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The generation time, representing the interval between infections in primary and secondary cases, is essential for understanding and predicting the transmission dynamics of seasonal influenza, including the real-time effective reproduction number (Rt). However, comprehensive generation time estimates for seasonal influenza, especially post the 2009 influenza pandemic, are lacking. We estimated the generation time utilizing data from a 7-site case-ascertained household study in the United States over two influenza seasons, 2021/2022 and 2022/2023. More than 200 individuals who tested positive for influenza and their household contacts were enrolled within 7 days of the first illness in the household. All participants were prospectively followed for 10 days completing daily symptom diaries and collecting nasal swabs, which were tested for influenza via RT-PCR. We analyzed these data by modifying a previously published Bayesian data augmentation approach that imputes infection times of cases to obtain both intrinsic (assuming no susceptible depletion) and realized (observed within household) generation times. We assessed the robustness of the generation time estimate by varying the incubation period, and generated estimates of the proportion of transmission before symptomatic onset, infectious period, and latent period. We estimated a mean intrinsic generation time of 3.2 (95% credible interval, CrI: 2.9-3.6) days, with a realized household generation time of 2.8 (95% CrI: 2.7-3.0) days. The generation time exhibited limited sensitivity to incubation period variation. Estimates of the proportion of transmission that occurred before symptom onset, the infectious period, and the latent period were sensitive to variation in incubation periods. Our study contributes to the ongoing efforts to refine estimates of the generation time for influenza. Our estimates, derived from recent data following the COVID-19 pandemic, are consistent with previous pre-pandemic estimates, and will be incorporated into real-time Rt estimation efforts.

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INTRODUCTION: We investigate the role of osteopontin (OPN) in participants with Pre-symptomatic Alzheimer's disease (AD), mild cognitive impairment (MCI), and in AD brains. METHODS: Cerebrospinal fluid (CSF) OPN, AD, and synaptic biomarker levels were measured in 109 cognitively unimpaired (CU), parental-history positive Pre-symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD) participants, and in 167 CU and 399 participants with MCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. OPN levels were examined as a function of amyloid beta (Aß) and tau positivity. Survival analyses investigated the link between OPN and rate of conversion to AD. RESULTS: In PREVENT-AD, CSF OPN was positively correlated with synaptic biomarkers. In PREVENT-AD and ADNI, OPN was elevated in CSF Aß42/40(+)/total tau(+) and CSF Aß42/40(+)/phosphorylated tau181(+) individuals. In ADNI, OPN was increased in Aß(+) positron emission tomography (PET) and tau(+) PET individuals, and associated with an accelerated rate of conversion to AD. OPN was elevated in autopsy-confirmed AD brains. DISCUSSION: Strong associations between CSF OPN and key markers of AD pathophysiology suggest a significant role for OPN in tau neurobiology, particularly in the early stages of the disease. HIGHLIGHTS: In the Pre-symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer's Disease cohort, we discovered that cerebrospinal fluid (CSF) osteopontin (OPN) levels can indicate early synaptic dysfunction, tau deposition, and neuronal loss in cognitively unimpaired elderly with a parental history. CSF OPN is elevated in amyloid beta(+) positron emission tomography (PET) and tau(+) PET individuals. Elevated CSF OPN is associated with an accelerated rate of conversion to Alzheimer's disease (AD). Elevated CSF OPN is associated with an accelerated rate of cognitive decline on the Alzheimer's Disease Assessment Scale-Cognitive subscale 13, Montreal Cognitive Assessment, Mini-Mental State Examination, and Clinical Dementia Rating Scale Sum of Boxes. OPN mRNA and protein levels are significantly upregulated in the frontal cortex of autopsy-confirmed AD brains.

