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Use of the herbicide atrazine (ATR) is banned in the European Union; yet, it is still widely used in the USA and Australia. ATR is known to alter testosterone and oestrogen production and thus reproductive characteristics in numerous species. In this proof of concept study, we examined the effect of ATR exposure, at a supra-environmental dose (5 mg/kg bw/day), beginning on E9.5 in utero, prior to sexual differentiation of the reproductive tissues, until 26 weeks of age, on the development of the mouse penis. Notably, this is the first study to specifically investigate whether ATR can affect penis characteristics. We show that ATR exposure, beginning in utero, causes a shortening (demasculinisation) of penis structures and increases the incidence of hypospadias in mice. These data indicate the need for further studies of ATR on human reproductive development and fertility, especially considering its continued and widespread use.
Anecdotal evidence suggests the use of bolus tube feeding is increasing in long term home enteral tube feed (HETF) patients. A cross-sectional survey to assess the prevalence of bolus tube feeding and to characterise these patients was undertaken. Dietitians from 10 centres across the UK collected data on all adult HETF patients on the dietetic caseload receiving bolus tube feeding, (n=604, 60% male, age 58years). Demographic data, reasons for tube and bolus feeding, tube and equipment types, feeding method and patients’ complete tube feeding regimens were recorded. Over a third of patients receiving HETF used bolus feeding (37%). Patients were long-term tube fed (4.1years tube feeding, 3.5years bolus tube feeding), living at home (71%) and sedentary (70%). The majority were head and neck cancer patients (22%) who were significantly more active (79%) and lived at home (97%), while those with cerebral palsy (12%) were typically younger (age 31years) but sedentary (94%). Most patients used bolus feeding as their sole feeding method (46%), because it was quick and easy to use, as a top up to oral diet or to mimic meal times. Importantly, oral nutritional supplements (ONS) were used for bolus feeding in 85% of patients, with 51% of these being compact-style ONS (2.4kcal/ml, 125ml). This survey shows that bolus tube feeding is common amongst UK HETF patients, is used by a wide variety of patient groups and can be adapted to meet the needs of a variety of patients, clinical conditions, nutritional requirements and lifestyles.
There is increasing evidence to support integration of simulation into medical training; however, no national emergency medicine (EM) simulation curriculum exists. Using Delphi methodology, we aimed to identify and establish content validity for adult EM curricular content best suited for simulation-based training, to inform national postgraduate EM training.
A national panel of experts in EM simulation iteratively rated potential curricular topics, on a 4-point scale, to determine those best suited for simulation-based training. After each round, responses were analyzed. Topics scoring <2/4 were removed and remaining topics were resent to the panel for further ratings until consensus was achieved, defined as Cronbach α ≥ 0.95. At conclusion of the Delphi process, topics rated ≥ 3.5/4 were considered “core” curricular topics, while those rated 3.0-3.5 were considered “extended” curricular topics.
Forty-five experts from 13 Canadian centres participated. Two hundred eighty potential curricular topics, in 29 domains, were generated from a systematic literature review, relevant educational documents and Delphi panellists. Three rounds of surveys were completed before consensus was achieved, with response rates ranging from 93-100%. Twenty-eight topics, in eight domains, reached consensus as “core” curricular topics. Thirty-five additional topics, in 14 domains, reached consensus as “extended” curricular topics.
Delphi methodology allowed for achievement of expert consensus and content validation of EM curricular content best suited for simulation-based training. These results provide a foundation for improved integration of simulation into postgraduate EM training and can be used to inform a national simulation curriculum to supplement clinical training and optimize learning.
To identify potential participants for clinical trials, electronic health records (EHRs) are searched at potential sites. As an alternative, we investigated using medical devices used for real-time diagnostic decisions for trial enrollment.
