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ABSTRACT: Keratomycosis is a serious corneal infection associated with high ocular morbidity that can lead to severe vision loss. It is estimated to affect more than 1 million patients annually, most commonly occurring in tropical climates, and represents a growing threat to patients worldwide. Despite aggressive medical management, fungal infections have a higher rate of perforation requiring surgical intervention compared with other infectious etiologies. Early diagnosis and appropriate treatment are keys to preserving vision and saving patients' eyes.Timely diagnosis of fungal keratitis helps minimize corneal damage and scarring and increases the likelihood of a favorable outcome. Studies have shown that correct identification of fungal infections is often delayed up to 2 to 3 weeks after initial presentation. This leads to incorrect or ineffective treatment for many patients. Diagnostic techniques explored in this study include corneal scrapings with staining and culture, visualization with in vivo confocal microscopy, molecular diagnostic techniques including polymerase chain reaction, and recently developed omics-based technologies.Treatment of fungal keratitis begins with topical antifungals. Medical management has been proven to be effective, but with limitations including poor drug penetration and low bioavailability. Cases that do not respond to topical therapy require more invasive and novel treatments to control the infection. We review the clinical trials that have shaped current practice patterns, with focus on the efficacy of topical natamycin as the primary therapy for filamentous fungal keratitis. We explore additional management strategies such as localized intrastromal and intracameral injections of antifungal medications, photodynamic therapy, and surgical intervention.
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Antifúngicos , Infecciones Fúngicas del Ojo , Queratitis , Humanos , Infecciones Fúngicas del Ojo/diagnóstico , Infecciones Fúngicas del Ojo/microbiología , Infecciones Fúngicas del Ojo/tratamiento farmacológico , Infecciones Fúngicas del Ojo/terapia , Antifúngicos/uso terapéutico , Queratitis/diagnóstico , Queratitis/microbiología , Queratitis/tratamiento farmacológico , Microscopía ConfocalRESUMEN
Background: Most Americans believe that gun-free zones make locations more vulnerable to violent crimes, particularly active shootings. However, there is no empirical evidence regarding the impact of gun-free zones on protecting locations from violence. The objective of this study was to estimate the association between gun-free zones and active shootings. Methods: We used a pair-matched case-control study where cases were all US establishments where active shootings occurred between 2014 and 2020, and controls were randomly selected US establishments where active shootings could have but did not occur, pair-matched by establishment type, year, and county. Gun-free status of included establishments was determined via local laws, company policy, news reporting, Google Maps and posted signage, and calling establishments. Findings: Of 150 active shooting cases, 72 (48.0%) were determined to have occurred in a gun-free zone. Of 150 controls where no active shooting occurred, 92 (61.3%) were determined to be gun-free. After accounting for matched pairs, the conditional odds of an active shooting in gun-free establishments were 0.38 times those in non-gun-free establishments, with a 95% confidence interval of 0.19-0.73 (p-value = 0.0038). Several robustness analyses affirmed these findings. Interpretation: It is unlikely that gun-free zones attract active shooters; gun-free zones may be protective against active shootings. This study challenges the proposition of repealing gun-free zones based on safety concerns. Funding: This work was funded in part by the National Collaborative on Gun Violence Research and the Arnold Foundation.
