Imaging Alzheimer's genetic risk using Diffusion MRI: a systematic review

Diffusion magnetic resonance imaging (dMRI) is an imaging technique which probes the random motion of water molecules in tissues and has been widely applied to investigate changes in white matter microstructure in Alzheimer’s Disease. This paper aims to systematically review studies that examined the effect of Alzheimer’s risk genes on white matter microstructure. We assimilated findings from 37 studies and reviewed their diffusion pre-processing and analysis methods. Most studies estimate the diffusion tensor (DT) and compare derived quantitative measures such as fractional anisotropy and mean diffusivity between groups. Those with increased AD genetic risk are associated with reduced anisotropy and increased diffusivity across the brain, most notably the temporal and frontal lobes, cingulum and corpus callosum. Structural abnormalities are most evident amongst those with established Alzheimer’s Disease. Recent studies employ signal representations and analysis frameworks beyond DT MRI but show that dMRI overall lacks specificity to disease pathology. However, as the field advances, these techniques may prove useful in pre-symptomatic diagnosis or staging of Alzheimer’s disease

The impact of genetic risk for Alzheimer’s disease on the structural brain networks of young adults

INTRODUCTION: We investigated the structural brain networks of 562 young adults in relation to polygenic risk for Alzheimer’s disease, using magnetic resonance imaging (MRI) and genotype data from the Avon Longitudinal Study of Parents and Children. METHODS: Diffusion MRI data were used to perform whole-brain tractography and generate structural brain networks for the whole-brain connectome, and for the default mode, limbic and visual subnetworks. The mean clustering coefficient, mean betweenness centrality, characteristic path length, global efficiency and mean nodal strength were calculated for these networks, for each participant. The connectivity of the rich-club, feeder and local connections was also calculated. Polygenic risk scores (PRS), estimating each participant’s genetic risk, were calculated at genome-wide level and for nine specific disease pathways. Correlations were calculated between the PRS and (a) the graph theoretical metrics of the structural networks and (b) the rich-club, feeder and local connectivity of the whole-brain networks. RESULTS: In the visual subnetwork, the mean nodal strength was negatively correlated with the genome-wide PRS (r = –0.19, p = 1.4 × 10(–3)), the mean betweenness centrality was positively correlated with the plasma lipoprotein particle assembly PRS (r = 0.16, p = 5.5 × 10(–3)), and the mean clustering coefficient was negatively correlated with the tau-protein binding PRS (r = –0.16, p = 0.016). In the default mode network, the mean nodal strength was negatively correlated with the genome-wide PRS (r = –0.14, p = 0.044). The rich-club and feeder connectivities were negatively correlated with the genome-wide PRS (r = –0.16, p = 0.035; r = –0.15, p = 0.036). DISCUSSION: We identified small reductions in brain connectivity in young adults at risk of developing Alzheimer’s disease in later life

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10 years; 78.2% included were male with a median age of 37 years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Extending the frontiers of neuroimaging: an introduction to Diffusion Tensor Imaging Tractography

Summary: The use of Diffusion Tensor Imaging (DTI) tractography has exploded over the past two decades, proving to be a major advancement in the current methods for exploring the architecture of white matter tracts in the living human brain. Despite making up 50% of brain tissue, investigations into the function of white matter have long remained in the background of medical research. Consequently, white matter pathology cited in neuropsychiatric disease remains a heavy burden of human illness. Nonetheless, with novel diffusion MRI techniques, including DTI tractography, we are able to visualise areas of the brain better than ever before, furthering our understanding of white matter beyond the crude depictions offered by conventional MRI. Relevance: It is important that medical students have an understanding of DTI tractography because it has the potential to illuminate mechanisms that underpin cognition and emotion through the creation of connectional maps. Furthermore, advances in MR technology should not be restricted to the territory of academics. Instead, both medical students and clinicians should be able to draw upon the current research methods to improve the care and understanding of patients with white matter pathology. Take Home Messages: 1. Diffusion Tensor Imaging is a diffusion MRI technique that depicts the movement of water molecules along major white matter pathways in the living brain. 2. Using information from DTI, tractography software virtually reconstructs white matter tracts and can be used to make dissections of major fasciculi in vivo. 3. DTI tractography remains the only non-invasive method to study white matter tracts in the living human brain. 4. Results from tractography are increasingly being used in neuropsychiatric research. 5. Despite its potential, DTI tractography still faces a number of challenges. The most prominent of these being its inability to accurately map crossing fibres within a voxel

Data_Sheet_1_The impact of genetic risk for Alzheimer’s disease on the structural brain networks of young adults.docx

IntroductionWe investigated the structural brain networks of 562 young adults in relation to polygenic risk for Alzheimer’s disease, using magnetic resonance imaging (MRI) and genotype data from the Avon Longitudinal Study of Parents and Children.MethodsDiffusion MRI data were used to perform whole-brain tractography and generate structural brain networks for the whole-brain connectome, and for the default mode, limbic and visual subnetworks. The mean clustering coefficient, mean betweenness centrality, characteristic path length, global efficiency and mean nodal strength were calculated for these networks, for each participant. The connectivity of the rich-club, feeder and local connections was also calculated. Polygenic risk scores (PRS), estimating each participant’s genetic risk, were calculated at genome-wide level and for nine specific disease pathways. Correlations were calculated between the PRS and (a) the graph theoretical metrics of the structural networks and (b) the rich-club, feeder and local connectivity of the whole-brain networks.ResultsIn the visual subnetwork, the mean nodal strength was negatively correlated with the genome-wide PRS (r = –0.19, p = 1.4 × 10–3), the mean betweenness centrality was positively correlated with the plasma lipoprotein particle assembly PRS (r = 0.16, p = 5.5 × 10–3), and the mean clustering coefficient was negatively correlated with the tau-protein binding PRS (r = –0.16, p = 0.016). In the default mode network, the mean nodal strength was negatively correlated with the genome-wide PRS (r = –0.14, p = 0.044). The rich-club and feeder connectivities were negatively correlated with the genome-wide PRS (r = –0.16, p = 0.035; r = –0.15, p = 0.036).DiscussionWe identified small reductions in brain connectivity in young adults at risk of developing Alzheimer’s disease in later life.</p

