Loss of the heterogeneous expression of flippase ATP11B leads to cerebral small vessel disease in a normotensive rat model.

Cerebral small vessel disease (SVD) is the leading cause of vascular dementia, causes a quarter of strokes, and worsens stroke outcomes. The disease is characterised by patchy cerebral small vessel and white matter pathology, but the underlying mechanisms are poorly understood. This microvascular and tissue damage has been classically considered secondary to extrinsic factors, such as hypertension, but this fails to explain the patchy nature of the disease, the link to endothelial cell (EC) dysfunction even when hypertension is absent, and the increasing evidence of high heritability to SVD-related brain damage. We have previously shown the link between deletion of the phospholipase flippase Atp11b and EC dysfunction in an inbred hypertensive rat model with SVD-like pathology and a single nucleotide polymorphism (SNP) in ATP11B associated with human sporadic SVD. Here, we generated a novel normotensive transgenic rat model, where Atp11b is deleted, and show pathological, imaging and behavioural changes typical of those in human SVD, but that occur without hypertension. Atp11bKO rat brain and retinal small vessels show ECs with molecular and morphological changes of dysfunction, with myelin disruption in a patchy pattern around some but not all brain small vessels, similar to the human brain. We show that ATP11B/ATP11B is heterogeneously expressed in ECs in normal rat and human brain even in the same transverse section of the same blood vessel, suggesting variable effects of the loss of ATP11B on each vessel and an explanation for the patchy nature of the disease. This work highlights a link between inherent EC dysfunction and vulnerability to SVD white matter damage with a marked heterogeneity of ECs in vivo which modulates this response, occurring even in the absence of hypertension. These findings refocus our strategies for therapeutics away from antihypertensive (and vascular risk factor) control alone and towards ECs in the effort to provide alternative targets to prevent a major cause of stroke and dementia.

Hand-guided qualitative deflectometry with a mobile device.

We introduce a system that exploits the screen and front-facing camera of a mobile device to perform three-dimensional deflectometry-based surface measurements. In contrast to current mobile deflectometry systems, our method can capture surfaces with large normal variation and wide field of view (FoV). We achieve this by applying automated multi-view panoramic stitching algorithms to produce a large FoV normal map from a hand-guided capture process without the need for external tracking systems, like robot arms or fiducials. The presented work enables 3D surface measurements of specular objects 'in the wild' with a system accessible to users with little to no technical imaging experience. We demonstrate high-quality 3D surface measurements without the need for a calibration procedure. We provide experimental results with our prototype Deflectometry system and discuss applications for computer vision tasks such as object detection and recognition.

The Human Immune Response to Respiratory Syncytial Virus Infection.

Respiratory syncytial virus (RSV) is an important etiological agent of respiratory infections, particularly in children. Much information regarding the immune response to RSV comes from animal models and in vitro studies. Here, we provide a comprehensive description of the human immune response to RSV infection, based on a systematic literature review of research on infected humans. There is an initial strong neutrophil response to RSV infection in humans, which is positively correlated with disease severity and mediated by interleukin-8 (IL-8). Dendritic cells migrate to the lungs as the primary antigen-presenting cell. An initial systemic T-cell lymphopenia is followed by a pulmonary CD8+ T-cell response, mediating viral clearance. Humoral immunity to reinfection is incomplete, but RSV IgG and IgA are protective. B-cell-stimulating factors derived from airway epithelium play a major role in protective antibody generation. Gamma interferon (IFN-γ) has a strongly protective role, and a Th2-biased response may be deleterious. Other cytokines (particularly IL-17A), chemokines (particularly CCL-5 and CCL-3), and local innate immune factors (including cathelicidins and IFN-λ) contribute to pathogenesis. In summary, neutrophilic inflammation is incriminated as a harmful response, whereas CD8+ T cells and IFN-γ have protective roles. These may represent important therapeutic targets to modulate the immunopathogenesis of RSV infection.

Development process of a consensus-driven CONSORT extension for randomised trials using an adaptive design.

