Expert Review and Consensus on the Treat-to-Target Management of Hereditary Angioedema: From Scientific Evidence to Clinical Practice

Background: Hereditary angioedema with C1 inhibitor deficiency (HAE-C1INH) is a rare disease characterized by swelling episodes. It affects quality of life (QOL) and can be fatal when the upper airways are involved. Treatment is individualized, with therapeutic options including on-demand treatment (ODT) and short- and long-term prophylaxis (STP, LTP). However, available guidelines are not always clear about the selection of treatment, the goals of treatment, or how achievement of these goals is assessed. Objective: To review available evidence for the management of HAE-C1INH and build a Spanish expert consensus to steer management towards a treat-to-target approach, while addressing some of the less clear aspects of the Spanish guidelines. Methods: We reviewed the literature on the treat-to-target management of HAE-C1INH, focusing on treatment selection and goals and the tools available to assess whether the goals have been achieved. We discussed the literature based on clinical experience and drew up 45 statements on undefined management aspects. A panel of 53 HAE experts validated the statements through a 2-round Delphi process. Results: The goals for ODT and STP are to minimize the morbidity and mortality of attacks and to prevent attacks caused by known triggers, respectively, while the main goal of LTP is to decrease the rate, severity, and duration of attacks. Furthermore, when prescribing, clinicians should consider the reduction in adverse effects, while increasing patient QOL and satisfaction. Appropriate instruments for assessing achievement of treatment goals are also indicated. Conclusions: We provide recommendations on previously unclear aspects of HAE-C1INH management with ODT, STP, and LTP, focusing on clinical and patient-oriented goals

Spherulitic and rotational crystal growth of Quartz thin films

To obtain crystalline thin films of alpha-Quartz represents a challenge due to the tendency for the material towards spherulitic growth. Thus, understanding the mechanisms that give rise to spherulitic growth can help regulate the growth process. Here the spherulitic type of 2D crystal growth in thin amorphous Quartz films was analyzed by electron back-scatter diffraction (EBSD). EBSD was used to measure the size, orientation, and rotation of crystallographic grains in polycrystalline SiO(2) and GeO(2) thin films with high spatial resolution. Individual spherulitic Quartz crystal colonies contain primary and secondary single crystal fibers, which grow radially from the colony center towards its edge, and fill a near circular crystalline area completely. During their growth, individual fibers form so-called rotational crystals, when some lattice planes are continuously bent. The directions of the lattice rotation axes in the fibers were determined by an enhanced analysis of EBSD data. A possible mechanism, including the generation of the particular type of dislocation(s), is suggested

Crystallization of GeO2 thin films into α-quartz: From spherulites to single crystals

Piezoelectric quartz (SiO2) crystals are widely used in industry as oscillators. As a natural mineral, quartz and its relevant silicates are also of interest in geoscience and mineralogy. However, the nucleation and growth of quartz crystals are difficult to control and not fully understood. Here we report successful solid-state crystallization of thin film of amorphous GeO2 into quartz on various substrates, including Al2O3, MgAl2O4, MgO, LaAlO3 and SrTiO3. At relatively low annealing temperatures, the crystallization process is spherulitic: with fibers growing radially from the nucleation centers and the crystal lattice rotating along the growth direction with a linear dependence between the rotation angle and the distance to the core. For increasingly higher annealing temperatures, quartz crystals begin to form. The edges of the sample play an important role in facilitating nucleation followed by growth sweeping inward until the whole film is crystallized. Control of the growth allows single crystalline quartz to be synthesized, with crystal sizes of hundreds of microns achieved on sapphire substrates, which is promising for further piezoelectric applications. Our study reveals the complexity of the nucleation and growth process of quartz and provides insight for further studies

Síntesis de capas de SiC en substrato de Si mediante implantación iónica

En este trabajo se investiga la síntesis de estructuras SiC/Si mediante implantación iónica de carbono en Si. Las implantaciones se han realizado a energías entre 25 y 300 keV y las dosis en el rango lO^^ylO^^ cm , manteniendo el substrato a temperatura ambiente o 500°C. Algunas estructuras han sido recocidas a 1150°C. Los resultados indican que implantando a temperatura ambiente se forma una capa de SiC amorfa y de composición gradual, que recristaliza formando precipitados de ß-SiC con orientaciones aleatorias después del recocido. Además se forma un capa superficial rica en carbono, debida a la difusión del carbono hacia la superficie durante la implantación, y que desaparece con el recocido. Implantando a 500°C se forma directamente una capa con una muy alta densidad de precipitados de ß-SiC orientados preferencialmente con la matriz de silicio. Dada la estabilidad térmica y química de dicha capa se han realizado membranas de SiC mediante técnicas fotolitográficas y ataque químico selectivo, cuya rugosidad superficial es inferior a 6 nm. Estas membranas muestran unos gradientes de tensiones residuales, que prácticamente desaparecen después del recocido. Los resultados confirman la potencialidad de la implantación iónica para la formación de estructuras microme-cánicas de SiC sobre Si

