RESUMEN

Ciguatera Poisoning (CP) is a widespread and complex poisoning syndrome caused by the consumption of fish or invertebrates contaminated with a suite of potent neurotoxins collectively known as ciguatoxins (CTXs), which are produced by certain benthic dinoflagellates species in the genera Gambierdiscus and Fukuyoa. Due to the complex nature of this HAB problem, along with a poor understanding of toxin production and entry in the coral reef food web, the development of monitoring, management, and forecasting approaches for CP has lagged behind those available for other HAB syndromes. Over the past two decades, renewed research on the taxonomy, physiology, and toxicology of CP-causing dinoflagellates has advanced our understanding of the species diversity that exists within these genera, including identification of highly toxic species (so called "superbugs") that likely contribute disproportionately to ciguatoxins entering coral reef food webs. The recent development of approaches for molecular analysis of field samples now provide the means to investigate in situ community composition, enabling characterization of spatio-temporal species dynamics, linkages between toxic species abundance and toxin flux, and the risk of ciguatoxin prevalence in fish. In this study we used species-specific fluorescent in situ hybridization (FISH) probes to investigate Gambierdiscus species composition and dynamics in St. Thomas (USVI) and the Florida Keys (USA) over multiple years (2018-2020). Within each location, samples were collected seasonally from several sites comprising varying depths, habitats, and algal substrates to characterize community structure over small spatial scales and across different host macrophytes. This approach enabled the quantitative determination of communities over spatiotemporal gradients, as well as the selective enumeration of species known to exhibit high toxicity, such as Gambierdiscus silvae. The investigation found differing community structure between St. Thomas and Florida Keys sites, driven in part by differences in the distribution of toxin-producing species G. silvae and G. belizeanus, which were present throughout sampling sites in St. Thomas but scarce or absent in the Florida Keys. This finding is significant given the high toxicity of G. silvae, and may help explain differences in fish toxicity and CP incidence between St. Thomas and Florida. Intrasite comparisons along a depth gradient found higher concentrations of Gambierdiscus spp. at deeper locations. Among the macrophytes sampled, Dictyota may be a likely vector for toxin transfer based on their widespread distribution, apparent colonization by G. silvae, and palatability to at least some herbivore grazers. Given its ubiquity throughout both study regions and sites, this taxa may also serve as a refuge, accumulating high concentrations of Gambierdiscus and other benthic dinoflagellates, which in turn can serve as source populations for highly palatable and ephemeral habitats nearby, such as turf algae. These studies further demonstrate the successful application of FISH probes in examining biogeographic structuring of Gambierdiscus communities, targeting individual toxin-producing species, and characterizing species-level dynamics that are needed to describe and model ecological drivers of species abundance and toxicity.

Asunto(s)

Intoxicación por Ciguatera , Ciguatoxinas , Dinoflagelados , Ciguatoxinas/toxicidad , Florida , Hibridación Fluorescente in Situ , Islas Virgenes de los Estados Unidos

Asunto(s)

Entrenamiento Aeróbico , Trasplante de Corazón , Humanos , Resistencia Física

RESUMEN

This article reports changes to virus taxonomy and taxon nomenclature that were approved and ratified by the International Committee on Taxonomy of Viruses (ICTV) in April 2023. The entire ICTV membership was invited to vote on 174 taxonomic proposals that had been approved by the ICTV Executive Committee in July 2022, as well as a proposed revision of the ICTV Statutes. All proposals and the revised ICTV Statutes were approved by a majority of the voting membership. Of note, the ICTV continued the process of renaming existing species in accordance with the recently mandated binomial format and included gene transfer agents (GTAs) in the classification framework by classifying them as viriforms. In total, one class, seven orders, 31 families, 214 genera, and 858 species were created.

