Structured analysis, evaluation and report of the emergency response to a terrorist attack in Wuerzburg, Germany using a new template of standardised quality indicators

Background: Until now there has been a reported lack of systematic reports and scientific evaluations of rescue missions during terror attacks. This however is urgently required in order to improve the performance of emergency medical services and to be able to compare different missions with each other. Aim of the presented work was to report the systematic evaluation and the lessons learned from the response to a terror attack that happened in Wuerzburg, Germany in 2016. Methods: A team of 14 experts developed a template of quality indicators and operational characteristics, which allow for the description, assessment and comparison of civil emergency rescue missions during mass killing incidents. The entire systematic evaluation process consisted of three main steps. The first step was the systematic data collection according to the quality indicators and operational characteristics. Second was the systematic stratification and assessment of the data. The last step was the prioritisation of the identified weaknesses and the definition of the lessons learned. Results: Five important “lessons learned” have been defined. First of all, a comprehensive concept for rescue missions during terror attacks is essential. Furthermore, the establishment of a defined high priority communication infrastructure between the different dispatch centres (“red phone”) is vital. The goal is to secure the continuity of information between a few well-defined individuals. Thirdly, the organization of the incident scene needs to be commonly decided and communicated between police, medical services and fire services during the mission. A successful mission tactic requires continuous flux of reports to the on-site command post. Therefore, a predefined and common communication infrastructure for all operational forces is a crucial point. Finally, all strategies need to be extensively trained before the real life scenario hits. Conclusion: According to a systematic evaluation, we defined the lessons learned from a terror attack in 2016. Further systematic reports and academic work surrounding life threatening rescue missions and mass killing incidents are needed in order to ultimately improve such mission outcomes. In the future, a close international collaboration might help to find the best database to report and evaluate major incidents but also mass killing events

A role for PACE4 in osteoarthritis pain: evidence from human genetic association and null mutant phenotype

Objectives The aim of this study was to assess if genetic variation in the PACE4 (paired amino acid converting enzyme 4) gene Pcsk6 influences the risk for symptomatic knee osteoarthritis (OA). Methods Ten PCSK6 single nucleotide polymorphisms were tested for association in a discovery cohort of radiographic knee OA (n=156 asymptomatic and 600 symptomatic cases). Meta-analysis of the minor allele at rs900414 was performed in three additional independent cohorts (total n=674 asymptomatic and 2068 symptomatic). Pcsk6 knockout mice and wild-type C57BL/6 mice were compared in a battery of algesiometric assays, including hypersensitivity in response to intraplantar substance P, pain behaviours in response to intrathecal substance P and pain behaviour in the abdominal constriction test. Results In the discovery cohort of radiographic knee OA, an intronic single nucleotide polymorphism at rs900414 was significantly associated with symptomatic OA. Replication in three additional cohorts confirmed that the minor allele at rs900414 was consistently increased among asymptomatic compared to symptomatic radiographic knee OA cases in all four cohorts. A fixed-effects meta-analysis yielded an OR=1.35 (95% CI 1.17 to 1.56; p=4.3×10−5 and no significant between-study heterogeneity). Studies in mice revealed that Pcsk6 knockout mice were significantly protected against pain in a battery of algesiometric assays. Conclusions These results suggest that a variant in PCSK6 is strongly associated with protection against pain in knee OA, offering some insight as to why, in the presence of the same structural damage, some individuals develop chronic pain and others are protected. Studies in Pcsk6 null mutant mice further implicate PACE4 in pain

CGRP receptor antagonists: design and screening

Importance of the field: Calcitonin gene-related peptide (CGRP) receptor antagonists have recently come to attention with the development of olcegepant and telcagepant for the treatment of migraine. The availability of high-affinity, non-peptide antagonists opens the way for trials of these compounds in other conditions where CGRP antagonism might be useful, such as septic shock and inhibition of angiogenesis. Areas covered in this review: This review summarises knowledge about the structure and signalling properties of the CGRP receptor. The clinical ramifications of targeting the CGRP receptor, the profiles of existing antagonists and the requirements for screening new compounds will be discussed. What the reader will gain: Readers will gain an overview of how current non-peptide antagonists seem to bind similar epitopes contributed by both calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1), the main CGRP receptor subunits. We will discuss how current antagonists have low bioavailability, limiting their use. For selectivity at CGRP receptors, it will be necessary to target parts of the receptor influenced by both RAMP1 and CLR. Take home message: For the design of radically new antagonists, more structural information on the receptor is needed. Current screens are largely based on measuring CGRP-mediated changes in cAMP. CGRP receptors can influence other signalling pathways and pathway-selective allosteric antagonists may be useful, but more information is needed about the mechanism of action of CGRP to assess the value of this