Non-invasive diagnostic test for lung cancer using biospectroscopy and variable selection techniques in saliva samples.

Lung cancer is one of the most commonly occurring malignant tumours worldwide. Although some reference methods such as X-ray, computed tomography or bronchoscope are widely used for clinical diagnosis of lung cancer, there is still a need to develop new methods for early detection of lung cancer. Especially needed are approaches that might be non-invasive and fast with high analytical precision and statistically reliable. Herein, we developed a swab "dip" test in saliva whereby swabs were analysed using attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy harnessed to principal component analysis-quadratic discriminant analysis (QDA) and variable selection techniques employing successive projections algorithm (SPA) and genetic algorithm (GA) for feature selection/extraction combined with QDA. A total of 1944 saliva samples (56 designated as lung-cancer positive and 1888 designed as controls) were obtained in a lung cancer-screening programme being undertaken in North-West England. GA-QDA models achieved, for the test set, sensitivity and specificity values of 100.0% and 99.1%, respectively. Three wavenumbers (1422 cm-1, 1546 cm-1 and 1578 cm-1) were identified using the GA-QDA model to distinguish between lung cancer and controls, including ring C-C stretching, CN adenine, Amide II [δ(NH), ν(CN)] and νs(COO-) (polysaccharides, pectin). These findings highlight the potential of using biospectroscopy associated with multivariate classification algorithms to discriminate between benign saliva samples and those with underlying lung cancer.

Point-of-Care Disease Screening in Primary Care Using Saliva: A Biospectroscopy Approach for Lung Cancer and Prostate Cancer.

Saliva is a largely unexplored liquid biopsy that can be readily obtained noninvasively. Not dissimilar to blood plasma or serum, it contains a vast array of bioconstituents that may be associated with the absence or presence of a disease condition. Given its ease of access, the use of saliva is potentially ideal in a point-of-care screening or diagnostic test. Herein, we developed a swab "dip" test in saliva obtained from consenting patients participating in a lung cancer-screening programme being undertaken in north-west England. A total of 998 saliva samples (31 designated as lung-cancer positive and 17 as prostate-cancer positive) were taken in the order in which they entered the clinic (i.e., there was no selection of participants) during the course of this prospective screening programme. Samples (sterile Copan blue rayon swabs dipped in saliva) were analysed using attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy. In addition to unsupervised classification on resultant infrared (IR) spectra using principal component analysis (PCA), a range of feature selection/extraction algorithms were tested. Following preprocessing, the data were split between training (70% of samples, 22 lung-cancer positive versus 664 other) and test (30% of samples, 9 lung-cancer positive versus 284 other) sets. The training set was used for model construction and the test set was used for validation. The best model was the PCA-quadratic discriminant analysis (QDA) algorithm. This PCA-QDA model was built using 8 PCs (90.4% of explained variance) and resulted in 93% accuracy for training and 91% for testing, with clinical sensitivity at 100% and specificity at 91%. Additionally, for prostate cancer patients amongst the male cohort (n = 585), following preprocessing, the data were split between training (70% of samples, 12 prostate-cancer positive versus 399 other) and test (30% of samples, 5 prostate-cancer positive versus 171 other) sets. A PCA-QDA model, again the best model, was built using 5 PCs (84.2% of explained variance) and resulted in 97% accuracy for training and 93% for testing, with clinical sensitivity at 100% and specificity at 92%. These results point to a powerful new approach towards the capability to screen large cohorts of individuals in primary care settings for underlying malignant disease.

ATR-FTIR Spectroscopy with Chemometrics for Analysis of Saliva Samples Obtained in a Lung-Cancer-Screening Programme: Application of Swabs as a Paradigm for High Throughput in a Clinical Setting.

