bluuebunny/crossref_metadata_2025 huggingface dataset:
Individual-Level Rewards and Appraisal
Authors: Gooderham Paul , Mayrhofer Wolfgang
Published: April 2021

Individual performance rewards and individual performance appraisals are key elements of calculative human resource management (HRM). As practices, they figure strongly in the most highly cited studies within strategic HRM research. However, these studies are generally located within a single, distinct context, the United States, a context in which there is an underlying assumption of firm latitude. Varieties of capitalism literature indicates that this assumption is inappropriate to the context of the coordinated market economies of Europe. This chapter reviews cross-national studies of the adoption of calculative HRM and observes a substantial influence of national context on its adoption by firms. In terms of how to conceive national context, recent research suggests that formal institutional influences are of more salience than informal influences. The relative importance of formal institutional influences has consequences for international management education that predominantly views context through a cultural lens. The chapter further observes that recent research of the uptake of calculative HRM perceives context as a constraint rather than as a determinant. Regardless of context, managers have at least some latitude to implement calculative HRM practices. However, the chapter suggests that their efforts need to be adapted to, and sensitive to, contextual constraints.
Well-Being in Industrialized Economies and the Case for Firms’ Investment in Employee Learning
Authors: Tregaskis Olga
Published: April 2021

The idea of enhancing the well-being of employees through employment and skills development has gained greater emphasis in economic growth strategies. This new performance lens challenges the primacy given to financial metrics over social metrics such as health and happiness and brings multiple stakeholder interests into play. This chapter examines the evidence base for employee learning as a pathway to well-being. The case is made for a renewed focus on employee learning enabling transformative change that supports individuals, organizations, and society.
Maguy Marin’s Social and Aesthetic Critique
Authors: Mandradjieff Mara
Published: April 2021

This chapter situates French choreographer Maguy Marin as a valuable figure in contemporary ballet history. In analyzing her works Cendrillon (Cinderella, 1985), Groosland (1989), and Coppélia (1993), one discovers Marin’s application of self-reflexive strategies, body-transforming costumes, and dancer “dollness.” With these elements in place, the three ballets initiate discussions on objectification, gender performativity, labor relations, and body aesthetics, for both society at large and the institution of ballet specifically. Cendrillon, Groosland, and Coppélia function as examples of how ballet choreography might implement social and aesthetic critique, while simultaneously reflecting on ballet’s participation in the structures under consideration.
Talking Shop
Authors: Sulcas Roslyn
Published: April 2021

Justin Peck, Benjamin Millepied, and Troy Schumacher are all current or former New York City Ballet dancers who have established prominent choreographic careers. In the interviews presented in this chapter, they talk about their initial introductions to dance, their early dance training, their desire to begin to choreograph, their formative influences, their choreographic processes, and how they have been shaped by a “City Ballet” training and an immersion in its repertory. They also discuss the challenges of juggling the roles of dancer and choreographer, music as a primary source of inspiration, and whether they are interested in experimentation with ballet’s parameters.
Gods, Angels, and Björk
Authors: Scholick Jennie
Published: April 2021

This chapter discusses two ballets created in 2018 for San Francisco Ballet’s “Unbound: A Festival of New Works”: Björk Ballet by Arthur Pita and Anima Animus by David Dawson. It considers these two ballets in relation to their creators’ divergent choreographic lineages and artistic processes. In so doing, it argues that despite their apparent differences, the choreography of Björk Ballet and Anima Animus engages with ballet’s legacy and, in particular, with the idea of the ballerina. Taken together, these two works put forth a conception of contemporary ballet that both dialogues with classical balletic values and creates space for contemporary ideas and concerns.
Balancing Reconciliation at the Royal Winnipeg Ballet
Authors: Cauthery Bridget , Newman Shawn
Published: April 2021

As part of efforts across Canada to address and reconcile the nation-state’s violent colonial histories, the Royal Winnipeg Ballet (RWB) premiered Mark Godden’s newest work, Going Home Star: Truth and Reconciliation, in 2014. The work narrates one element of settler colonialism in Canada: the Indian Residential School System. With no Indigenous dancers in the company, and few Indigenous people involved in the production overall, the project has received criticism as yet another non-Indigenous endeavor speaking for Indigenous peoples. In this chapter, we approach Going Home Star in ways that question the appropriateness of contemporary ballet as a medium for negotiating contemporaneous reconciliation between Indigenous and settler peoples in Canada and its checkered history of Indigenous representation.
Hans Van Manen
Authors: Seidl Anna
Published: April 2021

The Dutch avant-garde choreographer Hans van Manen (b. 1932) is frequently recognized as a game changer and pioneer for his fusion of ballet techniques with elements from dance theater, and for his scrutiny of ballet’s conventional use of authority, power, and patriarchy. Yet it still remains difficult to describe the “mysterious experience” one gains while watching his ballets, an experience characterized by an intriguing tension between formal austerity and dramatic expression—a type of “less is more.” In this chapter, Van Manen’s ballets are at once abstract and emotive; they are uncomplicated, tightly composed works of pure dance, and yet they are deeply social and political, with a clear emancipatory agenda. In short: Hans van Manen’s choreographies have an existential dimension, and can be described as abstract miniature dramas.
Liam Scarlett
Authors: Cooper Susan
Published: April 2021

