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Resumen Fundamento y objetivo La enfermedad del injerto contra el receptor (EICR) y las infecciones son complicaciones del trasplante alogenico de progenitores hematopoyeticos (alo-TPH). La globulina antitimocitica (ATG) es una estrategia empleada para la profilaxis de la EICR. Este estudio analiza los resultados y la frecuencia de infecciones en funcion del uso de ATG, despues de un alo-TPH de donante no emparentado (DNE) en pacientes con leucemia aguda y sindrome mielodisplasico. Pacientes y metodo Estudio retrospectivo de pacientes que recibieron un alo-TPH de DNE entre diciembre de 2007 y abril de 2019. Se compararon los principales resultados en funcion del uso de ATG. Resultados Se incluyo a 66 pacientes. No se encontraron diferencias significativas en el grupo ATG (n = 50) frente al no ATG (n = 16) en supervivencia global, incidencia acumulada de recaida, mortalidad no debida a recaida o incidencia acumulada de EICR aguda o cronica. Hubo mayor frecuencia de infecciones en el grupo ATG (60 frente a 19%; p = 0,004). Conclusiones En este estudio no se demostro diferencia en los principales resultados del alo-TPH en funcion del uso de ATG, pero hubo mas infecciones en el grupo que recibio ATG.

Background and purpose Graft-versus-host disease (GVHD) and infections are complications after allogeneic stem cell transplantation (alloSCT). Anti-thymocyte globulin (ATG) is a strategy used as prophylaxis for GVHD. The study analyses the outcomes and frequency of infections with or without ATG after an unrelated donor alloSCT in patients with acute leukaemia and myelodysplastic syndrome. Patients and methods Retrospective study of patients receiving an unrelated donor alloSCT between December 2007 and April 2019. The main outcomes were analysed according to use or not of ATG. Results Sixty-six patients were included. No significant differences were found between the ATG group (n = 50) vs. no-ATG group (n = 16) in overall survival, cumulative incidence of relapse, cumulative incidence of non-relapse mortality or cumulative incidence of acute GVHD or chronic GVHD. There was a greater frequency of infections in the ATG group (60% vs. 19%, p = .004). Conclusions In this study, no differences were shown in the main outcomes of alloSCT based on the use of ATG, although more infections were documented in the ATG group.

The consequences of extremely intense long-term exercise for brain health remain unknown. We studied the effects of strenuous exercise on brain structure and function, its dose-response relationship, and mechanisms in a rat model of endurance training. Five-week-old male Wistar rats were assigned to moderate (MOD) or intense (INT) exercise or a sedentary (SED) group for 16 weeks. MOD rats showed the highest motivation and learning capacity in operant conditioning experiments; SED and INT presented similar results. In vivo MRI demonstrated enhanced global and regional connectivity efficiency and clustering as well as a higher cerebral blood flow (CBF) in MOD but not INT rats compared with SED. In the cortex, downregulation of oxidative phosphorylation complex IV and AMPK activation denoted mitochondrial dysfunction in INT rats. An imbalance in cortical antioxidant capacity was found between MOD and INT rats. The MOD group showed the lowest hippocampal brain-derived neurotrophic factor levels. The mRNA and protein levels of inflammatory markers were similar in all groups. In conclusion, strenuous long-term exercise yields a lesser improvement in learning ability than moderate exercise. Blunting of MOD-induced improvements in CBF and connectivity efficiency, accompanied by impaired mitochondrial energetics and, possibly, transient local oxidative stress, may underlie the findings in intensively trained rats.

Background and objective Patients who survive beyond two years after haematopoietic stem cell transplantation (HSCT) have an increased risk of long-term complications, which impact on their survival and quality of life. The aim of this study was to design and apply a long-term follow-up protocol to detect unmet needs and treat these complications early. Patients and method A prospective study to detect and treat complications and long-term problems within an interdisciplinary functional unit was applied to survivors beyond 2 years of allogeneic HSCT (alloHSCT). Results Thirty-six (36%) of the 99 patients included, required intervention in a cardiovascular risk factor by health education or antihypertensive and lipid-lowering drugs. Nine of 36 (25%) patients required calcium and vitamin D intake. Low inclusion of women in gynaecological neoplasm detection protocols was detected, as well as a low adherence to dental follow-up after alloHSCT. Conclusion The follow-up of long-term survivors after alloHSCT in a multidisciplinary unit allowed unmet needs to be detected and controlled, especially in cardiovascular risk, bone metabolism, cancer prevention, and dental control.

Resumen Fundamento y objetivo Los pacientes que sobreviven mas alla de 2 anos del trasplante de progenitores hematopoyeticos (TPH), tienen un riesgo aumentado de complicaciones a largo plazo, que tienen impacto en su supervivencia y calidad de vida. El objetivo de este estudio fue disenar y aplicar un protocolo de seguimiento a largo plazo para detectar necesidades no cubiertas y tratar precozmente dichas complicaciones. Pacientes y metodo A los supervivientes mas alla de 2 anos del TPH alogenico (aloTPH) se aplico una sistematica de estudio para detectar y tratar complicaciones y problemas a largo plazo dentro de una unidad funcional interdisciplinar. Resultados Treinta y seis (36%) de los 99 pacientes incluidos, requirieron de intervencion en alguno de los factores de riesgo cardiovascular mediante educacion sanitaria o administracion de farmacos antihipertensivos e hipolipemiantes. Nueve (25%) de 36 pacientes requirieron aporte de calcio y vitamina D. Se detecto una baja reincorporacion de las mujeres a los protocolos de deteccion de neoplasias ginecologicas, y una baja adherencia al seguimiento odontologico tras el aloTPH. Conclusion El seguimiento de los largos supervivientes a un aloTPH en una unidad multidisciplinaria permitio detectar necesidades no cubiertas, que afectaron especialmente al riego cardiovascular, metabolismo oseo, prevencion del cancer y control odontologico.

Trabajo presentado en el XII Simposi de Neurobiologia, Societat Catalana de Biologia, celebrado en Barcelona (España), los días 7 y 8 de junio de 2022, Physically active lifestyle has huge benefits for the health and well-being of people of all ages. However, excessive training can lead to severe cardiovascular events such as heart fibrosis and arrhythmia. In addition, strenuous exercise may impair brain plasticity. Here we investigate the presence of any deleterious effects induced by chronic exercise at the level of high intensity, although not reaching exhaustion. We analyzed cardiovascular, cognitive and cerebral molecular changes in young adult male mice submitted to treadmill running for eight weeks at moderate or high intensity regimens compared to sedentary mice. Exercised mice showed decreased weight gain that was significant for the high intensity level group. Exercised mice showed cardiac hypertrophy, but no morphological changes in the aorta. High-intensity training induced decrease in heart rate and increase in motor skills. However, it did not impair recognition or spatial memory and, accordingly, the expression of hippocampal neuroplasticity markers was maintained. Interestingly, catalase expression and proteasome enzymatic activity were increased in the cerebral cortex of the high-intensity trained group; both first-line mechanisms contributing to maintain redox homeostasis and prevent the accumulation of damaged proteins. Therefore, physical exercise at an intensity that induces adaptive cardiovascular changes in parallel increases antioxidant defenses to prevent brain damage and build resilience against neurodegeneration., MCIN/AEI (PID2019 106285RB C22); AGAUR (2017 SGR 106); Instituto de Salud Carlos III (PI19/00443) and ERDF.

