Background: Access site vascular and bleeding complications remain problematic for patients undergoing transcatheter aortic valve replacement (TAVR). Ultrasound-guided transfemoral access approach has been suggested as a technique to reduce access site complications, but there is wide variation in adoption in TAVR. We performed a systematic review and meta-analysis to compare access site vascular and bleeding complications according to the Valve Academic Research Consortium-2 classification following the use of either ultrasound- or conventional fluoroscopy-guided transfemoral TAVR access. Methods: Medline, Embase, Web of Science, and The Cochrane Library were searched to November 2020 for studies comparing ultrasound- and fluoroscopy-guided access for transfemoral TAVR. A priori defined primary outcomes were extracted: (1) major, (2) minor, and (3) major and minor (total) access site vascular complications and (4) life-threatening/major, (5) minor, and (6) life-threatening, major, and minor (total) access site bleeding complications. Results: Eight observational studies (n=3875) were included, with a mean participant age of 82.8 years, STS score 5.81, and peripheral vascular disease in 23.5%. An ultrasound-guided approach was significantly associated with a reduced risk of total (Mantel-Haenszel odds ratio [MH-OR], 0.50 [95% CI, 0.35–0.73]), major (MH-OR, 0.51 [95% CI, 0.35–0.74]), and minor (MH-OR, 0.59 [95% CI, 0.38–0.91]) access site vascular complications. Ultrasound guidance was also significantly associated with total access site bleeding complications (MH-OR, 0.59 [95% CI, 0.39–0.90]). The association remained significant in sensitivity analyses of maximally adjusted minor and total vascular access site complications (MH-OR, 0.51 [95% CI, 0.29–0.90]; MH-OR, 0.44 [95% CI, 0.20–0.99], respectively). Conclusions: In the absence of randomized studies, our data suggests a potential benefit for ultrasound guidance to obtain percutaneous femoral access in TAVR. Registration: URL: https://www.crd.york.ac.uk/PROSPERO/ ; Unique identifier: CRD42020218259.

Objective To investigate the association of genetically proxied (using a surrogate biomarker) inhibition of phosphodiesterase 5 (PDE5), an established drug target for erectile dysfunction, with fertility, sexual behaviour, and subjective wellbeing. Design Two sample cis-mendelian randomisation study. Setting Summary data on genetic associations obtained from the International Consortium for Blood Pressure and UK Biobank. Participants Individuals of European ancestry from the International Consortium for Blood Pressure (n=757 601) for estimating PDE5 inhibition (using the surrogate biomarker of diastolic blood pressure reduction), and UK Biobank (n=211 840) for estimating the fertility, sexual behaviour, and subjective wellbeing outcomes in male participants. Intervention Genetically proxied PDE5 inhibition. Main outcome measures Number of children fathered, number of sexual partners, probability of never having had sexual intercourse, and subjective wellbeing. Results Genetically proxied PDE5 inhibition was associated with male participants having 0.28 (95% confidence interval 0.16 to 0.39) more children (false discovery rate corrected P<0.001). This association was not identified in female participants. No evidence was found of an association between genetically proxied PDE5 inhibition and number of sexual partners, probability of never having had sexual intercourse, or self-reported wellbeing in male participants. Conclusions The findings of this study provide genetic support for PDE5 inhibition potentially increasing the number of children fathered by male individuals. Absence of this association in female participants supports increased propensity for sustained and robust penile erections as a potential underlying mechanism. Further studies are required to confirm this, however, and these findings should not promote indiscriminate use of PDE5 inhibitors, which can also have harmful adverse effects.

Our increasing appreciation of adenosine as an endogenous signaling molecule that terminates inflammation has generated excitement regarding the potential to target adenosine receptors (ARs) in the treatment of multiple sclerosis (MS), a disease of chronic neuroinflammation. Of the four G protein-coupled ARs, A2ARs are the principal mediator of adenosine’s anti-inflammatory effects and accordingly, there is a growing body of evidence surrounding the role of A2ARs in experimental autoimmune encephalomyelitis (EAE), the dominant animal model of MS. Such evidence points to a complex, often paradoxical role for A2ARs in the immunopathogenesis of EAE, where they have the ability to both exacerbate and alleviate disease severity. This review seeks to interpret these paradoxical findings and evaluate the therapeutic promise of A2ARs. In essence, the complexities of A2AR signaling arise from two properties. Firstly, A2AR signaling downregulates the inflammatory potential of TH lymphocytes whilst simultaneously facilitating the recruitment of these cells into the CNS. Secondly, A2AR expression by myeloid cells – infiltrating macrophages and CNS-resident microglia – has the capacity to promote both tissue injury and repair in chronic neuroinflammation. Consequently, the therapeutic potential of targeting A2ARs is greatly undermined by the risk of collateral tissue damage in the periphery and/or CNS.

