Background and purpose
Previous studies suggested that the overall burden of prior infections contributes to cardiovascular diseases and stroke. In the present study, the association between ...infectious burden (IB) and Alzheimer's disease (AD) was examined.
Methods
Antibody titers to common infectious pathogens including cytomegalovirus (CMV), herpes simplex virus type 1 (HSV‐1), Borrelia burgdorferi, Chlamydophila pneumoniae and Helicobacter pylori were measured by enzyme‐linked immunosorbent assay in 128 AD patients and 135 healthy controls. IB was defined as a composite serological measure of exposure to these common pathogens.
Results
Seropositivities toward zero−two, three and four−five of these pathogens were found in 44%, 40% and 16% of healthy controls but in 20%, 44% and 36% of AD patients, respectively. IB, bacterial burden and viral burden were independently associated with AD after adjusting for age, gender, education, APOE genotype and various comorbidities. Mini‐Mental State Examination scores were negatively correlated with IB in all cases. Serum beta‐amyloid protein (Aβ) levels (i.e. Aβ40, Aβ42 and total Aβ) and inflammatory cytokines (i.e. interferon‐γ, tumor necrosis factor α, interleukin‐1β and interleukin‐6) in individuals exposed to four−five infectious pathogens were significantly higher than those exposed to zero−two or three pathogens.
Conclusions
IB consisting of CMV, HSV‐1, B. burgdorferi, C. pneumoniae and H. pylori is associated with AD. This study supports the role of infection/inflammation in the etiopathogenesis of AD.
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The extension of the cosmic-ray spectrum beyond 1 petaelectronvolt (PeV; 10
electronvolts) indicates the existence of the so-called PeVatrons-cosmic-ray factories that accelerate particles to PeV ...energies. We need to locate and identify such objects to find the origin of Galactic cosmic rays
. The principal signature of both electron and proton PeVatrons is ultrahigh-energy (exceeding 100 TeV) γ radiation. Evidence of the presence of a proton PeVatron has been found in the Galactic Centre, according to the detection of a hard-spectrum radiation extending to 0.04 PeV (ref.
). Although γ-rays with energies slightly higher than 0.1 PeV have been reported from a few objects in the Galactic plane
, unbiased identification and in-depth exploration of PeVatrons requires detection of γ-rays with energies well above 0.1 PeV. Here we report the detection of more than 530 photons at energies above 100 teraelectronvolts and up to 1.4 PeV from 12 ultrahigh-energy γ-ray sources with a statistical significance greater than seven standard deviations. Despite having several potential counterparts in their proximity, including pulsar wind nebulae, supernova remnants and star-forming regions, the PeVatrons responsible for the ultrahigh-energy γ-rays have not yet been firmly localized and identified (except for the Crab Nebula), leaving open the origin of these extreme accelerators.
High-energy photons from the Crab Nebula
The Crab Nebula contains a pulsar that excites the surrounding gas to emit high-energy radiation. The combination of the pulsar's youth and nearby location ...makes the nebula the brightest gamma-ray source in the sky. The LHAASO Collaboration report observations of this source at energies of tera– to peta–electron volts, extending the spectrum of this prototypical object. They combine these data with observations at lower energies to model the physics of the emission process. The multiwave-length data can be explained by a combination of synchrotron radiation and inverse Compton scattering.
Science
, abg5137, this issue p.
425
Detection of the Crab Nebula at peta–electron volt energies constrains the gamma-ray emission mechanism.
The Crab Nebula is a bright source of gamma rays powered by the Crab Pulsar’s rotational energy through the formation and termination of a relativistic electron-positron wind. We report the detection of gamma rays from this source with energies from 5 × 10
−4
to 1.1 peta–electron volts with a spectrum showing gradual steepening over three energy decades. The ultrahigh-energy photons imply the presence of a peta–electron volt electron accelerator (a pevatron) in the nebula, with an acceleration rate exceeding 15% of the theoretical limit. We constrain the pevatron’s size between 0.025 and 0.1 parsecs and the magnetic field to ≈110 microgauss. The production rate of peta–electron volt electrons, 2.5 × 10
36
ergs per second, constitutes 0.5% of the pulsar spin-down luminosity, although we cannot exclude a contribution of peta–electron volt protons to the production of the highest-energy gamma rays.
Large-scale, highly integrated and low-power-consuming hardware is becoming progressively more important for realizing optical neural networks (ONNs) capable of advanced optical computing. ...Traditional experimental implementations need N
units such as Mach-Zehnder interferometers (MZIs) for an input dimension N to realize typical computing operations (convolutions and matrix multiplication), resulting in limited scalability and consuming excessive power. Here, we propose the integrated diffractive optical network for implementing parallel Fourier transforms, convolution operations and application-specific optical computing using two ultracompact diffractive cells (Fourier transform operation) and only N MZIs. The footprint and energy consumption scales linearly with the input data dimension, instead of the quadratic scaling in the traditional ONN framework. A ~10-fold reduction in both footprint and energy consumption, as well as equal high accuracy with previous MZI-based ONNs was experimentally achieved for computations performed on the MNIST and Fashion-MNIST datasets. The integrated diffractive optical network (IDNN) chip demonstrates a promising avenue towards scalable and low-power-consumption optical computational chips for optical-artificial-intelligence.