Asunto(s)

Virus , Humanos , Virus/genética , Miembro de Comité

RESUMEN

ß-adrenergic (ß-AR) signaling is essential for the adaptation of the heart to exercise and stress. Chronic stress leads to the activation of Ca2+/calmodulin-dependent kinase II (CaMKII) and protein kinase D (PKD). Unlike CaMKII, the effects of PKD on excitation-contraction coupling (ECC) remain unclear. To elucidate the mechanisms of PKD-dependent ECC regulation, we used hearts from cardiac-specific PKD1 knockout (PKD1 cKO) mice and wild-type (WT) littermates. We measured calcium transients (CaT), Ca2+ sparks, contraction and L-type Ca2+ current in paced cardiomyocytes under acute ß-AR stimulation with isoproterenol (ISO; 100 nM). Sarcoplasmic reticulum (SR) Ca2+ load was assessed by rapid caffeine (10 mM) induced Ca2+ release. Expression and phosphorylation of ECC proteins phospholambam (PLB), troponin I (TnI), ryanodine receptor (RyR), sarcoendoplasmic reticulum Ca2+ ATPase (SERCA) were evaluated by western blotting. At baseline, CaT amplitude and decay tau, Ca2+ spark frequency, SR Ca2+ load, L-type Ca2+ current, contractility, and expression and phosphorylation of ECC protein were all similar in PKD1 cKO vs. WT. However, PKD1 cKO cardiomyocytes presented a diminished ISO response vs. WT with less increase in CaT amplitude, slower [Ca2+]i decline, lower Ca2+ spark rate and lower RyR phosphorylation, but with similar SR Ca2+ load, L-type Ca2+ current, contraction and phosphorylation of PLB and TnI. We infer that the presence of PKD1 allows full cardiomyocyte ß-adrenergic responsiveness by allowing optimal enhancement in SR Ca2+ uptake and RyR sensitivity, but not altering L-type Ca2+ current, TnI phosphorylation or contractile response. Further studies are necessary to elucidate the specific mechanisms by which PKD1 is regulating RyR sensitivity. We conclude that the presence of basal PKD1 activity in cardiac ventricular myocytes contributes to normal ß-adrenergic responses in Ca2+ handling.

Asunto(s)

Adrenérgicos , Agonistas Adrenérgicos beta , Miocitos Cardíacos , Proteína Quinasa C , Animales , Ratones , Adrenérgicos/farmacología , Agonistas Adrenérgicos beta/farmacología , Agonistas Adrenérgicos beta/metabolismo , Calcio/metabolismo , Señalización del Calcio , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Ratones Noqueados , Miocitos Cardíacos/metabolismo , Fosforilación , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Retículo Sarcoplasmático/metabolismo , Proteína Quinasa C/genética

RESUMEN

Stereotypies comprise a wide range of repeated and apparently functionless behaviors that develop in individuals whose neural condition or environment results in poor welfare. While stereotypies are an indicator of poor welfare at the time of occurrence, they may have various consequences. Environmental enrichment modifies causal factors and reduces the occurrence of stereotypies, providing evidence that stereotypies are an indicator of poor welfare. However, stereotypy occurrence and consequences change over time. Furthermore, there are complex direct and epigenetic effects when mother mammals that are kept in negative conditions do or do not show stereotypies. It is proposed that, when trying to deal with challenging situations, stereotypies might initially help animals to cope. After further time in the conditions, the performance of the stereotypy may impair brain function and change brain connections, neurophysiology and eventually neuroanatomy. It is possible that reported neuroanatomical changes are an effect of the stereotypy rather than a cause.

