6,581 research outputs found
Computertomographie-basierte Bestimmung von Aortenklappenkalk und seine Assoziation mit Komplikationen nach interventioneller Aortenklappenimplantation (TAVI)
Background: Severe aortic valve calcification (AVC) has generally been recognized as a key factor in the occurrence of adverse events after transcatheter aortic valve implantation (TAVI). To date, however, a consensus on a standardized calcium detection threshold for aortic valve calcium quantification in contrast-enhanced computed tomography angiography (CTA) is still lacking. The present thesis aimed at comparing two different approaches for quantifying AVC in CTA scans based on their predictive power for adverse events and survival after a TAVI procedure.
Methods: The extensive dataset of this study included 198 characteristics for each of the 965 prospectively included patients who had undergone TAVI between November 2012 and December 2019 at the German Heart Center Berlin (DHZB). AVC quantification in CTA scans was performed at a fixed Hounsfield Unit (HU) threshold of 850 HU (HU 850 approach) and at a patient-specific threshold, where the HU threshold was set by multiplying the mean luminal attenuation of the ascending aorta by 2 (+100 % HUAorta approach). The primary endpoint of this study consisted of a combination of post-TAVI outcomes (paravalvular leak ≥ mild, implant-related conduction disturbances, 30-day mortality, post-procedural stroke, annulus rupture, and device migration). The Akaike information criterion was used to select variables for the multivariable regression model. Multivariable analysis was carried out to determine the predictive power of the investigated approaches.
Results: Multivariable analyses showed that a fixed threshold of 850 HU (calcium volume cut-off 146 mm3) was unable to predict the composite clinical endpoint post-TAVI (OR=1.13, 95 % CI 0.87 to 1.48, p=0.35). In contrast, the +100 % HUAorta approach (calcium volume cut-off 1421 mm3) enabled independent prediction of the composite clinical endpoint post-TAVI (OR=2, 95 % CI 1.52 to 2.64, p=9.2x10-7). No significant difference in the Kaplan-Meier survival analysis was observed for either of the approaches.
Conclusions: The patient-specific calcium detection threshold +100 % HUAorta is more predictive of post-TAVI adverse events included in the combined clinical endpoint than the fixed HU 850 approach. For the +100 % HUAorta approach, a calcium volume cut-off of 1421 mm3 of the aortic valve had the highest predictive value.Hintergrund: Ein wichtiger Auslöser von Komplikationen nach einer Transkatheter-Aortenklappen-Implantation (TAVI) sind ausgeprägte Kalkablagerung an der Aortenklappe. Dennoch erfolgte bisher keine Einigung auf ein standardisiertes Messverfahren zur Quantifizierung der Kalklast der Aortenklappe in einer kontrastverstärkten dynamischen computertomographischen Angiographie (CTA). Die vorliegende Dissertation untersucht, inwieweit die Wahl des Analyseverfahrens zur Quantifizierung von Kalkablagerungen in der Aortenklappe die Prognose von Komplikationen und der Überlebensdauer nach einer TAVI beeinflusst.
Methodik: Der Untersuchung liegt ein umfangreicher Datensatz von 965 Patienten mit 198 Merkmalen pro Patienten zugrunde, welche sich zwischen 2012 und 2019 am Deutschen Herzzentrum Berlin einer TAVI unterzogen haben. Die Quantifizierung der Kalkablagerung an der Aortenklappe mittels CTA wurde einerseits mit einem starren Grenzwert von 850 Hounsfield Einheiten (HU) (HU 850 Verfahren) und andererseits anhand eines individuellen Grenzwertes bemessen. Letzterer ergibt sich aus der HU-Dämpfung in dem Lumen der Aorta ascendens multipliziert mit 2 (+100 % HUAorta Verfahren). Der primäre klinische Endpunkt dieser Dissertation besteht aus einem aus sechs Variablen zusammengesetzten klinischen Endpunkt, welcher ungewünschte Ereignisse nach einer TAVI abbildet (paravalvuläre Leckage ≥mild, Herzrhythmusstörungen nach einer TAVI, Tod innerhalb von 30 Tagen, post-TAVI Schlaganfall, Ruptur des Annulus und Prothesendislokation). Mögliche Störfaktoren, die auf das Eintreten der Komplikationen nach TAVI Einfluss haben, wurden durch den Einsatz des Akaike Informationskriterium ermittelt. Um die Vorhersagekraft von Komplikationen nach einer TAVI durch beide Verfahren zu ermitteln, wurde eine multivariate Regressionsanalyse durchgeführt.
