bluuebunny/crossref_metadata_2025 huggingface dataset:
Retrograde Control of Cytosolic Translation Targets Synthesis of Plastid Proteins and Nuclear Responses for High-Light Acclimation
Authors: Moore Marten , Smith Aaron B. , Wegener Melanie , Wesemann Corinna , Schmidtpott Sonja , Farooq Muhammad Ansar , Ganguly Diep Ray , Seidel Thorsten , Pogson Barry J. , Dietz Karl-Josef
Published: February 2021

Canonical retrograde signalling comprises information transmission from organelles to the nucleus and in particular controls gene expression for organellar proteins. The need to re-assess this paradigm was suggested by discrepancies between de novo protein synthesis and transcript abundance in response to excess light. Here we uncover major components of a translation-dependent retrograde signalling pathway that first impacts translation and then transcription. The response realization depends on the kinases Mitogen-activated protein kinase 6 (MPK6) and Sucrose non-fermenting 1-related kinase (SnRK1) subunit, AKIN10. Global ribosome foot-printing revealed differential ribosome association of 951 transcripts within 10 min after transfer from low to high light. Despite predominant translational repression, 15 % of transcripts were increased in translation and enriched for chloroplast-localized photosynthetic proteins. About one third of these transcripts, including Stress associated proteins (SAP) 2 and 3, share regulatory motifs in their 5′-UTR that act as binding sites for glyceraldehyde-3-phosphate dehydrogenase (GAPC) and light responsive RNA binding proteins (RBPs). SAP2 and 3 are both translationally regulated and interact with the calcium sensor Calmodulin-like 49 (CML49), which promotes relocation to the nucleus inducing a translation-dependent nuclear stress response. Thus, translation-dependent retrograde signalling bifurcates to directly regulate a translational circuit of chloroplast proteins and simultaneously initiate a nuclear circuit synchronizing retrograde and anterograde response pathways, serving as a rapid mechanism for functional acclimation of the chloroplast.
Fast A-type currents shape a rapidly adapting form of delayed short latency firing of excitatory superficial dorsal horn neurons that express the NPY Y1 receptor
Authors: Sinha Ghanshyam P. , Prasoon Pranav , Smith Bret N. , Taylor Bradley K.
Published: February 2021

Neuroanatomical and behavioral evidence indicates that neuropeptide Y Y1 receptor-expressing interneurons (Y1-INs) in the superficial dorsal horn (SDH) are predominantly excitatory and contribute to chronic pain. Using an adultex vivospinal cord slice preparation from Y1eGFP reporter mice, we characterized firing patterns in response to steady state depolarizing current injection of GFP-positive cells in lamina II, the great majority of which expressed Y1 mRNA (88%). Randomly sampled and Y1eGFP neurons exhibited five firing patterns: tonic (TF), initial burst (IBF), phasic (PF), delayed short-latency <180 ms (DSLF), and delayed long-latency >180 ms (DLLF). When studied at resting membrane potential, most RS neurons exhibited delayed firing, while most Y1eGFP neurons exhibited phasic firing and not delayed firing. A preconditioning membrane hyperpolarization produced only subtle changes in the firing patterns of randomly sampled neurons, but dramatically shifted Y1eGFP neurons to DSLF (46%) and DLLF (24%). In contrast to randomly sampled DSLF neurons which rarely exhibited spike frequency adaptation, Y1eGFP DSLF neurons were almost always rapidly adapting, a characteristic of nociceptive-responsive SDH neurons. Rebound spiking was more prevalent in Y1eGFP neurons (6% RS vs 32% Y1eGFP), indicating enrichment of T-type calcium currents. Y1eGFP DSLF neurons exhibited fast A-type potassium currents that are known to delay or limit action potential firing, and these were of smaller current density as compared to randomly sampled DSLF neurons. Our results inspire future studies to determine whether tissue or nerve injury downregulates channels that contribute to A-currents, thus potentially unmasking T-type calcium channel activity and membrane hyperexcitability in Y1-INs, leading to persistent pain.

KEYPOINTS

Neuropeptide Y Y1 receptor-expressing neurons in the dorsal horn of the spinal cord contribute to chronic pain.

For the first time, we characterized the firing patterns of Y1-expressing neurons in Y1eGFP reporter mice.

