Study design and methods: U.S. study to protect brain health through lifestyle intervention to reduce risk (U.S. POINTER).

INTRODUCTION: The U.S. study to protect brain health through lifestyle intervention to reduce risk (U.S. POINTER) is conducted to confirm and expand the results of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) in Americans. METHODS: U.S. POINTER was planned as a 2-year randomized controlled trial of two lifestyle interventions in 2000 older adults at risk for dementia due to well-established factors. The primary outcome is a global cognition composite that permits harmonization with FINGER. RESULTS: U.S. POINTER is centrally coordinated and conducted at five clinical sites (ClinicalTrials.gov: NCT03688126). Outcomes assessments are completed at baseline and every 6 months. Both interventions focus on exercise, diet, cognitive/social stimulation, and cardiovascular health, but differ in intensity and accountability. The study partners with a worldwide network of similar trials for harmonization of methods and data sharing. DISCUSSION: U.S. POINTER is testing a potentially sustainable intervention to support brain health and Alzheimer's prevention for Americans. Impact is strengthened by the targeted participant diversity and expanded scientific scope through ancillary studies.

Community engagement group model in basic and biomedical research: lessons learned from the BEAT-HIV Delaney Collaboratory towards an HIV-1 cure.

INTRODUCTION: Achieving effective community engagement has been an objective of U.S. National Institutes of Health-funded HIV research efforts, including participation of persons with HIV. Community Advisory Boards (CABs) have remained the predominant model for community engagement since their creation in 1989. As HIV cure-directed research efforts have grown into larger academic-industry partnerships directing resources toward both basic and clinical research under the Martin Delaney Collaboratories (MDC), community input models have also evolved. The BEAT-HIV MDC Collaboratory, based at The Wistar Institute in Philadelphia, United States, implemented a three-part model for community engagement that has shown success in providing greater impact for community engagement across basic, biomedical, and social sciences research efforts. DISCUSSION: In this paper, we review the case study of the formation of the BEAT-HIV Community Engagement Group (CEG) model, starting with the historical partnership between The Wistar Institute as a basic research center and Philadelphia FIGHT as a not-for-profit community-based organization (CBO), and culminating with the growth of community engagement under the BEAT-HIV MDC. Second, we present the impact of a cooperative structure including a Community Advisory Board (CAB), CBO, and researchers through the BEAT-HIV CEG model, and highlight collaborative projects that demonstrate the potential strengths, challenges, and opportunities of this model. We also describe challenges and future opportunities for the use of the CEG model. CONCLUSIONS: Our CEG model integrating a CBO, CAB and scientists could help move us towards the goal of effective, equitable and ethical engagement in HIV cure-directed research. In sharing our lessons learned, challenges and growing pains, we contribute to the science of community engagement into biomedical research efforts with an emphasis on HIV cure-directed research. Our documented experience with implementing the CEG supports greater discussion and independent implementation efforts for this model to engage communities into working teams in a way we find a meaningful, ethical, and sustainable model in support of basic, clinical/biomedical, social sciences and ethics research.

HIV biomedical research groups have prioritized community support and representation as exemplified by the creation of Community Advisory Boards (CABs). Most CABs bring diverse stakeholders to advise on research objectives as part of their activities. The BEAT-HIV Delaney Collaboratory, based at The Wistar Institute in Philadelphia, is a research program created in 2016 to advance HIV cure research. To better engage communities beyond the CAB, the BEAT-HIV Delaney Collaboratory created a Community Engagement Group (CEG) model composed of three distinct components. First, the involvement of a community-based organization (CBO) introduces the historical know-how and relationship with the community. Philadelphia FIGHT fulfills the CBO role as a provider of primary care, education, advocacy, and research support for persons with HIV. Second, the BEAT-HIV CAB provides individual experiences and community input into HIV cure research and gives updates to the broader community about the status of research. Third, basic, clinical/biomedical, and social scientists implement the scientific goals of the BEAT-HIV Collaboratory. In this paper, we aimed to highlight the strengths, challenges, lessons learned, and opportunities of the BEAT-HIV CEG model. We also present examples of collaborative community engagement projects. Our paper contributes to the literature on novel community engagement approaches beyond the CAB. Based on our experience to date using the CEG, a multi-part community engagement model could help move us towards the goal of inclusive, effective, equitable, and ethical engagement in HIV cure research.

