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1.  Assessment of Algorithms to Identify Patients with Thrombophilia following Venous Thromboembolism 
Thrombosis research  2015;137:97-102.
Introduction
Routine testing for thrombophilia following venous thromboembolism (VTE) is controversial. The use of large datasets to study the clinical impact of thrombophilia testing on patterns of care and patient outcomes may enable more efficient analysis of this practice in a wide range of settings. We set out to examine how accurately algorithms using International Classification of Diseases 9th Revision (ICD-9) codes and/or pharmacy data reflect laboratory-confirmed thrombophilia diagnoses.
Materials and Methods
A random sample of adult Kaiser Permanente Colorado patients diagnosed with unprovoked VTE between 1/2004 and 12/2010 underwent medical record abstraction of thrombophilia test results. Algorithms using “ICD-9” (positive if a thrombophilia ICD-9 code was present), “Extended anticoagulation (AC)” (positive if AC therapy duration was >6 months), and “ ICD-9 & Extended AC” (positive for both) criteria to identify possible thrombophilia cases were tested. Using positive thrombophilia laboratory results as the gold standard, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value of each algorithm were calculated, along with 95% confidence intervals (CIs).
Results
In our cohort of 636 patients, sensitivities were low (<50%) for each algorithm. “ICD-9” yielded the highest PPV (41.5%, 95% CI 26.3–57.9%) and a high specificity (95.9%, 95% CI 94.0–97.4%). “Extended AC” had the highest sensitivity but lowest specificity, and “ICD-9 & Extended AC” had the highest specificity, but the lowest sensitivity.
Conclusions
ICD-9 codes for thrombophilia are highly specific for laboratory-confirmed cases, but all algorithms had low sensitivities. Further development of methods to identify thrombophilia patients in large datasets is warranted.
doi:10.1016/j.thromres.2015.11.009
PMCID: PMC5123887  PMID: 26585762
Thrombophilia; venous thromboembolism; dataset; algorithms; sensitivity; specificity
2.  A bright cyan-excitable orange fluorescent protein facilitates dual-emission microscopy and enhances bioluminescence imaging in vivo 
Nature biotechnology  2016;34(7):760-767.
Orange-red fluorescent proteins (FPs) are widely used in biomedical research for multiplexed epifluorescence microscopy with GFP-based probes, but their different excitation requirements make multiplexing with new advanced microscopy methods difficult. Separately, orange-red FPs are useful for deep-tissue imaging in mammals due to the relative tissue transmissibility of orange-red light, but their dependence on illumination limits their sensitivity as reporters in deep tissues. Here we describe CyOFP1, a bright engineered orange-red FP that is excitable by cyan light. We show that CyOFP1 enables single-excitation multiplexed imaging with GFP-based probes in single-photon and two-photon microscopy, including time-lapse imaging in light-sheet systems. CyOFP1 also serves as an efficient acceptor for resonance energy transfer from the highly catalytic blue-emitting luciferase NanoLuc. An optimized fusion of CyOFP1 and NanoLuc, called Antares, functions as a highly sensitive bioluminescent reporter in vivo, producing substantially brighter signals from deep tissues than firefly luciferase and other bioluminescent proteins.
doi:10.1038/nbt.3550
PMCID: PMC4942401  PMID: 27240196
3.  ReCAP: Oncologists’ Selection of Genetic and Molecular Testing in the Evolving Landscape of Stage II Colorectal Cancer 
Journal of Oncology Practice  2016;12(3):259-260.
CONTEXT AND QUESTION ASKED:
Genetic testing can be used in the diagnosis of Lynch syndrome, formerly known as hereditary nonpolyposis colorectal cancer (CRC), the most common inherited disorder that increases the risk for CRC; however, test results related to Lynch syndrome screening may also be used for predictive and prognostic purposes in patients with stage II CRC. Although national guidelines recommend the use of several genetic and molecular tests for patients with CRC, little is known about how guidelines, particularly the complex testing recommendations for Lynch syndrome, are translated into clinical practice. In this study, we asked: how does the family history of patients with stage II CRC influence medical oncologists’ selection of genetic and molecular testing, both related and unrelated to Lynch syndrome?
SUMMARY ANSWER:
We found that oncologists’ self-reported ordering of Lynch syndrome–related tests was strongly associated with the strength of CRC family history, but even so, not all oncologists would order germline testing for mismatch repair (MMR) genes, much less screen for Lynch syndrome by ordering microsatellite instability and/or immunohistochemistry for MMR proteins, in a patient scenario with the strongest family history of CRC (Table 2). We also found overtesting of KRAS and Oncotype DX for stage II CRC associated with certain practice and provider characteristics, with graduates of non-US or non-Canadian medical schools and physicians compensated under fee-for-service or by productivity-based salaries being more likely to choose KRAS testing. Fee-for-service and productivity-based salaries were also associated with increased Oncotype DX testing.
Percentages of Oncologists Who Reported They Would Order Genetic and Molecular Testing for a Patient Newly Diagnosed With Stage II CRC, Unadjusted
Abbreviations: IHC, immunohistochemistry; MMR, mismatch repair; MSI, microsatellite instability.
