Indiana University-Purdue University Indianapolis (IUPUI) / Noble metal nanostructures display collective oscillation of the surface conduction electrons upon light irradiation as a form of localized surface plasmon resonance (LSPR) properties. Size, shape, and refractive index of the surrounding environment are the key features that control the LSPR properties. Surface passivating ligands on to the nanostructure can modify the charge density of nanostructures. Further, allow resonant wavelengths to match that of the incident light. This unique phenomenon called the “plasmoelectric effect.” According to the Drude model, red and blue shifts of LSPR peak of nanostructures are observed in the event of reducing and increasing charge density, respectively. However, herein, we report unusual LSPR properties of gold triangular nanoprisms (Au TNPs) upon functionalization with para-substituted thiophenols (X-Ph-SH, X = -NH2, -OCH3, -CH3, -H, -Cl, -CF3, and -NO2). Accordingly, we hypothesized that an appropriate energy level alignment between the Au Fermi energy and the HOMO or LUMO of ligands allows the delocalization of surface plasmon excitation at the hybrid inorganic-organic interface. Thus, provides a thermodynamically driven plasmoelectric effect. We further validated our hypothesis by calculating the HOMO and LUMO levels and work function changes of Au TNPs upon functionalization with para-substituted thiol. This reported unique finding then utilized to design ultrasensitive plasmonic substrate for biosensing of cancer microRNA in bladder cancer and cardiovascular diseases. In the discovery of early bladder cancer diagnosis platform, for the first time, we have been utilized to analyze the tumor suppressor microRNA for a more accurate diagnosis of BC. Additionally, we have been advancing our sensing platform to mitigate the false positive and negative responses of the sensing platform using surface-enhanced fluorescence technique. This noninvasive, highly sensitive, highly specific, also does not have false positives techniques that provide the strong key to detect cancer at a very early stage, hence increase the cancer survival rate. Moreover, the electromagnetic field enhancement of Surface-Enhanced Raman Scattering (SERS) and other related surface-enhanced spectroscopic processes resulted from the LSPR property. This dissertation describes the design and development of entirely new SERS nanosensors using a flexible SERS substrate based on the unique LSPR property of Au TNPs. The developed sensor shows an excellent SERS activity (enhancement factor = ~6.0 x 106) and limit of detection (as low as 56 parts-per-quadrillions) with high selectivity by chemometric analyses among three commonly used explosives (TNT, RDX, and PETN). Further, we achieved the programmable self-assembly of Au TNPs using molecular tailoring to form a 3D supper lattice array based on the substrate effect. Here we achieved the highest reported sensitivity for potent drug analysis, including opioids and synthetic cannabinoids from human plasma obtained from the emergency room. This exquisite sensitivity is mainly due to the two reasons, including molecular resonance of the adsorbate molecules and the plasmonic coupling among the nanoparticles. Altogether we are highly optimistic that our research will not only increase the patient survival rate through early detection of cancer but also help to battle the “war against drugs” that together are expected to enhance the quality of human life.

Le syndrome vache à terre (SVT) est rencontré chez la vache laitière et est une condition d’urgence à évolution rapide où le pronostic est réservé à sombre. Les seuls tests complémentaires disponibles actuellement nécessitent l’utilisation des services d’un laboratoire commercial. La présence d’hypoperfusion locale et systémique ainsi que de lésions cardiaques à la nécropsie rend potentiellement intéressant le dosage de la lactatémie (LAC) et de la troponinémie (cTnI) sanguine. Ces deux biomarqueurs pouvant être analysés à l’aide d’appareils portatifs. L’objectif de la présente étude était d’évaluer la valeur pronostique de la LAC et de la cTnI dosées à la ferme, directement au chevet de la vache laitière atteinte de SVT. Le pourcentage d’issue négative (mort ou euthanasie) à sept jours suivant l’inclusion (d7) était de 63.1 %. La lactatémie n’était pas associée au pronostic vital de l’animal lors de SVT. Par contre, une valeur sanguine de cTnI >0.7 ng/mL était associée à une issue négative à d7 (sensibilité, spécificité, valeurs prédictives positive et négative respectivement de 54.1 %, 78.4 %, 82.0 % et 48.3 %). L’utilisation d’un modèle de régression logistique multivariable a montré que cette hypertroponinémie était associée à un risque d’issue négative à d7 5.5 fois (IC95%: 2.1-14.6) plus grand que le groupe présentant une cTnI ≤ 0.07 ng/mL. De plus, les animaux ayant une FC >100 BPM étaient 3.7 fois plus à risque (IC95%: 1.5-10.2) de subir une issue négative à d7 que ceux présentant une FC≤100 BPM. / Downer cow syndrome (DCS) is observed in dairy cattle and is an emergency condition that progresses rapidly and whose prognosis is reserved to poor. The only available complementary tests require the services of a commercial laboratory. The presence of local and/or systemic hypoperfusion, along with the presence of cardiac lesions at necropsy renders the dosage of lactatemia (LAC) and cardiac troponin I (cTnI) in the blood potentially interesting. These two biomarkers being measurable through the analysis of portable equipment, the present study objective was to evaluate the prognostic value of measuring LAC and cTnl directly at the side of the dairy cow affected by DCS. The percentage of negative outcome (death or euthanasia; NO) seven days following the study inclusion (d7) was 63.1%. LAC was not associated with the prognosis of the animal suffering from DCS. However, a blood cTnl value of ˃0.7ng/mL was associated with a NO before d7 (sensitivity, positive and negative predictive values of 54.1, 78.4, 82.0, and 48.3%, respectively). The use of a logistic multivariable model demonstrated that hypertroponinemia was associated with a NO risk 5.5 greater (95%CI: 2.1-14.6) by d7 than animals presented with a blood cTnl value of ≤ 0,07ng/mL. The animals presenting a HR > 100BPM were 3.7 times more at risk (95%CI: 1.5-10.2) of exiting the herd by d7 than the animals with a HR of ≤ 100BPM.

