The genomic profiling of high-risk smoldering myeloma patients treated with an intensive strategy unveils potential markers of resistance and progression.

Smoldering multiple myeloma (SMM) precedes multiple myeloma (MM). The risk of progression of SMM patients is not uniform, thus different progression-risk models have been developed, although they are mainly based on clinical parameters. Recently, genomic predictors of progression have been defined for untreated SMM. However, the usefulness of such markers in the context of clinical trials evaluating upfront treatment in high-risk SMM (HR SMM) has not been explored yet, precluding the identification of baseline genomic alterations leading to drug resistance. For this reason, we carried out next-generation sequencing and fluorescent in-situ hybridization studies on 57 HR and ultra-high risk (UHR) SMM patients treated in the phase II GEM-CESAR clinical trial (NCT02415413). DIS3, FAM46C, and FGFR3 mutations, as well as t(4;14) and 1q alterations, were enriched in HR SMM. TRAF3 mutations were specifically associated with UHR SMM but identified cases with improved outcomes. Importantly, novel potential predictors of treatment resistance were identified: NRAS mutations and the co-occurrence of t(4;14) plus FGFR3 mutations were associated with an increased risk of biological progression. In conclusion, we have carried out for the first time a molecular characterization of HR SMM patients treated with an intensive regimen, identifying genomic predictors of poor outcomes in this setting.

Evaluación in vitro de múltiples agentes antibacterianos para el tratamiento de la blefaritis anterior crónica estafilocócica / In vitro evaluation of multiple antibacterial agents for the treatment of chronic staphylococcal anterior blepharitis

Objetivo Evaluar la eficacia bactericida de varios compuestos utilizados en el tratamiento de la blefaritis anterior estafilocócica crónica mediante un estudio in vitro. Materiales y métodos Se cultivaron cepas comerciales estándar de Staphylococcus aureus (SAu) (ATCC 25923 Culti-Loops) y Staphylococcus coagulasa-negativo (CoNS) (ATCC 12228 Culti-Loops). Se realizaron pruebas de sensibilidad a vancomicina 30μg, netilmicina 30μg, ácido hipocloroso (HOCl) al 0,01% (Ocudox™, Brill®), aceite de hoja de Melaleuca alternifolia (MeAl) (Navyblef® Cuidado diario, NOVAX®) y digluconato de clorhexidina al 1% (DGCH) (Cristalmina™, Salvat®) mediante el método de difusión en disco de agar (Rosco Neo-Sensitabs™). A las 24horas se midieron los halos inducidos con calibradores automáticos. Los resultados se analizaron con las guías EUCAST- y CLSI potency Neo-Sensitabs™. Resultados La vancomicina indujo un halo de 22,37mm y 21,81mm en SAu y CoNS, respectivamente. La netilmicina produjo halos de 24,45mm en SAu y de 32,49mm en CoNS. MeAl indujo halos de 12,65mm en SAu y de 15,83mm en CoNS. Se encontró un halo de 12,11mm en SAu y un halo de 18,38mm en CoNS utilizando HOCl. DGCH produjo halos de 26,55mm y 23,12mm en SAu y CoNS, respectivamente. Conclusión La netilmicina y la vancomicina demostraron actividad antibiótica frente a ambos patógenos, por lo que pueden ser terapias alternativas de rescate para tratar la blefaritis estafilocócica crónica. El DGCH presenta una eficacia frente a ambos comparable a los antibióticos, mientras que el HOCl y la MeAl demuestran menor eficacia (AU)