Maximum number of respondents for each scenario.
METHODS:
In 2012 and 2013, we surveyed medical oncologists in the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) and evaluated their selection of microsatellite instability and/or immunohistorchemistry for MMR proteins, germline testing for MMR genes, BRAF and KRAS mutation analysis, and Oncotype DX in stage II CRC. Physicians were randomly assigned to receive one of three vignettes, varying by strength of CRC family history. We compared differences in testing by family history and provider and practice characteristics, and we used multivariate logistic regression to identify provider and practice characteristics associated with testing.
BIAS, CONFOUNDING FACTOR(S), DRAWBACKS:
Although we surveyed a large cohort of oncologists from diverse geographic and practice settings, there were several limitations to this study. Whereas CanCORS patients are representative of the national patient population, participants were mostly oncologists who care for patients enrolled in CanCORS and who may be slightly older than US oncologists as a whole. Furthermore, our measures of testing relied on physician self-reporting rather than direct measures of use. In addition, we did not ask oncologists to report on the sequence in which they would order the various tests, and we were unable to determine whether such respondents would have ordered simultaneous or sequential testing. Finally, our study focused on patients with stage II CRC and may not be further generalizable.
REAL-LIFE IMPLICATIONS:
The high lifetime risk of CRC and other cancers among affected individuals and family members and low detection rates led the Centers for Disease Control and Prevention to recommend universal Lynch syndrome screening of all patients newly diagnosed with CRC. Previous efforts to increase the identification of patients and family members with Lynch syndrome have unfortunately achieved limited success. It remains to be seen whether the recapitulation by the National Comprehensive Cancer Network of the Centers for Disease Control and Prevention recommendation to screen all incident CRC specimens for Lynch syndrome can increase diagnoses. Undertesting related to Lynch syndrome screening and overtesting involving molecular tests among surveyed oncologists highlight the need for improved implementation, targeted education, and evaluation of organizational and financial arrangements to promote the appropriate use of genetic and molecular tests.
doi:10.1200/JOP.2015.007062
PMCID: PMC4960467  PMID: 26962170
4.  Association of Early Patient-Physician Care Planning Discussions and End-of-Life Care Intensity in Advanced Cancer 
Journal of Palliative Medicine  2015;18(10):834-841.
Abstract
Background: Early patient-physician care planning discussions may influence the intensity of end-of-life (EOL) care received by veterans with advanced cancer.
Objective: The study objective was to evaluate the association between medical record documentation of patient-physician care planning discussions and intensity of EOL care among veterans with advanced cancer.
Methods: This was a retrospective cohort study. Subjects were 665 veteran decedents diagnosed with stage IV colorectal, lung, or pancreatic cancer in 2008, and followed till death or the end of the study period in 2011. We estimated the effect of patient-physician care planning discussions documented within one month of metastatic diagnosis on the intensity of EOL care measured by receipt of acute care, intensive interventions, chemotherapy, and hospice care, using multivariate logistic regression models.
Results: Veterans in our study were predominantly male (97.1%), white (74.7%), with an average age at diagnosis of 66.4 years. Approximately 31% received some acute care, 9.3% received some intensive intervention, and 6.5% had a new chemotherapy regimen initiated in the last month of life. Approximately 41% of decedents received no hospice or were admitted within three days of death. Almost half (46.8%) had documentation of a care planning discussion within the first month after diagnosis and those who did were significantly less likely to receive acute care at EOL (OR: 0.67; p=0.025). Documented discussions were not significantly associated with intensive interventions, chemotherapy, or hospice care.
Conclusion: Early care planning discussions are associated with lower rates of acute care use at the EOL in a system with already low rates of intensive EOL care.
doi:10.1089/jpm.2014.0431
PMCID: PMC4599129  PMID: 26186553
5.  Rapid Synthesis of Near Infrared Polymeric Micelles for Real-time Sentinal Lymphnode Imaging 
Advanced healthcare materials  2012;1(5):582-589.
In this manuscript a synthetic methodology for developing sub 20 nm sized polymeric micellar nanoparticle designed for extravascular imaging and therapy is revealed. A simple, one-pot method is followed, which involved a rapid co-self assembly of an amphiphilic diblock copolymer (PS-b-PAA) and polyoxyethylene (80) sorbitan monooleate in water. Sorbitan monooleate imparts stability to the micelles and helps to drive down the particle size below 20 nm. The particles were incorporated with a water soluble dye ADS832WS, which absorbs in the near infrared range (λex= 832nm) for sensitive detection with optical and photoacoustic imaging techniques. A candidate lipophilic antiangiogenic therapeutic agent fumagillin was also incorporated with high entrapment (>95%) efficiency. We demonstrate the effectiveness of this theranostic platform for real-time high-resolution intraoperative photoacoustic imaging for facilitating direct assessment of the sentinel lymph nodes (SLN) in breast cancer staging. The technique offers huge potential providing faster resection of SLN and may minimize complications caused by axillary exploration due to mismarking with dyes or low resolution imaging techniques. Finally, the biodistribution and organ accumulation of the intravenously and intradermally injected particles were studied in rodent model by optical imaging. Data suggest that intraveneously injected NIR-polymeric nanoparticles follow a typical bio-distribution clearance path through the reticuloendothelial (RES) system. For the intradermally injected particles, a slower mechanism of clearance was noticed.
