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Two phase 3 clinical trials showed that use of a monthly vaginal ring containing 25 mg dapivirine was well tolerated and reduced HIV-1 incidence in women by approximately 30% compared with placebo. We aimed to evaluate use and safety of the dapivirine vaginal ring (DVR) in open-label settings with high background rates of HIV-1 infection, an important step for future implementation.We did a phase 3B open-label extension trial of the DVR (MTN-025/HIV Open-label Prevention Extension [HOPE]). Women who were HIV-1-negative and had participated in the MTN-020/ASPIRE phase 3 trial were offered 12 months of access to the DVR at 14 clinical research centres in Malawi, South Africa, Uganda, and Zimbabwe. At each visit (monthly for 3 months, then once every 3 months), women chose whether or not to accept the offer of the ring. Used, returned rings were tested for residual amounts of dapivirine as a surrogate marker for adherence. HIV-1 serological testing was done at each visit. Dapivirine amounts in returned rings and HIV-1 incidence were compared with data from the ASPIRE trial, and safety was assessed. This study is registered with ClinicalTrials.gov, NCT02858037.Between July 16, 2016, and Oct 10, 2018, of 1756 women assessed for eligibility, 1456 were enrolled and participated in the study. Median age was 31 years (IQR 27-37). At baseline, 1342 (92·2%) women chose to take the DVR; ring acceptance was more than 79% at each visit up until 12 months and 936 (73·2%) of 1279 chose to take the ring at all visits. 12 530 (89·3%) of 14 034 returned rings had residual dapivirine amounts consistent with some use during the previous month (0·9 mg released) and the mean dapivirine amount released was greater than in the ASPIRE trial (by 0·21 mg; p0·0001). HIV-1 incidence was 2·7 per 100 person-years (95% CI 1·9-3·8, 35 infections), compared with an expected incidence of 4·4 per 100 person-years (3·2-5·8) among a population matched on age, site, and presence of a sexually transmitted infection from the placebo group of ASPIRE. No serious adverse events or grade 3 or higher adverse events observed were assessed as related to the DVR.High uptake and persistent use in this open-label extension study support the DVR as an HIV-1 prevention option for women. With an increasing number of HIV-1 prophylaxis choices on the horizon, these results suggest that the DVR will be an acceptable and practical option for women in Africa.The Microbicide Trials Network and the National Institute of Allergy and Infectious Diseases, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health, all components of the US National Institutes of Health.

To increase the ecological realism in an economic analysis of invasive species management in a river network, this paper identifies optimal spatial-dynamic management while accounting for specific invasive species strategies, including long-distance dispersal, exogenous arrivals, propagule pressure, and seed fitness. Although a stylized framework, the inclusion of native species permits analysis of trade-offs between the management actions of invasive species control and of habitat restoration for a range of settings and species characteristics. In general, more aggressive invasive species and more invasion-susceptible ecosystems require greater investment in habitat restoration despite its relative expense. Explicitly modeling invasion strategies reveals that the specific ecological mechanism of invasion defines the location of management activities in the river network, and the choice between invasive species control and habitat restoration. The analysis of this bioeconomic model develops insights that help managers to harness the power of native-invasive species establishment interactions in stemming bio-invasions across time and space.

Recent analyses demonstrate that the spatial–temporal behavior of invasive species requires optimal management decisions over space and time. From a spatial perspective, this bioeconomic optimization model broadens away from invasive species spread at a frontier or to neighbors by examining short and long-distance dispersal, directionality in spread, and network geometry. In terms of uncertainty and dynamics, this framework incorporates several sources of stochasticity, decisions with multi-year implications, and temporal ecological processes. This paper employs a unique Markov decision process planning algorithm and a Monte Carlo simulation of the stochastic system to explore the spatial-dynamic optimal policy for a river network facing a bioinvasion, with Tamarisk as an example. In addition to exploring the spatial, stochastic, and dynamic aspects of management of invasions, the results demonstrate how the interaction of spatial and multi-period processes contributes to finding the optimal policy. Those interactions prove critical in determining the right management tool, in the right location, at the right time, which informs the management implications drawn from simpler frameworks. In particular, as compared to other modeling framework’s policy prescriptions, the framework here finds more use of the management tool restoration and more management in highly connected locations, which leads to a less invaded system over time.

