The Plasma Environment of Comet 67P/Churyumov-Gerasimenko.

The environment of a comet is a fascinating and unique laboratory to study plasma processes and the formation of structures such as shocks and discontinuities from electron scales to ion scales and above. The European Space Agency's Rosetta mission collected data for more than two years, from the rendezvous with comet 67P/Churyumov-Gerasimenko in August 2014 until the final touch-down of the spacecraft end of September 2016. This escort phase spanned a large arc of the comet's orbit around the Sun, including its perihelion and corresponding to heliocentric distances between 3.8 AU and 1.24 AU. The length of the active mission together with this span in heliocentric and cometocentric distances make the Rosetta data set unique and much richer than sets obtained with previous cometary probes. Here, we review the results from the Rosetta mission that pertain to the plasma environment. We detail all known sources and losses of the plasma and typical processes within it. The findings from in-situ plasma measurements are complemented by remote observations of emissions from the plasma. Overviews of the methods and instruments used in the study are given as well as a short review of the Rosetta mission. The long duration of the Rosetta mission provides the opportunity to better understand how the importance of these processes changes depending on parameters like the outgassing rate and the solar wind conditions. We discuss how the shape and existence of large scale structures depend on these parameters and how the plasma within different regions of the plasma environment can be characterised. We end with a non-exhaustive list of still open questions, as well as suggestions on how to answer them in the future.

Long-term predictors of dengue outbreaks in Bangladesh: A data mining approach.

The effects of weather variables on the transmission of vector-borne diseases are complex. Relationships can be non-linear, specific to particular geographic locations, and involve long lag times between predictors and outbreaks of disease. This study expands the geographical and temporal range of previous studies in Bangladesh of the mosquito-transmitted viral infection dengue, a major threat to human public health in tropical and subtropical regions worldwide. The analysis incorporates new compound variables such as anomalous events, running averages, consecutive days of particular weather characteristics, seasonal variables based on the traditional Bangla six-season annual calendar, and lag times of up to one year in predicting either the existence or the magnitude of each dengue epidemic. The study takes a novel, comprehensive data mining approach to show that different variables optimally predict the occurrence and extent of an outbreak. The best predictors of an outbreak are the number of rainy days in the preceding two months and the average daily minimum temperature one month prior to the outbreak, while the best predictor of the number of clinical cases is the average humidity six months prior to the month of outbreak. The magnitude of relationships between humidity 6, 7 and 8 months prior to the outbreak suggests the relationship is multifactorial, not due solely to the cyclical nature of prevailing weather conditions but likely due also to the immunocompetence of human hosts.

Excluding parental grief: A critical discourse analysis of bereavement accommodation in Canadian labour standards.

BACKGROUND: Grief following child loss is profoundly destabilizing with serious long-term repercussions for bereaved parents. Employed parents may need time away from work to deal with this loss. OBJECTIVE: The purpose of this study was to reflect upon the ways labour policies and practices respond to parental bereavement. METHODS: Critical discourse analysis was used to examine labour policies and practices related to employment leave for bereaved parents in Canada. Results were compared to international labour standards. RESULTS: Universally, employment policies provide only for the practical issues of bereavement. Commonly, leave is three days, unpaid, and meant to enable ceremonial obligations. Policies do not acknowledge the long-term suffering caused by grief or the variable intensity of different kinds of loss. Managerial, moral, normative and neoliberal values embedded in these policies efface the intensely personal experience of grief, thereby leaving employees at risk for serious health and workplace safety issues. CONCLUSIONS: Bereavement leave currently understands grief as a generic, time-limited state with instrumental tasks and ceremonial obligations. In contrast, research characterizes responses to child loss as intense, highly personal experiences for which healing and recovery can take years. This disconnect is especially problematic when viewed through the lens of employee wellbeing, reintegration and workplace productivity.

Synthesis and biological evaluation of acyclic phosphonic acid nucleoside derivatives.

As part of a project to generate a library of nucleosides as potential antiviral agents, a small subset of novel acyclic phosphonic acid nucleosides was prepared. Practical synthetic routes are described for three targets, which were then tested against HIV, hepatitis C virus (HCV), and Dengue virus.

Metaphors and medication: understanding medication use by seniors in everyday life.

The purpose of this study was to explore the use of metaphor by independent seniors taking medication for chronic health conditions. Narratives from a larger study using grounded theory were analyzed using constant comparative analysis and induction. A secondary analysis of the narratives of 21 participants was undertaken. Transcripts were read line-by-line and all relevant language was highlighted and reviewed with the aim of identifying relationships and themes. The narratives revealed a diverse range of metaphoric language. Four categories were identified: being shackled, hope, external authority, and communication fears. Three additional themes were interwoven into the narratives: aging and death, medication personified, and the body as object. The authors conclude that metaphor reveals the tension and unresolved dilemmas faced by seniors with regard to medication use.

Medication use in the context of everyday living as understood by seniors.

Recognizing that older adults are among the biggest consumers of medication, and the demographic group most likely to suffer an adverse drug reaction (ADR), this paper details the findings from a recent study on how older adults come to understand medication and its related use. Using a qualitative content analysis method, semi-structured interviews were conducted with 21 individuals from British Columbia, Canada. Study participants ranged in age from 65 to 89 years (male=9, female=11). Using NVIVO(®) 7 software, data were subjected to comparative thematic content analysis in an effort to capture the role of medication use in the context of everyday living as understood by older adults. While there was variability in how older adults come to understand their medication use, an overarching theme was revealed whereby most participants identified their prescription medications as being life-sustaining and prolonging. Deeper thematic content analysis of participant narratives drew attention to three key areas: (A) medications are viewed as a necessary, often unquestioned, aspect of day-to-day life (B) a relationship is perceived to exist between the amount of medications taken and ones current state of health (C) the overall medication experience is positively or negatively influenced by the doctor patient relationship and the assumption that it is the physicians role to communicate medication information that will support everyday living. The article concludes that medical authority and the complexities surrounding medication use need to undergo significant revision if community dwelling older adults are to experience greater success in safely managing their health and medication-related needs.

