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Neural correlates of action attribution in schizophrenia.

Patients with first-rank symptoms (FRS) of schizophrenia do not experience all of their actions and personal states as their own. FRS may be associated with an impaired ability to correctly attribute an action to its origin. In the present study, we examined regional cerebral blood flow (rCBF) with positron emission tomography during an action-attribution task in a group of patients with FRS. We used a device previously used with healthy subjects that allows the experimenter to modulate the subject's degree of movement control (and thus action attribution) of a virtual hand presented on a screen. In healthy subjects, the activity of the right angular gyrus and the insula cortex appeared to be modulated by the subject's degree of movement control of the virtual hand. In the present study, the schizophrenic patients did not show this pattern. We found an aberrant relationship between the subject's degree of control of the movements and rCBF in the right angular gyrus and no modulation in the insular cortex. The implications of these results for understanding pathological conditions such as schizophrenia are discussed.

Adult↗

Reaching in reality and virtual reality: a comparison of movement kinematics in healthy subjects and in adults with hemiparesis.

BACKGROUND: Virtual reality (VR) is an innovative tool for sensorimotor rehabilitation increasingly being employed in clinical and community settings. Despite the growing interest in VR, few studies have determined the validity of movements made in VR environments with respect to real physical environments. The goal of this study was to compare movements done in physical and virtual environments in adults with motor deficits to those in healthy individuals. METHODS: The participants were 8 healthy adults and 7 adults with mild left hemiparesis due to stroke. Kinematics of functional arm movements involving reaching, grasping and releasing made in physical and virtual environments were analyzed in two phases: 1) reaching and grasping the ball and 2) ball transport and release. The virtual environment included interaction with an object on a 2D computer screen and haptic force feedback from a virtual ball. Temporal and spatial parameters of reaching and grasping were determined for each phase. RESULTS: Individuals in both groups were able to reach, grasp, transport, place and release the virtual and real ball using similar movement strategies. In healthy subjects, reaching and grasping movements in both environments were similar but these subjects used less wrist extension and more elbow extension to place the ball on the virtual vertical surface. Participants with hemiparesis made slower movements in both environments compared to healthy subjects and during transport and placing of the ball, trajectories were more curved and interjoint coordination was altered. Despite these differences, patients with hemiparesis also tended to use less wrist extension during the whole movement and more elbow extension at the end of the placing phase. CONCLUSION: Differences in movements made by healthy subjects in the two environments may be explained by the use of a 2D instead of a 3D virtual environment and the absence of haptic feedback from the VR target. Despite these differences, our findings suggest that both healthy subjects and individuals with motor deficits used similar movement strategies when grasping and placing a ball in the two reality conditions. This suggests that training of arm movements in VR environments may be a valid approach to the rehabilitation of patients with motor disorders.

Journal Article↗

Data integration and warehousing: coordination between newborn screening and related public health programs.

At birth, patient demographic and health information begin to accumulate in varied databases. There are often multiple sources of the same or similar data. New public health programs are often created without considering data linkages. Recently, newborn hearing screening (NHS) programs and immunization programs have virtually ignored the existence of newborn dried blood spot (DBS) newborn screening databases containing similar demographic data, creating data duplication in their 'new' systems. Some progressive public health departments are developing data warehouses of basic, recurrent patient information, and linking these databases to other health program databases where programs and services can benefit from such linkages. Demographic data warehousing saves time (and money) by eliminating duplicative data entry and reducing the chances of data errors. While newborn screening data are usually the first data available, they should not be the only data source considered for early data linkage or for populating a data warehouse. Birth certificate information should also be considered along with other data sources for infants that may not have received newborn screening or who may have been born outside of the jurisdiction and not have birth certificate information locally available. This newborn screening serial number provides a convenient identification number for use in the DBS program and for linking with other systems. As a minimum, data linkages should exist between newborn dried blood spot screening, newborn hearing screening, immunizations, birth certificates and birth defect registries.

Birth Certificates↗

Yield of screening for new aneurysms after treatment for subarachnoid hemorrhage.

