As of 29 February 2020 there were 79,394 confirmed cases and 2,838 deaths from COVID-19 in mainland China. Of these, 48,557 cases and 2,169 deaths occurred in the epicenter, Wuhan. A key public ...health priority during the emergence of a novel pathogen is estimating clinical severity, which requires properly adjusting for the case ascertainment rate and the delay between symptoms onset and death. Using public and published information, we estimate that the overall symptomatic case fatality risk (the probability of dying after developing symptoms) of COVID-19 in Wuhan was 1.4% (0.9-2.1%), which is substantially lower than both the corresponding crude or naïve confirmed case fatality risk (2,169/48,557 = 4.5%) and the approximator
of deaths/deaths + recoveries (2,169/2,169 + 17,572 = 11%) as of 29 February 2020. Compared to those aged 30-59 years, those aged below 30 and above 59 years were 0.6 (0.3-1.1) and 5.1 (4.2-6.1) times more likely to die after developing symptoms. The risk of symptomatic infection increased with age (for example, at ~4% per year among adults aged 30-60 years).
Review: Somatic mutations in neurodegeneration Leija‐Salazar, M.; Piette, C.; Proukakis, C.
Neuropathology & applied neurobiology/Neuropathology and applied neurobiology,
April 2018, Letnik:
44, Številka:
3
Journal Article
Recenzirano
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Somatic mutations are postzygotic mutations which may lead to mosaicism, the presence of cells with genetic differences in an organism. Their role in cancer is well established, but detailed ...investigation in health and other diseases has only been recently possible. This has been empowered by the improvements of sequencing techniques, including single‐cell sequencing, which can still be error‐prone but is rapidly improving. Mosaicism appears relatively common in the human body, including the normal brain, probably arising in early development, but also potentially during ageing. In this review, we first discuss theoretical considerations and current evidence relevant to somatic mutations in the brain. We present a framework to explain how they may be integrated with current views on neurodegeneration, focusing mainly on sporadic late‐onset neurodegenerative diseases (Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis). We review the relevant studies so far, with the first evidence emerging in Alzheimer's in particular. We also discuss the role of mosaicism in inherited neurodegenerative disorders, particularly somatic instability of tandem repeats. We summarize existing views and data to present a model whereby the time of origin and spatial distribution of relevant somatic mutations, combined with any additional risk factors, may partly determine the development and onset age of sporadic neurodegenerative diseases.
Summary
The International Prognostic Index (IPI) is the most widely used score for non‐Hodgkin lymphoma but lacks the ability to identify a high‐risk population in diffuse large B‐cell lymphoma ...(DLBCL). Low absolute lymphocyte count and high monocytes have proved to be unfavourable factors. Red‐cell distribution width (RDW) has been associated with inflammation and beta‐2 microglobulin (B2M) with tumour load. The retrospective study included 992 patients with DLBCL treated with R‐CHOP. In the multivariate analysis, age, Eastern Cooperative Oncology Group performance status (ECOG‐PS), stage, bulky mass, B2M, RDW, and lymphocyte/monocyte ratio (LMR) were independently related to progression‐free survival (PFS). A new prognosis score was generated with these variables including age categorized into three groups (0, 1, 2 points); ECOG ≥ 3–4 with two; stage III/IV, bulky mass, high B2M, LMR < 2·25 and RDW > 0·96 with one each; for a maximum of 9. This score could improve the discrimination of a very high‐risk subgroup with five‐year PFS and overall survival (OS) of 19% and 24% versus 45% and 59% of R (revised)‐IPI respectively. This score also showed greater predictive ability than IPI. A new score is presented including complete blood cell count variables and B2M, which are readily available in real‐life practice without additional tests. Compared to R‐IPI, it shows a more precise high‐risk assessment and risk discrimination for both PFS and OS.
