A HIF-independent, CD133-mediated mechanism of cisplatin resistance in glioblastoma cells

Purpose Glioblastoma Multiforme (GBM) is the commonest brain tumour in adults. A population of cells, known as cancer stem cells (CSCs), is thought to mediate chemo/radiotherapy resistance. CD133 is a cell surface marker to identify and isolate CSCs. However, its functional significance and the relevant microenvironment in which to study CD133 remain unknown. We examined the influence of hypoxia on CD133 expression and the potential functional significance of CD133 in glioblastoma chemoresistance. Methods Gene expression was analysed by qRT-PCR. siRNA technique was used to downregulate genes and confirmed by flow cytometry. IC50 values was evaluated with the Alamar blue assay. Results CD133 expression was upregulated in hypoxia in 2D and 3D models. There was increased resistance to chemotherapeutics, cisplatin, temozolomide and etoposide, in cells cultured in hypoxia compared to normoxia. siRNA knockdown of either HIF1a or HIF2a resulted in reduced CD133 mRNA expression with HIF2a having a more prolonged effect on CD133 expression. HIF2a downregulation sensitized GBM cells to cisplatin to a greater extent than HIF1a but CD133 knockdown had a much more marked effect on cisplatin sensitisation than knockdown of either of the HIFs suggesting a HIF-independent mechanism of cisplatin resistance mediated via CD133. The same mechanism was not involved in temozolomide resistance since downregulation of HIF1a but not HIF2a or CD133 sensitized GBM cells to temozolomide. Conclusion Knowledge of the mechanisms involved in the novel hypoxia-induced CD133-mediated resistance to cisplatin observed might lead to identification of new strategies that enable more effective use of current therapeutic agents

Recurrence Risk of Autism in Siblings and Cousins: A Multinational, Population-Based Study

Objective:Familial recurrence risk is an important population-level measure of the combined genetic and shared familial liability of autism spectrumdisorder (ASD). Objectives were to estimate ASD recurrence risk among siblings and cousins by varying degree of relatedness and by sex.Method:This is a population-based cohort study of livebirths from 1998 to 2007 in California, Denmark, Finland, Israel, Sweden and WesternAustralia followed through 2011 to 2015. Subjects were monitored for an ASD diagnosis in their older siblings or cousins (exposure) and for their ASDdiagnosis (outcome). The relative recurrence risk was estimated for different sibling and cousin pairs, for each site separately and combined, and by sex.Results:During follow-up, 29,998 cases of ASD were observed among the 2,551,918 births used to estimate recurrence in ASD and 33,769 cases ofchildhood autism (CA) were observed among the 6,110,942 births used to estimate CA recurrence. Compared with the risk in unaffected families, therewas an 8.4-fold increase in the risk of ASD following an older sibling with ASD and a 17.4-fold increase in the risk of CA following an older sibling withCA. A 2-fold increase in the risk for cousin recurrence was observed for the 2 disorders. There also was a significant difference in sibling ASD recurrencerisk by sex.Conclusion:The present estimates of relative recurrence risks for ASD and CA will assist clinicians and families in understanding autism risk in thecontext of other families in their population. The observed variation by sex underlines the need to deepen the understanding of factors influencing ASD familial risk.</p

What is housing affordability? The case for the residual income approach

This article seeks to increase the awareness of and support for the residual income approach to housing affordability indicators and standards, especially in the United States. It begins with an overview of various semantic, substantive, and definitional issues relating to the notion of affordability, leading to an argument supporting the conceptual soundness of the residual income approach. The concept is then briefly set into the historical context of U.S. and British debates on affordability measures. This description is followed by a discussion of two of the principal issues involved in crafting an operational residual income standard: the selection of a normative standard for non-housing items and the treatment of taxes. The article concludes by considering some of the potential implications of the residual income paradigm for the analysis of housing problems and needs, for housing subsidy policy, and for mortgage underwriting practice

Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial

Background Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects. Methods FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762. Findings Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months. Interpretation Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function. Funding UK Stroke Association and NIHR Health Technology Assessment Programme

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

Comparison of two different optical coherence tomography angiography devices in detecting healthy versus glaucomatous eyes - an observational cross-sectional study

Background: To understand the differences between two different optical coherence tomography angiography (OCTA) devices in detecting glaucomatous from healthy eyes by comparing their vascular parameters, diagnostic accuracy and test-retest reliability. Methods: A cross-sectional observational study was performed on healthy and glaucoma subjects, on whom two sets of OCTA images of optic disc and macula were acquired using both AngioVue (Optovue, USA) and Swept Source (Topcon, Japan) OCTA devices during one visit. A novel in-house software was used to calculate the vessel densities. Diagnostic accuracy of the machines in differentiating healthy versus glaucomatous eyes was determined using area under the receiver operating characteristic curve (AUROC) and test-retest repeatability of the machines was also evaluated. Results: A total of 80 healthy and 38 glaucomatous eyes were evaluated. Glaucomatous eyes had reduced mean vessel density compared to healthy controls in all segmented layers of the optic disc and macula using AngioVue (p ≤ 0.001). However, glaucomatous eyes had higher mean vessel density on optic disc scans using Swept Source, with lack of statistically significant difference between healthy and glaucomatous eyes. The AUROC showed better diagnostic accuracy of AngioVue (0.761–1.000) compared to Swept Source (0.113–0.644). The test-retest reliability indices were generally better using AngioVue than Swept Source. Conclusions: AngioVue showed better diagnostic capability and test-retest reliability compared to Swept Source. Further studies need to be undertaken to evaluate if there is any significant difference between the various machines in diagnosing and monitoring glaucoma.Published versio

Comparison of efficacy and safety of XEN45 implant versus trabeculectomy in Asian eyes

Combined phacoemulsification and trabeculectomy is able to achieve greater reduction in intraocular pressure (IOP), higher rates of complete surgical success and fewer postoperative manipulations and visits compared with combined phacoemulsification and Xen implantation in glaucomatous eyes