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Newborn screening for 5qSMA offers the potential for early, ideally pre-symptomatic, therapeutic intervention. However, limited data exist on the outcomes of individuals with 4 copies of SMN2, and there is no consensus within the SMA treatment community regarding early treatment initiation in this subgroup. To provide evidence-based insights into disease progression, we performed a retrospective analysis of 268 patients with 4 copies of SMN2 from the SMArtCARE registry in Germany, Austria and Switzerland. Inclusion criteria required comprehensive baseline data and diagnosis outside of newborn screening. Only data prior to initiation of disease-modifying treatment were included. The median age at disease onset was 3.0 years, with a mean of 6.4 years. Significantly, 55% of patients experienced symptoms before the age of 36 months. 3% never learned to sit unaided, a further 13% never gained the ability to walk independently and 33% of ambulatory patients lost this ability during the course of the disease. 43% developed scoliosis, 6.3% required non-invasive ventilation and 1.1% required tube feeding. In conclusion, our study, in line with previous observations, highlights the substantial phenotypic heterogeneity in SMA. Importantly, this study provides novel insights: the median age of disease onset in patients with 4 SMN2 copies typically occurs before school age, and in half of the patients even before the age of three years. These findings support a proactive approach, particularly early treatment initiation, in this subset of SMA patients diagnosed pre-symptomatically. However, it is important to recognize that the register will not include asymptomatic individuals.

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Neurodegenerative disorders have a devastating disease course and an increasing prevalence due to prolonged life expectancy. In the last decades, it has become increasingly clear that these diseases often start much earlier, before the onset of symptoms, creating a potential window for pre-symptomatic treatment, a strategy that is desirable from both the biologic and the ethical point of view. However, studying treatments for a pre-symptomatic population presents objective difficulties. This article intends to give a perspective about opportunities and challenges of pre-symptomatic prevention of neurodegenerative diseases. Besides the requirement for biomarkers that would facilitate both the selection of study population and demonstrating a treatment effect, further considerations about balancing benefits, risks and uncertainties pertaining a pre-symptomatic population will be examined.

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Early screening to determine patient risk of developing Alzheimer's will allow better interventions and planning but necessitates accessible methods such as behavioral biomarkers. Previously, we showed that cognitively healthy older individuals whose cerebrospinal fluid amyloid/tau ratio indicates high risk of cognitive decline experienced implicit interference during a high-effort task, signaling early changes in attention. To further investigate attention's effect on implicit interference, we analyzed two experiments completed sequentially by the same high- and low-risk individuals. We hypothesized that if attention modulates interference, practice would affect the influence of implicit distractors. Indeed, while both groups experienced a strong practice effect, the association between practice and interference effects diverged between groups: stronger practice effects correlated with more implicit interference in high-risk participants, but less interference in low-risk individuals. Furthermore, low-risk individuals showed a positive correlation between implicit interference and EEG low-range alpha event-related desynchronization when switching from high- to low-load tasks. This suggests that lower attention on the task was correlated with stronger interference, a typical phenomenon in the younger population. These results demonstrate how attention impacts implicit interference and highlight early differences in perception between high- and low-risk individuals.

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Type 1 diabetes (T1D) is well-recognised as a continuum heralded by the development of islet autoantibodies, progression to islet autoimmunity causing beta cell destruction, culminating in insulin deficiency and clinical disease. Abnormalities of glucose homeostasis are known to exist well before the onset of typical symptoms. Laboratory-based tests such as the oral glucose tolerance test (OGTT) and glycated haemoglobin (HbA1c) have been used to stage T1D and assess the risk of progression to clinical T1D. Continuous glucose monitoring (CGM) can detect early glycaemic abnormalities and can therefore be used to monitor for metabolic deterioration in pre-symptomatic, islet autoantibody positive, at-risk individuals. Early identification of these children can not only reduce the risk of presentation with diabetic ketoacidosis (DKA), but also determine eligibility for prevention trials, which aim to prevent or delay progression to clinical T1D. Here, we describe the current state with regard to the use of the OGTT, HbA1c, fructosamine and glycated albumin in pre-symptomatic T1D. Using illustrative cases, we present our clinical experience with the use of CGM, and advocate for an increased role of this diabetes technology, for monitoring metabolic deterioration and disease progression in children with pre-symptomatic T1D.

