Monitoring metrics over time: Why clinical trialists need to systematically collect site performance metrics

Background: Over the last decade, there has been an increasing interest in risk-based monitoring (RBM) in clinical trials, resulting in a number of guidelines from regulators and its inclusion in ICH GCP. However, there is a lack of detail on how to approach RBM from a practical perspective, and insufficient understanding of best practice. Purpose: We present a method for clinical trials units to track their metrics within clinical trials using descriptive statistics and visualisations. Research Design: We suggest descriptive statistics and visualisations within a SWAT methodology. Study Sample: We illustrate this method using the metrics from TEMPER, a monitoring study carried out in three trials at the MRC Clinical Trials Unit at UCL. Data Collection: The data collection for TEMPER is described in DOI: 10.1177/1740774518793379. Results: We show the results and discuss a protocol for a Study-Within-A-Trial (SWAT 167) for those wishing to use the method. Conclusions: The potential benefits metric tracking brings to clinical trials include enhanced assessment of sites for potential corrective action, improved evaluation and contextualisation of the influence of metrics and their thresholds, and the establishment of best practice in RBM. The standardisation of the collection of such monitoring data would benefit both individual trials and the clinical trials community

Space Environments and Spacecraft Effects Organization Concept

The National Aeronautics and Space Administration (NASA) is embarking on a course to expand human presence beyond Low Earth Orbit (LEO) while also expanding its mission to explore the solar system. Destinations such as Near Earth Asteroids (NEA), Mars and its moons, and the outer planets are but a few of the mission targets. Each new destination presents an opportunity to increase our knowledge of the solar system and the unique environments for each mission target. NASA has multiple technical and science discipline areas specializing in specific space environments disciplines that will help serve to enable these missions. To complement these existing discipline areas, a concept is presented focusing on the development of a space environments and spacecraft effects (SENSE) organization. This SENSE organization includes disciplines such as space climate, space weather, natural and induced space environments, effects on spacecraft materials and systems and the transition of research information into application. This space environment and spacecraft effects organization will be composed of Technical Working Groups (TWG). These technical working groups will survey customers and users, generate products, and provide knowledge supporting four functional areas: design environments, engineering effects, operational support, and programmatic support. The four functional areas align with phases in the program mission lifecycle and are briefly described below. Design environments are used primarily in the mission concept and design phases of a program. Engineering effects focuses on the material, component, sub-system and system-level selection and the testing to verify design and operational performance. Operational support provides products based on real time or near real time space weather to mission operators to aid in real time and near-term decision-making. The programmatic support function maintains an interface with the numerous programs within NASA, other federal government agencies, and the commercial sector to ensure that communications are well established and the needs of the programs are being met. The programmatic support function also includes working in coordination with the program in anomaly resolution and generation of lessons learned documentation. The goal of this space environment and spacecraft effects organization is to develop decision-making tools and engineering products to support all mission phases from mission concept through operations by focusing on transitioning research to application. Products generated by this space environments and effects application are suitable for use in anomaly investigations. This paper will describe the scope of the TWGs and their relationship to the functional areas, and discuss an organizational structure for this space environments and spacecraft effects organization

Lack of transparent reporting of trial monitoring approaches in randomised controlled trials: A systematic review of contemporary protocol papers

Background: Monitoring is essential to ensure patient safety and data integrity in clinical trials as per Good Clinical Practice. The Standard Protocol Items: Recommendations for Interventional Trials Statement and its checklist guides authors to include monitoring in their protocols. We investigated how well monitoring was reported in published ‘protocol papers’ for contemporary randomised controlled trials. Methods: A systematic search was conducted in PubMed to identify eligible protocol papers published in selected journals between 1 January 2020 and 31 May 2020. Protocol papers were classified by whether they reported monitoring and, if so, by the details of monitoring. Data were summarised descriptively. Results: Of 811 protocol papers for randomised controlled trials, 386 (48%; 95% CI: 44%–51%) explicitly reported some monitoring information. Of these, 20% (77/386) reported monitoring information consistent with an on-site monitoring approach, and 39% (152/386) with central monitoring, 26% (101/386) with a mixed approach, while 14% (54/386) did not provide sufficient information to specify an approach. Only 8% (30/386) of randomised controlled trials reported complete details about all of scope, frequency and organisation of monitoring; frequency of monitoring was the least reported. However, 6% (25/386) of papers used the term ‘audit’ to describe ‘monitoring’. Discussion: Monitoring information was reported in only approximately half of the protocol papers. Suboptimal reporting of monitoring hinders the clinical community from having the full information on which to judge the validity of a trial and jeopardises the value of protocol papers and the credibility of the trial itself. Greater efforts are needed to promote the transparent reporting of monitoring to journal editors and authors

Creating a database of internet-based clinical trials to support a public-led research programme: A descriptive analysis