For ecosystem services analysis, a key to collaboration between natural and social scientists is the identification and measurement of linking indicators: biophysical indicators that facilitate social evaluation, including monetary valuation of ecological changes. As ecosystem service analysts and practitioners better recognize the various ways in which people benefit from ecosystems, natural scientists will be called on to develop, use, and report on metrics and indicators that link to those diverse benefits. The paper develops principles to guide the identification of linking indicators, compares their features with those of more commonly collected ecological measures, and reviews empirical evidence pertinent to their identification, definition, and performance, primarily from the point of view of conducting monetary valuation of ecological outcomes.

Lakes provide recreational benefits related to water quality. Using data from the 2007 and 2012 United States National Lake Assessments (N = 2067 lake visits), we developed indicators for three benefits: swimming, general recreational value, and aesthetic appeal. For two combined ecoregions (“Mountains” and “Plains”) we related objective measures of water clarity, including Secchi depth, turbidity, and water-column chlorophyll-a concentration to subjective visual assessments of recreational benefit quality. There were significant associations between water clarity measures and visual assessments from which we derived water-clarity based thresholds between benefit quality classes (exceptional, high, low, marginal) for each benefit type. More variation in Secchi depth and turbidity was explained by benefit quality than was variation in chlorophyll-a. Threshold values were different between combined ecoregions. Compared to lakes in the Mountains ecoregion, recreational users of Plains lakes have lower expectations for water clarity. Thresholds were generally in accord with water clarity thresholds and guidance derived from published regional studies. Including indicators of the quality of benefits humans receive from lakes in assessments of lake conditions can increase public participation in decision-making and reveal changes in benefit quality over time.

Background Metastatic melanoma in sentinel lymph nodes is often elusive to detect with morphology alone. Per American Joint Committee on Cancer staging guidelines, a single atypical melanocyte in lymph node qualifies as metastasis, whether identified by morphology or immunohistochemistry, but single cell staining must be convincing. We propose that the use of a second immunohistochemical run performed on a single slide will allow for more confident diagnosis of micrometastases. Materials and methods We designed a technical study to determine whether a second antibody application on previously stained slides can successfully detect the same population of cells. Melanocytic neoplasms were stained with SOX-10 using Ventana Benchmark Ultra stainers, coverslipped, and examined, followed by coverslip removal and application of MART-1 (Ventana A103). The order of antibody application and chromagen detection kit (AP-RED vs. DAB) was reversed to establish reliability and robustness of the protocol. Results All melanocytes marked with SOX-10 and MART-1, and produced a range of staining quality that varied based on order of stain application and chromagen kit were used. The optimal combination was red MART-1 applied first followed by brown SOX-10 applied second. Conclusions Consecutive staining of melanocytes with SOX-10 and MART-1 may improve diagnostic confidence of melanocyte identification, particularly in detection of single cell, micrometastases in sentinel lymph nodes or in situations where dual immunohistochemical stains may be unavailable.

3-Azabicyclo[3.1.0]hexane compounds were designed as novel achiral μ opioid receptor ligands for the treatment of pruritus in dogs. In this paper, we describe the SAR of this class of opioid ligand, highlighting changes to the lead structure which led to compounds having picomolar binding affinity, selective for the μ receptor over δ and κ subtypes. Some subtleties of functional activity will also be described.

Background: Cardiac contractility modulation (CCM) signals are nonexcitatory electrical signals delivered during the absolute refractory period intended to improve contraction. We previously tested the safety and efficacy of CCM in 428 NYHA functional class III/IV heart failure patients with EF #35% and narrow QRSrandomizedtooptimalmedicaltreatment(OMT)plusCCM(n5215)versusOMTalone(n5213)and found no significant effect on ventilatory anaerobic threshold (VAT), the study’s primary end point. In the present analysis, we sought to identify if there was a subgroup of patients who showed a response to CCM. Methods and Results: The protocol specified that multiregression analysis would be used to determine if baselineEF,NYHAfunctional class,pVO2,oretiologyofheartfailure influencedtheimpactofCCM onAT. Etiology and baseline pVO2 did not affect efficacy. However, baseline NYHA functional class III and EF $25% were significant predictors of increased efficacy. In this subgroup (comprising 97 OMTand 109 CCM patients, w48% of the entire population) VAT increased by 0.10 6 2.36 in CCM versus � 0.54 6 1.83 mL kg � 1 min � 1 in OMT (P 5 .03) and pVO2 increased by 0.34 6 3.11 in CCM versus � 0.97 6 2.31 (P 5 .001) at 24 weeks compared with baseline; 44% of CCM versus 23% of OMT subjects showed improvement of $1 class in NYHA functional class (P 5 .002), and 59% of CCM versus 42% of OMT subjects showed a $10-point reduction in Minnesota Living with Heart Failure Questionnaire (P 5 .01). All of these findings were similar to those seen at 50 weeks. Conclusions: The results of this retrospective hypothesis-generating analysis indicate that CCM significantlyimprovesobjectiveparametersofexercisetoleranceinasubgroupofpatientscharacterizedbynormal QRS duration, NYHA functional class III symptoms, and EF O25%. (J Cardiac Fail 2011;17:710e717)