Reduced expression of brain-derived neurotrophic factor (BDNF) has a crucial role in the pathogenesis of Alzheimer's disease (AD), which is characterized with the formation of neuritic plaques ...consisting of amyloid-beta (Aβ) and neurofibrillary tangles composed of hyperphosphorylated tau protein. A growing body of evidence indicates a potential protective effect of BDNF against Aβ-induced neurotoxicity in AD mouse models. However, the direct therapeutic effect of BDNF supplement on tauopathy in AD remains to be established. Here, we found that the BDNF level was reduced in the serum and brain of AD patients and P301L transgenic mice (a mouse model of tauopathy). Intralateral ventricle injection of adeno-associated virus carrying the gene encoding human BDNF (AAV-BDNF) achieved stable expression of BDNF gene and restored the BDNF level in the brains of P301L mice. Restoration of the BDNF level attenuated behavioral deficits, prevented neuron loss, alleviated synaptic degeneration and reduced neuronal abnormality, but did not affect tau hyperphosphorylation level in the brains of P301L mice. Long-term expression of AAV-BDNF in the brain was well tolerated by the mice. These findings suggest that the gene delivery of BDNF is a promising treatment for tau-related neurodegeneration for AD and other neurodegenerative disorders with tauopathy.
Essentials
Perioperative blood loss and inflammatory response can significantly affect recovery after surgery.
We studied the effects of multiple‐dose oral tranexamic acid on blood loss and ...inflammatory response.
A postoperative four‐dose regimen brought about maximum reduction in postoperative blood loss.
A postoperative four‐dose regimen reduced inflammatory response and promoted early rehabilitation.
Summary
Background
Tranexamic acid (TXA) can reduce blood loss and the inflammatory response at multiple doses in total knee arthroplasty patients. However, the optimal regimen has not been determined.
Objectives
To identify the most effective regimen for achieving maximum reductions in blood loss and the inflammatory response.
Patients/Methods
Two hundred and seventy‐five patients were randomized to receive a placebo (group A), a single 2‐g oral dose of TXA 2 h preoperatively followed by 1 g of oral TXA 3 h postoperatively (group B), a single dose followed by 1 g of oral TXA 3 h and 7 h postoperatively (group C), a single dose followed by 1 g of oral TXA 3 h, 7 h and 11 h postoperatively (group D), or a single dose followed by 1 g of oral TXA 3 h, 7 h, 11 h and 15 h postoperatively (group E). The primary outcome was total blood loss on postoperative day (POD) 3. Secondary outcomes included a decrease in the hemoglobin level, coagulation parameters, inflammatory marker levels, and thromboembolic complications.
Results
Groups D and E had significantly lower blood loss and smaller decreases in hemoglobin level than groups A, B, and C, with no significant difference on POD 3 between groups D and E. Significantly enhanced coagulation was identified for the four multiple‐dose regimens; however, all thromboelastographic parameters remained within normal ranges. Group E had the lowest inflammatory marker levels and pain, and the greatest range of motion. No thromboembolic complications were identified.
Conclusion
The four‐dose regimen yielded the maximum reductions in blood loss and inflammatory response, improved analgesia, and promoted early rehabilitation. Further studies are required to ensure that these findings are reproducible.
The amyloid-β protein (Aβ) protein plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). It is believed that Aβ deposited in the brain originates from the brain tissue itself. ...However, Aβ is generated in both brain and peripheral tissues. Whether circulating Aβ contributes to brain AD-type pathologies remains largely unknown. In this study, using a model of parabiosis between APPswe/PS1dE9 transgenic AD mice and their wild-type littermates, we observed that the human Aβ originated from transgenic AD model mice entered the circulation and accumulated in the brains of wild-type mice, and formed cerebral amyloid angiopathy and Aβ plaques after a 12-month period of parabiosis. AD-type pathologies related to the Aβ accumulation including tau hyperphosphorylation, neurodegeneration, neuroinflammation and microhemorrhage were found in the brains of the parabiotic wild-type mice. More importantly, hippocampal CA1 long-term potentiation was markedly impaired in parabiotic wild-type mice. To the best of our knowledge, our study is the first to reveal that blood-derived Aβ can enter the brain, form the Aβ-related pathologies and induce functional deficits of neurons. Our study provides novel insight into AD pathogenesis and provides evidence that supports the development of therapies for AD by targeting Aβ metabolism in both the brain and the periphery.
