Single-cell spatial immune landscapes of primary and metastatic brain tumours.

Single-cell technologies have enabled the characterization of the tumour microenvironment at unprecedented depth and have revealed vast cellular diversity among tumour cells and their niche. Anti-tumour immunity relies on cell-cell relationships within the tumour microenvironment1,2, yet many single-cell studies lack spatial context and rely on dissociated tissues3. Here we applied imaging mass cytometry to characterize the immunological landscape of 139 high-grade glioma and 46 brain metastasis tumours from patients. Single-cell analysis of more than 1.1 million cells across 389 high-dimensional histopathology images enabled the spatial resolution of immune lineages and activation states, revealing differences in immune landscapes between primary tumours and brain metastases from diverse solid cancers. These analyses revealed cellular neighbourhoods associated with survival in patients with glioblastoma, which we leveraged to identify a unique population of myeloperoxidase (MPO)-positive macrophages associated with long-term survival. Our findings provide insight into the biology of primary and metastatic brain tumours, reinforcing the value of integrating spatial resolution to single-cell datasets to dissect the microenvironmental contexture of cancer.

A landscape of driver mutations in melanoma.

Despite recent insights into melanoma genetics, systematic surveys for driver mutations are challenged by an abundance of passenger mutations caused by carcinogenic UV light exposure. We developed a permutation-based framework to address this challenge, employing mutation data from intronic sequences to control for passenger mutational load on a per gene basis. Analysis of large-scale melanoma exome data by this approach discovered six novel melanoma genes (PPP6C, RAC1, SNX31, TACC1, STK19, and ARID2), three of which-RAC1, PPP6C, and STK19-harbored recurrent and potentially targetable mutations. Integration with chromosomal copy number data contextualized the landscape of driver mutations, providing oncogenic insights in BRAF- and NRAS-driven melanoma as well as those without known NRAS/BRAF mutations. The landscape also clarified a mutational basis for RB and p53 pathway deregulation in this malignancy. Finally, the spectrum of driver mutations provided unequivocal genomic evidence for a direct mutagenic role of UV light in melanoma pathogenesis.

COATI: Multimodal Contrastive Pretraining for Representing and Traversing Chemical Space.

Creating a successful small molecule drug is a challenging multiparameter optimization problem in an effectively infinite space of possible molecules. Generative models have emerged as powerful tools for traversing data manifolds composed of images, sounds, and text and offer an opportunity to dramatically improve the drug discovery and design process. To create generative optimization methods that are more useful than brute-force molecular generation and filtering via virtual screening, we propose that four integrated features are necessary: large, quantitative data sets of molecular structure and activity, an invertible vector representation of realistic accessible molecules, smooth and differentiable regressors that quantify uncertainty, and algorithms to simultaneously optimize properties of interest. Over the course of 12 months, Terray Therapeutics has collected a data set of 2 billion quantitative binding measurements of small molecules to therapeutic targets, which directly motivates multiparameter generative optimization of molecules conditioned on these data. To this end, we present contrastive optimization for accelerated therapeutic inference (COATI), a pretrained, multimodal encoder-decoder model of druglike chemical space. COATI is constructed without any human biasing of features, using contrastive learning from text and 3D representations of molecules to allow for downstream use with structural models. We demonstrate that COATI possesses many of the desired properties of universal molecular embedding: fixed-dimension, invertibility, autoencoding, accurate regression, and low computation cost. Finally, we present a novel metadynamics algorithm for generative optimization using a small subset of our proprietary data collected for a model protein, carbonic anhydrase, designing molecules that satisfy the multiparameter optimization task of potency, solubility, and drug likeness. This work sets the stage for fully integrated generative molecular design and optimization for small molecules.

Injury outcomes across Canadian trauma systems: a historical cohort study.