Under hyperpolarized conditions, most Y1eGFP neurons exhibited fast A-type potassium currents and delayed, short-latency firing (DSLF).

Y1eGFP DSLF neurons were almost always rapidly adapting and often exhibited rebound spiking, characteristics of spinal pain neurons under the control of T-type calcium channels.

These results inspire future studies to determine whether tissue or nerve injury downregulates the channels that underlie A-currents, thus unmasking membrane hyperexcitability in Y1- expressing dorsal horn neurons, leading to persistent pain
Intracellular NASPM allows an unambiguous functional measure of GluA2-lacking calcium-permeable AMPA receptor prevalence
Authors: Coombs Ian D. , Bats Cécile , Sexton Craig A. , Cull-Candy Stuart G. , Farrant Mark
Published: February 2021

Calcium-permeable AMPA-type glutamate receptors (CP-AMPARs) contribute to many forms of synaptic plasticity and pathology. They can be distinguished from GluA2-containing calcium-impermeable AMPARs by the inward rectification of their currents, which reflects voltage-dependent block by intracellular spermine. However, the efficacy of this weakly permeant blocker is differentially altered by the presence of AMPAR auxiliary subunits – including transmembrane AMPAR regulatory proteins, cornichons and GSG1L – that are widely expressed in neurons and glia. This complicates the interpretation of rectification as a measure of CP-AMPAR expression. Here we show that inclusion of the spider toxin analogue 1-naphthylacetyl spermine (NASPM) in the intracellular recording solution results in complete block of GluA1-mediated outward currents irrespective of the type of associated auxiliary subunit. In neurons from GluA2-knockout mice expressing only CP-AMPARs, intracellular NASPM, unlike spermine, blocks all outward synaptic current. Thus, our results identify an unambiguous functional measure, sensitive solely to changes in CP-AMPAR prevalence.
Invasive atypical non-typhoidalSalmonellaserovars in The Gambia
Authors: Kanteh Abdoulie , Sesay Abdul Karim , Alikhan Nabil-Fareed , Ikumapayi Usman Nurudeen , Salaudeen Rasheed , Manneh Jarra , Olatunji Yekini , Page Andrew J , Mackenzie Grant
Published: February 2021

Background

Invasive non-typhoidalSalmonella(iNTS) disease continues to be a significant public health problem in sub-Saharan Africa. Common clinical misdiagnosis, antimicrobial resistance, high case fatality and lack of a vaccine make iNTS a priority for global health research. Using whole genome sequence analysis of 164 invasiveSalmonellaisolates obtained through population-based surveillance between 2008 and 2016, we conducted genomic analysis of the serovars causing invasiveSalmonelladiseases in rural Gambia.

Results

The incidence of iNTS varied over time. The proportion of atypical serovars causing disease increased over time from 40% to 65% compared to the typical serovars Enteritidis and Typhimurium decreasing from 30% to 12%. Overall iNTS case fatality was 10% with 10% fatality in cases of atypical iNTS. Genetic virulence factors were identified in 14/70 (20%) typical serovars and 45/68 (66%) of the atypical serovars and were associated with: invasion, proliferation and/or translocation (Clade A); and host colonization and immune modulation (Clade G). Among Enteritidis isolates, 33/40 were resistant to ≥4 the antimicrobials tested, except for ciprofloxacin, to which all isolates were susceptible. Resistance was low in Typhimurium isolates, however, all16 isolates were resistant to gentamicin.

Conclusion

The increase in incidence and proportion of iNTS disease caused by atypical serovars is concerning. The increased proportion of atypical serovars and the high associated case fatality may be related to acquisition of specific genetic virulence factors. These factors may provide a selective advantage to the atypical serovars. Investigations should be conducted elsewhere in Africa to identify potential changes in the distribution iNTS serovars and the extent of these virulence elements.
Predicting the zoonotic capacity of mammals to transmit SARS-CoV-2
Authors: Fischhoff Ilya R. , Castellanos Adrian A. , Rodrigues João P.G.L.M. , Varsani Arvind , Han Barbara A.
Published: February 2021

