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Background and ObjectivesLifetime risk of Alzheimer disease (AD) dementia is twofold higher in women compared with men, and low estrogen levels in postmenopause have been suggested as a possible contributor. We examined 3ER(GPER1,ER2, andER1) variants in association with AD traits as an indirect method to test the association between estrogen and AD in women. Although the study focus was on women, in a comparison, we separately examinedERmolecular variants in men.MethodsParticipants were followed for an average of 10 years in one of the 2 longitudinal clinical pathologic studies of aging. Global cognition was assessed using a composite score derived from 19 neuropsychological tests' scores. Postmortem pathologic assessment included examination of 3 AD (amyloid-β and tau tangles determined by immunohistochemistry, and a global AD pathology score derived from diffuse and neurotic plaques and neurofibrillary tangle count) and 8 non-AD pathology indices.ERmolecular genomic variants included genotyping and examiningERDNA methylation and RNA expression in brain regions including the dorsolateral prefrontal cortex (DLPFC) that are major players in cognition and often have AD pathology.ResultsThe mean age of women (N = 1711) at baseline was 78.0 (SD = 7.7) years. In women,GPER1molecular variants had the most consistent associations with AD traits.GPER1DNA methylation was associated with cognitive decline, tau tangle density, and global AD pathology score.GPER1RNA expression in DLPFC was related to cognitive decline and tau tangle density. Other associations included associations ofER2andER1sequence variants and DNA methylation with cognition. RNA expressions in DLPFC of genes involved in signaling mechanisms of activated ERs were also associated with cognitive decline and tau tangle density in women. In men (N = 651, average age at baseline: 77.4 [SD = 7.3]), there were less robust associations betweenERmolecular genomic variants and AD cognitive and pathologic traits. No consistent association was seen betweenERmolecular genomic variations and non-AD pathologies in either of the sexes.DiscussionERDNA methylation and RNA expression, and to some extentERpolymorphisms, were associated with AD cognitive and pathologic traits in women, and to a lesser extent in men.

Background and ObjectivesCognitive resilience is a well-recognized concept, but knowledge gaps about its underlying mechanisms have made it difficult to develop instruments that identify older adults with high or low resilience. We tested whether aggregating cortical peptides associated with cognitive resilience into an index can identify adults with higher or lower cognitive resilience.MethodsWe used data from 1,192 older decedents, including annual clinical testing, indices of 10 Alzheimer disease (AD) and related dementia (ADRD) pathologies, and 226 proteotypic peptides measured in the dorsal lateral prefrontal cortex. We used linear mixed-effects models to identify peptides that were related to cognitive resilience (i.e., cognitive decline not explained by ADRD pathologies [false discovery rate ResultsWe constructed a resilience index from 52 of 226 peptides related to cognitive resilience. A higher index was associated with slower cognitive decline (estimate 0.05, SE 0.003, p < 0.001) and slower motor decline (estimate 0.005, SE 0.001, p < 0.001). Most resilience peptides (70%) were specific to cognitive decline, but 30% also provided resilience for motor decline. A higher index was also related to a lower burden of AD pathologies (odds ratio [OR] 0.41, SE 0.01, p < 0.001) and modified the association of AD pathology with cognition in that a higher index modified the negative effects of AD pathology on AD dementia proximate to death (OR 0.70, SE 0.14, p = 0.010). Up to 90% of cognitive resilience peptides were related to AD pathologic phenotypes.DiscussionCortical proteins may provide some degree of cognitive resilience. These multifunctional proteins also seem to provide resilience to other AD clinical phenotypes and have independent associations with ADRD pathologies. Resilience proteins may be high-value therapeutic targets for drug discovery of interventions that maintain brain health in aging adults via multiple pathways.

