Key questions in the new hemophilia era: update on concomitant use of FVIII and emicizumab in hemophilia A patients with inhibitors

Introduction: Immune tolerance induction (ITI) is the primary therapeutic strategy and only proven method to eradicate inhibitors to coagulation factor VIII (FVIII) in hemophilia A. Emicizumab, a humanized bispecific monoclonal antibody that mimics the function of activated FVIII, has expanded options to treat hemophilia A. The availability of emicizumab necessitates a revisit of recommendations for managing patients with inhibitors. Areas covered: Current evidence is reviewed about the concomitant use of emicizumab and FVIII concentrates during and after ITI. Areas where data are lacking are highlighted and ongoing studies designed to address these issues are described. Expert opinion: Inhibitor eradication remains a desirable goal. All patients with inhibitors should be offered at least one attempt at ITI. Emicizumab monotherapy is an option for inhibitor patients who are not candidates for ITI. Evidence is emerging about the use of emicizumab during ITI to prevent bleeds. Studies are currently addressing the safety, efficacy, and feasibility of concomitant emicizumab and FVIII in ITI. As evidence regarding the risk of inhibitor recurrence and need for continued FVIII to maintain immune tolerance post-ITI is limited, the role of emicizumab alone or in combination with FVIII after ITI is the subject of an upcoming studyThis review is based on presentations from a Grifols-sponsored symposium at the International Society on Thrombosis and Haemostasis 2020 Virtual Congress. The paper is otherwise not funde

Optimization of code caves in malware binaries to evade machine learning detectors

Machine Learning (ML) techniques, especially Artificial Neural Networks, have been widely adopted as a tool for malware detection due to their high accuracy when classifying programs as benign or malicious. However, these techniques are vulnerable to Adversarial Examples (AEs), i.e., carefully crafted samples designed by an attacker to be misclassified by the target model. In this work, we propose a general method to produce AEs from existing malware, which is useful to increase the robustness of ML-based models. Our method dynamically introduces unused blocks (caves) in malware binaries, preserving their original functionality. Then, by using optimization techniques based on Genetic Algorithms, we determine the most adequate content to place in such code caves to achieve misclassification. We evaluate our model in a black-box setting with a well-known state-of-the-art architecture (MalConv), resulting in a successful evasion rate of 97.99 % from the 2k tested malware samples. Additionally, we successfully test the transferability of our proposal to commercial AV engines available at VirusTotal, showing a reduction in the detection rate for the crafted AEs. Finally, the obtained AEs are used to retrain the ML-based malware detector previously evaluated, showing an improve on its robustness.This research was supported by the Ministerio de Ciencia, Innovación y Universidades (Grant Refs. PGC2018-095322-B-C22 and PID2019-111429RB-C21), by the Region of Madrid grant CYNAMON- CM (P2018/TCS-4566), co-financed by European Structural Funds ESF and FEDER, and the Excellence Program EPUC3M17

Strategies to mitigate the impact of shifting from a milk and forage regimen to a high-concentrate diet in intensively reared beef cattle

El cebo de terneros en España se lleva a cabo mediante el aporte de dietas con un elevado porcentaje de concentrado en la ración y una mínima parte de forraje, con el fin de lograr un elevado crecimiento diario y acortar el ciclo de producción. Estas dietas son altamente fermentables en el rumen y pueden causar acidosis ruminal. El período de transición de los terneros a las dietas de cebo intensivo es una fase crítica, ya que habitualmente estos animales se destetan de forma abrupta e inmediatamente entran a cebadero. En el contexto de la presente tesis doctoral, se diseñaron tres experimentos con el fin de estudiar la efectividad de algunas estrategias para reducir el riesgo de padecer acidosis ruminal durante el período de transición de terneros de pasteros al cebo intensivo.El Experimento 1 se llevó a cabo para determinar el manejo alimentario previo al destete más adecuado (Leche, Leche+Heno o Leche+Pienso), en términos de desarrollo del rumen, rendimiento animal y rentabilidad económica, para terneros que son destetados de forma abrupta e inmediatamente introducidos al sistema de cebo intensivo.Teniendo en cuenta todo el ciclo de producción, la suplementación previa al destete con concentrado es la opción más interesante para los terneros de carne que van a entrar a cebadero ya que promovió una mayor adapatación del rumen y un mayor margen económico. El objetivo del Experimento 2 fue determinar el efecto de la sustitución parcial de la cebada por maíz y pulpa de remolacha en la dieta de adaptación de los terneros durante la transición a una ración de cebo intensivo sobre la ingestión y el rendimiento de los animales, la fermentación ruminal y la composición microbiana del rumen. El análisis de todas variables registradas denotó una falta de efecto tanto en los rendimientos, como en la fermentación ruminal y poblaciones microbianas. Por lo tanto, El uso de cebada o maíz como cereal predominante, o la inclusión de pulpa de remolacha, no tienen ningún efecto sobre la fermentación ruminal o las poblaciones microbianas en los terneros de engorde, y su uso dependerá del precio o la disponibilidad en el mercado de estos ingredientes.En el Experimento 3 se evaluó el efecto de la inclusión de una mezcla (65:35) de taninos de castaño y quebracho o de ácidos grasos de cadea media, como moduladores de la fermentación ruminal en la dieta de adaptación de terneros de carne, sobre la ingesta de alimento, el rendimiento animal, la fermentación ruminal y la composición microbiana del rumen. A las dosis utilizadas en el presente experimento, los taninos (20g/kg) y los AGCM (6g/kg) no ejercieron ningún efecto sobre la ingesta, el rendimiento animal, la fermentación ruminal y la población microbiana.<br /

