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Students around the world submit their essays to an online anti-plagiarism service known as Turnitin.com. Four students sued the service for copyright infringement because Turnitin added their papers to its database for use in future anti-plagiarism detection. The students lost their case, in both the district court and more recently in the court of appeals, based on a fair use analysis. This paper examines not only the copyright and fair use analysis that the court employs, but also the contracts and privacy issues that are applicable to this case.

The relative performance of Malaysian REITs and Property Developers are compared with non parametric tests and then re-compared with risk adjusted returns a la Modigliani Modigliani. The period covered is 2006-2007 from share and unit prices from the Kuala Lumpur Stock Market. The results may not fully satisfy our financial rectitude but, at least, they may satisfy our yearning for economic morality: apparently ‘Turning dust into paper pays more than simply turning brick into paper’.

Commentary on the Mort et al. paper. Assume that you are handed a paper randomly selected from an academic journal in your field. What is the likelihood that it contains useful knowledge?

By using short-term direct finance firms of the highest credit quality expose themselves to rollover risk in the public debt markets. Firms insure themselves against this risk by securing backup lines of credit from banks that they may use should market liquidity dry up. In a first step, this paper explains why high quality firms introduce a maturity mismatch into their balance sheets and do not simply use long-term direct finance. It also highlights why banks may be willing to roll over a firm's debt while direct investors may not. In a second step, I extend the model to allow for different levels of firm's publicly observable credit quality. Under plausible assumptions about the cost of bank borrowing the model generates a maturity structure choice broadly consistent with observed financing patterns: Low quality firms issue short-term direct debt, medium quality firms issue long-term direct debt, and high quality firms use short-term direct debt in normal times and bank debt in adverse times. The paper suggests that better publicly available information about firm quality and the moderation of the business cycle over the past decade help to explain the decrease in nonfinancial commercial paper outstanding since the beginning of the decade.

This paper is a response, from a business perspective, to Halton Cheadle’s concept paper titled ‘Regulating flexibility: Revisiting the LRA and the BCEA’ (DPRU Working Paper 06/109). This paper seeks to respond to each of the issues raised by Cheadle, and to his reflections on each. As previously noted, the paper has been drafted to present a business perspective. This brief presents its own difficulties. The business community in South Africa is a broad church, and encompasses manifold shades of opinion on the appropriate nature and extent of labour market regulation. Organised business, represented by national employer organisations, professional organisations and chambers of commerce, has been a party to the negotiations preceding the enactment of the legislation under review. In this sense, organised business is also a party to the broad agreements reached by the social partners on the conceptual underpinnings of the legislative reforms introduced in 1995.However, business is equally cognisant that the concept of regulated flexibility, as Cheadle observes, inherently recognises the diverse and dynamic nature of the labour market, and requires that regulatory frameworks should be capable of adaptation to meet the demands of changing circumstances. What this paper attempts primarily is a review of the existing legislative and regulatory package, questioning where necessary the appropriateness of the continued application of the limits and mechanisms that are intended to promote regulated flexibility, and reviewing the balance that the existing legislation seeks to achieve. The paper does not purport to present the mandated views of organised business or any other component of the business constituency, rather than to raise for discussion general and specific issues that might be relevant to the debate initiated by Cheadle’s paper. • Counting the Cost of Red Tape for Business in South Africa by SBP (2005); • Measurement of Value Added Tax Act and Regional Services Councils Act-induced Administrative Burdens for South African Small Businesses by Upstart Business Strategies (2004), commissioned by the Department of Trade and Industry (dti); and • SMME Facilitation Program (Report Version) by the South African Revenue Services (SARS) to be released in 2005. South African tax compliance costs cannot be judged in isolation. Available information on South African tax compliance costs and their impact on SMMEs are captured in the three reviewed studies. The SBP (2005) study estimates total regulatory compliance costs for formal firms in South Africa to have been approximately R79 billion in 2004, 6.5 per cent of GDP, and total tax compliance costs to have been roughly R20 billion in the same year. Due to the nature of the report, it makes no tax-specific recommendations and only focuses on broad regulatory compliance recommendations. The Upstart Business Strategies (2004) study focuses on two specific taxes, Value-Added Tax (VAT) and Regional Service Council Levies (not administered by SARS, but by regional service councils). The study employs Mistral®, a proprietary “bottom-up” technique to quantify tax compliance costs. The study finds that the average SMME spends approximately R6 027 on two compliance activities associated with VAT – recordkeeping and completion tax returns. The total VAT compliance cost for an average SMME is estimated to range between R6 000 and R8 000 annually. The recommendations of the study are of a broad practical nature and focused on reducing the time spent on specific tax compliance activities. It does not specify the how of its recommendations, for example, it suggests that the internal reliability of SARS logistics needs to be improved and that queing time spent at SARS needs to be reduced, but does not explain how these outcomes should be achieved. The SARS (2005) study does not generate its own empirical data. It reviews the empirical findings of the above two studies and findings of other studies broadly or specifically focused on SMMEs and the formal/informal economic divide. In addition, it draws on a number of qualitative insights gained during interaction with a range of individuals and organisations aware of small business concerns. A number of recommendations with regards to SARS structures (for example, creation of a Small Business Centre and Small Business help desks), SARS communication channels and SARS products (specifically VAT) are made. Rather than simply focusing on small “cosmetic” tax changes, what is required is intensive co-ordination of SMME policy across different government departments. The narrow focus of the reviewed studies, excluding the SARS report, strengthen the idea that relevant policy considerations do not extend beyond the implementation of technical changes to tax legislation. However, a strong case can be made for a number of other SMME policy-related issues to receive greater emphasis than tax compliance costs. Conclusions relative to tax compliance cost include the fact that a large component of tax compliance costs can be ascribed to firm-level inefficiencies. While a reduction in the tax compliance burden can help to create a more enabling environment for business, a special tax regime for small businesses might not be the best way to achieve lower compliance costs. Far more than simply tax changes will be required to unlock the South African SMME market.

Many lawyers, judges, law clerks, and legal scholars feel unprepared to make or evaluate claims about the original meaning of the Constitution based on the Federalist Papers. The typical law school curriculum acknowledges the importance of the Federalist Papers - usually by assigning Supreme Court cases which cite them - but does not treat the essays in depth. As a result, many law students and graduates still need accessible information about the creation, content, and distribution of the essays, manageable summaries of the theories under which the Federalist Papers might provide evidence of the original meaning, and instruction on possible grounds for impeaching claims about the original meaning based on the Federalist Papers. I hope to address these needs in this guide to the Federalist Papers. The guide provides the essential background that lawyers, judges, law clerks, and legal scholars ought to have before advancing, contesting, or evaluating claims about the original meaning of the Constitution based on the Federalist Papers. I have tried to keep the guide concise in the hope that the intended audience will have time to read it. At the same time, I believe that the guide is sufficiently analytical to promote critical thinking, careful judgment, and judicious evaluation of arguments that rely on the Federalist Papers.

