When Is Higher Neuroticism Protective Against Death? Findings From UK Biobank

We examined the association between neuroticism and mortality in a sample of 321,456 people from UK Biobank and explored the influence of self-rated health on this relationship. After adjustment for age and sex, a 1- SD increment in neuroticism was associated with a 6% increase in all-cause mortality (hazard ratio = 1.06, 95% confidence interval = [1.03, 1.09]). After adjustment for other covariates, and, in particular, self-rated health, higher neuroticism was associated with an 8% reduction in all-cause mortality (hazard ratio = 0.92, 95% confidence interval = [0.89, 0.95]), as well as with reductions in mortality from cancer, cardiovascular disease, and respiratory disease, but not external causes. Further analyses revealed that higher neuroticism was associated with lower mortality only in those people with fair or poor self-rated health, and that higher scores on a facet of neuroticism related to worry and vulnerability were associated with lower mortality. Research into associations between personality facets and mortality may elucidate mechanisms underlying neuroticism's covert protection against death

The influence of polygenic risk for bipolar disorder on neural activation assessed using fMRI

Genome-wide association studies (GWAS) have demonstrated a significant polygenic contribution to bipolar disorder (BD) where disease risk is determined by the summation of many alleles of small individual magnitude. Modelling polygenic risk scores may be a powerful way of identifying disrupted brain regions whose genetic architecture is related to that of BD. We determined the extent to which common genetic variation underlying risk to BD affected neural activation during an executive processing/language task in individuals at familial risk of BD and healthy controls. Polygenic risk scores were calculated for each individual based on GWAS data from the Psychiatric GWAS Consortium Bipolar Disorder Working Group (PGC-BD) of over 16 000 subjects. The familial group had a significantly higher polygene score than the control group (P=0.04). There were no significant group by polygene interaction effects in terms of association with brain activation. However, we did find that an increasing polygenic risk allele load for BD was associated with increased activation in limbic regions previously implicated in BD, including the anterior cingulate cortex and amygdala, across both groups. The findings suggest that this novel polygenic approach to examine brain-imaging data may be a useful means of identifying genetically mediated traits mechanistically linked to the aetiology of BD

Using a knowledge exchange event to assess study participants’ attitudes to research in a rapidly evolving research context [version 2; peer review: 3 approved]

Background: The UK hosts some of the world’s longest-running longitudinal cohort studies, which make repeated observations of their participants and use these data to explore health outcomes. An alternative method for data collection is record linkage; the linking together of electronic health and administrative records. Applied nationally, this could provide unrivalled opportunities to follow a large number of people in perpetuity. However, public attitudes to the use of data in research are currently unclear. Here we report on an event where we collected attitudes towards recent opportunities and controversies within health data science. / Methods: The event was attended by ~250 individuals (cohort members and their guests), who had been invited through the offices of their participating cohort studies. There were a series of presentations describing key research results and the audience participated in 15 multiple-choice questions using interactive voting pads. / Results: Our participants showed a high level of trust in researchers (87% scoring them 4/5 or 5/5) and doctors (81%); but less trust in commercial companies (35%). They supported the idea of researchers using information from both neonatal blood spots (Guthrie spots) (97% yes) and from electronic health records (95% yes). Our respondents were willing to wear devices like a ’Fit-bit’ (88% agreed) or take a brain scan that might predict later mental illness (73%). However, they were less willing to take a new drug for research purposes (45%). They were keen to encourage others to take part in research; whether that be offering the opportunity to pregnant mothers (97% agreed) or extending invitations to their own children and grandchildren (98%). / Conclusions: Our participants were broadly supportive of research access to data, albeit less supportive when commercial interests were involved. Public engagement events that facilitate two-way interactions can influence and support future research and public engagement efforts

Using a knowledge exchange event to assess study participants' attitudes to research in a rapidly evolving research context [version 1; peer review: 3 approved]

