Evolutionary and functional analysis of coagulase-positivity among the Staphylococci

The ability of some species of staphylococci to promote coagulation of plasma is a key pathogenic and diagnostic trait. Here, we provide a comprehensive analysis of the coagulase positivity of the staphylococci and its evolutionary genetic basis

Applying the Integrated Sustainability Framework to explore the long-term sustainability of nutrition education programs in schools: A systematic review

Abstract Objective: This review aimed to identify and synthesise the enablers and barriers that influence the long-term (≥2 years) sustainment of school-based nutrition programs. Design: Four databases (PubMed, Cochrane Library, Embase and Scopus) were searched to identify studies reporting on the international literature relating to food and nutrition programs aimed at school aged (5-14 years) children that had been running for ≥2 years (combined intervention and follow-up period). Eligible studies were analysed using the Integrated Sustainability Framework, which involved deductive coding of program enablers and barriers. A quality assessment was completed, using the Mixed-Methods Appraisal Tool and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Setting: International school-based nutrition programs. Subjects: Individuals involved with the implementation of school-based nutrition programs. Results: From the 7366 articles identified, 13 studies (seven qualitative, five mixed methods and one quantitative descriptive) were included, from which the enablers and barriers of 11 different nutrition-related programs were analysed. Thirty-four factors across the five domains of the Integrated Sustainability Framework were identified that influenced the sustained implementation of programs. The most common barrier was a lack of organisational readiness and resources, whereas the most common enabler was having adequate external partnerships and a supportive environment. Conclusions: These findings have application during the initiation and implementation phases of school-based nutrition programs. Paying attention to the ‘outer contextual factors’ of the ISF including the establishment and maintenance of robust relationships across whole of government systems, local institutions and funding bodies which are crucial factors for program sustainment

A Novel Core Genome-Encoded Superantigen Contributes to Lethality of Community-Associated MRSA Necrotizing Pneumonia

Bacterial superantigens (SAg) stimulate T-cell hyper-activation resulting in immune modulation and severe systemic illnesses such as Staphylococcus aureus toxic shock syndrome. However, all known S. aureus SAgs are encoded by mobile genetic elements and are made by only a proportion of strains. Here, we report the discovery of a novel SAg staphylococcal enterotoxin-like toxin X (SElX) encoded in the core genome of 95% of phylogenetically diverse S. aureus strains from human and animal infections, including the epidemic community-associated methicillin-resistant S. aureus (CA-MRSA) USA300 clone. SElX has a unique predicted structure characterized by a truncated SAg B-domain, but exhibits the characteristic biological activities of a SAg including Vβ-specific T-cell mitogenicity, pyrogenicity and endotoxin enhancement. In addition, SElX is expressed by clinical isolates in vitro, and during human, bovine, and ovine infections, consistent with a broad role in S. aureus infections of multiple host species. Phylogenetic analysis suggests that the selx gene was acquired horizontally by a progenitor of the S. aureus species, followed by allelic diversification by point mutation and assortative recombination resulting in at least 17 different alleles among the major pathogenic clones. Of note, SElX variants made by human- or ruminant-specific S. aureus clones demonstrated overlapping but distinct Vβ activation profiles for human and bovine lymphocytes, indicating functional diversification of SElX in different host species. Importantly, SElX made by CA-MRSA USA300 contributed to lethality in a rabbit model of necrotizing pneumonia revealing a novel virulence determinant of CA-MRSA disease pathogenesis. Taken together, we report the discovery and characterization of a unique core genome-encoded superantigen, providing new insights into the evolution of pathogenic S. aureus and the molecular basis for severe infections caused by the CA-MRSA USA300 epidemic clone

Prediction of disability-free survival in healthy older people

Prolonging survival in good health is a fundamental societal goal. However, the leading determinants of disability-free survival in healthy older people have not been well established. Data from ASPREE, a bi-national placebo-controlled trial of aspirin with 4.7 years median follow-up, was analysed. At enrolment, participants were healthy and without prior cardiovascular events, dementia or persistent physical disability. Disability-free survival outcome was defined as absence of dementia, persistent disability or death. Selection of potential predictors from amongst 25 biomedical, psychosocial and lifestyle variables including recognized geriatric risk factors, utilizing a machine-learning approach. Separate models were developed for men and women. The selected predictors were evaluated in a multivariable Cox proportional hazards model and validated internally by bootstrapping. We included 19,114 Australian and US participants aged ≥65 years (median 74 years, IQR 71.6–77.7). Common predictors of a worse prognosis in both sexes included higher age, lower Modified Mini-Mental State Examination score, lower gait speed, lower grip strength and abnormal (low or elevated) body mass index. Additional risk factors for men included current smoking, and abnormal eGFR. In women, diabetes and depression were additional predictors. The biased-corrected areas under the receiver operating characteristic curves for the final prognostic models at 5 years were 0.72 for men and 0.75 for women. Final models showed good calibration between the observed and predicted risks. We developed a prediction model in which age, cognitive function and gait speed were the strongest predictors of disability-free survival in healthy older people. Trial registration Clinicaltrials.gov (NCT01038583

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

Treatment patterns and outcomes in metastatic colorectal cancer (mCRC).