This chapter examines the work and career of British choreographer Liam Scarlett (born 1986), former artist in residence at The Royal Ballet (2012-2020), and artistic associate with Queensland Ballet (2016-2020). This chapter charts Scarlett’s meteoric rise to become one of the most highly sought-after contemporary ballet creators, placing his oeuvre within the British ballet heritage and the wider international dance field of the twenty-first century. A Royal Ballet School graduate, Scarlett began his global career subsequent to his first major Royal Ballet commission in 2010; therefore, this account is of a choreographer in what may be seen as his early years. Scarlett’s output comprises both plotless and narrative one-act ballets and full-evening works. He also produced The Royal Ballet’s Swan Lake in 2018. Scarlett’s choreographic style is rooted in classical ballet in the British tradition, following Sir Frederick Ashton and Sir Kenneth MacMillan, yet he grew up in a culture where contemporary dance was popular and respected, and he has worked alongside radical creator Wayne McGregor at The Royal Ballet. Scarlett’s works show a clear influence of non-traditional balletic norms, and his narrative ballets tend towards darkly dramatic themes. His international career includes commissions for major ballet companies in Australia, the United States of America, New Zealand, Denmark and Norway, and key works include Asphodel Meadows (2010), Viscera (2012), and Frankenstein (2016).
Gender Progress and Interpretation in Ballet Duets
Authors: Fisher Jennifer
Published: April 2021

Conservative ballet partnering protocols have been slow to change even in contemporary iterations, for reasons that relate to history, training, gender bias, and ballet’s tendency to operate as a closed and unified system. This chapter focuses not only on trends in gendered ballet duets but also on the way they have been analyzed and interpreted, drawing examples from the post-Diaghilev era of Balanchine to the present, including interpretation of Balanchine’s The Four Temperaments, and a discussion of gender in the work of Chase Johnsey, Édouard Lock and Ruth Page. While ballet’s “compulsory heterosexuality” may reflect the culture in which it originated, it is suggested that the contemporary ballet pas de deux should start reflecting the culture in which it now resides.
Tryptophan Metabolism and the Microbiome-Gut-Brain Axis
Authors: Clarke Gerard , Villalobos-Manriquez Francisca , Marin David Campos
Published: April 2021

The capacity of the gut microbiome to influence communication along the gut-brain axis relies in part on the microbial influence on neurotransmitter systems. Recent years have seen increasing surveillance of tryptophan in this regard, an essential amino acid and building block for a number of host-produced and microbial-derived bioactives. An appreciation of the important role for tryptophan in supporting microbiome-gut-brain axis signaling requires a reframing of what is currently known about this important precursor to integrate with newer concepts around the gut microbiota. The fate, distribution, metabolism, absorption, and distal availability of tryptophan for these pathways following dietary consumption is heavily influenced by the action of the gastrointestinal microbiota. This in turn has implications for local gastrointestinal enteric circuits and the neurobiology of a range of central nervous system and gastrointestinal disorders in which compositional and functional microbiota alterations have now been reported. Further research is required to bridge the knowledge gaps surrounding microbial regulation of tryptophan metabolism and availability. Mechanistic advances in our understanding of these important aspects of host–microbe dialogue offer the possibility of therapeutic targeting of the gut microbiome to fine-tune tryptophan metabolism in multiple pathways that contribute to symptom expression in disorders associated with the microbiome-gut-brain axis.
Transnational Tort Law
Authors: van Dam Cees
Published: April 2021

This chapter deals with harm caused and suffered across national borders, such as nuclear damage, road and air traffic accidents, defective products, and human rights violations by transnational corporations. First, it explores how supranational, international, and national tort law may respond to such harmful events. This also identifies gaps, such as the lack of international regulation of company behavior when it comes to protecting human rights. Subsequently, this chapter analyzes how soft law instruments are aimed at filling this void and how soft law is translated into binding regional and domestic regulation. This may in turn tort law standards to protect human rights. Finally, this chapter looks in more detail into various aspects of transnational tort law, from the perspective of the hurdles faced by victims and with references to key cases.
Contextualization as a (Feminist) Method for Transnational Legal Practice
Authors: Ghadery Farnush
Published: April 2021

Transitional justice and peacebuilding are expanding fields of global governance that have attracted increasing interest from transnational legal practice and scholarship. Focusing on women’s rights promotion in postconflict states, the chapter examines the UN “Women, Peace and Security” agenda and its challenging implementation in Afghanistan. By identifying the hegemony of Western liberal thought within peace and conflict studies and international human rights law as an obstacle to this implementation, the chapter explains how transnational legal practice could benefit from a greater engagement with feminist methodology and the significance it places on understanding “contexts.” As such, the chapter sets out “contextualization” as a method that could lead to more relevant and inclusive transnational legal practice in such disciplines.
Stakes of The Right to Food in the Politics of Transnational Law
Authors: Okano Naoyuki
Published: April 2021