We provide novel estimates of gender differences in the allocation of time by Italian adults and document their trends over the span 2002-2014, pooling three time-use surveys run by the Italian National Institute of Statistics (ISTAT). The positive gap (females-males) in time devoted to Household work and the negative gap in Market work and Leisure are found to have narrowed over the observed period, mainly due to changes in women's time allocation, while the positive gap in time devoted to Child care remained substantially constant. In 2014, the sharing of family duties appears still heavily unbalanced even when we look at the subsample of full-time working parents. Full-time working mothers devote to Market work about 4 hours per week less than their partners, but they devote 14 hours per week more to Household work and 3 hours and a half more to Basic child care. This translates in 13 hours per week more total (paid and unpaid) work and 11 hours per week less Leisure. On the positive side, the gender gap in time devoted to Quality child care exhibits a reversed sign in 2014. The change is driven by weekend days, when partners of full-time working mothers become the main provider of this type of care.

The milk addiction paradox refers to an empirical finding in which commodities that are typically considered to be non addictive, such as milk, appear instead to be addictive. This result seems more likely when there is persistence in consumption and when using aggregate data, and it suggests that the AR(2) model typically used in the addiction literature is prone to produce spurious result in favor of rational addiction. Using both simulated and real data, we show that the milk addiction paradox disappears when estimating the data using an AR(1) linear specification that describes the saddle-path solution of the rational addiction model. The AR(1) specification is able to correctly discriminate between rational addiction and simple persistence in the data, to test for the main features of rational addiction, and to produce unbiased estimates of the short and long-run elasticity of demand. These results hold both with individual and aggregated data, and they suggest that, for testing rational addiction, the AR(1) model is a better empirical alternative than the canonical AR(2) model.

It is now more than a decade since the judgment in Halifax, and nearly two since it was referred to the CJEU by a UK court. It is hard to overstate its significance: the decision is arguably one of the most important ever delivered by the Court within the field of taxation, and beyond. Whilst there seems to be unanimous agreement as regards the existence of the principle, its exact nature is still a contested issue. In particular, the question that still lingers is whether the principle of prohibition of abuse of law should be characterised as a general principle, or as an interpretative principle. This short paper presents the case in favour of characterising the principle of prohibition of abuse of law as a general principle of EU, arguing that not only does it display the key characteristics of such principles but that, following the most recent CJEU decisions, its characterisation as such is now settled case law.

This paper estimates the potential distributional consequences of the first phase of the COVID-19 lockdowns on poverty and labour income inequality in 20 Latin American and Caribbean (LAC) countries. We estimate the share of individuals that are potentially able to remain active under the lockdown by taking into account individuals’ teleworking capacity but also whether their occupation is affected by legal workplace closures or mobility restrictions. Furthermore, we compare the shares under the formal (de jure) lockdown policies assuming perfect compliance with the shares under de facto lockdowns where there is some degree of non-compliance. We then estimate individuals’ potential labour income losses and examine changes in poverty and labour income inequality. We find an increase in poverty and labour income inequality in most of the LAC countries due to social distancing; however, the observed changes are lower under de facto lockdowns, revealing the potential role of non-compliance as a coping strategy during the lockdowns. Social distancing measures have led to an increase in inequality both between and within countries. Lastly, we show that most of the dispersion in the labour income loss across countries is explained by the sectoral/occupational employment structure of the economies.

This report is the eighth in an annual series of publications, dating back to 2012, designed to share the latest stories, trends and research in social media usage from across the Middle East and North Africa (MENA). Using a wide variety of academic, industry and media sources, this White Paper identifies important insights from social media’s development over the previous year. Of particular note in 2019 is the continued, growing, importance of social media in the lives of Arab Youth, outside of Saudi Arabia and Turkey the declining usage of Twitter (once the poster child social network for the Arab Spring,) as well as greater scrutiny of social media usage by platform owners and governments alike. Last year’s report highlighted the increasing weaponization of social networks, a trend which continued in 2019. Facebook, Twitter and Telegram each closed hundreds of accounts due to inappropriate use by state sponsored actors and terrorist groups. Social networks were also the target of governments across MENA, in the midst of protests in many countries throughout the region. Meanwhile, the importance of social video and visually-led social networks, continued to grow from strength to strength. Snapchat introduced new advertising formats to the region and other exclusive functionality, Google highlighted the importance of YouTube in supporting parents and parenting, and in major markets such as Egypt, Saudi Arabia and the UAE, Twitter has emerged as a leading platform for online video consumption. The year ahead is likely to result in a continuation of many of the trends outlined in this report, as social media becomes increasingly engrained across the lives of businesses, governments and residents across the MENA region.

We consider a broad class of intertemporal economic problems and characterize the short-run and long-run responses of the demand for a good to a permanent increase in its market price. Depending on the interplay between self-productivity and time discounting, we show that dynamic substitution effects can generate price elasticities of opposite signs in the short run and in the long run. (JEL D11, D15, H20, J22, J24)

How large are government spending and tax multipliers? The fiscal proxy-SVAR literature provides heterogenous estimates, depending on which proxies - fiscal or non-fiscal - are used to identify fiscal shocks. We reconcile the existing estimates via a flexible vector autoregressive model that allows to achieve identification in presence of a number of structural shocks larger than that of the available instruments. Our two main findings are the following. First, the estimate of the tax multiplier is sensitive to the assumption of orthogonality between total factor productivity (non-fiscal proxy) and tax shocks. If this correlation is assumed to be zero, the tax multiplier is found to be around one. If such correlation is non-zero, as supported by our empirical evidence, we find a tax multiplier three times as large. Second, we find the spending multiplier to be robustly larger than one across different models that feature different sets of instruments. Our results are robust to the joint employment of different fiscal and non-fiscal instruments.

This paper aims to analyze the determinants of cash usage in a selection of European Union (EU) countries over the 2003–2016 period, based on a set of technological, socioeconomic, and socio-cultural indicators and cost components. Our results reveal the existence of both common and region-specific determinants for the EU advanced and Central and Eastern European (CEE) countries. In both groups cash usage is determined by payment system characteristics. Additionally, in the EU advanced countries cash usage can also be explained by the level of economic development and income inequalities and proliferation of Internet. In contrast, cash usage in CEE countries is negatively associated with consumer confidence and is inversely related to the technological progress, expressed in terms of mobile users.

The rapid spread of artificial intelligence (AI) systems has precipitated a rise in ethical and human rights-based frameworks intended to guide the development and use of these technologies. Despite the proliferation of these "AI principles," there has been little scholarly focus on understanding these efforts either individually or as contextualized within an expanding universe of principles with discernible trends. To that end, this white paper and its associated data visualization compare the contents of thirty-six prominent AI principles documents side-by-side. This effort uncovered a growing consensus around eight key thematic trends: privacy, accountability, safety and security, transparency and explainability, fairness and non-discrimination, human control of technology, professional responsibility, and promotion of human values. Underlying this “normative core,” our analysis examined the forty-seven individual principles that make up the themes, detailing notable similarities and differences in interpretation found across the documents. In sharing these observations, it is our hope that policymakers, advocates, scholars, and others working to maximize the benefits and minimize the harms of AI will be better positioned to build on existing efforts and to push the fractured, global conversation on the future of AI toward consensus.

