Determining the Relationship between Delivery Parameters and Ablation Distribution for Novel Gel Ethanol Percutaneous Therapy in Ex Vivo Swine Liver.

Ethyl cellulose-ethanol (ECE) is emerging as a promising formulation for ablative injections, with more controllable injection distributions than those from traditional liquid ethanol. This study evaluates the influence of salient injection parameters on forces needed for infusion, depot volume, retention, and shape in a large animal model relevant to human applications. Experiments were conducted to investigate how infusion volume (0.5 mL to 2.5 mL), ECE concentration (6% or 12%), needle gauge (22 G or 27 G), and infusion rate (10 mL/h) impacted the force of infusion into air using a load cell. These parameters, with the addition of manual infusion, were investigated to elucidate their influence on depot volume, retention, and shape (aspect ratio), measured using CT imaging, in an ex vivo swine liver model. Force during injection increased significantly for 12% compared to 6% ECE and for 27 G needles compared to 22 G. Force variability increased with higher ECE concentration and smaller needle diameter. As infusion volume increased, 12% ECE achieved superior depot volume compared to 6% ECE. For all infusion volumes, 12% ECE achieved superior retention compared to 6% ECE. Needle gauge and infusion rate had little influence on the observed depot volume or retention; however, the smaller needles resulted in higher variability in depot shape for 12% ECE. These results help us understand the multivariate nature of injection performance, informing injection protocol designs for ablations using gel ethanol and infusion, with volumes relevant to human applications.

Designing Dual Compartment HIV Prevention Products: Women's Sensory Perceptions and Experiences of Suppositories for Rectal and Vaginal Use.

Dual compartment suppositories are being developed to prevent HIV and other sexually transmitted infections. Such products, for use in the rectum, the vagina, or both, could have a significant public health impact by decreasing global incidence of these diseases. In this study, 16 women each used two rheologically distinct suppositories in their vagina and rectum. User Sensory Perception and Experience (USPE) scales assessed sensory experiences during sexual activity to understand whether, and how, women perceive formulation properties in the vagina and rectum. Qualitative data from individual in-depth interviews captured women's descriptions and comparisons of the experiences. Significant differences and large Cohen's d effect sizes between vaginal and rectal experiences of suppository-A were found for three scales: Application (APP): Product Awareness, SEX: Initial Penetration; and SEX: Effortful. Qualitative data provided user experience details that credibly align with these score differences. Near significant differences and large effect sizes were found for two additional scales: SEX: Perceived Wetness with suppository-A and SEX: Messiness with suppository-B. In addition, other scale scores showed medium-to-large effect sizes that correspond to hypothesized sensations associated with biophysical properties of the suppositories. Statistical significance combined with large effect sizes and qualitative data accurately represent the hypothesized perceptibility of suppository properties and identifies performance characteristics relevant to acceptability and adherence; together these data provide discernment of factors that can guide the development of dual compartment products. The Clinical Trial Registration number: NCT02744261.

Comparing Water Absorption of Food and Drug Administration-Approved Hyaluronic Acid Fillers.

BACKGROUND: To compare the water absorption of 12 FDA-approved hyaluronic acid (HA) facial fillers in vitro in conditions relevant to in vivo injection. OBJECTIVE: The goal of this study was to provide long-term insight into an improved, tailored facial rejuvenation approach and to understand sequelae that could affect preoperative surgical planning. METHODS: In 2 experiments, 12 FDA-approved HA fillers were loaded into test tubes with nonpreserved normal saline and then placed in a 94.5°F-96°F environment for 1 month to allow water absorption by passive diffusion. The test tubes were centrifuged so that the hydrated filler could pass to the bottom of the tube. The tubes were centrifuged for 12 minutes at 1,200 revolutions per minute in the first experiment and for 7 minutes in the second experiment. A blue dye was then instilled to demarcate the filler/saline interface. RESULTS: There was variation in the water absorption of different HAs. Low absorption occurred in non-animal-stabilized hyaluronic acid. CONCLUSION: The pattern of water absorption was similar in the 2 experiments. The results inform us about in vivo conditions and provide guidance for filler selection.