Altres ajuts: CERCA Programme/Generalitat de Catalunya, Fundaluce and "la Caixa" foundations (ID 100010434, agreement LCF/PR/HR19/52160010), Co-financed by the European Union Regional Development Fund within the framework of the ERDF Operational Program of Catalonia 2014-2020 Adrenoceptors are ubiquitous and mediate important autonomic functions as well as modulating arousal, cognition, and pain on a central level. Understanding these physiological processes and their underlying neural circuits requires manipulating adrenergic neurotransmission with high spatio-temporal precision. Here we present a first generation of photochromic ligands (adrenoswitches) obtained via azologization of a class of cyclic amidines related to the known ligand clonidine. Their pharmacology, photochromism, bioavailability, and lack of toxicity allow for broad biological applications, as demonstrated by controlling locomotion in zebrafish and pupillary responses in mice.

Objectives: We present here data on Gram-negative rods bacteremia (GNRB) rates, risk factors and associated mortality. Methods: Data on GNRB episodes were prospectively collected in 65 allo-/67 auto-HSCT centers in 24 countries (Europe, Asia, Australia). In patients with and without GNRB, we compared: demography, underlying disease, HSCT-related data, center' fluoroquinolone prophylaxis (FQP) policy and accreditation status, and involvement of infection control team (ICT). Results: The GNRB cumulative incidence among 2818 allo-HSCT was: pre-engraftment (pre-eng-alloHSCT), 8.4 (95% CI 7-9%), post-engraftment (post-eng-allo-HSCT), 5.8% (95%CI: 5-7%); among 3152 auto-HSCT, pre-eng-auto-HSCT, 6.6% (95%CI: 6-7%), post-eng-auto-HSCT, 0.7% (95%CI: 0.4-1.1%). GNRB, especially MDR, was associated with increased mortality. Multivariate analysis revealed the following GNRB risk factors: (a) pre-eng-allo-HSCT: south-eastern Europe center location, underlying diseases not at complete remission, and cord blood source; (b) post-eng-allo-HSCT: center location not in northwestern Europe; underlying non-malignant disease, not providing FQP and never accredited. (c) pre-eng-auto-HSCT: older age, autoimmune and malignant (vs. plasma cell) disease, and ICT absence. Conclusions: Benefit of FQP should be explored in prospective studies. Increased GNRB risk in auto-HSCT patients transplanted for autoimmune diseases is worrying. Infection control and being accredited are possibly protective against bacteremia. GNRB are associated with increased mortality. (C) 2020 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Introduction The impact of an admission to ICU before stem cell transplantation (SCT) on post-SCT outcome is not well established. Patients and methods We reviewed the medical records of patients who had received a first SCT between 2000 and 2016 in our institution. The outcome of 22 patients who required ICU admission during chemotherapy prior to SCT (ICU group) was compared with 44 matched patients (1:2) who did not need it (NO-ICU group). Results There were no differences in transplant complications, in time to neutrophil and platelet recovery or in the length of hospital stay during SCT between the ICU and NO-ICU groups. However, microbiologically documented infections were more common in the ICU group (16/20) than in the NO-ICU group (18/39) (p = .027). The 5-yr overall survival probability (CI 95%) was 49% (28–70%) in the ICU vs. 45% (29–61%) in the NO-ICU group (p = .353), while the 5-yr incidence of non-relapse mortality was 32% (14–52%) and 24% (12–38%) (p = .333), respectively. Six patients (27%) in the ICU group and 8 (18%) in the NO-ICU group required admission to the ICU during or after the SCT procedure (p = .293). Twelve (54%) patients in the ICU and 22 (50%) in the NO-ICU group died, the causes of death were similar in both groups. Conclusion Our results show that admission to the ICU prior to SCT does not have a negative impact on patient outcomes following SCT and should not be considered as an exclusion criterion for SCT.

Most cells release extracellular vesicles (EVs) that can be detected circulating in blood. We and others have shown that the microRNA contents of these vesicles induce transcriptomic changes in acceptor cells, contributing to the adjustment of metabolic homeostasis in response to environmental demands. Here, we explore the potential for modulating obesity- and exercise-derived EV-microRNAs to treat the metabolic dysfunction associated with obesity in mice. Treatment with EV-miRNAs alleviated glucose intolerance and insulin resistance in obese mice to an extent similar to that of high-intensity interval training, although only exercise improved cardiorespiratory fitness and decreased body weight. Mechanistically, EV-miRNAs decreased fatty acid and cholesterol biosynthesis pathways in the liver, reducing hepatic steatosis and increasing insulin sensitivity, resulting in decreased glycemia and triglyceridemia. Our data suggest that manipulation of EV-miRNAs may be a viable strategy to alleviate metabolic dysfunction in obese and diabetic patients who are unable to exercise, although actual physical activity is needed to improve cardiorespiratory fitness.

Moderate exercise has well-founded benefits in cardiovascular health. However, increasing, yet controversial, evidence suggests that extremely trained athletes may not be protected from cardiovascular events as much as moderately trained individuals. In our rodent model, intensive but not moderate training promoted aorta and carotid stiffening and elastic lamina ruptures, tunica media thickening of intramyocardial arteries, and an imbalance between vasoconstrictor and relaxation agents. An up-regulation of angiotensin-converter enzyme, miR-212, miR-132, and miR-146b might account for this deleterious remodeling. Most changes remained after a 4-week detraining. In conclusion, our results suggest that intensive training blunts the benefits of moderate exercise.

Growth arrest-specific 6 (GAS6) protein plays a key role in processes related to proliferation, inflammation, angiogenesis, and atherosclerotic plaque formation. In addition, it has been reported that plasma levels of GAS6 are related to cancer prognosis and other relevant pathologies, such as heart failure or sepsis. We report here the first electrochemical immunoplatform for the determination of GAS6, which has demonstrated to be competitive with other available methodologies in terms of cost, simplicity, and decentralized application. The developed immunoplatform involves a sandwich immunoassay using magnetic microparticles (MBs) and uses amperometric detection at disposable screen-printed carbon electrodes (SPCEs). The MBs were modified with an antibody specific to GAS6 for its selective capture, which is further recognized by a biotinylated secondary antibody subsequently labeled with a streptavidin-horseradish peroxidase (Strep-HRP) conjugate. The electrochemical detection was carried out using the hydroquinone (HQ)/H2O2 system. The developed bioplatform exhibits a great selectivity and low limit of detection (27 pg/mL) that allowed the determination of the GAS6 circulating level in plasma samples from patients suffering heart failure (HF) and diagnosed with pancreatic ductal adenocarcinoma (PDAC), as well as the determination of the target protein in raw secretomes of human colorectal cancer cell lines., This work is part of the POSITION-II project fundedby the ECSEL Joint Undertaking under grant numberEcsel-783132-Position-II-2017-IA;www.position-2.eu,and PCI2018-093067 (Spanish Ministerio de Ciencia eInnovación) to M.P. The financial support of PID2019-103899RB-I00 (Spanish Ministerio de Ciencia e Inno-vación) Research Project to S.C., PI17CIII/00045 andPI20CIII/00019 grants from the AES-ISCIII program toR.B. and the TRANSNANOAVANSENS-CM Program fromthe Comunidad de Madrid (Grant S2018/NMT-4349) toS.C., RTI2018-095672-B-I00 (Spanish Ministerio de Cienciae Innovación) to P.G.F.; Fundació la Marató de TV3 project081010toM.B.; researchprojectPI20/00625,fromtheAES-ISCIII/FEDER program, to P.N, are gratefully acknowl-edged. A. Montero-Calle acknowledges the support of theFPU predoctoral contracts by the Spanish Ministerio deEducación, Cultura y Deporte. G.S-F. is recipient of a pre-doctoral contract (grant number 1193818N) supported byThe Flanders Research Foundation (FWO). C. Muñoz-SanMartín acknowledges a predoctoral contract from Complutense University of Madrid. R.M. Torrente-Rodríguezacknowledges a Talento-Contract from Comunidad deMadrid (2019-T2/IND-15965).