This chapter explores stakes, viabilities, and politics of transnational law through case studies of practices and struggles of the right to food. This chapter first explores the emergence and particularities of transnational legal politics in a field of food security and discusses a changing meaning and renewed importance of locality. Then, case studies of private regulations of food production and food sovereignty movements are presented to illustrate how the politics of human rights unfolds with different spatiality and processes. The case studies illustrate that while transnational legal politics makes a question of political agency difficult to solve in a normatively satisfactory way, human rights have a potential to provide a ground to organize and network different sites of struggles. This chapter submits that, in transnational legal politics, human rights should be seen as being open to shift their meaning and normative contents in response to actual local struggles.
Transnational Law and Literatures: A Postcolonial Perspective
Authors: Lagji Amanda
Published: April 2021

This chapter argues that a transnational law and literature approach, paired with the insights and political commitments of previous postcolonial law and literature approaches, allows us to attend to transnational parties and entities (below and above the figure of the “state” in international law) with a critical eye toward the colonial histories embedded in Anglo-American, and Eurocentric law and literatures. In what follows, the chapter first discusses law and literature as it emerged in the 1970s, more recent postcolonial critiques, and the lacunae that a transnational law and literature approach might address differently. The chapter concludes that a transnational law and literature reading of Louise Erdrich’s The Round House shows how this approach can facilitate a decolonial understanding of sovereignty and knowledge, as well as a fuller appreciation of the novel’s representation of US federal law and the US Supreme Court opinions that have yielded the fragile sovereignties of contemporary tribal law.
Early Italian Lyric
Authors: Rea Roberto
Published: April 2021

In order to examine the relationship between Dante and the early Italian lyric, this chapter focuses on two key moments of Dante’s rewriting of his own story as lyric poet: first in the Vita nuova, which traces the relationship to fellow poet Guido Cavalcanti, and second in the encounters with Bonagiunta da Lucca and Guido Guinizzelli in Purgatorio XXIV and XXVI, which redefine the roles of the major poets of the past generation. These passages are less ambiguous than has often appeared: they doubtless intend to promote Dante’s poetic choices and literary authority, but they also testify to objective developments in the history of vernacular love poetry.
Visual Theory
Authors: Gilson Simon
Published: April 2021

This chapter provides an overview and assessment of Dante’s use of medieval visual theories in his writings. It first surveys his use of the medieval Aristotelian tradition of visual theory in the Convivio, and discusses his reliance on other models of vision in the Vita nova and Rime, including those found both in medical writings and in the works of other poets. The chapter then discusses how, in the Commedia, Dante incorporates a variety of other late medieval discourses about vision into his narrative. Dante does this—it is argued—in carefully structured and stratified ways that often reveal his characteristic syncretism. The poet continues to use neo-Aristotelian theory but also draws upon a rich body of material on seeing found in medieval theology, contemplation, and Biblical exegesis. Particular attention is paid to how these multiple traditions inform the presentation of Dante-character’s own visual experiences throughout the poem.
Exile
Authors: Bartuschat Johannes
Published: April 2021

This chapter examines the way the poet represents his exile. It is composed of three parts: the first considers the way Dante handles his exile in relation to authorship, and reveals how he constructs his authority from his position as an exile in the Convivio, De vulgari eloquentia, and his Epistles. The second analyses exile as a major element of the autobiographical dimension of the Commedia. It shows that the necessity to grasp the moral lesson of the exile constitutes the very heart of the poem. The third part explores the relationship between exile and pilgrimage, the latter being, from the Vita Nuova onwards, a symbol of the human condition, and demonstrates how Dante interprets his experience both as an exile and as a wanderer in the other world in the light of pilgrimage.
Color
Authors: Vartanian Oshin
Published: April 2021

The empirical study of the psychology of color dates back to the 19th century. Important in this line of research is the study of color preferences—wherein stimuli are characterized in terms of three properties: hue (i.e., wavelength), saturation (i.e., vividness), and brightness (i.e., black-to-white quality). Whereas early thinkers doubted the possibility of a systematic study of color preferences due to idiosyncrasies and individual differences in participants’ choices, a substantial body of empirical evidence has emerged to demonstrate that there are reliable regularities in color preference. Specifically, in terms of single colors, there is a clear maximum around blue and a clear minimum around yellow—a pattern also observed in animals. In terms of saturation, people tend to prefer more saturated to less saturated colors, particularly in context-free settings. In turn, results regarding brightness are more equivocal, although overall there appears to be a preference for lighter colors. Perhaps more interesting are the reasons for the aforementioned preference patterns, for which a number of theoretical explanations have been put forth based on physiology, psychophysics, emotion, and ecological objects—each of which enjoys some level of empirical support. The psychological study of color preferences is well poised for further advancement, with downstream effects in a number of settings ranging from consumer products to artworks and architecture.
Implementation of medicine take-back concept at community level in Nepal: a pilot study
Authors: Sapkota Binaya , Giri Anil , Bhatta Bigyan , Awasthi Krishna , Bhurtyal Kiran , Joshi Bimala , Joshi Khem Raj
Published: April 2021

Background

Most households may have leftover, unwanted, unused and expired (UUE) medicines. The present research aimed to analyze feasibility of implementation of medicine take-back in select communities in Nepal.

Methods

Exploratory (i.e. feasibility) study was conducted among 400 adults from July 2017 to January 2018. Study sites and participants were selected by simple random sampling and respondents were interviewed about their awareness about medicine disposal, hazards and willingness to support take-back program using semi-structured questionnaire. Multinomial logistic regression analysis was applied to explore relationship of take-back related outcomes with the predictors. The P-value < 0.05 was statistically significant at 95% confidence level.

