Attentional Bias, Pupillometry, and Spontaneous Blink Rate: Eye Characteristic Assessment Within a Translatable Nicotine Cue Virtual Reality Paradigm.

Background: Incentive salience processes are important for the development and maintenance of addiction. Eye characteristics such as gaze fixation time, pupil diameter, and spontaneous eyeblink rate (EBR) are theorized to reflect incentive salience and may serve as useful biomarkers. However, conventional cue exposure paradigms have limitations that may impede accurate assessment of these markers. Objective: This study sought to evaluate the validity of these eye-tracking metrics as indicators of incentive salience within a virtual reality (VR) environment replicating real-world situations of nicotine and tobacco product (NTP) use. Methods: NTP users from the community were recruited and grouped by NTP use patterns: nondaily (n=33) and daily (n=75) use. Participants underwent the NTP cue VR paradigm and completed measures of nicotine craving, NTP use history, and VR-related assessments. Eye-gaze fixation time (attentional bias) and pupillometry in response to NTP versus control cues and EBR during the active and neutral VR scenes were recorded and analyzed using ANOVA and analysis of covariance models. Results: Greater subjective craving, as measured by the Tobacco Craving Questionnaire-Short Form, following active versus neutral scenes was observed (F1,106=47.95; P<.001). Greater mean eye-gaze fixation time (F1,106=48.34; P<.001) and pupil diameter (F1,102=5.99; P=.02) in response to NTP versus control cues were also detected. Evidence of NTP use group effects was observed in fixation time and pupillometry analyses, as well as correlations between these metrics, NTP use history, and nicotine craving. No significant associations were observed with EBR. Conclusions: This study provides additional evidence for attentional bias, as measured via eye-gaze fixation time, and pupillometry as useful biomarkers of incentive salience, and partially supports theories suggesting that incentive salience diminishes as nicotine dependence severity increases.

Evaluation of Gaze-to-Object Mapping Algorithms for Use in "Real-World" Translatable Neuropsychological Paradigms.

Objective: Eye-tracking technology is commonly used for identifying objects of visual attention. However, applying this technology to virtual reality (VR) applications is challenging. This report analyzes the performance of two gaze-to-object mapping (GTOM) algorithms applied to eye-gaze data acquired during a "real-world" VR cue-reactivity paradigm. Methods: Two groups of participants completed a VR paradigm using an HTC Vive Pro Eye. The gazed objects were determined by the reported gaze rays and one of two GTOM algorithms - naïve ray-casting (n=18) or a combination of ray-casting and Tobii's G2OM algorithm (n=18). Percent gaze duration was calculated from 1-second intervals before each object interaction to estimate gaze accuracy. The object volume of maximal divergence between algorithms was determined by maximizing the difference in Hedge's G effect sizes between small and large percent gaze duration distributions. Differences in percent gaze duration based on algorithm and target object size were tested with a mixed ANOVA. Results: The maximum Hedge's G effect sizes differentiating large and small target objects was observed at an 800cm3 threshold. The combination algorithm performed better than the naïve ray-casting algorithm (p=.003, ηp2=.23), and large objects (>800cm3) were associated with a higher gaze duration percentage than small objects (≤800cm3; p<.001, ηp2=.76). No significant interaction between algorithm and size was observed. Conclusions: Results demonstrated that Tobii's G2OM method outperformed naïve ray-casting in this "real-world" paradigm. As both algorithms show a clear decrease in performance for detecting objects with volumes <800cm3, we recommend using gaze-interactable objects >800cm3 for future HTC Vive Pro Eye applications.

Using Virtual Reality to Induce and Assess Objective Correlates of Nicotine Craving: Paradigm Development Study.