Back and forth transmission of SARS-CoV-2 between humans and animals may lead to wild reservoirs of virus that can endanger efforts toward long-term control of COVID-19 in people, and protecting vulnerable animal populations that are particularly susceptible to lethal disease. Predicting high risk host species is key to targeting field surveillance and lab experiments that validate host zoonotic potential. A major bottleneck to predicting animal hosts is the small number of species with available molecular information about the structure of ACE2, a key cellular receptor required for viral cell entry. We overcome this bottleneck by combining species’ ecological and biological traits with 3D modeling of virus and host cell protein interactions using machine learning methods. This approach enables predictions about the zoonotic capacity of SARS-CoV-2 for over 5,000 mammals — an order of magnitude more species than previously possible. The high accuracy predictions achieved by this approach are strongly corroborated byin vivoempirical studies. We identify numerous common mammal species whose predicted zoonotic capacity and close proximity to humans may further enhance the risk of spillover and spillback transmission of SARS-CoV-2. Our results reveal high priority areas of geographic overlap between global COVID-19 hotspots and potential new mammal hosts of SARS-CoV-2. With molecular sequence data available for only a small fraction of potential host species, predictive modeling integrating data across multiple biological scales offers a conceptual advance that may expand our predictive capacity for zoonotic viruses with similarly unknown and potentially broad host ranges.
Pregnancy and weaning regulate human maternal liver size and function
Authors: Bartlett Alexandra Q , Vesco Kimberly K , Purnell Jonathan Q , Francisco Melanie , Goddard Erica , DeBarber Andrea , Leo Michael C , Baetscher Eric , Rooney William , Naugler Willscott , Guimaraes Alex , Catalano Patrick , Schedin Pepper
Published: February 2021

BACKGROUND

During pregnancy, the rodent liver undergoes hepatocyte proliferation and increases in size, followed by weaning-induced involution via hepatocyte cell death and stromal remodeling, creating a pro-metastatic niche. These data suggest a mechanism for increased liver metastasis in postpartum breast cancer patients.

OBJECTIVES

Investigate if the human liver changes in size and function during pregnancy and weaning.

METHODS

Abdominal imaging was obtained in healthy women at early and late pregnancy, and post-wean. During pregnancy time points, endogenous glucose production was measured and fasting blood taken to measure bile acids.

RESULTS

Independent of weight gain, most women’s livers increased in size with pregnancy, returning to baseline post-wean. Putative roles for bile acids in liver growth were observed in pregnant women and rodents.

CONCLUSIONS

The human liver is regulated by reproductive state with growth during pregnancy and volume loss post-wean. These findings may have broad implications for sex-specific liver diseases and cancer.
Analysis of Structural Variation Among Inbred Mouse Strains Identifies Genetic Factors for Autism-Related Traits
Authors: Arslan Ahmed , Fang Zhuoqing , Wang Meiyue , Cheng Zhuanfen , Yoo Boyoung , Bejerano Gill , Peltz Gary
Published: February 2021

The genomes of six inbred strains were analyzed using long read (LR) sequencing. The results revealed that structural variants (SV) were very abundant within the genome of inbred mouse strains (4.8 per gene), which indicates that they could impact genetic traits. Analysis of the relationship between SNP and SV alleles across 53 inbred strains indicated that we have a very limited ability to infer whether SV are present using short read sequence data, even when nearby SNP alleles are known. The benefit of having a more complete map of the pattern of genetic variation was demonstrated by identifying at least three genetic factors that could underlie the unique neuroanatomic and behavioral features of BTBR mice that resemble human Autism Spectrum Disorder (ASD). Similar to the genetic findings in human ASD cohorts, the identified BTBR-unique alleles are very rare, and they cause high impact changes in genes that play a role in neurodevelopment and brain function.
neurolib: a simulation framework for whole-brain neural mass modeling
Authors: Cakan Caglar , Jajcay Nikola , Obermayer Klaus
Published: February 2021

neurolibis a computational framework for whole-brain modeling written in Python. It provides a set of neural mass models that represent the average activity of a brain region on a mesoscopic scale. In a whole-brain network model, brain regions are connected with each other based on biologically informed structural connectivity, i.e. the connectome of the brain.neurolibcan load structural and functional datasets, set up a whole-brain model, manage its parameters, simulate it, and organize its outputs for later analysis. The activity of each brain region can be converted into a simulated BOLD signal in order to calibrate the model against empirical data from functional magnetic resonance imaging (fMRI). Extensive model analysis is possible using a parameter exploration module, which allows one to characterize the model’s behavior given a set of changing parameters. An optimization module can fit a model to multimodal empirical data using an evolutionary algorithm.neurolibis designed to be extendable such that custom neural mass models can be implemented easily, offering a versatile platform for computational neuroscientists for prototyping models, managing large numerical experiments, studying the structure-function relationship of brain networks, and for performing in-silico optimization of whole-brain models.
scMM: Mixture-of-experts multimodal deep generative model for single-cell multiomics data analysis
Authors: Minoura Kodai , Abe Ko , Nam Hyunha , Nishikawa Hiroyoshi , Shimamura Teppei
Published: February 2021