CHEMICAL COMPOSITION, in situ AND in vitro DEGRADATION OF Kochia scoparia IN RELATION TO DATE OF SOWING AND AGE OF CUT

The Kochia scoparia is an alternative source of medium-quality protein for food in ruminants, for this, it is important to know its chemical composition and its degradation and fermentation in the rumen, as this can vary depending on the date of establishment and cutting age. In the present study evaluated the chemical composition. The degradation assessment was performed using the technique of in vitro gas production and ruminal in sacco degradation. The Kochia scoparia cultured on three dates (D) of sowing(D1, 07/12/2001; D2, 06/01/2002; and D3, 05/02/2002) and the cut was made at two different ages (78 to 119 days post sowing, C1 and C2, respectively). OM content (g 100g DM) was higher (p ¿ 0.05) for D1 (90.8) Than for D2 and D3 (89.1) and CP content exchange between due dates, (P¿0.05) D3 > D2 > D1 (16.4, 15.3, 13.3 %, respectively) the in vitro production of gas(ml gas g-1 DM)was not different(P¿0.05) between planting dates (185) but for cuts(P¿0.05), being C1 > C2 (199.6 vs 171.7); in vitro degradation of dry matter, there were no differences observed (P¿0.05) between dates (53.11 mg 100 mg of DM) but C1 was superior (P¿0.05) to C2 (59.3 vs 46.9 mg 100 mg of DM).The Protein degradation was estimated by in situ ruminal incubation (RDP, g 100g of DM),being superior (p¿0.05) D2 (71.8) with regards to D1 and D3 (62.9 y 59.3) and C1 > C2 (P¿0.05) (67.6 vs 61.8). Due to the CP content of the Kochia scoparia it is suggested as an alternative source of medium-quality protein to ruminants, having degradation in the rumen of more than 60 %, which is influenced by the maturity of the plant and its date of establishment

Haematuria on the spanish registry of glomerulonephritis

Recent studies suggest a pathogenic role for glomerular haematuria among renal function. However, there is no data on the prevalence of haematuria from a large renal biopsy registry. We analysed the prevalence of gross (GH) and microscopic (mH) haematuria in 19,895 patients that underwent native renal biopsies from the Spanish Registry of Glomerulonephritis. Haematuria's overall incidence was 63% (GH 8.6% and mH 55.1%), being more frequent in males (64.7% vs. 62.4%). GH was more prevalent in patients &lt;18 years (21.3% vs. 7.7%). The commonest clinical presentation associated with GH was acute kidney injury (31.5%) and IgA Nephropathy (IgAN) (33.6%) was the most frequent histological finding. GH patients showed a significantly (p &lt; 0.05) lower eGFR and proteinuria levels as compared with patients with mH and without haematuria. Moreover, mH was more prevalent in adults (56.3%). Nephrotic syndrome was the commonest clinical presentation in mH patients (32.2%) and IgAN (18.5%) the most frequent histological finding. In conclusion, haematuria, is a frequent urinalysis finding in patients underwent native renal biopsy. The most frequent histological finding in both GH and mH is IgAN. Whereas, GH is more frequent in young males with acute kidney injury, mH is commoner among adults with nephrotic syndrome.This work has been supported by grants from FIS (Programa Miguel Servet: CP10/00479, PI13/00802 and PI14/00883), Fundación Renal Iñigo Alvarez de Toledo and Spanish Society of Nephrology to JA

