The DESAM toolbox: spectral analysis of musical audio

International audienceIn this paper is presented the DESAM Toolbox, a set of Matlab functions dedicated to the estimation of widely used spectral models for music signals. Although those models can be used in Music Information Retrieval (MIR) tasks, the core functions of the toolbox do not focus on any specific application. It is rather aimed at providing a range of state-of-the-art signal processing tools that decompose music files according to different signal models, giving rise to different ``mid-level'' representations. After motivating the need for such a toolbox, this paper offers an overview of the overall organization of the toolbox, and describes all available functionalities

Thresholds of Contaminants: A Synthesis

A fundamental problem in ecotoxicology is the prediction of long term population and ecosystem-level effects of contaminant exposure based on dose response data of few individuals obtained over a short time period. In addition, environmental fluctuations will always affect significantly the population/ecosystem resilience. However, these fluctuations are not taken into account under dose-response experiments on individuals. In the Thresholds project we have analyzed some of these questions by using experiments, data analysis tools and modelling approaches. Several important finding may be summarized as follows: 1 Molecular level effects are detected even at concentrations that did not affect the macroscopic end point studied, i.e. growth rate. 2 Natural populations are more sensitive that populations in cultures. 3 There are differences for the same species at different environments, e.g. Mediterranean, Black Seas and Atlantic Ocean. 4 The environmental conditions and the time of release of the contaminant cause a variability of the response at ecosystem level that can reach 50%. 5 At the actual level of knowledge it is difficult to assess if the legal approach, based on the precautionary principle, is over or under conservative, when considering molecular and its long term effects, the combined effects of mixtures and the environmental fluctuations that affect all ecosystems. 6 A similar colour code to the one adopted for biological quality elements should be adopted for the definition of EQS, with values higher than the EQS as orange (poor). This will allow assessing contamination trends and an early detection of a chemical contamination problems. 7 In aquatic environments ecosystem experience the combined effects of mixtures. Ecotoxicological risk assessment should be performed taking this aspect into account. However, with the amount of new chemicals being produced and the detection limits required it is clear that new integrated indicators are necessary. Limiting the levels of certain chemicals in the environment is one step to improve ecosystem health but alone it will not prevent further deterioration. 8 Due to practical limitations, knowledge on ecotoxicology is only available for a small fraction of the anthropogenic chemical pressure. The importance of this simplification has not been comprehensibly assessed and introduce uncertainty in the appropriate outcome of current legislation and managing practices.JRC.H.5-Rural, water and ecosystem resource

Evaluación de la respuesta serológica contra IBR a partir de la utilización de vacunas polivalentes disponibles en el mercado

La Rinotraqueítis infecciosa bovina (IBR) es una enfermedad de distribución mundial que provoca grandes pérdidas económicas en nuestro país y el mundo. En la provincia de La Pampa se ha reportado su presencia y amplia distribución territorial. En general la prevención de IBR ha estado centrada en la utilización de vacunas polivalentes. El objetivo del presente trabajo fue evaluar la respuesta serológica a través de los niveles de anticuerpos presentes. Para ello se utilizaron 3 vacunas comerciales polivalentes que contenían en su formulación Herpesvirus bovino tipo 1 (BVH1) inactivado. Se utilizaron 4 grupos de terneros. G1 estuvo integrado por 14 animales, G2 y G3 por 13 animales y G4 o control (-) por 9 animales. Los animales fueron vacunados en dos oportunidades con un intervalo de 21 días. Para la detección de anticuerpos se utilizó un kit de ELISA. Al finalizar el ensayo al día 42 el porcentaje de animales que presentaron anticuerpos vacunales contra IBR fue del 42,8%, 61,5% y 38,4% para los grupos G1, G2 y G3 respectivamente y de 0% para los animales de G4 o grupo control (-). Las medias geométricas del IRPC (Índice Relativo x 100) en la misma fecha fueron de 16,31; 27,7 y 15,12 para los grupos G1, G2 y G3 respectivamente. Las vacunas utilizadas desarrollaron anticuerpos contra IBR en todos los grupos inoculados existiendo diferencias en el porcentaje de animales positivos de cada grupo. Los niveles de anticuerpos generados por las diferentes vacunas no presentaron diferencias significativas entre sí. Por último, se encontraron diferencias significativas entre el nivel de anticuerpos generado por las vacunas y los niveles obtenidos por pasaje viral.Infectious Bovine Rhinotracheitis (IBR) is a worldwidedisease which causes great economic losses in Argentina and around the world. Its presence and high prevalence 3have been reported in the province of La Pampa. IBR prevention strategy has mostly been focused on the use of polyvalent vaccines. The objective of our research was to evaluate the serological response, assessing antibodieslevels applyingthree polyvalent commercial vaccines containing inactivated bovine herpesvirus type 1 (BVH1). To that aim, four groups of calves were used: G1 consisted of 14 animals, G2 and G3 of13 animals,and negative controlconsistedof9 animals. The animals were vaccinated twice with an interval of 21 days. Antibodies levelswere measured by means of ELISA. At the end of the trial, the percentage of animals in each group that showed vaccinal antibodies against IBR were: 42.8%, 61.5% and 38.4% for G1, G2 and G3 respectively,and 0% for G4 or negativecontrolgroup. The geometric means of the IRPC (Relative Index x 100) on the same date were 16.31; 27.7 and 15.12 for groups G1, G2 and G3 respectively. The vaccines used,developed antibodies in all the inoculated groups, with differencesin the percentage of positive animalsin each group. The levels of antibodies generated by the different vaccines did not present significant differences between them. Finally, significant differences were found between the levels of antibodies generated by the vaccines and the levels obtained by viral passage.AER Victorica, INTAFil: Lux, Juan. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Anguil. Agencia de Extensión Rural Victorica; ArgentinaFil: Gimenez, Hugo. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Anguil; ArgentinaFil: Torrado, Juan. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Anguil. Agencia de Extensión Rural Victorica; ArgentinaFil: Echeveste, Oscar. Escuela Provincial Agrotécnica “Florencio Peirone”. Victorica, La Pampa. ArgentinaFil: Fort, Marcelo Cristián. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Anguil; Argentin