PURPOSE: Most North American trauma systems have designated trauma centres (TCs) including level I (ultraspecialized high-volume metropolitan centres), level II (specialized medium-volume urban centres), and/or level III (semirural or rural centres). Trauma system configuration varies across provinces and it is unclear how these differences influence patient distributions and outcomes. We aimed to compare patient case mix, case volumes, and risk-adjusted outcomes of adults with major trauma admitted to designated level I, II, and III TCs across Canadian trauma systems. METHODS: In a national historical cohort study, we extracted data from Canadian provincial trauma registries on major trauma patients treated between 2013 and 2018 in all designated level I, II, or III TCs in British Columbia, Alberta, Quebec, and Nova Scotia; level I and II TCs in New Brunswick; and four TCs in Ontario. We used multilevel generalized linear models to compare mortality and intensive care unit (ICU) admission and competitive risk models for hospital and ICU length of stay (LOS). Ontario could not be included in outcome comparisons because there were no population-based data from this province. RESULTS: The study sample comprised 50,959 patients. Patient distributions in level I and II TCs were similar across provinces but we observed significant differences in case mix and volumes for level III TCs. There was low variation in risk-adjusted mortality and LOS across provinces and TCs but interprovincial and intercentre variation in risk-adjusted ICU admission was high. CONCLUSIONS: Our results suggest that differences in the functional role of TCs according to their designation level across provinces leads to significant variations in the distribution of patients, case volumes, resource use, and clinical outcomes. These results highlight opportunities to improve Canadian trauma care and underline the need for standardized population-based injury data to support national quality improvement efforts.

RéSUMé: OBJECTIF: La plupart des systèmes de traumatologie nord-américains disposent de centres de traumatologie (CT) désignés, y compris de niveau I (centres métropolitains ultraspécialisés à volume élevé), de niveau II (centres urbains spécialisés à volume moyen) et/ou de niveau III (centres semi-ruraux ou ruraux). La configuration des systèmes de traumatologie varie d'une province à l'autre et nous ne savons pas comment ces différences influent sur la répartition de la patientèle et sur les issues. Notre objectif était de comparer le mélange de cas des patient·es, le volume de cas et les issues ajustées en fonction du risque des adultes ayant subi un traumatisme majeur admis·es dans des CT désignés de niveaux I, II et III dans l'ensemble des systèmes de traumatologie canadiens. MéTHODE: Dans une étude de cohorte historique nationale, nous avons extrait des données des registres provinciaux canadiens de traumatologie sur les patient·es ayant subi un traumatisme majeur traité·es entre 2013 et 2018 dans tous les CT désignés de niveau I, II ou III en Colombie-Britannique, en Alberta, au Québec et en Nouvelle-Écosse, les CT de niveau I et II au Nouveau-Brunswick, et dans quatre CT en Ontario. Nous avons utilisé des modèles linéaires généralisés à plusieurs niveaux pour comparer la mortalité, les admissions en unité de soins intensifs (USI) et les modèles de risque compétitif pour la durée du séjour à l'hôpital et à l'USI. L'Ontario n'a pas pu être inclus dans les comparaisons des devenirs parce qu'il n'y avait pas de données démographiques pour cette province. RéSULTATS: L'échantillon de l'étude comptait 50 959 patient·es. La répartition des patient·es dans les CT de niveaux I et II était similaire d'une province à l'autre, mais nous avons observé des différences significatives dans le mélange des cas et les volumes pour les CT de niveau III. Il y avait une faible variation de la mortalité ajustée en fonction du risque et des durées de séjour entre les provinces et les CT, mais la variation interprovinciale et intercentre des admissions à l'USI ajustées en fonction du risque était élevée. CONCLUSION: Nos résultats suggèrent que les différences dans le rôle fonctionnel des CT selon leur niveau de désignation d'une province à l'autre entraînent des variations importantes dans la répartition des patient·es, le nombre de cas, l'utilisation des ressources et les issues cliniques. Ces résultats mettent en évidence les possibilités d'amélioration des soins de traumatologie au Canada et soulignent la nécessité de disposer de données normalisées sur les blessures dans la population pour appuyer les efforts nationaux d'amélioration de la qualité.

The clinical significance of adenomatous polyposis coli (APC) and catenin Beta 1 (CTNNB1) genetic aberrations in patients with melanoma.

