Diverse functions for acyltransferase-3 proteins in the modification of bacterial cell surfaces

The acylation of sugars, most commonly via acetylation, is a widely used mechanism in bacteria that uses a simple chemical modification to confer useful traits. For structures like lipopolysaccharide, capsule and peptidoglycan, that function outside of the cytoplasm, their acylation during export or post-synthesis requires transport of an activated acyl group across the membrane. In bacteria this function is most commonly linked to a family of integral membrane proteins - acyltransferase-3 (AT3). Numerous studies examining production of diverse extracytoplasmic sugar-containing structures have identified roles for these proteins in O-acylation. Many of the phenotypes conferred by the action of AT3 proteins influence host colonisation and environmental survival, as well as controlling the properties of biotechnologically important polysaccharides and the modification of antibiotics and antitumour drugs by Actinobacteria. Herein we present the first systematic review, to our knowledge, of the functions of bacterial AT3 proteins, revealing an important protein family involved in a plethora of systems of importance to bacterial function that is still relatively poorly understood at the mechanistic level. By defining and comparing this set of functions we draw out common themes in the structure and mechanism of this fascinating family of membrane-bound enzymes, which, due to their role in host colonisation in many pathogens, could offer novel targets for the development of antimicrobials

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Food fairness Illawarra: Factors enabling an effective coalition to ensure a fair food future

Food security, access to appropriate, nutritious food on a regular, reliable basis, is a human right and core to Australia’s future. However, it is increasingly recognised that groups in the Australian community are food insecure, including \u3e6% of Illawarra residents. In recognition of this, Food Fairness Illawarra formed as a community alliance to promote a fair food future for residents. Collaborative community partnerships and coalitions are a core Ottawa Charter strategy for enhancing health. It is important therefore to evaluate the effectiveness of such coalitions in promoting community food security. The effectiveness of Food Fairness Illawarra as a community coalition to enhance food security can be measured in terms of outcomes and processes. The coalition has been successful in a wide range of outcomes at a number of strategic levels to promote and enhance local food security. In addition, the coalition has surveyed members regularly concerning satisfaction, communication and capacity building to ensure that the coalition has appropriate processes for continuing effectiveness. This discussion will present the outcome and process measures used by Food Fairness Illawarra to demonstrate its effectiveness and highlight the factors contributing to the success of this community coalition in promoting community food security

Food security: mapping the environmental determinants for urban planning and infrastructure development.

Food security, access to appropriate, nutritious food on a regular and reliable basis, using socially and culturally acceptable means to acquire it, is a human right. There are groups in the Australian community who are food insecure, including low income families with children, the elderly, and other marginalised and disadvantaged groups. However, low income does not equate to food insecurity and urban infrastructure can ameliorate or exacerbate food access issues. This paper describes environmental aspects of urban food access in Wollongong NSW, using GIS software. It presents layered data on food outlets by type, food aid distributors, sociodemographic profiles (including SEIFA indices and other ABS data), transport routes, and aspects of the social and built environments. Through the use of mapping, clear differences within similar sociodemographic areas were identified that challenge simplistic interpretations linking food security and socioeconomic data. The visual demonstration of infrastructural aspects of the environment can be used to advocate to local government for consideration of infrastructure and planning impacts on food access and health. Mapping also can provide information to local food aid providers in planning for the appropriate distribution of food aid and as an advocacy tool through comparison with other Australian data. In addition, this project has acted as an important focal point for collaborative partnerships between the university and other agencies, including South Eastern Sydney Illawarra Health (NSW Health), NGOs, and the private sector, to develop sustainable action to promote health

Alcohol management practices in community football clubs: association with risky drinking at the club and overall hazardous alcohol consumption

Across the world, it has been estimated that approximately 270 million people participate in community football clubs. However, the community sports club setting is associated with high levels of risky alcohol consumption. The study examined if sporting club alcohol management practices are associated with risky consumption of alcohol by club members while at the club, and also whether such consumption is directly and indirectly associated with club member overall hazardous alcohol consumption

Workplace circulation design and movement: a case study of three Australian campus buildings

This paper explores the interconnections between a building’s spatial qualities and office workers’ health behaviours, specifically focusing on physical activity, circulation route usage, and sitting time. A mixed methods approach was adopted to examine three workplace buildings, using spatial analysis, physical activity measurement, and a survey of 99 participants. The findings revealed statistical differences in movement patterns among workers in the three case studies. The analysis highlighted the predominantly sedentary nature of the workplaces, staff’s prioritisation of the quickest route, their willingness to incorporate personal physical activity into the workday, and the significant impacts of circulation space design on movement patterns. In response to the pressing need for increased physical activity and reduced sedentary behaviour at work, a greater understanding of the embodied movement of workers must be central in workplace briefing, design, management, and research. We argue that circulation spaces in workplaces should be designed as more than just enablers of workplace functionality and emergency egress