A novel quantitative computer-assisted drug-induced liver injury causality assessment tool (DILI-CAT).

BACKGROUND AND AIMS: We hypothesized that a drug's clinical signature (or phenotype) of liver injury can be assessed and used to quantitatively develop a computer-assisted DILI causality assessment-tool (DILI-CAT). Therefore, we evaluated drug-specific DILI-phenotypes for amoxicillin-clavulanate (AMX/CLA), cefazolin, cyproterone, and Polygonum multiflorum using data from published case series, to develop DILI-CAT scores for each drug. METHODS: Drug specific phenotypes were made up of the following three clinical features: (1) latency, (2) R-value, and (3) AST/ALT ratio. A point allocation system was developed with points allocated depending on the variance from the norm (or "core") for the 3 variables in published datasets. RESULTS: The four drugs had significantly different phenotypes based on latency, R-value, and AST/ALT ratio. The median cyproterone latency was 150 days versus < 43 days for the other three drugs (median: 26 for AMX/CLA, 20 for cefazolin, and 20 for Polygonum multiflorum; p<0.001). The R-value for the four drugs was also significantly different among drugs (cyproterone [median 12.4] and Polygonum multiflorum [median 10.9]) from AMX/CLA [median 1.44] and cefazolin [median 1.57; p<0.001]). DILI-CAT scores effectively separated cyproterone and Polygonum multiflorum from AMX/CLA and cefazolin, respectively (p<0.001). As expected, because of phenotypic overlap, AMX/CLA and cefazolin could not be well differentiated. CONCLUSIONS: DILI-CAT is a data-driven, diagnostic tool built to define drug-specific phenotypes for DILI adjudication. The data provide proof of principle that a drug-specific, data-driven causality assessment tool can be developed for different drugs and raise the possibility that such a process could enhance causality assessment methods.

MAJIC: a phase III trial of acalabrutinib + venetoclax versus venetoclax + obinutuzumab in previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma.

Here we describe the rationale and design of MAJIC, a phase III, prospective, multicenter, randomized trial comparing the combination of the BTK inhibitor acalabrutinib plus the BCL2 inhibitor venetoclax versus the combination of venetoclax plus obinutuzumab as frontline treatment for chronic lymphocytic leukemia or small lymphocytic lymphoma. In both treatment arms, disease response (assessed by International Workshop on Chronic Lymphocytic Leukemia criteria) and minimal residual disease will be used to guide therapy duration, with all patients ultimately discontinuing treatment after a maximum of 2 years. The primary end point is progression-free survival. Key secondary end points include rates of undetectable minimal residual disease, overall response and overall survival. This study will address key unanswered questions in frontline chronic lymphocytic leukemia/small lymphocytic lymphoma therapy by investigating the optimal duration of finite treatment and identifying the optimal venetoclax doublet regimen.

This article describes the design of the MAJIC clinical trial, which investigates two different treatment combinations for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have not received treatment for their disease previously. Patients will be randomized (put into a group by chance) to receive either acalabrutinib + venetoclax (AV) or venetoclax + obinutuzumab (VO). VO is already an approved initial treatment option for CLL/SLL. Acalabrutinib is also an approved initial treatment option when given by itself, but the AV combination is not yet approved. We are doing this study to better understand and directly compare how well AV and VO work when used for the treatment of CLL/SLL. A test done on the blood and bone marrow called 'minimal residual disease' will be used to help guide the length of time that patients receive treatment. Clinical Trial Registration: NCT05057494 (ClinicalTrials.gov).

A Structured Methodology to Assess Safety Signal Strength and Inform Causality Assessment.