Results

Land pollution and effect on health of children was significantly related with inappropriate disposal of medicines such as site of disposal (P value < 0.01), river (P value, 0.02), garbage (P value, 0.04) and dumping site (P value, 0.01). Analysis of willingness to follow take-back program with the techniques of support showed significant relationship with the establishment of collection center and participation on seminar (P value < 0.01).

Conclusion

Most participants were interested to support take-back, if implemented in their community but main constraint was the budget. Take-back concept could be initiated and implemented on government funding or other sources.
Identifying local authority need for, and uptake of, school-based physical activity promotion in England–a cluster analysis
Authors: Venkatraman Tishya , Honeyford Kate , Ram Bina , M F van Sluijs Esther , Costelloe Céire E , Saxena Sonia
Published: April 2021

Background

School-based physical activity interventions such as The Daily Mile (TDM) are widely promoted in children’s physical activity guidance. However, targeting such interventions to areas of greatest need is challenging since determinants vary across geographical areas. Our study aimed to identify local authorities in England with the greatest need to increase children’s physical activity and assess whether TDM reaches school populations in areas with the highest need.

Methods

This was a cross-sectional study using routinely collected data from Public Health England. Datasets on health, census and the built environment were linked. We conducted a hierarchical cluster analysis to group local authorities by ‘need’ and estimated the association between ‘need’ and registration to TDM.

Results

We identified three clusters of high, medium and low need for physical activity interventions in 123 local authorities. Schools in high-need areas were more likely to be registered with TDM (incidence rate ratio 1.25, 95% confidence interval: 1.12–1.39) compared with low-need areas.

Conclusions

Determinants of children’s physical activity cluster geographically across local authorities in England. TDM appears to be an equitable intervention reaching schools in local authorities with the highest needs. Health policy should account for clustering of health determinants to match interventions with populations most in need.
Default Effects And Follow-On Behaviour: Evidence From An Electricity Pricing Program
Authors: Fowlie Meredith , Wolfram Catherine , Baylis Patrick , Spurlock C Anna , Todd-Blick Annika , Cappers Peter
Published: April 2021

We study default effects in the context of a residential electricity-pricing program. In the large-scale randomized controlled trial we analyse, one treatment group was given the option to opt-in to time-varying pricing while another was defaulted into the program but allowed to opt-out. We provide dramatic evidence of a default effect on program participation, consistent with previous research. A novel feature of our study is that we also observe how the default manipulation impacts customers’ subsequent electricity consumption. Passive consumers who did not opt-out but would not have opted in—comprising more than 70$\%$ of the sample—nonetheless reduce consumption in response to higher prices. Observing of this follow-on behaviour enables us to assess competing explanations for the default effect. We draw conclusions about the likely welfare effects of defaulting customers onto time-varying pricing.
Neonatal Abstinence Syndrome in Rural Appalachia
Authors: Cain Shannon M , Conway Anne , Combs-Orme Terri , Bruck Sarah L , Cook E Kyle , Thomas Elizabeth
Published: April 2021

As the United States faces the repercussions of the current opioid epidemic, it is important for social workers to be able to identify risks for poor birth outcomes in infants with neonatal abstinence syndrome (NAS). Although some studies have identified single risk factors, no studies have tested associations between total amount of risk (that is, cumulative risk) and birth outcomes in infants with NAS. Authors examined 318 mothers who used opioids during pregnancy and their infants’ birthweight, length, head circumference, and Apgar scores (which measure overall infant health after birth). All infants were admitted to a neonatal intensive care unit in Appalachia and were diagnosed with NAS. Authors found that high cumulative risk during pregnancy was associated with lower birthweight and Apgar scores one and five minutes after birth as well as shorter length and smaller head circumference at birth. Social workers are encouraged to assess for the quantity of prenatal adversity experienced by the mothers they serve and to consider multicomponent, comprehensive community-based interventions to reduce cumulative risk.
Antibody Testing for Suspected Autoimmune Autonomic Dysfunction and Small Fiber Neuropathies
Authors: Shouman Kamal , Sandroni Paola
Published: April 2021

Autonomic dysfunction and small fiber neuropathies are heterogeneous disorders with a wide array of potential etiologies. As with other neurologic diseases, autoantibodies specific to neural tissue, either in the setting of cancer or systemic autoimmunity, may cause autonomic abnormalities. Given the complex and varied functions of the autonomic nervous system, however, the presentation of these conditions may be quite variable. This, in addition to pitfalls of autonomic testing especially for the novice, can lead to inaccuracies in recognizing and characterizing these conditions. We now have a large number of autoantibodies available for testing with more in the pipeline thanks to unprecedented developments in the field of neuroimmunology. Those have been very helpful in uncovering potentially treatable mechanisms of autonomic disease, but also pose a challenge to the clinician given their multiplicity and variable specificity. Growing knowledge regarding autoimmune autonomic implications and the autonomic specificities of each antibody, in addition to the increasing attention to the relevance of antibody titers are of utmost importance for clinicians concerned with autonomic neurology. This review attempts to shed a light on the frequently encountered antibodies in relation to autonomic dysfunction.
Electrical Activity During Slow-Wave Sleep and the Relationship With Enlarged Perivascular Spaces in Arteriosclerotic Cerebral Small Vessel Disease
Authors: Zhang Miaoyi , Yu Huan , Wang Fei , Tang Jie , Liu Na , Xue Yang , Ren Xue , Shi Langfeng , Fu Jianhui
Published: April 2021

Purpose:

We sought to analyze EEG spectral power during slow-wave sleep among patients with arteriosclerotic cerebral small vessel disease (CSVD) compared with community-dwelling individuals. We also sought to determine the relationship between EEG activity and the severity of enlarged perivascular spaces (EPVSs).