Ergebnisse: Die multivariaten logistischen Regressionen zeigen, dass die Messung der Kalkablagerungen anhand der HU 850 Messung (Kalklast Grenzwert von 146 mm3) die Komplikationen und die Überlebensdauer nicht vorhersagen konnten (OR=1.13, 95 % CI 0.87 bis 1.48, p=0.35). Die nach dem +100 % HUAorta Verfahren (Kalklast Grenzwert von 1421 mm3) individualisierte Kalkmessung erwies sich hingegen als sehr aussagekräftig, da hiermit Komplikationen nach einer TAVI signifikant vorhergesagt werden konnten (OR=2, 95 % CI 1.52 bis 2.64, p=9.2x10-7). In Hinblick auf die postoperative Kaplan-Meier Überlebenszeitanalyse kann auch mit dem +100 % HUAorta Verfahren keine Vorhersage getroffen werden.
Fazit: Aus der Dissertation ergibt sich die Empfehlung, die Messung von Kalkablagerungen nach dem +100 % HUAorta Verfahren vorzunehmen, da Komplikationen wesentlich besser und zuverlässiger als nach der gängigen HU 850 Messmethode vorhergesagt werden können. Für das +100 % HUAorta Verfahren lag der optimale Kalklast Grenzwert bei 1421 mm3
Varastest embrüotest pärit ekstratsellulaarsed vesiikulid: potentsiaal embrüokvaliteedi markeritena ja roll embrüo-emaka suhtluses
Väitekirja elektrooniline versioon ei sisalda publikatsiooneViljatus on globaalne rahvatervise probleem, mis mõjutab miljoneid inimesi. Abistav reproduktiivtehnoloogia, sealhulgas in vitro viljastamine, on aidanud mitmeid viljatuid inimesi. Küll on sellel metoodikal üheks kitsaskohaks implantatsiooni ebaõnnestumine isegi morfoloogiliselt parimate embrüotega. Seetõttu toimuvad jätkuvalt uuringud tuvastamaks paremaid meetodeid, mis hindavad embrüo kvaliteeti ja ennustavad siirdamise edukust, olles peamiselt embrüokasvusöötme baasil.
Rakuvälised ehk ekstratsellulaarsed vesiikulid (EV) on membraaniga ümbritsetud nanoosakesed, mida toodavad peaaegu kõik rakutüübid erinevates füsioloogilistes ja patoloogilistes konditsioonides. Nende kaudu toimub rakuvaheline suhtlus. Mitmed uuringud, eriti vähi korral, on uurinud EVde potentsiaali biomarkerina ja ravimkandursüsteemina.
Antud doktoritöö uuris implantatsiooni-eelse perioodi embrüost vabanenud EVde potentsiaali embrüokvaliteedi markerina ja embrüo-emaka suhtluse vahendajana. Katsed viidi läbi kasutades veise-embrüoid ja inimrakukultuuride põhiseid eksperimentaalmudeleid. Esimene uuring tõestas, et individuaalselt kasvatatud implantatsiooni-eelse perioodi veise-embrüod eritavad EVsid kasvusöötmesse ning nende kontsentratsiooni- ja suurusprofiil sõltub embrüo kvaliteedist ja arengustaadiumist. Järgnevalt katsetati munajuharakkudel implantatsiooni-eelse perioodi embrüost pärit EVde funktsionaalsust. Katse käigus selgus, et EVd kõrge kvaliteediga embrüotest muutsid munajuharakkude geeniekspressiooni, mida aga ei teinud halva kvaliteediga embrüote EVd. Suurenenud ekspressiooniga geenide hulgas olid mitmed interferoon-τ raja interferooni stimuleerivad geenid. Interferoon-τ peetakse mäletsejaliste tiinuse tuvastusmolekuliks. See leid viitab, et munajuha tunneb ära kvaliteetse embrüo. Viimaseks uuriti embrüo EVde funktsionaalsuse spetsiifilisust. Leiti, et endomeetrium reageerib vaid embrüo päritolu EVdele. Uuringute käigus tuvastati embrüost vabanenud EVde potentsiaal ja spetsiifilisus embrüokvaliteedi biomarkerina.Infertility is a global public health problem that affects millions of people in their reproductive life. Assisted reproductive technologies (ARTs) such as in-vitro fertilization have enabled many patients to overcome this issue. However, a bottleneck in ART success is the implantation failure even after the transfer of morphologically best embryos. Hence, investigations continue to identify better or complementary methods of assessing embryo quality and predicting transfer success, mainly based on the embryo culture media.