Objectives The authors sought to evaluate cardiac activity of angiotensin-converting enzyme (ACE) and ACE2 after heart transplantation (HT) and its relation with acute rejection (AR) and chronic allograft vasculopathy (CAV). Background The renin-angiotensin system is altered in heart failure and HT. However, ACE and ACE2 activities in post-HT acute and chronic rejection have not been previously studied. Methods HT patients (n = 45) were included when appropriate serial endomyocardial biopsies (EMB) and coronary angiography were available for analysis. In 21 patients, three post-HT time points were selected for CAV study in EMB tissue: basal (0–3 wks), second (2–3 months) and third (4–5 months). At 10 years post-HT, CAV was evaluated by coronary angiography (CA) and patients were grouped by degree of CAV: 0–1, non-CAV (n = 15) and 2–3, CAV (n = 6). For the AR study, 28 HT patients with evidence of one EMB rejection at grade 3 and two EMB grade 1A and/or 1B rejections were selected. Results Post-HT, ACE2 activity was increased in the CAV group, compared to non-CAV. Patients with AR showed increased ACE, but not ACE2, activity. Conclusions Our results suggest that early post-HT cardiac ACE2 activity may have an important role in CAV development. In contrast, ACE activity was increased in AR. The renin-angiotensin system seems to be altered after HT and strategies to balance the system may be useful.

Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): TRAIN-HEART Innovative Training Network, funded by the European Union’s Horizon 2020 research and innovation program (under the Marie Sklodowska-Curie grant agreement no. 813716) Characterizing Atrial fibrillation by Translating its Causes into Health Modifiers in the Elderly (CATCH ME), funded by the European Union’s Horizon 2020 research and innovation program (under the grant agreement no. 633196) Background Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with heart failure (HF) and stroke. Clinical and experimental data from previous studies suggest gender differences in mechanisms and phenotypes of AF: women may have more atrial fibrosis, worse outcomes after catheter ablation, and some women carry a higher risk for thromboembolic complications than men. The molecular mechanisms underlying these differences are still poorly understood. Methods Gender-based transcriptional patterns were assessed using paired-end, directional RNA sequencing data generated from atrial tissue biopsies in 199 patients either in sinus rhythm or with paroxysmal or persistent AF as part of the CATCH-ME project. Transcript counts were compared between genders separately in the left and right atria using the DESeq2 package in R. The models were adjusted for potential sources of confounding (age, atrial fibrillation status, heart failure status and sequencing batch). Interaction models were implemented using DESeq2 to compare gender*morbidity interactions for persistent AF and HF. Significance was assessed using likelihood ratio tests comparing models with and without the interaction terms. Results with an adjusted P-value 0.05 were considered significant and utilized for subsequent downstream assessments. Differentially expressed (DE) genes were tested for enrichment of gene ontology (GO) terms and KEGG pathways using the WebGestalt toolkit. Results Transcriptome-wide profiling across the cohort identified 33 sex-differentiated genes in the left atria and 51 in the right atrial samples, with 21 of these showing bilateral differences. Interestingly, 36 (44%) of the results from these analyses were comprised of non-coding transcripts, including long non-coding RNAs (lncRNAs), antisense RNAs and pseudogenes. GO and pathway enrichment analyses for these genes revealed their involvement in critical pathways such as the complement and coagulation cascades and RNA transport. Interaction analyses between gender and AF identified two genes (MPP2 & GNAS-AS1) that were differentially transcribed in the right atria and one gene (MYL2) that was DE in the left atria by gender in persistent AF samples. A similar analysis comparing gender*HF morbidity also revealed evidence of DE. Four transcripts (HLA-DQB1-AS1, EIF1AY, UTY and ZFY-AS1) showed gender-specific differences in expression by HF status in left atria, while HLA-DQB1-AS1 was differentially regulated by gender and HF status in right atrial samples. Conclusions These RNA-seq analyses provide novel insights into gender-related differences in the transcriptional landscape of right and left adult human atrial appendages. Moreover, interaction analyses identified three genes DE in female atria in persistent AF and four DE genes in female atria in heart failure, providing a molecular anchor for the observed differences in atrial diseases phenotypes between men and women.

The potential role of active CMV infection in promoting acute Graft-versus-Host Disease (aGvHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a matter of debate. We further addressed this issue conducting a retrospective, observational, multicenter study of 632 patients subjected to allogeneic peripheral blood HSCT at 20 Spanish centers. Monitoring of CMV DNA load in plasma or whole blood was performed by real-time PCR assays. Cumulative incidence of CMV DNAemia was 48.9% (95% CI, 45%-52.9%), of any grade aGvHD, 45.6; 95% (CI, 41.3%-50.1%), and of grade II-IV aGvHD, 30.7 (95% CI, 24.9%-36.4%). Overall, development of CMV DNAemia at any level resulted in an increased risk of subsequent all grade (HR, 1.38; 95% CI, 1.08 - 1.76; P = .009) or grade II-IV (HR, 1.58; 95% CI, 1.22 - 2.06; P = .001) aGvHD. The increased risk of aGvHD linked to prior occurrence of CMV DNAemia was similar to the above when only clinically significant episodes were considered for the analyses (HR for all grade aGvHD, 1.48; 95% CI, 1.13 - 1.91; P = .041, and HR for grade II-IV aGvHD, 1.53; 95% CI. 1.13-1.81; P = .04). The CMV DNA doubling time in blood was comparable overall in episodes of CMV DNAemia whether followed by aGvHD or not. Whether CMV replication is a surrogate risk marker of aGvHD or it is causally involved is an important question to be addressed in future experimental research.

The net impact of cytomegalovirus (CMV) DNAemia on overall mortality (OM) and nonrelapse mortality (NRM) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a matter of debate. This was a retrospective, multicenter, noninterventional study finally including 749 patients. CMV DNA monitoring was conducted by real-time polymerase chain reaction (PCR) assays. Clinical outcomes of interest were OM and NRM through day 365 after allo-HSCT. The cumulative incidence of CMV DNAemia in this cohort was 52.6%. A total of 306 out of 382 patients with CMV DNAemia received preemptive antiviral therapy (PET). PET use for CMV DNAemia, but not the occurrence of CMV DNAemia, taken as a qualitative variable, was associated with increased OM and NRM in univariate but not in adjusted models. A subcohort analysis including patients monitored by the COBAS Ampliprep/COBAS Taqman CMV Test showed that OM and NRM were comparable in patients in whom either low or high plasma CMV DNA threshold (= 500 IU/mL) was used for PET initiation. In conclusion, CMV DNAemia was not associated with increased OM and NRM in allo-HSCT recipients. The potential impact of PET use on mortality was not proven but merits further research.

