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1.  Optical systems for point-of-care diagnostic instrumentation: analysis of imaging performance and cost 
Annals of biomedical engineering  2013;42(1):10.1007/s10439-013-0918-z.
One of the key elements in point-of-care (POC) diagnostic test instrumentation is the optical system required for signal detection and / or imaging. Many tests which use fluorescence, absorbance, or colorimetric optical signals are under development for management of infectious diseases in resource limited settings, where the overall size and cost of the device is of critical importance. At present, high-performance lenses are expensive to fabricate and difficult to obtain commercially, presenting barriers for developers of in vitro POC tests or microscopic image-based diagnostics. We recently described a compact “hybrid” objective lens incorporating both glass and plastic optical elements, with a numerical aperture of 1.0 and field-of-view of 250 m. This design concept may potentially enable mass-production of high-performance, low-cost optical systems which can be easily incorporated in the readout path of existing and emerging POC diagnostic assays.
In this paper, we evaluate the biological imaging performance of these lens systems in three broad POC diagnostic application areas; (1) bright field microscopy of histopathology slides, (2) cytologic examination of blood smears, and (3) immunofluorescence imaging. We also break down the fabrication costs and draw comparisons with other miniature optical systems. The hybrid lenses provided images with quality comparable to conventional microscopy, enabling examination of neoplastic pathology and infectious parasites including malaria and cryptosporidium. We describe how these components can be produced at below $10 per unit in full-scale production quantities, making these systems well suited for use within POC diagnostic instrumentation.
PMCID: PMC3872497  PMID: 24097204
POC optics; Miniature optics; Cost assessment; Diagnostic imaging performance
2.  Vital-dye-enhanced multimodal imaging of neoplastic progression in a mouse model of oral carcinogenesis 
Journal of Biomedical Optics  2013;18(12):126017.
In this longitudinal study, a mouse model of 4-nitroquinoline 1-oxide chemically induced tongue carcinogenesis was used to assess the ability of optical imaging with exogenous and endogenous contrast to detect neoplastic lesions in a heterogeneous mucosal surface. Widefield autofluorescence and fluorescence images of intact 2-NBDG-stained and proflavine-stained tissues were acquired at multiple time points in the carcinogenesis process. Confocal fluorescence images of transverse fresh tissue slices from the same specimens were acquired to investigate how changes in tissue microarchitecture affect widefield fluorescence images of intact tissue. Widefield images were analyzed to develop and evaluate an algorithm to delineate areas of dysplasia and cancer. A classification algorithm for the presence of neoplasia based on the mean fluorescence intensity of 2-NBDG staining and the standard deviation of the fluorescence intensity of proflavine staining was found to separate moderate dysplasia, severe dysplasia, and cancer from non-neoplastic regions of interest with 91% sensitivity and specificity. Results suggest this combination of noninvasive optical imaging modalities can be used in vivo to discriminate non-neoplastic from neoplastic tissue in this model with the potential to translate this technology to the clinic.
PMCID: PMC3869894  PMID: 24362926
optical imaging; fluorescence; microscopy; carcinogenesis; mouse cancer model; contrast agents
3.  Cost-effectiveness analysis of a low-cost bubble CPAP device in providing ventilatory support for neonates in Malawi – a preliminary report 
BMC Pediatrics  2014;14(1):288.
A low-cost bubble continuous positive airway pressure (bCPAP) device has been shown to be an excellent clinical alternative to nasal oxygen for the care of neonates with respiratory difficulty. However, the delivery of bCPAP requires more resources than the current routine care using nasal oxygen. We performed an economic evaluation to determine the cost-effectiveness of a low-cost bCPAP device in providing ventilatory support for neonates in Malawi.
We used patient-level clinical data from a previously published non-randomized controlled study. Economic data were based on the purchase price of supplies and equipment, adjusted for shelf life, as well as hospital cost data from the World Health Organization. Costs and benefits were discounted at 3%. The outcomes were measured in terms of cost, discounted life expectancy, cost/life year gained and net benefits of using bCPAP or nasal oxygen. The incremental cost-effectiveness ratio and incremental net benefits determined the value of one intervention compared to the other. Subgroup analysis on several parameters (birth weight categories, diagnosis of respiratory distress syndrome, and comorbidity of sepsis) was conducted to evaluate the effect of these parameters on the cost-effectiveness.