OBJECTIVE: Patients who have been successfully treated for subarachnoid hemorrhage (SAH) are at risk for new episodes. The authors studied the effect of screening with CT angiography (CTA) for new aneurysms. METHODS: In a decision model, the authors compared the strategies "screening" and "no screening" after SAH. A literature review yielded the risks of aneurysm recurrence, complications of CTA, and re-treatment. The authors estimated the expected number of quality-adjusted life-years (QALYs), the number of SAH, and the mortality and disability rates for both strategies. They evaluated screening at intervals of 2, 5, and 10 years after SAH, using 10 years and remaining life expectancy as time horizon. RESULTS: The expected number of QALYs 10 years after clipping was virtually the same for no screening (8.33), screening once after 5 years (8.28), and screening every 2 years (8.27). With screening every 2 years, the expected rate of new SAH decreased from 1.9 to 0.5%, and mortality decreased from 0.9 to 0.6%; however, the disability rate increased from 0.5 to 1.9%. Results were comparable with remaining life expectancy as time horizon and for screening after initial treatment with coils. The key estimates of the analyses were the incidence and rupture rate of new aneurysms, the risk of dying from recurrent SAH, the utility of disability, and the risk of complications from DSA and re-treatment. CONCLUSIONS: Presently, screening for new aneurysms after subarachnoid hemorrhage cannot be recommended. Screening may prevent new episodes of subarachnoid hemorrhage but with too high a cost in terms of complications from preventive treatment.

Adult↗

Drug discovery today.

In recent years, tools for the development of new drugs have been dramatically improved. These include genomic and proteomic research, numerous biophysical methods, combinatorial chemistry and screening technologies. In addition, early ADMET studies are employed in order to significantly reduce the failure rate in the development of drug candidates. As a consequence, the lead finding, lead optimization and development process has gained marked enhancement in speed and efficiency. In parallel to this development, major pharma companies are increasingly outsourcing many components of drug discovery research to biotech companies. All these measures are designed to address the need for a faster time to market. New screening methodologies have contributed significantly to the efficiency of the drug discovery process. The conventional screening of single compounds or compound libraries has been dramatically accelerated by high throughput screening methods. In addition, in silico screening methods allow the evaluation of virtual compounds. A wide range of new lead finding and lead optimization opportunities result from novel screening methods by NMR, which are the topic of this review article.

Animals↗

Global methylation screening in the Arabidopsis thaliana and Mus musculus genome: applications of virtual image restriction landmark genomic scanning (Vi-RLGS).

Understanding the role of 'epigenetic' changes such as DNA methylation and chromatin remodeling has now become critical in understanding many biological processes. In order to delineate the global methylation pattern in a given genomic DNA, computer software has been developed to create a virtual image of restriction landmark genomic scanning (Vi-RLGS). When using a methylation- sensitive enzyme such as NotI as the restriction landmark, the comparison between real and in silico RLGS profiles of the genome provides a methylation map of genomic NotI sites. A methylation map of the Arabidopsis genome was created that could be confirmed by a methylation-sensitive PCR assay. The method has also been applied to the mouse genome. Although a complete methylation map has not been completed, a region of methylation difference between two tissues has been tested and confirmed by bisulfite sequencing. Vi-RLGS in conjunction with real RLGS will make it possible to develop a more complete map of genomic sites that are methylated or demethylated as a consequence of normal or abnormal development.

Animals↗

A nanovolume crystallization robot that creates its crystallization screens on-the-fly.

Protein crystallization generally consists of an initial screen followed by optimization of promising conditions. Whereas the initial screen typically uses a standard set of pre-made crystallization cocktails, optimization requires new cocktails with small perturbations of the original composition. Highly parallel synchronous crystallization robots are ideal for initial screening, but they depend on pre-made crystallization cocktails. Asynchronous crystallization robots can create crystallization cocktails from stock solutions, but in practice this ability is rarely exploited. Instead, large-scale operations typically use a general liquid-handling robot to create optimization screens, whereas academics mostly rely on manual optimization. Here, the use of an asynchronous crystallization robot to create customized crystallization cocktails and set up nanovolume crystallization experiments without a compromise in speed or drop quality is described. This approach avoids the complex integration of hardware, software and dataflow between two robots and saves cost and space. As a proof of principle, a commercial crystal screen has been reproduced with the robot and shows that results are virtually identical to using the actual commercial screen.

Combinatorial Chemistry Techniques↗

Virtual Tumors Enable Prediction of Personalized Therapeutic Combinations for Non-Small Cell Lung Cancer.

