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Funder: National Institute for Health Research; Grant(s): GHR: 16/137/34, The literature on urban travel behaviour in Africa is sparse, limiting our understanding of how urban transport policies respond to human and planetary needs. We conducted a cross-sectional household telephone survey on 1334 participants, using a 24 h time-use diary, to investigate travel behaviour and barriers to active travel (walking and cycling) in Yaoundé, Cameroon. We found that two-thirds of all participants reported at least one trip; the median (IQR) numbers of trips per capita and per participant with trips were 2 (0−3) and 2 (2−3), respectively. The main trip modes were shared taxi (46%), walking (27%), private cars (11%), and motorcycle taxis (10%), with 25%, 56%, and 45% of all participants reporting the use of active, motorised, and public transport, respectively. The mean (IQR) trip duration was 48 (30−60) min; for participants who reported trips, the daily overall and active travel durations were 121 (60−150) and 28 (0−45) min, respectively. Women were less likely to travel, making fewer and shorter trips when they did. Participants in less wealthy households were more likely to travel. The primary barriers to both walking and cycling were the fear of road traffic injuries and the inconvenience of active travel modes. Therefore, local urban transport authorities need to improve the safety and convenience of active mobility and promote gender equity in transport. Restrictions to movements during the COVID-19 pandemic and the relatively small survey sample might have biased our results; thus, a representative travel survey could improve current estimates. More generally, high-quality research on travel behaviours and their correlates is needed in low-resource settings.

Background: The transportation sector accounts for approximately 23% of total energy-related carbon dioxide (CO2) emissions worldwide and 33% in the USA. At the same time, physical inactivity contribute to the adverse health through non-communicable diseases. If policies can increase active transport (walking and cycling) and reduce car use, they could benefit human health and environmental health but the relative impact of different approaches has been under researched. Methods: This study estimated change in all-cause mortality and CO2 emissions in greater Nashville, Tennessee (USA) for two scenarios: (a) the propensity to walk and cycle a trip of a given distance increases directly to the same levels as seen in England, and (b) walking and cycling trips increase and travel distance decrease indirectly as a result of a more compact urban form. Results: If the propensity to walk and cycle in Nashville were equal with England, about 339 deaths and about 36 ktCO2e (1%) of transportation-related CO2 emissions annually could be avoided. Compact urban form scenario could avoid 170 deaths and 370 ktCO2e (10%) of transportation-related CO2 emissions. Conclusion: In Nashville, both increasing the propensity to use active transport and more compact urban form would have notable public health gains, but a more compact form would have a much bigger effect on emissions.

Key messages • Technological, societal and nature-based solutions should work together to enable systemic change towards a regenerative society, and to deliver net-zero greenhouse gas (GHG) emissions. • Prioritise research into efficient, low-carbon and carbon-negative solutions for sectors that are difficult to decarbonise; i.e. energy storage, road transport, shipping, aviation and grid infrastructure. • Each solution should be assessed with respect to GHG emissions reductions, energy efficiency and societal implications to provide a basis for developing long-term policies, maximising positive impact of investment and research effort, and guiding industry investors in safe and responsible planning.

International audience; The traditional approach to biomarker discovery for any pathology has been through hypothesis-based research one candidate at a time. The objective of this study was to develop an agnostic approach for the simultaneous screening of plasma for consistent molecular differences between a group of individuals exhibiting a pathology and a group of healthy individuals. To achieve this, we focused on developing a predictive tool based on plasma for the amount of brain amyloid-β deposition as observed in PET scans. The accumulation of brain amyloid-β (Aβ) plaques is a key risk factor for the development of Alzheimer's disease. A contrast was established between cognitively normal individuals above the age of 70 that differed for the amount of brain amyloid-β observed in PET scans (INSIGHT study group). Positive selection was performed against a pool of plasma from individuals with high brain amyloid and negative selection against a pool of plasma from individuals with low brain amyloid This enriched, selected library was then applied to plasma samples from 11 individuals with high levels of brain amyloid and 11 individuals with low levels of brain Aβ accumulation. Each of these individually selected libraries was then characterized by next generation sequencing, and the relative frequency of 10,000 aptamer sequences that were observed in each selection was screened for ability to explain variation in brain amyloid using sparse partial least squares discriminant analysis. From this analysis a subset of 44 aptamers was defined, and the individual aptamers were synthesized. This subset was applied to plasma samples from 70 cognitively normal individuals all above the age of 70 that differed for brain amyloid deposition. 54 individuals were used as a training set, and 15 as a test set. Three of the 15 individuals in the test set were mis-classified resulting in an overall accuracy of 80% with 86% sensitivity and 75% specificity. The aptamers included in the subset serve directly as biomarkers, thus we have named them Aptamarkers. There are two potential applications of these results: extending the predictive capacity of these aptamers across a broader range of individuals, and/or using the individual aptamers to identify targets through covariance analysis and reverse omics approaches. We are currently expanding applications of the Aptamarker platform to other diseases and target matrices.

