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1.  Conserved Single Residue in the BK Potassium Channel Required for Activation by Alcohol and Intoxication in C. elegans 
The Journal of Neuroscience  2014;34(29):9562-9573.
Alcohol directly modulates the BK potassium channel to alter behaviors in species ranging from invertebrates to humans. In the nematode Caenorhabditis elegans, mutations that eliminate the BK channel, SLO-1, convey dramatic resistance to intoxication by ethanol. We hypothesized that certain conserved amino acids are critical for ethanol modulation, but not for basal channel function. To identify such residues, we screened C. elegans strains with different missense mutations in the SLO-1 channel. A strain with the SLO-1 missense mutation T381I in the RCK1 domain was highly resistant to intoxication. This mutation did not interfere with other BK channel-dependent behaviors, suggesting that the mutant channel retained normal in vivo function. Knock-in of wild-type versions of the worm or human BK channel rescued intoxication and other BK channel-dependent behaviors in a slo-1-null mutant background. In contrast, knock-in of the worm T381I or equivalent human T352I mutant BK channel selectively rescued BK channel-dependent behaviors while conveying resistance to intoxication. Single-channel patch-clamp recordings confirmed that the human BK channel engineered with the T352I missense mutation was insensitive to activation by ethanol, but otherwise had normal conductance, potassium selectivity, and only subtle differences in voltage dependence. Together, our behavioral and electrophysiological results demonstrate that the T352I mutation selectively disrupts ethanol modulation of the BK channel. The T352I mutation may alter a binding site for ethanol and/or interfere with ethanol-induced conformational changes that are critical for behavioral responses to ethanol.
PMCID: PMC4099540  PMID: 25031399
behavior; BK channel; C. elegans; ethanol
2.  Techniques for fluorescence detection of protoporphyrin IX in skin cancers associated with photodynamic therapy 
Photonics & lasers in medicine  2013;2(4):287-303.
Photodynamic therapy (PDT) is a treatment modality that uses a specific photosensitizing agent, molecular oxygen, and light of a particular wavelength to kill cells targeted by the therapy. Topically administered aminolevulinic acid (ALA) is widely used to effectively treat cancerous and precancerous skin lesions, resulting in targeted tissue damage and little to no scarring. The targeting aspect of the treatment arises from the fact that ALA is preferentially converted into protoporphyrin IX (PpIX) in neoplastic cells. To monitor the amount of PpIX in tissues, techniques have been developed to measure PpIX-specific fluorescence, which provides information useful for monitoring the abundance and location of the photosensitizer before and during the illumination phase of PDT. This review summarizes the current state of these fluorescence detection techniques. Non-invasive devices are available for point measurements, or for wide-field optical imaging, to enable monitoring of PpIX in superficial tissues. To gain access to information at greater tissue depths, multi-modal techniques are being developed which combine fluorescent measurements with ultrasound or optical coherence tomography, or with microscopic techniques such as confocal or multiphoton approaches. The tools available at present, and newer devices under development, offer the promise of better enabling clinicians to inform and guide PDT treatment planning, thereby optimizing therapeutic outcomes for patients.
PMCID: PMC4295789  PMID: 25599015
protoporphyrin IX; fluorescence; photodynamic therapy; treatment planning
3.  Automation Practices in Large Molecule Bioanalysis: Recommendations from Group L5 of the Global Bioanalytical Consortium 
The AAPS Journal  2013;16(1):164-171.
In recent years, the use of automated sample handling instrumentation has come to the forefront of bioanalytical analysis in order to ensure greater assay consistency and throughput. Since robotic systems are becoming part of everyday analytical procedures, the need for consistent guidance across the pharmaceutical industry has become increasingly important. Pre-existing regulations do not go into sufficient detail in regard to how to handle the use of robotic systems for use with analytical methods, especially large molecule bioanalysis. As a result, Global Bioanalytical Consortium (GBC) Group L5 has put forth specific recommendations for the validation, qualification, and use of robotic systems as part of large molecule bioanalytical analyses in the present white paper. The guidelines presented can be followed to ensure that there is a consistent, transparent methodology that will ensure that robotic systems can be effectively used and documented in a regulated bioanalytical laboratory setting. This will allow for consistent use of robotic sample handling instrumentation as part of large molecule bioanalysis across the globe.