Uso de los antihistamínicos en patología alérgica

Antihistamínic; Al·lèrgia; Urticària; Rinitis; Efectes adversos; InteraccionsAntihistamínico; Alergia; Urticaria; Rinitis; Efectos adversos; InteraccionesAntihistamine; Allergy; Urticaria; Rhinitis; Adverse effects; InteractionsEls antihistamínics anti-H1 són els fàrmacs més emprats per al tractament de les malalties al·lèrgiques. Es classifiquen en antihistamínics de primera generació (clorfeniramina, difenhidramina, hidroxizina) i de segona generació (bilastina, cetirizina, desloratadina, ebastina, fexofenadina, levocetirizina, loratadina, rupatadina). Actualment, per via oral, es recomana utilitzar sempre antihistamínics de segona generació amb una acció més selectiva sobre els receptors H1 i una baixa liposolubilitat que permet una distribució limitada al sistema nerviós central (SNC). En cas de necessitar un antihistamínic parenteral només es disposa de la dexclorfeniramina, que és de primera generació. Els antihistamínics són efectius en el tractament de les rinoconjuntivitis al·lèrgiques i les urticàries de qualsevol etiologia. L’elevada prevalença de la rinitis en la població general (20%) fa que la prescripció d’antihistamínics sigui molt elevada. En la rinitis són més efectius per tractar la mucositat, la pruïja i els esternuts que la congestió nasal. També s’utilitzen com a tractament de la urticària crònica espontània. Així mateix, els antihistamínics no controlen la pruïja de la dermatitis atòpica ni són el tractament de primera línia en l’anafilaxi. Els antihistamínics anti-H1 són, en general, fàrmacs ben tolerats. Els de primera generació creuen la barrera hematoencefàlica i poden produir sedació i efectes anticolinèrgics centrals (confusió, agitació, etc.) i perifèrics (retenció d’orina, sequedat de boca, xerostomia). En el cas que un pacient necessiti tractament antihistamínic és important tenir en compte la càrrega anticolinèrgica dels fàrmacs que està prenent; això resulta especialment rellevant en pacients d’edat avançada. Un altre efecte advers d’alguns antihistamínics, potencialment greu, és la prolongació de l’interval QT, que va motivar la retirada del mercat de fàrmacs com astemizole i terfenadina. Cal tenir present que hi ha certs grups de població (embarassades, lactants, edat avançada, insuficiència renal i/o hepàtica i nens i nenes) en els quals els antihistamínics s’han de prescriure amb precaució tenint en compte les recomanacions de la fitxa tècnica del fàrmac. En aquest Butlletí es revisen els antihistamínics disponibles per a les principals malalties al·lèrgiques al nostre entorn.Los antihistamínicos antiH1 son los fármacos más utilizados para el tratamiento de las enfermedades alérgicas. Se clasifican en antihistamínicos de primera generación (clorfeniramina, difenhidramina, hidroxicina) y de segunda generación (bilastina, cetirizina, desloratadina, ebastina, fexofenadina, levocetirizina, loratadina, rupatadina). Actualmente, por vía oral, se recomienda utilizar siempre antihistamínicos de segunda generación con una acción más selectiva sobre los receptores H1 y una baja liposolubilidad que permite una distribución limitada en el sistema nervioso central (SNC). En caso de precisar un antihistamínico parenteral solo se dispone de la dexclorfeniramina, que es de primera generación. Los antihistamínicos son efectivos en el tratamiento de las rinoconjuntivitis alérgicas y las urticarias de cualquier etiología. La elevada prevalencia de la rinitis en la población general (20%) hace que la prescripción de antihistamínicos sea muy elevada. En la rinitis son más efectivos para tratar la mucosidad, el prurito y los estornudos de la congestión nasal. También se utilizan como tratamiento de la urticaria crónica espontánea. Aun así, los antihistamínicos no controlan el prurito de la dermatitis atópica ni son el tratamiento de primera línea en la anafilaxis. Los antihistamínicos antiH1 son, en general, fármacos bien tolerados. Los de primera generación cruzan la barrera hematoencefálica y pueden producir sedación y efectos anticolinérgicos, centrales (confusión, agitación, etc.…) y periféricos (retención de orina, sequedad de boca, xerostomía). En el caso en el que un paciente precise tratamiento antihistamínico es importante tener en cuenta la carga anticolinérgica de los fármacos que está tomando; esto resulta especialmente relevante en pacientes de edad avanzada. Otro efecto adverso, potencialmente grave, de algunos antihistamínicos es la prolongación del intervalo QT, que motivó la retirada del mercado de fármacos como astemizol y terfenadina. Se ha de tener presente que hay ciertos grupos de población (embarazadas, mujeres en periodo de lactancia, edad avanzada, insuficiencia renal y/o hepática y niños) en los que los antihistamínicos se deben prescribir con precaución teniendo en cuenta las recomendaciones de la ficha técnica del fármaco. En este boletín se revisan los antihistamínicos disponibles para las principales enfermedades alérgicas de nuestro entorno

