Chest CT scoring for evaluation of lung sequelae in congenital diaphragmatic hernia survivors

Objectives Data on long-term structural lung abnormalities in survivors of congenital diaphragmatic hernia (CDH) is scarce. The purpose of this study was to develop a chest computed tomography (CT) score to assess the structural lung sequelae in CDH survivors and to study the correlation between the CT scoring and clinical parameters in the neonatal period and at 1 year of follow-up. Methods A prospective, clinical follow-up program is organised for CDH survivors at the University Hospital of Leuven including a chest CT at the age of 1 year. The CT scoring used and evaluated, named CDH-CT score, was adapted from the revised Aukland score for chronic lung disease of prematurity. Results Thirty-five patients were included. All CT scans showed some pulmonary abnormalities, ranging from very mild to severe. The mean total CT score was 16 (IQR: 9-23), with the greatest contribution from the subscores for decreased attenuation (5; IQR: 2-8), subpleural linear and triangular opacities (4; IQR: 3-5), and atelectasis/consolidation (2; IQR: 1-3). Interobserver and intraobserver agreement was very good for the total score (ICC coefficient > 0.9). Total CT score correlated with number of neonatal days ventilated/on oxygen as well as with respiratory symptoms and feeding problems at 1 year of age. Conclusion The CDH-CT scoring tool has a good intraobserver and interobserver repeatability and correlates with relevant clinical parameters. This holds promise for its use in clinical follow-up and as outcome parameter in clinical interventional studies

Multi-site genetic analysis of diffusion images and voxelwise heritability analysis : a pilot project of the ENIGMA–DTI working group

The ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Consortium was set up to analyze brain measures and genotypes from multiple sites across the world to improve the power to detect genetic variants that influence the brain. Diffusion tensor imaging (DTI) yields quantitative measures sensitive to brain development and degeneration, and some common genetic variants may be associated with white matter integrity or connectivity. DTI measures, such as the fractional anisotropy (FA) of water diffusion, may be useful for identifying genetic variants that influence brain microstructure. However, genome-wide association studies (GWAS) require large populations to obtain sufficient power to detect and replicate significant effects, motivating a multi-site consortium effort. As part of an ENIGMA–DTI working group, we analyzed high-resolution FA images from multiple imaging sites across North America, Australia, and Europe, to address the challenge of harmonizing imaging data collected at multiple sites. Four hundred images of healthy adults aged 18–85 from four sites were used to create a template and corresponding skeletonized FA image as a common reference space. Using twin and pedigree samples of different ethnicities, we used our common template to evaluate the heritability of tract-derived FA measures. We show that our template is reliable for integrating multiple datasets by combining results through meta-analysis and unifying the data through exploratory mega-analyses. Our results may help prioritize regions of the FA map that are consistently influenced by additive genetic factors for future genetic discovery studies. Protocols and templates are publicly available at (http://enigma.loni.ucla.edu/ongoing/dti-working-group/)

Hypomorphic PCNA mutation underlies a novel human DNA repair disorder

A number of human disorders, including Cockayne syndrome, UV-sensitive syndrome, xeroderma pigmentosum and trichothiodystrophy, result from the mutation of genes encoding molecules important for nucleotide excision repair. Here, we describe a novel syndrome in which the cardinal clinical features include postnatal growth retardation, hearing loss, premature aging, telangiectasia, neurological signs and photosensitivity, resulting from a homozygous missense (p.Ser228Ile) sequence alteration of the proliferating cell nuclear antigen (PCNA). PCNA is a highly conserved sliding clamp protein essential for DNA replication and repair. Due to this fundamental role, mutations in PCNA that profoundly impair protein function would be incompatible with life. Interestingly, while the p.Ser228Ile alteration appears to have no effect on protein levels or DNA replication, patient cells exhibit significant abnormalities in response to UV irradiation displaying substantial reductions in both UV survival and RNA synthesis recovery. The p.Ser228Ile change also profoundly alters PCNA’s interaction with Flap endonuclease 1 and DNA Ligase 1, DNA metabolism enzymes. Taken together our findings detail the first mutation of PCNA in humans, associated with a unique neurodegenerative disease displaying clinical and molecular features common to other DNA repair disorders, which we show to be attributable to a hypomorphic amino acid alteration

Reply to: New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process?

This work was supported by National Institute of Biomedical Imaging and Bioengineering Grant No. U54EB020403 (to the ENIGMA consortium)

Multi-Ancestry Genome-Wide Association Study of Cannabis Use Disorder Yields Insight Into Disease Biology and Public Health Implications

As recreational use of cannabis is being decriminalized in many places and medical use widely sanctioned, there are growing concerns about increases in cannabis use disorder (CanUD), which is associated with numerous medical comorbidities. Here we performed a genome-wide association study of CanUD in the Million Veteran Program (MVP), followed by meta-analysis in 1,054,365 individuals (ncases = 64,314) from four broad ancestries designated by the reference panel used for assignment (European n = 886,025, African n = 123,208, admixed American n = 38,289 and East Asian n = 6,843). Population-specific methods were applied to calculate single nucleotide polymorphism-based heritability within each ancestry. Statistically significant single nucleotide polymorphism-based heritability for CanUD was observed in all but the smallest population (East Asian). We discovered genome-wide significant loci unique to each ancestry: 22 in European, 2 each in African and East Asian, and 1 in admixed American ancestries. A genetically informed causal relationship analysis indicated a possible effect of genetic liability for CanUD on lung cancer risk, suggesting potential unanticipated future medical and psychiatric public health consequences that require further study to disentangle from other known risk factors such as cigarette smoking