Estimation of the effective reproductive number Rt is important for detecting changes in disease transmission over time. During the Coronavirus Disease 2019 (COVID-19) pandemic, policy makers and ...public health officials are using Rt to assess the effectiveness of interventions and to inform policy. However, estimation of Rt from available data presents several challenges, with critical implications for the interpretation of the course of the pandemic. The purpose of this document is to summarize these challenges, illustrate them with examples from synthetic data, and, where possible, make recommendations. For near real-time estimation of Rt, we recommend the approach of Cori and colleagues, which uses data from before time t and empirical estimates of the distribution of time between infections. Methods that require data from after time t, such as Wallinga and Teunis, are conceptually and methodologically less suited for near real-time estimation, but may be appropriate for retrospective analyses of how individuals infected at different time points contributed to the spread. We advise caution when using methods derived from the approach of Bettencourt and Ribeiro, as the resulting Rt estimates may be biased if the underlying structural assumptions are not met. Two key challenges common to all approaches are accurate specification of the generation interval and reconstruction of the time series of new infections from observations occurring long after the moment of transmission. Naive approaches for dealing with observation delays, such as subtracting delays sampled from a distribution, can introduce bias. We provide suggestions for how to mitigate this and other technical challenges and highlight open problems in Rt estimation.
Inflammation as a central mechanism in Alzheimer's disease Kinney, Jefferson W.; Bemiller, Shane M.; Murtishaw, Andrew S. ...
Alzheimer's & dementia : translational research & clinical interventions,
2018, Letnik:
4, Številka:
1
Journal Article
Recenzirano
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Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by cognitive decline and the presence of two core pathologies, amyloid β plaques and neurofibrillary ...tangles. Over the last decade, the presence of a sustained immune response in the brain has emerged as a third core pathology in AD. The sustained activation of the brain's resident macrophages (microglia) and other immune cells has been demonstrated to exacerbate both amyloid and tau pathology and may serve as a link in the pathogenesis of the disorder. In the following review, we provide an overview of inflammation in AD and a detailed coverage of a number of microglia-related signaling mechanisms that have been implicated in AD. Additional information on microglia signaling and a number of cytokines in AD are also reviewed. We also review the potential connection of risk factors for AD and how they may be related to inflammatory mechanisms.
•Poly-ICLC a synthetic dsRNA mimic stimulates both TLR3 and MDA5.•Poly-ICLC is a potent IFN-I and IL-15 inducer through MDA5 stimulation.•Poly-ICLC is a strong adjuvant for peptide cancer vaccines ...promoting the expansion of T cells.•Systemic poly-ICLC enhances T cell infiltration through MDA5 stimulation and IFN-I production.•Clinically, poly-ICLC induces in situ autovaccination and enhances T cell responses.
Immunotherapies have become the first line of treatment for many cancer types. Unfortunately, only a small fraction of patients benefits from these therapies. This low rate of success can be attributed to 3 main barriers: 1) low frequency of anti-tumor specific T cells; 2) lack of infiltration of the anti-tumor specific T cells into the tumor parenchyma and 3) accumulation of highly suppressive cells in the tumor mass that inhibit the effector function of the anti-tumor specific T cells. Thus, the identification of immunomodulators that can increase the frequency and/or the infiltration of antitumor specific T cells while reducing the suppressive capacity of the tumor microenvironment is necessary to ensure the effectiveness of T cell immunotherapies.
In this review, we discuss the potential of poly-ICLC as a multi-functional immune modulator for treating cancer and its impact on the 3 above mentioned barriers. We describe the unique capacity of poly-ICLC in stimulating 2 separate pattern recognition receptors, TLR3 and cytosolic MDA5 and the consequences of these activations on cytokines and chemokines production. We emphasize the role of poly-ICLC as an adjuvant in the setting of peptide-based cancer vaccines and in situ tumor vaccination by mimicking natural immune responses to infections. Finally, we summarize the impact of poly-ICLC in enhancing T infiltration into the tumor parenchyma and address the implication of this finding in the clinic.