There is an increasing need for inexpensive and rapid screening tests in point-of-care clinical oncology settings. Herein, we develop a swab "dip" test in saliva obtained from consenting patients participating in a lung-cancer-screening programme being undertaken in North West England. In a pilot study, a total of 211 saliva samples (n = 170 benign, 41 designated cancer-positive) were randomly taken during the course of this prospective lung-cancer-screening programme. The samples (sterile Copan blue rayon swabs dipped in saliva) were analysed using attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy. An exploratory analysis using principal component analysis (PCA,) with or without linear discriminant analysis (LDA), was then undertaken. Three pairwise comparisons were undertaken including: (1) benign vs. cancer following swab analysis; (2) benign vs. cancer following swab analysis with the subtraction of dry swab spectra; and (3) benign vs. cancer following swab analysis with the subtraction of wet swab spectra. Consistent and remarkably similar patterns of clustering for the benign control vs. cancer categories, irrespective of whether the swab plus saliva sample was analysed or whether there was a subtraction of wet or dry swab spectra, was observed. In each case, MANOVA demonstrated that this segregation of categories is highly significant. A k-NN (using three nearest neighbours) machine-learning algorithm also showed that the specificity (90%) and sensitivity (75%) are consistent for each pairwise comparison. In detailed analyses, the swab as a substrate did not alter the level of spectral discrimination between benign control vs. cancer saliva samples. These results demonstrate a novel swab "dip" test using saliva as a biofluid that is highly applicable to be rolled out into a larger lung-cancer-screening programme.

A comparison of centre of pressure behaviour and ground reaction force magnitudes when individuals walk overground and on an instrumented treadmill.

BACKGROUND: Instrumented treadmills facilitate analysis of consecutive strides in ways that typical overground gait data collections cannot. Researchers have quantified differences between joint kinetic measures whilst walking on an instrumented treadmill compared to those walking overground. The reason for such differences has not yet been established. RESEARCH QUESTION: Can we identify the source or sources of these errors by comparing centre of pressure and ground reaction force measurements recorded on a treadmill to those collected overground? METHODS: Kinematic and kinetic data were recorded while nineteen individuals walked continuously at their self-selected walking speed overground and on a treadmill. Comparisons of the centre of pressure and ground reaction forces were made between the two conditions using 2-tailed paired t-tests and Cohen's d effect size. RESULTS: The results indicated that participants had significantly faster backwards, lateral and medial centre of pressure velocities when walking on a treadmill compared to when they were walking overground. Additionally, participants also had significantly reduced peak propulsive ground reaction forces when walking on a treadmill than walking overground. SIGNIFICANCE: These results suggest that shear forces caused by the belts sliding over the treadmill force platforms affect the centre of pressure during early stance, and the minimal acceleration of a participant's centre of mass during treadmill walking results in reduced propulsive force during late stance. Therefore, care should be taken during studies when comparing kinetic gait variables between overground and treadmill walking.

Growth of Non-Halophilic Bacteria in the Sodium-Magnesium-Sulfate-Chloride Ion System: Unravelling the Complexities of Ion Interactions in Terrestrial and Extraterrestrial Aqueous Environments.

Motivated by an interest in understanding the habitability of aqueous environments on Earth and in extraterrestrial settings, this study investigated the influence of ions in an artificial sodium-magnesium-sulfate-chloride ion system on the growth parameters (lag phase, growth rate, and final cell concentration) of bacteria. These four ions, in different combinations, are key components of many aqueous environments on Earth and elsewhere. We investigated non-halophilic bacteria deliberately to remove the bias of prior adaptations to high concentrations of selected ions so that we could compare the effects of different ions. We tested the hypothesis that water activity determined the growth parameters independent of the ion types. Neither water activity or ionic strength alone could predict growth. However, when ionic strengths were matched, many differences in growth parameters could be explained by the water activity. We suggest that species-specific effects (caused by differences in biochemical and physiological influences), the role of individual ions in cellular processes, and potentially the chaotropicity and kosmotropicity of solutions influenced the growth. Our data show that although extreme combinations of these ions allow for general predictions on the habitability of extraterrestrial aqueous environments, a complex interplay of ionic effects influences the growth and thus the adaptations required for given ion combinations. The data also show that an accurate quantification of the habitability of ocean worlds, such as Europa and Enceladus, can only be made when samples are obtained from these water bodies and the ion combinations are determined.

