Small-molecule allosteric activators of PDE4 long form cyclic AMP phosphodiesterases

Cyclic AMP (cAMP) phosphodiesterase-4 (PDE4) enzymes degrade cAMP and underpin the compartmentalization of cAMP signaling through their targeting to particular protein complexes and intracellular locales. We describe the discovery and characterization of a small-molecule compound that allosterically activates PDE4 long isoforms. This PDE4-specific activator displays reversible, noncompetitive kinetics of activation (increased Vmax with unchanged Km), phenocopies the ability of protein kinase A (PKA) to activate PDE4 long isoforms endogenously, and requires a dimeric enzyme assembly, as adopted by long, but not by short (monomeric), PDE4 isoforms. Abnormally elevated levels of cAMP provide a critical driver of the underpinning molecular pathology of autosomal dominant polycystic kidney disease (ADPKD) by promoting cyst formation that, ultimately, culminates in renal failure. Using both animal and human cell models of ADPKD, including ADPKD patient-derived primary cell cultures, we demonstrate that treatment with the prototypical PDE4 activator compound lowers intracellular cAMP levels, restrains cAMP-mediated signaling events, and profoundly inhibits cyst formation. PDE4 activator compounds thus have potential as therapeutics for treating disease driven by elevated cAMP signaling as well as providing a tool for evaluating the action of long PDE4 isoforms in regulating cAMP-mediated cellular processes

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

The Choice, Design and Strategic Implications of Executive Incentive Pay Schemes at the Time of an Initial Public Offering

This paper presents a descriptive survey of the choice and design of executive pay incentive scheme arrangements implemented at the time of a company’s initial public offering. Using a unique sample of 311 entrepreneurial companies over a five year period (1998-2002) it illustrates the strategic choices made with regards to incentive pay schemes by the board of directors at this crucial time in a company’s development. Furthermore, it discusses the importance of the configuration of incentive schemes in respect of three critical elements: the performance target, comparator, and target level requirement for the shares to vest. It finds that company’s choices are split between schemes that do have performance targets linked and others that are contrary to the guidelines of the Combined Code and best practice. In light of this it proposes strategic reasons why this might be the case for initial public offerings and develops this discussion in line with the uniqueness of this event

The effects of company risk, founders' characteristics and corporate governance on executive incentive schemes in UK initial public offerings

Combining the agency perspective, resource-based view and upper echelon research, this paper examines factors affecting the implementation of equity based incentive schemes in initial public offerings (IPOs). In line with agency research, the probability of equity-based incentives is negatively associated with the IPO firm’s riskiness. The paper shows that performance-related incentive schemes are negatively associated with share ownership and board power of the IPO’s founding directors. Large-block share ownership is positively associated with the probability of conditional incentive schemes. However, board independence and non-executive directors’ interests do not have any effects on “toughness” of executive compensation. The paper suggests a number of avenues for a future analysis of governance development process in “threshold” firms

Executive share ownership, experience and basic salaries: the influence on IPO share option schemes and performance

Corporate governance research often focuses on two theoretical stands, agency theory and resource dependence theory. Whist both provide distinct theoretical roles, this paper combines them to argue that executive stock option plans (ESOs) can serve a dual role, that of re-alignment of managers’ and shareholders’ interests, and board stability, by ‘locking’ the executive to reward and thus retaining managerial talent. The paper focuses on a unique sample of 311 entrepreneurial initial public offerings. It examines their choice of schemes prior to and at the initial public offering (IPO). It gives consideration to ESO choices being associated with board ownership, executive wealth and cognitive characteristics of the IPO firm’s management team. Finally, it examines performance in line with signalling theory, showing that IPO underpricing is reduced by the presence of executive stock options and that high growth positively moderates the link between underpricing and conditional ESO plans

Key drivers of 'good' corporate governance and the appropriateness of UK policy responses : final report