PMCID: PMC3889521  PMID: 24311307
automation; documentation; large molecule bioanalysis; robotic system
4.  CT contrast predicts pancreatic cancer treatment response to verteporfin-based photodynamic therapy 
Physics in medicine and biology  2014;59(8):1911-1921.
The goal of the current study was to determine dominant factors affecting treatment response in pancreatic cancer photodynamic therapy (PDT), based on clinically available information in the VERTPAC-01 trial. This trial investigated the safety and efficacy of verteporfin PDT in 15 patients with locally advanced pancreatic adenocarcinoma.
CT scans before and after contrast enhancement from the 15 patients in the VERTPAC-01 trial were used to determine venous-phase blood contrast enhancement and this was correlated with necrotic volume determined from post-treatment CT scans, along with estimation of optical absorption in the pancreas for use in light modeling of the PDT treatment. Energy threshold contours yielded estimates for necrotic volume based on this light modeling.
Both contrast-derived venous blood content and necrotic volume from light modeling yielded strong correlations with observed necrotic volume (R2=0.85 and 0.91, respectively). These correlations were much stronger than those obtained by correlating energy delivered vs. necrotic volume in the VERTPAC-01 study and in retrospective analysis from a prior clinical study.
This demonstrates that contrast CT can provide key surrogate dosimetry information to assess treatment response. It also implies that light attenuation is likely the dominant factor in the VERTPAC treatment response, as opposed to other factors such as drug distribution. This study is the first to show that contrast CT provides needed surrogate dosimetry information to predict treatment response in a manner which uses standard-of-care clinical images, rather than invasive dosimetry methods.
PMCID: PMC4229843  PMID: 24651456
photodynamic therapy; dosimetry; NIRFAST; optical modeling
5.  Occupational Exposure to Magnetic Fields and Breast Cancer Among Women Textile Workers in Shanghai, China 
American Journal of Epidemiology  2013;178(7):1038-1045.
Exposure to magnetic fields (MFs) is hypothesized to increase the risk of breast cancer by reducing production of melatonin by the pineal gland. A nested case-cohort study was conducted to investigate the association between occupational exposure to MFs and the risk of breast cancer within a cohort of 267,400 female textile workers in Shanghai, China. The study included 1,687 incident breast cancer cases diagnosed from 1989 to 2000 and 4,702 noncases selected from the cohort. Subjects’ complete work histories were linked to a job–exposure matrix developed specifically for the present study to estimate cumulative MF exposure. Hazard ratios and 95% confidence intervals were calculated using Cox proportional hazards modeling that was adapted for the case-cohort design. Hazard ratios were estimated in relation to cumulative exposure during a woman's entire working years. No association was observed between cumulative exposure to MFs and overall risk of breast cancer. The hazard ratio for the highest compared with the lowest quartile of cumulative exposure was 1.03 (95% confidence interval: 0.87, 1.21). Similar null findings were observed when exposures were lagged and stratified by age at breast cancer diagnosis. The findings do not support the hypothesis that MF exposure increases the risk of breast cancer.
PMCID: PMC3783098  PMID: 24043439
breast cancer; electric and magnetic fields; occupation; textile industry
6.  Topical dual-stain difference imaging for rapid intra-operative tumor identification in fresh specimens 
Optics letters  2013;38(23):5184-5187.
Assessing tumor margin status during surgery is critical to ensure complete resection of cancer tissue; however, current approaches are ineffective and often result in repeat surgery. We present a novel optical imaging approach for margin assessment using topical application of two fluorescent stains, one targeted to a tumor biomarker and the other a non-targeted reference, to freshly excised specimens. Computing a normalized difference image from fluorescence images of the targeted and untargeted stains suppresses the confounding effects of non-specific uptake. Applying this approach in excised breast tumor models produced promising tumor-to-normal tissue contrasts that were significantly higher than single-targeted-stain imaging.