Introduction The longitudinal trajectories of functional brain dynamics and the impact of genetic risk factors in individuals at risk for Alzheimer's disease are poorly understood. Methods In a large-scale monocentric cohort of 224 amyloid stratified individuals at risk for Alzheimer's disease, default mode network (DMN) resting state functional connectivity (FC) was investigated between two serial time points across 2 years. Results Widespread DMN FC changes were shown in frontal and posterior areas, as well as in the right hippocampus. There were no cross-sectional differences, however, apolipoprotein E e4 (APOE e4) carriers demonstrated slower increase in FC in frontal lobes. There was no impact of individual brain amyloid load status. Discussion For the first time, we demonstrated that the pleiotropic biological effect of the APOE e4 allele impacts the dynamic trajectory of the DMN during aging. Dynamic functional biomarkers may become useful surrogate outcomes for the development of preclinical targeted therapeutic interventions.

Background: The Propensity to Cycle Tool (PCT) is a freely available, interactive tool help prioritise cycling initially launched in England in 2017 and based on adult commuting data. This paper applies the method to travel to school data, and assesses health and carbon benefits based on nationwide scenarios of cycling uptake.\ud \ud Methods: The 2011 National School Census provides origin-destination data for all state-funded schools in England (N = 7,442,532 children aged 2–18 in 21,443 schools). Using this dataset, we modelled propensity to cycle as a function of route distance and hilliness between home and school. We generated scenarios, including ‘Go Dutch’ – in which English children were as likely to cycle as Dutch children, accounting for trip distance and hilliness. We estimated changes in the level of cycling, walking, and driving, and associated impacts on physical activity and carbon emissions.\ud \ud Results: In 2011, 1.8% of children cycled to school (1.0% in primary school, 2.7% in secondary school). If Dutch levels of cycling were reached, under the Go Dutch scenario, this would rise to 41.0%, a 22-fold increase. This is larger than the 6-fold increase in Go Dutch for adult commuting. This would increase total physical activity among pupils by 57%, and reduce transport-related carbon emissions by 81 kilotonnes/year. These impacts would be substantially larger in secondary schools than primary schools (a 96% vs. 9% increase in physical activity, respectively).\ud \ud Conclusion: Cycling to school is uncommon in England compared with other Northern European countries. Trip distances and hilliness alone cannot explain the difference, suggesting substantial unmet potential. We show that policies resulting in substantial uptake of cycling to school would have important health and environmental benefits. At the level of road networks, the results can inform local investment in safe routes to school to help realise these potential benefits.

Background Plasma neurofilament light (NFL) and total Tau (t-Tau) proteins are candidate biomarkers for early stages of Alzheimer’s disease (AD). The impact of biological factors on their plasma concentrations in individuals with subjective memory complaints (SMC) has been poorly explored. We longitudinally investigate the effect of sex, age, APOE ε4 allele, comorbidities, brain amyloid-β (Aβ) burden, and cognitive scores on plasma NFL and t-Tau concentrations in cognitively healthy individuals with SMC, a condition associated with AD development. Methods Three hundred sixteen and 79 individuals, respectively, have baseline and three-time point assessments (at baseline, 1-year, and 3-year follow-up) of the two biomarkers. Plasma biomarkers were measured with an ultrasensitive assay in a mono-center cohort (INSIGHT-preAD study). Results We show an effect of age on plasma NFL, with women having a higher increase of plasma t-Tau concentrations compared to men, over time. The APOE ε4 allele does not affect the biomarker concentrations while plasma vitamin B12 deficiency is associated with higher plasma t-Tau concentrations. Both biomarkers are correlated and increase over time. Baseline NFL is related to the rate of Aβ deposition at 2-year follow-up in the left-posterior cingulate and the inferior parietal gyri. Baseline plasma NFL and the rate of change of plasma t-Tau are inversely associated with cognitive score. Conclusion We find that plasma NFL and t-Tau longitudinal trajectories are affected by age and female sex, respectively, in SMC individuals. Exploring the influence of biological variables on AD biomarkers is crucial for their clinical validation in blood.

