RESUMEN
1The COVID-19 pandemic has stimulated wastewater-based surveillance, allowing public health to track the epidemic by monitoring the concentration of the genetic fingerprints of SARS-CoV-2 shed in wastewater by infected individuals. Wastewater-based surveillance for COVID-19 is still in its infancy. In particular, the quantitative link between clinical cases observed through traditional surveillance and the signals from viral concentrations in wastewater is still developing and hampers interpretation of the data and actionable public-health decisions. We present a modelling framework that includes both SARS-CoV-2 transmission at the population level and the fate of SARS-CoV-2 RNA particles in the sewage system after faecal shedding by infected persons in the population. Using our mechanistic representation of the combined clinical/wastewater system, we perform exploratory simulations to quantify the effect of surveillance effectiveness, public-health interventions and vaccination on the discordance between clinical and wastewater signals. We also apply our model to surveillance data from three Canadian cities to provide wastewater-informed estimates for the actual prevalence, the effective reproduction number and incidence forecasts. We find that wastewater-based surveillance, paired with this model, can complement clinical surveillance by supporting the estimation of key epidemiological metrics and hence better triangulate the state of an epidemic using this alternative data source.
RESUMEN
Methods@#This is an Institutional Review Board-exempt review of 69 patients (static, n=32; expandable, n=37) diagnosed with DDD who underwent MIS-LLIF at 1–2 contiguous level(s) using static or expandable spacers. Radiographic and clinical outcomes were collected and compared at pre- and postoperative time points up to 12 months. @*Results@#The expandable group had a significantly higher mean change in Visual Analog Scale (VAS) scores at 6 weeks, 6 months, and 12 months vs. static (∆VAS at 12 months: expandable, 6.7±1.3; static, 5.1±2.6). Mean improvement of Oswestry Disability Index (ODI) scores at 3, 6, and 12 months were significantly better for the expandable group vs. static (∆ODI at 12 months: expandable, 63.2±13.2; static, 29.8±23.4). Mean DH and NH significantly increased at final follow-up for both groups, with no significant difference in DH improvement between groups. The expandable mean NH improvement at 6 weeks and 6 months was significantly greater vs. static. Segmental lordosis significantly improved in the expandable group at all time intervals vs static. Subsidence rate at 12 months was significantly lower in the expandable group (1/46, 2.2%) vs. static (12/37, 32.4%). @*Conclusions@#Expandable spacers resulted in a significantly lower subsidence rate, improve segmental lordosis, and VAS and ODI outcomes at 12 months vs. static.
RESUMEN
BackgroundPatient age is the most salient clinical indicator of risk from COVID-19. Age-specific distributions of known SARS-CoV-2 infections and COVID-19-related deaths are available for most countries. However, relatively little attention has been given to the age distributions of hospitalizations and serious healthcare interventions administered to COVID-19 patients. We examined these distributions in Ontario, Canada, in order to quantify the age-related impacts of COVID-19, and to identify potential risks should the healthcare system become overwhelmed with COVID-19 patients in the future. MethodsWe analysed known SARS-CoV-2 infection records from the integrated Public Health Information System (iPHIS) and the Toronto Public Health Coronavirus Rapid Entry System (CORES) between 23 January 2020 and 17 June 2020 (N = 30,546), and estimated the age distributions of hospitalizations, ICU admissions, intubations, and ventilations. We quantified the probability of hospitalization given known SARS-CoV-2 infection, and of survival given COVID-19-related hospitalization. ResultsThe distribution of COVID-19-related hospitalizations peaks with a wide plateau covering ages 54-90, whereas deaths are sharply concentrated in very old ages, with a maximum at age 90. The estimated probability of hospitalization given known SARS-CoV-2 infection reaches a maximum of 32.0% at age 75 (95% CI 27.5%-36.7%). The probability of survival given COVID-19-related hospitalization is uncertain for children (due to small sample size), and near 100% for adults younger than 40. After age 40, survival of hospitalized COVID-19 patients declines substantially; for example, a hospitalized 50-year-old patient has a 90.4% chance of surviving COVID-19 (95% CI 81.9%-95.7%). InterpretationConcerted efforts to control the spread of SARS-CoV-2 have kept prevalence of the virus low in the population of Ontario. The healthcare system has not been overstretched, yet the probability of survival given hospitalization for COVID-19 has been lower than is generally recognized for patients over 40. If prevalence of the virus were to increase and healthcare capacities were to be exceeded, survival of individuals in the broad age range requiring acute care would be expected to decrease, potentially expanding the distribution of COVID-19-related deaths toward younger ages.
