Proposing a framework for evidence-based road safety policy-making: Connecting crash causation, countermeasures and policy.

Effective evidence-based policy making within road safety is a several step cyclic process that involves gathering data about the causes of crashes, analysing these data, developing countermeasures and implementing and evaluating them. There are many examples of crash causation focused data collection activities available to policy makers but knowledge on how these finding may have led to countermeasure implementation and new policy is much less well established. This paper proposes a framework for best practice evidence-based policy making. To address existing gaps, the framework consists of three pillars: these are (1) Crash causation establishment; (2) Countermeasure development and implementation; and (3) road safety management. A key element in this framework is the recommendation for the establishment of an organisation responsible for road safety that has a strategic and coordination role. This framework, as a whole, aims to provide a practical high-level map by connecting evidence to policy at every point in the policy making cycle and ensuring that evidence-based road safety policy is a national priority. It is anticipated that using this framework to inform road safety policy development will enhance the success of any developed policy.

Discovery of an In Vivo Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones.

B-cell lymphoma 6 (BCL6) is a transcriptional repressor and oncogenic driver of diffuse large B-cell lymphoma (DLBCL). Here, we report the optimization of our previously reported tricyclic quinolinone series for the inhibition of BCL6. We sought to improve the cellular potency and in vivo exposure of the non-degrading isomer, CCT373567, of our recently published degrader, CCT373566. The major limitation of our inhibitors was their high topological polar surface areas (TPSA), leading to increased efflux ratios. Reducing the molecular weight allowed us to remove polarity and decrease TPSA without considerably reducing solubility. Careful optimization of these properties, as guided by pharmacokinetic studies, led to the discovery of CCT374705, a potent inhibitor of BCL6 with a good in vivo profile. Modest in vivo efficacy was achieved in a lymphoma xenograft mouse model after oral dosing.

Improved Binding Affinity and Pharmacokinetics Enable Sustained Degradation of BCL6 In Vivo.

The transcriptional repressor BCL6 is an oncogenic driver found to be deregulated in lymphoid malignancies. Herein, we report the optimization of our previously reported benzimidazolone molecular glue-type degrader CCT369260 to CCT373566, a highly potent probe suitable for sustained depletion of BCL6 in vivo. We observed a sharp degradation SAR, where subtle structural changes conveyed the ability to induce degradation of BCL6. CCT373566 showed modest in vivo efficacy in a lymphoma xenograft mouse model following oral dosing.

Optimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors.

To identify new chemical series with enhanced binding affinity to the BTB domain of B-cell lymphoma 6 protein, we targeted a subpocket adjacent to Val18. With no opportunities for strong polar interactions, we focused on attaining close shape complementarity by ring fusion onto our quinolinone lead series. Following exploration of different sized rings, we identified a conformationally restricted core which optimally filled the available space, leading to potent BCL6 inhibitors. Through X-ray structure-guided design, combined with efficient synthetic chemistry to make the resulting novel core structures, a >300-fold improvement in activity was obtained by the addition of seven heavy atoms.

Discovering cell-active BCL6 inhibitors: effectively combining biochemical HTS with multiple biophysical techniques, X-ray crystallography and cell-based assays.

By suppressing gene transcription through the recruitment of corepressor proteins, B-cell lymphoma 6 (BCL6) protein controls a transcriptional network required for the formation and maintenance of B-cell germinal centres. As BCL6 deregulation is implicated in the development of Diffuse Large B-Cell Lymphoma, we sought to discover novel small molecule inhibitors that disrupt the BCL6-corepressor protein-protein interaction (PPI). Here we report our hit finding and compound optimisation strategies, which provide insight into the multi-faceted orthogonal approaches that are needed to tackle this challenging PPI with small molecule inhibitors. Using a 1536-well plate fluorescence polarisation high throughput screen we identified multiple hit series, which were followed up by hit confirmation using a thermal shift assay, surface plasmon resonance and ligand-observed NMR. We determined X-ray structures of BCL6 bound to compounds from nine different series, enabling a structure-based drug design approach to improve their weak biochemical potency. We developed a time-resolved fluorescence energy transfer biochemical assay and a nano bioluminescence resonance energy transfer cellular assay to monitor cellular activity during compound optimisation. This workflow led to the discovery of novel inhibitors with respective biochemical and cellular potencies (IC50s) in the sub-micromolar and low micromolar range.

Post-trip safety interventions: State-of-the-art, challenges, and practical implications.