β-Secretase1 (BACE1) protein concentrations and rates of enzyme activity, analyzed in human bodily fluids, are promising candidate biological markers for guidance in clinical trials investigating BACE1 inhibitors to halt or delay the dysregulation of the amyloid-β pathway in Alzheimer’s disease (AD). A robust body of evidence demonstrates an association between cerebrospinal fluid/blood BACE1 biomarkers and core pathophysiological mechanisms of AD, such as brain protein misfolding and aggregration, neurodegeneration, and synaptic dysfunction.In pharmacological trials, BACE1 candidate biomarkers may be applied to a wide set of contexts of use (CoU), including proof of mechanism, dose-finding, response and toxicity dose estimation. For clinical CoU, BACE1 biomarkers show good performance for prognosis and disease prediction.The roadmap toward validation and qualification of BACE1 biomarkers requires standardized pre-analytical and analytical protocols to reduce inter-site variance that may have contributed to inconsistent results.BACE1 biomarker-drug co-development programs, including biomarker-guided outcomes and endpoints, may support the identification of sub-populations with a higher probability to benefit from BACE1 inhibitors with a reduced risk of adverse effects, in line with the evolving precision medicine paradigm.

Introduction Several neurodegenerative brain proteinopathies, including Alzheimer's disease (AD), are associated with cerebral deposition of insoluble aggregates of α-synuclein. Previous studies reported a trend toward increased cerebrospinal fluid (CSF) α-synuclein (α-syn) concentrations in AD compared with other neurodegenerative diseases and healthy controls. Methods The pathophysiological role of CSF α-syn in asymptomatic subjects at risk of AD has not been explored. We performed a large-scale cross-sectional observational monocentric study of preclinical individuals at risk for AD (INSIGHT-preAD). Results We found a positive association between CSF α-syn concentrations and brain β-amyloid deposition measures as mean cortical standard uptake value ratios. We demonstrate positive correlations between CSF α-syn and both CSF t-tau and p-tau 181 concentrations. Discussion Animal models presented evidence, indicating that α-syn may synergistically and directly induce fibrillization of both tau and β-amyloid. Our data indicate an association of CSF α-syn with AD-related pathophysiological mechanisms, during the preclinical phase of the disease.