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Excessive production of Transforming Growth Factor ß (TGFß) is commonly associated with dominant and recessive forms of OI. Previous reports have indicated that administration of TGFß-targeted antibodies maybe of potential therapeutic benefit to OI patients. However, direct targeting of TGFß is likely to cause multiple adverse effects including simulation of autoimmunity. In the current study we use patient-derived normal and OI fibroblasts, osteoblasts and OIM mouse models to determine the effects of Losartan, an angiotensin II receptor type 1 (AT1) antagonist, on TGFß signalling and bone morphology in OI. In OIM mice bred on a mixed background administration of 0.6 g/L losartan for 4 weeks was associated with a significant reduction in TGFß from 79.2 g/L in the control to 60.0 ng/ml following losartan (p < 0.05), reduced osteoclast activity as measured by CTX from 275.9 ng/ml in the control to 157.2 ng/ml following 0.6 g/L of losartan (p < 0.05) and increased cortical bone thickness (P < 0.001). Furthermore in OIM mice bred on a C57BL/6 background 0.6 g/L losartan increased trabecular bone volume in the tibiae (P < 0.05) and the vertebrae (P < 0.01), increased cortical bone thickness (P < 0.001) reduced the trabecular pattern factor (P < 0.01 and P < 0.001 for the tibiae and vertebrae respectively), reduced osteoclast (P < 0.05) and osteoblast (P < 0.01) numbers as well as reducing the area of bone covered by these cell types. Interestingly, losartan did not affect immune cells infiltrating into bone, nor did this drug alter TGFß signalling in normal or OI fibroblasts. Instead, losartan reduced SMAD2 phosphorylation in osteoblasts, inhibiting their ability to differentiate. Our data suggest that losartan may be an effective treatment for the bone-associated dysmorphia displayed in OI whilst minimising potential adverse immune cell-related effects.
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Understanding how gene-environment interactions (GEIs) influence the circulating proteome could aid in biomarker discovery and validation. The presence of GEIs can be inferred from single nucleotide polymorphisms that associate with phenotypic variability - termed variance quantitative trait loci (vQTLs). Here, vQTL association studies are performed on plasma levels of 1463 proteins in 52,363 UK Biobank participants. A set of 677 independent vQTLs are identified across 568 proteins. They include 67 variants that lack conventional additive main effects on protein levels. Over 1100 GEIs are identified between 101 proteins and 153 environmental exposures. GEI analyses uncover possible mechanisms that explain why 13/67 vQTL-only sites lack corresponding main effects. Additional analyses also highlight how age, sex, epistatic interactions and statistical artefacts may underscore associations between genetic variation and variance heterogeneity. This study establishes the most comprehensive database yet of vQTLs and GEIs for the human proteome.
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Bancos de Muestras Biológicas , Proteínas Sanguíneas , Interacción Gen-Ambiente , Polimorfismo de Nucleótido Simple , Proteoma , Sitios de Carácter Cuantitativo , Humanos , Reino Unido , Proteoma/metabolismo , Proteoma/genética , Femenino , Masculino , Proteínas Sanguíneas/metabolismo , Proteínas Sanguíneas/genética , Persona de Mediana Edad , Anciano , Adulto , Biomarcadores/sangre , Estudio de Asociación del Genoma Completo , Biobanco del Reino UnidoRESUMEN
Neural network potentials (NNPs) are an innovative approach for calculating the potential energy and forces of a chemical system. In principle, these methods are capable of modeling large systems with an accuracy approaching that of a high-level ab initio calculation, but with a much smaller computational cost. Due to their training to density-functional theory (DFT) data and neglect of long-range interactions, some classes of NNPs require an additional term to include London dispersion physics. In this Perspective, we discuss the requirements for a dispersion model for use with an NNP, focusing on the MLXDM (Machine Learned eXchange-Hole Dipole Moment) model developed by our groups. This model is based on the DFT-based XDM dispersion correction, which calculates interatomic dispersion coefficients in terms of atomic moments and polarizabilities, both of which can be approximated effectively using neural networks.
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To explore the possibility of oxygen dimerization-particularly, the formation of molecular oxygen-like species-in the bulk of LiNiO2 lithium ion cathode materials at high states of charge, we conduct a redox-product structure search inspired by recent methodological developments for point-defect structure prediction. We find that (1) delithiated Li1-x NiO2 (x = 1) has good kinetic stability toward decomposition into molecular oxygen and reduced transition-metal oxides but (2) defects can act as nucleation sites for oxygen dimerization. These results help reconcile conflicting reports on the formation of bulk molecular oxygen in LiNiO2 and other nickel-rich cathode materials, highlighting the role of defect chemistry in driving the bulk degradation of these compounds.