Sodium bicarbonate gels: a new promising strategy for the treatment of vulvovaginal candidosis.

Vulvovaginal candidosis (VVC), caused mainly by the yeast Candida albicans, is the second most prevalent vaginal infection. It has been found to have a large impact on women's quality of life, self-esteem and routines. The prevalence of recurrent vulvovaginal candidosis (RVVC) remains high so the development of alternative treatments is needed. The main objective of this study was to develop and characterize sodium bicarbonate gels to treat VVC. We described key formulation characteristics and analyzed their influence on in vitro performance evaluations. The potential to inhibit Candida albicans's growth, the pH, osmolality, viscosity and rheological performance in contact with vaginal fluid simulant and the bioadhesion's profile (using a vaginal ex vivo porcine model) were studied for all formulations. Among the formulations, formulation C (5% sodium bicarbonate, 1% carbomer and 94% water) was the most effective in inhibiting the C. albicans' growth. This gel presented the same potential (the same MIC 2.5%) to inhibit other etiological agents of VVC (C. glabrata, C. krusei, C. tropicalis and C. parapsilosis) for all species tested. Additionally, sensorial characteristics of gel C were in accord with users' preferences. This gel exhibited physicochemical characteristics acceptable for short term treatments, suggesting good overall performance for the treatment of VVC. Furthermore, Gel C was biocompatible with the HeLa cell line (MTT assay) and was classified as a non-severe irritant in the HET-CAM assay (irritation score 4 ± 1). Overall, gel C was deemed the best performing of the set tested, and suitable for further development.

Understanding Factors Governing Distribution Volume of Ethyl Cellulose-Ethanol to Optimize Ablative Therapy in the Liver.

OBJECTIVE: Ethanol ablation, the injection of ethanol to induce necrosis, was originally used to treat hepatocellular carcinoma, with survival rates comparable to surgery. However, efficacy is limited due to leakage into surrounding tissue. To reduce leakage, we previously reported incorporating ethyl cellulose (EC) with ethanol as this mixture forms a gel when injected into tissue. To further develop EC-ethanol injection as an ablative therapy, the present study evaluates the extent to which salient injection parameters govern the injected fluid distribution. METHODS: Utilizing ex vivo swine liver, injection parameters (infusion rate, EC%, infusion volume) were examined with fluorescein added to each solution. After injection, tissue samples were frozen, sectioned, and imaged. RESULTS: While leakage was higher for ethanol and 3%EC-ethanol at a rate of 10 mL/hr compared to 1 mL/hr, leakage remained low for 6%EC-ethanol regardless of infusion rate. The impact of infusion volume and pressure were also investigated first in tissue-mimicking surrogates and then in tissue. Results indicated that there is a critical infusion pressure beyond which crack formation occurs leading to fluid leakage. At a rate of 10 mL/hr, a volume of 50 µL remained below the critical pressure. CONCLUSIONS: Although increasing the infusion rate increases stress on the tissue and the risk of crack formation, injections of 6%EC-ethanol were localized regardless of infusion rate. To further limit leakage, multiple low-volume infusions may be employed. SIGNIFICANCE: These results, and the experimental framework developed to obtain them, can inform optimizing EC-ethanol to treat a range of medical conditions.

Deducing Mucosal Pharmacokinetics and Pharmacodynamics of the Anti-HIV Molecule Tenofovir from Measurements in Blood.