Alzheimer's disease (AD)-a complex disease showing multiple pathomechanistic alterations-is triggered by nonlinear dynamic interactions of genetic/epigenetic and environmental risk factors, which, ultimately, converge into a biologically heterogeneous disease. To tackle the burden of AD during early preclinical stages, accessible blood-based biomarkers are currently being developed. Specifically, next-generation clinical trials are expected to integrate positive and negative predictive blood-based biomarkers into study designs to evaluate, at the individual level, target druggability and potential drug resistance mechanisms. In this scenario, systems biology holds promise to accelerate validation and qualification for clinical trial contexts of use-including proof-of-mechanism, patient selection, assessment of treatment efficacy and safety rates, and prognostic evaluation. Albeit in their infancy, systems biology-based approaches are poised to identify relevant AD "signatures" through multifactorial and interindividual variability, allowing us to decipher disease pathophysiology and etiology. Hopefully, innovative biomarker-drug codevelopment strategies will be the road ahead towards effective disease-modifying drugs. .La Enfermedad de Alzheimer (EA) es una enfermedad compleja que presenta múltiples alteraciones patomecánicas, que se desencadena por interacciones dinámicas no lineales de factores de riesgo genéticos / epigenéticos y ambientales, los que, en definitiva, convergen en una enfermedad biológicamente heterogénea. Para hacer frente a la carga de la EA durante las etapas preclínicas tempranas, actualmente se están desarrollando biomarcadores sanguíneos de fácil accesibilidad. Específicamente, se espera que los ensayos clínicos de próxima generación integren biomarcadores sanguíneos predictivos tanto positivos como negativos en los diseños de los estudios para evaluar, a nivel individual, la capacidad de la droga objetivo y los posibles mecanismos de resistencia a los medicamentos. En este contexto, la biología de sistemas promete acelerar la validación y la calificación de su empleo en los ensayos clínicos, incluida la prueba del mecanismo, la selección de pacientes, la evaluación de la eficacia del tratamiento y los porcentajes de seguridad, y la evaluación pronóstica. A pesar de estar en sus comienzos, los enfoques basados en la biología de sistemas están preparados para identificar “firmas” de EA relevantes a través de la variabilidad multifactorial e interindividual, lo que nos permite descifrar la fisiopatología y la etiología de la enfermedad. Ojalá, las estrategias innovadoras conjuntas del desarrollo de biomarcadores y de medicamentos sean el camino adecuado para conseguir fármacos eficaces que modifiquen la enfermedad.La maladie d’Alzheimer (MA) — maladie complexe présentant des altérations nombreuses pathomécaniques — est déclenchée par des interactions dynamiques non linéaires entre des facteurs de risques génétiques et épigénétiques et environnementaux qui, au bout du compte, aboutissent à une maladie biologiquement hétérogène. Pour réduire la charge de morbidité de la MA durant ses premiers stades précliniques, des biomarqueurs sanguins sont actuellement développés. Spécifiquement, la prochaine génération d’essais cliniques devrait intégrer ces biomarqueurs sanguins positifs ou négatifs prédictifs de la maladie dans des études qui auront pour but d’évaluer, à un niveau individuel, des cibles pouvant être traitées par des candidats médicaments et de potentiels mécanismes de résistance à ces médicaments. Dans ce contexte, la biologie des systèmes devrait permettre d’accélérer la validation et la qualification de leur utilisation dans les études cliniques – incluant la preuve du mécanisme d’action, la sélection des patients, la confirmation de l’efficacité du traitement et son niveau de sécurité, ainsi que l’évaluation pronostique. Bien que nous en soyons au tout début, les approches reposant sur la biologie des systèmes sont sur le point d’identifier des « signatures » pertinentes de la MA grâce à des variables multifactorielles et interindividuelles, qui nous permettront d’élucider la pathophysiologie et l’étiologie de la maladie. Avec un peu de chance, les stratégies innovantes de codéveloppement de biomarqueurs et de médicaments nous mèneront vers des médicaments efficaces pour lutter contre la maladie.

Introduction: Successful development of effective beta-site amyloid precursor protein cleaving enzyme 1 (BACE1)-targeted therapies for early stages of Alzheimer's disease requires biomarker-guided intervention strategies. Methods: We investigated whether key biological factors such as sex, apolipoprotein E (APOE epsilon 4) allele, and age affect longitudinal plasma BACE1 concentrations in a large monocenter cohort of individuals at risk for Alzheimer's disease. We explored the relationship between plasma BACE1 concentrations and levels of brain amyloid-beta (A beta) deposition, using positron emission tomography global standard uptake value ratios. Results: Baseline and longitudinal mean concentrations of plasma BACE1 were significantly higher in women than men. We also found a positive significant impact of plasma BACE1 on baseline A beta-positron emission tomography global standard uptake value ratios. Discussion: Our results suggest a sexual dimorphism in BACE1-related upstream mechanisms of brain A beta production and deposition. We argue that plasma BACE1 should be considered in further biomarker validation and qualification studies as well as in BACE1 clinical trials. (C) 2019 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association.