BACKGROUND: The UK hosts some of the world’s longest-running longitudinal cohort studies, who make repeated observations of their participants and use these data to explore health outcomes. An alternative method for data collection is record linkage; the linking together of electronic health and administrative records. Applied nationally, this could provide unrivalled opportunities to follow a large number of people in perpetuity. However, public attitudes to the use of data in research are currently unclear. Here we report on an event where we collected attitudes towards recent opportunities and controversies within health data science. METHODS: The event was attended by ~250 individuals (cohort members and their guests), who had been invited through the offices of their participating cohort studies. There were a series of presentations describing key research results and the audience participated in 15 multiple-choice questions using interactive voting pads. RESULTS: Our participants showed a high level of trust in researchers (87% scoring them 4/5 or 5/5) and doctors (81%); but less trust in commercial companies (35%). They supported the idea of researchers using information from both neonatal blood spots (Guthrie spots) (97% yes) and from electronic health records (95% yes). Our respondents were willing to wear devices like a ’Fit-bit’ (78% agreed) or take a brain scan that might predict later mental illness (73%). However, they were less willing to take a new drug for research purposes (45%). They were keen to encourage others to take part in research; whether that be offering the opportunity to pregnant mothers (97% agreed) or extending invitations to their own children and grandchildren (98%). CONCLUSIONS: Our participants were broadly supportive of research access to data, albeit less supportive when commercial interests were involved. Public engagement events that facilitate two-way interactions can influence and support future research and public engagement efforts

Conditioning on a Collider May or May Not Explain the Relationship Between Lower Neuroticism and Premature Mortality in the Study by Gale et al. (2017): A Reply to Richardson, Davey Smith, and Munafò (2019)

We (Gale et al., 2017) analyzed data on 321,456 UK Biobank participants to address why higher neuroticism is sometimes related to lower mortality (e.g., Korten et al., 1999). We noted that the studies that revealed an inverse relationship between neuroticism and mortality included self-rated health as a predictor, perhaps because it is associated with mortality, even when multiple objective measures of health status are included in models (for reviews, see Benyamini & Idler, 1999; Idler & Benyamini, 1997). We therefore tested whether including self-rated health, which was modestly related to neuroticism, rS = .23 (Gale et al., p. 1348), in a model changed the sign of the neuroticism–mortality relationship. We found that it did so and then set out to test two possible explanations for this phenomenon

Conditioning on a Collider May or May Not Explain the Relationship Between Lower Neuroticism and Premature Mortality in the Study by Gale et al. (2017): A Reply to Richardson, Davey Smith, and Munafò (2019)

We (Gale et al., 2017) analyzed data on 321,456 UK Biobank participants to address why higher neuroticism is sometimes related to lower mortality (e.g., Korten et al., 1999). We noted that the studies that revealed an inverse relationship between neuroticism and mortality included self-rated health as a predictor, perhaps because it is associated with mortality, even when multiple objective measures of health status are included in models (for reviews, see Benyamini & Idler, 1999; Idler & Benyamini, 1997). We therefore tested whether including self-rated health, which was modestly related to neuroticism, rS = .23 (Gale et al., p. 1348), in a model changed the sign of the neuroticism–mortality relationship. We found that it did so and then set out to test two possible explanations for this phenomenon