doi:10.1002/adhm.201200087
PMCID: PMC5041307  PMID: 23184793
Polymer; self assembly; optical imaging; photoacoustics; drug delivery
6.  Tolerability in the elderly population of high-dose alpha lipoic acid: a potential antioxidant therapy for the eye 
Purpose
Alpha lipoic acid (ALA) is an antioxidant and iron-chelating supplement that has potential benefits for geographic atrophy in dry age-related macular degeneration as well as other eye diseases. The purpose of this study was to determine the tolerability of ALA in the elderly population.
Patients and methods
Fifteen subjects, age ≥65 years, took sequential ALA doses of 600, 800, and 1,200 mg. Each dose was taken once daily with a meal for 5 days. After each dose was taken by the subjects for 5 days, the subjects were contacted by phone, a review of systems was performed, and they were asked if they thought they could tolerate taking that dose of ALA for an extended period of time.
Results
The 600 mg dose was well tolerated. At the 800 mg dose, one subject had an intolerable flushing sensation. At the 1,200 mg dose, two subjects had intolerable upper gastrointestinal side effects and one subject had an intolerable flushing sensation. Subjects taking gastrointestinal prophylaxis medications had no upper gastrointestinal side effects.
Conclusion
High-dose ALA is not completely tolerated by the elderly. These preliminary data suggest that gastrointestinal prophylaxis may improve tolerability. (ClinicalTrials.gov, NCT02613572).
doi:10.2147/OPTH.S115900
PMCID: PMC5047711  PMID: 27729766
age-related macular degeneration; geographic atrophy; antioxidant; gastrointestinal; dietary supplements; lipoic acid
7.  Oncologists' Experiences With Drug Shortages 
Journal of Oncology Practice  2014;11(2):e154-e162.
Most oncologists encountered drug shortages in the year before our survey, but experiences with shortages varied with practice structure. Further research is needed to quantitatively assess the impact of drug shortages on patients.
Purpose:
There have been numerous reports of shortages of injectable drugs for cancer in the last decade. We assessed physician experiences with drug shortages in a population-based cohort of medical oncologists caring for patients with lung or colorectal cancer.
Methods:
We surveyed medical oncologists caring for patients with lung or colorectal cancer in the Cancer Care Outcomes Research and Surveillance Consortium from 2012 to 2013 (participation rate, 53%). Oncologists reported experiences with shortages of leucovorin, fluorouracil, dexamethasone, cyanocobalamin, paclitaxel, cisplatin, and etoposide in the prior year and whether they had used a less-effective alternative because of a shortage. We used multivariable logistic regression to assess for associations between physician or practice characteristics and encountering shortages.
Results:
Among 330 respondents, 74% reported experiences with a shortage of at least one drug in our survey, and 28% reported using a less-effective alternative because of a shortage. Although physician demographic characteristics did not predict reports of drug shortages, practice characteristics did. Veterans Affairs (VA) oncologists were less likely to report experiencing any shortage than oncologists in single-specialty group practice (odds ratio [OR], 0.4; 95% CI, 0.2 to 0.9). The reported use of a less effective alternative to any drug was also less common among VA oncologists (OR, 0.3; 95% CI, 0.1 to 0.9) and oncologists affiliated with health maintenance organizations (OR, 0.4; 95% CI, 0.2 to 0.9) compared with physicians in single-specialty groups.
Conclusion:
Most oncologists encountered drug shortages in the year before our survey, but experiences with shortages varied with practice structure. Further research is needed to quantitatively assess the impact of drug shortages on patients and evaluate various strategies for managing them.
doi:10.1200/JOP.2014.000380
PMCID: PMC4371121  PMID: 25549653
8.  A strategy for combating melanoma with oncogenic c-Myc inhibitors and targeted nanotherapy 
Nanomedicine (London, England)  2015;10(2):241-251.
Aims
The activity of the transcription factor c-Myc is dependent upon heterodimerization with Max to control target gene transcription. Small-molecule inhibitors of c-Myc–Max have exhibited low potency and poor water solubility and are therefore unsuitable for in vivo application. We hypothesized that a nanomedicine approach incorporating a cryptic c-Myc inhibitor prodrug could be delivered and enzymatically released in order to effectively inhibit melanoma.
Materials & methods
An Sn-2 lipase-labile Myc inhibitor prodrug was synthesized and included in two αvβ3-targeted nanoparticle platforms (20 and 200 nm). The inherent antiproliferate potency was compared with the lipid-free compound using human and mouse melanoma cell lines.
