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When astronauts return from a space mission they smile for the cameras, but behind the scenes they undergo grueling rehab to recover from the effects of space and may face long-term health consequences. Space flights lasting more than thirty days are considered long-duration and may impact astronauts' long-term health due to space exposure; this requires the National Aeronautics and Space Administration to develop new scientific, medical, and space operational knowledge to counteract and mitigate harmful effects. Understanding how knowledge production occurs is an important analytical and policy issue at NASA. This dissertation explores knowledge production about astronaut health risks using structured and unstructured interviews conducted at Johnson Space Center, the home of mission control for NASA. Applied Actor-Network Theory using a stage analysis shows how various human and non-human actors create this knowledge, constructing, combining, and passing facts across disciplinary boundaries about health risks. A normative analysis of informant statements demonstrates how knowledge and values regarding their understanding of long-term astronaut health risks impact the actions and policies developed at NASA. Steven Hilgartner (1992) suggests that risk research has done very little examination of the social construction of risk objects. He further suggests (1992) that studies fail to systematically examine the construction of causal attribution networks that link chains of risk objects to harm. (Hilgartner, 1992, p. 40-41) This study remedies that lack concerning space medicine by filling in the intellectual, social, and institutional processes that link space flight characteristics to physical harms.

© 2020 Elsevier B.V. Small interfering RNA (siRNA) therapy has significant potential for the treatment of myriad diseases, including cancer. While intravenous routes of delivery have been found to be effective for efficient targeting to the liver, achieving high accumulations selectively in other organs, including lung tissues, can be a challenge. We demonstrate the rational design and engineering of a layer-by-layer (LbL) nanoparticle-containing aerosol that is able to achieve efficient, multistage delivery of siRNA in vitro. For the purpose, LbL nanoparticles were, for the first time, encapsulated in composite porous micro scale particles using a supercritical CO2-assisted spray drying (SASD) apparatus using chitosan as an excipient. Such particles exhibited aerodynamic properties highly favorable for pulmonary administration, and effective silencing of mutant KRAS in lung cancer cells derived from tumors of a non-small cell lung cancer (NSCLC) autochthonous model. Furthermore, efficient alveolar accumulation following inhalation in healthy mice was also observed, corroborating in vitro aerodynamic results, and opening new perspectives for further studies of effective lung therapies These results show that multistage aerosols assembled by supercritical CO2-assisted spray drying can enable efficient RNA interference therapy of pulmonary diseases including lung cancer., NIBIB (Grant 1F32EB017614), National Science Foundation (Grant GFRP-1122374)

Advanced staged high-grade serous ovarian cancer (HGSOC) is the leading cause of gynecological cancer death in the developed world, with 5-year survival rates of only 25-30% due to late-stage diagnosis and the shortcomings of platinum-based therapies. A Phase I clinical trial of a combination of free cisplatin and poly(ADP-ribose) polymerase inhibitors (PARPis) showed therapeutic benefit for HGSOC. In this study, we address the challenge of resistance to platinum-based therapy by developing a targeted delivery approach. Novel electrostatic layer-by-layer (LbL) liposomal nanoparticles (NPs) with a terminal hyaluronic acid layer that facilitates CD44 receptor targeting are designed for selective targeting of HGSOC cells; the liposomes can be formulated to contain both cisplatin and the PARPi drug within the liposomal core and bilayer. The therapeutic effectiveness of LbL NP-encapsulated cisplatin and PARPi alone and in combination was compared with the corresponding free drugs in luciferase and CD44-expressing OVCAR8 orthotopic xenografts in female nude mice. The NPs exhibited prolonged blood circulation half-life, mechanistic staged drug release and targeted codelivery of the therapeutic agents to HGSOC cells. Moreover, compared to the free drugs, the NPs resulted in significantly reduced tumor metastasis, extended survival, and moderated systemic toxicity.

© 2020 Elsevier B.V. Small interfering RNA (siRNA) therapy has significant potential for the treatment of myriad diseases, including cancer. While intravenous routes of delivery have been found to be effective for efficient targeting to the liver, achieving high accumulations selectively in other organs, including lung tissues, can be a challenge. We demonstrate the rational design and engineering of a layer-by-layer (LbL) nanoparticle-containing aerosol that is able to achieve efficient, multistage delivery of siRNA in vitro. For the purpose, LbL nanoparticles were, for the first time, encapsulated in composite porous micro scale particles using a supercritical CO2-assisted spray drying (SASD) apparatus using chitosan as an excipient. Such particles exhibited aerodynamic properties highly favorable for pulmonary administration, and effective silencing of mutant KRAS in lung cancer cells derived from tumors of a non-small cell lung cancer (NSCLC) autochthonous model. Furthermore, efficient alveolar accumulation following inhalation in healthy mice was also observed, corroborating in vitro aerodynamic results, and opening new perspectives for further studies of effective lung therapies These results show that multistage aerosols assembled by supercritical CO2-assisted spray drying can enable efficient RNA interference therapy of pulmonary diseases including lung cancer.