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Adrenoleukodystrophy (ALD) is caused by pathogenic variants in the ABCD1 gene, encoding for the adrenoleukodystrophy protein (ALDP), leading to defective peroxisomal ß-oxidation of very long-chain and branched-chain fatty acids (VLCFA). ALD manifests in both sexes with a spectrum of phenotypes, but approximately 35% of affected males develop childhood cerebral adrenoleukodystrophy (CCALD), which is lethal without hematopoietic stem cell transplant performed before symptoms start. Hence, ALD was added to the Recommended Uniform Screening Panel after the successful implementation in New York State (2013-2016). To date, thirty-five states have implemented newborn screening (NBS) for ALD, and a few programs have reported on the successes and challenges experienced. However, the overall impact of NBS on early detection of ALD has yet to be fully determined. Here, we conducted a retrospective analysis of VLCFA testing performed by our reference laboratory (ARUP Laboratories, Salt Lake City, UT, USA) over 10 years. Rate of detection, age at diagnosis, and male-to-female ratio were evaluated in patients with abnormal results before and after NBS implementation. After NBS inclusion, a significant increase in abnormal results was observed (471/6930, 6.8% vs. 384/11,670, 3.3%; p < 0.0001). Patients with ALDP deficiency identified via NBS were significantly younger (median age: 30 days vs. 21 years; p < 0.0001), and males and females were equally represented. ALD inclusion in NBS programs has increased pre-symptomatic detection of this disease, which is critical in preventing adrenal crisis as well as the severe cerebral form.

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Early detection of pathogens can significantly reduce yield losses and improve the quality of agricultural products. This study compares the efficiency of hyperspectral (HS) imaging and pulse amplitude modulation (PAM) fluorometry to detect pathogens in plants. Reflectance spectra, normalized indices, and fluorescence parameters were studied in healthy and infected areas of leaves. Potato virus X with GFP fluorescent protein was used to assess the spread of infection throughout the plant. The study found that infection increased the reflectance of leaves in certain wavelength ranges. Analysis of the normalized reflectance indices (NRIs) revealed indices that were sensitive and insensitive to infection. NRI700/850 was optimal for virus detection; significant differences were detected on the 4th day after the virus arrived in the leaf. Maximum (Fv/Fm) and effective quantum yields of photosystem II (ΦPSII) and non-photochemical fluorescence quenching (NPQ) were almost unchanged at the early stage of infection. ΦPSII and NPQ in the transition state (a short time after actinic light was switched on) showed high sensitivity to infection. The higher sensitivity of PAM compared to HS imaging may be due to the possibility of assessing the physiological changes earlier than changes in leaf structure.

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Neurodegenerative diseases, such as Alzheimer's disease (AD), pose significant challenges in early diagnosis, leading to irreversible brain damage and cognitive decline. In this study, we present a novel diagnostic approach that utilizes whole molecule analysis of neuron-derived cell-free DNA (cfDNA) as a biomarker for early detection of neurodegenerative diseases. By analyzing Differential Methylation Regions (DMRs) between purified cortical neurons and blood plasma samples, we identified robust biomarkers that accurately distinguish between neuronal and non-neuronal cfDNA. The use of cfDNA offers the advantage of convenient and minimally invasive sample collection compared to traditional cerebrospinal fluid or tissue biopsies, making this approach more accessible and patient friendly. Targeted sequencing at the identified DMR locus demonstrated that a conservative cutoff of 5% of neuron-derived cfDNA in blood plasma accurately identifies 100% of patients diagnosed with AD, showing promising potential for early disease detection. Additionally, this method effectively differentiated between patients with mild cognitive impairment (MCI) who later progressed to AD and those who did not, highlighting its prognostic capabilities. Importantly, the differentiation between patients with neurodegenerative diseases and healthy controls demonstrated the specificity of our approach. Furthermore, this cfDNA-based diagnostic strategy outperforms recently developed protein-based assays, which often lack accuracy and convenience. While our current approach focused on a limited set of loci, future research should explore the development of a more comprehensive model incorporating multiple loci to increase diagnostic accuracy further. Although certain limitations, such as technical variance associated with PCR amplification and bisulfite conversion, need to be addressed, this study emphasizes the potential of cfDNA analysis as a valuable tool for pre-symptomatic detection and monitoring of neurodegenerative diseases. With further development and validation, this innovative diagnostic strategy has the potential to significantly impact the field of neurodegenerative disease research and patient care, offering a promising avenue for early intervention and personalized therapeutic approaches.