Background: In primary open-angle glaucoma (POAG), lowering intraocular pressure (IOP) is the only proven way of slowing vision loss. Schlemm’s canal (SC) is a hybrid vascular and lymphatic vessel that mediates aqueous humour drainage from the anterior ocular chamber. Animal studies support the importance of SC endothelial angiopoietin-TEK signalling, and more recently TIE1 signalling, in maintaining normal IOP. However, human genetic support for a causal role of TIE1 and TEK signalling in lowering IOP is currently lacking. Methods: GWAS summary statistics were obtained for plasma soluble TIE1 (sTIE1) protein levels (N = 35,559), soluble TEK (sTEK) protein levels (N = 35,559), IOP (N = 139,555) and POAG (N_cases = 16,677, N_controls = 199,580). Mendelian randomization (MR) was performed to estimate the association of genetically proxied TIE1 and TEK protein levels with IOP and POAG liability. Where significant MR estimates were obtained, genetic colocalization was performed to assess the probability of a shared causal variant (PP_shared) versus distinct (PP_distinct) causal variants underlying TIE1/TEK signalling and the outcome. Publicly available single-nucleus RNA-sequencing data were leveraged to investigate differential expression of TIE1 and TEK in the human ocular anterior segment. Results: Increased genetically proxied TIE1 signalling and TEK signalling associated with a reduction in IOP (− 0.21 mmHg per SD increase in sTIE1, 95% CI = − 0.09 to − 0.33 mmHg, P = 6.57 × 10^–4, and − 0.14 mmHg per SD decrease in sTEK, 95% CI = − 0.03 to − 0.25 mmHg, P = 0.011), but not with POAG liability. Colocalization analysis found that the probability of a shared causal variant was greater for TIE1 and IOP than for TEK and IOP (PP_shared/(PP_distinct + PP_shared) = 0.98 for TIE1 and 0.30 for TEK). In the anterior segment, TIE1 and TEK were preferentially expressed in SC, lymphatic, and vascular endothelium. Conclusions: This study provides novel human genetic support for a causal role of both TIE1 and TEK signalling in regulating IOP. Here, combined evidence from cis-MR and colocalization analyses provide stronger support for TIE1 than TEK as a potential IOP-lowering therapeutic target.

Primary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide; however, the molecular and cellular causes are not well understood. Elevated intraocular pressure (IOP) is a major risk factor, but many patients have normal IOP. Colocalization and Mendelian randomization analysis of >240 POAG and IOP GWAS loci and of overlapping eQTLs and sQTLs in 49 GTEx tissues and retina prioritized causal genes for 60% of loci. These genes were enriched in pathways implicated in extracellular matrix organization, cell adhesion, and vascular development. Analysis of single-nucleus RNA-seq of glaucoma-relevant eye tissues revealed that the colocalizing genes and genome-wide POAG and IOP associations were enriched in specific cell types in the aqueous outflow pathways, retina, optic nerve head, peripapillary sclera, and choroid. This study nominated IOP-dependent and independent regulatory mechanisms, genes, and cell types that may contribute to POAG pathogenesis.

Synchronous tumors of female genital tract have been uncommonly reported in literature. The most likely scenario would represent a metastatic disease from a primary tumor within the genital tract as the presence of primary synchronous tumors of the genital tract is an extremely rare event. Most primary synchronous tumors tend to involve the endometrium and ovary, while the incidence of synchronous primary tumors involving the uterine cervix and endometrium as documented in a few case series has been around 0.4%. We present a 41-year-old lady with an extremely rare occurrence of synchronous tumors of the uterus with an endometrioid adenocarcinoma of the uterine fundus and a squamous cell carcinoma of the uterine cervix. The patient presented to us with cerebral metastasis, which was successfully managed surgically.