Background
The aim of this study was to evaluate whether adjuvant chemotherapy is associated with improved survival in patients with resectable gastric neuroendocrine carcinomas (G‐NECs) or mixed ...adenoneuroendocrine carcinomas (G‐MANECs).
Methods
The study included patients with G‐NECs or G‐MANECs who underwent surgery in one of 21 centres in China between 2004 and 2016. Propensity score matching analysis was used to reduce selection bias, and overall survival (OS) in different treatment groups was estimated by the Kaplan–Meier method.
Results
In total, 804 patients with resectable G‐NECs or G‐MANECs were included, of whom 490 (60·9 per cent) received adjuvant chemotherapy. After propensity score matching, OS in the chemotherapy group was similar to that in the no‐chemotherapy group. Among patients with G‐NECs, survival in the fluorouracil (5‐FU)‐based chemotherapy group and the non‐5‐FU‐based chemotherapy group was similar to that in the no‐chemotherapy group. Similarly, etoposide plus cisplatin or irinotecan plus cisplatin was not associated with better OS in patients with G‐NECs. Among patients with G‐MANECs, OS in the non‐5‐FU‐based chemotherapy group was worse than that in the no‐chemotherapy group. Patients with G‐MANECs did not have better OS when platinum‐based chemotherapy was
used.
Conclusion
There was no survival benefit in patients who received adjuvant chemotherapy for G‐NECs or G‐MANECs.
Antecedentes
El objetivo de este estudio fue evaluar si la quimioterapia adyuvante mejoraba la supervivencia en pacientes con carcinomas gástricos resecables neuroendocrinos (gastric neuroendocrine carcinomas, G‐NECs) y carcinomas adenoneuroendocrinos mixtos (mixed adenoneuroendocrine carcinomas, G‐MANECs).
Métodos
Se incluyeron pacientes con G‐NECs y G‐MANECs tratados quirúrgicamente en 21 centros en China entre 2004 y 2016. Se utilizó un análisis de emparejamiento por puntaje de propensión para reducir el sesgo de selección y el método de Kaplan‐Meier para estimar la supervivencia global (overall survival, OS) de los pacientes en los diferentes grupos de tratamiento.
Resultados
En total, se incluyeron en el estudio 804 pacientes con G‐NECs y G‐MANECs resecables y 490 pacientes (60,9%) recibieron quimioterapia adyuvante. Después del emparejamiento por puntaje de propensión, la OS del grupo con quimioterapia fue similar a la del grupo sin quimioterapia. En los pacientes con G‐NECs, la supervivencia en los grupos con quimioterapia basada en 5‐FU (fluorouracilo) y de quimioterapia sin 5‐FU fue similar a la del grupo sin quimioterapia. Asimismo, la combinación de etopósido y cisplatino o de irinotecán y cisplatino no se asoció con una mejor OS en pacientes con G‐NECs. En pacientes con G‐MANECs, la OS del grupo con quimioterapia sin 5‐FU fue peor que la del grupo sin quimioterapia. Los pacientes con G‐MANECs no presentaron una mejor OS cuando se administró quimioterapia basada en platinos.
Conclusión
La administración de quimioterapia adyuvante en pacientes con G‐NECs y G‐MANECs no mejoró la supervivencia.
This multicentre study enrolled 804 patients with resectable gastric neuroendocrine carcinomas and gastric mixed adenoneuroendocrine carcinomas. In propensity score matching analysis, there were no associations between the use of adjuvant chemotherapy and improved overall survival. Similar results were obtained in stratified analysis according to different chemotherapy regimens.
No benefit
We report a study of the processes of e^{+}e^{-}→K^{+}D_{s}^{-}D^{*0} and K^{+}D_{s}^{*-}D^{0} based on e^{+}e^{-} annihilation samples collected with the BESIII detector operating at BEPCII at five ...center-of-mass energies ranging from 4.628 to 4.698 GeV with a total integrated luminosity of 3.7 fb^{-1}. An excess of events over the known contributions of the conventional charmed mesons is observed near the D_{s}^{-}D^{*0} and D_{s}^{*-}D^{0} mass thresholds in the K^{+} recoil-mass spectrum for events collected at sqrts=4.681 GeV. The structure matches a mass-dependent-width Breit-Wigner line shape, whose pole mass and width are determined as (3982.5_{-2.6}^{+1.8}±2.1) MeV/c^{2} and (12.8_{-4.4}^{+5.3}±3.0) MeV, respectively. The first uncertainties are statistical and the second are systematic. The significance of the resonance hypothesis is estimated to be 5.3 σ over the contributions only from the conventional charmed mesons. This is the first candidate for a charged hidden-charm tetraquark with strangeness, decaying into D_{s}^{-}D^{*0} and D_{s}^{*-}D^{0}. However, the properties of the excess need further exploration with more statistics.
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