BACKGROUND: Craving is a clinically important phenotype for the development and maintenance of nicotine addiction. Virtual reality (VR) paradigms are successful in eliciting cue-induced subjective craving and may even elicit stronger craving than traditional picture-cue methods. However, few studies have leveraged the advances of this technology to improve the assessment of craving. OBJECTIVE: This report details the development of a novel, translatable VR paradigm designed to both elicit nicotine craving and assess multiple eye-related characteristics as potential objective correlates of craving. METHODS: A VR paradigm was developed, which includes three Active scenes with nicotine and tobacco product (NTP) cues present, and three Neutral scenes devoid of NTP cues. A pilot sample (N=31) of NTP users underwent the paradigm and completed subjective measures of nicotine craving, sense of presence in the VR paradigm, and VR-related sickness. Eye-gaze fixation time ("attentional bias") and pupil diameter toward Active versus Neutral cues, as well as spontaneous blink rate during the Active and Neutral scenes, were recorded. RESULTS: The NTP Cue VR paradigm was found to elicit a moderate sense of presence (mean Igroup Presence Questionnaire score 60.05, SD 9.66) and low VR-related sickness (mean Virtual Reality Sickness Questionnaire score 16.25, SD 13.94). Scene-specific effects on attentional bias and pupil diameter were observed, with two of the three Active scenes eliciting greater NTP versus control cue attentional bias and pupil diameter (Cohen d=0.30-0.92). The spontaneous blink rate metrics did not differ across Active and Neutral scenes. CONCLUSIONS: This report outlines the development of the NTP Cue VR paradigm. Our results support the potential of this paradigm as an effective laboratory-based cue-exposure task and provide early evidence of the utility of attentional bias and pupillometry, as measured during VR, as useful markers for nicotine addiction.

Variable Stiffness Devices Using Fiber Jamming for Application in Soft Robotics and Wearable Haptics.

Variable stiffness actuation has applications in a wide range of fields, including wearable haptics, soft robots, and minimally invasive surgical devices. There have been numerous design approaches to control and tune stiffness and rigidity; however, most have relatively low specific load-carrying capacities (especially for flexural loads) in the most rigid state that restricts their use in small or slender devices. In this article, we present an approach to the design of slender, high flexural stiffness modules based on the principle of fiber jamming. The proposed fiber jamming modules (FJMs) consist of axially packed fibers in an airtight envelope that transition from a flexible to a rigid beam when a vacuum is created inside the envelope. This FJM can provide the flexural stiffness of up to eight times that of a particle jamming module in the rigid state. Unlike layer jamming modules, the design of FJMs further allows them to control stiffness while bending in space. We present an analytical model to guide the parameter choices for the design of fiber jamming devices. Finally, we demonstrate applications of FJMs, including as a versatile tool, as part of a kinesthetic force feedback haptic glove and as a programmable structure.

Deep learning improves contrast in low-fluence photoacoustic imaging.

Low fluence illumination sources can facilitate clinical transition of photoacoustic imaging because they are rugged, portable, affordable, and safe. However, these sources also decrease image quality due to their low fluence. Here, we propose a denoising method using a multi-level wavelet-convolutional neural network to map low fluence illumination source images to its corresponding high fluence excitation map. Quantitative and qualitative results show a significant potential to remove the background noise and preserve the structures of target. Substantial improvements up to 2.20, 2.25, and 4.3-fold for PSNR, SSIM, and CNR metrics were observed, respectively. We also observed enhanced contrast (up to 1.76-fold) in an in vivo application using our proposed methods. We suggest that this tool can improve the value of such sources in photoacoustic imaging.

Wayfinding and Glaucoma: A Virtual Reality Experiment.

