RESUMEN
PURPOSE: To investigate the influence of temporary cementation and subsequent bonding on the durability during in-vitro aging-simulation and fracture force of resin-based composite crowns. METHODS: Identical molar crowns (n=48, n=8 per group) were milled from resin-based composites and temporarily cemented and finally bonded to human molars. To simulate temporary application, crowns were cemented either with zinc-oxide-eugenol-cement (Tempbond) or with eugenol free zinc-oxide-cement (Tempbond NE). For a first simulation of a long-term provisional clinical application, thermal cycling, and mechanical loading (TCML 2 x 600 x 5°C-55°C, 2 minutes each cycle, distilled water, 240,000 cycles at 50N) was performed. After TCML all crowns were removed, cleaned, and luted either by using etch-and-rinse technique (Vococid, Futurabond U, Bifix QM) or a self-adhesive (Bifix SE) cementation system. A second thermal cycling and mechanical loading (TCML 2 x3,000 x 5°C/55°C, 2 minutes each cycle, distilled water, 1.2 x 106 at 50N) was accomplished to simulate 5 years of clinical application. To assess the survival of the crowns, the failure rates during TCML were documented. As controls, crowns were included without prior provisional cementation. After TCML all crowns were loaded to failure. Failure was categorized as fracture of the crown and partial loosening of the crown. RESULTS: All crowns survived both TCML procedures without any failures. The fracture values after TCML varied between 3,538.0 ± 1,041.2 N and 4,612.0 ± 801.5 N without significant (P= 0.146) differences between the individual groups. No correlation was found between fracture force and type of provisional cementation (zinc-oxide-eugenol vs. zinc-oxide: Pearson: -0.063/P= 0.672) or type of bonding (adhesive vs. self-adhesive: Pearson: -0.151/ P= 0.307). No different failure pattern was observed between the tested systems. CLINICAL SIGNIFICANCE: Regardless of the type of temporary cementation, there was no effect on the in-vitro performance or strength of the final permanently bonded crowns. Resin-based crowns might be bonded with adhesive or self-adhesive systems even after previous temporary cementation.
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Cementación , Resinas Compuestas , Coronas , Humanos , Cementación/métodos , Resinas Compuestas/química , Fracaso de la Restauración Dental , Análisis del Estrés Dental , Recubrimiento Dental Adhesivo/métodos , Cemento de Óxido de Zinc-Eugenol/química , Cementos Dentales/química , Ensayo de Materiales , Cementos de Resina/químicaRESUMEN
PURPOSE: To analyze long-term outcomes in a large cohort of patients with acute peripheral facial palsy (APFP). METHODS: Hospital-based, cross-sectional study. Data were abstracted from the electronic medical record. Time to recovery was assessed with Kaplan-Meier survival analyses. Binary logistic regression analysis was used to identify factors associated with outcome. RESULTS: Three hundred seventy-two patients with APFP seen at a tertiary hospital between February 2015 and March 2021 were analyzed. Seasonal variation of APFP peaked in the early fall (September 29) and had a peak-to-low ratio of 1.36 (R 2 = 0.329, p < 0.001). Patients who tested positive for Lyme disease (10%) had an earlier peak (July 16) compared with those who were negative (October 15). Eighty-seven percent of patients had complete recovery (averaging 64 ± 61 days). Patients, with higher House-Brackmann (H-B) grades at presentation took longer to recover, were more likely to have aberrant regeneration and had lower final rates of recovery compared with those with lower H-B grades (χ 2 = 12.03, p < 0.001). Of the patients with residual palsies, 70% had evidence of aberrant regeneration, and nearly half of those had hemifacial spasm. CONCLUSIONS: Most patients with APFP achieve complete recovery within 1 year, including those positive for Lyme. More severe palsy at presentation portends a worse outcome.