BACKGROUND: Melanoma-intrinsic activated ß-catenin pathway, the product of the catenin beta 1 (CTNNB1) gene, has been associated with low/absent tumor-infiltrating lymphocytes, accelerated tumor growth, metastases development, and resistance to anti-PD-L1/anti-CTLA-4 agents in mouse melanoma models. Little is known about the association between the adenomatous polyposis coli (APC) and CTNNB1 gene mutations in stage IV melanoma with immunotherapy response and overall survival (OS). METHODS: We examined the prognostic significance of somatic APC/CTNNB1 mutations in the Cancer Genome Atlas Project for Skin Cutaneous Melanoma (TCGA-SKCM) database. We assessed APC/CTNNB1 mutations as predictors of response to immunotherapies in a clinicopathologically annotated metastatic patient cohort from three US melanoma centers. RESULTS: In the TCGA-SKCM patient cohort (n = 434) presence of a somatic APC/CTNNB1 mutation was associated with a worse outcome only in stage IV melanoma (n = 82, median OS of APC/CTNNB1 mutants vs. wild-type was 8.15 vs. 22.8 months; log-rank hazard ratio 4.20, p = 0.011). APC/CTNNB1 mutation did not significantly affect lymphocyte distribution and density. In the 3-melanoma institution cohort, tumor tissues underwent targeted panel sequencing using two standards of care assays. We identified 55 patients with stage IV melanoma and APC/CTNNB1 genetic aberrations (mut) and 169 patients without (wt). At a median follow-up of more than 25 months for both groups, mut compared with wt patients had slightly more frequent (44% vs. 39%) and earlier (66% vs. 45% within six months from original diagnosis of stage IV melanoma) development of brain metastases. Nevertheless, time-to-development of brain metastases was not significantly different between the two groups. Fortunately, mut patients had similar clinical benefits from PD-1 inhibitor-based treatments compared to wt patients (median OS 26.1 months vs. 29.9 months, respectively, log-rank p = 0.23). Less frequent mutations in the NF1, RAC1, and PTEN genes were seen in the mut compared with wt patients from the 3-melanoma institution cohort. Analysis of brain melanoma tumor tissues from a separate craniotomy patient cohort (n = 55) showed that melanoma-specific, activated ß-catenin (i.e., nuclear localization) was infrequent (n = 3, 6%) and not prognostic in established brain metastases. CONCLUSIONS: APC/CTNNB1 mutations are associated with a worse outcome in stage IV melanoma and early brain metastases independent of tumor-infiltrating lymphocyte density. However, PD1 inhibitor-based treatments provide comparable benefits to both mut and wt patients with stage IV melanoma.

Long-term follow-up and future direction on the management of chronic lymphocytic leukemia/small lymphocytic leukemia.

OBJECTIVE: Chronic lymphocytic leukemia and small lymphocytic lymphoma remain the most prevalent adult leukemia in Western countries. Novel therapeutics have established long-term efficacy and have changed the landscape in patient management. In contrast, novel approaches pose opportunities for patients to be treated for finite durations. In this manuscript, we highlight long-term safety and efficacy data with Bruton's tyrosine kinase inhibitors and combination BCL2 + anti-CD20 therapies. We also offer key considerations for treatment selection and outline ongoing trials which may continue to expand therapeutic options and approaches. DATA SOURCES: An electronic search of the PubMed database was performed to obtain key literature in chronic lymphocytic leukemia and small lymphocytic lymphoma published using the following search terms: chronic lymphocytic leukemia/small lymphocytic lymphoma, Richter syndrome, and histologic transformation. The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types: Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV; Guideline; Randomized Controlled Trial; Meta-Analysis; Systematic Reviews; and Validation Studies. DATA SUMMARY: Chronic lymphocytic leukemia and small lymphocytic lymphoma are different manifestations of the same disease and are managed in much the same way. Bruton's tyrosine kinase inhibitors have demonstrated long and durable efficacy benefits in patients with newly diagnosed chronic lymphocytic leukemia/small lymphocytic lymphoma and in the relapsed/refractory setting. Despite these benefits, long terms adverse events have posed challenges for patients and have led to treatment discontinuations. Additionally, the use of monotherapy Bruton's tyrosine kinase inhibitor's requires chronic use of the medications leading to added financial implications. BCL2 inhibition with venetoclax in combination with anti-CD20 monoclonal antibodies has offered a novel and finite treatment approach in frontline and relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Ongoing clinical trials are in investigating this modality further to enhance durable responses utilizing a combination Bruton's tyrosine kinase inhibitor's and BCL2 inhibitors. CONCLUSION: The treatment armamentarium of chronic lymphocytic leukemia/small lymphocytic lymphoma continues to evolve. Despite the long term, durable responses with Bruton's tyrosine kinase inhibitor's, it is likely that finite treatment durations could become the standard of care as a result of continued, long-term responses.

