Abstracts from The Cold Weather Operations Conference 2021.

A common effort for both military and civil healthcare is to achieve knowledge-based health care in cold weather injuries and fatal accidents in harsh arctic environment. The Cold Weather Operations Conference in November 2021, having more than 300 participants from 20 countries, was addressing the prevention and treatment of injuries and trauma care in cold weather conditions and the challenges for military prehospital casualty care. The intention of the programme was to stimulate further research and systematic knowledge-based clinical work. The abstracts from the conference present cold weather research and clinical experience relevant for readers of the International Journal of Circumpolar Health.

Correlation of magnetic resonance and arthroscopy in the diagnosis of shoulder injury.

BACKGROUND: Advances in shoulder magnetic resonance imaging (MRI) and arthrography (MRA) have revolutionised musculoskeletal diagnosis and surgical planning. Despite this, the overall accuracy of MRI, with or without intra-articular contrast, can be variable. METHODS: In this prospective non-randomised analysis, 200 participants (74.5% males) with suspected shoulder injuries underwent MRI (41.0%) or MRA followed by arthroscopy. A study specific proforma was developed to ensure consistency of reporting by radiologists and surgeons. The reports were compared to assess the predictive power of MRI/MRA. Specific assessment of rotator cuff tendon appearance, long head of biceps (LHB) tendon appearance, position and anchor, subacromial space, glenoid labrum and humeral cartilage grade were included. RESULTS: Shoulder MRA demonstrated a higher agreement with arthroscopy than MRI for supraspinatus, infraspinatus and subscapularis tendon appearance (κ = 0.77 vs. κ = 0.61, κ = 0.55 vs. κ = 0.53 and κ = 0.58 vs. κ = 0.46 respectively). There were also superior agreement rates with MRA compared to MRI for LHB tendon appearance (κ = 0.70 vs. κ =0.54) and position (κ = 0.89 vs. κ = 0.72). As an overall assessor of shoulder pathology we found significantly higher total agreement scores when MRA was used (p = 0.002). DISCUSSION: Whilst magnetic resonance imaging with arthrography is an extremely useful tool to assess underlying pathological shoulder states it does not confer 100% accuracy. In cases whereby this modality is inconclusive, an examination under anaesthesia and diagnostic arthroscopic assessment for the detection of intra-articular shoulder pathology may be considered.

RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies.

INTRODUCTION: Novel rearranged in transfection (RET)-specific tyrosine kinase inhibitors (TKIs) such as selpercatinib (LOXO-292) have shown unprecedented efficacy in tumors positive for RET fusions or mutations, notably RET fusion-positive NSCLC and RET-mutated medullary thyroid cancer (MTC). However, the mechanisms of resistance to these agents have not yet been described. METHODS: Analysis was performed of circulating tumor DNA and tissue in patients with RET fusion-positive NSCLC and RET-mutation positive MTC who developed disease progression after an initial response to selpercatinib. Acquired resistance was modeled preclinically using a CCDC6-RET fusion-positive NSCLC patient-derived xenograft. The inhibitory activity of anti-RET multikinase inhibitors and selective RET TKIs was evaluated in enzyme and cell-based assays. RESULTS: After a dramatic initial response to selpercatinib in a patient with KIF5B-RET NSCLC, analysis of circulating tumor DNA revealed emergence of RET G810R, G810S, and G810C mutations in the RET solvent front before the emergence of clinical resistance. Postmortem biopsy studies reported intratumor and intertumor heterogeneity with distinct disease subclones containing G810S, G810R, and G810C mutations in multiple disease sites indicative of convergent evolution on the G810 residue resulting in a common mechanism of resistance. Acquired mutations in RET G810 were identified in tumor tissue from a second patient with CCDC6-RET fusion-positive NSCLC and in plasma from patients with additional RET fusion-positive NSCLC and RET-mutant MTC progressing on an ongoing phase 1 and 2 trial of selpercatinib. Preclinical studies reported the presence of RET G810R mutations in a CCDC6-RET patient-derived xenograft (from a patient with NSCLC) model of acquired resistance to selpercatinib. Structural modeling predicted that these mutations sterically hinder the binding of selpercatinib, and in vitro assays confirmed loss of activity for both anti-RET multikinase inhibitors and selective RET TKIs. CONCLUSIONS: RET G810 solvent front mutations represent the first described recurrent mechanism of resistance to selective RET inhibition with selpercatinib. Development of potent inhibitor of these mutations and maintaining activity against RET gatekeeper mutations could be an effective strategy to target resistance to selective RET inhibitors.

A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors.