Crude oil recovery processes generate large volumes of crude oil-contaminated water. Crude oil-contaminated water was noted to contain hydrocarbons (including saturates and aromatics) as well as non-hydrocarbons. Some hydrocarbons in the contaminated water are found to be carcinogenic, neurotoxic, and genotoxic to humans and other organisms. Thus, the exposure of human being and other organism like fishes in the marine environment to these hydrocarbons through skin contact to such contaminated water or consumption of contaminated food and water may be very dangerous. The remediation of such oil contaminated water has become a crucial problem in oil producing countries and requires more drastic attention. Several technologies have been deployed at solving this problem. Utilization of agricultural wastes as adsorbents has however, been found to be more attractive to researches due to its environmental friendly tendencies and economic viability. This paper reviewed the attempt of researchers at addressing this problem by using agricultural wastes like banana peel, rice husk, etc as sorbent for removal of the oil from the crude oil-contaminated water. It was observed that agricultural wastes compete favourably with synthetic adsorbents in oil removal from crude oil contaminated water. Though many agricultural products have been investigated, there are some like plantain peel, papaya peel and water melon rind that need to be considered for this treatment.

This paper investigates Samuelson's [Samuelson, P. A. “Where Ricardo and Mill Rebut and Confirm Arguments of Mainstream Economists Supporting Globalization.” Journal of Economic Perspectives, 18(3), 2004, 135–46] argument that technical progress of the trade partner may hurt the home country. We illustrate this prospect in a simple Ricardian model for situations with outward knowledge spillovers. Within this framework Samuelson's Act II effects may occur. Based on industry level panel data for 17 OECD countries for the period 1973–2000 we show econometrically that the outflow of domestic knowledge via exports or foreign direct investment (FDI) to the rest of the world may have a negative impact on industry output in the home country. This is particularly so when exporting to technologically less advanced countries and, more specifically, China.

The paper is about the political consequences of increasing economic inequality in Western economies. Political theorists have often stressed that democracy is in troubles when its population is not broadly uniform in income and wealth because unequal economic resources can easily translate into a surplus of political resources in the hands of the few. The connections between economic inequality and democracy, however, are not easy to detect and the body of literature is not so large to provide robust assessments of their complex relationship. The aim of this paper is to review the links between the two and to offer some hints on the political relevance of the inequality consequences, if any, on democracy.

This paper represents one of the first attempts to benchmarking public procurement practices for the same product categories. Questionnaires from European procurement agencies provide several insights on procurement contest design and on participation and competition patterns of two important supply contracts: fix line telephone services and paper for printers. Data show that while in the former public procurement practices are rather similar, in the latter, they vary significantly across EU Countries, despite the standardized nature of products. Moreover, some cases of cross-border participation to tenders, suggest that players consider the European market as a single market.

Education is a key element in the prevention of child labour; at the same time, child labour is one of the main obstacles to Education for All (EFA). Understanding the interplay between education and child labour is therefore critical to achieving both EFA and child labour elimination goals. This paper forms part of UCW broader efforts towards improving this understanding of education-child labour links, providing a brief overview of relevant research and key knowledge gaps. The study largely confirm the conventional wisdom that child labour harms children's ability to enter and survive in the school system, and makes it more difficult for children to derive educational benefit from schooling once in the system. The evidence also suggested that these negative effects are not limited to economic activity but also extend to household chores, and that the intensity of work (in economic activity or household chores) is particularly important in determining the impact of work on schooling. As regards the link between education provision and child labour, it pointed to the important role of inadequate schooling in keeping children out of the classroom and into work. This evidence indicated that both the school quality and school access can play an important role in household decisions concerning whether children study or work.

Corporate Social Responsibility (CSR) has been an increasingly important issue for private and non-government businesses to consider when investing in countries. The paper specifically addresses transnational corporations and how they can negatively affect the development of countries when socially irresponsible and notes the increasing consumer awareness of corporate irresponsibility. It argues that better relationships between governments and corporations need to be established to reduce low living standards, exploitation, poverty, and unemployment, which would contribute to overall sustainable development. The paper recommends having CSR indicators for measurement, addresses why CSR should matter to business corporations, and gives insight into how the ILO can act and relate to CSR. This paper was written as an insight into the work of the World Commission on the Social Dimension of Globalization 2004 that aims to provide a fairer globalization for all.

Economists have long recognized that the time costs of using different forms of money can be significant and potentially affect the type of media of exchange used. But although there is theoretical research and anecdotal evidence that suggest time is an important element in determining the use of media of exchange, there is little empirical work documenting the magnitude of this effect. To fill this gap, this paper uses scanner data from grocery store transactions to examine time costs associated with media of exchange. Scanner data is an ideal medium for examining time costs associated with media of exchange, as these data represent actual market exchanges, grocery store retailers spend much time and effort in minimizing the length of time for checkout transactions, and everyone goes grocery shopping - this type of exchange is arguably one of the more frequent that a typical consumer makes. Using check and debit card transactions only to control for the effects of availability of different payment instruments, census tract information to proxy for demographic characteristics, and econometric procedures to control for the endogeneity of the choice of payment instrument and the realized length of time of the transaction, the results indicate that check transactions are, on average, predicted to be approximately 40 seconds longer than debit card transactions. Interestingly, the results suggest that debit card users are, on an absolute basis, more time sensitive than check users, and in particular, these sensitivities vary by the demographics of the local market. Overall, the results in this paper support the theoretical literature on media of exchange and the empirical literature using survey data.

Over the past several years, the emergence and adoption of electronic payment instruments have acutely affected check usage. This transition has been especially evident at the point of sale as debit and credit cards have become pervasive. Today, the rapid growth of online bill payment looks to threaten checks' last redoubt. However, bill payment technology is still in its adolescence; the interplay of many stakeholders in the industry, including technology firms, banks, billers, payment cards, and customers, has led to rapid, unscripted innovation in just a few years. This paper quantifies some of the trends in the industry while addressing the interests and impact of the market's prime movers in an effort to determine to what extent the displacement of checks will continue.

The G8 is considering committing to purchase vaccines against diseases concentrated in low-income countries (if and when desirable vaccines are developed) as a way to spur research and development on vaccines for these diseases. Under such an "advance market commitment," one or more sponsors would commit to a minimum price to be paid per person immunized for an eligible product, up to a certain number of individuals immunized. For additional purchases, the price would eventually drop to close to marginal cost. If no suitable product were developed, no payments would be made. We estimate the offer size which would make revenues similar to the revenues realized from investments in typical existing commercial pharmaceutical products, as well as the degree to which various model contracts and assumptions would affect the cost-effectiveness of such a commitment. We make adjustments for lower marketing costs under an advance market commitment and the risk that a developer may have to share the market with subsequent developers. We also show how this second risk could be reduced, and money saved, by introducing a superiority clause to a commitment. Under conservative assumptions, we document that a commitment comparable in value to sales earned by the average of a sample of recently launched commercial products (adjusted for lower marketing costs) would be a highly cost-effective way to address HIV/AIDS, malaria, and tuberculosis. Sensitivity analyses suggest most characteristics of a hypothetical vaccine would have little effect on the cost-effectiveness, but that the duration of protection conferred by a vaccine strongly affects potential cost-effectiveness. Readers can conduct their own sensitivity analyses employing a web-based spreadsheet tool.

