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Background As the use of nanopore sequencing for metagenomic analysis increases, tools capable of performing long-read taxonomic classification (ie. determining the composition of a sample) in a fast and accurate manner are needed. Existing tools were either designed for short-read data (eg. Centrifuge), take days to analyse modern sequencer outputs (eg. MetaMaps) or suffer from suboptimal accuracy (eg. CDKAM). Additionally, all tools require command line expertise and do not scale in the cloud. Results We present BugSeq, a novel, highly accurate metagenomic classifier for nanopore reads. We evaluate BugSeq on simulated data, mock microbial communities and real clinical samples. On the ZymoBIOMICS Even and Log communities, BugSeq (F1 = 0.95 at species level) offers better read classification than MetaMaps (F1 = 0.89–0.94) in a fraction of the time. BugSeq significantly improves on the accuracy of Centrifuge (F1 = 0.79–0.93) and CDKAM (F1 = 0.91–0.94) while offering competitive run times. When applied to 41 samples from patients with lower respiratory tract infections, BugSeq produces greater concordance with microbiological culture and qPCR compared with “What’s In My Pot” analysis. Conclusion BugSeq is deployed to the cloud for easy and scalable long-read metagenomic analyses. BugSeq is freely available for non-commercial use at https://bugseq.com/free.

INTRODUCTION: Hemophilia A is an inherited disorder that is characterized by decreased or absent factor (F)VIII and an increased risk of bleeding. Clinical presentation of the severe form of the disease includes spontaneous bleeding into the joints and muscles, while patients with milder forms usually exhibit trauma-associated bleeding. The treatment of hemophilia aims to prevent bleeding. A number of clotting FVIII concentrates are available for managing hemophilia A, which have different safety and efficacy characteristics. Advancements in biotechnology have enabled development of recombinant factor concentrates, which thus minimize the risk of transmitting infectious diseases. Turoctocog alfa (NovoEight®, Novo Nordisk A/S, Bagsvaerd, Denmark) was the first third-generation B-domain truncated recombinant FVIII. AREAS COVERED: The manuscript describes the characteristics of turoctocog alfa, as well as its efficacy and safety for prophylaxis and on-demand treatment for patients with severe hemophilia A without inhibitors. EXPERT OPINION: In clinical trials, turoctocog alfa has demonstrated very good efficacy and safety for the prophylaxis and on-demand treatment of hemophilia A patients, as well as high hemostatic activity during surgery and in managing bleeding episodes. Post-marketing studies and real-life data are anticipated to further reinforce the value of long-term prophylaxis, and estimate the incidence of inhibitors to FVIII.

Many cities engage in diverse experimentation, innovation, and development activities with a broad variety of environments and stakeholders to the benefit of citizens, companies, municipalities, and other organizations. Hence, this article discusses such engagement in terms of next-generation living lab networks in the city context. In so doing, the study contributes to the discussion on living labs by introducing a framework of collaborative innovation networks in cities and suggesting a typology of third-generation living labs. Our framework is characterized by diverse platforms and participation approaches, resulting in four distinctive modes of collaborative innovation networks where the city is: i) a provider, ii) a neighbourhood participator, iii) a catalyst, or iv) a rapid experimenter. The typology is based on an analysis of 118 interviews with participants in six Finnish cities and reveals various ways to organize innovation activities in the city context. In particular, cities can benefit from innovation networks by simultaneously exploiting multiple platforms such as living labs for innovation. We conclude by discussing implications to theory and practice, and suggesting directions for future research.

S Rico1,2, RM Antonijoan1,3, MJ Barbanoj1,2,31Centre d’lnvestigació de Medicaments, Institut de Recerca; Servei de Farmacologia Clínica, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 2Departament de Farmacologia i Terapèutica, Universitat Autònoma de Barcelona, Barcelona, Spain; 3Centro de investigación Biomédica en Red de Salud Mental CIBERSAM, SpainAbstract: In 2003 a consensus group on new-generation antihistamines (CONGA) defined the characteristics required for a third-generation H1 antihistamine as there had been much controversy about this issue since the early 1990s. One of the antihistamines that had been claimed to belong to such a group is the second-generation antihistamine, ebastine. The objective of this review is to analyze the pharmacology of ebastine, in light of the CONGA recommendations for the development of new-generation antihistamines: (1) anti-inflammatory properties, (2) potency, efficacy and effectiveness, (3) lack of cardiotoxicity, (4) lack of drug interactions, (5) lack of CNS effects, and (6) pharmacological approach. Ebastine seems to have anti-inflammatory properties that help to ameliorate nasal congestion, though this has not yet been conclusively demonstrated. Its pharmacological–therapeutic profile does not differ greatly from that of other second-generation antihistamines. Its cardiac safety has been widely assessed and no cardiac toxicity has been found at therapeutic doses despite initial concerns. The risk of potentially relevant drug interactions has been investigated and ruled out. Ebastine does not produce sedation at therapeutic doses and drug interaction studies with classical CNS depressants have not demonstrated a synergistic effect. Pharmacologically, ebastine is an H1 inverse agonist. Perhaps the answer to the quest for new-generation antihistamines lies not only in H1 but in a combined approach with other histamine receptors.Keywords: ebastine, antihistamines, third-generation, CONGA, allergy