Are we there yet? A machine learning architecture to predict organotropic metastases.

BACKGROUND & AIMS: Cancer metastasis into distant organs is an evolutionarily selective process. A better understanding of the driving forces endowing proliferative plasticity of tumor seeds in distant soils is required to develop and adapt better treatment systems for this lethal stage of the disease. To this end, we aimed to utilize transcript expression profiling features to predict the site-specific metastases of primary tumors and second, to identify the determinants of tissue specific progression. METHODS: We used statistical machine learning for transcript feature selection to optimize classification and built tree-based classifiers to predict tissue specific sites of metastatic progression. RESULTS: We developed a novel machine learning architecture that analyzes 33 types of RNA transcriptome profiles from The Cancer Genome Atlas (TCGA) database. Our classifier identifies the tumor type, derives synthetic instances of primary tumors metastasizing to distant organs and classifies the site-specific metastases in 16 types of cancers metastasizing to 12 locations. CONCLUSIONS: We have demonstrated that site specific metastatic progression is predictable using transcriptomic profiling data from primary tumors and that the overrepresented biological processes in tumors metastasizing to congruent distant loci are highly overlapping. These results indicate site-specific progression was organotropic and core features of biological signaling pathways are identifiable that may describe proliferative plasticity in distant soils.

Alginate/Chitosan Particle-Based Drug Delivery Systems for Pulmonary Applications.

Cystic fibrosis (CF) is a complex, potentially life-threatening disease that is most effectively treated through the administration of antibiotics (e.g., colistimethate sodium). Chronic infection with Pseudomonas aeruginosa is one of the most significant events in the pathogenesis of cystic fibrosis, and tobramycin is the treatment of choice for those patients with chronic P. aeruginosa infection who are deteriorating despite regular administration of colistimethate sodium. Effective treatment can be challenging due to the accumulation of thickened mucus in the pulmonary environment, and here we describe the results of our investigation into the development of alginate/chitosan particles prepared via precipitation for such environments. Tobramycin loading and release from the alginate/chitosan particles was investigated, with evidence of both uptake and release of sufficient tobramycin to inhibit P. aeruginosa in vitro. Functionalisation of the alginate/chitosan particles with secretory leukocyte protease inhibitor (SLPI) was shown to help inhibit the inflammatory response associated with lung infections (via inhibition of neutrophil elastase activity) and enhance their interaction with cystic fibrosis mucus (assayed via reduction of the depth of particle penetration into the mucus) in vitro, which have prospects to enhance their efficacy in vivo.

Formulation of Antimicrobial Tobramycin Loaded PLGA Nanoparticles via Complexation with AOT.

Tobramycin is a potent antimicrobial aminoglycoside and its effective delivery by encapsulation within nanoparticle carriers could increase its activity against infections through a combination of sustained release and enhanced uptake. Effective antimicrobial therapy against a clinically relevant model bacteria (Pseudomonas aeruginosa) requires sufficient levels of therapeutic drug to maintain a drug concentration above the microbial inhibitory concentration (MIC) of the bacteria. Previous studies have shown that loading of aminoglycoside drugs in poly(lactic-co-glycolic) acid (PLGA)-based delivery systems is generally poor due to weak interactions between the drug and the polymer. The formation of complexes of tobramycin with dioctylsulfosuccinate (AOT) allows the effective loading of the drug in PLGA-nanoparticles and such nanoparticles can effectively deliver the antimicrobial aminoglycoside with retention of tobramycin antibacterial function.

Thiamethoxam: Long-term effects following honey bee colony-level exposure and implications for risk assessment.

