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Macrophages are among the phylogenetically oldest cells of the immune system and are found in all tissues and organs. In addition to playing an important role in immune response against pathogenic microorganisms, these cells were previously described to play a vital role in chronic inflammatory diseases such as rheumatoid arthritis. Using novel techniques such as single-cell sequencing and advanced microscopy techniques it has now been shown that macrophages are far more versatile. Thus, these cells contribute considerably to tissue homeostasis and tissue regeneration. As each tissue has to fulfill special requirements, macrophages vary in their phenotype and function between organs. New data have now identified a specialised population of epithelioid macrophages that exert a protective and anti-inflammatory function in synovial tissue and prevent the initial onset as well as episodes of joint inflammation in rheumatoid arthritis.

Shared decision making has been widely advocated and evaluated in diverse ways for 4 decades.But there is scant evidence that it is commonly accepted by or has influence on practitioners' behaviour or that it positively affects patient health outcomes. This situation may be due in part to the absence of a commonly agreed operational definition of the construct. This is admitted in the literature and has led to multiple approaches to evaluation.An operational definition is proposed based on ethical parity among parties, sharing of mutually interacting expectations and analysis of decisions as commitment to action rather than information.Shared decision making occurs when two autonomous and uncoerced agents both commit to actions that neither has reason to want to change based on their understanding of anticipated outcomes given the situation at hand and of the intended actions of the other party.It is a broader concept than providing information regarding treatment alternatives in the office.

The increased use of chest computed tomography (CT) has led to an increased detection of pulmonary nodules requiring diagnostic evaluation and/or excision. Many of these nodules are identified and excised via minimally invasive thoracic surgery; however, subcentimeter and subsolid nodules are frequently difficult to identify intra-operatively. This can be mitigated by the use of electromagnetic transthoracic needle localization. This protocol delineates the step-by-step process of electromagnetic localization from the pre-operative period to the postoperative period and is an adaptation of the electromagnetically guided percutaneous biopsy previously described by Arias et al. Pre-operative steps include obtaining a same day CT followed by the generation of a three-dimensional virtual map of the lung. From this map, the target lesion(s) and an entry site are chosen. In the operating room, the virtual reconstruction of the lung is then calibrated with the patient and the electromagnetic navigation platform. The patient is then sedated, intubated, and placed in the lateral decubitus position. Using a sterile technique and visualization from multiple views, the needle is inserted into the chest wall at the prechosen skin entry site and driven down to the target lesion. Dye is then injected into the lesion and, then, continuously during needle withdrawal, creating a tract for visualization intra-operatively. This method has many potential benefits when compared to the CT-guided localization, including a decreased radiation exposure and decreased time between the dye injection and the surgery. Dye diffusion from the pathway occurs over time, thereby limiting intra-operative nodule identification. By decreasing the time to surgery, there is a decrease in wait time for the patient, and less time for dye diffusion to occur, resulting in an improvement in nodule localization. When compared to electromagnetic bronchoscopy, airway architecture is no longer a limitation as the target nodule is accessed via a transparenchymal approach. Details of this procedure are described in a step-by-step fashion.

Siglec-15 is a conserved sialic acid–binding Ig-like lectin, which is expressed on osteoclasts. Deficiency of Siglec-15 leads to an impaired osteoclast development, resulting in a mild osteopetrotic phenotype. The role of Siglec-15 in arthritis is still largely unclear. To address this, we generated Siglec-15 knockout mice and analyzed them in a mouse arthritis model. We could show that Siglec-15 is directly involved in pathologic bone erosion in the K/BxN serum-transfer arthritis model. Histological analyses of joint destruction provided evidence for a significant reduction in bone erosion area and osteoclast numbers in Siglec-15−/− mice, whereas the inflammation area and cartilage destruction was comparable to wild-type mice. Thus, Siglec-15 on osteoclasts has a crucial function for bone erosion during arthritis. In addition, we generated a new monoclonal anti–Siglec-15 Ab to clarify its expression pattern on immune cells. Whereas this Ab demonstrated an almost exclusive Siglec-15 expression on murine osteoclasts and hardly any other expression on various other immune cell types, human Siglec-15 was more broadly expressed on human myeloid cells, including human osteoclasts. Taken together, our findings show a role of Siglec-15 as a regulator of pathologic bone resorption in arthritis and highlight its potential as a target for future therapies, as Siglec-15 blocking Abs are available.