Objective To evaluate the bactericidal efficacy of several compounds used in the treatment of chronic staphylococcal anterior blepharitis through an in vitro study. Materials and methods Standard commercial strains of Staphylococcus aureus (SAu) (ATCC 25923 Culti-Loops) and coagulase-negative Staphylococcus (CoNS) (ATCC 12228 Culti-Loops) were cultured. Susceptibility tests were performed to vancomycin 30μg, netilmicin 30μg, hypochlorous acid (HOCl) 0.01% (Ocudox™, Brill®), Melaleuca alternifolia leaf oil (MeAl) (Navyblef® Daily Care, NOVAX®) and 1% chlorhexidine digluconate (DGCH) (Cristalmina™, Salvat®) using the agar disk diffusion method (Rosco Neo-Sensitabs®). After 24hours, the induced halos were measured with automatic calipers. The results were analyzed using the EUCAST- and CLSI potency Neo-Sensitabs® guidelines. Results Vancomycin induced a halo of 22.37mm and 21.81mm in SAu and CoNS, respectively. Netilmicin produced halos of 24.45mm in SAu and 32.49mm in CoNS. MeAl induced halos of 12.65mm in SAu and 15.83mm in CoNS. A 12.11mm halo was found in SAu and an 18.38mm halo in CoNS using HOCl. DGCH produced halos of 26.55mm and 23.12mm in SAu and CoNS, respectively. Conclusion Netilmicin and vancomycin demonstrated antibiotic activity against both pathogens, so they can be alternative rescue therapies to treat chronic staphylococcal blepharitis. DGCH has efficacy against both comparable to antibiotics, while HOCl and MeAl show less efficacy (AU)

In vitro evaluation of multiple antibacterial agents for the treatment of chronic staphylococcal anterior blepharitis.

OBJECTIVE: To evaluate the bactericidal efficacy of several compounds used in the treatment of chronic staphylococcal anterior blepharitis through an in vitro study. MATERIALS AND METHODS: Standard commercial strains of Staphylococcus aureus (SAu) (ATCC 25923 Culti-Loops) and coagulase-negative Staphylococcus (CoNS) (ATCC 12228 Culti-Loops) were cultured. Susceptibility tests were performed to vancomycin 30 µg, netilmicin 30 µg, hypochlorous acid (HOCl) 0.01% (Ocudox™, Brill®), Melaleuca alternifolia leaf oil (MeAl) (Navyblef® Daily Care, NOVAX®) and 1% chlorhexidine digluconate (DGCH) (Cristalmina™, Salvat®) using the agar disk diffusion method (Rosco Neo-Sensitabs®). After 24 h, the induced halos were measured with automatic calipers. The results were analyzed using the EUCAST- and CLSI potency Neo-Sensitabs® guidelines. RESULTS: Vancomycin induced a halo of 22.37 mm and 21.81 mm in SAu and CoNS, respectively. Netilmicin produced halos of 24.45 mm in SAu and 32.49 mm in CoNS. MeAl induced halos of 12.65 mm in SAu and 15.83 mm in CoNS. A 12.11 mm halo was found in SAu and an 18.38 mm halo in CoNS using HOCl. DGCH produced halos of 26.55 mm and 23.12 mm in SAu and CoNS, respectively. CONCLUSION: Netilmicin and vancomycin demonstrated antibiotic activity against both pathogens, so they can be alternative rescue therapies to treat chronic staphylococcal blepharitis. DGCH has efficacy against both comparable to antibiotics, while HOCl and MeAl show less efficacy.

Revisiting the Phlebotominae subfamily records in Bahia, Brazil.

Brazil is one of the countries that concentrates 90% of all tegumentary and visceral leishmaniases cases and Bahia is one of the highly affected states. In the present report, we consolidated secondary data from several complementary databases that allowed us to record the sand fly species identified including areas of Leishmania spp. transmission in the state of Bahia. We then overlayed the geographical distribution data onto maps of vegetational aspects found across the state. Overall, 21 602 records of phlebotomine sand flies occurrence between 1949 and 2016 were analysed, encompassing 85% of Bahia's municipalities. Seventy-six sand fly species under 17 genera were enlisted. Among described species, 27 were proven or putative Leishmania spp. vectors and three were considered exclusively endemic in the state. Lutzomyia longipalpis, Nyssomyia intermedia and Nyssomyia whitmani were found in 74, 29 and 27% of municipalities, respectively. Salvador, the state capital and major city presented records for 21 different sand fly species, including known vectors for leishmaniasis. In particular, a wide distribution of Evandromyia sallesi was detected for this city. This consolidated account on phebotomine fauna and distribution may be explored for improving the planning and deployment of vector-focused leishmaniasis control measures in affected areas of Bahia.

Agreements and uncertainties in autologous haematopoietic stem cell mobilization and collection. A Spanish consensus document.

