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th guidance. We believe there is scope for more specialised and targeted support for future returning cataract surgeons thereby optimising patient care.
This audit assesses communication between community optometrists (COs) and hospital eye service (HES) in Scotland and England.

Optometric referrals and replies were extracted from six practices in Scotland and England. If no reply was found, replies/records were copied from HES records. De-identified referrals, replies and records were audited against established standards, evaluating whether referrals were necessary, accurate and directed to the appropriate professional. The referral rate (RR) and referral reply rate (RRR) were calculated.

From 905 de-identified referrals, RR ranged from 2.6 to 8.7%. From COs' perspective, the proportion of referrals for which they received replies ranged from 37 to 84% (Scotland) and 26 to 49% (England). A total of 88-96% of referrals (Scotland) and 63-76% (England) were seen in the HES. Adjusting for cases when it is reasonable to expect replies, RRR becomes 45-92% (Scotland) and 38-62% (England) with RRR significantly greater in Scotland (P = 0.015). Replies were cos and minimising unnecessary HES appointments.More than 40% of men with intermediate-risk or high-risk prostate cancer will experience a biochemical recurrence after radical prostatectomy. Clinical guidelines for the management of these patients largely focus on the use of salvage radiotherapy with or without systemic therapy. However, not all patients with biochemical recurrence will go on to develop metastases or die from their disease. The optimal pre-salvage therapy investigational workup for patients who experience biochemical recurrence should, therefore, include novel techniques such as PET imaging and genomic analysis of radical prostatectomy specimen tissue, as well as consideration of more traditional clinical variables such as PSA value, PSA kinetics, Gleason score and pathological stage of disease. In patients without metastatic disease, the only known curative intervention is salvage radiotherapy but, given the therapeutic burden of this treatment, importance must be placed on accurate timing of treatment, radiation dose, fractionation and field size. Systemic therapy also has a role in the salvage setting, both concurrently with radiotherapy and as salvage monotherapy.Diabetic nephropathy has been traditionally diagnosed based on persistently high albuminuria and a subsequent decline in glomerular filtration rate (GFR), which is widely recognized as the classical phenotype of diabetic kidney disease (DKD). Several studies have emphasized that trajectories of kidney function in patients with diabetes (specifically, changes in GFR and albuminuria over time) can differ from this classical DKD phenotype. Three alternative DKD phenotypes have been reported to date and are characterized by albuminuria regression, a rapid decline in GFR, or non-proteinuric or non-albuminuric DKD. Although kidney biopsies are not typically required for the diagnosis of DKD, a few studies of biopsy samples from patients with DKD have demonstrated that changes in kidney function associate with specific histopathological findings in diabetes. In addition, various clinical and biochemical parameters are related to trajectories of GFR and albuminuria. Collectively, pathological and clinical characteristics can be used to predict trajectories of GFR and albuminuria in diabetes. Furthermore, cohort studies have suggested that the risks of kidney and cardiovascular outcomes might vary among different phenotypes of DKD. A broader understanding of the clinical course of DKD is therefore crucial to improve risk stratification and enable early interventions that prevent adverse outcomes.Recent advances in molecular biology have led to the CRISPR revolution, but the lack of an efficient and safe delivery system into cells and tissues continues to hinder clinical translation of CRISPR approaches. Polymeric vectors offer an attractive alternative to viruses as delivery vectors due to their large packaging capacity and safety profile. In this paper, we have demonstrated the potential use of a highly branched poly(β-amino ester) polymer, HPAE-EB, to enable genomic editing via CRISPRCas9-targeted genomic excision of exon 80 in the COL7A1 gene, through a dual-guide RNA sequence system. The biophysical properties of HPAE-EB were screened in a human embryonic 293 cell line (HEK293), to elucidate optimal conditions for efficient and cytocompatible delivery of a DNA construct encoding Cas9 along with two RNA guides, obtaining 15-20% target genomic excision. When translated to human recessive dystrophic epidermolysis bullosa (RDEB) keratinocytes, transfection efficiency and targeted genomic excision dropped. However, upon delivery of CRISPR-Cas9 as a ribonucleoprotein complex, targeted genomic deletion of exon 80 was increased to over 40%. Our study provides renewed perspective for the further development of polymer delivery systems for application in the gene editing field in general, and specifically for the treatment of RDEB.Glaucoma is a prevalent neurodegenerative disease that is characterized by progressive visual field loss. It is the leading cause of irreversible blindness in the world. The main risk factor for glaucoma is elevated intraocular pressure that results in the damage and death of retinal ganglion cells (RGCs) and their axons. The death of RGCs has been shown to be apoptotic. We tested the hypothesis that blocking the activation of apoptosis may be an effective strategy to prevent RGC death and preserve functional vision in glaucoma. In the magnetic microbead mouse model of induced ocular hypertension, inhibition of RGC apoptosis was targeted through viral-mediated ocular delivery of the X-linked inhibitor of apoptosis (XIAP) gene, a potent caspase inhibitor. Pattern electroretinograms revealed that XIAP therapy resulted in significant protection of both somal and axonal RGC function in glaucomatous eyes. Histology confirmed that the treated optic nerves showed preservation of axon counts and reduced glial cell infiltration. These results show that XIAP is able to provide both functional and structural protection of RGCs in the microbead model of glaucoma and provide important proof-of-principle for XIAP's efficacy as a neuroprotective treatment for glaucoma.
Dysregulation of endocrine pathways related to steroid and growth hormones may modify endometrial cancer risk; however, prospective data on testosterone, sex hormone-binding globulin (SHBG) and insulin-like growth factor (IGF)-1 are limited. To elucidate the role of these hormones in endometrial cancer risk we conducted complementary observational and Mendelian randomization (MR) analyses.

