Attitudes to ageing and objectively-measured sedentary and walking behaviour in older people: the Lothian Birth Cohort 1936

Background:Prolonged sitting and low activity—both common in older people—are associated with increased mortality and poorer health. Whether having a more negative attitude to ageing is associated with higher levels of these behaviours is unclear.Objective:We investigated the prospective relationship between attitudes to ageing and objectively measured sedentary and walking behaviour.Methods:Participants were 271 members of the Lothian Birth Cohort 1936. At age 72 years, participants completed the Attitudes to Ageing Questionnaire which assesses attitudes on three domains—Psychosocial loss, Physical change and Psychological growth. At age 79 years, participants wore an activPAL activity monitor for seven days. The outcome measures were average daily time spent sedentary, number of sit-to-stand transitions, and step count.Results:There were no significant associations between any of the Attitude to Ageing domain scores and time spent sedentary or number of sit-to-stand transitions. In sex-adjusted analysis, having a more positive attitude to ageing as regards Physical change was associated with a slightly higher daily step count, for a SD increment in score, average daily step count was greater by 1.5% (95% CI 0.6%, 2.4%). On further adjustment for potential confounding factors these associations were no longer significant.Conclusion:We found no evidence that attitudes to ageing at age 72 were predictive of sedentary or walking behaviour seven years later. Future studies should examine whether attitudes to ageing are associated with objectively measured walking or sedentary behaviour at the same point in time. The existence of such an association could inform the development of interventions.<br/

Quark-Gluon Plasma at RHIC and the LHC: Perfect Fluid too Perfect?

Relativistic heavy ion collisions have reached energies that enable the creation of a novel state of matter termed the quark-gluon plasma. Many observables point to a picture of the medium as rapidly equilibrating and expanding as a nearly inviscid fluid. In this article, we explore the evolution of experimental flow observables as a function of collision energy and attempt to reconcile the observed similarities across a broad energy regime in terms of the initial conditions and viscous hydrodynamics. If the initial spatial anisotropies are very similar for all collision energies from 39 GeV to 2.76 TeV, we find that viscous hydrodynamics might be consistent with the level of agreement for v2 of unidentified hadrons as a function of pT . However, we predict a strong collision energy dependence for the proton v2(pT). The results presented in this paper highlight the need for more systematic studies and a re-evaluation of previously stated sensitivities to the early time dynamics and properties of the medium.Comment: 11 pages, 9 figures, submitted to the New Journal of Physics focus issue "Strongly Correlated Quantum Fluids: From Ultracold Quantum Gases to QCD Plasmas

Intelligence in youth and mental health at age 50

Background: Few cognitive epidemiology studies on mental health have focused on the links between pre-morbid intelligence and self-reports of common mental disorders, such as depression, sleep difficulties, and mental health status. The current study examines these associations in 50-year-old adults. Methods: The study uses data from the 5793 participants in the National Longitudinal Survey of Youth 1979 cohort (NLSY-79) who responded to questions on mental health at age 50 and had IQ measured with the Armed Forces Qualification Test (AFQT) when they were aged between 15 and 23 years in 1980. Mental health outcomes were: life-time diagnosis of depression; the mental component score of the 12-item short-form Health Survey (SF-12); the 7-item Center for Epidemiological Studies Depression Scale (CES-D); and a summary measure of sleep difficulty. Results and conclusion: Higher intelligence in youth is associated with a reduced risk of self-reported mental health problems at age 50, with age-at-first-interview and sex adjusted Bs as follows: CES-depression (B = − 0.16, C.I. − 0.19 to − 0.12, p &lt; 0.001), sleep difficulties (B = − 0.11, C.I. − 0.13 to − 0.08, p &lt; 0.001), and SF-12 mental health status (OR = 0.78, C.I. 0.72 to 0.85, p &lt; 0.001; r = − 0.03 p = 0.075). Conversely, intelligence in youth is linked with an increased risk of receiving a diagnosis of depression by the age of 50 (OR 1.11, C.I. 1.01 to 1.22, p = 0.024; r = 0.03, p = 0.109). No sex differences were observed in the associations. Adjusting for adult SES accounted for most of the association between IQ and the mental health outcomes, except for having reported a diagnosis of depression, in which case adjusting for adult SES led to an increase in the size of the positive association (OR = 1.32, C.I. 1.16 to 1.51, p &lt; 0.001)