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Parálisis de Bell , Parálisis Facial , Espasmo Hemifacial , Estudios de Cohortes , Estudios Transversales , Parálisis Facial/diagnóstico , Humanos , Estimación de Kaplan-MeierRESUMEN
BACKGROUND: This study applies an umbrella review approach to summarise the global evidence on the risk of severe COVID-19 outcomes in patients with pre-existing health conditions. METHODS: Systematic reviews (SRs) were identified in PubMed, Embase/Medline and seven pre-print servers until December 11, 2020. Due to the absence of age-adjusted risk effects stratified by geographical regions, a re-analysis of the evidence was conducted. Primary studies were extracted from SRs and evaluated for inclusion in the re-analysis. Studies were included if they reported risk estimates (odds ratio (OR), hazard ratio (HR), relative risk (RR)) for hospitalisation, intensive care unit admission, intubation or death. Estimated associations were extracted from the primary studies for reported pre-existing conditions. Meta-analyses were performed stratified for each outcome by regions of the World Health Organization. The evidence certainty was assessed using GRADE. Registration number CRD42020215846. RESULTS: In total, 160 primary studies from 120 SRs contributed 464 estimates for 42 pre-existing conditions. Most studies were conducted in North America, European, and Western Pacific regions. Evidence from Africa, South/Latin America, and the Eastern Mediterranean region was scarce. No evidence was available from the South-East Asia region. Diabetes (HR range 1.2-2.0 (CI range 1.1-2.8)), obesity (OR range 1.5-1.75 (CI range 1.1-2.3)), heart failure (HR range 1.3-3.3 (CI range 0.9-8.2)), COPD (HR range 1.12-2.2 (CI range 1.1-3.2)) and dementia (HR range 1.4-7.7 (CI range 1.2-39.6)) were associated with fatal COVID-19 in different regions, although the estimates varied. Evidence from Europe and North America showed that liver cirrhosis (OR range 3.2-5.9 (CI range 0.9-27.7)) and active cancer (OR range 1.6-4.7 (CI range 0.5-14.9)) were also associated with increased risk of death. Association between HIV and undesirable COVID-19 outcomes showed regional heterogeneity, with an increased risk of death in Africa (HR 1.7 (CI 1.3-2.2)). GRADE certainty was moderate to high for most associations. CONCLUSION: Risk of undesirable COVID-19 health outcomes is consistently increased in certain patient subgroups across geographical regions, showing high variability in others. The results can be used to inform COVID-19 vaccine prioritisation or other intervention strategies.
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COVID-19 , Vacunas contra la COVID-19 , Humanos , Unidades de Cuidados Intensivos , Cobertura de Afecciones Preexistentes , SARS-CoV-2RESUMEN
Dozens of genes have been implicated in late onset Alzheimer's disease (AD) risk, but none has a defined mechanism of action in neurons. Here, we show that the risk factor Pyk2 (PTK2B) localizes specifically to neurons in adult brain. Absence of Pyk2 has no major effect on synapse formation or the basal parameters of synaptic transmission in the hippocampal Schaffer collateral pathway. However, the induction of synaptic LTD is suppressed in Pyk2-null slices. In contrast, deletion of Pyk2 expression does not alter LTP under control conditions. Of relevance for AD pathophysiology, Pyk2-/- slices are protected from amyloid-ß-oligomer (Aßo)-induced suppression of LTP in hippocampal slices. Acutely, a Pyk2 kinase inhibitor also prevents Aßo-induced suppression of LTP in WT slices. Female and male transgenic AD model mice expressing APPswe/PSEN1ΔE9 require Pyk2 for age-dependent loss of synaptic markers and for impairment of learning and memory. However, absence of Pyk2 does not alter Aß accumulation or gliosis. Therefore, the Pyk2 risk gene is directly implicated in a neuronal Aßo signaling pathway impairing synaptic anatomy and function.SIGNIFICANCE STATEMENT Genetic variation at the Pyk2 (PTK2B) locus is a risk for late onset Alzheimer's disease (AD), but the pathophysiological role of Pyk2 is not clear. Here, we studied Pyk2 neuronal function in mice lacking expression with and without transgenes generating amyloid-ß (Aß) plaque pathology. Pyk2 is not required for basal synaptic transmission or LTP, but participates in LTD. Hippocampal slices lacking Pyk2 are protected from AD-related Aß oligomer suppression of synaptic plasticity. In transgenic AD model mice, deletion of Pyk2 rescues synaptic loss and learning/memory deficits. Therefore, Pyk2 plays a central role in AD-related synaptic dysfunction mediating Aß-triggered dysfunction.
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Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/toxicidad , Quinasa 2 de Adhesión Focal/genética , Sinapsis/patología , Animales , Conducta Animal , Femenino , Gliosis/genética , Gliosis/patología , Aprendizaje/fisiología , Potenciación a Largo Plazo/genética , Depresión Sináptica a Largo Plazo/genética , Masculino , Memoria/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Factores de Riesgo , Transducción de Señal/genéticaRESUMEN
Biochemical and genetic evidence implicate soluble oligomeric amyloid-ß (Aßo) in triggering Alzheimer's disease (AD) pathophysiology. Moreover, constitutive deletion of the Aßo-binding cellular prion protein (PrPC) prevents development of memory deficits in APPswe/PS1ΔE9 mice, a model of familial AD. Here, we define the role of PrPC to rescue or halt established AD endophenotypes in a therapeutic disease-modifying time window after symptom onset. Deletion of Prnp at either 12 or 16 months of age fully reverses hippocampal synapse loss and completely rescues preexisting behavioral deficits by 17 months. In contrast, but consistent with a neuronal function for Aßo/PrPC signaling, plaque density, microgliosis, and astrocytosis are not altered. Degeneration of catecholaminergic neurons remains unchanged by PrPC reduction after disease onset. These results define the potential of targeting PrPC as a disease-modifying therapy for certain AD-related phenotypes after disease onset.SIGNIFICANCE STATEMENT The study presented here further elucidates our understanding of the soluble oligomeric amyloid-ß-Aßo-binding cellular prion protein (PrPC) signaling pathway in a familial form of Alzheimer's disease (AD) by implicating PrPC as a potential therapeutic target for AD. In particular, genetic deletion of Prnp rescued several familial AD (FAD)-associated phenotypes after disease onset in a mouse model of FAD. This study underscores the therapeutic potential of PrPC deletion given that patients already present symptoms at the time of diagnosis.