Endoscopical and pathological dissociation in severe colitis induced by immune-checkpoint inhibitors

Checkpoint inhibitors have improved the survival of patients with advanced tumors and show a manageable toxicity profile. However, auto-immune colitis remains a relevant side effect, and combinations of anti-PD1/PDL1 and anti-CTLA-4 increase its incidence and severity. Here, we report the case of a 50-year-old patient diagnosed with stage IV cervical cancer that relapsed following radical surgery, external radiation/brachytherapy and standard chemotherapy. She was subsequently treated with Nivolumab and Ipilimumab combination and developed grade 2 colitis presenting a dissociation between endoscopic and pathological findings. At cycle 10 the patient reported grade 3 diarrhea and abdominal discomfort, without blood or mucus in the stools. Immunotherapy was withheld and a colonoscopy was performed, showing normal mucosa in the entire colon. Puzzlingly, histologic evaluation of randomly sampled mucosal biopsy of the distal colon showed an intense intraepithelial lymphocyte infiltration with crypt loss and some regenerating crypts with a few apoptotic bodies set in a chronically inflamed lamina propria, consistent with the microscopic diagnosis of colitis. Treatment with methylprednisolone 2 mg/kg was initiated which led to a decrease in the number of stools to grade 1. Additional investigations to exclude other causes of diarrhea rendered negative results. The patient experienced a major partial response and, following the resolution of diarrhea, she was re-challenged again with immunotherapy, with the reappearance of grade 2 diarrhea, leading to permanent immunotherapy interruption. We conclude and propose that performing random colonic biopsies should be considered in cases of immune checkpoint-associated unexplained diarrhea, even when colonoscopy shows macroscopically normal colonic mucosa inflammatory lesions

Heterogenous presence of neutrophil extracellular traps in human solid tumours is partially dependent on IL-8

Neutrophil extracellular traps (NETs) are webs of extracellular nuclear DNA extruded by dying neutrophils infiltrating tissue. NETs constitute a defence mechanism to entrap and kill fungi and bacteria. Tumours induce the formation of NETs to the advantage of the malignancy via a variety of mechanisms shown in mouse models. Here, we investigated the presence of NETs in a variety of human solid tumours and their association with IL-8 (CXCL8) protein expression and CD8+ T-cell density in the tumour microenvironment. Multiplex immunofluorescence panels were developed to identify NETs in human cancer tissues by co-staining with the granulocyte marker CD15, the neutrophil marker myeloperoxidase and citrullinated histone H3 (H3Cit), as well as IL-8 protein and CD8+ T cells. Three ELISA methods to detect and quantify circulating NETs in serum were optimised and utilised. Whole tumour sections and tissue microarrays from patients with non-small cell lung cancer (NSCLC; n = 14), bladder cancer (n = 14), melanoma (n = 11), breast cancer (n = 31), colorectal cancer (n = 20) and mesothelioma (n = 61) were studied. Also, serum samples collected retrospectively from patients with metastatic melanoma (n = 12) and NSCLC (n = 34) were ELISA assayed to quantify circulating NETs and IL-8. NETs were detected in six different human cancer types with wide individual variation in terms of tissue density and distribution. At least in NSCLC, bladder cancer and metastatic melanoma, NET density positively correlated with IL-8 protein expression and inversely correlated with CD8+ T-cell densities. In a series of serum samples from melanoma and NSCLC patients, a positive correlation between circulating NETs and IL-8 was found. In conclusion, NETs are detectable in formalin-fixed human biopsy samples from solid tumours and in the circulation of cancer patients with a considerable degree of individual variation. NETs show a positive association with IL-8 and a trend towards a negative association with CD8+ tumour-infiltrating lymphocytes