Zinc-Mediated Transmetalation as a Route to Anionic N-Heterocyclic Olefin Complexes in the p-Block.

Anionic N-heterocyclic olefins (aNHOs) are suited well for the stabilization of low-coordinate inorganic complexes, due to their steric tunability and strong σ- and π-electron donating abilities. In this study, the new two-coordinate zinc complex (MeIPrCH)2Zn (MeIPrCH = [(MeCNDipp)2C═CH]-, Dipp = 2,6-diisopropylphenyl) is shown to participate in a broad range of metathesis reactions with main group element-based halides and hydrides. In the case of the group 14 halides, Cl2E·dioxane (E = Ge and Sn), transmetalation occurs to form dinuclear propellane-shaped cations, [(MeIPrCHE)2(µ-Cl)]+, while the aNHO-capped phosphine ligand MeIPrCH-PPh2 is obtained when (MeIPrCH)2Zn is combined with ClPPh2. Lastly, ZnH2 elimination drives transmetalation between (MeIPrCH)2Zn and hydroboranes and hydroalumanes, leading to Lewis acidic aNHO-supported -boryl and -alane products.

Caring for Indigenous Data to Evaluate the Benefits of Indigenous Environmental Programs.

Advances in open data, big data and data linkage allow us to analyse more data and on a larger scale than ever before. However, this brings with it the challenge of ensuring that Indigenous data sets are used in a way that protects Indigenous rights to that data and maximises benefits for Indigenous peoples. The CARE principles for Indigenous data governance-Collective Benefit, Authority to Control, Responsibility and Ethics-were developed to protect Indigenous data sovereignty, but there are few examples of how to translate these principles into practice. In this paper, we show how these CARE principles can be applied to data collection, integration, analysis and translation practices. Our case study is a project that used data reported by Indigenous ranger groups to capture the multiple benefits of Indigenous land and water management activities. Through this case study, we offer a framework for the design and use of CARE-informed data practices, which can be embedded into project design to enable the ethical and responsible use of Indigenous data to improve Indigenous policies and services. Such practices are critical in the context of ongoing demand for Indigenous data for bureaucratic purposes, and Indigenous interest in using that data to influence management and policy decisions affecting their estates and resources.

p66ShcA functions as a contextual promoter of breast cancer metastasis.

BACKGROUND: The p66ShcA redox protein is the longest isoform of the Shc1 gene and is variably expressed in breast cancers. In response to a variety of stress stimuli, p66ShcA becomes phosphorylated on serine 36, which allows it to translocate from the cytoplasm to the mitochondria where it stimulates the formation of reactive oxygen species (ROS). Conflicting studies suggest both pro- and anti-tumorigenic functions for p66ShcA, which prompted us to examine the contribution of tumor cell-intrinsic functions of p66ShcA during breast cancer metastasis. METHODS: We tested whether p66ShcA impacts the lung-metastatic ability of breast cancer cells. Breast cancer cells characteristic of the ErbB2+/luminal (NIC) or basal (4T1) subtypes were engineered to overexpress p66ShcA. In addition, lung-metastatic 4T1 variants (4T1-537) were engineered to lack endogenous p66ShcA via Crispr/Cas9 genomic editing. p66ShcA null cells were then reconstituted with wild-type p66ShcA or a mutant (S36A) that cannot translocate to the mitochondria, thereby lacking the ability to stimulate mitochondrial-dependent ROS production. These cells were tested for their ability to form spontaneous metastases from the primary site or seed and colonize the lung in experimental (tail vein) metastasis assays. These cells were further characterized with respect to their migration rates, focal adhesion dynamics, and resistance to anoikis in vitro. Finally, their ability to survive in circulation and seed the lungs of mice was assessed in vivo. RESULTS: We show that p66ShcA increases the lung-metastatic potential of breast cancer cells by augmenting their ability to navigate each stage of the metastatic cascade. A non-phosphorylatable p66ShcA-S36A mutant, which cannot translocate to the mitochondria, still potentiated breast cancer cell migration, lung colonization, and growth of secondary lung metastases. However, breast cancer cell survival in the circulation uniquely required an intact p66ShcA S36 phosphorylation site. CONCLUSION: This study provides the first evidence that both mitochondrial and non-mitochondrial p66ShcA pools collaborate in breast cancer cells to promote their maximal metastatic fitness.