BACKGROUND: Adequate reporting of adaptive designs (ADs) maximises their potential benefits in the conduct of clinical trials. Transparent reporting can help address some obstacles and concerns relating to the use of ADs. Currently, there are deficiencies in the reporting of AD trials. To overcome this, we have developed a consensus-driven extension to the CONSORT statement for randomised trials using an AD. This paper describes the processes and methods used to develop this extension rather than detailed explanation of the guideline. METHODS: We developed the guideline in seven overlapping stages: 1) Building on prior research to inform the need for a guideline; 2) A scoping literature review to inform future stages; 3) Drafting the first checklist version involving an External Expert Panel; 4) A two-round Delphi process involving international, multidisciplinary, and cross-sector key stakeholders; 5) A consensus meeting to advise which reporting items to retain through voting, and to discuss the structure of what to include in the supporting explanation and elaboration (E&E) document; 6) Refining and finalising the checklist; and 7) Writing-up and dissemination of the E&E document. The CONSORT Executive Group oversaw the entire development process. RESULTS: Delphi survey response rates were 94/143 (66%), 114/156 (73%), and 79/143 (55%) in rounds 1, 2, and across both rounds, respectively. Twenty-seven delegates from Europe, the USA, and Asia attended the consensus meeting. The main checklist has seven new and nine modified items and six unchanged items with expanded E&E text to clarify further considerations for ADs. The abstract checklist has one new and one modified item together with an unchanged item with expanded E&E text. The E&E document will describe the scope of the guideline, the definition of an AD, and some types of ADs and trial adaptations and explain each reporting item in detail including case studies. CONCLUSIONS: We hope that making the development processes, methods, and all supporting information that aided decision-making transparent will enhance the acceptability and quick uptake of the guideline. This will also help other groups when developing similar CONSORT extensions. The guideline is applicable to all randomised trials with an AD and contains minimum reporting requirements.

Nonlinear Unmixing of Hyperspectral Datasets for the Study of Painted Works of Art.

Nonlinear unmixing of hyperspectral reflectance data is one of the key problems in quantitative imaging of painted works of art. The approach presented is to interrogate a hyperspectral image cube by first decomposing it into a set of reflectance curves representing pure basis pigments and second to estimate the scattering and absorption coefficients of each pigment in a given pixel to produce estimates of the component fractions. This two-step algorithm uses a deep neural network to qualitatively identify the constituent pigments in any unknown spectrum and, based on the pigment(s) present and Kubelka-Munk theory to estimate the pigment concentration on a per-pixel basis. Using hyperspectral data acquired on a set of mock-up paintings and a well-characterized illuminated folio from the 15th century, the performance of the proposed algorithm is demonstrated for pigment recognition and quantitative estimation of concentration.

Optimizing the analysis strategy for the CANVAS Program: A prespecified plan for the integrated analyses of the CANVAS and CANVAS-R trials.

Two large cardiovascular outcome trials of canagliflozin, comprising the CANVAS Program, will complete in early 2017: the CANagliflozin cardioVascular Assessment Study (CANVAS) and the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R). Accruing data for the sodium glucose co-transporter 2 (SGLT2) inhibitor class has identified questions and opportunities that were not apparent when the trials were designed. Accordingly, a series of modifications have been made to the planned analyses. These updates will ensure that the data from the CANVAS Program will maximize advances in scientific knowledge and patient care. The specification of the analysis strategy prior to knowledge of the trial results, their design by the independent scientific trial Steering Committee, the detailed a priori definition of the analysis plans, and the external review provided by the US Food and Drug Administration all provide maximally efficient and robust utilization of the data. The CANVAS Program should significantly advance our understanding of the effects of canagliflozin, and the broader SGLT2 inhibitor class, on a range of important efficacy and safety outcomes.

Clinician-Reported Outcome Assessments of Treatment Benefit: Report of the ISPOR Clinical Outcome Assessment Emerging Good Practices Task Force.

