Admixture mapping of cognitive function in diverse Hispanic and Latino adults: Results from the Hispanic Community Health Study/Study of Latinos.

INTRODUCTION: We conducted admixture mapping and fine-mapping analyses to identify ancestry-of-origin loci influencing cognitive abilities. METHODS: We estimated the association of local ancestry intervals across the genome with five neurocognitive measures in 7140 diverse Hispanic and Latino adults (mean age 55 years). We prioritized genetic variants in associated loci and tested them for replication in four independent cohorts. RESULTS: We identified nine local ancestry-associated regions for the five neurocognitive measures. There was strong biological support for the observed associations to cognitive function at all loci and there was statistical evidence of independent replication at 4q12, 9p22.1, and 13q12.13. DISCUSSION: Our study identified multiple novel loci harboring genes implicated in cognitive functioning and dementia, and uncovered ancestry-relevant genetic variants. It adds to our understanding of the genetic architecture of cognitive function in Hispanic and Latino adults and demonstrates the power of admixture mapping to discover unique haplotypes influencing cognitive function, complementing genome-wide association studies. HIGHLIGHTS: We identified nine ancestry-of-origin chromosomal regions associated with five neurocognitive traits. In each associated region, we identified single nucleotide polymorphisms (SNPs) that explained, at least in part, the admixture signal and were tested for replication in independent samples of Black, non-Hispanic White, and Hispanic/Latino adults with the same or similar neurocognitive tests. Statistical evidence of independent replication of the prioritized SNPs was observed for three of the nine associations, at chr4q12, chr9p22.1, and chr13q12.13. At all loci, there was strong biological support for the observed associations to cognitive function and dementia, prioritizing genes such as KIT, implicated in autophagic clearance of neurotoxic proteins and on mast cell and microglial-mediated inflammation; SLC24A2, implicated in synaptic plasticity associated with learning and memory; and MTMR6, implicated in phosphoinositide lipids metabolism.

Independent inheritance of cognition and bipolar disorder in a family sample.

Cognitive deficits in people with bipolar disorder (BD) may be the result of the illness or its treatment, but they could also reflect genetic risk factors shared between BD and cognition. We investigated this question using empirical genetic relationships within a sample of patients with BD and their unaffected relatives. Participants with bipolar I, II, or schizoaffective disorder ("narrow" BD, n = 69), related mood disorders ("broad" BD, n = 135), and their clinically unaffected relatives (n = 227) completed five cognitive tests. General cognitive function (g) was quantified via principal components analysis (PCA). Heritability and genetic correlations were estimated with SOLAR-Eclipse. Participants with "narrow" or "broad" diagnoses showed deficits in g, although affect recognition was unimpaired. Cognitive performance was significantly heritable (h2 = 0.322 for g, p < 0.005). Coheritability between psychopathology and g was small (0.0184 for narrow and 0.0327 for broad) and healthy relatives of those with BD were cognitively unimpaired. In this family sample, cognitive deficits were present in participants with BD but were not explained by substantial overlaps in genetic determinants of mood and cognition. These findings support the view that cognitive deficits in BD are largely the result of the illness or its treatment.

Imaging local genetic influences on cortical folding.

Recent progress in deciphering mechanisms of human brain cortical folding leave unexplained whether spatially patterned genetic influences contribute to this folding. High-resolution in vivo brain MRI can be used to estimate genetic correlations (covariability due to shared genetic factors) in interregional cortical thickness, and biomechanical studies predict an influence of cortical thickness on folding patterns. However, progress has been hampered because shared genetic influences related to folding patterns likely operate at a scale that is much more local (<1 cm) than that addressed in prior imaging studies. Here, we develop methodological approaches to examine local genetic influences on cortical thickness and apply these methods to two large, independent samples. We find that such influences are markedly heterogeneous in strength, and in some cortical areas are notably stronger in specific orientations relative to gyri or sulci. The overall, phenotypic local correlation has a significant basis in shared genetic factors and is highly symmetric between left and right cortical hemispheres. Furthermore, the degree of local cortical folding relates systematically with the strength of local correlations, which tends to be higher in gyral crests and lower in sulcal fundi. The relationship between folding and local correlations is stronger in primary sensorimotor areas and weaker in association areas such as prefrontal cortex, consistent with reduced genetic constraints on the structural topology of association cortex. Collectively, our results suggest that patterned genetic influences on cortical thickness, measurable at the scale of in vivo MRI, may be a causal factor in the development of cortical folding.