Methods:

Consecutive subjects with arteriosclerotic CSVD (n = 36) and community-dwelling individuals (n = 26) between 50 and 80 years of age were included. Nocturnal polysomnography was performed, and EEG spectral analysis was conducted during slow-wave sleep using the F4/M1 and C4/M1 channel. Regionalized EPVSs in the basal ganglia and centrum semiovale were assessed on a validated 4-point visual rating scale (0 = none, 1 = 1–10, 2 = 11–20, 3 = 21–40, and 4 = >40) using MRI.

Results:

CSVD group showed lower delta:beta ratios in the frontal (P = 0.017) and central (P = 0.038) regions after adjusting for age, sex, mini–mental state examination score, and arousal index. The significance still remained in the frontal region when including age, sex, mini–mental state examination, and apnea–hypopnea index as covariates (P = 0.037). Among patients with arteriosclerotic CSVD, decreased delta power (P = 0.031) and theta power (P = 0.034) in the frontal region were associated with a higher degree of EPVSs in the centrum semiovale rather than in the basal ganglia. Delta power in the central region showed an extremely weak association with EPVSs in the centrum semiovale (P = 0.047).

Conclusions:

Among patients with arteriosclerotic CSVD, the intrusion of high-frequency EEG activity into slow-wave sleep was identified, and slow-wave activity during slow-wave sleep might be negatively associated with the severity of EPVSs in the centrum semiovale. Further studies are required to corroborate the conclusions.
The impact of increasing the minimum legal drinking age to 20 years in Lithuania on all-cause mortality – an interrupted time-series analysis
Authors: Tran Alexander , Jiang Huan , Lange Shannon , Livingston Michael , Manthey Jakob , Neufeld Maria , Room Robin , Štelemėkas Mindaugas , Telksnys Tadas , Petkevičienė Janina , Radišauskas Ričardas , Rehm Jürgen
Published: April 2021

Aims

To determine the effect of an alcohol policy change, which increased the minimum legal drinking age (MLDA) from 18 years of age to 20 years of age on all-cause mortality rates in young adults in Lithuania.

Methods

An interrupted time series analysis was conducted on a dataset from 2001 to 2019 (n= 228 months). The model tested the effects of the MLDA on all-cause mortality rates (deaths per 100,000 individuals) in 3 age categories (15-17 years old, 18-19 years old, 20-22 years old). Additional models that included GDP as a covariate and taxation policy were tested as well.

Results

There was a significant effect of the MLDA on all-cause mortality rates in those 18-19 years old, when modelled alone. Additional analyses controlling for the mortality rate of other age groups showed similar findings. Inclusion of confounding factors (policies on alcohol taxation, GDP) eliminated the effects of MLDA.

Conclusions

Although there was a notable decline in all-cause mortality rates among young adults in Lithuania, a direct causal impact of MLDA on all-cause mortality rates in young adults was not definitively found.

Short Summary

We investigated the effect of an increase in minimum legal drinking age (MLDA) on all-cause mortality in young adults (aged 18-19). MLDA had a negative effect on all-cause mortality (even when controlling for mortality rates in other age groups), however when confounding factors were included, these effects were attenuated.
Impact of unequal cluster sizes for GEE analyses of stepped wedge cluster randomized trials with binary outcomes
Authors: Tian Zibo , Preisser John , Esserman Denise , Turner Elizabeth , Rathouz Paul , Li Fan
Published: April 2021

The stepped wedge design is a type of unidirectional crossover design where cluster units switch from control to intervention condition at different pre-specified time points. While a convention in study planning is to assume the cluster-period sizes are identical, stepped wedge cluster randomized trials (SW-CRTs) involving repeated cross-sectional designs frequently have unequal cluster-period sizes, which can impact the efficiency of the treatment effect estimator. In this article, we provide a comprehensive investigation of the efficiency impact of unequal cluster sizes for generalized estimating equation analyses of SW-CRTs, with a focus on binary outcomes as in the Washington State Expedited Partner Therapy trial. Several major distinctions between our work and existing work include: (i) we consider multilevel correlation structures in marginal models with binary outcomes; (ii) we study the implications of both the between-cluster and within-cluster imbalances in sizes; and (iii) we provide a comparison between the independence working correlation versus the true working correlation and detail the consequences of ignoring correlation estimation in SW-CRTs with unequal cluster sizes. We conclude that the working independence assumption can lead to substantial efficiency loss and a large sample size regardless of cluster-period size variability in SW-CRTs, and recommend accounting for correlations in the analysis. To improve study planning, we additionally provide a computationally efficient search algorithm to estimate the sample size in SW-CRTs accounting for unequal cluster-period sizes, and conclude by illustrating the proposed approach in the context of the Washington State study.
Direct and indirect effectiveness of mRNA vaccination against SARS-CoV-2 infection in long-term care facilities in Spain
Authors: Monge Susana , Olmedo Carmen , Alejos Belén , Lapeña María Fé , Sierra María José , Limia Aurora ,   COVID-19 registries study group
Published: April 2021

Objectives

To estimate indirect and total (direct plus indirect) effects of COVID-19 vaccination in residents in long-term care facilities (LTCF).