Abstract

The recent development in single-cell multiomics analysis has enabled simultaneous detection of multiple traits at the single-cell level, thus providing deeper insights into the cellular phenotypes and functions in diverse tissues. However, currently, it is challenging to infer the joint representations and learn relationships among multiple modalities from complex multimodal single-cell data. Herein, we present scMM, a novel deep generative model-based framework for the extraction of interpretable joint representations and cross-modal generation. scMM addresses the complexity of data by leveraging a mixture-of-experts multimodal variational autoencoder. The pseudocell generation strategy of scMM compensates for the limited interpretability of deep learning models and discovered multimodal regulatory programs associated with latent dimensions. Analysis of recently produced datasets validated that scMM facilitates high-resolution clustering with rich interpretability. Furthermore, we show that cross-modal generation by scMM leads to more precise prediction and data integration compared with the state-of-the-art and conventional approaches.
BREVIPEDICELLUS and ERECTA mediate expression ofAtPRX17in preventing Arabidopsis callus retardation and browning
Authors: Xie Junyan , Qi Bin , Wu Yuanyuan , Mou Chenghong , Wang Lihua , Jiao Yuwei , Dou Yanhui , Zheng Huiqiong
Published: February 2021

Efficient in vitro callus generation is fundamental to tissue culture propagation, a process required for plant regeneration and transgenic breeding for desired phenotypes. Identifying genes and regulatory elements that prevent callus retardation and browning is essential to facilitate the development of vitro callus systems. Here we show thatBREVIPEDICELLUS(BP) andERECTA(ER) pathways inArabidopsiscallus are converged to prevent callus browning and positively regulate an isoperoxidase gene AtPRX17expression in the rapid growth callus. Loss of functions in bothBPandERresulted in markedly increasing callus browning. Transgenic lines withpro35S::AtPRX17in thebp-5 er105double mutant background fully rescued this phenotypic abnormality. Using plantin vitroDNA-binding assays, we observed that BP protein bound directly to the upstream sequence ofAtPRX17to promote its transcription during callus growth. ER is a universally presenting factor required for cell proliferation and growth, we show thatERpositively regulates expression of a transcription factorWRKY6, which also directly binds to an additional site of the AtPRX17promoter for its high expression. Our data reveals an important molecular mechanism in regulating expression of peroxidase isozyme to reduce Arabidopsis callus browning.

Highlight

BREVIPEDICELLUSandERECTAare involved in regulating Arabidopsis callus browning by controlling expression ofAtPRX17.
West Nile virus in crocodiles and mosquitoes in Zimbabwe
Authors: Roy Marlène , Mufunda Fortunate , Slawski Deirdre , Mutswiri Charmaine , Mvere Irene , Slawski Katherine , Kelly Pamela , Piras Ilaria , Bezuidenhout Annemarie , Hanyire Tapiwanashe , Markey Bryan , Barry Gerald
Published: February 2021

We detected, for the first time, West Nile virus lineages 1 and 2 in Zimbabwe in mosquitoes and crocodile tissue samples, including fluid from egg waste. Our results provide evidence of WNV circulation in Zimbabwe, suggesting that an evaluation of the risk to humans and susceptible animals should be considered.
Rapid neural categorization of facelike objects predicts the perceptual awareness of a face (face pareidolia)
Authors: Rekow Diane , Baudouin Jean-Yves , Brochard Renaud , Rossion Bruno , Leleu Arnaud
Published: February 2021