How could online NHS 111 reduce demand for the telephone NHS 111 service? Qualitative study of user and staff views.

BACKGROUND: Online NHS111 was introduced in 2018 in response to increasing and unsustainable demand for telephone NHS111. Despite high levels of use, there is little evidence of channel shift from the telephone to the online service. We explored user and staff perspectives of online NHS111 to understand how and why online NHS111 is used and whether there may be potential for shift from the telephone to online service. METHODS: As part of a wider mixed-methods study, we used qualitative semistructured interviews to explore perspectives of recent users of online 111 who had responded to a user survey (n=32) and NHS 111 staff (n=16) between November 2019 and June 2020. Interviews were recorded and transcribed verbatim. The data sets were analysed separately using framework analysis (user interviews) and thematic analysis (staff interviews). RESULTS: Telephone NHS111 health adviser skills in probing and obtaining 'soft information' were perceived as key to obtaining advice that was considered more appropriate and trusted than advice from online interactions, which relied on oversimplified or irrelevant questions.Online NHS111 was perceived to provide a useful and convenient adjunct to the telephone service and widened access to NHS111 services for some subgroups of users who would not otherwise access the telephone service (eg, communication barriers, social anxiety) or were concerned about 'bothering' a health professional. The nature of the online consultation meant that online NHS111 was perceived as more disposable and used more speculatively. CONCLUSION: Online 111 was perceived as a useful adjunct but not a replacement for telephone NHS 111 with potential for channel shift hindered by reduced confidence in the online service due to the lack of human interaction. Further development of OL111 algorithms will be required if it is to meet the needs of people with more complex health needs.

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected ("concordant") direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive ("discordant") relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10-8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms-early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways-that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness.

Genetic influence on cognitive development between childhood and adulthood.

Successful cognitive development between childhood and adulthood has important consequences for future mental and physical wellbeing, as well as occupational and financial success. Therefore, delineating the genetic influences underlying changes in cognitive abilities during this developmental period will provide important insights into the biological mechanisms that govern both typical and atypical maturation. Using data from the Philadelphia Neurodevelopmental Cohort (PNC), a large population-based sample of individuals aged 8 to 21 years old (n = 6634), we used an empirical relatedness matrix to establish the heritability of general and specific cognitive functions and determine if genetic factors influence cognitive maturation (i.e., Gene × Age interactions) between childhood and early adulthood. We found that neurocognitive measures across childhood and early adulthood were significantly heritable. Moreover, genetic variance on general cognitive ability, or g, increased significantly between childhood and early adulthood. Finally, we did not find evidence for decay in genetic correlation on neurocognition throughout childhood and adulthood, suggesting that the same genetic factors underlie cognition at different ages throughout this developmental period. Establishing significant Gene × Age interactions in neurocognitive functions across childhood and early adulthood is a necessary first step in identifying genes that influence cognitive development, rather than genes that influence cognition per se. Moreover, since aberrant cognitive development confers risk for several psychiatric disorders, further examination of these Gene × Age interactions may provide important insights into their etiology.

Comparative efficacy of ravulizumab and eculizumab in the treatment of atypical hemolytic uremic syndrome: An indirect comparison using clinical trial data.

