81 results on '"Richards-Kortum RR"'
Search Results
2. Imaging quality assessment of multi-modal miniature microscope
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Lee, J., Jeremy Rogers, DESCOUR, MR, Hsu, E., Aaron, Js, Sokolov, K., and Richards-Kortum, Rr
3. A multiplexed, allele-specific recombinase polymerase amplification assay with lateral flow readout for sickle cell disease detection.
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Chang MM, Natoli ME, Wilkinson AF, Tubman VN, Airewele GE, and Richards-Kortum RR
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- Humans, beta-Globins genetics, Point Mutation, Anemia, Sickle Cell genetics, Anemia, Sickle Cell diagnosis, Nucleic Acid Amplification Techniques, Alleles, Recombinases metabolism
- Abstract
Isothermal nucleic acid amplification tests have the potential to improve disease diagnosis at the point of care, but it remains challenging to develop multiplexed tests that can detect ≥3 targets or to detect point mutations that may cause disease. These capabilities are critical to enabling informed clinical decision-making for many applications, such as sickle cell disease (SCD). To address this, we describe the development of a multiplexed allele-specific recombinase polymerase amplification (RPA) assay with lateral flow readout. We first characterize the specificity of RPA using primer design strategies employed in PCR to achieve point mutation detection, and demonstrate the utility of these strategies in achieving selective isothermal amplification and detection of genomic DNA encoding for the healthy β
A globin allele, or genomic DNA containing point mutations encoding for pathologic βS and βC globin alleles, which are responsible for most sickle cell disorders. We then optimize reaction conditions to achieve multiplexed amplification and identification of the three alleles in a single reaction. Finally, we perform a small pilot study with 20 extracted genomic DNA samples from SCD patients and healthy volunteers - of the 13 samples with valid results, the assay demonstrated 100% sensitivity and 100% specificity for detecting pathologic alleles, and an overall accuracy of 92.3% for genotype prediction. This multiplexed assay is rapid, minimally instrumented, and when combined with point-of-care sample preparation, could enable DNA-based diagnosis of SCD in low-resource settings. The strategies reported here could be applied to other challenges, such as detection of mutations that confer drug resistance.- Published
- 2024
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4. Use of topical methylene blue to image nuclear morphometry with a low-cost scanning darkfield microendoscope.
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Hou H, Carns J, Schwarz RA, Gillenwater AM, Anandasabapathy S, and Richards-Kortum RR
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- Animals, Humans, Cell Nucleus, Fiber Optic Technology instrumentation, Equipment Design, Endoscopy methods, Endoscopy instrumentation, Administration, Topical, Methylene Blue chemistry
- Abstract
Significance: Fiber-optic microendoscopy is a promising approach to noninvasively visualize epithelial nuclear morphometry for early cancer and precancer detection. However, the broader clinical application of this approach is limited by a lack of topical contrast agents available for in vivo use., Aim: The aim of this study was to evaluate the ability to image nuclear morphometry in vivo with a novel fiber-optic microendoscope used together with topical application of methylene blue (MB), a dye with FDA approval for use in chromoendoscopy in the gastrointestinal tract., Approach: The low-cost, high-resolution microendoscope implements scanning darkfield imaging without complex optomechanical components by leveraging programmable illumination and the rolling shutter of the image sensor. We validate the integration of our system and MB staining for visualizing epithelial cell nuclei by performing ex vivo imaging on fresh animal specimens and in vivo imaging on healthy volunteers., Results: The results indicate that scanning darkfield imaging significantly reduces specular reflection and resolves epithelial nuclei with enhanced image contrast and spatial resolution compared to non-scanning widefield imaging. The image quality of darkfield images with MB staining is comparable to that of fluorescence images with proflavine staining., Conclusions: Our approach enables real-time microscopic evaluation of nuclear patterns and has the potential to be a powerful noninvasive tool for early cancer detection., (© 2024 The Authors.)
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- 2024
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5. DeepDOF-SE: affordable deep-learning microscopy platform for slide-free histology.
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Jin L, Tang Y, Coole JB, Tan MT, Zhao X, Badaoui H, Robinson JT, Williams MD, Vigneswaran N, Gillenwater AM, Richards-Kortum RR, and Veeraraghavan A
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- Fluorescent Dyes, Hematoxylin, Eosine Yellowish-(YS), Microscopy, Deep Learning
- Abstract
Histopathology plays a critical role in the diagnosis and surgical management of cancer. However, access to histopathology services, especially frozen section pathology during surgery, is limited in resource-constrained settings because preparing slides from resected tissue is time-consuming, labor-intensive, and requires expensive infrastructure. Here, we report a deep-learning-enabled microscope, named DeepDOF-SE, to rapidly scan intact tissue at cellular resolution without the need for physical sectioning. Three key features jointly make DeepDOF-SE practical. First, tissue specimens are stained directly with inexpensive vital fluorescent dyes and optically sectioned with ultra-violet excitation that localizes fluorescent emission to a thin surface layer. Second, a deep-learning algorithm extends the depth-of-field, allowing rapid acquisition of in-focus images from large areas of tissue even when the tissue surface is highly irregular. Finally, a semi-supervised generative adversarial network virtually stains DeepDOF-SE fluorescence images with hematoxylin-and-eosin appearance, facilitating image interpretation by pathologists without significant additional training. We developed the DeepDOF-SE platform using a data-driven approach and validated its performance by imaging surgical resections of suspected oral tumors. Our results show that DeepDOF-SE provides histological information of diagnostic importance, offering a rapid and affordable slide-free histology platform for intraoperative tumor margin assessment and in low-resource settings., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
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- 2024
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6. Optical imaging technologies for in vivo cancer detection in low-resource settings.
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Hou H, Mitbander R, Tang Y, Azimuddin A, Carns J, Schwarz RA, and Richards-Kortum RR
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Cancer continues to affect underserved populations disproportionately. Novel optical imaging technologies, which can provide rapid, non-invasive, and accurate cancer detection at the point of care, have great potential to improve global cancer care. This article reviews the recent technical innovations and clinical translation of low-cost optical imaging technologies, highlighting the advances in both hardware and software, especially the integration of artificial intelligence, to improve in vivo cancer detection in low-resource settings. Additionally, this article provides an overview of existing challenges and future perspectives of adapting optical imaging technologies into clinical practice, which can potentially contribute to novel insights and programs that effectively improve cancer detection in low-resource settings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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- 2023
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7. Scanning darkfield high-resolution microendoscope for label-free microvascular imaging.
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Hou H, Tang Y, Coole JB, Kortum A, Schwarz RA, Carns J, Gillenwater AM, Ramalingam P, Milbourne A, Salcedo MP, Schmeler KM, and Richards-Kortum RR
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Characterization of microvascular changes during neoplastic progression has the potential to assist in discriminating precancer and early cancer from benign lesions. Here, we introduce a novel high-resolution microendoscope that leverages scanning darkfield reflectance imaging to characterize angiogenesis without exogenous contrast agents. Scanning darkfield imaging is achieved by coupling programmable illumination with a complementary metal-oxide semiconductor (CMOS) camera rolling shutter, eliminating the need for complex optomechanical components and making the system portable, low-cost (<$5,500) and simple to use. Imaging depth is extended by placing a gradient-index (GRIN) lens at the distal end of the imaging fiber to resolve subepithelial microvasculature. We validated the capability of the scanning darkfield microendoscope to visualize microvasculature at different anatomic sites in vivo by imaging the oral cavity of healthy volunteers. Images of cervical specimens resected for suspected neoplasia reveal distinct microvascular patterns in columnar and squamous epithelium with different grades of precancer, indicating the potential of scanning darkfield microendoscopy to aid in efforts to prevent cervical cancer through early diagnosis., Competing Interests: The authors declare no competing interests., (© 2023 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement.)
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- 2023
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8. An integrated isothermal nucleic acid amplification test to detect HPV16 and HPV18 DNA in resource-limited settings.
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Kundrod KA, Barra M, Wilkinson A, Smith CA, Natoli ME, Chang MM, Coole JB, Santhanaraj A, Lorenzoni C, Mavume C, Atif H, Montealegre JR, Scheurer ME, Castle PE, Schmeler KM, and Richards-Kortum RR
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- Female, Humans, Human papillomavirus 16 genetics, Human papillomavirus 18 genetics, Resource-Limited Settings, Early Detection of Cancer methods, DNA, Viral genetics, Nucleic Acid Amplification Techniques methods, Uterine Cervical Neoplasms diagnosis, Uterine Cervical Neoplasms genetics, Papillomavirus Infections diagnosis
- Abstract
High-risk human papillomavirus (HPV) DNA testing is widely acknowledged as the most sensitive cervical cancer screening method but has limited availability in resource-limited settings, where the burden of cervical cancer is highest. Recently, HPV DNA tests have been developed for use in resource-limited settings, but they remain too costly for widespread use and require instruments that are often limited to centralized laboratories. To help meet the global need for low-cost cervical cancer screening, we developed a prototype, sample-to-answer, point-of-care test for HPV16 and HPV18 DNA. Our test relies on isothermal DNA amplification and lateral flow detection, two technologies that reduce the need for complex instrumentation. We integrated all test components into a low-cost, manufacturable platform, and performance of the integrated test was evaluated with synthetic samples, provider-collected clinical samples in a high-resource setting in the United States, and self-collected clinical samples in a low-resource setting in Mozambique. We demonstrated a clinically relevant limit of detection of 1000 HPV16 or HPV18 DNA copies per test. The test requires six user steps, yields results in 45 min, and can be performed using a benchtop instrument and minicentrifuge by minimally trained personnel. The projected per-test cost is <$5, and the projected instrumentation cost is <$1000. These results show the feasibility of a sample-to-answer, point-of-care HPV DNA test. With the inclusion of other HPV types, this test has the potential to fill a critical gap for decentralized and globally accessible cervical cancer screening.
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- 2023
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9. A low-cost, paper-based hybrid capture assay to detect high-risk HPV DNA for cervical cancer screening in low-resource settings.