PMCID: PMC4180285  PMID: 24281541
7.  Trends in the Use of Neurotoxins and Dermal Fillers by US Physicians 
Background: Demand for minimally invasive cosmetic procedures have led to an increased market of available products for facial rejuvenation. Objective: To characterize trends in the usage of aesthetic products, specifically the use of botulinum toxins and dermal fillers, by United States physicians. Methods: Data from the National Ambulatory Medical Care Survey was analyzed from 1993 to 2010 to evaluate the use of dermal fillers and neurotoxins in the United States outpatient setting. The types of physician specialties administering these products and their preferences in products were characterized. Results: There were an estimated 100,000 annual cosmetic visits at which a dermal filler was administered from 1993 to 2010. From 2002 to 2010, there were 140,000 annual cosmetic visits for a dermal filler and 440,000 visits for a neurotoxin. While collagen was the most common filler used over the entire study period, its use declined eight percent annually. Hyaluronic acid fillers were preferred from 2002 to 2010, followed by calcium hydroxylapatite filler, representing 50 percent and 16.1 percent of visits, respectively. The leading neurotoxin was onabotulinumtoxin A, used at 87.1 percent of visits. Dermatologists were the leading specialty for the cosmetic use of both dermal fillers and neurotoxins. Conclusion: Providers’ preference for cosmetic products appears to be influenced by their familiarity with them, with products that first came to market, such as the neurotoxin onabotulinumtoxin A and the hyaluronic acid fillers being used most frequently from 2002 to 2010.
PMCID: PMC4174914  PMID: 25276271
8.  Fast segmentation and high-quality three-dimensional volume mesh creation from medical images for diffuse optical tomography 
Journal of Biomedical Optics  2013;18(8):086007.
Multimodal approaches that combine near-infrared (NIR) and conventional imaging modalities have been shown to improve optical parameter estimation dramatically and thus represent a prevailing trend in NIR imaging. These approaches typically involve applying anatomical templates from magnetic resonance imaging/computed tomography/ultrasound images to guide the recovery of optical parameters. However, merging these data sets using current technology requires multiple software packages, substantial expertise, significant time-commitment, and often results in unacceptably poor mesh quality for optical image reconstruction, a reality that represents a significant roadblock for translational research of multimodal NIR imaging. This work addresses these challenges directly by introducing automated digital imaging and communications in medicine image stack segmentation and a new one-click three-dimensional mesh generator optimized for multimodal NIR imaging, and combining these capabilities into a single software package (available for free download) with a streamlined workflow. Image processing time and mesh quality benchmarks were examined for four common multimodal NIR use-cases (breast, brain, pancreas, and small animal) and were compared to a commercial image processing package. Applying these tools resulted in a fivefold decrease in image processing time and 62% improvement in minimum mesh quality, in the absence of extra mesh postprocessing. These capabilities represent a significant step toward enabling translational multimodal NIR research for both expert and nonexpert users in an open-source platform.
PMCID: PMC3739873  PMID: 23942632
optical tomography; medical imaging; image segmentation; mesh creation
9.  Čerenkov Excited Fluorescence Tomography using External Beam Radiation 
Optics letters  2013;38(8):1364-1366.
Radiation treatment of cancer induces an optical Čerenkov emission throughout the treated volume, which could be used to excite molecular reporters in vivo, allowing molecular sensing of tissue response during fractionated therapy. In this letter, the idea that spatial mapping of this signal can be achieved with tomographic recovery of the fluorophore distribution is tested for the first time, using 6 MeV photons from a linear accelerator in a heterogeneous tissue phantom. Čerenkov light excited fluorophore throughout the tissue phantom, and diffuse tomography was used to recover images. Measurements from13 locations were used, with spectrometer detection and spectral fitting, to separate the fluorophore emission from the Čerenkov continuum. Fluorescent diffuse tomographic images showed a linear response between the concentration and the reconstructed values. The potential to apply this molecular imaging in treatment with molecular reporters appears promising.
PMCID: PMC4129509  PMID: 23595486
10.  Pulsed-light imaging for fluorescence guided surgery under normal room lighting 
Optics letters  2013;38(17):3249-3252.
Fluorescence guided surgery (FGS) is an emerging technology that has demonstrated improved surgical outcomes. However, dim lighting conditions required bycurrent FGS systems are disruptive to standard surgical workflow. We present a novel FGS system capable of imaging fluorescence under normal room lightby using pulsed excitation and gated acquisition. Images from tissue-simulating phantoms confirm visual detection down to 0.25 μM of protopor-phyrin IX under 125 μW/cm2 of ambient light, more than an order of magnitude lower than that measured with the Zeiss Pentero in the dark. Resection of orthotopic brain tumors in mice also suggests that the pulsed-light system provides superior sensitivity in vivo.
PMCID: PMC4051311  PMID: 23988926
(110.0110) Imaging systems; (110.2970) Image detection systems; (170.1610) Clinical applications; (170.3890) Medical optics instrumentation; (230.3670) Light-emitting diodes
11.  Monitoring Wildlife-Vehicle Collisions in the Information Age: How Smartphones Can Improve Data Collection 
PLoS ONE  2014;9(6):e98613.