Microbicide pharmacokinetic (PK) studies typically sample drug in luminal fluid, mucosal tissue, and blood. Blood measurements can be conducted most frequently, serially within subjects. Antiretroviral drugs, however, act against HIV in mucosal tissue/cells. We computationally modeled the extent measurements in blood can predict concentrations in tissue, focusing on the antiretroviral drug tenofovir delivered by a vaginal gel. Deterministic PK models input host and product factors and output spatiotemporal drug concentrations in luminal fluid, epithelium, stroma/host cells, and blood. Pharmacodynamic (PD) analysis referenced stroma/host cell concentrations to prophylactic values; summary metrics were time from product insertion to protection (tlag) and degree of protection (PPmax). Results incorporated host factors characteristic of population variability. Neural nets (NN) linked simulated blood PK metrics (Cmax, tmax, AUC, C24) to mucosal PK/PD metrics. The NNs delivered high-performance mapping of these multiparametric relationships. Given multi-log variability typical of biopsy data for tenofovir and other topical microbicides, results suggest downstream but higher fidelity measurements in blood could help improve determination of PK and create inferences about PD. Analysis here is for a tenofovir gel, but this approach offers promise for application to other microbicide modalities and to topical drug delivery to vaginal mucosa more generally.

Effects of gel volume on pharmacokinetics for vaginal and rectal applications of combination DuoGel-IQB4012, a dual chamber-dual drug HIV microbicide gel, in pigtailed macaques.

This study evaluated effects of differing gel volumes on pharmacokinetics (PK). IQB4012, a gel containing the non-nucleoside reverse transcriptase inhibitor IQP-0528 and tenofovir (TFV), was applied to the pigtailed macaque vagina and rectum. Vaginal gel volumes (1% loading of both drugs) were 0.5 or 1.5 ml; following wash-out, 1 or 4 ml of gel were then applied rectally. Blood, vaginal, and rectal fluids were collected at 0, 2, 4, and 24 h. Vaginal and rectal tissue biopsies were collected at 4 and 24 h. There were no statistically significant differences in concentrations for either drug between gel volumes within compartments at matched time points. After vaginal gel application, median IQP-0528 concentrations were ~ 104-105 ng/g, 105-106 ng/ml, and 103-105 ng/ml in vaginal tissues, vaginal fluids, and rectal fluids, respectively (over 24 h). Median vaginal TFV concentrations were 1-2 logs lower than IQP-0528 levels at matched time points. After rectal gel application, median IQP-0528 and TFV concentrations in rectal fluids were ~ 103-105 ng/ml and ~ 102-103 ng/ml, respectively. Concentrations of both drugs sampled in rectal tissues were low (~ 101-103 ng/g). For 1 ml gel, half of sampled rectal tissues had undetectable concentrations of either drug, and over half of sampled rectal fluids had undetectable TFV concentrations. These results indicate differences in drug delivery between the vaginal and rectal compartments, and that smaller vaginal gel volumes may not significantly compromise microbicide PK and prophylactic potential. However, effects of rectal gel volume on PK for both drugs were less definitive.

Full depth measurement of tenofovir transport in rectal mucosa using confocal Raman spectroscopy and optical coherence tomography.

The prophylactic activity of antiretroviral drugs applied as microbicides against sexually transmitted HIV is dependent upon their concentrations in infectable host cells. Within mucosal sites of infection (e.g., vaginal and rectal mucosa), those cells exist primarily in the stromal layer of the tissue. Traditional pharmacokinetic studies of these drugs have been challenged by poor temporal and spatial specificity. Newer techniques to measure drug concentrations, involving Raman spectroscopy, have been limited by laser penetration depth into tissue. Utilizing confocal Raman spectroscopy (RS) in conjunction with optical coherence tomography (OCT), a new lateral imaging assay enabled concentration distributions to be imaged with spatial and temporal specificity throughout the full depth of a tissue specimen. The new methodology was applied in rectal tissue using a clinical rectal gel formulation of 1% tenofovir (TFV). Confocal RS revealed diffusion-like behavior of TFV through the tissue specimen, with significant partitioning of the drug at the interface between the stromal and adipose tissue layers. This has implications for drug delivery to infectable tissue sites. The new assay can be applied to rigorously analyze microbicide transport and delineate fundamental transport parameters of the drugs (released from a variety of delivery vehicles) throughout the mucosa, thus informing microbicide product design.

