Clinical outcomes of temporary mechanical circulatory support as a direct bridge to heart transplantation: a nationwide Spanish registry

Background: In Spain, listing for high-urgent heart transplantation is allowed for critically ill candidates not weanable from temporary mechanical circulatory support (T-MCS). We sought to analyse the clinical outcomes of this strategy. Methods and results: We conducted a case-by-case, retrospective review of clinical records of 291 adult patients listed for high-urgent heart transplantation under temporary devices from 2010 to 2015 in 16 Spanish institutions. Survival after listing and adverse clinical events were studied. At the time of listing, 169 (58%) patients were supported on veno-arterial extracorporeal membrane oxygenation (VA-ECMO), 70 (24%) on temporary left ventricular assist devices (T-LVAD) and 52 (18%) on temporary biventricular assist devices (T-BiVAD). Seven patients transitioned from VA-ECMO to temporary ventricular assist devices while on the waiting list. Mean time on T-MCS was 13.1 ± 12.6 days. Mean time from listing to transplantation was 7.6 ± 8.5 days. Overall, 230 (79%) patients were transplanted and 54 (18.6%) died during MCS. In-hospital postoperative mortality after transplantation was 33.3%, 11.9% and 26.2% for patients bridged on VA-ECMO, T-LVAD and T-BiVAD, respectively (P = 0.008). Overall survival from listing to hospital discharge was 54.4%, 78.6% and 55.8%, respectively (P = 0.002). T-LVAD support was independently associated with a lower risk of death over the first year after listing (hazard ratio 0.52, 95% confidence interval 0.30–0.92). Patients treated with VA-ECMO showed the highest incidence rate of adverse clinical events associated with T-MCS. Conclusion: Temporary devices may be used to bridge critically ill candidates directly to heart transplantation in a setting of short waiting list times, as is the case of Spain. In our series, bridging with T-LVAD was associated with more favourable outcomes than bridging with T-BiVAD or VA-ECMO

Empleo del balón de contrapulsación intraaórtico como puente al trasplante cardiaco en España: resultados del estudio ASIS-TC

Introducción y objetivos En España, el balón de contrapulsación intraaórtico (BCIA) se ha usado frecuentemente como puente al trasplante cardiaco (TxC) urgente. El propósito es analizar los resultados de esta estrategia. Métodos Se realizó una revisión retrospectiva caso por caso de los registros clínicos de 281 pacientes adultos listados para TxC urgente asistidos con BCIA en 16 hospitales españoles entre 2010 y 2015. Se analizaron la supervivencia antes y después del trasplante y la incidencia de eventos adversos. Resultados Se trasplantó a 194 pacientes (69%; IC95%, 63, 3-74, 4) y 20 (7, 1%; IC95%, 4, 4-10, 8) fallecieron durante la asistencia, cuya duración media fue de 10, 9 ± 9, 7 días. El BCIA se explantó antes de obtener un órgano a 32 pacientes (11, 4%). En 35 pacientes (12, 5%; IC95%, 8, 8-16, 9) se implantó un dispositivo de asistencia circulatoria mecánica completa. El tiempo en la lista de espera urgente se incrementó desde 5, 9 ± 6, 3 días en 2010 hasta 15 ± 11, 7 días en 2015 (p = 0, 001). La supervivencia a 30 días y a 1 y 5 años tras el TxC fue del 88, 1% (IC95%, 85, 7-90, 5), 76% (IC95%, 72, 9-79, 1) y 67, 8% (IC95%, 63, 7-71, 9) respectivamente. La tasa de incidencia de eventos adversos mayores —disfunción del BCIA, ictus, hemorragia o infección— durante la asistencia fue de 26 (IC95%, 20, 6-32, 4) eventos/1.000 pacientes-día. La tasa de incidencia de explante del BCIA por complicaciones fue de 7, 2 (IC95%, 4, 5-10, 8) casos/1.000 pacientes-día. Conclusiones En el contexto de listas de espera cortas, el BCIA puede utilizarse como puente al TxC urgente con resultados aceptables. Esta estrategia conlleva una incidencia significativa de eventos adversos. Introduction and objectives: In Spain, intra-aortic balloon pump (IABP) has been used frequently as a bridge to urgent heart transplant (HT). We sought to analyze the clinical outcomes of this strategy. Methods: We conducted a case-by-case, retrospective review of clinical records of 281 adult patients listed for urgent HT under IABP support in 16 Spanish institutions from 2010 to 2015. Pre- and post-transplant survival and adverse clinical events were analyzed. Results: A total of 194 (69%, 95%CI, 63.3-74.4) patients were transplanted and 20 (7.1%, 95%CI, 4.4-10.8) died during a mean period of IABP support of 10.9 ± 9.7 days. IABP support was withdrawn before an organ became available in 32 (11.4%) patients. Thirty-five (12.5%, 95%CI, 8.8-16.9) patients transitioned from IABP to full-support mechanical devices. Mean urgent waiting list time increased from 5.9 ± 6.3 days in 2010 to 15 ± 11.7 days in 2015 (P =.001). Post-transplant survival rates at 30-days, 1-year, and 5-years were 88.1% (95%CI, 85.7-90.5), 76% (95%CI, 72.9-79.1), and 67.8% (95%CI, 63.7-71.9), respectively. The incidence rate of major adverse clinical outcomes—device dysfunction, stroke, bleeding or infection—during IABP support was 26 (95%CI, 20.6-32.4) episodes per 1000 patient-days. The incidence rate of IABP explantation due to complications was 7.2 (95%CI, 4.5-10.8) cases per 1000 patient-days. Conclusions: In a setting of short waiting list times, IABP can be used to bridge candidates to urgent HT with acceptable postoperative results, but there were significant rates of adverse clinical events during support. Full English text available from:www.revespcardiol.org/e