Causality assessment of safety signals observed with medicinal products is a foundational element of pharmacovigilance and regulatory practice, typically performed by a global introspection process. We have developed a novel, structured methodological framework to support the global introspection process for safety signal causality assessment. This Signal Assessment Guide (SAGe) tool was developed by AstraZeneca and is used internally, both to assess safety signal strength and to inform causality decisions related to safety signals. The term 'safety signal' refers to information arising from one or multiple sources, which suggests a new potentially causal association, or a new aspect of a known association, between an intervention and an adverse event. The key concept underlying the SAGe tool is that safety signal data can be reliably sorted into one of three categories: aggregate safety data, plausibility data, and case-level data. When applying the tool, an evidence grade score (Levels A, B, C, and D) is transparently assigned to the available data in each category. This information can then be summarised and presented for formal decision making regarding causality for safety signals. By using a transparent method to categorise the grade of evidence for causal association, with an option to additionally derive a quantitative strength of safety signal score, the SAGe tool can support the global introspection process for causality decisions, contributing to the quality of safety information for medicinal products provided to healthcare professionals and patients. Our anecdotal experience of using the SAGe tool at AstraZeneca is that it has resulted in more efficient and robust conversations regarding the strength of safety signals and the causality question. Wider use of the SAGe tool may bring increased levels of transparency and consistency to the evaluation of safety signals.

A novel phenotype-based drug-induced liver injury causality assessment tool (DILI-CAT) allows for signal confirmation in early drug development.

BACKGROUND: Drug-induced liver injury (DILI) requires accurate case adjudication, with expert opinion being the current best practice. AIM: We utilised a novel DILI causality assessment tool (DILI-CAT), which uses drug-specific liver injury phenotypes, to examine potential DILI in early phase ximelagatran clinical development. METHODS: We conducted a retrospective analysis of liver injury events from four Stroke Prevention using an ORal Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) trials, in which patients were randomised to receive oral ximelagatran or adjusted-dose warfarin. A stepwise process was used with iterative adjustments. The DILI phenotype was characterised by latency, R-value, and AST/ALT ratio. A scoring algorithm was applied to liver events to assess how closely the liver events matched the Interquatile-Range for the working phenotype for each of the three parameters. FINDINGS: Data from 3115 patients included in the SPORTIF trials as above were available. The initial ximelagatran phenotype was developed based on five liver injury cases from the ximelagatran arm and was then validated against an additional eight cases (5 ximelagatran, 3 warfarin); in these eight cases, there was a statistically significant difference in the total DILI-CAT scores of the two drugs (p = 0.016) between ximelagatran and warfarin. Together, these ten ximelagatran cases generated a second, refined ximelagatran phenotype, which was validated against an additional 75 cases (53 ximelagatran/22 warfarin)-again with statistically significant different DILI-CAT ximelagatran vs. warfarin scores (p < 0.001). CONCLUSION: DILI-CAT, a clinically intuitive, data-driven, computer-assisted scoring algorithm, is a useful tool for early detection of drug's hepatotoxicity in clinical drug development.

Patient Global Impression of Benefit-Risk (PGI-BR): Incorporating Patients' Views of Clinical Benefit-Risk into Assessment of New Medicines.

INTRODUCTION: There is a need to understand how patients assess perceived benefits and risks of treatments. OBJECTIVES: The study aimed to (i) elucidate how patients evaluate treatment experiences and (ii) develop a brief patient-reported outcome (PRO) instrument for use across disease areas for perceived benefit-risk evaluation of a new medicine in a clinical trial setting. METHODS: Concepts relating to patient-perceived benefit-risk were identified from literature reviews and qualitative concept elicitation interviews with patients across a variety of primary medical conditions. Draft instrument items were developed from identified concepts and evaluated for clarity, relevance and appropriateness of response options in cognitive interviews. Items were iteratively revised to address patient feedback. RESULTS: Qualitative interviews were conducted with 47 patients (primary condition: 20 oncological, 12 respiratory, 10 metabolic, 5 cardiovascular), of whom 32 contributed to concept elicitation and 42 to cognitive debriefing. Elicited concepts could be grouped into four medication-related categories: effectiveness of treatment, burden of side effects, convenience of use and overall acceptance/satisfaction. Cost, trial experience and altruism were additional concept categories unrelated to medication. The final instrument contained one item each on the medication's effectiveness, side effects and convenience, and an overall item capturing patient benefit-risk assessment. An upfront question was included to separate out non-medication aspects of patients' experiences. CONCLUSION: We developed a brief PRO instrument, the Patient Global Impression of Benefit-Risk (PGI-BR), which can be applied across disease areas to assess patient views of benefit-risk of a new medicine in the clinical trial setting.

Defining Patient Safety Events in Inpatient Psychiatry.