Background Little is known about characteristics of seasonal human coronaviruses (HCoVs) (NL63, 229E, OC43, and HKU1) after allogeneic stem cell transplantation (allo-HSCT). Methods This was a collaborative Spanish and European bone marrow transplantation retrospective multicenter study, which included allo-HSCT recipients (adults and children) with upper respiratory tract disease (URTD) and/or lower respiratory tract disease (LRTD) caused by seasonal HCoV diagnosed through multiplex polymerase chain reaction assays from January 2012 to January 2019. Results We included 402 allo-HSCT recipients who developed 449 HCoV URTD/LRTD episodes. Median age of recipients was 46 years (range, 0.3–73.8 years). HCoV episodes were diagnosed at a median of 222 days after transplantation. The most common HCoV subtype was OC43 (n = 170 [38%]). LRTD involvement occurred in 121 episodes (27%). HCoV infection frequently required hospitalization (18%), oxygen administration (13%), and intensive care unit (ICU) admission (3%). Three-month overall mortality after HCoV detection was 7% in the whole cohort and 16% in those with LRTD. We identified 3 conditions associated with higher mortality in recipients with LRTD: absolute lymphocyte count Conclusions Seasonal HCoV after allo-HSCT may involve LRTD in many instances, leading to a significant morbidity.

Introduction: There is emerging evidence in men that sustained high-intensity training promotes an adverse cardiovascular remodeling, thereby increasing the risk of atrial fibrillation, ventricular arrhythmias and coronary calcification. Whether men and women are similarly affected by high intensity exercise-induced harm is unclear. Our aim was to study sex differences in a long-term endurance training rat model. Methods: Male and female Wistar rats were subjected to high intensity training for 16 weeks (INT, 60min 60cm/s, male n=20, female n=15). Sedentary rats (SED, male n=20, female n=18) were used as controls. At the end of the training period, rats had an electrocardiogram and echocardiography performed. Vascular fibrosis was assessed in descending aorta, left carotid, and intramyocardial arteries (IMA), right and left atria, and left ventricle (LV) histological samples. mRNA levels of cardiac hypertrophy, fibrosis, oxidative stress and inflammation genes were assessed in LV samples by Real-Time PCR. Results: INT male rats presented lower heart rate (382±9, 340±10, SED vs INT, p Conclusions: Male and female rats exhibit qualitatively different cardiovascular remodeling after extreme exercise. Nevertheless, both sexes might develop exercise-induced adverse vascular and cardiac effects.

Introduction: A U-shaped relationship between exercise load and cardiovascular risk has been demonstrated. In the brain, moderate exercise improves cognitive performance but the consequences of intense exercise remain unknown. We aimed to describe the effects of moderate and intensive exercise load on brain structure and function. Methods: Male Wistar rats were subjected to moderate (MOD, 35 cm/s for 45 min, n=8) or intense (INT, 60 cm/s for 60 min, n=8) exercise for 16 weeks, 5 days/week; sedentary rats (SED, n=10) were used as controls. At 16 weeks, learning and motivation tests, and brain magnetic resonance (MR) were obtained. In MR, structural brain networks were analyzed using fractional anisotropy normalized connectomes, and cerebral blood flow (CBF) was assessed using pulsed arterial spin labelling. BDNF levels were analysed in plasma, hippocampus and frontal cortex samples with ELISA. Results: MOD rats showed a greater motivation than SED rats and enhanced learning capacity than INT rats. In the MR, only moderate exercise increased global and local efficiency and average clustering coefficient. Global CBF was increased by moderate but not intensive exercise (Fig A). CBF was subsequently assessed at specific brain regions. In comparison to SED, MOD rats presented a higher CBF in the right and left cortex, and in the left hippocampus; in INT rats, CBF was higher only in the left cortex compared to SED (Fig B). MOD training induced a significant decrease in BDNF protein levels in the hippocampus compared to both SED and INT groups. No significant differences were found on BDNF levels in plasma and frontal cortex samples among groups. Conclusions: In a rat model, moderate exercise induces brain structural and functional improvements that are not perpetuated with intensive exercise, supporting the existence of a U-shaped relationship between exercise load and brain function.

There is limited information on the impact of CMV DNAemia episodes developing prior to engraftment (pre-CMV DNAemia) on clinical outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). This issue was addressed in the current retrospective multicenter study including 878 patients. All participant centers used preemptive antiviral therapy strategies for prevention of CMV disease. CMV DNA load in blood was monitored by real-time PCR assays. A total of 144 patients (cumulative incidence 16.5%, 95% CI, 14%-19%) had an episode of pre-CMV DNAemia at a median of 10 days after allo-HSCT. Patients who developed pre-CMV DNAemia had a significantly higher (P = < 0.001) probability of recurrent episodes (50%) than those who experienced post-CMV DNAemia (32.9%); Nevertheless, the incidence of CMV disease was comparable (P = 0.52). Cumulative incidences of overall mortality (OM) and non-relapse mortality (NRM) at 1-year after allo-HSCT were 32% (95% CI, 29-35%) and 23% (95% CI 20-26%), respectively. The risk of OM and NRM in adjusted models appeared comparable in patients developing a single episode of CMV DNAemia, regardless of whether it occurred before or after engraftment, in patients with pre- and post-engraftment CMV DNAemia episodes or in those without CMV DNAemia.

Patient-ventilator asynchronies can be detected by close monitoring of ventilator screens by clinicians or through automated algorithms. However, detecting complex patient-ventilator interactions (CP-VI), consisting of changes in the respiratory rate and/or clusters of asynchronies, is a challenge. Sample Entropy (SE) of airway flow (SE-Flow) and airway pressure (SE-Paw) waveforms obtained from 27 critically ill patients was used to develop and validate an automated algorithm for detecting CP-VI. The algorithm’s performance was compared versus the gold standard (the ventilator’s waveform recordings for CP-VI were scored visually by three experts; Fleiss’ kappa = 0.90 (0.87–0.93)). A repeated holdout cross-validation procedure using the Matthews correlation coefficient (MCC) as a measure of effectiveness was used for optimization of different combinations of SE settings (embedding dimension, m, and tolerance value, r), derived SE features (mean and maximum values), and the thresholds of change (Th) from patient’s own baseline SE value. The most accurate results were obtained using the maximum values of SE-Flow (m = 2, r = 0.2, Th = 25%) and SE-Paw (m = 4, r = 0.2, Th = 30%) which report MCCs of 0.85 (0.78–0.86) and 0.78 (0.78–0.85), and accuracies of 0.93 (0.89–0.93) and 0.89 (0.89–0.93), respectively. This approach promises an improvement in the accurate detection of CP-VI, and future study of their clinical implications.

Background Febrile neutropenia (FN) is a very common complication in patients with haematological malignancies and is associated with considerable morbidity and mortality. Broad-spectrum antipseudomonal β-lactam antibiotics (BLA) are routinely used for the treatment of cancer patients with FN. However, the clinical efficacy of BLA may be diminished in these patients because they present with pathophysiological variations that compromise the pharmacokinetic (PK) parameters of these antibiotics. Optimized administration of BLA in prolonged infusions has demonstrated better clinical outcomes in critically ill patients. However, there is a paucity of data on the usefulness of this strategy in patients with FN. The aim of this study is to test the hypothesis that the administration of BLA would be clinically more effective by extended infusion (EI) than by intermittent infusion (II) in haematologic patients with FN.Methods A randomised, multicentre, open-label, superiority clinical trial will be performed. Patients with haematological malignancies undergoing chemotherapy or haematopoietic stem cell transplant and who have FN and receive empirical antibiotic therapy with cefepime, piperacillin-tazobactam or meropenem will be randomised (1:1) to receive the antibiotic by EI (during half the time of the dosing interval) in the study group, or by II (30 minutes) in the control group. The primary endpoint will be clinical efficacy, defined as defervescence without modifying the antibiotic treatment administered within the first 5 days of therapy. The primary endpoint will be analysed in the intention-to-treat population. The secondary endpoints will be pharmacokinetic/pharmacodynamic (PK/PD) target achievement, bacteraemia clearance, decrease in C-reactive protein, overall (30-day) case-fatality rate, adverse events and development of a population PK model of the BLA studied.Discussion Data on the usefulness of BLA administration in patients with FN are scant. Only three clinical studies addressing this issue have been published thus far, with contradictory results. Moreover, these studies had some methodological flaws that limit the interpretation of their findings. If this randomised, multicentre, phase IV, open-label, superiority clinical trial validates the hypothesis that the administration of BLA is clinically more effective by EI than by II in haematologic patients with FN, then the daily routine management of these high-risk patients could be changed to improve their outcomes.Trial registration: European Clinical Trials Database: EudraCT 2018-001476-37ClinicalTrials.gov Identifier: NCT04233996