Profiles of physical, emotional and psychosocial wellbeing in the Lothian birth cohort 1936

<p>Abstract</p> <p>Background</p> <p>Physical, emotional, and psychosocial wellbeing are important domains of function. The aims of this study were to explore the existence of separable groups among 70-year olds with scores representing physical function, perceived quality of life, and emotional wellbeing, and to characterise any resulting groups using demographic, personality, cognition, health and lifestyle variables.</p> <p>Methods</p> <p>We used latent class analysis (LCA) to identify possible groups.</p> <p>Results</p> <p>Results suggested there were 5 groups. These included High (n = 515, 47.2% of the sample), Average (n = 417, 38.3%), and Poor Wellbeing (n = 37, 3.4%) groups. The two other groups had contrasting patterns of wellbeing: one group scored relatively well on physical function, but low on emotional wellbeing (Good Fitness/ Low Spirits,n = 60, 5.5%), whereas the other group showed low physical function but relatively well emotional wellbeing (Low Fitness/Good Spirits, n = 62, 5.7%). Salient characteristics that distinguished all the groups included smoking and drinking behaviours, personality, and illness.</p> <p>Conclusions</p> <p>Despite there being some evidence of these groups, the results also support a largely one-dimensional construct of wellbeing in old age—for the domains assessed here—though with some evidence that some individuals have uneven profiles.</p

Positive and negative well-being and objectively measured sedentary behaviour in older adults: evidence from three cohorts

Background: Sedentary behaviour is related to poorer health independently of time spent in moderate to vigorous physical activity. The aim of this study was to investigate whether wellbeing or symptoms of anxiety or depression predict sedentary behaviour in older adults. Method: Participants were drawn from the Lothian Birth Cohort 1936 (LBC1936) (n = 271), and the West of Scotland Twenty-07 1950s (n = 309) and 1930s (n = 118) cohorts. Sedentary outcomes, sedentary time, and number of sit-to-stand transitions, were measured with a three-dimensional accelerometer (activPAL activity monitor) worn for 7 days. In the Twenty-07 cohorts, symptoms of anxiety and depression were assessed in 2008 and sedentary outcomes were assessed ~ 8 years later in 2015 and 2016. In the LBC1936 cohort, wellbeing and symptoms of anxiety and depression were assessed concurrently with sedentary behaviour in 2015 and 2016. We tested for an association between wellbeing, anxiety or depression and the sedentary outcomes using multivariate regression analysis. Results: We observed no association between wellbeing or symptoms of anxiety and the sedentary outcomes. Symptoms of depression were positively associated with sedentary time in the LBC1936 and Twenty-07 1950s cohort, and negatively associated with number of sit-to-stand transitions in the LBC1936. Meta-analytic estimates of the association between depressive symptoms and sedentary time or number of sit-to-stand transitions, adjusted for age, sex, BMI, long-standing illness, and education, were β = 0.11 (95% CI = 0.03, 0.18) and β = − 0.11 (95% CI = − 0.19, −0.03) respectively. Conclusion: Our findings indicate that depressive symptoms are positively associated with sedentary behavior. Future studies should investigate the causal direction of this association

GWAS on family history of Alzheimer’s disease

Alzheimer’s disease (AD) is a public health priority for the 21st century. Risk reduction currently revolves around lifestyle changes with much research trying to elucidate the biological underpinnings. We show that self-report of parental history of Alzheimer’s dementia for case ascertainment in a genome-wide association study of 314,278 participants from UK Biobank (27,696 maternal cases, 14,338 paternal cases) is a valid proxy for an AD genetic study. After meta-analysing with published consortium data (n = 74,046 with 25,580 cases across the discovery and replication analyses), three new AD-associated loci (P &lt; 5 × 10−8) are identified. These contain genes relevant for AD and neurodegeneration: ADAM10, BCKDK/KAT8 and ACE. Novel gene-based loci include drug targets such as VKORC1 (warfarin dose). We report evidence that the association of SNPs in the TOMM40 gene with AD is potentially mediated by both gene expression and DNA methylation in the prefrontal cortex. However, it is likely that multiple variants are affecting the trait and gene methylation/expression. Our discovered loci may help to elucidate the biological mechanisms underlying AD and, as they contain genes that are drug targets for other diseases and disorders, warrant further exploration for potential precision medicine applications

The science of clinical practice: disease diagnosis or patient prognosis? Evidence about "what is likely to happen" should shape clinical practice.