Currently there is a critical need for accurate and standardized wildlife-vehicle collision data, because it is the underpinning of mitigation projects that protect both drivers and wildlife. Gathering data can be challenging because wildlife-vehicle collisions occur over broad areas, during all seasons of the year, and in large numbers. Collecting data of this magnitude requires an efficient data collection system. Presently there is no widely adopted system that is both efficient and accurate.
Methodology/Principal Findings
Our objective was to develop and test an integrated smartphone-based system for reporting wildlife-vehicle collision data. The WVC Reporter system we developed consisted of a mobile web application for data collection, a database for centralized storage of data, and a desktop web application for viewing data. The smartphones that we tested for use with the application produced accurate locations (median error = 4.6–5.2 m), and reduced location error 99% versus reporting only the highway/marker. Additionally, mean times for data entry using the mobile web application (22.0–26.5 s) were substantially shorter than using the pen/paper method (52 s). We also found the pen/paper method had a data entry error rate of 10% and those errors were virtually eliminated using the mobile web application. During the first year of use, 6,822 animal carcasses were reported using WVC Reporter. The desktop web application improved access to WVC data and allowed users to easily visualize wildlife-vehicle collision patterns at multiple scales.
The WVC Reporter integrated several modern technologies into a seamless method for collecting, managing, and using WVC data. As a result, the system increased efficiency in reporting, improved accuracy, and enhanced visualization of data. The development costs for the system were minor relative to the potential benefits of having spatially accurate and temporally current wildlife-vehicle collision data.
PMCID: PMC4045807  PMID: 24897502
12.  Use of electronic medical records differs by specialty and office settings 
To assess differences in the use of electronic medical records (EMRs) among medical specialties and practice settings.
A cross-sectional retrospective study using nationally representative data from the National Ambulatory Medical Care Survey for the period 2003–2010 was performed. Bivariate and multivariate analyzes compared EMR use among physicians of 14 specialties and assessed variation by practice setting. Differences in EMR use by geographic region, patient characteristics, and physician office settings were also assessed.
Bivariate and multivariate analysis demonstrated increased EMR use from 2003 to 2010, with 16% reporting at least partial use in 2003, rising to 52% in 2010 (p<0.001). Cardiologists, orthopedic surgeons, urologists, and family/general practitioners had higher frequencies of EMR use whereas psychiatrists, ophthalmologists, and dermatologists had the lowest EMR use. Employed physicians had higher EMR uptake than physicians who owned their practice (48% vs 31%, p<0.001). EMR uptake was lower among solo practitioners (23%) than non-solo practitioners (42%, p<0.001). Practices owned by Health Maintenance Organizations had higher frequencies of EMR use (83%) than practices owned by physicians, community health centers, or academic centers (all <45%, p<0.001). Patient demographics did not affect EMR use (p>0.05).
Uptake of EMR is increasing, although it is significantly slower in dermatology, ophthalmology, and psychiatry. Solo practitioners and owners of a practice have low frequencies of EMR use compared with non-solo practitioners and those who do not own their practice. Despite incentives for EMR adoption, physicians should carefully weigh which, if any, EMR to adopt in their practices.
PMCID: PMC3715335  PMID: 23538721
EMR; technology; NAMCS
14.  Oxygen tomography by Čerenkov-excited phosphorescence during external beam irradiation 
Journal of Biomedical Optics  2013;18(5):050503.
The efficacy of radiation therapy depends strongly on tumor oxygenation during irradiation. However, current techniques to measure this parameter in vivo do not facilitate routine monitoring in patients. Herein, we demonstrate a noninvasive method for tomographic imaging of oxygen partial pressure (pO2) in deep tissue using the phosphorescence decay of an oxygen-sensitive probe excited by Čerenkov radiation induced by external beam radiotherapy. Tissue-simulating scattering phantoms (60 mm diameter with a 20 mm anomaly) containing platinum(II)-G4 (PtG4), a dendritic porphyrin-based phosphor, whose phosphorescence is quenched in the presence of oxygen, were irradiated with a clinical linear accelerator. The emitted phosphorescence was measured at various positions on the phantom boundary using a spectrograph coupled to an intensified charge-coupled device (ICCD). At each position, PtG4 phosphorescence decay curves were measured by synchronizing the ICCD to the linear accelerator pulses. Tomographic images of phosphorescence yield and lifetime were recovered for phantoms with homogenous PtG4 concentrations and heterogeneous pO2. Since PtG4 lifetime is strongly and predictably dependent on pO2 through the Stern-Volmer relationship, tomographic images of pO2 were also reported, and showed excellent agreement with independent oxygenation measurements. Translating this approach to the clinic could facilitate direct sensing of pO2 during radiotherapy.