Background and objective Patients submitted to haematopoietic stem cell transplantation (HSCT) are at increased risk of late complications, such as second neoplasm (SN). The incidence and risk factors of SN in patients receiving HSCT at a single centre were analyzed. Patients and methods The follow-up of adult patients who received a first HSCT (autologous [auto-HSCT] or allogeneic [allo-HSCT]) between January 2000 and December 2015 was reviewed. We collected their demographic characteristics, the primary disease and type of HSCT, and analyzed the cumulative incidence of SN and their risk factors. Results Of 699 transplanted patients (auto-HSCT, n = 451; allo-HSCT, n = 248), 42 (6%) developed SN (17 haematological and 25 solid), 31 post-auto-HSCT and 11 post-allo-HSCT. Haematologic SN were more frequent after auto-HSCT than after allo-HSCT. The median time between HSCT and SN was 4.09 years [range 0.07–13.15], with no differences between auto-HSCT and allo-HSCT. The cumulative incidence of SN was 5% (95% CI 3–6) at 5 years, 7% (95% CI 5–10) at 10 years and 11% (95% CI 8–15) at 15 years, without differences according to the type of HSCT. Only the age over 40 years correlated with an increased risk of SN. Conclusions In this series, the incidence of post-HSCT SN was similar to that previously described. Patients submitted to an auto-HSCT showed a higher frequency of haematologic SN. A higher incidence of SN was detected in patients older than 40 at the time of HSCT.

Resumen Fundamento y objetivo Los receptores de un trasplante de progenitores hematopoyeticos (TPH) tienen un mayor riesgo de complicaciones tardias, como las segundas neoplasias (SN). Se analizo la incidencia de SN en pacientes receptores de un TPH en un centro. Pacientes y metodos Estudio retrospectivo de pacientes adultos receptores de un primer TPH (autogenico [auto-TPH] o alogenico [alo-TPH]) entre enero de 2000 y diciembre de 2015. Se recogieron sus caracteristicas demograficas, la enfermedad de base y el tipo de TPH, y se analizo la incidencia acumulada de SN y sus factores de riesgo. Resultados De 699 pacientes receptores de un auto-TPH (n = 451) o alo-TPH (n = 248), 42 (6%) desarrollaron una SN (17 hematologicas y 25 solidas), 31 postauto-TPH y 11 postalo-TPH. Se observo un mayor numero de SN hematologicas tras auto-TPH que tras alo-TPH. La mediana de tiempo entre el TPH y la SN fue de 4,09 anos [extremos 0,07-13,15], sin diferencias entre auto-TPH y alo-TPH. La incidencia acumulada de SN post-TPH fue de 5% (IC 95% 3-6) a 5 anos, 7% (IC 95% 5-10) a 10 anos y 11% (IC 95% 8-15) a 15 anos, sin diferencias en funcion del tipo de TPH. Solo la edad superior a los 40 anos se correlaciono con un mayor riesgo de SN. Conclusiones En esta serie, la incidencia de SN post-TPH fue similar a la descrita. Los receptores de un auto-TPH presentaron mayor frecuencia de SN hematologicas. Se detecto una mayor incidencia de SN en pacientes de mas de 40 anos en el momento del TPH.

The outcome of relapsed adult acute lymphoblastic leukemia (ALL) remains dismal despite new therapeutic approaches. Previous studies analyzing relapse samples have shown a high degree of heterogeneity regarding gene alterations without an evident relapse signature. Bone marrow or peripheral blood samples from 31 adult B-cell precursor ALL patients at first relapse, and 21 paired diagnostic samples were analyzed by multiplex ligation probe-dependent amplification (MLPA). Nineteen paired diagnostic and relapse samples of these 21 patients were also analyzed by SNP arrays. A trend to acquire homozygous CDKN2A/B deletions and a significant increase in the number of copy number alterations (CNA) was observed from diagnosis to first relapse. Evolution from an ancestral clone was the main pattern of clonal evolution. Relapse samples were extremely heterogeneous regarding CNA frequencies. However, CDKN2A/B, PAX5, ETV6, ATM, IKZF1, VPREB1, and TP53 deletions and duplications of 1q, 8q, 17q, 21, X/Y PAR1, and Xp were frequently detected at relapse. Duplications of genes involved in cell proliferation, drug resistance and stem cell homeostasis regulation, as well as deletions of KDM6A and STAG2 genes emerged as specific alterations at relapse. Genomics of relapsed adult B-cell precursor ALL is highly heterogeneous, although some recurrent lesions involved in essential pathways deregulation were frequently observed. Selective and simultaneous targeting of these deregulated pathways may improve the results of current salvage therapies.

Summary Objectives Onco-haematological patients are prone to develop infections, and antibiotic prophylaxis may lead to negative blood cultures. Thus, the microbiological diagnosis and subsequent administration of a targeted antimicrobial therapy is often difficult. The goal of this study was to evaluate the usefulness of IRIDICA (PCR/ESI-MS technology) for the molecular diagnosis of bloodstream infections in this patient group. Methods A total of 463 whole blood specimens from different sepsis episodes in 429 patients were analysed using the PCR/ESI-MS platform, comparing the results with those of blood culture and other clinically relevant information. Results The sensitivity of PCR/ESI-MS by specimen (excluding polymicrobial infections, n = 25) in comparison with blood culture was 64.3% overall, 69.0% in oncological patients, and 59.3% in haematological patients. When comparing with a clinical infection criterion, overall sensitivity rose to 74.7%, being higher in oncological patients (80.0%) than in haematological patients (67.7%). Thirty-one microorganisms isolated by culture were not detected by IRIDICA, whereas 42 clinically relevant pathogens not isolated by culture were detected moleculary. Conclusions PCR/ESI-MS offers a reliable identification of pathogens directly from whole blood. While additional studies are needed to confirm our findings, the system showed a lower sensitivity in onco-haematological patients in comparison with previously reported results in patients from the Intensive Care Unit.

Aberrant expression of the sodium channel gene (SCN5A) has been proposed to disrupt cardiac action potential and cause human cardiac arrhythmias, but the mechanisms of SCN5A gene regulation and dysregulation still remain largely unexplored. To gain insight into the transcriptional regulatory networks of SCN5A, we surveyed the promoter and first intronic regions of the SCN5A gene, predicting the presence of several binding sites for GATA transcription factors (TFs). Consistent with this prediction, chromatin immunoprecipitation (ChIP) and sequential ChIP (Re-ChIP) assays show co-occupancy of cardiac GATA TFs GATA4 and GATA5 on promoter and intron 1 SCN5A regions in fresh-frozen human left ventricle samples. Gene reporter experiments show GATA4 and GATA5 synergism in the activation of the SCN5A promoter, and its dependence on predicted GATA binding sites. GATA4 and GATA6 mRNAs are robustly expressed in fresh-frozen human left ventricle samples as measured by highly sensitive droplet digital PCR (ddPCR). GATA5 mRNA is marginally but still clearly detected in the same samples. Importantly, GATA4 mRNA levels are strongly and positively correlated with SCN5A transcript levels in the human heart. Together, our findings uncover a novel mechanism of GATA TFs in the regulation of the SCN5A gene in human heart tissue. Our studies suggest that GATA5 but especially GATA4 are main contributors to SCN5A gene expression, thus providing a new paradigm of SCN5A expression regulation that may shed new light into the understanding of cardiac disease.

