Estimating Site Performance (ESP) : can trial managers predict recruitment success at trial sites? An exploratory study

Availability of data and materials All quantitative data generated and analysed during this study are included in this published article [and its supplementary information files] Additional file 3. The dataset of predictions used and analysed during the current study are available from the corresponding author on reasonable request. The transcript of the group discussion generated and analysed during the current study is not publicly available due it containing information that could compromise research participant consent (it would be a relatively simple matter to identify trials and trial managers) but are available from the corresponding author on reasonable request.Peer reviewedPublisher PD

Survey of rehabilitation support for children 0-15 years in a rural part of Kenya

Abstract Purpose: Information regarding the nature, availability and distribution of rehabilitation services for children with disabilities across developing countries is scarce, and data that do exist are of variable quality. If planning and development are to progress, information about service provision is vital. The aim was to establish the scope and nature of rehabilitation support available to children with disabilities (0-15 years) and their families in rural Kenya. Method: A comprehensive sample comprising service provision in the health and special education sectors was established. Non-governmental and community-based organisations were also included. A survey of rehabilitation services was conducted through examination of service-related documentation and key informant interviews with the heads of services. Results: Rehabilitation comprised hospital-based occupational therapy, physiotherapy and orthopaedic technology; and seven special education establishments plus an education assessment resource centre. There was one non-government organisation and one community-based organisation relevant to children with disabilities. Activities focused on assessment, diagnosis and raising community awareness. Provision was challenged by inadequate staffing, resources and transport. Government funding was supplemented variously by donations and self-sufficiency initiatives. Rehabilitation approaches appeared to be informed by professional background of practitioner, rather than the needs of child. Service documentation revealed use of inconsistent recording methods. Conclusions: The data highlight the challenges of rehabilitation, demanding greater investment in personnel and their training, more material resources, improved access to the community and better recording mechanisms. Implications for Rehabilitation There needs to be greater investment in rehabilitation provision in developing countries. Consideration of community-based initiatives is required to support better access for all. In order to argue the case for improved resources, better skills and mechanisms for recording, monitoring and evaluating practice are needed

Catchment characteristics and seasonality control the composition of microbial assemblages exported from three outlet glaciers of the Greenland Ice Sheet

Glacial meltwater drains into proglacial rivers where it interacts with the surrounding landscape, collecting microbial cells as it travels downstream. Characterizing the composition of the resulting microbial assemblages in transport can inform us about intra-annual changes in meltwater flowpaths beneath the glacier as well as hydrological connectivity with proglacial areas. Here, we investigated how the structure of suspended microbial assemblages evolves over the course of a melt season for three proglacial catchments of the Greenland Ice Sheet (GrIS), reasoning that differences in glacier size and the proportion of glacierized versus non-glacierized catchment areas will influence both the identity and relative abundance of microbial taxa in transport. Streamwater samples were taken at the same time each day over a period of 3 weeks (summer 2018) to identify temporal patterns in microbial assemblages for three outlet glaciers of the GrIS, which differed in glacier size (smallest to largest; Russell, Leverett, and Isunnguata Sermia [IS]) and their glacierized: proglacial catchment area ratio (Leverett, 76; Isunnguata Sermia, 25; Russell, 2). DNA was extracted from samples, and 16S rRNA gene amplicons sequenced to characterize the structure of assemblages. We found that microbial diversity was significantly greater in Isunnguata Sermia and Russell Glacier rivers compared to Leverett Glacier, the latter of which having the smallest relative proglacial catchment area. Furthermore, the microbial diversity of the former two catchments continued to increase over monitored period, presumably due to increasing hydrologic connectivity with proglacial habitats. Meanwhile, diversity decreased over the monitored period in Leverett, which may have resulted from the evolution of an efficient subglacial drainage system. Linear discriminant analysis further revealed that bacteria characteristic to soils were disproportionately represented in the Isunnguata Sermia river, while putative methylotrophs were disproportionately abundant in Russell Glacier. Meanwhile, taxa typical for glacierized habitats (i.e., Rhodoferax and Polaromonas) dominated in the Leverett Glacier river. Our findings suggest that the proportion of deglaciated catchment area is more influential to suspended microbial assemblage structure than absolute glacier size, and improve our understanding of hydrological flowpaths, particulate entrainment, and transport

Trastuzumab-associated cardiac events in the Persephone trial.