Background and Objectives:Identifying protein targets that provide cognitive reserve is a strategy to prevent and treat AD/ADRD. Previous studieFFs using bulk human brain tissue reported 12 proteins associated with cognitive reserve. This study examined whether the same proteins from induced neurons (iNs) are associated with cognitive reserve of their human donors.Methods:Induced pluripotent stem cell (iPSC) lines were generated from cryopreserved peripheral blood mononuclear cells of older adults who were autopsied as part of the Religious Orders Study or Rush Memory and Aging Project. Neurons were induced from iPSCs using a standard neurogenin2 protocol. Tandem mass tag proteomics analyses were conducted on iNs Day 21. Cognitive reserve of their human donors was measured as person-specific slopes of cognitive change not accounted for by common neuropathologies.Results:The 53 human donors died at a mean age of 91, all were non-Latino White and 36 (67.9%) were female. Eighteen were diagnosed with Alzheimer’s dementia proximate to death, and 34 had pathologic AD diagnosis at autopsy. Approximately 60% of the donors had above-average cognitive reserve such that their cognition declined slower than an average person with comparable burdens of neuropathologies. Eight of the 12 candidate proteins were quantified in iNs proteomics analyses. Higher adenylate kinase 4 (AK4) expression in iNs was associated with lower cognitive reserve, consistent with the prior report for brain AK4 expression.Discussion:By replicating cortical protein associations with cognitive reserve in human iNs, these data provide a valuable molecular readout for studying complex clinical phenotypes like cognitive reserve in a dish.

The classification of multiple sclerosis (MS) has been established by Lublin in 1996 and revised in 2013. The revision includes clinically isolated syndrome, relapsing-remitting, primary progressive and secondary progressive MS, and has added activity (i.e., formation of white matter lesions or clinical relapses) as a qualifier. This allows for the distinction between active and nonactive progression, which has been shown to be of clinical importance. We propose that a logical extension of this classification is the incorporation of additional key pathological processes, such as chronic perilesional inflammation, neuroaxonal degeneration, and remyelination. This will distinguish MS phenotypes that may present as clinically identical but are driven by different combinations of pathological processes. A more precise description of MS phenotypes will improve prognostication and personalized care as well as clinical trial design. Thus, our proposal provides an expanded framework for conceptualizing MS and for guiding development of biomarkers for monitoring activity along the main pathological axes in MS. Published version Study Funding: Supported in part by NIH grants R01 NS102267 and R01 NS112907 (D.P.) and a career transition fellowship from the Consortium of Multiple Sclerosis Centers and the National Multiple Sclerosis Society (M.R.L.). The Article Processing Charge was funded by the authors.

The growing complexity of biobanking requires dedicated professional staff who are literate with the multiple aspects of the biobanking process, including technical, managerial, regulatory, and ethical aspects, and who have a good understanding of the challenges of biospecimen research. Here we describe the structure and achievements of a systematic 2-year training program at the Master’s level intended for students with a background in life sciences and providing them with a professional qualification as a “Biobank Manager”. This course was initiated in 2010 as a program of the Catholic University of Lyon (France). The multidisciplinary training program includes courses on biobank design and infrastructure, on pre- and post-analytical biospecimen processing, on protocol development, on ethical and regulatory aspects as well as a primer to epidemiology, high-throughput molecular biology, and translational research. In parallel, students also receive generic training in management, budget planning, data analysis, and statistics, as well as 11 months of hands-on internship training in biobanks handling human, animal, plant, or microbial biospecimens. A total of 81 students have graduated since 2012, all of whom found a job within 6 months of graduation.

Introduction: Adverse nutritional factors in early life, such as food insecurity, may affect the risk of developing asthma in childhood, and worsen asthma control. Aim: To systematically review literature on the impact of family food insecurity on prevalence of childhood asthma, and asthma control. Methods: We included cohort, case-control, and cross-sectional studies evaluating food insecurity and the risk of children developing asthma in childhood or having poor asthma control. We used the SCOPUS platform to search several databases, using a predefined strategy. We used the CASP tool to evaluate study quality. We extracted effect sizes for risk of developing asthma or having poor asthma control. Results: From 109 abstracts we included 8 studies. The studies were of adequate quality but methodological heterogeneity precluded meta-analysis. Six studies evaluated the impact of food insecurity on the risk of developing childhood asthma. Of these, five large studies (n 54,207) found that family food insecurity significantly increased risk of children developing asthma (Odds ratio 1.04 – 2.08). One study (n 486) found no increased risk. Two studies evaluated the impact of food insecurity on asthma control. In one (n 553) food insecurity doubled the risk of poor asthma control (OR 2.01) but in the other (n 127) there was no increased risk. Conclusions: Food insecurity may increase the risk of childhood asthma but the impact on asthma control is uncertain. Large epidemiological studies with standardised methodology are required to evaluate the impact of food insecurity on childhood asthma outcomes.