Extracellular vesicles (EVs) are membrane-bound nanoparticles released by almost all types of cells under different physiological and pathological conditions. They mediate intercellular communication. Many studies, especially related to cancer, have investigated EVs' potential as biomarkers and therapeutic drug delivery systems.
This project investigated preimplantation embryo-derived extracellular vesicles as a potential embryo quality marker and a mediator of embryo-maternal communication. Experiments were performed using bovine embryos and human cell-culture based experimental models. The first study showed that individually cultured preimplantation bovine embryos release EVs to their culture media, and their concentration and size profile are dependent on the quality and development stage of embryos. Subsequently, the functionality of preimplantation embryo-derived EVs were tested in the oviduct. It was observed that EVs from good quality embryos, but not the EVs from embryos of low developmental potential quality, could alter the gene expression of the oviduct. Among the up-regulated genes, many were interferon-stimulated genes of the interferon-τ pathway. Interferon-τ is considered the pregnancy recognition molecule in ruminant pregnancy. This finding suggests that the oviduct can serve as a biosensor of embryo quality. Finally, the functional specificity of embryonic EVs were investigated. It was observed that endometrium only react to embryonic EVs but not to the non-embryonic EVs. All these studies support the potential and specificity of embryo-derived EVs as a biomarker of embryo quality.https://www.ester.ee/record=b548409
Statistical Learning for Gene Expression Biomarker Detection in Neurodegenerative Diseases
In this work, statistical learning approaches are used to detect biomarkers for neurodegenerative diseases (NDs). NDs are becoming increasingly prevalent as populations age, making understanding of disease and identification of biomarkers progressively important for facilitating early diagnosis and the screening of individuals for clinical trials. Advancements in gene expression profiling has enabled the exploration of disease biomarkers at an unprecedented scale. The work presented here demonstrates the value of gene expression data in understanding the underlying processes and detection of biomarkers of NDs. The value of novel approaches to previously collected -omics data is shown and it is demonstrated that new therapeutic targets can be identified. Additionally, the importance of meta-analysis to improve power of multiple small studies is demonstrated. The value of blood transcriptomics data is shown in applications to researching NDs to understand underlying processes using network analysis and a novel hub detection method. Finally, after demonstrating the value of blood gene expression data for investigating NDs, a combination of feature selection and classification algorithms were used to identify novel accurate biomarker signatures for the diagnosis and prognosis of Parkinson’s disease (PD) and Alzheimer’s disease (AD). Additionally, the use of feature pools based on previous knowledge of disease and the viability of neural networks in dimensionality reduction and biomarker detection is demonstrated and discussed. In summary, gene expression data is shown to be valuable for the investigation of ND and novel gene biomarker signatures for the diagnosis and prognosis of PD and AD
Optimizing transcriptomics to study the evolutionary effect of FOXP2
The field of genomics was established with the sequencing of the human genome, a pivotal achievement that has allowed us to address various questions in biology from a unique perspective. One question in particular, that of the evolution of human speech, has gripped philosophers, evolutionary biologists, and now genomicists. However, little is known of the genetic basis that allowed humans to evolve the ability to speak. Of the few genes implicated in human speech, one of the most studied is FOXP2, which encodes for the transcription factor Forkhead box protein P2 (FOXP2). FOXP2 is essential for proper speech development and two mutations in the human lineage are believed to have contributed to the evolution of human speech. To address the effect of FOXP2 and investigate its evolutionary contribution to human speech, one can utilize the power of genomics, more specifically gene expression analysis via ribonucleic acid sequencing (RNA-seq).