Purpose: Wayfinding, the process of determining and following a route between an origin and a destination, is an integral part of everyday tasks. The purpose of this study was to investigate the impact of glaucomatous visual field loss on wayfinding behavior using an immersive virtual reality (VR) environment. Methods: This cross-sectional study included 31 glaucomatous patients and 20 healthy subjects without evidence of overall cognitive impairment. Wayfinding experiments were modeled after the Morris water maze navigation task and conducted in an immersive VR environment. Two rooms were built varying only in the complexity of the visual scene in order to promote allocentric-based (room A, with multiple visual cues) versus egocentric-based (room B, with single visual cue) spatial representations of the environment. Wayfinding tasks in each room consisted of revisiting previously visible targets that subsequently became invisible. Results: For room A, glaucoma patients spent on average 35.0 seconds to perform the wayfinding task, whereas healthy subjects spent an average of 24.4 seconds (P = 0.001). For room B, no statistically significant difference was seen on average time to complete the task (26.2 seconds versus 23.4 seconds, respectively; P = 0.514). For room A, each 1-dB worse binocular mean sensitivity was associated with 3.4% (P = 0.001) increase in time to complete the task. Conclusions: Glaucoma patients performed significantly worse on allocentric-based wayfinding tasks conducted in a VR environment, suggesting visual field loss may affect the construction of spatial cognitive maps relevant to successful wayfinding. VR environments may represent a useful approach for assessing functional vision endpoints for clinical trials of emerging therapies in ophthalmology.

Visualization of three-dimensional ultra-high resolution OCT in virtual reality.

Three-dimensional reconstruction of optical coherence tomography (OCT) images is a modern technique that helps interpret the images and understand the underlying disease. However, the 3D reconstruction displayed on commercial devices is of limited quality: images are shown on 2D screens and it is difficult or impossible to adjust the view point and capture the data set from a meaningful perspective. We did a preliminary study to evaluate the applicability of a novel, 3D TV-based virtual reality system with interactive volume rendering software to clinical diagnostics and present a workflow, which can incorporate virtual reality technology at various levels of immersion into the daily medical practice, from interactive VR systems to printed media.

Wireless physiological monitoring and ocular tracking: 3D calibration in a fully-immersive virtual health care environment.

Wireless physiological/neurological monitoring in virtual reality (VR) offers a unique opportunity for unobtrusively quantifying human responses to precisely controlled and readily modulated VR representations of health care environments. Here we present such a wireless, light-weight head-mounted system for measuring electrooculogram (EOG) and electroencephalogram (EEG) activity in human subjects interacting with and navigating in the Calit2 StarCAVE, a five-sided immersive 3-D visualization VR environment. The system can be easily expanded to include other measurements, such as cardiac activity and galvanic skin responses. We demonstrate the capacity of the system to track focus of gaze in 3-D and report a novel calibration procedure for estimating eye movements from responses to the presentation of a set of dynamic visual cues in the StarCAVE. We discuss cyber and clinical applications that include a 3-D cursor for visual navigation in VR interactive environments, and the monitoring of neurological and ocular dysfunction in vision/attention disorders.

Multi-Channel Transfer Function with Dimensionality Reduction.

The design of transfer functions for volume rendering is a difficult task. This is particularly true for multi-channel data sets, where multiple data values exist for each voxel. In this paper, we propose a new method for transfer function design. Our new method provides a framework to combine multiple approaches and pushes the boundary of gradient-based transfer functions to multiple channels, while still keeping the dimensionality of transfer functions to a manageable level, i.e., a maximum of three dimensions, which can be displayed visually in a straightforward way. Our approach utilizes channel intensity, gradient, curvature and texture properties of each voxel. The high-dimensional data of the domain is reduced by applying recently developed nonlinear dimensionality reduction algorithms. In this paper, we used Isomap as well as a traditional algorithm, Principle Component Analysis (PCA). Our results show that these dimensionality reduction algorithms significantly improve the transfer function design process without compromising visualization accuracy. In this publication we report on the impact of the dimensionality reduction algorithms on transfer function design for confocal microscopy data.

Clinical trial: probiotic treatment of acute distal ulcerative colitis with rectally administered Escherichia coli Nissle 1917 (EcN).