Results & conclusion
These data demonstrate for the first time a successful nanodelivery of c-Myc inhibitors and their potential use to prevent melanoma.
doi:10.2217/nnm.14.101
PMCID: PMC4665613  PMID: 25600969
c-Myc inhibitor; melanoma; nanotherapy; prodrug
9.  “Starry sky” 
JAMA ophthalmology  2014;132(11):1340.
doi:10.1001/jamaophthalmol.2014.563
PMCID: PMC4427039  PMID: 25210891
10.  Endocrine disruptors alter social behaviors and indirectly influence social hierarchies via changes in body weight 
Environmental Health  2015;14:64.
Background
In humans, the causal link between socioeconomic status (SES) and body weight (BW) is bidirectional, as chronic stress associated with low SES may increase risk of obesity and excess weight may worsen career opportunities resulting in lower SES. We hypothesize that environmental factors affecting BW and/or social stress might reprogram physiological and social trajectories of individuals.
Objectives
To analyze interactions between BW and social behaviors in mice perinatally exposed to one of several environmental endocrine disruptors.
Methods
CD-1 mice were fed 0.2 mg/kg BW/day tetrabromobisphenol-A (TBBPA), 2,2,4,4-tetrabromodiphenyl ether (BDE-47), bisphenol S (BPS), or oil (vehicle) from pregnancy day 8 through postpartum day 21. Three male offspring (triad) from each litter were housed together until week 15 and subjected to a Sociability Test and Tube Tests. Cages were then rearranged so that animals of the same social rank from the four exposure groups were housed together in tetrads. Social hierarchy in tetrads was again analyzed by Tube Tests.
Results
In Sociability Tests, the mean velocity of all exposed animals increased when they encountered a stranger mouse and less time was spent with conspecifics. BW and social dominance of animals in triads and tetrads were inversely associated. BDE-47 and BPS caused transient decreases in BW.
Conclusions
Developmental exposure to environmental xenobiotics shifted behavior towards increased anxiety and decreased interest in social interactions. Our mouse model reproduces negative associations between social hierarchy status and BW. These results suggest that manipulation of BW by endocrine disruptors may affect social ranking.
Electronic supplementary material
The online version of this article (doi:10.1186/s12940-015-0051-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12940-015-0051-6
PMCID: PMC4524022  PMID: 26242739
Body weight; Social status; Social dominance; Sociability; Endocrine disruption; Tetrabromobisphenol-A; TBBPA; 2,2,4,4-tetrabromodiphenyl ether; BDE-47; Bisphenol S; BPS
11.  Sporadic Visual Acuity Loss in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) 
American journal of ophthalmology  2014;158(1):128-135.e10.
Purpose
To evaluate transient, large visual acuity (VA) decreases, termed sporadic vision loss, during anti-vascular endothelial growth factor treatment for neovascular age-related macular degeneration (AMD).
Design
Cohort within a randomized clinical trial.
Methods
Setting
Comparison of AMD Treatments Trials (CATT).
Study Population
1185 CATT patients.
Main Outcome Measures
incidence of sporadic vision loss and odds ratio (OR) for association with patient and ocular factors. Sporadic vision loss was a decline of ≥ 15 letters from the previous visit, followed by a return at the next visit to no more than 5 letters worse than the visit before the VA loss.
Results
There were 143 sporadic vision loss events in 122/1185 (10.3%) patients. Mean VA at two years for those with and without sporadic vision loss was 58.5 (~20/63) and 68.4 (~20/40) letters, respectively (P < 0.001). Among patients treated pro re nata, no injection was given for 27.6% (27/98) of sporadic vision loss events. Multivariate analysis demonstrated that baseline predictors for sporadic vision loss included worse baseline VA (OR 2.92, 95%CI:1.65–5.17 for ≤ 20/200 compared with ≥ 20/40), scar (OR 2.21, 95%CI:1.22–4.01), intraretinal foveal fluid on optical coherence tomography (OR 1.80, 95%CI:1.11–2.91), and medical history of anxiety (OR 1.90, 95%CI:1.12–3.24) and syncope (OR 2.75, 95%CI:1.45–5.22). Refraction decreased the likelihood of sporadic vision loss (OR 0.62, 95%CI:0.42–0.91).
Conclusions
Approximately 10% of CATT patients had sporadic vision loss. Baseline predictors included AMD-related factors and factors independent of AMD. These data are relevant for clinicians in practice and those involved in clinical trials.
doi:10.1016/j.ajo.2014.04.004
PMCID: PMC4301065  PMID: 24727261
12.  Recognition and Sensing of Low-Epitope Targets via Ternary Complexes with Oligonucleotides and Synthetic Receptors 
Nature chemistry  2014;6(11):1003-1008.