To this end, I first contributed in developing mcSCRB-seq, a highly sensitive, powerful, and efficient single cell RNA-seq (scRNA-seq) protocol. Previously having emerged as a central method for studying cellular heterogeneity and identifying cellular processes, scRNA-seq was a powerful genomic tool but lacked the sensitivity and cost-efficiency of more established protocols. By systematically evaluating each step of the process, I helped find that the addition of polyethylene glycol increased sensitivity by enhancing the cDNA synthesis reaction. This, along with other optimizations resulted in developing a sensitive and flexible protocol that is cost-efficient and ideal in many research settings.
A primary motivation driving the extensive optimizations surrounding single cell transcriptomics has been the generation of cellular atlases, which aim to identify and characterize all of the cells in an organism. As such efforts are carried out in a variety of research groups using a number of different RNA-seq protocols, I contributed in an effort to benchmark and standardize scRNA-seq methods. This not only identified methods which may be ideal for the purpose of cell atlas creation, but also highlighted optimizations that could be integrated into existing protocols.
Using mcSCRB-seq as a foundation as well as the findings from the scRNA-seq benchmarking, I helped develop prime-seq, a sensitive, robust, and most importantly, affordable bulk RNA-seq protocol. Bulk RNA-seq was frequently overlooked during the efforts to optimize and establish single-cell techniques, even though the method is still extensively used in analyzing gene expression. Introducing early barcoding and reducing library generation costs kept prime-seq cost-efficient, but basing it off of single-cell methods ensured that it would be a sensitive and powerful technique. I helped verify this by benchmarking it against TruSeq generated data and then helped test the robustness by generating prime-seq libraries from over seventeen species. These optimizations resulted in a final protocol that is well suited for investigating gene expression in comprehensive and high-throughput studies.
Finally, I utilized prime-seq in order to develop a comprehensive gene expression atlas to study the function of FOXP2 and its role in speech evolution. I used previously generated mouse models: a knockout model containing one non-functional Foxp2 allele and a humanized model, which has a variant Foxp2 allele with two human-specific mutations. To study the effect globally across the mouse, I helped harvest eighteen tissues which were previously identified to express FOXP2. By then comparing the mouse models to wild-type mice, I helped highlight the importance of FOXP2 within lung development and the importance of the human variant allele in the brain.
Both mcSCRB-seq and prime-seq have already been used and published in numerous studies to address a variety of biological and biomedical questions. Additionally, my work on FOXP2 not only provides a thorough expression atlas, but also provides a detailed and cost-efficient plan for undertaking a similar study on other genes of interest. Lastly, the studies on FOXP2 done within this work, lay the foundation for future studies investigating the role of FOXP2 in modulating learning behavior, and thereby affecting human speech
Hunting Wildlife in the Tropics and Subtropics
The hunting of wild animals for their meat has been a crucial activity in the evolution of humans. It continues to be an essential source of food and a generator of income for millions of Indigenous and rural communities worldwide. Conservationists rightly fear that excessive hunting of many animal species will cause their demise, as has already happened throughout the Anthropocene. Many species of large mammals and birds have been decimated or annihilated due to overhunting by humans. If such pressures continue, many other species will meet the same fate. Equally, if the use of wildlife resources is to continue by those who depend on it, sustainable practices must be implemented. These communities need to remain or become custodians of the wildlife resources within their lands, for their own well-being as well as for biodiversity in general. This title is also available via Open Access on Cambridge Core
Nonunion of the clavicle: novel use of clinical recovery and ultrasound to improve our ability to predict fracture healing
The aim of this thesis was to progress our understanding of clavicle nonunion and the ability
to accurately predict fracture healing in order to improve the current management of these
injuries.
