Design of FLAIR:a Phase 2b Study of the 5-Lipoxygenase Activating Protein Inhibitor AZD5718 in Patients With Proteinuric CKD

Introduction: Patients with chronic kidney disease (CKD) remain at risk for kidney and cardiovascular events resulting from residual albuminuria, despite available treatments. Leukotrienes are proinflammatory and vasoconstrictive lipid mediators implicated in the etiology of chronic inflammatory diseases. AZD5718 is a potent, selective, and reversible 5-lipoxygenase activating protein (FLAP) inhibitor that suppresses leukotriene production. Methods: FLAIR (FLAP Inhibition in Renal disease) is an ongoing phase 2b, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of AZD5718 in patients with proteinuric CKD with or without type 2 diabetes. Participants receive AZD5718 at 3 different doses or placebo once daily for 12 weeks, followed by an 8-week extension in which they also receive dapagliflozin (10 mg/d) as anticipated future standard of care. The planned sample size is 632 participants, providing 91% power to detect 30% reduction in urinary albumin-to-creatinine ratio (UACR) between the maximum dose of AZD5718 and placebo. The dose–response effect of AZD5718 on UACR after the dapagliflozin extension is the primary efficacy objective. Key secondary objectives are the dose–response effect of AZD5718 plus current standard of care on UACR and acute effects of treatment on the estimated glomerular filtration rate. Safety, tolerability, AZD5718 pharmacokinetics, and analyses of biomarkers that may predict or reflect response to AZD5718 are additional objectives. Conclusion: FLAIR will provide data on the effects of 5-lipoxygenase pathway inhibition in patients with proteinuric CKD with or without type 2 diabetes, and will form the basis for future clinical trials (ClinicalTrials.gov: NCT04492722)

Antagonistic effects of transforming growth factor-beta on vitamin D3 enhancement of osteocalcin and osteopontin transcription: reduced interactions of vitamin D receptor/retinoid X receptor complexes with vitamin E response elements

Osteocalcin and osteopontin are noncollagenous proteins secreted by osteoblasts and regulated by a complex interplay of systemic and locally produced factors, including growth factors and steroid hormones. We investigated the mechanism by which transforming growth factor-beta (TGF beta) inhibits 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3)-enhanced expression of the osteocalcin (OC) and osteopontin (OP) genes. ROS 17/2.8 cells, in which both genes are expressed, were transfected with reporter constructs driven by native (i.e. wild-type) rat OC and mouse OP promoters. TGF beta abrogated the 1,25-(OH)2D3 enhanced transcription of both the OC and OP genes. The inhibitory TGF beta response for each requires vitamin D response element (VDRE) sequences, although there are additional contributions from proximal basal regulatory elements. These transcriptional effects were further investigated for contribution of the trans-activating factors, which interact with OC and OP VDREs, involving the vitamin D receptor (VDR) and retinoid X receptor (RXR). Gel mobility shift assays show that TGF beta significantly reduces induction of the heterodimers VDR/RXR complexes in 1,25-(OH)2D3-treated ROS 17/2.8 cells. However, Western blot and ligand binding analysis reveal that TGF beta does not affect nuclear availability of the VDR. We also show that activator protein-1 activity is up-regulated by TGF beta; thus, activator protein-1 binding sites in the OC promoter may potentially contribute to inhibitory effects of TGF beta on basal transcription. Our studies demonstrate that the inhibitory action of TGF beta on the 1,25-(OH)2D3 enhancement of OC and OP transcription in osteoblastic cells results from modulations of protein-DNA interactions at the OC and OP VDRE, which cannot be accounted for by changes in VDR protein levels. As OC and OP participate in bone turnover, our results provide insight into the contributions of TGF beta and 1,25-(OH)2D3 to VDR-mediated gene regulatory mechanism operative in bone formation and/or resorption events

Measuring the nature and duration of symptoms of cervical cancer in young women: Developing an interview-based approach