RESUMEN
A novel coronavirus (SARS-CoV-2) has recently emerged as a global threat. As the epidemic progresses, many disease modelers have focused on estimating the basic reproductive number[R] 0- the average number of secondary cases caused by a primary case in an otherwise susceptible population. The modeling approaches and resulting estimates of[R] 0 vary widely, despite relying on similar data sources. Here, we present a novel statistical framework for comparing and combining different estimates of[R] 0 across a wide range of models by decomposing the basic reproductive number into three key quantities: the exponential growth rate r, the mean generation interval [Formula], and the generation-interval dispersion{kappa} . We then apply our framework to early estimates of[R] 0 for the SARS-CoV-2 outbreak. We show that many early[R] 0 estimates are overly confident. Our results emphasize the importance of propagating uncertainties in all components of[R] 0, including the shape of the generation-interval distribution, in efforts to estimate[R] 0 at the outset of an epidemic.
RESUMEN
Hepcidin regulates iron metabolism by down-regulating ferroportin-1 (Fpn1). We demonstrated that hepcidin is complexed to the blood transport protein, α2-macroglobulin (α2M) (Peslova, G., Petrak, J., Kuzelova, K., Hrdy, I., Halada, P., Kuchel, P. W., Soe-Lin, S., Ponka, P., Sutak, R., Becker, E., Huang, M. L., Suryo Rahmanto, Y., Richardson, D. R., and Vyoral, D. (2009) Blood 113, 6225-6236). However, nothing is known about the mechanism of hepcidin binding to α2M or the effects of the α2M·hepcidin complex in vivo. We show that decreased Fpn1 expression can be mediated by hepcidin bound to native α2M and also, for the first time, hepcidin bound to methylamine-activated α2M (α2M-MA). Passage of high molecular weight α2M·hepcidin or α2M-MA·hepcidin complexes (≈725 kDa) through a Sephadex G-25 size exclusion column retained their ability to decrease Fpn1 expression. Further studies using ultrafiltration indicated that hepcidin binding to α2M and α2M-MA was labile, resulting in some release from the protein, and this may explain its urinary excretion. To determine whether α2M-MA·hepcidin is delivered to cells via the α2M receptor (Lrp1), we assessed α2M uptake and Fpn1 expression in Lrp1(-/-) and Lrp1(+/+) cells. Interestingly, α2M·hepcidin or α2M-MA·hepcidin demonstrated similar activities at decreasing Fpn1 expression in Lrp1(-/-) and Lrp1(+/+) cells, indicating that Lrp1 is not essential for Fpn1 regulation. In vivo, hepcidin bound to α2M or α2M-MA did not affect plasma clearance of α2M/α2M-MA. However, serum iron levels were reduced to a significantly greater extent in mice treated with α2M·hepcidin or α2M-MA·hepcidin relative to unbound hepcidin. This effect could be mediated by the ability of α2M or α2M-MA to retard kidney filtration of bound hepcidin, increasing its half-life. A model is proposed that suggests that unlike proteases, which are irreversibly bound to activated α2M, hepcidin remains labile and available to down-regulate Fpn1.
Asunto(s)
Proteínas de Transporte de Catión/biosíntesis , Regulación de la Expresión Génica/fisiología , Hepcidinas/sangre , Hierro/sangre , Modelos Biológicos , Complejos Multiproteicos/sangre , alfa-Macroglobulinas/metabolismo , Animales , Proteínas de Transporte de Catión/genética , Línea Celular , Hepcidinas/genética , Humanos , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Ratones , Ratones Noqueados , Complejos Multiproteicos/genética , Receptores de LDL/genética , Receptores de LDL/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , alfa-Macroglobulinas/genéticaRESUMEN
Friedreich ataxia (FA) is a neurodegenerative and cardiodegenerative disease resulting from marked frataxin deficiency. The condition is characterized by ataxia with fatal cardiomyopathy, but the pathogenic mechanisms are unclear. We investigated the association between gene expression and progressive histopathological and functional changes using the muscle creatine kinase conditional frataxin knockout (KO) mouse; this mouse develops a severe cardiac phenotype that resembles that of FA patients. We examined KO mice from 3 weeks of age, when they are asymptomatic, to 10 weeks of age, when they die of the disease. Positive iron staining was identified in KO mice from 5 weeks of age, with markedly reduced cardiac function from 6 weeks. We identified an early and marked up-regulation of a gene cohort responsible for stress-induced amino acid biosynthesis and observed markedly increased phosphorylation of eukaryotic translation initiation factor 2α (p-eIF2α), an activator of the integrated stress response, in KO mice at 3 weeks of age, relative to wild-type mice. Importantly, the eIF2α-mediated integrated stress response has been previously implicated in heart failure via downstream processes such as autophagy and apoptosis. Indeed, expression of a panel of autophagy and apoptosis markers was enhanced in KO mice. Thus, the pathogenesis of cardiomyopathy in FA correlates with the early and persistent eIF2α phosphorylation, which precedes activation of autophagy and apoptosis.