OBJECTIVES: The past 20 years have seen the emergence of a national movement to improve hospital-based healthcare safety in the United States. However, much of the foundational work and subsequent research have neglected inpatient psychiatry. The aim of this article was to advance a comprehensive approach for conceptualizing patient safety in inpatient psychiatry as framed by an application of the Institute of Medicine patient safety framework. METHODS: This article develops a framework for characterizing patient safety in hospital-based mental health care. We discuss some of the conceptual and methodological issues related to defining what constitutes a patient safety event in inpatient psychiatry and then enumerate a comprehensive set of definitions of the types of safety events that occur in this setting. RESULTS: Patient safety events in inpatient psychiatry are broadly categorized as adverse events and medical errors. Adverse events are composed of adverse drug events and nondrug adverse events, including self-harm or injury to self, assault, sexual contact, patient falls, and other injuries. Medical errors include medication errors and nonmedication errors, such as elopement and contraband. We have developed clear definitions that would be appropriate for use in epidemiological studies of inpatient mental health treatment. CONCLUSIONS: Psychiatry has not been an integral part of the national safety movement. As a first step toward breaching this chasm, we have considered how psychiatric events fit into the safety framework adopted across much of medicine. Patient safety should become a key part of inpatient psychiatry's mission and pursued rigorously as the subject of research and intervention efforts.

An overview of critical decision-points in the medical product lifecycle: Where to include patient preference information in the decision-making process?

BACKGROUND: Patient preference (PP) information is not effectively integrated in decision-making throughout the medical product lifecycle (MPLC), despite having the potential to improve patients' healthcare options. A first step requires an understanding of existing processes and decision-points to know how to incorporate PP information in order to improve patient-centric decision-making. OBJECTIVES: The aims were to: 1) identify the decision-making processes and decision-points throughout the MPLC for industry, regulatory authorities, and reimbursement/HTA, and 2) determine which decision-points can potentially include PP information. METHODS: A scoping literature review was conducted using five scientific databases. Semi-structured interviews were conducted with representatives from seven European countries and the US, including industry (n = 24), regulatory authorities (n = 23), reimbursement/HTA (n = 23). Finally, validation meetings with key stakeholders (n = 11) were conducted. RESULTS: Six critical decision-points were identified for industry decision-making, three for regulatory decision-making, and six for reimbursement/HTA decision-making. Stakeholder groups agreed that PP information is not systematically integrated, either as obligatory information or pre-set criteria, but would benefit all the listed decision-points in the future. CONCLUSION: Currently, PP information is not considered as obligatory information to submit for any of the MPLC decision-points. However, PP information is considered an important component by most stakeholders to inform future decision-making across the MPLC. The integration of PP information into 15 identified decision-points needs continued discussion and collaboration between stakeholders.

Are Laboratory Parameter (Biomarker) Values Similar to the Healthy Volunteer Reference Range in Individuals with Diabetes.

BACKGROUND: Identification of laboratory parameter clinical safety signals depends on the terminology and scoring criteria. Grade 1 scoring criteria in the Common Terminology Criteria for Adverse Events (CTCAE) is typically based on the healthy volunteer reference range (HVRR). The objectives of this study were to determine 1) what laboratory parameters in individuals with diabetes are potentially different from the HVRR and 2) what fold change from baseline should be expected in this population. MATERIALS AND METHODS: Baseline data from the individuals with diabetes clinical trial data (TransCelerate dataset) were compared to the HVRR using a 10% threshold above HVRR to classify laboratory parameters as potentially different from the HVRR. These parameters were then evaluated longitudinally to determine the expected x-baseline values for individuals with diabetes for potential use in identifying drug-induced changes. RESULTS: The baseline data determined that 28% of the laboratory parameters evaluated were potentially different from the HVRR. Longitudinal data analysis determined 1) thresholds for 13 of these laboratory parameters with the subjects above the threshold having greater variability than those below the threshold, and 2) the expected upper limits (x-baseline) were calculated for the laboratory parameters. For example, a 1.8-2.6 x-baseline value for alanine aminotransferase, depending on how the baseline is calculated, is expected in individuals with diabetes. CONCLUSION: It is not uncommon for laboratory parameters in individuals with diabetes clinical trials to be potentially different from the HVRR, and the x-baseline criteria for 13 of these laboratory biomarkers was determined for this population. This suggests consideration in modifying the current CTCAE grade 1 criteria of >1.5-3.0 x-baseline should be further investigated as to if the current criteria detects too many false-positive signals in this population.