Oligonucleotide-based receptors or aptamers can interact with small molecules, but the ability to achieve high-affinity and selectivity of these interactions depends strongly on functional groups or epitopes displayed by the binding targets. Some classes of targets are particularly challenging: for example, monosaccharides have scarce functionalities and no aptamers have been reported to recognize, let alone distinguish from each other, glucose and other hexoses. Here we report aptamers that differentiate low-epitope targets such as glucose, fructose, or galactose by forming ternary complexes with high-epitope organic receptors for monosaccharides. In a follow-up example, we expand this method to isolate high-affinity oligonucleotides against aromatic amino acids complexed in situ with a non-specific organometallic receptor. The method is general and enables broad clinical use of aptamers for detection of small molecules in mix-and-measure assays, as demonstrated by monitoring postprandial waves of phenylalanine in human subjects.
doi:10.1038/nchem.2058
PMCID: PMC4339820  PMID: 25343606
13.  Breast Implant–associated Anaplastic Large Cell Lymphoma: Updated Results from a Structured Expert Consultation Process 
Background:
Despite increased cases published on breast implant–associated anaplastic large cell lymphoma (BIA-ALCL), important clinical issues remain unanswered. We conducted a second structured expert consultation process to rate statements related to the diagnosis, management, and surveillance of this disease, based on their interpretation of published evidence.
Methods:
A multidisciplinary panel of 12 experts was selected based on nominations from national specialty societies, academic department heads, and recognized researchers in the United States.
Results:
Panelists agreed that (1) this disease should be called “BIA-ALCL”; (2) late seromas occurring >1 year after breast implantation should be evaluated via ultrasound, and if a seroma is present, the fluid should be aspirated and sent for culture, cytology, flow cytometry, and cell block to an experienced hematopathologist; (3) surgical removal of the affected implant and capsule (as completely as possible) should occur, which is sufficient to eradicate capsule-confined BIA-ALCL; (4) surveillance should consist of clinical follow-up at least every 6 months for at least 5 years and breast ultrasound yearly for at least 2 years; and (5) BIA-ALCL is generally a biologically indolent disease with a good prognosis, unless it extends beyond the capsule and/or presents as a mass. They firmly disagreed with statements that chemotherapy and radiation therapy should be given to all patients with BIA-ALCL.
Conclusions:
Our assessment yielded consistent results on a number of key, incompletely addressed issues regarding BIA-ALCL, but additional research is needed to support these statement ratings and enhance our understanding of the biology, treatment, and outcomes associated with this disease.
doi:10.1097/GOX.0000000000000268
PMCID: PMC4323400  PMID: 25674377
14.  Low serum sphingolipids in children with attention deficit-hyperactivity disorder 
Background: Attention deficit-hyperactivity disorder (ADHD) is the most prevalent neuropsychiatric condition in childhood. ADHD is a multifactorial trait with a strong genetic component. One neurodevelopmental hypothesis is that ADHD is associated with a lag in brain maturation. Sphingolipids are essential for brain development and neuronal functioning, but their role in ADHD pathogenesis is unexplored. We hypothesized that serum sphingolipid levels distinguish ADHD patients from unaffected subjects.
Methods: We characterized serum sphingolipid profiles of ADHD patients and two control groups: non-affected relatives and non-affected subjects without a family history of ADHD. Sphingolipids were measured by LC-MS/MS in 77 participants (28 ADHD patients, 28 related controls, and 21 unrelated controls). ADHD diagnosis was based on the Diagnostic and Statistical Manual of Mental Disorders (DSM IV-TR). Diagnostic criteria were assessed by two independent observers. Groups were compared by parametrical statistics.
Results: Serum sphingomyelins C16:0, C18:0, C18:1, C24:1, ceramide C24:0, and deoxy-ceramide C24:1 were significantly decreased in ADHD patients at 20–30% relative reductions. In our sample, decreased serum sphingomyelin levels distinguished ADHD patients with 79% sensitivity and 78% specificity.
Conclusions: Our results showed lower levels of all major serum sphingomyelins in ADHD. These findings may reflect brain maturation and affect neuro-functional pathways characteristic for ADHD.
doi:10.3389/fnins.2015.00300
PMCID: PMC4548182  PMID: 26379487
ADHD; sphingolipids; sphingomyelins; ceramides; biomarker; endophenotype
15.  A Brief Account of Nanoparticle Contrast Agents for Photoacoustic Imaging 
Photoacoustic imaging (PAI) is a hybrid, nonionizing modality offering excellent spatial resolution, deep penetration, and high soft tissue contrast. In PAI, signal is generated based on the absorption of laser-generated optical energy by endogenous tissues or exogenous contrast agents leading to acoustic emissions detected by an ultrasound transducer. Research in this area over the years has shown that PAI has the ability to provide both physiological and molecular imaging, which can be viewed alone or used in a hybrid modality fashion to extend the anatomic and hemodynamic sensitivities of clinical ultrasound. PAI may be performed using inherent contrast afforded by light absorbing molecules such as hemoglobin, myoglobin, and melanin or exogenous small molecule contrast agent such as near infrared dyes and porphyrins. However, this review summarizes the potential of exogenous nanoparticle-based agents for PAI applications including contrast based on gold particles, carbon nanotubes, and encapsulated copper compounds.
doi:10.1002/wnan.1231
PMCID: PMC4067981  PMID: 23983210
Photoacoustic imaging; gold nanoparticle; copper nanoparticle; carbon nanoparticle; NIR dyes; porphyrins; fibrin; angiogenesis; melanoma; sentinel lymphnode; thrombus
16.  Sustained Visual Acuity Loss in the Comparison of Age-Related Macular Degeneration Treatments Trials 
JAMA ophthalmology  2014;132(8):915-921.
