The Impact of Lower Extremity Skeletal Muscle Atrophy and Myosteatosis on Revascularization Outcomes in Patients with Peripheral Arterial Disease

Background: This study investigated whether lower extremity muscle atrophy and myosteatosis in patients with peripheral arterial disease (PAD) are correlated to postoperative outcomes, such as reintervention or amputation-free survival. Methods: In this single-center retrospective cohort study of 462 patients treated for peripheral arterial disease scheduled for intervention, muscle mass and the presence of fattening of the lower extremity muscles were measured semiautomatically in a single computed tomography slice of the treated leg. Binary logistic regression models and Cox proportional hazards models were used to determine the effect of muscle atrophy and myosteatosis on reintervention and amputation. Results: Muscle atrophy and myosteatosis increased in PAD patients with Fontaine class IV compared with Fontaine class IIa. In PAD patients with muscle atrophy or myosteatosis, no association was found with the reintervention rate or reintervention-free survival, but an association was found with amputation-free survival, even after adjustment for patient-related, disease-severity, and comorbidities-related factors. Conclusion: Muscle atrophy and mysosteatosis increased in PAD patients with increasing disease severity. Lower extremity muscle atrophy and myosteatosis are associated with amputation rate and amputation-free survival in PAD patients. No association with reintervention rate or reintervention-free survival was found. Muscle atrophy and myosteatosis may serve as additional risk factors in decision making in the often frail vascular patient

Validation of a Length-Adjusted Abdominal Arterial Calcium Score Method for Contrast-Enhanced CT Scans

BACKGROUND: The Agatston score on noncontrast computed tomography (CT) scans is the gold standard for calcium load determination. However, contrast-enhanced CT is commonly used for patients with atherosclerotic cardiovascular diseases (ASCVDs), such as peripheral arterial occlusive disease (PAOD) and abdominal aortic aneurysm (AAA). Currently, there is no validated method to determine calcium load in the aorta and peripheral arteries with a contrast-enhanced CT. This study validated a length-adjusted calcium score (LACS) method for contrast-enhanced CT scans.METHOD: The LACS (calcium volume in mm 3/arterial length in cm) in the abdominal aorta was calculated using four-phase liver CT scans of 30 patients treated between 2017 and 2021 at the University Medical Center Groningen (UMCG) with no aortic disease. Noncontrast CT scans were segmented with a 130 Hounsfield units (HU) threshold, and a patient-specific threshold was used for contrast-enhanced CTs. The LACS was calculated and compared from both segmentations. Secondly, the interobserver variability and the influence of slice thickness (0.75 mm vs. 2.0 mm) was determined. RESULTS: There was a high correlation between the LACS from contrast-enhanced CT scans and the LACS of noncontrast CTs ( R 2 = 0.98). A correction factor of 1.9 was established to convert the LACS derived from contrast-enhanced CT to noncontrast CT scans. LACS interobserver agreement on contrast-enhanced CT was excellent (1.0, 95% confidence interval = 1.0-1.0). The 0.75 mm CT threshold was 541 (459-625) HU compared with 500 (419-568) HU on 2 mm CTs ( p = 0.15). LACS calculated with both thresholds was not significantly different ( p = 0.63). CONCLUSION: The LACS seems to be a robust method for scoring calcium load on contrast-enhanced CT scans in arterial segments with various lengths.</p

The combined effect of two mutations that alter serially homologous color pattern elements on the fore and hindwings of a butterfly

<p>Abstract</p> <p>Background</p> <p>The ability for serially homologous structures to acquire a separate identity has been primarily investigated for structures dependent on Hox gene input but is still incompletely understood in other systems. The fore and hindwings of butterflies are serially homologous structures as are the serially homologous eyespots that can decorate each of these wings. Eyespots can vary in number between fore and hindwings of the same individual and mutations of large effect can control the total number of eyespots that each of the wings displays. Here we investigate the genetics of a new spontaneous color pattern mutation, <it>Missing</it>, that alters eyespot number in the nymphalid butterfly, <it>Bicyclus anynana</it>. We further test the interaction of <it>Missing </it>with a previously described mutation, <it>Spotty</it>, describe the developmental stage affected by <it>Missing</it>, and test whether <it>Missing </it>is a mutant variant of the gene <it>Distal-less </it>via a linkage association study.</p> <p>Results</p> <p><it>Missing </it>removes or greatly reduces the size of two of the hindwing eyespots from the row of seven eyespots, with no detectable effect on the rest of the wing pattern. Offspring carrying a single <it>Missing </it>allele display intermediate sized eyespots at these positions. <it>Spotty </it>has the opposite effect of <it>Missing</it>, i.e., it introduces two extra eyespots in homologous wing positions to those affected by <it>Missing</it>, but on the forewing. When <it>Missing </it>is combined with <it>Spotty </it>the size of the two forewing eyespots decreases but the size of the hindwing spots stays the same, suggesting that these two mutations have a combined effect on the forewing such that <it>Missing </it>reduces eyespot size when in the presence of a <it>Spotty </it>mutant allele, but that <it>Spotty </it>has no effect on the hindwing. <it>Missing </it>prevents the complete differentiation of two of the eyespot foci on the hindwing. We found no evidence for any linkage between the <it>Distal-less </it>and <it>Missing </it>genes.</p> <p>Conclusion</p> <p>The spontaneous mutation <it>Missing </it>controls the differentiation of the signaling centers of a subset of the serial homologous eyespots present on both the fore and the hindwing in a dose-dependent fashion. The effect of <it>Missing </it>on the forewing, however, is only observed when the mutation <it>Spotty </it>introduces additional eyespots on this wing. <it>Spotty</it>, on the other hand, controls the differentiation of eyespot centers only on the forewing. <it>Spotty</it>, unlike <it>Missing</it>, may be under Ubx gene regulation, since it affects a subset of eyespots on only one of the serially homologous wings.</p