Complicaciones infecciosas relacionadas con la asistencia circulatoria mecánica de corta duración en candidatos a trasplante cardiaco urgente

Introducción y objetivos El uso de dispositivos de asistencia circulatoria mecánica de corta duración como puente a trasplante es frecuente en España. Se desconocen la epidemiología y la repercusión de las complicaciones infecciosas en estos pacientes. Métodos Descripción sistemática de la epidemiología y análisis de la repercusión pronóstica de las complicaciones infecciosas en un registro multicéntrico retrospectivo de pacientes tratados con dispositivos de asistencia circulatoria mecánica de corta duración como puente a trasplante cardiaco urgente entre 2010 y 2015 en 16 hospitales españoles. Resultados Se estudió a 249 pacientes; 87 (34, 9%) de ellos tuvieron un total de 102 infecciones. La vía respiratoria fue la localización más frecuente (n = 47; 46, 1%). En 78 casos (76, 5%) se obtuvo confirmación microbiológica; se aislaron en total 100 gérmenes causales, con predominio de bacterias gramnegativas (n = 58, 58%). Los pacientes con complicaciones infecciosas presentaron mayor mortalidad durante el periodo de asistencia circulatoria mecánica (el 25, 3 frente al 12, 3%; p = 0, 009) y menor probabilidad de recibir un trasplante (el 73, 6 frente al 85, 2%; p = 0, 025) que los pacientes sin infección. La mortalidad posoperatoria tras el trasplante fue similar en ambos grupos (con infección, el 28, 3%; sin infección, el 23, 4%; p = 0, 471). Conclusiones Los pacientes tratados con dispositivos de asistencia circulatoria mecánica de corta duración como puente al trasplante cardiaco están expuestos a un alto riesgo de complicaciones infecciosas, las cuales se asocian con una mayor mortalidad en espera del órgano. Introduction and objectives Short-term mechanical circulatory support is frequently used as a bridge to heart transplant in Spain. The epidemiology and prognostic impact of infectious complications in these patients are unknown. Methods Systematic description of the epidemiology of infectious complications and analysis of their prognostic impact in a multicenter, retrospective registry of patients treated with short-term mechanical devices as a bridge to urgent heart transplant from 2010 to 2015 in 16 Spanish hospitals. Results We studied 249 patients, of which 87 (34.9%) had a total of 102 infections. The most frequent site was the respiratory tract (n = 47; 46.1%). Microbiological confirmation was obtained in 78 (76.5%) episodes, with a total of 100 causative agents, showing a predominance of gram-negative bacteria (n = 58, 58%). Compared with patients without infection, those with infectious complications showed higher mortality during the support period (25.3% vs 12.3%, P = .009) and a lower probability of receiving a transplant (73.6% vs 85.2%, P = .025). In-hospital posttransplant mortality was similar in the 2 groups (with infection: 28.3%; without infection: 23.4%; P = .471). Conclusions Patients supported with temporary devices as a bridge to heart transplant are exposed to a high risk of infectious complications, which are associated with higher mortality during the organ waiting period

New insights into the genetic etiology of Alzheimer's disease and related dementias.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Erratum: Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

Interpretation: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning

Registro Español de Trasplante Cardiaco. XXXI Informe Oficial de la Asociación de Insuficiencia Cardiaca de la Sociedad Española de Cardiología