Resumen Fundamento La infeccion bacteriana continua siendo una complicacion frecuente en pacientes receptores de un trasplante de progenitores hematopoyeticos (TPH). No obstante, el impacto de la profilaxis antibacteriana en la mortalidad de estos pacientes es controvertido. Pacientes y metodos Comparacion retrospectiva de 2 grupos consecutivos de receptores de TPH segun recibieran (n = 132) o no (n = 107) profilaxis antibacteriana con levofloxacino. Resultados En el 41% de los procedimientos de TPH en los que se administro profilaxis con levofloxacino se constato infeccion microbiologicamente documentada (IMD) con bacteriemia, frente a un 40% de los que no recibieron levofloxacino. La frecuencia de bacteriemia por bacilos gramnegativos fue del 11 y del 38%, la resistencia a levofloxacino fue del 39 y del 14%, y hubo un 8 y 7% de muertes, respectivamente. Conclusiones En nuestra experiencia, el uso de levofloxacino se asocio a una menor frecuencia de bacteriemia por microorganismos gramnegativos, pero no se asocio a disminucion en la tasa de IMD ni influyo en su evolucion. En cambio, hubo un aumento de la resistencia a quinolonas en los pacientes tratados con levofloxacino.

Context IKZF1 (Ikaros) deletion has been proposed as a poor prognostic factor in B-cell precursor acute lymphoblastic leukemia (BCP ALL) in children and adults. Objective To analyze the frequency and prognostic impact of IKZF1 deletions in adult BCP ALL patients. To identify the IKZF1 gene expression signature to find patients with different deletion isoforms and therapeutic opportunities. Patients and methods MLPA or SNP array samples of 151 (109 Ph-negative and 42 Ph+) adult BCP ALL patients treated with MRD-oriented protocols from the PETHEMA Group. RNAseq was performed in 48 of them (27 Ph-negative and 21 Ph+). Results Median age was 40 [15–72] years. Ph+ patients showed older age (52 [20;72] vs. 36 [15;68] years, p 1.5 in RNAseq data analysis, we identified a robust IKZF1 deletion gene expression profile. This resulted in 119 significantly upregulated genes after multi-comparison adjustment (i.e. CCND1, LAMA3, SLC2A9, SNAI1, LDHC, CD34, ID3, CDH2, MAF) and 39 downregulated genes (i.e. ROBO1, HES6, KREMEN1, DHCR24, ABHD15). Downregulated genes were involved in Slit/Robo/EMT, Notch, Wnt/beta-catenin, and glucose and fatty acid metabolism pathways, while upregulated genes were involved in focal adhesion, ROS homeostasis, histone modification, anaerobic metabolism, stem cell quiescence, and IL-6/STAT pathways. A significant number of dysregulated gene targets of chemotherapeutic agents (retinoic acid, doxorubicin, cisplatin, gemcitabine) and targeted therapies, such as FAKi, ERKi, BCL2i, mTORi, JAKi, BRKi, EGFRi and CDKi, were identified. Conclusions Adult BCP ALL patients with IKZF1 partial gene deletions showed poor prognosis. Gene expression analysis enables the identification of potentially targetable lesions. Funding Supported in part by a grant from the Instituto de Salud Carlos III, Ministerio de Economia y Competividad, Spain (PI14/01971); 2017 SGR288 (GRC) Generalitat de Catalunya; and support from CERCA Programme/Generalitat de Catalunya, Fundacio Internacional Josep Carreras. The research leading to this invention has received funding from “la Caixa” Foundation.

Remote control of physiological functions with light offers the promise of unveiling their complex spatiotemporal dynamics in vivo, and enabling highly focalized therapeutic interventions with reduced systemic toxicity. Optogenetic methods have been implemented in the heart, but the need of genetic manipulation jeopardizes clinical applicability. This study aims at developing, testing and validating the first light-regulated drug with cardiac effects, in order to avoid the requirement of genetic manipulation offered by optogenetic methods. A M2 muscarinic acetylcholine receptors (mAChRs) light-regulated drug (PAI) was designed, synthesized and pharmacologically characterized. The design was based on the orthosteric mAChRs agonist Iperoxo, an allosteric M2 ligand, and a photoswitchable azobenzene linker. PAI can be reversibly photoisomerized between cis and trans configurations under ultraviolet (UV) and visible light, respectively, and it reversibly photoswitches the activity of M2 muscarinic acetylcholine receptors. We have evaluated in vitro photoresponses using a calcium imaging assay in genetically unmodified receptors overexpressed in mammalian cells. Furthermore, using this new chemical tool, we demonstrate for the first time photoregulation of cardiac function in vivo in wildtype frog tadpoles and in rats with a method that does not require genetic manipulation. Such a new approach may enable enhanced spatial and temporal selectivity for cardiovascular drugs.

Aims Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in cardiac remodelling. Available information regarding their prognostic utility in heart failure (HF) and cardiac resynchronization therapy (CRT) is controversial. The aim of this study was to analyse MMP-2 and TIMP-1 levels as predictors of long-term mortality in HF patients treated with CRT. Methods and results We prospectively included 42 consecutive patients with successfully implanted CRT. Matrix metalloproteinase-2 and TIMP-1 assays were performed prior to implant. Patients were evaluated at baseline and at the outpatient clinic at 6-month intervals. Clinical response, left ventricular (LV) remodelling, and mortality were analysed. During a mean follow-up of 60 ± 34 months, long-term mortality from any cause was 36% (15 patients). The cause of death was end stage of HF in 12 patients, sudden death in 2 patients, and 1 unknown. After adjustment using a Cox regression model, the independent predictors of long-term mortality were baseline TIMP-1, hazard ratio (HR) 1.18 (95% confidence interval (95% CI) [1.05–1.33], P = 0.007), baseline glomerular filtration rate (GFR), HR 0.97 (95% CI [0.94–1.00], P = 0.05), and permanent atrial fibrillation (AF), HR 3.14 (95% CI [1.02–9.67], P = 0.04). Area under receiver operating characteristic curve for TIMP-1 was 0.79 (95% CI [0.63–0.94]). Tissue inhibitor of matrix metalloproteinase-1 ≥ 248 ng/mL predicts mortality with 80% sensitivity and 71% specificity. Conclusion Tissue inhibitor of matrix metalloproteinase-1 is a powerful predictor of long-term mortality in HF patients treated with CRT.

A sensitive and rapid method for the determination of the clinically relevant biomarker receptor tyrosine kinase AXL in serum involving amperometric disposable immunosensors is reported. The target protein was sandwiched between a specific capture antibody covalently immobilized on screen-printed carbon electrodes modified with electropolymerized poly(pyrrolepropionic acid) and a biotinylated detector antibody labeled with a streptavidin-horseradish peroxidase conjugate. The amperometric responses were measured at −0.20 V vs the Ag pseudo-reference electrode of the SPCE upon the addition of H2O2 in the presence of hydroquinone (HQ) as mediator. This integrated immunosensing platform showed a low limit of detection (337 pg mL−1), a good selectivity against other non-target serum proteins, and provided results statistically in agreement with those obtained by using a commercial ELISA kit. These attractive features together with the simplicity and easy automation and miniaturization of the required instrumentation make the developed methodology a promising alternative in the development of devices for on-site clinical analysis., The financial support of projects: Retos Colaboración RTC2015-4184-1 (cofinanced by the Ministry of Economy and Competitivity and FEDER), CTQ2015-70023-R and CTQ2015- 64402-C2-1-R (Spanish Ministry of Economy and Competitivity Research Projects) and S2013/MT-3029 (NANOAVANSENS Program from the Comunidad de Madrid) are gratefully acknowledged. R.M. Torrente-Rodríguez acknowledges a predoctoral contract from the Spanish Ministerio de Economía y Competitividad.

