized. This approach, distribution analysis by nonlinear fitting of integrated probabilities, allows analysis of normally distributed samples, truncated data sets, and multimodal distributions with a single, powerful data processing procedure.

Data Interpretation, Statistical↗

Acute pain control and accelerated postoperative surgical recovery.

Postoperative pain relief continues to demand our awareness, and surgeons should be fully aware of the potential physiologic benefits of effective dynamic pain relief regimens and the great potential to improve postoperative outcome if such analgesia is used for rehabilitation. To achieve advantageous effects, accelerated multimodal postoperative recovery programs should be developed as a multidisciplinary effort, with integration of postoperative pain management into a postoperative rehabilitation program. This requires revision of traditional care programs, which should be adjusted according to recent knowledge within surgical pathophysiology. Such efforts must be expected to lead to improved quality of care for patients, with less pain and reduced morbidity leading to cost efficiency.

Analgesia↗

Spatial remapping of touch: confusion of perceived stimulus order across hand and foot.

The "body schema," a spatial representation of the body in its environment, has been suggested to be an emergent property of a widespread network of effector-specific frontal and parietal areas, many of which integrate sensory input from the different modalities. On a behavioral level, such multimodality has been shown with temporal order judgment tasks, in which participants decide which of the two hands received a tactile stimulus first. The accuracy of these judgments is influenced by body posture, indicating that tactile stimuli are not simply represented in an anatomical reference frame, but are transformed into external spatial coordinates. So far, these studies have only investigated the hands. It is therefore unclear whether a default remapping of touch into external space is a special feature of visual-manual control or whether all body parts are represented in a common nonanatomically anchored reference frame. In the present study, blindfolded participants made temporal order judgments of stimuli presented to both hands, both feet, or one hand and one foot. The stimulated limbs were held in either a parallel or a crossed posture. Judgments were equally impaired by limb crossing in all limb combinations (hands only, feet only, hand and foot). These results suggest a remapping of tactile location of all body parts into a nonanatomically anchored and, importantly, common reference frame rather than a specific remapping for eye-hand coordination only.

Adult↗

Teaching young children about HIV and AIDS.

AIDS education initiatives need to begin early, within the elementary grades, to be effective. We should no longer underestimate the capacity of young children to understand and benefit from this instruction. In addition, we should not overestimate the impact of brief interventions, and should plan for continued AIDS prevention instruction throughout the school years, involving sequential, developmentally appropriate curricula that respond to the preadolescent's and adolescent's changing cognitive capabilities, social skills, and expanding exposure to sexual experiences. We should require that new approaches and methodologies for AIDS prevention education be developed and evaluated rigorously for efficacy with the same fervor required for the development and evaluation of new drugs to combat this illness on the biologic front. New modalities and approaches should be integrated with those that have already been shown to be effective, creating multimodal and comprehensive educational initiatives comparable to the multidrug treatment regimens. We should be skeptical of those who are satisfied with the implementation of one interesting and simplistic slogan for health promotion efforts for children (e.g., "Just say no"). Even if such efforts were effective in the short term, sole reliance on this approach is likely to result in the development of resistance. As the field of AIDS prevention looks for novel approaches and theoretic constructs, it should borrow ideas from other fields of study and foster interdisciplinary collaborations with professionals from complementary fields. In this manner, educational interventions can move beyond the individual context to begin to address the social influences on sexual behaviors. Sexual behavior is interpersonal and occurs in a social context. Programs must therefore address peer and social pressures to engage in sexual activity. Although attempts are being made to address the social network of children through such efforts as peer education, we cannot ignore the broader social context (e.g., poverty) within which these behaviors occur. For example, efforts to promote increased condom usage will be ineffective until we learn more about why significant numbers of adolescents practice unprotected sex. We are unlikely to affect behavioral change unless we understand fully the motivation for such behavior. We must also recognize that children are more than what they do and study outcomes other than behavior. There is a need for further research on the development of attitudes, fears, stigma, and coping in children, as well as means of promoting the development of healthy sexual relationships.

Acquired Immunodeficiency Syndrome↗

Results and follow-up of locally advanced cancer of the exocrine pancreas treated with radiochemotherapy.

UNLABELLED: In locally advanced carcinoma of the exocrine pancreas combined radiochemotherapy has been established as a standard treatment. MATERIALS AND METHODS: Two different treatment schemes have been consecutively used. Between 1/1994 and 12/2001, a total of 110 patients with locally advanced adenocarcinoma of the pancreas were treated with hyperfractionated accelerated radiotherapy to a total dose of 44.8 Gy combined with 5-fluorouracil (5-FU) (600 mg/m2) and folinic acid (FA) (300 mg/m2) injection. Chemotherapy was repeated monthly in non-progressive disease. From 1/2002 to 11/2003, in another 15 consecutive patients, chemotherapy was changed to gemcitabine (Gem) (300 mg/m2) and cisplatinum (Cis) (30 mg/m2), followed by gemcitabine (1000 mg/m2) every 2 weeks in non-progressive patients. RESULTS: Median survival in the 5-FU/FA group was 10.3 months with a 1-year survival of 46.6% and a 2-year survival of 20.1%. Median time to progression was 8.6 months. Treatment was well tolerated with nausea/vomiting grade I/II in 58.2%, grade III/IV in 14.5%, diarrhea grade I/II in 27.3%, leucopenia/thrombopenia grade I/II in 21.8%, grade III/IV in 7.2%, and mucositis grade III/IV in 7.2%. In the Gem/Cis group, median survival was 13.8 months with a 1-year survival of 54.9% and a 2-year survival of 24.4%. The toxicity data also revealed comparable feasibility: nausea/vomiting grade I/II in 46.7%, grade III/IV in 20%, diarrhea grade I/II in 20%, leucopenia/thrombopenia grade I/II in 26. 7%, and grade III/IV in 13.3%. CONCLUSION: Radiochemotherapy in locally advanced pancreatic cancer is an effective and well-tolerated treatment. The long-term efficacy concerning survival is limited. The integration of predictive factors and new chemotherapeutic agents like gemcitabine in the multimodality treatment may give a more promising perspective. Because of the narrow therapeutic index of gemcitabine-based radiochemotherapy schemes, a feasible combination of radiotherapy treatment volume and gemcitabine dose must be found.

Adult↗