BACKGROUNDStability and transport challenges make hemoglobin (Hb) A1c measurement from EDTA whole blood (WB) inconvenient and costly for large-scale population studies. This study investigated Hb A1c measurement from WB blotted on filter paper (FP) in a Level I National Glycohemoglobin Standardization Program (NGSP)-accredited laboratory.METHODSThree Bio-Rad Variant™ II HPLC instruments and WB and FP specimens were used. Precision, accuracy, linearity, and readable total area of the 6.5-min (β-thalassemia method) Variant II HbA2/HbA1c Dual Program were assessed. Hb A1c stability was measured using in-house FP QC samples. The INTERHEART (a study of the effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries) and CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) studies provided chromatographs for morphometric analyses and interoperator variability experiments. Statistical analyses were performed to assess long-term sample stability, WB vs FP agreement, and significance of Hb A1c peak integration.RESULTSIntra- and interassay CVs were ≤2.00%. Total area counts between 0.8 and 5.5 × 106 μV/s produced accurate Hb A1c results. The regression equation for agreement between WB(x) and FP(y) was as follows: y = 0.933x + 0.4 (n = 85). FP QC samples stored at −70 °C and tested over approximately 3 years yielded CVs of 1.72%–2.73% and regression equations with slopes of −1.08 × 10−4 to 7.81 × 10−4. The CURE study, with better preanalytical preparation, achieved a 97% reportable rate, and the reportable rate of the INTERHEART study was 85%.CONCLUSIONSThe FP collection method described provided accurate, robust, and reproducible measurement of Hb A1c using the Bio-Rad Variant II HPLC autoanalyzer when FP specimens were prepared according to standardized protocols, and analyses were performed in an NGSP-certified laboratory, supporting the use of FP collection cards in large multinational studies.

In this study we compared alternative measures of early writing performance to identify an indicator of writing proficiency that teachers could use to monitor student growth and evaluate instructional effectiveness. The participants were 15 second-grade students in a summer school program for students at risk. The performance sampled was word copying, sentence copying, word dictation, and sentence dictation. Two- to three-minute samples of performance were obtained and several different scores were examined. The criterion validity of the early writing measures was examined using both global judgments of competence and quantitative scoring of story writing as criteria. Writing from word and sentence dictation entered into very high correlations with both criteria, showing promise as indicators of early writing proficiency. The results are discussed in terms of desirable features of assessment procedures including technical adequacy, administrative efficiency, and consumer acceptability.

Students solved mathematics problems from 4 assignment pairs. Each control assignment contained 18 target multiplication problems that were 4 × 1-digit (4 × 1), 4 × 2, 4 × 3, or 4 × 4. Each paired experimental assignment contained 18 similar problems plus 6 interspersed 1 × 1-digit problems. After computing problems from each pair of assignments, the students rated them and chose 1 for homework. Across all assignment pairs, problem completion rates were greater on the experimental assignments, and significantly more students chose a new experimental, rather than control, assignment for homework. Furthermore, as the discrepancy between problem completion rates increased across assignment pairs, the probability of students' choosing the experimental assignment for homework and rating the experimental assignment more favorably with respect to difficulty, effort, and time also increased. The relationship between student choice behaviors and relative problem completion rates has theoretical and applie...

This report presents a capstone summary of the results of the Options and Opportunities for Whole-of-Government Contributions in the Campaign against International Piracy Project. It addresses the issues of the incidence of piracy in Africa, the pirate enterprises in Somalia and the Gulf of Guinea viewed as businesses, the international and national legal authorities for counterpiracy, and our framework for a whole-of-government approach to counterpiracy.