A clinician-reported outcome (ClinRO) assessment is a type of clinical outcome assessment (COA). ClinRO assessments, like all COAs (patient-reported, observer-reported, or performance outcome assessments), are used to 1) measure patients' health status and 2) define end points that can be interpreted as treatment benefits of medical interventions on how patients feel, function, or survive in clinical trials. Like other COAs, ClinRO assessments can be influenced by human choices, judgment, or motivation. A ClinRO assessment is conducted and reported by a trained health care professional and requires specialized professional training to evaluate the patient's health status. This is the second of two reports by the ISPOR Clinical Outcomes Assessment-Emerging Good Practices for Outcomes Research Task Force. The first report provided an overview of COAs including definitions important for an understanding of COA measurement practices. This report focuses specifically on issues related to ClinRO assessments. In this report, we define three types of ClinRO assessments (readings, ratings, and clinician global assessments) and describe emerging good measurement practices in their development and evaluation. The good measurement practices include 1) defining the context of use; 2) identifying the concept of interest measured; 3) defining the intended treatment benefit on how patients feel, function, or survive reflected by the ClinRO assessment and evaluating the relationship between that intended treatment benefit and the concept of interest; 4) documenting content validity; 5) evaluating other measurement properties once content validity is established (including intra- and inter-rater reliability); 6) defining study objectives and end point(s) objectives, and defining study end points and placing study end points within the hierarchy of end points; 7) establishing interpretability in trial results; and 8) evaluating operational considerations for the implementation of ClinRO assessments used as end points in clinical trials. Applying good measurement practices to ClinRO assessment development and evaluation will lead to more efficient and accurate measurement of treatment effects. This is important beyond regulatory approval in that it provides evidence for the uptake of new interventions into clinical practice and provides justification to payers for reimbursement on the basis of the clearly demonstrated added value of the new intervention.

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: III. The 2014 Biomarker Working Group Report.

Biology-based markers to confirm or aid in the diagnosis or prognosis of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation or monitor its progression are critically needed to facilitate evaluation of new therapies. Biomarkers have been defined as any characteristic that is objectively measured and evaluated as an indicator of a normal biological or pathogenic process, or of a pharmacologic response to a therapeutic intervention. Applications of biomarkers in chronic GVHD clinical trials or patient management include the following: (1) diagnosis and assessment of chronic GVHD disease activity, including distinguishing irreversible damage from continued disease activity; (2) prognostic risk to develop chronic GVHD; and (3) prediction of response to therapy. Sample collection for chronic GVHD biomarkers studies should be well documented following established quality control guidelines for sample acquisition, processing, preservation, and testing, at intervals that are both calendar and event driven. The consistent therapeutic treatment of subjects and standardized documentation needed to support biomarker studies are most likely to be provided in prospective clinical trials. To date, no chronic GVHD biomarkers have been qualified for use in clinical applications. Since our previous chronic GVHD Biomarkers Working Group report in 2005, an increasing number of chronic GVHD candidate biomarkers are available for further investigation. This paper provides a 4-part framework for biomarker investigations: identification, verification, qualification, and application with terminology based on Food and Drug Administration and European Medicines Agency guidelines.

Clinical Outcome Assessments: Conceptual Foundation-Report of the ISPOR Clinical Outcomes Assessment - Emerging Good Practices for Outcomes Research Task Force.

An outcome assessment, the patient assessment used in an endpoint, is the measuring instrument that provides a rating or score (categorical or continuous) that is intended to represent some aspect of the patient's health status. Outcome assessments are used to define efficacy endpoints when developing a therapy for a disease or condition. Most efficacy endpoints are based on specified clinical assessments of patients. When clinical assessments are used as clinical trial outcomes, they are called clinical outcome assessments (COAs). COAs include any assessment that may be influenced by human choices, judgment, or motivation. COAs must be well-defined and possess adequate measurement properties to demonstrate (directly or indirectly) the benefits of a treatment. In contrast, a biomarker assessment is one that is subject to little, if any, patient motivational or rater judgmental influence. This is the first of two reports by the ISPOR Clinical Outcomes Assessment - Emerging Good Practices for Outcomes Research Task Force. This report provides foundational definitions important for an understanding of COA measurement principles. The foundation provided in this report includes what it means to demonstrate a beneficial effect, how assessments of patients relate to the objective of showing a treatment's benefit, and how these assessments are used in clinical trial endpoints. In addition, this report describes intrinsic attributes of patient assessments and clinical trial factors that can affect the properties of the measurements. These factors should be considered when developing or refining assessments. These considerations will aid investigators designing trials in their choice of using an existing assessment or developing a new outcome assessment. Although the focus of this report is on the development of a new COA to define endpoints in a clinical trial, these principles may be applied more generally. A critical element in appraising or developing a COA is to describe the treatment's intended benefit as an effect on a clearly identified aspect of how a patient feels or functions. This aspect must have importance to the patient and be part of the patient's typical life. This meaningful health aspect can be measured directly or measured indirectly when it is impractical to evaluate it directly or when it is difficult to measure. For indirect measurement, a concept of interest (COI) can be identified. The COI must be related to how a patient feels or functions. Procedures are then developed to measure the COI. The relationship of these measurements with how a patient feels or functions in the intended setting and manner of use of the COA (the context of use) could then be defined. A COA has identifiable attributes or characteristics that affect the measurement properties of the COA when used in endpoints. One of these features is whether judgment can influence the measurement, and if so, whose judgment. This attribute defines four categories of COAs: patient reported outcomes, clinician reported outcomes, observer reported outcomes, and performance outcomes. A full description as well as explanation of other important COA features is included in this report. The information in this report should aid in the development, refinement, and standardization of COAs, and, ultimately, improve their measurement properties.