Design

Registries-based cohort study including all residents in LTCF ≥65 years offered vaccination between 27 December 2020 and 10 March 2021. Risk of SARS-CoV-2 infection following vaccination was compared with the risk in the same individuals in a period before vaccination. Risk in non-vaccinated was also compared to a period before the vaccination programme to estimate indirect protection. Standardized cumulative risk was computed adjusted by previous documented infection (before the start of follow-up) and daily-varying SARS-CoV-2 incidence and reproductive number.

Participants

573,533 records of 299,209 individuals in the National vaccination registry were selected; 99.0% had ≥1 vaccine-dose, 99.8% was Pfizer/BioNTech (BNT162b2). Residents mean age was 85.9, 70.9% were females. A previous SARS-CoV-2 infection was found in around 25% and 13% of participants, respectively, at the time of vaccine offer and in the reference period.

Main outcome measures

Documented SARS-CoV-2 infection identified in the National COVID-19 laboratory registry.

Results

Total VE was 57.2% (95% Confidence Interval: 56.1%-58.3%), and was highest ≥28 days after the first vaccine-dose (proxy of ≥7 days after the second dose) and for individuals naïve to SARS-CoV-2 [81.8% (81.0%-82.7%)] compared to those with previous infection [56.8% (47.1%-67.7%)]. Vaccination prevented up to 9.6 (9.3-9.9) cases per 10.000 vaccinated per day; 11.6 (11.3-11.9) if naïve vs. 0.8 (0.5-1.0) if previous infection. Indirect protection in the non-vaccinated could only be estimated for naïve individuals, at 81.4% (73.3%-90.3%) and up to 12.8 (9.4-16.2) infections prevented per 10.000 indirectly protected per day.

Conclusions

Our results confirm the effectiveness of mRNA vaccination in institutionalized elderly population, endorse the policy of universal vaccination in this setting, including in people with previous infection, and suggest that even non-vaccinated individuals benefit from indirect protection.

Key messages

COIVD-19 vaccination reduced the risk of documented SARS-CoV-2 infection in institutionalized elderly by 57.2% (56.1% to 58.3%), which increased to 81.2% (80.2% to 82%) for the fully vaccinated.

In individuals naïve to SARS-CoV-2 vaccination reduced the risk by up to 81.8% and averted up to 11.6 cases per 10,000 vaccinated persons per day.

Those with previous infection also benefited from a risk reduction of 57%, which translated in less than 1 infection averted per 10,000 vaccinated persons per day.

Non-vaccinated individuals living in facilities where the majority (residents and staff) had been vaccinated showed a risk reduction similar to those actually vaccinated.
A multi-scale transcriptional regulatory network knowledge base forEscherichia coli
Authors: Lamoureux Cameron R. , Decker Katherine T. , Sastry Anand V. , Rychel Kevin , Gao Ye , McConn John Luke , Zielinski Daniel C. , Palsson Bernhard O.
Published: April 2021

Transcriptomic data is accumulating rapidly; thus, development of scalable methods for extracting knowledge from this data is critical. We assembled a top-down transcriptional regulatory network forEscherichia colifrom a 1035-sample, single-protocol, high-quality RNA-seq compendium. The compendium contains diverse growth conditions, including: 4 temperatures; 9 media; 39 supplements, including antibiotics; and 76 unique gene knockouts. Using unsupervised machine learning, we extracted 117 regulatory modules that account for 86% of known regulatory network interactions. We also identified two novel regulons. After expanding the compendium with 1675 publicly available samples, we extracted similar modules, highlighting the method’s scalability and stability. We provide workflows to enable analysis of new user data against this knowledge base, and demonstrate its utility for experimental design. This work provides a blueprint for top-down regulatory network elucidation across organisms using existing data, without any prior annotation and using existing data.

Highlights

- Single protocol, high quality RNA-seq dataset contains 1035 samples fromEscherichia colicovering a wide range of growth conditions

- Machine learning identifies 117 regulatory modules that capture the majority of known regulatory interactions

- Resulting knowledge base combines expression levels and module activities to enable regulon discovery and empower novel experimental design

- Standard workflows provided to enable application of knowledge base to new user data

Graphical Abstract
Multicenter evaluation of a fully automated high-throughput SARS-CoV-2 antigen immunoassay
Authors: Nörz Dominik , Olearo Flaminia , Perisic Stojan , Bauer Matthias F. , Riester Elena , Schneider Tanja , Schönfeld Kathrin , Laengin Tina , Lütgehetmann Marc
Published: April 2021

Introduction

Molecular testing for SARS-CoV-2 continues to suffer from delays and shortages. Antigen tests have recently emerged as a viable alternative to detect patients with high viral loads, associated with elevated risk of transmission. While rapid lateral flow tests greatly improved accessibility of SARS-CoV-2 detection in critical areas, their manual nature limits scalability and suitability for large-scale testing schemes. The Elecsys® SARS-CoV-2 Antigen assay allows antigen immunoassays to be carried out on fully automated high-throughput serology platforms.

