To help adapt cardiovascular disease risk prediction approaches to low-income and middle-income countries, WHO has convened an effort to develop, evaluate, and illustrate revised risk models. Here, ...we report the derivation, validation, and illustration of the revised WHO cardiovascular disease risk prediction charts that have been adapted to the circumstances of 21 global regions.
In this model revision initiative, we derived 10-year risk prediction models for fatal and non-fatal cardiovascular disease (ie, myocardial infarction and stroke) using individual participant data from the Emerging Risk Factors Collaboration. Models included information on age, smoking status, systolic blood pressure, history of diabetes, and total cholesterol. For derivation, we included participants aged 40–80 years without a known baseline history of cardiovascular disease, who were followed up until the first myocardial infarction, fatal coronary heart disease, or stroke event. We recalibrated models using age-specific and sex-specific incidences and risk factor values available from 21 global regions. For external validation, we analysed individual participant data from studies distinct from those used in model derivation. We illustrated models by analysing data on a further 123 743 individuals from surveys in 79 countries collected with the WHO STEPwise Approach to Surveillance.
Our risk model derivation involved 376 177 individuals from 85 cohorts, and 19 333 incident cardiovascular events recorded during 10 years of follow-up. The derived risk prediction models discriminated well in external validation cohorts (19 cohorts, 1 096 061 individuals, 25 950 cardiovascular disease events), with Harrell's C indices ranging from 0·685 (95% CI 0·629–0·741) to 0·833 (0·783–0·882). For a given risk factor profile, we found substantial variation across global regions in the estimated 10-year predicted risk. For example, estimated cardiovascular disease risk for a 60-year-old male smoker without diabetes and with systolic blood pressure of 140 mm Hg and total cholesterol of 5 mmol/L ranged from 11% in Andean Latin America to 30% in central Asia. When applied to data from 79 countries (mostly low-income and middle-income countries), the proportion of individuals aged 40–64 years estimated to be at greater than 20% risk ranged from less than 1% in Uganda to more than 16% in Egypt.
We have derived, calibrated, and validated new WHO risk prediction models to estimate cardiovascular disease risk in 21 Global Burden of Disease regions. The widespread use of these models could enhance the accuracy, practicability, and sustainability of efforts to reduce the burden of cardiovascular disease worldwide.
World Health Organization, British Heart Foundation (BHF), BHF Cambridge Centre for Research Excellence, UK Medical Research Council, and National Institute for Health Research.
Prostate cancer is initially androgen-dependent but, over time, usually develops hormone- and chemo-resistance. The present study investigated a role for p21-activated kinase 4 (PAK4) in prostate ...cancer progression. PAK4 activation was markedly inhibited by H89, a specific protein kinase A (PKA) inhibitor, and PAK4 was activated by the elevation of cAMP. The catalytic subunit of PKA interacted with the regulatory domain of PAK4, and directly phosphorylated PAK4 at serine 474 (S474). Catalytically active PAK4 enhanced the transcriptional activity of CREB independent of S133 phosphorylation. Stable knockdown of PAK4 in PC-3 and DU145 prostate cancer cells inhibited tumor formation in nude mice. Decreased tumorigenicity correlated with decreased expression of CREB and its targets, including Bcl-2 and cyclin A1. Additionally, in androgen-dependent LNCap-FGC cells, PAK4 regulated cAMP-induced neuroendocrine differentiation, which is known to promote tumor progression. Finally, PAK4 enhanced survival and decreased apoptosis following chemotherapy. These results suggested that PAK4 regulates progression toward hormone- and chemo-resistance in prostate cancer, and this study identified both a novel activation mechanism and potential downstream effector pathways. Therefore, PAK4 may be a promising therapeutic target in prostate cancer.
In this study, we reviewed the magnetic resonance (MR, n=5), computed tomography (CT, n=3), and angiography (n=3) of six patients with pathologically confirmed choroid plexus papilloma (CPP) in the ...posterior cranial fossa. CPPs in the posterior cranial fossa have several features, including a propensity to arise at the foramen of Luschka with extraventricular extension, occasional peritumoral signal voids/cysts or calcification, weaker enhancement on MR or CT, and less strong tumor staining by the anterior or posterior inferior cerebellar artery or angiography.