The human brain rapidly and automatically categorizes facesvs. other visual objects. However, whether face-selective neural activity predicts the subjective experience of a face –perceptual awareness– is debated. To clarify this issue, here we useface pareidolia, i.e., the illusory perception of a face, as a proxy to relate the neural categorization of a variety of facelike objects to conscious face perception. In Experiment 1, scalp electroencephalogram (EEG) is recorded while pictures of human faces or facelike objects – in different stimulation sequences – are interleaved every second (i.e., at 1 Hz) in a rapid 6-Hz train of natural images of nonface objects. Participants do not perform any explicit face categorization task during stimulation, and report whether they perceived illusory faces post-stimulation. A robust categorization response to facelike objects is identified at 1 Hz and harmonics in the EEG frequency spectrum with a facelike occipito-temporal topography. Across all individuals, the facelike categorization response is of about 20% of the response to human faces, but more strongly right-lateralized. Critically, its amplitude is much larger in participants who report having perceived illusory faces. In Experiment 2, facelike or matched nonface objects from the same categories appear at 1 Hz in sequences of nonface objects presented at variable stimulation rates (60 Hz to 12 Hz) and participants explicitly report after each sequence whether they perceived illusory faces. The facelike categorization response already emerges at the shortest stimulus duration (i.e., 17 ms at 60 Hz) and predicts the behavioral report of conscious perception. Strikingly, neural facelike-selectivity emerges exclusively when participants report illusory faces. Collectively, these experiments characterize a neural signature of face pareidolia in the context of rapid categorization, supporting the view that face-selective brain activity reliably predicts the subjective experience of a face from a single glance at a variety of stimuli.

Highlights

- EEG frequency-tagging measures the rapid categorization of facelike objects

- Facelike objects elicit a facelike neural categorization response

- Neural face categorization predicts conscious face perception across variable inputs
A copper complex of an unusual hydroxy–carboxylate ligand: [Cu(bpy)(C4H4O6)]
Authors: Gao Sen , Fronczek Frank R. , Maverick Andrew W.
Published: February 2021

A copper(II) complex, (2,2′-bipyridine-κ2
N,N′)[2-hydroxy-2-(hydroxymethyl-κO)propanedioato-κ2
O
1,O
3]copper(II), [Cu(C4H4O6)(C10H8N2)], containing the unusual anionic chelating ligand 2-(hydroxymethyl)tartronate, has been synthesized. [Cu(bpy)2(NO3)](NO3) was mixed with ascorbic acid and Dabco (1,4-diazabicyclo[2.2.2]octane) in DMF (dimethylformamide) solution in the presence of air to produce the title compound. The structure consists of square-pyramidal complexes that are joined by Cu...O contacts [2.703 (2) Å] into centrosymmetric dimers. The C4H4O6
2− ligand, which occupies three coordination sites at Cu, has previously been identified as an oxidation product of ascorbate ion.
Comparison of toll and annuity PPPs: a case study of highway projects in India
Authors: Mangu Samhita , Annamalai Thillai Rajan , Deep Akash
Published: February 2021

Purpose

The use of public–private partnership (PPP) approaches for developing infrastructure has been well recognized. The allocation of risk between public authority and private sector differs among the different types of PPP projects. The objective of the paper is to analyze the factors that influence the type of PPP and the performance of different types of PPP contracts.

Design/methodology/approach

A unique data set of 202 national highway PPP projects from India, comprising 154 toll and 48 annuity projects formed the basis of the study.

Findings

There are significant differences between toll and annuity PPP projects. The former are longer, are implemented in better developed states but are also characterized by higher cost over-runs. The latter are characterized by higher debt–equity ratio.

Practical implications

Mitigating revenue risk can significantly enhance the debt capacity of the projects, thereby reducing the overall cost of capital. To make toll roads attractive for bidders, they have to be developed as longer stretches. Toll projects that are immediately ready for development at the time of award would reduce cost overruns of toll projects and sustain the interest of private developers.

Originality/value

Comparison of toll and annuity PPP road projects has never been done previously. The unique data set used in this study highlights the differences in characterization and performance for both the project types. The study provides evidence support to “intuition” and enables policymakers to choose the right form of PPP to realize their objectives.
Prediction of SLS parts properties using reprocessing powder
Authors: Lopes Ana C. , Sampaio Álvaro M. , Silva Cátia S. , Pontes António J.
Published: February 2021

Purpose

Owing to the operating principle of powder bed fusion processes, selective laser sintering (SLS) requires effective management of the mixture ratio of processed material previously exposed to the high temperatures of processing with new virgin material. Therefore, this paper aims to fully understand the effect that the successive reprocessing has in the powder material and to evaluate its influence on the properties of SLS parts produced at different building orientations.