Ravulizumab and eculizumab are approved terminal complement inhibitor treatments for atypical hemolytic uremic syndrome (aHUS). Ravulizumab was engineered from eculizumab to have an increased half-life allowing for reduced dosing frequency (8-weekly vs. 2-weekly). To account for differences in respective clinical trials, a validated balancing technique was used to enable an indirect comparison of ravulizumab and eculizumab treatment efficacy in aHUS. Patient-level data from four eculizumab clinical trials were available for pooling and comparison with data from two ravulizumab trials. In the primary analysis, adult native kidney data were compared. Propensity scores were calculated from baseline characteristics (dialysis status, estimated glomerular filtration rate, platelet count, serum lactate dehydrogenase). Stabilized inverse probability weighting was used to balance groups. Changes in outcomes from baseline to 26 weeks were compared between treatment groups. Sensitivity and subgroup analyses were conducted to assess the robustness of findings. Overall, 85 patients (46 ravulizumab, 39 eculizumab) were included in the primary analysis. Demographic and clinical characteristics were well balanced after weighting at baseline. At 26 weeks, clinical outcomes (including renal function, hematological markers, and dialysis prevalence), and fatigue and quality of life measures were improved with eculizumab and ravulizumab treatment. No differences between treatment groups reached statistical significance, although confidence intervals were wide. Sensitivity and subgroup analysis results were consistent with those of the primary analysis. Using appropriate methodology for indirect comparison of studies, no differences in outcomes were seen between ravulizumab and eculizumab, although, owing to small sample sizes, confidence intervals were wide.

Tendency to call an ambulance or attend an emergency department for minor or non-urgent problems: a vignette-based population survey in Britain.

BACKGROUND: There are concerns about high levels of demand for emergency health services. The aim was to identify the characteristics of the British population with a tendency to contact emergency medical services and EDs for minor or non-urgent problems. METHODS: A survey of the British adult population in 2018. Six vignettes were constructed about illness in adults (cough/sore throat or diarrhoea/vomiting), injury in adults (sore rib or back pain) and fever in children (occurring weekday or weekend). RESULTS: The response rate was 42%, with 2906 respondents. 11% (319/2716) of respondents selected to contact an ambulance and 43% ED, mainly for the vignettes about fever in children and sore rib. Males, people from ethnic minority communities and older people had a tendency to contact emergency services for minor problems. Tendency to call an ambulance was also characterised by 'low resources' (manual or unskilled occupations, no car, low health literacy), worry that a symptom might be serious, distress (feeling overwhelmed by health problems) and frequent use of EDs. For EDs, there was an attraction to EDs because of availability of tests. CONCLUSION: Whereas use of emergency ambulances for minor or non-urgent problems appeared to be driven by people's lack of resources, including lack of transport, use of EDs appeared to be driven by their attractive characteristic of offering tests quickly.

Associations of cannabis use disorder with cognition, brain structure, and brain function in African Americans.

Although previous studies have highlighted associations of cannabis use with cognition and brain morphometry, critical questions remain with regard to the association between cannabis use and brain structural and functional connectivity. In a cross-sectional community sample of 205 African Americans (age 18-70) we tested for associations of cannabis use disorder (CUD, n = 57) with multi-domain cognitive measures and structural, diffusion, and resting state brain-imaging phenotypes. Post hoc model evidence was computed with Bayes factors (BF) and posterior probabilities of association (PPA) to account for multiple testing. General cognitive functioning, verbal intelligence, verbal memory, working memory, and motor speed were lower in the CUD group compared with non-users (p < .011; 1.9 < BF < 3,217). CUD was associated with altered functional connectivity in a network comprising the motor-hand region in the superior parietal gyri and the anterior insula (p < .04). These differences were not explained by alcohol, other drug use, or education. No associations with CUD were observed in cortical thickness, cortical surface area, subcortical or cerebellar volumes (0.12 < BF < 1.5), or graph-theoretical metrics of resting state connectivity (PPA < 0.01). In a large sample collected irrespective of cannabis used to minimize recruitment bias, we confirm the literature on poorer cognitive functioning in CUD, and an absence of volumetric brain differences between CUD and non-CUD. We did not find evidence for or against a disruption of structural connectivity, whereas we did find localized resting state functional dysconnectivity in CUD. There was sufficient proof, however, that organization of functional connectivity as determined via graph metrics does not differ between CUD and non-user group.

Genetic Contributions to Multivariate Data-Driven Brain Networks Constructed via Source-Based Morphometry.