Label-free analysis of tenofovir delivery to vaginal tissue using co-registered confocal Raman spectroscopy and optical coherence tomography.

Vaginally applied microbicide products offer a female-controlled strategy for preventing sexual transmission of HIV. Microbicide transport processes are central to their functioning, and there is a clear need for a better understanding of them. To contribute to that end, we developed an assay to analyze mass transport rates of microbicide molecules within the epithelial and stromal layers of polarized vaginal mucosal tissue during contact with a gel vehicle. The assay utilizes a new diffusion chamber mounted in a custom instrument that combines confocal Raman spectroscopy and optical coherence tomography. This measures depth-resolved microbicide concentration distributions within epithelium and stroma. Data for a tenofovir gel were fitted with a compartmental diffusion model to obtain fundamental transport properties: the molecular diffusion and partition coefficients in different compartments. Diffusion coefficients in epithelium and stroma were computed to be 6.10 ± 2.12 x 10-8 and 4.52 ± 1.86 x 10-7 cm2/sec, respectively. The partition coefficients between epithelium and gel and between stroma and epithelium were found to be 0.53 ± 0.15 and 1.17 ± 0.16, respectively. These drug transport parameters are salient in governing the drug delivery performance of different drug and gel vehicle systems. They can be used to contrast drugs and vehicles during product design, development and screening. They are critical inputs to deterministic transport models that predict the gels' pharmacokinetic performance, which can guide improved design of products and optimization of their dosing regimens.

Development of enhanced ethanol ablation as an alternative to surgery in treatment of superficial solid tumors.

While surgery is at the foundation of cancer treatment, its access is limited in low-income countries. Here, we describe development of a low-cost alternative therapy based on intratumoral ethanol injection suitable for resource-limited settings. Although ethanol-based tumor ablation is successful in treating hepatocellular carcinomas, the necessity for multiple treatments, injection of large fluid volumes, and decreased efficacy in treatment of non-capsulated tumors limit its applicability. To address these limitations, we investigated an enhanced ethanol ablation strategy to retain ethanol within the tumor through the addition of ethyl cellulose. This increases the viscosity of injected ethanol and forms an ethanol-based gel-phase upon exposure to the aqueous tumor environment. This technique was first optimized to maximize distribution volume, using tissue-simulating phantoms. Then, chemically-induced epithelial tumors in the hamster cheek pouch were treated. As controls, pure ethanol injections of either four times or one-fourth the tumor volume induced complete regression of 33% and 0% of tumors, respectively. In contrast, ethyl cellulose-ethanol injections of one-fourth the tumor volume induced complete regression in 100% of tumors. These results contribute to proof-of-concept for enhanced ethanol ablation as a novel and effective alternative to surgery for tumor treatment, with relevance to resource-limited settings.

Contemporary Trends in Oral Anticoagulant Prescription in Atrial Fibrillation Patients at Low to Moderate Risk of Stroke After Guideline-Recommended Change in Use of the CHADS2 to the CHA2DS2-VASc Score for Thromboembolic Risk Assessment: Analysis From the National Cardiovascular Data Registry's Outpatient Practice Innovation and Clinical Excellence Atrial Fibrillation Registry.