PMCID: PMC3643897  PMID: 23644902
Čerenkov; phosphorescence; optics tomography; oxygen partial pressure; LINAC; time domain gating; external beam radiotherapy
15.  White light-informed optical properties improve ultrasound-guided fluorescence tomography of photoactive protoporphyrin IX 
Journal of Biomedical Optics  2013;18(4):046008.
Subsurface fluorescence imaging is desirable for medical applications, including protoporphyrin-IX (PpIX)-based skin tumor diagnosis, surgical guidance, and dosimetry in photodynamic therapy. While tissue optical properties and heterogeneities make true subsurface fluorescence mapping an ill-posed problem, ultrasound-guided fluorescence-tomography (USFT) provides regional fluorescence mapping. Here USFT is implemented with spectroscopic decoupling of fluorescence signals (auto-fluorescence, PpIX, photoproducts), and white light spectroscopy-determined bulk optical properties. Segmented US images provide a priori spatial information for fluorescence reconstruction using region-based, diffuse FT. The method was tested in simulations, tissue homogeneous and inclusion phantoms, and an injected-inclusion animal model. Reconstructed fluorescence yield was linear with PpIX concentration, including the lowest concentration used, 0.025  μg/ml. White light spectroscopy informed optical properties, which improved fluorescence reconstruction accuracy compared to the use of fixed, literature-based optical properties, reduced reconstruction error and reconstructed fluorescence standard deviation by factors of 8.9 and 2.0, respectively. Recovered contrast-to-background error was 25% and 74% for inclusion phantoms without and with a 2-mm skin-like layer, respectively. Preliminary mouse-model imaging demonstrated system feasibility for subsurface fluorescence measurement in vivo. These data suggest that this implementation of USFT is capable of regional PpIX mapping in human skin tumors during photodynamic therapy, to be used in dosimetric evaluations.
PMCID: PMC3639786  PMID: 23584445
tomography; high-frequency ultrasound; dermatology; photodynamic; spectroscopy; subsurface fluorescence
16.  Dietary flavonoid intake and non-Hodgkin lymphoma risk 
The role of dietary factors in non-Hodgkin lymphoma (NHL) risk is not yet well understood. Dietary flavonoids are polyphenolic compounds proposed to be anticarcinogenic. Flavonoids are well-characterized antioxidants and metal chelators, and certain flavonoids exhibit antiproliferative and antiestrogenic effects.
We aimed to evaluate the hypothesis that higher flavonoid intake is associated with lower NHL risk.
During 1998–2000, we identified incident NHL cases aged 20–74 y from 4 US Surveillance, Epidemiology, and End Results cancer registries. Controls without history of NHL were selected by random-digit dialing or from Medicare files and frequency-matched to cases by age, center, race, and sex. Using 3 recently developed US Department of Agriculture nutrient-specific databases, flavonoid intake was estimated from participant responses to a 117-item food-frequency questionnaire (n = 466 cases and 390 controls). NHL risk in relation to flavonoid intake in quartiles was evaluated after adjustment for age, sex, registry, education, NHL family history, and energy intake.
Higher total flavonoid intake was significantly associated with lower risk of NHL (P for trend < 0.01): a 47% lower risk in the highest quartile of intake than in the lowest (95% CI: 31%, 73%). Higher intakes of flavonols, epicatechins, anthocyanidins, and proanthocyanidins were each significantly associated with decreased NHL risk. Similar patterns of risk were observed for the major NHL subtypes—diffuse large B-cell lymphoma (n = 167) and follicular lymphoma (n = 146).
A higher intake of flavonoids, dietary components with several putative anticarcinogenic activities, may be associated with lower NHL risk.
PMCID: PMC3971470  PMID: 18469269
17.  Racial Differences in the Association Between Night Shift Work and Melatonin Levels Among Women 
American Journal of Epidemiology  2013;177(5):388-393.
