bluuebunny/crossref_metadata_2025 huggingface dataset:
“Bind, cleave and leave”: multiple turnover catalysis of RNA cleavage by bulge–loop inducing supramolecular conjugates
Authors: Amirloo Bahareh , Staroseletz Yaroslav , Yousaf Sameen , Clarke David J , Brown Tom , Aojula Harmesh , Zenkova Marina A , Bichenkova Elena V
Published: December 2021

Antisense sequence-specific knockdown of pathogenic RNA offers opportunities to find new solutions for therapeutic treatments. However, to gain a desired therapeutic effect, the multiple turnover catalysis is critical to inactivate many copies of emerging RNA sequences, which is difficult to achieve without sacrificing the sequence-specificity of cleavage. Here, engineering two or three catalytic peptides into the bulge–loop inducing molecular framework of antisense oligonucleotides achieved catalytic turnover of targeted RNA. Different supramolecular configurations revealed that cleavage of the RNA backbone upon sequence-specific hybridization with the catalyst accelerated with increase in the number of catalytic guanidinium groups, with almost complete demolition of target RNA in 24 h. Multiple sequence-specific cuts at different locations within and around the bulge–loop facilitated release of the catalyst for subsequent attacks of at least 10 further RNA substrate copies, such that delivery of only a few catalytic molecules could be sufficient to maintain knockdown of typical RNA copy numbers. We have developed fluorescent assay and kinetic simulation tools to characterise how the limited availability of different targets and catalysts had restrained catalytic reaction progress considerably, and to inform how to accelerate the catalytic destruction of shorter linear and larger RNAs even further.
scMAGIC: accurately annotating single cells using two rounds of reference-based classification
Authors: Zhang Yu , Zhang Feng , Wang Zekun , Wu Siyi , Tian Weidong
Published: December 2021

Here, we introduce scMAGIC (Single Cell annotation using MArker Genes Identification and two rounds of reference-based Classification [RBC]), a novel method that uses well-annotated single-cell RNA sequencing (scRNA-seq) data as the reference to assist in the classification of query scRNA-seq data. A key innovation in scMAGIC is the introduction of a second-round RBC in which those query cells whose cell identities are confidently validated in the first round are used as a new reference to again classify query cells, therefore eliminating the batch effects between the reference and the query data. scMAGIC significantly outperforms 13 competing RBC methods with their optimal parameter settings across 86 benchmark tests, especially when the cell types in the query dataset are not completely covered by the reference dataset and when there exist significant batch effects between the reference and the query datasets. Moreover, when no reference dataset is available, scMAGIC can annotate query cells with reasonably high accuracy by using an atlas dataset as the reference.
Systematic characterization of short intronic splicing-regulatory elements in SMN2 pre-mRNA
Authors: Gao Yuan , Lin Kuan-Ting , Jiang Tao , Yang Yang , Rahman Mohammad A , Gong Shuaishuai , Bai Jialin , Wang Li , Sun Junjie , Sheng Lei , Krainer Adrian R , Hua Yimin
Published: December 2021

Intronic splicing enhancers and silencers (ISEs and ISSs) are two groups of splicing-regulatory elements (SREs) that play critical roles in determining splice-site selection, particularly for alternatively spliced introns or exons. SREs are often short motifs; their mutation or dysregulation of their cognate proteins frequently causes aberrant splicing and results in disease. To date, however, knowledge about SRE sequences and how they regulate splicing remains limited. Here, using an SMN2 minigene, we generated a complete pentamer-sequence library that comprises all possible combinations of 5 nucleotides in intron 7, at a fixed site downstream of the 5′ splice site. We systematically analyzed the effects of all 1023 mutant pentamers on exon 7 splicing, in comparison to the wild-type minigene, in HEK293 cells. Our data show that the majority of pentamers significantly affect exon 7 splicing: 584 of them are stimulatory and 230 are inhibitory. To identify actual SREs, we utilized a motif set enrichment analysis (MSEA), from which we identified groups of stimulatory and inhibitory SRE motifs. We experimentally validated several strong SREs in SMN1/2 and other minigene settings. Our results provide a valuable resource for understanding how short RNA sequences regulate splicing. Many novel SREs can be explored further to elucidate their mechanism of action.
Theoretical and practical approaches for dietary behavior change in urban socioeconomically disadvantaged adolescents: a systematic review
Authors: Bel-Serrat Silvia , Greene Ellen , Mullee Amy , Murrin Celine M
Published: December 2021

Context

There is limited evidence on strategies used to promote dietary behavior changes in socioeconomically disadvantaged urban adolescents and on their effectiveness.

Objective

A synthesis of nutrition interventions used in this group of adolescents is provided in this systematic review.

Data Sources

Five electronic databases (PubMed, Web of Science, CINAHL, PsycINFO, and ERIC) were searched until November 2020 to identify relevant studies.

Data Extraction

Forty-six manuscripts (n = 38 intervention studies) met the inclusion criteria. Quality was assessed with the Effective Public Health Practice Project Quality Assessment Tool. A qualitative synthesis summarizing data on study characteristics was conducted.

