Clinical trials and Haemophilia during the COVID-19 pandemic: Madrid's experience

This is the peer reviewed version of the following article: "Clinical trials and Haemophilia during the COVID‐19 pandemic: Madrid's experience". Haemophilia (2020): 16 May, which has been published in final form at https://doi.org/10.1111/hae.14055. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Version

Two-year clinical outcome from the Iberian registry patients after left atrial appendage closure

AIMS: The aim of this study was to observe the percentage of thromboembolic and haemorrhagic events over a 2-year follow-up in patients with non-valvular atrial fibrillation (NVAF) undergoing closure of the left atrial appendage (LAA) with an occlusion device. Observed events and CHADS2 (congestive heart failure, hypertension, age, diabetes, stroke history), CHA2DS2-VASc (also adding: vascular disease and sex) and HAS-BLED (hypertension, abnormal liver/renal function, stroke history, bleeding predisposition, labile international normalised ratios, elderly, drugs/alcohol use)-predicted events were compared. METHODS: LAA closure with an occlusion device was performed in 167 NVAF patients contraindicated for oral anticoagulants and recruited from 12 hospitals between 2009 and 2013. At least two transoesophageal echocardiograms were performed in the first 6 months postimplantation. Antithrombotics included clopidogrel and aspirin. Patients were monitored for death, stroke, major and relevant bleeding and hospitalisation for concomitant conditions. Mean age was 74.68±8.58, median follow-up was 24 months, 5.38% had intraoperative complications and implantation was successful in 94.6% of subjects. Mortality during follow-up was 10.8%, mostly (9.5%) non-cardiac related. Bleeding occurred in 10.1% of subjects, 5.7% major and 4.4% minor though relevant, and 4.4% suffered stroke. Major bleeding and stroke/transient ischaemic attack events within 2 years (annual event rates, 290 patients/year) were less frequent than expected from CHADS2 (2.4% vs 9.6%), CHA2DS2-VASc (2.4% vs 8.3%) and HAS-BLED (3.1% vs 6.6%) risk scores (p<0.001, p=0.003, p=0.047, respectively). CONCLUSIONS: LAA closure with an occlusion device in patients contraindicated for oral anticoagulants is a therapeutic option associated with fewer thromboembolic and haemorrhagic events than expected from risk scores, particularly in the second year postimplantation

The importance of platelet glycoside residues in the haemostasis of patients with immune thrombocytopaenia

Loss of sialic acid from the carbohydrate side chains of platelet glycoproteins can affect platelet clearance, a proposed mechanism involved in the etiopathogenesis of immune thrombocy-topaenia (ITP). We aimed to assess whether changes in platelet glycosylation in patients with ITP affected platelet counts, function, and apoptosis. This observational, prospective, and transversal study included 82 patients with chronic primary ITP and 115 healthy controls. We measured platelet activation markers and assayed platelet glycosylation and caspase activity, analysing samples using flow cytometry. Platelets from patients with ITP with a platelet count &lt;30 × 103/µL presented less sialic acid. Levels of α1,6-fucose (a glycan residue that can directly regulate antibody-dependent cellular cytotoxicity) and α-mannose (which can be recognised by mannose-binding-lectin and acti-vate the complement pathway) were increased in the platelets from these patients. Platelet surface exposure of other glycoside residues due to sialic acid loss inversely correlated with platelet count and the ability to be activated. Moreover, loss of sialic acid induced the ingestion of platelets by human hepatome HepG2 cells. Changes in glycoside composition of glycoproteins on the platelets’ surface impaired their functional capacity and increased their apoptosis. These changes in platelet glycoside residues appeared to be related to ITP severity.This research was funded by FIS-Fondos FEDER PI19/00631, FIS-Fondos FEDER PI19/00772 and Platelet Disorder Support Associatio

Impact of Covid-19 pandemic on patients with immune thrombocytopaenia

Background and Objectives: The aim of this study was to determine the impact of the COVID-19 pandemic on the lives of patients with immune thrombocytopaenia (ITP) treated at our hospital. Materials and Methods: The study was conducted in the Community of Madrid, which has the highest number of COVID-19 cases in Spain. We included 143 adult patients with ITP (130 with chronic ITP, 8 with persistent ITP, and 5 with newly diagnosed ITP). We conducted a telephone survey to collect the data and created a registry. Materials and Methods: Overall, 24 patients presented symptoms suggestive of COVID-19, which was confirmed by RT-PCR in 8 cases. The cumulative incidence of confirmed SARS-CoV-2 infection was higher in the patients with ITP than in the Madrid population. There were no differences in the disease incidence or clinical course of infection in the patients treated with immunosuppressants. Almost all of the patients reported adherence to the prescribed treatment, although 49.2% of the hospital visits were either cancelled or postponed, 17.2% because of the patients’ fear of coming to the centre. Nearly half of the cohort was considered vulnerable, and 17% had been granted a dependency or disability benefit. Conclusions: COVID-19 had a major impact on the psychosocial, occupational, and quality of care of patients with ITP.This study was supported by FIS-Fondos FEDER PI19/00631 and PI19/00772 and by the Platelet Disorder Support Associatio

2013. Documento Sevilla de Consenso sobre Alternativas a la Transfusión de Sangre Alogénica. Actualización del Documento Sevilla