Introduction There is no curative treatment available for patients with chemotherapy relapsed or refractory CD19+ B cells-derived acute lymphoblastic leukaemia (r/r B-ALL). Although CD19-targeting second-generation (2nd-G) chimeric antigen receptor (CAR)-modified T cells carrying CD28 or 4-1BB domains have demonstrated potency in patients with advanced B-ALL, these 2 signalling domains endow CAR-T cells with different and complementary functional properties. Preclinical results have shown that third-generation (3rd-G) CAR-T cells combining 4-1BB and CD28 signalling domains have superior activation and proliferation capacity compared with 2nd-G CAR-T cells carrying CD28 domain. The aim of the current study is therefore to investigate the safety and efficacy of 3rd-G CAR-T cells in adults with r/r B-ALL. Methods and analysis This study is a phase I clinical trial for patients with r/r B-ALL to test the safety and preliminary efficacy of 3rd-G CAR-T cells. Before receiving lymphodepleting conditioning regimen, the peripheral blood mononuclear cells from eligible patients will be leukapheresed, and the T cells will be purified, activated, transduced and expanded ex vivo. On day 6 in the protocol, a single dose of 1 million CAR-T cells per kg will be administrated intravenously. The phenotypes of infused CAR-T cells, copy number of CAR transgene and plasma cytokines will be assayed for 2 years after CAR-T infusion using flow cytometry, real-time quantitative PCR and cytometric bead array, respectively. Moreover, several predictive plasma cytokines including interferon-γ, interleukin (IL)-6, IL-8, Soluble Interleukin (sIL)-2R-α, solubleglycoprotein (sgp)130, sIL-6R, Monocyte chemoattractant protein (MCP1), Macrophage inflammatory protein (MIP1)-α, MIP1-β and Granulocyte-macrophage colony-stimulating factor (GM-CSF), which are highly associated with severe cytokine release syndrome (CRS), will be used to forecast CRS to allow doing earlier intervention, and CRS will be managed based on a revised CRS grading system. In addition, patients with grade 3 or 4 neurotoxicities or persistent B-cell aplasia will be treated with dexamethasone (10 mg intravenously every 6 hours) or IgG, respectively. Descriptive and analytical analyses will be performed. Ethics and dissemination Ethical approval for the study was granted on 10 July 2014 (YLJS-2014-7-10). Written informed consent will be taken from all participants. The results of the study will be reported, through peer-reviewed journals, conference presentations and an internal organisational report. Trial registration number NCT02186860.

To summarise the advances in the hormonal treatment of post-menopausal metastatic breast cancer, this paper reviews the published literature regarding the randomised trials comparing aromatase inhibitors (AIs) versus tamoxifen as a first-line therapeutic choice, or AIs versus megestrole acetate (MEG) as a second-line option. The pooled analysis of these authors on AI versus MEG as a second-line option for post-menopausal metastatic breast cancer suggested that AIs do not add any significant benefit over MEG in terms of overall response rate (ORR) and time to progression. According to the Cochrane Database, use of an AI as a second-line therapy versus any other endocrine therapy (mostly MEG) has shown a significant benefit in terms of overall survival, but not for progression-free survival, clinical benefit (CB) or ORR. Concerning the authors' comparisons between AIs versus tamoxifen as a first-line endocrine option in post-menopausal women with metastatic breast carcinoma, AIs seem to be superior to tamoxifen, with a significant benefit in terms of ORR, CB and time to progression being observed in favour of AIs over tamoxifen with fixed effects estimates. According to the Cochrane Database, there was an advantage to the use of AIs over tamoxifen in terms of progression-free survival and CB, but not for overall survival or ORR. With regards to toxicity, AIs show similar levels of hot flushes and arthralgia, increased risks of nausea, diarrhoea and vomiting, but a decreased risk of vaginal bleeding and thromboembolic events compared with other endocrine therapies. Weight gain, dyspnoea and peripheral oedema seem to be more frequent with MEG. At present, there is no proved overall survival difference in patients who are treated first with an AI and then with tamoxifen compared with the opposite sequence. In the metastatic setting, results are limited and are based on retrospective analyses.

Summary Background In approximately the year 2000, the results of a number of important studies of non-small-cell lung cancer (NSCLC) were published. Methods Between July 1992 and December 2003, 223 patients with NSCLC aged ≥70 years received chemotherapy alone as their initial treatment at the National Cancer Center Hospital East. These patients were divided into 2 groups: those that began treatment between 1992 and 1999 (group A) and between 2000 and 2003 (group B). The details of chemotherapy regimens and outcomes were compared. Results In group A, 83% of patients received platinum-based chemotherapy, two-thirds of these regimens comprised platinum plus second-generation combination chemotherapy. In contrast, although 55% of patients received platinum-based chemotherapy in group B, 41% of patients received non-platinum-based chemotherapy. Among patients in group B, performance status was significantly associated with the selection of platinum-based or non-platinum-based chemotherapy; age was marginally associated with this selection. Median survival time (MST), 1-year survival rate, and 2-year survival rate were 6.7 months, 14%, and 7%, respectively, in group A, and 8.1 months, 35%, and 20% in group B (p = 0.0109). Multivariate analysis revealed that clinical stage and administration of salvage chemotherapy were independent prognostic factors. Conclusions In and after the year 2000, chemotherapy regimens changed greatly and survival of elderly patients significantly improved in our institute, and this improvement appears to be attributable mostly to the effect of salvage chemotherapy. These results suggest that even elderly patients should be offered salvage chemotherapy regardless of age, if possible.