Identification, transformations and mobility of hazardous arsenic-based pigments on 19th century bookbindings in accessible library collections.

This study focused on the non-destructive characterization of potentially hazardous Victorian-era books found in the Northwestern University Libraries. XRF, Raman and FTIR were used to identify and isolate hazardous books containing As-based pigments. These techniques also permitted, on selected books, to characterize the pigment as being Emerald green. However, none allowed for the identification of equally hazardous degradation products or potential transfer to adjacent books. These analytical gaps create limits in thoroughly identifying the level of risks associated with these books for library users and hampered the application of effective risk mitigation measures. Such limitations were overcome with synchrotron radiation (SR) techniques. Through SR-XRF, Cu/As distributions were mapped across covers and spines of green and neighboring books, whereas SR-X-ray absorption near edge structure (SR-XANES) was used to characterize the As oxidation state, leading to the identification of arsenates as degradation products. Besides successfully identifying hazardous books, this study demonstrated that hazards extend beyond As-containing green books to innocuous, long-standing neighboring books and non-colored pages due to migration and transfer of pigment and degradation products. Aside from helping to implement workplace health and safety measures, this study also informs how other libraries can identify and characterize potentially hazardous items in their collections.

Defining Clinical Trial Estimands: A Practical Guide for Study Teams with Examples Based on a Psychiatric Disorder.

While the ICH E9(R1) Addendum on "Estimands and Sensitivity Analysis in Clinical Trials" was released in late 2019, the widespread implementation of defining and reporting estimands across clinical trials is still in progress and the engagement of non-statistical functions in this process is also in progress. Case studies are sought after, especially those with documented clinical and regulatory feedback. This paper describes an interdisciplinary process for implementing the estimand framework, devised by the Estimands and Missing Data Working Group (a group with clinical, statistical, and regulatory representation) of the International Society for CNS Clinical Trials and Methodology. This process is illustrated by specific examples using various types of hypothetical trials evaluating a treatment for major depressive disorder. Each of the estimand examples follows the same template and features all steps of the proposed process, including identifying the trial stakeholder(s), the decisions they need to make about the investigated treatment in their specific role and the questions that would support their decision making. Each of the five strategies for handling intercurrent events are addressed in at least one example; the featured endpoints are also diverse, including continuous, binary and time to event. Several examples are presented that include specifications for a potential trial design, key trial implementation elements needed to address the estimand, and main and sensitivity estimator specifications. Ultimately this paper highlights the need to incorporate multi-disciplinary collaborations into implementing the ICH E9(R1) framework.

Evaluating cognitive outcome measures for MS clinical trials: what is a clinically meaningful change?

Brief cognitive assessments are increasingly emphasized in MS treatment studies and clinical care. While much is known about the reliability of several widely-used neuropsychological tests, interpretation of the changes in individual patients is inadequate. The FDA offers guidance on the issue, as related to patient-reported outcomes. Unfortunately, cognitive ability is only weakly correlated with the frequency and severity of self-reported cognitive problems. In this review, we critically examined the psychometrics of neuropsychological testing in MS, emphasizing statistical and anchor-based approaches to interpreting clinically meaningful change. We suggest that there are two paths forward that should be currently pursued. First, to employ co-primary outcomes, including a brief cognitive test and a clinician or observer's impression on a scale of change, where successful treatment would require showing significant improvement in both measures. Secondly, to work toward showing that when reliable brief cognitive tests are employed, increments of statistically-relevant change would correlate with changes in clinically-relevant anchors (such as vocational disability or clinical relapses with cognitive impairment). The latter goal will allow a more parsimonious and scientifically efficient approach of utilizing only the brief cognitive test as a primary outcome. While some progress has been made in this direction, more research is needed. We are of the opinion that data from both the statistical and clinically meaningful approaches will be necessary to develop valid definitions of meaningful change on cognitive outcome measures, and that it would be best to pursue research using tests that already have well-established reliability and validity.