The observational analyses included 159,702 women (80% postmenopausal) enrolled in the UK Biobank. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. For MR analyses, genetic variants associated with hormone levels were identified and their association with endometrial cancer (12,906 cases/108,979 controls) was examined using two-sample MR.

In the observational analysis, higher circulating concentrations of total (HR per unit inverse normal scale = 1.38, 95% CI = 1.22-1.57) and free testosterone (HR per unit log scale = 2.07, 95% CI = 1.66-2.58) were associated with higher endometrial cancer risk. An inverse association was found for SHBG (HR per unit inverse normal scale = 0.76, 95% CI = 0.67-0.86). Results for testosterone and SHBG were supported by the MR analyses. No association was found between genetically predicted IGF-1 concentration and endometrial cancer risk.

Our results support probable causal associations between circulating concentrations of testosterone and SHBG with endometrial cancer risk.
Our results support probable causal associations between circulating concentrations of testosterone and SHBG with endometrial cancer risk.Background Class III malocclusions with maxillary retrognathia are commonly treated with single jaw Le Fort I maxillary advancement. The three-dimensional (3D) effects of surgery on the nasolabial region varies among the clinical studies. Quantifying these changes is of great importance for surgical planning and obtaining valid consent. Objectives To investigate the 3D relationship between soft tissue and skeletal changes secondary to Le Fort I maxillary advancement surgery in skeletal class III patients.Search methods Comprehensive search of multiple electronic databases supplemented by a manual and grey literature search were undertaken from inception to 9 June 2020.Selection criteria Studies that evaluated the 3D soft tissue changes of patients before and after maxillary advancement surgery alone.Data collection and analysis Study selection, data extraction and risk of bias assessment were performed independently by two reviewers, with disputes resolved by a third reviewer. selleck chemicals llc A quantitative synthesis of the round the central zone of the nasolabial region. Future prospective studies on maxillary advancement osteotomy with a standardised method of assessment, taking into consideration the confounding factors, are required.Circular RNAs (circRNAs) regulate gene expression and participate in various biological and pathological processes. However, little is known about the effects of specific circRNAs on T helper cell 17 (Th17) differentiation and related autoimmune diseases, such as multiple sclerosis (MS). Here, using transcriptome microarray analysis at different stages of experimental autoimmune encephalomyelitis (EAE), we identified the EAE progression-related circINPP4B, which showed upregulated expression in Th17 cells from mice with EAE and during Th17 differentiation in vitro. Silencing of circINPP4B inhibited Th17 differentiation and alleviated EAE, characterized by less demyelination and Th17 infiltration in the spinal cord. Mechanistically, circINPP4B served as a sponge that directly targeted miR-30a to regulate Th17 differentiation. Furthermore, circINPP4B levels were associated with the developing phases of clinical relapsing-remitting MS patients. Our results indicate that circINPP4B plays an important role in promoting Th17 differentiation and progression of EAE by targeting miR-30a, which provides a potential diagnostic and therapeutic target for Th17-mediated MS.Multikinase inhibitors, such as sorafenib, are used for the treatment of advanced carcinomas but the response shows limited efficacy or varies a lot with patients. Here we adopted the systems approach combined with high-throughput data analysis to discover key mechanism embedded in the drug response. When analyzing the transcriptomic data from the Cancer Cell Line Encyclopedia (CCLE) database, endothelin 1 (EDN1) was enriched in cancer cells with low responsiveness to sorafenib. We found that the level of EDN1 is higher in the tissue and blood of hepatocellular carcinoma (HCC) patients showing poor response to sorafenib. In vitro experiment showed that EDN1 not only induces activation of angiogenic-promoting pathways in HCC cells but also stimulates proliferation and migration. Moreover, EDN1 is related with poor responsiveness to sorafenib by mitigating unfolded protein response (UPR), which was validated in both transcriptomic data analysis and in silico simulation. Finally, we found that endothelin receptor B (EDNRB) antagonists can enhance the efficacy of sorafenib in both HCC cells and xenograft mouse models.
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