Although only one in seven fractures go onto nonunion, these are challenging to predict. It is
unclear if the recent widespread increase in the use of acute plate fixation for displaced
fractures is justified on current evidence. It is unknown whether the early accurate prediction
of fractures at high risk of nonunion is advantageous. Currently the perceived risk of nonunion
is largely based on factors available at time of injury alone. The evaluation of clinical recovery
following non-operative management and the novel use of ultrasound may advance our ability
to accurately predict fracture healing for these injuries.
The cost-effectiveness of acute clavicle plate fixation versus non-operative treatment was
estimated from randomized controlled trial data that had been previously published. This was
completed prior to the start of this thesis and the author was not involved in the original trial.
A large retrospective review of clavicle fracture fixations was undertaken to determine whether
delayed clavicle fixation has an increased risk of complications compared to acute operative
management. A prospective study of displaced midshaft fractures was carried out over a two-year period to determine the influence of functional recovery on the ability to predict fracture
healing. The influence of clavicle fracture management on the early functional recovery was
evaluated with data from a randomized controlled trial and second prospective cohort. Finally,
the novel use of ultrasound to detect early callus formation and determine whether this allows
accurate prediction of fracture healing was evaluated for a cohort of clavicle and tibia fractures.
The estimated cost per quality-of-life adjusted year of acute plate fixation over non-operative
treatment is £480,309.41/QALY. For a threshold of £20,000/QALY the benefit of acute
fixation would need to be present for 24 years to be cost-effective over conservative treatment.
Linear regression analysis identified nonunion as the only factor to negatively influence the
SF-6D at 12-months (p<0.001).
A ten-year cohort of 259 clavicle plate fixations found failed primary surgery requiring revision
fixation occurred in 7.7% of all patients. Smoking (p<0.001), presence of a post-operative
infection (<0.001), increasing age (p=0.018), and greater time delay from injury to surgery
(p=0.015) was identified as significant independent predictors on regression analysis. Receiver
operating curve analysis (ROC) revealed that surgery beyond 96 days from injury has an
increased rate of major complications and revision surgery. Using a matched case cohort of
cases before (n=67) and after the ‘safe window’ (n=77), the risk of post-operative infection
increased (Odds ratio (OR) 7.7, p=0.028), fixation failure (OR 3.8, p=0.017) and revision
surgery (OR 4.8 p=0.004). A delay to operative fixation beyond 3 months following injury
would appear to be associated with an increased risk of major operative complications and
revision surgery.
A large prospective cohort of 200 patients managed non-operatively with a displaced midshaft
clavicle fracture were recruited. Regression modelling found a QuickDASH ≥40 (p=0.001), no
callus on radiograph (p=0.004) and fracture movement on examination (p=0.001) were
significant predictors of nonunion. If none were present the predicted nonunion risk was 3%,
found in 40% of the cohort. Conversely if two or more of the predictors were present, found in
23.5% of the cohort, the predicted nonunion risk was 60%. The delayed assessment nonunion
model appeared to have superior accuracy when compared to the estimation of nonunion at
time of injury alone healing on ROC curve analysis (Area Under Curve analysis; 87.3% vs
64.8% respectively).
Data from a randomized controlled trial was used to compare 86 patients who underwent
operative fixation against 76 patients that united with non-operative treatment. The recovery
of normal shoulder function, as defined by a DASH score within the predicted 95% confidence
interval for each respective patient was similar between each group at six-weeks (operative
26.7% vs non-operative 25.0%, p=0.80), three-months (52.3% vs 44.2%, p=0.77) and six-months post-injury (86.0% vs 90.8%, p=0.35). The mean DASH score and return to work was
also comparable at each time point. Regression analysis found no specific patient, injury or
fracture predictor was associated with an early return of function following non-operative
management at six or twelve weeks.