INTRODUCTION: Currently, risky driving behaviour is a major contributor to road crashes and as a result, wide array of tools have been developed in order to record and improve driving behaviour. Within that group of tools, interventions have been indicated to significantly enhance driving behaviour and road safety. This study critically reviews monitoring technologies that provide post-trip interventions, such as retrospective visual feedback, gamification, rewards or penalties, in order to inform an appropriate driver mentoring strategy delivered after each trip. METHOD: The work presented here is part of the European Commission H2020 i-DREAMS project. The reviewed platform characteristics were obtained through commercially available solutions as well as a comprehensive literature search in popular scientific databases, such as Scopus and Google Scholar. Focus was given on state-of-the-art-technologies for post-trip interventions utilized in four different transport modes (i.e. car, truck, bus and rail) associated with risk prevention and mitigation. RESULTS: The synthesized results revealed that smartphone applications and web-based platforms are the most accepted, frequently and easiest to use tools in cars, buses and trucks across all papers considered, while limited evidence of post-trip interventions in -rail was found. The majority of smartphone applications detected mobile phone use and harsh events and provided individual performance scores, while in-vehicle systems provided delayed visual reports through a web-based platform. CONCLUSIONS: Gamification and appropriate rewards appeared to be effective solutions, as it was found that they keep drivers motivated in improving their driving skills, but it was clear that these cannot be performed in isolation and a combination with other strategies (i.e. driver coaching and support) might be beneficial. Nevertheless, as there is no holistic and cross-modal post-trip intervention solution developed in real-world environments, challenges associated with post-trip feedback provision and suggestions on practical implementation are also provided.

Into Deep Water: Optimizing BCL6 Inhibitors by Growing into a Solvated Pocket.

We describe the optimization of modestly active starting points to potent inhibitors of BCL6 by growing into a subpocket, which was occupied by a network of five stably bound water molecules. Identifying potent inhibitors required not only forming new interactions in the subpocket but also perturbing the water network in a productive, potency-increasing fashion while controlling the physicochemical properties. We achieved this goal in a sequential manner by systematically probing the pocket and the water network, ultimately achieving a 100-fold improvement of activity. The most potent compounds displaced three of the five initial water molecules and formed hydrogen bonds with the remaining two. Compound 25 showed a promising profile for a lead compound with submicromolar inhibition of BCL6 in cells and satisfactory pharmacokinetic (PK) properties. Our work highlights the importance of finding productive ways to perturb existing water networks when growing into solvent-filled protein pockets.

Why are powered two wheeler riders still fatally injured in road junction crashes? - A causation analysis.

INTRODUCTION: Powered Two Wheeler (PTW) crashes continue to be a road safety concern with a plateauing of the number of associated fatalities. METHOD: Forty one UK fatal or serious injury crashes involving a PTW and another vehicle at a junction were examined. Crash causation was analysed using the Driver Reliability and Error Analysis Method (DREAMv3.2). Crashes were split into two groups: Group A, where the other vehicle was travelling in the opposite direction to the PTW and commenced a right turn across the PTW's path; and Group B where the other vehicle turned right out of a side road (or entrance) across the PTW's path. RESULTS: Overall, the factor that led directly to the crash (phenotype) was most commonly 'too high speed' or 'too late action' for the motorcyclist and 'too early action' for the other driver. Missed or late observations were contributory factors for both PTW riders and other vehicle drivers. Some differences between groups were observed with the PTW riders in Group B more likely to have 'insufficient skills' and the other vehicle drivers in Group A more likely to have 'attention allocation' as a causation factor. For both groups the crashes occurred because the other vehicle failed to give way to the PTW with causation chains that suggest 'looked but failed to see' is still an issue in this type of crash. The excessive speed of the PTW contributed to some crashes. CONCLUSIONS: This analysis suggests that drivers failing to give way to PTW riders at junctions is still a problem. This may relate to the 'looked but did not see' phenomenon. Causation differences were observed between the examined groups. Practical considerations: The DREAM methodology is an effective tool in analysing crash data from police collision investigation reports. Different countermeasures may be necessary to prevent different types of junction crashes.

Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders.

Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of germinal center B-cells, and hence BCL6 has been proposed as a therapeutic target for the treatment of diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of benzimidazolone inhibitors of the protein-protein interaction between BCL6 and its co-repressors. A subset of these inhibitors were found to cause rapid degradation of BCL6, and optimization of pharmacokinetic properties led to the discovery of 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (CCT369260), which reduces BCL6 levels in a lymphoma xenograft mouse model following oral dosing.

Addressing mental health stigma: A pilot educational video intervention for caregivers to facilitate psychiatric consultation in inpatient pediatric care settings.