La transfusión de sangre alogénica (TSA) no es inocua, y como consecuencia han surgido múltiples alternativas a la misma (ATSA). Existe variabilidad respecto a las indicaciones y buen uso de las ATSA. Dependiendo de la especialidad de los médicos que tratan a los pacientes, el grado de anemia, la política transfusional, la disponibilidad de las ATSA y el criterio personal, estas se usan de forma variable. Puesto que las ATSA tampoco son inocuas y pueden no cumplir criterios de coste-efectividad, la variabilidad en su uso es inaceptable. Las sociedades españolas de Anestesiología y Reanimación (SEDAR), Hematología y Hemoterapia (SEHH), Farmacia Hospitalaria (SEFH), Medicina Intensiva y Unidades Coronarias (SEMICYUC), Trombosis y Hemostasia (SETH) y Transfusiones Sanguíneas (SETS) han elaborado un documento de consenso para el buen uso de la ATSA. Un panel de expertos de las 6 sociedades ha llevado a cabo una revisión sistemática de la literatura médica y elaborado el 2013. Documento Sevilla de Consenso sobre Alternativas a la Transfusión de Sangre Alogénica. Solo se contempla las ATSA dirigidas a disminuir la transfusión de concentrado de hematíes. Se definen las ATSA como toda medida farmacológica y no farmacológica encaminada a disminuir la transfusión de concentrado de hematíes, preservando siempre la seguridad del paciente. La cuestión principal que se plantea en cada ítem se formula, en forma positiva o negativa, como: «La ATSA en cuestión reduce/no reduce la tasa transfusional». Para formular el grado de recomendación se ha usado la metodología Grades of Recommendation Assessment, Development and Evaluation (GRADE)

Phenology of Tempranillo and Cabernet-Sauvignon varieties cultivated in the Ribera del Duero DO: observed variability and predictions under climate change scenarios

Aim: This research examined relationships between grapevine phenology and climate in the Ribera del Duero DO (Spain). The observed varieties included Tempranillo, the main variety planted in the region, and Cabernet-Sauvignon. Methods and Results: Phenological events for stages C (budbreak), I (bloom), M (véraison) and N (maturity) were analyzed for 2004-2015. Dormant period chilling and late winter heating requirements to initiate growth were evaluated and accumulated temperature (growing degree days-GDD) prior to each phenological event and in between events were examined for the role they play in influencing growth timing. The results were then used to examine future phenological changes due to climate change using eight models integrated in the Coupled Model Intercomparison Project (CMIP5) and for two Representative Concentration Pathways (RCP) scenarios – RCP4.5 and RCP8.5 – for 2030, 2050, and 2070. Accumulated temperatures after March 20th become important for initiating phenology and are strongly correlated to all growth events. The influence of water availability between budbreak and bloom and between bloom and véraison on phenological timing was also confirmed. Conclusions: The projections showed that for the RCP4.5 emission scenario, budbreak is predicted earlier by approximately 2 days for 2030, 3 days for 2050 and 5 days for 2070, while bloom is predicted to be 3 to 8 days earlier and véraison 6 to 19 days earlier for the same time periods. For the RCP8.5 emission scenario, budbreak is modeled to take place about 3 days, 5 days and 9 days earlier, respectively for 2030, 2050 and 2070. Bloom is predicted to occur about 5, 10 and 16 days earlier; véraison is predicted earlier by 10 days for 2030, 19 days for 2050, and 28 days for 2070. Maturity and the timing of harvest could be up to 23 days earlier under the RCP4.5 emission scenario and up to 35 days earlier under the RCP8.5 emission scenario. Compared to Cabernet-Sauvignon, Tempranillo exhibited greater phenological sensitivity to temperature changes in the observed time period that is likely to continue into the future with greater changes to earlier growth events projected. This sensitivity could be problematic for the region due to the variety’s historic importance and points to the need to examine adaptive measures that can help growers to respond to projected changes in climate. Significance and impact of the study: The projected climate changes in the future indicate the potential for significant changes in the phenology of Tempranillo in the Ribera del Duero DO, Spain. Given that this variety has the largest contribution and importance in this region, these changes could have impacts on wine quality, indicating the need of establishing strategies to reduce or mitigate the impact from future changes in climate

New live attenuated tuberculosis vaccine MTBVAC induces trained immunity and confers protection against experimental lethal pneumonia

Among infectious diseases, tuberculosis is the leading cause of death worldwide, and represents a serious threat, especially in developing countries. The protective effects of Bacillus Calmette-Guerin (BCG), the current vaccine against tuberculosis, have been related not only to specific induction of T-cell immunity, but also with the long-term epigenetic and metabolic reprogramming of the cells from the innate immune system through a process termed trained immunity. Here we show that MTBVAC, a live attenuated strain of Mycobacterium tuberculosis, safe and immunogenic against tuberculosis antigens in adults and newborns, is also able to generate trained immunity through the induction of glycolysis and glutaminolysis and the accumulation of histone methylation marks at the promoters of proinflammatory genes, facilitating an enhanced response after secondary challenge with non-related bacterial stimuli. Importantly, these findings in human primary myeloid cells are complemented by a strong MTBVAC-induced heterologous protection against a lethal challenge with Streptococcus pneumoniae in an experimental murine model of pneumonia.M.G.N. was supported by an ERC Advanced grant (#833247) and by a Spinoza Grant of the Netherlands Organization for Scientific Research (https://erc.europa.eu/). UNIZAR Team was supported by Ministry of Science and Universities Grant RTI2018-097625-B-100 (http://www.ciencia.gob.es/portal/site/MICINN/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S