Factors and Situations Affecting the Value of Patient Preference Studies: Semi-Structured Interviews in Europe and the US.

Objectives: Patient preference information (PPI) is gaining recognition among the pharmaceutical industry, regulatory authorities, and health technology assessment (HTA) bodies/payers for use in assessments and decision-making along the medical product lifecycle (MPLC). This study aimed to identify factors and situations that influence the value of patient preference studies (PPS) in decision-making along the MPLC according to different stakeholders. Methods: Semi-structured interviews (n = 143) were conducted with six different stakeholder groups (physicians, academics, industry representatives, regulators, HTA/payer representatives, and a combined group of patients, caregivers, and patient representatives) from seven European countries (the United Kingdom, Sweden, Italy, Romania, Germany, France, and the Netherlands) and the United States. Framework analysis was performed using NVivo 11 software. Results: Fifteen factors affecting the value of PPS in the MPLC were identified. These are related to: study organization (expertise, financial resources, study duration, ethics and good practices, patient centeredness), study design (examining patient and/or other preferences, ensuring representativeness, matching method to research question, matching method to MPLC stage, validity and reliability, cognitive burden, patient education, attribute development), and study conduct (patients' ability/willingness to participate and preference heterogeneity). Three types of situations affecting the use of PPS results were identified (stakeholder acceptance, market situations, and clinical situations). Conclusion: The factors and situation types affecting the value of PPS, as identified in this study, need to be considered when designing and conducting PPS in order to promote the integration of PPI into decision-making along the MPLC.

Patient Preferences in the Medical Product Life Cycle: What do Stakeholders Think? Semi-Structured Qualitative Interviews in Europe and the USA.

BACKGROUND: Patient preferences (PP), which are investigated in PP studies using qualitative or quantitative methods, are a growing area of interest to the following stakeholders involved in the medical product lifecycle: academics, health technology assessment bodies, payers, industry, patients, physicians, and regulators. However, the use of PP in decisions along the medical product lifecycle remains limited. As the adoption of PP heavily relies on these stakeholders, knowledge of their perceptions of PP is critical. OBJECTIVE: This study aimed to characterize stakeholders' attitudes, needs, and concerns with respect to PP in decision making along the medical product lifecycle. METHODS: Semi-structured interviews (n = 143) were conducted with academics (n = 24), health technology assessment/payer representatives (n = 24), industry representatives (n = 24), patients, caregivers and patient representatives (n = 24), physicians (n = 24), and regulators (n = 23) from seven European countries and the USA. Interviews were conducted between April and August 2017. The framework method was used to organize the data and identify themes and key findings in each interviewed stakeholder group. RESULTS: Interviewees reported being unfamiliar (43%), moderately familiar (42%), or very familiar (15%) with preference methods and studies. Interviewees across stakeholder groups generally supported the idea of using PP in the medical product lifecycle but expressed mixed opinions about the feasibility and impact of using PP in decision making. Interviewees from all stakeholder groups stressed the importance of increasing stakeholders' understanding of the concept of PP and preference methods and ensuring patients' understanding of the questions asked in PP studies. Key concerns and needs in each interviewed stakeholder group were as follows: (1) academics: investigating the validity, reliability, reproducibility, and generalizability of preference methods; (2) health technology assessment/payer representatives: developing quality criteria for evaluating PP studies and gaining insights into how to weigh them in reimbursement/payer decision making; (3) industry representatives: obtaining guidance on PP studies and recognition on the importance of PP from decision makers; (4) patients, caregivers, and patient representatives: providing an incentive and adequate information towards patients when participating in PP studies; (5) physicians: avoiding bias as a result of commercial agendas in PP studies and clarifying how to deal with subjective and emotional elements when measuring PP; and (6) regulators: avoiding the misuse of PP study results to overrule the traditional efficacy and safety criteria used for marketing authorization and obtaining robust PP study results. CONCLUSIONS: Despite the interest all interviewed stakeholder groups reported in PP, the effective use of PP in decision making across the medical product lifecycle is currently hampered by a lack of standardization and consensus on how to both measure and use PP.