Reduced suppression of melatonin in response to working the night shift among people of Asian ancestry has been suggested as a possible explanation for the null results observed in a recent analysis of shift work and breast cancer risk in a Chinese cohort. The authors analyzed the impact of Asian versus white race on previously reported differences in urinary 6-sulfatoxymelatonin levels in a 2003–2008 study in Seattle, Washington, of female health-care workers that exclusively worked night or day shifts. A total of 225 white and 51 Asian participants were included in the analysis. Although 6-sulfatoxymelatonin levels were affected by night shift work in both racial groups, Asian night shift workers consistently showed 6-sulfatoxymelatonin levels that were closer to levels in day shift workers than did white night shift workers. Furthermore, differences in 6-sulfatoxymelatonin levels between white and Asian night shift workers relative to day shift workers were statistically significant in every instance (P < 0.05). These results suggest that Asians may be better able to maintain a “normal” circadian pattern of melatonin production compared with whites and suggest a biological mechanism by which Asian night shift workers may be at a reduced risk of cancer.
PMCID: PMC3626046  PMID: 23380044
cancer; melatonin; race; shift work
18.  Non-Hodgkin lymphoma and Obesity: a pooled analysis from the InterLymph consortium 
Nutritional status is known to alter immune function, a suspected risk factor for non-Hodgkin lymphoma (NHL). To investigate whether long-term over, or under, nutrition is associated with NHL self-reported anthropometric data on weight and height from over 10000 cases of NHL and 16000 controls were pooled across 18 case-control studies identified through the International Lymphoma Epidemiology Consortium. Study-specific odds ratios (OR) were estimated using logistic regression and combined using a random-effects model. Severe obesity, defined as BMI of 40 kg m−2 or more, was not associated with NHL overall (pooled OR=1.00, 95% confidence interval (CI) 0.70–1.41) or the majority of NHL subtypes. An excess was however observed for diffuse large B-cell lymphoma (pooled OR=1.80, 95% CI 1.24–2.62), although not all study-specific ORs were raised. Among the overweight (BMI 25–29.9 kg m−2) and obese (BMI 30–39.9 kg m−2), associations were elevated in some studies and decreased in others, while no association was observed among the underweight (BMI<18.5 kg m−2). There was little suggestion of increasing ORs for NHL or its subtypes with every 5 kg m−2 rise in BMI above 18.5 kg m−2. BMI components height and weight were also examined, and the tallest men, but not women, were at marginally increased risk (pooled OR=1.19, 95% CI 1.06–1.34). In summary, whilst we conclude that there is no evidence to support the hypothesis that obesity is a determinant of all types of NHL combined, the association between severe obesity and diffuse large B-cell lymphoma may warrant further investigation.
PMCID: PMC3928289  PMID: 18167059
non-Hodgkin lymphoma; lymphoma; body mass index; weight; height; epidemiology
19.  Projection imaging of photon beams using Čerenkov-excited fluorescence 
Physics in medicine and biology  2013;58(3):601-619.
Full 3D beam profiling and quality assurance (QA) of therapeutic megavoltage linear accelerator (LINAC) x-ray photon beams is not routinely performed due to the slow point-by-point measurement nature of conventional scanning ionization chamber systems. In this study we explore a novel optical-based dose imaging approach using a standard commercial camera, water tank, and fluorescent dye, which when excited by the Čerenkov emission induced by the radiation beam, allows 2D projection imaging in a fast timeframe, potentially leading towards 3D tomographic beam profiling. Detailed analysis was done to optimize the imaging parameters in the experimental setup. The results demonstrate that the captured images are linear with delivered dose, independent of dose rate, and comparison of experimentally captured images to a reference dose distribution for a 4×4 cm 6 MV x-ray photon beam yielded results with improved accuracy over a previous study which used direct imaging and Monte Carlo calibration of the Čerenkov emission itself. The agreement with the reference dose distribution was within 1-2% in the lateral direction, and ± 3 % in the depth direction. The study was restricted to single 2D image projection, with the eventual goal of creating full 3D profiles after tomographic reconstruction from multiple projections. Given the increasingly complex advances in radiation therapy, and the increased emphasis on patient-specific treatment plans, further refinement of the technique could prove to be an important tool for fast and robust QA of x-ray photon LINAC beams.