Nasal oxygen therapy was less costly (US$29.29) than the low-cost bCPAP device ($57.78). Incremental effectiveness associated with bCPAP was 6.78 life years (LYs). In the base case analysis, the incremental cost-effectiveness ratio for bCPAP relative to nasal oxygen therapy was determined to be $4.20 (95% confidence interval, US$2.29–US$16.67) per LY gained. The results were highly sensitive for all tested subgroups, particularly for neonates with birth weight 1– < 1.5 kg, respiratory distress syndrome, or comorbidity of sepsis; these subgroups had a higher probability that bCPAP would be cost effective.
The bCPAP is a highly cost-effective strategy in providing ventilatory support for neonates in Malawi.
PMCID: PMC4247223  PMID: 25421903
Cost-effectiveness analysis; Neonate; Malawi; Prematurity; Respiratory distress syndrome; Sepsis; Ventilatory support; Bubble continuous positive airway pressure
4.  Confocal fluorescence microscopy for rapid evaluation of invasive tumor cellularity of inflammatory breast carcinoma core needle biopsies 
Tissue sampling is a problematic issue for inflammatory breast carcinoma, and immediate evaluation following core needle biopsy is needed to evaluate specimen adequacy. We sought to determine if confocal fluorescence microscopy provides sufficient resolution to evaluate specimen adequacy by comparing invasive tumor cellularity estimated from standard histologic images to invasive tumor cellularity estimated from confocal images of breast core needle biopsy specimens. Grayscale confocal fluorescence images of breast core needle biopsy specimens were acquired following proflavine application. A breast-dedicated pathologist evaluated invasive tumor cellularity in histologic images with hematoxylin and eosin staining and in grayscale and false-colored confocal images of cores. Agreement between cellularity estimates was quantified using a kappa coefficient. 23 cores from 23 patients with suspected inflammatory breast carcinoma were imaged. Confocal images were acquired in an average of less than 2 min per core. Invasive tumor cellularity estimated from histologic and grayscale confocal images showed moderate agreement by kappa coefficient: κ = 0.48 ± 0.09 (p < 0.001). Grayscale confocal images require less than 2 min for acquisition and allow for evaluation of invasive tumor cellularity in breast core needle biopsy specimens with moderate agreement to histologic images. We show that confocal fluorescence microscopy can be performed immediately following specimen acquisition and could indicate the need for additional biopsies at the initial visit.
PMCID: PMC4298669  PMID: 25417171
Inflammatory breast cancer; Core needle biopsy; Confocal fluorescence microscopy; Tissue sampling
5.  Equipment-Free Incubation of Recombinase Polymerase Amplification Reactions Using Body Heat 
PLoS ONE  2014;9(11):e112146.
The development of isothermal amplification platforms for nucleic acid detection has the potential to increase access to molecular diagnostics in low resource settings; however, simple, low-cost methods for heating samples are required to perform reactions. In this study, we demonstrated that human body heat may be harnessed to incubate recombinase polymerase amplification (RPA) reactions for isothermal amplification of HIV-1 DNA. After measuring the temperature of mock reactions at 4 body locations, the axilla was chosen as the ideal site for comfortable, convenient incubation. Using commonly available materials, 3 methods for securing RPA reactions to the body were characterized. Finally, RPA reactions were incubated using body heat while control RPA reactions were incubated in a heat block. At room temperature, all reactions with 10 copies of HIV-1 DNA and 90% of reactions with 100 copies of HIV-1 DNA tested positive when incubated with body heat. In a cold room with an ambient temperature of 10 degrees Celsius, all reactions containing 10 copies or 100 copies of HIV-1 DNA tested positive when incubated with body heat. These results suggest that human body heat may provide an extremely low-cost solution for incubating RPA reactions in low resource settings.