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Smith CA, Chang MM, Kundrod KA, Novak EN, Parra SG, López L, Mavume C, Lorenzoni C, Maza M, Salcedo MP, Carns JL, Baker E, Montealegre J, Scheurer M, Castle PE, Schmeler KM, and Richards-Kortum RR
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- Female, Humans, Early Detection of Cancer methods, User-Computer Interface, Papillomaviridae genetics, DNA, Uterine Cervical Neoplasms diagnosis, Uterine Cervical Neoplasms prevention & control, Papillomavirus Infections diagnosis
- Abstract
Cervical cancer is a leading cause of cancer death for women in low-resource settings. The World Health Organization recommends that cervical cancer screening programs incorporate HPV DNA testing, but available tests are expensive, require laboratory infrastructure, and cannot be performed at the point-of-care. We developed a two-dimensional paper network (2DPN), hybrid-capture, signal amplification assay and a point-of-care sample preparation protocol to detect high-risk HPV DNA from exfoliated cervical cells within an hour. The test does not require expensive equipment and has an estimated cost of <$3 per test without the need for batching. We evaluated performance of the paper HPV DNA assay with short synthetic and genomic HPV DNA targets, HPV positive and negative cellular samples, and two sets of clinical samples. The first set of clinical samples consisted of 16 biobanked, provider-collected cervical samples from a study in El Salvador previously tested with careHPV and subsequently tested in a controlled laboratory environment. The paper HPV DNA test correctly identified eight of eight HPV-negative clinical samples and seven of eight HPV-positive clinical samples. We then performed a field evaluation of the paper HPV DNA test in a hospital laboratory in Mozambique. Cellular controls generated expected results throughout field testing with fully lyophilized sample preparation and 2DPN reagents. When evaluated with 16 residual self-collected cervicovaginal samples previously tested by the GeneXpert HPV assay ("Xpert"), the accuracy of the HPV DNA paper test in the field was reduced compared to testing in the controlled laboratory environment, with positive results obtained for all eight HPV-positive samples as well as seven of eight HPV-negative samples. Further evaluation showed reduction in performance was likely due in part to increased concentration of exfoliated cells in the self-collected clinical samples from Mozambique compared with provider-collected samples from El Salvador. Finally, a formal usability assessment was conducted with users in El Salvador and Mozambique; the assay was rated as acceptable to perform after minimal training. With additional optimization for higher cell concentrations and inclusion of an internal cellular control, the paper HPV DNA assay offers promise as a low-cost, point-of-care cervical cancer screening test in low-resource settings.
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- 2023
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10. Mildly dysplastic oral lesions with optically-detectable abnormalities share genetic similarities with severely dysplastic lesions.
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Brenes DR, Nipper AJ, Tan MT, Gleber-Netto FO, Schwarz RA, Pickering CR, Williams MD, Vigneswaran N, Gillenwater AM, Sikora AG, and Richards-Kortum RR
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- Humans, Hyperplasia pathology, Cell Nucleus genetics, Cell Nucleus pathology, Optical Imaging, Mouth Mucosa pathology, Precancerous Conditions pathology
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Objective: Optical imaging studies of oral premalignant lesions have shown that optical markers, including loss of autofluorescence and altered morphology of epithelial cell nuclei, are predictive of high-grade pathology. While these optical markers are consistently positive in lesions with moderate/severe dysplasia or cancer, they are positive only in a subset of lesions with mild dysplasia. This study compared the gene expression profiles of lesions with mild dysplasia (stratified by optical marker status) to lesions with severe dysplasia and without dysplasia., Materials and Methods: Forty oral lesions imaged in patients undergoing oral surgery were analyzed: nine without dysplasia, nine with severe dysplasia, and 22 with mild dysplasia. Samples were submitted for high throughput gene expression analysis., Results: The analysis revealed 116 genes differentially expressed among sites without dysplasia and sites with severe dysplasia; 50 were correlated with an optical marker quantifying altered nuclear morphology. Ten of 11 sites with mild dysplasia and positive optical markers (91%) had gene expression similar to sites with severe dysplasia. Nine of 11 sites with mild dysplasia and negative optical markers (82%) had similar gene expression as sites without dysplasia., Conclusion: This study suggests that optical imaging may help identify patients with mild dysplasia who require more intensive clinical follow-up. If validated, this would represent a significant advance in patient care for patients with oral premalignant lesions., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RR Richards-Kortum, AM Gillenwater, and RA Schwarz are recipients of licensing fees for intellectual property licensed from the University of Texas at Austin by Remicalm LLC. All other authors disclosed no potential conflicts of interest relevant to this publication., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2022
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11. Cervical cancer prevention in El Salvador: A prospective evaluation of screening and triage strategies incorporating high-resolution microendoscopy to detect cervical precancer.
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Parra SG, López-Orellana LM, Molina Duque AR, Carns JL, Schwarz RA, Smith CA, Ortiz Silvestre M, Diaz Bazan S, Escobar PA, Felix JC, Ramalingam P, Castle PE, Cremer ML, Maza M, Schmeler KM, and Richards-Kortum RR
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Cervical cancer remains a leading cause of cancer death for women in low- and middle-income countries. The goal of our study was to evaluate screening and triage strategies, including high-resolution microendoscopy (HRME), to detect cervical abnormalities concerning for precancer at the point of care. Women (n = 1824) were enrolled at the Instituto de Cáncer de El Salvador. All underwent screening by both human papillomavirus (HPV) testing using careHPV and visual inspection with acetic acid (VIA). Screen-positives, along with 10% of screen-negatives, were invited to return for a follow-up examination that included triage with VIA, colposcopy and HRME imaging. Biopsies were taken of any abnormalities identified. If no abnormalities were identified, then the worst scoring site by HRME was biopsied. The sensitivities of HPV testing and VIA to screen for cervical intraepithelial neoplasia Grade 2 or more severe diagnoses (CIN2+) were 82.1% and 75% (P = .77), while the specificities were 90.4% and 80.9% (P < .001), respectively. The sensitivities of VIA, colposcopy and HRME as triage tests for CIN2+ were 82.1%, 82.1% and 71.4%, respectively (P ≥ .38). HRME had a significantly higher specificity (66.7%) than VIA (51.9%) (P < .001) and colposcopy (53.3%) (P < .001). When evaluating different theoretical screening and triage strategies, screening with HPV testing followed by triage with HRME would result in more women receiving appropriate care (97%) compared to screening with VIA (75%) or HPV alone (90%). Our findings demonstrate that screening with HPV is superior to VIA, and that triage with HRME imaging increases the specificity of detecting CIN2+ at the point of care in a low-resource setting., (© 2020 UICC.)
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- 2021
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12. Reply to: Comments on Cervical cancer prevention in El Salvador: A prospective evaluation of screening and triage strategies incorporating high-resolution microendoscopy to detect cervical precancer.
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Parra SG, López-Orellana LM, Molina Duque AR, Carns JL, Schwarz RA, Smith CA, Ortiz Silvestre M, Diaz Bazan S, Felix JC, Ramalingam P, Castle PE, Cremer ML, Maza M, Schmeler KM, and Richards-Kortum RR
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- 2021
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13. Automated software-assisted diagnosis of esophageal squamous cell neoplasia using high-resolution microendoscopy.
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Tan MC, Bhushan S, Quang T, Schwarz R, Patel KH, Yu X, Li Z, Wang G, Zhang F, Wang X, Xu H, Richards-Kortum RR, and Anandasabapathy S
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- Epithelial Cells, Esophagoscopy, Humans, Sensitivity and Specificity, Software, Esophagus diagnostic imaging, Neoplasms
- Abstract
Background and Aims: High-resolution microendoscopy (HRME) is an optical biopsy technology that provides subcellular imaging of esophageal mucosa but requires expert interpretation of these histopathology-like images. We compared endoscopists with an automated software algorithm for detection of esophageal squamous cell neoplasia (ESCN) and evaluated the endoscopists' accuracy with and without input from the software algorithm., Methods: Thirteen endoscopists (6 experts, 7 novices) were trained and tested on 218 post-hoc HRME images from 130 consecutive patients undergoing ESCN screening/surveillance. The automated software algorithm interpreted all images as neoplastic (high-grade dysplasia, ESCN) or non-neoplastic. All endoscopists provided their interpretation (neoplastic or non-neoplastic) and confidence level (high or low) without and with knowledge of the software overlay highlighting abnormal nuclei and software interpretation. The criterion standard was histopathology consensus diagnosis by 2 pathologists., Results: The endoscopists had a higher mean sensitivity (84.3%, standard deviation [SD] 8.0% vs 76.3%, P = .004), lower specificity (75.0%, SD 5.2% vs 85.3%, P < .001) but no significant difference in accuracy (81.1%, SD 5.2% vs 79.4%, P = .26) of ESCN detection compared with the automated software algorithm. With knowledge of the software algorithm, the specificity of the endoscopists increased significantly (75.0% to 80.1%, P = .002) but not the sensitivity (84.3% to 84.8%, P = .75) or accuracy (81.1% to 83.1%, P = .13). The increase in specificity was among novices (P = .008) but not experts (P = .11)., Conclusions: The software algorithm had lower sensitivity but higher specificity for ESCN detection than endoscopists. Using computer-assisted diagnosis, the endoscopists maintained high sensitivity while increasing their specificity and accuracy compared with their initial diagnosis. Automated HRME interpretation would facilitate widespread usage in resource-poor areas where this portable, low-cost technology is needed., (Published by Elsevier Inc.)
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- 2021
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14. Allele-Specific Recombinase Polymerase Amplification to Detect Sickle Cell Disease in Low-Resource Settings.
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Natoli ME, Chang MM, Kundrod KA, Coole JB, Airewele GE, Tubman VN, and Richards-Kortum RR
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- Alleles, Child, Preschool, Hemoglobin, Sickle analysis, Humans, Infant, Newborn, Nucleic Acid Amplification Techniques, Point-of-Care Systems, Sensitivity and Specificity, Anemia, Sickle Cell diagnosis, Anemia, Sickle Cell genetics, Recombinases
- Abstract
Sickle cell disease (SCD) is a group of common, life-threatening disorders caused by a point mutation in the β globin gene. Early diagnosis through newborn and early childhood screening, parental education, and preventive treatments are known to reduce mortality. However, the cost and complexity of conventional diagnostic methods limit the feasibility of early diagnosis for SCD in resource-limited areas worldwide. Although several point-of-care tests are commercially available, most are antibody-based tests, which cannot be used in patients who have recently received a blood transfusion. Here, we describe the development of a rapid, low-cost nucleic acid test that uses real-time fluorescence to detect the point mutation encoding hemoglobin S (HbS) in one round of isothermal recombinase polymerase amplification (RPA). When tested with a set of clinical samples from SCD patients and healthy volunteers, our assay demonstrated 100% sensitivity for both the β
A globin and βS globin alleles and 94.7 and 97.1% specificities for the βA globin allele and βS globin allele, respectively ( n = 91). Finally, we demonstrate proof-of-concept sample-to-answer genotyping of genomic DNA from capillary blood using an alkaline lysis procedure and direct input of diluted lysate into RPA. The workflow is performed in <30 min at a cost of <$5 USD on a commercially available benchtop fluorimeter and an open-source miniature fluorimeter. This study demonstrates the potential utility of a rapid, sample-to-answer nucleic acid test for SCD that may be implemented near the point of care and could be adapted to other disease-causing point mutations in genomic DNA.- Published
- 2021
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15. Deep learning extended depth-of-field microscope for fast and slide-free histology.