RESUMEN

The efficacy of convalescent plasma for coronavirus disease 2019 (COVID-19) is unclear. Although most randomized controlled trials have shown negative results, uncontrolled studies have suggested that the antibody content could influence patient outcomes. We conducted an open-label, randomized controlled trial of convalescent plasma for adults with COVID-19 receiving oxygen within 12 d of respiratory symptom onset ( NCT04348656 ). Patients were allocated 2:1 to 500 ml of convalescent plasma or standard of care. The composite primary outcome was intubation or death by 30 d. Exploratory analyses of the effect of convalescent plasma antibodies on the primary outcome was assessed by logistic regression. The trial was terminated at 78% of planned enrollment after meeting stopping criteria for futility. In total, 940 patients were randomized, and 921 patients were included in the intention-to-treat analysis. Intubation or death occurred in 199/614 (32.4%) patients in the convalescent plasma arm and 86/307 (28.0%) patients in the standard of care arm-relative risk (RR) = 1.16 (95% confidence interval (CI) 0.94-1.43, P = 0.18). Patients in the convalescent plasma arm had more serious adverse events (33.4% versus 26.4%; RR = 1.27, 95% CI 1.02-1.57, P = 0.034). The antibody content significantly modulated the therapeutic effect of convalescent plasma. In multivariate analysis, each standardized log increase in neutralization or antibody-dependent cellular cytotoxicity independently reduced the potential harmful effect of plasma (odds ratio (OR) = 0.74, 95% CI 0.57-0.95 and OR = 0.66, 95% CI 0.50-0.87, respectively), whereas IgG against the full transmembrane spike protein increased it (OR = 1.53, 95% CI 1.14-2.05). Convalescent plasma did not reduce the risk of intubation or death at 30 d in hospitalized patients with COVID-19. Transfusion of convalescent plasma with unfavorable antibody profiles could be associated with worse clinical outcomes compared to standard care.

Asunto(s)

COVID-19/terapia , Adulto , Anciano , Anciano de 80 o más Años , Brasil/epidemiología , COVID-19/epidemiología , Canadá/epidemiología , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Inmunización Pasiva , Análisis de Intención de Tratar , Masculino , Persona de Mediana Edad , SARS-CoV-2/inmunología , Resultado del Tratamiento , Estados Unidos/epidemiología , Sueroterapia para COVID-19

RESUMEN

Ciguatera poisoning (CP) poses a significant threat to ecosystem services and fishery resources in coastal communities. The CP-causative ciguatoxins (CTXs) are produced by benthic dinoflagellates including Gambierdiscus and Fukuyoa spp., and enter reef food webs via grazing on macroalgal substrates. In this study, we report on a 3-year monthly time series in St. Thomas, US Virgin Islands where Gambierdiscus spp. abundance and Caribbean-CTX toxicity in benthic samples were compared to key environmental factors, including temperature, salinity, nutrients, benthic cover, and physical data. We found that peak Gambierdiscus abundance occurred in summer while CTX-specific toxicity peaked in cooler months (February-May) when the mean water temperatures were approximately 26-28 °C. These trends were most evident at deeper offshore sites where macroalgal cover was highest year-round. Other environmental parameters were not correlated with the CTX variability observed over time. The asynchrony between Gambierdiscus spp. abundance and toxicity reflects potential differences in toxin cell quotas among Gambierdiscus species with concomitant variability in their abundances throughout the year. These results have significant implications for monitoring and management of benthic harmful algal blooms and highlights potential seasonal and highly-localized pulses in reef toxin loads that may be transferred to higher trophic levels.

Asunto(s)

Ciguatoxinas/análisis , Dinoflagelados , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Intoxicación por Ciguatera , Ciguatoxinas/toxicidad , Monitoreo del Ambiente , Ratones , Salinidad , Estaciones del Año , Islas Virgenes de los Estados Unidos , Tiempo (Meteorología)

RESUMEN

Anchored mesh screens have been suggested as a standardized approach to monitor the cell abundances of epiphytic dinoflagellates in benthic habitats, including toxigenic members of the Gambierdiscus genus responsible for ciguatera poisoning (CP). Here we deployed screens for 24h at eight sites in the Florida Keys and St. Thomas (US Virgin Islands) to evaluate their performance relative to the traditional method of assessing Gambierdiscus abundance in which cell counts are normalized to wet weight of host algae. The 30-month study (April 2013 - August 2015) involved monthly sampling at sites where screens were suspended at near-bottom locations for a 24h period and retrieved, with concurrent collections of macrophytes; including Halimeda, Laurencia, and Thalassia in the Florida Keys, and Dictyota in both regions. Gambierdiscus cells were identified and enumerated in the screen and macrophyte samples, and several regression techniques were evaluated (linear regression using untransformed and log-transformed data; negative binomial distribution (NBD) regression) to determine how well the screen-derived data could estimate algal cell concentrations on the host algae. In all cases, the NBD models performed the best based on Akaike Information Criteria values, although 38% of the regressions were not statistically-significant, including all of the St. Thomas sites. The r2 values were all < 0.75 and averaged 0.36, indicating relatively poor fit of the screen data. False negative results (regression models underestimating actual cell abundances) were common occurrences, ranging from 5 to 74% of the scenarios tested. In summary, these results indicate that 24h screen deployments do not appear to be consistent in all situations. Caution is therefore needed when considering 24h screens as a standardized monitoring approach for quantifying Gambierdiscus population dynamics across geography and ecosystems. Furthermore, neutral (artificial) substrates may not adequately capture either the host preference or palatability that likely influence the initial vector of toxin incorporation in the food web via herbivory on these macrophytes.