From a pilot study of twenty clavicle fractures, six-week sonographic bridging callus appeared
to be the most accurate, and repeatable, predictor of fracture healing with a strong agreement
on intra class correlation (ICC) between four reviewers (ICC 0.82, 95% confidence interval
0.68-0.91). In a large prospective study of 112 patients, sonographic bridging callus was
detected in 62.5% (n=70/112) of the cohort at six weeks post-injury. If present, union occurred
in 98.6% of the fractures (n=69/70). If absent, nonunion developed in 40.5% of cases
(n=17/42). The sensitivity to predict union with sonographic bridging callus at six weeks was
73.4% and the specificity was 94.4%. Three-dimensional fracture reconstruction can be created
using multiple ultrasound images in order to evaluate the presence of bridging callus. This
imaging modality has the potential to enhance the usability and accuracy of identification of
fracture healing at an early stage following injury.
Nonunion following a displaced midshaft clavicle fractures accounts for the majority of poor
functional recovery and impaired quality of life over the first-year post-injury. Prediction of
clavicle fracture healing at six weeks following injury maybe a safe and effective strategy to
identify patients at greatest risk of nonunion. The use of functional recovery enables a more
accurate estimation of nonunion risk compared to conventional prediction at time of injury
alone. The use of ultrasound may further refine our ability to predict fracture healing
Novel Cardiac Mapping Approaches and Multimodal Techniques to Unravel Multidomain Dynamics of Complex Arrhythmias Towards a Framework for Translational Mechanistic-Based Therapeutic Strategies
[ES] Las arritmias cardíacas son un problema importante para los sistemas de salud en el mundo desarrollado debido a su alta incidencia y prevalencia a medida que la población envejece. La fibrilación auricular (FA) y la fibrilación ventricular (FV) se encuentran entre las arritmias más complejas observadas en la práctica clínica. Las consecuencias clínicas de tales alteraciones arrítmicas incluyen el desarrollo de eventos cardioembólicos complejos en la FA, y repercusiones dramáticas debido a procesos fibrilatorios sostenidos que amenazan la vida infringiendo daño neurológico tras paro cardíaco por FV, y que pueden provocar la muerte súbita cardíaca (MSC). Sin embargo, a pesar de los avances tecnológicos de las últimas décadas, sus mecanismos intrínsecos se comprenden de forma incompleta y, hasta la fecha, las estrategias terapéuticas carecen de una base mecanicista suficiente y poseen bajas tasas de éxito.
Entre los mecanismos implicados en la inducción y perpetuación de arritmias cardíacas, como la FA, se cree que las dinámicas de las fuentes focales y reentrantes de alta frecuencia, en sus diferentes modalidades, son las fuentes primarias que mantienen la arritmia. Sin embargo, se sabe poco sobre los atractores, así como, de la dinámica espacio-temporal de tales fuentes fibrilatorias primarias, específicamente, las fuentes focales o rotacionales dominantes que mantienen la arritmia. Por ello, se ha desarrollado una plataforma computacional, para comprender los factores (activos, pasivos y estructurales) determinantes, y moduladores de dicha dinámica. Esto ha permitido establecer un marco para comprender la compleja dinámica de los rotores con énfasis en sus propiedades deterministas para desarrollar herramientas basadas en los mecanismos para ayuda diagnóstica y terapéutica.
Comprender los procesos fibrilatorios es clave para desarrollar marcadores y herramientas fisiológica- y clínicamente relevantes para la ayuda de diagnóstico temprano. Específicamente, las propiedades espectrales y de tiempo-frecuencia de los procesos fibrilatorios han demostrado resaltar el comportamiento determinista principal de los mecanismos intrínsecos subyacentes a las arritmias y el impacto de tales eventos arrítmicos. Esto es especialmente relevante para determinar el pronóstico temprano de los supervivientes comatosos después de un paro cardíaco debido a fibrilación ventricular (FV).