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Enfermedad de Alzheimer/fisiopatología , Encéfalo/fisiopatología , Trastornos Mentales/fisiopatología , Proteínas Priónicas/metabolismo , Sinapsis/metabolismo , Transmisión Sináptica , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/patología , Animales , Animales Modificados Genéticamente , Encéfalo/patología , Progresión de la Enfermedad , Femenino , Eliminación de Gen , Masculino , Trastornos Mentales/etiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Sinapsis/patologíaRESUMEN
Synaptic loss is critical in Alzheimer's disease (AD), but the dynamics of synapse turnover are poorly defined. We imaged dendritic spines in transgenic APPswe/PSen1∆E9 (APP/PS1) cerebral cortex. Dendritic spine turnover is increased far from plaque in aged APP/PS1 mice, and in young APP/PS1 mice prior to plaque formation. Dysregulation occurs in the presence of soluble Aß oligomer and requires cellular prion protein (PrPC). APP/PS1 mice lack responsiveness of spine turnover to sensory stimulation. Critically, enhanced spine turnover is coupled with the loss of persistent spines starting early and continuing with age. To evaluate mechanisms of experience-independent supranormal spine turnover, we analyzed the transcriptome of young APP/PS1 mouse brain when turnover is altered but synapse density and memory are normal, and plaque and inflammation are absent. Early PrPC-dependent expression changes occur in synaptic and lipid-metabolizing genes. Thus, pathologic synaptic dysregulation underlying AD begins at a young age prior to Aß plaque.
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Enfermedad de Alzheimer/patología , Corteza Cerebral/patología , Espinas Dendríticas/patología , Hipocampo/patología , Placa Amiloide/patología , Privación Sensorial , Factores de Edad , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Análisis de Varianza , Animales , Espinas Dendríticas/ultraestructura , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Imagenología Tridimensional , Inmunoprecipitación , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación/genética , Neuroimagen , Placa Amiloide/etiología , Presenilina-1/genética , Proteínas Priónicas/genética , Proteínas Priónicas/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Factores de Tiempo , Vibrisas/inervaciónRESUMEN
The dysfunction and loss of synapses in Alzheimer disease are central to dementia symptoms. We have recently demonstrated that pathological Amyloid ß oligomer (Aßo) regulates the association between intracellular protein mediators and the synaptic receptor complex composed of cellular prion protein (PrP(C)) and metabotropic glutamate receptor 5 (mGluR5). Here we sought to determine whether Aßo alters the physiological signaling of the PrP(C)-mGluR5 complex upon glutamate activation. We provide evidence that acute exposure to Aßo as well as chronic expression of familial Alzheimer disease mutant transgenes in model mice prevents protein-protein interaction changes of the complex induced by the glutamate analog 3,5-dihydroxyphenylglycine. We further show that 3,5-dihydroxyphenylglycine triggers the phosphorylation and activation of protein-tyrosine kinase 2-ß (PTK2B, also referred to as Pyk2) and of calcium/calmodulin-dependent protein kinase II in wild-type brain slices but not in Alzheimer disease transgenic brain slices or wild-type slices incubated with Aßo. This study further distinguishes two separate Aßo-dependent signaling cascades, one dependent on extracellular Ca(2+) and Fyn kinase activation and the other dependent on the release of Ca(2+) from intracellular stores. Thus, Aßo triggers multiple distinct PrP(C)-mGluR5-dependent events implicated in neurodegeneration and dementia. We propose that targeting the PrP(C)-mGluR5 complex will reverse aberrant Aßo-triggered states of the complex to allow physiological fluctuations of glutamate signaling.