It is often thought that the arrival of the Black–Scholes–Merton (BSM) model of option pricing in the early 1970s allowed traders to understand how to price and value options with greater precision. However, our study suggests that interwar commodity options traders may have been able to intuit ‘fair’ value and to adjust their prices to changes in the market environment well before the advent of this innovative model. A scarcity of historical price data has limited empirical tests of option price efficiency well before BSM to studies of stock options in the 1870s and the early twentieth century which revealed contrasting findings. This study deals with option pricing in a different market—commodities—during the interwar period. We conclude that option prices were closer to their BSM theoretical values than prior studies suggest. Institutional differences between interwar commodity options markets and stock options markets in the 1870s and the early twentieth century may partly account for this result. Furthermore, we find that interwar option prices were no more mispriced than in modern times, and were as sensitive to changes in volatility—the key valuation parameter in the BSM model.

Objective: Determine the state-of-the-art in dynamic scheduling techniques for cloud manufacturing.Significance: This paper firmly establishes the underexplored technique of Deep Reinforcement Learning as the state-of-the-art for dynamic scheduling in cloud manufacturing, exposes a significant gap in the literature, and sets out critical future research objectives.Abstract:For many years, metaheuristic algorithms have represented the state of the art in manufacturing scheduling techniques, proving to be exceptionally reliable for optimising schedules. However, metaheuristics suffer from inherent weaknesses that inhibit their ability to be applied to dynamic cloud manufacturing (CMfg) scheduling problems in practice. Thanks to the very recent and rapidly accelerating development in deep reinforcement learning (DRL), a small sample of studies have described how those approaches have thoroughly outperformed metaheuristic algorithms in dynamic manufacturing scheduling problems, establishing a new state of the art. However, a significant lag in maturity exists between the algorithms used in CMfg and state-of-the-art DRL. This paper systematically reviews the CMfg scheduling literature published between 2010 and 2020, summarises the development of deep reinforcement learning in this context and offers valuable directions for future research.

In 2008 there was an expectation of major reform to social and economic structures following the financial crisis. The European Union (EU) referendum of 2016, and the UK’s subsequent exit from the EU in 2020, was also signalled as a turning point that would bring about epochal change. Now, in the waning of the coronavirus pandemic, we are experiencing a similar rhetoric. There is widespread agreement that the pandemic will usher in big changes for the economy and society, with the potential for major policy reform. But what will be the long-term impacts of the pandemic on the UK economy? Is the right response a “new settlement” or is some alternative approach likely to be more beneficial? This report puts forward a new perspective on the pandemic-related changes that could be ahead. The central theme is assessing the viability of epochal reform in policymaking. There seems to be a relentless desire for making big changes; however, there is arguably not enough recognition of how current settings and history can hold back these efforts. Foreword by: Dame Frances Cairncross, CBE, FRSE.

Current medical society guidelines recommend a procedural number for obtaining electromagnetic navigational bronchoscopy (ENB) competency and for institutional volume for training.To assess learning curves and estimate the number of ENB procedures for interventional pulmonology (IP) fellows to reach competency.We conducted a prospective multicenter study of IP fellows in the United States learning ENB. A tool previously validated in a similar population was used to assess IP fellows by their local faculty and two blinded independent reviewers using virtual recording of the procedure. Competency was determined by performing three consecutive procedures with a competency score on the assessment tool. Procedural time, faculty global rating scale, and periprocedural complications were also recorded.A total of 184 ENB procedures were available for review with assessment of 26 IP fellows at 16 medical centers. There was a high correlation between the two blinded independent observers (rho = 0.8776). There was substantial agreement for determination of procedural competency between the faculty assessment and blinded reviewers (kappa = 0.7074; confidence interval, 0.5667-0.8482). The number of procedures for reaching competency for ENB bronchoscopy was determined (median, 4; mean, 5; standard deviation, 3.83). There was a wide variation in the number of procedures to reach competency, ranging from 2 to 15 procedures. There were six periprocedural complications reported, four (one pneumomediastinum, three pneumothorax) of which occurred before reaching competence and two pneumothoraces after achieving competence.There is a wide variation in acquiring competency for ENB among IP fellows. Virtual competency assessment has a potential role but needs further studies.