Design/methodology/approach

Polyamide 12 material with 0%, 30% and 50% of virgin powder and parts produced from them were studied through five consecutive building cycles and their mass, mechanical, thermal and microstructural properties were evaluated. Then, the experimental data was used to validate a theoretical algorithm of prediction capable to define the minimum amount of virgin powder to be added on the processed material to produce parts without significant loss of properties.

Findings

Material degradation during SLS influences the mass and mechanical properties of the parts, exhibiting an exponential decay property loss until 50% of the initial values. The theoretical algorithms of reprocessing proved the appropriateness to use a mixture of 30% of virgin with 70% of processed material for the most common purposes.

Practical implications

This paper validates a methodology to define the minimum amount of virgin material capable to fulfil the operational specifications of SLS parts as a function of the number of building cycles, depending on the requirements of the final application.

Originality/value

The use of theoretical models of prediction allows to describe the degradation effects of SLS materials during the sintering, ensuring the sustainable management of the processed powder and the economic viability of the process.
Commentary on “What are the experiences of professionals working with parents with learning disabilities? A meta-ethnography”
Authors: MacIntyre Gillian , Stewart Ailsa
Published: February 2021

Purpose

The purpose of this paper is to provide a commentary on Pytlowana and Stenfert Kroese’s article on the experiences of professionals working with parents with learning disabilities by exploring challenges and good practice in this area.

Design/methodology/approach

Key areas of practice were identified for further exploration by drawing on research studies with parents with learning disabilities.

Findings

While there is growing evidence of good practice around working with parents with learning disabilities, a number of challenges around communication and relationship-based practice remain. The paper recommends further training and education for those working in this complex area of practice.

Originality/value

The paper adds value by bringing together evidence from across a number of studies to highlight good practice.
Early head‐to‐pelvis computed tomography in out‐of‐hospital circulatory arrest without obvious etiology
Authors: Branch Kelley R. H. , Strote Jared , Gunn Martin , Maynard Charles , Kudenchuk Peter J. , Brusen Robin , Petek Bradley J. , Sayre Michael R. , Edwards Rachael , Carlbom David , Counts Catherine R. , Probstfield Jeffrey L. , Gatewood Medley O.
Published: February 2021

Objectives

Patients resuscitated from an out‐of‐hospital circulatory arrest (OHCA) commonly present without an obvious etiology. We assessed the diagnostic capability and safety of early head‐to‐pelvis computed tomography (CT) imaging in such patients.

Methods

From November 2015 to February 2018, we enrolled 104 patients resuscitated from OHCA without obvious cause (idiopathic OHCA) to an early sudden‐death CT (SDCT) scan protocol within 6 h of hospital arrival. The SDCT protocol included a noncontrast CT head, an electrocardiogram‐gated cardiac and thoracic CT angiogram, and a nongated venous‐phase abdominopelvic CT angiogram. Patients needing urgent cardiac catheterization or hemodynamically unable to tolerate SDCT were excluded. Cardiac CT analyses were blinded, but other SDCT findings were clinically available. Primary endpoints were the number of OHCA causes identified by SDCT compared to the adjudicated cause and critical diagnoses identified by SDCT, including resuscitation complications. Safety endpoints were acute kidney injury (AKI) and inappropriate treatments based on SDCT findings. Acute coronary syndrome was the presumed etiology if any major coronary artery had a >50% stenosis without another OHCA cause.

Results

SDCT scans occurred within 1.9 ± 1.0 h of hospital arrival and identified 39% (41/104) of all OHCA causes and 95% (39/41) of causes potentially identifiable by SDCT. Critical findings were identified by SDCT in 98% (43/44) of patients that included potentially life‐threatening resuscitation complications of liver or spleen laceration (n = 6); pneumothorax or thoracic organ laceration (n = 8); and mediastinal, pericardial, or vascular hemorrhage (n = 3). SDCT exclusively identified 13 (13%) OHCA causes that would otherwise not be identified without SDCT imaging. No inappropriate treatments resulted from SDCT findings. AKI was common (28%) but only one (1%) patient required new dialysis.