IMPORTANCE
Although anti–vascular endothelial growth factor treatment of neovascular age-related macular degeneration (AMD) results in improved vision overall, loss of substantial vision can occur. Understanding the processes that lead to loss of vision may lead to preventive strategies.
OBJECTIVE
To determine the incidence, characteristics, causes, and baseline predictors of sustained visual acuity loss after 2 years of treatment with ranibizumab or bevacizumab for neovascular AMD.
DESIGN, SETTING, AND PARTICIPANTS
A cohort study within a randomized clinical trial of participants in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT).
INTERVENTIONS
Participants were randomly assigned to treatment with ranibizumab or bevacizumab and to 2 years of monthly or as needed injections or monthly injections for 1 year and as needed injections the following year.
MAIN OUTCOMES AND MEASURES
Sustained visual acuity loss, defined as loss of 15 or more letters from baseline at weeks 88 and 104.
RESULTS
Among 1030 participants, 61 eyes (5.9%) developed sustained visual acuity loss in 2 years. Within this group, visual acuity decreased gradually over time, with a mean decrease of 2, 19, and 33 letters from baseline at 4 weeks, 1 year, and 2 years, respectively. At 2 years, eyes with sustained visual acuity loss had more scarring (60.0% vs 41.4%, P = .007), more geographic atrophy (GA) (31.6% vs 20.7%, P = .004), larger lesions (16 vs 8 mm2, P < .001), and higher proportions of intraretinal fluid (82.5% vs 51.0%, P < .001), subretinal hyperreflective material (84.5% vs 44.2%, P < .001), retinal thinning (43.3% vs 23.0%, P < .001), and thickening (20.0% vs 12.1%, P < .001). Likely causes of sustained visual acuity loss included foveal scarring (44.3%), pigmentary abnormalities (27.9%), and foveal GA (11.5%). Baseline factors independently associated with a higher incidence of sustained visual acuity loss were the presence of nonfoveal GA (odds ratio [OR], 2.86; 95% CI, 1.35–6.08; P = .006), larger area of choroidal neovascularization (OR for a >4-disc area vs ≤1-disc area, 3.91; 95% CI, 1.70–9.03; P = .007), and bevacizumab treatment (OR, 1.83; 95% CI, 1.07–3.14; P = .03).
CONCLUSIONS AND RELEVANCE
Sustained visual acuity loss was relatively rare in CATT. The development of foveal scar, pigmentary abnormalities, or GA contributed to most of the sustained visual acuity loss. Risk was 3% higher among eyes treated with bevacizumab. Treatment that targeted the prevention of scarring or GA may improve vision outcomes.
TRIAL REGISTRATION
clinicaltrials.gov Identifier: NCT00593450
doi:10.1001/jamaophthalmol.2014.1019
PMCID: PMC4151260  PMID: 24875610
17.  Optobiology: Optical control of biological processes via protein engineering 
Biochemical Society transactions  2013;41(5):1183-1188.
Enabling optical control over biological processes is a defining goal of the new field of optogenetics. Control of membrane voltage by natural rhodopsin-family ion channels has found widespread acceptance in neuroscience, due to the fact that these natural proteins control membrane voltage without further engineering. In contrast, optical control of intracellular biological processes has been a fragmented effort, with various laboratories engineering light-responsive properties into proteins in different manners. Here, we review the various systems that have been developed for controlling protein functions with light based on vertebrate rhodopsins, plant photoregulatory proteins, and, most recently, the photoswitchable fluorescent protein Dronpa. By allowing biology to be controlled with spatiotemporal specificity and tunable dynamics, light-controllable proteins will find applications in the understanding of cellular and organismal biology and in synthetic biology.
doi:10.1042/BST20130150
PMCID: PMC4076147  PMID: 24059506
optogenetics; LOV domain; cryptochrome; phytochrome; UVR8; fluorescent protein
18.  Anti-Angiogenesis Therapy in the Vx2 Rabbit Cancer Model with a Lipase-cleavable Sn 2 Taxane Phospholipid Prodrug using αvβ3-Targeted Theranostic Nanoparticles 
Theranostics  2014;4(6):565-578.
