Health inequalities in cardiopulmonary resuscitation and use of automated electrical defibrillators in out-of-hospital cardiac arrest.

Out of hospital cardiac arrest (OHCA) outcomes can be improved by strengthening the chain of survival, namely prompt cardiopulmonary resuscitation (CPR) and automated external defibrillator (AED). However, provision of bystander CPR and AED use remains low due to individual patient factors ranging from lack of education to socioeconomic barriers and due to lack of resources such as limited availability of AEDs in the community. Although the impact of health inequalities on survival from OHCA is documented, it is imperative that we identify and implement strategies to improve public health and outcomes from OHCA overall but with a simultaneous emphasis on making care more equitable. Disparities in CPR delivery and AED use in OHCA exist based on factors including sex, education level, socioeconomic status, race and ethnicity, all of which we discuss in this review. Most importantly, we discuss the barriers to AED use, and strategies on how these may be overcome.

Modelling renal defects in Bardet-Biedl syndrome patients using human iPS cells.

Bardet-Biedl syndrome (BBS) is a ciliopathy with pleiotropic effects on multiple tissues, including the kidney. Here we have compared renal differentiation of iPS cells from healthy and BBS donors. High content image analysis of WT1-expressing kidney progenitors showed that cell proliferation, differentiation and cell shape were similar in healthy, BBS1, BBS2, and BBS10 mutant lines. We then examined three patient lines with BBS10 mutations in a 3D kidney organoid system. The line with the most deleterious mutation, with low BBS10 expression, expressed kidney marker genes but failed to generate 3D organoids. The other two patient lines expressed near normal levels of BBS10 mRNA and generated multiple kidney lineages within organoids when examined at day 20 of organoid differentiation. However, on prolonged culture (day 27) the proximal tubule compartment degenerated. Introducing wild type BBS10 into the most severely affected patient line restored organoid formation, whereas CRISPR-mediated generation of a truncating BBS10 mutation in a healthy line resulted in failure to generate organoids. Our findings provide a basis for further mechanistic studies of the role of BBS10 in the kidney.

Integrated Multiparametric High-Content Profiling of Endothelial Cells.

Endothelial cells (ECs) are widely heterogeneous at the cell level and serve different functions at the vessel and tissue levels. EC-forming colonies derived from induced pluripotent stem cells (iPSC-ECFCs) alongside models such as primary human umbilical vein ECs (HUVECs) are slowly becoming available for research with future applications in cell therapies, disease modeling, and drug discovery. We and others previously described high-content analysis approaches capturing unbiased morphology-based measurements coupled with immunofluorescence and used these for multidimensional reduction and population analysis. Here, we report a tailored workflow to characterize ECs. We acquire images at high resolution with high-magnification water-immersion objectives with Hoechst, vascular endothelial cadherin (VEC), and activated NOTCH staining. We hypothesize that via these key markers alone we would be able to distinguish and assess different EC populations. We used cell population software analysis to phenotype HUVECs and iPSC-ECFCs in the absence or presence of vascular endothelial growth factor (VEGF). To our knowledge, this study presents the first parallel quantitative high-content multiparametric profiling of EC models. Importantly, it highlights a simple strategy to benchmark ECs in different conditions and develop new approaches for biological research and translational applications for regenerative medicine.

Intervertebral Disc Biology: Genetic Basis of Disc Degeneration.

PURPOSE OF REVIEW: This review aims to highlight recent advances in understanding the genetic basis of intervertebral disc degeneration (IDD). RECENT FINDINGS: It has been known for some time that IDD is highly heritable. Recent studies, and in particular the availability of agnostic techniques such as genome-wide association studies, have identified new variants in a variety of genes which contribute to the risk of IDD and to back pain. SUMMARY: A variety of genetic variants are involved in IDD. Some are shared with variants predisposing to back pain, but few have been identified reliably in either phenotype. Further research is required to explain fully the high heritability and how the genetic variants influence cell biology to lead to IDD.

Endplate Defect Is Heritable, Associated With Low Back Pain and Triggers Intervertebral Disc Degeneration: A Longitudinal Study From TwinsUK.

STUDY DESIGN: Longitudinal study of spine magnetic resonance imaging (MRI) in a large-scale population-based study. OBJECTIVE: To determine the order of appearance of degenerative change in vertebral bodies and intervertebral discs. We also sought to define the influence of endplate defect on low back pain (LBP) and to determine whether there is a genetic influence on endplate defect. SUMMARY OF BACKGROUND DATA: Endplate defect is a magnetic resonance imaging trait, found to be associated with intervertebral disc degeneration. There is a lack of understanding regarding the mechanism underlying lumbar disc degeneration (LDD). Recent attention has shifted to vertebral endplate defects and their role in spine degeneration pathology. METHODS: Individuals from the TwinsUK spine study having longitudinal T2-weighted lumbar MR scans at baseline (n = 996) and a decade later (n = 438) were included. LDD, vertebral endplate defect by calculating a total endplate score, and Modic change (MC) were assessed using standard techniques. Mixed-effects models were used to determine the association between the features of spine pathology, adjusted for covariates. Endplate defect heritability was estimated using variance component analysis. RESULTS: Significant association was found between endplate defect, LDD, MRI features of LDD and MC was observed. Endplate defect was associated with severe disabling LBP (P ≤ 0.013) in multivariate analysis. An association between disc degeneration (DD) at baseline and MC at follow-up was shown at upper lumbar levels. Total endplate score was heritable with estimated additive genetic component A = 55.3% (95% CI 43.0-65.4). CONCLUSION: Endplate defect, LDD, and MC are all independent risk factors for episodes of severe and disabling LBP. Longitudinal analysis showed DD is followed by MC. Endplate defect has significant heritability of 55%. However, whether endplate defect triggers DD or these pathological changes occur concurrently could not be conclusively determined. LEVEL OF EVIDENCE: 2.

Association of Raynaud's phenomenon with a polymorphism in the NOS1 gene.

BACKGROUND: Raynaud's phenomenon (RP) describes the phenomenon of recurrent vasospasm of digital arteries, associated with skin colour changes: pallor, cyanosis and erythema. Twin studies have indicated a genetic predisposition for RP; however, the precise aetiology of RP remains unknown. It is thought that genetic variation in temperature-responsive or vasospastic genes might underlie RP so performed a candidate gene study in a large, population based sample. We assessed the association between RP and single nucleotide polymorphisms (SNPs) in the TRPA1, TRPM8, CALCA, CALCB and NOS1 genes. METHODS: Analysis included a total of 4276 individuals from the TwinsUK database. RP status had been determined using validated, self-administered questionnaires and was diagnosed in 640 individuals (17.6%). 66 tag SNPs across the candidate genes were tested for association with RP status using a linear regression model, accounting for covariates. Adjustment was made for multiple testing. RegulomeDB and GTEx databases were used to assess possible functional effects of the polymorphisms. RESULTS: Nominally significant associations between RP and four SNPs in NOS1 and one in CALCB were identified. After permutation testing, rs527590 SNP in NOS1 passed the significance threshold. RegulomeDB scores indicated an unlikely functional effect of this variant, while the survey of the GTEx database found the SNP and several variants in linkage disequilibrium to be cis-eQTLs in skin. CONCLUSION: Results indicate that RP is associated with variation in gene NOS1. This finding may be related to the observation that the significant SNP in NOS1 is known to exhibit functional influence on the gene expression.