Enhanced Phagocytic Activity of HIV-Specific Antibodies Correlates with Natural Production of Immunoglobulins with Skewed Affinity for FcγR2a and FcγR2b

While development of an HIV vaccine that can induce neutralizing antibodies remains a priority, decades of research have proven that this is a daunting task. However, accumulating evidence suggests that antibodies with the capacity to harness innate immunity may provide some protection. While significant research has focused on the cytolytic properties of antibodies in acquisition and control, less is known about the role of additional effector functions. In this study, we investigated antibody-dependent phagocytosis of HIV immune complexes, and we observed significant differences in the ability of antibodies from infected subjects to mediate this critical effector function. We observed both quantitative differences in the capacity of antibodies to drive phagocytosis and qualitative differences in their FcγR usage profile. We demonstrate that antibodies from controllers and untreated progressors exhibit increased phagocytic activity, altered Fc domain glycosylation, and skewed interactions with FcγR2a and FcγR2b in both bulk plasma and HIV-specific IgG. While increased phagocytic activity may directly influence immune activation via clearance of inflammatory immune complexes, it is also plausible that Fc receptor usage patterns may regulate the immune response by modulating downstream signals following phagocytosis—driving passive degradation of internalized virus, release of immune modulating cytokines and chemokines, or priming of a more effective adaptive immune response

Future making and visual artefacts : an ethnographic study of a design project

Current research on strategizing and organizing has explored how practitioners make sense of an uncertain future, but provides limited explanations of how they actually make a realizable course of action for the future. A focus on making rather than sensemaking brings into view the visual artefacts that practitioners use in giving form to what is ‘not yet’ – drawings, models and sketches. We explore how visual artefacts are used in making a realizable course of action, by analysing ethnographic data from an architectural studio designing a development strategy for their client. We document how visual artefacts become enrolled in practices of imagining, testing, stabilizing and reifying, through which abstract imaginings of the future are turned into a realizable course of action. We then elaborate on higher-order findings that are generalizable to a wide range of organizational settings, and discuss their implications for future research in strategizing and organizing. This paper contributes in two ways: first, it offers future making as an alternative perspective on how practitioners orient themselves towards the future (different from current perspectives such as foreseeing, future perfect thinking and wayfinding). Second, it advances our understanding of visual artefacts and their performativity in the making of organizational futures

On the way to Ithaka [1] : Commemorating the 50th Anniversary of the publication of Karl E. Weick’s The Social Psychology of Organizing

Karl E. Weick’s The Social Psychology of Organizing has been one of the most influential books in organization studies, providing the theoretical underpinnings of several research programs. Importantly, the book is widely credited with initiating the process turn in the field, leading to the ‘gerundizing’ of management and organization studies: the persistent effort to understand organizational phenomena as ongoing accomplishments. The emphasis of the book on organizing (rather than on organizations) and its links with sensemaking have made it the most influential treatise on organizational epistemology. In this introduction, we review Weick’s magnum opus, underline and assess its key themes, and suggest ways in which several of them may be taken forward

Managing action research: the PEArL framework

The difficulty of managing and validating Action Research field studies has been widely discussed. Several different approaches to Action Research have emerged, and one of the most widely used models is Checkland’s FMA model, where a framework is provided to facilitate interested individuals in ‘recovering’ the route of the inquiry. In this paper, I argue that the FMA model is a valuable tool for planning the application of theoretical ideas in a practical situation, but that, as a guide to Action Research, it still fails to provide a sense of the manner in which an inquiry is undertaken. The PEArL mnemonic has been previously offered as a guide to facilitate researchers, participants, and those interested in gaining an appreciation of the manner in which an inquiry is conducted. In this paper, it is argued that applying the PEArL elements does not provide insight into the dynamic nature of collaborative inquiry. In order to gain a sense of the manner in which an inquiry was undertaken it is necessary to apply the PEArL mnemonic alongside a framework that facilitates the flow of the action research cycle. To illustrate the framework, an Action Research field study is described that was undertaken with residents and key workers in a shelter for the homeless, where the aim was to create a shared understanding of complex needs and support requirements

‘Reflection is embedded in my brain forever now!’: personal development as a core module on an Executive MBA

Professional progression and skills development are the main expectations of mid-career managers when enrolling on an Executive MBA (EMBA), yet it can be personal development (PD) that turns out to be the unexpected benefit of management education. Joining a growing number of voices making a case for personal development and self-awareness in management education, and calling for schools to incorporate it in the curriculum, this paper advances the case for personal development as a core Executive MBA module. The paper sets out the holistic rationale and philosophic principles used to design and deliver a course underpinned by curiosity and self-reflection on an EMBA in the United Kingdom, and presents empirical findings from a survey conducted among 230 students and alumni. These suggest that the focus on reflective practice and integration of PD promotes a richer and deeper appreciation of the value of reflection for lasting and sometimes unexpected personal growth. In addition, the raising of awareness of self also brings awareness of others, and develops critical thinking in application of the MBA at work. The paper concludes with a discussion re-evaluating the subject of tacit knowledge in reflective practice

Thinking together: What makes Communities of Practice work?

