bluuebunny/crossref_metadata_2025 huggingface dataset:
Epithelioid haemangioendothelioma of the mandible – A case report and review of the literature
Authors: Rizvi Ali , Blackburn Tim K. , Betts Guy N. J.
Published: June 2021

Epithelioid haemangioendothelioma (EHE) is a rare vascular tumour that can occur in a wide variety of anatomical sites including the liver, lungs, skin, bone and is rarely reported in the oral cavity. The condition is classified as a tumour of intermediate malignancy as, in contrast to other types of haemangioendothelioma, EHE can result in distant metastasis and the death of the patient. Due to the minimal number of cases reported of individuals diagnosed with EHE, no definitive data on different treatment options exist and complete excision with follow up and consideration of adjuvant radiotherapy is the universal treatment option. This case report highlights the investigation, diagnosis and treatment of a 25‐year‐old man who was diagnosed with EHE arising within the mandible. The article also presents the published literature of documented cases of mandibular and maxillary EHE.
Reference genomes of the two cultivated jute species
Authors: Zhang Lilan , Ma Xiaokai , Zhang Xingtan , Xu Yi , Ibrahim Aminu Kurawa , Yao Jiayu , Huang Huaxing , Chen Shuai , Liao Zhenyang , Zhang Qing , Niyitanga Sylvain , Yu Jiaxin , Liu Yi , Xu Xiuming , Wang Jingjing , Tao Aifen , Xu Jiantang , Chen Siyuan , Yang Xin , He Qingyao , Lin Lihui , Fang Pingping , Zhang Liemei , Ming Ray , Qi Jianmin , Zhang Liwu
Published: June 2021

Cultivated jute, which comprises the two species Corchorus capsularis and C. olitorius, is the second most important natural fibre source after cotton. Here we describe chromosome‐level assemblies of the genomes of both cultivated species. The C. capsularis and C. olitorius assemblies are each comprised of seven pseudo‐chromosomes, with the C. capsularis assembly consisting of 336 Mb with 25,874 genes and the C. olitorius assembly containing 361 Mb with 28 479 genes. Although the two Corchorus genomes exhibit collinearity, the genome of C. olitorius contains 25 Mb of additional sequences than that of C. capsularis with 13 putative inversions, which might give a hint to the difference of phenotypic variants between the two cultivated jute species. Analysis of gene expression in isolated fibre tissues reveals candidate genes involved in fibre development. Our analysis of the population structures of 242 cultivars from C. capsularis and 57 cultivars from C. olitorius by whole‐genome resequencing resulted in post‐domestication bottlenecks occurred ~2000 years ago in these species. We identified hundreds of putative significant marker‐trait associations (MTAs) controlling fibre fineness, cellulose content and lignin content of fibre by integrating data from genome‐wide association studies (GWAS) with data from analyses of selective sweeps due to natural and artificial selection in these two jute species. Among them, we further validated that CcCOBRA1 and CcC4H1 regulate fibre quality in transgenic plants via improving the biosynthesis of the secondary cell wall. Our results yielded important new resources for functional genomics research and genetic improvement in jute and allied fibre crops.
Experimental warming across a tropical forest canopy height gradient reveals minimal photosynthetic and respiratory acclimation
Authors: Carter Kelsey R. , Wood Tana E. , Reed Sasha C. , Butts Kaylie M. , Cavaleri Molly A.
Published: June 2021

Tropical forest canopies cycle vast amounts of carbon, yet we still have a limited understanding of how these critical ecosystems will respond to climate warming. We implemented in situ leaf‐level + 3°C experimental warming from the understory to the upper canopy of two Puerto Rican tropical tree species, Guarea guidonia and Ocotea sintenisii. After approximately 1 month of continuous warming, we assessed adjustments in photosynthesis, chlorophyll fluorescence, stomatal conductance, leaf traits and foliar respiration. Warming did not alter net photosynthetic temperature response for either species; however, the optimum temperature of Ocotea understory leaf photosynthetic electron transport shifted upward. There was no Ocotea respiratory treatment effect, while Guarea respiratory temperature sensitivity (Q10) was down‐regulated in heated leaves. The optimum temperatures for photosynthesis (Topt) decreased 3–5°C from understory to the highest canopy position, perhaps due to upper canopy stomatal conductance limitations. Guarea upper canopy Topt was similar to the mean daytime temperatures, while Ocotea canopy leaves often operated above Topt. With minimal acclimation to warmer temperatures in the upper canopy, further warming could put these forests at risk of reduced CO2 uptake, which could weaken the overall carbon sink strength of this tropical forest.
Citizenship as a Form of Anticipatory Obedience? Implications of Preventive Health Policy in Germany
Authors: Ewert Benjamin
Published: June 2021

This article scrutinizes citizenship implications in the field of preventive health policy in Germany. While at first glance prevention policies seem fairly uncontroversial, they have intricate links concerning the impact on preventive policies to social citizenship and to the notion of the “good” citizen. I argue that prevention is a future‐oriented permanent task that requires constant alertness and the commitment of responsible citizens to being “ahead of time.” Although originally based on the principles of voluntary compliance and self‐responsibility in Germany, preventive policies are likely to become more compulsory in the aftermath of the COVID‐19 pandemic that has, in effect, been a collective crash course on the importance of prevention and its range of policy tools. Under the prevention paradigm, active citizenship requires anticipatory action—that may turn into obedience—due to the imminent danger of assumed health risks.