Data Analysis

Studies were classified by intervention type as those focusing on hedonic determinants of dietary intake (n = 1), environmental changes to promote a specific dietary intake (n = 3), cognitive determinants (n = 29), and multicomponent strategies (n = 13). The social cognitive theory was the most applied theoretical framework, either alone or combined with other frameworks. Most of the intervention studies targeted multiple dietary outcomes, and success was not always reported for each.

Conclusions

Despite the heterogeneity of the studies and lack of combination of dietary outcomes into dietary scores or patterns to evaluate changes on the individuals’ whole diets, long-term, theory-driven interventions targeting a single dietary factor seem promising in obtaining sustainable dietary behavior changes.

Systematic Review Registration

PROSPERO registration no. CRD42020188219.
Ocular occupational injuries in the United States between 2011–2018
Authors: Hom Grant L , Kalur Aneesha , Iyer Amogh , Singh Rishi P
Published: December 2021

Background

Current advocacy literature in occupational eye injury focuses on demographics and industries with the largest number of injuries. Additional demographics may also benefit from targeted advocacy that experience a greater proportion of eye injuries relative to all other occupational injuries.

Aims

To characterize which demographic groups are experiencing occupational ocular injuries in the United States.

Methods

This cross-sectional study examined de-identified individuals who experienced ocular workplace injuries from 2011 to 2018 and were reported to the survey of occupational injuries and illnesses (SOII). Data were stratified and analysed based on SOII reported characteristics.

Results

197 160 out of 9 197 350 (2%) ocular workplace injuries were reported. 152 940 (78%) injuries occurred in males. Relative to all workplace injuries experienced by industry, farming, fishing and forestry saw the highest percentage of ocular injuries (6%), followed by production, and installation (4%), maintenance and repairs (4%). Employers cited contact with objects (65%) and exposure to harmful substances (26%) as leading reasons for eye injury. Relative to all injuries, chemicals frequently injured the eye (27%).

Conclusions

A disproportionate number of American ocular workplace injuries occur in males who are likely relatively young. Industries such as fishing, farming and forestry see a high frequency of ocular injury relative to all occupational injuries. Hispanics see a slight increase in ocular occupational injury relative to other injuries. Advocates of occupational ocular safety should consider expanding their targeted audiences to include individuals who are part of demographics and occupations that more frequently experience an ocular workplace injury relative to all injuries.
Narrative Criminology and Ethnography
Authors: Fleetwood Jennifer , Sandberg Sveinung
Published: December 2021

This chapter outlines how criminological researchers can attend to narrative as part of their ethnographic practice. Attention to the narrativity of speech, conversations, and texts pertaining to both individuals and groups has the potential to enrich ethnographic research on crime, criminal justice, and victims/survivors. It accentuates that stories told in field, between research participants—and to the researcher—are paramount for most ethnographic fieldwork. Ethnographers can draw much from contemporary developments in narrative criminology. We outline two insights in particular: talk is a kind of social action that does things and, second, stories motivate and guide behaviour. We review research in narrative criminology to demonstrate the importance of stories for understanding crime and justice: they delineate insiders and outsiders, convey identity, supply know-how, and display criminal capital. Vengeance and violence are also a way to tell or enact stories. This chapter also explores questions of methodology and discusses some practical issues such as how to invite storytelling and how to use recording devices in the field. We conclude with some thoughts about future directions for narrative criminology and ethnography.
Nightlife Ethnography: A Phenomenological Approach
Authors: Tutenges Sébastien
Published: December 2021

This chapter offers advice on how to conduct phenomenological ethnographic research in nightlife settings such as bars, nightclubs, and music festivals. It argues that phenomenological ethnography focuses on studying experiences as they occur to the people living them. Phenomenological ethnographers use their bodies as research instruments to develop an experiential connection and understanding of the people they are studying. Priority is given to clarifying essential properties of embodied, emotional, and sensory experiences, and to describing these as precisely as possible. The chapter proposes that the Durkheimian concept of collective effervescence may be used as a sensitizing tool to understand and describe some of the essence of what people search for, and sometimes experience, in nightlife settings. In particular, the concept is helpful in the study of intensive forms of celebration and intoxication. The chapter concludes with policy recommendations and suggestions to direct future research.
Mining and Minerals in South Africa
Authors: Makgetla Neva Seidman
Published: December 2021

Although the mining value chain only accounted for around 13% of the GDP and 6% of employment in 2020, it remained a central link between the South African economy and international markets. As a result, it had an outsized impact on the production structure, income distribution, infrastructure and legal frameworks. After the transition to democracy in 1994, the value chain underwent significant changes, notably a shift away from coal into platinum, iron ore, coal and ferroalloys, and significant divestment by international mining companies. Still, deep-seated developmental challenges persisted, including limited mining-based industrialisation, the exercise of monopoly power within value chains, and deeply inequitable and oppressive payscales and work organisation. These structural weaknesses emerged clearly in the 2010s, as the end of the global metals prices boom (2002 to 2011) brought plummeting revenues, revealing a range of economic, workplace, and policy conflicts across the value chain.
The Economics of Education in South Africa
Authors: Branson Nicola , Lam David
Published: December 2021