In our specialist clinic we emphasise the importance of healthy living but evidence around prevalence of obesity & fitness in this group is sparse Aim: To explore the prevalence of obesity & poor fitness levels in our asthma clinic & identify risk factors for poor fitness Method: Database analysis of routinely collected data for children who attended clinic since July 2018. BMI percentiles were calculated according to the National Child Measurement Programme, UK (93rd-97th percentile=overweight, 98th-99th percentile=very overweight). Fitness levels were assessed using the Chester step test, giving a valid approximation of VO2 max score. Poor fitness and overweight/very overweight were compared (chi-square or Person’s correlation) against demographic details, socioeconomic status (Postcode index of multiple deprivation index), and markers of asthma control, airway obstruction, and airway inflammation. Results: 99 children (median 12 years IQR 10-15;64% male),of whom 79 (80%) completed a fitness test. 44/99 (44%) were overweight/very overweight (15/99 (15%) and 29/99 (29%) respectively). 31/79 (39%) had sub-average or very low fitness levels. This was associated with female sex (p 0.047), older age (p 0.017) & baseline BMI category (p 0.03). Poor fitness was not associated with clinical or physiological markers of asthma severity, or socioeconomic status. Conclusion: Obesity & poor fitness are highly prevalent in children with asthma. Those at risk include girls, older teenagers & overweight children. Proactive screening to identify poor fitness should be conducted in clinics managing children with severe asthma.The impact of improved fitness on asthma control should also be explored.

Introduction: It is difficult to accurately identify aetiological factors causing breathlessness (symptoms disproportionate to those expected from a given diagnosis that impacts on the ability to exercise). Effective management relies on an accurate diagnosis. Aims: To review routinely collected diagnostic and clinical data of children referred to the complex breathlessness clinic. Methods: Routinely collected data was analysed from May 2017-Jan 2019 from one of the only paediatric complex breathlessness clinics in Europe. Children (including high level athletes) were referred across North West England. The structured diagnostic process included clinical assessment (respiratory, physiotherapy, ENT), physiological measurement, and laryngoscopy pre and post exercise. Tailored follow-up therapy was directed by a specialist physiotherapist. Results: 32 children attended clinic (age 7-18 [mean 14] years; 25/32 [78%] female). 12/32 (38%) were high level athletes; 4/32 (12.5%) were ex-athletes. Aetiological diagnoses identified were: Dysfunctional breathing 17/32 (53%), Deconditioning 12/32 (39%), Anxiety or other psychosocial factors 12/32 (38%), Laryngeal obstruction 9/32 (29%), Asthma 7/32 (22%), Exercise-induced bronchoconstriction 2/32 (6%) and Reaching maximal exercise capacity 2/32 (6%). Following specialist therapies, 23/32(72%) children were discharged due to resolution of symptoms, 6/32 (19%) are currently receiving treatment and 3/32 (9%) did not attend follow-up therapy. Conclusion: Complex breathlessness is caused by multiple factors, and requires a multispecialty diagnostic approach. Tailored therapies had a positive impact on children with complex breathlessness.

Objective This double-blind, randomised, placebo-controlled, two-part study assessed the impact of GSK2981710, a medium-chain triglyceride (MCT) that liberates ketone bodies, on cognitive function, safety, and tolerability in healthy older adults. Methods Part 1 was a four-period dose-selection study (n = 8 complete). Part 2 was a two-period crossover study (n = 80 complete) assessing the acute (Day 1) and prolonged (Day 15) effects of GSK2981710 on cognition and memory-related neuronal activity. Safety and tolerability of MCT supplementation were monitored in both parts of the study. Results The most common adverse event was diarrhoea (100% and 75% of participants in Parts 1 and 2, respectively). Most adverse events were mild to moderate, and 11% participants were withdrawn due to one or more adverse events. Although GSK2981710 (30 g/day) resulted in increased peak plasma β-hydroxybutyrate (BHB) concentrations, no significant improvements in cognitive function or memory-related neuronal activity were observed. Conclusion Over a duration of 14 days, increasing plasma BHB levels with daily administration of GSK2981710 had no effects on neuronal activity or cognitive function. This result indicates that modulating plasma ketone levels with GSK2981710 may be ineffective in improving cognitive function in healthy older adults, or the lack of observed effect could be related to several factors including study population, plasma BHB concentrations, MCT composition, or treatment duration.