Related Articles in this Special Issue

Barrault‐Stella, Lorenzo, and Thomas Douniès. 2021. “Introduction to the Special Issue: Citizenship as a Tool of Government in Europe.” Politics & Policy 49 (4).

Haapajärvi, Linda. 2021. “On the Importance of Playing House: Belonging‐Work and the Making of Relational Citizens in Finnish Immigrant Integration Policies.” Politics & Policy 49 (4).

Mioni, Michele. 2021. “The ‘Good Citizen’ as ‘Respectable Worker:' State, Unemployment, and Social Policy in the United Kingdom and Italy, 1930 to 1950.” Politics & Policy 49 (4).
Rethinking Climate Change Leadership: An Analysis of the Ambitiousness of State GHG Targets
Authors: Glasgow Derek , Zhao Shuang , Rai Saatvika
Published: June 2021

Traditionally, diffusion policy scholars sought to understand state climate change policy leadership by exploring the speed of policy adoption. This study moves beyond these approaches by exploring factors that influence adoption as well as those that influence the content of a policy or policy goal intensity. Through the exploration of the first “wave” of state GHG reduction targets during the early 2000s, we create an innovative policy commitment variable that standardizes state emissions targets and explores the specific factors influencing these mitigation goals. Our results suggest that internal political factors (Democratic control of the legislature), lower state carbon dioxide emissions and dependency on coal production increases the likelihood of target adoption. However, the degree of GHG reduction commitments (content) are dependent on both internal and external factors, such as neighboring states adoption, carbon dioxide emission levels, citizen ideology, environmental interest groups, natural gas production and solar energy potential. These results support the growing literature on differentiating adoption and the content of a policy when analyzing the spread of policy ideas. Additionally, it suggests the limitations of states as climate leaders.
Drainage and environmental evolution across the Permo–Triassic boundary in the south‐east Germanic Basin (north‐east Bavaria)
Authors: Ravidà Domenico C. G. , Caracciolo Luca , Henares Saturnina , Janßen Meike , Stollhofen Harald
Published: June 2021

The identification of the factors triggering continental environmental changes at the Permian–Triassic transition is of general interest as they allow a better understanding of the most controversial mass extinction of the Phanerozoic. This study investigates the environmental response to external forcings on continental successions at the south‐east‐margin of the Central European Basin System in Germany. Studies from this area are scarce, and its evolution is poorly understood. This work integrates high‐resolution core‐logging and quantitative sedimentary petrography of Middle Permian–Early Triassic successions recovered from the wells Obernsees‐1 and Lindau‐1. The sedimentological investigation reveals major vertical variations in the depositional settings marked by changes in grain‐size trends and facies associations: (i) the progradation of mass flow/fluvial fans over sandflat environments denotes the Guadalupian–Lopingian; (ii) sabkha to shallow‐marine conditions occur during the uppermost Permian; (iii) the onset of braided fluvial sequences marks the Permian–Triassic boundary; (iv) changes in fluvial style, reflecting increased river sinuosity, and aeolian deposition characterize the remaining Triassic. Environmental changes are accentuated by variations in sediment composition. Proximal deposits (for example, alluvial fan) are lithic arkoses, while more distal associations reveal arkosic composition. Detrital modes point to: (i) a high‐grade metamorphic source feeding the drainage of Lindau‐1 (metamorphic index, MI 441–500); and (ii) a mixed low‐grade and high‐grade metamorphic source (MI 277–395) feeding the Permian of Obernsees‐1, passing upward to high‐grade metamorphic (MI 441–500) and subordinate granitoid sources. Compositional signatures and environmental changes suggest distinct drainage evolutions regulated by upstream climate and tectonic controls. The higher plutonic clast content coeval to the onset of fluvial sedimentation and coarse‐grained influxes reflects local tectonic perturbations attributed to the Early Triassic reactivation of Variscan faults. The evidence of perennial fluvial systems during the lowermost Triassic reflects wetter climate conditions in the upstream catchment area, which contradicts the common view of increased aridity at the Permian–Triassic boundary.
Effect of race distance on performance fatigability in male trail and ultra‐trail runners
Authors: Temesi John , Besson Thibault , Parent Audrey , Singh Benjamin , Martin Vincent , Brownstein Callum G. , Espeit Loïc , Royer Nicolas , Rimaud Diana , Lapole Thomas , Féasson Léonard , Millet Guillaume Y.
Published: June 2021

The etiology of changes in lower‐limb neuromuscular function, especially to the central nervous system, may be affected by exercise duration. Direct evidence is lacking as few studies have directly compared different race distances. This study aimed to investigate the etiology of deficits in neuromuscular function following short versus long trail‐running races. Thirty‐two male trail runners completed one of five trail‐running races as LONG (>100 km) or SHORT (<60 km). Pre‐ and post‐race, maximal voluntary contraction (MVC) torque and evoked responses to electrical nerve stimulation during MVCs and at rest were used to assess voluntary activation and muscle contractile properties of knee‐extensor (KE) and plantar‐flexor (PF) muscles. Transcranial magnetic stimulation (TMS) was used to assess evoked responses and corticospinal excitability in maximal and submaximal KE contractions. Race distance correlated with KE MVC (ρ = −0.556) and twitch (ρ = −0.521) torque decreases (p ≤ .003). KE twitch torque decreased more in LONG (−28 ± 14%) than SHORT (−14 ± 10%,p = .005); however, KE MVC time × distance interaction was not significant (p = .073). No differences between LONG and SHORT for PF MVC or twitch torque were observed. Maximal voluntary activation decreased similarly in LONG and SHORT in both muscle groups (p ≥ .637). TMS‐elicited silent period decreased in LONG (p = .021) but not SHORT (p = .912). Greater muscle contractile property impairment in longer races, not central perturbations, contributed to the correlation between KE MVC loss and race distance. Conversely, PF fatigability was unaffected by race distance.
Statistics education from a data‐centric perspective
Authors: Gehrke Matthias , Kistler Tanja , Lübke Karsten , Markgraf Norman , Krol Bianca , Sauer Sebastian
Published: June 2021