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Xylella fastidiosa, a gram-negative bacterium vectored to plants via feeding of infected insects, causes a number of notorious plant diseases throughout the world, such as Pierce's disease (grapes), olive quick decline syndrome, and coffee leaf scorch. Detection of Xf in infected plants can be challenging because the early foliar disease symptoms are subtle and may be attributed to multiple minor physiological stresses and/or borderline nutrient deficiencies. Furthermore, Xf may reside within an infected plant for one or more growing seasons before traditional visible diagnostic disease symptoms emerge. Any method that can identify infection during the latent period or pre-diagnostic disease progress state could substantially improve the outcome of disease control interventions. Because Xf locally and gradually impairs water movement through infected plant stems and leaves over time, infected plants may not be able to effectively dissipate heat through transpiration-assisted cooling, and this heat signature may be an important pre-diagnostic disease trait. Here, we report on the association between thermal imaging, the early stages of Xf infection, and disease development in blueberry plants, and discuss the benefits and limitations of using thermal imaging to detect bacterial leaf scorch of blueberries.

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BACKGROUND: Pre-symptomatic screening methods for detecting a higher risk of Alzheimer's disease (AD) are gaining popularity; thus, more people are seeking these tests. However, to date, not much is known about the attitudes toward pre-symptomatic AD screening. OBJECTIVE: The goal of this study is to examine the psychometric properties of a tool for assessing the attitudes, barriers, and motivations to pre-symptomatic AD screening. METHODS: This is a cross-sectional study performed on 208 Greek participants (189 students and 19 caregivers) provided with an online questionnaire. Psychometric properties were assessed through the examination of its construct validity (principal component analysis) and internal consistency. RESULTS: Exploratory factor analysis revealed the presence of four factors. The first factor is labeled as "Perceived harms of testing" (10 items), the second "Acceptance of testing" (5 items), the third "Perceived benefits of testing" (6 items), and the fourth factor "Need for knowledge" (4 items). The reliability (internal consistency) of each factor separately was acceptable to good (0.70-0.87) while the internal consistency of the overall questionnaire (25 items) was good (Cronbach's α=0.82). CONCLUSION: PRE-ADS is a valid questionnaire that might help in the research of peoples' attitudes related to the pros and cons of pre-symptomatic screening for AD, and the development of effective counseling programs and prevention strategies. However, future research is required in the target population.

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Children with tuberous sclerosis complex (TSC), may experience a variety of seizure types in the first year of life, most often focal seizure sand epileptic spasms. Drug resistance is seen early in many patients, and the management of TSC associated epilepsy remain a major challenge for clinicians. In 2018 clinical recommendations for the management of TSC associated epilepsy were published by a panel of European experts. In the last five years considerable progress has been made in understanding the neurobiology of epileptogenesis and three interventional randomized controlled trials have changed the therapeutic approach for the management of TSC associated epilepsy. Pre-symptomatic treatment with vigabatrin may delay seizure onset, may reduce seizure severity and reduce the risk of epileptic encephalopathy. The efficacy of mTOR inhibition with adjunctive everolimus was documented in patients with TSC associated refractory seizures and cannabidiol could be another therapeutic option. Epilepsy surgery has significantly improved seizure outcome in selected patients and should be considered early in all patients with drug resistant epilepsy. There is a need to identify patients who may have a higher risk of developing epilepsy and autism spectrum disorder (ASD). In the recent years significant progress has been made owing to the early identification of risk factors for the development of drug-resistant epilepsy. Better understanding of the mechanism underlying epileptogenesis may improve the management for TSC-related epilepsy. Developmental neurobiology and neuropathology give opportunities for the implementation of concepts related to clinical findings, and an early genetic diagnosis and use of EEG and MRI biomarkers may improve the development of pre-symptomatic and disease-modifying strategies.