Identifying genetic factors underlying neuroanatomical variation has been difficult. Traditional methods have used brain regions from predetermined parcellation schemes as phenotypes for genetic analyses, although these parcellations often do not reflect brain function and/or do not account for covariance between regions. We proposed that network-based phenotypes derived via source-based morphometry (SBM) may provide additional insight into the genetic architecture of neuroanatomy given its data-driven approach and consideration of covariance between voxels. We found that anatomical SBM networks constructed on ~ 20 000 individuals from the UK Biobank were heritable and shared functionally meaningful genetic overlap with each other. We additionally identified 27 unique genetic loci that contributed to one or more SBM networks. Both GWA and genetic correlation results indicated complex patterns of pleiotropy and polygenicity similar to other complex traits. Lastly, we found genetic overlap between a network related to the default mode and schizophrenia, a disorder commonly associated with neuroanatomic alterations.

Minimal Relationship between Local Gyrification and General Cognitive Ability in Humans.

Previous studies suggest that gyrification is associated with superior cognitive abilities in humans, but the strength of this relationship remains unclear. Here, in two samples of related individuals (total N = 2882), we calculated an index of local gyrification (LGI) at thousands of cortical surface points using structural brain images and an index of general cognitive ability (g) using performance on cognitive tests. Replicating previous studies, we found that phenotypic and genetic LGI-g correlations were positive and statistically significant in many cortical regions. However, all LGI-g correlations in both samples were extremely weak, regardless of whether they were significant or nonsignificant. For example, the median phenotypic LGI-g correlation was 0.05 in one sample and 0.10 in the other. These correlations were even weaker after adjusting for confounding neuroanatomical variables (intracranial volume and local cortical surface area). Furthermore, when all LGIs were considered together, at least 89% of the phenotypic variance of g remained unaccounted for. We conclude that the association between LGI and g is too weak to have profound implications for our understanding of the neurobiology of intelligence. This study highlights potential issues when focusing heavily on statistical significance rather than effect sizes in large-scale observational neuroimaging studies.

Understanding young adults' reasons for seeking 'clinically unnecessary' urgent and emergency care: A qualitative interview study.

BACKGROUND: Studies have identified young adults as more likely to use emergency departments for 'clinically unnecessary' problems, with limited similar evidence for emergency ambulance use. Media portrayals depict young adults as motivated by 'convenience', but little research has explored the reasons for their help-seeking behaviour. METHODS: Qualitative interviews with 16 young adults (18-30) considered by clinicians to have made unnecessary use of emergency ambulance, emergency department or an urgent GP appointment. Data analysis was informed by interpretive phenomenological analysis. FINDINGS: A number of interrelated factors contributed to participants' decisions. They were anxious about the seriousness of their symptoms, sometimes exacerbated by reduced coping capacity due to poor mental health or life stresses. They looked to others to facilitate their decision making, who sometimes encouraged urgent contact. They wanted to avoid impact on existing day-to-day commitments including work or study. They had strong views about different health services, sometimes based on frustration with lack of resolution of on-going health problems. Convenience was not identified as a significant factor, although some actions could be interpreted in this light if the context was not considered. CONCLUSIONS: Young adults make 'clinically unnecessary' use of urgent and emergency care for more than convenience. Their decisions need to be understood in relation to the complexity of their experience, including lack of confidence in making health-related decisions, lowered coping capacity and concern to maintain normal daily life.

Neurocognitive impairment in type 2 diabetes: evidence for shared genetic aetiology.