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Transcription factor (TF) gene knockout or knockdown experiments provide comprehensive downstream effects on gene regulation. However, distinguishing primary direct effects from secondary effects remains challenging. To assess the direct effect of TF binding events, we present a protocol for establishing a doxycycline (Dox)-inducible CRISPRd system in human pluripotent stem cells (hPSCs). We describe the steps for establishing CRISPRd host hPSCs, designing and preparing single-guide RNA (sgRNA) expression lentivirus vectors, generating CRISPRd hPSCs transduced with sgRNAs, and analyzing CRISPRd TF-block effects by chromatin immunoprecipitation (ChIP)-qPCR. For complete details on the use and execution of this protocol, please refer to Matsui et al.1.
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High refractive index, low birefringence photopolymers were created via the radical-mediated, ring opening homopolymerization of 1,2-dithiolane functionalized monomers and were subsequently evaluated as holographic recording media. This investigation systematically characterized the reaction kinetics, thermodynamics, and volume shrinkage of the 1,2-dithiolane homopolymerization as well as the optical transparency, refractive index, birefringence, and holographic performance of multifunctional 1,2-dithiolane functionalized monomers and their resultant polymers. Real-time kinetic and thermodynamic analyses of a monofunctional 1,2-dithiolane monomer, lipoic acid methyl ester (LipOMe), indicated rapid monomer conversion, exceeding 90% in 60 s, with an overall enthalpy of reaction of 18 ± 1 kJ/mol. The ring-opening polymerization resulted in low shrinkage (10.6 ± 0.3 cm3/mol dithiolane) and a significant bulk refractive index increase (0.030 ± 0.003). The resulting photopolymers exhibited high optical transparency, minimal haze, and negligible birefringence, suggesting the potential of 1,2-homopolymers as optical materials. To further explore the specific capabilities for use as high-performance holographic recording applications, several multifunctional monomers were synthesized with the ethanedithiol lipoic acid monomer (EDT-Lip2) selected for experimentation. Holographic diffraction gratings written using this monomer achieved a peak-to-mean refractive index modulation of 0.008 with minimal haze and birefringence.
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The efficacy of fake news corrections in improving memory and belief accuracy may depend on how often adults see false information before it is corrected. Two experiments tested the competing predictions that repeating fake news before corrections will either impair or improve memory and belief accuracy. These experiments also examined whether fake news exposure effects would differ for younger and older adults due to age-related differences in the recollection of contextual details. Younger and older adults read real and fake news headlines that appeared once or thrice. Next, they identified fake news corrections among real news headlines. Later, recognition and cued recall tests assessed memory for real news, fake news, if corrections occurred, and beliefs in retrieved details. Repeating fake news increased detection and remembering of corrections, correct real news retrieval, and erroneous fake news retrieval. No age differences emerged for detection of corrections, but younger adults remembered corrections better than older adults. At test, correct fake news retrieval for earlier-detected corrections was associated with better real news retrieval. This benefit did not differ between age groups in recognition but was greater for younger than older adults in cued recall. When detected corrections were not remembered at test, repeated fake news increased memory errors. Overall, both age groups believed correctly retrieved real news more than erroneously retrieved fake news to a similar degree. These findings suggest that fake news repetition effects on subsequent memory accuracy depended on age differences in recollection-based retrieval of fake news and that it was corrected.