Although many experts position statements on autologous stem cell mobilization have been published, there are some aspects that are still under discussion. A Spanish Hematologist expert group was summoned to settle on agreements and uncertainties on PBSCs mobilization, including factors not always considered; as apheresis and cytometry key factors that determine a successful PBSC collection. This document reviews critical factors that define poor mobilizer patients and the tools to better collect the desired stem cells for a successful autologous haematopoietic stem cell transplant.

Multiple myeloma patients in long-term complete response after autologous stem cell transplantation express a particular immune signature with potential prognostic implication.

The proportion of multiple myeloma patients in long-term complete response (LTCR-MM) for more than 6 years after autologous stem cell transplantation (ASCT) is small. To evaluate whether this LTCR is associated with a particular immune signature, peripheral blood samples from 13 LTCR-MM after ASCT and healthy blood donors (HBD) were analysed. Subpopulations of T-cells (naïve, effector, central memory and regulatory), B-cells (naïve, marginal zone-like, class-switched memory, transitional and plasmablasts) and NK-cells expressing inhibitory and activating receptors were quantified by multiparametric flow cytometry (MFC). Heavy/light chains (HLC) were quantified by nephelometry. The percentage of CD4+ T-cells was lower in patients, whereas an increment in the percentage of CD4+ and CD8+ effector memory T-cells was associated with the LTCR. Regulatory T-cells and NK-cells were similar in both groups but a particular redistribution of inhibitory and activating receptors in NK-cells were found in patients. Regarding B-cells, an increase in naïve cells and a corresponding reduction in marginal zone-like and class-switched memory B-cells was observed. The HLC values were normal. Our results suggest that LTCR-MM patients express a particular immune signature, which probably reflects a 'high quality' immune reconstitution that could exert a competent anti-tumor immunological surveillance along with a recovery of the humoral immunity.

Bortezomib and thalidomide maintenance after stem cell transplantation for multiple myeloma: a PETHEMA/GEM trial.

The phase III trial GEM05MENOS65 randomized 390 patients 65 years old or younger with newly diagnosed symptomatic multiple myeloma (MM) to receive induction with thalidomide/dexamethasone, bortezomib/thalidomide/dexamethasone and Vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, doxorubicin, dexamethasone bortezomib (VBMCP/VBAD/B) followed by autologous stem cell transplantation (ASCT) with MEL-200. After ASCT, a second randomization was performed to compare thalidomide/bortezomib (TV), thalidomide (T) and alfa-2b interferon (alfa2-IFN). Maintenance treatment consisted of TV (thalidomide 100 mg daily plus one cycle of intravenous bortezomib at 1.3 mg/m2 on days 1, 4, 8 and 11 every 3 months) versus T (100 mg daily) versus alfa2-IFN (3 MU three times per week) for up to 3 years. A total of 271 patients were randomized (TV: 91; T: 88; alfa2-IFN: 92). The complete response (CR) rate with maintenance was improved by 21% with TV, 11% with T and 17% with alfa2-IFN (P, not significant). After a median follow-up of 58.6 months, the progression-free survival (PFS) was significantly longer with TV compared with T and alfa2-IFN (50.6 vs 40.3 vs 32.5 months, P=0.03). Overall survival was not significantly different among the three arms. Grade 2-3 peripheral neuropathy was observed in 48.8%, 34.4% and 1% of patients treated with TV, T and alfa2-IFN, respectively. In conclusion, bortezomib and thalidomide maintenance resulted in a significantly longer PFS when compared with thalidomide or alfa2-IFN. (no. EUDRA 2005-001110-41).

Determination of trace levels of benzophenone-type ultra-violet filters in real matrices by bar adsorptive micro-extraction using selective sorbent phases.

