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Skin lesions are caused due to multiple factors, like allergies, infections, exposition to the sun, etc. These skin diseases have become a challenge in medical diagnosis due to visual similarities, where image classification is an essential task to achieve an adequate diagnostic of different lesions. Melanoma is one of the best-known types of skin lesions due to the vast majority of skin cancer deaths. In this work, we propose an ensemble of improved convolutional neural networks combined with a test-time regularly spaced shifting technique for skin lesion classification. The shifting technique builds several versions of the test input image, which are shifted by displacement vectors that lie on a regular lattice in the plane of possible shifts. These shifted versions of the test image are subsequently passed on to each of the classifiers of an ensemble. Finally, all the outputs from the classifiers are combined to yield the final result. Experiment results show a significant improvement on the well-known HAM10000 dataset in terms of accuracy and F-score. In particular, it is demonstrated that our combination of ensembles with test-time regularly spaced shifting yields better performance than any of the two methods when applied alone. Yes

The high prevalence of allergy to β-lactam antibiotics is a worldwide issue. Accuracy of diagnostic methods is important to prove tolerance or allergy, with skin test considered the best validated in vivo method for diagnosing immediate reactions to β-lactams. Although drug provocation test is the reference standard, it cannot be performed in highly risk reactions or in those with positive skin tests. For skin tests, the inclusion of major and minor determinants of benzylpenicillin (BP) is recommended. Commercial skin test reagents have changed along time, including as minor determinants benzylpenicillin, benzylpenicilloate (BPO), and benzylpenilloate (PO). Major determinants consists of multivalent conjugates of benzylpenicilloyl coupled through amide bond to a carrier polymer, such as penicilloyl-polylysine (PPL) or benzylpenicilloyl-octalysine (BP-OL). The chemical stability of such reagents has influenced the evolution of the composition of the commercial kits, as this requirement is necessary for improving the quality and standardization of the product. In this work, we provide a detailed study of the chemical stability of BP determinants. We observed that those structures suffer from an epimerization process in C-5 at different rates. Butylamine-Benzylpenicilloyl conjugates (5R,6R)-Bu-BPO and (5S,6R)-Bu-BPO were selected as a simple model for mayor determinant to evaluate the role of the different epimers in the immunoreactivity with sera from penicillin-allergic patients. In vitro immunoassays indicate that any change in the chemical structure of the antigenic determinant of BP significantly affects IgE recognition. The inclusion of stereochemically pure compounds or mixtures may have important implications for both the reproducibility and sensitivity of in vivo and in vitro diagnostic tests.

Immunotoxins appear as promising therapeutic molecules, alternative to allergen-specific-immunotherapy. In this work, we achieved the development of a protein chimera able to promote specific cell death on effector cells involved in the allergic reaction. Der p 1 allergen was chosen as cell-targeting domain and the powerful ribotoxin α-sarcin as the toxic moiety. The resultant construction, named proDerp1αS, was produced and purified from the yeast Pichia pastoris. Der p 1-protease activity and α-sarcin ribonucleolytic action were effectively conserved in proDerp1αS. Immunotoxin impact was assayed by using effector cells sensitized with house dust mite-allergic sera. Cell degranulation and death, triggered by proDerp1αS, was exclusively observed on Der p 1 sera sensitized-humRBL-2H3 cells, but not when treated with non-allergic sera. Most notably, equivalent IgE-binding and degranulation were observed with both proDerp1αS construct and native Der p 1 when using purified basophils from sensitized patients. However, proDerp1αS did not cause any cytotoxic effect on these cells, apparently due to its lack of internalization after their surface IgE-binding, showing the complex in vivo panorama governing allergic reactions. In conclusion, herein we present proDerp1αS as a proof of concept for a potential and alternative new designs of therapeutic tools for allergies. Development of new, and more specific, second-generation of immunotoxins following proDerp1αS, is further discussed.