AIMS/HYPOTHESIS: Type 2 diabetes is associated with cognitive impairments, but it is unclear whether common genetic factors influence both type 2 diabetes risk and cognition. METHODS: Using data from 1892 Mexican-American individuals from extended pedigrees, including 402 with type 2 diabetes, we examined possible pleiotropy between type 2 diabetes and cognitive functioning, as measured by a comprehensive neuropsychological test battery. RESULTS: Negative phenotypic correlations (ρp) were observed between type 2 diabetes and measures of attention (Continuous Performance Test [CPT d']: ρp = -0.143, p = 0.001), verbal memory (California Verbal Learning Test [CVLT] recall: ρp = -0.111, p = 0.004) and face memory (Penn Face Memory Test [PFMT]: ρp = -0.127, p = 0.002; PFMT Delayed: ρp = -0.148, p = 2 × 10-4), replicating findings of cognitive impairment in type 2 diabetes. Negative genetic correlations (ρg) were also observed between type 2 diabetes and measures of attention (CPT d': ρg = -0.401, p = 0.001), working memory (digit span backward test: ρg = -0.380, p = 0.005), and face memory (PFMT: ρg = -0.476, p = 2 × 10-4; PFMT Delayed: ρg = -0.376, p = 0.005), suggesting that the same genetic factors underlying risk for type 2 diabetes also influence poor cognitive performance in these domains. Performance in these domains was also associated with type 2 diabetes risk using an endophenotype ranking value approach. Specifically, on measures of attention (CPT d': ß = -0.219, p = 0.005), working memory (digit span backward: ß = -0.326, p = 0.035), and face memory (PFMT: ß = -0.171, p = 0.023; PFMT Delayed: ß = -0.215, p = 0.005), individuals with type 2 diabetes showed the lowest performance, while unaffected/unrelated individuals showed the highest performance, and those related to an individual with type 2 diabetes performed at an intermediate level. CONCLUSIONS/INTERPRETATION: These findings suggest that cognitive impairment may be a useful endophenotype of type 2 diabetes and, therefore, help to elucidate the pathophysiological underpinnings of this chronic disease. DATA AVAILABILITY: The data analysed in this study is available in dbGaP: www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001215.v2.p2.

Cognitive impairment from early to middle adulthood in patients with affective and nonaffective psychotic disorders.

BACKGROUND: Cognitive impairment is a core feature of psychotic disorders, but the profile of impairment across adulthood, particularly in African-American populations, remains unclear. METHODS: Using cross-sectional data from a case-control study of African-American adults with affective (n = 59) and nonaffective (n = 68) psychotic disorders, we examined cognitive functioning between early and middle adulthood (ages 20-60) on measures of general cognitive ability, language, abstract reasoning, processing speed, executive function, verbal memory, and working memory. RESULTS: Both affective and nonaffective psychosis patients showed substantial and widespread cognitive impairments. However, comparison of cognitive functioning between controls and psychosis groups throughout early (ages 20-40) and middle (ages 40-60) adulthood also revealed age-associated group differences. During early adulthood, the nonaffective psychosis group showed increasing impairments with age on measures of general cognitive ability and executive function, while the affective psychosis group showed increasing impairment on a measure of language ability. Impairments on other cognitive measures remained mostly stable, although decreasing impairments on measures of processing speed, memory and working memory were also observed. CONCLUSIONS: These findings suggest similarities, but also differences in the profile of cognitive dysfunction in adults with affective and nonaffective psychotic disorders. Both affective and nonaffective patients showed substantial and relatively stable impairments across adulthood. The nonaffective group also showed increasing impairments with age in general and executive functions, and the affective group showed an increasing impairment in verbal functions, possibly suggesting different underlying etiopathogenic mechanisms.

Rediscovering the value of families for psychiatric genetics research.

As it is likely that both common and rare genetic variation are important for complex disease risk, studies that examine the full range of the allelic frequency distribution should be utilized to dissect the genetic influences on mental illness. The rate limiting factor for inferring an association between a variant and a phenotype is inevitably the total number of copies of the minor allele captured in the studied sample. For rare variation, with minor allele frequencies of 0.5% or less, very large samples of unrelated individuals are necessary to unambiguously associate a locus with an illness. Unfortunately, such large samples are often cost prohibitive. However, by using alternative analytic strategies and studying related individuals, particularly those from large multiplex families, it is possible to reduce the required sample size while maintaining statistical power. We contend that using whole genome sequence (WGS) in extended pedigrees provides a cost-effective strategy for psychiatric gene mapping that complements common variant approaches and WGS in unrelated individuals. This was our impetus for forming the "Pedigree-Based Whole Genome Sequencing of Affective and Psychotic Disorders" consortium. In this review, we provide a rationale for the use of WGS with pedigrees in modern psychiatric genetics research. We begin with a focused review of the current literature, followed by a short history of family-based research in psychiatry. Next, we describe several advantages of pedigrees for WGS research, including power estimates, methods for studying the environment, and endophenotypes. We conclude with a brief description of our consortium and its goals.