UNLABELLED: The disease burden from non-small cell lung cancer (NSCLC) adenocarcinoma is substantial, with a million new cases diagnosed globally each year and a 5-year survival rate of less than 20%. The lack of therapeutic options personalized to individual patients leads to high variation in survival. The combination of patient stratification with personalized treatment has the potential to improve outcomes; however, the variation in mutations found in patients with NSCLC adenocarcinoma makes experimentally determining treatment combinations time-consuming and expensive. In this study, we developed an interpretable mechanistic model to decipher complex signaling interplay and guide personalized therapy in NSCLC adenocarcinoma. This "virtual tumor" model encompassed key tumor-intrinsic oncogenic signaling pathways for efficiently predicting rational drug-drug and drug-radiotherapy combination therapies in NSCLC. Diverse genetic profiles were simulated for testing more than 10,000 therapeutic strategies to identify optimal approaches to overcome resistance mechanisms specific to genetic profiles and p53 status. The virtual tumor model reproduced drug additivity screens, predicted radiosensitizing genes validated in a CRISPR screen, and identified 53BP1 as a potential drug target that improved the therapeutic window during radiotherapy. A 19-gene signature derived from the virtual tumor framework stratified patients most likely to benefit from radiotherapy, which was validated using The Cancer Genome Atlas (TCGA) data. These results show the utility of virtual tumors to predict effective therapeutic combinations and present a computational resource for large-scale screening of personalized therapies to guide clinical decision-making in patients with NSCLC. SIGNIFICANCE: A computational framework that simulates thousands of personalized treatment strategies offers a scalable, cost-effective way to tailor therapies and improve outcomes for patients with genetically diverse NSCLC.

Humans↗

Label-free screening of bio-molecular interactions.

The majority of techniques currently employed to interrogate a biomolecular interaction require some type of radio- or enzymatic- or fluorescent-labelling to report the binding event. However, there is an increasing awareness of novel techniques that do not require labelling of the ligand or the receptor, and that allow virtually any complex to be screened with minimal assay development. This review focuses on three major label-free screening platforms: surface plasmon resonance biosensors, acoustic biosensors, and calorimetric biosensors. Scientists in both academia and industry are using biosensors in areas that encompass almost all areas drug discovery, diagnostics, and the life sciences. The capabilities and advantages of each technique are compared and key applications involving small molecules, proteins, oligonucleotides, bacteriophage, viruses, bacteria, and cells are reviewed. The role of the interface between the biosensor surface (in the case of SPR and acoustic biosensors) and the chemical or biological systems to be studied is also covered with attention to the covalent and non-covalent coupling chemistries commonly employed.

Binding, Competitive↗

[Lung cancer with ground glass opacity diagnosed by transbronchial lung biopsy using an ultrathin bronchoscope and virtual bronchoscopy].

Although thoracic computed tomography (CT) screening indicated that there are many patients who have pulmonary shadow with ground glass opacity, it is sometimes difficult to obtain the appropriate specimens for histological diagnosis of such patients. We herein report a lung cancer patient with ground glass opacity who was diagnosed preoperatively by an ultrathin bronchoscope and virtual bronchoscopy. A 78-year-old female was admitted to our hospital due to bacterial pneumonia. At the admission, CT showed another abnormal small shadow in her right middle lobe. Since the shadow was not visible by fluoroscopy, we reconstructed the images of virtual bronchoscopy using the data obtained by multidetector CT. The location of the shadow was determined in the peripheral area of a dorsal branch of right B4aialpha. Then the transbronchial lung biopsy using an ultrathin bronchoscope with simultaneous CT guidance was performed. The histological findings of the biopsy specimens revealed that the shadow was highly suspicious for malignancy. Therefore, the right middle lobectomy was conducted, and the tumor was diagnosed as an adenocarcinoma. An ultrathin bronchoscope with virtual bronchoscopy is useful to diagnose a pulmonary shadow with ground glass opacity.

Aged↗

DETECTION OF CERVICAL CANCER; A STUDY OF MOTIVATION FOR CYTOLOGICAL SCREENING.

Annual cytological examination of cervical scrapings should virtually eliminate deaths from cervical cancer, but many deaths still occur because not all women are sufficiently motivated to have the examination. As part of a San Diego County Medical Society cancer control project, 2000 women were interviewed to evaluate motivating influences. It was found that most of the 70 per cent who had had the examination were motivated by the advice of physicians, rather than directly by lay publicity. Women who had not had the examination, more commonly the old and the poor, were not antagonistic but mostly unmotivated. Lay education to induce women to seek medical advice, and education of physicians to get them to urge and to carry out their part in routine annual cytologic examination of cervical exudate probably could bring about virtual elimination of death from cervical cancer.

Adult↗

Spiral CT pneumocolon: applications, status and limitations.