Alan S Bell,1,2 Philip J Lawrence,1 Dave Singh,1–3 Alexander Horsley2–4 1The Medicines Evaluation Unit, Wythenshawe Hospital, Manchester, UK; 2Division of Infection Immunity and Respiratory Medicine, Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK; 3Manchester Academic Health Science Centre, Manchester, UK; 4Manchester Adult Cystic Fibrosis Centre, Manchester University NHS Foundation Trust, Manchester, UK Background: Lung clearance index (LCI), derived from multiple-breath washout (MBW), is a well-established assessment of ventilation inhomogeneity in cystic fibrosis but has not been widely applied in other conditions characterized by heterogeneous airways disease, such as COPD. The aim of this study was to evaluate the sensitivity, repeatability, and practicality of LCI in patients with COPD. Methods: Fifty-four COPD patients completed MBW using nitrogen as the washout tracer gas (MBWN2, measured using an Exhalyzer™ device), spirometry, and plethysmography. Twenty patients repeated MBWN2, MBWSF6 (using a separate Innocor™ gas analyzer to measure washout of the exogenous trace sulphur hexafluoride), and spirometry at a second visit ≥24 hours later. Results: Mean (SD) COPD LCI measured by nitrogen washout (LCIN2) was 12.1 (2.2); mean (SD) LCI Z-score 5.8 (2.0). LCIN2 increased across Global Initiative for Obstructive Lung Disease stages 1 to 3 and was abnormal (Z-score >1.65) in all COPD patients, including those with forced expiratory volume in 1 second (FEV1) ≥80% predicted. LCI was repeatable (median intra-test coefficient of variation 4.1%) and reproducible (limits of agreement -1.8 to 1.6) after mean of 16 days. Functional residual capacity (FRC) measurements were significantly greater using nitrogen than SF6 or plethysmography: mean FRC measured by nitrogen washout (FRCN2) 139% predicted versus FRC measured by plethysmography 125% predicted, p

Background There are few data concerning the association between season and cognition and its neurobiological correlates in older persons—effects with important translational and therapeutic implications for the diagnosis and treatment of Alzheimer disease (AD). We aimed to measure these effects. Methods and findings We analyzed data from 3,353 participants from 3 observational community-based cohort studies of older persons (the Rush Memory and Aging Project [MAP], the Religious Orders Study [ROS], and the Minority Aging Research Study [MARS]) and 2 observational memory-clinic-based cohort studies (Centre de Neurologie Cognitive [CNC] study at Lariboisière Hospital and the Sunnybrook Dementia Study [SDS]). We performed neuropsychological testing and, in subsets of participants, evaluated cerebrospinal fluid AD biomarkers, standardized structured autopsy measures, and/or prefrontal cortex gene expression by RNA sequencing. We examined the association between season and these variables using nested multiple linear and logistic regression models. There was a robust association between season and cognition that was replicated in multiple cohorts (amplitude = 0.14 SD [a measure of the magnitude of seasonal variation relative to overall variability; 95% CI 0.07–0.23], p = 0.007, in the combined MAP, ROS, and MARS cohorts; amplitude = 0.50 SD [95% CI 0.07–0.66], p = 0.017, in the SDS cohort). Average composite global cognitive function was higher in the summer and fall compared to winter and spring, with the difference equivalent in cognitive effect to 4.8 years’ difference in age (95% CI 2.1–8.4, p = 0.002). Further, the odds of meeting criteria for mild cognitive impairment or dementia were higher in the winter and spring (odds ratio 1.31 [95% CI 1.10–1.57], p = 0.003). These results were robust against multiple potential confounders including depressive symptoms, sleep, physical activity, and thyroid status and persisted in cases with AD pathology. Moreover, season had a marked effect on cerebrospinal fluid Aβ 42 level (amplitude 0.30 SD [95% CI 0.10–0.64], p = 0.003), which peaked in the summer, and on the brain expression of 4 cognition-associated modules of co-expressed genes (m6: amplitude = 0.44 SD [95% CI 0.21–0.65], p = 0.0021; m13: amplitude = 0.46 SD [95% CI 0.27–0.76], p = 0.0009; m109: amplitude = 0.43 SD [95% CI 0.24–0.67], p = 0.0021; and m122: amplitude 0.46 SD [95% CI 0.20–0.71], p = 0.0012), which were in phase or anti-phase to the rhythms of cognition and which were in turn associated with binding sites for several seasonally rhythmic transcription factors including BCL11A, CTCF, EGR1, MEF2C, and THAP1. Limitations include the evaluation of each participant or sample once per annual cycle, reliance on self-report for measurement of environmental and behavioral factors, and potentially limited generalizability to individuals in equatorial regions or in the southern hemisphere. Conclusions Season has a clinically significant association with cognition and its neurobiological correlates in older adults with and without AD pathology. There may be value in increasing dementia-related clinical resources in the winter and early spring, when symptoms are likely to be most pronounced. Moreover, the persistence of robust seasonal plasticity in cognition and its neurobiological correlates, even in the context of concomitant AD pathology, suggests that targeting environmental or behavioral drivers of seasonal cognitive plasticity, or the key transcription factors and genes identified in this study as potentially mediating these effects, may allow us to substantially improve cognition in adults with and without AD.