BACKGROUND: We report cardiac events in the Persephone trial which compares 6-12 months of adjuvant trastuzumab in women with confirmed HER2-positive, early-stage breast cancer. METHODS: Clinical cardiac events were defined as any of the following: symptoms and/or signs of congestive heart failure (CHF) and new or altered CHF medication. In addition, left ventricular ejection fraction (LVEF) was measured at baseline and then 3 monthly for 12 months. RESULTS: A total of 2500 patients, aged 22-82, were included: 1251 randomised to 12 months and 1249 to 6 months of trastuzumab treatment. A total of 93% (2335/2500) received anthracyclines, 49% of these (1136/2335) with taxanes. Cardiotoxicity delayed treatment in 6% of 12-month and 4% of 6-month patients (P=0.01), and stopped treatment early in 8% (96/1214) of 12-month and 4% (45/1216) of 6-month patients (P3 cycles of anthracycline was associated with higher risk of cardiac events only for 12-month patients (OR 1.41 (1.04-1.90)), and not for 6-month patients (OR 1.28 (0.91-1.79)). CONCLUSIONS: We demonstrate significantly fewer cardiac events from 6 months of adjuvant trastuzumab compared with that from 12 months. This cardiac signal adds importance to the question of the optimum duration of adjuvant trastuzumab treatment. If 6 months is proven to have non-inferior outcomes to 12 months treatment, these data would support 6 months as the standard of care.National Institute of Health Research Health Technology Assessment (NIHR HTA) Programme UK. Funding reference number - 06/303/98This is the author accepted manuscript. The final version is available from Nature Publishing Group via https://doi.org/10.1038/bjc.2016.35

Runx1 deficiency protects against adverse cardiac remodeling following myocardial infarction

Background: Myocardial infarction (MI) is a leading cause of heart failure and death worldwide. Preservation of contractile function and protection against adverse changes in ventricular architecture (cardiac remodeling) are key factors to limiting progression of this condition to heart failure. Consequently, new therapeutic targets are urgently required to achieve this aim. Expression of the Runx1 transcription factor is increased in adult cardiomyocytes after MI; however, the functional role of Runx1 in the heart is unknown. Methods: To address this question, we have generated a novel tamoxifen-inducible cardiomyocyte-specific Runx1-deficient mouse. Mice were subjected to MI by means of coronary artery ligation. Cardiac remodeling and contractile function were assessed extensively at the whole-heart, cardiomyocyte, and molecular levels. Results: Runx1-deficient mice were protected against adverse cardiac remodeling after MI, maintaining ventricular wall thickness and contractile function. Furthermore, these mice lacked eccentric hypertrophy, and their cardiomyocytes exhibited markedly improved calcium handling. At the mechanistic level, these effects were achieved through increased phosphorylation of phospholamban by protein kinase A and relief of sarco/endoplasmic reticulum Ca2+-ATPase inhibition. Enhanced sarco/endoplasmic reticulum Ca2+-ATPase activity in Runx1-deficient mice increased sarcoplasmic reticulum calcium content and sarcoplasmic reticulum–mediated calcium release, preserving cardiomyocyte contraction after MI. Conclusions: Our data identified Runx1 as a novel therapeutic target with translational potential to counteract the effects of adverse cardiac remodeling, thereby improving survival and quality of life among patients with MI

DETECT schools study protocol: A prospective observational cohort surveillance study investigating the impact of COVID-19 in Western Australian schools

Introduction: Amidst the evolving COVID-19 pandemic, understanding the transmission dynamics of the SARS-CoV-2 virus is key to providing peace of mind for the community and informing policy-making decisions. While available data suggest that school-aged children are not significant spreaders of SARS-CoV-2, the possibility of transmission in schools remains an ongoing concern, especially among an aging teaching workforce. Even in low-prevalence settings, communities must balance the potential risk of transmission with the need for students\u27 ongoing education. Through the roll out of high-throughput school-based SARS-CoV-2 testing, enhanced follow-up for individuals exposed to COVID-19 and wellbeing surveys, this study investigates the dynamics of SARS-CoV-2 transmission and the current psychosocial wellbeing impacts of the pandemic in school communities. Methods: The DETECT Schools Study is a prospective observational cohort surveillance study in 79 schools across Western Australia (WA), Australia. To investigate the incidence, transmission and impact of SARS-CoV-2 in schools, the study comprises three “modules”: Module 1) Spot-testing in schools to screen for asymptomatic SARS-CoV-2; Module 2) Enhanced surveillance of close contacts following the identification of any COVID-19 case to determine the secondary attack rate of SARS-CoV-2 in a school setting; and Module 3) Survey monitoring of school staff, students and their parents to assess psycho-social wellbeing following the first wave of the COVID-19 pandemic in WA. Clinical Trial Registration: Trial registration number: ACTRN1262000092297

Six versus 12 months' adjuvant trastuzumab in patients with HER2-positive early breast cancer: the PERSEPHONE non-inferiority RCT