Quantitative comparison of plasmon resonances and field enhancements of near-field optical antennae using FDTD simulations.

Plasmon resonances and electric field enhancements of several near-field optical antennae with plasmonic nanostructures engineered at their apices were quantitatively compared using finite difference time domain simulations. Although many probe designs have been tested experimentally, a systematic comparison of field enhancements has not been possible, due to differences in instrument configuration, reporter mechanism, excitation energy, and plasmonic materials used. For plasmonic nanostructures attached to a non-plasmonic support (e.g., a nanoparticle functionalized AFM tip), we find that the complex refractive index of the support material is critical in controlling the overall plasmonic behavior of the antenna. Supports with strong absorption at optical energies (Pt, W) dampen plasmon resonances and lead to lower enhancements, while those with low absorption (SiO2, Si3N4, Si) boost enhancement by increasing the extinction cross-section of the apex nanostructure. Using a set of physically realistic constraints, probes were optimized for peak plasmonic enhancement at common near-field optical wavelengths (633-647 nm) and those with focused ion-beam milled grooves near the apex were found to give the largest local field enhancements (~30x). Compared to unstructured metal cones, grooved probes gave a 300% improvement in field strength, which can boost tip-enhanced Raman spectroscopy (TERS) signals by 1-2 orders of magnitude. Moreover, grooved probe resonances can be easily tuned over visible and near-infrared energies by varying the plasmonic metal (Ag or Au) and groove location. Overall, this work shows that probes with strong localized surface plasmon resonances at their apices can be engineered to provide large field enhancements and boost signals in near-field optical experiments.

Are laboratory parameter (biomarker) values similar to the healthy volunteer reference range in all patient populations?

BACKGROUND: Liver biomarkers alanine aminotransferase (ALT) and bilirubin in patients with hepatitis are above the healthy volunteer reference range (HVRR) at baseline (prior to receiving the clinical trial medication). Discussions continue as how to best distinguish drug-induced liver injury in patients with abnormal baseline values participating in clinical trials. This study investigated if other baseline routine clinical safety biomarkers (lab parameters) are different from the HVRR. MATERIALS AND METHODS: Clinical trial data (TransCelerate dataset) from placebo and standard of care treated patients were compared to the HVRR using a 10% threshold above or below the HVRR to classify a lab parameter in a patient population as potentially different from the HVRR at baseline. The TransCelerate dataset, batch 4, contained data from patients with Alzheimer's, asthma, COPD, cardiovascular disease, diabetes, hidradenitis, hypercholesterolemia, rheumatoid arthritis, schizophrenia, stroke, and ulcerative colitis. A subset of the 200 biomarkers in Trans-Celerate were evaluated in this pilot: glucose, platelet count, neutrophil count, ALT, aspartate aminotransferase (AST), and bilirubin. RESULTS: Glucose was potentially higher than the HVRR in patients with diabetes, COPD, cardiovascular disease, hypercholesterolemia, and schizophrenia. At least one or more of the hematology and hepatic biomarkers were different from the HVRR in at least one patient population, except bilirubin. All the patient populations, except Alzheimer's and asthma, had at least one biomarker that was higher than the HVRR. SUMMARY: The routine biomarkers evaluated in this pilot study demonstrated that not all lab parameters in patient populations are similar to the HVRR. Further efforts are needed to determine which biomarkers are different from the HVRR and how to evaluate the biomarkers in patient populations for detecting drug-induced altered lab values in clinical trials.

Predictors of Adverse Events and Medical Errors Among Adult Inpatients of Psychiatric Units of Acute Care General Hospitals.