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Jin L, Tang Y, Wu Y, Coole JB, Tan MT, Zhao X, Badaoui H, Robinson JT, Williams MD, Gillenwater AM, Richards-Kortum RR, and Veeraraghavan A
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- Algorithms, Animals, Biopsy instrumentation, Biopsy methods, Biopsy standards, Calibration, Humans, Image Processing, Computer-Assisted instrumentation, Image Processing, Computer-Assisted standards, Microscopy, Fluorescence instrumentation, Microscopy, Fluorescence methods, Microscopy, Fluorescence standards, Swine, Carcinoma pathology, Deep Learning, Image Processing, Computer-Assisted methods, Mouth Neoplasms pathology
- Abstract
Microscopic evaluation of resected tissue plays a central role in the surgical management of cancer. Because optical microscopes have a limited depth-of-field (DOF), resected tissue is either frozen or preserved with chemical fixatives, sliced into thin sections placed on microscope slides, stained, and imaged to determine whether surgical margins are free of tumor cells-a costly and time- and labor-intensive procedure. Here, we introduce a deep-learning extended DOF (DeepDOF) microscope to quickly image large areas of freshly resected tissue to provide histologic-quality images of surgical margins without physical sectioning. The DeepDOF microscope consists of a conventional fluorescence microscope with the simple addition of an inexpensive (less than $10) phase mask inserted in the pupil plane to encode the light field and enhance the depth-invariance of the point-spread function. When used with a jointly optimized image-reconstruction algorithm, diffraction-limited optical performance to resolve subcellular features can be maintained while significantly extending the DOF (200 µm). Data from resected oral surgical specimens show that the DeepDOF microscope can consistently visualize nuclear morphology and other important diagnostic features across highly irregular resected tissue surfaces without serial refocusing. With the capability to quickly scan intact samples with subcellular detail, the DeepDOF microscope can improve tissue sampling during intraoperative tumor-margin assessment, while offering an affordable tool to provide histological information from resected tissue specimens in resource-limited settings., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)
- Published
- 2020
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16. Algorithm to quantify nuclear features and confidence intervals for classification of oral neoplasia from high-resolution optical images.
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Yang EC, Brenes DR, Vohra IS, Schwarz RA, Williams MD, Vigneswaran N, Gillenwater AM, and Richards-Kortum RR
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Purpose: In vivo optical imaging technologies like high-resolution microendoscopy (HRME) can image nuclei of the oral epithelium. In principle, automated algorithms can then calculate nuclear features to distinguish neoplastic from benign tissue. However, images frequently contain regions without visible nuclei, due to biological and technical factors, decreasing the data available to and accuracy of image analysis algorithms. Approach: We developed the nuclear density-confidence interval (ND-CI) algorithm to determine if an HRME image contains sufficient nuclei for classification, or if a better image is required. The algorithm uses a convolutional neural network to exclude image regions without visible nuclei. Then the remaining regions are used to estimate a confidence interval (CI) for the number of abnormal nuclei per mm 2 , a feature used by a previously developed algorithm (called the ND algorithm), to classify images as benign or neoplastic. The range of the CI determines whether the ND-CI algorithm can classify an image with confidence, and if so, the predicted category. The ND and ND-CI algorithm were compared by calculating their positive predictive value (PPV) and negative predictive value (NPV) on 82 oral biopsies with histopathologically confirmed diagnoses. Results: After excluding the images that could not be classified with confidence, the ND-CI algorithm had higher PPV (65% versus 59%) and NPV (78% versus 75%) than the ND algorithm. Conclusions: The ND-CI algorithm could improve the real-time classification of HRME images of the oral epithelium by informing the user if an improved image is required for diagnosis., (© The Authors. Published by SPIE under a Creative Commons Attribution 4.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.)
- Published
- 2020
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17. Prospective evaluation of oral premalignant lesions using a multimodal imaging system: a pilot study.
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Yang EC, Vohra IS, Badaoui H, Schwarz RA, Cherry KD, Jacob J, Rodriguez J, Williams MD, Vigneswaran N, Gillenwater AM, and Richards-Kortum RR
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- Biopsy, Humans, Multimodal Imaging, Pilot Projects, Prospective Studies, Precancerous Conditions diagnostic imaging
- Abstract
Background: Multimodal optical imaging, incorporating reflectance and fluorescence modalities, is a promising tool to detect oral premalignant lesions in real-time., Methods: Images were acquired from 171 sites in 66 patient visits for clinical evaluation of oral lesions. An automated algorithm was used to classify lesions as high- or low-risk for neoplasia. Biopsies were acquired at clinically indicated sites and those classified as high-risk by imaging, at the surgeon's discretion., Results: Twenty sites were biopsied based on clinical examination or imaging. Of these, 12 were indicated clinically and by imaging; 58% were moderate dysplasia or worse. Four biopsies were indicated by imaging evaluation only; 75% were moderate dysplasia or worse. Finally, four biopsies were indicated by clinical evaluation only; 75% were moderate dysplasia or worse., Conclusion: Multimodal imaging identified more cases of high-grade dysplasia than clinical evaluation, and can improve detection of high grade precancer in patients with oral lesions., (© 2019 The Authors. Head & Neck published by Wiley Periodicals, Inc.)
- Published
- 2020
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18. A PIK3CA transgenic mouse model with chemical carcinogen exposure mimics human oral tongue tumorigenesis.
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Tan MT, Wu JG, Callejas-Valera JL, Schwarz RA, Gillenwater AM, Richards-Kortum RR, and Vigneswaran N
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- 4-Nitroquinoline-1-oxide, Animals, Cell Proliferation, Cell Transformation, Neoplastic pathology, Disease Models, Animal, Disease Progression, Lymphocytes pathology, Mice, Inbred CBA, Mice, Transgenic, Oncogene Proteins, Viral genetics, Squamous Cell Carcinoma of Head and Neck pathology, Time Factors, Tongue Neoplasms pathology, Cell Transformation, Neoplastic chemically induced, Cell Transformation, Neoplastic genetics, Class I Phosphatidylinositol 3-Kinases genetics, Mutation, Quinolones, Squamous Cell Carcinoma of Head and Neck chemically induced, Squamous Cell Carcinoma of Head and Neck genetics, Tongue Neoplasms chemically induced, Tongue Neoplasms genetics
- Abstract
Oral cancer causes significant global mortality and has a five-year survival rate of around 64%. Poor prognosis results from late-stage diagnosis, highlighting an important need to develop better approaches to detect oral premalignant lesions (OPLs) and identify which OPLs are at highest risk of progression to oral squamous cell carcinoma (OSCC). An appropriate animal model that reflects the genetic, histologic, immunologic, molecular and gross visual features of human OSCC would aid in the development and evaluation of early detection and risk assessment strategies. Here, we present an experimental PIK3CA + 4NQO transgenic mouse model of oral carcinogenesis that combines the PIK3CA oncogene mutation with oral exposure to the chemical carcinogen 4NQO, an alternate experimental transgenic mouse model with PIK3CA as well as E6 and E7 mutations, and an existing wild-type mouse model based on oral exposure to 4NQO alone. We compare changes in dorsal and ventral tongue gross visual appearance, histologic features and molecular biomarker expression over a time course of carcinogenesis. Both transgenic models exhibit cytological and architectural features of dysplasia that mimic human disease and exhibit slightly increased staining for Ki-67, a cell proliferation marker. The PIK3CA + 4NQO model additionally exhibits consistent lymphocytic infiltration, presents with prominent dorsal and ventral tongue tumours, and develops cancer quickly relative to the other models. Thus, the PIK3CA + 4NQO model recapitulates the multistep genetic model of human oral carcinogenesis and host immune response in carcinogen-induced tongue cancer, making it a useful resource for future OSCC studies., (© 2020 The Authors. International Journal of Experimental Pathology © 2020 International Journal of Experimental Pathology.)
- Published
- 2020
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19. In vivo imaging of cervical precancer using a low-cost and easy-to-use confocal microendoscope.
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Tang Y, Kortum A, Parra SG, Vohra I, Milbourne A, Ramalingam P, Toscano PA, Schmeler KM, and Richards-Kortum RR
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Cervical cancer incidence and mortality rates remain high in medically underserved areas. In this study, we present a low-cost (<$5,000), portable and user-friendly confocal microendoscope, and we report on its clinical use to image precancerous lesions in the cervix. The confocal microendoscope employs digital apertures on a digital light projector and a CMOS sensor to implement line-scanning confocal imaging. Leveraging its versatile programmability, we describe an automated aperture alignment algorithm to ensure clinical ease-of-use and to facilitate technology dissemination in low-resource settings. Imaging performance is then evaluated in ex vivo and in vivo pilot studies; results demonstrate that the confocal microendoscope can enhance visualization of nuclear morphology, contributing to significantly improved recognition of clinically important features for detection of cervical precancer., Competing Interests: One author (Richards-Kortum R) is named as an inventor on patent applications for high resolution imaging owned by Rice University and The University of Texas. The authors report no other conflicts of interest., (© 2019 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)
- Published
- 2019
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20. Low-cost, high-resolution imaging for detecting cervical precancer in medically-underserved areas of Texas.
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Parra SG, Rodriguez AM, Cherry KD, Schwarz RA, Gowen RM, Guerra LB, Milbourne AM, Toscano PA, Fisher-Hoch SP, Schmeler KM, and Richards-Kortum RR
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- Female, Humans, Image Processing, Computer-Assisted, Neoplasm Grading, Precancerous Conditions economics, Prospective Studies, Sensitivity and Specificity, Texas, United States, Uterine Cervical Neoplasms pathology, Uterine Cervical Dysplasia diagnostic imaging, Uterine Cervical Dysplasia economics, Colonoscopy economics, Colonoscopy methods, Medically Underserved Area, Precancerous Conditions diagnostic imaging, Uterine Cervical Neoplasms diagnostic imaging
- Abstract
Objective: Cervical cancer rates in the United States have declined since the 1940's, however, cervical cancer incidence remains elevated in medically-underserved areas, especially in the Rio Grande Valley (RGV) along the Texas-Mexico border. High-resolution microendoscopy (HRME) is a low-cost, in vivo imaging technique that can identify high-grade precancerous cervical lesions (CIN2+) at the point-of-care. The goal of this study was to evaluate the performance of HRME in medically-underserved areas in Texas, comparing results to a tertiary academic medical center., Methods: HRME was evaluated in five different outpatient clinical settings, two in Houston and three in the RGV, with medical providers of varying skill and training. Colposcopy, followed by HRME imaging, was performed on eligible women. The sensitivity and specificity of traditional colposcopy and colposcopy followed by HRME to detect CIN2+ were compared and HRME image quality was evaluated., Results: 174 women (227 cervical sites) were included in the final analysis, with 12% (11% of cervical sites) diagnosed with CIN2+ on histopathology. On a per-site basis, a colposcopic impression of low-grade precancer or greater had a sensitivity of 84% and a specificity of 45% to detect CIN2+. While there was no significant difference in sensitivity (76%, p = 0.62), the specificity when using HRME was significantly higher than that of traditional colposcopy (56%, p = 0.01). There was no significant difference in HRME image quality between clinical sites (p = 0.77) or medical providers (p = 0.33)., Conclusions: HRME imaging increased the specificity for detecting CIN2+ when compared to traditional colposcopy. HRME image quality remained consistent across different clinical settings., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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21. Development of an integrated multimodal optical imaging system with real-time image analysis for the evaluation of oral premalignant lesions.