A Low-Diversity Microbiota Inhabits Extreme Terrestrial Basaltic Terrains and Their Fumaroles: Implications for the Exploration of Mars.

A major objective in the exploration of Mars is to test the hypothesis that the planet hosted life. Even in the absence of life, the mapping of habitable and uninhabitable environments is an essential task in developing a complete understanding of the geological and aqueous history of Mars and, as a consequence, understanding what factors caused Earth to take a different trajectory of biological potential. We carried out the aseptic collection of samples and comparison of the bacterial and archaeal communities associated with basaltic fumaroles and rocks of varying weathering states in Hawai'i to test four hypotheses concerning the diversity of life in these environments. Using high-throughput sequencing, we found that all these materials are inhabited by a low-diversity biota. Multivariate analyses of bacterial community data showed a clear separation between sites that have active fumaroles and other sites that comprised relict fumaroles, unaltered, and syn-emplacement basalts. Contrary to our hypothesis that high water flow environments, such as fumaroles with active mineral leaching, would be sites of high biological diversity, alpha diversity was lower in active fumaroles compared to relict or nonfumarolic sites, potentially due to high-temperature constraints on microbial diversity in fumarolic sites. A comparison of these data with communities inhabiting unaltered and weathered basaltic rocks in Idaho suggests that bacterial taxon composition of basaltic materials varies between sites, although the archaeal communities were similar in Hawai'i and Idaho. The taxa present in both sites suggest that most of them obtain organic carbon compounds from the atmosphere and from phototrophs and that some of them, including archaeal taxa, cycle fixed nitrogen. The low diversity shows that, on Earth, extreme basaltic terrains are environments on the edge of sustaining life with implications for the biological potential of similar environments on Mars and their exploration by robots and humans.

Electromagnetically tracked personalized templates for surgical navigation.

PURPOSE: An electromagnetic (EM) surgical tracking system was developed for orthopedic navigation. The reportedly poor accuracy of point-based EM navigation was improved by using anatomical impressions, which were EM-tracked personalized templates. Lines, rather than points, were consistently used for calibration and error evaluation. METHODS: Technical accuracy was tested using models derived from CT scans of ten cadaver shoulders. Tracked impressions were first designed, calibrated, and tested using lines as fiducial objects. Next, tracked impressions were tested against EM point-based navigation and optical point-based navigation, in environments that were either relatively empty or that included surgical instruments. Finally, a tracked impression was tested on a cadaver forearm in a simulated fracture-repair task. RESULTS: Calibration of anatomical impressions to EM tracking was highly accurate, with mean fiducial localization errors in positions of 0.3 mm and in angles of [Formula: see text]. Technical accuracy on physical shoulder models was also highly accurate; in an EM field with surgical instruments, the mean of target registration errors in positions was 2.2 mm and in angles was [Formula: see text]. Preclinical accuracy in a cadaver forearm in positions was 0.4 mm and in angles was [Formula: see text]. The technical accuracy was significantly better than point-based navigation, whether by EM tracking or by optical tracking. The preclinical accuracy was comparable to that achieved by point-based optical navigation. CONCLUSIONS: EM-tracked impressions-a hybrid of personalized templates and EM navigation-are a promising technology for orthopedic applications. The two technical contributions are the novel hybrid navigation and the consistent use of lines as fiducial objects, replacing traditional point-based computations. The accuracy improvement was attributed to the combination of physical surfaces and line directions in the processes of calibration and registration. The technical studies and preclinical trial suggest that EM-tracked impressions are an accurate, ergonomic innovation in image-guided orthopedic surgery.

Personalized Guides for Registration in Surgical Navigation.