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Multiple sources of evidence suggest that changes in metabolism may precede the onset of motor symptoms in amyotrophic lateral sclerosis. This study aimed to seek evidence for alterations in the levels of blood indices collected routinely in the primary care setting prior to the onset of motor symptoms in amyotrophic lateral sclerosis. Premorbid data, measured as part of routine health screening, for total cholesterol, high-density and low-density lipoprotein cholesterol, triglyceride, glycated haemoglobin A1c and creatinine were collected retrospectively from (i) a cohort of amyotrophic lateral sclerosis patients attending a specialist clinic (n = 143) and (ii) from primary care-linked data within UK Biobank. Data were fitted using linear mixed effects models with linear b-splines to identify inflection points, controlling for age and sex. In specialist amyotrophic lateral sclerosis clinic cases, models indicated decreasing levels of total and low-density lipoprotein cholesterol prior to an inflection point in the years before symptom onset (total cholesterol 3.25 years, low-density lipoprotein cholesterol 1.25 years), after which they stabilized or rose. A similar pattern was observed in amyotrophic lateral sclerosis cases within UK Biobank, occurring several years prior to diagnosis (total cholesterol 7 years, low-density lipoprotein cholesterol 7.25 years), differing significantly from matched controls. High-density lipoprotein cholesterol followed a similar pattern but was less robust to sensitivity analyses. Levels of triglyceride remained stable throughout. Glycated haemoglobin temporal profiles were not consistent between the clinic and biobank cohorts. Creatinine level trajectories prior to amyotrophic lateral sclerosis did not differ significantly from controls but decreased significantly in the symptomatic period after an inflection point of 0.25 years after symptom onset (clinic cohort) or 0.5 years before diagnosis (UK Biobank). These data provide further evidence for a pre-symptomatic period of dynamic metabolic change in amyotrophic lateral sclerosis, consistently associated with alterations in blood cholesterols. Such changes may ultimately contribute to biomarkers applicable to population screening and for pathways guiding the targeting of preventative therapy.

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The roots of Polygonum multiflorum Thunberg (Polygonaceae) are used as a crude drug Kashu that is considered to improve blood deficiency based on a Kampo concept. Kashu has been included in Kampo formulas, such as Tokiinshi, which is used to treat eczema and dermatitis with itchiness by inhibiting inflammation and facilitating blood circulation in the skin. However, the effects of P. multiflorum roots on erythropoiesis are unclear. Previously, we isolated six phenolic constituents from an ethyl acetate (EtOAc)-soluble fraction of P. multiflorum root extract and identified them as (E)-2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucopyranoside [(E)-THSG], emodin, emodin-8-O-ß-D-glucopyranoside, physcion, physcion-8-O-ß-D-glucopyranoside, and catechin. To examine whether P. multiflorum roots facilitate erythropoiesis, the EtOAc-soluble fraction was orally administered to healthy ICR mice. When compared with mice fed a standard diet alone (Controls), the mice fed a diet including the EtOAc-soluble fraction exhibited significantly higher serum erythropoietin (Epo) levels. The renal Epo mRNA levels in EtOAc-soluble fraction-administered mice were significantly higher than those in the control mice. Then, we administered roxadustat, which is a drug to treat the patient suffering with renal anemia by specifically inhibiting hypoxia-inducible factor prolyl hydroxylases. Roxadustat slightly increased renal Epo mRNA levels in healthy mice. Administration of (E)-THSG, a major constituent, significantly increased serum Epo levels. It is likely that (E)-THSG may facilitate the process to convert inactive renal Epo-producing cells to active Epo-producing cells. Collectively, it is implied that (E)-THSG in the EtOAc-soluble fraction of P. multiflorum roots may primarily improve blood deficiency of Kampo concept by promoting erythropoiesis.