At the end of 2002, FEEM celebrated a major achievement in its publication history: 1000 published working papers. This paper provides an analysis of FEEM working papers according to different viewpoints. First, it assesses the evolution of the contents of FEEM working papers by identifying the main research areas that they cover and how these research areas have evolved over time. Then, it quantifies the success of FEEM working papers by computing the number of downloads from FEEM web site and the quantity and quality of subsequent publications in top economic journals. Finally, it compares the number of working papers published by FEEM with those published by other leading research institutions both in Europe and the US.

I review two papers, addressing the issue of competition and quality determination in the market for Internet access services (Cremer, Rey, and Tirole (2000), Foros and Hansen (2001)). These two works come to seemingly opposite conclusions. After having summarized the two papers, I try to highlight what lies behind the differences in the results.

This paper argues that banks have a unique ability to hedge against market-wide liquidity shocks. Deposit inflows provide a natural hedge for loan demand shocks that follow declines in market liquidity. Consequently, one dimension of bank "specialness" is that banks can insure firms against systematic declines in market liquidity at lower cost than other financial institutions. We provide supporting empirical evidence from the commercial paper (CP) market. When market liquidity dries up and CP spreads increase, banks experience funding inflows. These allow banks to meet increased loan demand from borrowers drawing funds from pre-existing commercial paper backup lines, without running down their holdings of liquid assets. Moreover, the supply of cheap funds is sufficiently large so that pricing on new lines of credit actually falls as market spreads widen.

I introduce binscatterhist, a command that extends the functionality of the popular binscatter command (Stepner, 2013, Statistical Software Components S457709, Department of Economics, Boston College). binscatter allows researchers to summarize the relationship between two variables in an informative and versatile way by collapsing scattered points into bins. However, information about the variables’ frequencies gets lost in the process. binscatterhist solves this issue by allowing the user to further enrich the graphs by plotting the variables’ underlying distribution. The binscatterhist command includes options for different regression methods, including reghdfe (Correia, 2014, Statistical Software Components S457874, Department of Economics, Boston College) and areg, and robust and clustered standard errors, with automatic reporting of estimation results and sample size., The Stata Journal, 22 (2), ISSN:1536-867X, ISSN:1536-8734

Background: The Timeless (TIM) and its interacting partner TIPIN protein complex is well known for its role in replication checkpoint and normal DNA replication processes. TIM appears to be an essential component of the DNA damage response. Recent studies revealed the involvement of TIM and TIPIN in human malignancies; however, no evidence is available regarding TIM/TIPIN protein complex expression and its potential role in melanoma. Therefore, we investigated the role of TIM as well as TIPIN in melanoma. Methods: To assess the role of TIM/TIPIN in melanoma, we analyzed TIM/TIPIN expression data from the publicly accessible TCGA online database, Western blot analysis, and RT-qPCR in a panel of melanoma cell lines. Lentivirus-mediated TIM/TIPIN knockdown in A375 melanoma cells was used to examine cell proliferation, colony formation, and apoptosis. A xenograft tumor formation assay was performed using shTIM, shTIPIN, and shMock cells. Findings: The TIM/TIPIN complex was frequently overexpressed in melanoma cells compared to normal melanocytes. We also discovered that the overexpression of TIM and TIPIN was significantly associated with poorer prognosis of melanoma patients. Furthermore, we observed that shRNA-mediated knockdown of TIM and TIPIN reduced cell viability and proliferation due to the induction of apoptosis and increased levels of γH2AX, a marker of DNA damage. In a xenograft tumor nude mouse model, shRNA-knockdown of TIM/TIPIN significantly reduced tumor growth. Interpretation: Our results suggest that TIM and TIPIN play an important role in tumorigenesis of melanoma, which might reveal novel approaches for the development of new melanoma therapies. Further mechanistic investigations are needed to determine this complex’s potential as a biomarker of melanoma susceptibility. Targeting TIM/TIPIN might be a potential therapeutic strategy against melanoma. Funding Statement: This work was supported by the Hormel Foundation (Z. Dong). Declaration of Interests: All authors have agreed to publish this manuscript and declare no competing interests. Ethics Approval Statement: All animal studies were performed following the guidelines approved by the University of Minnesota Institutional Animal Care and Use Committee (Protocol ID: 1803-35739A).

In light of the COVID-19 pandemic, we scrutinize what has been established in the literature on whether entrepreneurship can cause and resolve extreme events, the immediate and long-run impacts of extreme events on entrepreneurship, and whether extreme events can positively impact (some) entrepreneurship and innovation. Based on this, we utilize a partial equilibrium model to provide several conjectures on the impact of COVID-19 on entrepreneurship, and to derive policy recommendations for recovery. We illustrate that while entrepreneurship recovery will benefit from measures such as direct subsidies for start-ups, firms’ revenue losses, and loan liabilities, it will also benefit from aggregate demand-side support and income redistribution measures, as well as from measures that facilitate the innovation-response to the Keynesian supply-shock caused by the pandemic, such as access to online retail and well-functioning global transportation and logistics.

We document a causal effect of the conservative Fox News Channel in the USA on physical distancing during COVID-19 pandemic. We measure county-level mobility covering all US states and District of Columbia produced by GPS pings to 15–17 million smartphones and zip-code-level mobility using Facebook location data. Using the historical position of Fox News Channel in the cable lineup as the source of exogenous variation, we show that increased exposure to Fox News led to a smaller reduction in distance traveled and a smaller increase in the probability of staying home after the national emergency declaration in the USA. Our results show that slanted media can have a harmful effect on containment efforts during a pandemic by affecting people’s behavior.

Introduction:\ud This systematic review of randomized controlled trials (RCTs) evaluated the efficacy and safety of electronic cigarettes (e-cigarettes, ENDS) in helping people who smoke to achieve abstinence compared with electronic non-nicotine delivery systems (ENNDS, no nicotine) or any smoking cessation comparator treatment or combination of treatments at 24–26 weeks and at 52 weeks.\ud \ud Methods:\ud Systematic review techniques involved searches of three databases in February 2020 with update searches run on 14 May 2021, two-person independent screening, two-person independent assessment of bias, formal extraction of data with verification by a second person, a feasibility assessment to decide if meta-analysis was appropriate, and network meta-analysis (NMA) of data at 24–26 weeks. Data at 52 weeks were narratively summarized.\ud \ud Results:\ud Ten RCTs met the inclusion criteria, eight for efficacy and ten for safety. Eight of the nine RCTs were assessed as at high risk of bias. The sample sizes of the RCTs were 30–2012. Using nicotine replacement therapy (NRT) as the reference treatment, the incidences of smoking cessation at 24–26 weeks were comparable between ENDS and NRT groups (RR=1.17; 95% CrI: 0.66–1.86). Three sensitivity analyses were carried out indicating the main findings for 24–26 weeks were robust to assumptions. The findings at 52 weeks were inconclusive.\ud \ud Conclusions:\ud This systematic review and NMA indicates that there is no clear evidence of a difference in effect between nicotine containing e-cigarettes and NRT on incidences of smoking cessation at 24–26 weeks, and substantial uncertainty remains.