Background: Online trials are rapidly growing in number, offering potential benefits but also methodological, ethical and social challenges. The International Network for Knowledge on Well-being (ThinkWell™) aims to increase public and patient participation in the prioritisation, design and conduct of research through the use of technologies. Objective: We aim to provide a baseline understanding of the online trial environment, determining how many trials have used internet-based technologies; how they have been used; and how use has developed over time. Methods: We searched a range of bibliographic databases to March 2015, with no date limits, supplemented by citation searching and references provided by experts in the field. Results were screened against inclusion and exclusion criteria, and included studies mapped against a number of key dimensions, with key themes developed iteratively throughout the process. Results: We identified 1992 internet-based trials to March 2015. The number of reported studies increased substantially over the study timeframe. The largest number of trials were conducted in the USA (49.7%), followed by The Netherlands (10.2%); Australia (8.5%); the United Kingdom (5.8%); Sweden (4.6%); Canada (4%); and Germany (2.6%). South Korea (1.5%) has the highest number of reported trials for other continents. There is a predominance of interventions addressing core public health challenges including obesity (8.6%), smoking cessation (5.9%), alcohol abuse (7.7%) and physical activity (10.2%); in mental health issues such as depression (10.9%) and anxiety (5.6%); and conditions where self-management (16.6%) or monitoring (8.1%) is a major feature of care. Conclusions: The results confirm an increase in the use of the internet in trials. Key themes have emerged from the analysis and further research will be undertaken in order to investigate how the data can be used to improve trial design and recruitment, and to build an open access resource to support the public-led research agenda

An Overview of the Space Environments and Spacecraft Effects Organization Concept

The National Aeronautics and Space Administration (NASA) is embarking on a course to expand human presence beyond Low Earth Orbit (LEO) while also expanding its mission to explore our Earth, and the solar system. Destinations such as Near Earth Asteroids (NEA), Mars and its moons, and the outer planets are but a few of the mission targets. Each new destination presents an opportunity to increase our knowledge on the solar system and the unique environments for each mission target. NASA has multiple technical and science discipline areas specializing in specific space environments fields that will serve to enable these missions. To complement these existing discipline areas, a concept is presented focusing on the development of a space environment and spacecraft effects (SESE) organization. This SESE organization includes disciplines such as space climate, space weather, natural and induced space environments, effects on spacecraft materials and systems, and the transition of research information into application. This space environment and spacecraft effects organization will be composed of Technical Working Groups (TWG). These technical working groups will survey customers and users, generate products, and provide knowledge supporting four functional areas: design environments, engineering effects, operational support, and programmatic support. The four functional areas align with phases in the program mission lifecycle and are briefly described below. Design environments are used primarily in the mission concept and design phases of a program. Environment effects focuses on the material, component, sub-system, and system-level response to the space environment and include the selection and testing to verify design and operational performance. Operational support provides products based on real time or near real time space weather to mission operators to aid in real time and near-term decision-making. The programmatic support function maintains an interface with the numerous programs within NASA, other federal government agencies, and the commercial sector to ensure that communications are well established and the needs of the programs are being met. The programmatic support function also includes working in coordination with the program in anomaly resolution and generation of lessons learned documentation. The goal of this space environment and spacecraft effects organization is to develop decision-making tools and engineering products to support all mission phases from mission concept through operations by focusing on transitioning research to application. Products generated by this space environments and effects application are suitable for use in anomaly investigations. This paper will describe the scope and purpose of the space environments and spacecraft effects organization and describe the TWG's and their relationship to the functional areas

Atomic oxygen durability evaluation of the flexible batten for the photovoltaic array mast on Space Station

A test program was conducted at the National Aeronautics and Space Administration's Lewis Research Center (LeRC) to evaluate the long term low Earth orbital (LEO) atomic oxygen (AO) durability of a flexible (fiberglass-epoxy composite) batten. The flexible batten is a component used to provide structural rigidity in the photovoltaic array mast on Space Station. The mast is used to support and articulate the photovoltaic array, therefore, the flexible batten must be preloaded for the 15 year lifetime of an array blanket. Development hardware and composite materials were evaluated in ground testing facilities for AO durability and dynamic retraction-deployment cyclic loading representative of expected full life in-space application. The CV1144 silicone (AO protective) coating was determined to provide adequate protection against AO degradation of the composite material and provided fiber containment, thus the structural integrity of the flexible batten was maintained. Both silicone coated and uncoated flexible battens maintained load carrying capabilities. Results of the testing did indicate that the CV1144 silicone protective coating was oxidized by AO reactions to form a brittle glassy (SiO2) skin that formed cracking patterns on all sides of the coated samples. The cracking was observed in samples that were mechanically stressed as well as samples in non-stressed conditions. The oxidized silicon was observed to randomly spall in small localized areas, on the flexible battens that underwent retraction-deployment cycling. Some darkening of the silicon, attributed to vacuum ultraviolet (VUV) radiation, was observed