Macrophages are among the phylogenetically oldest cells of the immune system and are found in all tissues and organs. In addition to playing an important role in immune response against pathogenic microorganisms, these cells were previously described to play a vital role in chronic inflammatory diseases such as rheumatoid arthritis. Using novel techniques such as single-cell sequencing and advanced microscopy techniques it has now been shown that macrophages are far more versatile. Thus, these cells contribute considerably to tissue homeostasis and tissue regeneration. As each tissue has to fulfill special requirements, macrophages vary in their phenotype and function between organs. New data have now identified a specialised population of epithelioid macrophages that exert a protective and anti-inflammatory function in synovial tissue and prevent the initial onset as well as episodes of joint inflammation in rheumatoid arthritis.Makrophagen zählen zu den phylogenetisch ältesten Zellen des Immunsystems und sind in allen Geweben und Organen zu finden. Neben einer wichtigen Rolle in der Immunantwort gegen pathogene Mikroorganismen wurde diesen Zellen bisher v. a. eine pathologische Rolle bei chronisch entzündlichen Erkrankungen wie der rheumatoiden Arthritis zugeschrieben. Durch neuartige Techniken wie Einzelzellsequenzierung und verbesserte Mikroskopieverfahren konnte inzwischen gezeigt werden, dass Makrophagen weitaus vielseitiger sind. So tragen diese Zellen wesentlich zur Gewebehomöostase und Geweberegeneration bei. Da jedes Gewebe spezielle Anforderungen erfüllen muss, variieren Makrophagen in ihrer Gestalt und Funktion sehr stark von Organ zu Organ. Neue Daten identifizierten nun eine spezialisierte Population von epitheloiden Makrophagen, welche im Synovialgewebe eine protektive und antientzündliche Funktion ausüben und den initialen Ausbruch sowie Schübe von Gelenkentzündungen bei rheumatoider Arthritis verhindern.

The authors contrast and evaluate two of the most popular responsible investing strategies employed at present: negative screening and engagement. As a backdrop, they consider the challenges faced by the University of Cambridge, which mirror those experienced by institutional investors worldwide. Specifically, they make use of issues raised at the recent “Divest or Engage?” conference at the university. The authors discuss emerging academic evidence from recent, and hitherto unpublished, papers to provide an up-to-date perspective. They describe the challenges in excluding undesirable assets from investment portfolios and present evidence on the effectiveness of engaging with investee companies. The strategies of divestment and engagement are often employed as complements to each other, and this can be advantageous. The authors caution that investors need to be aware of the disquieting evidence that ESG metrics differ considerably across rating services, and the choice of data provider can have a fundamental impact on the ESG credentials of institutional portfolios. TOPICS:ESG investing, portfolio theory, portfolio construction Key Findings • Engagement: On average, companies with whom engagement has proven successful have subsequently demonstrated enhanced financial and stock market performance. • Divestment: Responsible investing strategies often incorporate both exclusion policies and engagement. Support for exclusion can vary based on its motivations. • Ratings: Environmental, social, and governance (ESG) scores from different providers have low correlations among one another. Choosing an ESG provider involves buy-in to their choice of methodology.

An increasing number of investors face the dilemma of whether to divest from environmentally damaging businesses or enter into a dialogue with them. This debate has now taken root in Cambridge, England, where the ancient University of Cambridge confronts great pressure from students and staff members to respond to the threat of climate breakdown. Having already received two reports on its approach to responsible investment, the university appointed a new chief investment officer (CIO) who, alongside the Cambridge University Endowment Fund (CUEF) Trustee and the wider university community, needs to consider the question of whether to divest from, or to engage with, fossil fuel firms. What would be the financial effects of each choice, and what would be the outcome in terms of environmental impact? This case study describes the background and the research behind the debate. The new CIO and her colleague, the chief financial officer, reflect on both sides of this debate as they consider the position the university should adopt. In contrast with other journal articles, this one does not propose solutions. Instead, it asks the reader to consider the arguments and to take a position. TOPICS:ESG investing, equity portfolio management, foundations and endowments Key Findings • Climate activism has accelerated and is supported not only by students but also by respected scholars in many disciplines. This article represents a case study of the debate over divestment and engagement at one of the world’s leading universities where sizable endowment funds are also under management. • The article reveals how pressures on institutional investors to respond to climate activism can accelerate. Investment professionals need to understand the forces for change. A head-in-the-sand response is counterproductive. • Changes in investment policy should be based on evidence. The article summarizes relevant research and challenges the reader to form a view on the choice between divestment and engagement.

Innovations in the world of alternative finance such as online consumer lending, fund-raising platforms and cryptocurrencies are proceeding apace. In this article, we examine three historical case studies of newly emerged non-bank financial markets and discuss the possible implications for today's alternative finance markets. The first insight is that the private sector can generally be counted on to meet previously unmet needs. Moneylenders filled a gap unaddressed by the banking system of the day. Junior market IPOs provided access to funds for smaller companies that might otherwise have struggled to raise external finance. Private currencies replaced sovereign coins in transactions at various points in history. The second insight, however, is that new financial markets and instruments eventually attract the attention of regulators. Finally, these examples are a warning to industry not to take for granted that an initially laissez-faire regulatory regime precludes a stronger response at some point in the future. In all three cases, tougher regulation – in some cases even to the point of shutting down the products and markets concerned – arrived after long periods of observation and deliberation by the state.