PMCID: PMC4221156  PMID: 25372030
6.  Endoscopic ultrasound-assisted direct peritoneal visualization with a small-caliber scope: A proof of concept study in a swine model 
Endoscopic Ultrasound  2014;3(4):226-231.
Laparoscopic and natural orifice transluminal endoscopic surgery techniques can diagnose peritoneal findings that suggest tumor cell dissemination. However, they have not been incorporated into routine practice, mainly owing to their complexity. To develop a minimally invasive endoscopic technique for the diagnosis of peritoneal findings, we conducted feasibility study using an acute swine model.
Materials and Methods:
This study involved six domestic pigs. Trans-gastric access to the peritoneal cavity was performed utilizing an endoscopic ultrasound fine needle aspiration (EUS-FNA) technique. After dilation of the needle hole with a biliary dilatation catheter and balloon, a small-caliber scope was inserted into the peritoneal cavity. Peritoneal images were obtained with the scope and a high-resolution microendoscope (HRME). Main outcome measurements were technical feasibility and time needed to access the peritoneal cavity.
Direct visualization of the peritoneum was successful in all six pigs and gained access to the gross appearance of the peritoneal cavity. HRME imaging with topical contrast agent also obtained reasonable quality images representing nuclei of the peritoneal mesothelium. Average operation time from the initiation of EUS-FNA to acquiring peritoneal images was 26.5 min (range 15-40 min). Autopsy found no damage to the adjacent organs, and stomach wall defects were tightly closed with hemostasis clips.
EUS-assisted direct peritoneal visualization with small-caliber scope is technically feasible. HRME may assist in the diagnosis of findings on the peritoneum.
PMCID: PMC4247530  PMID: 25485270
Cancer staging; endoscopic ultrasound-guided fine needle aspiration; natural orifice transluminal endoscopic surgery; peritoneoscopy; tumor implant
7.  Optical Molecular Imaging in the Gastrointestinal Tract 
Recent developments in optical molecular imaging allow for real-time identification of morphological and biochemical changes in tissue associated with gastrointestinal neoplasia. This review summarizes widefield and high resolution imaging modalities currently in pre-clinical and clinical evaluation for the detection of colorectal cancer and esophageal cancer. Widefield techniques discussed include high definition white light endoscopy, narrow band imaging, autofluoresence imaging, and chromoendoscopy; high resolution techniques discussed include probe-based confocal laser endomicroscopy, high-resolution microendoscopy, and optical coherence tomography. Finally, new approaches to enhance image contrast using vital dyes and molecular-specific targeted contrast agents are evaluated.
PMCID: PMC3746803  PMID: 23735112
optical molecular imaging; white light endoscopy; narrow band imaging; autofluorescence imaging; chromoendoscopy; confocal laser endomicroscopy; high resolution microendoscopy; optical coherence tomography
8.  In vivo diagnostic accuracy of high resolution microendoscopy in differentiating neoplastic from non-neoplastic colorectal polyps: a prospective study 
High-resolution microendoscopy (HRME) is a low-cost, “optical biopsy” technology that allows for subcellular imaging. The purpose of this study was to determine the in vivo diagnostic accuracy of the HRME for the differentiation of neoplastic from non-neoplastic colorectal polyps and compare it to that of high-definition white-light endoscopy (WLE) with histopathology as the gold standard. Three endoscopists prospectively detected a total of 171 polyps from 94 patients that were then imaged by HRME and classified in real-time as neoplastic (adenomatous, cancer) or non-neoplastic (normal, hyperplastic, inflammatory). HRME had a significantly higher accuracy (94%), specificity (95%), and positive predictive value (87%) for the determination of neoplastic colorectal polyps compared to WLE (65%, 39%, and 55%, respectively). When looking at small colorectal polyps (less than 10 mm), HRME continued to significantly outperform WLE in terms of accuracy (95% vs. 64%), specificity (98% vs. 40%) and positive predictive value (92% vs. 55%). These trends continued when evaluating diminutive polyps (less than 5 mm) as HRME's accuracy (95%), specificity (98%), and positive predictive value (93%) were all significantly greater than their WLE counterparts (62%, 41%, and 53%, respectively). In conclusion, this in vivo study demonstrates that HRME can be a very effective modality in the differentiation of neoplastic and non-neoplastic colorectal polyps. A combination of standard white-light colonoscopy for polyp detection and HRME for polyp classification has the potential to truly allow the endoscopist to selectively determine which lesions can be left in situ, which lesions can simply be discarded, and which lesions need formal histopathologic analysis.