Students` attitudes towards open innovation

In order to most efficiently utilize knowledge and technology, companies are increasingly developing open innovation models. Open innovation places emphasis on the inflow of external resources and outflow of idle assets. Human resources are considered to be a crucial element in the successful implementation of open innovation. Instead of emphasizing the internal elements of the work community and individual input and success, employees are encouraged to invest in collaboration and flexibility. Due to the increasing development and implementation of open innovation strategies, this thesis sought out to study students’ attitudes concerning open innovation. The research was built on describing the attitudes students have and determining where these attitudes stem from. Additionally, the thesis discusses the use of incentives to attract employees. The empirical study was conducted in the form of an online questionnaire sent to international business students of Turku University of Applied Sciences. The responses indicated that many elements of open innovation where found to be positive. The main appealing elements were flexibility, cost reduction of R&D and the collaboration between different actors. Elements that were found disruptive were the lack of structure and the necessity of communication between companies. The conclusions that were drawn based on the research were, that the subjects were influenced by still being amidst studies and though valued the idea of knowledge flow, felt uneasy with the communicational aspect. Additionally, it was concluded that developing an incremental system of enforcing flexibility may hinder the uncomfortable attitudes created by a lack of structure.Saadakseen mahdollisimman tehokkaasti hyödynnettyä tietoa ja teknologiaa, yritykset kehittävät enenevissä määrin avoimen innovaation malleja. Avoin innovaatio korostaa ulkoisten resurssien sisäänvirtausta ja turhien voimavarojen ulosvirtausta. Henkilöstöä pidetään keskeisenä tekijänä avoimen innovaation menestyksekkään toteutuksen kannalta. Sen sijaan, että korostetaan työympäristön sisäisiä tekijöitä ja yksilön panosta ja menestystä, työntekijät kannustetaan yhteistyöhön ja joustavuuteen. Avoimen innovaation strategioiden kasvava kehitys ja toimeenpano oli taustalla siihen, että tässä opinnäytetyössä lähdettiin selvittämään millaisia asenteita opiskelijoilla on avointa innovaatiota kohtaan. Tutkimuksen tavoitteena oli kuvailla opiskelijoiden asenteet ja määritellä mistä nämä asenteet juontuvat. Lisäksi, tämä opinnäytetyö pohtii kannustimien käyttöä työntekijöiden houkuttelemiseksi. Empiirinen tutkimus tehtiin verkkokyselyn merkeissä, joka lähetettiin kansainvälisen liiketalouden opiskeljoille (Turun Ammattikorkeakoulussa). Vastaukset osoittivat, että positiivisia asenteita koskien avointa innovaatiota, oli moneen tekijään. Positiiviset asenteet koskivat joustavuutta, kustannusten alenemista tuotekehityksessä ja yhteistyötä eri toimijoiden välillä. Häiritseviä tekijöitä olivat rakenteen puute ja kommunikaation välttämättömyys yritysten välillä. Tutkimuksen johtopäätökset on, että kohteiden olo vielä opiskelemassa vaikuttaa heidän asenteisiin ja vaikka tiedon virtausta arvostetaan, kommunikaatio tarve aiheuttaa rauhattomuutta. Lisäksi esitetään, että rakenteen puutteesta johtuvia epämielyttäviä asenteita voidaan välttää lisäämällä vähitellen joustavia työtapoja

Changes in foot posture during pregnancy and their relation with musculoskeletal pain: A longitudinal cohort study

Aim: To examine foot posture changes during the three trimesters of pregnancy and to determine whether there is a relationship between these changes and the pain experienced in this period. Methods: The study sample consisted of 62 pregnant women who attended the Gynaecology Service at Hospital Santa María del Puerto (Cádiz, Spain), between January 2013 and May 2014. In their first visit, the following sociodemographic and anthropometric data were recorded: age, weight, height and foot size. In addition, information was obtained regarding pain in the lower back, knees, ankles and feet. In this first visit, too, the Foot Posture Index (FPI) was assessed, and three subsequent controls were performed during the first, second and third months of pregnancy (termed Stages 1, 2 and 3, respectively). Results: In Stage 1, the average foot size (i.e., shoe size) was 38.3 (SD 1.5). This size did not change between Stages 1, 2 and 3. However, body weight and BMI did present statistically significant changes during this period (p < 0.0001). The FPI varied during pregnancy but no relation was observed between these changes and the onset of pain. Conclusions: During pregnancy, pronation increases but this does not appear to influence the onset of pain in the lower limb

Comportamiento de las comunidades microbianas del suelo frente al cambio climático en los encinares mediterráneos