Introducción y objetivos Se presentan las características clínicas y los resultados de los trasplantes cardiacos realizados en España con la actualización correspondiente a 2019. Métodos Se describen las características clínicas y los resultados de los trasplantes cardiacos realizados en 2019, así como las tendencias de estos en el periodo 2010-2018. Resultados En 2019 se realizaron 300 trasplantes (8.794 desde 1984; 2.745 entre 2010 y 2019). Respecto a años previos, los cambios más llamativos son el descenso hasta el 38% de los trasplantes realizados en código urgente, y la consolidación en el cambio de asistencia circulatoria pretrasplante, con la práctica desaparición del balón de contrapulsación (0, 7%), la estabilización del uso del oxigenador extracorpóreo de membrana (9, 6%) y el aumento de los dispositivos de asistencia ventricular (29%). La supervivencia en el trienio 2016-2018 es similar a la del trienio 2013-2015 (p = 0, 34), y ambas mejores que la del trienio 2010-2012 (p = 0, 002 y p = 0, 01 respectivamente). Conclusiones Se mantienen estables tanto la actividad del trasplante cardiaco en España como los resultados en supervivencia en los últimos 2 trienios. Hay una tendencia a realizar menos trasplantes urgentes, la mayoría con dispositivos de asistencia ventricular. Introduction and objectives: The present report describes the clinical characteristics and outcomes of heart transplants in Spain and updates the data to 2019. Methods: We describe the clinical characteristics and outcomes of heart transplants performed in Spain in 2019, as well as trends in this procedure from 2010 to 2018. Results: In 2019, 300 transplants were performed (8794 since 1984; 2745 between 2010 and 2019). Compared with previous years, the most notable findings were the decreasing rate of urgent transplants (38%), and the consolidation of the type of circulatory support prior to transplant, with an almost complete disappearance of counterpulsation balloon (0.7%), stabilization in the use of extracorporeal membrane oxygenation (9.6%), and an increase in the use of ventricular assist devices (29.0%). Survival from 2016 to 2018 was similar to that from 2013 to 2015 (P = .34). Survival in both these periods was better than that from 2010 to 2012 (P = .002 and P = .01, respectively). Conclusions: Heart transplant activity has remained stable during the last few years, as have outcomes (in terms of survival). There has been a trend to a lower rate of urgent transplants and to a higher use of ventricular assist devices prior to transplant

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Highly-parallelized simulation of a pixelated LArTPC on a GPU

The rapid development of general-purpose computing on graphics processing units (GPGPU) is allowing the implementation of highly-parallelized Monte Carlo simulation chains for particle physics experiments. This technique is particularly suitable for the simulation of a pixelated charge readout for time projection chambers, given the large number of channels that this technology employs. Here we present the first implementation of a full microphysical simulator of a liquid argon time projection chamber (LArTPC) equipped with light readout and pixelated charge readout, developed for the DUNE Near Detector. The software is implemented with an end-to-end set of GPU-optimized algorithms. The algorithms have been written in Python and translated into CUDA kernels using Numba, a just-in-time compiler for a subset of Python and NumPy instructions. The GPU implementation achieves a speed up of four orders of magnitude compared with the equivalent CPU version. The simulation of the current induced on 10^3 pixels takes around 1 ms on the GPU, compared with approximately 10 s on the CPU. The results of the simulation are compared against data from a pixel-readout LArTPC prototype

The DUNE far detector vertical drift technology. Technical design report

DUNE is an international experiment dedicated to addressing some of the questions at the forefront of particle physics and astrophysics, including the mystifying preponderance of matter over antimatter in the early universe. The dual-site experiment will employ an intense neutrino beam focused on a near and a far detector as it aims to determine the neutrino mass hierarchy and to make high-precision measurements of the PMNS matrix parameters, including the CP-violating phase. It will also stand ready to observe supernova neutrino bursts, and seeks to observe nucleon decay as a signature of a grand unified theory underlying the standard model. The DUNE far detector implements liquid argon time-projection chamber (LArTPC) technology, and combines the many tens-of-kiloton fiducial mass necessary for rare event searches with the sub-centimeter spatial resolution required to image those events with high precision. The addition of a photon detection system enhances physics capabilities for all DUNE physics drivers and opens prospects for further physics explorations. Given its size, the far detector will be implemented as a set of modules, with LArTPC designs that differ from one another as newer technologies arise. In the vertical drift LArTPC design, a horizontal cathode bisects the detector, creating two stacked drift volumes in which ionization charges drift towards anodes at either the top or bottom. The anodes are composed of perforated PCB layers with conductive strips, enabling reconstruction in 3D. Light-trap-style photon detection modules are placed both on the cryostat's side walls and on the central cathode where they are optically powered. This Technical Design Report describes in detail the technical implementations of each subsystem of this LArTPC that, together with the other far detector modules and the near detector, will enable DUNE to achieve its physics goals