Asunto(s)

Intoxicación por Ciguatera , Dinoflagelados , Ecosistema , Florida , Islas Virgenes de los Estados Unidos

RESUMEN

OBJECTIVES: To describe study design considerations and to simulate a trial of biomarker-guided sepsis management aimed to reduce acute kidney injury (acute kidney injury). Tissue inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein 7, urinary biomarkers of cell-cycle arrest, and indicators of kidney stress can detect acute kidney injury before clinical manifestations. We sought to determine the event rates for acute kidney injury as a function of serial measurements of urinary (tissue inhibitor of metalloproteinases-2)•(insulin-like growth factor-binding protein 7) in patients at risk of sepsis-associated acute kidney injury, so that an escalating series of kidney-sparing sepsis bundles based on international guidelines could be applied. DESIGN: We described the study protocol of "Limiting acute kidney injury Progression In Sepsis," a phase 4, multicenter, adaptive, randomized controlled trial. We performed simulations to estimate the rates for the trial's primary endpoint using patient-level data from two previous studies (Sapphire and Protocolized Care for Early Septic Shock). SETTING: Academic and community ICUs. PATIENTS: Critically ill patients with sepsis or septic shock, without evidence of stage 2/3 acute kidney injury at enrollment. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Our primary endpoint is progression of two or more stages of acute kidney injury, death, or dialysis within 72 hours after enrollment. In the Sapphire simulation, 45 of 203 patients (22%) with sepsis met the endpoint. In Protocolized Care for Early Septic Shock, 144 of 607 patients (24%) with septic shock met the endpoint. In both simulations, (tissue inhibitor of metalloproteinases-2)•(insulin-like growth factor-binding protein 7) patterns, suggested by Limiting acute kidney injury Progression In Sepsis protocol, stratified the risk for the endpoint from 6% (three negative tests) to 41% (for patients eligible for the highest level of kidney-sparing sepsis bundle) in Sapphire, and 14% (two negative tests) to 46% (for the highest level of kidney-sparing sepsis bundle) in Protocolized Care for Early Septic Shock. CONCLUSIONS: Findings of our Limiting acute kidney injury Progression In Sepsis trial simulation confirmed that (tissue inhibitor of metalloproteinases-2)•(insulin-like growth factor-binding protein 7) could identify patients with different rates of progression to moderate/severe acute kidney injury, death, or dialysis in 72 hours. The Limiting acute kidney injury Progression In Sepsis protocol algorithm is therefore feasible in terms of identifying suitably high-risk individuals for kidney-sparing sepsis bundle.

Asunto(s)

Lesión Renal Aguda/etiología , Protocolos Clínicos , Sepsis/complicaciones , APACHE , Biomarcadores/análisis , Biomarcadores/sangre , Distribución de Chi-Cuadrado , Estudios de Cohortes , Femenino , Humanos , Riñón/fisiopatología , Masculino , Persona de Mediana Edad