The DTI’s Corporate Law and Governance strategy aims to promote and deliver an effective framework for corporate governance in the UK, giving confidence to investors, business, and other stakeholders to underpin the relationship between an organisation and those who hold future financial claims against that organisation. However, corporate governance involves various problems of asymmetric information and incomplete contracts that generate a need for public policy responses to mitigate market failures and ensuring that companies moves towards ‘good’ corporate governance. Since the early 1990s, the UK has been very active in undertaking policy reforms that includes a number of corporate governance codes, expert reports, a high level review of company law, and new regulations and legislation. These policy initiatives need to be monitored and evaluated in terms of their success in influencing the key drivers of ‘good’ corporate governance. This Report undertaken for the DTI has several aims: to identify key drivers of good corporate governance based on a review of social science literature; to describe the content of UK regulatory initiatives with regard to those drivers; and to evaluate gaps in the content and implementation of UK policy regarding corporate governance, using those drivers as benchmarks. In addition, some further implications of this study are discussed for future policy and research on UK corporate governance. The Report identifies key drivers of good corporate governance based on extensive review of the broad social science literature. Good corporate governance is defined here with regard to the rights and responsibilities of company stakeholders, and the wealth-creating and wealthprotecting functions of corporate governance within this context. Based on this definition, a detailed review of the theoretical and empirical social science literature on corporate governance was undertaken across seven broad areas: boards of directors, shareholder activism, information disclosure, auditing and internal controls, executive pay, the market for corporate control, and stakeholders. The result was the identification of 18 key ‘drivers’ or governance mechanisms, which promote ‘good’ corporate governance. An internet-based survey of international corporate governance experts was conducted in order to confirm and further specify these drivers in relation to the UK context. Next, key gaps in the UK regulatory framework are explored with reference to the drivers of good corporate governance. A comprehensive review was undertaken to evaluate corporate governance-related developments in UK regulation since 1990. Policy initiatives were analysed with regard to both their content and effectiveness in promoting each of the identified drivers. Several potential gaps in coverage were identified in the areas of executive pay and employees stakeholders. A number of potential gaps in effectiveness were also identified with regard to other key drivers such as boards, shareholder involvement, information disclosure, auditing, and the market for corporate control. The analysis was supported by feedback from a Focus Group of expert practitioners that took place at the DTI in January 2006. The Report also emphasises that the effectiveness of corporate governance regulation depends very much on balancing different governance demands and regulatory trade-offs. Corporate governance is shaped by a number of contingencies, complementarities, and costs. Various organisational contingencies may place different demands on corporate governance drivers, and their implementation is also associated with different sorts of costs. Looking more generally, different drivers may act as complements or substitutes for one another. Better appreciation of such interdependencies is crucial to formulating a coherent regulatory strategy and balancing important regulatory trade-offs between the following - mandatory regulation (uniform requirements) and more flexible forms of soft-law such as codes based on comply-or-explain principles and self-regulatory norms of professional groups. This analysis suggests a number of areas for future research. Bearing in mind the depth and breadth of the UK regulatory initiatives, it is important to verify whether they were followed by behavioural changes of the participants in corporate governance mechanisms, including unintended consequences such as the development of ‘gaming’ practices. Further research is needed on a potential ‘gatekeeper failure’ in situations where reliance on ‘reputational intermediaries’, such as auditors, securities analysts, attorneys, and other professionals, is not fully justified. Other research recommendations are related to wealth creation and performance trade-offs. It is important to go beyond the question of maximizing shareholder returns and consider to what extent different corporate governance configurations promote long-term, value-creating economic production in a fashion that benefits not only shareholders but also other groups that make specific investments in corporations. Finally, a more holistic approach to the effectiveness of corporate governance drivers requires further research on such aspects as stakeholder involvement, contingencies, complementarities, and cost aspects that may affect the effectiveness of corporate governance mechanisms. The authors would like to point out that, since the report was written, there have been various developments, not least changes in UK law, which have overtaken some of the details in our analysis. However, the basic review of the evidence basis and the perspectives offered remain very much current

There is power in the top management team: team based learning and immediate feedback assessment in strategic management

When looking at the creation of strategy in business, we usually find that it is a collaboration of skills and practice that enables the business to develop effective strategic plans. Yet so often in the teaching context, we hear that students, particularly in their final year of undergraduate studies, resist summative assessment based on groups or teams. For strategic management modules, this provides a dilemma. The essence of the subject requires students going beyond theory in to practice, and the practice of strategy and the constructs of problem solving that this brings in industry is often reliant on the team, and in particular the top management team. This paper explores the individual’s performance against that of the team. It uses a team based learning approach, with immediate feedback assessment technique to open discussions around individual and team performance within the context of strategic management knowledge and understanding. It discusses the team context as something that improves understanding of the subject material, and that receiving real-time immediate feedback enhances learning, whilst giving the opportunity to clarify any misconceptions of the underpinning subject matter via team discussions

Executive incentive pay strategies in entrepreneurial UK initial public offering companies: an empirical study

Purpose – The purpose of this paper is to use a sample of UK entrepreneurial initial public offering (IPO) companies to investigate whether they change their compensation strategies as they undertake the crucial transformation of the business from private to public status. Design/methodology/approach – The paper uses the agency perspective to underpin an examination of the changes within the compensation packages of companies at the stage of the initial public offering, particularly with regard to the use of executive director incentive schemes, and compares this to ‘‘best practice’’ guidelines issued within the UK. Findings – The paper discovers that even though incentive schemes are adopted, the majority are unconditional and requiring only an improvement in share price and the executive to remain employed in order for gains to be made. The general finding is that before IPO most companies did not have an incentive pay scheme in place, and those that did, operated unconditional option schemes. However, after IPO most companies introduced an incentive pay scheme, but the majority were unconditional rather than conditional (i.e. schemes requiring executives to meet pre-determined performance criteria – as recommended by ‘‘best practice’’ guidelines). Originality/value – The paper exposes that, contrary to ‘‘best practice’’ guidelines and regulations, many of these schemes reward executives unconditionally with the only factor being them remaining in employment over the vesting period. Despite ‘‘best practice’’ and regulations, firms still appear to be defensive and protect the executives from rigorous scrutiny by shareholders