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Señales (Psicología) , Decepción , Recuerdo Mental , Reconocimiento en Psicología , Humanos , Adulto Joven , Anciano , Recuerdo Mental/fisiología , Femenino , Masculino , Adulto , Reconocimiento en Psicología/fisiología , Persona de Mediana Edad , Envejecimiento/fisiología , Adolescente , Factores de Edad , Anciano de 80 o más AñosRESUMEN
BACKGROUND: The use of 3D imaging techniques, such as X-ray CT, in root phenotyping has become more widespread in recent years. However, due to the complexity of the root structure, analyzing the resulting 3D volumes to obtain detailed architectural root traits remains a challenging computational problem. When it comes to image-based phenotyping of excavated maize root crowns, two types of root features that are notably missing from existing methods are the whorls and soil line. Whorls refer to the distinct areas located at the base of each stem node from which roots sprout in a circular pattern (Liu S, Barrow CS, Hanlon M, Lynch JP, Bucksch A. Dirt/3D: 3D root phenotyping for field-grown maize (zea mays). Plant Physiol. 2021;187(2):739-57. https://doi.org/10.1093/plphys/kiab311 .). The soil line is where the root stem meets the ground. Knowledge of these features would give biologists deeper insights into the root system architecture (RSA) and the below- and above-ground root properties. RESULTS: We developed TopoRoot+, a computational pipeline that produces architectural traits from 3D X-ray CT volumes of excavated maize root crowns. Building upon the TopoRoot software (Zeng D, Li M, Jiang N, Ju Y, Schreiber H, Chambers E, et al. Toporoot: A method for computing hierarchy and fine-grained traits of maize roots from 3D imaging. Plant Methods. 2021;17(1). https://doi.org/10.1186/s13007-021-00829-z .) for computing fine-grained root traits, TopoRoot + adds the capability to detect whorls, identify nodal roots at each whorl, and compute the soil line location. The new algorithms in TopoRoot + offer an additional set of fine-grained traits beyond those provided by TopoRoot. The addition includes internode distances, root traits at every hierarchy level associated with a whorl, and root traits specific to above or below the ground. TopoRoot + is validated on a diverse collection of field-grown maize root crowns consisting of nine genotypes and spanning across three years. TopoRoot + runs in minutes for a typical volume size of [Formula: see text] on a desktop workstation. Our software and test dataset are freely distributed on Github. CONCLUSIONS: TopoRoot + advances the state-of-the-art in image-based phenotyping of excavated maize root crowns by offering more detailed architectural traits related to whorls and soil lines. The efficiency of TopoRoot + makes it well-suited for high-throughput image-based root phenotyping.
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The circulating proteome offers insights into the biological pathways that underlie disease. Here, we test relationships between 1,468 Olink protein levels and the incidence of 23 age-related diseases and mortality in the UK Biobank (n = 47,600). We report 3,209 associations between 963 protein levels and 21 incident outcomes. Next, protein-based scores (ProteinScores) are developed using penalized Cox regression. When applied to test sets, six ProteinScores improve the area under the curve estimates for the 10-year onset of incident outcomes beyond age, sex and a comprehensive set of 24 lifestyle factors, clinically relevant biomarkers and physical measures. Furthermore, the ProteinScore for type 2 diabetes outperforms a polygenic risk score and HbA1c-a clinical marker used to monitor and diagnose type 2 diabetes. The performance of scores using metabolomic and proteomic features is also compared. These data characterize early proteomic contributions to major age-related diseases, demonstrating the value of the plasma proteome for risk stratification.
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Proteínas Sanguíneas , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Biomarcadores/sangre , Proteínas Sanguíneas/metabolismo , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/análisis , Diabetes Mellitus Tipo 2/mortalidad , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genética , Incidencia , Proteómica , Biobanco del Reino Unido , Reino Unido/epidemiologíaRESUMEN
Objective: There is currently a lack of validated questionnaires designed specifically to assess mental health within patients with chronic gastroduodenal symptoms. This research describes the multi-phase process used to develop and validate a novel mental health scale for patients with chronic gastroduodenal symptoms, the Alimetry® Gut-Brain Wellbeing (AGBW) Survey. Methods: A patient-centered multi-phase process was implemented. In Phase 1, the most relevant concepts for this patient population were selected from existing mental health scales, using data from 79 patients. In Phase 2, an interdisciplinary panel of experts generated scale items. In Phase 3, the scale underwent pre-testing with gastroenterologists (n = 9), health psychologists (n = 3), and patients (n = 12), with feedback incorporated over multiple rounds. Lastly, the psychometric properties of the scale were assessed in a sample of 311 patients via an online survey. Results: The AGBW Survey comprises a patient preface, 10 close-ended questions, and an optional open-ended question. This multidimensional scale assesses general mental health, alongside specific subscales relating to depression, stress, and anxiety. The subscale and total scores demonstrated high internal consistency (α = 0.91 for the total scale; α = 0.72-0.86 for subscales) and good convergent, divergent, concurrent validity, and known groups validity, with large effect sizes. Conclusion: The AGBW Survey is a brief, valid, and reliable scale for assessing mental health in patients with chronic gastroduodenal symptoms. It can be used as a tool to complement physiological tests and has the potential to guide psychological referrals, inform multidisciplinary management, and evaluate treatment outcomes.