RESUMEN

The dictyochophyte microalga Pseudochattonella verruculosa was responsible for the largest farmed fish mortality ever recorded in the world, with losses for the Chilean salmon industry amounting to US$ 800 M in austral summer 2016. Super-scale climatic anomalies resulted in strong vertical water column stratification that stimulated development of a dynamic P. verruculosa thin layer (up to 38 µg chl a L-1) for several weeks in Reloncaví Sound. Hydrodynamic modeling (MIKE 3D) indicated that the Sound had extremely low flushing rates (between 121 and 200 days) in summer 2016. Reported algal cell densities of 7000-20,000 cells mL-1 generated respiratory distress in fish that was unlikely due to low dissolved oxygen (permanently >4 mg L-1). Histological examination of salmon showed that gills were the most affected organ with significant tissue damage and circulatory disorders. It is possible that some of this damage was due to a diatom bloom that preceded the Pseudochattonella event, thereby rendering the fish more susceptible to Pseudochattonella. No correlation between magnitude of fish mortality and algal cell abundance nor fish age was evident. Algal cultures revealed rapid growth rates and high cell densities (up to 600,000 cells mL-1), as well as highly complex life cycle stages that can be easily overlooked in monitoring programs. In cell-based bioassays, Chilean P. verruculosa was only toxic to the RTgill-W1 cell line following exposures to high cell densities of lysed cells (>100,000 cells mL-1). Fatty acid profiles of a cultured strain showed elevated concentrations of potentially ichthyotoxic, long-chain polyunsaturated fatty acids (PUFAs) (69.7% ± 1.8%)- stearidonic (SDA, 18:4ω3-28.9%), and docosahexaenoic acid (DHA, 22:6ω3-22.3%), suggesting that lipid peroxidation may help to explain the mortalities, though superoxide production by Pseudochattonella was low (< 0.21 ± 0.19 pmol O2- cell-1 h-1). It therefore remains unknown what the mechanisms of salmon mortality were during the Pseudochattonella bloom. Multiple mitigation strategies were used by salmon farmers during the event, with only delayed seeding of juvenile fish into the cages and towing of cages to sanctuary sites being effective. Airlift pumping, used effectively against other fish-killing HABs in the US and Canada was not effective, perhaps because it brought subsurface layers of Pseudochattonella to the surface, or and it also may have lysed the fragile cells, rendering them more lethal. The present study highlights knowledge gaps and inefficiency of contingency plans by the fish farming industry to overcome future fish-killing algal blooms under future climate change scenarios. The use of new technologies based on molecular methods for species detection, good farm practices by fish farms, and possible mitigation strategies are discussed.

Asunto(s)

Floraciones de Algas Nocivas , Estramenopilos , Animales , Canadá , Chile

RESUMEN

Introduction: Ephuta Say is a widespread New World genus of mutillid wasp whose ecology is poorly understood. Objective: The objective of this study was to determine how Ephuta species abundance varies annually and seasonally driven by weather conditions and hosts. Methods: Ephuta specimens, located in the "old forest" at Barro Colorado Island, were examined from weekly samples (2001-2006) of ten Malaise traps. The monthly abundance of each Ephuta species was compared with monthly average humidity, solar radiation, temperature and rainfall. Results: Nine species and ten morphospecies were identified. Most specimens were collected from March to June. April was the month reported with the greatest abundance. Of the four abiotic variables measured, only average monthly temperature was correlated with Ephuta abundance. Months with the highest number of Ephuta specimens were correlated with suspected host abundance, as indicated by the monthly abundance of Pompilidae (Hymenoptera) captured during the year 2007. Conclusions: We concluded that Ephuta display strong seasonal variation in abundance, with the peaks occurring during the end of the dry season and beginning of the rainy season, which correlate broadly with temperature and the abundance of their pompilid hosts.

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Introducción: Ephuta es un género de avispas mutílidas ampliamente distribuido en el Nuevo Mundo y cuya ecología es poco conocida. Objetivo: El objetivo de este trabajo fue determinar cómo varía la abundancia de especies de Ephuta anualmente y estacionalmente debido a las condiciones climáticas y sus hospederos. Métodos: Se examinaron especímenes de Ephuta tomados de muestras semanales (2001-2006) de diez trampas Malaise, ubicadas en el "bosque viejo" de Isla Barro Colorado. La abundancia mensual de cada especie de Ephuta se comparó con el promedio mensual de la humedad, la radiación solar, la temperatura y las precipitaciones. Resultados: Se identificaron nueve especies y diez morfoespecies. La mayoría de los especímenes fueron recolectados de marzo a junio. La mayor abundancia mensual promedio se dio en abril. De las cuatro variables abióticas medidas, solo la temperatura mensual promedio se correlacionó con la abundancia de Ephuta. Los meses con el mayor número de especímenes de Ephuta se correlacionan con la sospechosa abundancia del huésped, como lo indica la abundancia mensual de Pompilidae (Hymenoptera) capturada durante el 2007. Conclusiones: Ephuta muestra una fuerte variación estacional en la abundancia, con picos durante el final de la estación seca y el comienzo de la temporada de lluvias. Esta se correlaciona ampliamente con la temperatura y la abundancia de sus huéspedes pompílidos.