Background: Success of cardiac resynchronization therapy (CRT) depends on altering electrical ventricular activation (VA) to achieve mechanical benefit. That increases in stimulus strength (SS) can affect VA has been demonstrated previously in cardiomyopathy patients undergoing ablation. Objective: To determine whether increasing SS can alter VA during CRT. Methods: In 71 patients with CRT devices, left ventricle (LV) pacing was performed at escalating SS. Timing from pacing stimulus to right ventricular (RV) electrogram, ECG morphology, and maximal QRS duration on 12 lead ECG were recorded. Results: Demographics: Baseline QRS duration 153 ± 25 ms, ischemic cardiomyopathy 48%, ejection fraction 24%± 7%. With increased SS, conduction time from LV to right ventricle (RV) decreased from 125 ± 56 ms to 111 ± 59 ms (P = 0.006). QRS duration decreased from 212 ± 46 ms to 194 ± 42 ms (P = 0.0002). A marked change in QRS morphology occurred in 11/71 patients (15%). The RV ring was the anode in 6, while the RV coil was the anode in 5. Sites with change in QRS morphology showed decrease in conduction time from LV to RV from 110 ± 60 ms to 64 ± 68 ms (P = 0.04). Twelve patients (16%) had diaphragmatic stimulation with increased SS. Conclusions: Increasing LV SS reduces QRS duration and conduction time from LV to RV. Recognition of significant QRS morphology change is likely clinically important during LV threshold programming to avoid unintended VA change.

KHJ Enterprise, LLC presents: The Black & Blues Brunch @ Warmdaddy's Restaurant An event to increase awareness and screening for colorectal cancer in the African American community. The black represents African American and the blue(s) is for the color associated with colorectal cancer. The purpose of this project is to increase awareness about the critical need for colorectal screening in the African American community, in addition to understanding what early detection, diagnosis, and treatment options are available. The hope is that by providing critical information in a nontraditional, relaxed, “edu-tainment” setting more Philadelphians of African American descent will leave equipped with information to improve their health outcomes and the willingness and commitment to participate in a life-saving cancer screening Citation Format: Kim Hall Jackson. The success of the Black and Blues Brunch. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr B57.

Liposomal formulations have been used to encapsulate and deliver a wide variety of therapeutic and diagnostic agents. Their circulation can be prolonged by the addition of neutral, hydrophilic polymers such as poly(ethylene glycol) (PEG) to the outer surface. An extended circulation lifetime allows them to take advantage of the enhanced permeability and retention effect (EPR), resulting in increased delivery to target sites. Incorporation of PEG also prevents aggregation and aids in the formation of uniform, small mono-disperse particles. This is often accomplished with the use of PEG-lipid conjugates, PEG molecules with a hydrophobic domain to anchor them into the liposomal bilayer upon formulation. Here we present data showing that some commonly used PEG-lipids are chemically unstable due to the presence of carboxylic ester bonds. This instability limits their utility in aqueous environments common to many liposomal preparations. To address this problem, we designed and synthesized three alternative PEG-lipids. Using SPLP (PEG-stabilized liposomal vesicles encapsulating plasmid DNA) as a model system, we investigated the properties of the novel PEG-lipids. An accelerated stability study was conducted at 37 degrees C for 42 days to confirm chemical stability and an in vivo model was used to assess the pharmacokinetics, toxicity and activity of the SPLP. We show that the novel PEG-lipids are more stable in liposomal formulation, less toxic upon systemic administration, and accordingly, are suitable replacements for the PEG-lipids described previously.

Prior research has shown a higher incidence of a repressive adaptive style in children with cancer. To explore whether repressive adaptation in this population is premorbid or reactive, adaptive style was assessed longitudinally in children with cancer at the time of diagnosis and at 6 months and 1 year after diagnosis. Comparison groups included healthy children and children with other serious but nonmalignant chronic illnesses. At diagnosis, children with cancer showed a higher incidence of a repressive adaptive style than healthy children, and the incidence of repressive adaptation remained stable over time. Children with other chronic illnesses also showed levels of repressive adaptive style comparable to the cancer group. These findings suggest a shift toward repressiveness in response to the diagnosis of cancer that is then maintained over time and necessitate further examination of the health consequences of adaptive style in this population.