Health literacy levels of British adults: a cross-sectional survey using two domains of the Health Literacy Questionnaire (HLQ).

BACKGROUND: A person's health literacy determines whether they are able to make appropriate health decisions and are able to follow treatment instructions. This is important because low health literacy is associated with mortality and extra costs to the healthcare system. Our aim was to describe the health literacy levels of British adults using a nationally representative population survey, and show how health literacy levels vary by population characteristics. METHODS: A population based cross-sectional survey including questions from two domains from the Health Literacy Questionnaire™: 1) Understanding health information well enough to know what to do, and 2) Ability to actively engage with health care providers. Both domains are made up of 5 Likert style questions with 5 levels ranging from 'cannot do or always difficult' (1) to 'always easy' (5). The survey was conducted by NatCen in Britain (2018) as part of the annual British Social Attitudes survey. We used weighted descriptive analyses and regression to explore the relationship between population characteristics and health literacy. Weighted analyses were used to ensure the sample was representative of the British population. RESULTS: A total of 2309 responded to the questionnaire. The mean score for 'understanding information' was 3.98 (95% CI: 3.94, 4.02) and for 'ability to engage' was 3.83 (95% CI: 3.80, 3.87), where 5 is the highest score. 19.4% had some level of difficulty reading and understanding written health information, and 23.2% discussing health concerns with health care providers. The adjusted logistic regression for 'understanding information' showed that those with lower health literacy were more likely to be in the most socially deprived quintile (OR 2.500 95% CI: 1.180, 5.296), have a limiting health condition or disability (OR 4.326 95% CI: 2.494, 7.704), and have no educational qualifications (OR 7.588 95% CI: 3.305, 17.422). This was similar for the 'ability to engage' domain. CONCLUSIONS: This study described the distribution of health literacy levels for the British population in 2018. Interventions to improve health literacy will best be targeted at those with lower levels of education, those living in the most deprived areas, and those with a limiting health condition or disability.

Evidence for genetic correlation between human cerebral white matter microstructure and inflammation.

White matter microstructure is affected by immune system activity via the actions of circulating pro-inflammatory cytokines. Although white matter microstructure and inflammatory measures are significantly heritable, it is unclear if overlapping genetic factors influence these traits in humans. We conducted genetic correlation analyses of these traits using randomly ascertained extended pedigrees from the Genetics of Brain Structure and Function Study (N = 1862, 59% females, ages 18-97 years; 42 ± 15.7). White matter microstructure was assessed using fractional anisotropy (FA) calculated from diffusion tensor imaging (DTI). Circulating levels (pg/mL) of pro-inflammatory cytokines (IL-6, IL-8, and TNFα) phenotypically associated with white matter microstructure were quantified from blood serum. All traits were significantly heritable (h2 ranging from 0.41 to 0.66 for DTI measures and from 0.18 to 0.30 for inflammatory markers). Phenotypically, higher levels of circulating inflammatory markers were associated with lower FA values across the brain (r = -.03 to r = -.17). There were significant negative genetic correlations between most DTI measures and IL-8 and TNFα, although effects for TNFα were no longer significant when covarying for body mass index. Genetic correlations between DTI measures and IL-6 were not significant. Understanding the genetic correlation between specific inflammatory markers and DTI measures may help researchers focus questions related to inflammatory processes and brain structure.

The impact of closing emergency departments on mortality in emergencies: an observational study.