Advanced staged high-grade serous ovarian cancer (HGSOC) is the leading cause of gynecological cancer death in the developed world, with 5-year survival rates of only 25-30% due to late-stage diagnosis and the shortcomings of platinum-based therapies. A Phase I clinical trial of a combination of free cisplatin and poly(ADP-ribose) polymerase inhibitors (PARPis) showed therapeutic benefit for HGSOC. In this study, we address the challenge of resistance to platinum-based therapy by developing a targeted delivery approach. Novel electrostatic layer-by-layer (LbL) liposomal nanoparticles (NPs) with a terminal hyaluronic acid layer that facilitates CD44 receptor targeting are designed for selective targeting of HGSOC cells; the liposomes can be formulated to contain both cisplatin and the PARPi drug within the liposomal core and bilayer. The therapeutic effectiveness of LbL NP-encapsulated cisplatin and PARPi alone and in combination was compared with the corresponding free drugs in luciferase and CD44-expressing OVCAR8 orthotopic xenografts in female nude mice. The NPs exhibited prolonged blood circulation half-life, mechanistic staged drug release and targeted codelivery of the therapeutic agents to HGSOC cells. Moreover, compared to the free drugs, the NPs resulted in significantly reduced tumor metastasis, extended survival, and moderated systemic toxicity.

Background Forty-three out of 53 of the WHO European Member States have set up political and institutional mechanisms to implement the United Nations (UN) 2030 Agenda for Sustainable Development. This includes governance and institutional mechanisms, engaging stakeholders, identifying targets and indicators, setting governmental and sectoral priorities for action and reporting progress regularly. Still, growing evidence suggests that there is room for advancing implementation of some of the Sustainable Development Goals (SDGs) and targets at a higher pace in the WHO European Region. This article proposes the E4A approach to support WHO European Member States in their efforts to achieve the health-related SDG targets. Methods The E4A approach was developed through a 2-year, multi-stage process, starting with the endorsement of the SDG Roadmap by all WHO European Member States in 2017. This approach resulted from a mix of qualitative methods: a semi-structured desk review of existing committal documents and tools; in-country policy dialogs, interviews and reports; joint UN missions and discussion among multi-lateral organizations; consultation with an advisory group of academics and health policy experts across countries. Results The E—engage—functions as the driver and pace-maker; the 4 As—assess, align, accelerate and account—serve as building blocks composed of policies, processes, activities and interventions operating in continuous and synchronized action. Each of the building blocks is an essential part of the approach that can be applied across geographic and institutional levels. Conclusion While the E4A approach is being finalized, this article aims to generate debate and input to further refine and test this approach from a public health and user perspective.

United Nations member states agreed Agenda 2030 and the Sustainable Development Goals (SDGs) in 2015. Countries report their progress through Voluntary National Reviews. In this paper, we look at the extent to which the World Health Organisation (WHO) Europe SDG Roadmap (the Roadmap) on Agenda 2030 implementation is reflected in the first 20 Voluntary National Reviews (VNRs) submitted from the WHO European region. In particular, we wanted to look at how integrated the three dimensions of sustainable development were, the identification of health co-benefits and potential-added value from the health sector. This was a semi-quantitative analysis of 20 VNRs using an ordinal scale (no evidence, limited evidence, good evidence). Results are presented as frequency tables by criteria and by country. We devised an assessment template consisting of 41 criteria based on the nine key areas and a selection of the proposed areas for action in the Roadmap. Each VNR was then assessed and scored against these criteria to produce country-specific and average scores for each of the nine key areas and the 25 measures we selected. Countries generally have good evidence on key areas such as governance, monitoring, leaving no-one behind and multipartner cooperation. They have less evidence on the key areas of health determinants, healthy settings, health literacy and investing for health. Many countries link the economic and environmental dimensions of sustainable development but not the interplay with the social (health and well-being) dimension. Some countries specifically highlighted commitments to support developing nations but few recognised the impact of domestic policies on planetary boundaries or the health of future generations. We found little evidence that the health sector has had a major strategic influence on actions which affect wider determinants (or health co-benefits). The WHO Europe SDG Roadmap offers a means and an opportunity for redressing this weakness, but this ma

This paper reports on the second Workshop of a World University Network (WUN) Research Development Funded project on “The trans-nationalization of Indigenous movements: The role of digital technologies” at the University of Southampton, UK. The workshop explored interdisciplinarity and how interdisciplinary collaboration can help scholars study complex social phenomenon, such as the ways in which marginalized Indigenous communities use and shape digital technologies (such as social media) to enhance their cause. The workshop brought together scholars from diverse disciplines to engage in a critical debate. In addition to scholars from information systems, scholars from history, political science, geography, literature, arts, and anthropology came together to discuss how marginalized Indigenous communities can use digital media. The workshop highlighted the need for more interdisciplinary research and called for more critical approaches to bring such marginalized topics to the forefront of research in information systems. We consider three broad areas of inquiry in this paper: demarginalizing methodology for interdisciplinary research, interdisciplinary perspectives for demarginalization, and interdisciplinary contexts for demarginalization.

Objectives: Tuberculosis (TB) is a serious re-emergent public health problem in the UK. In response to rising case incidence a National TB Strain-Typing Service based on molecular strain-typing was established. This facilitates early detection and investigation of clusters, targeted public health action, and prevention of further transmission. We review the added public health value of investigating molecular TB straintyped (ST) clusters. Methods: A structured questionnaire for each ST cluster investigated in England between 1 January 2010 and 30 June 2013 was completed. Questions related to epidemiological links and public health action and the perceived benefits of ST cluster investigation. Results: There were 278 ST cluster investigations (CIs) involving 1882 TB cases. Cluster size ranged from 2 to 92. CIs identified new epidemiological links in 36% of clusters; in 18% STs were discordant refuting transmission thought to have occurred. Additional public health action was taken following 23% of CI. Conclusions: We found positive benefits of TB molecular ST and CI, in identifying new epidemiological links between cases and taking public health action and in refuting transmission and saving resources. This needs to be translated to a decrease in transmission to provide evidence of public health value in this low prevalence high resource setting.