PMCID: PMC3947255  PMID: 24296752
Colorectal polyps; adenoma classification; microendoscopy; neoplasia; diagnostic accuracy
9.  Optical Imaging with a High Resolution Microendoscope to Identify Cholesteatoma of the Middle Ear 
The Laryngoscope  2013;123(4):1016-1020.
High resolution optical imaging is an imaging modality which allows visualization of structural changes in epithelial tissue in real time. Our prior studies using contrast-enhanced microendoscopy to image squamous cell carcinoma in the head and neck demonstrated that the contrast agent, proflavine, has high affinity for keratinized tissue. Thus, high-resolution microendoscopy with proflavine provides a potential mechanism to identify ectopic keratin production, such as that associated with cholesteatoma formation and distinguish between uninvolved mucosa and residual keratin at the time of surgery.
Study Design
Ex vivo imaging of histopathologically-confirmed samples of cholesteatoma and uninvolved middle-ear epithelium.
Seven separate specimens collected from patients who underwent surgical treatment for cholesteatoma were imaged ex vivo with the fiberoptic endoscope after surface staining with proflavine. Following imaging, the specimens were submitted for hematoxylin &eosin staining to allow histopathological correlation.
Cholesteatoma and surrounding middle ear epithelium have distinct imaging characteristics. Keratin-bearing areas of cholesteatoma lack nuclei and appear as confluent hyperfluorescence, while nuclei are easily visualized in specimens containing normal middle ear epithelium. Hyperfluorescence and loss of cellular detail is the imaging hallmark of keratin allowing for discrimination of cholesteatoma from normal middle ear epithelium.
This study demonstrates the feasibility of high-resolution optical imaging to discriminate cholesteatoma from uninvolved middle ear mucosa, based on the unique staining properties of keratin. Use of real-time imaging may facilitate more complete extirpation of cholesteatoma by identifying areas of residual disease.
PMCID: PMC3609873  PMID: 23299781
cholesteatoma; keratin; optical imaging; otology; high-resolution microendoscopy
10.  Multispectral optical imaging device for in vivo detection of oral neoplasia 
Journal of biomedical optics  2008;13(2):024019.
A multispectral digital microscope (MDM) is designed and constructed as a tool to improve detection of oral neoplasia. The MDM acquires in vivo images of oral tissue in fluorescence, narrowband (NB) reflectance, and orthogonal polarized reflectance (OPR) modes, to enable evaluation of lesions that may not exhibit high contrast under standard white light illumination. The device rapidly captures image sequences so that the diagnostic value of each modality can be qualitatively and quantitatively evaluated alone and in combination. As part of a pilot clinical trial, images are acquired from normal volunteers and patients with precancerous and cancerous lesions. In normal subjects, the visibility of vasculature can be enhanced by tuning the reflectance illumination wavelength and polarization. In patients with histologically confirmed neoplasia, we observe decreased blue/green autofluorescence and increased red autofluorescence in lesions, and increased visibility of vasculature using NB and OPR imaging. The perceived lesion borders change with imaging modality, suggesting that multimodal imaging has the potential to provide additional diagnostic information not available using standard white light illumination or by using a single imaging mode alone.
PMCID: PMC3970814  PMID: 18465982
oral cancer; diagnosis; noninvasive; optical imaging; fluorescence; decreased autofluorescence; reflectance; polarized; orthogonal; porphyrin; vasculature; monochromatic
11.  Modular video endoscopy for in vivo cross-polarized and vital-dye fluorescence imaging of Barrett’s-associated neoplasia 
Journal of Biomedical Optics  2013;18(2):026007.