PMCID: PMC3568662  PMID: 23318469
20.  Blood Transfusion, Anesthesia, Surgery and Risk of Non-Hodgkin Lymphoma in a Population-Based Case-Control Study 
The incidence of NHL has increased dramatically since at least the 1950s, and during this timeframe there has been a major increase in the use of blood transfusions, invasive surgical procedures, and anesthesia, all of which can impact immune function. We evaluated these factors with NHL risk in a population-based study of 759 cases and 589 frequency-matched controls. Risk factor data were collected during in-person interviews. Unconditional logistic regression was used to estimate ORs and 95% CIs, adjusted for the matching factors. History of transfusion was associated with a 26% higher risk of NHL (95% CI 0.91–1.73), and the elevated risk was specific to transfusions first given 5–29 years before the reference date (OR=1.69; 95% CI 1.08–2.62) and transfusions given for a medical condition (OR=2.09; 95% CI 1.03–4.26). The total number of surgeries and dental procedures (OR=1.53 for 26+ surgeries compared to 0–6; 95% CI 1.02–2.29) and to a lesser extent the total number of exposures to general or local/regional anesthesia (OR=1.35 for 24+ times compared to 0–6; 95% CI 0.91–2.02) were positively associated with risk of NHL. Inclusion of transfusion and surgery or transfusion and anesthesia in the same model did not attenuate these associations. All results were broadly consistent for both DLBCL and follicular subtypes. Blood transfusions were associated with NHL risk, but appear to be a marker for underlying medical conditions. Multiple surgical procedures and/or repeated administration of anesthesia have not been previously reported to be associated with risk of NHL and these exposures warrant further evaluation.
PMCID: PMC3913466  PMID: 18506687
anesthesia; blood transfusion; non-Hodgkin lymphoma; surgery
21.  Magnitude of the Freshwater Turtle Exports from the US: Long Term Trends and Early Effects of Newly Implemented Harvest Management Regimes 
PLoS ONE  2014;9(1):e86478.
Unregulated commercial harvest remains a major threat for turtles across the globe. Due to continuing demand from Asian markets, a significant number of turtles are exported from the United States of America (US). Beginning in 2007, several southeastern states in the US implemented restrictions on the commercial harvest of turtles, in order to address the unsustainable take. We have summarized freshwater turtle exports from the US between 2002 and 2012 and demonstrated that the magnitude of turtle exports from the US remained high although the exports decreased throughout the decade. Louisiana and California were the major exporters. The majority of exports were captive bred, and from two genera, Pseudemys and Trachemys. We review the changes over the decade and speculate that the increase in export of wild turtles out of Louisiana after 2007 could be a consequence of strict regulations in surrounding states (e.g., Alabama, Florida). We suggest that if wild turtle protection is a goal for conservation efforts, then these states should work together to develop comprehensive regulation reforms pertaining to the harvest of wild turtles.
PMCID: PMC3903576  PMID: 24475128
22.  Dual-tracer background subtraction approach for fluorescent molecular tomography 
Journal of Biomedical Optics  2013;18(1):016003.
Diffuse fluorescence tomography requires high contrast-to-background ratios to accurately reconstruct inclusions of interest. This is a problem when imaging the uptake of fluorescently labeled molecularly targeted tracers in tissue, which can result in high levels of heterogeneously distributed background uptake. We present a dual-tracer background subtraction approach, wherein signal from the uptake of an untargeted tracer is subtracted from targeted tracer signal prior to image reconstruction, resulting in maps of targeted tracer binding. The approach is demonstrated in simulations, a phantom study, and in a mouse glioma imaging study, demonstrating substantial improvement over conventional and homogenous background subtraction image reconstruction approaches.
PMCID: PMC3537325  PMID: 23292612
image reconstruction; cancer; targeted imaging agent; small animal
23.  Autoverification in a core clinical chemistry laboratory at an academic medical center 
Autoverification is a process of using computer-based rules to verify clinical laboratory test results without manual intervention. To date, there is little published data on the use of autoverification over the course of years in a clinical laboratory. We describe the evolution and application of autoverification in an academic medical center clinical chemistry core laboratory.
Subjects and Methods:
At the institution of the study, autoverification developed from rudimentary rules in the laboratory information system (LIS) to extensive and sophisticated rules mostly in middleware software. Rules incorporated decisions based on instrument error flags, interference indices, analytical measurement ranges (AMRs), delta checks, dilution protocols, results suggestive of compromised or contaminated specimens, and ‘absurd’ (physiologically improbable) values.