Effective treatment for glioblastoma (GBM) is limited by the presence of the blood-brain barrier (BBB) and rapid resistance to single agent therapies. To address these issues, we developed a transferrin-functionalized nanoparticle (Tf-NP) that can deliver dual combination therapies. Using intravital imaging, we show the ability of Tf-NPs to traverse intact BBB in mice as well as achieve direct tumor binding in two intracranial orthotopic models of GBM. Treatment of tumor-bearing mice with Tf-NPs loaded with temozolomide and the bromodomain inhibitor JQ1 leads to increased DNA damage and apoptosis that correlates with a 1.5-to 2-fold decrease in tumor burden and corresponding increase in survival compared to equivalent free-drug dosing. Immunocompetent mice treated with Tf-NP-loaded drugs also show protection from the effects of systemic drug toxicity, demonstrating the preclinical potential of this nanoscale platform to deliver novel combination therapies to gliomas and other central nervous system tumors., National Institutes of Health (U.S.) (Grant R01-ES015339), National Institutes of Health (U.S.) (Grant R35-ES028374), National Cancer Institute (U.S.) (Grant P30-CA14051)

Introduction The Sustainable Development Goals (SDGs) are a set of global goals for fair and sustainable health at every level: from planetary biosphere to local community. The aim is to end poverty, protect the planet and ensure that all people enjoy peace and prosperity, now and in the future. Sources of data The UN has established web-sites to inform the implementation of the SDGs and an Inter-Agency and Expert Group on an Indicator Framework. We have searched for independent commentaries and analysis. Areas of agreement The goals represent a framework that is scientifically robust, and widely intuitive intended to build upon the progress established by the Millennium Development Goals (MDGs). There is a need for system wide strategic planning to integrate the economic, social and environmental dimensions into policy and actions. Areas of controversy Many countries have yet to understand the difference between the MDGs and the SDGs, particularly their universality, the huge potential of new data methods to help with their implementation, and the systems thinking that is needed to deliver the vision. The danger is that individual goals may be prioritized without an understanding of the potential positive interactions between goals. Growing points There is an increasing understanding that sustainable development needs a paradigm shift in our understanding of the interaction between the real economy and quality of life. There would be many social, environmental and economic benefits in changing our current model. Areas timely for developing research We need to develop systems wide understanding of what supports a healthy environment and the art and science of making change.

An important aspect in the design of nanomaterials for delivery is an understanding of its uptake and ultimate release to the cytosol of target cells. Real-time chemical sensing using a nanoparticle-based platform affords exquisite insight into the trafficking of materials and their cargo into cells. This versatile and tunable technology provides a powerful tool to probe the mechanism of cellular entry and cytosolic delivery of a variety of materials, allowing for a simple and convenient means to screen materials towards efficient delivery of therapeutics such as nucleic acids.

Translation of micelles from the laboratory to the clinic is limited by a poor understanding of their in vivo fate following administration. In this paper, we establish a robust approach to real-time monitoring of the in vivo stability of micelles using Förster Resonance Energy Transfer (FRET). This characterization method allows for exquisite insight into the fate of micellar constituents, affording the capabilities to rapidly and efficiently evaluate a library of synthetically derived micellar systems as new therapeutic platforms in vivo. FRET-enabled biological characterization further holds potential to tailor material systems being uniquely investigated across the delivery community towards the next generation of stable therapeutics for disease management., National Cancer Institute (U.S.) (P30-CA14051), National Institutes of Health (U.S.) (5 U54 CA151884-02)

Layer-by-Layer (LbL) nanoparticles are an emerging class of therapeutic carriers that afford precise control over key design parameters that facilitate improved drug and carrier pharmacokinetics, and enhanced molecular-targeting capabilities. This paper advances the development of these systems by establishing them as drug carriers, with the means to control drug release in a systemic environment and retard particle clearance from circulation, promoting improved biodistribution of the drug-containing system. Using dual-fluorescent tracking in vivo, this work establishes a robust means of screening libraries of LbL systems generated, affording simultaneous resolution over persistence and biodistribution of both the drug and carrier following systemic administration of a single particle formulation. Employing a PLGA drug-containing core as a substrate for LbL deposition, a range of coated systems were fabricated to investigate the abilities of these films to stabilize drug for delivery as well as to improve the pharmacokinetics of both the drug and carrier. Significant reductions in liver accumulation were observed for different formulations of the layered architectures within the first 30 min of systemic circulation. LbL architectures diminished liver localization of the surrogate drug, cardiogreen, by 10–25% ID/g relative to native PLGA nanoparticles and modulated carrier accumulation in the liver >50% ID/g. Further, enhanced persistence of the drug was observed with the coated systems, significantly increasing the drug half-life from 2 to 3 min for free drug and 1.87 h for the uncoated core to 4.17 h and 4.54 h for the coated systems. These systems provide an exciting, modular platform that improves the pharmacokinetic properties of the therapeutic, reduces bolus release of drug from nanoparticles, and enhances the safety and circulation half-life of the drug in vivo, proving them to be highly clinically-relevant and a promising approach for future development of m, Janssen Pharmaceutical Ltd. (TRANSCEND Partnership), National Science Foundation (U.S.). Graduate Research Fellowship