Resumen de una presentación realizada en: I Simposio sobre Interacciones Planta-Suelo (ICA-CSIC, Madrid, 25-26 Febrero 2016)En las últimas décadas hemos comprobado como el cambio climático ha causado un aumento de las sequías a nivel peninsular, provocando que especies tan adaptadas a las condiciones de sequía estacional Mediterráneas como la encina (Quercus ilex) se estén viendo afectadas por fenómenos de decaimiento a lo largo de toda la Península Ibérica. Esta pérdida de salud de los encinares se relaciona íntimamente con la ecología de las comunidades microbianas de los suelos que juegan una labor esencial en el funcionamiento ecosistémico. En esta tesis vamos a estudiar el papel de las comunidades microbianas de suelos frente al fenómeno de decaimiento del encinar y su relación con cambios en las dinámicas de carbono (C) y nutrientes. Para ello, proponemos un diseño experimental multidisciplinar en el que se estudiarán cambios potenciales en la estructura (diversidad y composición taxonómica) y el funcionamiento de las comunidades microbianas (bacterias y hongos) a lo largo de gradientes de decaimiento (suelos de encinas sanas, defoliadas, muertas y suelos sin cobertura de la encina) y climático (cubriendo el área de distribución de Q. ilex subsp ballota), así como su asociación con cambios en los ciclos biogeoquímicos del suelo (mineralización de C y N). Para esto, se seleccionaron 18 parcelas a lo largo de la Península Ibérica abarcando gran parte de su área de distribución. En estas parcelas se realizó un muestreo extensivo en el que se recogieron por una lado datos del hábitat de la encina, desde el grado de defoliación hasta la cobertura que la rodeaba; y por otro, muestras para el estudio de las características físicoquímicas del suelo así como la estructura y funcionamiento de las comunidades microbianas que lo habitan. De este modo, tendremos un mejor conocimiento del funcionamiento de sistema planta-suelo, y su relación con las dinámicas de C y nutrientes integrando escalas micro (comunidades microbianas) hasta macro (área de distribución de la encina) en ambientes con defoliación.Peer reviewe

Post-hoc analysis on the long-term response to fixed-dose prophylaxis with N8-GP in patients with haemophilia A

Challenges with personalised prophylaxis in haemophilia remain, including designing unique dosing schedules that require continual adjustments and monitoring using complex sampling procedures. Aim To assess long-term efficacy and pharmacokinetic outcomes with fixed-dose N8-GP prophylaxis. Methods Descriptive analyses were performed on data from the pathfinder 2 and pathfinder 5 trials of patients with severe haemophilia A. Bleed frequency and reoccurrence were assessed in relation to several clinical criteria of interest. Bleed risk relative to time since last dose was assessed using calculated annualised bleeding rate (ABR). Long-term ABR and mean factor VIII (FVIII) trough levels were assessed in patients who received consistent N8-GP prophylaxis every 4 days (Q4D). Results During pathfinder 2, 117/136 patients with study-drug exposure of ≥600 days experienced bleeding episodes; 8.6% of bleeds were reoccurring bleeds; bleed reoccurrence decreased over time. For patients who received consistent Q4D prophylaxis across the trial (n = 61), mean ABR decreased from 3.5 bleeds/year (Year 1) to 1.6 bleeds/year (Year 6); mean FVIII trough levels stabilised at approximately 5% (Year 6). Across patients who received prophylaxis at some point during pathfinder 2 (n = 177), 125/126 (99%) reoccurring bleeds were joint bleeds. For patients receiving Q4D prophylaxis, bleeding risk generally increased as the time since the last prophylaxis dose increased. A similar reduction in ABR and stabilisation of trough level was observed in pathfinder 5. Conclusion Long-term exposure (> 5 years) to fixed-dose N8-GP prophylaxis resulted in a protective haemostatic effect, with reduction in bleed frequency and reoccurrence, and stabilisation of FVIII trough level over tim

Survival effects of antibiotic exposure during the larval and adult stages in the West Nile virus vector Culex pipiens

The ability of mosquitoes to transmit a pathogen is affected, among other factors, by their survival rate, which is partly modulated by their microbiota. Mosquito microbiota is acquired during the larval phase and modified during their development and adult feeding behavior, being highly dependent on environmental factors. Pharmaceutical residues including antibiotics are widespread pollutants potentially being present in mosquito breeding waters likely affecting their microbiota. Here, we used Culex pipiens mosquitoes to assess the impact of antibiotic exposure during the larval and adult stages on the survival rate of adult mosquitoes. Wild-collected larvae were randomly assigned to two treatments: larvae maintained in water supplemented with antibiotics and control larvae. Emerged adults were subsequently assigned to each of two treatments, fed with sugar solution with antibiotics and fed only with sugar solution (controls). Larval exposure to antibiotics significantly increased the survival rate of adult females that received a control diet. In addition, the effect of adult exposure to antibiotics on the survival rate of both male and female mosquitoes depended on the number of days that larvae fed ad libitum in the laboratory before emergence. In particular, shorter larval ad libitum feeding periods reduced the survival rate of antibiotic-treated adult mosquitoes compared with those that emerged after a longer larval feeding period. These differences were not found in control adult mosquitoes. Our results extend the current understanding of the impact of antibiotic exposure of mosquitoes on a key component of vectorial capacity, that is the vector survival rate.MCIN/AEI/10.13039/501100011033 [grant number PID2020-118205GB-I00]Spanish Ministry of Science and Innovation [grant numbers PRE2021-098544 and FJC2021-048057-I]Spanish Ministry of Universities [Margarita Salas and María Zambrano programs]Funding for open access charge: Universidad de Granada / CBU