South Africa has made significant progress in raising education levels and reducing racial and gender gaps in education. Significant challenges remain, however, and progress in many dimensions has been disappointing. There continue to be substantial racial gaps in educational attainment, especially in the proportions completing secondary school and earning post-secondary qualifications. Although most learners attend nationally funded public schools, large differences persist in the quality of schools. These differences are reflected in large racial and socio-economic differences in test scores and low rankings in international comparisons. Education is strongly related to employment and earnings, with some of the steepest income-education gradients in the world. Returns to post-secondary education have increased, while there has been limited progress in access to post-secondary education. The combination of highly unequal education combined with strong effects of schooling on earnings and employment create a cycle in which inequality is transmitted across generations.
Social Security and Social Development in South Africa
Authors: Patel Leila
Published: December 2021

Abstract: South Africa has made significant strides in growing its social security and social development system to reduce poverty and inequality since the advent of democracy in 1994. The country’s rights-based and redistributive social protection system builds on earlier social policies and was substantively refashioned to address the country’s colonial and apartheid legacy. This chapter documents the South African case with reference to the following themes: first, it sets out the social and economic challenges facing the country in relation to poverty and inequality. Second, it demonstrates the conceptual and policy significance of the South African case in relation to the rise of social protection policies to promote inclusive development in countries in the Global South. The South African welfare regime is the third theme. It focuses on the evolution of social security and social development, discusses the features of the approach, the nature and scope of social protection policies and their impacts. Finally, the chapter concludes by considering the policy issues and future trajectory of social protection in South Africa.
Modern Assessments of Quintilian
Authors: Dominik William J.
Published: December 2021

The recent history of scholarship on Quintilian makes for intriguing and sometimes contradictory reading. While some modern assessments of Quintilian are ambivalent about his abilities as a rhetorician as revealed in the Institutio Oratoria, there has been a marked shift during the last part of the twentieth century and the beginning of the twenty-first century towards a more positive appraisal of his achievements. One reflection of this changed perception is the tendency by recent scholars to steer away from some of the disparaging criticism made by previous generations of scholars of Quintilian’s supposed shortcomings as a rhetorical theoretician, especially as a rhetor who is steeped in the faults of his age. Another indication of a more positive approach to Quintilian is the increased scholarly focus on seemingly almost every aspect of his rhetorical treatise. This growing interest in Quintilian is reflected in the over 600 publications that were published in 1980–2016, which is far more in number than for any period of similar length in the past. The discussion is intended to serve primarily as a statement about current worldwide opinions concerning Quintilian, with scholarly assessment of his significant role in Imperial rhetoric being the general focus. This chapter features the following main sections: topics of academic investigation; general praise of Quintilian; originality of Quintilian; modern relevance and utility of Quintilian; Quintilian, education, and law; Quintilian, literary criticism, and stylistic issues; general criticism of Quintilian; antiquated attitudes and speculative criticism; pseudo-academic scholarship: Wikipedia; and journalism and popular writing.
Intentions and Cyberterrorism
Authors: Egloff Florian J.
Published: December 2021

This chapter focuses on intentions and cyberterrorists. In defining cyberterrorism as the use, or threat of use, of cyberspace to deliver violence, through the disruption or destruction of digital data, the chapter captures potentially novel behaviour. It highlights the claims made by intelligence officials about terrorists’ intentions of using cyberspace. It then interrogates to what extent this matches the literature on terrorist motivations and intentions, and whether cyberspace is an attractive means for carrying out terrorist attacks. Finding that a simple cost–benefit analysis does not favour cyberspace as a means of carrying out terrorist acts, the chapter interrogates the vectors of change both on the intentions and capability side of the assessment. It closes with the analysis of a hypothetical case that would match the definition of cyberterror: a religiously inspired version of the Ashley Madison hack.
French Colonialism and The Making of the Modern Sahel
Authors: Mann Gregory
Published: December 2021

French colonial rule played an important but not determinative role in making the modern Sahel. By the 1950s, the region was more integrated politically and infrastructurally than it would be in the decades that followed. At independence, the new governments of the Sahel featured identical, if parallel, political institutions modeled on those of the French Fifth Republic (1958–). They also shared a secular character, a military culture, a history of slavery, entrenched inequality, and labor migration, and the subordination—without integration—of Saharan societies to their southern neighbors. Yet, if colonialism contributed to making the modern Sahel in an institutional sense, it did not represent a profound epistemological break. Rather, longue durée internal dynamics continued to prevail. If any single event or phenomenon “made” the modern Sahel, it was postcolonial drought and its political effects rather than imperial domination.
Public Attitudes
Authors: Kumlin Staffan , Goerres Achim , Spies Dennis C.
Published: December 2021

This chapter discusses developments in research on citizens’ attitudes towards the welfare state. The introduction briefly reminds the reader about older, and still vibrant, research traditions. From then on, however, the focus is on four distinct ‘new directions’ that became prominent recently and were only present on the fringe of the field a decade ago. One key development concerns conceptualizations and measures. A second, fast-growing literature deals with the consequences of ethnic diversity and immigration on welfare attitudes. A third literature examines whether demographic change has triggered intergenerational conflict in such attitudes. A fourth research programme concerns an increasing attention to the causes and effects of welfare state ‘performance evaluations’. Taken together, these subfields demonstrate how the broader field of welfare attitude research is responding to the significant welfare state challenges and changes documented elsewhere in this Handbook.
The Social Rights of Citizenship
Authors: Stephens John D.
Published: December 2021