Methods

A total of 3139 nasopharyngeal and oropharyngeal swabs were collected at 3 different testing sites in Germany. Swab samples were pre-characterized by RT-qPCR and consecutively subjected to the antigen immunoassay on either the cobas e 411 or cobas e 801 analyzers.

Results

Of the tested respiratory samples, 392 were PCR positive for SARS-CoV-2 RNA. Median concentration was 2.95×104 (interquartile range [IQR] 5.1×102–3.5×106) copies/mL. Overall sensitivity and specificity of the antigen immunoassay were 60.2% (95% confidence interval [CI] 55.2–65.1) and 99.9% (95% CI 99.6–100), respectively. A 93.7% (95% CI 89.7–96.5) sensitivity was achieved at a viral RNA concentration ≥104 copies/mL (∼cycle threshold (Ct) value<29.9).

Conclusion

The Elecsys SARS-CoV-2 Antigen assay reliably detected patient samples with viral loads of 10,000 copies/mL and higher. It thus represents a viable high-throughput alternative for screening of patients, or in situations where PCR testing is not readily available.

Key Summary Points

Why carry out this study?

The SARS-CoV-2 pandemic has led to a surge in demand for reliable, mass diagnostic tests worldwide.

A thorough clinical evaluation of a fully automated high-throughput Elecsys® SARS-CoV-2 Antigen assay on a total of 3139 clinical samples pre-characterized by quantitative RT-PCR was carried out.

What was learned from the study?

The assay demonstrated excellent specificity (99.9%) and good relative sensitivity, with an overall sensitivity of 60.2% and a sensitivity of 93.7% for samples containing ≥104 viral RNA copies/mL.

The Elecsys SARS-CoV-2 Antigen assay is a viable high-throughput, automated alternative to manual lateral-flow antigen tests.
Selective Laser Sintering of a Photosensitive Drug: Impact of Processing and Formulation Parameters on Degradation, Solid-State, and Quality of 3D Printed Dosage Forms
Authors: Thakkar Rishi , Davis Daniel A. , Williams Robert O. , Maniruzzaman Mohammed
Published: April 2021

This research study utilized a light-sensitive drug, nifedipine (NFD), to understand the impact of processing parameters, and formulation composition on drug degradation, crystallinity, and quality attributes (dimensions, hardness, disintegration time) of selective laser sintering (SLS) based 3D printed dosage forms. Selective laser sintering (SLS), in most cases, uses an ultraviolet laser source, and drugs tend to absorb radiation at varying intensities around this wavelength (455 nm). This phenomenon may lead to chemical degradation, and solid-state transformation, which was assessed for nifedipine in formulations with varying amounts of vinyl pyrrolidone-vinyl acetate copolymer (Kollidon® VA 64) and potassium aluminum silicate-based pearlescent pigment (Candurin®), processed under different SLS conditions in the presented work. After preliminary screening Candurin®, surface temperature (ST), and laser speed (LS) were identified as the significant independent variables. Further, using the identified independent variables a 17-run, randomized, Box-Behnken design was developed to understand the correlation trends and quantify the impact on degradation (%), crystallinity, quality attributes (dimensions, hardness, disintegration time) employing qualitative and quantitative analytical tools. The design of experiments (DoE) and statistical analysis observed that LS and Candurin® (%wt) had a strong negative correlation on drug degradation, hardness, and weight, whereas ST had a strong positive correlation with, drug degradation, amorphous conversion, and hardness of the 3D printed dosage form. From this study, it can be concluded that formulation and processing parameters have a critical impact on stability and performance; hence these parameters should be evaluated and optimized before exposing light-sensitive drugs to the SLS processes.
TRIMER: Transcription Regulation Integrated with MEtabolic Regulation
Authors: Niu Puhua , Soto Maria J. , Yoon Byung-Jun , Dougherty Edward R. , Alexander Francis J. , Blaby Ian , Qian Xiaoning
Published: April 2021

Advances in bioengineering have enabled numerous bio-based commodities. Yet most traditional approaches do not extend beyond a single metabolic pathway and do not attempt to modify gene regulatory networks in order to buffer metabolic perturbations. This is despite access to near universal technologies allowing genome-scale engineering. To help overcome this limitation, we have developed a pipeline enabling analysis of Transcription Regulation Integrated with MEtabolic Regulation (TRIMER). TRIMER utilizes a Bayesian network (BN) inferred from transcriptomic data to model the transcription factor regulatory network. TRIMER then infers the probabilities of gene states that are of relevance to the metabolism of interest, and predicts metabolic fluxes resulting from deletion of transcription factors at the genome scale. Additionally, we have developed a simulation framework to mimic the TF-regulated metabolic network, capable of generating both gene expression states and metabolic fluxes, thereby providing a fair evaluation platform for benchmarking models and predictions. Here, we present this computational pipeline. We demonstrate TRIMER’s applicability to both simulated and experimental data and show that it outperforms current approaches on both data types.
Genetic regulation of homeostatic immune architecture in the lungs of Collaborative Cross mice
Authors: Hampton Brea K. , Jensen Kara L. , Whitmore Alan C. , Linnertz Colton L. , Maurizio Paul , Miller Darla R. , Morrison Clayton R. , Noll Kelsey E. , Plante Kenneth S. , Shaw Ginger D. , West Ande , Baric Ralph S. , de Villena Fernando Pardo-Manuel , Heise Mark T. , Ferris Martin T.
Published: April 2021