The autoverification rate for tests performed in the core clinical chemistry laboratory has increased over the course of 13 years from 40% to the current overall rate of 99.5%. A high percentage of critical values now autoverify. The highest rates of autoverification occurred with the most frequently ordered tests such as the basic metabolic panel (sodium, potassium, chloride, carbon dioxide, creatinine, blood urea nitrogen, calcium, glucose; 99.6%), albumin (99.8%), and alanine aminotransferase (99.7%). The lowest rates of autoverification occurred with some therapeutic drug levels (gentamicin, lithium, and methotrexate) and with serum free light chains (kappa/lambda), mostly due to need for offline dilution and manual filing of results. Rules also caught very rare occurrences such as plasma albumin exceeding total protein (usually indicative of an error such as short sample or bubble that evaded detection) and marked discrepancy between total bilirubin and the spectrophotometric icteric index (usually due to interference of the bilirubin assay by immunoglobulin (Ig) M monoclonal gammopathy).
Our results suggest that a high rate of autoverification is possible with modern clinical chemistry analyzers. The ability to autoverify a high percentage of results increases productivity and allows clinical laboratory staff to focus attention on the small number of specimens and results that require manual review and investigation.
PMCID: PMC4023033  PMID: 24843824
Algorithms; clinical chemistry; clinical laboratory information system; Epstein-Barr virus; informatics
24.  Streamlined sign-out of capillary protein electrophoresis using middleware and an open-source macro application 
Interfacing of clinical laboratory instruments with the laboratory information system (LIS) via “middleware” software is increasingly common. Our clinical laboratory implemented capillary electrophoresis using a Sebia® Capillarys-2™ (Norcross, GA, USA) instrument for serum and urine protein electrophoresis. Using Data Innovations Instrument Manager, an interface was established with the LIS (Cerner) that allowed for bi-directional transmission of numeric data. However, the text of the interpretive pathology report was not properly transferred. To reduce manual effort and possibility for error in text data transfer, we developed scripts in AutoHotkey, a free, open-source macro-creation and automation software utility.
Materials and Methods:
Scripts were written to create macros that automated mouse and key strokes. The scripts retrieve the specimen accession number, capture user input text, and insert the text interpretation in the correct patient record in the desired format.
The scripts accurately and precisely transfer narrative interpretation into the LIS. Combined with bar-code reading by the electrophoresis instrument, the scripts transfer data efficiently to the correct patient record. In addition, the AutoHotKey script automated repetitive key strokes required for manual entry into the LIS, making protein electrophoresis sign-out easier to learn and faster to use by the pathology residents. Scripts allow for either preliminary verification by residents or final sign-out by the attending pathologist.
Using the open-source AutoHotKey software, we successfully improved the transfer of text data between capillary electrophoresis software and the LIS. The use of open-source software tools should not be overlooked as tools to improve interfacing of laboratory instruments.
PMCID: PMC4204301  PMID: 25337433
Capillary electrophoresis; instrumentation; laboratory information system; middleware; open-source software
25.  Quantifying receptor density in vivo using a dual-probe approach with fluorescence molecular imaging 
Proceedings of SPIE  2011;7965:10.1117/12.891720.
Molecular imaging technologies are advancing rapidly and optical techniques in particular are set to play a large role in preclinical pharmaceutical testing. These approaches, however, are generally unable to quantify the level of expression of imaging probe reporters. In this study a novel method of quantification is presented using dual-probe fluorescence imaging, where an endothelial growth factor receptor (EGFR) fluorescent probe was paired with a non-targeted probe before being injected, and tracer kinetic compartmental modeling was used to determine EGFR expression in a region of interest from the uptake curves of the two drugs in that region. The approach was tested out in a simulation experiment and then applied in an in vivo study in one mouse to investigate EGFR expression in various tissue types (pancreas, pancreas tumor, and leg). The binding potentials (a unitless correlate of target availability) of EGFR expression in the various tissue types were 8.57, 25.64, and 0.11 for the pancreas, pancreas tumor, respectively. For the pancreas and leg, these results correlate well with expected levels of EGFR expression, with the pancreas demonstrating a much higher expression than the skin and also as expected, the tumor expressed much more EGFR than either healthy tissue.
PMCID: PMC3874279  PMID: 24379938
fluorescence molecular imaging; tracer kinetic modeling; dual probe imaging

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