Brain age predicts mortality

Age-associated disease and disability are placing a growing burden on society. However, ageing does not affect people uniformly. Hence, markers of the underlying biological ageing process are needed to help identify people at increased risk of age-associated physical and cognitive impairments and ultimately, death. Here, we present such a biomarker, ‘brain-predicted age’, derived using structural neuroimaging. Brain-predicted age was calculated using machine-learning analysis, trained on neuroimaging data from a large healthy reference sample (N = 2001), then tested in the Lothian Birth Cohort 1936 (N = 669), to determine relationships with age-associated functional measures and mortality. Having a brain-predicted age indicative of an older-appearing brain was associated with: weaker grip strength, poorer lung function, slower walking speed, lower fluid intelligence, higher allostatic load and increased mortality risk. Furthermore, while combining brain-predicted age with grey matter and cerebrospinal fluid volumes (themselves strong predictors) not did improve mortality risk prediction, the combination of brain-predicted age and DNA-methylation-predicted age did. This indicates that neuroimaging and epigenetics measures of ageing can provide complementary data regarding health outcomes. Our study introduces a clinically-relevant neuroimaging ageing biomarker and demonstrates that combining distinct measurements of biological ageing further helps to determine risk of age-related deterioration and death

Primary Human mDC1, mDC2, and pDC Dendritic Cells Are Differentially Infected and Activated by Respiratory Syncytial Virus

Respiratory syncytial virus (RSV) causes recurrent infections throughout life. Vaccine development may depend upon understanding the molecular basis for induction of ineffective immunity. Because dendritic cells (DCs) are critically involved in early responses to infection, their interaction with RSV may determine the immunological outcome of RSV infection. Therefore, we investigated the ability of RSV to infect and activate primary mDCs and pDCs using recombinant RSV expressing green fluorescent protein (GFP). At a multiplicity of infection of 5, initial studies demonstrated ∼6.8% of mDC1 and ∼0.9% pDCs were infected. We extended these studies to include CD1c−CD141+ mDC2, finding mDC2 infected at similar frequencies as mDC1. Both infected and uninfected cells upregulated phenotypic markers of maturation. Divalent cations were required for infection and maturation, but maturation did not require viral replication. There is evidence that attachment and entry/replication processes exert distinct effects on DC activation. Cell-specific patterns of RSV-induced maturation and cytokine production were detected in mDC1, mDC2, and pDC. We also demonstrate for the first time that RSV induces significant TIMP-2 production in all DC subsets. Defining the influence of RSV on the function of selected DC subsets may improve the likelihood of achieving protective vaccine-induced immunity

Status Update and Interim Results from the Asymptomatic Carotid Surgery Trial-2 (ACST-2)

Objectives: ACST-2 is currently the largest trial ever conducted to compare carotid artery stenting (CAS) with carotid endarterectomy (CEA) in patients with severe asymptomatic carotid stenosis requiring revascularization. Methods: Patients are entered into ACST-2 when revascularization is felt to be clearly indicated, when CEA and CAS are both possible, but where there is substantial uncertainty as to which is most appropriate. Trial surgeons and interventionalists are expected to use their usual techniques and CE-approved devices. We report baseline characteristics and blinded combined interim results for 30-day mortality and major morbidity for 986 patients in the ongoing trial up to September 2012. Results: A total of 986 patients (687 men, 299 women), mean age 68.7 years (SD ± 8.1) were randomized equally to CEA or CAS. Most (96%) had ipsilateral stenosis of 70-99% (median 80%) with contralateral stenoses of 50-99% in 30% and contralateral occlusion in 8%. Patients were on appropriate medical treatment. For 691 patients undergoing intervention with at least 1-month follow-up and Rankin scoring at 6 months for any stroke, the overall serious cardiovascular event rate of periprocedural (within 30 days) disabling stroke, fatal myocardial infarction, and death at 30 days was 1.0%. Conclusions: Early ACST-2 results suggest contemporary carotid intervention for asymptomatic stenosis has a low risk of serious morbidity and mortality, on par with other recent trials. The trial continues to recruit, to monitor periprocedural events and all types of stroke, aiming to randomize up to 5,000 patients to determine any differential outcomes between interventions. Clinical trial: ISRCTN21144362. © 2013 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved

Thrombectomy is a cost-saving procedure up to 24 h after onset

The treatment of ischemic stroke due to large-vessel occlusion has been revolutionized by mechanical thrombectomy (MT), as multiple trials have consistently shown improved functional outcomes compared to standard medical management both in the early and late time windows after symptom onset. However, MT is an interventional procedure that is more costly than best supportive care (BSC). We set out to study the cost-utility and budget impact of MT + BSC versus BSC alone for large-vessel occlusion using a combined decision tree and Markov model. The analysis was conducted from a Belgian payer perspective over a lifetime horizon, and health states were defined by the modified Rankin Scale (mRS). The treatment effect of MT + BSC combined clinical outcomes from all published early and late treatment window studies showing improved mRS after 90 days. Resource use and utilities were informed by an observational Belgian study of 569 stroke patients. Long-term mRS transitions were sourced from the Oxford Vascular study. MT + BSC generated 1.31 additional quality-adjusted life years and resulted in cost savings of €10,216 per patient over lifetime. Deterministic sensitivity analyses demonstrated dominance of MT over a wide range of parameter inputs. In a Belgian setting, adding MT to BSC within an early time window for 1575 eligible stroke patients every year produced cost savings between €6.3 million (year 1) and €14.6 million (year 5), or a total cost saving of €56.2 million over 5 years. Mechanical thrombectomy is a highly cost-effective treatment for ischemic stroke patients, providing quality-adjusted survival at lower health care cost, both when given in an early time window, as well as in a late time window