Active targeting of nanoscale drug carriers can improve tumor-specific delivery; however, cellular heterogeneity both within and among tumor sites is a fundamental barrier to their success. Here, we describe a tumor microenvironment-responsive layer-by-layer (LbL) polymer drug carrier that actively targets tumors based on two independent mechanisms: pH-dependent cellular uptake at hypoxic tumor pH and hyaluronan-directed targeting of cell-surface CD44 receptor, a well-characterized biomarker for breast and ovarian cancer stem cells. Hypoxic pH-induced structural reorganization of hyaluronan-LbL nanoparticles was a direct result of the nature of the LbL electrostatic complex, and led to targeted cellular delivery in vitro and in vivo, with effective tumor penetration and uptake. The nanoscale drug carriers selectively bound CD44 and diminished cancer cell migration in vitro, while co-localizing with the CD44 receptor in vivo. Multimodal targeting of LbL nanoparticles is a powerful strategy for tumor-specific cancer diagnostics and therapy that can be accomplished using a single bilayer of polyamine and hyaluronan that, when assembled, produce a dynamic and responsive cell–particle interface., Janssen Pharmaceutical Ltd. (TRANSCEND Partnership), National Institutes of Health (U.S.) (Ruth L. Kirschstein National Research Service Award 1F32EB017614-02), National Science Foundation (U.S.), Natural Sciences and Engineering Research Council of Canada, National Health and Medical Research Council (Australia), National Cancer Institute (U.S.) (Koch Institute Support (Core) Grant P30-CA14051), National Science Foundation (U.S.). Materials Research Science and Engineering Centers (Program) (Award DMR-0819762), Singapore. National Research Foundation (NRF-NRFF2011-01)

A single nanoparticle platform has been developed through the modular and controlled layer-by-layer process to codeliver siRNA that knocks down a drug-resistance pathway in tumor cells and a chemotherapy drug to challenge a highly aggressive form of triple-negative breast cancer. Layer-by-layer films were formed on nanoparticles by alternately depositing siRNA and poly-l-arginine; a single bilayer on the nanoparticle surface could effectively load up to 3500 siRNA molecules, and the resulting LbL nanoparticles exhibit an extended serum half-life of 28 h. In animal models, one dose via intravenous administration significantly reduced the target gene expression in the tumors by almost 80%. By generating the siRNA-loaded film atop a doxorubicin-loaded liposome, we identified an effective combination therapy with siRNA targeting multidrug resistance protein 1, which significantly enhanced doxorubicin efficacy by 4 fold in vitro and led to up to an 8-fold decrease in tumor volume compared to the control treatments with no observed toxicity. The results indicate that the use of layer-by-layer films to modify a simple liposomal doxorubicin delivery construct with a synergistic siRNA can lead to significant tumor reduction in the cancers that are otherwise nonresponsive to treatment with Doxil or other common chemotherapy drugs. This approach provides a potential strategy to treat aggressive and resistant cancers, and a modular platform for a broad range of controlled multidrug therapies customizable to the cancer type in a singular nanoparticle delivery system., Janssen Pharmaceutical Ltd. (TRANSCEND Grant), National Cancer Institute (U.S.) (Koch Institute Support (Core) Grant P30-CA14051), National Health and Medical Research Council (Australia) (CJ Martin Fellowship), National Science Foundation (U.S.). Graduate Research Fellowship, Natural Sciences and Engineering Research Council of Canada (Postdoctoral Fellowship)

Purpose: Cross-talk and feedback between the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR cell signaling pathways is critical for tumor initiation, maintenance, and adaptive resistance to targeted therapy in a variety of solid tumors. Combined blockade of these pathways—horizontal blockade—is a promising therapeutic strategy; however, compounded dose-limiting toxicity of free small molecule inhibitor combinations is a significant barrier to its clinical application. Experimental Design: AZD6244 (selumetinib), an allosteric inhibitor of Mek1/2, and PX-866, a covalent inhibitor of PI3K, were co-encapsulated in a tumor-targeting nanoscale drug formulation—layer-by-layer (LbL) nanoparticles. Structure, size, and surface charge of the nanoscale formulations were characterized, in addition to in vitro cell entry, synergistic cell killing, and combined signal blockade. In vivo tumor targeting and therapy was investigated in breast tumor xenograft-bearing NCR nude mice by live animal fluorescence/bioluminescence imaging, Western blotting, serum cytokine analysis, and immunohistochemistry. Results: Combined MAPK and PI3K axis blockade from the nanoscale formulations (160 ± 20 nm, −40 ± 1 mV) was synergistically toxic toward triple-negative breast (MDA-MB-231) and RAS-mutant lung tumor cells (KP7B) in vitro, effects that were further enhanced upon encapsulation. In vivo, systemically administered LbL nanoparticles preferentially targeted subcutaneous MDA-MB-231 tumor xenografts, simultaneously blocked tumor-specific phosphorylation of the terminal kinases Erk and Akt, and elicited significant disease stabilization in the absence of dose-limiting hepatotoxic effects observed from the free drug combination. Mice receiving untargeted, but dual drug-loaded nanoparticles exhibited progressive disease. Conclusions: Tumor-targeting nanoscale drug formulations could provide a more safe and effective means to synergistically block MAPK and PI3K in the clinic., United States. Department of Defense (OCRP Teal Innovator Award), National Institutes of Health (U.S.) (Grant NIBIB 1F32EB017614-02), Misrock Foundation, National Science Foundation (U.S.), Swiss National Science Foundation, David H. Koch Institute for Integrative Cancer Research at MIT (Support Grant P30-CA14051), National Cancer Institute (U.S.), National Science Foundation (U.S.) (Massachusetts Institute of Technology. Materials Research Science and Engineering Center. Shared Experimental Facilities Grant DMR-0819762), Breast Cancer Alliance (Exceptional Project Grant)