- Author
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Yang EC, Vohra IS, Badaoui H, Schwarz RA, Cherry KD, Quang T, Jacob J, Lang A, Bass N, Rodriguez J, Williams MD, Vigneswaran N, Gillenwater AM, and Richards-Kortum RR
- Subjects
- Algorithms, Biopsy, Cell Transformation, Neoplastic, Endoscopy, Humans, Microscopy, Fluorescence methods, Mouth Diseases diagnostic imaging, Mouth Neoplasms pathology, Mouth Neoplasms surgery, Pattern Recognition, Automated, Point-of-Care Systems, Reproducibility of Results, Software, Image Processing, Computer-Assisted methods, Mouth Neoplasms diagnostic imaging, Multimodal Imaging methods, Optical Imaging methods, Precancerous Conditions diagnostic imaging
- Abstract
Oral premalignant lesions (OPLs), such as leukoplakia, are at risk of malignant transformation to oral cancer. Clinicians can elect to biopsy OPLs and assess them for dysplasia, a marker of increased risk. However, it is challenging to decide which OPLs need a biopsy and to select a biopsy site. We developed a multimodal optical imaging system (MMIS) that fully integrates the acquisition, display, and analysis of macroscopic white-light (WL), autofluorescence (AF), and high-resolution microendoscopy (HRME) images to noninvasively evaluate OPLs. WL and AF images identify suspicious regions with high sensitivity, which are explored at higher resolution with the HRME to improve specificity. Key features include a heat map that delineates suspicious regions according to AF images, and real-time image analysis algorithms that predict pathologic diagnosis at imaged sites. Representative examples from ongoing studies of the MMIS demonstrate its ability to identify high-grade dysplasia in OPLs that are not clinically suspicious, and to avoid unnecessary biopsies of benign OPLs that are clinically suspicious. The MMIS successfully integrates optical imaging approaches (WL, AF, and HRME) at multiple scales for the noninvasive evaluation of OPLs.
- Published
- 2019
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22. Quantitative analysis of in vivo high-resolution microendoscopic images for the detection of neoplastic colorectal polyps.
- Author
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Tang Y, Polydorides AD, Anandasabapathy S, and Richards-Kortum RR
- Subjects
- Algorithms, Colon diagnostic imaging, Humans, Colonic Polyps diagnostic imaging, Colonoscopy methods, Colorectal Neoplasms diagnostic imaging, Image Interpretation, Computer-Assisted methods
- Abstract
Colonoscopy is routinely performed for colorectal cancer screening but lacks the capability to accurately characterize precursor lesions and early cancers. High-resolution microendoscopy (HRME) is a low-cost imaging tool to visualize colorectal polyps with subcellular resolution. We present a computer-aided algorithm to evaluate HRME images of colorectal polyps and classify neoplastic from benign lesions. Using histopathology as the gold standard, clinically relevant features based on luminal morphology and texture are quantified to build the classification algorithm. We demonstrate that adenomatous polyps can be identified with a sensitivity and specificity of 100% and 80% using a two-feature linear discriminant model in a pilot test set. The classification algorithm presented here offers an objective framework to detect adenomatous lesions in the colon with high accuracy and can potentially improve real-time assessment of colorectal polyps., ((2018) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE).)
- Published
- 2018
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23. In Vivo Multimodal Optical Imaging: Improved Detection of Oral Dysplasia in Low-Risk Oral Mucosal Lesions.
- Author
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Yang EC, Schwarz RA, Lang AK, Bass N, Badaoui H, Vohra IS, Cherry KD, Williams MD, Gillenwater AM, Vigneswaran N, and Richards-Kortum RR
- Subjects
- Adult, Dental Impression Technique, Disease Progression, Endoscopy instrumentation, Endoscopy methods, Feasibility Studies, Humans, Image Processing, Computer-Assisted, Mouth Mucosa pathology, Mouth Neoplasms diagnosis, Mouth Neoplasms pathology, Multimodal Imaging instrumentation, Multimodal Imaging methods, Optical Imaging instrumentation, Precancerous Conditions pathology, ROC Curve, Young Adult, Early Detection of Cancer methods, Mouth Mucosa diagnostic imaging, Mouth Neoplasms prevention & control, Optical Imaging methods, Precancerous Conditions diagnostic imaging
- Abstract
Early detection of oral cancer and oral premalignant lesions (OPL) containing dysplasia could improve oral cancer outcomes. However, general dental practitioners have difficulty distinguishing dysplastic OPLs from confounder oral mucosal lesions in low-risk populations. We evaluated the ability of two optical imaging technologies, autofluorescence imaging (AFI) and high-resolution microendoscopy (HRME), to diagnose moderate dysplasia or worse (ModDys
+ ) in 56 oral mucosal lesions in a low-risk patient population, using histopathology as the gold standard, and in 46 clinically normal sites. AFI correctly diagnosed 91% of ModDys+ lesions, 89% of clinically normal sites, and 33% of benign lesions. Benign lesions with severe inflammation were less likely to be correctly diagnosed by AFI (13%) than those without (42%). Multimodal imaging (AFI+HRME) had higher accuracy than either modality alone; 91% of ModDys+ lesions, 93% of clinically normal sites, and 64% of benign lesions were correctly diagnosed. Photos of the 56 lesions were evaluated by 28 dentists of varied training levels, including 26 dental residents. We compared the area under the receiver operator curve (AUC) of clinical impression alone to clinical impression plus AFI and clinical impression plus multimodal imaging using k -Nearest Neighbors models. The mean AUC of the dental residents was 0.71 (range: 0.45-0.86). The addition of AFI alone to clinical impression slightly lowered the mean AUC (0.68; range: 0.40-0.82), whereas the addition of multimodal imaging to clinical impression increased the mean AUC (0.79; range: 0.61-0.90). On the basis of these findings, multimodal imaging could improve the evaluation of oral mucosal lesions in community dental settings. Cancer Prev Res; 11(8); 465-76. ©2018 AACR ., (©2018 American Association for Cancer Research.)- Published
- 2018
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24. Noninvasive diagnostic adjuncts for the evaluation of potentially premalignant oral epithelial lesions: current limitations and future directions.
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Yang EC, Tan MT, Schwarz RA, Richards-Kortum RR, Gillenwater AM, and Vigneswaran N
- Subjects
- Biopsy, Diagnostic Imaging, Disease Progression, Early Detection of Cancer, Humans, Risk Factors, Cell Transformation, Neoplastic pathology, Diagnosis, Oral trends, Erythroplasia diagnostic imaging, Erythroplasia pathology, Leukoplakia, Oral diagnostic imaging, Leukoplakia, Oral pathology, Mouth Neoplasms diagnostic imaging, Mouth Neoplasms pathology, Precancerous Conditions diagnostic imaging, Precancerous Conditions pathology
- Abstract
Potentially premalignant oral epithelial lesions (PPOELs) are a group of clinically suspicious conditions, of which a small percentage will undergo malignant transformation. PPOELs are suboptimally diagnosed and managed under the current standard of care. Dysplasia is the most well-established marker to distinguish high-risk PPOELs from low-risk PPOELs, and performing a biopsy to establish dysplasia is the diagnostic gold standard. However, a biopsy is limited by morbidity, resource requirements, and the potential for underdiagnosis. Diagnostic adjuncts may help clinicians better evaluate PPOELs before definitive biopsy, but existing adjuncts, such as toluidine blue, acetowhitening, and autofluorescence imaging, have poor accuracy and are not generally recommended. Recently, in vivo microscopy technologies, such as high-resolution microendoscopy, optical coherence tomography, reflectance confocal microscopy, and multiphoton imaging, have shown promise for improving PPOEL patient care. These technologies allow clinicians to visualize many of the same microscopic features used for histopathologic assessment at the point of care., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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25. Paper-based detection of HIV-1 drug resistance using isothermal amplification and an oligonucleotide ligation assay.
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Natoli ME, Rohrman BA, De Santiago C, van Zyl GU, and Richards-Kortum RR
- Subjects
- Anti-HIV Agents pharmacology, DNA, Viral drug effects, Drug Resistance, Viral drug effects, HIV Reverse Transcriptase antagonists & inhibitors, Anti-HIV Agents analysis, DNA, Viral genetics, Enzyme-Linked Immunosorbent Assay, HIV Reverse Transcriptase genetics, Oligonucleotide Array Sequence Analysis, Paper
- Abstract
Regular HIV-1 viral load monitoring is the standard of care to assess antiretroviral therapy effectiveness in resource-rich settings. Persistently elevated viral loads indicate virologic failure (VF), which warrants HIV drug resistance testing (HIVDRT) to allow individualized regimen switches. However, in settings lacking access to HIVDRT, clinical decisions are often made based on symptoms, leading to unnecessary therapy switches and increased costs of care. This work presents a proof-of-concept assay to detect M184V, the most common drug resistance mutation after first-line antiretroviral therapy failure, in a paper format. The first step isothermally amplifies a section of HIV-1 reverse transcriptase containing M184V using a recombinase polymerase amplification (RPA) assay. Then, an oligonucleotide ligation assay (OLA) is used to selectively label the mutant and wild type amplified sequences. Finally, a lateral flow enzyme-linked immunosorbent assay (ELISA) differentiates between OLA-labeled products with or without M184V. Our method shows 100% specificity and 100% sensitivity when tested with samples that contained 200 copies of mutant DNA and 800 copies of wild type DNA prior to amplification. When integrated with sample preparation, this method may detect HIV-1 drug resistance at a low cost and at a rural hospital laboratory., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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26. Point-of-care device to diagnose and monitor neonatal jaundice in low-resource settings.
- Author
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Keahey PA, Simeral ML, Schroder KJ, Bond MM, Mtenthaonnga PJ, Miros RH, Dube Q, and Richards-Kortum RR
- Subjects
- Female, Health Resources, Humans, Infant, Newborn, Malawi, Male, Monitoring, Physiologic instrumentation, Monitoring, Physiologic methods, Reproducibility of Results, Jaundice, Neonatal diagnosis, Point-of-Care Testing
- Abstract
Newborns are at increased risk of jaundice, a condition in which excess bilirubin accumulates in blood. Left untreated, jaundice can lead to neurological impairment and death. Jaundice resulting from unconjugated hyperbilirubinemia is easily treated with exposure to blue light, and phototherapy systems have been developed for low-resource settings; however, there are no appropriate solutions to diagnose and monitor jaundice in these settings. To address this need we present BiliSpec, a low-cost reader and disposable lateral flow card designed to measure the concentration of total bilirubin from several drops of blood at the point of care. We evaluated the performance of BiliSpec, using blood from normal volunteers spiked with varying amounts of bilirubin; results measured using BiliSpec correlated well with a reference laboratory bilirubinometer ( r = 0.996). We then performed a pilot clinical study using BiliSpec to measure total bilirubin in neonates at risk for jaundice at Queen Elizabeth Central Hospital in Blantyre, Malawi. Concentrations measured using BiliSpec correlated well with those measured using a laboratory reference standard in 94 patient samples ranging from 1.1 mg/dL to 23.0 mg/dL in concentration ( r = 0.973). The mean difference between bilirubin levels measured with BiliSpec and the reference standard was 0.3 mg/dL (95[Formula: see text] CI: -1.7-2.2 mg/dL)., Competing Interests: The authors declare no conflict of interest., (Copyright © 2017 the Author(s). Published by PNAS.)