Bar adsorptive micro-extraction (BAµE), using selective sorbent phases, followed by liquid desorption in combination with high performance liquid chromatography-diode array detection (BAµE-LD/HPLC-DAD), is proposed for the determination of trace levels of four benzophenone-type UV filters (benzophenone, 2-hydroxy-4-methoxy-benzophenone, 2,4-hydroxybenzophenone and 4-hydroxybenzophenone) in real matrices. By comparing three polymers (P1, P2 and P3) and five activated carbons (AC1, AC2, AC3, AC4 and AC5) phases, P2 (a modified pyrrolidone polymer) and AC4 coatings showed much higher selectivity and capacity through BAµE, where the former offers multiple mechanisms of interaction and faster equilibrium kinetics. Assays performed on 25mL of ultra-pure water samples spiked at the 8.0µg/L level, yielded recoveries ranging from 76.6±8.3% to 103.5±6.4% depending on the sorbent phase used (P2 or AC4), under optimized experimental conditions. The analytical performance showed convenient detection limits (0.3-0.5µg/L) and good linear dynamic ranges (1.0-24.0µg/L) with remarkable determination coefficients (r(2)>0.9969). Excellent repeatability was also achieved through intraday (RSD<13.0%) and interday (RSD<8.9%) experiments. By using the standard addition methodology, the application of the present analytical approach on sea water, wastewater, commercial cosmetic products and urine samples revealed good sensitivity, absence of matrix effects and the occurrence of levels of some benzophenones. The proposed methodology that uses nanostructured particles and operates under the floating sampling technology proved to be a sorption-based static micro-extraction alternative to monitor benzophenone-type UV filters in real matrices. Moreover, is easy to implement, reliable, sensitive, requiring low sample volume and the possibility to choose the most selective sorbent coating according to the target compounds involved.

A multiparameter flow cytometry immunophenotypic algorithm for the identification of newly diagnosed symptomatic myeloma with an MGUS-like signature and long-term disease control.

Achieving complete remission (CR) in multiple myeloma (MM) translates into extended survival, but two subgroups of patients fall outside this paradigm: cases with unsustained CR, and patients that do not achieve CR but return into a monoclonal gammopathy of undetermined significance (MGUS)-like status with long-term survival. Here, we describe a novel automated flow cytometric classification focused on the analysis of the plasma-cell compartment to identify among newly diagnosed symptomatic MM patients (N=698) cases with a baseline MGUS-like profile, by comparing them to MGUS (N=497) patients and validating the classification model in 114 smoldering MM patients. Overall, 59 symptomatic MM patients (8%) showed an MGUS-like profile. Despite achieving similar CR rates after high-dose therapy/autologous stem cell transplantation vs other MM patients, MGUS-like cases had unprecedented longer time-to-progression (TTP) and overall survival (OS; ~60% at 10 years; P<0.001). Importantly, MGUS-like MM patients failing to achieve CR showed similar TTP (P=0.81) and OS (P=0.24) vs cases attaining CR. This automated classification also identified MGUS patients with shorter TTP (P=0.001, hazard ratio: 5.53) and ultra-high-risk smoldering MM (median TTP, 15 months). In summary, we have developed a biomarker that identifies a subset of symptomatic MM patients with an occult MGUS-like signature and an excellent outcome, independently of the depth of response.

Risk factors associated with pleuritis and cranio-ventral pulmonary consolidation in slaughter-aged pigs.

Examination of lung lesions at the slaughterhouse is a useful tool to estimate the importance of respiratory disease at farm, regional or national level. The objective of the present work was to describe the prevalence of gross lung lesions at slaughter, with a special focus on pleuritis and cranio-ventral pulmonary consolidation, and to identify major risk factors for these lesions. Data from 107 farms involving approximately 11,000 pigs enabled gross lung lesions to be correlated with serology to different swine respiratory pathogens as well as with production system characteristics and vaccination schedules. Pleuritis and cranio-ventral pulmonary consolidation lesions were recorded in 26.8% and 55.7% of slaughter-aged pigs, respectively. Among lungs with pleuritis, 50.1% had lesions compatible with Actinobacillus pleuropneumoniae (App) infection. Antibodies to porcine reproductive and respiratory syndrome (PRRSV), three subtypes (H1N1, H1N2 and H3N2) of swine influenza virus (SIV), App and Mycoplasma hyopneumoniae (Mhyo) were highly prevalent (>82%) in most of the farms. In a multivariable analysis, it was estimated (R(2)=0.40) that the percentage of animals with pleuritis compatible with App infection depended on the existence of an all in-all out by room management system and App and PRRSV herd seroprevalence. Moreover, it was possible to foresee (R(2)=0.59) that cranio-ventral pulmonary consolidation lesions (EP-like lesions) were affected by the type of farm ventilation, the presence of respiratory symptoms during the fattening period and Mhyo and SIV H1N2 herd seroprevalence.