Depth of Response in Multiple Myeloma: A Pooled Analysis of Three PETHEMA/GEM Clinical Trials

[EN] Purpose—To perform a critical analysis on the impact of depth of response in newly diagnosed multiple myeloma (MM). Patients and Methods—Data were analyzed from 609 patients who were enrolled in the GEM (Grupo Español de Mieloma) 2000 and GEM2005MENOS65 studies for transplant-eligible MM and the GEM2010MAS65 clinical trial for elderly patients with MM who had minimal residual disease (MRD) assessments 9 months after study enrollment. Median follow-up of the series was 71 months. Results—Achievement of complete remission (CR) in the absence of MRD negativity was not associated with prolonged progression-free survival (PFS) and overall survival (OS) compared with near-CR or partial response (median PFS, 27, 27, and 29 months, respectively; median OS, 59, 64, and 65 months, respectively). MRD-negative status was strongly associated with prolonged PFS (median, 63 months; P < .001) and OS (median not reached; P < .001) overall and in subgroups defined by prior transplantation, disease stage, and cytogenetics, with prognostic superiority of MRD negativity versus CR particularly evident in patients with high-risk cytogenetics. Accordingly, Harrell C statistics showed higher discrimination for both PFS and OS in Cox models that included MRD (as opposed to CR) for response assessment. Superior MRD-negative rates after different induction regimens anticipated prolonged PFS. Among 34 MRD-negative patients with MM and a phenotypic pattern of bone marrow involvement similar to monoclonal gammopathy of undetermined significance at diagnosis, the probability of “operational cure” was high; median PFS was 12 years, and the 10-year OS rate was 94%. Conclusion—Our results demonstrate that MRD-negative status surpasses the prognostic value of CR achievement for PFS and OS across the disease spectrum, regardless of the type of treatment or patient risk group. MRD negativity should be considered as one of the most relevant end points for transplant-eligible and elderly fit patients with MM

Mutational screening of newly diagnosed multiple myeloma patients by deep targeted sequencing

S

Differentiation stage of myeloma plasma cells: biological and clinical significance

[EN] The notion that plasma cells (PCs) are terminally differentiated has prevented intensive research in multiple myeloma (MM) about their phenotypic plasticity and differentiation. Here, we demonstrated in healthy individuals (n = 20) that the CD19 − CD81 expression axis identifies three bone marrow (BM)PC subsets with distinct age-prevalence, proliferation, replication-history, immunoglobulin-production, and phenotype, consistent with progressively increased differentiation from CD19+CD81+ into CD19 − CD81+ and CD19 − CD81 − BMPCs. Afterwards, we demonstrated in 225 newly diagnosed MM patients that, comparing to normal BMPC counterparts, 59% had fully differentiated (CD19 − CD81 −) clones, 38% intermediate-differentiated (CD19 − CD81+) and 3% less-differentiated (CD19+CD81+) clones. The latter patients had dismal outcome, and PC differentiation emerged as an independent prognostic marker for progression-free (HR: 1.7; P = 0.005) and overall survival (HR: 2.1; P = 0.006). Longitudinal comparison of diagnostic vs minimal-residual-disease samples (n = 40) unraveled that in 20% of patients, less-differentiated PCs subclones become enriched after therapy-induced pressure. We also revealed that CD81 expression is epigenetically regulated, that less-differentiated clonal PCs retain high expression of genes related to preceding B-cell stages (for example: PAX5), and show distinct mutation profile vs fully differentiated PC clones within individual patients. Together, we shed new light into PC plasticity and demonstrated that MM patients harbouring less-differentiated PCs have dismal survival, which might be related to higher chemoresistant potential plus different molecular and genomic profiles

Multiple Myeloma Treatment in Real-world Clinical Practice : Results of a Prospective, Multinational, Noninterventional Study