Three novel mutations (G159D, L29Q and E59D/D75Y) in cardiac troponin C (CTnC) associate their clinical outcomes with a given cardiomyopathy. Current paradigms propose that sarcomeric mutations associated with dilated cardiomyopathy (DCM) decrease the myofilament calcium sensitivity while those associated with hypertrophic (HCM) cardiomyopathy increase it. Therefore, we incorporated the mutant CTnCs into skinned cardiac muscle in order to determine if their effects on the calcium regulation of tension and ATPase activity coincide with the current paradigms and phenotypic outcomes. This required the development of new calculator programs to solve complex ionic equilibria to more accurately buffer and expand the free calcium range of our test solutions. In accordance with the DCM paradigms, our result show that G159D and E59D/D75Y CTnC decrease the myofilament calcium sensitivity and force generating capabilities which would likely increase the rate of muscle relaxation and weaken the contractile force of the myocardium. Alternatively, the lack of myofilament change from L29Q CTnC (associated with HCM) may explain why the only proband is seemingly unaffected. Notably, the changes in the calcium sensitivity of tension (in fibers) do not necessarily occur in the isolated CTnC and vice versa. These counter-intuitive findings are justified through a transition in calcium affinity occurring at the level of cardiac troponin (CTn) and higher, implying that the true effects of these mutations become apparent as the hierarchal level of the myofilament increases. Despite these limitations, the regulated thin filament (RTF) retains its role as the calcium regulatory unit and best indicates a mutation's ability to sensitize (+) or desensitize (-) the muscle to calcium. Since multiple forms of cardiomyopathies exist, the identification of new drugs that sensitize (+) or desensitize (-) the calcium sensitivity could potentially reverse (+ or -) these aberrant changes in myofilament sensitivity. Therefore, we have developed an RTF mediated High Throughput Screening assay to identify compounds in libraries of molecules that can specifically modulate the calcium sensitivity of cardiac contraction. The knowledge gained from these studies will help us and others to uncover new pharmacological agents for the investigation and treatments of cardiomyopathies, hypertension and other forms of cardiovascular diseases.

Introduction: Type 2 diabetes continues to be one of the most common non-communicable diseases worldwide and complications due to type 2 diabetes, such as cardiovascular disease (CVD) can cause severe disability and even death. Despite advances in the development and validation of cardiovascular risk scores, those used in clinical practice perform inadequately for people with type 2 diabetes. Research has suggested that particular non-traditional biomarkers and novel omics data may provide additional value to risk scores over-and-above traditional predictors. Aims: To determine whether a small panel of non-traditional biomarkers improve prediction models based on a current cardiovascular risk score (QRISK2), either individually or in combination, in people with type 2 diabetes. Furthermore, to investigate a set of 228 metabolites and their associations with CVD, independent of well-established cardiovascular risk factors, in order to identify potential new predictors of CVD for future research. Methods: Analyses used the Edinburgh Type 2 Diabetes Study (ET2DS), a prospective cohort of 1066 men and women with type 2 diabetes aged 60-75 years at baseline. Participants were followed for eight years, during which time 205 had a cardiovascular event. Additionally, for omics analyses, four cohorts from the UCL-LSHTM-Edinburgh-Bristol (UCLEB) consortium were combined with the ET2DS. Across all studies, 1005 (44.73%) participants had CVD at baseline or experienced a cardiovascular event during follow-up. Results: In the ET2DS, higher levels of high sensitivity cardiac troponin (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) and lower levels of ankle brachial pressure index (ABI) were associated with incident cardiovascular events, independent of QRISK2 and pre-existing cardiovascular disease (odds ratios per one SD increase in biomarker 1.35 (95% CI: 1.13, 1.61), 1.23 (1.02, 1.49) and 0.86 (0.73, 1.00) respectively). The addition of each biomarker to a model including just QRISK2 variables improved the c-statistic, with the biggest increase for hs-cTnT (from 0.722 (0.681, 0.763) to 0.732 (0.690, 0.774)). When multiple biomarkers were considered in combination, the greatest c-statistic was found for a model which included ABI, hs-cTnT and gamma-glutamyl transpeptidase (0.740 (0.699, 0.781)). In the combined cohorts from the UCLEB consortium, a small number of high-density lipoprotein (HDL) particles were found to be significantly associated with CVD: concentration of medium HDL particles, total lipids in medium HDL, phospholipids in medium HDL and phospholipids in small HDL. These associations persisted after adjustment for a range of traditional cardiovascular risk factors including age, sex, blood pressure, smoking and HDL to total cholesterol ratio. Conclusions: In older people with type 2 diabetes, a range of non-traditional biomarkers increased predictive ability for cardiovascular events over-and-above the commonly used QRISK2 score, and a combination of biomarkers may provide the best improvement. Furthermore, a small number of novel omics biomarkers were identified which may further improve risk scores or provide better prediction than traditional lipid measurements such as HDL cholesterol.