BACKGROUND: Use of the CHA2DS2-VASc score instead of the CHADS2 score for thromboembolic risk stratification and initiation of oral anticoagulation (OAC) was recommended in the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society atrial fibrillation (AF) guidelines. We sought to define the proportion of patients with AF qualifying for and receiving OAC in contemporary practice by applying the CHA2DS2-VASc score to patients with a low CHADS2 score. METHODS AND RESULTS: Among patients with AF enrolled in the American College of Cardiology National Cardiovascular Data Registry's outpatient Practice Innovation and Clinical Excellence registry (2008-2014) CHADS2 score of 0 or 1, we calculated the impact of adoption of the CHA2DS2-VASc score on the proportion of patients with an indication for OAC. We examined trends in prescription of OAC overall, direct OAC (dabigatran/rivaroxaban/apixaban), and multivariable associations between clinical characteristics and OAC use. Of 346 068 patients with AF aged 65±12 years, 61% were men and 65% were white. In total, 24% of those with CHADS2=0 and 81% of those with a CHADS2=1 were reclassified as having a definite indication for OAC (CHA2DS2-VASc score ≥2). OAC use increased from 37% to 48% during the study period, and direct OAC use increased from 5% to 30%. Increasing CHA2DS2-VASc score (odds ratio, 2.07; 95% confidence interval, 1.97-2.19 for score of 4 versus 0) and rhythm control strategy (odds ratio, 1.34; 95% confidence interval, 1.30-1.39) were associated with increased OAC use. CONCLUSIONS: Adoption of the CHA2DS2-VASc score reclassifies 64.5% of patients with AF with low CHADS2 scores into a class I indication for OAC prescription. Overall OAC prescription increased between 2011 and 2014.

Multicompartmental Pharmacokinetic Model of Tenofovir Delivery to the Rectal Mucosa by an Enema.

Rectal enemas that contain prophylactic levels of anti-HIV microbicides such as tenofovir have emerged as a promising dosage form to prevent sexually transmitted HIV infections. The enema vehicle is promising due to its likely ability to deliver a large amount of drug along the length of the rectal canal. Computational models of microbicide drug delivery by enemas can help their design process by determining key factors governing drug transport and, more specifically, the time history and degree of protection. They can also inform interpretations of experimental pharmacokinetic measures such as drug concentrations in biopsies. The present work begins rectal microbicide PK modeling, for enema vehicles. Results here show that a paramount factor in drug transport is the time of enema retention; direct connectivity between enema fluid and the fluid within rectal crypts is also important. Computations of the percentage of stromal volume protected by a single enema dose indicate that even with only a minute of enema retention, protection of 100% can be achieved after around 14 minutes post dose. Concentrations in biopsies are dependent on biopsy thickness; and control and/or knowledge of thickness could improve accuracy and decrease variability in biopsy measurements. Results here provide evidence that enemas are a promising dosage form for rectal microbicide delivery, and offer insights into their rational design.

Outcomes Among Older Patients Receiving Implantable Cardioverter-Defibrillators for Secondary Prevention: From the NCDR ICD Registry.

BACKGROUND: Clinical trials of implantable cardioverter-defibrillators (ICDs) for secondary prevention of sudden cardiac death were conducted nearly 2 decades ago and enrolled few older patients. OBJECTIVES: This study assessed morbidity and mortality of older patients receiving ICDs for secondary prevention in contemporary clinical practice. METHODS: We identified 12,420 Medicare beneficiaries from the National Cardiovascular Data Registry ICD Registry undergoing first-time secondary prevention ICD implantation between 2006 and 2009 in 956 U.S. hospitals. Risks of death, hospitalization, and admission to a skilled nursing facility (SNF) were assessed over 2 years in age strata (65 to 69, 70 to 74, 75 to 79, and ≥80 years of age) using Medicare claims. The adjusted association between age and outcomes was evaluated using multivariable models. RESULTS: The mean age was 75 years at the time of implantation; 25.3% were <70 years of age and 25.7% were ≥80 years of age. Overall, the risk of death at 2 years was 21.8%, ranging from 14.7% among those <70 years of age to 28.9% among those ≥80 years of age (adjusted risk ratio [aRR]: 2.01; 95% confidence interval [CI]: 1.85 to 2.33; p for trend <0.001). The cumulative incidence of hospitalizations was 65.4%, ranging from 60.5% in those <70 years of age to 71.5% in those ≥80 years of age (aRR: 1.27; 95% CI: 1.19 to 1.36; p for trend <0.001). The cumulative incidence of admission to a SNF ranged from 13.1% among those <70 years of age to 31.9% among those ≥80 years of age (aRR: 2.67; 95% CI: 2.37 to 3.01; p for trend <0.001); SNF admission risk was highest in the first 30 days. CONCLUSIONS: Almost 4 in 5 older patients receiving a secondary prevention ICD survives at least 2 years. High hospitalization and SNF admission rates, particularly among the oldest patients, identify substantial care needs after device implantation.