Background: Development and implementation of effective family-based intervention and treatment strategies during COVID-19, and future public health crises, will require a detailed understanding of the ways that COVID-19 has affected parents, children, and families. Qualitative and mixed-methods research is an important means of gaining such detailed information, particularly in the early phases of the pandemic, when the research community continues to explore the meaning of this experience. Methods: We employed thematic analysis to identify themes in parents’ and children’s reflective writing about COVID-19, and explored how citation of certain themes mapped onto quantitative measures of distress commonly used in past psychosocial research on pandemics. Data were collected from N = 56 parents and N = 43 children between April to May 2020.Findings: Analysis of parent and child written reports revealed positive and negative thematic content, though parents expressed more positive themes than children. The most common themes identified from parent reports surrounded concerns about the impact of COVID-19 on their children, health concerns for others, and the stressful balancing act of parenting, schooling, and working from home. In addition, many parents reported gratitude for what they had, and reflected on the upsides of the pandemic for family relations. For children, the most common themes identified surrounded missing school and social relationships. When children expressed positive themes, they tended to be more egocentric reflections (e.g. learning to ride a bike). Both parent and child thematic content mapped onto parent-proxy and parent-self reported quantitative dimensions of parent and child distress. Finally, we observed that parents who reflected on gratitude in their written reports exhibited a decrease in negative affect pre- to -post-writing.Interpretation: Both parents and children are suffering from reduced wellbeing during the COVID-19 pandemic, particularly with the burdens imposed by the closure of in-person schooling. The psychosocial impact of the pandemic on families would likely be even greater in magnitude within less advantaged populations. Future research and policy should focus on identifying how to fulfill children’s social needs and lessen the caregiving burdens during this time.

After scrutinizing technical, legal, financial, and actuarial aspects of cyber risk, a new approach for modelling cyber risk using marked point processes is proposed. Key covariates, required to model frequency and severity of cyber claims, are identified. The presented framework explicitly takes into account incidents from malicious untargeted and targeted attacks as well as accidents and failures. The resulting model is able to include the dynamic nature of cyber risk, while capturing accumulation risk in a realistic way. The model is studied with respect to its statistical properties and applied to the pricing of cyber insurance and risk measurement. The results are illustrated in a simulation study.

Background: We assessed the effect of bisphosphonates (BPs) on breast cancer (BCa) patient survival and explored how long the effect can persist after treatment. Methods: We performed a meta-analysis and trial sequential analysis (TSA) of prospective studies including randomized controlled trials (RCTs) and cohort studies and reported effect estimates with 95% confidence intervals (CIs). We performed extensive sensitivity analyses to assess the robustness of the findings.\ Results: Seventeen RCTs and eight cohorts with 81508 BCa patients were identified. A significant beneficial effect of BPs on BCa survival was found (RR, 0·725; 95%CI, 0·627-0·839), and TSA results also suggested firm evidence for this beneficial effect. Both summarized results from RCTs and cohorts provides firm evidence for this effect, though the effect estimates were stronger from cohorts than RCTs (RR, 0·892; 95%CI, 0·829-0·961; 0·570; 95%CI, 0·436-0·745; respectively). This beneficial effect was confirmed for bone-metastases (RR, 0·713; 95%CI, 0·602-0·843) and postmenopausal women (RR, 0·737; 95%CI, 0·640-0·850). Importantly, our results demonstrated that this beneficial effect retained at least 1-2 years after treatment completion (RR, 0·780; 95%CI, 0·638-0·954) and could persist for up to more than 4 years after treatment completion (RR, 0·906; 95%CI, 0·832-0·987). Extensive sensitivity analyses showed the robustness of our results. The GRADE quality of evidence was generally judged to be moderate to high. Conclusions: The present study provides firm evidence for a significant beneficial effect of BPs on BCa survival in patients with early-stage BCa, particularly for bone metastases and postmenopausal patients; and this effect retained at least 1-2 years after BP treatment completion. Systematic Review Registration: PROSPERO CRD42014014699. Funding Statement: This work was supported by the China Postdoctoral Science Foundation (grant number 2018M641875 to YPL); the Natural Science Foundation of Heilongjiang Province (grant number YQ2019H021to YPL); the National Key Research and Development Program of China (grant number 2017YFC0108602 to XDL). Declaration of Interests: None.

Background: We describe implementation, evaluate performance, and report outcomes from the first program serving an entire metropolitan area designed to rapidly deliver extracorporeal membrane oxygenation (ECMO)-facilitated resuscitation to patients with refractory ventricular fibrillation/ventricular tachycardia (VF/VT) out-of-hospital (OH) cardiac arrest (CA). Methods: This observational cohort study analyzed 63 consecutive patients prospectively enrolled in the Minnesota Mobile Resuscitation Consortium’s ECMO-facilitated resuscitation program. Entry criteria included: 1) adults (aged 18-75), 2) VF/VT OHCA, 3) no return of spontaneous circulation following 3 shocks, 4) automated cardiopulmonary resuscitation with a Lund University CA System (LUCAS™), and 5) estimated transfer time of < 30 minutes. The primary endpoint was functionally favorable survival to hospital discharge with Cerebral Performance Category (CPC) 1 or 2. Secondary endpoints included program benchmarks, ECMO cannulation rate, and safety. Essential program components included emergency medical services, 3 community ECMO Initiation Hospitals with emergency department ECMO cannulation sites and 24/7 cardiac catheterization laboratories, a 24/7 mobile ECMO cannulation team, and a single, centralized ECMO intensive care unit. Results: From December 1, 2019 to April 1, 2020, 63 consecutive patients were transported and 58 (92%) met criteria and were treated by the mobile ECMO service. Mean age was 57 ± 1.8 years; 46/58 (79%) were male. Program benchmarks were variably met, 100% of patients were successfully cannulated, and no safety issues were identified. Of the 58 patients, 25/58 (43%) were discharged from the hospital with CPC 1 or 2. Conclusions: This first, community-wide ECMO-facilitated resuscitation program in the US demonstrated 100% successful cannulation, good functionally favorable survival rates, safety, and appears potentially generalizable. Funding Statement: This community implementation program was made possible by a grant from the Leona M. and Harry B. Helmsley Charitable Trust Declaration of Interests: None of the authors have any financial or personal relationships with people or organizations that could have inappropriately influenced this study. Ethics Approval Statement: The Institutional Review Board at the University of Minnesota approved this study (No. 1703M11301) with waiver of informed consent.

