BackgroundWe present the results of a Phase 2a randomized controlled trial investigating the safety, and secondary endpoints of subretinal rAAV.sFLT-1 gene therapy in patients with active wet age-related macular degeneration (wAMD).MethodsAll patients (n = 32), (ClinicalTrials.gov; NCT01494805), received ranibizumab injections at baseline and week 4, and thereafter according to prespecified criteria. Patients in the gene therapy group (n = 21) received rAAV.sFLT-1 (1 × 1011 vg). All patients were assessed every 4 weeks to the week 52 primary endpoint.FindingsOcular adverse events (AEs) in the rAAV.sFLT-1 group were mainly procedure related and self-resolved. All 11 phakic patients in the rAAV.sFLT-1 group showed progression of cataract following vitrectomy. No systemic safety signals were observed and none of the serious AEs were associated with rAAV.sFLT-1. AAV2 capsid was not detected and rAAV.sFLT-1 DNA was detected transiently in the tears of 13 patients. ELISPOT analysis did not identify any notable changes in T-cell response. In the rAAV.sFLT-1 group 12 patients had neutralizing antibodies (nAb) to AAV2. There was no change in sFLT-1 levels in bodily fluids. In the rAAV.sFLT-1 group, Best Corrected Visual Acuity (BCVA) improved by a median of 1.0 (IQR: − 3.0 to 9.0) Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline compared to a median of − 5.0 (IQR: − 17.5 to 1.0) ETDRS letters change in the control group. Twelve (57%) patients in the rAAV.sFLT-1 group maintained or improved vision compared to 4 (36%) in the control group. The median number of ranibizumab retreatments was 2.0 (IQR: 1.0 to 6.0) for the gene therapy group compared to 4.0 (IQR: 3.5 to 4.0) for the control group.Interpretation rAAV.sFLT-1 combined with the option for co-treatment appears to be a safe and promising approach to the treatment of wAMD.FundingNational Health and Medical Research Council of Australia (AP1010405), Lions Eye Institute, Perth Australia, Avalanche Biotechnologies, Menlo Pk, CA, USA.

A fundamental issue in the clinical and neuropathological assessment of Alzheimer''s disease patients is quantification of dementia severity progression. Several methods have been advanced for the purpose of staging dementia with various sensitivities at different phases of the disease, but no mathematical function has been developed to link these measures to a physical continuum. Using a dynamic method for quantifying illness severity, change in severity over time was referenced to a cumulative temporal index, a physical dimension. Data from 33 patients with probable Alzheimer''s disease with at least 2 successive assessments on three 50-point scales measuring cognitive, behavioral, and daily living skills were used to determine rate of change. ''Fuzzy-logic'' smoothing of the data, integration over time, and least-squares regression were used to derive a cubic polynomial function to calculate a severity measure in which ''days of illness'' was estimated from the severity score. This method can be used to improve the comparability of performance across various mental status tests, and to link measures of very early phases of preclinical dementia and late profound dementia phases. This method also provides a description of an ''average'' time course for any population from which the index is derived.

Background. The Oncotype DX recurrence score (RS) assay has been validated for prediction of 10-year risk of distant recurrence and likelihood of benefit from chemotherapy in patients with estrogen receptor (ER)-positive, HER2-negative early breastcancer. Patients with high RS tumors have substantial benefit, and patients with low RS tumors have minimal if any benefit from chemotherapy. Tumor size is used as a key parameter when selecting patients for neoadjuvant chemotherapy. The aim of this study was to assess the distribution of RS in patients selected for neoadjuvant chemotherapy primarily according to tumor size. Patients and Methods. Patients with ER-positive and HER2-negative tumors that were node-negative or had no more than 1 positive node from three trials were included in this study. Oncotype DX was performed at Genomic Health, Inc., blinded