Background Coronavirus Disease-2019 (COVID-19) affected elderly individuals disproportionately in terms of hospitalization and adverse outcome. Objective This cross-sectional study examined the associations of COVID-19 diagnosis (COVID-negative versus COVID-positive) with levels of four clinical markers – cardiac troponin T (cTnT), high-sensitive C-reactive protein (hsCRP), D-dimer and b-type natriuretic peptide (NT-proBNP) – along with potential differences in associations by sex in a hospital-based sample of elderly individuals. Methods The sample comprised individuals aged ≥80 years visiting the Emergency at Karolinska universitetssjukhuset (Huddinge) between January 2020 and December 2021 for whom data on polymerase chain reaction-based COVID-19 testing were available (n=2668). Plasma levels of the markers were measured using standard methods. Right skewed outcome variables were natural-log (Ln) transformed. Multivariable linear regression models were fitted. Results Participants’ median age was 87 years (interquartile range: 85–90) and 58.4% were female. Approximately 13% of the participants were COVID-19 positive. There was no statistically significant association between COVID-positive diagnosis and any of the markers after controlling for age and sex. On sex stratification, COVID-19 positive males had 55.3% (95% confidence interval (CI): 1.1%–138.4%; P=0.044) higher hsCRP levels than COVID-negative males. Additionally, age was positively associated with cTnT (Ln cTnT βadjusted: 0.041; 95% CI: 0.033–0.050; P<0.001) and NT-proBNP (Ln NTproBNP βadjusted: 0.059; 95% CI: 0.015–0.102; P=0.008). Conclusion COVID-positive diagnosis was not related with the markers apart from a sex-specific, positive association with hsCRP observed among males. Future studies should explore the relationship of these markers with mortality to determine their prognostic utility among elderly individuals.

[ES] El cuidado de la salud es un campo en el que la detección precoz de enfermedades está cobrando cada vez más importancia. Hoy en día, profesionales y ciudadanos demandan que las técnicas de diagnóstico sean de alta calidad, tanto para el sistema de sanidad privado como para el público. Cuando se utilizan técnicas de diagnóstico de manera inadecuada, eso puede acarrear bastantes consecuencias, tales como un serio peligro sobre la salud y la sobrecarga técnica y económica de los servicios de salud. Eso es debido a que las técnicas de diagnóstico disponibles hoy en día son demasiado costosas, centralizadas en laboratorios y necesitan profesionales altamente cualificados para poder llevar a cabo dichas tareas, lo que conllevaría una demora en el tiempo, siendo este muchas veces vital para los enfermos. Es muy necesario, por lo tanto, reflexionar sobre la necesidad y emergencia de tales prácticas preventivas, especialmente para enfermedades de alto riesgo como el cáncer, el Alzheimer o la primera causa de muerte en el mundo, las enfermedades cardiovasculares. En este contexto, el objetivo principal del trabajo realizado durante esta Tesis Doctoral es ayudar a superar estos problemas mediante la exploración de la posibilidad de utilizar tecnología fotónica para el desarrollo de sistemas de análisis que puedan ser utilizados para el diagnóstico y pronóstico de las enfermedades cardiovasculares. Este objetivo se ha abordado mediante la combinación de la tecnología nanofotónica, consistiendo en la nanofabricación de las estructuras PBG de sensado que ofrece varios beneficios, como una alta sensibilidad, una extrema reducción de tamaño y un proceso de fabricación compatible con el de la industria microelectrónica, con un método de biofuncionalización obteniendo una capa de bioreconocimiento estable y selectiva mediante el uso de la reacción TEC asistida por luz capaz de proporcionar unas capas de bio-reconocimiento extremadamente finas con una inmovilización espacialmente selectiva. / [CAT] L'atenció a la salut és un camp en què la detecció precoç de malalties està cobrant cada vegada més importància. Hui en dia, professionals i ciutadans demanen que les tècniques de diagnòstic siguin d'alta qualitat, tant per al sistema de sanitat privat com per al públic. Quan s'utilitzen tècniques de diagnòstic de manera inadequada, això pot comportar bastants conseqüències, com ara, un seriós perill sobre la salut i la sobrecàrrega tècnica i econòmica dels serveis de salut. Això és degut al fet que les tècniques de diagnòstic