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Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Ácido Glutámico/metabolismo , Fragmentos de Péptidos/metabolismo , Proteínas PrPC/metabolismo , Agregación Patológica de Proteínas/metabolismo , Receptor del Glutamato Metabotropico 5/metabolismo , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/genética , Animales , Modelos Animales de Enfermedad , Femenino , Ácido Glutámico/genética , Masculino , Ratones , Ratones Transgénicos , Fragmentos de Péptidos/genética , Proteínas PrPC/genética , Agregación Patológica de Proteínas/genética , Receptor del Glutamato Metabotropico 5/genéticaRESUMEN
Alzheimer's disease-related phenotypes in mice can be rescued by blockade of either cellular prion protein or metabotropic glutamate receptor 5. We sought genetic and biochemical evidence that these proteins function cooperatively as an obligate complex in the brain. We show that cellular prion protein associates via transmembrane metabotropic glutamate receptor 5 with the intracellular protein mediators Homer1b/c, calcium/calmodulin-dependent protein kinase II, and the Alzheimer's disease risk gene product protein tyrosine kinase 2 beta. Coupling of cellular prion protein to these intracellular proteins is modified by soluble amyloid-ß oligomers, by mouse brain Alzheimer's disease transgenes or by human Alzheimer's disease pathology. Amyloid-ß oligomer-triggered phosphorylation of intracellular protein mediators and impairment of synaptic plasticity in vitro requires Prnp-Grm5 genetic interaction, being absent in transheterozygous loss-of-function, but present in either single heterozygote. Importantly, genetic coupling between Prnp and Grm5 is also responsible for signalling, for survival and for synapse loss in Alzheimer's disease transgenic model mice. Thus, the interaction between metabotropic glutamate receptor 5 and cellular prion protein has a central role in Alzheimer's disease pathogenesis, and the complex is a potential target for disease-modifying intervention.
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Enfermedad de Alzheimer/metabolismo , Líquido Intracelular/metabolismo , Priones/metabolismo , Receptor del Glutamato Metabotropico 5/metabolismo , Transducción de Señal/fisiología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Animales , Lóbulo Frontal/metabolismo , Lóbulo Frontal/patología , Células HEK293 , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Técnicas de Cultivo de Órganos , Proteínas Priónicas , Priones/genética , Unión Proteica/fisiología , Receptor del Glutamato Metabotropico 5/genéticaRESUMEN
Alzheimer disease (AD) is characterized by amyloid-ß accumulation, with soluble oligomers (Aßo) being the most synaptotoxic. However, the multivalent and unstable nature of Aßo limits molecular characterization and hinders research reproducibility. Here, we characterized multiple Aßo forms throughout the life span of various AD mice and in post-mortem human brain. Aßo exists in several populations, where prion protein (PrP(C))-interacting Aßo is a high molecular weight Aß assembly present in multiple mice and humans with AD. Levels of PrP(C)-interacting Aßo match closely with mouse memory and are equal or superior to other Aß measures in predicting behavioral impairment. However, Aßo metrics vary considerably between mouse strains. Deleting PrP(C) expression in mice with relatively low PrP(C)-interacting Aßo (Tg2576) results in partial rescue of cognitive performance as opposed to complete recovery in animals with a high percentage of PrP(C)-interacting Aßo (APP/PSEN1). These findings highlight the relative contributions and interplay of Aßo forms in AD.
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Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Trastornos de la Memoria/metabolismo , Priones/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/genética , Animales , Conducta Animal , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Trastornos de la Memoria/etiología , Trastornos de la Memoria/psicología , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Ratones Transgénicos , Persona de Mediana Edad , Peso Molecular , Proteínas PrPC/química , Proteínas PrPC/genética , Proteínas PrPC/metabolismo , Corteza Prefrontal/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo , Priones/química , Priones/genética , Estructura Cuaternaria de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMEN
OBJECTIVE: Currently no effective disease-modifying agents exist for the treatment of Alzheimer disease (AD). The Fyn tyrosine kinase is implicated in AD pathology triggered by amyloid-ß oligomers (Aßo) and propagated by Tau. Thus, Fyn inhibition may prevent or delay disease progression. Here, we sought to repurpose the Src family kinase inhibitor oncology compound, AZD0530, for AD. METHODS: The pharmacokinetics and distribution of AZD0530 were evaluated in mice. Inhibition of Aßo signaling to Fyn, Pyk2, and Glu receptors by AZD0530 was tested by brain slice assays. After AZD0530 or vehicle treatment of wild-type and AD transgenic mice, memory was assessed by Morris water maze and novel object recognition. For these cohorts, amyloid precursor protein (APP) metabolism, synaptic markers (SV2 and PSD-95), and targets of Fyn (Pyk2 and Tau) were studied by immunohistochemistry and by immunoblotting. RESULTS: AZD0530 potently inhibits Fyn and prevents both Aßo-induced Fyn signaling and downstream phosphorylation of the AD risk gene product Pyk2, and of NR2B Glu receptors in brain slices. After 4 weeks of treatment, AZD0530 dosing of APP/PS1 transgenic mice fully rescues spatial memory deficits and synaptic depletion, without altering APP or Aß metabolism. AZD0530 treatment also reduces microglial activation in APP/PS1 mice, and rescues Tau phosphorylation and deposition abnormalities in APP/PS1/Tau transgenic mice. There is no evidence of AZD0530 chronic toxicity. INTERPRETATION: Targeting Fyn can reverse memory deficits found in AD mouse models, and rescue synapse density loss characteristic of the disease. Thus, AZD0530 is a promising candidate to test as a potential therapy for AD.