Identifying a core outcome set for pulmonary sarcoidosis research - the Foundation for Sarcoidosis Research - Sarcoidosis Clinical OUtcomes Taskforce (SCOUT).

Background: Pulmonary sarcoidosis is a rare granulomatous disease of unknown aetiology. Heterogeneity in the outcomes measured in trials of treatment for pulmonary sarcoidosis has impacted on the ability to systematically compare findings, contributing to research inefficiency. The FSR-SCOUT study has aimed to address this heterogeneity by developing a core outcome set that represents a patient and health professional consensus on the most important outcomes to measure in future research for the treatment of pulmonary sarcoidosis. Research design and methods: systematic review of trial registries, narrative synthesis of published qualitative literature on the patient experience and results of a patient survey contributed to the development of a comprehensive list of outcomes that were rated in a two round online Delphi survey. The Delphi survey was completed by patients/carers and health professionals and the results discussed and ratified at an online consensus meeting. Results: 259 patients/carers and 51 health professionals completed both rounds of the Delphi survey. A pre-agreed definition of consensus was applied and the results discussed at an online consensus meeting attended by 17 patients and 7 health professionals). Fifteen outcomes, across five domains (physiological/clinical, treatment, resource use, quality of life, and death), reached the definition of consensus and were included in the core outcome set. Conclusions: The core outcome set represents a patient and health professional consensus on the most important outcomes for pulmonary sarcoidosis research. The use of the core outcome set in future trials, and efforts to validate its components, will enhance the relevance of trials to stakeholders and will increase the opportunity for the research to contribute to evidence synthesis.

Application of Uniform Manifold Approximation and Projection (UMAP) in spectral imaging of artworks.

This study assesses the potential of Uniform Manifold Approximation and Projection (UMAP) as an alternative tool to t-distributed Stochastic Neighbor Embedding (t-SNE) for the reduction and visualization of visible spectral images of works of art. We investigate the influence of UMAP parameters-such as, correlation distance, minimum embedding distance, as well as number of embedding neighbors- on the reduction and visualization of spectral images collected from Poèmes Barbares (1896), a major work by the French artist Paul Gauguin in the collection of the Harvard Art Museums. The use of a cosine distance metric and number of neighbors equal to 10 preserves both the local and global structure of the Gauguin dataset in a reduced two-dimensional embedding space thus yielding simple and clear groupings of the pigments used by the artist. The centroids of these groups were identified by locating the densest regions within the UMAP embedding through a 2D histogram peak finding algorithm. These centroids were subsequently fit to the dataset by non-negative least square thus forming maps of pigments distributed across the work of art studied. All findings were correlated to macro XRF imaging analyses carried out on the same painting. The described procedure for reduction and visualization of spectral images of a work of art is quick, easy to implement, and the software is opensource thus promising an improved strategy for interrogating reflectance images from complex works of art.

Scout - sarcoidosis outcomes taskforce. A systematic review of outcomes to inform the development of a core outcome set for pulmonary sarcoidosis.