Neonicotinoid insecticides have been used in a wide range of crops through seed treatment, soil and foliar applications and a large database exists on both their lethal and sub-lethal effects on honey bees under controlled laboratory conditions. However, colony-level studies on the effects of neonicotinoids in field studies are limited, primarily due to their complexity and the resources required. This paper reports the combined results of two large-scale colony-feeding studies, each with 6 weeks of continuous dosing of 12 colonies per treatment (24 control) to 12.5, 25, 37.5, 50 or 100 ng thiamethoxam/g sucrose solution. Exposure continued beyond dosing with residues present in stored nectar and bee-bread. The studies were conducted in an area with limited alternative forage and colonies were required to forage for pollen and additional nectar The studies provide colony-level endpoints: significant effects (reductions in bees, brood) were observed after exposure to the two highest dose rates, colony loss occurred at the highest dose rate, but colonies were able to recover (2-3 brood cycles after the end of dosing) after dosing with 50 ng thiamethoxam/g sucrose. No significant colony-level effects were observed at lower dose rates. The data reported here support the conclusions of previous colony-level crop-based field studies with thiamethoxam, in which residues in pollen and nectar were an order of magnitude below the colony-level NOEC of 37.5 ng thiamethoxam/g sucrose. The feeding study data are also compared to the outcomes of regulatory Tier 1 risk assessments conducted using guidance provided by the USA, Canada, Brazil and the EU regulatory authorities. We propose an adaptation of the European chronic adult bee risk assessment that takes into account the full dataset generated in laboratory studies while still providing an order of magnitude of safety compared with the colony feeding study NOEC.

The effects of iprodione fungicide on survival, behavior, and brood development of honeybees (Apis mellifera L.) after one foliar application during flowering on mustard.

A semifield study to assess the effects of iprodione on honeybees at label use rates was conducted on a bloom mustard crop. The present study followed the Organisation for Economic Co-operation and Development guideline 75 tunnel test and consisted of 3 groups: the iprodione-treated group, the untreated control group, and the toxic reference item group. In addition to the tunnels used for biological assessments, a tunnel was set up in the treatment and control groups to determine the level of residues in flowers, nectar, and pollen. The major endpoints to assess the effects of the application of iprodione were mortality, flight intensity, behavior, condition of the colonies, and development of the brood. Residue analysis showed that honeybees were exposed to significant residues of iprodione. However, no adverse effects were observed on overall mortality, flight intensity, behavior, or brood development of honeybees compared to control. It is concluded that iprodione does not adversely affect the health of honeybees when applied in agriculture at commercially relevant rates in a worst-case exposure scenario. Environ Toxicol Chem 2018;37:3086-3094. © 2018 SETAC.

Thiamethoxam honey bee colony feeding study: Linking effects at the level of the individual to those at the colony level.

Neonicotinoid insecticides have been used globally on a wide range of crops through seed treatment as well as soil and foliar applications and have been increasingly studied in relation to the potential risk to bees because of their detection in pollen and nectar of bee-attractive crops. The present article reports the results of laboratory studies (10-d adult and 22-d larval toxicity studies assessing the chronic toxicity of thiamethoxam to adult honey bees and larvae, respectively) and a colony feeding study, with 6 wk of exposure in an area with limited alternative forage, to provide a prewintering colony-level endpoint. The endpoints following exposure of individuals in the laboratory (10-d adult chronic no-observed-effect concentration [NOEC] for mortality 117 µg thiamethoxam/kg sucrose solution, 141 µg thiamethoxam/L sucrose solution; 22-d larval chronic NOEC 102 µg thiamethoxam/kg diet) are compared with those generated at the colony level, which incorporates sublethal effects (no-observed-adverse-effect concentration [NOAEC] 50 µg thiamethoxam/L sucrose solution, 43 µg thiamethoxam/kg sucrose solution). The data for sucrose-fed honey bee colonies support the lack of effects identified in previous colony-level field studies with thiamethoxam. However, unlike these field studies demonstrating no effects, colony feeding study data also provide a threshold level of exposure likely to result in adverse effects on the colony in the absence of alternative forage, and a basis by which to evaluate the potential risk of thiamethoxam residues detected in pollen, nectar, or water following treatment of bee-attractive crops. Environ Toxicol Chem 2018;37:816-828. © 2017 SETAC.