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.
PMCID: PMC3561596  PMID: 23370452
endoscopy; imaging; fluorescence; cross-polarization; contrast agent; vital-dye; Barrett’s esophagus; esophageal adenocarcinoma
12.  Efficacy of a Low-Cost Bubble CPAP System in Treatment of Respiratory Distress in a Neonatal Ward in Malawi 
PLoS ONE  2014;9(1):e86327.
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.
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.
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.
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.
PMCID: PMC3906032  PMID: 24489715
13.  Feasibility and preliminary accuracy of high-resolution imaging of the liver and pancreas using FNA compatible microendoscopy 
Gastrointestinal endoscopy  2012;76(2):293-300.
Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is one of the few techniques which can obtain cells and tissue from the liver and pancreas. However, the technique remains vulnerable to poor specimen quality and sampling error.
To evaluate the ability of a high-resolution microendoscope (HRME) to visualize the cellular and architectural features of normal and malignant liver and pancreatic tissue ex vivo. To assess the ability of endosonographers to identify normal and neoplastic tissue using HRME images. To demonstrate preliminary technical feasibility of in vivo HRME imaging via EUS-fine needle puncture (FNP).
Ex vivo, pilot feasibility study in human tissue; in vivo swine model.
Two academic medical centers
Patients and Interventions
Co-registered HRME images and biopsies were obtained from surgically resected hepatic and pancreatic tissues from a total of 44 patients. Images were divided into training (12 images) and test sets (80 images) containing a range of normal and pathologic conditions for each organ. After viewing the training sets, nine endosonographers attempted to distinguish malignant tissue from normal or benign lesions in the test sets, each of which contained 40 unique images with individual diagnoses from pathology.
Main Outcome Measurements
Image acquisition feasibility, ex vivo and in vivo. Ability of endosonographers to recognize features of normal/benign or malignant tissue from the liver and pancreas.
Overall, the nine endosonographers achieved median accuracy figures of 85% in the liver and 90% in the pancreas. The endosonographers with prior experience in reading HRME images achieved accuracy rates between 90% and 95%. Technical feasibility of HRME imaging through a 19-gauge EUS-FNP needle was demonstrated in an in vivo swine model.
Ex vivo study
High-resolution microendoscopy allows real-time imaging of cellular-level morphology and tissue architecture in the liver and pancreas. The techniques appears to have a short learning curve, after which endosonographers achieved high accuracy rates in distinguishing malignant tissue from normal and benign pathology in both organs. Translating this imaging platform to the in vivo setting appears technically feasible.
PMCID: PMC3904224  PMID: 22817784
14.  Gold Nanoparticle Aggregation for Quantification of Oligonucleotides: Optimization and Increased Dynamic Range 
Analytical biochemistry  2012;431(2):99-105.
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 required to produce a result. This study aims 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 endpoint of incubation, we find that the assay is capable of producing quantifiable results at room temperature in 30 minutes with a linear dynamic range spanning from 150 amoles to 15 fmoles of target. If changes in light scattering are measured dynamically during the incubation process, the linear range can be expanded 2-fold, spanning 50 amoles to 500 fmoles, while decreasing the time to result down to 10 minutes.