An on-line and real-time impedimetric system was developed to monitor and quantify cell attachment on interdigitated microelectrodes. Changes in admittance at frequency lower than 10kHz were ...positively correlated with the extent of cell attachment (10(2) to 10(7)cells/cm(2)). As judged from the admittance change, the onset and the extent of cell attachment were facilitated when the electrodes were modified with RGD-C peptide, an artificial peptide with a high affinity toward cellulose surface. The system is useful in estimating seeding cell density and characterizing bio-compatible materials with suitable cell affinity.
Experiments have revealed much about top‐down and bottom‐up control in ecosystems, but manipulative experiments are limited in spatial and temporal scale. To obtain a more nuanced understanding of ...trophic control over large scales, we explored long‐term time‐series data from 13 globally distributed lakes and used empirical dynamic modelling to quantify interaction strengths between zooplankton and phytoplankton over time within and across lakes. Across all lakes, top‐down effects were associated with nutrients, switching from negative in mesotrophic lakes to positive in oligotrophic lakes. This result suggests that zooplankton nutrient recycling exceeds grazing pressure in nutrient‐limited systems. Within individual lakes, results were consistent with a ‘seasonal reset’ hypothesis in which top‐down and bottom‐up interactions varied seasonally and were both strongest at the beginning of the growing season. Thus, trophic control is not static, but varies with abiotic conditions – dynamics that only become evident when observing changes over large spatial and temporal scales.
We estimated time‐varying trophic interaction strength between zooplankton and phytoplankton in 13 globally‐distributed lakes over decadal timescales using empirical dynamic modelling. Trophic interactions were not static, but varied seasonally (within lakes) and with abiotic conditions (across lakes) ‐ nonlinear dynamics which are only evident when pairing long‐term observational data with cutting edge modelling techniques.
We tested the influence of blood pressure variability on the reproducibility of dynamic cerebral autoregulation (DCA) estimates. Data were analyzed from the 2nd CARNet bootstrap initiative, where ...mean arterial blood pressure (MABP), cerebral blood flow velocity (CBFV) and end tidal CO2 were measured twice in 75 healthy subjects. DCA was analyzed by 14 different centers with a variety of different analysis methods. Intraclass Correlation (ICC) values increased significantly when subjects with low power spectral density MABP (PSD-MABP) values were removed from the analysis for all gain, phase and autoregulation index (ARI) parameters. Gain in the low frequency band (LF) had the highest ICC, followed by phase LF and gain in the very low frequency band. No significant differences were found between analysis methods for gain parameters, but for phase and ARI parameters, significant differences between the analysis methods were found. Alternatively, the Spearman-Brown prediction formula indicated that prolongation of the measurement duration up to 35 minutes may be needed to achieve good reproducibility for some DCA parameters. We conclude that poor DCA reproducibility (ICC<0.4) can improve to good (ICC > 0.6) values when cases with low PSD-MABP are removed, and probably also when measurement duration is increased.
The JSNS\(^{2}\) (J-PARC Sterile Neutrino Search at J-PARC Spallation Neutron Source) experiment aims to search for neutrino oscillations over a 24 m short baseline at J-PARC. The JSNS\(^{2}\) inner ...detector is filled with 17 tons of gadolinium(Gd)-loaded liquid scintillator (LS) with an additional 31 tons of unloaded LS in the intermediate \(\gamma\)-catcher and an optically separated outer veto volumes. A total of 120 10-inch photomultiplier tubes observe the scintillating optical photons and each analog waveform is stored with the flash analog-to-digital converters. We present details of the data acquisition, processing, and data quality monitoring system. We also present two different trigger logics which are developed for the beam and self-trigger.
Magnetospheric compression due to impact of enhanced solar wind dynamic pressure Pdyn has long been considered as one of the generation mechanisms of electromagnetic ion cyclotron (EMIC) waves. With ...the Van Allen Probe‐A observations, we identify three EMIC wave events that are triggered by Pdyn enhancements under prolonged northward interplanetary magnetic field (IMF) quiet time preconditions. They are in contrast to one another in a few aspects. Event 1 occurs in the middle of continuously increasing Pdyn while Van Allen Probe‐A is located outside the plasmapause at postmidnight and near the equator (magnetic latitude (MLAT) ~ −3°). Event 2 occurs by a sharp Pdyn pulse impact while Van Allen Probe‐A is located inside the plasmapause in the dawn sector and rather away from the equator (MLAT ~ 12°). Event 3 is characterized by amplification of a preexisting EMIC wave by a sharp Pdyn pulse impact while Van Allen Probe‐A is located outside the plasmapause at noon and rather away from the equator (MLAT ~ −15°). These three events represent various situations where EMIC waves can be triggered by Pdyn increases. Several common features are also found among the three events. (i) The strongest wave is found just above the He+ gyrofrequency. (ii) The waves are nearly linearly polarized with a rather oblique propagation direction (~28° to ~39° on average). (iii) The proton fluxes increase in immediate response to the Pdyn impact, most significantly in tens of keV energy, corresponding to the proton resonant energy. (iv) The temperature anisotropy with T⊥ > T|| is seen in the resonant energy for all the events, although its increase by the Pdyn impact is not necessarily always significant. The last two points (iii) and (iv) may imply that in addition to the temperature anisotropy, the increase of the resonant protons must have played a critical role in triggering the EMIC waves by the enhanced Pdyn impact.