This chapter reviews the welfare state literature which conceives of welfare state entitlements as ‘social rights of citizenship’, following the conceptualization of T. H. Marshall in his 1950 essay on citizenship. Beginning with Marshall’s influential essay, the first section of the chapter discusses how social rights of citizenship have been defined in the literature on comparative welfare states. Marshall argues that the defining feature of the social rights of citizenship is that they entail a claim for public transfers, goods, and services ‘which is not proportionate to the market value of the claimant’. Early quantitative studies of welfare state development measured welfare state effort with social expenditure, which was seen as a proxy for the variables of real interest, social rights, or welfare state redistribution. In the 1980s, ambitious efforts to measure social rights through time and across countries were initiated, though these measures did not find their way into the public domain until after 2000. These measures focus on rights to welfare state transfers and thus neglect services. The chapter ends with reviews of the literature on the causes of variations in social rights across countries and through time and on the outcomes of variations in social rights.
Religion and the European External Action Service
Authors: Foret François
Published: December 2021

This contribution analyses the diplomacy of religion carried out by the European External Action Service (EEAS), and questions its autonomy and distinctiveness vis-à-vis other diplomacies. Several dimensions are studied: how foreign policy is dealing with the ‘return’ of religion in international affairs; the practices of the EEAS regarding religion against the general background of what Member States, third countries, and international organizations do in this respect; how the EEAS balances the interests of Member States, the requirements of the geopolitical contexts and field realities; the EEAS’s advocacy for specific causes such as the freedom of religion and belief (FoRB) and the establishment of religion as a standard diplomatic issue. The conclusion characterizes the EU’s external strategy on religion as the outcome of both its political and institutional logic and Europe’s societal secularization in a world that is still highly religious.
Too Many Hats? The Role of Police Officers in Drug Enforcement and the Community
Authors: Zakimi Naomi , Greer Alissa , Butler Amanda
Published: December 2021

Research on police attitudes and opinions about drugs and drug enforcement is particularly relevant amidst current critiques of policing that put their role into question. The aim of this qualitative study is to examine the role of police officers in providing public health and social support to the community and people who use drugs. Semi-structured interviews were conducted with 16 police officers working across British Columbia, Canada. Interviews were analysed thematically. We discuss two main themes: (1) the roles of police officers and (2) role strain among officers. The findings show that officers have multiple roles or wear multiple ‘hats’, including the crime fighter, the helper, the health responder, and the administrator. Collectively, wearing ‘too many hats’ caused role strain as well as tense relations with the community. Findings highlight the importance of establishing clear role definitions and expectations for police, as well as providing resources to address public health and social service needs for the community.
The First Shakespearean Forgeries
Authors: Dunne Derek
Published: December 2021

The term ‘Shakespearean forgery’ generally conjures up nineteenth-century figures such as J.P. Collier or W.H. Ireland. This paper proposes an alternative history of Shakespeare and forgery, by establishing the prevalence of forgery as a crime in Shakespeare’s own lifetime. This had a material impact on early modern players, who were frequently accused of forging documents of authentication when touring. Bringing together legislation and actual cases of forgery, I demonstrate a symbiotic relationship between authors and forgers, which then makes its presence felt in the literary output of the time, from Nashe’s pamphlet war with Gabriel Harvey to Jonson’s suspect documentation in Bartholomew Fair. For Shakespeare, examples from Hamlet, King Lear, and Twelfth Night are paired with historical cases to show how Shakespeare’s forgeries are more than just a plot device. I finish by drawing parallels between Malvolio and the Earl of Essex, himself a prominent victim of forgery, to reveal new connections made possible through a serious consideration of forgery.
Tolerance of glucocorticoids in giant cell arteritis: a study of patient-reported adverse events
Authors: de Boysson Hubert , Barakat Clivia , Dumont Anael , Boutemy Jonathan , Martin Silva Nicolas , Maigné Gwénola , Nguyen Alexandre , Lavergne Amandine , Castan Paul , Gallou Sophie , Sultan Audrey , Deshayes Samuel , Aouba Achille
Published: December 2021

Objective

To assess patients’ self-reported glucocorticoid (GC)-related adverse events (AEs) in a GCA population.

Methods

A questionnaire was sent to the 100 patients most recently diagnosed with GCA in a tertiary centre. This questionnaire included open- and close-ended questions on the disease and GC effects. Eight primary AE areas were analysed: cardiovascular, metabolic, muscle, cognitive and psychologic, bone, cutaneous and hairiness, infective and visual complications. Including derivative subitems from preceding areas, a total of 18 GC-related AEs were analysed separately and according to GC duration.

Results

Ninety patients were analysed and 89 (99%) reported at least one GC-related AE [median 6 (range 1–11)]. Cognitive and psychological changes, primarily insomnia (72%), affected 90% of patients. Cutaneous changes and muscle loss affected 70% of patients, with frequent impairment of physical autonomy (P = 0.007) associated with this event. Metabolic issues, especially weight gain (40%) and diabetes mellitus (20%), affected 49% of patients. Conversely, vision troubles and bone fractures were mentioned by 42% and 9% of patients, respectively, and more frequently in patients who received GCs for >18 months (P = 0.01 and P = 0.007, respectively). Cardiovascular changes and infections affected 30% and 26% of patients, respectively.