The ubiquitous acquisition and generation of data require a reworking of curricula in introductory statistics in tertiary education. We present a renewed curriculum that focuses on scientific thinking, modeling, and simulation‐based inference, utilizing R and various R tools such as shiny and learnr apps. We teach statistics from a data‐centric perspective, enabling the students to become data literate. Initial feedback of students and educators at our university of applied sciences shows that students' conceptual understanding improved and they understood the practical applicability of statistics better.
Toward data‐scientific thinking
Authors: Gould Robert
Published: June 2021

The growth of the data culture has led to calls for improving data literacy among primary and secondary students and their teachers. One approach to improving data literacy is to teach a course devoted to data science but, given the lack of consensus over the term “data science,” just what should an introductory data science course include? The author argues that at the secondary level, an introductory data science course should strive to teach data‐scientific thinking, which has statistical thinking at its core, blended with some computational thinking, and with a dash of mathematics.
Covid and data science: Understanding R0 could change your life
Authors: Ridgway Jim
Published: June 2021

The Covid epidemic has provided an excellent example of the need to call on a wide variety of statistical tools to address a global problem, and can give students insights into some of the dimensions of data science. Here, we describe some of the characteristics of data that students encounter as citizens. We set out some teaching ideas, which focus on a few familiar core ideas—such as exponential growth, estimation, interpreting graphs, measurement, and sampling—set in the authentic context of containing a pandemic. In the final section, we sketch some more ideas on activities to develop student skills essential for civic engagement in a data‐rich world.
A first introduction to data science education in secondary schools: Teaching and learning about data exploration with CODAP using survey data
Authors: Frischemeier Daniel , Biehler Rolf , Podworny Susanne , Budde Lea
Published: June 2021

In this paper, we will describe an introduction to Data Science for secondary school students. We will report on the design and implementation of an introductory unit on “Data and data detectives with CODAP” in which secondary school students used the online tool CODAP to explore real and meaningful survey data on leisure time activities and media use (so‐called JIM‐PB data) in a statistical project setting as a starting point for data science. The JIM‐PB data set served as a valuable data set that offered meaningful and exciting opportunities for data exploration for secondary school students, and CODAP proved to be a valuable tool for the first explorations of this data.
Patient decision aids for adults with advanced chronic kidney disease with a medical recommendation to start dialysis: a scoping review protocol
Authors: Salas-Gama Karla , Díaz Juan Manuel , Coronado Jorge , Pérez-Bracchiglione Javier , Requeijo Carolina , Samsó Laura , Suclupe Stefanie , Bolíbar Ignasi
Published: June 2021

Objective:

This review will identify and describe the content and assess the quality of available decision aids aimed at adults with advanced chronic kidney disease with medical indication to start dialysis who need to choose one of the two dialysis modalities.

Introduction:

The lack of evidence regarding the superiority of the different options for dialysis, hemodialysis, and peritoneal dialysis, indicated in advanced chronic kidney disease, makes the shared decision-making process especially important.

Inclusion criteria:

We will include decision aids from published studies and non-published material aimed at adults with advanced chronic kidney disease.

Methods:

We will perform searches in MEDLINE, CINAHL, Embase, PsycINFO, the Cochrane Library, and Epistemonikos. In addition, we will search unpublished studies in OpenGrey, ClinicalTrials.gov, and Open Access Theses and Dissertations. We will also identify decision aids through a specific search in Google and by searching websites of nephrology societies or associations. We will include decision aids in English or Spanish aimed at adults with advanced chronic kidney disease with medical indication to start dialysis. Two independent reviewers will screen, select, and extract the data. General aspects and attributes of the decision aids will be collected. Their quality will be evaluated, and their recommendations for implementation in clinical practice will be analyzed.
Brief introductory group education programs for chronic disease patients in chronic disease management: a scoping review protocol
Authors: Tan Celia , Searle Amelia , Wall Cindy , Herriot Peter
Published: June 2021

Objective:

This review will scope the literature and map the features of brief introductory group education programs implemented in chronic disease management.

Introduction:

Brief introductory group education programs are resource-efficient interventions used in chronic disease management to educate patients about basic disease concepts, self-management strategies, and to introduce specialist services. There is a lack of published research that synthesizes the characteristics, guiding principles, and outcomes reported in brief group education programs in chronic disease management. This scoping review will seek to identify brief introductory group education programs and describe the i) scope of literature available on such programs, ii) characteristics of the programs, iii) guiding self-management principles used and the extent to which programs follow such principles, and iv) types of outcomes reported.

Inclusion criteria:

This review will consider studies describing an introductory or brief group patient education program (one to four sessions, no more than eight hours) for the management of chronic disease in adults with ongoing chronic disease.