CT pneumocolon is a promising new technique in the diagnosis and management of colon pathology. CT pneumocolon can detect (sensitivity >95%) and stage (accuracy 79%) colorectal cancer and is very accurate in the differentiation of malignant from benign colonic pathologies. It has excellent detection rates for polyps >10 mm in diameter. Several studies using 3D virtual colonoscopy have already proven its high sensitivity and specificity in polyp detection making this technique robust as a screening tool. The combined results for virtual colonoscopy, from all centres, show a sensitivity of >85% in the detection of polyps 10 mm or greater in size, 70-80% for 5-9 mm polyps and an overall specificity of 90%. CT pneumocolon is a safe, non-invasive and cost-effective method for detecting colonic carcinomas and adenomas and correctly identifying which patients need further colonoscopy. The technique is quick, well tolerated and non-operator dependent. It can also image the proximal colon when distal stenoses prevent endoscopic and barium examination. CT pneumocolon is able to identify the features and complications of inflammatory bowel disease. Further research is warranted to fully assess its impact in terms of a screening tool, acceptability, availability and cost benefit.

Air↗

The role of parietal cortex in awareness of self-generated movements: a transcranial magnetic stimulation study.

Awareness of self-generated movements arises from comparing motor plans, and the accompanying (hypothetical) efference copy, with the visual and proprioceptive consequences of movement. Here we used repetitive transcranial magnetic stimulation (rTMS) to investigate the role of a posterior region in the superior parietal lobule (SPL) in this process. Nine healthy volunteers performed a finger extension actively and passively while wearing a CyberGlove; the glove recorded these (actual) finger movements and used this information in real time to move a virtual hand displayed on a computer screen. To assess the participant's awareness of movement onset, we introduced a delay between the onset of the actual and virtual movement (60-270 ms, 30 ms increments); the task was to judge whether the virtual hand movements were delayed relative to the actual hand movements. Low-frequency rTMS (15 min, 0.6 Hz) was applied either over the left SPL or the left temporal cortex (control site) to decrease excitability of these regions and, in turn, test their role in the awareness of self-generated movement. Following the SPL stimulation, participants' assessments of asynchrony were impaired for active but not passive movements. No significant changes were observed after rTMS applied over the control site. We suggest that these findings are consistent with the role of the SPL in evaluating the temporal congruency of peripheral (visual) and central (efference copy) signals associated with self-generated movements. As such, this region may contribute to the sense of 'agency' and its disturbances in disorders such as apraxia and schizophrenia.

Adult↗

The virtual colonoscopy study: a large multicenter clinical trial designed to compare two diagnostic screening procedures.

This paper reviews the design of a large multicenter clinical trial currently being conducted to test the equivalence of two screening procedures for colorectal polyps. The primary outcome is the sensitivity and specificity of the new and standard procedures for detecting subjects with and without polyps of a size > or =6 mm, respectively. An important secondary outcome is the accuracy of these procedures in detecting individual polyps. A total of 619 participants underwent virtual colonoscopy, the new procedure, followed by conventional colonoscopy, the standard procedure. Strategies for the design and implementation of the study are shared as well as the challenges encountered.

Bias↗

Reliability of linear measurements on a virtual bilateral cleft lip and palate model.

OBJECTIVE: To assess the reliability and validity of measurements performed on three-dimensional virtual models of neonatal bilateral cleft lip and palate patients, compared with measurements performed on plaster cast models. MATERIALS AND METHODS: Ten high-quality plaster cast models of bilateral cleft lip and palate patients were scanned with an LDI-scanner to obtain a three-dimensional virtual model. Linear measurements were performed on the plaster cast models using a digital caliper and also on the three-dimensional virtual model using Viscam RP version 2.1 software. The measurements were performed by two observers on two occasions. RESULTS: Intraclass correlations ranging from .81 to .96 were found for all measurements except the measurement between the constructed reference point pr and reference point i (intraclass correlation = .40). A post hoc procedure in which top-view screen prints of the three-dimensional virtual model were used to perform the measurement between reference points pr and i demonstrated an intraclass coefficient of .90. CONCLUSIONS: Three-dimensional virtual models obtained by laser scanning neonatal cast models of bilateral cleft lip and palate patients can be used reliably and validly to perform linear measurements between existing reference points on the surface of the model using Viscam RP version 2.1 software. Measurements between reference points constructed outside the surface of the model cannot be validly performed on the three-dimensional virtual model with the software used in this study. For these measurements, top-view screen prints of the three-dimensional virtual model can be used.