Dynamic Neutrophil-to-Lymphocyte Ratio: A Novel Prognosis Measure for Triple-Negative Breast Cancer.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a measure of systemic inflammation and a prognostic factor for multiple malignancies. This study assesses the value of the NLR as an independent prognostic marker in triple-negative breast cancer (TNBC) and explores the association between dynamic NLR changes and patient outcomes. METHODS: The study retrospectively analyzed a prospectively maintained database including patients 18 to 80 years old with TNBC treated at the authors' institution between 2006 to 2016. Clinical and demographic data were collected, including blood test results and treatments received. Age at diagnosis, stage of disease, and NLR scores were tested for association with overall and disease-free survival in uni- and multivariate Cox models. RESULTS: The inclusion criteria were met by 329 women with a median age of 58. Most of the patients had early-stage disease (30.1% with stage 1 and 47% with stage 2 malignancy). An NLR higher than 2.84 at diagnosis was associated with decreased overall survival (hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.023-3.176), whereas an NLR higher than 7.82 at any time during the follow-up period was a strong predictor of 5-year mortality (HR, 10.76; 95% CI, 4.193-26.58), independent of age or stage of disease. Patients who experienced recurrence had a higher NLR than their counterparts during the 6 months before recurrence. The NLR also significantly rose during the final 18 months of life (p < 0.01). CONCLUSION: The NLR is an important prognostic marker in TNBC, both at diagnosis and during the course of the disease. Moreover, dynamic changes in NLR strongly correlate with disease recurrence and the time of death.

Does self-rated health status influence receipt of an annual flu vaccination?

Despite 79,400 deaths due to the influenza (flu) virus during the 2017-18 season, <50% of US adults receive an annual flu vaccination (AFV). Self-rated health status (SRH) is associated with health behavior utilization. The current study aims to determine if an association exists between an individual's SRH and their receipt of an AFV. In the 2017 US Behavioral Risk Factor Surveillance System survey, 39.1% of respondents had received a flu vaccination within the last 12 months. There was a statistically significant difference (p < 0.0001) between the vaccination rates of men (35.7%) and women (42.4%). There was a significant positive association between SRH and AFV for individuals who self-reported an SRH of either "Fair" (AOR 1.19; 95% CI 1.12-1.27) or "Poor" (AOR 1.24; 95% CI 1.14-1.35), compared to those reporting a status of "Excellent". For those reporting an SRH status of "Fair", there was a significant positive association for both men (AOR 1.20; 95% CI 1.10-1.32) and women (AOR 1.17; 95% CI 1.08-1.28). An association was also found for men (AOR 1.203; 95% CI 1.09-1.39) and women (AOR 1.23; 95% CI 1.09-1.399) who reported their SRH as "Poor". Only women showed a significant association (AOR 1.12; 95% CI 1.04-1.20) among those whose SRH was "Good". No association was found for individuals who reported SRH as "Very Good". These findings are of interest to health policy makers as they show there is still work required to convince individuals with a high SRH that they too need to receive an AFV.

Context Aware Data-Driven Retrosynthetic Analysis.

Modern drug discovery is an iterative process relying on hypothesis generation through exploitation of available data and hypothesis testing that produces informative results necessary for subsequent rounds of exploration. In this setting, hypothesis generation consists of designing chemical structures likely to meet the pharmaceutically relevant objectives of the discovery project pursued while hypothesis testing involves the compound synthesis and biological assays to query the hypothesis. While much attention has been placed on effective compound design, it is often the case that hypothesis generation efforts lead to novel chemical structure designs with no established chemical synthesis route. We introduce a chemical context aware data-driven method built upon millions of available reactions, with attractive run-time characteristics, to recommend synthetic routes matching a precedent-derived template. Coupled with modern automated synthesis platforms and available building block collections, the method enables drug discovery researchers to identify easy to interpret and implement routes for target compounds. Results of this in-house computer-aided synthesis platform termed ChemoPrint are presented here demonstrating how such tools can bridge chemical synthesis knowledge with synthetic resources and facilitate hypothesis testing, thereby reducing the time required to complete an idea-to-data drug discovery cycle.