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Enfermedad de Alzheimer/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Benzodioxoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-fyn/antagonistas & inhibidores , Quinazolinas/farmacología , Transducción de Señal/efectos de los fármacos , Péptidos beta-Amiloides/efectos de los fármacos , Animales , Benzodioxoles/farmacocinética , Modelos Animales de Enfermedad , Quinasa 2 de Adhesión Focal/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Inhibidores de Proteínas Quinasas/farmacocinética , Quinazolinas/farmacocinéticaRESUMEN
Soluble Amyloid-ß oligomers (Aßo) can trigger Alzheimer disease (AD) pathophysiology by binding to cell surface cellular prion protein (PrP(C)). PrP(C) interacts physically with metabotropic glutamate receptor 5 (mGluR5), and this interaction controls the transmission of neurotoxic signals to intracellular substrates. Because the interruption of the signal transduction from PrP(C) to mGluR5 has therapeutic potential for AD, we developed assays to explore the effect of endogenous ligands, agonists/antagonists, and antibodies on the interaction between PrP(C) and mGluR5 in cell lines and mouse brain. We show that the PrP(C) segment of amino acids 91-153 mediates the interaction with mGluR5. Agonists of mGluR5 increase the mGluR5-PrP(C) interaction, whereas mGluR5 antagonists suppress protein association. Synthetic Aßo promotes the protein interaction in mouse brain and transfected HEK-293 cell membrane preparations. The interaction of PrP(C) and mGluR5 is enhanced dramatically in the brains of familial AD transgenic model mice. In brain homogenates with Aßo, the interaction of PrP(C) and mGluR5 is reversed by mGluR5-directed antagonists or antibodies directed against the PrP(C) segment of amino acids 91-153. Silent allosteric modulators of mGluR5 do not alter Glu or basal mGluR5 activity, but they disrupt the Aßo-induced interaction of mGluR5 with PrP(C). The assays described here have the potential to identify and develop new compounds that inhibit the interaction of PrP(C) and mGluR5, which plays a pivotal role in the pathogenesis of Alzheimer disease by transmitting the signal from extracellular Aßo into the cytosol.
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Péptidos beta-Amiloides/antagonistas & inhibidores , Anticuerpos/farmacología , Proteínas PrPC/antagonistas & inhibidores , Receptor del Glutamato Metabotropico 5/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Animales , Sitios de Unión , Bioensayo , Química Encefálica , Membrana Celular/química , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Células HEK293 , Humanos , Ligandos , Ratones , Ratones Transgénicos , Mapeo Peptídico , Proteínas PrPC/química , Proteínas PrPC/genética , Proteínas PrPC/metabolismo , Unión Proteica , Estructura Terciaria de Proteína , Receptor del Glutamato Metabotropico 5/química , Receptor del Glutamato Metabotropico 5/genética , Receptor del Glutamato Metabotropico 5/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transducción de SeñalRESUMEN
Combination COVID-19/influenza rapid tests provide a way to quickly and accurately differentiate between the two infections. The goal of this economic evaluation was to assess the cost and health benefits of a combination COVID-19/influenza Rapid Diagnostic Test (RDT) vs. current standard-of-care in the Brazilian private healthcare setting. A dual decision tree model was developed to estimate the impact of rapid differentiation of COVID-19 and influenza in a hypothetical cohort of 1,000 adults with influenza-like illness in an ambulatory healthcare setting. The model compared the use of a combination COVID-19/influenza RDT to Brazil standard diagnostic practice of a COVID-19 RDT and presumptive influenza diagnosis. Different levels of influenza prevalence were modeled with co-infection estimated as a function of the COVID-19 prevalence. Outcomes included accuracy of diagnosis, antiviral prescriptions and healthcare resource use (hospital bed days and ICU occupancy). Depending on influenza prevalence, considering 1,000 patients with influenza-like illness, a combination RDT compared to standard practice was estimated to result in between 88 and 149 fewer missed diagnoses of influenza (including co-infection), 161 to 185 fewer cases of over-diagnosis of influenza; a 24 to 34% reduction in hospital bed days and a 16 to 26% reduction in ICU days. In the base case scenario (20% influenza, 5% COVID-19), the combination RDT was estimated to result in cohort cost savings of $99. Based upon a de novo economic model, this analysis indicates that use of a combination RDT could positively impact influenza antiviral prescriptions and lower healthcare resource use.