699 Background: Treatment (tx) selection for mCRC is multifactorial and affected by patient (pt) and disease factors, comorbidities, and previous tx. Few agents existed for therapy after second progression (i.e. third line (3L) at the time of this study. We aimed to capture mCRC tx patterns up to 3L and associated clinical and economic outcomes. Methods: A retrospective observational study of mCRC pts initiating 1L tx from 1/1/07 to 6/30/11 and 3L tx before 6/30/12. Data was extracted from The US Oncology Network (USON)/McKesson Specialty Health EHR and claims database. Pts on clinical trial or with another cancer diagnosis were excluded. Tx was organized into tx backbone categories and lines of therapy (LOTs), and adherence to NCCN guidelines and USON pathways assessed. The Kaplan-Meier method was used to estimate overall survival (OS). A multivariable generalized linear regression model was used to evaluate total costs during 3L tx as a function of 3L covariates by Medicare allowable. Clinical outcomes in 3L have been previously reported. Additional information on cost and other utilization is provided. Results: Of756 eligible 1L pts, 577 pts received 3L tx. At 1L, median age was 61 yrs (range 26-90+), male (55%), normal BMI (43%), ECOG performance status (PS) of 1 (65%), and Medicare (39%) insurance. The most utilized txs in 1L, 2L, and 3L were oxaliplatin-based (FOLFOX + bevacizumab, 46%), irinotecan-based (FOLFIRI + bevacizumab, 23%), and irinotecan + anti-EGFR (irinotecan + cetuximab, 24%) respectively. Adherence to NCCN and USON recommendations for 1L, 2L, and 3L was 88%/75%/55% and 84%/62%/38% respectively. OS in 3L was influenced by PS, BMI, and KRAS (p &lt; 0.05), but was not different by tx backbone (p = 0.47). In the multivariable model of total cost per pt in 3L, there were no significant predictors. Conclusions: Knowledge of tx sequencing aids in understanding selection choices and outcomes in pts who are candidates for later lines of therapy of mCRC. High utilization of targeted therapies was observed in each line. Adherence to guidelines decreased with increasing lines of therapy. Utilization and costs by tx backbone in the 3L during this time frame varied. 3L OS did not differ according to tx backbone. </jats:p

Updated use of first-line chemotherapy for advanced pancreatic cancer: FOLFIRINOX versus gemcitabine.

6607 Background: Pancreatic cancer (PC) is the fourth leading cause of death in the United States. It is estimated that 45,220 patients will be diagnosed in 2013 and 38,460 will die (Siegel, CA Cancer J Clin 2013). Gemcitabine has long been the standard of care chemotherapy. Recent advances in treatment created a combination regimen (oxaliplatin, irinotecan, leucovorin, fluorouracil [FOLFIRINOX]) for patients with good Karnofsky performance status (PS) (Conroy, NEJM 2011). This retrospective analysis was conducted as an update to results reported at ASCO 2012 (Ginsburg Arlen, JCO 2012) to evaluate characteristics and overall survival (OS) of patients receiving FOLFIRINOX and gemcitabine-based treatments in a large outpatient community setting. This is the largest study describing FOLFIRINOX patients to date. Methods: Patients with advanced PC treated within The US Oncology Network entered into the iKnowMed (iKM) database between June 2010 and November 2012 were included. Patterns of treatment were characterized by the median age at diagnosis, sex, PS, and first-line metastatic chemotherapy prescribed. The primary endpoints of the analysis were OS and uptake of FOLFIRINOX within the network. Results: Compared to ASCO 2012 results, 1,000 additional patients were identified in iKM. Of the 1,714 total patients, 24% received FOLFIRINOX (up from 13% in 2012) and 76% gemcitabine-based therapy (87% in 2012). Increased utilization of FOLFIRINOX for patients with good PS began in June 2010. For all patients (55% male), the median age at diagnosis was 67 years and the majority (85%) had a PS of 70% or greater. The OS was significantly longer for FOLFIRINOX (9.6 mos) versus gemcitabine (6.3 mos) (p&lt;0.0001). This held true for PS of 70% or greater patient given FOLFIRINOX (9.6 mos) versus gemcitabine (7 mos) (p&lt;0.0001). Conclusions: Utilization of FOLFIRINOX has continued to expand after the publication of phase III trials. Our data in a community setting supports a survival advantage for FOLFIRINOX. Although the magnitude of benefit may be smaller in the community, we agree that FOLFIRINOX should become a standard of care for good PS patients. </jats:p