BACKGROUND: Probiotics are effective in inflammatory bowel diseases. Clinical effectiveness and dose dependency of E. coli Nissle (EcN) enemas were investigated in ulcerative colitis (UC). METHODS: In a double-blind study, 90 patients with moderate distal activity in UC were randomly assigned to treatment with either 40, 20, or 10 ml enemas (N = 24, 23, 23) containing 10E8 EcN/ml or placebo (N = 20). The study medication was taken once daily for at least 2 weeks. After 2, 4 and/or 8 weeks the clinical DAI was assessed together with tolerance to treatment. Patients who reached clinical DAI

Dimensionality Reduction on Multi-Dimensional Transfer Functions for Multi-Channel Volume Data Sets.

The design of transfer functions for volume rendering is a non-trivial task. This is particularly true for multi-channel data sets, where multiple data values exist for each voxel, which requires multi-dimensional transfer functions. In this paper, we propose a new method for multi-dimensional transfer function design. Our new method provides a framework to combine multiple computational approaches and pushes the boundary of gradient-based multi-dimensional transfer functions to multiple channels, while keeping the dimensionality of transfer functions at a manageable level, i.e., a maximum of three dimensions, which can be displayed visually in a straightforward way. Our approach utilizes channel intensity, gradient, curvature and texture properties of each voxel. Applying recently developed nonlinear dimensionality reduction algorithms reduces the high-dimensional data of the domain. In this paper, we use Isomap and Locally Linear Embedding as well as a traditional algorithm, Principle Component Analysis. Our results show that these dimensionality reduction algorithms significantly improve the transfer function design process without compromising visualization accuracy. We demonstrate the effectiveness of our new dimensionality reduction algorithms with two volumetric confocal microscopy data sets.

Yeasts in the gut: from commensals to infectious agents.

BACKGROUND: Controversy still surrounds the question whether yeasts found in the gut are causally related to disease, constitute a health hazard, or require treatment. METHODS: The authors present the state of knowledge in this area on the basis of a selective review of articles retrieved by a PubMed search from 2005 onward. The therapeutic recommendations follow the current national and international guidelines. RESULTS: Yeasts, mainly Candida species, are present in the gut of about 70% of healthy adults. Mucocutaneous Candida infections are due either to impaired host defenses or to altered gene expression in formerly commensal strains. The expression of virulence factors enables yeasts to form biofilms, destroy tissues, and escape the immunological attacks of the host. Yeast infections of the intestinal mucosa are of uncertain clinical significance, and their possible connection to irritable bowel syndrome, while plausible, remains unproved. Yeast colonization can trigger allergic reactions. Mucosal yeast infections are treated with topically active polyene antimycotic drugs. The adjuvant administration of probiotics is justified on the basis of positive results from controlled clinical trials. CONCLUSION: The eradication of intestinal yeasts is advised only for certain clearly defined indications.

High-precision radiocarbon dating and historical biblical archaeology in southern Jordan.

Recent excavations and high-precision radiocarbon dating from the largest Iron Age (IA, ca. 1200-500 BCE) copper production center in the southern Levant demonstrate major smelting activities in the region of biblical Edom (southern Jordan) during the 10th and 9th centuries BCE. Stratified radiocarbon samples and artifacts were recorded with precise digital surveying tools linked to a geographic information system developed to control on-site spatial analyses of archaeological finds and model data with innovative visualization tools. The new radiocarbon dates push back by 2 centuries the accepted IA chronology of Edom. Data from Khirbat en-Nahas, and the nearby site of Rujm Hamra Ifdan, demonstrate the centrality of industrial-scale metal production during those centuries traditionally linked closely to political events in Edom's 10th century BCE neighbor ancient Israel. Consequently, the rise of IA Edom is linked to the power vacuum created by the collapse of Late Bronze Age (LB, ca. 1300 BCE) civilizations and the disintegration of the LB Cypriot copper monopoly that dominated the eastern Mediterranean. The methodologies applied to the historical IA archaeology of the Levant have implications for other parts of the world where sacred and historical texts interface with the material record.

Probiotic Escherichia coli Nissle 1917 versus placebo for treating diarrhea of greater than 4 days duration in infants and toddlers.