In nanomedicine, the hydrophobic nature of paclitaxel has favored its incorporation into many nanoparticle formulations for anti-cancer chemotherapy. At lower doses taxanes are reported to elicit anti-angiogenic responses. In the present study, the facile synthesis, development and characterization of a new lipase-labile docetaxel prodrug is reported and shown to be an effective anti-angiogenic agent in vitro and in vivo. The Sn 2 phosphatidylcholine prodrug was stably incorporated into the lipid membrane of αvβ3-integrin targeted perfluorocarbon (PFC) nanoparticles (αvβ3-Dxtl-PD NP) and did not appreciably release during dissolution against PBS buffer or plasma over three days. Overnight exposure of αvβ3-Dxtl-PD NP to plasma spiked with phospholipase enzyme failed to liberate the taxane from the membrane until the nanoparticle integrity was compromised with alcohol. The bioactivity and efficacy of αvβ3-Dxtl-PD NP in endothelial cell culture was as effective as Taxol® or free docetaxel in methanol at equimolar doses over 96 hours. The anti-angiogenesis effectiveness of αvβ3-Dxtl-PD NP was demonstrated in the Vx2 rabbit model using MR imaging of angiogenesis with the same αvβ3-PFC nanoparticle platform. Nontargeted Dxtl-PD NP had a similar MR anti-angiogenesis response as the integrin-targeted agent, but microscopically measured decreases in tumor cell proliferation and increased apoptosis were detected only for the targeted drug. Equivalent dosages of Abraxane® given over the same treatment schedule had no effect on angiogenesis when compared to control rabbits receiving saline only. These data demonstrate that αvβ3-Dxtl-PD NP can reduce MR detectable angiogenesis and slow tumor progression in the Vx2 model, whereas equivalent systemic treatment with free taxane had no benefit.
doi:10.7150/thno.7581
PMCID: PMC3982128  PMID: 24723979
lipase-labile docetaxel prodrug; perfluorocarbon; nanoparticles
19.  Synthesis and characterization of membrane stable bis(arylimino)isoindole dyes and their potential application in nano-biotechnology 
Tetrahedron letters  2012;53(32):4134-4137.
A synthetic methodology of preparing novel membrane stable, responsive dyes is revealed in this manuscript. 1,3-bis(arylimino)isoindole dyes were synthesized and their properties to undergo intramolecular hydrogen bonding was studied with fluorescence spectroscopy in varying solvent polarities. Based on the functional moieties, compound that is capable of hydrogen donor and acceptor interactions produces predominant photoexcitation in comparison to the responsive dyes that lack these functionalities. These dyes, by the virtue of the presence of long chain acyl groups could be incorporated stably within the phospholipids membrane of core-shell nanoparticles. Nanoparticle was ‘cracked’ to release the dye from a hydrophobic to a hydrophilic environment, A significant change in florescence intensity was then observed, indicating the direct change in effect of intramolecular hydrogen bonding based on solvent polarity changes. This unique study provided implications of many further applications towards nanomedicine and nano-biotechnology.
doi:10.1016/j.tetlet.2012.05.128
PMCID: PMC3398693  PMID: 22822276
Fluorescence dye; Bis(imino)isoindole; Responsive dyes; Membrane stable; Nano-biotechnology
20.  Antiangiogenic nanotherapy with lipase-labile Sn-2 fumagillin prodrug 
Nanomedicine (London, England)  2012;7(10):1507-1519.
Background
The chemical instability of antiangiogenic fumagillin, combined with its poor retention during intravascular transit, requires an innovative solution for clinical translation. We hypothesized that an Sn-2 lipase-labile fumagillin prodrug in combination with a contact-facilitated drug delivery mechanism, could be used to address these problems.
Methods
αvβ3-targeted and nontargeted nanoparticles with and without fumagillin in the prodrug or native forms were evaluated in vitro and in vivo in the Matrigel™ (BD Biosciences, CA, USA) plug model of angiogenesis in mice.
Results
In vitro experiments demonstrated that the new fumagillin prodrug decreased viability at least as efficacious as the parent compound, on an equimolar basis. In the Matrigel mouse angiogenesis model, αvβ3-fumagillin prodrug decreased angiogenesis as measured by MRI (3T), while the neovasculature was unaffected with the control nanoparticles.
Conclusion
The present approach resolved the previously intractable problems of drug instability and premature release in transit to target sites.
doi:10.2217/nnm.12.27
PMCID: PMC3498609  PMID: 22709347
angiogenesis; fumagillin; nanomedicine; nanoparticle; prodrug; therapy
21.  Sensitive Biological Detection with a Soluble and Stable Polymeric Paramagnetic Nano Cluster 
Journal of the American Chemical Society  2012;134(25):10377-10380.
We describe the design, synthesis and biological characterization of manganese oxocluster-based “single molecule magnets (SMMs)”. We demonstrate that polymeric micellar nanoparticles can serve as a carrier and help to stabilize delicate SMM molecules from breaking down easily and thus prevent their property loss. Concentrating thousands of Mn-clusters per micelle provided a high ionic and per-particle relaxivity allowing sensitive MR imaging in vivo. This reports one of the earliest examples of in vivo imaging of a rationally designed polymeric micelles that features SMM.
doi:10.1021/ja3040366
PMCID: PMC3397310  PMID: 22693958
23.  Influence of Patient Preferences on the Cost-Effectiveness of Screening for Lynch Syndrome 
Journal of Oncology Practice  2012;8(3 Suppl):e24s-e30s.
This cost-utility analysis reports on the effect of quality of life on the value of screening all new patients with colorectal cancer for Lynch syndrome.