The authors’ 2012 article on the Norway model spotlighted that country’s sovereign wealth fund. They argued that Norway provides a coherent and compelling approach to managing long-term pools of assets. Since then, the Norwegian Government Pension Fund has grown in scale and complexity, and its structure has evolved. Meanwhile, other models for asset management have been put forward. In this article, the authors review Norway’s investment strategy in the light of the last decade’s experience, put it in a broader context by comparing Norway with alternative approaches, and reexamine the fund’s commitment to responsible investing. Since the authors wrote their earlier paper, environmental and social issues have come to the fore, and there is still much to learn from the Norway model. TOPICS:Foundations & endowments, portfolio theory, portfolio construction, ESG investing Key Findings ▪ Today the Norwegian Government Pension Fund is the world’s largest sovereign wealth fund. It remains a model for long-horizon investors, including those of more modest size. ▪ Norway has considerable freedom in how to invest its assets. It is an asset allocator, not a liability matcher. ▪ Norway is cost conscious and emphasizes transparency, and this influences its strategy. Other investors favor private assets and may prefer different approaches, such as the Yale model or the Canada model. ▪ The fund provides a model for financial investors who wish to be known for transparency and clarity of governance, low management costs, high liquidity, and high standards of ethical behavior.

Technological advances often allow innovations in finance to emerge or develop more quickly. History offers numerous examples of such innovations. In this chapter, we focus on four historical case studies in microfinance, junior market initial public offerings, consumer lending and private currency. We show that while the private sector can generally be counted on to address previously unmet needs, financial innovations attract the attention of the state. As something of a warning to present-day practitioners, all four cases illustrate how an initially laissez-faire regulatory regime preceded restrictive regulation, in some cases to the point of completely eliminating the emerging industry.

University endowments invest for future generations, so their strategy should reflect their long horizon. Our research question is whether they really do behave like long-term investors. We examine the behavior of U.S. endowments since 1945 and draw comparisons with earlier periods. Employing a long-run dataset on 12 major universities, we examine their preferences for risky assets and document their big strategic moves into equities and later into alternatives. We then analyse how they invest around crises and the extent to which they exploit their long-horizon advantage. We find that on average endowments do indeed invest countercyclically at such times, particularly when increasing their allocation to risky assets after a crisis.

Intravenous infusions are required when a drug has a short half-life or a narrow therapeutic window. Pharmacokinetic models are employed to calculate the infusion rate for a particular target plasma concentration. While the one-compartment model is based on relatively simple mathematics, it is of little practical use. Multi-compartment models involve complex mathematics: a bolus-infusion regimen requires a variable-infusion rate. In clinical practice, this means incorporating the pharmacokinetic models into specially designed target-controlled infusion pumps. The physicochemical properties of different drugs result in very different behaviours, especially following cessation of intravenous infusion.

This study of over 1,000 initial public offerings (IPOs) on the Berlin stock exchange from German unification to the eve of World War II draws attention to the importance of regulation and deepens our understanding of German stock market development. An increasingly exacting regulatory environment from the early 1880s to 1914 made a vital contribution to the higher likelihood of firms going public surviving. In the inhospitable regulatory setting of the 1930s, IPO activity drew to a halt and the development in the German stock market over the preceding decades reversed. As a complement to our analysis of the impact of regulation, we document the increased involvement of leading universal banks (D-banks) in the IPO market over the whole period.

We study market segmentation effects using data on U.S. railroads that list their bonds in New York and London between 1873 and 1913. This sample provides a unique setting for such analysis because of the precision offered by bond yields in cost of capital estimation, the geography-specific nature of railroad assets, and ongoing substantial technological change. We document a significant reduction in market segmentation over time. Whilst New York bond yields exceeded those in London in the 1870s, this premium disappeared by the early 1900s. However, the segmentation premium persisted in the more remote regions of the United States.

Pleural effusions occur in 1.5 million patients yearly and are a common cause of dyspnea. For nonmalignant effusions, initial treatment is directed at the underlying cause, but when effusions become refractory to medical therapy, palliative options are limited. Tunneled pleural catheters (TPCs) are commonly used for palliation of malignant effusions, but many clinicians are reluctant to recommend these devices for palliation of nonmalignant effusions, citing concerns of infection, renal failure, electrolyte disturbances and protein-loss malnutrition. Based on the published experience to date, TPCs relieve dyspnea and can result in spontaneous pleurodesis in patients with nonmalignant effusions. The infection rate compares favorably to that for malignant effusions with possible increased risk in patients with hepatic hydrothorax and posttransplant patients. Renal failure, electrolyte disturbance and protein-loss malnutrition have not been observed. TPCs are a reasonable option in select patients to palliate nonmalignant effusions refractory to maximal medical therapy.

This was written by Natalia Krymova for her unfinished book about Michael Chekhov.Krymova was arguably the leading Russian theatre critic of her era. Born in Moscow in 1930, she studied at GITIS un...