OBJECTIVE: The aim of this study was to identify factors associated with the occurrence of adverse events (AEs) or medical errors (MEs) during inpatient psychiatric hospitalizations. METHODS: A full-probability random sample of 4,371 charts from 14 inpatient psychiatric units at acute care general hospitals in Pennsylvania were reviewed in a two-stage process that comprised screening and flagging by nurses followed by review by psychiatrists. AE and ME rates were calculated overall and then stratified by patient and hospital factors. Unadjusted and adjusted logistic regression models examined predictors of AEs and MEs. RESULTS: An AE was identified in 14.5% of hospitalizations (95% confidence interval [CI]=11.7-17.9), and an ME was identified in 9.0% (CI=7.5-11.0). In adjusted analyses, patients with a longer length of stay and older patients had higher odds of experiencing an AE or an ME. Patients ages 31-42 (compared with ages 18-30), with commercial insurance (compared with Medicare or Medicaid or uninsured), or treated at high-volume hospitals (compared with low, medium, or very high) had lower odds of an AE. Patients age 54 or older (compared with ages 18-30), admitted during the weekend, admitted to rural hospitals (compared with urban), or treated at very-high-volume hospitals (compared with high) were more likely to experience an ME. CONCLUSIONS: This study provides insight into factors that put patients and hospitals at increased risk of patient safety events. This information can be used to tailor improvement strategies that enhance the safety of patients treated on general hospital psychiatric units.

Nanoscale Optical Microscopy and Spectroscopy Using Near-Field Probes.

Light-matter interactions can provide a wealth of detailed information about the structural, electronic, optical, and chemical properties of materials through various excitation and scattering processes that occur over different length, energy, and timescales. Unfortunately, the wavelike nature of light limits the achievable spatial resolution for interrogation and imaging of materials to roughly λ/2 because of diffraction. Scanning near-field optical microscopy (SNOM) breaks this diffraction limit by coupling light to nanostructures that are specifically designed to manipulate, enhance, and/or extract optical signals from very small regions of space. Progress in the SNOM field over the past 30 years has led to the development of many methods to optically characterize materials at lateral spatial resolutions well below 100 nm. We review these exciting developments and demonstrate how SNOM is truly extending optical imaging and spectroscopy to the nanoscale.

Safety of Psychiatric Inpatients at the Veterans Health Administration.

OBJECTIVE: Although reducing adverse events and medical errors has become a central focus of the U.S. health care system over the past two decades both within and outside the Veterans Health Administration (VHA) hospital systems, patients treated in psychiatric units of acute care general hospitals have been excluded from major research in this field. METHODS: The study included a random sample of 40 psychiatric units from medical centers in the national VHA system. Standardized abstraction tools were used to assess the electronic health records from 8,005 hospitalizations. Medical record administrators screened the records for the presence of ten specific types of patient safety events, which, when present, were evaluated by physician reviewers to assess whether the event was the result of an error, whether it caused harm, and whether it was preventable. RESULTS: Approximately one in five patients experienced a patient safety event. The most frequently occurring events were medication errors (which include delayed and missed doses) (17.2%), followed by adverse drug events (4.1%), falls (2.8%), and assault (1.0%). Most patient safety events (94.9%) resulted in little harm or no harm, and more than half (56.6%) of the events were deemed preventable. CONCLUSIONS: Although patient safety events in VHA psychiatric inpatient units were relatively common, a great majority of these events resulted in little or no patient harm. Nevertheless, many were preventable, and the study provides data with which to target future initiatives that may improve the safety of this vulnerable patient population.

Adverse events in veterans affairs inpatient psychiatric units: Staff perspectives on contributing and protective factors.

OBJECTIVES: This study sought to identify risk factors and protective factors in hospital-based mental health settings in the Veterans Health Administration (VHA), with the goal of informing interventions to improve care of persons with serious mental illness. METHODS: Twenty key informants from a stratified sample of 7 VHA inpatient psychiatric units were interviewed to gain their insights on causes of patient safety events and the factors that constrain or facilitate patient safety efforts. RESULTS: Respondents identified threats to patient safety at the system-, provider-, and patient-levels. Protective factors that, when in place, made patient safety events less likely to occur included: promoting a culture of safety; advocating for patient-centeredness; and engaging administrators and organizational leadership to champion these changes. CONCLUSIONS: Findings highlight the impact of systems-level policies and procedures on safety in inpatient mental health care. Engaging all stakeholders, including patients, in patient safety efforts and establishing a culture of safety will help improve the quality of inpatient psychiatric care. Successful implementation of changes require the knowledge of local experts most closely involved in patient care, as well as support and buy-in from organizational leadership.