Validation of a mouse model of chemical-induced asthma using trimellitic anhydride, a respiratory sensitizer, and dinitrochlorobenzene, a dermal sensitizer

Background: Occupational asthma can be caused by chemicals. Previously, we established a murine model of immunologically mediated chemical-induced asthma using toluene diisocyanate. Objective: We sought to verify this model using trimellitic anhydride (TMA), a respiratory sensitizer, and 1-chloro-2,4-dinitrobenzene (DNCB), a dermal sensitizer. Methods: BALB/c mice received dermal applications (vehicle or chemical) on days 1 and 7. On day 10, they received an intranasal instillation (vehicle or chemical). Whole-body plethysmography (enhanced pause) was used to monitor changes in ventilatory function and methacholine reactivity. Pulmonary inflammation was assessed by using bronchoalveolar lavage (cells, TNF-\u3b1 levels, and macrophage inflammatory protein 2 levels). Immunologic parameters included total serum IgE levels, lymphocyte distribution in auricular and cervical lymph nodes, and IL-4 and IFN-\u3b3 levels in supernatants of lymph node cells incubated with or without concanavalin A. Results: Mice dermally treated and intranasally challenged with TMA experienced markedly increased enhanced pause immediately after intranasal challenge and increased methacholine reactivity (24 hours later). Mice similarly treated with DNCB did not show any ventilatory changes. Neutrophil influx and increased macrophage inflammatory protein 2 and TNF-\u3b1 levels were found in bronchoalveolar lavage fluid in both TMA- and DNCB-treated mice. The proportion of CD19 + B cells was increased in auricular and cervical lymph nodes of TMA-treated mice. IL-4 and IFN-\u3b3 levels were increased in supernatants of concanavalin A-stimulated auricular and cervical lymph node cells of TMA- or DNCB-treated mice; however, the relative proportions of IL-4 and IFN-\u3b3 levels differed between TMA- and DNCB-treated mice. Serum total IgE levels were increased in TMA-treated mice only. Conclusion: Both compounds induce a mixed T H1-T H2 response, but only TMA induced ventilatory changes. Clinical implications: In the workplace avoiding skin contact with chemical sensitizers might be advised to prevent chemical-induced asthma

N-glycomic biomarkers of biological aging and longevity: A link with inflammaging

Glycosylation is a frequent co/post-translational modification of proteins which modulates a variety of biological functions. The analysis of N-glycome, i.e. the sugar chains N-linked to asparagine, identified new candidate biomarkers of aging such as N-glycans devoid of galactose residues on their branches, in a variety of human and experimental model systems, such as healthy old people, centenarians and their offspring and caloric restricted mice. These agalactosylated biantennary structures mainly decorate Asn297 of Fc portion of IgG (IgG-G0), and are present also in patients affected by progeroid syndromes and a variety of autoimmune/inflammatory diseases. IgG-G0 exert a pro-inflammatory effect through different mechanisms, including the lectin pathway of complement, binding to Fcgamma receptors and formation of autoantibody aggregates. The age-related accumulation of IgG-G0 can contribute to inflammaging, the low-grade pro-inflammatory status that characterizes elderly, by creating a vicious loop in which inflammation is responsible for the production of aberrantly glycosylated IgG which, in turn, would activate the immune system, exacerbating inflammation. Moreover, recent data suggest that the N-glycomic shift observed in aging could be related not only to inflammation but also to alteration of important metabolic pathways. Thus, altered N-glycans are both powerful markers of aging and possible contributors to its pathogenesi

Stroke coach: a pilot study of a personal digital coaching program for patients after ischemic stroke

Despite recent advances in acute stroke care, the risk of recurrent stroke remains high. On behalf of the Belgian Stroke Council (BSC), a nurse-led self-management program was developed, using a personal coach and digital platform with the aim of improving cardiovascular risk factor control in patients after ischemic stroke. The program was implemented in four Belgian hospitals. The stroke coach provided one educational session during hospitalization. After discharge, the patient received tips and tricks concerning a healthy lifestyle through the customized platform. The stroke coach set up video appointments through the platform at regular intervals. Primary endpoint of our study was the change in SCORE (Systematic COronary Risk Evaluation: High and Low cardiovascular Risk Charts) risk at baseline and 6 months compared with a historical control group who received standard care. A total of 147 patients were included for a follow-up period of 6 months. The mean SCORE in the intervention group showed a statistically significant reduction of 3.2 (p < 0.001) at 6 months. However, comparison between control and intervention groups was non-significant (p = 0.55). Secondary endpoints are promising with a medication adherence of 96%. Reported quality of life also improved (p < 0.001). No significant improvement in the modified Rankin scale (mRS) was observed (p = 0.720). Five percent of patients suffered a recurrent stroke. Our project consisting of a coached lifestyle intervention and digital platform shows promise in improving stroke recurrence rates, therapeutic adherence and quality of life in a Belgian healthcare setting.status: publishe