disponibles hui en dia són molt costoses, centralitzades en laboratoris i necessiten professionals altament qualificats per poder realitzar aquestes tasques, lo que comportaria a una demora en el temps que moltes vegades es vital pels malalts. És molt necessari, per tant, reflexionar sobre la necessitat i emergència de tals practiques preventives, especialment per a malalties d'alt risc com el càncer, l'Alzheimer o la primera causa de mort al món, les malalties cardiovasculars. En aquest context, l'objectiu principal del treball realitzat durant aquesta Tesi Doctoral és ajudar a superar aquests problemes mitjançant l'exploració de la possibilitat d'utilitzar tecnologia fotònica per al desenvolupament de sistemes d'anàlisis que puguin ser utilitzats per al diagnòstic i pronòstic de les malalties cardiovasculars. Aquest objectiu s'ha abordat mitjançant la combinació de la tecnologia nanofotònica, consistint en la nanofabricació de les estructures de detecció de PBG fotòniques que ofereix diversos beneficis, com una alta sensibilitat, una extrema reducció de mida i un procés de fabricació compatible amb el de la indústria microelectrònica, amb un mètode de biofuncionalització obtenint una capa de bio-reconeixement estable i selectiva mitjançant l'ús de la reacció TEC assistida per llum capaç de proporcionar unes capes de bioreconeixement extremadament fines amb una immobilització espacialment selectiva. preventives, especialment per a malalties d'alt risc com el càncer, l'Alzheimer o la primera causa de mort al món, les malalties cardiovasculars. En aquest context, l'objectiu principal del treball realitzat durant aquesta Tesi Doctoral és ajudar a superar aquests problemes mitjançant l'exploració de la possibilitat d'utilitzar tecnologia fotònica per al desenvolupament de sistemes d'anàlisis que puguin ser utilitzats per al diagnòstic i pronòstic de les malalties cardiovasculars. Aquest objectiu s'ha abordat mitjançant la combinació de la tecnologia nanofotònica, consistint en la nanofabricació de les estructures de detecció de PBG fotòniques que ofereix diversos beneficis, com una alta sensibilitat, una extrema reducció de mida i un procés de fabricació compatible amb el de la indústria microelectrònica, amb un mètode de biofuncionalització obtenint una capa de bio-reconeixement estable i selectiva mitjançant l'ús de la reacció TEC assistida per llum capaç de proporcionar unes capes de bioreconeixement extremadament fines amb una immobilització espacialment selectiva. / [EN] Healthcare is a field where the early detection of diseases is becoming more and more important. Nowadays, professionals and citizens demand high quality diagnosis techniques offered by both private and public health systems. When the application of diagnostic tests is not adequate, different consequences can be observed such as health hazard and technical and economic overload of health services. This is due to the fact that the diagnostic techniques available are expensive, centralized in laboratories and with the need for highly qualified professionals to carry out these tasks, what can fundamentally lead to delays in time, being critical for the patient's health. It is very necessary, therefore, to reflect on the need and emergency of such preventive practices, especially for high-risk diseases such as cancer, Alzheimer or the first cause of death in the world, the cardiovascular diseases. Within this context, the main objective of the work done during this PhD Thesis is to help on overcoming these problems by exploring the possibility of using photonic technology for the development of analysis devices which might be used for the early diagnosis and prognosis of cardiovascular diseases. This objective has been addressed by combining nanophotonic technology, by the nanofabrication of the photonic PBG sensing structures, which provides several benefits such as a high sensitivity, an extreme size reduction and a fabrication process being compatible with that from the microelectronics industry, with a light-assisted biofunctionalization method forming a stable and selective biorecognition layer using TEC reaction able to provide extremely thin biorecognition layers with a spatially-selective immobilization. / Sabek, J. (2019). Combination of nanophotonic biosensors and light-assisted immobilization procedures for the detection of cardiac biomarkers [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/124821 / TESIS