The mediating role of neuroimaging-derived biological brain age in the association between risk factors for dementia and cognitive decline in middle-aged and older individuals without cognitive impairment: a cohort study

Background: Neuroimaging-based brain-age delta has been shown to be a mediator linking cardiovascular risk factors to cognitive function. We aimed to assess the mediating role of brain-age delta in the association between modifiable risk factors of dementia and longitudinal cognitive decline in middle-aged and older individuals who are asymptomatic, stratified by Alzheimer's disease pathology. We also explored whether the mediation effect is specific to cognitive domain. Methods: In this cohort study, we included participants from the ALFA+ cohort aged between 45 years and 65 years who were cognitively unimpaired and who had available structural MRI, cerebrospinal fluid β-amyloid (Aβ)42 and Aβ40 measurements obtained within 1 year of each other, modifiable risk factors assessment, and cognitive evaluation over 3 years. Participants were recruited from the Barcelonaβeta Brain Research Center (Barcelona, Spain). Included individuals underwent a first assessment between Oct 25, 2016, and Jan 28, 2020, and a follow-up cognitive assessment 3·28 (SD 0·27) years later. We computed brain-age delta and composites of different cognitive function domains (preclinical Alzheimer's cognitive composite [PACC], attention, executive function, episodic memory, visual processing, and language). We used partial least squares path modelling to explore mediation effects in the associations between modifiable risk factors (including cardiovascular, mental health, mood, metabolic or endocrine history, and alcohol use) and changes in cognitive composites. To assess the role of Alzheimer's disease pathology, we computed separate models for Aβ-negative and Aβ-positive individuals. Findings: Of the 419 participants enrolled in ALFA+, 302 met our inclusion criteria, of which 108 participants were classified as Aβ-positive and 194 as Aβ-negative. In Aβ-positive individuals, brain-age delta partially mediated (percent mediation proportion 15·73% [95% CI 14·22-16·66]) the association between modifiable risk factors and decline in overall cognition (across cognitive domains). Brain-age delta fully mediated (mediation proportion 28·03% [26·25-29·21]) the effect of modifiable risk factors on the PACC, wherein increased values for risk factors correlated with an older brain-age delta, and, consequently, an older brain-age delta was linked to greater PACC decline. This effect appears to be primarily driven by memory decline. Mediation was not significant in Aβ-negative individuals (3·52% [0·072-4·17]) on PACC, although path coefficients were not significantly different from those in the Aβ-positive group. Interpretation: Our findings suggest that brain-age delta captures the association between modifiable risk factors and longitudinal cognitive decline in middle-aged and older people. In asymptomatic middle-aged and older individuals who are Aβ-positive, the pathology might be the strongest driver of cognitive decline, whereas the effect of risk factors is smaller. Our results highlight the potential of brain-age delta as an objective outcome measure for preventive lifestyle interventions targeting cognitive decline. Funding: La Caixa Foundation, the TriBEKa Imaging Platform, and the Universities and Research Secretariat of the Catalan Government. Translation: For the Spanish translation of the abstract see Supplementary Materials section

Ordered magnetic fields around the 3C 84 central black hole

Context. 3C 84 is a nearby radio source with a complex total intensity structure, showing linear polarisation and spectral patterns. A detailed investigation of the central engine region necessitates the use of very-long-baseline interferometry (VLBI) above the hitherto available maximum frequency of 86 GHz.Aims. Using ultrahigh resolution VLBI observations at the currently highest available frequency of 228 GHz, we aim to perform a direct detection of compact structures and understand the physical conditions in the compact region of 3C 84.Methods. We used Event Horizon Telescope (EHT) 228 GHz observations and, given the limited (u; v)-coverage, applied geometric model fitting to the data. Furthermore, we employed quasi-simultaneously observed, ancillary multi-frequency VLBI data for the source in order to carry out a comprehensive analysis of the core structure.Results. We report the detection of a highly ordered, strong magnetic field around the central, supermassive black hole of 3C 84. The brightness temperature analysis suggests that the system is in equipartition. We also determined a turnover frequency of gamma(m) = (113 +/- 4) GHz, a corresponding synchrotron self-absorbed magnetic field of B-SSA = (2.9 +/- 1.6) G, and an equipartition magnetic field of B-eq = (5.2 +/- 0.6) G. Three components are resolved with the highest fractional polarisation detected for this object (m(net) = (17.0 +/- 3.9)%). The positions of the components are compatible with those seen in low-frequency VLBI observations since 2017-2018. We report a steeply negative slope of the spectrum at 228 GHz. We used these findings to test existing models of jet formation, propagation, and Faraday rotation in 3C 84.Conclusions. The findings of our investigation into di fferent flow geometries and black hole spins support an advection-dominated accretion flow in a magnetically arrested state around a rapidly rotating supermassive black hole as a model of the jet-launching system in the core of 3C 84. However, systematic uncertainties due to the limited (u, v)-coverage, however, cannot be ignored. Our upcoming work using new EHT data, which offer full imaging capabilities, will shed more light on the compact region of 3C 84