Asunto(s)
Factor 2 Eucariótico de Iniciación/metabolismo , Ataxia de Friedreich/genética , Ataxia de Friedreich/patología , Transducción de Señal , Estrés Fisiológico , Factor de Transcripción Activador 4/metabolismo , Aminoácidos/biosíntesis , Animales , Apoptosis , Autofagia , Cardiomegalia/patología , Cardiomegalia/fisiopatología , Modelos Animales de Enfermedad , Femenino , Ataxia de Friedreich/diagnóstico por imagen , Ataxia de Friedreich/fisiopatología , Perfilación de la Expresión Génica , Pruebas de Función Cardíaca , Humanos , Proteínas de Unión a Hierro/metabolismo , Masculino , Ratones , Ratones Noqueados , Modelos Biológicos , Miocardio/metabolismo , Miocardio/patología , Miocitos Cardíacos/enzimología , Miocitos Cardíacos/patología , Fenotipo , Fosforilación , Proteínas Quinasas/metabolismo , Transducción de Señal/genética , Estrés Fisiológico/genética , Ultrasonografía , FrataxinaRESUMEN
FRDA (Friedreich's ataxia) is a debilitating mitochondrial disorder leading to neural and cardiac degeneration, which is caused by a mutation in the frataxin gene that leads to decreased frataxin expression. The most common cause of death in FRDA patients is heart failure, although it is not known how the deficiency in frataxin potentiates the observed cardiomyopathy. The major proposed biochemical mechanisms for disease pathogenesis and the origins of heart failure in FRDA involve metabolic perturbations caused by decreased frataxin expression. Additionally, recent data suggest that low frataxin expression in heart muscle of conditional frataxin knockout mice activates an integrated stress response that contributes to and/or exacerbates cardiac hypertrophy and the loss of cardiomyocytes. The elucidation of these potential mechanisms will lead to a more comprehensive understanding of the pathogenesis of FRDA, and will contribute to the development of better treatments and therapeutics.
Asunto(s)
Cardiomiopatías/metabolismo , Ataxia de Friedreich/metabolismo , Enfermedades Mitocondriales/metabolismo , Animales , Apoptosis/fisiología , Cardiomiopatías/fisiopatología , Ataxia de Friedreich/fisiopatología , Humanos , Proteínas de Unión a Hierro/metabolismo , Enfermedades Mitocondriales/fisiopatología , Estrés Oxidativo/fisiología , FrataxinaRESUMEN
The mitochondrion plays vital roles in various aspects of cellular metabolism, ranging from energy transduction and apoptosis to the synthesis of important molecules such as heme. Mitochondria are also centrally involved in iron metabolism, as exemplified by disruptions in mitochondrial proteins that lead to perturbations in whole-cell iron processing. Recent investigations have identified a host of mitochondrial proteins (e.g., mitochondrial ferritin; mitoferrins 1 and 2; ABCBs 6, 7, and 10; and frataxin) that may play roles in the homeostasis of mitochondrial iron. These mitochondrial proteins appear to participate in one or more processes of iron storage, iron uptake, and heme and iron-sulfur cluster synthesis. In this review, we present and critically discuss the evidence suggesting that the mitochondrion may contribute to the regulation of whole-cell iron metabolism. Further, human diseases that arise from a dysregulation of these mitochondrial molecules reveal the ability of the mitochondrion to communicate with cytosolic iron metabolism to coordinate whole-cell iron processing and to fulfill the high demands of this organelle for iron. This review highlights new advances in understanding iron metabolism in terms of novel molecular players and diseases associated with its dysregulation.