Asunto(s)

Animales , Avispas/clasificación , Panamá , Ecología

RESUMEN

Glioblastoma (GBM) is the deadliest form of brain cancer and recurs uniformly. Despite aggressive treatment with maximal safe surgical resection, adjuvant radiation with temozolomide chemotherapy, and alternating electrical field therapy, median survival for newly diagnosed GBM remains <2 years. Novel therapies are desperately needed. Immunotherapy, which has led to significant improvement in patient outcomes across many tumor types, is currently being studied in a large number of GBM clinical trials. One of the biggest challenges in immunotherapy trials in GBM has been accurate response assessment using currently available imaging modalities, including magnetic resonance imaging. In this review, we will discuss the rationale for immunotherapy for GBM, immunotherapeutic modalities currently under clinical evaluation in GBM, and the challenges and recent advances in imaging response assessment in GBM immunotherapy.

Asunto(s)

Neoplasias Encefálicas/terapia , Glioma/terapia , Inmunoterapia/métodos , Animales , Encéfalo/diagnóstico por imagen , Neoplasias Encefálicas/patología , Glioma/patología , Humanos , Resultado del Tratamiento

RESUMEN

OBJECTIVE: Incident type 2 diabetes is common among patients with recent acute coronary syndrome and is associated with an adverse prognosis. Some data suggest that cholesteryl ester transfer protein (CETP) inhibitors reduce incident type 2 diabetes. We compared the effect of treatment with the CETP inhibitor dalcetrapib or placebo on incident diabetes in patients with recent acute coronary syndrome. RESEARCH DESIGN AND METHODS: In the dal-OUTCOMES trial, 15,871 patients were randomly assigned to treatment with dalcetrapib 600 mg daily or placebo, beginning 4-12 weeks after an acute coronary syndrome. Absence of diabetes at baseline was based on medical history, no use of antihyperglycemic medication, and hemoglobin A1c and serum glucose levels below diagnostic thresholds. Among these patients, incident diabetes after randomization was defined by any diabetes-related adverse event, new use of antihyperglycemic medication, hemoglobin A1c ≥6.5%, or a combination of at least two measurements of serum glucose ≥7.0 mmol/L (fasting) or ≥11.1 mmol/L (random). RESULTS: At baseline, 10,645 patients (67% of the trial cohort) did not have diabetes. During a median follow-up of 30 months, incident diabetes was identified in 403 of 5,326 patients (7.6%) assigned to dalcetrapib and in 516 of 5,319 (9.7%) assigned to placebo, corresponding to absolute risk reduction of 2.1%, hazard ratio of 0.77 (95% CI 0.68-0.88; P < 0.001), and a need to treat 40 patients for 3 years to prevent 1 incident case of diabetes. Considering only those with prediabetes at baseline, the number needed to treat for 3 years to prevent 1 incident case of diabetes was 25. Dalcetrapib also decreased the number of patients who progressed from normoglycemia to prediabetes and increased the number who regressed from diabetes to no diabetes. CONCLUSIONS: In patients with a recent acute coronary syndrome, incident diabetes is common and is reduced substantially by treatment with dalcetrapib.