Methods:

MEDLINE, Scopus, CINAHL, Emcare, Web of Science, and PsycINFO will be searched for English-language articles published from 2001 to the present. Titles and abstracts will be screened against inclusion/exclusion criteria, followed by full-text review, independently assessed by two reviewers. Eligible articles will be extracted and charted using a standardized data extraction form. A descriptive review to summarize and contextualize the extracted data will be conducted.
The Fatigue of Metals—Its Nature and Significance
Authors: Moore H. F.
Published: June 2021

The essential feature of “fatigue” failure in metals is a spreading crack. Studies of fatigue failure in single crystals of metal indicate that such cracks frequently start by slip along planes of atomic weakness. The study of fatigue failure of metals has shown certain limitations of the mathematical theory of elasticity when applied to actual non-homogeneous metals. The importance of the ability of a metal to resist occasional slight plastic action without starting a fatigue crack is emphasized. The relation between atomic strength and the strength of a multi-grained piece of metal is briefly discussed and a “crack-interference” hypothesis of fatigue failure suggested. The phenomenon of spreading cracks in metal under steady load at elevated temperatures is noted, and its significance discussed.
The Present State of the Turbulence Problem
Authors: Tollmien Walter
Published: June 2021

In this survey the author first describes certain types of turbulent flow, following which he deals successively with the production of turbulent motion; the instability of the laminar motion; fully developed turbulence; momentum interchange and mixing lengths; and relations between the shearing stress at the wall and the mean velocity distributions. Finally he takes up the calculation of skin friction for simple cases of fully developed turbulence, especially for that of the flat plate. Although the methods outlined have often led to practically useful results, it is the author’s belief that they should be considered only as advances toward the real goal of the turbulence theory. The derivation of turbulence phenomena from the hydrodynamical equations will, in his opinion, be possible only by the application of statistical methods.
The Elastic Behavior of Vulcanized Rubber
Authors: Hencky H.
Published: June 2021

Up to extensions of about 270 per cent the elastic behavior of vulcanized rubber can be represented analytically by a very simple function. The stress-strain diagrams for tension and compression are quite different; nevertheless this asymmetrical behavior is satisfactorily taken care of by employing only two elastic coefficients.
An Experimental and Analytical Investigation of Creep in Bending
Authors: MacCullough Gleason H.
Published: June 2021

This paper describes an experimental and analytical study of the phenomenon of creep as it occurs in bending. Creep tests upon a lead beam were made to determine the behavior of originally plane sections during pure bending accompanied by creep. From the results of these tests and of creep tests in tension and compression, a method is devised whereby the results of the usual tensile creep test may be utilized to predict the rate of creep for transverse sections of the beam. The paper concludes with several analytical examples involving creep as it occurs in pure bending.
Applications of Creep Tests
Authors: MacCullough Gleason H.
Published: June 2021

Analytical solutions of problems which involve creep phenomena and which are of practical interest are at present very limited in number. This paper discusses four specific problems for which solutions have been presented: namely, the problem of the flanged and bolted pipe joint under creep conditions, and the three problems of stress distribution and creep in thick-walled cylinders under internal pressure, in a beam subjected to pure bending, and in a solid circular shaft under torsion. These solutions will illustrate the kind of creep data which the designer desires the experimenter to furnish.
Working Stresses
Authors: Soderberg C. Richard
Published: June 2021

This paper gives a general review of the fundamental aspects of the problem of strength and safety of machine parts. After an introductory discussion of the nature and scope of the problem, it offers suggestions for selecting working stresses for those conditions of applications of materials for which adequate knowledge is available.
Uncertainty Quantification of Deep Neural Network-Based Turbulence Model for Reactor Transient Analysis
Authors: Liu Yang , Hu Rui , Balaprakash Prasanna
Published: June 2021

Deep neural networks (DNNs) have demonstrated good performance in learning highly non-linear relationships in large datasets, thus have been considered as a promising surrogate modeling tool for parametric partial differential equations (PDEs). On the other hand, quantifying the predictive uncertainty in DNNs is still a challenging problem. The Bayesian neural network (BNN), a sophisticated method assuming the weights of the DNNs follow certain uncertainty distributions, is considered as a state-of-the-art method for the UQ of DNNs. However, the method is too computationally expensive to be used in complicated DNN architectures.

In this work, we utilized two more methods for the UQ of complicated DNNs, i.e. Monte Carlo dropout and deep ensemble. Both methods are computationally efficient and scalable compared to BNN. We applied these two methods to a densely connected convolutional network, which is developed and trained as a coarse-mesh turbulence closure relation for reactor safety analysis. In comparison, the corresponding BNN with the same architecture is also developed and trained. The computational cost and uncertainty evaluation performance of these three UQ methods are comprehensively investigated. It is found that the deep ensemble method is able to produce reasonable uncertainty estimates with good scalability and relatively low computational cost compared to BNN.
A Framework for In Silico Clinical Trials for Medical Devices Using Concepts From Model Verification, Validation, and Uncertainty Quantification (VVUQ)
Authors: Bodner Jeff , Kaul Vikas
Published: June 2021