Conclusion

This real-life study of GC tolerance assessed using a self-evaluation provides pragmatic and updated data reminding us that GC tolerance remains more noteworthy than ever. This study suggests carefully monitoring GC-related AEs during follow-up and encourages GC-sparing strategies in some patients.
Specific early signs and long-term follow-up findings of progressive pseudorheumatoid dysplasia (PPRD) in the Turkish cohort
Authors: Uludağ Alkaya Dilek , Kasapçopur Özgür , Bursalı Ayşegül , Adrovic Amra , Demir Bilal , Aykut Ayça , Tüysüz Beyhan
Published: December 2021

Objectives

Progressive pseudorheumatoid dysplasia (PPRD) is a spondyloepiphyseal dysplasia caused by biallelic variants in CCN6. This study aimed to describe the early signs and follow-up findings in 44 Turkish PPRD patients.

Methods

The patients with progressive stiffness of multiple joints, characteristic wide metaphysis of interphalangeal (IP) joints and platyspondyly were clinically diagnosed with PPRD. Fifteen patients who had first symptoms under 3 years of age were grouped as early-onset, while others were grouped as classical. CCN6 sequencing was performed in 43 patients.

Results

Thirteen pathogenic/likely pathogenic variants were identified, five were novel. c.156C>A(p.Cys52*) variant was found in 53.3% of the families. The initial symptom in the early-onset group was genu varum deformity, while it was widening of IP joints in the classical group. The median age of onset of symptoms and of diagnosis was 4 and 9.7 years, respectively. The mean follow-up duration was 5.6 years. The median age of onset of IP, elbow, knee and hip stiffness, which became progressive with growth was 5, 9, 9 and 12.2 years, respectively. Waddling gait occurred in 97.7% of the patients. A total of 47.7% lost independent walking ability at the median age of 12 years. In the early-onset group, waddling gait occurred earlier than in classical group (P < 0.001). Two patients had atypical presentation with late-onset and mild or lack of IP involvement.

Conclusion

We observed that genu varum deformity before the age of 3 years was an early sign for PPRD and almost half of the patients lost walking ability at the median age of 12 years.
Morphology-based phylogeny of oval palm and flower beetles (Coleoptera: Mycteridae: Eurypinae), with descriptions of new genera and species from Australia
Authors: Hsiao Yun , Pollock Darren A
Published: December 2021

Mycteridae are a small group of Tenebrionoidea, comprising three subfamilies and over 180 species. Eurypinae are the most species-rich subfamily, with diverse external morphology of adults at both generic and species levels. To date, no study of mycterid systematics using phylogenetic approaches has been conducted. In this paper, we reconstruct a phylogeny of eurypine beetles based on morphological characters, covering most described genera. This is the first attempt to investigate the evolution and relationships of Mycteridae. The phylogenetic positions of several systematically enigmatic genera can thus be hypothesized based on the topology. Recent molecular phylogenetic frameworks and fossil records reveal that most eurypine lineages probably evolved during the Late Mesozoic to Early Cenozoic. Our results also indicate that the fauna of the current regions of the world and Early Cenozoic Europe consist(ed) of various eurypine lineages, supporting the previously proposed hypothesis that Eurypinae were once widely distributed, but underwent a subsequent partial extinction. Two new genera and three new species are described from Australia, based on comparative anatomy and cladistic analysis, namely Austroconomorphus slipinskii gen. et sp. nov., Austrophaeogala lawrencei gen. et sp. nov. and Austrophaeogala ovipennis sp. nov. We demonstrate that the phylogenetic diversity of Mycteridae in Australia is greater than previously suspected.
A New Approach for Lip Filler Injection Using an Inverted Mercedes Benz Sign
Authors: Adel Noury
Published: December 2021

Lip fillers have a great impact on the facial aesthetic industry, where several techniques have been proposed for lip beautification in terms of both the results and delivering a safe injection procedure. The study aimed to report a personal experience with a new lip filler technique, via inserting a microcannula through three entry points, resembling an inverted Mercedes Benz sign. Ten female patients between 22 and 29 years of age had a lip filler treatment with a cross-linked hyaluronic acid injected using a microcannula through two entry points at both Glogau-Klein points of the upper lip and one entry point at the midline of the lower lip. The filler product was deposited in both retrograde and aliquots fashion in the superficial muscular plane. All patients reported a high degree of satisfaction with the results of the procedure, with slight swelling and bruising transiently present in some of the patients. Unlike the conventional cannula technique, this new technique offers artistry in accentuating the cupid’s bow and redrawing the lips.
Impact of COVID-19-associated Mucormycosis in Kidney Transplant Recipients: A Multicenter Cohort Study.
Authors: Meshram Hari Shankar , Kute Vivek B. , Yadav Dinesh Kumar , Godara Suraj , Dalal Sonal , Guleria Sandeep , Bhalla Anil K. , Pathak Vivek , Anandh Urmila , Bansal Shyam , Patel Himanshu , Hegde Umapati , Dave Ruchir , Chauhan Sanshriti , Dave Rutul , Kumar Deepak , Jamale Tukaram , Bajpai Divya , Kenwar Deepesh , Sil Keshab , Vardhan Harsh , Balwani Manish , Patil Mayur , Deshpande Rushi , Nandwani Ashish , Jha Pranaw Kumar , Jain Manish , Das Pratik , Mishra Vineet , Segev Dorry L. , Kher Vijay
Published: December 2021

Background.