Weight gain in pregnancy and risk of maternal hyperglycemia

OBJECTIVE: The purpose of this study was to examine associations of weight gain from prepregnancy to glycemic screening with glucose tolerance status. STUDY DESIGN: Main outcomes were failed glycemic screening (1-hour glucose result \u3eor= 140 mg/dL) with either 1 high value on 3-hour oral glucose tolerance testing (impaired glucose tolerance in pregnancy) or \u3eor= 2 high values on 3-hour oral glucose tolerance testing (gestational diabetes mellitus). We performed multinomial logistic regression to determine the odds of these glucose intolerance outcomes by quartile of gestational weight gain among 1960 women in Project Viva. RESULTS: Mean gestational weight gain was 10.2 +/- 4.3 (SD) kg. Compared with the lowest quartile of weight gain, participants in the highest quartile had an increased odds of impaired glucose tolerance in pregnancy (adjusted odds ratio, 2.54; 95% confidence interval, 1.25-5.15), but not gestational diabetes mellitus (odds ratio, 0.93; 95% confidence interval, 0.50-1.70). CONCLUSION: Higher weight gain predicted impaired glucose tolerance in pregnancy, but not gestational diabetes mellitus

Misperceived pre-pregnancy body weight status predicts excessive gestational weight gain: findings from a US cohort study

<p>Abstract</p> <p>Background</p> <p>Excessive gestational weight gain promotes poor maternal and child health outcomes. Weight misperception is associated with weight gain in non-pregnant women, but no data exist during pregnancy. The purpose of this study was to examine the association of misperceived pre-pregnancy body weight status with excessive gestational weight gain.</p> <p>Methods</p> <p>At study enrollment, participants in Project Viva reported weight, height, and perceived body weight status by questionnaire. Our study sample comprised 1537 women who had either normal or overweight/obese pre-pregnancy BMI. We created 2 categories of pre-pregnancy body weight status misperception: normal weight women who identified themselves as overweight ('overassessors') and overweight/obese women who identified themselves as average or underweight ('underassessors'). Women who correctly perceived their body weight status were classified as either normal weight or overweight/obese accurate assessors. We performed multivariable logistic regression to determine the odds of excessive gestational weight gain according to 1990 Institute of Medicine guidelines.</p> <p>Results</p> <p>Of the 1029 women with normal pre-pregnancy BMI, 898 (87%) accurately perceived and 131 (13%) overassessed their weight status. 508 women were overweight/obese, of whom 438 (86%) accurately perceived and 70 (14%) underassessed their pre-pregnancy weight status. By the end of pregnancy, 823 women (54%) gained excessively. Compared with normal weight accurate assessors, the adjusted odds of excessive gestational weight gain was 2.0 (95% confidence interval [CI]: 1.3, 3.0) in normal weight overassessors, 2.9 (95% CI: 2.2, 3.9) in overweight/obese accurate assessors, and 7.6 (95% CI: 3.4, 17.0) in overweight/obese underassessors.</p> <p>Conclusion</p> <p>Misperceived pre-pregnancy body weight status was associated with excessive gestational weight gain among both normal weight and overweight/obese women, with the greatest likelihood of excessive gain among overweight/obese underassessors. Future interventions should test the potential benefits of correcting misperception to reduce the likelihood of excessive gestational weight gain.</p

Novel mutations in penicillin-binding protein genes in clinical Staphylococcus aureus isolates that are methicillin resistant on susceptibility testing, but lack the mec gene.

OBJECTIVES: Methicillin-resistant Staphylococcus aureus (MRSA) is an important global health problem. MRSA resistance to β-lactam antibiotics is mediated by the mecA or mecC genes, which encode an alternative penicillin-binding protein (PBP) 2a that has a low affinity to β-lactam antibiotics. Detection of mec genes or PBP2a is regarded as the gold standard for the diagnosis of MRSA. We identified four MRSA isolates that lacked mecA or mecC genes, but were still phenotypically resistant to pencillinase-resistant β-lactam antibiotics. METHODS: The four human S. aureus isolates were investigated by whole genome sequencing and a range of phenotypic assays. RESULTS: We identified a number of amino acid substitutions present in the endogenous PBPs 1, 2 and 3 that were found in the resistant isolates but were absent in closely related susceptible isolates and which may be the basis of resistance. Of particular interest are three identical amino acid substitutions in PBPs 1, 2 and 3, occurring independently in isolates from at least two separate multilocus sequence types. Two different non-conservative substitutions were also present in the same amino acid of PBP1 in two isolates from two different sequence types. CONCLUSIONS: This work suggests that phenotypically resistant MRSA could be misdiagnosed using molecular methods alone and provides evidence of alternative mechanisms for β-lactam resistance in MRSA that may need to be considered by diagnostic laboratories