The rising costs of clinical trials for medical devices in recent years has led to an increased interest in so-called in silico clinical trials, where simulation results are used to supplement or to replace those obtained from human patients. Here we present a framework for executing such a trial. This framework relies heavily on ideas already developed for model verification, validation, and uncertainty quantification. The framework uses results from an initial cohort of human patients as model validation data, recognizing that the best model credibility evidence usually comes from real patients. The validation exercise leads to an assessment of the model’s suitability based on pre-defined acceptance criteria. If the model meets these criteria, then no additional human patients are required and the study endpoints that can be addressed using the model are met using the simulation results. Conversely, if the model is found to be inadequate, it is abandoned, and the clinical study continues using only human patients in a second cohort. Compared to other frameworks described in the literature based on Bayesian methods, this approach follows a strict model build-validate-predict structure. It can handle epistemic uncertainties in the model inputs, which is a common trait of models of biomedical systems. Another idea discussed here is that the outputs of engineering models rarely coincide with measures that are the basis for clinical endpoints. This manuscript discusses how the link between the model and clinical measure can be established during the trial.
Van der Waals epitaxy and remote epitaxy of LiNbO3 thin films by pulsed laser deposition
Authors: Jia Ru , Kum Hyun S. , Sun Xin , Guo Yuwei , Wang Baiwei , Fang Peijiao , Jiang Jie , Gall Daniel , Lu Toh-Ming , Washington Morris , Kim Jeehwan , Shi Jian
Published: June 2021

Nonlinear oxides such as LiNbO3 have found many applications in both conventional electro-optics and quantum optics. In this work, we demonstrate the van der Waals and remote epitaxy of LiNbO3 films on muscovite mica and graphene-buffered sapphire, respectively, by pulsed laser deposition. Structural analysis shows that the epitaxial relation in van der Waals epitaxy is LiNbO3 (0001) || mica (001) and LiNbO3 [011¯0] || mica [010] with LiNbO3 [101¯0] || mica [010], a 60°-rotated twin structure. The relation in remote epitaxy is LiNbO3 (0001) || sapphire (0001) and LiNbO3 [011¯0] || sapphire [011¯0] with twin structure LiNbO3 [1¯010] || sapphire [011¯0]. Furthermore, in remote epitaxy, Raman scattering analysis confirms the existence of graphene after deposition. Finally, we find that the oxygen partial pressure influences the presence of impurity phases significantly. The successful demonstration of van der Waals and remote epitaxy promises the feasibility of developing thin film LiNbO3 on demanded substrates toward scalable electro-optics.
At DOE, efforts to address climate and diversity dovetail
Authors: Cho Adrian
Published: June 2021

Proposed urban integrated field laboratories would reach out to minority communities.
Ubiquitination is essential for recovery of cellular activities after heat shock
Authors: Maxwell Brian A. , Gwon Youngdae , Mishra Ashutosh , Peng Junmin , Nakamura Haruko , Zhang Ke , Kim Hong Joo , Taylor J. Paul
Published: June 2021

Tailoring stress responses

When faced with environmental stress, cells respond by shutting down cellular processes such as translation and nucleocytoplasmic transport. At the same time, cells preserve cytoplasmic messenger RNAs in structures known as stress granules, and many cellular proteins are modified by the covalent addition of ubiquitin, which has long been presumed to reflect degradation of stress-damaged proteins (see the Perspective by Dormann). Maxwell
et al.
show that cells generate distinct patterns of ubiquitination in response to different stressors. Rather than reflecting the degradation of stress-damaged proteins, this ubiquitination primes cells to dismantle stress granules and reinitiate normal cellular activities once the stress is removed. Gwon
et al.
show that persistent stress granules are degraded by autophagy, whereas short-lived granules undergo a process of disassembly that is autophagy independent. The mechanism of this disassembly depends on the initiating stress.

Science
, abc3593 and abf6548, this issue p.
eabc3593
and p.
eabf6548
; see also abj2400, p.
1393
MeCP2 is a microsatellite binding protein that protects CA repeats from nucleosome invasion
Authors: Ibrahim Abdulkhaleg , Papin Christophe , Mohideen-Abdul Kareem , Le Gras Stéphanie , Stoll Isabelle , Bronner Christian , Dimitrov Stefan , Klaholz Bruno P. , Hamiche Ali
Published: June 2021

MeCP2 binds hydroxymethylated CA repeats

Despites of decades of research on the Rett syndrome protein MeCP2, its function remains unclear. Ibrahim
et al.
show that MeCP2 is a hydroxymethylated cytosine-adenosine (CA) repeat-binding protein that modulates chromatin architecture at a distance from the transcription start site (see the Perspective by Zhou and Zoghbi). MeCP2 accumulates and spreads around modified CA repeats and competes for nucleosome occupancy. Loss of MeCP2 results in a widespread increase in nucleosome density inside lamina-associated domains and transcriptional dysregulation of genes enriched in CA repeats. These results shed light on the underlying molecular mechanism of Rett syndrome, a severe disease associated with mutations in MeCP2.

Science
, abd5581, this issue p.
eabd5581
; see also abj5027, p.
1390
First-principles design of a single-atom–alloy propane dehydrogenation catalyst
Authors: Hannagan Ryan T. , Giannakakis Georgios , Réocreux Romain , Schumann Julia , Finzel Jordan , Wang Yicheng , Michaelides Angelos , Deshlahra Prashant , Christopher Phillip , Flytzani-Stephanopoulos Maria , Stamatakis Michail , Sykes E. Charles H.
Published: June 2021

Rhodium atoms for alkane dehydrogenation

Nanoparticles of rhodium dispersed on metal oxides are generally poor catalysts for alkane dehydrogenation because the reactants bind too strongly to the metal. Hannagan
et al.
performed first-principle calculations indicating that single rhodium atoms in a copper surface should be stable and selective for conversion of propane to propene and hydrogen. Model studies of single rhodium atoms embedded in a copper (111) surface revealed a very high selectivity to propene and high resistance to the formation of surface carbon that would deactivate the catalyst.