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COVID-19 , Gripe Humana , Humanos , COVID-19/diagnóstico , Brasil/epidemiología , Gripe Humana/diagnóstico , Gripe Humana/economía , Análisis Costo-Beneficio , Adulto , SARS-CoV-2 , Prueba de COVID-19/economía , Prueba de COVID-19/métodos , Coinfección , Prueba de Diagnóstico RápidoRESUMEN
OBJECTIVES: To compare marginal gap width and depth with different cementation systems, excess removal, and after polishing. METHOD AND MATERIALS: In total, 80 composite crowns were milled, divided into ten groups, and cemented on identical artificial teeth. Eight crowns per group were fixed with (i) zinc phosphate cement (ZnOPh), (ii) glass-ionomer cement (GIC), (iii) resin-reinforced glass-ionomer cement (GIC mod), (iv) dual-curing adhesive composite (Comp dual), or (v) dual-curing self-adhesive composite (Comp SE dual). Excess removal was performed with a scaler after brief light-cure (tack-cure), final light-cure, during rubber or gel phase or by wiping with foam pellet. Curing was completed in chemical, dark cure, or light-curing modus. The specimens were polished and stored in water (37°C). The margins were digitized using a 3D laser-scanning microscope (VK-X100 series, Keyence). The width and the depth of the marginal gap were measured at 10 points between the crown margin and the preparation margin. RESULTS: The width after excess removal varied between 65.1 ± 15.7 µm (Comp dual, wipe, with polishing) and 208.6 ± 266.7 µm (Comp SE dual, dark cure, without polishing). The depth varied between 29.8 ± 22.2 µm (Comp dual, wipe, with polishing) and 89.5 ± 45.2 µm (Comp SE dual, dark cure, without polishing). The impact on gap width and depth was detected for fixation material, excess removal, and polishing. CONCLUSION: The gap depth and width depend on the luting material and the mode of access removal. Polishing can improve the gap quality, especially for GIC and resin-based systems.
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Cementos Dentales , Cementos de Resina , Humanos , Propiedades de Superficie , Cementos de Ionómero Vítreo , Cementación/métodos , Coronas , Ensayo de Materiales , Resinas CompuestasRESUMEN
OBJECTIVES: To estimate vaccine effectiveness (VE) and duration of protection of single primary and booster immunisation with meningococcal C (MenC) and ACWY (MenACWY) conjugate vaccines in preventing MenC invasive meningococcal disease (IMD). METHODS: We performed a systematic review on studies of VE and immunogenicity (rSBA/hSBA titers) of participants aged 12-23 months for primary and 6-18 years for booster immunisation (last search: 18 August 2023). Risk of bias and certainty of evidence were evaluated (PROSPERO: CRD42020178773). RESULTS: We identified 10 studies. Two studies reported VE of primary immunisation with MenC vaccines ranging between 90% (74.9 - 96.1) and 84.1% (41.5 - 95.7) for periods of 2 and 7 years, respectively. Eight studies reported immunogenicity of primary immunisation with MenC and/or MenACWY vaccines, of which two reported -in addition- on booster immunisation. The percentage of participants with protective rSBA titers was high after primary immunisation but waned over the following 6 years. A single booster at the age of 7 years or older seems to prolong protection for several years. CONCLUSIONS: A single dose of MenC or MenACWY vaccine at 12-23 months of age provides robust protection against MenC IMD. Data on booster immunisation are sparse, but indicate prolonged protection for three years at least.
