More effort — more results: recent advances in integrative ‘omics’ data analysis

The development of ‘omics’ technologies has progressed to address complex biological questions that underlie various plant functions thereby producing copious amounts of data. The need to assimilate large amounts of data into biologically meaningful interpretations has necessitated the development of statistical methods to integrate multidimensional information. Throughout this review, we provide examples of recent outcomes of ‘omics’ data integration together with an overview of available statistical methods and tools

TIE1 and TEK signalling, intraocular pressure, and primary open-angle glaucoma: a Mendelian randomization study

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 (Ncases = 16,677, Ncontrols = 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 (PPshared) versus distinct (PPdistinct) 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 (PPshared/(PPdistinct + PPshared) = 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

Morning Cortisol and Circulating Inflammatory Cytokine Levels: A Mendelian Randomisation Study.

Cortisol exerts a broad anti-inflammatory effect on the immune system. Inflammatory cytokines contribute to the molecular signalling pathways implicated in various autoimmune and inflammatory conditions. However, the mechanisms by which cortisol modulates such signalling pathways remain uncertain. Leveraging summary-level data from the CORtisol NETwork (CORNET, n = 25,314) and FINRISK (n = 8293) genome-wide association studies, we used two-sample Mendelian randomisation to investigate the causal effect of genetically proxied morning cortisol levels on 42 circulating cytokines. We found that increased genetically proxied morning cortisol levels were associated with reduced levels of IL-8 and increased levels of MIF. These results provide mechanistic insight into the immunomodulatory effects of endogenous cortisol and the therapeutic effects of exogenous corticosteroids. Clinically, our findings underline the therapeutic importance of steroids in inflammatory conditions where IL-8 and MIF play a central pathophysiological role in the onset and progression of disease

TIE1 and TEK signalling, intraocular pressure, and primary open-angle glaucoma: a Mendelian randomization study

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 (Ncases = 16,677, Ncontrols = 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 (PPshared) versus distinct (PPdistinct) 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 (PPshared/(PPdistinct + PPshared) = 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

Gangrenous cholecystitis in an asymptomatic patient found during an elective laparoscopic cholecystectomy: a case report

<p>Abstract</p> <p>Introduction</p> <p>Gangrenous cholecystitis is a severe complication of acute cholecystitis. We present an unusual case of gangrenous cholecystitis which was totally asymptomatic, with normal pre-operative parameters, and was discovered incidentally during a laparoscopic cholecystectomy. We have not found any similar cases in the published literature.</p> <p>Case presentation</p> <p>A 79-year-old British Caucasian man presented initially with acute cholecystitis which responded to conservative management. After six weeks he was asymptomatic and had normal blood parameters. An elective laparoscopic cholecystectomy was performed and our patient was found to have a totally gangrenous gall bladder.</p> <p>Conclusion</p> <p>It is important to keep a high index of suspicion for the diagnosis of gangrenous cholecystitis in order to avoid potentially serious complications.</p

Routine Left Ventricular Pacing for Patients Undergoing Transcatheter Aortic Valve Replacement

ABSTRACTBackground: Rapid ventricular pacing is often required during transcatheter aortic valve replacement (TAVR) procedures. Pacing via the retrograde left ventricular guidewire (LV-GW) is an al..

Ultrasound- Versus Fluoroscopy-Guided Strategy for Transfemoral Transcatheter Aortic Valve Replacement Access: A Systematic Review and Meta-Analysis

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

Deep analysis of CD4 T cells in the rhesus CNS during SIV infection

Virologic suppression with antiretroviral therapy (ART) has significantly improved health outcomes for people living with HIV, yet challenges related to chronic inflammation in the central nervous system (CNS)—known as Neuro-HIV- persist. As primary targets for HIV-1 with the ability to survey and populate the CNS and interact with myeloid cells to co-ordinate neuroinflammation, CD4 T cells are pivotal in Neuro-HIV. Despite their importance, our understanding of CD4 T cell distribution in virus-targeted CNS tissues, their response to infection, and potential recovery following initiation of ART remain limited. To address these gaps, we studied ten SIVmac251-infected rhesus macaques using an ART regimen simulating suboptimal adherence. We evaluated four macaques during the acute phase pre-ART and six during the chronic phase. Our data revealed that HIV target CCR5+ CD4 T cells inhabit both the brain parenchyma and adjacent CNS tissues, encompassing choroid plexus stroma, dura mater, and the skull bone marrow. Aligning with the known susceptibility of CCR5+ CD4 T cells to viral infection and their presence within the CNS, high levels of viral RNA were detected in the brain parenchyma and its border tissues during acute SIV infection. Single-cell RNA sequencing of CD45+ cells from the brain revealed colocalization of viral transcripts within CD4 clusters and significant activation of antiviral molecules and specific effector programs within T cells, indicating CNS CD4 T cell engagement during infection. Acute infection led to marked imbalance in the CNS CD4/CD8 ratio which persisted into the chronic phase. These observations underscore the functional involvement of CD4 T cells within the CNS during SIV infection, enhancing our understanding of their role in establishing CNS viral presence. Our findings offer insights for potential T cell-focused interventions while underscoring the challenges in eradicating HIV from the CNS, particularly in the context of sub-optimal ART