Discovery of novel GPVI receptor antagonists by structure-based repurposing.

Inappropriate platelet aggregation creates a cardiovascular risk that is largely managed with thienopyridines and aspirin. Although effective, these drugs carry risks of increased bleeding and drug 'resistance', underpinning a drive for new antiplatelet agents. To discover such drugs, one strategy is to identify a suitable druggable target and then find small molecules that modulate it. A good and unexploited target is the platelet collagen receptor, GPVI, which promotes thrombus formation. To identify inhibitors of GPVI that are safe and bioavailable, we docked a FDA-approved drug library into the GPVI collagen-binding site in silico. We now report that losartan and cinanserin inhibit GPVI-mediated platelet activation in a selective, competitive and dose-dependent manner. This mechanism of action likely underpins the cardioprotective effects of losartan that could not be ascribed to its antihypertensive effects. We have, therefore, identified small molecule inhibitors of GPVI-mediated platelet activation, and also demonstrated the utility of structure-based repurposing

A case-series study to explore the efficacy of foot orthoses in treating first metatarsophalangeal joint pain

Background: First metatarsophalangeal (MTP) joint pain is a common foot complaint which is often considered to be a consequence of altered mechanics. Foot orthoses are often prescribed to reduce 1 stMTP joint pain with the aim of altering dorsiflexion at propulsion. This study explores changes in 1 stMTP joint pain and kinematics following the use of foot orthoses.Methods: The effect of modified, pre-fabricated foot orthoses (X-line ®) were evaluated in thirty-two patients with 1 stMTP joint pain of mechanical origin. The primary outcome was pain measured at baseline and 24 weeks using the pain subscale of the foot function index (FFI). In a small sub-group of patients (n = 9), the relationship between pain and kinematic variables was explored with and without their orthoses, using an electromagnetic motion tracking (EMT) system.Results: A significant reduction in pain was observed between baseline (median = 48 mm) and the 24 week endpoint (median = 14.50 mm, z = -4.88, p < 0.001). In the sub-group analysis, we found no relationship between pain reduction and 1 stMTP joint motion, and no significant differences were found between the 1 stMTP joint maximum dorsiflexion or ankle/subtalar complex maximum eversion, with and without the orthoses.Conclusions: This observational study demonstrated a significant decrease in 1 stMTP joint pain associated with the use of foot orthoses. Change in pain was not shown to be associated with 1 stMTP joint dorsiflexion nor with altered ankle/subtalar complex eversion. Further research into the effect of foot orthoses on foot function is indicated. © 2010 Welsh et al; licensee BioMed Central Ltd

Finding, retrieving and evaluating journal and web-based information for evidence-based optometry

How can optometrists ensure they are basing their advice to patients on the most reliable information available? This paper discusses search tools, databases, websites and journals, which provide free, full-text, web-based access to evidence-based literature. Brief tips on searching these resources are provided for the time-poor practitioner or researcher. Criteria, such as credibility, currency and bias are used to evaluate written material and will be discussed with particular reference to the problems inherent in evaluating web pages

Increasing uptake of influenza vaccine by pregnant women post H1N1 pandemic: a longitudinal study in Melbourne, Australia, 2010 to 2014

BACKGROUND: A Melbourne (Australia) university affiliated, tertiary obstetric hospital provides lay and professional education about influenza vaccine in pregnancy annually each March, early in the local influenza season. Responding to a 2011 survey of new mothers' opinions, the hospital made influenza vaccine freely available in antenatal clinics from 2012. We wished to determine influenza vaccination uptake during pregnancy with these strategies 5 years after 2009 H1N1. METHODS: Face to face interviews based on US Center for Disease Control and Prevention Pregnancy Risk Assessment Monitoring System with new mothers in postnatal wards each July, 2010 to 2014. We calculated recalled influenza vaccine uptake each year and assessed trends with chi square tests, and logistic regression. RESULTS: We recorded 1086 interviews. Influenza vaccination during pregnancy increased by 6% per year (95% confidence interval 4 to 8%): from 29.6% in 2010 to 51.3% in 2014 (p < 0.001). Lack of discussion from maternity caregivers was a persistent reason for non-vaccination, recalled by 1 in 2 non-vaccinated women. Survey respondents preferred face to face consultations with doctors and midwives, internet and text messaging as information sources about influenza vaccination. Survey responses indicate messages about vaccine safety in pregnancy and infant benefits are increasingly being heeded. However, there was progressively lower awareness of maternal benefits of influenza vaccination, especially for women with risk factors for severe disease. CONCLUSIONS: We observed improving influenza vaccination during pregnancy. There is potential to integrate technology such as text message or internet with antenatal consultations to increase vaccination coverage further. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12884-015-0486-3) contains supplementary material, which is available to authorized users

Inhibition of destructive autoimmune arthritis in Fc?RIIa transgenic mice by small chemical entities