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Inmunización Secundaria , Infecciones Meningocócicas , Vacunas Meningococicas , Humanos , Vacunas Meningococicas/inmunología , Vacunas Meningococicas/administración & dosificación , Infecciones Meningocócicas/prevención & control , Infecciones Meningocócicas/inmunología , Adolescente , Niño , Neisseria meningitidis Serogrupo C/inmunología , Eficacia de las Vacunas , Lactante , Vacunas Conjugadas/inmunología , Vacunas Conjugadas/administración & dosificación , Esquemas de Inmunización , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , Masculino , FemeninoRESUMEN
PURPOSE: To investigate the influence of milling parameters on the durability during in-vitro aging-simulation, and fracture force of resin-based composite crowns. MATERIALS AND METHODS: Identical molar crowns (n=8 per group) were milled from resin-based composite crowns (Grandio, VOCO, Germany) with different processing speed (soft, normal, fast) or level of details (very high, high, low) form 98mm discs. To investigate the influence of cooling, one group was milled wet. The influence of polishing was tested in two groups. All crowns were adhesively bonded on standardized resin-based composite molars. Aging was performed with thermal cycling and mechanical loading (2x3000x5°C/55°C, 2min, H20 dist., 1.2x106 force 50N). Fracture forces were determined (v=1mm/min, Z010, Zwick, Germany). STATISTICS: Pearson-correlation, one-way ANOVA, Bonferroni post-hoc-tests (α=0.05). RESULTS: All crowns survived TCML without any failures. The fracture values varied between 1237.3 ± 326.7N and 3308.6 ± 655.8N. Significant (p<0.001) differences between the individual manufacturing approaches were detected. Failure was categorized as a fracture of the crown and partial loosening of the crown. No different failure pattern was observed between the tested systems. CONCLUSION: A medium level of detail seems to be ideal to achieve highest fracture forces. No relationship existed between machining speed and fracture force. Fracture force was not affected by wet grinding. In individual cases, polishing reduced crown fracture values, due to reduced wall thickness.
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PURPOSE: To assess artifact burden and image quality of different MRI T1 mapping techniques of the prostate. METHODS: Participants with suspected prostate cancer (PCa) were prospectively enrolled from June-October 2022 and examined with multiparametric prostate MRI (mpMRI; 3 T scanner; T1wi, T2wi, DWI und DCE). T1 mapping was performed before and after administration of gadolinium-based contrast-agent (GBCA) using (i) a modified Look-Locker inversion (MOLLI) technique and (ii) a novel single-shot T1FLASH inversion recovery technique. T2wi, DWI, T1FLASH and MOLLI sequences were systematically examined regarding prevalence of artifacts and image quality using a 5-point Likert-Scale. RESULTS: A total of n = 100 patients were included (median age: 68 years). T1FLASH maps (pre-and post-GBCA) showed metal artifacts in 7% of cases and susceptibility artifacts in 1%. For MOLLI maps, pre-GBCA metal and susceptibility artifacts were documented in 6.5% of cases each. MOLLI maps post-GBCA showed artifacts in 59% of cases resulting primarily from urinary GBCA excretion and GBCA accumulation at the bladder base (p < 0.01 versus T1FLASH post-GBCA). Image quality for T1FLASH pre-GBCA was rated at a mean 4.9+/-0.4 and for MOLLI at 4.8+/-0.6 (p = 0.14). Post-GBCA image quality was rated at a mean 4.9+/-0.4 for T1FLASH and at 3.7+/-1.1 for MOLLI (p < 0.001). CONCLUSIONS: T1FLASH maps provide a fast and robust method for quantification of T1 relaxation times of the prostate. T1FLASH is suitable for T1 mapping of the prostate following administration of contrast agents, while MOLLI T1 mapping is impaired through GBCA accumulation at the bladder base leading to severe image artifacts and reduced image quality.
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Artefactos , Imágenes de Resonancia Magnética Multiparamétrica , Masculino , Humanos , Anciano , Próstata/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Medios de Contraste , Fantasmas de Imagen , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVE: In German inpatient psychosomatics per diem lump sums will be introduced as reimbursement rates by 2013. It was the aim to calculate total inpatient costs per case for the psychosomatic treatment of patients with anorexia nervosa and to identify cost predictors. METHOD: The sample comprised of 127 inpatients. Cost calculation was executed from the hospital's perspective, mainly using microcosting. Medical records provided data on patient characteristics and individual resource use. Two generalized linear models with gamma distribution and log link function were estimated to determine cost predictors by means of demographic data, comorbidities, and body-mass-index at admission. RESULTS: Inpatient costs amounted to 4,647 /6,831 US$ per case (standard deviation 3,714 /5,460 US$).The admission BMI and "Disorders of Adult Personality and Behavior" were significant cost predictors (p < 0.05). DISCUSSION: The formation of patient groups within the diagnosis anorexia nervosa should be oriented towards the determined cost predictors.