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Atrial fibrillation (AF) is the most common clinical arrhythmia, however there is limited understanding of its pathophysiology including the cellular and ultrastructural changes rendered by the irregular rhythm, which limits pharmacological therapy development. Prior work has demonstrated the importance of reactive oxygen species (ROS) and mitochondrial dysfunction in the development of AF. Mitochondrial structure, interactions with other organelles such as sarcoplasmic reticulum (SR) and T-tubules (TT), and degradation of dysfunctional mitochondria via mitophagy are important processes to understand ultrastructural changes due to AF. However, most analysis of mitochondrial structure and interactome in AF has been limited to two-dimensional (2D) modalities such as transmission electron microscopy (EM), which does not fully visualize the morphological evolution of the mitochondria during mitophagy. Herein, we utilize focused ion beam-scanning electron microscopy (FIB-SEM) and perform reconstruction of three-dimensional (3D) EM from murine left atrial samples and measure the interactions of mitochondria with SR and TT. We developed a novel 3D quantitative analysis of FIB-SEM in a murine model of AF to quantify mitophagy stage, mitophagosome size in cardiomyocytes, and mitochondrial structural remodeling when compared with control mice. We show that in our murine model of spontaneous and continuous AF due to persistent late sodium current, left atrial cardiomyocytes have heterogenous mitochondria, with a significant number which are enlarged with increased elongation and structural complexity. Mitophagosomes in AF cardiomyocytes are located at Z-lines where they neighbor large, elongated mitochondria. Mitochondria in AF cardiomyocytes show increased organelle interaction, with 5X greater contact area with SR and are 4X as likely to interact with TT when compared to control. We show that mitophagy in AF cardiomyocytes involves 2.5X larger mitophagosomes that carry increased organelle contents. In conclusion, when oxidative stress overcomes compensatory mechanisms, mitophagy in AF faces a challenge of degrading bulky complex mitochondria, which may result in increased SR and TT contacts, perhaps allowing for mitochondrial Ca2+ maintenance and antioxidant production.
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How the microbiome regulates responses of systemic innate immune cells is unclear. In the present study, our purpose was to document a novel mechanism by which the microbiome mediates crosstalk with the systemic innate immune system. We have identified a family of microbiome Bacteroidota-derived lipopeptides-the serine-glycine (S/G) lipids, which are TLR2 ligands, access the systemic circulation, and regulate proinflammatory responses of splenic monocytes. To document the role of these lipids in regulating systemic immunity, we used oral gavage with an antibiotic to decrease the production of these lipids and administered exogenously purified lipids to increase the systemic level of these lipids. We found that decreasing systemic S/G lipids by decreasing microbiome Bacteroidota significantly enhanced splenic monocyte proinflammatory responses. Replenishing systemic levels of S/G lipids via exogenous administration returned splenic monocyte responses to control levels. Transcriptomic analysis demonstrated that S/G lipids regulate monocyte proinflammatory responses at the level of gene expression of a small set of upstream inhibitors of TLR and NF-κB pathways that include Trem2 and Irf4. Consistent with enhancement in proinflammatory cytokine responses, decreasing S/G lipids lowered gene expression of specific pathway inhibitors. Replenishing S/G lipids normalized gene expression of these inhibitors. In conclusion, our results suggest that microbiome-derived S/G lipids normally establish a level of buffered signaling activation necessary for well-regulated innate immune responses in systemic monocytes. By regulating gene expression of inflammatory pathway inhibitors such as Trem2, S/G lipids merit broader investigation into the potential dysfunction of other innate immune cells, such as microglia, in diseases such as Alzheimer's disease.