Broadband multi-wavelength properties of M87 during the 2018 EHT campaign including a very high energy flaring episode

Context. The nearby elliptical galaxy M87 contains one of only two supermassive black holes whose emission surrounding the event horizon has been imaged by the Event Horizon Telescope (EHT). In 2018, more than two dozen multi-wavelength (MWL) facilities (from radio to γ-ray energies) took part in the second M87 EHT campaign. Aims. The goal of this extensive MWL campaign was to better understand the physics of the accreting black hole M87*, the relationship between the inflow and inner jets, and the high-energy particle acceleration. Understanding the complex astrophysics is also a necessary first step towards performing further tests of general relativity. Methods. The MWL campaign took place in April 2018, overlapping with the EHT M87* observations. We present a new, contemporaneous spectral energy distribution (SED) ranging from radio to very high-energy (VHE) γ-rays as well as details of the individual observations and light curves. We also conducted phenomenological modelling to investigate the basic source properties. Results. We present the first VHE γ-ray flare from M87 detected since 2010. The flux above 350 GeV more than doubled within a period of ≈36 hours. We find that the X-ray flux is enhanced by about a factor of two compared to 2017, while the radio and millimetre core fluxes are consistent between 2017 and 2018. We detect evidence for a monotonically increasing jet position angle that corresponds to variations in the bright spot of the EHT image. Conclusions. Our results show the value of continued MWL monitoring together with precision imaging for addressing the origins of high-energy particle acceleration. While we cannot currently pinpoint the precise location where such acceleration takes place, the new VHE γ-ray flare already presents a challenge to simple one-zone leptonic emission model approaches, and it emphasises the need for combined image and spectral modelling

Effects of pre-operative isolation on postoperative pulmonary complications after elective surgery: an international prospective cohort study

We aimed to determine the impact of pre-operative isolation on postoperative pulmonary complications after elective surgery during the global SARS-CoV-2 pandemic. We performed an international prospective cohort study including patients undergoing elective surgery in October 2020. Isolation was defined as the period before surgery during which patients did not leave their house or receive visitors from outside their household. The primary outcome was postoperative pulmonary complications, adjusted in multivariable models for measured confounders. Pre-defined sub-group analyses were performed for the primary outcome. A total of 96,454 patients from 114 countries were included and overall, 26,948 (27.9%) patients isolated before surgery. Postoperative pulmonary complications were recorded in 1947 (2.0%) patients of which 227 (11.7%) were associated with SARS-CoV-2 infection. Patients who isolated pre-operatively were older, had more respiratory comorbidities and were more commonly from areas of high SARS-CoV-2 incidence and high-income countries. Although the overall rates of postoperative pulmonary complications were similar in those that isolated and those that did not (2.1% vs 2.0%, respectively), isolation was associated with higher rates of postoperative pulmonary complications after adjustment (adjusted OR 1.20, 95%CI 1.05-1.36, p = 0.005). Sensitivity analyses revealed no further differences when patients were categorised by: pre-operative testing; use of COVID-19-free pathways; or community SARS-CoV-2 prevalence. The rate of postoperative pulmonary complications increased with periods of isolation longer than 3 days, with an OR (95%CI) at 4-7 days or ≥ 8 days of 1.25 (1.04-1.48), p = 0.015 and 1.31 (1.11-1.55), p = 0.001, respectively. Isolation before elective surgery might be associated with a small but clinically important increased risk of postoperative pulmonary complications. Longer periods of isolation showed no reduction in the risk of postoperative pulmonary complications. These findings have significant implications for global provision of elective surgical care

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Individual and combined effects of chemical and mechanical power on postoperative pulmonary complications: a secondary analysis of the REPEAT study

Introduction: Intra-operative supplemental oxygen and mechanical ventilation expose the lungs to potentially injurious energy. This can be quantified as 'chemical power' and 'mechanical power', respectively. In this study, we sought to determine if intra-operative chemical and mechanical power, individually and/or in combination, are associated with postoperative pulmonary complications. Methods: Using an individual patient data analysis of three randomised clinical trials of intra-operative ventilation, we summarised intra-operative chemical and mechanical power using time-weighted averages. We evaluated the association between intra-operative chemical and mechanical power and a collapsed composite of postoperative pulmonary complications using multivariable logistic regression to estimate the odds ratios related to the effect of 1 J.min-1 increase in chemical or mechanical power with adjustment for demographic and intra-operative characteristics. We also included an interaction term to assess for potential synergistic effects of chemical and mechanical power on postoperative pulmonary complications. Results: Of 3837 patients recruited to three individual trials, 2492 with full datasets were included in the analysis. Intra-operative time-weighted average (SD) chemical power was 10.2 (3.9) J.min-1 and mechanical power was 10.5 (4.4) J.min-1. An increase of 1 J.min-1 in chemical power was associated with 8% higher odds of postoperative pulmonary complications (OR 1.08, 95%CI 1.05-1.10, p < 0.001), while the same increase in mechanical power raised odds by 5% (OR 1.05, 95%CI 1.02-1.08, p = 0.003). We did not find evidence of a significant interaction between chemical and mechanical power (p = 0.40), suggestive of an additive rather than synergistic effect on postoperative pulmonary complications. Discussion: Both chemical and mechanical power are independently associated with postoperative pulmonary complications. Further work is required to determine causality