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Anorexia Nerviosa/economía , Hospitalización/economía , Pacientes Internos , Adulto , Anorexia Nerviosa/psicología , Anorexia Nerviosa/terapia , Índice de Masa Corporal , Costos de la Atención en Salud , HumanosRESUMEN
Adaptor proteins mediate signal transduction from cell surface receptors to downstream signaling pathways. The Grb7 protein family of adaptor proteins is constituted by Grb7, Grb10, and Grb14. This protein family has been shown to be overexpressed in certain cancers and cancer cell lines. Grb7-mediated cell migration has been shown to proceed through a focal adhesion kinase (FAK)/Grb7 pathway, although the specific participants downstream of Grb7 in cell migration signaling have not been fully determined. In this study, we report that Grb7 interacts with Hax-1, a cytoskeletal-associated protein found overexpressed in metastatic tumors and cancer cell lines. Additionally, in yeast 2-hybrid assays, we show that the interaction is specific to the Grb7-RA and -PH domains. We have also demonstrated that full-length Grb7 and Hax-1 interact in mammalian cells and that Grb7 is tyrosine phosphorylated. Isothermal titration calorimetry measurements demonstrate the Grb7-RA-PH domains bind to the Grb7-SH2 domain with micromolar affinity, suggesting full-length Grb7 can exist in a head-to-tail conformational state that could serve a self-regulatory function.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteína Adaptadora GRB7/química , Proteína Adaptadora GRB7/metabolismo , Proteínas Adaptadoras Transductoras de Señales/química , Células HeLa , Humanos , Inmunoprecipitación , Fosforilación , Fosfotirosina , Unión Proteica , Relación Estructura-Actividad , Termodinámica , Transfección , Dominios Homologos srcRESUMEN
AIMS: Considering that healthcare systems' financial resources are limited, we aimed to analyze the number needed to treat (NNT) and cost of preventing an event (COPE) related to drug use from Supplementary Health System (SSS) perspective. METHODS: Data from KEYNOTE-189 (NCT02578680) were considered, comparing pembrolizumab + chemotherapy to chemotherapy alone. A cost-per-responder model was developed considering the 24- and 12-month time horizons for overall survival (OS) and progression-free survival (PFS) endpoints, respectively. Restricted mean survival time (RMST) and restricted mean time-on-treatment (ToT) were determined for NNT and COPE calculation. Costs were reported in American dollars (USD) and reflect those related to drug use. The analysis was conducted for the total indicated population, and an exploratory assessment was carried out for subgroups with different programmed death-ligand 1 (PD-L1) expression levels. RESULTS: Considering PFS data, the overall population NNTRMST to prevent a progression event with pembrolizumab + chemotherapy versus chemotherapy was 2.63 (95%CI: 1.90-4.02) with an estimated COPE of 251,038 USD (95%CI: 181,359-383,717) in the 12-months follow-up. Regarding OS endpoint, overall NNTRMST and COPE were 3.18 (95%CI: 2.20-5.31) and 414,163 (95%CI: 286,528-691,573) USD respectively, in the 24 months follow-up. The PFS NNT was lower with higher levels of PD-L1 expression (1.71, 3.22 and 5.53 for PD-L1 ≥ 50%, PD-L1 1%-49%, and PD-L1 < 1% groups, respectively), while there was no such apparent relationship for OS (3.23, 4.37 and 2.80 for PD-L1 ≥ 50%, PD-L1 1%-49%, and PD-L1 < 1% groups, respectively). The 95%CIs overlapped for PFS and OS NNT across the PD-L1 subgroups. CONCLUSION: The magnitude of benefit of the pembrolizumab combination used for first-line non-small cell lung cancer (NSCLC) treatment to improve survival compared to chemotherapy alone was confirmed. The exploratory analysis from the SSS perspective suggests no differences among the PDL-1 subgroups in terms of clinical benefit or economic impact.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Humanos , Neoplasias Pulmonares/tratamiento farmacológicoRESUMEN
BACKGROUND: Considering clinical benefits of new combination therapies for metastatic renal-cell carcinoma (mRCC), this study aims to calculate the number needed to treat (NTT) and the cost of preventing an event (COPE) for pembrolizumab plus axitinib (P + A), and nivolumab plus ipilimumab (N + I) as first-line treatments, from the Brazilian private perspective. METHODS: Overall survival (OS) and progression-free survival (PFS) data for intermediate- and poor-risk groups were obtained from KEYNOTE-426 and CHECKMATE-214 trials for P + A and N + I, respectively, versus sunitinib as mRCC first-line treatment. RESULTS: Considering a 12-month time horizon, 6 patients should be treated with P + A to prevent one death with sunitinib use, resulting in a COPE of 3,773,865 BRL. Using N + I, NNT for 12-month OS rate was 13 compared to sunitinib, with a COPE of 6,357,965 BRL. Regarding PFS data, NNT was also 6 when comparing P + A versus sunitinib, with an estimated COPE of 3,773,865 BRL. Estimated NNT was 20 comparing N + I and sunitinib, resulting in a COPE of 10,172,744 BRL. Cost differences between two treatment options, reached more than 6 million BRL for PFS, and 2 million BRL for OS. CONCLUSION: At the 12-month landmark, P + A suggests better economic scenario versus N + I as first-line mRCC treatment option for intermediate- and poor-risk groups, through an indirect comparison using sunitinib as a common comparator.