Personalized guides are increasingly used in orthopedic procedures but do not provide for intraoperative re-planning. This work presents a tracked guide that used physical registration to provide an anatomy-to-tracking coordinate frame transformation for surgical navigation. In a study using seven femoral models derived from clinical CT scans used for hip resurfacing, a guide characterization FRE of 0.4°±0.2°, drill-path drill-path angular TRE of 0.9°±0.4° and a positional TRE of 1.2mm±0.4mm were found; these values are comparable to conventional optical tracking accuracy. This novel use of a tracked guide may be particularly applicable to procedures that require a small surgical exposure, or when operating on anatomical regions with small bones that are difficult to track or reliably register.

A Toroidal Probe for Measuring Surgically Exposed Joint Centers.

Maintaining the hip center can improve the success of a total hip arthroplasty. A novel probe design, based on mating a toroid with a sphere, was used for kinematic measurements of the femoral head center and implant center in a pre-clinical study of hip joints. In an electromagnetically tracked implementation tested in a laboratory environment, the device measured a spherical center to within 1.2±0.2 mm in a technical validation. Applied to a plastic model of a cadaveric femur, the center of the femoral head was measured to 1.8±0.4 mm and the implant was measured to within 1.5±0.5 mm. Because leg length changes and offset changes in conventional hip arthroplasty can be as much as 16 mm, this device has relatively high accuracy that may improve implant localization for the hip.

Overall wrist biomechanics are conserved by phenol-based embalming.

Although cadaveric specimens that have been fresh-frozen then thawed are considered the gold standard for biomechanics research, because they most closely represent in vivo tissues, potential problems include a relatively short useful time-span and risk of infection. A recently reported new method of phenol-based "soft" embalming has been found to preserve tissues in a fresh-like state over an extended period of time and simultaneously reduced infection risks. This study presents radio-ulnar deviation end-range data from 4 soft-embalmed and refrigerated human cadaveric forearm specimens over 12 months. All end-range comparisons were found to be statistically equivalent to within a clinically acceptable range of ±5 degrees of radio-ulnar deviation with a 95% con. dence measure of p < 0.01 in every case. These soft-embalmed specimens provide promising results for further use in biomechanical studies.

SimITK: visual programming of the ITK image-processing library within Simulink.

The Insight Segmentation and Registration Toolkit (ITK) is a software library used for image analysis, visualization, and image-guided surgery applications. ITK is a collection of C++ classes that poses the challenge of a steep learning curve should the user not have appropriate C++ programming experience. To remove the programming complexities and facilitate rapid prototyping, an implementation of ITK within a higher-level visual programming environment is presented: SimITK. ITK functionalities are automatically wrapped into "blocks" within Simulink, the visual programming environment of MATLAB, where these blocks can be connected to form workflows: visual schematics that closely represent the structure of a C++ program. The heavily templated C++ nature of ITK does not facilitate direct interaction between Simulink and ITK; an intermediary is required to convert respective data types and allow intercommunication. As such, a SimITK "Virtual Block" has been developed that serves as a wrapper around an ITK class which is capable of resolving the ITK data types to native Simulink data types. Part of the challenge surrounding this implementation involves automatically capturing and storing the pertinent class information that need to be refined from an initial state prior to being reflected within the final block representation. The primary result from the SimITK wrapping procedure is multiple Simulink block libraries. From these libraries, blocks are selected and interconnected to demonstrate two examples: a 3D segmentation workflow and a 3D multimodal registration workflow. Compared to their pure-code equivalents, the workflows highlight ITK usability through an alternative visual interpretation of the code that abstracts away potentially confusing technicalities.

The aspherical human hip: implication for early osteoarthritis.

One marker for early-onset hip arthritis is femoral acetabular impingement. The current standard way of quantifying impingement is manual calculation of anatomical measures on plain radiographs, including the α-angle. Such measurements are user-dependent and prone to error. We provided a robust computational alternative and proposed using numerical fitting of geometrical shapes. We applied least-squares fitting of an ellipse to the femoral head contour and used the difference between the ellipse axes as a quantification method. The results showed a good correlation between the new measure and previous definitions of the α-angle.