Background: Predicting the progression of cognitive decline in Alzheimer's disease (AD) is important for treatment selection and patient counseling. Structural MRI markers such as hippocampus or basal forebrain volumes might represent useful instruments for the prediction of cognitive decline. The primary objective was to determine the predictive value of hippocampus and basal forebrain volumes for global and domain specific cognitive decline in AD dementia during cholinergic treatment.Methods: We used MRI and cognitive data from 124 patients with the clinical diagnosis of AD dementia, derived from the ADNI-1 cohort, who were on standard of care cholinesterase inhibitor treatment during a follow-up period between 0.4 and 3.1 years. We used linear mixed effects models with cognitive function as outcome to assess the main effects as well as two-way interactions between baseline volumes and time controlling for age, sex, and total intracranial volume. This model accounts for individual variation in follow-up times.Results: Basal forebrain volume, but not hippocampus volume, was a significant predictor of rates of global cognitive decline. Larger volumes were associated with smaller rates of cognitive decline. Left hippocampus volume had a modest association with rates of episodic memory decline. Baseline performance in global cognition and memory was significantly associated with hippocampus and basal forebrain volumes; in addition, basal forebrain volume was associated with baseline performance in executive function.Conclusions: Our findings indicate that in AD dementia patients, basal forebrain volume may be a useful marker to predict subsequent cognitive decline during cholinergic treatment.

Background A modal shift to cycling has the potential to reduce greenhouse gas emissions and provide health co-benefits. Methods, models, and tools are needed to estimate the potential for cycling uptake and communicate to policy makers the range of impacts this would have. Methods and findings The Impacts of Cycling Tool (ICT) is an open source model with a web interface for visualising travel patterns and comparing the impacts of different scenarios of cycling uptake. It is currently applied to England. The ICT allows users to visualise individual and trip-level data from the English National Travel Survey (NTS), 2004–2014 sample, 132,000 adults. It models scenarios in which there is an increase in the proportion of the population who cycle regularly, using a distance-based propensity approach to model which trips would be cycled. From this, the model estimates likely impact on travel patterns, health, and greenhouse gas emissions. Estimates of nonoccupational physical activity are generated by fusing the NTS with the English Active People Survey (APS, 2013–2014, 559,515 adults) to create a synthetic population. Under ‘equity’ scenarios, we investigate what would happen if cycling levels increased equally among all age and gender categories, as opposed to in proportion to the profile of current cyclists. Under electric assist bike (pedelecs or ‘e-bike’) scenarios, the probability of cycling longer trips increases, based on the e-bike data from the Netherlands, 2013–2014 Dutch Travel Survey (50,868 adults).Outcomes are presented across domains including transport (trip duration and trips by mode), health (physical activity levels, years of life lost), and car transport–related CO2 emissions. Results can be visualised for the whole population and various subpopulations (region, age, gender, and ethnicity). The tool is available at www.pct.bike/ict. If the proportion of the English population who cycle regularly increased from 4.8% to 25%, then there would be notable reductions in car miles and passenger related CO2 emissions (2.2%) and health benefits (2.1% reduction in years of life lost due to premature mortality). If the new cyclists had access to e-bikes, then mortality reductions would be similar, while the reduction in car miles and CO2 emissions would be larger (2.7%). If take-up of cycling occurred equally by gender and age (under 80 years), then health benefits would be marginally greater (2.2%) but reduction in CO2 slightly smaller (1.8%). The study is limited by the quality and comparability of the input data (including reliance on self-report behaviours). As with all modelling studies, many assumptions are required and potentially important pathways excluded (e.g. injury, air pollution, and noise pollution). Conclusion This study demonstrates a generalisable approach for using travel survey data to model scenarios of cycling uptake that can be applied to a wide range of settings. The use of individual-level data allows investigation of a wide range of outcomes, and variation across subgroups. Future work should investigate the sensitivity of results to assumptions and omissions, and if this varies across setting., James Woodcock and colleagues present the ICT cycling tool, an open source model for calculating reductions of CO2 emissions and health benefits if cycling replaces car journeys., Author summary Why was this study done? Physical activity, such as from regular cycling, is associated with lower rates of mortality and chronic disease. Previous studies have modelled the health impacts of people taking up cycling, but the scenarios have tended to be simplistic. Policy makers and practitioners need methods and tools to apply to local data to investigate cycling potential and its impacts. What did the researchers do and find? We developed a method to investigate the impacts on health, greenhouse gas emissions, and other outcomes if people were as likely to cycle a trip of a given distance as existing cyclists. We applied this method to the English travel survey. We developed a web interface to display results for England as a whole, for the nine English regions, and for different groups in the population. We found that if the percentage of the English population regularly cycling increased from less than 5% to 25%, there would be approximately a 2% reduction in passenger transport greenhouse gas emissions and years of life lost due to premature mortality. What do these findings mean? The method created can be applied to travel survey data in other countries, and because the code is open source it can be freely improved on by others. The study is limited by the assumptions used in the model and by not looking at potentially important health pathways, such as from air pollution and road traffic injuries.