Literature review of visual representation of the results of benefit-risk assessments of medicinal products.

BACKGROUND: The PROTECT Benefit-Risk group is dedicated to research in methods for continuous benefit-risk monitoring of medicines, including the presentation of the results, with a particular emphasis on graphical methods. METHODS: A comprehensive review was performed to identify visuals used for medical risk and benefit-risk communication. The identified visual displays were grouped into visual types, and each visual type was appraised based on five criteria: intended audience, intended message, knowledge required to understand the visual, unintentional messages that may be derived from the visual and missing information that may be needed to understand the visual. RESULTS: Sixty-six examples of visual formats were identified from the literature and classified into 14 visual types. We found that there is not one single visual format that is consistently superior to others for the communication of benefit-risk information. In addition, we found that most of the drawbacks found in the visual formats could be considered general to visual communication, although some appear more relevant to specific formats and should be considered when creating visuals for different audiences depending on the exact message to be communicated. CONCLUSION: We have arrived at recommendations for the use of visual displays for benefit-risk communication. The recommendation refers to the creation of visuals. We outline four criteria to determine audience-visual compatibility and consider these to be a key task in creating any visual. Next we propose specific visual formats of interest, to be explored further for their ability to address nine different types of benefit-risk analysis information.

Hurdles in therapy with regulatory T cells.

Improper activation of the immune system contributes to a variety of clinical conditions, including autoimmune and allergic diseases as well as solid organ and bone marrow transplantation. One approach to counteract this activation is through adoptive therapy with regulatory T cells (Tregs). Efforts to manufacture these cells have led to good maunfacturing practice-compliant protocols, and Treg products are entering early clinical trials. Here, we report the stance of the European Union Cooperation in Science and Technology Action BM1305, "Action to Focus and Accelerate Cell-based Tolerance-inducing Therapies-A FACTT," which identifies hurdles hindering Treg clinical applications in Europe and provides possible solutions.

Reactive Liftoff of Crystalline Cellulose Particles.

The condition of heat transfer to lignocellulosic biomass particles during thermal processing at high temperature (>400 °C) dramatically alters the yield and quality of renewable energy and fuels. In this work, crystalline cellulose particles were discovered to lift off heated surfaces by high speed photography similar to the Leidenfrost effect in hot, volatile liquids. Order of magnitude variation in heat transfer rates and cellulose particle lifetimes was observed as intermediate liquid cellulose droplets transitioned from low temperature wetting (500-600 °C) to fully de-wetted, skittering droplets on polished surfaces (>700 °C). Introduction of macroporosity to the heated surface was shown to completely inhibit the cellulose Leidenfrost effect, providing a tunable design parameter to control particle heat transfer rates in industrial biomass reactors.

Benefit-risk assessment in a post-market setting: a case study integrating real-life experience into benefit-risk methodology.

PURPOSE: Difficulties may be encountered when undertaking a benefit-risk assessment for an older product with well-established use but with a benefit-risk balance that may have changed over time. This case study investigates this specific situation by applying a formal benefit-risk framework to assess the benefit-risk balance of warfarin for primary prevention of patients with atrial fibrillation. METHODS: We used the qualitative framework BRAT as the starting point of the benefit-risk analysis, bringing together the relevant available evidence. We explored the use of a quantitative method (stochastic multi-criteria acceptability analysis) to demonstrate how uncertainties and preferences on multiple criteria can be integrated into a single measure to reduce cognitive burden and increase transparency in decision making. RESULTS: Our benefit-risk model found that warfarin is favourable compared with placebo for the primary prevention of stroke in patients with atrial fibrillation. This favourable benefit-risk balance is fairly robust to differences in preferences. The probability of a favourable benefit-risk for warfarin against placebo is high (0.99) in our model despite the high uncertainty of randomised clinical trial data. In this case study, we identified major challenges related to the identification of relevant benefit-risk criteria and taking into account the diversity and quality of evidence available to inform the benefit-risk assessment. CONCLUSION: The main challenges in applying formal methods for medical benefit-risk assessment for a marketed drug are related to outcome definitions and data availability. Data exist from many different sources (both randomised clinical trials and observational studies), and the variability in the studies is large.