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

African Linguistics in Central and Eastern Europe, and in the Nordic Countries

Non peer reviewe

Gene set enrichment analysis and expression pattern exploration implicate an involvement of neurodevelopmental processes in bipolar disorder

Bipolar disorder (BD) is a common and highly heritable disorder of mood. Genome-wide association studies (GWAS) have identified several independent susceptibility loci. In order to extract more biological information from GWAS data, multi-locus approaches represent powerful tools since they utilize knowledge about biological processes to integrate functional sets of genes at strongly to moderately associated loci.We conducted gene set enrichment analyses (GSEA) using 2.3 million single-nucleotide polymorphisms, 397 Reactome pathways and 24,025 patients with BD and controls. RNA expression of implicated individual genes and gene sets were examined in post-mortem brains across lifespan.Two pathways showed a significant enrichment after correction for multiple comparisons in the GSEA: GRB2 events in ERBB2 signaling, for which 6 of 21 genes were BD associated (PFDR = 0.0377), and NCAM signaling for neurite out-growth, for which 11 out of 62 genes were BD associated (PFDR = 0.0451). Most pathway genes showed peaks of RNA co-expression during fetal development and infancy and mapped to neocortical areas and parts of the limbic system.Pathway associations were technically reproduced by two methods, although they were not formally replicated in independent samples. Gene expression was explored in controls but not in patients.Pathway analysis in large GWAS data of BD and follow-up of gene expression patterns in healthy brains provide support for an involvement of neurodevelopmental processes in the etiology of this neuropsychiatric disease. Future studies are required to further evaluate the relevance of the implicated genes on pathway functioning and clinical aspects of BD

The genetics of the mood disorder spectrum:genome-wide association analyses of over 185,000 cases and 439,000 controls

Background Mood disorders (including major depressive disorder and bipolar disorder) affect 10-20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Despite their diagnostic distinction, multiple approaches have shown considerable sharing of risk factors across the mood disorders. Methods To clarify their shared molecular genetic basis, and to highlight disorder-specific associations, we meta-analysed data from the latest Psychiatric Genomics Consortium (PGC) genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; non-overlapping N = 609,424). Results Seventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More genome-wide significant loci from the PGC analysis of major depression than bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell-types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment – positive in bipolar disorder but negative in major depressive disorder. Conclusions The mood disorders share several genetic associations, and can be combined effectively to increase variant discovery. However, we demonstrate several differences between these disorders. Analysing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

publisher: Elsevier articletitle: Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes journaltitle: Cell articlelink: https://doi.org/10.1016/j.cell.2018.05.046 content_type: article copyright: © 2018 Elsevier Inc

Genetic Overlap Between Alzheimer’s Disease and Bipolar Disorder Implicates the MARK2 and VAC14 Genes

Background: Alzheimer's disease (AD) and bipolar disorder (BIP) are complex traits influenced by numerous common genetic variants, most of which remain to be detected. Clinical and epidemiological evidence suggest that AD and BIP are related. However, it is not established if this relation is of genetic origin. Here, we applied statistical methods based on the conditional false discovery rate (FDR) framework to detect genetic overlap between AD and BIP and utilized this overlap to increase the power to identify common genetic variants associated with either or both traits. Methods: We obtained genome wide association studies data from the International Genomics of Alzheimer's Project part 1 (17,008 AD cases and 37,154 controls) and the Psychiatric Genetic Consortium Bipolar Disorder Working Group (20,352 BIP cases and 31,358 controls). We used conditional QQ-plots to assess overlap in common genetic variants between AD and BIP. We exploited the genetic overlap to re-rank test-statistics for AD and BIP and improve detection of genetic variants using the conditional FDR framework. Results: Conditional QQ-plots demonstrated a polygenic overlap between AD and BIP. Using conditional FDR, we identified one novel genomic locus associated with AD, and nine novel loci associated with BIP. Further, we identified two novel loci jointly associated with AD and BIP implicating the MARK2 gene (lead SNP rs10792421, conjunctional FDR=0.030, same direction of effect) and the VAC14 gene (lead SNP rs11649476, conjunctional FDR=0.022, opposite direction of effect). Conclusions: We found polygenic overlap between AD and BIP and identified novel loci for each trait and two jointly associated loci. Further studies should examine if the shared loci implicating the MARK2 and VAC14 genes could explain parts of the shared and distinct features of AD and BIP