The interaction of immune complexes with the human Fc receptor, Fc?RIIa, initiates the release of inflammatory mediators and is implicated in the pathogenesis of human autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus, so this FcR is a potential target for therapy. We have used the three-dimensional structure of an Fc?RIIa dimer to design small molecule inhibitors, modeled on a distinct groove and pocket created by receptor dimerization, adjacent to the ligand-binding sites. These small chemical entities (SCEs) blocked immune complex-induced platelet activation and aggregation and tumor necrosis factor secretion from macrophages in a human cell line and transgenic mouse macrophages. The SCE appeared specific for Fc?RIIa, as they inhibited only immune complex-induced responses and had no effect on responses to stimuli unrelated to FcR, for example platelet stimulation with arachidonic acid. In vivo testing of the SCE in Fc?RIIa transgenic mice showed that they inhibited the development and stopped the progression of collagen-induced arthritis (CIA). The SCEs were more potent than methotrexate and anti-CD3 in sustained suppression of CIA. Thus, in vitro and in vivo activity of these SCE Fc?RIIa receptor antagonists demonstrated their potential as anti-inflammatory agents for autoimmune diseases involving immune complexes. © 2009 Australasian Society for Immunology Inc. All rights reserved

Using HIV Surveillance Registry Data to Re-Link Persons to Care: The RSVP Project in San Francisco

BackgroundPersons with unsuppressed HIV viral load (VL) who disengage from care may experience poor clinical outcomes and potentially transmit HIV. We assessed the feasibility and yield of using the San Francisco Department of Public Health (SFDPH) enhanced HIV surveillance system (eHARS) to identify and re-engage such persons in care.MethodsUsing SFDPH eHARS data as of 4/20/2012 (index date), we selected HIV-infected adults who were alive, had no reported VL or CD4 cell count results in the past nine months (proxy for "out-of-care") and a VL >200 copies/mL drawn nine to 15 months earlier. We prioritized cases residing locally for investigation, and used information from eHARS and medical and public health databases to contact them for interview and referral to the SFDPH linkage services (LINCS). Twelve months later, we matched-back to eHARS data to assess how HIV laboratory reporting delays affected original eligibility, and if persons had any HIV laboratory results performed and reported within 12 months after index date ('new labs').ResultsAmong 434 eligible persons, 282 were prioritized for investigation, of whom 75 (27%) were interviewed, 79 (28%) could not be located, and 48 (17%) were located out of the area. Among the interviewed, 54 (72%) persons accepted referral to LINCS. Upon match-back to eHARS data, 324 (75%) in total were confirmed as eligible, including 221 (78%) of the investigated; most had new labs.ConclusionsAmong the investigated persons presumed out-of-care, we interviewed and offered LINCS referral to about one-quarter, demonstrating the feasibility but limited yield of our project. Matching to updated surveillance data revealed that a substantial minority did not disengage from care and that most re-engaged in HIV care. Verifying persons' HIV care status with medical providers and improving timeliness of transfer and cross-jurisdictional sharing of HIV laboratory data may aid future efforts

Community-associated versus healthcare-associated methicillin-resistant Staphylococcus aureus bacteraemia: A 10-year retrospective review

The objective was to compare the epidemiology and outcome of healthcare- (HA-) and community-associated (CA-) MRSA bacteraemia. A 10-year retrospective study of MRSA bacteraemia was carried out. Episodes were classified according to established criteria. Molecular typing was performed on a subset of isolates. Of 197 MRSA bacteraemia episodes, 178 (90.4%) were classified as HA-MRSA and 19 (9.6%) as CA-MRSA. All-cause 7- and 30-day mortality rates were similar in the HA and CA-MRSA bacteraemia groups; however, 1-year mortality was higher in the HA-MRSA bacteraemia group (48.3% vs 21.1% [p?=?0.023]). Thirty-day all-cause mortality was significantly lower if empiric antimicrobial therapy included agent(s) to which the isolate tested susceptible, compared with patients receiving "inactive" therapy (19% vs 35.1% [p?=?0.011]). The majority of MRSA bacteraemia episodes were caused by clones known to circulate in the community. All-cause mortality is as high in HA- as in CA-MRSA bacteraemia. Thirty-day mortality was significantly reduced if the patient received an antibiotic with activity against the MRSA isolate. © 2008 Springer-Verlag

Transformational capacity in Australian peanut farmers for better climate adaptation

The food industry is vulnerable to climate change. Producers will need to adapt to climate change if they, and the communities dependent on them, are to remain viable. There are essentially two ways to adapt - incrementally and transformationally. We differentiate between incremental and transformative adaptation mostly on the basis of the size of the change needed. Here, we studied the Australian peanut industry, which is already experiencing the effects of climate change. We expand on the notion of adaptive capacity and refer to 'transformational capacity' and test its association with resource dependency. Resource dependency is a measure of the interactions that primary producers have with a natural resource and includes factors such as occupational identity, networks, resource use as well as a range of financial factors. We hypothesized that some primary producers were more likely to demonstrate higher levels of transformational capacity if they possessed lower levels of resource dependency. We surveyed, by phone, 69 farmers representing 87 % of the peanut industry in northern Australia. Our results show that the capacity to transform depends upon individual's networks, their employability, tendency for strategic thinking and planning, business profitability, local knowledge, environmental awareness, use of irrigation and use of climate technology. Barriers to transformational change were occupational identity, place attachment and dependents. Our study is one of the first to focus on transformational capacity. This approach allows us to understand why some individuals are better able to adapt to change than others and also to assist industry and community leaders to develop broad-scale strategies