Stimuli-responsive multimodality imaging agents have broad potential in medical diagnostics. Herein, we report the development of a new class of branched-bottlebrush polymer dual-modality organic radical contrast agents—ORCAFluors—for combined magnetic resonance and near-infrared fluorescence imaging in vivo. These nitroxide radical-based nanostructures have longitudinal and transverse relaxation times that are on par with commonly used heavy-metal-based magnetic resonance imaging (MRI) contrast agents. Furthermore, these materials display a unique compensatory redox response: fluorescence is partially quenched by surrounding nitroxides in the native state; exposure to ​ascorbate or ​ascorbate/​glutathione leads to nitroxide reduction and a concomitant 2- to 3.5-fold increase in fluorescence emission. This behaviour enables correlation of MRI contrast, fluorescence intensity and spin concentration with tissues known to possess high concentrations of ​ascorbate in mice. Our in vitro and in vivo results, along with our modular synthetic approach, make ORCAFluors a promising new platform for multimodality molecular imaging., Massachusetts Institute of Technology. Department of Chemistry, Massachusetts Institute of Technology. Research Support Committee, Lincoln Laboratory, National Institutes of Health (U.S.) (NIBIB 1R21EB018529-01A1), National Institutes of Health (U.S.) (Ruth L. Kirschstein National Research Service Award 1F32EB017614-01), United States. Dept. of Defense. Ovarian Cancer Research Program (Teal Innovator Award), National Cancer Institute (U.S.) (Koch Institute Support (Core) Grant P30-CA14051)

Antisense oligonucleotides can be employed as a potential approach to effectively treat cancer. However, the inherent instability and inefficient systemic delivery methods for antisense therapeutics remain major challenges to their clinical application. Here, we present a polymerized oligonucleotides (ODNs) that self-assemble during their formation through an enzymatic elongation method (rolling circle replication) to generate a composite nucleic acid/magnesium pyrophosphate sponge-like microstructure, or DNA microsponge, yielding high molecular weight nucleic acid product. In addition, this densely packed ODN microsponge structure can be further condensed to generate polyelectrolyte complexes with a favorable size for cellular uptake by displacing magnesium pyrophosphate crystals from the microsponge structure. Additional layers are applied to generate a blood-stable and multifunctional nanoparticle via the layer-by-layer (LbL) assembly technique. By taking advantage of DNA nanotechnology and LbL assembly, functionalized DNA nanostructures were utilized to provide extremely high numbers of repeated ODN copies for efficient antisense therapy. Moreover, we show that this formulation significantly improves nucleic acid drug/carrier stability during in vivo biodistribution. These polymeric ODN systems can be designed to serve as a potent means of delivering stable and large quantities of ODN therapeutics systemically for cancer treatment to tumor cells at significantly lower toxicity than traditional synthetic vectors, thus enabling a therapeutic window suitable for clinical translation., United States. Dept. of Defense. Ovarian Cancer Research Program (Teal Innovator Award Grant OC120504), Natural Sciences and Engineering Research Council of Canada (Postdoctoral Fellowship), National Institutes of Health (U.S.) (Ruth L. Kirschstein National Research Service Award 1F32EB017614-01), National Science Foundation (U.S.). Graduate Research Fellowship

Background We report a widespread foodborne outbreak of Cryptosporidium parvum in England and Scotland in May 2012. Cases were more common in female adults, and had no history of foreign travel. Over 300 excess cases were identified during the period of the outbreak. Speciation and microbiological typing revealed the outbreak strain to be C. parvum gp60 subtype IIaA15G2R1. Methods Hypothesis generation questionnaires were administered and an unmatched case control study was undertaken to test the hypotheses raised. Cases and controls were interviewed by telephone. Controls were selected using sequential digit dialling. Information was gathered on demographics, foods consumed and retailers where foods were purchased. Results Seventy-four laboratory confirmed cases and 74 controls were included in analyses. Infection was found to be strongly associated with the consumption of pre-cut mixed salad leaves sold by a single retailer. This is the largest documented outbreak of cryptosporidiosis attributed to a food vehicle.