N-Heterocyclic Olefin-Ligated Palladium(II) Complexes as Pre-Catalysts for Buchwald-Hartwig Aminations.

New N-heterocyclic olefins (NHOs) are described with functionalization on the ligand heterocyclic backbone and terminal alkylidene positions. Various PdII -NHO complexes have been formed and their use as pre-catalysts in Buchwald-Hartwig aminations was explored. The most active system for catalytic C-N bond formation between hindered arylamine and arylhalide substrates was accessed by combining a backbone methylated NHO with [Pd(cinnamyl)Cl]2 in the presence of NaOtBu as a base. In these active systems evidence suggests that catalysis is mediated by colloidal palladium metal, highlighting a different coordination ability of NHOs in comparison with commonly used N-heterocyclic carbene co-ligands.

Emerging patterns of somatic mutations in cancer.

Recent advances in technological tools for massively parallel, high-throughput sequencing of DNA have enabled the comprehensive characterization of somatic mutations in a large number of tumour samples. In this Review, we describe recent cancer genomic studies that have assembled emerging views of the landscapes of somatic mutations through deep-sequencing analyses of the coding exomes and whole genomes in various cancer types. We discuss the comparative genomics of different cancers, including mutation rates and spectra, as well as the roles of environmental insults that influence these processes. We highlight the developing statistical approaches that are used to identify significantly mutated genes, and discuss the emerging biological and clinical insights from such analyses, as well as the future challenges of translating these genomic data into clinical impacts.

A patient focused relationship for specialists in laboratory medicine.

Technological change is driving individualized healthcare delivery including laboratory medicine. Ensuring patients gain from their empowerment it is essential that they access data that enables them to utilize reliable information. The potential difficulties of comprehension, information retention and imperfect modes of communication can significantly impair utilization of information by patients. Support for understanding and decision-making needs to be clinically competent and integrated within the healthcare team. Specialists in laboratory medicine are well placed to undertake such a role, the issues around this are explored and proposals for better direct engagement with patients made.

Quality evaluation of smartphone applications for laboratory medicine.

Background Many of the mobile applications (apps) used for delivering health interventions involve laboratory medicine data. This survey was conducted to search the online market for health apps that manage laboratory medicine data. The aim was to review them and perform a quality evaluation. Methods Apps search criteria were "Lab results blood work", "Lab results", and "Health apps". After the stepwise exclusion process, 52 selected apps were downloaded and analyzed. For review and content analysis of the apps, a multidimensional tool for classifying and rating the quality of mobile health apps - Mobile App Rating Scale (MARS), was used. Results Selected apps were classified into five categories according to their intended use by patients or physicians, and the type of data engaged. Spearman's correlation analysis found significant correlations between MARS individual scoring items, as with the subjective quality and number of technical aspects. Kruskal-Wallis analysis showed a significant difference in the number of technical aspects employed, MARS engagement and informational quality score items, total score, and subjective quality. The lowest values for all of these items were in the category of apps designed for patients, and the post hoc test showed that the difference was statistically significant between this and the values in all other categories. Conclusions Apps designed for patients, are of the poorest quality, considering the total quality of the content and information they provide, estimated using the MARS tool. This estimation needs to be validated for laboratory medicine apps, and eventually modified after consideration of specific quality benchmarks.

Role of laboratory medicine in collaborative healthcare.