Survival After Secondary Prevention Implantable Cardioverter-Defibrillator Placement: An Analysis From the NCDR ICD Registry.

OBJECTIVES: This study sought to define the characteristics and risks of death of patients receiving a physician-designated secondary prevention implantable cardioverter-defibrillator (ICD) in contemporary clinical practice. BACKGROUND: Data on utilization and outcomes of ICDs for the secondary prevention of sudden cardiac death (SCD) are limited. METHODS: Patients enrolled in the National Cardiovascular Data Registry's (NCDR) ICD Registry from 2006 to 2009 with a physician-designated secondary prevention indication for ICD implantation were identified and linked to the Social Security Death Master File. Those patients with a history either of tachycardic arrest or sustained ventricular tachycardia (SCD/VT) or of syncope without SCD/VT were included. Kaplan-Meier survival analysis was used to assess mortality. Cox proportional hazards survival modeling was used to assess the risk of death in these groups, adjusting for patient characteristics. RESULTS: In the study cohort of 46,685 patients (mean age 66 ± 14 years, 73.5% male, 85% white), 78% had SCD/VT and 22% had syncope. Overall mortality was 10.4% at 1 year and 16.4% at 2 years. Compared with patients having SCD/VT, the adjusted hazard of death at 1 year was lower in the patients having syncope (hazard ratio: 0.89; 95% confidence interval: 0.83 to 0.96) but was not significantly different by 2 years (hazard ratio: 0.96; 95% confidence interval: 0.90 to 1.01). CONCLUSIONS: Nearly 9 of 10 patients receiving a secondary prevention ICD in clinical practice are alive 1 year after implantation. The risk of death varies by indication and is highest among patients who survive SCD or sustained VT in the first year after device implantation.

Label-Free Measurements of Tenofovir Diffusion Coefficients in a Microbicide Gel Using Raman Spectroscopy.

Confocal Raman spectroscopy was implemented in a new label-free technique to quantify molecular diffusion coefficients within gels. A leading anti-HIV drug, tenofovir, was analyzed in a clinical microbicide gel. The gel was tested undiluted, and in 10%-50% wt/wt dilutions with vaginal fluid simulant to capture the range of conditions likely occurring in vivo. The concentration distributions of tenofovir in gel over time and space were measured and input to a mathematical diffusion model to deduce diffusion coefficients. These were 3.16 ± 0.11 × 10-6 cm2/s in undiluted gel, and increased by 11%-46% depending on the extent of dilution. Results were interpreted with respect to traditional release rate measurements in devices such as Franz cells. This comparison highlighted an advantage of our assay in that it characterizes the diffusive barrier within the gel material itself; in contrast, release rate in the traditional assay is affected by external conditions, such as drug partitioning at the gel/liquid sink interface. This new assay is relevant to diffusion in polymeric hydrogels over pharmacologically relevant length scales, for example, those characteristic of topical drug delivery. Resulting transport parameters are salient measures of drug delivery potential, and serve as inputs to computational models of drug delivery performance.

Oral Anticoagulant Therapy Prescription in Patients With Atrial Fibrillation Across the Spectrum of Stroke Risk: Insights From the NCDR PINNACLE Registry.