Herein we report the potential of click chemistry-modified polypeptide-based block copolymers for the facile fabrication of pH-sensitive nanoscale drug delivery systems. PEG–polypeptide copolymers with pendant amine chains were synthesized by combining N-carboxyanhydride-based ring-opening polymerization with post-functionalization using azide–alkyne cycloaddition. The synthesized block copolymers contain a polypeptide block with amine-functional side groups and were found to self-assemble into stable polymersomes and disassemble in a pH-responsive manner under a range of biologically relevant conditions. The self-assembly of these block copolymers yields nanometer-scale vesicular structures that are able to encapsulate hydrophilic cytotoxic agents like doxorubicin at physiological pH but that fall apart spontaneously at endosomal pH levels after cellular uptake. When drug-encapsulated copolymer assemblies were delivered systemically, significant levels of tumor accumulation were achieved, with efficacy against the triple-negative breast cancer cell line, MDA-MB-468, and suppression of tumor growth in an in vivo mouse model., Novartis Institutes of Biomedical Research, National Institutes of Health (U.S.) (Centers for Cancer Nanotechnology Excellence Grant P30 CA14051), National Institutes of Health (U.S.) (Centers for Cancer Nanotechnology Excellence Grant 5 U54 CA151884-02), National Science Foundation (U.S.). Graduate Research Fellowship, Natural Sciences and Engineering Research Council of Canada (Postdoctoral Fellowship)

The synthesis of polymer therapeutics capable of controlled loading and synchronized release of multiple therapeutic agents remains a formidable challenge in drug delivery and synthetic polymer chemistry. Herein, we report the synthesis of polymer nanoparticles (NPs) that carry precise molar ratios of doxorubicin, camptothecin, and cisplatin. To our knowledge, this work provides the first example of orthogonally triggered release of three drugs from single NPs. The highly convergent synthetic approach opens the door to new NP-based combination therapies for cancer., MIT Research Support Committee, Lincoln Laboratory. Advanced Concepts Committee, United States. Dept. of Defense (Ovarian Cancer Research Program Teal Innovator Award), National Institutes of Health (U.S.) (Ruth L. Kirschstein National Research Service Award 1F32EB017614-01), Natural Sciences and Engineering Research Council of Canada (Postdoctoral Fellowship), Natural Sciences and Engineering Research Council of Canada (Graduate Fellowship), National Cancer Institute (U.S.) (Koch Institute Support (Core) Grant P30-CA14051)

Students making the transition from high school to university often encounter many stressors and new experiences. Many students adjust successfully to university; however, some students do not, often resulting in attrition from the university and mental health issues. The primary aim of the current study was to examine the effects that optimism, self-efficacy, depression, and anxiety have on an individual's life stress and adaptation to university. Eighty-four first-year, full-time students from the Queensland University of Technology (60 female, 24 male) who had entered university straight from high school completed the study. Participants completed a questionnaire assessing their levels of optimism, self-efficacy, depression, anxiety, perceived level of life stress and adaptation to university. In line with predictions, results showed that optimism, depression, and anxiety each had a significant relationship with students’ perceived level of stress. Furthermore, self-efficacy and depression had a significant relationship with adaptation to university. We conclude that students with high levels of optimism and low levels of depression and anxiety will adapt better when making the transition from high school to university. In addition, students with high levels of self-efficacy and low levels of depression will experience less life stress in their commencement year of university. The implications of this study are outlined.

Exposure to the EGFR (epidermal growth factor receptor) inhibitor erlotinib promotes the dynamic rewiring of apoptotic pathways, which sensitizes cells within a specific period to subsequent exposure to the DNA-damaging agent doxorubicin. A critical challenge for translating this therapeutic network rewiring into clinical practice is the design of optimal drug delivery systems. We report the generation of a nanoparticle delivery vehicle that contained more than one therapeutic agent and produced a controlled sequence of drug release. Liposomes, representing the first clinically approved nanomedicine systems, are well-characterized, simple, and versatile platforms for the manufacture of functional and tunable drug carriers. Using the hydrophobic and hydrophilic compartments of liposomes, we effectively incorporated both hydrophobic (erlotinib) and hydrophilic (doxorubicin) small molecules, through which we achieved the desired time sequence of drug release. We also coated the liposomes with folate to facilitate targeting to cancer cells. When compared to the time-staggered application of individual drugs, staggered release from tumor-targeted single liposomal particles enhanced dynamic rewiring of apoptotic signaling pathways, resulting in improved tumor cell killing in culture and tumor shrinkage in animal models., National Institutes of Health (U.S.) (NIH and Center for Cancer Nanotechnology Excellence, grant no. P30-CA14051), National Institutes of Health (U.S.) (NIH and Center for Cancer Nanotechnology Excellence, grant no. U54-CA151884), National Institutes of Health (U.S.) (NIH and Center for Cancer Nanotechnology Excellence, grant no. U54-CA112967), National Institutes of Health (U.S.) (NIH and Center for Cancer Nanotechnology Excellence, grant no. R01-ES015339), National Institutes of Health (U.S.) (NIH and Center for Cancer Nanotechnology Excellence, grant no. R21-ES020466), Breast Cancer Alliance (Exceptional Project Grant), National Science Foundation (U.S.) (Graduate Research Fellowship), National Health and Medical Research Council (Australia) (CJ Martin Fellowship), National Institutes of Health (U.S.) (Kirschstein NRSA 1F32EB017614-01), Natural Sciences and Engineering Research Council of Canada (post-doctoral fellowship), Kathy and Curt Marble Cancer Research Fund, David H. Koch Institute for Integrative Cancer Research at MIT (Koch Institute Frontier Research Program)

Scalable methods, PRINT particle fabrication, and spray-assisted Layer-by-Layer deposition are combined to generate uniform and functional nanotechnologies with precise control over composition, size, shape, and surface functionality. A modular and tunable approach towards design of built-to-order nanoparticle systems, spray coating on PRINT particles is demonstrated to achieve technologies capable of targeted interactions with cancer cells for applications in drug delivery., National Cancer Institute (U.S.) (Center for Cancer Nanotechnology Excellence Grant 5 U54 CA151884-02), National Science Foundation (U.S.). Graduate Research Fellowship, Natural Sciences and Engineering Research Council of Canada (Postdoctoral Fellowship)