Background The addition of adjuvant trastuzumab to chemotherapy has significantly improved outcomes in human epidermal growth factor receptor 2 (HER2) positive early, potentially curable breast cancer. Twelve months’ trastuzumab tested in the registration trials was adopted for standard adjuvant treatment in 2006. Subsequently similar outcomes were demonstrated using 9 weeks trastuzumab. Shorter durations were therefore tested for non-inferiority. Objectives To establish whether 6 months’ adjuvant trastuzumab is non-inferior to 12 months in HER2-positive early breast cancer using a primary endpoint of 4-year disease-free-survival (DFS). Design Phase III randomised, controlled, non-inferiority trial. Setting 152 NHS Hospitals. Participants 4088 patients with HER2-positive early breast cancer planned to receive both chemotherapy and trastuzumab. Intervention Randomisation (1:1) between six months’ or twelve months’ trastuzumab. Main outcomes Primary endpoint was DFS four years after diagnosis. Secondary endpoints were overall survival (OS), cost effectiveness, and cardiac function during trastuzumab. Assuming a 4-year DFS rate of 80% with 12 months, 4000 patients were required to demonstrate non-inferiority of 6-months (5% 1-sided significance, 85% power), defining the non-inferiority limit as no worse than 3% below the standard arm. Costs and quality-adjusted life years (QALYs) were estimated by within-trial analysis and a lifetime decision-analytic model. Results Between 4th October 2007 and 31st July 2015, 2045 patients were randomised to 12-months’ trastuzumab and 2043 to 6-months. Sixty-nine percent had ER-positive disease; 90% received anthracyclines (49% with taxanes; 41% without taxanes); 10% received taxanes without anthracyclines; 54% had trastuzumab sequentially after chemotherapy; 85% received adjuvant chemotherapy (58% were node negative). At 6.1 years median follow-up with 389 (10%) deaths, and 566 (14%) DFS events, 4-year DFS rates for the 4088 patients were 89.5% (95% CI, 88.1-90.8) in the 6-month group and 90.3% (95% CI 88.9- 91.5) in the 12-month group (Hazard Ratio 1.10; 90% CI 0.96–1.26, non-inferiority p=0.01), demonstrating non-inferiority of 6-months’ trastuzumab. Congruent results were found for OS (non-inferiority p=0.0003), and landmark analyses 6 months from starting trastuzumab (non-inferiority p=0.03 (DFS) and p=0.006 (OS)). 6-months’ trastuzumab resulted in fewer patients reporting adverse events of severe grade (365/1929 (19%) versus 460/1935 (24%) 12-month patients, p=0.0003) or stopping early because of cardiotoxicity (61/1977 (3%) versus 146/1941 (8%) 12-month patients, p<0.0001). Health economic analysis showed significantly lower lifetime costs and similar lifetime QALYs, and thus a high probability that 6 months is cost-effective compared to 12 months. Patient reported experiences on the trial highlighted fatigue, and aches and pains most frequently. Limitations The type of chemotherapy and timing of trastuzumab changed through the recruitment phase of the study as standard practice altered. Conclusions PERSEPHONE demonstrated that in HER2-positive early breast cancer 6 months’ adjuvant trastuzumab was non-inferior to 12 months. There was significantly less cardiac toxicity and fewer severe adverse events with 6 months’ treatment. Future work On-going translational work investigates patient and tumour genetic determinants of toxicity, and trastuzumab efficacy. An individual patient data meta-analysis with PHARE and other trastuzumab duration trials is planned. Trial registration ISRCTN 52968807 Funding National Institute for Health Research, Health Technology Assessment Programme (HTA Project: 06/303/98).National Institute for Health Research, Health Technology Assessment Programme (HTA Project: 06/303/98)

The Eighth Data Release of the Sloan Digital Sky Survey: First Data from SDSS-III

The Sloan Digital Sky Survey (SDSS) started a new phase in August 2008, with new instrumentation and new surveys focused on Galactic structure and chemical evolution, measurements of the baryon oscillation feature in the clustering of galaxies and the quasar Ly alpha forest, and a radial velocity search for planets around ~8000 stars. This paper describes the first data release of SDSS-III (and the eighth counting from the beginning of the SDSS). The release includes five-band imaging of roughly 5200 deg^2 in the Southern Galactic Cap, bringing the total footprint of the SDSS imaging to 14,555 deg^2, or over a third of the Celestial Sphere. All the imaging data have been reprocessed with an improved sky-subtraction algorithm and a final, self-consistent photometric recalibration and flat-field determination. This release also includes all data from the second phase of the Sloan Extension for Galactic Understanding and Evolution (SEGUE-2), consisting of spectroscopy of approximately 118,000 stars at both high and low Galactic latitudes. All the more than half a million stellar spectra obtained with the SDSS spectrograph have been reprocessed through an improved stellar parameters pipeline, which has better determination of metallicity for high metallicity stars.Comment: Astrophysical Journal Supplements, in press (minor updates from submitted version