IMPORTANCE: Patients with atrial fibrillation (AF) are at a proportionally higher risk of stroke based on accumulation of well-defined risk factors. OBJECTIVE: To examine the extent to which prescription of an oral anticoagulant (OAC) in US cardiology practices increases as the number of stroke risk factors increases. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional registry study of outpatients with AF enrolled in the American College of Cardiology National Cardiovascular Data Registry's PINNACLE (Practice Innovation and Clinical Excellence) Registry between January 1, 2008, and December 30, 2012. As a measure of stroke risk, we calculated the CHADS2 score and the CHA2DS2-VASc score for all patients. Using multinomial logistic regression models adjusted for patient, physician, and practice characteristics, we examined the association between increased stroke risk score and prescription of an OAC. MAIN OUTCOMES AND MEASURES: The primary outcome was prescription of an OAC with warfarin sodium or a non-vitamin K antagonist OAC. RESULTS: The study cohort comprised 429 417 outpatients with AF. Their mean (SD) age was 71.3 (12.9) years, and 55.8% were male. Prescribed treatment consisted of an OAC (192 600 [44.9%]), aspirin only (111 134 [25.9%]), aspirin plus a thienopyridine (23 454 [5.5%]), or no antithrombotic therapy (102 229 [23.8%]). Each 1-point increase in risk score was associated with increased odds of OAC prescription compared with aspirin-only prescription using the CHADS2 score (adjusted odds ratio, 1.158; 95% CI, 1.144-1.172; P < .001) and the CHA2DS2-VASc score (adjusted odds ratio, 1.163; 95% CI, 1.157-1.169; P < .001). Overall, OAC prescription prevalence did not exceed 50% even in higher-risk patients with a CHADS2 score exceeding 3 or a CHA2DS2-VASc score exceeding 4. CONCLUSIONS AND RELEVANCE: In a large quality improvement registry of outpatients with AF, prescription of OAC therapy increased with a higher CHADS2 score and CHA2DS2-VASc score. However, a plateau of OAC prescription was observed, with less than half of high-risk patients receiving an OAC prescription.

Aspirin Instead of Oral Anticoagulant Prescription in Atrial Fibrillation Patients at Risk for Stroke.

BACKGROUND: Oral anticoagulation (OAC), rather than aspirin, is recommended in patients with atrial fibrillation (AF) at moderate to high risk of stroke. OBJECTIVES: This study sought to examine patient and practice-level factors associated with prescription of aspirin alone compared with OAC in AF patients at intermediate to high stroke risk in real-world cardiology practices. METHODS: The authors identified 2 cohorts of outpatients with AF and intermediate to high thromboembolic risk (CHADS2 score ≥2 and CHA2DS2-VASc ≥2) enrolled in the American College of Cardiology PINNACLE (Practice Innovation and Clinical Excellence) registry between 2008 and 2012. Using hierarchical modified Poisson regression models adjusted for patient and practice characteristics, the authors examined the prevalence and predictors of aspirin alone versus OAC prescription in AF patients at risk for stroke. RESULTS: Of 210,380 identified patients with CHADS2 score ≥2 on antithrombotic therapy, 80,371 (38.2%) were treated with aspirin alone, and 130,009 (61.8%) were treated with warfarin or non-vitamin K antagonist OACs. In the cohort of 294,642 patients with CHA2DS2-VASc ≥2, 118,398 (40.2%) were treated with aspirin alone, and 176,244 (59.8%) were treated with warfarin or non-vitamin K antagonist OACs. After multivariable adjustment, hypertension, dyslipidemia, coronary artery disease, prior myocardial infarction, unstable and stable angina, recent coronary artery bypass graft, and peripheral arterial disease were associated with prescription of aspirin only, whereas male sex, higher body mass index, prior stroke/transient ischemic attack, prior systemic embolism, and congestive heart failure were associated with more frequent prescription of OAC. CONCLUSIONS: In a large, real-world cardiac outpatient population of AF patients with a moderate to high risk of stroke, more than 1 in 3 were treated with aspirin alone without OAC. Specific patient characteristics predicted prescription of aspirin therapy over OAC.