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Since February 2020, COVID-19 has spread rapidly to more than 200 countries in the world. During the pandemic, local governments in China have implemented different interventions to efficiently control the spread of the epidemic. Characterizing transmission of COVID-19 under some typical interventions is essential to help countries develop appropriate interventions. Based on the pre-symptomatic transmission patterns of COVID-19, we established a novel compartmental model: Susceptible-Infectious-Confirmed-Removed (SICR) model, which allowed the effective reproduction number to change over time, thus the effects of policies could be reasonably estimated. Using the epidemic data of Wuhan, Wenzhou, and Shenzhen, we migrated the corresponding estimated policy modes to South Korea, Italy, and the United States and simulated the potential outcomes for these countries when they adopted similar policy strategies to China. We found that the mild interventions implemented in Shenzhen were effective in controlling the epidemic in the early stage, while more stringent policies which were implemented in Wuhan and Wenzhou were necessary if the epidemic became severe and needed to be controlled in a short time.

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People with Huntington's disease (HD) face difficult emotional and practical challenges throughout their illness, including in the pre-symptomatic stage. There are, however, extremely limited psychosocial interventions adapted to or researched for HD. We adapted and piloted an 8-week mindfulness-based stress reduction (MBSR) program in people with pre-symptomatic HD to determine if the program (i) was feasible and acceptable to participants, (ii) resulted in increased mindfulness understanding and skills, and (iii) led to improved psychological adjustment. Quantitative measures of mindfulness, emotion regulation, mood, and quality of life were administered pre and post the MBSR program and at 3-month follow-up. Measures of mindfulness practice and session clarity were administered weekly. Qualitative participant feedback was collected with a post-program interview conducted by independent clinicians. Seven participants completed the 8-week course. The program's feasibility and acceptability was supported by excellent retention and participation rates and acceptable rates of home practice completion. In addition, qualitative feedback indicated participant satisfaction with the program structure and content. Two core mindfulness skills (observing and non-judgment) showed significant improvement from pre- to post-assessment. Participant qualitative feedback indicated increased confidence and capacity to use mindfulness techniques, particularly in emotionally challenging situations. Participant questionnaire data showed good psychological adjustment at baseline, which did not change after treatment. Psychological benefits of the program identified in qualitative data included fewer ruminations about HD, reduced isolation and stigma, and being seen by others as calmer. These findings justify expansion of the program to determine its efficacy in a larger, controlled study.

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Early screening to determine patient risk of developing Alzheimer's will allow better interventions and planning but necessitates accessible methods such as behavioral biomarkers. Previously, we showed that cognitively healthy older individuals whose cerebrospinal fluid amyloid / tau ratio indicates high risk of cognitive decline experienced implicit interference during a high-effort task, signaling early changes in attention. To further investigate attention's effect on implicit interference, we analyzed two experiments completed sequentially by the same high- and low-risk individuals. We hypothesized that if attention modulates interference, practice would affect the influence of implicit distractors. Indeed, while both groups experienced a strong practice effect, the association between practice and interference effects diverged between groups: stronger practice effects correlated with more implicit interference in high-risk participants, but less interference in low-risk individuals. Furthermore, low-risk individuals showed a positive correlation between implicit interference and EEG low-range alpha event-related desynchronization when switching from high- to low-load tasks. These results demonstrate how attention impacts implicit interference and highlight early differences in cognition between high- and low-risk individuals.