Background: Some young women experience delays in diagnosis of cervical cancer, but little research about ways of studying these delays has been published. A major challenge is that gynaecological symptoms are common in young women, but cervical cancer is rare. This study describes the development and testing of a measure for studying delays in diagnosis in young women with cervical cancer. Methods: Prospective development of an interview measure and testing of its ability to reliably and systematically collect relevant data in two large hospitals in London, UK using 27 women aged 18–40 diagnosed with cervical cancer in the previous two years. We developed a semi-structured interview schedule and data extraction form to systematically collect data on symptoms (including nature and duration) and risk factors for delayed diagnosis from young women with cervical cancer. We piloted the measure among young women with cervical cancer (audiorecording it with their permission), refining it iteratively. To complete the measure, we developed a database for managing the data and a manual for using the schedule. Two researchers extracted data from the recorded interviews to assess inter-rater reliability. Results: The final interview schedule yielded quantitative data on the nature and duration of symptoms and risk factors for delayed diagnosis. Inter-rater reliability was high. In the pilot, 12 of the 27 women were diagnosed via symptomatic presentation. Median time from the symptom triggering presentation to presentation was one month (interquartile range 0–4 months). Median time from presentation to diagnosis was three months (interquartile range 1–8.5 months). Conclusions: We have developed a reliable tool for measuring the nature and duration of symptoms in young women with cervical cancer. Pilot data suggest that a substantial proportion of women experience delay between first presentation and diagnosis

Guidance Statement On BRCA1/2 Tumor Testing in Ovarian Cancer Patients

International audienceThe approval, in 2015, of the first poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi; olaparib, Lynparza) for platinum-sensitive relapsed high-grade ovarian cancer with either germline or somatic BRCA1/2 deleterious mutations is changing the way that BRCA1/2 testing services are offered to patients with ovarian cancer. Ovarian cancer patients are now being referred for BRCA1/2 genetic testing for treatment decisions, in addition to familial risk estimation, and irrespective of a family history of breast or ovarian cancer. Furthermore, testing of tumor samples to identify the estimated 3%-9% of patients with somatic BRCA1/2 mutations who, in addition to germline carriers, could benefit from PARPi therapy is also now being considered. This new testing paradigm poses some challenges, in particular the technical and analytical difficulties of analyzing chemically challenged DNA derived from formalin-fixed, paraffin-embedded specimens. The current manuscript reviews some of these challenges and technical recommendations to consider when undertaking BRCA1/2 testing in tumor tissue samples to detect both germline and somatic BRCA1/2 mutations. Also provided are considerations for incorporating genetic analysis of ovarian tumor samples into the patient pathway and ethical requirements

Leveraging the sport participation legacy of the London 2012 Olympics: Senior managers’ perceptions

The purpose of this study was to understand how a sports mega event (SME) was leveraged to try and increase participation, through the investigation of national governing bodies (NGBs) opinions and atti- tudes. Critical realism (CR) was used as a tool to aid understanding of leveraging and legacy conceptualisation, through an empirical investiga- tion. An extensive, mixed method online survey was conducted post London 2012 with senior staff members of NGBs, the main delivery agent chosen to support the participation initiatives associated with the London 2012 Olympics. This research provides valuable findings surrounding the use of CR as a tool to investigate legacy creation, whilst at the same time offering insights to enhance the policy implementation process within the sports development sector. The importance of com- munication, competitive nature of sports system, media, club engage- ment, organisational capacity and monitoring and evaluation were highlighted, which provided useful insights into the multidimensional constructs that can aid future leveraging strategies prior to hosting SMEs

Socioeconomic inequalities in attitudes to cancer: an international cancer benchmarking study

Socioeconomic status (SES) differences in attitudes towards cancer have been implicated in the differential screening uptake and the timeliness of symptomatic presentation. However, the predominant emphasis of this work has been on cancer fatalism, and many studies focus on specific community subgroups. This study aimed to assess SES differences in positive and negative attitudes towards cancer in UK adults. A population-based sample of UK adults (n=6965, age?50 years) completed the Awareness and Beliefs about Cancer scale, including six belief items: three positively framed (e.g. ‘Cancer can often be cured’) and three negatively framed (e.g. ‘A cancer diagnosis is a death sentence’). SES was indexed by education. Analyses controlled for sex, ethnicity, marital status, age, self-rated health, and cancer experience. There were few education-level differences for the positive statements, and overall agreement was high (all>90%). In contrast, there were strong differences for negative statements (all Ps<0.001). Among respondents with lower education levels, 57% agreed that ‘treatment is worse than cancer’, 27% that cancer is ‘a death sentence’ and 16% ‘would not want to know if I have cancer’. Among those with university education, the respective proportions were 34, 17 and 6%. Differences were not explained by cancer experience or health status. In conclusion, positive statements about cancer outcomes attract near-universal agreement. However, this optimistic perspective coexists alongside widespread fears about survival and treatment, especially among less-educated groups. Health education campaigns targeting socioeconomically disadvantaged groups might benefit from a focus on reducing negative attitudes, which is not necessarily achieved by promoting positive attitudes