A genetically engineered chimeric vaccine against porcine circovirus type 2 (PCV2) improves clinical, pathological and virological outcomes in postweaning multisystemic wasting syndrome affected farms.

The present study describes the effects of a commercially available genetically engineered chimeric vaccine against porcine circovirus type 2 (PCV2) on clinical, pathological and virological features in three multi-site farms suffering from postweaning multisystemic wasting syndrome (PMWS). The vaccine product was able to reduce clinical signs, PCV2 viral load in lymphoid organs and/or sera, and overall mortality in nurseries and fattening units. This is the first time in which is shown that a PCV2 vaccine is able to decrease specifically PMWS-associated mortality. Another novelty of this study is the assessment of PMWS-like histological lesions in a large number of vaccinated and non-vaccinated pigs under field conditions.

[Development of a program of nutritional education and valuation of the change of healthful nourishing habits in a population of students of Obligatory Secondary Education]. / Desarrollo de un programa de educación nutricional y valoración del cambio de hábitos alimentarios saludables en una población de estudiantes de Enseñanza Secundaria Obligatoria.

INTRODUCTION: Adolescence is a critical period for the acquisition and configuration of healthy dietary habits and lifestyle for the young future, which will likely persist throughout the adulthood. Paediatric and juvenile obesity is a public health problem which control necessarily implies prevention and nutritional education. OBJECTIVES: To evaluate the nutritional status of the adolescents and determine the proportion with overweight or obesity, and to establish a Nutritional Intervention Programme and analyse the improvement in the pattern of dietary habits among the adolescents. METHODS: The study has been carried out in a population of 372 Obligatory Secondary Education (OSE) students from the Institute of Secondary Education of Gandía (Valencia). RESULTS: 37.8% of the adolescents have improved the level of their diet quality. Those consuming a high quality diet have increased from 30.0% to 58.6%. Also significant is the number of students that have taken up having breakfast and those having discontinued taking industrial bakery with this meal. The decrease in the number of adolescents going to fast food places and of those that have discontinued eating candies regularly is statistically significant. The data from the KIDMED index show that 47.4% (p < 0.001) of de the students have improved the quality of their diet and in none of them it has worsened. DISCUSSION: Before starting the programme, 30% of the students followed a high quality diet comparable to the traditional Mediterranean Diet, and after the education programme, this percentage increased to 58.6%. Forty-seven point four percent of overweighed or obese students receiving the Nutritional Education and Intervention have improved their diet quality and the percentage of those following a high quality diet varied from 28.9% to 71.0%.

Desarrollo de un programa de educación nutricional y valoración del cambio de hábitos alimentarios saludables en una población de estudiantes de Enseñanza Secundaria Obligatoria / Development of a program of nutritional education and valuation of the change of healthful nourishing habit in a population of students of obligatory secondary education

Introducción: La adolescencia se considera un periodo crítico en la adquisición y configuración de hábitos alimentarios y de un estilo de vida saludable para el futuro joven y que probablemente serán perdurables en la edad adulta. La obesidad infantil y juvenil es un problema de Salud Pública cuyo control pasa necesariamente por la prevención y la educación nutricional. Objetivos: Evaluar el estado nutricional de los adolescentes y determinar la proporción con sobrepeso u obesidad y establecer un programa de Intervención Nutricional y analizar la mejora en el patrón de hábitos alimentarios en los adolescentes. Métodos: El estudio se ha realizado sobre una población de 372 alumnos de ESO del IES de la ciudad de Gandía (Valencia). Resultados: El 37,8% de los adolescentes ha mejorado el grado de la calidad de la dieta. Aquellos que consumen una dieta de muy buena calidad ha pasado de ser del 30,0% al 58,6%. También es significativo el número de alumnos que han comenzado a desayunar y los que han dejado de tomar bollería industrial en esta ingesta. Es estadísticamente significativo el descenso de adolescentes que acuden habitualmente a un local de comida rápida y de aquellos que han dejado de tomar de forma regular "chucherías" y golosinas. Los datos del Índice KIDMED muestran que (p < 0,001) el 47,4% de los alumnos han mejorado en cuanto ala calidad de la dieta y ninguno ha empeorado. Discusión: Antes de comenzar el programa un 30% de los alumnos seguía una dieta de buena calidad equiparable a la Dieta Mediterránea tradicional y tras la Educación este porcentaje pasó a ser del 58,6%. El 47,4% de los alumnos con sobrepeso u obesidad que recibieron Educación e Intervención Nutricional han mejorado la calidad de su dieta y el porcentaje de los que seguían una dieta de muy buena calidad pasó de 28,9% al 71,0% (AU)