COVID-19-associated mucormycosis (CAM) is a recently emerging entity. There is a lack of reports of CAM in organ transplant recipients.

Methods.

We conducted a multicenter (n = 18) retrospective research in India during November 2020 to July 2021. The purpose of this study was to explore the clinical spectrum, outcome and risk factors for mortality of CAM in kidney transplant recipients (KTRs).

Results.

The incidence of CAM was 4.4% (61/1382 COVID-19-positive KTRs) with 26.2% mortality. The median age of the cohort was 45 (38–54) y. Twenty (32%) were not hospitalized and 14 (22.9%) were on room air during COVID-19. The proportion of postdischarge CAM was 59.1%, while concurrent CAM was reported in 40.9%. The presentation of CAM was 91.8% rhino-orbital-cerebral mucormycosis and 8.2% pulmonary with 19.6% and 100% mortality, respectively. In the univariable analysis, older age, obesity, difficulty of breathing, high-flow oxygen requirement, and delay in starting therapy were significantly associated with mortality. In the multivariable logistic regression analysis, patients requiring high-flow oxygen therapy [odds ratio (95% confidence interval) = 9.3 (1.6-51); P = 0.01] and obesity [odds ratio (95% confidence interval) = 5.2 (1-28); P = 0.05] was associated with mortality. The median follow-up of the study was 60 (35–60) d.

Conclusions.

We describe the largest case series of CAM in KTRs. Morality in pulmonary CAM is extremely high. Severe COVID-19 pose extra risk for the development of CAM and associated mortality. Our report will help in better understanding the conundrum and management of CAM.
Donor Cardiac Troponin for Prognosis of Adverse Outcomes in Cardiac Transplantation Recipients: a Systematic Review and Meta-analysis
Authors: Liu Zhengyang , Perry Luke A. , Penny-Dimri Jahan C. , Handscombe Michael , Overmars Isabella , Plummer Mark , Segal Reny , Smith Julian A.
Published: December 2021

Background.

Cardiac troponin is a highly specific and widely available marker of myocardial injury, and elevations in cardiac transplant donors may influence donor selection. We aimed to investigate whether elevated donor troponin has a role as a prognostic biomarker in cardiac transplantation.

Methods.

In a systematic review and meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library, without language restriction, from inception to December 2020. We included studies reporting the association of elevated donor troponin with recipient outcome after cardiac transplant. We generated summary odds ratios and hazard ratios for the association of elevated donor troponin with short- and long-term adverse outcomes. Methodological quality was monitored using the Quality In Prognosis Studies tool, and interstudy heterogeneity was assessed using a series of sensitivity and subgroup analyses.

Results.

We included 17 studies involving 15 443 patients undergoing cardiac transplantation. Elevated donor troponin was associated with increased odds of graft rejection at 1 y (odds ratio, 2.54; 95% confidence interval, 1.22-5.28). No significant prognostic relationship was found between donor troponin and primary graft failure, short- to long-term mortality, cardiac allograft vasculopathy, and pediatric graft loss.

Conclusions.

Elevated donor troponin is not associated with an increased short- or long-term mortality postcardiac transplant despite increasing the risk of graft rejection at 1 y. Accordingly, an elevated donor troponin in isolation should not exclude donation.
Surgical Planning and Optimization of Patient-Specific Fontan Grafts With Uncertain Post-Operative Boundary Conditions and Anastomosis Displacement
Authors: Liu Xiaolong , Hibino Narutoshi , Loke Yue-Hin , Kim Byeol , Mass Paige , Fuge Mark D. , Olivieri Laura , Krieger Axel
Published: December 2021

Objective

Fontan surgical planning involves designing grafts to perform optimized hemodynamic performance for the patient’s long-term health benefit. The uncertainty of post-operative boundary conditions (BC) and graft anastomisis displacements may significantly affect the optimized graft designs and lead to undesired outcomes, especially for hepatic flow distribution (HFD). We aim to develop a computation framework to automatically optimize patient-specific Fontan grafts with the maximized possibility of keeping the post-operative results within clinical acceptable thresholds.

Methods

The uncertainties of BC and anastomosis displacements were modeled by using Gaussian distributions according to prior research studies. By parameterizing the Fontan grafts, we built surrogate models of hemodynamic parameters by taking the design parameters and BC as inputs. A two-phased reliability-based robust optimization (RBRO) strategy was developed by combining deterministic optimization (DO) and optimization under uncertainty (OUU) to reduce the computation cost.