To project cohorts for a trial in acute coronary syndromes (ACS), we used electrocardiograph-based algorithms that identify ACS or ST elevation myocardial infarction (STEMI) that prompt clinicians to offer patients trial enrollment. We searched six hospitals’ electrocardiograph systems for electrocardiograms (ECGs) meeting the planned trial’s enrollment criterion: ECGs with STEMI or > 75% probability of ACS by the acute cardiac ischemia time-insensitive predictive instrument (ACI-TIPI). We revised the ACI-TIPI regression to require only data directly from the electrocardiograph, the e-ACI-TIPI using the same data used for the original ACI-TIPI (development set n = 3,453; test set n = 2,315). We also tested both on data from emergency department electrocardiographs from across the US (n = 8,556). We then used ACI-TIPI and e-ACI-TIPI to identify potential cohorts for the ACS trial and compared performance to cohorts from EHR data at the hospitals.
Receiver-operating characteristic (ROC) curve areas on the test set were excellent, 0.89 for ACI-TIPI and 0.84 for the e-ACI-TIPI, as was calibration. On the national electrocardiographic database, ROC areas were 0.78 and 0.69, respectively, and with very good calibration. When tested for detection of patients with > 75% ACS probability, both electrocardiograph-based methods identified eligible patients well, and better than did EHRs.
Using data from medical devices such as electrocardiographs may provide accurate projections of available cohorts for clinical trials.
Breakthrough Listen is a 10-yr initiative to search for signatures of technologies created by extraterrestrial civilisations at radio and optical wavelengths. Here, we detail the digital data recording system deployed for Breakthrough Listen observations at the 64-m aperture CSIRO Parkes Telescope in New South Wales, Australia. The recording system currently implements two modes: a dual-polarisation, 1.125-GHz bandwidth mode for single-beam observations, and a 26-input, 308-MHz bandwidth mode for the 21-cm multibeam receiver. The system is also designed to support a 3-GHz single-beam mode for the forthcoming Parkes ultra-wideband feed. In this paper, we present details of the system architecture, provide an overview of hardware and software, and present initial performance results.
This article explores the case of a musician performing pro-Zapatista revolutionary songs in a restaurant in a city in southern Mexico which has undergone rapid gentrification since the turn of the century. It highlights the particular set of constraints on, and possibilities for, musical creativity that emerged in an urban setting in which space was increasingly ordered around the accumulation of rents. Exploring relationships between commercial strategy and musical detail, it examines tensions arising around the performance of a revolutionary body of song in such a setting. To conclude, and drawing on the recent work of Anna Tsing, it introduces the notion of musical ‘salvage’ to make sense of the relationship between protest and commerce. Recognizing the incompleteness of revolutionary songs’ translation into the rapidly gentrifying context of San Cristóbal, it is argued here, may help to underline performer agency and creativity.
Significant increases in excess all-cause mortality, particularly in the elderly, were observed during the winter of 2014/15 in England. With influenza A(H3N2) the dominant circulating influenza A subtype, this paper determines the contribution of influenza to this excess controlling for weather. A standardised multivariable Poisson regression model was employed with weekly all-cause deaths the dependent variable for the period 2008–2015. Adjusting for extreme temperature, a total of 26 542 (95% CI 25 301–27 804) deaths in 65+ and 1942 (95% CI 1834–2052) in 15–64-year-olds were associated with influenza from week 40, 2014 to week 20, 2015. This is compatible with the circulation of influenza A(H3N2). It is the largest estimated number of influenza-related deaths in England since prior to 2008/09. The findings highlight the potential health impact of influenza and the important role of the annual influenza vaccination programme that is required to protect the population including the elderly, who are vulnerable to a severe outcome.