Asunto(s)
Hierro/metabolismo , Mitocondrias/metabolismo , Enfermedades Mitocondriales/metabolismo , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Humanos , Transporte Iónico , Proteínas de Unión a Hierro/metabolismo , Redes y Vías Metabólicas , FrataxinaRESUMEN
We used the muscle creatine kinase (MCK) conditional frataxin knockout mouse to elucidate how frataxin deficiency alters iron metabolism. This is of significance because frataxin deficiency leads to Friedreich's ataxia, a disease marked by neurologic and cardiologic degeneration. Using cardiac tissues, we demonstrate that frataxin deficiency leads to down-regulation of key molecules involved in 3 mitochondrial utilization pathways: iron-sulfur cluster (ISC) synthesis (iron-sulfur cluster scaffold protein1/2 and the cysteine desulferase Nfs1), mitochondrial iron storage (mitochondrial ferritin), and heme synthesis (5-aminolevulinate dehydratase, coproporphyrinogen oxidase, hydroxymethylbilane synthase, uroporphyrinogen III synthase, and ferrochelatase). This marked decrease in mitochondrial iron utilization and resultant reduced release of heme and ISC from the mitochondrion could contribute to the excessive mitochondrial iron observed. This effect is compounded by increased iron availability for mitochondrial uptake through (i) transferrin receptor1 up-regulation, increasing iron uptake from transferrin; (ii) decreased ferroportin1 expression, limiting iron export; (iii) increased expression of the heme catabolism enzyme heme oxygenase1 and down-regulation of ferritin-H and -L, both likely leading to increased "free iron" for mitochondrial uptake; and (iv) increased expression of the mammalian exocyst protein Sec15l1 and the mitochondrial iron importer mitoferrin-2 (Mfrn2), which facilitate cellular iron uptake and mitochondrial iron influx, respectively. Our results enable the construction of a model explaining the cytosolic iron deficiency and mitochondrial iron loading in the absence of frataxin, which is important for understanding the pathogenesis of Friedreich's ataxia.
Asunto(s)
Ataxia de Friedreich/genética , Proteínas de Unión a Hierro/genética , Hierro/metabolismo , Mitocondrias/metabolismo , Animales , Péptidos Catiónicos Antimicrobianos/genética , Péptidos Catiónicos Antimicrobianos/metabolismo , Western Blotting , Liasas de Carbono-Azufre/genética , Liasas de Carbono-Azufre/metabolismo , Coproporfirinógeno Oxidasa/genética , Coproporfirinógeno Oxidasa/metabolismo , Modelos Animales de Enfermedad , Ferroquelatasa/genética , Ferroquelatasa/metabolismo , Ataxia de Friedreich/metabolismo , Ataxia de Friedreich/patología , Perfilación de la Expresión Génica , Hemo/metabolismo , Hepcidinas , Humanos , Proteínas de Unión a Hierro/metabolismo , Riñón/metabolismo , Hígado/metabolismo , Ratones , Ratones Noqueados , Miocardio/citología , Miocardio/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Bazo/metabolismo , Uroporfirinógeno III Sintetasa/genética , Uroporfirinógeno III Sintetasa/metabolismo , FrataxinaRESUMEN
Hepcidin is a major regulator of iron metabolism. Hepcidin-based therapeutics/diagnostics could play roles in hematology in the future, and thus, hepcidin transport is crucial to understand. In this study, we identify alpha2-macroglobulin (alpha2-M) as the specific hepcidin-binding molecule in blood. Interaction of 125I-hepcidin with alpha2-M was identified using fractionation of plasma proteins followed by native gradient polyacrylamide gel electrophoresis and mass spectrometry. Hepcidin binding to nonactivated alpha2-M displays high affinity (Kd 177 +/- 27 nM), whereas hepcidin binding to albumin was nonspecific and displayed nonsaturable kinetics. Surprisingly, the interaction of hepcidin with activated alpha2-M exhibited a classical sigmoidal binding curve demonstrating cooperative binding of 4 high-affinity (Kd 0.3 microM) hepcidin-binding sites. This property probably enables efficient sequestration of hepcidin and its subsequent release or inactivation that may be important for its effector functions. Because alpha2-M rapidly targets ligands to cells via receptor-mediated endocytosis, the binding of hepcidin to alpha2-M may influence its functions. In fact, the alpha2-M-hepcidin complex decreased ferroportin expression in J774 cells more effectively than hepcidin alone. The demonstration that alpha2-M is the hepcidin transporter could lead to better understanding of hepcidin physiology, methods for its sensitive measurement and the development of novel drugs for the treatment of iron-related diseases.