Automatic detection of cone photoreceptors in split detector adaptive optics scanning light ophthalmoscope images.

Quantitative analysis of the cone photoreceptor mosaic in the living retina is potentially useful for early diagnosis and prognosis of many ocular diseases. Non-confocal split detector based adaptive optics scanning light ophthalmoscope (AOSLO) imaging reveals the cone photoreceptor inner segment mosaics often not visualized on confocal AOSLO imaging. Despite recent advances in automated cone segmentation algorithms for confocal AOSLO imagery, quantitative analysis of split detector AOSLO images is currently a time-consuming manual process. In this paper, we present the fully automatic adaptive filtering and local detection (AFLD) method for detecting cones in split detector AOSLO images. We validated our algorithm on 80 images from 10 subjects, showing an overall mean Dice's coefficient of 0.95 (standard deviation 0.03), when comparing our AFLD algorithm to an expert grader. This is comparable to the inter-observer Dice's coefficient of 0.94 (standard deviation 0.04). To the best of our knowledge, this is the first validated, fully-automated segmentation method which has been applied to split detector AOSLO images.

Sensitivity Analysis of a Pharmacokinetic Model of Vaginal Anti-HIV Microbicide Drug Delivery.

Uncertainties in parameter values in microbicide pharmacokinetics (PK) models confound the models' use in understanding the determinants of drug delivery and in designing and interpreting dosing and sampling in PK studies. A global sensitivity analysis (Sobol' indices) was performed for a compartmental model of the pharmacokinetics of gel delivery of tenofovir to the vaginal mucosa. The model's parameter space was explored to quantify model output sensitivities to parameters characterizing properties for the gel-drug product (volume, drug transport, initial loading) and host environment (thicknesses of the mucosal epithelium and stroma and the role of ambient vaginal fluid in diluting gel). Greatest sensitivities overall were to the initial drug concentration in gel, gel-epithelium partition coefficient for drug, and rate constant for gel dilution by vaginal fluid. Sensitivities for 3 PK measures of drug concentration values were somewhat different than those for the kinetic PK measure. Sensitivities in the stromal compartment (where tenofovir acts against host cells) and a simulated biopsy also depended on thicknesses of epithelium and stroma. This methodology and results here contribute an approach to help interpret uncertainties in measures of vaginal microbicide gel properties and their host environment. In turn, this will inform rational gel design and optimization.

Perceptibility and the "Choice Experience": User Sensory Perceptions and Experiences Inform Vaginal Prevention Product Design.

The development of pericoital (on demand) vaginal HIV prevention technologies remains a global health priority. Clinical trials to date have been challenged by nonadherence, leading to an inability to demonstrate product efficacy. The work here provides new methodology and results to begin to address this limitation. We created validated scales that allow users to characterize sensory perceptions and experiences when using vaginal gel formulations. In this study, we sought to understand the user sensory perceptions and experiences (USPEs) that characterize the preferred product experience for each participant. Two hundred four women evaluated four semisolid vaginal formulations using the USPE scales at four randomly ordered formulation evaluation visits. Women were asked to select their preferred formulation experience for HIV prevention among the four formulations evaluated. The scale scores on the Sex-associated USPE scales (e.g., Initial Penetration and Leakage) for each participant's selected formulation were used in a latent class model analysis. Four classes of preferred formulation experiences were identified. Sociodemographic and sexual history variables did not predict class membership; however, four specific scales were significantly related to class: Initial Penetration, Perceived Wetness, Messiness, and Leakage. The range of preferred user experiences represented by the scale scores creates a potential target range for product development, such that products that elicit scale scores that fall within the preferred range may be more acceptable, or tolerable, to the population under study. It is recommended that similar analyses should be conducted with other semisolid vaginal formulations, and in other cultures, to determine product property and development targets.