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Monocitos , Transducción de Señal , Monocitos/inmunología , Monocitos/metabolismo , Monocitos/efectos de los fármacos , Animales , Ratones , Microbiota/inmunología , Ratones Endogámicos C57BL , Inmunidad Innata , Receptor Toll-Like 2/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Lipopéptidos/farmacología , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/genética , FN-kappa B/metabolismo , Inflamación/inmunología , Factores Reguladores del Interferón/metabolismo , Factores Reguladores del Interferón/genética , Masculino , Lípidos , Bazo/inmunología , Bazo/metabolismo , Citocinas/metabolismo , FemeninoRESUMEN
The first observations of JWST have revolutionized our understanding of the Universe by identifying for the first time galaxies at z â¼ 13 1-3. In addition, the discovery of many luminous galaxies at Cosmic Dawn ( z > 10 ) has suggested that galaxies developed rapidly, in apparent tension with many standard models4-8. However, most of these galaxies lack spectroscopic confirmation, so their distances and properties are uncertain. We present JADES JWST/NIRSpec spectroscopic confirmation of two luminous galaxies at redshifts of z = 14.32 - 0.20 + 0.08 and z = 13.90 ± 0.17 . The spectra reveal ultraviolet continua with prominent Lyman- α breaks but no detected emission lines. This discovery proves that luminous galaxies were already in place 300 million years after the Big Bang and are more common than what was expected before JWST. The most distant of the two galaxies is unexpectedly luminous and is spatially resolved with a radius of 260 parsecs. Considering also the very steep ultraviolet slope of the second galaxy, we conclude that both are dominated by stellar continuum emission, showing that the excess of luminous galaxies in the early Universe cannot be entirely explained by accretion onto black holes. Galaxy formation models will need to address the existence of such large and luminous galaxies so early in cosmic history.
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INTRODUCTION: Firearm violence is a major public health issue in the USA. There is growing evidence that firearm violence is associated with higher ambient temperatures. The aim of this study was to test competing hypotheses that could explain associations between temperature and firearm violence: temperature-aggression theory and routine activities theory. METHODS: We examined associations between elevated daily temperatures and shooting incidents in four US cities: Chicago, Illinois; Cincinnati, Ohio; New York, New York and Philadelphia, Pennsylvania. Temperature was operationalised using two different measures: daily maximum temperature and deviations of the daily maximum temperature from 30-year averages. Generalised linear autoregressive moving average models related temperature to shooting incidence while controlling for seasonal effects. RESULTS: As maximum daily temperature deviates from the expected, there was an association with increased shooting incidents in all four cities (eg, New York: b=0.014, 95% CI=0.011 to 0.017). An interaction term created by multiplying daily maximum temperature by the daily difference of maximum temperature from a 30-year average was also found to have a positive association in all four cities (eg, New York: b=0.020, 95% CI=0.016 to 0.025). DISCUSSION: These findings accord with previous studies demonstrating a positive relationship between temperature and firearm violence and further support temperature-aggression theory as the primary causal mechanism.
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Inducible loss-of-function strategies are crucial for understanding gene function. However, creating inducible, multiple-gene knockout models is challenging and time-consuming. Here, we present a protocol for establishing a doxycycline-inducible CRISPR interference (CRISPRi) system to concurrently silence multiple genes in human induced pluripotent stem cells (hPSCs). We describe the steps for establishing host CRISPRi hPSCs, designing and cloning single-guide RNAs (sgRNAs) into a lentivirus plasmid, and establishing monoclonal CRISPRi hPSC lines transduced with sgRNAs. We also detail the procedures for selecting effective CRISPRi clones. For complete details on the use and execution of this protocol, please refer to Matsui et al.1.