BACKGROUND: In England the demand for emergency care is increasing, while there is also a staffing shortage. This has implications for quality of care and patient safety. One solution may be to concentrate resources on fewer sites by closing or downgrading emergency departments (EDs). Our aim was to quantify the impact of such reorganisation on population mortality. METHODS: We undertook a controlled interrupted time series analysis to detect the impact of closing or downgrading five EDs, which occurred due to concerns regarding sustainability. We obtained mortality data from 2007 to 2014 using national databases. To establish ED resident catchment populations, estimated journey times by road were supplied by the Department for Transport. Other major changes in the emergency and urgent care system were determined by analysis of annual NHS Trust reports in each geographical area studied. Our main outcome measures were mortality and case fatality for a set of 16 serious emergency conditions. RESULTS: For residents in the areas affected by closure, journey time to the nearest ED increased (median change 9 min, range 0-25 min). We found no statistically reliable evidence of a change in overall mortality following reorganisation of ED care in any of the five areas or overall (+2.5% more deaths per month on average; 95% CI -5.2% to +10.2%; p=0.52). There was some evidence to suggest that, on average across the five areas, there was a small increase in case fatality, an indicator of the 'risk of death' (+2.3%, 95% CI +0.9% to+3.6%; p<0.001), but this may have arisen due to changes in hospital admissions. CONCLUSIONS: We found no evidence that reorganisation of emergency care was associated with a change in population mortality in the five areas studied. Further research should establish the economic consequences and impact on patient experience and neighbouring hospitals.

Epigenetic Age Acceleration Assessed with Human White-Matter Images.

The accurate estimation of age using methylation data has proved a useful and heritable biomarker, with acceleration in epigenetic age predicting a number of age-related phenotypes. Measures of white matter integrity in the brain are also heritable and highly sensitive to both normal and pathological aging processes across adulthood. We consider the phenotypic and genetic interrelationships between epigenetic age acceleration and white matter integrity in humans. Our goal was to investigate processes that underlie interindividual variability in age-related changes in the brain. Using blood taken from a Mexican-American extended pedigree sample (n = 628; age = 23.28-93.11 years), epigenetic age was estimated using the method developed by Horvath (2013). For n = 376 individuals, diffusion tensor imaging scans were also available. The interrelationship between epigenetic age acceleration and global white matter integrity was investigated with variance decomposition methods. To test for neuroanatomical specificity, 16 specific tracts were additionally considered. We observed negative phenotypic correlations between epigenetic age acceleration and global white matter tract integrity (ρpheno = -0.119, p = 0.028), with evidence of shared genetic (ρgene = -0.463, p = 0.013) but not environmental influences. Negative phenotypic and genetic correlations with age acceleration were also seen for a number of specific white matter tracts, along with additional negative phenotypic correlations between granulocyte abundance and white matter integrity. These findings (i.e., increased acceleration in epigenetic age in peripheral blood correlates with reduced white matter integrity in the brain and shares common genetic influences) provide a window into the neurobiology of aging processes within the brain and a potential biomarker of normal and pathological brain aging.SIGNIFICANCE STATEMENT Epigenetic measures can be used to predict age with a high degree of accuracy and so capture acceleration in biological age, relative to chronological age. The white matter tracts within the brain are also highly sensitive to aging processes. We show that increased biological aging (measured using epigenetic data from blood samples) is correlated with reduced integrity of white matter tracts within the human brain (measured using diffusion tensor imaging) with data from a large sample of Mexican-American families. Given the family design of the sample, we are also able to demonstrate that epigenetic aging and white matter tract integrity also share common genetic influences. Therefore, epigenetic age may be a potential, and accessible, biomarker of brain aging.

Shared Genetic Factors Influence Head Motion During MRI and Body Mass Index.

Head movements are typically viewed as a nuisance to functional magnetic resonance imaging (fMRI) analysis, and are particularly problematic for resting state fMRI. However, there is growing evidence that head motion is a behavioral trait with neural and genetic underpinnings. Using data from a large randomly ascertained extended pedigree sample of Mexican Americans (n = 689), we modeled the genetic structure of head motion during resting state fMRI and its relation to 48 other demographic and behavioral phenotypes. A replication analysis was performed using data from the Human Connectome Project, which uses an extended twin design (n = 864). In both samples, head motion was significantly heritable (h2 = 0.313 and 0.427, respectively), and phenotypically correlated with numerous traits. The most strongly replicated relationship was between head motion and body mass index, which showed evidence of shared genetic influences in both data sets. These results highlight the need to view head motion in fMRI as a complex neurobehavioral trait correlated with a number of other demographic and behavioral phenotypes. Given this, when examining individual differences in functional connectivity, the confounding of head motion with other traits of interest needs to be taken into consideration alongside the critical important of addressing head motion artifacts.