Current treatment options for debilitating bone diseases such as osteosarcoma, osteoporosis, and bone metastatic cancer are suboptimal and have low efficacy. New treatment options for these pathologies require targeted therapy that maximizes exposure to the diseased tissue and minimizes off-target side effects. This work investigates an approach for generating functional and targeted drug carriers specifically for treating primary osteosarcoma, a disease in which recurrence is common and the cure rate has remained around 20%. This approach utilizes the modularity of Layer-by-Layer (LbL) assembly to generate tissue-specific drug carriers for systemic administration. This is accomplished via surface modification of drug-loaded nanoparticles with an aqueous polyelectrolyte, poly(acrylic acid) (PAA), side-chain functionalized with alendronate, a potent clinically used bisphosphonate. Nanoparticles coated with PAA-alendronate are observed to bind and internalize rapidly in human osteosarcoma 143B cells. Encapsulation of doxorubicin, a front-line chemotherapeutic, in an LbL-targeted liposome demonstrates potent toxicity in vitro. Active targeting of 143B xenografts in NCR nude mice with the LbL-targeted doxorubicin liposomes promotes enhanced, prolonged tumor accumulation and significantly improved efficacy. This report represents a tunable approach towards the synthesis of drug carriers, in which LbL enables surface modification of nanoparticles for tissue-specific targeting and treatment., National Institutes of Health (U.S.) (P30 CA14051 (NCI)), National Institutes of Health (U.S.) (5 U54 CA151884–02 (CCNE)), National Institutes of Health (U.S.) (R01 AG029601 (NIA)), National Institutes of Health (U.S.) (R01 EB010246 (NIBIB)), David H. Koch Institute for Integrative Cancer Research at MIT (Koch Institute Swanson Biotechnology Center), National Science Foundation (U.S.) (Graduate Research Fellowship), National Health and Medical Research Council (Australia), Massachusetts Institute of Technology (David H. Koch (1962) Chair Professorship in Engineering)

Inorganic nanostructures have been used extensively to package nucleic acids into forms useful for therapeutic applications. Here we report that the two products of transcription, RNA and inorganic pyrophosphate, can self-assemble to form composite microsponge structures composed of nanocrystalline magnesium pyrophosphate sheets (Mg[subscript 2]P[subscript 2]O[subscript 7]•3.5H[subscript 2]O) with RNA adsorbed to their surfaces. The microsponge particles contain high loadings of RNA (15–21 wt.%) that are protected from degradation and can be obtained through a rolling circle mechanism as large concatemers capable of mediating RNAi. The morphology of the RNAi microsponges is influenced by the time-course of the transcription reaction and interactions between RNA and the inorganic phase. Previous work demonstrated that polycations can be used to condense RNAi microsponges into nanoparticles capable of efficient transfection with low toxicity. Our new findings suggest that the formation of these nanoparticles is mediated by the gradual dissolution of magnesium pyrophosphate that occurs in the presence of polycations. The simple one-pot approach for assembling RNAi microsponges along with their unique properties could make them useful for RNA-based therapeutics., National Cancer Institute (U.S.) (Koch Institute Support (Core) Grant P30-CA14051), National Cancer Institute (U.S.) (Center for Cancer Nanotechnology Excellence Grant 5 U54 CA151884-02), Natural Sciences and Engineering Research Council of Canada (Postdoctoral Fellowship), National Health and Medical Research Council (Australia) (CJ Martin Fellowship), National Science Foundation (U.S.). Graduate Research Fellowship

This paper demonstrates the generation of systemically deliverable layer-by-layer (LbL) nanoparticles for cancer applications. LbL-based nanoparticles designed to navigate the body and deliver therapeutics in a programmable fashion are promising new and alternative systems for drug delivery, but there have been very few demonstrations of their systemic delivery in vivo due to a lack of knowledge in building LbL nanofilms that mimic traditional nanoparticle design to optimize delivery. The key to the successful application of these nanocarriers in vivo requires a systematic analysis of the influence of film architecture and adsorbed polyelectrolyte outer layer on their pharmacokinetics, which has thus far not been examined for this new approach to nanoparticle delivery. Herein, we have taken the first steps in stabilizing and controlling the systemic distribution of multilayer nanoparticles. Our findings highlight the unique character of LbL systems; the electrostatically assembled nanoparticles gain increased stability in vivo with larger numbers of deposited layers, and the final layer adsorbed generates a critical surface cascade, which dictates the surface chemistry and biological properties of the nanoparticle. This outer polyelectrolyte layer dramatically affects not only the degree of nonspecific particle uptake, but also the nanoparticle biodistribution. For hyaluronic acid (HA) outer layers, a long blood elimination half-life (9 h) and low accumulation (10–15% recovered fluorescence/g) in the liver were observed, illustrating that these systems can be designed to be highly appropriate for clinical translation., National Institutes of Health (U.S.) (NIBIB Grant R01EB008082), David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies

Este artículo es un capítulo del libro Gayatri Chakravorti Spivak, de la «Serie Routledge de Pensadores Críticos» (Londres: Routledge, 2003), pp. 71-89.Traducción por Gabriela Castellanos.Resumen: Este artículo recoge las principales ideas de la filósofa y teórica del lenguaje Gayatri Spivak sobre las mujeres del llamado Tercer Mundo, haciendo uso de los conceptos acuñados o re-significados por ella sobre subalternidad y esencialismo estratégico. Se resumen y analizan varios artículos de Spivak, incluyendo sus críticas al feminismo europeo, y retomando sus análisis de obras narrativas de autoras de países tercermundistas,de Asia.Palabras clave: Gayatri Spivak, mujeres del Tercer Mundo, feminismo, subalternidad, esencialismo estratégicoAbstract: This article summarizes the major ideas on Third World women by the philosopher and language theorist Gayatri Spivak, using concepts coined or resignified by her such as subalternity and strategic essentialism. Several articles by Spivak are summarized, including her criticism of European feminism, and her analyses of narrative works by Asian women writers.Key words: Gayatri Spivak, Third World women, feminism, subalternity, strategic essentialism.

An outbreak of cryptosporidiosis occurred in and around Clitheroe, Lancashire, in northwest England, during March 2000. Fifty-eight cases of diarrhea with Cryptosporidium identified in stool specimens were reported. Cryptosporidium oocysts were identified in samples from the water treatment works as well as domestic taps. Descriptive epidemiology suggested that drinking unboiled tap water in a single water zone was the common factor linking cases. Environmental investigation suggested that contamination with animal feces was the likely source of the outbreak. This outbreak was unusual in that hydrodynamic modeling was used to give a good estimate of the peak oocyst count at the time of the contamination incident. The oocysts’ persistence in the water distribution system after switching to another water source was also unusual. This persistence may have been due to oocysts being entrapped within biofilm. Despite the continued presence of oocysts, epidemiologic evidence suggested that no one became ill after the water source was changed.

This paper uses 85 semistructured interviews with people with type 2 diabetes, and with the health professionals who deliver their diabetes care, to explore the issues that they perceive as central to effective management of diabetes, primarily within a primary care setting. Attention is especially focused on the nature of the patient–practitioner relationship, and on the implications of this for patient empowerment and the effective self-management of diabetes. The paper is organized around five key concepts identified in the qualitative analysis: the importance of having sufficient time for consultations, the significance of continuity of care through a named individual, the need for patients to have an opportunity to ask questions during a consultation, the extent to which patients feel that they are listened to by health professionals, and the variability of each patient’s individual experience of living with diabetes. In conclusion, these themes are briefly related to key issues in the geography of health.

A community outbreak of infection with Vero cytotoxin producing Escherichia coli O157 (VTEC 0157) occurred in a small area of north west England in 1996. An outbreak control team was established to investigate the outbreak and implement control measures. Nine people developed symptomatic infections with VTEC O157, and a further three were found to be excreting the bacteria. All were infected with the same genotype of VTEC O157. Three children under 5 years of age and one adult were admitted to hospital. One child developed haemolytic uraemic syndrome. All cases recovered. All primary cases had consumed milk from a particular farm dairy. No other common foods were identified. The farm dairy had a faulty pasteuriser and the potential for post pasteurisation contamination existed. VTEC O157 was isolated from a milk sock specimen and from two cows, but these strains differed from that infecting the cases. All local doctors and the public were alerted and advised about preventative measures. Distribution of unpasteurised milk from the farm was discontinued as was the sale of pasteurised milk when the faulty pasteuriser was discovered. A replacement pasteuriser was installed and checked before milk was released for human consumption. No conclusive evidence of the origin of this outbreak was found, but the farm was the most probable source. The investigations raised concerns about the distribution of VTEC O157 colonised dairy cattle, the natural history of such colonisation, the effectiveness of pasteurisation with respect to the elimination of VTEC O157, and the effectiveness of current legislation for the prevention and control of milkborne infection.

An outbreak of gastroenteritis due to Salmonella indiana occurred in the maternity unit of a district general hospital in January 1986. The organism affected mainly new-born infants but a number of the infants' relatives, most of whom were asymptomatic, were also found to have been infected. The organism was also isolated from one non-clinical member of staff who was apparently well. Despite fairly intensive investigation, the source of introduction and means of transmission of the organism could not be clearly identified. The authors feel, however, that spread of the organism was from infant to infant via hands or clothing of uninfected members of staff and suggest that, because of the susceptibility of the neonate, such transmission takes place despite apparently adequate hygiene measures. It is recommended that detailed epidemiological investigations are undertaken early in such outbreaks, and that 'enteric measures' are implemented when the problem is first identified.

In September and October 1981 six cases of pneumonia occurred among men working in a power station under construction. Three were identified as cases of legionella pneumonia and two others had serology suggestive of legionella infection. In a sample of 92 men from the site 10 had low levels of antibodies to legionella; a similar sample of men working on an adjacent site showed none with positive serology. In a case control study it was found that cases of pneumonia were more likely than controls to have worked on a part of the site where four small capacity cooling towers were located. Legionella pneumophila serogroup 1 was isolated from the water systems of these four towers but was not found in samples from any other cooling towers or hot or cold water outlets on the site. It would appear that there was airborne spread of the organism from these cooling water systems which had not received conventional treatment to inhibit corrosion and organic growth. This is the first outbreak of legionnaires' disease to be recorded in an industrial setting in the United Kingdom. No cases of legionella infection have occurred on the site since the introduction of control measures.