Las técnicas de mapeo electrofisiológico, el mapeo eléctrico y óptico cardíaco, han demostrado ser recursos muy valiosos para dar forma a nuevas hipótesis y desarrollar nuevos enfoques mecanicistas y estrategias terapéuticas mejoradas. Esta tecnología permite además el trabajo multidisciplinar entre clínicos y bioingenieros, para el desarrollo y validación de dispositivos y metodologías para identificar biomarcadores multi-dominio que permitan rastrear con precisión la dinámica de las arritmias identificando fuentes dominantes y atractores con alta precisión para ser dianas de estrategias terapeúticas innovadoras. Es por ello que uno de los objetivos fundamentales ha sido la implantación y validación de nuevos sistemas de mapeo en distintas configuraciones que sirvan de plataforma de desarrollo de nuevas estrategias terapeúticas. Aunque el mapeo panorámico es el método principal y más completo para rastrear simultáneamente biomarcadores electrofisiológicos, su adopción por la comunidad científica es limitada principalmente debido al coste elevado de la tecnología. Aprovechando los avances tecnológicos recientes, nos hemos enfocado en desarrollar, y validar, sistemas de mapeo óptico de alta resolución para registro panorámico cardíaco, utilizando modelos clínicamente relevantes para la investigación básica y la bioingeniería.[CA] Les arítmies cardíaques són un problema important per als sistemes de salut del món desenvolupat a causa de la seva alta incidència i prevalença a mesura que la població envelleix. La fibril·lació auricular (FA) i la fibril·lació ventricular (FV), es troben entre les arítmies més complexes observades a la pràctica clínica. Les conseqüències clíniques d'aquests trastorns arítmics inclouen el desenvolupament d'esdeveniments cardioembòlics complexos en FA i repercussions dramàtiques a causa de processos fibril·latoris sostinguts que posen en perill la vida amb danys neurològics posteriors a la FV, que condueixen a una aturada cardíaca i a la mort cardíaca sobtada (SCD). Tanmateix, malgrat els avanços tecnològics de les darreres dècades, els seus mecanismes intrínsecs s'entenen de forma incompleta i, fins a la data, les estratègies terapèutiques no tenen una base mecanicista suficient i tenen baixes taxes d'èxit.
La majoria dels avenços en el desenvolupament de biomarcadors òptims i noves estratègies terapèutiques en aquest camp provenen de tècniques valuoses en la investigació de mecanismes d'arítmia. Entre els mecanismes implicats en la inducció i perpetuació de les arítmies cardíaques, es creu que les fonts primàries subjacents a l'arítmia són les fonts focals reingressants d'alta freqüència dinàmica i AF, en les seves diferents modalitats. Tot i això, se sap poc sobre els atractors i la dinàmica espaciotemporal d'aquestes fonts primàries fibril·ladores, específicament les fonts rotacionals o focals dominants que mantenen l'arítmia. Per tant, s'ha desenvolupat una plataforma computacional per entendre determinants actius, passius, estructurals i moduladors d'aquestes dinàmiques. Això va permetre establir un marc per entendre la complexa dinàmica multidomini dels rotors amb ènfasi en les seves propietats deterministes per desenvolupar enfocaments mecanicistes per a l'ajuda i la teràpia diagnòstiques.
La comprensió dels processos fibril·latoris és clau per desenvolupar puntuacions i eines rellevants fisiològicament i clínicament per ajudar al diagnòstic precoç. Concretament, les propietats espectrals i de temps-freqüència dels processos fibril·latoris han demostrat destacar un comportament determinista important dels mecanismes intrínsecs subjacents a les arítmies i l'impacte d'aquests esdeveniments arítmics. Mitjançant coneixements previs, processament de senyals, tècniques d'aprenentatge automàtic i anàlisi de dades, es va desenvolupar una puntuació de risc mecanicista a la aturada cardíaca per FV.