OBJECTIVES/SPECIFIC AIMS: Key factors causing irreproducibility of research include those related to inappropriate study design methodologies and statistical analysis. In modern statistical practice irreproducibility could arise due to statistical (false discoveries, p-hacking, overuse/misuse of p-values, low power, poor experimental design) and computational (data, code and software management) issues. These require understanding the processes and workflows practiced by an organization, and the development and use of metrics to quantify reproducibility. METHODS/STUDY POPULATION: Within the Foundation of Discovery – Population Health Research, Center for Clinical and Translational Science, University of Utah, we are undertaking a project to streamline the study design and statistical analysis workflows and processes. As a first step we met with key stakeholders to understand the current practices by eliciting example statistical projects, and then developed process information models for different types of statistical needs using Lucidchart. We then reviewed these with the Foundation’s leadership and the Standards Committee to come up with ideal workflows and model, and defined key measurement points (such as those around study design, analysis plan, final report, requirements for quality checks, and double coding) for assessing reproducibility. As next steps we are using our finding to embed analytical and infrastructural approaches within the statisticians’ workflows. This will include data and code dissemination platforms such as Box, Bitbucket, and GitHub, documentation platforms such as Confluence, and workflow tracking platforms such as Jira. These tools will simplify and automate the capture of communications as a statistician work through a project. Data-intensive process will use process-workflow management platforms such as Activiti, Pegasus, and Taverna. RESULTS/ANTICIPATED RESULTS: These strategies for sharing and publishing study protocols, data, code, and results across the spectrum, active collaboration with the research team, automation of key steps, along with decision support. DISCUSSION/SIGNIFICANCE OF IMPACT: This analysis of statistical methods and process and computational methods to automate them ensure quality of statistical methods and reproducibility of research.
OBJECTIVES/SPECIFIC AIMS: The objective of this research is to determine under what conditions endpoints based on estimated glomerular filtration rate (eGFR) slope or on relatively small declines in eGFR provide valid and useful surrogate endpoints for pivotal clinical trials in chronic kidney disease (CKD) patients. METHODS/STUDY POPULATION: We consider 2 classes of surrogate endpoints. The first class includes endpoints defined by the average rate of change in eGFR during defined portions of the follow-up period of the trial, following initiation of the randomized treatment interventions. The second class includes composite endpoints defined by the time from randomization until the occurrence of a designated decline in eGFR or kidney failure. The true clinical endpoint is considered to be the time from randomization until kidney failure, irrespective of the trajectory in eGFR measurements prior to kidney failure. We apply statistical simulation to determine conditions under which alternative endpoints within the 2 classes are (1) valid surrogate endpoints, in the sense of preserving a low probability of rejecting the null hypothesis of no treatment effect on the surrogate endpoint when there is no treatment effect on the clinical endpoints and are also (2) useful surrogate endpoints, in the sense of providing increased statistical power that allows significant reductions in sample size and/or duration of follow-up. Input parameters for the simulations include (a) characteristics of the joint distribution of the longitudinal eGFR measurements and the time to occurrence of renal failure, (b) characteristics of the short-term and long-term effects of the treatment, and (c) design parameters, including the duration of accrual and follow-up and the spacing of eGFR measurements during the follow-up period. We use joint analyses of 19 treatment comparisons across 13 previous clinical trials of CKD patients to guide the selection of input parameters for the simulations. We apply longitudinal mixed effects models for analysis of endpoints based on eGFR slope, and Cox regression for analyses of the composite time-to-event endpoints. RESULTS/ANTICIPATED RESULTS: We have previously shown that surrogate endpoints defined by eGFR declines of 30% or 40% can provide valid and useful alternative endpoints in CKD clinical trials for interventions that do not produce short-term effects on eGFR which differ from the longer-term effects of the interventions. Other factors influencing the validity and utility of these endpoints include the average baseline eGFR, the mean rate of change in eGFR, and the extent to which the size of the treatment effect depends on the patient’s underling rate of eGFR decline. We will extend these results by presenting preliminary results describing conditions under which outcomes based on eGFR slope provide valid and useful alternatives to the clinical endpoint of time until occurrence of kidney failure. DISCUSSION/SIGNIFICANCE OF IMPACT: The statistical simulation strategy described in this research can be used during the design of clinical trials of chronic kidney disease to assist in the selection of endpoints that maximize savings in sample size and duration of follow-up while retaining a low risk of producing a false positive conclusion in the absence of a true effect of the treatment on the time until kidney failure.