In this article, we develop the founding elements of the concept of Communities of Practice by elaborating on the learning processes happening at the heart of such communities. In particular, we provide a consistent perspective on the notions of knowledge, knowing and knowledge sharing that is compatible with the essence of this concept – that learning entails an investment of identity and a social formation of a person. We do so by drawing richly from the work of Michael Polanyi and his conception of personal knowledge, and thereby we clarify the scope of Communities of Practice and offer a number of new insights into how to make such social structures perform well in professional settings. The conceptual discussion is substantiated by findings of a qualitative empirical study in the UK National Health Service. As a result, the process of ‘thinking together’ is conceptualized as a key part of meaningful Communities of Practice where people mutually guide each other through their understandings of the same problems in their area of mutual interest, and this way indirectly share tacit knowledge. The collaborative learning process of ‘thinking together’, we argue, is what essentially brings Communities of Practice to life and not the other way round

A robust, high-throughput assay to determine the phagocytic activity of clinical antibody samples

Phagocytosis can be induced via the engagement of Fcγ receptors by antibody-opsonized material. Furthermore, the efficiency of antibody-induced effector functions has been shown to be dramatically modulated by changes in antibody glycosylation. Because infection can modulate antibody glycans, which in turn modulate antibody functions, assays capable of determining the induction of effector functions rather than neutralization or titer provide a valuable opportunity to more fully characterize the quality of the adaptive immune response. Here we describe a robust and high-throughput flow cytometric assay to define the phagocytic activity of antigen-specific antibodies from clinical samples. This assay employs a monocytic cell line that expresses numerous Fc receptors: including inhibitory and activating, and high and low affinity receptors—allowing complex phenotypes to be studied. We demonstrate the adaptability of this high-throughput, flow-based assay to measure antigen-specific antibody-mediated phagocytosis against an array of viruses, including influenza, HIV, and dengue. The phagocytosis assay format further allows for simultaneous analysis of cytokine release, as well as determination of the role of specific Fcγ-receptor subtypes, making it a highly useful system for parsing differences in the ability of clinical and vaccine induced antibody samples to recruit this critical effector function.Neutralizing Antibody Consortium (International AIDS Vaccine Initiative)National Institute of Allergy and Infectious Diseases (U.S.)National Institutes of Health (U.S.) (AI055332)National Institutes of Health (U.S.) (AI080289)Ragon Institute of MGH, MIT and Harvar

Factors Associated With the Frequency of Monitoring of Liver Enzymes, Renal Function and Lipid Laboratory Markers Among Individuals Initiating Combination Antiretroviral Therapy: A Cohort Study

Background As the average age of the HIV-positive population increases, there is increasing need to monitor patients for the development of comorbidities as well as for drug toxicities. Methods We examined factors associated with the frequency of measurement of liver enzymes, renal function tests, and lipid levels among participants of the Canadian Observational Cohort (CANOC) collaboration which follows people who initiated HIV antiretroviral therapy in 2000 or later. We used zero-inflated negative binomial regression models to examine the associations of demographic and clinical characteristics with the rates of measurement during follow-up. Generalized estimating equations with a logit link were used to examine factors associated with gaps of 12 months or more between measurements. Results Electronic laboratory data were available for 3940 of 7718 CANOC participants. The median duration of electronic follow-up was 3.5 years. The median (interquartile) rates of tests per year were 2.76 (1.60, 3.73), 2.55 (1.44, 3.38) and 1.42 (0.50, 2.52) for liver, renal and lipid parameters, respectively. In multivariable zero-inflated negative binomial regression models, individuals infected through injection drug use (IDU) were significantly less likely to have any measurements. Among participants with at least one measurement, rates of measurement of liver, renal and lipid tests were significantly lower for younger individuals and Aboriginal Peoples. Hepatitis C co-infected individuals with a history of IDU had lower rates of measurement and were at greater risk of having 12 month gaps between measurements. Conclusions Hepatitis C co-infected participants infected through IDU were at increased risk of gaps in testing, despite publicly funded health care and increased risk of comorbid conditions. This should be taken into consideration in analyses examining factors associated with outcomes based on laboratory parameters