Results

We evaluated the performance of the RBRO framework by comparing it with the DO method on four Fontan patient cases. The results showed that the surgical plans computed from the proposed method yield up to 79.2% improvement on the reliability of HFD than those from the DO method (p <0.0001). The mean values of iPL and %WSS satisfied the clinically acceptable thresholds.

Conclusion

This study demonstrated the effectiveness of our RBRO framework to address uncertainties of BC and anastomosis displacements for Fontan surgical planning.

Significance

The technique developed in this paper demonstrates a significant improvement in the reliability of predicted post-operative outcomes for Fontan surgical planning. This planning technique is immediately applicable as a building block to enable technology for optimal long-term outcomes for pediatric Fontan patients and can also be used to other pediatric and adult cardiac surgeries.
Effects of racial/ethnic disparities in healthcare utilization on antibiotic use, United States, 2016/2018
Authors: Olesen Scott W. , Kanjilal Sanjat , Kissler Stephen M. , Sun Daphne S. , Grad Yonatan H.
Published: December 2021

White Americans make more office-based and emergency department visits per capita than other races/ethnicities, but the proportion of visits during which antibiotics are administered or prescribed is similar across races/ethnicities. Racial/ethnic disparities in antibiotic use may be due more to disparities in healthcare access and utilization than to prescriber behavior.
Burden of influenza hospitalization among high-risk groups in the United States
Authors: Near Aimee , Tse Jenny , Young-Xu Yinong , Hong David K. , Reyes Carolina M.
Published: December 2021

Background

Seasonal influenza poses a substantial clinical and economic burden in the United States and vulnerable populations, including the elderly and those with comorbidities, are at elevated risk for influenza-related medical complications.

Methods

We conducted a retrospective cohort study using the IQVIA PharMetrics® Plus claims database in two stages. In Stage 1, we identified patients with evidence of medically-attended influenza during influenza seasons from October 1, 2014 to May 31, 2018 (latest available data for Stage 1) and used a multivariable logistic regression model to identify patient characteristics that predicted 30-day influenza-related hospitalization. Findings from Stage 1 informed high-risk subgroups of interest for Stage 2, where we selected cohorts of influenza patients during influenza seasons from October 1, 2014 to March 1, 2019 and used 1:1 propensity score matching to patient without influenza with similar high-risk characteristics to compare influenza-attributable rates of all-cause hospital and emergency department visits during follow-up (30-day and in index influenza season).

Results

In Stage 1, more than 1.6 million influenza cases were identified, of which 18,509 (1.2%) had a hospitalization. Elderly age was associated with 9 times the odds of hospitalization (≥65 years vs. 5-17 years; OR=9.4, 95% CI 8.8-10.1) and select comorbidities were associated with 2-3 times the odds of hospitalization. In Stage 2, elderly influenza patients with comorbidities had 3 to 7 times higher 30-day hospitalization rates compared to matched patients without influenza, including patients with congestive heart failure (41.0% vs.7.9%), chronic obstructive pulmonary disease (34.6% vs. 6.1%), coronary artery disease (22.8% vs. 3.8%), and late-stage chronic kidney disease (44.1% vs. 13.1%; all p<0.05).

Conclusions

The risk of influenza-related complications is elevated in the elderly, especially those with certain underlying comorbidities, leading to excess healthcare resource utilization. Continued efforts, beyond currently available vaccines, are needed to reduce influenza burden in high-risk populations.
Molecular architecture of 40S initiation complexes on the Hepatitis C virus IRES: from ribosomal attachment to eIF5B-mediated reorientation of initiator tRNA
Authors: Brown Zuben P. , Abaeva Irina S. , De Swastik , Hellen Christopher U.T. , Pestova Tatyana V. , Frank Joachim
Published: December 2021

Hepatitis C virus mRNA contains an internal ribosome entry site (IRES) that mediates end-independent translation initiation, requiring a subset of eukaryotic initiation factors (eIFs). Direct binding of the IRES to the 40S subunit places the initiation codon into the P site, where it base-pairs with eIF2-bound Met-tRNAiMet forming a 48S initiation complex. Then, eIF5 and eIF5B mediate subunit joining. Initiation can also proceed without eIF2, in which case Met-tRNAiMet is recruited directly by eIF5B. Here, we present cryo-EM structures of IRES initiation complexes at resolutions up to 3.5 Å that cover all major stages from initial ribosomal association, through eIF2-containing 48S initiation complexes, to eIF5B-containing complexes immediately prior to subunit joining. These structures provide insights into the dynamic network of 40S/IRES contacts, highlight the role for IRES domain II, and reveal conformational changes that occur during the transition from eIF2- to eIF5B-containing 48S complexes that prepare them for subunit joining.
Microbial associations with Microscopic Colitis
Authors: Sun Shan , Blakley Ivory C. , Fodor Anthony A. , Keku Temitope O. , Woosley John T. , Peery Anne F. , Sandler Robert S.
Published: December 2021

BACKGROUND AND OBJECTIVE

Microscopic colitis is a relatively common cause of chronic diarrhea and may be linked to luminal factors. Given the essential role of the microbiome in human gut health, analysis of microbiome changes associated with microscopic colitis could provide insights into the development of the disease.