Variation in immune homeostasis, immune system stability, in organ systems such as the lungs is likely to shape the host response to infection at these exposed tissues. We evaluated immune homeostasis in immune cell populations in the lungs of the Collaborative Cross (CC) mouse genetic reference population. We found vast heritable variation in leukocyte populations with the frequency of many of these cell types showing distinct patterns relative to classic inbred strains C57BL/6J and BALB/cJ. We identified 28 quantitative trait loci (QTL) associated with variation in baseline lung immune cell populations, including several loci that broadly regulate the abundance of immune populations from distinct developmental lineages, and found that many of these loci have predictive value for influenza disease outcomes, demonstrating that genetic determinants of homeostatic immunity in the lungs regulate susceptibility to virus-induced disease. All told, we highlight the need to assess diverse mouse strains in understanding immune homeostasis and resulting immune responses.
Flashfm: A Flexible and Shared Information Fine-mapping Approach for Multiple Quantitative Traits
Authors: Hernández N , Soenksen J , Newcombe P , Sandhu M , Barroso I , Wallace C , Asimit J
Published: April 2021

Joint fine-mapping that leverages information between quantitative traits could improve accuracy and resolution over single-trait fine-mapping. Using summary statistics, flashfm (FLexible And SHared information Fine-Mapping) fine-maps signals for multiple traits, allowing for missing trait measurements and use of related individuals. In a Bayesian framework, prior model probabilities are formulated to favour model combinations that share causal variants to capitalise on information between traits. Simulation studies demonstrate that both approaches produce broadly equivalent results when traits have no shared causal variants. When traits share at least one causal variant, flashfm reduces the number of potential causal variants by 30% compared with single-trait fine-mapping. In a Ugandan cohort with 33 cardiometabolic traits, flashfm gave a 20% reduction in the total number of potential causal variants from single-trait fine-mapping. Flashfm is computationally efficient and can easily be deployed across publicly available summary statistics for signals in up to six traits.
Single-cell transcriptomics reveals a conserved metaplasia program in pancreatic injury
Authors: Ma Zhibo , Lytle Nikki K. , Chen Bob , Jyotsana Nidhi , Novak Sammy Weiser , Cho Charles J. , Caplan Leah , Ben-Levy Olivia , Neininger Abigail C. , Burnette Dylan T. , Trinh Vincent Q. , Tan Marcus C.B. , Patterson Emilee A. , Drigo Rafael Arrojo e , Giraddi Rajshekhar R. , Ramos Cynthia , Means Anna L. , Matsumoto Ichiro , Manor Uri , Mills Jason C. , Goldenring James R. , Lau Ken S. , Wahl Geoffrey M. , DelGiorno Kathleen E.
Published: April 2021

BACKGROUND & AIMS

Acinar to ductal metaplasia (ADM) occurs in the pancreas in response to tissue injury and is a potential precursor for adenocarcinoma. The goal of these studies was to define the populations arising from ADM, the associated transcriptional changes, and markers of disease progression.

METHODS

Acinar cells were lineage-traced with enhanced yellow fluorescent protein (EYFP) to follow their fate upon injury. Transcripts of over 13,000 EYFP+ cells were determined using single-cell RNA sequencing (scRNA-seq). Developmental trajectories were generated. Data were compared to gastric metaplasia,KrasG12D-induced neoplasia, and human pancreatitis. Results were confirmed by immunostaining and electron microscopy.KrasG12Dwas expressed in injury-induced ADM using several inducible Cre drivers. Surgical specimens of chronic pancreatitis from 15 patients were evaluated by immunostaining.

RESULTS

scRNA-seq of ADM revealed emergence of a mucin/ductal population resembling gastric pyloric metaplasia. Lineage trajectories suggest that some pyloric metaplasia cells can generate tuft and enteroendocrine cells (EECs). Comparison toKrasG12D-induced ADM identifies populations associated with disease progression. Activation ofKrasG12Dexpression in HNF1B+ or POU2F3+ ADM populations leads to neoplastic transformation and formation of MUC5AC+ gastric-pit-like cells. Human pancreatitis samples also harbor pyloric metaplasia with a similar transcriptional phenotype.

CONCLUSIONS

Under conditions of chronic injury, acinar cells undergo a pyloric-type metaplasia to mucinous progenitor-like populations, which seed disparate tuft cell and EEC lineages. ADM-derived EEC subtypes are diverse.KrasG12Dexpression is sufficient to drive neoplasia from injury-induced ADM and offers an alternative origin for tumorigenesis. This program is conserved in human pancreatitis, providing insight into early events in pancreas diseases.