Background— Pulmonary hypertension (PH) and collagen metabolism abnormalities are prevalent in patients with heart failure with preserved ejection fraction (HFpEF). Peripheral endothelial dysfunction (PED) has been described in HF and in pulmonary arterial hypertension. Our aim is to determine whether PH is associated with PED and impaired collagen metabolism in patients with HFpEF.; Methods and Results— Flow-mediated dilation of the brachial artery, matrix metalloproteinase-2 and matrix metalloproteinase-9, tissue metalloproteinase inhibitor 1, and C-terminal propeptide of type I procollagen were determined in 28 patients with HFpEF and 42 hypertensive controls. Patients with systolic pulmonary artery pressure >35 mm Hg on echocardiogram underwent a right heart catheterization. Patients with HFpEF had more severe PED than controls: flow-mediated dilation 1.95% (−0.81 to 4.92) versus 5.02% (3.90 to 10.12), P =0.002. Twenty patients with PH underwent right heart catheterization: mean pulmonary artery pressure 38 (27–52) mm Hg, wedge capillary pressure 18 (16–22) mm Hg, pulmonary vascular resistance 362 (235–603) dyn s cm -5 . There was a significant inverse correlation between flow-mediated dilation and pulmonary vascular resistance in patients with HFpEF and PH ( r =−0.679; P =0.002). Patients with HFpEF showed higher matrix metalloproteinase-2 and C-terminal propeptide of type I procollagen values than hypertensive controls. Patients with HFpEF and higher C-terminal propeptide of type I procollagen values also had higher mean pulmonary artery pressure ( r =0.553; P =0.014), transpulmonary gradient ( r =0.560; P =0.013), and pulmonary vascular resistance ( r =0.626; P =0.004). Conclusions— In patients with HFpEF, there is a significant correlation between PED and pulmonary vascular resistance. Collagen metabolism was more impaired in patients with HFpEF and PH. PED and collagen metabolism assessment could be useful tools to identify patients with HFpEF at risk of developing PH.

BACKGROUND Long QT syndrome (LQTS) is associated with sudden cardiac death and the prolongation of the QT interval on the electrocardiogram. A comprehensive screening of all genes previously associated with this disease leaves 30% of the patients without a genetic diagnosis. Pathogenic mutations in the sodium channel β subunits have been associated with cardiac channelopathies, including SCN4B mutations in LQTS. OBJECTIVE To evaluate the role of mutations in the sodium channel β subunits in LQTS. METHODS We screened for mutations in the genes encoding the 5 sodium β subunits (SCN1B isoforms a and b, SCN2B, SCN3B, and SCN4B) from 30 nonrelated patients who were clinically diagnosed with LQTS without mutations in common LQTS-related genes. We used the patch-clamp technique to study the properties of sodium currents and the action potential duration in human embryonic kidney and HL-1 cells, respectively, in the presence of β1b subunits. RESULTS The genetic screening revealed a novel mutation in the SCN1Bb gene (β1bP213T) in an 8-year-old boy. Our electrophysiological analysis revealed that β1bP213T increases late sodium current. In addition, β1bP213T subtly altered Nav1.5 function by shifting the window current, accelerating recovery from inactivation, and decreasing the slow inactivation rate. Moreover, experiments using HL-1 cells revealed that the action potential duration significantly increases when the mutant β1b was overexpressed compared with β1bWT. CONCLUSION These data revealed SCN1Bb as a susceptibility gene responsible for LQTS, highlighting the importance of continuing the search for new genes and mechanisms to decrease the percentage of patients with LQTS remaining without genetic diagnosis.

Background aims The increasing scarcity of young related donors has led to the use of older donors for related allogeneic hematopoietic stem cell transplantation (HSCT). This study analyzed the influence of age on the results of mobilization of peripheral blood stem cells (PBSCs) in healthy donors as well as on the engraftment and outcome of HSCT. Methods A retrospective analysis from a single center was performed comparing the results of PBSC mobilization from related healthy donors according to their age. Results The study included 133 consecutive related donors. The median age was 50 years (range, 4–77 years); 70 (53%) donors were males, and 44 (33%) were >55 years old. All donors were mobilized with granulocyte colony-stimulating factor for 5 days. The peak CD34 + cell count in peripheral blood was higher in younger than in older donors (median, 90.5 CD34 + cells/μL [range, 18–240 CD34 + cells/μL] versus 72 CD34 + cells/μL [range, 20–172.5 CD34 + cells/μL], P = 0.008). The volume processed was lower in younger than in older donors (16,131 mL [range, 4424–36,906 mL] versus 18,653 mL [range, 10,003–26,261 mL], P = 0.002) with similar CD34 + cells collected (579.3 × 10 6 cells [range, 135.14 × 10 6 –1557.24 × 10 6 cells] versus 513.69 × 10 6 cells [range, 149.81 × 10 6 –1290 × 10 6 cells], P = 0.844). There were no differences in time to recovery of neutrophils and platelets or in the incidences of acute and chronic graft-versus-host disease, overall survival, non-relapse mortality and relapse incidence. Conclusions Donors >55 years old mobilized fewer CD34 + cells and required a greater volume to collect a similar number of CD34 + cells. The outcome of HSCT was not influenced by donor age. Donor age should not be a limitation for related allogeneic HSCT.

Highly infectious diseases (HIDs) are defined as being transmissible from person to person, causing life-threatening illnesses and presenting a serious public health hazard. In most European Union member states specialized isolation facilities are responsible for the management of such cases. Ground ambulances are often affiliated with those facilities because rapid relocation of patients is most desirable. To date, no pooled data on the accessibility, technical specifications and operational procedures for such transport capacities are available. During 2009, the ‘European Network for HIDs’ conducted a cross-sectional analysis of hospitals responsible for HID patients in Europe including an assessment of (a) legal aspects; (b) technical and infrastructure aspects; and (c) operational procedures for ground ambulances used for HID transport. Overall, 48 isolation facilities in 16 European countries were evaluated and feedback rates ranged from 78% to 100% (n = 37 to n = 48 centres). Only 46.8% (22/47) of all centres have both national and local guidelines regulating HID patient transport. If recommended, specific equipment is found in 90% of centres (9/10), but standard ambulances in only 6/13 centres (46%). Exclusive entrances (32/45; 71%) and pathways (30/44; 68.2%) for patient admission, as well as protocols for disinfection of ambulances (34/47; 72.3%) and equipment (30/43; 69.8%) exist in most centres. In conclusion, the availability and technical specifications of ambulances broadly differ, reflecting different preparedness levels within the European Union. Hence, regulations for technical specifications and operational procedures should be harmonized to promote patient and healthcare worker safety.