Purpose:
Patients and relatives have varying preferences for genetic testing and interventions related to hereditary cancer syndromes. We examined how the impact of these services on quality of life (QoL) affects the cost-effectiveness of screening for Lynch syndrome among probands newly diagnosed with colorectal cancer and their relatives.
Methods:
We constructed a state-transition model comparing screening strategies (clinical criteria, prediction algorithms, tumor testing, and upfront germline testing) with no screening to identify Lynch syndrome. The model incorporated individuals' health state utilities after screening, germline testing, and risk-reducing surgeries, with utilities persisting for 12 months in the base case. Outcomes consisted of quality-adjusted life-years (QALYs), costs, and cost per QALY gained. Sensitivity analyses assessed how the duration and magnitude of changes in QoL influenced results.
Results:
Multiple screening strategies yielded gains in QALYs at acceptable costs compared with no screening. The preferred strategy—immunohistochemistry of tumors followed by BRAF mutation testing (IHC/BRAF)—cost $59,700 per QALY gained in the base case. The duration and magnitude of decreases in QoL after decisions related to germline testing and surgeries were key determinants of the cost-effectiveness of screening. IHC/BRAF cost > $100,000 per QALY gained when decrements to QoL persisted for 21 months.
Conclusion:
Screening for Lynch syndrome in the population is likely to yield long-term gains in life expectancy that outweigh any short-term decreases in QoL, at acceptable costs. Counseling for individuals should aim to mitigate potential negative impact of genetic testing and risk-reducing interventions on QoL.
doi:10.1200/JOP.2011.000535
PMCID: PMC3348599  PMID: 22942831
24.  Use of Colony-Stimulating Factors With Chemotherapy: Opportunities for Cost Savings and Improved Outcomes 
Myeloid colony-stimulating factors (CSFs) decrease the risk of febrile neutropenia (FN) from high-risk chemotherapy regimens administered to patients at 20% or greater risk of FN, but little is known about their use in clinical practice. We evaluated CSF use in a multiregional population-based cohort of lung and colorectal cancer patients (N = 1849). Only 17% (95% confidence interval [CI] = 8% to 26%) patients treated with high-risk chemotherapy regimens received CSFs, compared with 18% (95% CI = 16% to 20%) and 10% (95% CI = 8% to 12%) of patients treated with intermediate- (10%–20% risk of FN) and low-risk (<10% risk of FN) chemotherapy regimens, respectively. Using a generalized estimating equation model, we found that enrollment in a health maintenance organization (HMO) was strongly associated with a lower adjusted odds of discretionary CSF use, compared with non-HMO patients (odds ratio = 0.44, 95% CI = 0.32 to 0.60, P < .001). All statistical tests were two-sided. Overall, 96% (95% CI = 93% to 98%) of CSFs were administered in scenarios where CSF therapy is not recommended by evidence-based guidelines. This finding suggests that policies to decrease CSF use in patients at lower or intermediate risk of FN may yield substantial cost savings without compromising patient outcomes.
doi:10.1093/jnci/djr152
PMCID: PMC3119647  PMID: 21670423
25.  Two Mechanistic Pathways for Thienopyridine-Associated Thrombotic Thrombocytopenic Purpura 
Objectives
We sought to describe clinical and laboratory findings for a large cohort of patients with thienopyridine-associated thrombotic thrombocytopenic purpura (TTP).
Background
The thienopyridine derivatives, ticlopidine and clopidogrel, are the 2 most common drugs associated with TTP in databases maintained by the U.S. Food and Drug Administration (FDA).
Methods
Clinical reports of TTP associated with clopidogrel and ticlopidine were identified from medical records, published case reports, and FDA case reports (n = 128). Duration of thienopyridine exposure, clinical and laboratory findings, and survival were recorded. ADAMTS13 activity (n = 39) and inhibitor (n = 30) were measured for a subset of individuals.
Results
Compared with clopidogrel-associated TTP cases (n = 35), ticlopidine-associated TTP cases (n = 93) were more likely to have received more than 2 weeks of drug (90% vs. 26%), to be severely thrombocytopenic (84% vs. 60%), and to have normal renal function (72% vs. 45%) (p < 0.01 for each). Compared with TTP patients with ADAMTS13 activity >15% (n = 13), TTP patients with severely deficient ADAMTS13 activity (n = 26) were more likely to have received ticlopidine (92.3% vs. 46.2%, p < 0.003). Among patients who developed TTP >2 weeks after thienopyridine, therapeutic plasma exchange (TPE) increased likelihood of survival (84% vs. 38%, p < 0.05). Among patients who developed TTP within 2 weeks of starting thienopyridines, survival was 77% with TPE and 78% without.
Conclusions
Thrombotic thrombocytopenic purpura is a rare complication of thienopyridine treatment. This drug toxicity appears to occur by 2 different mechanistic pathways, characterized primarily by time of onset before versus after 2 weeks of thienopyridine administration. If TTP occurs after 2 weeks of ticlopidine or clopidogrel therapy, therapeutic plasma exchange must be promptly instituted to enhance likelihood of survival.
doi:10.1016/j.jacc.2007.04.093
PMCID: PMC3167088  PMID: 17868804

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