- Published
- 2017
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27. Tools To Reduce Newborn Deaths In Africa.
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Richards-Kortum RR
- Subjects
- Africa, Developing Countries, Female, Humans, Infant, Infant, Newborn, Pregnancy, Equipment Design, Infant Mortality, Inventions, Premature Birth mortality
- Abstract
An engineering team designs a breathing device specifically for premature babies born in low-resource health care settings.
- Published
- 2017
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28. Line-scanning confocal microendoscope for nuclear morphometry imaging.
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Tang Y, Carns J, and Richards-Kortum RR
- Subjects
- Animals, Cell Nucleus ultrastructure, Colon diagnostic imaging, Endoscopy economics, Esophagus diagnostic imaging, Mice, Optics and Photonics, Endoscopy instrumentation
- Abstract
Fiber-optic endomicroscopy is a minimally invasive method to image cellular morphology in vivo. Using a coherent fiber bundle as an image relay, it allows additional imaging optics to be placed at the distal end of the fiber outside the body. In this research, we use this approach to demonstrate a compact, low-cost line-scanning confocal fluorescence microendoscope that can be constructed for <$5000. Confocal imaging is enabled without the need for mechanical scanning by synchronizing a digital light projector with the rolling shutter of a CMOS camera. Its axial performance is characterized in comparison with a nonscanned high-resolution microendoscope. We validate the optical sectioning capability of the microendoscope by imaging a two-dimensional phantom and ex vivo mouse esophageal and colon tissues. Results show that optical sectioning using this approach improves visualization of nuclear morphometry and suggest that this low-cost line-scanning microendoscope can be used to evaluate various pathological conditions., ((2017) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE).)
- Published
- 2017
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29. High-resolution microendoscopy: a point-of-care diagnostic for cervical dysplasia in low-resource settings.
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Grant BD, Fregnani JH, Possati Resende JC, Scapulatempo-Neto C, Matsushita GM, Mauad EC, Quang T, Stoler MH, Castle PE, Schmeler KM, and Richards-Kortum RR
- Subjects
- Adolescent, Adult, Aged, Brazil epidemiology, Colposcopy standards, Female, Fiber Optic Technology economics, Fiber Optic Technology standards, Health Resources standards, Humans, Hysteroscopy economics, Hysteroscopy standards, Microscopy, Fluorescence economics, Microscopy, Fluorescence standards, Middle Aged, Pilot Projects, Point-of-Care Systems standards, Retrospective Studies, Uterine Cervical Dysplasia diagnosis, Uterine Cervical Dysplasia epidemiology, Young Adult, Colposcopy economics, Health Resources economics, Medically Underserved Area, Point-of-Care Systems economics, Uterine Cervical Dysplasia economics
- Abstract
Cervical cancer is the third leading cause of cancer-related death among women in low-to-middle income countries. Pap testing and pathological services are difficult to implement under these settings. Alternative techniques for the diagnosis of cervical precancer in these settings are needed to reduce the burden of the disease. The objective of this study was to evaluate the diagnostic accuracy of a low-cost, high-resolution microendoscope imaging system in identifying precancerous lesions of the cervix in vivo. A retrospective study of 59 patients undergoing colposcopy for an abnormal Pap test was performed at Hospital de Câncer de Barretos in Brazil. All patients underwent colposcopy as per standard of care, and acetowhite lesions were recorded. High-resolution microendoscopy (HRME) images were obtained from one colposcopically normal region and from all lesions observed on colposcopy. Biopsies of abnormal areas were obtained and reviewed by three independent, blinded pathologists and compared with HRME findings. The mean nuclear area and the median nuclear eccentricity were calculated from HRME images acquired from each site. A diagnostic algorithm to distinguish histopathologically diagnosed cervical intraepithelial neoplasias of grade 2 or more severe lesions (high grade) from less severe lesions (low grade) was developed using these parameters. A test of trend was used to analyze the relationship between HRME positivity and severity of histopathogical diagnosis. Fisher's exact test was used to analyze differences in HRME positivity between high-grade and low-grade lesions. Evaluable images were obtained from 108 of 143 discrete sites. Of these, 71 sites were colposcopically normal or low grade according to histopathology and 37 were diagnosed as high grade on the basis of histopathology. Using the mean nuclear area and the median nuclear eccentricity, HRME images from 59 colposcopically abnormal sites were classified as high grade or low grade with 92% sensitivity and 77% specificity compared with histopathological findings. Increasing HRME positivity showed a significant trend with increasing severity of diagnosis (Ptrend<0.001). We found a strong association (P<0.001) between HRME positivity and a histopathological diagnosis of cervical intraepithelial neoplasia of grade 2 or higher. HRME demonstrated an accurate in-situ diagnosis of high-grade dysplasia. In low-resource settings in which colposcopy and histopathology services are severely limited or unavailable, HRME may provide a low-cost, accurate method for diagnosis of cervical precancer without the need for biopsy, allowing for a single 'screen-and-treat' approach.
- Published
- 2017
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30. Differential structured illumination microendoscopy for in vivo imaging of molecular contrast agents.
- Author
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Keahey P, Ramalingam P, Schmeler K, and Richards-Kortum RR
- Subjects
- Animals, Colon anatomy & histology, Epithelium anatomy & histology, Female, Mice, Inbred C57BL, Microspheres, Contrast Media chemistry, Endoscopy, Imaging, Three-Dimensional methods
- Abstract
Fiber optic microendoscopy has shown promise for visualization of molecular contrast agents used to study disease in vivo. However, fiber optic microendoscopes have limited optical sectioning capability, and image contrast is limited by out-of-focus light generated in highly scattering tissue. Optical sectioning techniques have been used in microendoscopes to remove out-of-focus light but reduce imaging speed or rely on bulky optical elements that prevent in vivo imaging. Here, we present differential structured illumination microendoscopy (DSIMe), a fiber optic system that can perform structured illumination in real time for optical sectioning without any opto-mechanical components attached to the distal tip of the fiber bundle. We demonstrate the use of DSIMe during in vivo fluorescence imaging in patients undergoing surgery for cervical adenocarcinoma in situ. Images acquired using DSIMe show greater contrast than standard microendoscopy, improving the ability to detect cellular atypia associated with neoplasia., Competing Interests: The authors declare no conflict of interest.
- Published
- 2016
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31. Efficacy of a low-cost bubble CPAP system in treatment of respiratory distress in a neonatal ward in Malawi.
- Author
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Kawaza K, Machen HE, Brown J, Mwanza Z, Iniguez S, Gest A, O'Brian Smith E, Oden M, Richards-Kortum RR, and Molyneux E
- Abstract
Background: Respiratory failure is a leading cause of neonatal mortality in the developing world. Bubble continuous positive airway pressure (bCPAP) is a safe, effective intervention for infants with respiratory distress and is widely used in developed countries. Because of its high cost, bCPAP is not widely utilized in low-resource settings. We evaluated the performance of a new bCPAP system to treat severe respiratory distress in a low resource setting, comparing it to nasal oxygen therapy, the current standard of care., Methods: We conducted a non-randomized convenience sample study to test the efficacy of a low-cost bCPAP system treating newborns with severe respiratory distress in the neonatal ward of Queen Elizabeth Central Hospital, in Blantyre, Malawi. Neonates weighing >1,000 g and presenting with severe respiratory distress who fulfilled inclusion criteria received nasal bCPAP if a device was available; if not, they received standard care. Clinical assessments were made during treatment and outcomes compared for the two groups., Findings: 87 neonates (62 bCPAP, 25 controls) were recruited. Survival rate for neonates receiving bCPAP was 71.0% (44/62) compared with 44.0% (11/25) for controls. 65.5% (19/29) of very low birth weight neonates receiving bCPAP survived to discharge compared to 15.4% (1/13) of controls. 64.6% (31/48) of neonates with respiratory distress syndrome (RDS) receiving bCPAP survived to discharge, compared to 23.5% (4/17) of controls. 61.5% (16/26) of neonates with sepsis receiving bCPAP survived to discharge, while none of the seven neonates with sepsis in the control group survived., Interpretation: Use of a low-cost bCPAP system to treat neonatal respiratory distress resulted in 27% absolute improvement in survival. The beneficial effect was greater for neonates with very low birth weight, RDS, or sepsis. Implementing appropriate bCPAP devices could reduce neonatal mortality in developing countries.
- Published
- 2016
32. In vivo white light and contrast-enhanced vital-dye fluorescence imaging of Barrett's-related neoplasia in a single-endoscopic insertion.
- Author
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Tang Y, Carns J, Polydorides AD, Anandasabapathy S, and Richards-Kortum RR
- Subjects
- Animals, Barrett Esophagus diagnostic imaging, Esophagoscopy instrumentation, Mice, Pilot Projects, Esophageal Neoplasms diagnostic imaging, Esophagoscopy methods, Optical Imaging
- Abstract
A modular video endoscope is developed to enable both white light imaging (WLI) and vital-dye fluorescence imaging (VFI) in a single-endoscopic insertion for the early detection of cancer in Barrett’s esophagus (BE). We demonstrate that VFI can be achieved in conjunction with white light endoscopy, where appropriate white balance is used to correct for the presence of the emission filter. In VFI mode, a contrast enhancement feature is implemented in real time to further highlight glandular patterns in BE and related malignancies without introducing artifacts. In a pilot study, we demonstrate accurate correlation of images in two widefield modalities, with representative images showing the disruption and effacement of glandular architecture associated with cancer development in BE. VFI images of these alterations exhibit enhanced contrast when compared to WLI. Results suggest that the usefulness of VFI in the detection of BE-related neoplasia should be further evaluated in future in vivo studies.
- Published
- 2016
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33. Physical and chemical stability of proflavine contrast agent solutions for early detection of oral cancer.