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BACKGROUND: Age-related macular degeneration (AMD) is an irreversible blinding eye condition with complex genetic and environmental etiologies. Genetic testing for AMD for previously identified multiple-risk single nucleotide polymorphisms can help determine an individual's future susceptibility. However, such testing has been discouraged until evidence shows that providing such information to symptomatic or pre-symptomatic individuals will alter their disease course. Therefore, we designed this study to investigate whether knowledge of AMD risk could stimulate the adoption of a healthier lifestyle that could lower the incidence of AMD later in life. We hypothesize that pre-symptomatic individuals informed of a high genetic risk of AMD are more likely to make quantifiable, positive lifestyle changes relative to participants informed of lower genetic risk or randomized to deferred disclosure of genetic testing results. METHODS: The Moran AMD Genetic Testing Assessment (MAGENTA) study is a phase 2, single-center, prospective, double-masked, randomized controlled trial conducted at the John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. Participants are randomized by a 3:1 allocation ratio to immediate and deferred disclosure groups and followed for 12 months. Skin, ocular, and serum carotenoid status, as well as nutritional and social surveys, are assessed at study visits. Skin carotenoid assessment is by resonance Raman spectroscopy and reflectance spectroscopy, ocular carotenoids are measured with Heidelberg Spectralis autofluorescence imaging and fluorescence lifetime imaging ophthalmoscopy (FLIO), and serum carotenoids are quantified using high-performance liquid chromatography. The primary outcome evaluates changes in skin carotenoid status in response to genetic risk disclosure. The secondary outcomes examine changes in ocular and serum carotenoid status in response to genetic risk disclosure. Also, we will correlate AMD genetic risk with baseline ocular and systemic carotenoid status and FLIO. DISCUSSION: MAGENTA will provide much-needed evidence on whether pre-symptomatic testing for AMD risk can lead to quantifiable long-term changes in behavior and lifestyle associated with a lower incidence of AMD later in life. Findings from the MAGENTA trial will facilitate the design of a future larger, longer-term, multicenter phase 3 trial that could feature subgroup analysis, expanded measures of lifestyle modification, and potential active nutritional interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT05265624 . Registered on March 3, 2022.

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Background: Currently-used tools for early recognition of clinical deterioration have high sensitivity, but with low specificity and are based on infrequent measurements. We aimed to develop a pre-symptomatic and real-time detection and warning tool for potential patients' deterioration based on multi-parameter real-time warning score (MPRT-WS). Methods: A total of more than 2 million measurements were collected, pooled, and analyzed from 521 participants, of which 361 were patients in general wards defined at high-risk for deterioration and 160 were healthy participants allocation as controls. The risk score stratification was based on cutoffs of multiple physiological parameters predefined by a panel of specialists, and included heart rate, blood oxygen saturation (SpO2), respiratory rate, cuffless systolic and diastolic blood pressure (SBP and DBP), body temperature, stroke volume (SV), cardiac output, and systemic vascular resistance (SVR), recorded every 5 min for a period of up to 72 h. The data was used to define the various risk levels of a real-time detection and warning tool, comparing it with the clinically-used National Early Warning Score (NEWS). Results: When comparing risk levels among patients using both tools, 92.6%, 6.1%, and 1.3% of the readings were defined as "Low", "Medium", and "High" risk with NEWS, and 92.9%, 6.4%, and 0.7%, respectively, with MPRT-WS (p = 0.863 between tools). Among the 39 patients that deteriorated, 30 patients received 'High' or 'Urgent' using the MPRT-WS (42.7 ± 49.1 h before they deteriorated), and only 6 received 'High' score using the NEWS. The main abnormal vitals for the MPRT-WS were SpO2, SBP, and SV for the "Urgent" risk level, DBP, SVR, and SBP for the "High" risk level, and DBP, SpO2, and SVR for the "Medium" risk level. Conclusion: As the new detection and warning tool is based on highly-frequent monitoring capabilities, it provides medical teams with timely alerts of pre-symptomatic and real-time deterioration.

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We report on the use of leaf diffuse reflectance spectroscopy for plant disease detection. A smartphone-operated, compact diffused reflectance spectrophotometer is used for field collection of leaf diffuse reflectance spectra to enable pre-symptomatic detection of the progression of potato late blight disease post inoculation with oomycete pathogen Phytophthora infestans. Neural-network-based analysis predicts infection with >96% accuracy, only 24 h after inoculation with the pathogen, and nine days before visual late blight symptoms appear. Our study demonstrates the potential of using portable optical spectroscopy in tandem with machine learning analysis for early diagnosis of plant diseases.

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