PMCID: PMC3496753  PMID: 23000603
Gold nanoparticles; oligonucleotides; optical scattering; quantification
15.  A pilot study of low-cost, high-resolution microendoscopy as a tool for identifying women with cervical precancer 
Cervical cancer remains one of the leading causes of death among women in developing countries. Without resources to support Pap smear cytology and colposcopy, cost-effective approaches which enable single-visit “see-and-treat” protocols offer the potential to reduce morbidity and mortality due to this preventable disease. We carried out a pilot clinical study in Shanxi province, China, to evaluate a low-cost, high-resolution microendoscope (HRME) imaging system which enables evaluation of epithelial cell morphology in vivo. HRME images were obtained at discrete sites on the cervix in 174 women, in addition to visual inspection with acetic acid (VIA), and colposcopic examination. Out of 69 sites appearing abnormal on colposcopy, only 12 showed high-grade disease (CIN2+) on pathology. Quantification of the nuclear-to-cytoplasm ratio by HRME enabled an ad hoc threshold to be defined, which correctly classified all 12 sites as abnormal, whilst classifying 38 of the remaining 57 pathology normal sites as normal. All patients with biopsy confirmed high-grade disease also tested positive for high-risk HPV DNA, and were classified as abnormal by HRME. Among the remaining patients who tested positive for HPV but were either normal by colposcopy or showed < CIN2 on pathology, only 6/32 (18.8%) were classified as abnormal by HRME.
Visual examination techniques for cervical cancer screening may overestimate the prevalence of precancerous lesions, leading to unnecessary treatment, expense, and patient stress. The results of this study suggest that evaluation of suspicious lesions by HRME may assist in ruling out immediate cryotherapy, thus increasing the efficiency of current see-and-treat programs.
PMCID: PMC3494281  PMID: 22926339
Optical imaging; clinical diagnostics; HPV testing
16.  Discrimination of Benign and Neoplastic Mucosa with a High-Resolution Microendoscope (HRME) in Head and Neck Cancer 
Annals of surgical oncology  2012;19(11):3534-3539.
The efficacy of ablative surgery for head and neck squamous cell carcinoma (HNSCC) depends critically on obtaining negative margins. While intraoperative "frozen section" analysis of margins is a valuable adjunct, it is expensive, time-consuming, and highly dependent on pathologist expertise. Optical imaging has potential to improve the accuracy of margins by identifying cancerous tissue in real time. Our aim was to determine the accuracy and inter-rater reliability of head and neck cancer specialists using high-resolution microendoscopic (HRME) images to discriminate between cancerous and benign mucosa.
Thirty-eight patients diagnosed with HNSCC were enrolled in this single-center study. HRME was used to image each specimen after application of proflavine, with concurrent standard histopathologic analysis. Images were evaluated for quality control, and a training set containing representative images of benign and neoplastic tissue was assembled. After viewing training images, seven head and neck cancer specialists with no prior HRME experience reviewed 37 test images and were asked to classify each.
The mean accuracy of all reviewers in correctly diagnosing neoplastic mucosa was 97 percent (95% Cl = 94–99%). The mean sensitivity and specificity were 98 percent (97–100%) and 92 percent (87–98%), respectively. The Fleiss kappa statistic for inter-rater reliability was 0.84 (0.77–0.91).
Medical professionals can be quickly trained to use HRME to discriminate between benign and neoplastic mucosa in the head and neck. With further development, the HRME shows promise as a method of real-time margin determination at the point of care.
PMCID: PMC3421068  PMID: 22492225
17.  A Paper and Plastic Device for Performing Recombinase Polymerase Amplification of HIV DNA 
Lab on a chip  2012;12(17):3082-3088.
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 minutes. 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.
PMCID: PMC3569001  PMID: 22733333
18.  Novel open-source electronic medical records system for palliative care in low-resource settings 
BMC Palliative Care  2013;12:31.
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.
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.
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.
PMCID: PMC3751569  PMID: 23941694
Palliative care; Electronic medical records system; Evidence-based medicine; Africa; Database
19.  Accuracy of in vivo multi-modal optical imaging for detection of oral neoplasia 
If detected early, oral cancer is eminently curable. However, survival rates for oral cancer patients remain low, largely due to late stage diagnosis and subsequent difficulty of treatment. To improve clinicians’ ability to detect early disease and to treat advanced cancers, we developed a multi-modal optical imaging system (MMIS) to evaluate tissue in situ, at macroscopic and microscopic scales. The MMIS was used to measure anatomical 100 sites in 30 patients, correctly classifying 98% of pathologically confirmed normal tissue sites, and 95% of sites graded as moderate dysplasia, severe dysplasia, or cancer. When used alone, MMIS classification accuracy was 35% for sites determined by pathology as mild dysplasia. However, MMIS measurements correlated with expression of candidate molecular markers in 87% of sites with mild dysplasia. These findings support the ability of non-invasive multi-modal optical imaging to accurately identify neoplastic tissue and pre-malignant lesions. This in turn may have considerable impact on detection and treatment of patients with oral cancer and other epithelial malignancies.