Science
, abg8389, this issue p.
1444
Middle Pleistocene
Homo
behavior and culture at 140,000 to 120,000 years ago and interactions with
Homo sapiens
Authors: Zaidner Yossi , Centi Laura , Prévost Marion , Mercier Norbert , Falguères Christophe , Guérin Gilles , Valladas Hélène , Richard Maïlys , Galy Asmodée , Pécheyran Christophe , Tombret Olivier , Pons-Branchu Edwige , Porat Naomi , Shahack-Gross Ruth , Friesem David E. , Yeshurun Reuven , Turgeman-Yaffe Zohar , Frumkin Amos , Herzlinger Gadi , Ekshtain Ravid , Shemer Maayan , Varoner Oz , Sarig Rachel , May Hila , Hershkovitz Israel
Published: June 2021

Middle Pleistocene
Homo
in the Levant

Our understanding of the origin, distribution, and evolution of early humans and their close relatives has been greatly refined by recent new information. Adding to this trend, Hershkovitz
et al.
have uncovered evidence of a previously unknown archaic
Homo
population, the “Nesher Ramla
Homo
” (see the Perspective by Mirazon Lahr). The authors present comprehensive qualitative and quantitative analyses of fossilized remains from a site in Israel dated to 140,000 to 120,000 years ago indicating the presence of a previously unrecognized group of hominins representing the last surviving populations of Middle Pleistocene
Homo
in Europe, southwest Asia, and Africa. In a companion paper, Zaidner
et al.
present the radiometric ages, stone tool assemblages, faunal assemblages, and other behavioral and environmental data associated with these fossils. This evidence shows that these hominins had fully mastered technology that until only recently was linked to either
Homo sapiens
or Neanderthals. Nesher Ramla
Homo
was an efficient hunter of large and small game, used wood for fuel, cooked or roasted meat, and maintained fires. These findings provide archaeological support for cultural interactions between different human lineages during the Middle Paleolithic, suggesting that admixture between Middle Pleistocene
Homo
and
H. sapiens
had already occurred by this time.

Science
, abh3169 and abh3020, this issue p.
1424
and p.
1429
; see also abj3077, p.
1395
A Middle Pleistocene
Homo
from Nesher Ramla, Israel
Authors: Hershkovitz Israel , May Hila , Sarig Rachel , Pokhojaev Ariel , Grimaud-Hervé Dominique , Bruner Emiliano , Fornai Cinzia , Quam Rolf , Arsuaga Juan Luis , Krenn Viktoria A. , Martinón-Torres Maria , de Castro José María Bermúdez , Martín-Francés Laura , Slon Viviane , Albessard-Ball Lou , Vialet Amélie , Schüler Tim , Manzi Giorgio , Profico Antonio , Di Vincenzo Fabio , Weber Gerhard W. , Zaidner Yossi
Published: June 2021

Middle Pleistocene
Homo
in the Levant

Our understanding of the origin, distribution, and evolution of early humans and their close relatives has been greatly refined by recent new information. Adding to this trend, Hershkovitz
et al.
have uncovered evidence of a previously unknown archaic
Homo
population, the “Nesher Ramla
Homo
” (see the Perspective by Mirazon Lahr). The authors present comprehensive qualitative and quantitative analyses of fossilized remains from a site in Israel dated to 140,000 to 120,000 years ago indicating the presence of a previously unrecognized group of hominins representing the last surviving populations of Middle Pleistocene
Homo
in Europe, southwest Asia, and Africa. In a companion paper, Zaidner
et al.
present the radiometric ages, stone tool assemblages, faunal assemblages, and other behavioral and environmental data associated with these fossils. This evidence shows that these hominins had fully mastered technology that until only recently was linked to either
Homo sapiens
or Neanderthals. Nesher Ramla
Homo
was an efficient hunter of large and small game, used wood for fuel, cooked or roasted meat, and maintained fires. These findings provide archaeological support for cultural interactions between different human lineages during the Middle Paleolithic, suggesting that admixture between Middle Pleistocene
Homo
and
H. sapiens
had already occurred by this time.

Science
, abh3169 and abh3020, this issue p.
1424
and p.
1429
; see also abj3077, p.
1395
The complex landscape of recent human evolution
Authors: Lahr Marta Mirazón
Published: June 2021

Archaic hominins in the Middle East underscore local demographic diversity in the last half million years
MyD88 signaling by neurons induces chemokines that recruit protective leukocytes to the virus-infected CNS
Authors: Ghita Luca , Spanier Julia , Chhatbar Chintan , Mulenge Felix , Pavlou Andreas , Larsen Pia-Katharina , Waltl Inken , Lueder Yvonne , Kohls Moritz , Jung Klaus , Best Sonja M. , Förster Reinhold , Stangel Martin , Schreiner Dietmar , Kalinke Ulrich
Published: June 2021

During viral CNS infection, MyD88 signaling in infected neurons orchestrates recruitment of protective peripheral immune cells.
Severe acute orthostatic headache: spontaneous intracranial hypotension (SIH)
Authors: Renjen Pushpendra Nath , Chaudhari Dinesh Mohan , Goyal Nidhi , Ahmed Kamal
Published: June 2021