Cephalometry↗

An initial experience with screening for colon polyps using spiral CT with and without CT colography (virtual colonoscopy)

BACKGROUND: Computed tomographic (CT) colography (virtual colonoscopy) is a new imaging method for detection of colon polyps and cancer. OBJECTIVE: To evaluate the sensitivity of CT colography for polyp detection in a population without symptoms that included persons without colon neoplasia and with radiologists blinded to colonoscopic findings. METHODS: Forty-six persons without symptoms underwent spiral CT followed by same-day colonoscopy with subsequent inspection of two-dimensional axial CT images, interactive multiplanar images, and surfaced and volume-rendered images of the colon (three-dimensional CT colography). RESULTS: Three-dimensional CT colography was superior to two-dimensional axial imaging for detection of colon polyps. Three-dimensional CT colography depicted 1 of 4 (25%) adenomas 2 cm in diameter or larger, 6 of 10 (60%) adenomas 1 to 1.9 cm, 6 of 14 (43%) 6 to 9 mm, and 7 of 65 (11%) 5 mm in diameter or smaller. Three-dimensional CT colography showed a polyp that might have led to colonoscopy in 3 of 4 (75%) patients whose largest adenoma was 2 cm or larger, 5 of 6 (83%) patients with largest adenoma 1 to 1.9 cm, 3 of 7 (43%) patients with largest adenoma 6 to 9 mm, and 4 of 16 patients (25%) with largest adenoma 5 mm or smaller. Large, flat adenomas of the right colon were difficult to identify with three-dimensional CT colography. The specificity of three-dimensional CT colography for patients with adenomas 1 cm in diameter or larger was 89%. Examination of patients with missed adenomas after unblinding indicated that meticulous bowel preparation and adequate distention are critical to accurate interpretation. Perceptual errors were common. CONCLUSIONS: CT colography as performed in this study is not adequate as a colorectal cancer screening test. Several technical factors that appear critical to accurate performance of CT colography are defined.

Adenocarcinoma↗

The development and clinical trial of a Driving Simulator for the handicapped.

We developed a Virtual Reality Driving Simulator in order to safely evaluate and improve the driving ability of the handicapped. The Virtual Environment consists of 18 sections (e.g. a speed limited road, a strait road, a curved road, a left turn course, etc) and each section is linked naturally. For the interface of our driving simulator, an actual car was adapted for realism and then connected to a computer. We also equipped it with hand control driving devices especially adapted for the handicapped. A beam projector was used so that the subjects could see the virtual scene on a large screen which was set in front of them. The subjects selected for this trial were 10 normal drivers with valid driving licenses and 15 patients with thoracicor lumber cord injuries who had prior driving experience. For evaluation, 5 driving skills were measured including average speed, steering stability, centerline violations, traffic signal violations, and driving time in various road conditions such as strait and curved roads. The normal subjects manipulated the gas pedal and the brake with their feet while the patients manipulated a hand control with their hands. After they finished driving the whole course, the participants answered the questions such as "How realistic did the Virtual Reality Driving Simulator seeme to you?" and "How much was your fear reduced". The five driving skills measured between the two groups (normal vs. handicapped) did not show any significant differences (p > 0.05). And in the three kinds of road conditions (a speed limited road and roads with a sharp curve and left-hand turn), the average speed of the handicapped group was 45.6 Km, less than 61.2 Km (p<0.05) of the normal group. In all, 11 patients (73%) reported that their fear of driving was reduced. Furthermore, their average score on the degree of realism question was 51.5%.

Adult↗

Computer assisted pelvic surgery: registration based on a modified external fixator.

A fundamental step in Computer Assisted Surgery (CAS) is the registration, when the preoperative virtual data and the corresponding operative anatomy of the region of interest are merged. To provide exact landmarks for anatomical registration, a tubular external fixator was modified. Two intact pelvic bones (one artificial foam pelvis and one cadaver specimen) were used for the experimental setup. Registration was carried out using a standardized protocol for anatomy-based registration in the control group; anatomical registration was achieved using a modified external fixator in the study group. This external fixator had titanium fiducials wedged into the fixator carbon tubes serving as landmarks for paired-point registration. The tubes were used for surface registration. The standard anterior pelvis fixator assembly was augmented with additional bilateral tubes oriented towards the posterior, enabling registration of the sacroiliac areas. The accuracy of registration was checked by "reversed verification", where the examiner used only the screen display to control the virtual position of the pointer tip in relation to selected landmarks. By virtual matching, the real distance was measured with a digital caliper. We defined the verification as "accurate" when the residual distance was less than 1 mm; "acceptable" when it was between 1 mm and 2 mm; and "insufficient" when it exceeded 2 mm. The paired T-test with significance levels of p < 0.05 was used for statistical analysis. The anatomical registration based on the external fixator landmarks was statistically as accurate as that obtained using anatomical landmarks on the pelvic bone. This study concludes that the external fixator, a conventional tool in the management of acute traumatic pelvic instability, can also be useful for landmark registration in CAS.

External Fixators↗