Genomic reconstruction of the SARS-CoV-2 epidemic in England

AbstractThe evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus leads to new variants that warrant timely epidemiological characterization. Here we use the dense genomic surveillance data generated by the COVID-19 Genomics UK Consortium to reconstruct the dynamics of 71 different lineages in each of 315 English local authorities between September 2020 and June 2021. This analysis reveals a series of subepidemics that peaked in early autumn 2020, followed by a jump in transmissibility of the B.1.1.7/Alpha lineage. The Alpha variant grew when other lineages declined during the second national lockdown and regionally tiered restrictions between November and December 2020. A third more stringent national lockdown suppressed the Alpha variant and eliminated nearly all other lineages in early 2021. Yet a series of variants (most of which contained the spike E484K mutation) defied these trends and persisted at moderately increasing proportions. However, by accounting for sustained introductions, we found that the transmissibility of these variants is unlikely to have exceeded the transmissibility of the Alpha variant. Finally, B.1.617.2/Delta was repeatedly introduced in England and grew rapidly in early summer 2021, constituting approximately 98% of sampled SARS-CoV-2 genomes on 26 June 2021.</jats:p

Prospective observational cohort study on grading the severity of postoperative complications in global surgery research

Background The Clavien–Dindo classification is perhaps the most widely used approach for reporting postoperative complications in clinical trials. This system classifies complication severity by the treatment provided. However, it is unclear whether the Clavien–Dindo system can be used internationally in studies across differing healthcare systems in high- (HICs) and low- and middle-income countries (LMICs). Methods This was a secondary analysis of the International Surgical Outcomes Study (ISOS), a prospective observational cohort study of elective surgery in adults. Data collection occurred over a 7-day period. Severity of complications was graded using Clavien–Dindo and the simpler ISOS grading (mild, moderate or severe, based on guided investigator judgement). Severity grading was compared using the intraclass correlation coefficient (ICC). Data are presented as frequencies and ICC values (with 95 per cent c.i.). The analysis was stratified by income status of the country, comparing HICs with LMICs. Results A total of 44 814 patients were recruited from 474 hospitals in 27 countries (19 HICs and 8 LMICs). Some 7508 patients (16·8 per cent) experienced at least one postoperative complication, equivalent to 11 664 complications in total. Using the ISOS classification, 5504 of 11 664 complications (47·2 per cent) were graded as mild, 4244 (36·4 per cent) as moderate and 1916 (16·4 per cent) as severe. Using Clavien–Dindo, 6781 of 11 664 complications (58·1 per cent) were graded as I or II, 1740 (14·9 per cent) as III, 2408 (20·6 per cent) as IV and 735 (6·3 per cent) as V. Agreement between classification systems was poor overall (ICC 0·41, 95 per cent c.i. 0·20 to 0·55), and in LMICs (ICC 0·23, 0·05 to 0·38) and HICs (ICC 0·46, 0·25 to 0·59). Conclusion Caution is recommended when using a treatment approach to grade complications in global surgery studies, as this may introduce bias unintentionally

The surgical safety checklist and patient outcomes after surgery: a prospective observational cohort study, systematic review and meta-analysis

© 2017 British Journal of Anaesthesia Background: The surgical safety checklist is widely used to improve the quality of perioperative care. However, clinicians continue to debate the clinical effectiveness of this tool. Methods: Prospective analysis of data from the International Surgical Outcomes Study (ISOS), an international observational study of elective in-patient surgery, accompanied by a systematic review and meta-analysis of published literature. The exposure was surgical safety checklist use. The primary outcome was in-hospital mortality and the secondary outcome was postoperative complications. In the ISOS cohort, a multivariable multi-level generalized linear model was used to test associations. To further contextualise these findings, we included the results from the ISOS cohort in a meta-analysis. Results are reported as odds ratios (OR) with 95% confidence intervals. Results: We included 44 814 patients from 497 hospitals in 27 countries in the ISOS analysis. There were 40 245 (89.8%) patients exposed to the checklist, whilst 7508 (16.8%) sustained ≥1 postoperative complications and 207 (0.5%) died before hospital discharge. Checklist exposure was associated with reduced mortality [odds ratio (OR) 0.49 (0.32–0.77); P\u3c0.01], but no difference in complication rates [OR 1.02 (0.88–1.19); P=0.75]. In a systematic review, we screened 3732 records and identified 11 eligible studies of 453 292 patients including the ISOS cohort. Checklist exposure was associated with both reduced postoperative mortality [OR 0.75 (0.62–0.92); P\u3c0.01; I2=87%] and reduced complication rates [OR 0.73 (0.61–0.88); P\u3c0.01; I2=89%). Conclusions: Patients exposed to a surgical safety checklist experience better postoperative outcomes, but this could simply reflect wider quality of care in hospitals where checklist use is routine

Critical care admission following elective surgery was not associated with survival benefit: prospective analysis of data from 27 countries

This was an investigator initiated study funded by Nestle Health Sciences through an unrestricted research grant, and by a National Institute for Health Research (UK) Professorship held by RP. The study was sponsored by Queen Mary University of London