Results of an Early Access Treatment Protocol of Daratumumab Monotherapy in Spanish Patients With Relapsed or Refractory Multiple Myeloma

Daratumumab is a human CD38-targeted monoclonal antibody approved as monotherapy for heavily pretreated relapsed and refractory multiple myeloma. We report findings for the Spanish cohort of an open-label treatment protocol that provided early access to daratumumab monotherapy and collected safety and patient-reported outcomes data for patients with relapsed or refractory multiple myeloma. At 15 centers across Spain, intravenous daratumumab (16 mg/kg) was administered to 73 patients who had >= 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or who were double refractory to both. The median duration of daratumumab treatment was 3.3 (range: 0.03-13.17) months, with a median number of 12 (range: 1-25) infusions. Grade 3/4 treatment-emergent adverse events were reported in 74% of patients and included lymphopenia (28.8%), thrombocytopenia (27.4%), neutropenia (21.9%), leukopenia (19.2%), and anemia (15.1%). Common (>5%) serious treatmentemergent adverse events included respiratory tract infection (9.6%), general physical health deterioration (6.8%), and back pain (5.5%). Infusion-related reactions occurred in 45% of patients. The median change from baseline in all domains of the EQ-5D-5L and EORTC QLQ-C30 was mostly 0. A total of 18 (24.7%) patients achieved a partial response or better, with 10 (13.7%) patients achieving a very good partial response or better. Median progression-free survival was 3.98 months. The results of this early access treatment protocol are consistent with previously reported trials of daratumumab monotherapy and confirm its safety and antitumoral efficacy in Spanish patients with heavily treated relapsed or refractory multiple myeloma

Five microRNAs in Serum Are Able to Differentiate Breast Cancer Patients From Healthy Individuals

Breast cancer is the cancer with the most incidence and mortality in women. microRNAs are emerging as novel prognosis/diagnostic tools. Our aim was to identify a serum microRNA signature useful to predict cancer development. We focused on studying the expression levels of 30 microRNAs in the serum of 96 breast cancer patients vs. 92 control individuals. Bioinformatic studies provide a microRNA signature, designated as a predictor, based on the expression levels of five microRNAs. Then, we tested the predictor in a group of 60 randomly chosen women. Lastly, a proteomic study unveiled the overexpression and downregulation of proteins differently expressed in the serum of breast cancer patients vs. that of control individuals. Twenty-six microRNAs differentiate cancer tissue from healthy tissue, and 16 microRNAs differentiate the serum of cancer patients from that of the control group. The tissue expression of miR-99a, miR-497, miR-362, and miR-1274, and the serum levels of miR-141 correlated with patient survival. Moreover, the predictor consisting of miR-125b, miR-29c, miR-16, miR-1260, and miR-451 was able to differentiate breast cancer patients from controls. The predictor was validated in 20 new cases of breast cancer patients and tested in 60 volunteer women, assigning 11 out of 60 women to the cancer group. An association of low levels of miR-16 with a high content of CD44 protein in serum was found. Circulating microRNAs in serum can represent biomarkers for cancer prediction. Their clinical relevance and the potential use of the predictor here described are discussed

A Ranking System for Reference Libraries of DNA Barcodes: Application to Marine Fish Species from Portugal

BACKGROUND: The increasing availability of reference libraries of DNA barcodes (RLDB) offers the opportunity to the screen the level of consistency in DNA barcode data among libraries, in order to detect possible disagreements generated from taxonomic uncertainty or operational shortcomings. We propose a ranking system to attribute a confidence level to species identifications associated with DNA barcode records from a RLDB. Here we apply the proposed ranking system to a newly generated RLDB for marine fish of Portugal. METHODOLOGY/PRINCIPAL FINDINGS: Specimens (n = 659) representing 102 marine fish species were collected along the continental shelf of Portugal, morphologically identified and archived in a museum collection. Samples were sequenced at the barcode region of the cytochrome oxidase subunit I gene (COI-5P). Resultant DNA barcodes had average intra-specific and inter-specific Kimura-2-parameter distances (0.32% and 8.84%, respectively) within the range usually observed for marine fishes. All specimens were ranked in five different levels (A-E), according to the reliability of the match between their species identification and the respective diagnostic DNA barcodes. Grades A to E were attributed upon submission of individual specimen sequences to BOLD-IDS and inspection of the clustering pattern in the NJ tree generated. Overall, our study resulted in 73.5% of unambiguous species IDs (grade A), 7.8% taxonomically congruent barcode clusters within our dataset, but awaiting external confirmation (grade B), and 18.7% of species identifications with lower levels of reliability (grades C/E). CONCLUSION/SIGNIFICANCE: We highlight the importance of implementing a system to rank barcode records in RLDB, in order to flag taxa in need of taxonomic revision, or reduce ambiguities of discordant data. With increasing DNA barcode records publicly available, this cross-validation system would provide a metric of relative accuracy of barcodes, while enabling the continuous revision and annotation required in taxonomic work