This proposal envisions a way of holding platforms accountable through a programme of research focused on fair work. It operates under a governing belief that core transparent production networks can lead to better working conditions for digital workers around the world. The establishment of the Foundation and a certification scheme will provide demonstrable impact for digital workers, customers, and platforms. For digital workers, it addresses the twofold structural weakness that they face: first, the lack of ability to collectively bargain due to the fragmentation of the work process; and second, the asymmetry of information between workers and platforms. The certification process provides an important means to address these two challenges, along with building and developing connections between workers and institutions like trade unions and regulatory bodies. New kinds of work require innovations in organising techniques and regulations, and the Fairwork Foundation provides an important starting point for developing these in practice.\ud \ud As millions of people turn to platform work for their livelihoods, it is no longer good enough to imagine that there is nothing beyond the screen. Our clicks tie us to the lives and livelihoods of platform workers, as much as buying clothes tie us to the lives of sweatshop workers. And with that realisation of our interwoven digital positionalities comes the power to bring into being a fairer world of work.

Physical activity can affect ‘need’ for healthcare both by reducing the incidence rate of some diseases and by increasing longevity (increasing the time lived at older ages when disease incidence is higher). However, it is common to consider only the first effect, which may overestimate any reduction in need for healthcare. We developed a hybrid micro-simulation lifetable model, which made allowance for both changes in longevity and risk of disease incidence, to estimate the effects of increases in physical activity (all adults meeting guidelines) on measures of healthcare need for diseases for which physical activity is protective. These were compared with estimates made using comparative risk assessment (CRA) methods, which assumed that longevity was fixed. Using the lifetable model, life expectancy increased by 95 days (95% uncertainty intervals: 68–126 days). Estimates of the healthcare need tended to decrease, but the magnitude of the decreases were noticeably smaller than those estimated using CRA methods (e.g. dementia: change in person- years, -0.6%, 95% uncertainty interval -3.7% to +1.6%; change in incident cases, -0.4%, -3.6% to +1.9%; change in person-years (CRA methods), -4.0%, -7.4% to -1.6%). The pattern of results persisted under different scenarios and sensitivity analyses. For most diseases for which physical activity is protective, increases in physical activity are associated with decreases in indices of healthcare need. However, disease onset may be delayed or time lived with disease may increase, such that the decreases in need may be relatively small and less than is sometimes expected.

Transport and travel can bring enormous benefits, as economies have become globalised, and as many transactions are now facilitated through relatively cheap networks and communications infrastructures. Many people in high income countries have the ability to travel globally, and their aspirations are raised through media coverage, through more educational and leisure opportunities, and through increasing wealth. But we also live in a carbon dependent society, and carbon emissions are affecting the global climate with irreversible long term consequences. Transport is the one major sector that has not made any contribution to a reduction in energy use and emissions. Equity is also a major issue as many of the new opportunities for greater mobility have been restricted to a small proportion of the rich global population, while lower income groups typically suffer more of the adverse consequences. The environmental limits and social inequities make it economically unsustainable and the situation has become worse over the last twenty years since global awareness of the potential impact of climate change was recognised at the Rio Summit.

This is a book chapter from Ensuring a sustainable future : making progress on environment and equity: There is very little argument that the world is facing severe environmental challenges. Ongoing air and water pollution, increasing energy consumption, and the depletion of natural resources have all placed considerable stress on the capacity of our environment to support the present quality of human life in a sustainable manner. Ensuring a Sustainable Future does what few previous works have: it examines these trends' disproportionate impact on the poor and the economically viable solutions that can serve to remedy them — solutions that simultaneously address environmental and economic problems. This gap in previous research, evidence, and writing has left low-income countries often unwilling to take on major environmental problems and many poor communities believing they faced impossible choices between improving the environment in which they live and increasing the jobs and income available. Bringing together evidence-based recommendations and in-depth case studies of successful policies and programs around the world, Ensuring a Sustainable Future examines innovative solutions to this crucial challenge. In doing so, it addresses a comprehensive range of environmental sustainability challenges affecting low-, middle-, and high-income countries.