Key Points
Three EMIC wave events triggered by various dynamic pressure conditions
Exhibit proton flux increases in expected resonant energy
Exhibit temperature anisotropy with T⊥ > T|| in the resonant energy
Er:YAG laser has been studied as a potential tool for restorative dentistry due to its ability to selectively remove oral hard tissue with minimal or no thermal damage to the surrounding tissues. The ...purpose of this study was to evaluate in vitro the tensile bond strength (TBS) of an adhesive/composite resin system to human enamel surfaces treated with 37% phosphoric acid, Er:YAG laser (lambda=2.94 mum) with a total energy of 16 J (80 mJ/pulse, 2Hz, 200 pulses, 250 ms pulse width), and Er:YAG laser followed by phosphoric acid etching. Analysis of the treated surfaces was performed by scanning electron microscopy (SEM) to assess morphological differences among the groups. TBS means (in MPa) were as follows: Er:YAG laser + acid (11.7 MPa) > acid (8.2 MPa) > Er:YAG laser (6.1 MPa), with the group treated with laser+acid being significantly from the other groups (p=0.0006 and p= 0.00019, respectively). The groups treated with acid alone and laser alone were significantly different from each other (p=0.0003). The SEM analysis revealed morphological changes that corroborate the TBS results, suggesting that the differences in TBS means among the groups are related to the different etching patterns produced by each type of surface treatment. The findings of this study indicate that the association between Er:YAG laser and phosphoric acid can be used as a valuable resource to increase bond strength to laser-prepared enamel.
A tecnologia a laser tem sido estudada como uma ferramenta potencial para uso em odontologia devido à sua habilidade em remover tecido ósseo com um mínimo ou nenhum dano aos tecidos vizinhos. O objetivo deste estudo é comparar in vitro a resistência à tração do sistema adesivo em esmalte tratado com ácido fosfórico a 37 %, laser Er:YAG (lambda=2,94 mim) com energia total de 16 J (80 mJ/pulso, 2 Hz, 200 pulsos e largura de pulso de 250 ms) e com a combinação laser Er:YAG seguido por ácido fosfórico. O teste de resistência à tração foi usado para comparar a resistência à tração em cada grupo. Foi também realizada microscopia eletrônica de varredura para permitir a análise das diferenças morfológicas entre os grupos. Foram obtidos os seguintes valores médios de resistência para os grupos tratados com: laser (6,1 MPa), ácido fosfórico (8,2 MPa) e laser mais ácido (11,7 Mpa). Amostras tratadas com laser e ácido apresentaram valores maiores de resistência do que amostras com laser ou ácido isoladamente. A análise da microscopia eletrônica revelou diferenças que corroboram os resultados, demonstrando que diferenças de resistência entre os grupos são devidas às diferenças entre os padrões superficiais resultantes. Nossos resultados sugerem que a combinação do laser Er:YAG com ácido fosfórico pode ser usada como um método para aumentar a resistência à tração do sistema esmalte resina.
The absence of effective therapeutics against Alzheimer's disease (AD) is a result of the limited understanding of its multifaceted aetiology. Because of the lack of chemical tools to identify ...pathological factors, investigations into AD pathogenesis have also been insubstantial. Here we report chemical regulators that demonstrate distinct specificity towards targets linked to AD pathology, including metals, amyloid-β (Aβ), metal-Aβ, reactive oxygen species, and free organic radicals. We obtained these chemical regulators through a rational structure-mechanism-based design strategy. We performed structural variations of small molecules for fine-tuning their electronic properties, such as ionization potentials and mechanistic pathways for reactivity towards different targets. We established in vitro and/or in vivo efficacies of the regulators for modulating their targets' reactivities, ameliorating toxicity, reducing amyloid pathology, and improving cognitive deficits. Our chemical tools show promise for deciphering AD pathogenesis and discovering effective drugs.
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