Background: In the first month of the epidemic in Iran, we had 19644 and 306 confirmed cases of COVID-19 in Iran and Shahroud, respectively. The aim of this study was to estimate the basic reproduction number (R0) of COVID-19 in the early stage of the epidemic and predict the expected number of new cases in Shahroud, Northeast of Iran. Methods: The R0 of COVID-19 was estimated using the serial interval distribution and the number of incidence cases in the early stage of the epidemic. The serial interval (mean ±standard deviation of 7·5±3·4) was fit with a gamma distribution. The probable incidence and cumulative incidence in the next 30 days were predicted using the assumption that daily incidence follows a Poisson distribution determined by daily infectiousness. Data analysis was done using “earlyR” and “projections” packages in R software. Findings: The maximum-likelihood value of R0 was 2.3 (95% confidence interval (CI): 1·9-2·9) for the COVID-19 epidemic in the early 14 days and decreased to 1.26 (95% CI: 1·1-1·4) by the end of the first month. The expected average number of new cases in Shahroud is 18·3±7·2 case/day, which means an estimated total of 550 (range: 388-710) new cases in the next 30 days. Interpretation: It is essential to reduce the R0 to values below 1. Therefore, we strongly recommend enforcing and continuing the current preventive measures, mass screening of suspected cases, restricting travel, and providing screening tests for a larger proportion of the population. Funding Statement: This Study is funded by Shahroud University of Medical Sciences (Grant No. 98126). Declaration of Interests: The authors declare that there is no conflict of interest. Ethics Approval Statement: The protocol of this study was reviewed and approved by the Institutional Review Board of Shahroud University of Medical Science (IR.SHMU.REC.1398.160).

Background: Fibroblast growth factor 21 (FGF21) has become a promising therapeutic target for metabolic diseases such as type 2 diabetes (T2D), obesity and non-alcoholic steatohepatitis (NASH). However, the clinical application of natural FGF21 molecule is limited because of its instability in vitro and short half-life in vivo. To improve FGF21’s therapeutic property, we screened high receptor binding FGF21 analogs and made FGF21-Fc-GLP-1 dual-targeted constructs to investigate their activity in a number of experiments. Methods: Utilizing phage display high-throughput screening we identified mutations that could improve β-Klotho binding property of FGF21. IgG4 Fc was fused to FGF21 variants to extend the in vivo half-life. We further explored the potential synergistic actions of FGF21 with the incretin glucagon-like peptide-1 (GLP-1) by generating GLP-1-Fc-FGF21 dual agonists. Findings: Two Fc-FGF21 variants showed enhanced β-Klotho binding affinity in vitroin vivo. One of the dual agonists, GLP-1-Fc-FGF21 D1, provided potent and sustained glucose lowering effect in diabetic mice models. It also demonstrated superior weight loss effect to GLP-1 or FGF21 alone. Moreover, GLP-1-Fc-FGF21 D1 exhibited strong anti-NASH effect in the high-fat diet-induced ob/ob model as it improved liver function, serum and hepatic lipid profile and reduced NAFLD activity score with an efficacy superior to either FGF21 or GLP-1 analogs alone. Interpretation: This novel GLP-1/FGF21 dual agonist is worth clinical development for the treatment of T2D, obesity and NASH. Funding Statement: HEC Pharm R&D Co., Ltd Declaration of Interests: The authors have nothing to disclose. Ethics Approval Statement: Animal studies were performed according to protocol procedure approved by the Institutional Animal Care and Use Committee at the Laboratory Animal Center of Sunshine Lake Pharma Co., LTD.

Background: West African studies have suggested that national immunisation campaigns with oral polio vaccine (C-OPV) may non-specifically reduce all-cause child mortality rate by 15-25%. We investigated whether C-OPVs had similar non-specific effects in rural Bangladesh from 2004 to 2019. Methods: Chakaria, is a health and demographic surveillance system (HDSS) in Southern Bangladesh. From 2004-2011 the HDSS covered a random sample of households; from 2012-2019 it covered a random sample of villages. Using Cox proportional hazards models, we calculated hazard ratios (HR) comparing mortality for children under 3 years of age after campaigns with OPV-only (C-OPV) versus before C-OPV to assess the “intention-to-treat”-effect of C-OPV. We allowed for different baseline hazard function in the two periods (2004-2011, 2012-2019), with separate models for each period. In the main analysis children were only followed prospectively. Findings: In the main analysis, including 736 deaths (2.0%) among 36,155 children, the HR for after C-OPV was 0.68 (95% confidence interval: 0.51-0.90). No other type of health campaign had similar beneficial results. Each additional dose of C-OPV lowered the mortality rate by 8% (0 to 15%). The number needed to treat (NNT) with C-OPV to save one life between 0-35 months of age was only 109 (100-119) (data not shown). Interpretation: This is the fourth study to show that C-OPV has huge beneficial non-specific effects on child survival. No study has found the opposite. Stopping OPV as planned could have detrimental effects for overall child health in low-income countries. Funding Statement: This research study is funded by core donors who provide unrestricted support to icddr,b for its operations and research. icddr,b is grateful to the Government of Bangladesh, Canada, Sweden and the UK for providing core/unrestricted support. The work on non-specific effects of vaccines has been supported by the Danish Council for Development Research, Ministry of Foreign Affairs, Denmark [grant number 104.Dan.8.f.], Novo Nordisk Foundation and European Union FP7 support for OPTIMUNISE (grant: Health-F3-2011-261375). Declaration of Interests: Nothing to declare. Ethics Approval Statement: Ethical Review Committee of International Centre of Diarrhoeal Disease Research, Bangladesh provided approval for the study.

Background COVID-19 outbreaks in aged care facilities (ACFs) often have devastating consequences. However, epidemiologically these outbreaks are not well defined. We aimed to define such outbreaks in ACFs by systematically reviewing literature published during the current COVID-19 pandemic. Methods We searched 11 bibliographic databases for literature published on COVID-19 in ACFs between December 2019 and September 2020. Original studies reporting extractable epidemiological data as part of outbreak investigations or non-outbreak surveillance of ACFs were included in this systematic review and meta-analysis. PROSPERO registration: CRD42020211424. Findings We identified 5,148 publications and selected 49 studies from four continents reporting data on 214,380 residents in 8,502 ACFs with 25,567 confirmed cases of COVID-19. Aged care residents form a distinct vulnerable population with single-facility attack rates of 45% [95% CI 32–58%] and case fatality rates of 23% [95% CI 18–28%]. Of the cases, 31% [95% CI 28–34%] were asymptomatic. The rate of hospitalization amongst residents was 37% [95% CI 35–39%]. Data from 21 outbreaks identified a resident as the index case in 58% of outbreaks and a staff member in 42%. Findings from the included studies were heterogeneous and of low to moderate quality in risk of bias assessment. Interpretation The clinical presentation of COVID-19 varies widely in ACFs residents, from asymptomatic to highly serious cases. Preventing the introduction of COVID-19 into ACFs is key, and both residents and staff are a priority group for COVID-19 vaccination. Rapid diagnosis, identification of primary and secondary cases and close contacts plus their isolation and quarantine are of paramount importance. Funding Queensland Advancing Clinical Research Fellowship awarded to Prof. Gulam Khandaker by Queensland Health's Health Innovation, Investment and Research Office (HIRO), Office of the Director-General.

The personal experience of events such as financial crises and natural disasters can alter economic preferences. We administered a repeated cross-sectional preference survey during the early stages of the COVID-19 outbreak, collecting three bi-weekly samples from participants recruited through Amazon Mechanical Turk. The survey elicits economic preferences, self-reported fear of the pandemic, and beliefs about economic and health consequences. Preferences varied over time and across regions, and self-reported fear of the pandemic explains this variation. These findings suggest caution about the generalizability of some types of experimental work during times of heightened fear. Supplementary Information The online version contains supplementary material available at 10.1007/s40881-021-00111-x.