METHODS

We enrolled patients who underwent colonoscopy for diarrhea. An experienced pathologist classified patients as having microscopic colitis (n=52) or controls (n=153). Research biopsies were taken from the ascending and descending colon, and the microbiome was characterized with Illumina sequencing. We analyzed the associations between microscopic colitis and microbiome with a series of increasingly complex models adjusted for a range of demographic and health factors.

RESULTS

We found that alpha-diversity was significantly lower in microscopic colitis cases compared to controls in the descending colon microbiome. In the descending colon, a series of models that adjusted for an increasing number of co-variates found taxa significantly associated with microscopic colitis, including Proteobacteria that was enriched in cases and Collinsella enriched in controls. While the alpha-diversity and taxa were not significantly associated with microscopic colitis in the ascending colon microbiome, the inference p-values based on ascending and descending microbiomes were highly correlated.

CONCLUSION

Our study demonstrates an altered microbiome in microscopic colitis cases compared to controls. Because both the cases and controls had diarrhea, we have identified candidate taxa that could be mechanistically responsible for the development of microscopic colitis independent of changes to the microbial community caused by diarrhea.

Significance of this study

What is already known about this subject?

Microscopic colitis is a common cause of chronic diarrhea. The exact etiology of microscopic colitis is unknown, but the gut microbiome is considered to play an important role.

Prior studies have reported microbial changes associated with microscopic colitis, but the results are not consistent. Prior studies have generally involved small numbers of patients, fecal samples, and comparison to healthy controls.

What are the new findings?

The microbiome was altered in microscopic colitis patients.

Microscopic colitis was associated with lower alpha-diversity, increase of inflammation related taxa and decrease of Collinsella in the descending colon microbiome independent of diarrhea status.

The changes of microbial features were consistent between ascending and descending colon microbiomes, but with smaller changes in the ascending colon microbiome.

How might it impact on clinical practice in the foreseeable future?

The altered microbial communities in patients with microscopic colitis suggest that the patients might benefit from prevention or treatment with live biotherapeutic products.
Flexibility in the social structure of male chimpanzees (Pan troglodytes schweinfurthii) in the Budongo Forest, Uganda
Authors: Badihi Gal , Bodden Kelsey , Zuberbühler Klaus , Samuni Liran , Hobaiter Catherine
Published: December 2021

Individuals of social species face a trade-off between the competitive costs and social benefits of group living. Species show a range of social strategies to deal with this trade-off, for example atomistic fission-fusion dynamics in which temporary social groups of varying size and membership form and re-form; or molecular fission-fusion dynamics which contain stable sets of multilevel nested subgroups. Chimpanzees are considered an archetypical atomistic fission-fusion species, using dynamic changes in day-to-day association to moderate the costs of within-group competition. It has been argued that humans’ highly flexible social organisation allows us to live in extremely large groups. Using four years of association data from two neighbouring communities of East African chimpanzees (Pan troglodytes schweinfurthii), we describe new levels of flexibility in chimpanzee social organisation and confirm the presence of subgrouping in a second, large community of chimpanzees. We show that males from the larger Waibira community (N males 24-31) exhibited additional levels of semi-stable subgrouping, while males from the smaller Sonso community (N males 10-13) did not. Subgroup membership showed stability across some years, but flexibility across others. Our data support the hypothesis that chimpanzees can incorporate strategies other than fission-fusion to overcome costs of social living, and that their social organisation may be closer to that of modern humans than previously described.

SIGNIFICANCE STATEMENT

Social living offers benefits and costs; groups can more easily locate and defend resources, but experience increased individual competition. Many species, or individuals, flexibly adjust their social organization when faced with different competitive pressures. It is argued that humans are unique among primates in combining multigroup social organisation with fission-fusion dynamics flexibly within and across groups, and that doing so allows us to live in extremely large groups. Using four-years of association data we show new levels of flexibility in chimpanzee social organization. Males from a typically-sized community employed atomistic fission-fusion dynamics, but males in an unusually large community incorporated additional semi-stable levels of subgrouping. Our data support the hypothesis that chimpanzee males combine social organization strategies, and that doing so may allow them, like humans, to mitigate individual costs at larger community sizes.
CD90 is not constitutively expressed in functional innate lymphoid cells
Authors: Schroeder J-H , Beattie G , Lo JW , Zabinski T , Jenner RG , Powell N , Neves J F , Lord GM
Published: December 2021

Huge progress has been made in understanding the biology of innate lymphoid cells (ILC) by adopting several well-known concepts in T cell biology. As such, flow cytometry gating strategies and markers, such as CD90, to identify ILC have been applied. Here, we report that most non-NK intestinal ILC have a high expression of CD90 as expected, but surprisingly a sub-population of cells exhibit low or even no expression of this marker. CD90-negative and CD90-low CD127+ILC were present amongst all ILC subsets in the gut. The frequency of CD90-negative and CD90-low CD127+ILC was dependent on stimulatory cuesin vitroand enhanced due to dysbiosisin vivo. CD90-negative and CD90-low CD127+ILC played a functional role as a source of IL-13, IFNγ and IL-17A at steady state and upon dysbiosis- and dextran sulphate sodium-elicited colitis. Hence, this study reveals that, contrary to expectations, CD90 is not constitutively expressed by functional ILC in the gut.