The most common cause of spontaneous intracranial hypotension headache is a cerebrospinal fluid (CSF) leakage, but the underlying mechanisms remain unknown. Intracranial hypotension is characterised by diffuse pachymeningeal enhancement on cranial MRI features, low CSF pressure and orthostatic headaches mostly caused by the dural puncture. We report a 31-year-old woman who presented to our services with reports of continuous severe bifrontal headache, which increased on sitting up and resolved on lying down. MRI of the cervical and lumbosacral spine showed signs of CSF leak; hence, patient was diagnosed with spontaneous intracranial hypotension headache. A CT-guided epidural blood patch was done at L4–5 with fibrin glue injected at the site of leak. The patient’s signs and symptoms improved after the procedure.
Improving access to primary care: a mixed-methods approach studying a new review appointment system in a Scottish GP practice
Authors: Slater Jay , Malik Salahuddin , Davey Peter , Grant Suzanne
Published: June 2021

A Scottish general practitioner (GP) practice proposed an improvement intervention, shorter pre-bookable ‘review’ appointments, to increase appointment capacity and meet their patients’ demand for appointments. Staff are now able to pre-book these review appointments for patients, guaranteeing that the patient will see the same GP or advanced nurse practitioner (ANP) for both initial and review appointments. By shortening the review appointments, more patients were seen each day, hence the appointment capacity increased. The aim of this project was to examine the impact of the improvement intervention, pre-bookable review appointments, using a mixed-methods approach. Ethnographic methods (non-participant observation, participant observation and eight semistructured interviews with administrative staff) provided qualitative data, to understand the appointment system and to identify areas for further improvement. Quantitative data were then collected to assess: the number of patients receiving ‘on the day’ appointments, with the aim for this to be 95% (outcome measure); by how much the number of appointments available had increased (process measure) and the administrative staff workload (balancing measure). During a 7-week period, 3 months post-intervention, a median of 93% of patients received an ‘on the day’ appointment when they phoned for one between 08:00 and 09:00. The number of appointments available increased by 43%. Administrative staff workload (number of calls received per day) remained the same. Patients prefer being able to book in to see the same GP (continuity of care) and the ability to book in advance. Administrative staff workload decreased in terms of dealing with less frustrated patients. Main suggestions for improvement include introducing later appointments for workers and text reminders for pre-booked (review and online) appointments. The introduction of pre-bookable review appointments improved patient accessibility in the practice. Next steps for improving the appointment system include gaining clinician (GP/ANP) opinions on review appointments and trialling later appointments.
Performance monitoring of EBUS for the staging and diagnosis of lung cancer: auditing the Greater Manchester EBUS service against new national standards
Authors: Punjabi Anshu , Al-Najjar Haider , Teng Benjamin , Borrill Zoe , Brown Louise , Nagarajan Thapas , Gallagher Joanna , Grundy Seamus , Sundar Ram , Higgins Coral , Shackley David , Sinnott Nicola , Balata Haval , Lyons Judith , Martin Julie , Brocklesby Christopher , Crosbie Phil , Booton Richard , Evison Matthew
Published: June 2021

Introduction

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a pivotal test in lung cancer staging and diagnosis, mandating robust audit and performance monitoring of EBUS services. We present the first regional cancer alliance EBUS performance audit against the new National EBUS specification.

Methods

Across the five EBUS centres in the Greater Manchester Cancer Alliance, data are recorded at the point of procedure, when pathological results are available and at 6 months postprocedure to review any further pathological sampling (eg, at surgical resection) and the outcome of clinical–radiological follow-up. Outcomes across all five centres were compared with national standards for all lung cancer EBUS procedures from 01 January 2017 to 31 December 2018.

Results

1899 lung cancer staging or diagnostic EBUS procedures were performed across the five centres during the study period; 1309 staging EBUS procedures and 590 diagnostic EBUS procedures. Major complications were seen in six cases (<1%). All five trusts demonstrated performance above that set national standards in key metrics for both staging and diagnostic EBUS, however the provision of adequate tissue for predictive marker testing was below national standards at one trust. Across Greater Manchester, 72% and 64% of patients had their EBUS procedure performed within 7 days of referral in 2017 and 2018, respectively. Only one out of five trusts met the national targets of >85% of procedures performed within 7 days of referral.

Conclusion

The National EBUS service specification is an important framework to drive the quality of EBUS services across the UK. Our data provide assurance of appropriate performance and safety while also highlighting specific areas for attention that can be addressed with the support of the cancer alliance.
Impact of walking aids on estimating physical activity using a tri-axial accelerometer in frail older adults
Authors: Nishida Yuki , Tanaka Shigeho , Hatamoto Yoichi , Hatanaka Mana , Ishikawa-Takata Kazuko , Abe Takayuki , Higaki Yasuki , Katsukawa Fuminori
Published: June 2021

Objectives

This study aimed to compare the estimation error of physical activity level (PAL) estimated using a tri-axial accelerometer between an independent walking group and an assisted walking group with walking aids.

Methods

Subjects were 6 older adults who could walk independently and 10 older adults requiring walking assistance during gait. Total energy expenditure (TEE) was measured using the doubly labelled water (DLW) method over 2 weeks and PAL was calculated as the measured TEE divided by the basal metabolic rate measured using indirect calorimetry (PALDLW). The participants wore a tri-axial accelerometer (Active style Pro HJA-750C) on the waist simultaneously as the DLW period, and the estimated PAL was derived from it (PALACC).