Mold growth in on-reserve homes in Canada: the need for research, education, policy, and funding.

The impact of mold growth in homes located on First Nations reserves in Canada is part of a national housing crisis that has not been adequately studied. Nearly half of the homes on reserves contain mold at levels of contamination associated with high rates of respiratory and other illnesses to residents. Mold thrives due to increased moisture levels in building envelopes and interior spaces. Increased moisture stems from several deficiencies in housing conditions, including structural damage to the building envelope, overcrowding and insufficient use of ventilation systems, and other moisture-control strategies. These deficiencies have developed due to a series of historical and socioeconomic factors, including disenfranchisement from traditional territory, environmentally inappropriate construction, high unemployment rates, lack of home ownership, and insufficient federal funding for on-reserve housing and socioeconomic improvements. The successful, long-term reduction of mold growth requires increased activity in several research and policy areas. First, the actual impacts on health need to be studied and associated with comprehensive experimental data on mold growth to understand the unique environmental conditions that permit the germination and growth of toxic mold species. Second, field data documenting the extent of mold growth in on-reserve homes do not exist but are essential in understanding the full extent of the crisis. Third, current government initiatives to educate homeowners in mold remediation and prevention techniques must be long lasting and effective. Finally, and most importantly, the federal government must make a renewed and lasting commitment to improve the socioeconomic conditions on reserves that perpetuate mold growth in homes. Without such improvement, the mold crisis will surely persist and likely worsen.

An imidazopiperidine series of CCR5 antagonists for the treatment of HIV: the discovery of N-{(1S)-1-(3-fluorophenyl)-3-[(3-endo)-3-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]propyl}acetamide (PF-232798).

Preventing entry of HIV into human host cells has emerged as an attractive approach to controlling viral replication. Maraviroc 1 is an approved antagonist of the human CCR5 receptor which prevents the entry of HIV. Herein, we report the design and discovery of a series of imidazopiperidine CCR5 antagonists which retain the attractive antiviral profile and window over hERG activity of maraviroc 1, combined with improved absorption profiles in rat and dog. Furthermore, this series of compounds has been shown to retain activity against a laboratory generated maraviroc-resistant HIV-1 strain, which indicates an alternative resistance profile to that of maraviroc 1. Compound 41f (PF-232798) was selected as a clinical candidate from the imidazopiperidine series and is currently in phase II clinical trials.

Design and optimisation of potent gp120-CD4 inhibitors.

The synthesis and structure-activity relationship of a series of novel gp120-CD4 inhibitors are described. Pharmacokinetic studies and antiviral spectrum assessment of lead compounds led to the identification of compound 36, a potent gp120-CD4 inhibitor which exhibited antiviral potency across a spectrum of 25 clade B isolates.

Discovery of a small molecule inhibitor through interference with the gp120-CD4 interaction.

A series of piperazine derivatives were designed and synthesised as gp120-CD4 inhibitors. SAR studies led to the discovery of potent inhibitors in a cell based anti viral assay represented by compounds 9 and 28. The rat pharmacokinetic and antiviral profiles of selected compounds are also presented.

SAR of a series of inhaled A(2A) agonists and comparison of inhaled pharmacokinetics in a preclinical model with clinical pharmacokinetic data.

COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. The pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists is described leading through to human pharmacokinetic data for a clinical candidate.

The design and discovery of novel amide CCR5 antagonists.

The synthesis of a range of novel amine-containing structures and their primary potency as inhibitors of HIV-1 fusion via blocking of the CCR5 receptor is described. The development of the medicinal chemistry strategy and SAR's which led to the identification of the piperidine amide compounds 33 and 36 as excellent leads for further evaluation is described, along with key physicochemical data which highlighted their lead potential.

Inhaled adenosine A(2A) receptor agonists for the treatment of chronic obstructive pulmonary disease.

COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. A strategy of minimizing side-effect liability by maximizing systemic clearance was followed and pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists described. A sevenfold improvement in potency and 150-fold reduction in side-effect liability over the lead compound CGS-21680, were obtained.

Monofluorinated di- and tetrahydropyrans via Prins-type cyclisations.

The synthesis of a range of fluorinated heterocycles is described via a Lewis acid-mediated Prins-type cyclisation.

Novel mutation in ferroportin1 is associated with autosomal dominant hemochromatosis.

Hemochromatosis is a common disorder characterized by excess iron absorption and accumulation of iron in tissues. Usually hemochromatosis is inherited in an autosomal recessive pattern and is caused by mutations in the HFE gene. Less common non-HFE-related forms of hemochromatosis have been reported and are caused by mutations in the transferrin receptor 2 gene and in a gene localized to chromosome 1q. Autosomal dominant forms of hemochromatosis have also been described. Recently, 2 mutations in the ferroportin1 gene, which encodes the iron transport protein ferroportin1, have been implicated in families with autosomal dominant hemochromatosis from the Netherlands and Italy. We report the finding of a novel mutation (V162del) in ferroportin1 in an Australian family with autosomal dominant hemochromatosis. We propose that this mutation disrupts the function of the ferroportin1 protein, leading to impaired iron homeostasis and iron overload.