Purpose The purpose of this paper is to explore the Diversity Project’s Build Back Better report, which considers leadership practice while maintaining the fight for equality through and beyond COVID-19, through the lens of ambidextrous leadership. Design/methodology/approach The authors succinctly present findings from the Build Back Better report that explores an industry response of investment and savings practitioners to managing diversity and inclusion through and beyond COVID-19. Ambidextrous leadership is applied to the discussion to offer greater theoretical discussion and practical consideration for HR leaders and their strategic approaches to the subject at hand. Findings The Build Back Better report offers numerous recommendations for leadership practice within these unprecedented times. An ambidextrous leadership approach can assist in supporting many of the recommendations, as they are complex and potentially paradoxical. Originality/value The Build Back Better report offers a practitioner’s immediate response to supporting business leaders shape their strategies as national lockdown periods ease while also ensuring the fight for equality is not lost within the COVID-19 crisis.

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BackgroundAdolescence is a critical developmental stage when young people make lifestyle choices that have the potential to impact on their current and future health and social wellbeing. The relationship between substance use and criminal activity is complex but there is clear evidence that the prevalence of problematic substance use is far higher among adolescent offenders than the general adolescent population. Adolescent offenders are a marginalized and vulnerable population who are significantly more likely to experience health and social inequalities in later life than their non-offending peers.There is a paucity of evidence on effective interventions to address substance use and risk-taking behaviours in adolescent offender populations but it is clear that preventative or abstinence orientated interventions are not effective. RISKIT-CJS is an intervention developed in collaboration with young people taking account of the current best evidence. Feasibility and pilot studies have found the intervention addresses the needs of adolescents, is acceptable and has demonstrated potential in reducing substance use and risk-taking behavior.MethodsThe study is a mixed method, two-armed, prospective, pragmatic randomized controlled trial with individual randomisation to either treatment as usual alone or the RISKIT-CJS intervention in addition to treatment as usual. Adolescents, aged 13 to 17 years inclusive, engaged with the criminal justice system who are identified as having problematic substance use are eligible to participate. The study will be conducted across three geographical areas; South and South East England, London and North East England between March 2017 and February 2019.DiscussionThe study represents an ambitious programme of work to address an area of need for a marginalized and vulnerable population.Trial registration ISRCTN77037777 registered 15/09/2016.

Purpose The purpose of this paper is to explore the impact of the Diversity Project, a cross company initiative that has been applied in the investment and savings profession to accelerate progress towards a more inclusive culture across the industry. This is with a view to providing a template for other industries considering impactful change. Design/methodology/approach This paper considers the approach taken by the investment and savings industry to drive change towards a more inclusive culture by using a summative content analysis approach. The authors framework this application using Sustainable Development Goal 10 (reduced inequalities) to increase relevance and contribution beyond this context. Findings The Diversity Project demonstrates numerous examples of driving change within the investment and savings industry by galvanising cross company support for events, publications, charters and action. These experiences will provide policymakers and practitioners in other industrial sectors insight to achieve similar change. Originality/value The Diversity Project established in 2016 has gained significant traction in the investment and savings industry through membership of 70 firms and 30 partner firms, supporting 18 cross company diversity and inclusion work streams focussed on developing collaborative and cohesive action plans.

Purpose This paper aims to explore the emerging HR practice of midlife reviews which are being implemented as the mechanism to stimulate a conversation between employers and employees about next steps, second careers and flexible career solutions. Design/methodology/approach This paper considers the approaches taken by Legal & General and AVIVA to implementing a midlife review programme within their organisation by interviews with senior managers involved in the implementation. Findings A midlife review helps employees plan the important second phase of their career and enables employers to work with them to decide how they can best be supported. The midlife review includes deciding what kind of training or upskilling they might need, considering any changes to working patterns and tailoring the benefits package to suit older workers. Originality/value The midlife review was introduced by the National Institute of Adult Continuing Education in 2015 and is only just starting to gain traction as a HR practice to retain older talent within an organisation. This paper attempts to raise awareness for the purpose of future research.