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BACKGROUND: The multi-centre two-stage SCALOP-2 trial (ISRCTN50083238) assessed whether dose escalation of consolidative chemoradiotherapy (CRT) or concurrent sensitization using the protease inhibitor nelfinavir improve outcomes in locally advanced pancreatic cancer (LAPC) following four cycles of gemcitabine/nab-paclitaxel. METHODS: In stage 1, the maximum tolerated dose (MTD) of nelfinavir concurrent with standard-dose CRT (50.4 Gy in 28 fractions) was identified from a cohort of 27 patients. In stage 2, 159 patients were enrolled in an open-label randomized controlled comparison of standard versus high dose (60 Gy in 30 fractions) CRT, with or without nelfinavir at MTD. Primary outcomes following dose escalation and nelfinavir use were respectively overall survival (OS) and progression free survival (PFS). Secondary endpoints included health-related quality of life (HRQoL). RESULTS: High dose CRT did not improve OS (16.9 (60 % confidence interval, CI 16.2-17.7) vs. 15.6 (60 %CI 14.3-18.2) months; adjusted hazard ratio, HR 1.13 (60 %CI 0.91-1.40; p = 0.68)). Similarly, median PFS was not improved by nelfinavir (10.0 (60 %CI 9.9-10.2) vs. 11.1 (60 %CI 10.3-12.8) months; adjusted HR 1.71 (60 %CI 1.38-2.12; p = 0.98)). Local progression at 12 months was numerically lower with high-dose CRT than with standard dose CRT (n = 11/46 (23.9 %) vs. n = 15/45 (33.3 %)). Neither nelfinavir nor radiotherapy dose escalation impacted on treatment compliance or grade 3/4 adverse event rate. There were no sustained differences in HRQoL scores between treatment groups over 28 weeks post-treatment. CONCLUSIONS: Dose-escalated CRT may improve local tumour control and is well tolerated when used as consolidative treatment in LAPC but does not impact OS. Nelfinavir use does not improve PFS.
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Protocolos de Quimioterapia Combinada Antineoplásica , Quimioradioterapia , Nelfinavir , Neoplasias Pancreáticas , Humanos , Nelfinavir/uso terapéutico , Nelfinavir/administración & dosificación , Nelfinavir/efectos adversos , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/mortalidad , Masculino , Femenino , Persona de Mediana Edad , Anciano , Quimioradioterapia/efectos adversos , Quimioradioterapia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adulto , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Dosis Máxima Tolerada , Desoxicitidina/análogos & derivados , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Gemcitabina , Anciano de 80 o más Años , Calidad de Vida , Albúminas/administración & dosificación , Albúminas/uso terapéutico , Albúminas/efectos adversos , Supervivencia sin Progresión , Inhibidores de Proteasas/efectos adversos , Inhibidores de Proteasas/uso terapéutico , Inhibidores de Proteasas/administración & dosificaciónRESUMEN
BACKGROUND: Chat Generative Pre-trained Transformer (ChatGPT) and other ChatBots have emerged as tools for interacting with information in manners resembling natural human speech. Consequently, the technology is used across various disciplines, including business, education, and even in biomedical sciences. There is a need to better understand how ChatGPT can be used to advance gerontology research. Therefore, we evaluated ChatGPT responses to questions on specific topics in gerontology research, and brainstormed recommendations for its use in the field. METHODS: We conducted semistructured brainstorming sessions to identify uses of ChatGPT in gerontology research. We divided a team of multidisciplinary researchers into 4 topical groups: (a) gero-clinical science, (b) basic geroscience, (c) informatics as it relates to electronic health records, and (d) gero-technology. Each group prompted ChatGPT on a theory-, methods-, and interpretation-based question and rated responses for accuracy and completeness based on standardized scales. RESULTS: ChatGPT responses were rated by all groups as generally accurate. However, the completeness of responses was rated lower, except by members of the informatics group, who rated responses as highly comprehensive. CONCLUSIONS: ChatGPT accurately depicts some major concepts in gerontological research. However, researchers have an important role in critically appraising the completeness of its responses. Having a single generalized resource like ChatGPT may help summarize the preponderance of evidence in the field to identify gaps in knowledge and promote cross-disciplinary collaboration.