Larotrectinib, a selective TRK tyrosine kinase inhibitor (TKI), has demonstrated histology-agnostic efficacy in patients with TRK fusion-positive cancers. Although responses to TRK inhibition can be dramatic and durable, duration of response may eventually be limited by acquired resistance. LOXO-195 is a selective TRK TKI designed to overcome acquired resistance mediated by recurrent kinase domain (solvent front and xDFG) mutations identified in multiple patients who have developed resistance to TRK TKIs. Activity against these acquired mutations was confirmed in enzyme and cell-based assays and in vivo tumor models. As clinical proof of concept, the first 2 patients with TRK fusion-positive cancers who developed acquired resistance mutations on larotrectinib were treated with LOXO-195 on a first-in-human basis, utilizing rapid dose titration guided by pharmacokinetic assessments. This approach led to rapid tumor responses and extended the overall duration of disease control achieved with TRK inhibition in both patients.Significance: LOXO-195 abrogated resistance in TRK fusion-positive cancers that acquired kinase domain mutations, a shared liability with all existing TRK TKIs. This establishes a role for sequential treatment by demonstrating continued TRK dependence and validates a paradigm for the accelerated development of next-generation inhibitors against validated oncogenic targets. Cancer Discov; 7(9); 963-72. ©2017 AACR.See related commentary by Parikh and Corcoran, p. 934This article is highlighted in the In This Issue feature, p. 920.

Biopharmaceutics data management system for anonymised data sharing and curation: First application with orbito IMI project.

The OrBiTo IMI project was designed to improve the understanding and modelling of how drugs are absorbed. To achieve this 13 pharmaceutical companies agreed to share biopharmaceutics drug properties and performance data, as long as they were able to hide certain aspects of their dataset if required. This data was then used in simulations to test how three in silico Physiological Based Pharmacokinetic (PBPK) tools performed. A unique database system was designed and implemented to store the drug data. The database system was unique, in that it had the ability to make different sections of a dataset visible or hidden depending on the stage of the project. Users were also given the option to hide identifying API attributes, to help prevent identification of project members from previously published data. This was achieved by applying blinding strategies to data parameters and the adoption of a unique numbering system. An anonymous communication tool was proposed to exchange comments about data, which enabled its curation and evolution. This paper describes the strategy adopted for numbering and blinding of the data, the tools developed to gather and search data as well as the tools used for communicating around the data with the aim of publicising the approach for other pre-competitive research between organisations.

Demonstration of broad photonic crystal stop band in a freely-suspended microfiber perforated by an array of rectangular holes.

It is shown that photonic crystal (PhC) optical reflectors with reflectance in excess of 60% and fractional bandwidths greater than 10% can be fabricated by ion beam milling of fewer than ten periods of rectangular cross section through-holes in micron-scale tapered fibers. The optical characteristics agree well with numerical simulations when allowance is made for fabrication artefacts and we show that the radiation loss, which is partly determined by optical interference, can be suppressed by design. The freely-suspended devices are compact and robust and could form the basic building block of optical cavities and filters.

Why patients need leaders: introducing a ward safety checklist.

The safety and consistency of the care given to hospital inpatients has recently become a particular political and public concern. The traditional 'ward round' presents an obvious opportunity for systematically and collectively ensuring that proper standards of care are being achieved for individual patients. This paper describes the design and implementation of a 'ward safety checklist' that defines a set of potential risk factors that should be checked on a daily basis, and offers multidisciplinary teams a number of prompts for sharing and clarifying information between themselves, and with the patient, during a round. The concept of the checklist and the desire to improve ward rounds were well received in many teams, but the barriers to adoption were informative about the current culture on many inpatient wards. Although the 'multidisciplinary ward round' is widely accepted as good practice, the medical and nursing staff in many teams are failing to coordinate their workloads well enough to make multidisciplinary rounds a working reality. 'Nursing' and 'medical' care on the ward have become 'de-coupled' and the potential consequences for patient safety and good communication are largely self-evident. This problem is further complicated by a medical culture which values the primacy of clinical autonomy and as a result can be resistant to perceived attempts to 'systematize' medical care through instruments such as checklists.

Life in the slow lane: making hospitals safer, slowly but surely.

Recognition that serious deficiencies in mutual respect and team work were hampering safe and effective patient care led to the creation of the cultural change initiative described here. We feel this has widespread applicability to other healthcare settings. The After Action Review (AAR) concept was adapted for use in the NHS for the first time as it provides a deceptively simple vehicle to structure healthy blame free team interactions with the aim of improving practice and team behaviours. The organizational and psychological barriers to being able to do this in multi-professional teams are accentuated by the hierarchical nature of the clinical context, but this project has begun to make lasting change so that AAR is an approach that is now widely understood and frequently used.

Terahertz surface plasmon-polariton propagation and focusing on periodically corrugated metal wires.

In this Letter, we show how the dispersion relation of surface plasmon polaritons (SPPs) propagating along a perfectly conducting wire can be tailored by corrugating its surface with a periodic array of radial grooves. In this way, highly localized SPPs can be sustained in the terahertz region of the electromagnetic spectrum. Importantly, the propagation characteristics of these spoof SPPs can be controlled by the surface geometry, opening the way to important applications such as energy concentration on cylindrical wires and superfocusing using conical structures.