Bacteremia is the most frequent infectious complication during neutropenia in patients receiving autologous hematopoietic stem cell transplantation (ASCT). The objective of this study was to analyze the incidence, characteristics, risk factors, and outcome of bacteremia during the early period after ASCT. A total of 720 patients undergoing ASCT in two observational prospective consecutive multicenter studies of the Programa Espanol para el Tratamiento de las Hemopatias group were analyzed. Bacteremia occurred in 20 % of patients. Coagulase-negative Staphylococcus was the most frequent (66 %) among the gram-positive agents and Escherichia coli (49 %) among the gram-negative agents. Multivariate analysis showed that the length of neutropenia

Caspofungin is an echinocandin with proven effi cacy in invasive candidiasis (IC) and invasive aspergillosis (IA). This multicenter, prospective, non-comparative, observational ProCAS study was aimed to assess the effectiveness and safety of caspofungin in adult hematological patients with IC or IA under everyday clinical conditions. Favorable outcomes included complete and partial responses on the last day of caspofungin therapy. Safety was assessed up to 14 days post-caspofungin. A total of 115 patients (69 male) with a median age of 52 years (range, 23 – 78 years) were analyzed. Underlying disease was acute myeloid leukemia in 45 patients (39%), and 21 (18%) were allogeneic stem cell transplant recipients. Thirty-four (29.5%) patients had a diagnosis of IA and 26 (22.6%) had IC (candidemia). The median duration of caspofungin therapy was 14 days (range, 1 – 100). The overall favorable response rate was 77% (20/26) for patients with IC (69% fi rst-line) and 79% (27/34) for those with IA. Antifungal therapy with caspofungin was generally well tolerated, only two (1.7%) patients having a non-serious drug-related adverse reaction. These results suggest that caspofungin, either alone or in combination, should be considered an effective and safe option for the treatment of invasive mycoses in patients with severe hematological disorders.

It is unclear whether higher CD34 + cell doses infused for ASCT have any influence on survival or relapse in patients with lymphoma. We analyzed the correlation of infused CD34 + cell dose with relapse, survival, and hematopoietic recovery in 146 consecutive patients undergoing ASCT for lymphoma. Higher doses (>5 × 106/kg) were significantly correlated with earlier hematopoietic recovery, fewer infectious episodes, lower transfusion needs. No differences were observed in lymphoma outcomes (4-year relapse incidence of 38% [95%CI: 29%–48%] in the lower dose group versus 51% [95%CI: 30%–69%] in the higher dose group, 10-year OS probabilities of 58% [95%CI: 48%–68%] versus 75% [95%CI: 59%–91%], 10-year DFS probabilities of 47% [95%CI: 37%–57%] versus 42% [95%CI: 23%–61%], p = NS for all outcomes). In this series, a higher infused CD34 + cell dose did not correlate with survival or relapse but correlated with earlier hematopoietic recovery and lower resource consumption.

Background Prognostic biomarkers are needed to improve the management of the heart failure (HF) epidemic, being the brain natriuretic peptides the most valuable. Here we evaluate 3 biomarkers, high sensitivity troponin T (hs-TnT), galectin-3 (Gal-3) and C-terminal propeptide of type I procollagen (CICP), compare them with a recently described new candidate (sAXL), and analyze their relationship with BNP. Methods HF patients with reduced ejection fraction (n = 192) were included in this prospective observational study, with measurements of candidate biomarkers, functional, clinical and echocardiographic variables. A Cox regression model was used to determine predictors for clinical events, i.e. all-cause mortality and heart transplantation. Results Hs-TnT circulating values were correlated to clinical characteristics indicative of more advanced HF. When analyzing the event-free survival at a mean follow-up of 3.6 years, patients in the higher quartile of either BNP, hs-TnT, CICP and sAXL had increased risk of suffering a clinical event, but not Gal-3. Combination of high sAXL and BNP values had greater predictive value (HR 6.8) than high BNP alone (HR 4.9). In a multivariate Cox regression analysis, BNP, sAXL and NYHA class were independent risk factors for clinical events. Conclusions In this HF cohort, hs-TnT is a good HF marker and has a very significant prognostic value. The prognostic value of CICP and sAXL was of less significance. However, hs-TnT did not add predictive value to BNP, while sAXL did. This suggests that elevated troponin has a common origin with BNP, while sAXL could represent an independent pathological mechanism., This work was supported by grants from the Fundació la Marató de TV3 2008 [project 081010, project 080121]; from the Spanish Network on Heart Failure REDINSCOR [V-2006-RET0308-O] and Red de Investigaciones Cardiovasculares RIC[RD12/0042] by the Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo and by Fondo Europeo de Desarrollo Regional FEDER[RD12/0042] and by a Retos-Colaboración 2015 grant [RTC-2015-4184-1] from the Ministerio de Economía y Competitividad.

Background In haematopoietic stem cell transplant (HSCT) recipients, cytomegalovirus (CMV) infection contributes significantly to morbidity and mortality in both the early and late post-transplant period. Ganciclovir (GCV) is the treatment of choice for CMV, but requires intravenous administration, a fact that complicates its long-term use. Oral valganciclovir (VGCV) and intravenous GCV were recently shown to have similar efficacy for pre-emptive CMV treatment in solid organ transplant recipients, but relatively limited data are available in HSCT recipients. The objectives of this study were to compare the efficacy of VGCV versus intravenous GCV or foscarnet (FOS) for pre-emptive therapy of active CMV infection in allogeneic HSCT and to determine the incidence of adverse effects and relapses. Methods This was a 2-year prospective, comparative cohort study in which 237 episodes of pre-emptive therapy for active CMV infection were collected in 166 allogeneic HSCT recipients out of 717 included in the Spanish Network for Research on Infection in Transplantation (RESITRA/REIPI) database. Intravenous GCV was the first-line treatment in 112 episodes, intravenous FOS in 38 episodes, and oral VGCV in 87 episodes. Results VGCV was used as pre-emptive therapy for active CMV infection in 87 episodes. Excluding episodes considered as relapse, VGCV was as successful (91.4% [74/81]) as GCV (83.7% [87/14]) or FOS (75.8% [25/33]). In the VGCV arm, 7 (8.6%) cases were considered treatment failures: 4 (4.9%) because of adverse events, 1 (1.2%) due to persistent viral activity and 2 (2.5%) based on clinical decision. There were also 6 (7.4%) cases of recurrent infection. No statistically significant differences were found when compared to GCV or FOS. Conclusions In allogeneic HSCT recipients, VGCV seemed effective and safe in the pre-emptive therapy of active CMV infection.

Resumen Fundamento y objetivo La enfermedad del injerto contra el huesped (EICH) aguda grave y la cronica extensa resistentes a glucocorticoides tienen mal pronostico. El infliximab ha demostrado eficacia en algunos pacientes con EICH. Se evaluo la eficacia y la toxicidad del infliximab en pacientes con EICH en un centro. Pacientes y metodo Analisis retrospectivo de la evolucion de 9 pacientes con EICH aguda o cronica resistente a glucocorticoides tratados con infliximab. Resultados Seis pacientes con EICH aguda y 3 con EICH cronica recibieron infliximab semanal como tratamiento de rescate. La fuente de progenitores fue la sangre periferica en 8 y la sangre de cordon umbilical en 1 paciente. Seis recibieron un trasplante de progenitores hematopoyeticos (TPH) alogenico emparentado y 3 un TPH alogenico no emparentado. El numero de dosis de infliximab administradas oscilo entre 2 y 7. Cinco pacientes alcanzaron una respuesta parcial y el resto no fueron evaluables. Todos presentaron complicaciones infecciosas. Conclusiones El infliximab proporciona una respuesta transitoria en el tratamiento de la EICH resistente a glucocorticoides, pero se asocia con una alta tasa de infecciones. La administracion precoz de infliximab podria reducir su frecuencia y gravedad.