16 p.-7 fig.-2 tab.-1 graph. abst., Serum and cellular proteins are targets for the formation of adducts with the β-lactam antibiotic amoxicillin. This process could be important for the development of adverse, and in particular, allergic reactions to this antibiotic. In studies exploring protein haptenation by amoxicillin, we observed that reducing agents influenced the extent of amoxicillin-protein adducts formation. Consequently, we show that several thiol-containing compounds, including dithiothreitol, N-acetyl-L-cysteine, and glutathione, perform a nucleophilic attack on the amoxicillin molecule that is followed by an internal rearrangement leading to amoxicillin diketopiperazine, a known amoxicillin metabolite with residual activity. Increased diketopiperazine conversion is also observed with human serum albumin but not with L-cysteine, which mainly forms the amoxicilloyl amide. The effect of thiols is catalytic and can render complete amoxicillin conversion. Interestingly, this process is dependent on the presence of an amino group in the antibiotic lateral chain, as in amoxicillin and ampicillin. Furthermore, it does not occur for other β-lactam antibiotics, including cefaclor or benzylpenicillin. Biological consequences of thiol-mediated amoxicillin transformation are exemplified by a reduced bacteriostatic action and a lower capacity of thiol-treated amoxicillin to form protein adducts. Finally, modulation of the intracellular redox status through inhibition of glutathione synthesis influenced the extent of amoxicillin adduct formation with cellular proteins. These results open novel perspectives for the understanding of amoxicillin metabolism and actions, including the formation of adducts involved in allergic reactions., This work was supported by grant SAF2015-68590-R from MINECO/FEDER, RTI2018-097624-B-I00 and RETIC Aradyal from ISCIII/FEDER RD16/0006/0021 to DP-S; RD16/0006/0001 to MT, RD16/0006/0024 to MB; grants CP15/00103 and PI17/ 01237 from ISCIII/ERDF and PI-0179-2014 from Andalusian Regional Ministry Health to MM. AA holds a “Sara Borrell” research contract (CD17/0146) supported by ISCIII from MINECO [confounded by the European Social Fund (ESF)]. We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI)

Non-steroidal anti-inflammatory drugs (NSAIDs), the most commonly prescribed and consumed medicines worldwide, are the main triggers of drug hypersensitivity reactions (DHRs). The underlying mechanisms of NSAID-DHRs may be related to COX-1 inhibition (cross-hypersensitivity reactions, CRs) or to immunological recognition (selective reactions, SRs), being the latter remarkably less studied. SRs include those usually appearing within the first hour after drug intake (single-NSAID-induced urticaria/angioedema or anaphylaxis, SNIUAA), and those usually occurring more than 24 h after (single-NSAID-induced delayed reactions, SNIDR). We have evaluated the largest series of patients with SRs, analyzing the number of episodes and drugs involved, the latency for reaction onset, the clinical entities, among other variables, as well as the value of available diagnostic methods. Globally, pyrazolones and arylpropionics were the most frequent culprits (39.3% and 37.3%, respectively). Pyrazolones were the most frequent triggers in SNIUAA and arylpropionics in SNIDR. Urticaria was the most common clinical entity in SNIUAA (42.4%) followed by anaphylaxis (33.3%); whereas SNIDR induced mostly fixed drug eruption (41.1%) and maculopapular exanthema (32.6%). The percentage of patients diagnosed by clinical history was higher in SNIUAA compared with SNIDR (62.7% versus 35.3%, p = 0.00015), whereas the percentage of those diagnosed by skin tests was higher in SNIDR than in SNIUAA (47.1% versus 22.8%, p = 0.00015). Drug provocation test with the culprit was performed in 67 SNIUAA (14.5%) and in 9 SNIDR (17.6%) patients. Our results may be of interest not only for allergologists but also for other clinicians dealing with these drugs, and can be useful for the correct identification of subjects experiencing DHRs to NSAIDs, and for avoiding mislabeling. Moreover, as NSAIDs are highly consumed worldwide, our results may be of interest for evaluating other populations exposed to these drugs. Yes