BACKGROUND: Clinical trials evaluating different management strategies for pulmonary sarcoidosis may measure different outcomes. This heterogeneity in outcomes can lead to waste in research due to the inability to compare and combine data. Core outcome sets (COS) have the potential to address this issue and here we describe a systematic review of outcomes as the first step in the development of a COS for pulmonary sarcoidosis research. METHODS: A search of clinical trial registries for phase II, III and IV trials of pulmonary sarcoidosis was undertaken along with a rapid review of the patient perspective literature. Each study was screened for eligibility and outcomes extracted verbatim from the registry entry or publication then reviewed, grouped and categorised using the COMET taxonomy. RESULTS: 36 trial registry entries and 6 studies on patients' perspective of pulmonary sarcoidosis were included reporting 56 and 82 unique outcomes respectively across 23 domains. The most frequently reported outcome domain was "respiratory, thoracic and mediastinal outcomes". However, the patients' perspective literature identified outcomes in the "personal circumstances" and "societal/carer burden" domains that were not reported in any of the included trial registrations. CONCLUSIONS: Using both clinical trial registry data and published literature on patients' perspective has allowed rapid review of outcomes measured and reported in pulmonary sarcoidosis research. The use of multiple sources has led to the development of a comprehensive list of outcomes that represents the first step in the development of a COS for use in future pulmonary sarcoidosis research.

The adaptive designs CONSORT extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design.

Adaptive designs (ADs) allow pre-planned changes to an ongoing trial without compromising the validity of conclusions and it is essential to distinguish pre-planned from unplanned changes that may also occur. The reporting of ADs in randomised trials is inconsistent and needs improving. Incompletely reported AD randomised trials are difficult to reproduce and are hard to interpret and synthesise. This consequently hampers their ability to inform practice as well as future research and contributes to research waste. Better transparency and adequate reporting will enable the potential benefits of ADs to be realised.This extension to the Consolidated Standards Of Reporting Trials (CONSORT) 2010 statement was developed to enhance the reporting of randomised AD clinical trials. We developed an Adaptive designs CONSORT Extension (ACE) guideline through a two-stage Delphi process with input from multidisciplinary key stakeholders in clinical trials research in the public and private sectors from 21 countries, followed by a consensus meeting. Members of the CONSORT Group were involved during the development process.The paper presents the ACE checklists for AD randomised trial reports and abstracts, as well as an explanation with examples to aid the application of the guideline. The ACE checklist comprises seven new items, nine modified items, six unchanged items for which additional explanatory text clarifies further considerations for ADs, and 20 unchanged items not requiring further explanatory text. The ACE abstract checklist has one new item, one modified item, one unchanged item with additional explanatory text for ADs, and 15 unchanged items not requiring further explanatory text.The intention is to enhance transparency and improve reporting of AD randomised trials to improve the interpretability of their results and reproducibility of their methods, results and inference. We also hope indirectly to facilitate the much-needed knowledge transfer of innovative trial designs to maximise their potential benefits. In order to encourage its wide dissemination this article is freely accessible on the BMJ and Trials journal websites."To maximise the benefit to society, you need to not just do research but do it well" Douglas G Altman.

The Adaptive designs CONSORT Extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design.

Adaptive designs (ADs) allow pre-planned changes to an ongoing trial without compromising the validity of conclusions and it is essential to distinguish pre-planned from unplanned changes that may also occur. The reporting of ADs in randomised trials is inconsistent and needs improving. Incompletely reported AD randomised trials are difficult to reproduce and are hard to interpret and synthesise. This consequently hampers their ability to inform practice as well as future research and contributes to research waste. Better transparency and adequate reporting will enable the potential benefits of ADs to be realised.This extension to the Consolidated Standards Of Reporting Trials (CONSORT) 2010 statement was developed to enhance the reporting of randomised AD clinical trials. We developed an Adaptive designs CONSORT Extension (ACE) guideline through a two-stage Delphi process with input from multidisciplinary key stakeholders in clinical trials research in the public and private sectors from 21 countries, followed by a consensus meeting. Members of the CONSORT Group were involved during the development process.The paper presents the ACE checklists for AD randomised trial reports and abstracts, as well as an explanation with examples to aid the application of the guideline. The ACE checklist comprises seven new items, nine modified items, six unchanged items for which additional explanatory text clarifies further considerations for ADs, and 20 unchanged items not requiring further explanatory text. The ACE abstract checklist has one new item, one modified item, one unchanged item with additional explanatory text for ADs, and 15 unchanged items not requiring further explanatory text.The intention is to enhance transparency and improve reporting of AD randomised trials to improve the interpretability of their results and reproducibility of their methods, results and inference. We also hope indirectly to facilitate the much-needed knowledge transfer of innovative trial designs to maximise their potential benefits.

Characterization of lapis lazuli pigments using a multitechnique analytical approach: implications for identification and geological provenancing.