Background: Treatment options for outpatients with COVID-19 could reduce morbidity and prevent SARS-CoV-2 transmission. Methods: In this randomized, double-blind, three-arm (1:1:1) placebo-equivalent control trial conducted remotely throughout the United States, adult outpatients with laboratory-confirmed SARS-CoV-2 infection were recruited. Participants were randomly assigned to receive HCQ (400mg BID x1day, followed by 200mg BID x9days) or placebo-equivalent (ascorbic acid) and AZ (500mg, then 250mg daily x4days) or placebo-equivalent (folic acid), stratified by risk for progression to severe COVID-19 (high-risk vs. low-risk). Self-collected mid-turbinate nasal swabs for SARS-CoV-2 PCR, FLUPro symptom surveys, EKGs and vital signs collected daily. Primary endpoints were: (a) 14-day progression to lower respiratory tract infection (LRTI), 28-day COVID-19 related hospitalization, or death; (b) 14-day time to viral clearance; secondary endpoints included time to symptom resolution (ClinicalTrials.gov: NCT04354428). Due to the low rate of clinical outcomes, the study was terminated for operational futility. Findings: Between 15th April and 27th July 2020, 231 participants were enrolled and 219 initiated medication a median of 5.9 days after symptom onset. Incident LRTI occurred in six participants (two control, four HCQ/AZ) and COVID-19 related hospitalization in nine (four control, two HCQ, three HCQ/AZ). There were no deaths. Median time to clearance was 5 days (95% CI=4-6) in HCQ, 6 days (95% CI=4-8) in HCQ/AZ, and 8 days (95% CI=6-10) in control. HCQ but not HCQ/AZ had faster time to viral clearance (HR=1.62, 95% CI=1.01-2.60, p=0.047 & HR=1.25, 95% CI=0.75-2.07, p=0.39) compared to control. Among 197 participants who met the COVID-19 definition at enrollment, time to symptom resolution did not differ by group. Interpretation: Neither HCQ nor HCQ/AZ shortened the clinical course of outpatients with COVID-19, and HCQ, but not HCQ/AZ, had only a modest effect on SARS-CoV-2 viral shedding. HCQ and HCQ/AZ are not effective therapies for outpatient treatment of SARV-CoV-2 infection. Trial Registration Number: ClinicalTrials.gov: NCT04354428 Funding: The COVID-19 Early Treatment Study was funded by the Bill & Melinda Gates Foundation (INV-017062) through the COVID-19 Therapeutics Accelerator. University of Washington Institute of Translational Health Science (ITHS) grant support (UL1 TR002319), KL2 TR002317, and TL1 TR002318 from NCATS/NIH funded REDCap. The content is solely the responsibility of the authors and does not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated. PAN and MJA were supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. Conflict of Interest: Declaration of interests: CJ reports grants from BMGF for conduct of the study, and grants from CDC and NIH outside of the submitted work. HSK reports funding from NIH. PAN and MJA have a potential financial relationship with AliveCor related to QT assessment using the device, however the investigators would receive no financial benefit for use of the technology for patients at Mayo Clinic or for its use in the current study. AB reports consulting for Gates Ventures and grants from BMGF and NIH outside of the submitted work. HYC reports consulting for BMGF, Pfizer, Ellume, and Merck, and grants from Gates Ventures, NIH, CDC, BMGF, DARPA, Apple Inc., Sanofi-Pasteur, and Roche-Genentech, outside of the submitted work. Ethical Approval: Study visits were conducted via Health Insurance Portability and Accountability Act (HIPAA)-compliant telemedicine. The Western Institutional Review Board (WIRB) approved this study with reliance agreements with collaborating institutions.

Sphingolipid metabolism is one of the top dysregulated pathways in NSCLC. However, the molecular control of sphingolipid metabolic reprogramming in cancer progression remains unknown. Here, we first provide clinical evidence that expression of sphingolipid metabolic enzymes, B3GNT5 and GAL3ST1, but not the others, is most significantly associated with patient prognosis, whilst sphingolipidomics analysis of NSCLC patient sera identifies their metabolites, neolacto-series glycosphingolipid and sulfatide, as biomarkers that outperformed current clinical biomarkers for staging patients. Further network analysis of the sphingolipidomes reveals a circular network of coregulated sphingolipids, indicating that the neolacto-series glycosphingolipid/sulfatide balance functions as a checkpoint to determine sphingolipid metabolic reprograming during patient progression. Importantly, sphingolipidomics analysis of B3GNT5/GAL3ST1 genetically perturbed NSCLC cell lines confirms their key regulatory role in sphingolipid metabolism, while B3GNT5 and GAL3ST1 expression has an opposite role on tumorigenesis in vitro and in vivo. Overall, our results provide new insights whereby B3GNT5 and GAL3ST1 differentially regulate sphingolipid metabolism in lung cancer growth and progression. Funding Statement: This work was supported by the Natural Science Foundation of China (81920108028, 81872142); Guangzhou Science and Technology Program (201904020008); Young Teacher Foundation of Sun Yat-sen University (18ykzd07); Guangdong Science and Technology Department (2020B1212060018, 2019A1515011802, 2020A1515011280, 2020A0505100029); China Postdoctoral Science Foundation (2019M650226, 2019M650227). Declaration of Interests: No potential conflicts of interest were disclosed. Ethics Approval Statement: Serum samples were collected from healthy individuals and NSCLC patients (age-matched and body-mass index –matched) with informed consent, and the research program and all the related procedures were approved by the Ethics Committee of Sun Yat-sen Memorial Hospital (Guangzhou, China) and stored according to standard operating procedures for Good Clinical Laboratory Practice standards. All animal procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of Sun Yat-Sen University.

Many governments have implemented social distancing and lockdown measures to curb the spread of the novel coronavirus (COVID-19). Using province-level geolocation data from Italy, we document that political disbelief can limit government policy effectiveness. Residents in provinces leaning towards extreme right-wing parties show lower rates of compliance with social distancing order. We also find that, during the Italian lockdown, provinces with high protest votes virtually disregarded all social distancing orders. On the contrary, in provinces with higher political support for the current political legislation, we found a higher degree of social distancing compliance. These results are robust to controlling for other factors, including time, geography, local COVID-19 cases and deaths, healthcare hospital beds, and other sociodemographic and economic characteristics. Our research shows that bipartisan support and national responsibility are essential to implement and manage social distancing efficiently. From a broader perspective, our findings suggest that partisan politics and discontent with the political class (i.e., protest voting) might significantly affect human health and the economy.

