Development of low-cost instrumentation for single point autofluorescence lifetime measurements

Autofluorescence lifetime measurements, which can provide label-free readouts in biological tissues, contrasting e.g. different types and states of tissue matrix components and different cellular metabolites, may have significant clinical potential for diagnosis and to provide surgical guidance. However, the cost of the instrumentation typically used currently presents a barrier to wider implementation. We describe a low-cost single point time-resolved autofluorescence instrument, exploiting modulated laser diodes for excitation and FPGA-based circuitry for detection, together with a custom constant fraction discriminator. Its temporal accuracy is compared against a “gold-standard” instrument incorporating commercial TCSPC circuitry by resolving the fluorescence decays of reference fluorophores presenting single and double exponential decay profiles. To illustrate the potential to read out intrinsic contrast in tissue, we present preliminary measurements of autofluorescence lifetime measurements of biological tissues ex vivo. We believe that the lower cost of this instrument could enhance the potential of autofluorescence lifetime metrology for clinical deployment and commercial development

Behavioral and Psychological Symptoms of Dementia

Behavioral and psychological symptoms of dementia (BPSD), also known as neuropsychiatric symptoms, represent a heterogeneous group of non-cognitive symptoms and behaviors occurring in subjects with dementia. BPSD constitute a major component of the dementia syndrome irrespective of its subtype. They are as clinically relevant as cognitive symptoms as they strongly correlate with the degree of functional and cognitive impairment. BPSD include agitation, aberrant motor behavior, anxiety, elation, irritability, depression, apathy, disinhibition, delusions, hallucinations, and sleep or appetite changes. It is estimated that BPSD affect up to 90% of all dementia subjects over the course of their illness, and is independently associated with poor outcomes, including distress among patients and caregivers, long-term hospitalization, misuse of medication, and increased health care costs. Although these symptoms can be present individually it is more common that various psychopathological features co-occur simultaneously in the same patient. Thus, categorization of BPSD in clusters taking into account their natural course, prognosis, and treatment response may be useful in the clinical practice. The pathogenesis of BPSD has not been clearly delineated but it is probably the result of a complex interplay of psychological, social, and biological factors. Recent studies have emphasized the role of neurochemical, neuropathological, and genetic factors underlying the clinical manifestations of BPSD. A high degree of clinical expertise is crucial to appropriately recognize and manage the neuropsychiatric symptoms in a patient with dementia. Combination of non-pharmacological and careful use of pharmacological interventions is the recommended therapeutic for managing BPSD. Given the modest efficacy of current strategies, there is an urgent need to identify novel pharmacological targets and develop new non-pharmacological approaches to improve the adverse outcomes associated with BPSD

Correction Approach for Delta Function Convolution Model Fitting of Fluorescence Decay Data in the Case of a Monoexponential Reference Fluorophore

A correction is proposed to the Delta function convolution method (DFCM) for fitting a multiexponential decay model to time-resolved fluorescence decay data using a monoexponential reference fluorophore. A theoretical analysis of the discretised DFCM multiexponential decay function shows the presence an extra exponential decay term with the same lifetime as the reference fluorophore that we denote as the residual reference component. This extra decay component arises as a result of the discretised convolution of one of the two terms in the modified model function required by the DFCM. The effect of the residual reference component becomes more pronounced when the fluorescence lifetime of the reference is longer than all of the individual components of the specimen under inspection and when the temporal sampling interval is not negligible compared to the quantity (τ(R)(−1) – τ(−1))(−1), where τ(R) and τ are the fluorescence lifetimes of the reference and the specimen respectively. It is shown that the unwanted residual reference component results in systematic errors when fitting simulated data and that these errors are not present when the proposed correction is applied. The correction is also verified using real data obtained from experiment

The Immunology of Delirium

Delirium is an acute neuropsychiatric syndrome characterized by acute-onset global cognitive deficits, perceptual and behavioural disturbances affecting mainly elderly subjects with underlying medical or surgical conditions. The pathophysiology of delirium is complex and inflammation is a relevant precipitant factor of this syndrome, although it remains unclear how acute systemic inflammation induces the clinical picture of delirium. The central nervous system is able to detect peripheral infection or tissue destruction through circulating immune mediators and neural ascending signs. Activated microglia is responsible for an acute neuroinflammatory reaction underlying the symptoms of sickness. In healthy conditions descending pathways from the paraventricular nucleus, locus coeruleus and dorsal motor nucleus organize a centralized response to influence the immune response at the periphery and restore homeostasis. In the context of ageing and chronic neurodegeneration, adaptive changes to acute insults are characterized by exaggerated production of pro-inflammatory cytokines by primed microglia coupled with dysfunction of brain-to-immune pathways. In animal models, these changes underlie a more severe manifestation of sickness behaviour with working memory deficits suggesting that inattention, a core feature of delirium, can be a clinical correlate of an increased neuroinflammatory reaction. In patients with delirium, higher levels of pro-inflammatory cytokines and cortisol were identified in plasma and cerebrospinal fluid. However, to date it has not been clarified how peripheral inflammatory or endocrine biomarkers can reflect the likelihood or severity of delirium symptoms. In the future, a better understanding of the interaction between the brain and peripheral organs and the exact mechanism by which systemic inflammation can lead to delirium, will allow the development of new therapeutic agents

Combining various dissimilarity measures for clustering electricity market prices

The analysis of electricity markets of the European countries aims to better understand their degree of integration, which is relevant for the development of an internal market of electricity in the European Union. This study resorts to clustering of time series of hourly prices of electricity (in e/MWh) observed in the day-ahead market in 2018. The proposed approach relies on the combination of different dissimilarity measures which can capture differences in time series trends, (prices) values, cyclical behaviors and autocorrelation patterns. The results obtained, enable to provide some insights on the role of the different dissimilarity measures in the clustering process. Furthermore, they provide a clustering solution with coherent substantive interpretation and, interestingly, one that reveals the natural patterns of geographic proximity.info:eu-repo/semantics/publishedVersio