BACKGROUND: Administering probiotics can prevent or cure some forms of diarrhea. The efficacy of probiotic Escherichia coli Nissle 1917 (EcN) in infants and toddlers with diarrhea >4 days was tested by a double-blind trial. METHODS: One hundred fifty-one children aged 1-47 months with nonspecific diarrhea were randomized to receive either EcN suspension (N = 75) or placebo (N = 76). Diarrhea had to meet the following definition: >3 watery or loose nonbloody stools in 24 hours of a diarrheal episode persisting for >4 consecutive days but < or =14 days. All children were well nourished or only moderately malnourished, mildly dehydrated, and received oral rehydration at study commencement. They were treated orally with 1-3 mL EcN suspension (1 mL contains 10 viable cells) or placebo daily for 21 days. Primary objective was to confirm a better response rate (reduction of daily stool frequency to < or =3 watery or loose stools over > or =4 days) with EcN. RESULTS: The 7-day response was higher for the EcN group than placebo (EcN 78.7%, placebo 59.2%). Significant differences were observed on days 14 (EcN 93.3%, placebo 65.8%, P = 0.0017) and 21 (EcN 98.7%, placebo 71.1%, P < 0.001). Kaplan-Meier survival analysis resulted in a significant difference of 3.3 days between the groups (P < 0.0001); median time to response for EcN was 2.4 and 5.7 for placebo. EcN was safe and well tolerated. CONCLUSIONS: In the conditions of this trial EcN was a suitable remedy for diarrhea >4 days in young children.

The probiotic Escherichia coli strain Nissle 1917 (EcN) stops acute diarrhoea in infants and toddlers.

In most cases, acute diarrhoea will become self-limiting during the first few days after onset. For young children, however, health risks may develop when the disease lasts longer than 3 days. The purpose of the present trial was to determine whether the stool frequency of infants and toddlers suffering from acute diarrhoea could be normalised more quickly by administering the probiotic Escherichia coli Nissle 1917 (EcN) solution than by administering a placebo. The safety of EcN were also assessed. A total of 113 children (aged 2-47 months) with acute diarrhoea (> three watery or loose stools in 24 h) were randomised to either a group receiving the probiotic EcN suspension (n = 55) or a group receiving the placebo suspension (n = 58) in a confirmative, double-blind clinical trial. Depending on the age of patients, 1-3 ml per day of verum suspension (10(8) viable EcN cells per millilitre) or placebo were administered orally. The causes of the diarrhoea were viral rather than bacterial, but they were mainly unspecific infections. The median onset of treatment response (reduction of daily stool frequency to

The effect of intestinal colonization of germ-free pigs with Escherichia coli on calprotectin levels in plasma, intestinal and bronchoalveolar lavages.

Calprotectin levels were measured by ELISA in plasma, terminal small bowel lavage and bronchoalveolar lavage from 8-day-old germ-free piglets or gnotobiotic piglets 24 h after colonization with one of the following Escherichia coli strains: non-pathogenic O86, probiotic Nissle 1917 or enteropathogenic O55. The concentration of calprotectin in plasma was about 30 ng/ml only in germ-free piglets and piglets associated with non-pathogenic E. coli. Piglets infected with O55 showed a significant increase of plasma calprotectin and the highest mean level of calprotectin in the bronchoalveolar lavage, which was coincident with septicaemia. However, in the lumen of the small intestine, E. coli Nissle 1917 alone elicited a significant increase of the calprotectin level which was confirmed by immunofluorescence and APAAP immunohistochemistry on cryostat sections through the small bowel. The relevance of this finding to the therapeutic effect of E. coli Nissle 1917 in inflammatory bowel disease is discussed.

Analysis of the genome structure of the nonpathogenic probiotic Escherichia coli strain Nissle 1917.