Background: Many patients with acute low back pain (LBP) first seek care from primary care physicians. Evidence is lacking for interventions to prevent transition to chronic LBP in this setting. We aimed to test if implementation of a risk-stratified approach to care would result in lower rates of chronic LBP and improved self-reported disability. Methods: We conducted a pragmatic, cluster randomized trial using 77 primary care clinics in four health care systems across the United States. Practices were randomly assigned to a stratified approach to care (intervention) or usual care (control). Using the STarTBack screening tool, adults with acute low back pain were screened low, medium, and high-risk. Patients screened as high-risk were eligible. The intervention included electronic best practice alerts triggering referrals for psychologically informed physical therapy (PIPT). PIPT education was targeted to community clinics geographically close to intervention primary care clinics. Primary outcomes were transition to chronic LBP and self-reported disability at six months. Findings: Between May 2016 and June 2018, 1207 patients from 38 intervention and 1093 from 37 control practices were followed. In the intervention arm, around 50% of patients were referred for physical therapy (36% for PIPT) compared to 30% in the control. At 6 months, 47% of patients reported transition to chronic LBP in the intervention arm (38 practices, n=658) versus 51% of patients in the control arm (35 practices, n=635; OR=0.83 95% CI 0·64, 1·09; p=0·18). No differences in function were detected (difference -2·1, 95% CI -4·9-0·6; p=0·12). Opioids and imaging were prescribed 25% (21%, 28%) and 27% (23%, 31%) of initial visits, respectively. Twelve-month LBP utilization was similar in the two groups. Interpretation: There were no differences in transition to chronic LBP among patients presenting with acute LBP using a stratified approach to care. Opioid and imaging prescribing rates were non-concordant with clinical guidelines. Trial Registration: ClinicalTrials.gov NCT02647658. Funding Statement: Patient-Centered Outcomes Research Institute (PCORI) contract # PCS-1402-10867. Declaration of Interests: We declare that we have no conflicts of interest. Ethics Approval Statement: Approval of the study protocol by all site institutional research ethics boards specified: (1) for processes conducted at the primary care clinics, the study was viewed as a quality improvement initiative, (2) for the follow-up assessments at six months, the study was viewed as research requiring patient informed consent for collection of patient-reported primary outcomes, and (3) for the 12-month EMR review patient consent or waiver of HIPAA authorization and patient consent was required.

Background Erythrocyte mass contributes to maintaining systemic oxygen delivery and blood viscosity, with the latter being one of the determinants of blood pressure. However, the physiological response to blood pressure changes under anaemic conditions remain unknown. Methods and findings We show that anaemia decreases blood pressure in human patients and mouse models. Analyses of pathways related to blood pressure regulation demonstrate that anaemia enhances the expression of the gene encoding the vasopressor substance renin in kidneys. Although kidney juxtaglomerular cells are known to continuously produce renin, renal interstitial fibroblasts are identified in the present study as a novel site of renin induction under anaemic hypotensive conditions in mice and rats. Notably, some renal interstitial fibroblasts are found to simultaneously express renin and the erythroid growth factor erythropoietin in the anaemic mouse kidney. Antihypertensive agents but not hypoxic stimuli induced interstitial renin expression, suggesting that blood pressure reduction triggers interstitial renin induction in anaemic mice. The interstitial renin expression was also detected in injured fibrotic kidneys of the mouse and human, and the renin-expressing interstitial cells in murine fibrotic kidneys were identified as myofibroblasts originating from renal interstitial fibroblasts. Since the elevated expression levels of renin in fibrotic kidneys along with progression of renal fibrosis were well correlated to the systemic blood pressure increase, the renal interstitial renin production seemed to affect systemic blood pressure. Interpretation Renal interstitial fibroblasts function as central controllers of systemic oxygen delivery by producing both renin and erythropoietin. Funding Grants-in-Aid from Japan Society for the Promotion of Science (JSPS) KAKENHI (17K19680, 15H04691, and 26111002) and the Takeda Science Foundation.

Objective: Tubercular meningitis (TBM) is associated with high mortality and stroke with chronic neurological sequelae even with best of care and antitubercular therapy. Studies have shown that aspirin as an adjunctive therapy might play some role in management of TBM. This systematic review and meta-analysis has been planned to evaluate the efficacy and safety of aspirin as an adjunctive therapy in TBM patients. Design and Method: We conducted a systematic search of randomized controlled trials in patients with tubercular meningitis published till October 2019 in all major clinical journals. Articles were tested for eligibility and assessed for quality and various bias. Data synthesis and analysis was done using Review manager 5.3. The primary end point for assessment of efficacy was mortality at three months. The secondary end point was stroke or composite outcome of stroke and mortality at three months. Adverse effects were also assessed as secondary safety end point. Results: Overall, three eligible randomized controlled trials with 365 participants were included that provided quantitative data for this meta-analysis. The analysis of primary and secondary end points was done using fixed effect model. There was not significant reduction in mortality [hazard ratio 0.78 (95% CI 0.45-1.35, p=0.37)] and composite outcome of mortality and new onset stroke [hazard ratio 0.86 (95% CI 0.60 - 1.24, p=0.43)] in aspirin group as compared to placebo. However, aspirin as compared to placebo significantly reduced new onset stroke [hazard ratio of 0.51 (95% CI 0.29-0.87, p=0.01)]. Conclusion: We did not find significant reduction in mortality and composite outcome (mortality and new onset stroke) with aspirin as compared to placebo but there was significant reduction in new onset stroke in aspirin group as compared to placebo with Number Needed to Treat (NNT) = 10, which might be of clinical importance since stroke is responsible for high mortality and morbidity in these subset of patients. However, a large well conducted randomized controlled trial is required to put more light on the available evidence. Funding Statement: No grant or funding was taken from any funding agencies Declaration of Interests: None to declare.

Background: Recurring outbreaks of infectious diseases highlight the importance of population vaccination strategies. We aimed to assess the impact of national vaccination strategies on vaccine-preventable infectious diseases (VPDs) in Shanghai, China and to identify vulnerable groups that may benefit from future vaccination policies. Methods: Infectious disease data from 1953 to 2018 was obtained from Xuhui District Center for Disease Control and Prevention, Shanghai China. We used joinpoint regression to show incidence, mortality and fatality trends and to determine annual percent change in incidence of 12 VPDs among three eras of national immunization strategies: (1)1953-1977, (2)1978-2007, and (3)2008-2018. Findings: Incidence, mortality, and fatality from VPDs have decreased drastically over the three eras, despite the inclusion of more diseases over time. Strikingly, the overall yearly incidence of VPDs shows an increasing trend from 2000 to 2018 in Shanghai (Annual percentage changes, APC: 7.7, p =0.025). In the third era (2008-2018), the three VPDs with the highest incidence were varicella (80.2 cases/100,000), hand-foot-mouth disease (HFMD) (73.6 cases /100,000), and hepatitis (43.5 cases /100,000). A significant upward trend was also observed in hepatitis (APC: 24.9, p

While a considerable number of employees across the globe are being forced to work from home due to the COVID-19 crisis, it is a guessing game as to how they are experiencing this current surge in telework. Therefore, we examined employee perceptions of telework on various life and career aspects, distinguishing between typical and extended telework during the COVID-19 crisis. To this end, we conducted a state-of-the-art web survey among Flemish employees. Notwithstanding this exceptional time of sudden, obligatory and high-intensity telework, our respondents mainly attribute positive characteristics to telework, such as increased efficiency and a lower risk of burnout. The results also suggest that the overwhelming majority of the surveyed employees believe that telework (85%) and digital conferencing (81%) are here to stay. In contrast, some fear that telework diminishes their promotion opportunities and weakens ties with their colleagues and employer.