•3D printed model using a polymeric material was an alternative to traditional waxing.•CAD/CAM milled crowns showed greater gap in the occlusal region than the press group.•CAD/CAM milled and 3D ...printed/press ceramic crowns had similar fatigue behavior.•The radial crack was the most frequent failure mode after fatigue loading.
this study aimed to evaluate the adaptation and fatigue behavior of lithium disilicate glass-ceramic (LD) monolithic crowns produced by press (combined with 3D-printing) and CAD/CAM milling (control) techniques.
thirty abutment preparations with a chamfer finish line were produced with a dentin analogue material and scanned with extraoral scanner. Captured images were processed using CAD software to design a premolar. Blocks of LD were milled using CAD/CAM system. For the press technique, crowns were first 3D-printed using a polymeric material and the heat-pressing protocol was performed. Crowns were adhesively cemented to the abutments and scanned using micro-CT. Files were processed and cross-sectional images were analysed in five measuring points: marginal, axial angle, axial, occlusal angle and occlusal. Fatigue test was performed in a MTS universal testing machine (2 Hz, 37°C distilled water) using an anatomic composite piston, following the step-stress method. Failures were detected with an acoustic system and confirmed by transillumination. A cumulative damage-Weibull distribution (95% CI) was used to analyze the fatigue data. Gap thickness data were analyzed using Kruskal-Wallis and Student-Newman-Keuls tests (α=0.05).
CAD/CAM milling resulted in larger gap thickness in the occlusal area and smaller gap thickness in the axial angle and axial area than press (p<0.05). The probability of failure was similar for crowns produced with CAD/CAM milling and press. The most frequent failure mode was radial crack.
LD crowns produced using the combination of 3D-printing/press technique showed similar fatigue behavior than CAD/CAM milled control group, and resulted in smaller gap thickness at the occlusal region.
A more controlled process can be achieved by replacing conventional restoration waxing with 3D printing, which in combination with the press technique produces lithium disilicate glass-ceramic monolithic crowns with good adaptation and high fatigue survival.
Place attachment is an affective bond that people establish with specific areas where they prefer to remain and where they feel comfortable and safe. Place identity, however, has been defined as a ...component of personal identity, a process by which, through interaction with places, people describe themselves in terms of belonging to a specific place. Most research has observed positive correlations between these variables in populations that have maintained ongoing interactions over long periods of time. This work presents two studies in which we compare place attachment to place identity in samples differentiated according to birthplace and length of residence, and the magnitude of these bonds to different places. The results of the first study revealed differences between intensity of attachment and identity depending on place of origin and place assessed. The second study found that identity and attachment tend to coincide in natives, while individuals from other places give higher scores for attachment than for identity. Results from the two studies have enabled us to consider that place attachment develops before place identity, at least in the case of the non-natives. Both studies reveal that bonds are stronger with the city than with the neighbourhood, but that attachment and identity with the island are stronger than either of them.
The concepts of active disturbance rejection control and flatness-based control are used in this paper to regulate the response of a dc-to-dc buck power converter affected by unknown, exogenous, ...time-varying load current demands. The generalized proportional integral observer is used to estimate and cancel the time-varying disturbance signals. A key element in the proposed control for the buck converter-dc motor combination is that even if the control input gain is imprecisely known, the control strategy still provides proper regulation and tracking. The robustness of this method is further extended to the case of a double buck topology driving two different dc motors affected by different load torque disturbances. Simulation results are provided.
Although advancements in CAD/CAM technology allow for more personalized treatments, it is not clear how modifications in the CAD/CAM milling process could affect the restoration surface conditions ...and their mechanical behavior. The objective of this study was to evaluate the effect of different CAD/CAM milling protocols on the topography and fracture behavior of zirconia monolithic crowns (3Y-PSZ) subjected to a chewing simulation. Monolithic 3Y-PSZ premolar crowns were milled using three protocols (n = 13) (slow (S), normal (N), and fast (F)). Crowns were cemented on a dentin analog abutment and subjected to mechanical aging (200 N, 2 Hz, 1,500,000 cycles, 37 °C water). Surviving crowns were subjected to compressive load test and analyzed using fractography. Fracture load data were analyzed with two-parameter Weibull analysis. The surface topography of the crowns was examined with a stereomicroscope and a 3D non-contact profiler. All crowns survived the chewing simulation. Crowns milled using the F protocol had the greatest characteristic fracture load, while crowns produced with the S protocol showed high Weibull modulus. Groups N and S had a more uniform surface and detailed occlusal anatomy than group F. The CAD/CAM milling protocol affected the topography and mechanical behavior of 3Y-PSZ monolithic crowns.
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