Most antibiotics are prescribed in primary care, and commonly for respiratory tract infections (RTIs). Narrow-spectrum phenoxymethylpenicillin is the antibiotic of choice for RTIs in the Scandinavian countries, while broader spectrum amoxicillin is used in most other European countries. This review summarizes the knowledge of the effect of phenoxymethylpenicillin versus amoxicillin for infections treated in ambulatory care. We searched PubMed/Medline and Embase for trials comparing the clinical effect of phenoxymethylpenicillin and amoxicillin. The Norwegian Knowledge Centre for the Health Services’ checklist was used to assess risk of bias. In total, 1687 studies were identified, and 18 of these fulfilled the inclusion criteria. One additional study was found as a reference. The randomized controlled trials revealed no significant differences in clinical effect in acute sinusitis (three RCTs), GAS tonsillitis (11 RCTs) and Lyme borreliosis (two RCTs). One RCT on community-acquired pneumonia found amoxicillin to be superior, while the results were conflicting in the two RCTs on acute otitis. The results suggest that non-Scandinavian countries should consider phenoxymethylpenicillin as the treatment of choice for RTIs because of its narrower spectrum. More studies should be conducted on the clinical effect of phenoxymethylpenicillin versus amoxicillin for acute otitis and lower RTIs.

International audience; The surface glycoprotein (GP) is responsible for Ebola virus (EBOV) attachment and membrane fusion during virus entry. Surface expression of highly glycosylated GP causes marked cytotoxicity via masking of a wide range of cellular surface molecules, including integrins. Considerable amounts of surface GP are shed from virus-infected cells in a soluble truncated form by tumor necrosis factor α-converting enzyme. In this study, the role of GP shedding was investigated using a reverse genetics approach by comparing recombinant viruses possessing amino acid substitutions at the GP shedding site. Virus with an L635V substitution showed a substantial decrease in shedding, whereas a D637V substitution resulted in a striking increase in the release of shed GP. Variations in shedding efficacy correlated with observed differences in the amounts of shed GP in the medium, GP present in virus-infected cells, and GP present on virions. An increase in shedding appeared to be associated with a reduction in viral cytotoxicity, and, vice versa, the virus that shed less was more cytotoxic. An increase in shedding also resulted in a reduction in viral infectivity, whereas a decrease in shedding efficacy enhanced viral growth characteristics in vitro. Differences in shedding efficacy and, as a result, differences in the amount of mature GP available for incorporation into budding virions did not equate to differences in overall release of viral particles. Likewise, data suggest that the resulting differences in the amount of mature GP on the cell surface led to variations in the GP content of released particles and, as a consequence, in infectivity. In conclusion, fine-tuning of the levels of EBOV GP expressed at the surface of virus-infected cells via GP shedding plays an important role in EBOV replication by orchestrating the balance between optimal virion GP content and cytotoxicity caused by GP.

