The autoimmune disease systemic sclerosis (SSc) causes microvascular changes that can be easily observed cutaneously at the finger nailfold. Optoacoustic imaging (OAI), a combination of optical and ...ultrasound imaging, specifically raster-scanning optoacoustic mesoscopy (RSOM), offers a non-invasive high-resolution 3D visualization of capillaries allowing for a better view of microvascular changes and an extraction of volumetric measures. In this study, nailfold capillaries of patients with SSc and healthy controls are imaged and compared with each other for the first time using OAI. The nailfolds of 23 patients with SSc and 19 controls were imaged using RSOM. The acquired images were qualitatively compared to images from state-of-the-art imaging tools for SSc, dermoscopy and high magnification capillaroscopy. The vascular volume in the nailfold capillaries were computed from the RSOM images. The vascular volumes differ significantly between both cohorts (0.216 ± 0.085 mm
and 0.337 ± 0.110 mm
; p < 0.0005). In addition, an artificial neural network was trained to automatically differentiate nailfold images from both cohorts to further assess whether OAI is sensitive enough to visualize anatomical differences in the capillaries between the two cohorts. Using transfer learning, the model classifies images with an area under the ROC curve of 0.897, and a sensitivity of 0.783 and specificity of 0.895. In conclusion, this study demonstrates the capabilities of RSOM as an imaging tool for SSc and establishes it as a modality that facilitates more in-depth studies into the disease mechanisms and progression.
The objective of our study was to describe the clinical experience in offering noninvasive prenatal testing (NIPT) for aneuploidy to pregnant patients, highlighting the clinical utility, barriers to ...acceptance and limitations of this novel test. Data were collected from 961 patients offered NIPT from 3/1/12 to 9/30/12. Univariate and multivariate logistic regression analysis was performed. Twenty-eight percent of patients elected NIPT and 72 % declined. Women continue to elect less sensitive and less specific screening through biochemical markers and nuchal translucency. Women considering all options at average risk for aneuploidy were less likely to accept NIPT testing than women who had a risk adjustment from an ultrasound marker or routine screening test. In our multi-ethnic population, Filipina women were significantly less likely to elect NIPT compared to other ethnicities. Five percent of NIPT ordered failed analysis. Several chromosome abnormalities were detected through CVS or amniocentesis that would not have been detected by NIPT. Even though NIPT offers a non-invasive, highly sensitive and specific analysis for aneuploidy, the majority of women in our study declined this option. NIPT should be offered in the context of genetic counseling so that women understand the limitations of the testing and make an educated decision about the testing option best suited to their situation.
Endometriosis is found in 5–15% of women of reproductive age and is more frequent in relatives of women with the disease. Activation of KRAS results in de novo endometriosis in mice, however, ...activating KRAS mutations have not been identified in women. We screened 150 women with endometriosis for a polymorphism in a let‐7 microRNA (miRNA) binding site in the 3'‐UTR of KRAS and detected a KRAS variant allele in 31% of women with endometriosis as opposed to 5% of a large diverse control population. KRAS mRNA and protein expression were increased in cultured endometrial stromal cells of women with the KRAS variant. Increased KRAS protein was due to altered miRNA binding as demonstrated in reporter assays. Endometrial stromal cells from women with the KRAS variant showed increased proliferation and invasion. In a murine model, endometrial xenografts containing the KRAS variant demonstrated increased proliferation and decreased progesterone receptor levels. These findings suggest that an inherited polymorphism of a let‐7 miRNA binding site in KRAS leads to abnormal endometrial growth and endometriosis. The LCS6 polymorphism is the first described genetic marker of endometriosis risk.
Nailfold videocapillaroscopy is being increasingly used as a marker of SSc-related microvascular disease, including in response to treatment. However, it requires further validation. Our aim was to ...assess the inter-observer, intra-observer and test-retest variability of semi-automated measurement of capillary features as well as of a manual density measurement.
All capillary apexes in images from 58 patients with SSc were marked up independently by two trained observers (inter-observer variability). The first observer then re-marked the images (intra-observer variability), and finally, the first observer marked up a second image of the same nailfold (test-retest). Mark-up of capillaries was carried out on cropped mosaic images (cropped independently by the observers to a fixed width, to allow the same length of nail bed to be studied for each patient) and on whole mosaic images (examining the whole nail bed).
Reproducibility of independently cropped mosaic images was poor and was due to the variation in the positioning of the cropped area. However, quantification of whole mosaic images was highly reproducible, e.g. for inter-capillary distance, the intra-class correlation coefficient for inter-observer, intra-observer and test-retest reliability was 0.95, 0.98 and 0.90 (compared with 0.88, 0.79 and 0.89 for cropped mosaic images), respectively. Intra-observer limits of agreement for whole mosaic images were better than inter-observer reproducibility.
Quantitative assessment of SSc-related change in nailfold capillaries is unreliable if examination of the same set of capillaries cannot be guaranteed. Conversely a wide-field, high-magnification system that allows visualization of the whole nail bed offers a highly reproducible approach for quantitative assessment and therefore has potential as an outcome measure.
Objective
Systemic sclerosis (SSc) affects both microvascular structure and function. Laser Doppler imaging (LDI) and thermal imaging can be used to measure cutaneous blood vessel function. Nailfold ...capillaroscopy (NC) measures capillary morphology. The aim of this study was to investigate the relationship between capillary morphology and blood flow, and to determine which combination of techniques allows the best discrimination between patients with SSc, primary Raynaud's phenomenon (RP), and healthy controls.