BACKGROUND: Diagnosis is the traditional basis for decision-making in clinical practice. Evidence is often lacking about future benefits and harms of these decisions for patients diagnosed with and without disease. We propose that a model of clinical practice focused on patient prognosis and predicting the likelihood of future outcomes may be more useful. DISCUSSION: Disease diagnosis can provide crucial information for clinical decisions that influence outcome in serious acute illness. However, the central role of diagnosis in clinical practice is challenged by evidence that it does not always benefit patients and that factors other than disease are important in determining patient outcome. The concept of disease as a dichotomous 'yes' or 'no' is challenged by the frequent use of diagnostic indicators with continuous distributions, such as blood sugar, which are better understood as contributing information about the probability of a patient's future outcome. Moreover, many illnesses, such as chronic fatigue, cannot usefully be labelled from a disease-diagnosis perspective. In such cases, a prognostic model provides an alternative framework for clinical practice that extends beyond disease and diagnosis and incorporates a wide range of information to predict future patient outcomes and to guide decisions to improve them. Such information embraces non-disease factors and genetic and other biomarkers which influence outcome. SUMMARY: Patient prognosis can provide the framework for modern clinical practice to integrate information from the expanding biological, social, and clinical database for more effective and efficient care

Assessment of pre-clinical liver models based on their ability to predict the liver-tropism of AAV vectors

The liver is a prime target for in vivo gene therapies using recombinant adeno-associated viral vectors (rAAV). Multiple clinical trials have been undertaken for this target in the past 15 years, however we are still to see market approval of the first liver-targeted AAV-based gene therapy. Inefficient expression of the therapeutic transgene, vector-induced liver toxicity and capsid, and/or transgene-mediated immune responses reported at high vector doses are the main challenges to date. One of the contributing factors to the insufficient clinical outcomes, despite highly encouraging preclinical data, is the lack of robust, biologically- and clinically-predictive preclinical models. To this end, this study reports findings of a functional evaluation of six AAV vectors in twelve preclinical models of the human liver, with the aim to uncover which combination of models is the most relevant for the identification of AAV capsid variant for safe and efficient transgene delivery to primary human hepatocytes. The results, generated by studies in models ranging from immortalized cells, iPSC-derived and primary hepatocytes, and primary human hepatic organoids to in vivo models, increased our understanding of the strengths and weaknesses of each system. This should allow the development of novel gene therapies targeting the human liver

New mechanism for Notch signaling to endothelium at a distance by Delta-like 4 incorporation into exosomes.

Notch signaling is an evolutionary conserved pathway that is mediated by cell-cell contact. It is involved in a variety of developmental processes and has an essential role in vascular development and angiogenesis. Delta-like 4 (Dll4) is a Notch ligand that is up-regulated during angiogenesis. It is expressed in endothelial cells and regulates the differentiation between tip cells and stalk cells of neovasculature. Here, we present evidence that Dll4 is incorporated into endothelial exosomes. It can also be incorporated into the exosomes of tumor cells that overexpress Dll4. These exosomes can transfer the Dll4 protein to other endothelial cells and incorporate it into their cell membrane, which results in an inhibition of Notch signaling and a loss of Notch receptor. Transfer of Dll4 was also shown in vivo from tumor cells to host endothelium. Addition of Dll4 exosomes confers a tip cell phenotype on the endothelial cell, which results in a high Dll4/Notch-receptor ratio, low Notch signaling, and filopodia formation. This was further evidenced by increased branching in a tube-formation assay and in vivo. This reversal in phenotype appears to enhance vessel formation and is a new form of signaling for Notch ligands that expands their signaling potential beyond cell-cell contact