Healthcare delivery and responsibility is changing. Patient-centered care is gaining international acceptance with the patient taking greater responsibility for his/her health and sharing decision making for the diagnosis and management of illness. Laboratory medicine must embrace this change and work in a tripartite collaboration with patients and with the clinicians who use clinical laboratory services. Improved communication is the key to participation, including the provision of educational information and support. Knowledge management should be targeted to each stakeholder group. As part of collaborative healthcare clinical laboratory service provision needs to be more flexible and available, with implications for managers who oversee the structure and governance of the service. Increased use of managed point of care testing will be essential. The curriculum content of laboratory medicine training programs will require trainees to undertake practice-based learning that facilitates interaction with patients, clinicians and managers. Continuing professional development for specialists in laboratory medicine should also embrace new sources of information and opportunities for collaborative healthcare.

Melanoma genome sequencing reveals frequent PREX2 mutations.

Melanoma is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life. To obtain a comprehensive genomic view of melanoma in humans, we sequenced the genomes of 25 metastatic melanomas and matched germline DNA. A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-ultraviolet-exposed hairless skin of the extremities (3 and 14 per megabase (Mb) of genome), intermediate in those originating from hair-bearing skin of the trunk (5-55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb). Analysis of whole-genome sequence data identified PREX2 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2)--a PTEN-interacting protein and negative regulator of PTEN in breast cancer--as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumour formation of immortalized human melanocytes in vivo. Thus, whole-genome sequencing of human melanoma tumours revealed genomic evidence of ultraviolet pathogenesis and discovered a new recurrently mutated gene in melanoma.

A traumatic tale of two cities: does EMS level of care and transportation model affect survival in patients with trauma at level 1 trauma centres in two neighbouring Canadian provinces?

BACKGROUND: Two distinct Emergency Medical Services (EMS) systems exist in Atlantic Canada. Nova Scotia operates an Advanced Emergency Medical System (AEMS) and New Brunswick operates a Basic Emergency Medical System (BEMS). We sought to determine if survival rates differed between the two systems. METHODS: This study examined patients with trauma who were transported directly to a level 1 trauma centre in New Brunswick or Nova Scotia between 1 April 2011 and 31 March 2013. Data were extracted from the respective provincial trauma registries; the lowest common Injury Severity Score (ISS) collected by both registries was ISS≥13. Survival to hospital and survival to discharge or 30 days were the primary endpoints. A separate analysis was performed on severely injured patients. Hypothesis testing was conducted using Fisher's exact test and the Student's t-test. RESULTS: 101 cases met inclusion criteria in New Brunswick and were compared with 251 cases in Nova Scotia. Overall mortality was low with 93% of patients surviving to hospital and 80% of patients surviving to discharge or 30 days. There was no difference in survival to hospital between the AEMS (232/251, 92%) and BEMS (97/101, 96%; OR 1.98, 95% CI 0.66 to 5.99; p=0.34) groups. Furthermore, when comparing patients with more severe injuries (ISS>24) there was no significant difference in survival (71/80, 89% vs 31/33, 94%; OR 1.96, 95% CI 0.40 to 9.63; p=0.50). CONCLUSION: Overall survival to hospital was the same between advanced and basic Canadian EMS systems. As numbers included are low, individual case benefit cannot be excluded.

A survey of patients' views from eight European countries of interpretive support from Specialists in Laboratory Medicine.

BACKGROUND: There is increasing interest in direct patient engagement including receiving their laboratory medicine results. We previously established an appetite for Specialists in Laboratory Medicine to support patients in understanding results. The aim of this study was to establish whether patients agreed with such an approach, determined through surveying views in eight European countries. METHODS: A standardized five-question survey was administered across eight European countries to a total of 1084 individuals attending medical outpatient clinics, with 100 patients each in Poland, Serbia, Netherlands, Turkey and Czech Republic, 101 in Estonia, 116 in Denmark and 367 in Norway. The responses across countries were compared using the chi-square test (p<0.05). RESULTS: Patients wanting their results ranged from 50% to 94% (mean 65%) of those responding positively, a mean of 72% wanted additional information with their results; direct receipt was preferred over referral to a website. Specialists in Laboratory Medicine providing such information were acceptable to a mean of 62% of those respondents wishing their results; in countries where payment was possible, there was little interest in making additional payment for such a service. CONCLUSIONS: A clear proportion of patients are interested in receiving their laboratory medicine results, the majority with explanatory notes; a role for Specialists in Laboratory Medicine is acceptable and raises the potential for direct engagement by such specialists with patients offering a new paradigm for the provision of laboratory medicine activities.