Many of the Raman spectra obtained from areas painted with ultramarine pigments in illuminated manuscript leaves from the 14th century Italian manuscript the Laudario of Sant'Agnese, in the collection of the J. Paul Getty Museum, also contain strong bands not typically associated with this pigment. The source of these features was investigated using a multitechnique analytical approach. Techniques employed include Raman microspectroscopy, scanning electron microscopy with energy-dispersive spectroscopy, electron probe microanalysis, and laser ablation inductively coupled plasma mass spectrometry. The results indicate the presence of diopside (CaMgSi(2)O(6)), a mineral commonly associated with lapis lazuli in nature, and suggest that transition metal dopants in the diopside may be responsible for the Raman features, likely the result of fluorescence with vibronic coupling. The implication of this result with respect to using Raman spectroscopy as a fast, noninvasive, and nondestructive method for determining the geological provenance of natural lapis lazuli pigments used in art is discussed.

Addressing and advancing the problem of missing data.

Missing data can pose substantial risk of reaching incorrect conclusions from clinical studies. Imputation for the missing values is common, but can supply only an approximate result desired to be "close enough" to the intended true result. Prevention optimally addresses the issue. Knowledge of the effective techniques to minimize the problem, likely to vary with clinical setting, is presently inadequate. Formal evaluation of preventative methods should be encouraged and lead to publication of the assessments. Designers of clinical trials should also plan for study analysis where missing values occur. Simple imputation methods have been used and may be sufficient in some settings, but have potential to introduce bias and inaccuracy into the statistical analysis. More complex methods such as multiple imputation potentially offer reduced risk of bias. Multiple imputation also offers the potential for study designers to include some auxiliary outcome assessments that may substantially improve the quality of the imputation with limited added burden to the study. In all cases, sensitivity analyses examining the importance of the specific preferred method as compared to methods with different underlying assumptions is essential to assessing how adequately the missing data issue has been addressed.

Use of Mobile Devices to Measure Outcomes in Clinical Research, 2010-2016: A Systematic Literature Review.

BACKGROUND: The use of mobile devices in clinical research has advanced substantially in recent years due to the rapid pace of technology development. With an overall aim of informing the future use of mobile devices in interventional clinical research to measure primary outcomes, we conducted a systematic review of the use of and clinical outcomes measured by mobile devices (mobile outcomes) in observational and interventional clinical research. METHOD: We conducted a PubMed search using a range of search terms to retrieve peer-reviewed articles on clinical research published between January 2010 and May 2016 in which mobile devices were used to measure study outcomes. We screened each publication for specific inclusion and exclusion criteria. We then identified and qualitatively summarized the use of mobile outcome assessments in clinical research, including the type and design of the study, therapeutic focus, type of mobile device(s) used, and specific mobile outcomes reported. RESULTS: The search retrieved 2,530 potential articles of interest. After screening, 88 publications remained. Twenty-five percent of the publications (n = 22) described mobile outcomes used in interventional research, and the rest (n = 66) described observational clinical research. Thirteen therapeutic areas were represented. Five categories of mobile devices were identified: (1) inertial sensors, (2) biosensors, (3) pressure sensors and walkways, (4) medication adherence monitors, and (5) location monitors; inertial sensors/accelerometers were most common (reported in 86% of the publications). Among the variety of mobile outcomes, various assessments of physical activity were most common (reported in 74% of the publications). Other mobile outcomes included assessments of sleep, mobility, and pill adherence, as well as biomarkers assessed using a mobile device, including cardiac measures, glucose, gastric reflux, respiratory measures, and intensity of head-related injury. CONCLUSION: Mobile devices are being widely used in clinical research to assess outcomes, although their use in interventional research to assess therapeutic effectiveness is limited. For mobile devices to be used more frequently in pivotal interventional research - such as trials informing regulatory decision-making - more focus should be placed on: (1) consolidating the evidence supporting the clinical meaningfulness of specific mobile outcomes, and (2) standardizing the use of mobile devices in clinical research to measure specific mobile outcomes (e.g., data capture frequencies, placement of device). To that aim, this manuscript offers a broad overview of the various mobile outcome assessments currently used in observational and interventional research, and categorizes and consolidates this information for researchers interested in using mobile devices to assess outcomes in interventional research.