A strategy-as-practice approach to strategy research and education

This conclusion to the Dialog proposes a strategy-as-practice based approach to bringing strategy research and education closer to practice. Strategy-as-practice rejects the choice, proposed in the previous articles, between theory and practice. The authors argue for strategy research based rigorously on sociological theories of practice. Such research complements the parsimony and generalizability of economics-driven theory, extending strategy research to incorporate the messy realities of doing strategy in practice, with a view to developing theory that is high in accuracy. The authors suggest that practice-based research can also inform strategy teaching by providing students with rich case studies of strategy work as actually practiced, analyzed through such sociological lenses as ethnomethodology, dramaturgy, and institutional theory. Strategy-as-practice research does not aim to give students parsimonious models for analysis or expose them to cases of best practice but rather to help them develop practical wisdom through a better understanding of strategy in practice

Anti-interleukin-21 antibody and liraglutide for the preservation of β-cell function in adults with recent-onset type 1 diabetes : a randomised, double-blind, placebo-controlled, phase 2 trial

Publisher Copyright: © 2021 Elsevier LtdBackground: Type 1 diabetes is characterised by progressive loss of functional β-cell mass, necessitating insulin treatment. We aimed to investigate the hypothesis that combining anti-interleukin (IL)-21 antibody (for low-grade and transient immunomodulation) with liraglutide (to improve β-cell function) could enable β-cell survival with a reduced risk of complications compared with traditional immunomodulation. Methods: This randomised, parallel-group, placebo-controlled, double-dummy, double-blind, phase 2 trial was done at 94 sites (university hospitals and medical centres) in 17 countries. Eligible participants were adults aged 18–45 years with recently diagnosed type 1 diabetes and residual β-cell function. Individuals with unstable type 1 diabetes (defined by an episode of severe diabetic ketoacidosis within 2 weeks of enrolment) or active or latent chronic infections were excluded. Participants were randomly assigned (1:1:1:1), with stratification by baseline stimulated peak C-peptide concentration (mixed-meal tolerance test [MMTT]), to the combination of anti-IL-21 and liraglutide, anti-IL-21 alone, liraglutide alone, or placebo, all as an adjunct to insulin. Investigators, participants, and funder personnel were masked throughout the treatment period. The primary outcome was the change in MMTT-stimulated C-peptide concentration at week 54 (end of treatment) relative to baseline, measured via the area under the concentration-time curve (AUC) over a 4 h period for the full analysis set (intention-to-treat population consisting of all participants who were randomly assigned). After treatment cessation, participants were followed up for an additional 26-week off-treatment observation period. This trial is registered with ClinicalTrials.gov, NCT02443155. Findings: Between Nov 10, 2015, and Feb 27, 2019, 553 adults were assessed for eligibility, of whom 308 were randomly assigned to receive either anti-IL-21 plus liraglutide, anti-IL-21, liraglutide, or placebo (77 assigned to each group). Compared with placebo (ratio to baseline 0·61, 39% decrease), the decrease in MMTT-stimulated C-peptide concentration from baseline to week 54 was significantly smaller with combination treatment (0·90, 10% decrease; estimated treatment ratio 1·48, 95% CI 1·16–1·89; p=0·0017), but not with anti-IL-21 alone (1·23, 0·97–1·57; p=0·093) or liraglutide alone (1·12, 0·87–1·42; p=0·38). Despite greater insulin use in the placebo group, the decrease in HbA1c (a key secondary outcome) at week 54 was greater with all active treatments (−0·50 percentage points) than with placebo (−0·10 percentage points), although the differences versus placebo were not significant. The effects diminished upon treatment cessation. Changes in immune cell subsets across groups were transient and mild (<10% change over time). The most frequently reported adverse events included gastrointestinal disorders, in keeping with the known side-effect profile of liraglutide. The rate of hypoglycaemic events did not differ significantly between active treatment groups and placebo, with an exception of a lower rate in the liraglutide group than in the placebo group during the treatment period. No events of diabetic ketoacidosis were observed. One participant died while on liraglutide (considered unlikely to be related to trial treatment) in connection with three reported adverse events (hypoglycaemic coma, pneumonia, and brain oedema). Interpretation: The combination of anti-IL-21 and liraglutide could preserve β-cell function in recently diagnosed type 1 diabetes. The efficacy of this combination appears to be similar to that seen in trials of other disease-modifying interventions in type 1 diabetes, but with a seemingly better safety profile. Efficacy and safety should be further evaluated in a phase 3 trial programme. Funding: Novo Nordisk.Peer reviewe