- Author
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Kawedia JD, Zhang YP, Myers AL, Richards-Kortum RR, Kramer MA, Gillenwater AM, and Culotta KS
- Subjects
- Drug Storage methods, Mouth Neoplasms drug therapy, Pharmaceutical Solutions therapeutic use, Proflavine therapeutic use, Refrigeration methods, Contrast Media chemistry, Drug Stability, Pharmaceutical Solutions chemistry, Proflavine chemistry
- Abstract
Background and Purpose: Proflavine hemisulfate solution is a fluorescence contrast agent to visualize cell nuclei using high-resolution optical imaging devices such as the high-resolution microendoscope. These devices provide real-time imaging to distinguish between normal versus neoplastic tissue. These images could be helpful for early screening of oral cancer and its precursors and to determine accurate margins of malignant tissue for ablative surgery. Extemporaneous preparation of proflavine solution for these diagnostic procedures requires preparation in batches and long-term storage to improve compounding efficiency in the pharmacy. However, there is a paucity of long-term stability data for proflavine contrast solutions., Methods: The physical and chemical stability of 0.01% (10 mg/100 ml) proflavine hemisulfate solutions prepared in sterile water was determined following storage at refrigeration (4-8℃) and room temperature (23℃). Concentrations of proflavine were measured at predetermined time points up to 12 months using a validated stability-indicating high-performance liquid chromatography method., Results: Proflavine solutions stored under refrigeration were physically and chemically stable for at least 12 months with concentrations ranging from 95% to 105% compared to initial concentration. However, in solutions stored at room temperature increased turbidity and particulates were observed in some of the tested vials at 9 months and 12 months with peak particle count reaching 17-fold increase compared to baseline. Solutions stored at room temperature were chemically stable up to six months (94-105%)., Conclusion: Proflavine solutions at concentration of 0.01% were chemically and physically stable for at least 12 months under refrigeration. The solution was chemically stable for six months when stored at room temperature. We recommend long-term storage of proflavine solutions under refrigeration prior to diagnostic procedure., (© The Author(s) 2014.)
- Published
- 2016
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34. Quantitative analysis of high-resolution microendoscopic images for diagnosis of neoplasia in patients with Barrett's esophagus.
- Author
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Shin D, Lee MH, Polydorides AD, Pierce MC, Vila PM, Parikh ND, Rosen DG, Anandasabapathy S, and Richards-Kortum RR
- Subjects
- Adenocarcinoma diagnosis, Barrett Esophagus diagnosis, Esophageal Neoplasms diagnosis, Esophagoscopy, Humans, Image Processing, Computer-Assisted, Intravital Microscopy, Pilot Projects, Sensitivity and Specificity, Adenocarcinoma pathology, Algorithms, Barrett Esophagus pathology, Esophageal Neoplasms pathology, Esophagus pathology
- Abstract
Background and Aims: Previous studies show that microendoscopic images can be interpreted visually to identify the presence of neoplasia in patients with Barrett's esophagus (BE), but this approach is subjective and requires clinical expertise. This study describes an approach for quantitative image analysis of microendoscopic images to identify neoplastic lesions in patients with BE., Methods: Images were acquired from 230 sites from 58 patients by using a fiberoptic high-resolution microendoscope during standard endoscopic procedures. Images were analyzed by a fully automated image processing algorithm, which automatically selected a region of interest and calculated quantitative image features. Image features were used to develop an algorithm to identify the presence of neoplasia; results were compared with a histopathology diagnosis., Results: A sequential classification algorithm that used image features related to glandular and cellular morphology resulted in a sensitivity of 84% and a specificity of 85%. Applying the algorithm to an independent validation set resulted in a sensitivity of 88% and a specificity of 85%., Conclusions: This pilot study demonstrates that automated analysis of microendoscopic images can provide an objective, quantitative framework to assist clinicians in evaluating esophageal lesions from patients with BE. (, Clinical Trial Registration Number: NCT01384227 and NCT02018367.)., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
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35. Outcomes of Patients with Respiratory Distress Treated with Bubble CPAP on a Pediatric Ward in Malawi.
- Author
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Machen HE, Mwanza ZV, Brown JK, Kawaza KM, Newberry L, Richards-Kortum RR, Oden ZM, and Molyneux EM
- Subjects
- Bronchiolitis pathology, Continuous Positive Airway Pressure economics, Cost-Benefit Analysis, Female, Humans, Infant, Infant, Newborn, Malawi epidemiology, Male, Oxygen Inhalation Therapy, Pneumocystis carinii, Pneumonia pathology, Respiratory Distress Syndrome, Newborn mortality, Respiratory Distress Syndrome, Newborn pathology, Survival Analysis, Survival Rate trends, Treatment Outcome, Bronchiolitis therapy, Continuous Positive Airway Pressure instrumentation, Continuous Positive Airway Pressure methods, Pneumonia therapy, Respiratory Distress Syndrome, Newborn therapy
- Abstract
Objective: To describe the outcomes of infants and young children with respiratory distress when treated with a novel, low-cost, stand-alone bubble Continuous Positive Airway Pressure (bCPAP) system in a resource-limited setting., Methods: A non-randomized, convenience sample study in a pediatric unit in Blantyre, Malawi, 2013. Patients weighing ≤10 kg with respiratory distress were eligible. We compared outcomes for patients with bronchiolitis, pneumonia and Pneumocystis jiroveci pneumonia (PJP) after treatment with bCPAP., Results: Seventy percent of patients treated with bCPAP survived. Outcomes were best for patients with bronchiolitis and worst for those with PJP. Most survivors (80%) showed improvement within 24 h. All treating physicians found bCPAP useful, leading to a change in practice., Conclusions: Bubble CPAP was most beneficial to patients with bronchiolitis. Children, who were going to get well, tended to get well quickly. Physicians believed the bCPAP system provided a higher level of care than nasal oxygen., (© The Author [2015]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2015
- Full Text
- View/download PDF
36. Drop-to-drop variation in the cellular components of fingerprick blood: implications for point-of-care diagnostic development.
- Author
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Bond MM and Richards-Kortum RR
- Subjects
- Fingers, Humans, Pilot Projects, Reproducibility of Results, Blood Specimen Collection standards, Hematologic Tests standards, Point-of-Care Systems standards
- Abstract
Objectives: Blood obtained via fingerprick is commonly used in point-of-care assays, but few studies have assessed variability in parameters obtained from successive drops of fingerprick blood, which may cause problems for clinical decision making and for assessing accuracy of point-of-care tests., Methods: We used a hematology analyzer to analyze the hemoglobin concentration, total WBC count, three-part WBC differential, and platelet count in six successive drops of blood collected from one fingerprick from each of 11 donors, and we used a hemoglobinometer to measure the hemoglobin concentration of 10 drops of fingerprick blood from each of 7 donors., Results: The average percent coefficient of variation (CV) for successive drops of fingerprick blood was higher by up to 3.4 times for hemoglobin, 5.7 times for WBC count, 3 times for lymphocyte count, 7.7 times for granulocyte count, and 4 times for platelets than in venous controls measured using a hematology analyzer. The average percent CV for fingerprick blood was up to 5 times higher for hemoglobin than venous blood measured using a point-of-care hemoglobinometer. Fluctuations in blood parameters with increasing volume of fingerprick blood are within instrument variability for volumes equal to or greater than 60 to 100 μL., Conclusions: These data suggest caution when using measurements from a single drop of fingerprick blood., (Copyright© by the American Society for Clinical Pathology.)
- Published
- 2015
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37. A paper and plastic device for the combined isothermal amplification and lateral flow detection of Plasmodium DNA.
- Author
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Cordray MS and Richards-Kortum RR
- Subjects
- Costs and Cost Analysis, DNA, Protozoan genetics, DNA, Ribosomal genetics, Humans, Molecular Diagnostic Techniques economics, Nucleic Acid Amplification Techniques economics, Paper, Plastics, RNA, Ribosomal, 18S genetics, Time Factors, DNA, Protozoan analysis, Equipment and Supplies, Malaria diagnosis, Molecular Diagnostic Techniques methods, Nucleic Acid Amplification Techniques methods, Plasmodium genetics
- Abstract
Background: Isothermal amplification techniques are emerging as a promising method for malaria diagnosis since they are capable of detecting extremely low concentrations of parasite target while mitigating the need for infrastructure and training required by other nucleic acid based tests. Recombinase polymerase amplification (RPA) is promising for further development since it operates in a short time frame (<30 min) and produces a product that can be visually detected on a lateral flow dipstick. A self-sealing paper and plastic system that performs both the amplification and detection of a malaria DNA sequence is presented., Methods: Primers were designed using the NCBI nBLAST tools and screened using gel electrophoresis. Paper and plastic devices were prototyped using commercial design software and parts were cut using a laser cutter and assembled by hand. Synthetic copies of the Plasmodium 18S gene were spiked into solution and used as targets for the RPA reaction. To test the performance of the device the same samples spiked with synthetic target were run in parallel both in the paper and plastic devices and using conventional bench top methods., Results: Novel RPA primers were developed that bind to sequences present in the four species of Plasmodium which infect humans. The paper and plastic devices were found to be capable of detecting as few as 5 copies/µL of synthetic Plasmodium DNA (50 copies total), comparable to the same reaction run on the bench top. The devices produce visual results in an hour, cost approximately $1, and are self-contained once the device is sealed., Conclusions: The device was capable of carrying out the RPA reaction and detecting meaningful amounts of synthetic Plasmodium DNA in a self-sealing and self-contained device. This device may be a step towards making nucleic acid tests more accessible for malaria detection.
- Published
- 2015
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38. Detection of Entamoeba histolytica by Recombinase Polymerase Amplification.
- Author
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Nair G, Rebolledo M, White AC Jr, Crannell Z, Richards-Kortum RR, Pinilla AE, Ramírez JD, López MC, and Castellanos-Gonzalez A
- Subjects
- DNA, Protozoan metabolism, Entamoeba, Entamoebiasis parasitology, Humans, Real-Time Polymerase Chain Reaction, Entamoeba histolytica, Entamoebiasis diagnosis, Nucleic Acid Amplification Techniques methods, Recombinases metabolism
- Abstract
Amebiasis is an important cause of diarrheal disease worldwide and has been associated with childhood malnutrition. Traditional microscopy approaches are neither sensitive nor specific for Entamoeba histolytica. Antigen assays are more specific, but many cases are missed unless tested by molecular methods. Although polymerase chain reaction (PCR) is effective, the need for sophisticated, expensive equipment, infrastructure, and trained personnel limits its usefulness, especially in the resource-limited, endemic areas. Here, we report development of a recombinase polymerase amplification (RPA) method to detect E. histolytica specifically. Using visual detection by lateral flow (LF), the test was highly sensitive and specific and could be performed without additional equipment. The availability of this inexpensive, sensitive, and field-applicable diagnostic test could facilitate rapid diagnosis and treatment of amebiasis in endemic regions., (© The American Society of Tropical Medicine and Hygiene.)