PMCID: PMC3560936  PMID: 22551901
Optical imaging; clinical diagnostics; fluorescence imaging; biomarker imaging
20.  Multimodal snapshot spectral imaging for oral cancer diagnostics: a pilot study 
Biomedical Optics Express  2013;4(6):938-949.
Optical imaging and spectroscopy have emerged as effective tools for detecting malignant changes associated with oral cancer. While clinical studies have demonstrated high sensitivity and specificity for detection, current devices either interrogate a small region or can have reduced performance for some benign lesions. We describe a snapshot imaging spectrometer that combines the large field-of-view of widefield imaging with the diagnostic strength of spectroscopy. The portable device can stream RGB images at 7.2 frames per second and record both autofluorescence and reflectance spectral datacubes in < 1 second. We report initial data from normal volunteers and oral cancer patients.
PMCID: PMC3675872  PMID: 23760882
(170.0170) Medical optics and biotechnology; (170.6510) Spectroscopy, tissue diagnostics; (110.4234) Multispectral and hyperspectral imaging
21.  Vital-dye enhanced fluorescence imaging of gastrointestinal mucosa: metaplasia, neoplasia, inflammation 
Gastrointestinal Endoscopy  2012;75(4):877-887.
Confocal endomicroscopy has revolutionized endoscopy by offering sub-cellular images of gastrointestinal epithelium; however, field-of-view is limited. There is a need for multi-scale endoscopy platforms that use widefield imaging to better direct placement of high-resolution probes.
Feasibility Study
This study evaluates the feasibility of a single agent, proflavine hemisulfate, as a contrast medium during both widefield and high resolution imaging to characterize morphologic changes associated with a variety of gastrointestinal conditions.
U.T. M.D. Anderson Cancer Center (Houston, TX) and Mount Sinai Medical Center (New York, NY)
Patients, Interventions, and Main Outcome Measurements
Surgical specimens were obtained from 15 patients undergoing esophagectomy/colectomy. Proflavine, a vital fluorescent dye, was applied topically. Specimens were imaged with a widefield multispectral microscope and a high-resolution microendoscope. Images were compared to histopathology.
Widefield-fluorescence imaging enhanced visualization of morphology, including the presence and spatial distribution of glands, glandular distortion, atrophy and crowding. High-resolution imaging of widefield-abnormal areas revealed that neoplastic progression corresponded to glandular heterogeneity and nuclear crowding in dysplasia, with glandular effacement in carcinoma. These widefield and high-resolution image features correlated well with histopathology.
This imaging approach must be validated in vivo with a larger sample size.
Multi-scale proflavine-enhanced fluorescence imaging can delineate epithelial changes in a variety of gastrointestinal conditions. Distorted glandular features seen with widefield imaging could serve as a critical ‘bridge’ to high-resolution probe placement. An endoscopic platform combining the two modalities with a single vital-dye may facilitate point-of-care decision-making by providing real-time, in vivo diagnoses.
PMCID: PMC3336371  PMID: 22301343
fluorescence imaging; Barrett's esophagus; esophageal adenocarcinoma; colonic adenocarcinoma; inflammatory bowel disease
22.  A High-Value, Low-Cost Bubble Continuous Positive Airway Pressure System for Low-Resource Settings: Technical Assessment and Initial Case Reports 
PLoS ONE  2013;8(1):e53622.