Background The characteristics and natural history of GOLD B COPD patients are not well described. The clinical characteristics and natural history of GOLD B patients over 1 year in a multicentre cohort of COPD patients in the COPDMAP study were assessed. We aimed to identify the subgroup of patients who progressed to GOLD D (unstable GOLD B patients) and identify characteristics associated with progression. Methods Three hundred seventy COPD patients were assessed at baseline and 12 months thereafter. Demographics, lung function, health status, 6 min walk tests and levels of systemic inflammation were assessed. Students t tests and Mann Whitney-U tests were used. Results One hundred seven (28.9%) of patients were categorised as GOLD B at baseline. These GOLD B patients had similar FEV1 to GOLD A patients (66% predicted). More GOLD B patients were current smokers (p = 0.031), had chronic bronchitis (p = 0.0003) and cardiovascular comorbidities (p = 0.019) compared to GOLD A. At 12 months, 25.3% of GOLD B patients progressed to GOLD D. These patients who progressed (unstable patients) had worse health status and symptoms (SGRQ-C Total, 50.0 v 41.1, p = 0.019 and CAT, 21.0 v 14.0, p = 0.006) and lower FEV1 (60% v 69% p = 0.014) at baseline compared to stable patients who remained in GOLD B. Conclusions Unstable GOLD B patients who progressed to GOLD D had a higher level of symptoms at baseline. A high symptom burden may predict an increased likelihood of disease progression in GOLD B patients. Electronic supplementary material The online version of this article (doi:10.1186/s12890-017-0384-8) contains supplementary material, which is available to authorized users.

Highlights • Chain of pathogen transmission between individual donor and recipient is modeled. • Related pairs of efficient and inefficient ‘airborne’ pathogens are contrasted. • Drivers operate on tissue, individual, community, country, and global levels. • Pandemic risk is heightened by pathogen evolution and changes in host interaction. • Ultimate drivers include socio-economic developments and climate changes., Airborne pathogens — either transmitted via aerosol or droplets — include a wide variety of highly infectious and dangerous microbes such as variola virus, measles virus, influenza A viruses, Mycobacterium tuberculosis, Streptococcus pneumoniae, and Bordetella pertussis. Emerging zoonotic pathogens, for example, MERS coronavirus, avian influenza viruses, Coxiella, and Francisella, would have pandemic potential were they to acquire efficient human-to-human transmissibility. Here, we synthesize insights from microbiological, medical, social, and economic sciences to provide known mechanisms of aerosolized transmissibility and identify knowledge gaps that limit emergency preparedness plans. In particular, we propose a framework of drivers facilitating human-to-human transmission with the airspace between individuals as an intermediate stage. The model is expected to enhance identification and risk assessment of novel pathogens.

International audience; Ever since the first recognised outbreak of Ebolavirus in 1976, retrospective epidemiological analyses and extensive studies with animal models have given us insight into the nature of the pathology and transmission mechanisms of this virus. In this review focusing on Ebolavirus, we present an outline of our current understanding of filovirus human-to-human transmission and of our knowledge concerning the molecular basis of viral transmission and potential for adaptation, with particular focus on what we have learnt from the 2014 outbreak in West Africa. We identify knowledge gaps relating to transmission and pathogenicity mechanisms, molecular adaptation and filovirus ecology.

Rationale The orexin-hypocretin system is important for translating peripheral metabolic signals and central neuronal inputs to a diverse range of behaviors, from feeding, motivation and arousal, to sleep and wakefulness. Orexin signaling is thus an exciting potential therapeutic target for disorders of sleep, feeding, addiction, and stress. Objectives/methods Here, we investigated the low dose pharmacology of orexin receptor antagonist, SB-649868, on neuroendocrine, sympathetic nervous system, and behavioral responses to insulin-induced hypoglycemic stress, in 24 healthy male subjects (aged 18–45 years; BMI 19.0–25.9 kg/m2), using a randomized, double-blind, placebo-controlled, within-subject crossover design. Alprazolam, a licensed benzodiazepine anxiolytic, was used as a positive comparator, as it has previously been validated using the insulin tolerance test (ITT) model in humans. Results Of the primary endpoints, ITT induced defined increases in pulse rate, plasma cortisol, and adrenocorticotropic hormone in the placebo condition, but these responses were not significantly impacted by alprazolam or SB-649868 pre-treatment. Of the secondary endpoints, ITT induced a defined increase in plasma concentrations of adrenaline, noradrenaline, growth hormone (GH), and prolactin in the placebo condition. Alprazolam pre-treatment significantly reduced the GH response to ITT (p