- Published
- 2015
- Full Text
- View/download PDF
39. New technologies for essential newborn care in under-resourced areas: what is needed and how to deliver it.
- Author
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Maynard KR, Causey L, Kawaza K, Dube Q, Lufesi N, Maria Oden Z, Richards-Kortum RR, and Molyneux EM
- Subjects
- Global Health, Humans, Infant, Newborn, Infant, Newborn, Diseases prevention & control, Delivery of Health Care methods, Health Services Accessibility, Health Services Administration, Infant Health, Infant, Newborn, Diseases diagnosis, Infant, Newborn, Diseases therapy
- Abstract
Globally, the largest contributors to neonatal mortality are preterm birth, intrapartum complications and infection. Many of these deaths could be prevented by providing temperature stability, respiratory support, hydration and nutrition; preventing and treating infections; and diagnosing and treating neonatal jaundice and hypoglycaemia. Most neonatal health-care technologies which help to accomplish these tasks are designed for high-income countries and are either unavailable or unsuitable in low-resource settings, preventing many neonates from receiving the gold standard of care. There is an urgent need for neonatal health-care technologies which are low-cost, robust, simple to use and maintain, affordable and able to operate from various power supplies. Several technologies have been designed to meet these requirements or are currently under development; however, unmet technology needs remain. The distribution of an integrated set of technologies, rather than separate components, is essential for effective implementation and a substantial impact on neonatal health. Close collaboration between stakeholders at all stages of the development process and an increased focus on implementation research are necessary for effective and sustainable implementation.
- Published
- 2015
- Full Text
- View/download PDF
40. Low-Cost High-Resolution Microendoscopy for the Detection of Esophageal Squamous Cell Neoplasia: An International Trial.
- Author
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Protano MA, Xu H, Wang G, Polydorides AD, Dawsey SM, Cui J, Xue L, Zhang F, Quang T, Pierce MC, Shin D, Schwarz RA, Bhutani MS, Lee M, Parikh N, Hur C, Xu W, Moshier E, Godbold J, Mitcham J, Hudson C, Richards-Kortum RR, and Anandasabapathy S
- Subjects
- Adult, Aged, Aged, 80 and over, Biopsy, China, Esophageal Neoplasms pathology, Female, Humans, Iodides, Male, Middle Aged, Neoplasms, Squamous Cell pathology, Precancerous Conditions pathology, Prospective Studies, Sensitivity and Specificity, United States, Early Detection of Cancer methods, Esophageal Neoplasms diagnosis, Esophagoscopy methods, Neoplasms, Squamous Cell diagnosis, Optical Imaging methods, Precancerous Conditions diagnosis
- Abstract
Background & Aims: Esophageal squamous cell neoplasia has a high mortality rate as a result of late detection. In high-risk regions such as China, screening is performed by Lugol's chromoendoscopy (LCE). LCE has low specificity, resulting in unnecessary tissue biopsy with a subsequent increase in procedure cost and risk. The purpose of this study was to evaluate the accuracy of a novel, low-cost, high-resolution microendoscope (HRME) as an adjunct to LCE., Methods: In this prospective trial, 147 consecutive high-risk patients were enrolled from 2 US and 2 Chinese tertiary centers. Three expert and 4 novice endoscopists performed white-light endoscopy followed by LCE and HRME. All optical images were compared with the gold standard of histopathology., Results: By using a per-biopsy analysis, the sensitivity of LCE vs LCE + HRME was 96% vs 91% (P = .0832), specificity was 48% vs 88% (P < .001), positive predictive value was 22% vs 45% (P < .0001), negative predictive value was 98% vs 98% (P = .3551), and overall accuracy was 57% vs 90% (P < .001), respectively. By using a per-patient analysis, the sensitivity of LCE vs LCE + HRME was 100% vs 95% (P = .16), specificity was 29% vs 79% (P < .001), positive predictive value was 32% vs 60%, 100% vs 98%, and accuracy was 47% vs 83% (P < .001). With the use of HRME, 136 biopsies (60%; 95% confidence interval, 53%-66%) could have been spared, and 55 patients (48%; 95% confidence interval, 38%-57%) could have been spared any biopsy., Conclusions: In this trial, HRME improved the accuracy of LCE for esophageal squamous cell neoplasia screening and surveillance. HRME may be a cost-effective optical biopsy adjunct to LCE, potentially reducing unnecessary biopsies and facilitating real-time decision making in globally underserved regions. ClinicalTrials.gov, NCT 01384708., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
41. High-resolution microendoscopy for esophageal cancer screening in China: A cost-effectiveness analysis.
- Author
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Hur C, Choi SE, Kong CY, Wang GQ, Xu H, Polydorides AD, Xue LY, Perzan KE, Tramontano AC, Richards-Kortum RR, and Anandasabapathy S
- Subjects
- Age Factors, Aged, Aged, 80 and over, Carcinoma, Squamous Cell mortality, China epidemiology, Coloring Agents economics, Cost-Benefit Analysis, Early Detection of Cancer methods, Esophageal Neoplasms mortality, Esophageal Squamous Cell Carcinoma, Esophagoscopy methods, Female, Humans, Image Enhancement, Iodides economics, Male, Markov Chains, Microscopy methods, Middle Aged, Models, Economic, Predictive Value of Tests, Prognosis, Quality of Life, Quality-Adjusted Life Years, Retrospective Studies, Time Factors, Carcinoma, Squamous Cell economics, Carcinoma, Squamous Cell pathology, Early Detection of Cancer economics, Esophageal Neoplasms economics, Esophageal Neoplasms pathology, Esophagoscopy economics, Health Care Costs, Microscopy economics
- Abstract
Aim: To study the cost-effectiveness of high-resolution microendoscopy (HRME) in an esophageal squamous cell carcinoma (ESCC) screening program in China., Methods: A decision analytic Markov model of ESCC was developed. Separate model analyses were conducted for cohorts consisting of an average-risk population or a high-risk population in China. Hypothetical 50-year-old individuals were followed until age 80 or death. We compared three different strategies for both cohorts: (1) no screening; (2) standard endoscopic screening with Lugol's iodine staining; and (3) endoscopic screening with Lugol's iodine staining and an HRME. Model parameters were estimated from the literature as well as from GLOBOCAN, the Cancer Incidence and Mortality Worldwide cancer database. Health states in the model included non-neoplasia, mild dysplasia, moderate dysplasia, high-grade dysplasia, intramucosal carcinoma, operable cancer, inoperable cancer, and death. Separate ESCC incidence transition rates were generated for the average-risk and high-risk populations. Costs in Chinese currency were converted to international dollars (I$) and were adjusted to 2012 dollars using the Consumer Price Index., Results: The main outcome measurements for this study were quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER). For the average-risk population, the HRME screening strategy produced 0.043 more QALYs than the no screening strategy at an additional cost of I$646, resulting in an ICER of I$11808 per QALY gained. Standard endoscopic screening was weakly dominated. Among the high-risk population, when the HRME screening strategy was compared with the standard screening strategy, the ICER was I$8173 per QALY. For both the high-risk and average-risk screening populations, the HRME screening strategy appeared to be the most cost-effective strategy, producing ICERs below the willingness-to-pay threshold, I$23500 per QALY. One-way sensitivity analysis showed that, for the average-risk population, higher specificity of Lugol's iodine (> 40%) and lower specificity of HRME (< 70%) could make Lugol's iodine screening cost-effective. For the high-risk population, the results of the model were not substantially affected by varying the follow-up rate after Lugol's iodine screening, Lugol's iodine test characteristics (sensitivity and specificity), or HRME specificity., Conclusion: The incorporation of HRME into an ESCC screening program could be cost-effective in China. Larger studies of HRME performance are needed to confirm these findings.
- Published
- 2015
- Full Text
- View/download PDF
42. Optimizing modulation frequency for structured illumination in a fiber-optic microendoscope to image nuclear morphometry in columnar epithelium.
- Author
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Keahey PA, Tkaczyk TS, Schmeler KM, and Richards-Kortum RR
- Abstract
Fiber-optic microendoscopes have shown promise to image the changes in nuclear morphometry that accompany the development of precancerous lesions in tissue with squamous epithelium such as in the oral mucosa and cervix. However, fiber-optic microendoscopy image contrast is limited by out-of-focus light generated by scattering within tissue. The scattering coefficient of tissues with columnar epithelium can be greater than that of squamous epithelium resulting in decreased image quality. To address this challenge, we present a small and portable microendoscope system capable of performing optical sectioning using structured illumination (SI) in real-time. Several optical phantoms were developed and used to quantify the sectioning capabilities of the system. Columnar epithelium from cervical tissue specimens was then imaged ex vivo, and we demonstrate that the addition of SI achieves higher image contrast, enabling visualization of nuclear morphology.
- Published
- 2015
- Full Text
- View/download PDF
43. Quantitative analysis of high-resolution microendoscopic images for diagnosis of esophageal squamous cell carcinoma.
- Author
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Shin D, Protano MA, Polydorides AD, Dawsey SM, Pierce MC, Kim MK, Schwarz RA, Quang T, Parikh N, Bhutani MS, Zhang F, Wang G, Xue L, Wang X, Xu H, Anandasabapathy S, and Richards-Kortum RR
- Subjects
- Biopsy, China, Esophageal Squamous Cell Carcinoma, Hospitals, Humans, Mass Screening methods, United States, Carcinoma, Squamous Cell diagnosis, Carcinoma, Squamous Cell pathology, Esophageal Neoplasms diagnosis, Esophageal Neoplasms pathology, Esophagoscopy methods, Image Processing, Computer-Assisted methods
- Abstract
Background & Aims: High-resolution microendoscopy is an optical imaging technique with the potential to improve the accuracy of endoscopic screening for esophageal squamous neoplasia. Although these microscopic images can be interpreted readily by trained personnel, quantitative image analysis software could facilitate the use of this technology in low-resource settings. In this study, we developed and evaluated quantitative image analysis criteria for the evaluation of neoplastic and non-neoplastic squamous esophageal mucosa., Methods: We performed an image analysis of 177 patients undergoing standard upper endoscopy for screening or surveillance of esophageal squamous neoplasia, using high-resolution microendoscopy, at 2 hospitals in China and at 1 hospital in the United States from May 2010 to October 2012. Biopsy specimens were collected from imaged sites (n = 375), and a consensus diagnosis was provided by 2 expert gastrointestinal pathologists and used as the standard., Results: Quantitative information from the high-resolution images was used to develop an algorithm to identify high-grade squamous dysplasia or invasive squamous cell cancer, based on histopathology findings. Optimal performance was obtained using the mean nuclear area as the basis for classification, resulting in sensitivities and specificities of 93% and 92% in the training set, 87% and 97% in the test set, and 84% and 95% in an independent validation set, respectively., Conclusions: High-resolution microendoscopy with quantitative image analysis can aid in the identification of esophageal squamous neoplasia. Use of software-based image guides may overcome issues of training and expertise in low-resource settings, allowing for widespread use of these optical biopsy technologies., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