Funding Information: The authors would like to thank all patients and their families and all the EMMOS investigators for their valuable contributions to the study. The authors would like to acknowledge Robert Olie for his significant contribution to the EMMOS study. Writing support during the development of our report was provided by Laura Mulcahy and Catherine Crookes of FireKite, an Ashfield company, a part of UDG Healthcare plc, which was funded by Millennium Pharmaceuticals, Inc, and Janssen Global Services, LLC. The EMMOS study was supported by research funding from Janssen Pharmaceutical NV and Millennium Pharmaceuticals, Inc. Funding Information: The authors would like to thank all patients and their families and all the EMMOS investigators for their valuable contributions to the study. The authors would like to acknowledge Robert Olie for his significant contribution to the EMMOS study. Writing support during the development of our report was provided by Laura Mulcahy and Catherine Crookes of FireKite, an Ashfield company, a part of UDG Healthcare plc, which was funded by Millennium Pharmaceuticals, Inc, and Janssen Global Services, LLC. The EMMOS study was supported by research funding from Janssen Pharmaceutical NV and Millennium Pharmaceuticals, Inc. Funding Information: M.M. has received personal fees from Janssen, Celgene, Amgen, Bristol-Myers Squibb, Sanofi, Novartis, and Takeda and grants from Janssen and Sanofi during the conduct of the study. E.T. has received grants from Janssen and personal fees from Janssen and Takeda during the conduct of the study, and grants from Amgen, Celgene/Genesis, personal fees from Amgen, Celgene/Genesis, Bristol-Myers Squibb, Novartis, and Glaxo-Smith Kline outside the submitted work. M.V.M. has received personal fees from Janssen, Celgene, Amgen, and Takeda outside the submitted work. M.C. reports honoraria from Janssen, outside the submitted work. M. B. reports grants from Janssen Cilag during the conduct of the study. M.D. has received honoraria for participation on advisory boards for Janssen, Celgene, Takeda, Amgen, and Novartis. H.S. has received honoraria from Janssen-Cilag, Celgene, Amgen, Bristol-Myers Squibb, Novartis, and Takeda outside the submitted work. V.P. reports personal fees from Janssen during the conduct of the study and grants, personal fees, and nonfinancial support from Amgen, grants and personal fees from Sanofi, and personal fees from Takeda outside the submitted work. W.W. has received personal fees and grants from Amgen, Celgene, Novartis, Roche, Takeda, Gilead, and Janssen and nonfinancial support from Roche outside the submitted work. J.S. reports grants and nonfinancial support from Janssen Pharmaceutical during the conduct of the study. V.L. reports funding from Janssen Global Services LLC during the conduct of the study and study support from Janssen-Cilag and Pharmion outside the submitted work. A.P. reports employment and shareholding of Janssen (Johnson & Johnson) during the conduct of the study. C.C. reports employment at Janssen-Cilag during the conduct of the study. C.F. reports employment at Janssen Research and Development during the conduct of the study. F.T.B. reports employment at Janssen-Cilag during the conduct of the study. The remaining authors have stated that they have no conflicts of interest. Publisher Copyright: © 2018 The AuthorsMultiple myeloma (MM) remains an incurable disease, with little information available on its management in real-world clinical practice. The results of the present prospective, noninterventional observational study revealed great diversity in the treatment regimens used to treat MM. Our results also provide data to inform health economic, pharmacoepidemiologic, and outcomes research, providing a framework for the design of protocols to improve the outcomes of patients with MM. Background: The present prospective, multinational, noninterventional study aimed to document and describe real-world treatment regimens and disease progression in multiple myeloma (MM) patients. Patients and Methods: Adult patients initiating any new MM therapy from October 2010 to October 2012 were eligible. A multistage patient/site recruitment model was applied to minimize the selection bias; enrollment was stratified by country, region, and practice type. The patient medical and disease features, treatment history, and remission status were recorded at baseline, and prospective data on treatment, efficacy, and safety were collected electronically every 3 months. Results: A total of 2358 patients were enrolled. Of these patients, 775 and 1583 did and did not undergo stem cell transplantation (SCT) at any time during treatment, respectively. Of the patients in the SCT and non-SCT groups, 49%, 21%, 14%, and 15% and 57%, 20%, 12% and 10% were enrolled at treatment line 1, 2, 3, and ≥ 4, respectively. In the SCT and non-SCT groups, 45% and 54% of the patients had received bortezomib-based therapy without thalidomide/lenalidomide, 12% and 18% had received thalidomide/lenalidomide-based therapy without bortezomib, and 30% and 4% had received bortezomib plus thalidomide/lenalidomide-based therapy as frontline treatment, respectively. The corresponding proportions of SCT and non-SCT patients in lines 2, 3, and ≥ 4 were 45% and 37%, 30% and 37%, and 12% and 3%, 33% and 27%, 35% and 32%, and 8% and 2%, and 27% and 27%, 27% and 23%, and 6% and 4%, respectively. In the SCT and non-SCT patients, the overall response rate was 86% to 97% and 64% to 85% in line 1, 74% to 78% and 59% to 68% in line 2, 55% to 83% and 48% to 60% in line 3, and 49% to 65% and 36% and 45% in line 4, respectively, for regimens that included bortezomib and/or thalidomide/lenalidomide. Conclusion: The results of our prospective study have revealed great diversity in the treatment regimens used to manage MM in real-life practice. This diversity was linked to factors such as novel agent accessibility and evolving treatment recommendations. Our results provide insight into associated clinical benefits.publishersversionPeer reviewe