Asunto(s)

Amidas/uso terapéutico , Enfermedad Coronaria/tratamiento farmacológico , Diabetes Mellitus Tipo 2/prevención & control , Ésteres/uso terapéutico , Compuestos de Sulfhidrilo/uso terapéutico , Síndrome Coronario Agudo/complicaciones , Síndrome Coronario Agudo/tratamiento farmacológico , Síndrome Coronario Agudo/epidemiología , Anciano , Anticolesterolemiantes/uso terapéutico , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Estudios de Cohortes , Enfermedad Coronaria/complicaciones , Enfermedad Coronaria/epidemiología , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estado Prediabético/complicaciones , Estado Prediabético/tratamiento farmacológico , Estado Prediabético/epidemiología , Estado Prediabético/patología , Factores de Riesgo , Conducta de Reducción del Riesgo

RESUMEN

PURPOSE: To construct a multi-institutional radiomic model that supports upfront prediction of progression-free survival (PFS) and recurrence pattern (RP) in patients diagnosed with glioblastoma multiforme (GBM) at the time of initial diagnosis. PATIENTS AND METHODS: We retrospectively identified data for patients with newly diagnosed GBM from two institutions (institution 1, n = 65; institution 2, n = 15) who underwent gross total resection followed by standard adjuvant chemoradiation therapy, with pathologically confirmed recurrence, sufficient follow-up magnetic resonance imaging (MRI) scans to reliably determine PFS, and available presurgical multiparametric MRI (MP-MRI). The advanced software suite Cancer Imaging Phenomics Toolkit (CaPTk) was leveraged to analyze standard clinical brain MP-MRI scans. A rich set of imaging features was extracted from the MP-MRI scans acquired before the initial resection and was integrated into two distinct imaging signatures for predicting mean shorter or longer PFS and near or distant RP. The predictive signatures for PFS and RP were evaluated on the basis of different classification schemes: single-institutional analysis, multi-institutional analysis with random partitioning of the data into discovery and replication cohorts, and multi-institutional assessment with data from institution 1 as the discovery cohort and data from institution 2 as the replication cohort. RESULTS: These predictors achieved cross-validated classification performance (ie, area under the receiver operating characteristic curve) of 0.88 (single-institution analysis) and 0.82 to 0.83 (multi-institution analysis) for prediction of PFS and 0.88 (single-institution analysis) and 0.56 to 0.71 (multi-institution analysis) for prediction of RP. CONCLUSION: Imaging signatures of presurgical MP-MRI scans reveal relatively high predictability of time and location of GBM recurrence, subject to the patients receiving standard first-line chemoradiation therapy. Through its graphical user interface, CaPTk offers easy accessibility to advanced computational algorithms for deriving imaging signatures predictive of clinical outcome and could similarly be used for a variety of radiomic and radiogenomic analyses.

Asunto(s)

Neoplasias Encefálicas/mortalidad , Glioblastoma/mortalidad , Interpretación de Imagen Asistida por Computador/métodos , Imágenes de Resonancia Magnética Multiparamétrica/métodos , Recurrencia Local de Neoplasia/mortalidad , Fenómica/métodos , Programas Informáticos , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/cirugía , Femenino , Glioblastoma/metabolismo , Glioblastoma/patología , Glioblastoma/cirugía , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Supervivencia sin Progresión , Curva ROC , Estudios Retrospectivos , Tasa de Supervivencia , Adulto Joven

RESUMEN

BACKGROUND: High-density lipoprotein cholesterol (HDL-C) concentration is inversely related to risk of major adverse cardiovascular events (MACE) in epidemiologic studies but is a poorer predictor of MACE in patients with established coronary heart disease. HDL particle concentration (HDLP) has been proposed as a better predictor of risk. We investigated whether HDLP is associated with risk of MACE after acute coronary syndrome (ACS). METHODS: The dal-Outcomes trial compared the CETP inhibitor dalcetrapib with placebo in patients with recent ACS. In a nested case-cohort analysis, total, large, medium, and small HDLPs were measured by nuclear magnetic resonance spectroscopy at baseline (4-12 weeks after ACS) in 476 cases with MACE and 902 controls. Hazard ratios (HRs; case-control) for 1-SD increment of HDLP or HDL-C at baseline were calculated with and without adjustment for demographic, clinical, laboratory, and treatment variables. Similarly, HRs for MACE were calculated for changes in HDLP or HDL-C from baseline to month 3 of assigned treatment. RESULTS: Over median follow-up of 28 months, the risk of MACE was not associated with baseline HDLP (adjusted HR = 0.98, 95% CI = 0.84-1.15, P = .81), any HDLP subclass, or HDL-C. Dalcetrapib increased HDL-C and total, medium, and large HDLP and decreased small HDLP but had no effect on MACE compared with placebo. There were no association of risk of MACE with change in HDLP or HDL-C and no interaction with assigned study treatment. CONCLUSIONS: Neither baseline HDLP nor the change in HDLP on treatment with dalcetrapib or placebo was associated with risk of MACE after ACS.