Associations between alcohol use and accelerated biological ageing

Harmful alcohol use is a leading cause of premature death and is associated with age-related disease. Biological ageing is highly variable between individuals and may deviate from chronological ageing, suggesting that biomarkers of biological ageing (derived from DNA methylation or brain structural measures) may be clinically relevant. Here, we investigated the relationships between alcohol phenotypes and both brain and DNA methylation age estimates. First, using data from UK Biobank and Generation Scotland, we tested the association between alcohol consumption (units/week) or hazardous use (Alcohol Use Disorders Identification Test [AUDIT] scores) and accelerated brain and epigenetic ageing in 20,258 and 8051 individuals, respectively. Second, we used Mendelian randomisation (MR) to test for a causal effect of alcohol consumption levels and alcohol use disorder (AUD) on biological ageing. Alcohol use showed a consistent positive association with higher predicted brain age (AUDIT-C: β = 0.053, p = 3.16 × 10−13; AUDIT-P: β = 0.052, p = 1.6 × 10−13; total AUDIT score: β = 0.062, p = 5.52 × 10−16; units/week: β = 0.078, p = 2.20 × 10−16), and two DNA methylation-based estimates of ageing, GrimAge (units/week: β = 0.053, p = 1.48 × 10−7) and PhenoAge (units/week: β = 0.077, p = 2.18x10−10). MR analyses revealed limited evidence for a causal effect of AUD on accelerated brain ageing (β = 0.118, p = 0.044). However, this result should be interpreted cautiously as the significant effect was driven by a single genetic variant. We found no evidence for a causal effect of alcohol consumption levels on accelerated biological ageing. Future studies investigating the mechanisms associating alcohol use with accelerated biological ageing are warranted

A Schwarz lemma for K\"ahler affine metrics and the canonical potential of a proper convex cone

This is an account of some aspects of the geometry of K\"ahler affine metrics based on considering them as smooth metric measure spaces and applying the comparison geometry of Bakry-Emery Ricci tensors. Such techniques yield a version for K\"ahler affine metrics of Yau's Schwarz lemma for volume forms. By a theorem of Cheng and Yau there is a canonical K\"ahler affine Einstein metric on a proper convex domain, and the Schwarz lemma gives a direct proof of its uniqueness up to homothety. The potential for this metric is a function canonically associated to the cone, characterized by the property that its level sets are hyperbolic affine spheres foliating the cone. It is shown that for an $n$-dimensional cone a rescaling of the canonical potential is an $n$-normal barrier function in the sense of interior point methods for conic programming. It is explained also how to construct from the canonical potential Monge-Amp\`ere metrics of both Riemannian and Lorentzian signatures, and a mean curvature zero conical Lagrangian submanifold of the flat para-K\"ahler space.Comment: Minor corrections. References adde

Inhibiting heat-shock protein 90 reverses sensory hypoalgesia in diabetic mice

Increasing the expression of Hsp70 (heat-shock protein 70) can inhibit sensory neuron degeneration after axotomy. Since the onset of DPN (diabetic peripheral neuropathy) is associated with the gradual decline of sensory neuron function, we evaluated whether increasing Hsp70 was sufficient to improve several indices of neuronal function. Hsp90 is the master regulator of the heat-shock response and its inhibition can up-regulate Hsp70. KU-32 (N-{7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2-yloxy]-8-methyl-2-oxo-2H-chromen-3-yl}acetamide) was developed as a novel, novobiocin-based, C-terminal inhibitor of Hsp90 whose ability to increase Hsp70 expression is linked to the presence of an acetamide substitution of the prenylated benzamide moiety of novobiocin. KU-32 protected against glucose-induced death of embryonic DRG (dorsal root ganglia) neurons cultured for 3 days in vitro. Similarly, KU-32 significantly decreased neuregulin 1-induced degeneration of myelinated Schwann cell DRG neuron co-cultures prepared from WT (wild-type) mice. This protection was lost if the co-cultures were prepared from Hsp70.1 and Hsp70.3 KO (knockout) mice. KU-32 is readily bioavailable and was administered once a week for 6 weeks at a dose of 20 mg/kg to WT and Hsp70 KO mice that had been rendered diabetic with streptozotocin for 12 weeks. After 12 weeks of diabetes, both WT and Hsp70 KO mice developed deficits in NCV (nerve conduction velocity) and a sensory hypoalgesia. Although KU-32 did not improve glucose levels, HbA1c (glycated haemoglobin) or insulin levels, it reversed the NCV and sensory deficits in WT but not Hsp70 KO mice. These studies provide the first evidence that targeting molecular chaperones reverses the sensory hypoalgesia associated with DPN