Introduction: Adolescence is a critical period for the acquisition and configuration of healthy dietary habits and lifestyle for the young future, which will likely persist throughout the adulthood. Paediatric and juvenile obesity is a public health problem which control necessarily implies prevention and nutritional education. Objectives: To evaluate the nutritional status of the adolescents and determine the proportion with overweight or obesity, and to establish a Nutritional Intervention Programme and analyse the improvement in the pattern of dietary habits among the adolescents. Methods: The study has been carried out in a population of 372 Obligatory Secondary Education (OSE) students from the Institute of Secondary Education of Gandía (Valencia). Results: 37.8% of the adolescents have improved the level of their diet quality. Those consuming a high quality diet have increased from 30.0% to 58.6%. Also significant is the number of students that have taken up having breakfast and those having discontinued taking industrial bakery with this meal. The decrease in the number of adolescents going to fast food places and of those that have discontinued eating candies regularly is statistically significant. The data from the KIDMED index show that 47.4% (p < 0.001) of de the students have improved the quality of their diet and in none of them it has worsened. Discussion: Before starting the programme, 30% of the students followed a high quality diet comparable to the traditional Mediterranean Diet, and after the education programme, this percentage increased to 58.6%. Forty-seven point four percent of overweighed or obese students receiving the Nutritional Education and Intervention have improved their diet quality and the percentage of those following a high quality diet varied from 28.9% to 71.0% (AU)

A prospective observational study of the effectiveness, safety, and effect on fatigue of darbepoetin alfa for the treatment of chemotherapy-induced anaemia.

OBJECTIVE: Anaemia is common in cancer patients treated with chemotherapy. Darbepoetin alfa (DA) is the only erythropoiesis-stimulating protein approved for administration at weekly and every-three-week intervals in cancer patients receiving chemotherapy. This article investigates the effectiveness, tolerability and effect on fatigue of DA. METHODS: Prospective, observational study performed in 30 Spanish centres. Eligible patients were > or = 18 years of age, anaemic (haemoglobin [Hb] < or = 11 g/dL), with non-myeloid malignancies, receiving chemotherapy. DA (150 mug) was administered weekly for a maximum of 16 weeks (dosage doubled if Hb increased < 1 g/dL after 4 weeks). MAIN OUTCOME MEASURES: Haematopoietic response (Hb increase > or = 2 g/dL or Hb > or = 12 g/dL in the absence of transfusions in the previous 28 days), transfusion required between Weeks 5 and 16 and fatigue measured by the Fatigue subscale of the Functional Assessment of Cancer Therapy. RESULTS: 293 adults were recruited (56.4% women), with lymphoproliferative malignancies (44.3%) or solid tumours (55.7%). Baseline Hb was 9-11 g/dL in 83.7% of patients. Sixty-four per cent (95% CI: 58.1-69.4%) had a haematopoietic response and 12% required transfusions. After adjusting for performance status, concomitant diseases and chemotherapy type, an increase in Hb level was significantly associated with an improvement in Fatigue subscale (+1.9 points per 1 g/dL). Only 2% of patients had treatment-related adverse events: thromboembolic pulmonary disease (0.3%); hypersensitivity reaction (0.3%); local pain following DA administration (0.3%); insomnia (0.3%); thrombocytosis (0.3%) and deep vein thrombosis (0.3%). CONCLUSIONS: Fixed-dose DA administered once weekly seems to be an effective, well-tolerated treatment for chemotherapy-induced anaemia in patients with non-myeloid malignancies, and there is an indication of a possible benefit on fatigue in the clinical practice.