44. Low-Cost Disposable Cartridge for Performing a White Blood Cell Count and Partial Differential at the Point-of-Care.
- Author
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Majors CE, Pawlowski ME, Tkaczyk T, and Richards-Kortum RR
- Abstract
Being able to perform a white blood cell (WBC) count and differential is a crucial laboratory test for basic diagnostic practices. In this paper, we demonstrate proof of concept results for a disposable cartridge that could be used to perform a WBC count and 3-part differential at the point-of-care. The cartridge is composed of a glass slide, a layer of transfer tape, and a glass cover slip and incorporates acridine orange for cell staining and sub-type differentiation; the stained blood is then imaged, and image analysis techniques return a WBC count and 3-part differential. The cartridge was tested on a laboratory microscope with 3 normal samples, and had promising results with 85.7% of images resulting in a WBC count with ±15% of the true value. Further, the 3-part differential concentrations determined using the disposable cartridge had strong correlations with the true concentrations (R
2 values of 0.9986, 0.9421, and 0.6942 for granulocytes, lymphocytes, and monocytes, respectively). Preliminary designs for a low-cost, portable microscope have been created and are currently being prototyped.- Published
- 2014
- Full Text
- View/download PDF
45. Efficacy of a low-cost bubble CPAP system in treatment of respiratory distress in a neonatal ward in Malawi.
- Author
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Kawaza K, Machen HE, Brown J, Mwanza Z, Iniguez S, Gest A, Smith EO, Oden M, Richards-Kortum RR, and Molyneux E
- Subjects
- Continuous Positive Airway Pressure economics, Continuous Positive Airway Pressure instrumentation, Developing Countries, Female, Humans, Infant, Infant, Newborn, Infant, Premature, Infant, Very Low Birth Weight, Malawi, Male, Oxygen Inhalation Therapy, Respiratory Distress Syndrome, Newborn mortality, Respiratory Distress Syndrome, Newborn pathology, Survival Analysis, Treatment Outcome, Continuous Positive Airway Pressure methods, Respiratory Distress Syndrome, Newborn therapy
- Abstract
Background: Respiratory failure is a leading cause of neonatal mortality in the developing world. Bubble continuous positive airway pressure (bCPAP) is a safe, effective intervention for infants with respiratory distress and is widely used in developed countries. Because of its high cost, bCPAP is not widely utilized in low-resource settings. We evaluated the performance of a new bCPAP system to treat severe respiratory distress in a low resource setting, comparing it to nasal oxygen therapy, the current standard of care., Methods: We conducted a non-randomized convenience sample study to test the efficacy of a low-cost bCPAP system treating newborns with severe respiratory distress in the neonatal ward of Queen Elizabeth Central Hospital, in Blantyre, Malawi. Neonates weighing >1,000 g and presenting with severe respiratory distress who fulfilled inclusion criteria received nasal bCPAP if a device was available; if not, they received standard care. Clinical assessments were made during treatment and outcomes compared for the two groups., Findings: 87 neonates (62 bCPAP, 25 controls) were recruited. Survival rate for neonates receiving bCPAP was 71.0% (44/62) compared with 44.0% (11/25) for controls. 65.5% (19/29) of very low birth weight neonates receiving bCPAP survived to discharge compared to 15.4% (1/13) of controls. 64.6% (31/48) of neonates with respiratory distress syndrome (RDS) receiving bCPAP survived to discharge, compared to 23.5% (4/17) of controls. 61.5% (16/26) of neonates with sepsis receiving bCPAP survived to discharge, while none of the seven neonates with sepsis in the control group survived., Interpretation: Use of a low-cost bCPAP system to treat neonatal respiratory distress resulted in 27% absolute improvement in survival. The beneficial effect was greater for neonates with very low birth weight, RDS, or sepsis. Implementing appropriate bCPAP devices could reduce neonatal mortality in developing countries.
- Published
- 2014
- Full Text
- View/download PDF
46. Novel open-source electronic medical records system for palliative care in low-resource settings.
- Author
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Shah KG, Slough TL, Yeh PT, Gombwa S, Kiromera A, Oden ZM, and Richards-Kortum RR
- Abstract
Background: The need for palliative care in sub-Saharan Africa is staggering: this region shoulders over 67% of the global burden of HIV/AIDS and cancer. However, provisions for these essential services remain limited and poorly integrated with national health systems in most nations. Moreover, the evidence base for palliative care in the region remains scarce. This study chronicles the development and evaluation of DataPall, an open-source electronic medical records system that can be used to track patients, manage data, and generate reports for palliative care providers in these settings.DataPall was developed using design criteria encompassing both functional and technical objectives articulated by hospital leaders and palliative care staff at a leading palliative care center in Malawi. The database can be used with computers that run Windows XP SP 2 or newer, and does not require an internet connection for use. Subsequent to its development and implementation in two hospitals, DataPall was tested among both trained and untrained hospital staff populations on the basis of its usability with comparison to existing paper records systems as well as on the speed at which users could perform basic database functions. Additionally, all participants evaluated this program on a standard system usability scale., Results: In a study of health professionals in a Malawian hospital, DataPall enabled palliative care providers to find patients' appointments, on average, in less than half the time required to locate the same record in current paper records. Moreover, participants generated customizable reports documenting patient records and comprehensive reports on providers' activities with little training necessary. Participants affirmed this ease of use on the system usability scale., Conclusions: DataPall is a simple, effective electronic medical records system that can assist in developing an evidence base of clinical data for palliative care in low resource settings. The system is available at no cost, is specifically designed to chronicle care in the region, and is catered to meet the technical needs and user specifications of such facilities.
- Published
- 2013
- Full Text
- View/download PDF
47. Modular video endoscopy for in vivo cross-polarized and vital-dye fluorescence imaging of Barrett's-associated neoplasia.
- Author
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Thekkek N, Pierce MC, Lee MH, Polydorides AD, Flores RM, Anandasabapathy S, and Richards-Kortum RR
- Subjects
- Esophagoscopy instrumentation, Fluorescent Dyes, Humans, Optical Phenomena, Pilot Projects, Video Recording, Adenocarcinoma diagnosis, Barrett Esophagus diagnosis, Esophageal Neoplasms diagnosis, Esophagoscopy methods, Optical Imaging methods
- Abstract
A modular video endoscope is developed and tested to allow imaging in different modalities. This system incorporates white light imaging (WLI), cross-polarized imaging (CPI), and vital-dye fluorescence imaging (VFI), using interchangeable filter modules. CPI and VFI are novel endoscopic modalities that probe mucosal features associated with Barrett's neoplasia. CPI enhances vasculature, while VFI enhances glandular architecture. In this pilot study, we demonstrate the integration of these modalities by imaging areas of Barrett's metaplasia and neoplasia in an esophagectomy specimen. We verify that those key image features are also observed during an in vivo surveillance procedure. CPI images demonstrate improved visualization of branching blood vessels associated with neoplasia. VFI images show glandular architecture with increased glandular effacement associated with neoplasia. Results suggests that important pathologic features seen in CPI and VFI are not visible during standard endoscopic white light imaging, and thus the modalities may be useful in future in vivo studies for discriminating neoplasia from Barrett's metaplasia. We further demonstrate that the integrated WLI/CPI/VFI endoscope is compatible with complementary high-resolution endomicroscopy techniques such as the high-resolution microendoscope, potentially enabling two-step ("red-flag" widefield plus confirmatory high-resolution imaging) protocols to be enhanced.
- Published
- 2013
- Full Text
- View/download PDF
48. Gold nanoparticle aggregation for quantification of oligonucleotides: optimization and increased dynamic range.
- Author
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Cordray MS, Amdahl M, and Richards-Kortum RR
- Subjects
- Humans, Light, Scattering, Radiation, Gold chemistry, Nanoparticles chemistry, Oligonucleotides analysis, Oligonucleotides isolation & purification
- Abstract
A variety of assays have been proposed to detect small quantities of nucleic acids at the point of care. One approach relies on target-induced aggregation of gold nanoparticles functionalized with oligonucleotide sequences complementary to adjacent regions on the targeted sequence. In the presence of the target sequence, the gold nanoparticles aggregate, producing an easily detectable shift in the optical scattering properties of the solution. The major limitations of this assay are that it requires heating and that long incubation times are needed to produce a result. This study aimed to optimize the assay conditions and optical readout, with the goals of eliminating the need for heating and reducing the time to result without sacrificing sensitivity or dynamic range. By optimizing assay conditions and measuring the spectrum of scattered light at the end point of incubation, we found that the assay is capable of producing quantifiable results at room temperature in 30min with a linear dynamic range spanning 150amol to 15fmol of target. If changes in light scattering are measured dynamically during the incubation process, the linear range can be expanded 2-fold, spanning 50amol to 500fmol, while decreasing the time to result to 10min., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
49. A paper and plastic device for performing recombinase polymerase amplification of HIV DNA.
- Author
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Rohrman BA and Richards-Kortum RR
- Subjects
- Dried Blood Spot Testing, Humans, Infant, Paper, Plastics, Point-of-Care Systems, DNA, Viral analysis, DNA-Directed DNA Polymerase metabolism, HIV genetics, Nucleic Acid Amplification Techniques, Recombinases metabolism
- Abstract
Despite the importance of early diagnosis and treatment of HIV, only a small fraction of HIV-exposed infants in low- and middle-income countries are tested for the disease. The gold standard for early infant diagnosis, DNA PCR, requires resources that are unavailable in poor settings, and no point-of-care HIV DNA test is currently available. We have developed a device constructed of layers of paper, glass fiber, and plastic that is capable of performing isothermal, enzymatic amplification of HIV DNA. The device is inexpensive, small, light-weight, and easy to assemble. The device stores lyophilized enzymes, facilitates mixing of reaction components, and supports recombinase polymerase amplification in five steps of operation. Using commercially available lateral flow strips as a detection method, we demonstrate the ability of our device to amplify 10 copies of HIV DNA to detectable levels in 15 min. Our results suggest that our device, which is designed to be used after DNA extraction from dried-blood spots, may serve in conjunction with lateral flow strips as part of a point-of-care HIV DNA test to be used in low resource settings.
- Published
- 2012
- Full Text
- View/download PDF
50. Emerging nucleic acid-based tests for point-of-care detection of malaria.
- Author
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Cordray MS and Richards-Kortum RR
- Subjects
- Animals, Humans, Malaria parasitology, Nucleic Acid Amplification Techniques economics, Nucleic Acid Amplification Techniques standards, Plasmodium genetics, Malaria diagnosis, Nucleic Acid Amplification Techniques methods, Parasitemia diagnosis, Plasmodium isolation & purification, Point-of-Care Systems
- Abstract
Malaria remains a serious disease in the developing world. There is a growing consensus that new diagnostics are needed in low-resource settings. The ideal malaria diagnostic should be able to speciate; measure parasitemia; low-cost, quick, and simple to use; and capable of detecting low-level infections. A promising development are nucleic acid tests (NATs) for the diagnosis of malaria, which are well suited for point-of-care use because of their ability to detect low-level infections and speciate, and because they have high sensitivity and specificity. The greatest barrier to NAT use in the past has been its relatively high cost, and the amount of infrastructure required in the form of equipment, stable power, and reagent storage. This review describes recent developments to decrease the cost and run time, and increase the ease of use of NAT while maintaining their high sensitivity and specificity and low limit of detection at the point-of-care.
- Published
- 2012
- Full Text
- View/download PDF
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