Methods
NC was performed in 16 patients with SSc, 14 patients with primary RP, and 16 healthy controls. In addition, participants underwent cold stimulus with cold water. Hands were imaged to monitor rewarming and reperfusion. Nailfold morphologic features were measured and baseline images and rewarming curves were analyzed.
Results
Significant differences were found between groups (analysis of variance) for capillary morphologic features and rewarming curve characteristics. A correlation (P < 0.001) was found between LDI and thermal imaging at baseline (0.667) and maximum (0.729) blood flow and skin temperature, and for the areas under the rewarming curves (0.684). Receiver operating characteristic curves indicated that NC, thermal imaging, and LDI allowed 89%, 74%, and 72%, respectively, of SSc patient data to be correctly classified versus primary RP patients and controls.
Conclusion
NC, LDI, and thermal imaging each independently provide good discrimination between patients with SSc and those with primary RP and healthy controls (NC being the most suitable technique for classifying patient groups). However, a combination of all 3 techniques improves classification. LDI and thermal imaging give equivalent information on dynamic changes in the cutaneous microcirculation; however, these only weakly correspond to capillary morphology.
Hereditary dysphasic disinhibition dementia (HDDD) describes a familial disorder characterized by personality changes, and language and memory deficits. The neuropathology includes frontotemporal ...lobar atrophy, neuronal loss and gliosis and, in most cases, abundant Abeta plaques and neurofibrillary tangles (NFTs). A Pick/Alzheimer's spectrum was proposed for the original family (HDDD1). Here we report the clinicopathologic case of an HDDD1 individual using modern immunohistochemical methods, contemporary neuropathologic diagnostic criteria to distinguish different frontotemporal lobar degenerations (FTLDs), and progranulin (PRGN) mutation analysis. Clinical onset was at age 62 years with personality changes and disinhibition, followed by nonfluent dysphasia, and memory loss that progressed to muteness and total dependence with death at age 84 years. There was severe generalized brain atrophy (weight=570 g). Histopathology showed superficial microvacuolation, marked neuronal loss, gliosis, and ubiquitin-positive, tau-negative cytoplasmic and intranuclear neuronal inclusions in frontal, temporal, and parietal cortices. There were also frequent neuritic plaques and NFTs in parietal and occipital cortices. The case met neuropathologic criteria for both FTLD with ubiquitin-positive, tau-negative inclusions (FTLD-U), and Alzheimer disease (Braak NFT stage V). We discovered a novel pathogenic PGRN mutation c.5913 A>G (IVS6-2 A>G) segregating with FTLD-U in this kindred. In conclusion, HDDD1 is an FTLD-U caused by a PGRN mutation and is neuropathologically heterogeneous with Alzheimer disease as a common comorbidity.
Abstract
Background
Nailfold capillaroscopy offers a non-invasive route to observation of systemic sclerosis (SSc)-related microvascular changes and is used routinely for inspection of the ...capillaries at the finger nailfold. The characteristic changes in capillary structure (increased capillary width, decreased capillary density and abnormal angiogenesis) are included in the 2013 classification criteria for SSc. Optoacoustic mesoscopy is a combination of optical and ultrasound imaging enabling a 3D perspective of capillaries at a similar resolution to commercial nailfold capillaroscopy systems. We have previously reported that quantitative measures of vascular volume and density extracted from optoacoustic images differ significantly between patients with SSc and healthy controls. The aim of this study was to determine whether an artificial neural network (deep machine learning) could correctly differentiate between images from patients with SSc and healthy controls.
Methods
Optoacoustic (3D, iThera, Germany) and ‘standard’ capillaroscopy images (2D, Optillia, Sweden) of the right and left ring finger nailfolds were acquired. Images were taken at the centre of the nailfold. Acquisition of the same capillaries was difficult in some cases. 2D, greyscale, maximum intensity projections were created from the 3D optoacoustic images. Capillaroscopy images were downsized to match the optoacoustic image resolution. For data augmentation purposes each image, from both the optoacoustic and capillaroscopy data sets, was sliced into multiple overlapping image sections of fixed size. Transfer learning was used to train the model on 'disease' classification (SSc vs control). The pre-trained neural networks learn general image features and subsequently, are fine-tuned on the image data to classify based on the previously learned features.
Results
Twenty four patients with SSc (19% female; median age 65 IQR 57-69; duration of Raynaud’s phenomenon 18 12-28 years; time since onset of first non-Raynaud’s feature 11 (5-18) years) and 19 controls (17% female; age 15 39-55 years) took part in the study. Fifty random data splits were used to validate the model and showed an average classification accuracy of 0.81 ± 0.15, with an area under the ROC curve of 0.88 ± 0.13 for optoacoustic data. The classification specificity and sensitivity were 0.84 ± 0.22 and 0.77 ± 0.21 respectively for optoacoustic mesoscopy. Performing the same task on capillaroscopy images, achieved an average accuracy of 0.86 ± 0.12 (AUC: 0.92 ± 0.09).
Conclusion
Deep learning is able to achieve excellent differentiation between images from patients with SSc and controls for both optoacoustic and standard capillaroscopy. Limitations of the study include the relatively small participant numbers and direct comparison of the same capillaries not always being possible. Optoacoustic mesoscopy offers huge potential to increase our understanding of the microvasculature in SSc.
Disclosures
S. Nitkunanantharajah None. K. Haedicke Corporate appointments; KH is an employee of iThera. T.L. Moore None. J.B. Manning None. G. Dinsdale None. M. Berks None. D. Jüstel None. V. Ntziachristos None. C. Taylor None. M. Dickinson None. A. Herrick None. A.K. Murray None.
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