Asunto(s)

Síndrome Coronario Agudo/sangre , Angina Inestable/epidemiología , Enfermedad Coronaria/mortalidad , Hospitalización/estadística & datos numéricos , Lipoproteínas HDL/sangre , Infarto del Miocardio/epidemiología , Accidente Cerebrovascular/epidemiología , Síndrome Coronario Agudo/tratamiento farmacológico , Anciano , Amidas , Anticolesterolemiantes/uso terapéutico , Estudios de Casos y Controles , HDL-Colesterol/sangre , Ésteres , Femenino , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Persona de Mediana Edad , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Compuestos de Sulfhidrilo/uso terapéutico

Asunto(s)

Antibacterianos/uso terapéutico , Guías de Práctica Clínica como Asunto , Polipéptido alfa Relacionado con Calcitonina/sangre , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Infecciones Bacterianas/tratamiento farmacológico , Biomarcadores/sangre , Humanos , Estimación de Kaplan-Meier , Pautas de la Práctica en Medicina , Infecciones del Sistema Respiratorio/mortalidad

RESUMEN

BACKGROUND: Lower pulmonary artery acceleration time (PAcT) is correlated with higher pulmonary artery pressure. The aim of this study was to test the hypothesis that PAcT measured in young adulthood would be associated with future cardiovascular outcomes. METHODS: In the Coronary Artery Risk Development in Young Adults year 5 examination (1990-1991), PAcT was measured as the time interval from onset to peak flow velocity at the pulmonary valve annulus on Doppler echocardiography. The primary outcome was a composite of fatal or nonfatal cardiovascular disease events: myocardial infarction, non-myocardial infarction acute coronary syndrome, coronary revascularization, congestive heart failure, stroke, transient ischemic attack, carotid artery disease, and peripheral arterial disease. RESULTS: PAcT was obtained in 4,171 participants (mean age, 30 ± 4 years, 55% women, 51% white). PAcT groups obtained using linear spline methodology were as follows: group I, PAcT ≥ 196 msec (n = 122); group II, PAcT < 196 and ≥115 msec (n = 3,195); and group III, PAcT < 115 msec (n = 854). During follow-up (median, 24.9 years), the primary outcome occurred in 216 participants (5.2%); 66 of 854 (7.7%) of those with PAcT < 115 msec, 149 of 3,195 (4.7%) of those with intermediate PAcT level, and one of 122 (0.8%) of those with PAcT ≥ 196 msec. In a fully adjusted model, the lowest and intermediate PAcT groups had hazard ratios of 8.3 (95% CI, 1.1-62.1; P = .04) and 6.8 (95% CI, 0.9-50.5; P = .06), respectively, in comparison with the highest PAcT group. CONCLUSIONS: PAcT is useful for better identifying young adults at higher risk for cardiovascular events, who may benefit from a strict control of modifiable cardiovascular risk factors.

Asunto(s)

Enfermedades Cardiovasculares/fisiopatología , Vasos Coronarios/fisiopatología , Ecocardiografía Doppler/métodos , Arteria Pulmonar/fisiopatología , Adolescente , Adulto , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/fisiopatología , Vasos Coronarios/diagnóstico por imagen , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Valor Predictivo de las Pruebas , Estudios Prospectivos , Arteria Pulmonar/diagnóstico por imagen , Medición de Riesgo/métodos , Factores de Riesgo , Estados Unidos/epidemiología , Adulto Joven