First Sagittarius A* Event Horizon Telescope Results. VIII. Physical Interpretation of the Polarized Ring

In a companion paper, we present the first spatially resolved polarized image of Sagittarius A* on event horizon scales, captured using the Event Horizon Telescope, a global very long baseline interferometric array operating at a wavelength of 1.3 mm. Here we interpret this image using both simple analytic models and numerical general relativistic magnetohydrodynamic (GRMHD) simulations. The large spatially resolved linear polarization fraction (24%–28%, peaking at ∼40%) is the most stringent constraint on parameter space, disfavoring models that are too Faraday depolarized. Similar to our studies of M87*, polarimetric constraints reinforce a preference for GRMHD models with dynamically important magnetic fields. Although the spiral morphology of the polarization pattern is known to constrain the spin and inclination angle, the time-variable rotation measure (RM) of Sgr A* (equivalent to ≈46° ± 12° rotation at 228 GHz) limits its present utility as a constraint. If we attribute the RM to internal Faraday rotation, then the motion of accreting material is inferred to be counterclockwise, contrary to inferences based on historical polarized flares, and no model satisfies all polarimetric and total intensity constraints. On the other hand, if we attribute the mean RM to an external Faraday screen, then the motion of accreting material is inferred to be clockwise, and one model passes all applied total intensity and polarimetric constraints: a model with strong magnetic fields, a spin parameter of 0.94, and an inclination of 150°. We discuss how future 345 GHz and dynamical imaging will mitigate our present uncertainties and provide additional constraints on the black hole and its accretion flow

The persistent shadow of the supermassive black hole of M 87

In April 2019, the Event Horizon Telescope (EHT) Collaboration reported the first-ever event-horizon-scale images of a black hole, resolving the central compact radio source in the giant elliptical galaxy M 87. These images reveal a ring with a southerly brightness distribution and a diameter of ∼42 μas, consistent with the predicted size and shape of a shadow produced by the gravitationally lensed emission around a supermassive black hole. These results were obtained as part of the April 2017 EHT observation campaign, using a global very long baseline interferometric radio array operating at a wavelength of 1.3 mm. Here, we present results based on the second EHT observing campaign, taking place in April 2018 with an improved array, wider frequency coverage, and increased bandwidth. In particular, the additional baselines provided by the Greenland telescope improved the coverage of the array. Multiyear EHT observations provide independent snapshots of the horizon-scale emission, allowing us to confirm the persistence, size, and shape of the black hole shadow, and constrain the intrinsic structural variability of the accretion flow. We have confirmed the presence of an asymmetric ring structure, brighter in the southwest, with a median diameter of 43.3−3.1+1.5 μas. The diameter of the 2018 ring is remarkably consistent with the diameter obtained from the previous 2017 observations. On the other hand, the position angle of the brightness asymmetry in 2018 is shifted by about 30° relative to 2017. The perennial persistence of the ring and its diameter robustly support the interpretation that the ring is formed by lensed emission surrounding a Kerr black hole with a mass ∼6.5 × 109 M⊙. The significant change in the ring brightness asymmetry implies a spin axis that is more consistent with the position angle of the large-scale jet

The Dynamical State of the Didymos System before and after the DART Impact

NASA's Double Asteroid Redirection Test (DART) spacecraft impacted Dimorphos, the natural satellite of (65803) Didymos, on 2022 September 26, as a first successful test of kinetic impactor technology for deflecting a potentially hazardous object in space. The experiment resulted in a small change to the dynamical state of the Didymos system consistent with expectations and Level 1 mission requirements. In the preencounter paper, predictions were put forward regarding the pre- and postimpact dynamical state of the Didymos system. Here we assess these predictions, update preliminary findings published after the impact, report on new findings related to dynamics, and provide implications for ESA's Hera mission to Didymos, scheduled for launch in 2024 October with arrival in 2026 December. Preencounter predictions tested to date are largely in line with observations, despite the unexpected, flattened appearance of Didymos compared to the radar model and the apparent preimpact oblate shape of Dimorphos (with implications for the origin of the system that remain under investigation). New findings include that Dimorphos likely became prolate due to the impact and may have entered a tumbling rotation state. A possible detection of a postimpact transient secular decrease in the binary orbital period suggests possible dynamical coupling with persistent ejecta. Timescales for damping of any tumbling and clearing of any debris are uncertain. The largest uncertainty in the momentum transfer enhancement factor of the DART impact remains the mass of Dimorphos, which will be resolved by the Hera mission