Acute respiratory infections are the leading cause of global child mortality. In the developing world, nasal oxygen therapy is often the only treatment option for babies who are suffering from respiratory distress. Without the added pressure of bubble Continuous Positive Airway Pressure (bCPAP) which helps maintain alveoli open, babies struggle to breathe and can suffer serious complications, and frequently death. A stand-alone bCPAP device can cost $6,000, too expensive for most developing world hospitals. Here, we describe the design and technical evaluation of a new, rugged bCPAP system that can be made in small volume for a cost-of-goods of approximately $350. Moreover, because of its simple design—consumer-grade pumps, medical tubing, and regulators—it requires only the simple replacement of a <$1 diaphragm approximately every 2 years for maintenance. The low-cost bCPAP device delivers pressure and flow equivalent to those of a reference bCPAP system used in the developed world. We describe the initial clinical cases of a child with bronchiolitis and a neonate with respiratory distress who were treated successfully with the new bCPAP device.
PMCID: PMC3553107  PMID: 23372661
23.  Advances in molecular imaging: targeted optical contrast agents for cancer diagnostics 
Nanomedicine (London, England)  2012;7(3):429-445.
Over the last three decades, our understanding of the molecular changes associated with cancer development and progression has advanced greatly. This has led to new cancer therapeutics targeted against specific molecular pathways; such therapies show great promise to reduce mortality, in part by enabling physicians to tailor therapy for patients based on a molecular profile of their tumor. Unfortunately, the tools for definitive cancer diagnosis – light microscopic examination of biopsied tissue stained with nonspecific dyes – remain focused on the analysis of tissue ex vivo. There is an important need for new clinical tools to support the molecular diagnosis of cancer. Optical molecular imaging is emerging as a technique to help meet this need. Targeted, optically active contrast agents can specifically label extra-and intracellular biomarkers of cancer. Optical images can be acquired in real time with high spatial resolution to image-specific molecular targets, while still providing morphologic context. This article reviews recent advances in optical molecular imaging, highlighting the advances in technology required to improve early cancer detection, guide selection of targeted therapy and rapidly evaluate therapeutic efficacy.
PMCID: PMC3327054  PMID: 22385200
biomarkers; cancer; contrast agents; early diagnosis; image-guided therapeutics; nanoparticles; optical imaging
24.  The Use of in vivo Real-Time Optical Imaging for Esophageal Neoplasia 
Esophageal adenocarcinoma carries a poor prognosis, as it typically presents at a late stage. Thus, a major research priority is the development of novel diagnostic imaging strategies that can detect neoplastic lesions earlier and more accurately than current techniques. Advances in optical imaging allow clinicians to obtain real-time histopathologic information with instant visualization of cellular architecture and the potential to identify neoplastic tissue. The various endoscopic imaging modalities for esophageal neoplasia can be grouped into two major categories: (a) wide-field imaging, a comparatively lower-resolution view for imaging larger surface areas, and (b) high-resolution imaging, which allows individual cells to be visualized. This review will provide an overview of the various forms of real-time optical imaging in the diagnosis and management of Barrett's esophagus and esophageal adenocarcinoma.
PMCID: PMC3466051  PMID: 22069213
Barrett esophagus; neoplasms; cancer; endoscopy; optical imaging; diagnostic imaging
25.  A Lateral Flow Assay for Quantitative Detection of Amplified HIV-1 RNA 
PLoS ONE  2012;7(9):e45611.
Although the accessibility of HIV treatment in developing nations has increased dramatically over the past decade, viral load testing to monitor the response of patients receiving therapy is often unavailable. Existing viral load technologies are often too expensive or resource-intensive for poor settings, and there is no appropriate HIV viral load test currently available at the point-of-care in low resource settings. Here, we present a lateral flow assay that employs gold nanoparticle probes and gold enhancement solution to detect amplified HIV RNA quantitatively. Preliminary results show that, when coupled with nucleic acid sequence based amplification (NASBA), this assay can detect concentrations of HIV RNA that match the clinically relevant range of viral loads found in HIV patients. The lateral flow test is inexpensive, simple and rapid to perform, and requires few resources. Our results suggest that the lateral flow assay may be integrated with amplification and sample preparation technologies to serve as an HIV viral load test for low-resource settings.
PMCID: PMC3448666  PMID: 23029134

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