Mental health stigma continues to be a significant barrier for psychiatric care in youth. Parental misperceptions regarding mental health may interfere with their child's care and negatively influence their child's view of mental health. For some children, their first experience with psychiatry occurs during medical hospitalization when they are seen by the Pediatric Consultation-Liaison (C/L) Psychiatry Service. Despite this unique role, there is sparse research on how to address mental health stigma with patients and families within the context of Pediatric C/L Psychiatry. This study explores the use of a brief educational video with messages from the Pediatric C/L Psychiatry team, families who have accessed mental health consultation in the hospital, and brief video interactions between family and the C/L team, to address mental health stigma. Common misconceptions are addressed during the video with the intent of reducing negative parental perceptions relating to mental health care. Families are given a survey highlighting these concerns, prior to and after watching the video. Pre- and post-intervention responses were compared using paired sample's t-tests. Results indicated that the video did positively change parent's confidence that psychiatry can be helpful, reduced their preconceived stigma regarding confidentiality, while alleviating concerns regarding psychotropic medication use in youth. Use of an educational video may be feasible, time efficient, and effective at reducing parental mental health stigma.

The European road safety decision support system on risks and measures.

The European Road Safety Decision Support System (roadsafety-dss.eu) is an innovative system providing the available evidence on a broad range of road risks and possible countermeasures. This paper describes the scientific basis of the DSS. The structure underlying the DSS consists of (1) a taxonomy identifying risk factors and measures and linking them to each other, (2) a repository of studies, and (3) synopses summarizing the effects estimated in the literature for each risk factor and measure, and (4) an economic efficiency evaluation instrument (E3-calculator). The DSS is implemented in a modern web-based tool with a highly ergonomic interface, allowing users to get a quick overview or go deeper into the results of single studies according to their own needs.

Fatal and serious collisions involving pedal cyclists and trucks in London between 2007 and 2011.

OBJECTIVE: Increased numbers of people riding pedal cycles have led to a greater focus on pedal cycle safety. The aim of this article is to explore factors that are associated with fatal and a small number of serious-injury pedal cyclist crashes involving trucks that occurred in London between 2007 and 2011. METHODS: Data were collected from police collision files for 53 crashes, 27 of which involved a truck (≥3.5 tonnes) and a pedal cycle. A systematic case review approach was used to identify the infrastructure, vehicle road user, and management factors that contributed to these crashes and injuries and how these factors interacted. RESULTS: Trucks turning left conflicting with pedal cyclists traveling straight ahead was a common crash scenario. Key contributory factors identified included the pedal cyclists not being visible to the truck drivers, road narrowing, and inappropriate positioning of pedal cyclists. CONCLUSIONS: Crashes involving trucks and pedal cyclists are complex events that are caused by multiple interacting factors; therefore, multiple measures are required to prevent them from occurring.

Exploring inattention and distraction in the SafetyNet Accident Causation Database.

Distraction and inattention are considered to be very important and prevalent factors in the causation of road accidents. There have been many recent research studies which have attempted to understand the circumstances under which a driver becomes distracted or inattentive and how distraction/inattention can be prevented. Both factors are thought to have become more important in recent times partly due to the evolution of in-vehicle information and communication technology. This study describes a methodology that was developed to understand when factors such as distraction and inattention may have been contributors to crashes and also describes some of the consequences of distraction and inattention in terms of subsequent driver actions. The study uses data relating to distraction and inattention from the SafetyNet Accident Causation Database. This database was formulated as part of the SafetyNet project to address the lack of representative in-depth accident causation data within the European Union. Data were collected in 6 European countries using 'on-scene' and 'nearly on-scene' crash investigation methodologies. 32% of crashes recorded in the database, involved at least one driver, rider or pedestrian, who was determined to be 'Inattentive' or 'Distracted'. 212 of the drivers were assigned 'Distraction' and 140 drivers were given the code 'Inattention'. It was found that both distraction and inattention often lead to missed observations within the driving task and consequently 'Timing' or 'Direction' become critical events in the aetiology of crashes. In addition, the crash types and outcomes may differ according to the type and nature of the distraction and inattention as determined by the in-depth investigations. The development of accident coding methodology is described in this study as is its evolution into the Driver Reliability and Error Analysis Model (DREAM) version 3.0.

Identifying the causes of road crashes in Europe.

This research applies a recently developed model of accident causation, developed to investigate industrial accidents, to a specially gathered sample of 997 crashes investigated in-depth in 6 countries. Based on the work of Hollnagel the model considers a collision to be a consequence of a breakdown in the interaction between road users, vehicles and the organisation of the traffic environment. 54% of road users experienced interpretation errors while 44% made observation errors and 37% planning errors. In contrast to other studies only 11% of drivers were identified as distracted and 8% inattentive. There was remarkably little variation in these errors between the main road user types. The application of the model to future in-depth crash studies offers the opportunity to identify new measures to improve safety and to mitigate the social impact of collisions. Examples given include the potential value of co-driver advisory technologies to reduce observation errors and predictive technologies to avoid conflicting interactions between road users.