Population vulnerability to COVID-19 in Europe: A burden of disease analysis

Background: Evidence has emerged showing that elderly people and those with pre-existing chronic health conditions may be at higher risk of developing severe health consequences from COVID-19. In Europe, this is of particular relevance with ageing populations living with non-communicable diseases, multi-morbidity and frailty. Published estimates of Years Lived with Disability (YLD) from the Global Burden of Disease (GBD) study help to characterise the extent of these effects. Our aim was to identify the countries across Europe that have populations at highest risk from COVID-19 by using estimates of population age structure and YLD for health conditions linked to severe illness from COVID-19. Methods: Population and YLD estimates from GBD 2017 were extracted for 45 countries in Europe. YLD was restricted to a list of specific health conditions associated with being at risk of developing severe consequences from COVID-19 based on guidance from the United Kingdom Government. This guidance also identified individuals aged 70 years and above as being at higher risk of developing severe health consequences. Study outcomes were defined as: (i) proportion of population aged 70 years and above; and (ii) rate of YLD for COVID-19 vulnerable health conditions across all ages. Bivariate groupings were established for each outcome and combined to establish overall population-level vulnerability. Results: Countries with the highest proportions of elderly residents were Italy, Greece, Germany, Portugal and Finland. When assessments of population-level YLD rates for COVID-19 vulnerable health conditions were made, the highest rates were observed for Bulgaria, Czechia, Croatia, Hungary and Bosnia and Herzegovina. A bivariate analysis indicated that the countries at high-risk across both measures of vulnerability were: Bulgaria; Portugal; Latvia; Lithuania; Greece; Germany; Estonia; and Sweden. Conclusion: Routine estimates of population structures and non-fatal burden of disease measures can be usefully combined to create composite indicators of vulnerability for rapid assessments, in this case to severe health consequences from COVID-19. Countries with available results for sub-national regions within their country, or national burden of disease studies that also use sub-national levels for burden quantifications, should consider using non-fatal burden of disease estimates to estimate geographical vulnerability to COVID-19

An aggravated trajectory of depression and anxiety co-morbid with hepatitis C: : A 21 to 62 month follow-up study in 61 South Australian outpatients

BACKGROUND: This study aimed to explore the course of depression and anxiety in chronic hepatitis C patients. METHODS:   Data were combined from two studies: (1) Hospital Anxiety and Depression Scale (HADS) scores in 395 consecutive Australian outpatients from 2006 to 2010 formed the baseline measurement; and (2) Depression Anxiety Stress Scales (DASS) scores in a survey of a sub-sample of these patients in 2011 formed the follow-up measurement. After converting DASS to HADS scores, changes in symptom scores and rates of case-ness (≥8), and predictors of follow-up symptoms were assessed. RESULTS:   Follow-up data were available for 61 patients (70.5% male) whose age ranged from 24.5 to 74.6 years (M=45.6). The time to follow-up ranged from 20.7 to 61.9 months (M=43.8). Baseline rates of depression (32.8%) and anxiety (44.3%) increased to 62.3% and 67.2%, respectively. These findings were confirmed, independent of the conversion, by comparing baseline HADS and follow-up DASS scores with British community norms. Baseline anxiety and younger age predicted depression, while baseline anxiety, high school non-completion, and single relationship status predicted anxiety. CONCLUSION:  This study demonstrated a worsening trajectory of depression and anxiety. Further controlled and prospective research in a larger sample is required to confirm these findings

The mammalian gene function resource: The International Knockout Mouse Consortium

In 2007, the International Knockout Mouse Consortium (IKMC) made the ambitious promise to generate mutations in virtually every protein-coding gene of the mouse genome in a concerted worldwide action. Now, 5 years later, the IKMC members have developed highthroughput gene trapping and, in particular, gene-targeting pipelines and generated more than 17,400 mutant murine embryonic stem (ES) cell clones and more than 1,700 mutant mouse strains, most of them conditional. A common IKMC web portal (www.knockoutmouse.org) has been established, allowing easy access to this unparalleled biological resource. The IKMC materials considerably enhance functional gene annotation of the mammalian genome and will have a major impact on future biomedical research