Intensive archaeobotanical investigations at Çatalhöyük have created a unique opportunity to explore change and continuity in plant use through the ca 1,500-year Neolithic to early Chalcolithic sequence of an early established farming community. The combination of crops and herd animals in the earliest (Aceramic) part of the sequence reflects a distinct and diverse central Anatolian ‘package’ at the end of the eighth millennium cal. BC. Here we report evidence for near continual adjustment of cropping regimes through time at Çatalhöyük, featuring recruitment of minor crops or crop contaminants to become major staples. We use panarchy theory to frame an understanding of Çatalhöyük's long-term sustainability, arguing that its resilience was a function of three key factors: its diverse initial crop spectrum, which acted as an archive for later innovations; its modular social structure, enabling small-scale experimentation and innovation in cropping at the household level; and its agglomerated social morphology, allowing successful developments to be scaled up across the wider community. This case study in long-term sustainability through flexible, changeable cropping strategies is significant not only for understanding so-called boom and bust cycles elsewhere but also for informing wider agro-ecological understanding of sustainable development in central Anatolia and beyond.
The CMP challenges for advanced technology nodes are discussed. Global and local uniformity challenges and their cumulative effects are presented. Uniformity improvements for advanced node integration were achieved through slurry, pad and platen optimization, innovative integration schemes, the reduction of incoming variation and the reduction of cumulative effects. We discuss reduction of typical CMP defect types. Defects resulting from simple mechanisms (foreign material, polish residues) and those resulting from chemical and physical interactions (corrosion, chemical attack, scratches, physical migration) and strategies for control are studied. Defectivity reduction measures include new post-CMP clean chemicals, new slurries and pads and reduction of incoming defectivity. Finally we discuss an observed tradeoff between good defectivity and good uniformity.
To assess knowledge about infection prevention among nursing home personnel and identify gaps potentially addressable through a quality improvement collaborative.
Baseline knowledge assessment of catheter-associated urinary tract infection, asymptomatic bacteriuria, antimicrobial stewardship, and general infection prevention practices for healthcare-associated infections.
Nursing homes across 14 states participating in the national “Agency for Healthcare Research and Quality Safety Program for Long-Term Care: Healthcare-Associated Infections/Catheter-Associated Urinary Tract Infection.”
Each facility aimed to obtain responses from at least 10 employees (5 licensed and 5 unlicensed). We assessed the percentage of correct responses.
A total of 184 (78%) of 236 participating facilities provided 1 response or more. Of the 1,626 respondents, 822 (50.6%) were licensed; 117 facilities (63.6%) were for-profit. While 99.1% of licensed personnel recognized the definition of asymptomatic bacteriuria, only 36.1% knew that pyuria could not distinguish a urinary tract infection from asymptomatic bacteriuria. Among unlicensed personnel, 99.6% knew to notify a nurse if a resident developed fever or confusion, but only 27.7% knew that cloudy, smelly urine should not routinely be cultured. Although 100% of respondents reported receiving training in hand hygiene, less than 30% knew how long to rub hands (28.5% licensed, 25.2% unlicensed) or the most effective agent to use (11.7% licensed, 10.6% unlicensed).
This national assessment demonstrates an important need to enhance infection prevention knowledge among healthcare personnel working in nursing homes to improve resident safety and quality of care.
Astronomy is rapidly approaching an impasse: very large datasets require remote or cloud-based parallel processing, yet many astronomers still try to download the data and develop serial code locally. Astronomers understand the need for change, but the hurdles remain high. We are developing a data archive designed from the ground up to simplify and encourage cloud-based parallel processing. While the volume of data we host remains modest by some standards, it is still large enough that download and processing times are measured in days and even weeks. We plan to implement a python based, notebook-like interface that automatically parallelises execution. Our goal is to provide an interface sufficiently familiar and user-friendly that it encourages the astronomer to run their analysis on our system in the cloud—astroinformatics as a service. We describe how our system addresses the approaching impasse in astronomy using the SAMI Galaxy Survey as an example.