Les tècniques de cartografia òptica cardíaca i electrofisiològica han demostrat ser recursos inestimables per donar forma a noves hipòtesis i desenvolupar nous enfocaments mecanicistes i estratègies terapèutiques. Aquesta tecnologia ha permès durant molts anys provar noves estratègies terapèutiques farmacològiques o ablatives i desenvolupar mètodes multidominis per fer un seguiment precís de la dinàmica d'arrímies que identifica fonts i atractors dominants. Tot i que el mapatge panoràmic és el mètode principal per al seguiment simultani de paràmetres electrofisiològics, la seva adopció per part de la comunitat multidisciplinària d'investigació cardiovascular està limitada principalment pel cost de la tecnologia. Aprofitant els avenços tecnològics recents, ens centrem en el desenvolupament i la validació de sistemes de mapes òptics de baix cost per a imatges panoràmiques mitjançant models clínicament rellevants per a la investigació bàsica i la bioenginyeria.[EN] Cardiac arrhythmias are a major problem for health systems in the developed world due to their high incidence and prevalence as the population ages. Atrial fibrillation (AF) and ventricular fibrillation (VF), are amongst the most complex arrhythmias seen in the clinical practice. Clinical consequences of such arrhythmic disturbances include developing complex cardio-embolic events in AF, and dramatic repercussions due to sustained life-threatening fibrillatory processes with subsequent neurological damage under VF, leading to cardiac arrest and sudden cardiac death (SCD). However, despite the technological advances in the last decades, their intrinsic mechanisms are incompletely understood, and, to date, therapeutic strategies lack of sufficient mechanistic basis and have low success rates.
Most of the progress for developing optimal biomarkers and novel therapeutic strategies in this field has come from valuable techniques in the research of arrhythmia mechanisms. Amongst the mechanisms involved in the induction and perpetuation of cardiac arrhythmias such AF, dynamic high-frequency re-entrant and focal sources, in its different modalities, are thought to be the primary sources underlying the arrhythmia. However, little is known about the attractors and spatiotemporal dynamics of such fibrillatory primary sources, specifically dominant rotational or focal sources maintaining the arrhythmia. Therefore, a computational platform for understanding active, passive and structural determinants, and modulators of such dynamics was developed. This allowed stablishing a framework for understanding the complex multidomain dynamics of rotors with enphasis in their deterministic properties to develop mechanistic approaches for diagnostic aid and therapy.
Understanding fibrillatory processes is key to develop physiologically and clinically relevant scores and tools for early diagnostic aid. Specifically, spectral and time-frequency properties of fibrillatory processes have shown to highlight major deterministic behaviour of intrinsic mechanisms underlying the arrhythmias and the impact of such arrhythmic events. Using prior knowledge, signal processing, machine learning techniques and data analytics, we aimed at developing a reliable mechanistic risk-score for comatose survivors of cardiac arrest due to VF.
Cardiac optical mapping and electrophysiological mapping techniques have shown to be unvaluable resources to shape new hypotheses and develop novel mechanistic approaches and therapeutic strategies. This technology has allowed for many years testing new pharmacological or ablative therapeutic strategies, and developing multidomain methods to accurately track arrhymia dynamics identigying dominant sources and attractors. Even though, panoramic mapping is the primary method for simultaneously tracking electrophysiological parameters, its adoption by the multidisciplinary cardiovascular research community is limited mainly due to the cost of the technology. Taking advantage of recent technological advances, we focus on developing and validating low-cost optical mapping systems for panoramic imaging using clinically relevant models for basic research and bioengineering.Calvo Saiz, CJ. (2022). Novel Cardiac Mapping Approaches and Multimodal Techniques to Unravel Multidomain Dynamics of Complex Arrhythmias Towards a Framework for Translational Mechanistic-Based Therapeutic Strategies [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/182329TESI
Skin disease analysis with limited data in particular Rosacea: a review and recommended framework
Recently, the rapid advancements in Deep Learning and Computer Vision technologies have introduced a new and exciting era in the field of skin disease analysis. However, there are certain challenges in the roadmap towards developing such technologies for real-life applications that must be investigated. This study considers one of the key challenges in data acquisition and computation, viz. data scarcity. Data scarcity is a central problem in acquiring medical images and applying machine learning techniques to train Convolutional Neural Networks for disease diagnosis. The main objective of this study is to explore the possible methods to deal with the data scarcity problem and to improve diagnosis with small datasets. The challenges in data acquisition for a few lamentably neglected skin conditions such as rosacea are an excellent instance to explore the possibilities of improving computer-aided skin disease diagnosis. With data scarcity in mind, the possible techniques explored and discussed include Generative Adversarial Networks, Meta-Learning, Few-Shot classification, and 3D face modelling. Furthermore, the existing studies are discussed based on skin conditions considered, data volume and implementation choices. Some future research directions are recommended
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