Results

The median PAL estimation error in the assisted walking group was −0.30 kcal/day (range: −0.77 to −0.01 kcal/day) and more underestimated than that in the independent walking group (p=0.02). The estimation error of PALACCwas significantly correlated with PALDLW(r=−0.80, p<0.01).

Conclusions

Using the accelerometer, PAL was underestimated for older adults who used walking aids but not for those who walked independently under free-living conditions.
Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events
Authors: Brahmer Julie R , Abu-Sbeih Hamzah , Ascierto Paolo Antonio , Brufsky Jill , Cappelli Laura C , Cortazar Frank B , Gerber David E , Hamad Lamya , Hansen Eric , Johnson Douglas B , Lacouture Mario E , Masters Gregory A , Naidoo Jarushka , Nanni Michele , Perales Miguel-Angel , Puzanov Igor , Santomasso Bianca D , Shanbhag Satish P , Sharma Rajeev , Skondra Dimitra , Sosman Jeffrey A , Turner Michelle , Ernstoff Marc S
Published: June 2021

Immune checkpoint inhibitors (ICIs) are the standard of care for the treatment of several cancers. While these immunotherapies have improved patient outcomes in many clinical settings, they bring accompanying risks of toxicity, specifically immune-related adverse events (irAEs). There is a need for clear, effective guidelines for the management of irAEs during ICI treatment, motivating the Society for Immunotherapy of Cancer (SITC) to convene an expert panel to develop a clinical practice guideline. The panel discussed the recognition and management of single and combination ICI irAEs and ultimately developed evidence- and consensus-based recommendations to assist medical professionals in clinical decision-making and to improve outcomes for patients.
Loss-of-function variants in DNM1 cause a specific form of developmental and epileptic encephalopathy only in biallelic state
Authors: Yigit Gökhan , Sheffer Ruth , Daana Muhannad , Li Yun , Kaygusuz Emrah , Mor-Shakad Hagar , Altmüller Janine , Nürnberg Peter , Douiev Liza , Kaulfuss Silke , Burfeind Peter , Wollnik Bernd , Brockmann Knut
Published: June 2021

Background

Developmental and epileptic encephalopathies (DEEs) represent a group of severe neurological disorders characterised by an onset of refractory seizures during infancy or early childhood accompanied by psychomotor developmental delay or regression. DEEs are genetically heterogeneous with, to date, more than 80 different genetic subtypes including DEE31 caused by heterozygous missense variants in DNM1.

Methods

We performed a detailed clinical characterisation of two unrelated patients with DEE and used whole-exome sequencing to identify causative variants in these individuals. The identified variants were tested for cosegregation in the respective families.

Results

We excluded pathogenic variants in known, DEE-associated genes. We identified homozygous nonsense variants, c.97C>T; p.(Gln33*) in family 1 and c.850C>T; p.(Gln284*) in family 2, in the DNM1 gene, indicating that biallelic, loss-of-function pathogenic variants in DNM1 cause DEE.

Conclusion

Our finding that homozygous, loss-of-function variants in DNM1 cause DEE expands the spectrum of pathogenic variants in DNM1. All parents who were heterozygous carriers of the identified loss-of-function variants were healthy and did not show any clinical symptoms, indicating that the type of mutation in DNM1 determines the pattern of inheritance.
Sick leave in early axial spondyloarthritis: the role of clinical and socioeconomic factors. Five-year data from the DESIR cohort
Authors: Nikiphorou Elena , Carvalho Pedro D , Boonen Annelies , Fautrel Bruno , Richette Pascal , Machado Pedro M , van der Heijde Desirée , Landewé Robert , Ramiro Sofia
Published: June 2021

Objectives

To investigate the occurrence of sick leave (SL) and the impact of clinical and socioeconomic factors on SL in early axial spondyloarthritis (axSpA).

Methods

Patients with a clinical diagnosis of axSpA from the DEvenir des Spondyloarthrites Indifférenciées Récentes (DESIR) cohort with work-related data and up to 5-year follow-up were studied. Incidence, time to first SL and potential role of baseline and time-varying clinical and socioeconomic factors (age, gender, ethnicity, education, job type, marital and parental status) were analysed. Univariable analyses, followed by collinearity and interaction tests, guided subsequent multivariable time-varying Cox survival model building.

Results

In total, 704 axSpA patients were included (mean (SD) age 33.8 (8.6); 46% men). At baseline, 80% of patients were employed; of these, 5.7% reported being on SL. The incidence of SL among those at risk during the study period (n=620, 88%) was 0.05 (95% CI 0.03 to 0.06) per 1000 days of follow-up. Mean (SD) time to first SL was 806 (595) days (range: 175–2021 days). In multivariable models, male gender (HR 0.41 (95% CI 0.20 to 0.86)) and higher education (HR 0.48 (95% CI 0.24 to 0.95)) were associated with lower hazard of SL, while higher disease activity (HR 1.49 (95% CI 1.04 to 2.13)), older age, smoking and use of tumour necrosis factor inhibitors were associated with higher hazard of SL.

Conclusions

In this early axSpA cohort of young, working-age individuals, male gender and higher education were independently associated with a lower hazard of SL, whereas older age and higher disease activity were associated with higher hazard of SL. The findings suggest a role of socioeconomic factors in adverse work outcomes, alongside active disease.