International audience; Marburg virus (MARV) has a high fatality rate in humans, causing hemorrhagic fever characterized by massive viral replication and dysregulated inflammation. Here, we demonstrate that VP24 of MARV binds Kelch-like ECH-associated protein 1 (Keap1), a negative regulator of nuclear transcription factor erythroid-derived 2 (Nrf2). Binding of VP24 to Keap1 Kelch domain releases Nrf2 from Keap1-mediated inhibition promoting persistent activation of a panoply of cytoprotective genes implicated in cellular responses to oxidative stress and regulation of inflammatory responses. Increased expression of Nrf2-dependent genes was demonstrated both during MARV infection and upon ectopic expression of MARV VP24. We also show that Nrf2-deficient mice can control MARV infection when compared to lethal infection in wild-type animals, indicating that Nrf2 is critical for MARV infection. We conclude that VP24-driven activation of the Nrf2-dependent pathway is likely to contribute to dysregulation of host antiviral inflammatory responses and that it ensures survival of MARV-infected cells despite these responses.

Episodic memory deficits are a core feature of neurodegenerative disorders. Muscarinic M1 receptors play a critical role in modulating learning and memory and are highly expressed in the hippocampus. We examined the effect of GSK1034702, a potent M1 receptor allosteric agonist, on cognitive function, and in particular episodic memory, in healthy smokers using the nicotine abstinence model of cognitive dysfunction. The study utilized a randomized, double-blind, placebo-controlled, cross-over design in which 20 male nicotine abstained smokers were tested following single doses of placebo, 4 and 8 mg GSK1034702. Compared to the baseline (nicotine on-state), nicotine abstinence showed statistical significance in reducing immediate (p=0.019) and delayed (p=0.02) recall. GSK1034702 (8 mg) significantly attenuated (i.e. improved) immediate recall (p=0.014) but not delayed recall. None of the other cognitive domains was modulated by either nicotine abstinence or GSK1034702. These findings suggest that stimulating M1 receptor mediated neurotransmission in humans with GSK1034702 improves memory encoding potentially by modulating hippocampal function. Hence, selective M1 receptor allosteric agonists may have therapeutic benefits in disorders of impaired learning including Alzheimer's disease.

Background The characteristics and natural history of GOLD B patients are not well described. Aims Objectives To assess the clinical characteristics and natural history of GOLD B patients over one year in a multicentre cohort of COPD patients in the COPDMAP study. We aimed to identify the subgroup of patients who progressed to GOLD D (unstable GOLD B patients) and identify characteristics associated with progression. Methods 370 COPD patients were assessed at baseline and 12 months thereafter. Demographics, lung function, health status, 6 minute walk test and levels of systemic inflammation were assessed. Students t tests and Mann Whitney-U test were used as appropriate. Results 107 (28.9%) of patients were categorised as GOLD B at baseline. These GOLD B patients had similar FEV1 to GOLD A patients (66% predicted). More GOLD B patients were current smokers ( p =0.031), had chronic bronchitis ( p =0.0003) and cardiovascular comorbidities ( p =0.019) compared to GOLD A. At 12 months, 25.3% of GOLD B patients progressed to GOLD D. These patients who progressed (unstable patients) had worse health status and symptoms (SGRQ-C Total, 50.0 v 41.1, p =0.019 and CAT, 21.0 v 14.0, p =0.006) and lower FEV 1 (60% v 69% p =0.014) at baseline compared to stable patients who remained in GOLD B. Conclusions Unstable GOLD B patients who progressed to GOLD D had a higher level of symptoms at baseline. A high symptom burden may predict an increased likelihood of disease progression in GOLD B patients.