The main objective was to evaluate the cost-effectiveness of protocol use of palivizumab in premature established by consensus in our Hospital comparing it based on the recommendations of various Scientific Societies. As a secondary objective risk factors and severity of hospitalized patients attending the established protocol in our Hospital were analyzed.The study period was 4 seasons with the expanded protocol (retrospective data) versus 2 with restricted or agreed protocol (prospective data). The perspective of the study was the Health System, including the costs of hospitalization and palivizumab our center. The calculation of the effectiveness was determined with the admission rate of premature patients stratified by weeks of gestational agelt;29,lt;32; andlt;35. For the analysis of risk factors and severity in patients admitted seasons with the new protocol are collected prospectively clinical data and environmental and social factors.In the range of gestational agelt;29 years old and lt;32 greater effectiveness of the extended protocol was not demonstrated against the consensus. Only more effective for EGlt;35 in the accumulated data and comparing seasons 12/13 and 08/09 to 13/14 for individual data was observed. This range has an associated incremental cost effectiveness ratio of € 53 250,07 (range: € 14 793,39 to € 90 446,47 for singles data and € 50 525,53 (€ 28 688.22 to € 211 575,65) for accumulated. The establishment of this protocol in our center meant an average saving per season € 169 911,51. A cost-effectiveness of the extended protocol appropriate relationship is found if the cost of palivizumab per patient was less than € 1 206,67 (calculated for maximum use of the vial) and a higher rate of hospitalization of 9.21%. Children entering the season with the new protocol (season 12/13 and 13/14) are 63.4% in children under 3 months and 90% are term infants who do not belong to any population at risk, while many of them have associated risk factors you vary as have school-age siblings, rural residence, parental smoking, poor educational background of parents, lack of artificial feeding and family history of allergy.The consensus protocol has not been a significant increase in hospitalization rates in preterm infantslt;32 weeks gestational age patients. In thoselt;35 has been observed a higher rate of hospitalization, with a very unfavorable cost-effectiveness for all clinical scenarios valued relationship.Objetivo: El objetivo principal fue evaluar el coste-efectividad del protocolo de uso de palivizumab en prematuros instaurado por consenso en nuestro hospital comparándolo con el basado en las recomendaciones de diferentes sociedades científicas. Como objetivo secundario se analizaron los factores de riesgo y gravedad de los pacientes hospitalizados atendiendo al protocolo establecido en nuestro centro.Material y métodos: El periodo de estudio fue de cuatro temporadas con el protocolo ampliado (datos retrospectivos) frente a dos con el protocolo restringido o consensuado (datos prospectivos). La perspectiva del estudio fue la del sistema sanitario, incluyendo los costes de hospitalización y del palivizumab en nuestro centro. El cálculo de la efectividad se determinó con la tasa de ingresos de pacientes prematuros estratificados por semanas de edad gestacional:lt; de 29,lt;32 ylt;35. Para el análisis de los factores de riesgo y gravedad en pacientes ingresados en las temporadas con el nuevo protocolo se recogen, de forma prospectiva, datos clínicos y factores ambientales y sociales. Resultados: En los estratos de edad gestacionallt;29 ylt;32 no se demostró una mayor efectividad del protocolo ampliado frente al consensuado. Solamente se objetivó una mayor efectividad para EGlt;35 en los datos acumulados y al comparar las temporadas 08/09 con la 12/13 y 13/14 para datos individuales. Este estrato lleva asociado un cociente coste eficacia incremental de 53.250,07 € (rango: 14.793,39 € a 90.446,47 € para los datos individuales y 50.525,53 € (28.688,22 € a 211.575,65 €) para los acumulados. La instauración de este protocolo en nuestro centro supuso un ahorro medio por temporada de 169.911,51 €. Se constata una relación coste-efectividad adecuada del protocolo ampliado si el coste del palivizumab por paciente fuese menor de 1.206,67 € (calculados para el máximo aprovechamiento del vial) y para una tasa de hospitalización mayor de 9,21%. Los niños que ingresan en las temporadas con el nuevo protocolo (temporada 12/13 y 13/14) son en un 63,4% niños menores de 3 meses y el 90% son neonatos a término que no pertenecen a ninguna población de riesgo, mientras que muchos de ellos tienen asociados varías factores de riesgo como tener hermanos en edad escolar, residencia rural, padres fumadores, escasa formación académica de los progenitores, ausencia de lactancia artificial e historia familiar de alergia.Conclusiones: El protocolo consensuado no ha supuesto un aumento significativo en las tasas de hospitalización en los pacientes prematuroslt;32 semanas de EG. En aquelloslt;35 se ha observado una mayor tasa de hospitalización, con una relación coste-efectividad muy desfavorable para todos los escenarios clínicos valorados.

JOURNAL ARTICLE; INTRODUCTION Hymenoptera venom immunotherapy (VIT) is an effective treatment but not one devoid of risk as both local and systemic adverse reactions may occur especially in the initial stages of treatment. We compared the tolerance to three buildup protocols of VIT and analyzed risk factors associated with adverse reactions occurring in this phase. METHODS We enrolled 165 patients divided into three groups based on the buildup protocol used (3, 4, 9 weeks). Severity of systemic reactions was evaluated according to World Allergy Organization model. Results were analyzed using exploratory descriptive statistics and variables were compared using analysis of variance. RESULTS Fifty-three patients (32%) experienced some form of adverse reaction, 43 were local and 10 systemic. Local reactions were immediate in 27 patients (63%) and delayed in 16 (37%). Severity of local reaction was slight/moderate in 15 patients and severe in 13. Systemic reactions were grade 1-2. No significant association was found between the treatment modality and the appearance of local or systemic adverse reactions or the type of local reaction. We only found a statistically significant association of severity of the local reaction with female gender. As for the risk factors associated with systemic reactions at buildup phase, we found no significant differences in these values depending on protocol used or the insect responsible. CONCLUSIONS The buildup protocols compared proved to be safe and did not differ significantly from one another. In the population studied the 9-week schedule presented no systemic reactions, so it can be considered the safest protocol. Yes