Nonpathogenic Escherichia coli strain Nissle 1917 (O6:K5:H1) is used as a probiotic agent in medicine, mainly for the treatment of various gastroenterological diseases. To gain insight on the genetic level into its properties of colonization and commensalism, this strain's genome structure has been analyzed by three approaches: (i) sequence context screening of tRNA genes as a potential indication of chromosomal integration of horizontally acquired DNA, (ii) sequence analysis of 280 kb of genomic islands (GEIs) coding for important fitness factors, and (iii) comparison of Nissle 1917 genome content with that of other E. coli strains by DNA-DNA hybridization. PCR-based screening of 324 nonpathogenic and pathogenic E. coli isolates of different origins revealed that some chromosomal regions are frequently detectable in nonpathogenic E. coli and also among extraintestinal and intestinal pathogenic strains. Many known fitness factor determinants of strain Nissle 1917 are localized on four GEIs which have been partially sequenced and analyzed. Comparison of these data with the available knowledge of the genome structure of E. coli K-12 strain MG1655 and of uropathogenic E. coli O6 strains CFT073 and 536 revealed structural similarities on the genomic level, especially between the E. coli O6 strains. The lack of defined virulence factors (i.e., alpha-hemolysin, P-fimbrial adhesins, and the semirough lipopolysaccharide phenotype) combined with the expression of fitness factors such as microcins, different iron uptake systems, adhesins, and proteases, which may support its survival and successful colonization of the human gut, most likely contributes to the probiotic character of E. coli strain Nissle 1917.

Development of strain-specific PCR reactions for the detection of the probiotic Escherichia coli strain Nissle 1917 in fecal samples.

PCR was used to establish a specific detection system for the non-pathogenic Escherichia coli strain Nissle 1917 (DSM6601), which is used as a probiotic drug against intestinal disorders and diseases. Five PCR assays have been developed which are based on the chromosomally encoded major fimbrial subunit genes fimA (type 1 fimbriae) and focA (F1C fimbriae), and the two small cryptic plasmids pMUT1 and pMUT2. The assays were validated by testing a collection of 354 different pathogenic and non-pathogenic E. coli strains from various origins, including E. coli K-12, fecal and environmental as well as pathogenic extraintestinal and intestinal E. coli strains. The most specific results were obtained with primers based on DNA sequences from plasmid pMUT2. The plasmid-based PCR assays described can be used to detect E. coli strain Nissle 1917 in feces from patients without prior cultivation.

A single nucleotide exchange in the wzy gene is responsible for the semirough O6 lipopolysaccharide phenotype and serum sensitivity of Escherichia coli strain Nissle 1917.

Structural analysis of lipopolysaccharide (LPS) isolated from semirough, serum-sensitive Escherichia coli strain Nissle 1917 (DSM 6601, serotype O6:K5:H1) revealed that this strain's LPS contains a bisphosphorylated hexaacyl lipid A and a tetradecasaccharide consisting of one E. coli O6 antigen repeating unit attached to the R1-type core. Configuration of the GlcNAc glycosidic linkage between O-antigen oligosaccharide and core (beta) differs from that interlinking the repeating units in the E. coli O6 antigen polysaccharide (alpha). The wa(*) and wb(*) gene clusters of strain Nissle 1917, required for LPS core and O6 repeating unit biosyntheses, were subcloned and sequenced. The DNA sequence of the wa(*) determinant (11.8 kb) shows 97% identity to other R1 core type-specific wa(*) gene clusters. The DNA sequence of the wb(*) gene cluster (11 kb) exhibits no homology to known DNA sequences except manC and manB. Comparison of the genetic structures of the wb(*)(O6) (wb(*) from serotype O6) determinants of strain Nissle 1917 and of smooth and serum-resistant uropathogenic E. coli O6 strain 536 demonstrated that the putative open reading frame encoding the O-antigen polymerase Wzy of strain Nissle 1917 was truncated due to a point mutation. Complementation with a functional wzy copy of E. coli strain 536 confirmed that the semirough phenotype of strain Nissle 1917 is due to the nonfunctional wzy gene. Expression of a functional wzy gene in E. coli strain Nissle 1917 increased its ability to withstand antibacterial defense mechanisms of blood serum. These results underline the importance of LPS for serum resistance or sensitivity of E. coli.