A phased introduction of routine influenza vaccination of healthy children was recommended in the UK in 2012, with the aim of protecting both vaccinated children and the wider population through reducing transmission. In the first year of the programme in 2013–2014, 4- to 11-year-olds were targeted in pilot areas across England. This study assesses if this was associated with school absenteeism, an important societal burden of influenza. During the spring 2014 term when influenza predominantly circulated, the proportion of absence sessions due to illness was compared between vaccination pilot and non-pilot areas for primary schools (to measure overall impact) and secondary schools (to measure indirect impact). A linear multilevel regression model was applied, adjusting for clustering within schools and potential school-level confounders, including deprivation, past absenteeism, and ethnicity. Low levels of influenza activity were reported in the community in 2013–2014. Primary schools in pilot areas had a significantly adjusted decrease in illness absenteeism of 0·05% relative to non-pilot schools; equivalent to an average of 4 days per school. In secondary schools, there was no significant indirect impact of being located in a pilot area on illness absenteeism. These insights can be used in conjunction with routine healthcare surveillance data to evaluate the full benefits of such a programme.
The South African coast contains abundant estuaries and lagoons, most of which originated as river valleys incised during Quaternary sea-level fall and subsequently drowned and/or infilled during rising interglacial sea levels. This chapter discusses these changes and highlights the geomorphological and sedimentological evolution of several southern African estuaries during the Pleistocene to present. The development, infilling and positioning of incised valley systems is mainly controlled by sea-level variation as well as fluvial and marine sediment supply. Most contemporary estuaries in southern Africa show dramatic responses to shorter term sea-level fluctuations and sediment supply during the Holocene. Barring anthropogenic interference, the dynamic behaviour of estuaries, dictated by their transient position and geomorphic character within an incised valley, is considered to fluctuate on centennial to millennial timescales.
The most recent work at Vindolanda has produced some startling results which both support and challenge our standing interpretations of some aspects of the frontier zone in Roman Britain. These include the timeline for the development of forts on the frontier, the foundation of extramural settlements and the relationship between fort and extramural settlement. The work raises questions not only about Vindolanda but more generally about the formation of the frontier itself and the interpretation of the archaeology of other sites.
Although peri-conceptional folic acid (FA) supplementation can prevent a proportion of neural tube defects (NTD), there is increasing evidence that many NTD are FA non-responsive. The vitamin-like molecule inositol may offer a novel approach to preventing FA-non-responsive NTD. Inositol prevented NTD in a genetic mouse model, and was well tolerated by women in a small study of NTD recurrence. In the present study, we report the Prevention of Neural Tube Defects by Inositol (PONTI) pilot study designed to gain further experience of inositol usage in human pregnancy as a preliminary trial to a future large-scale controlled trial to evaluate efficacy of inositol in NTD prevention. Study subjects were UK women with a previous NTD pregnancy who planned to become pregnant again. Of 117 women who made contact, ninety-nine proved eligible and forty-seven agreed to be randomised (double-blind) to peri-conceptional supplementation with inositol plus FA or placebo plus FA. In total, thirty-three randomised pregnancies produced one NTD recurrence in the placebo plus FA group (n 19) and no recurrences in the inositol plus FA group (n 14). Of fifty-two women who declined randomisation, the peri-conceptional supplementation regimen and outcomes of twenty-two further pregnancies were documented. Two NTD recurred, both in women who took only FA in their next pregnancy. No adverse pregnancy events were associated with inositol supplementation. The findings of the PONTI pilot study encourage a large-scale controlled trial of inositol for NTD prevention, but indicate the need for a careful study design in view of the unwillingness of many high-risk women to be randomised.
This article explores the ways in which anger may travel across different musical and extra-musical contexts, looking in particular at the rap metal band Rage Against The Machine (RATM). Focusing on this band's appropriation of expressions of anger found in a documentary film about the Zapatistas in Mexico, it suggests that RATM can be read as a politico-emotional project, channelling anger towards political resistance which is then performed through, and upon, the body. Just as performances of anger need discourse to be sustainable, so music can simultaneously entrain the listener into a certain modality of feeling and expressing, and embed this modality in a discursive rationale. However, anger is a deeply ambiguous emotion, and cannot be easily focused; it may transcend the constraints some seek to place on it, and travel quickly between discursive contexts. Such slippages mark the limits of anger, as well as its power.