Conclusions

This observational cohort study suggests that early SDCT scanning is safe, can expedite the diagnosis of potential causes, and can meaningfully change clinical management after idiopathic OHCA.
Boundary management and accounting visibility in social services: a case study
Authors: Alam Manzurul , Hoque Zahirul
Published: February 2021

This paper examines how accounting systems are disseminated in different ways as organisations seek to use accounting information to manage social services across organisational boundaries. Drawing upon qualitative field research within a New Zealand community‐care provider and using the literature on bounded management and accounting visibility, our findings reveal that the government's increasing screening and monitoring of social support services create an extra burden on carers and families. We reflect on how internal accounting practices only capture the visible costs endured by government‐funded programmes, ignoring a significant part of disability care costs incurred by family members and other carers.
A case of lymphangioma circumscriptum with new reflectance confocal microscopy findings
Authors: Karaarslan Isil , Oraloglu Gokturk , Yaman Banu
Published: February 2021

In vivo reflectance confocal microscopy (RCM) findings of lymphangiomas have been scarcely reported. We report a lymphangioma circumscriptum (LC) with some new observations.
Short‐term repeatability of the peguero‐lo presti electrocardiographic left ventricular hypertrophy criteria
Authors: Drager Dominique , Soliman Elsayed Z. , Meyer Michelle L. , Zhang Zhu‐Ming , Alonso Alvaro , Heiss Gerardo , Whitsel Eric A.
Published: February 2021

Background

Electrocardiographic left ventricular hypertrophy (ECG‐LVH) represents preclinical cardiovascular disease and predicts cardiovascular disease morbidity and mortality. While the newly developed Peguero‐Lo Presti ECG‐LVH criteria have greater sensitivity for LVH than the Cornell voltage and Sokolow–Lyon criteria, its short‐term repeatability is unknown. Therefore, we characterized the short‐term repeatability of Peguero‐Lo Presti ECG‐LVH criteria and evaluate its agreement with Cornell voltage and Sokolow–Lyon ECG‐LVH criteria.

Methods

Participants underwent two resting, standard, 12‐lead ECGs at each of two visits one week apart (n = 63). We defined a Peguero‐Lo Presti index as a sum of the deepest S wave amplitude in any single lead and lead V4 (i.e., SD + SV4) and defined Peguero‐Lo Presti LVH index as ≥ 2,300 µV among women and ≥ 2,800 µV among men. We estimated repeatability as an intraclass correlation coefficient (ICC), agreement as a prevalence‐adjusted bias‐adjusted kappa coefficient (κ), and precision using 95% confidence intervals (CIs).

Results

The Peguero‐Lo Presti index was repeatable: ICC (95% CI) = 0.94 (0.91–0.97). Within‐visit agreement of Peguero‐Lo Presti LVH was high at the first and second visits: κ (95% CI) = 0.97 (0.91–1.00) and 1.00 (1.00–1.00). Between‐visit agreement of the first and second measurements at each visit was comparable: κ (95% CI) = 0.90 (0.80–1.00) and 0.93 (0.85–1.00). Agreement of Peguero‐Lo Presti and Cornell or Sokolow–Lyon LVH on any one of the four ECGs was slightly lower: κ (95% CI) = 0.71 (0.54–0.89).

Conclusion

The Peguero‐Lo Presti index and LVH have excellent repeatability and agreement, which support their use in clinical and epidemiological studies.
Predicting distant metastatic disease in differentiated thyroid cancer: a matchedcase–controlstudy
Authors: Jaffar Sukaina , Jayasekara Jayani , Aniss Ahmad M. , Tsang Venessa H. M. , Learoyd Diana L. , Clifton‐Bligh Roderick , Gill Anthony J. , Glover Anothony R. , Sidhu Stan B. , Robinson Bruce , Sywak Mark
Published: February 2021

Background

The occurrence of distant metastasis (DM) is the most important prognostic factor influencing survival outcomes in differentiated thyroid cancer (DTC). Identifying patients who are likely to develop DM and offering these cases more aggressive surgical approaches and I‐131 therapy, is paramount to achieving the best possible outcomes. DM on presentation in DTC are uncommon, with an incidence of 1–9%. However, the incidence of DTC is rising and the disease affects a relatively young cohort of patients. The aims of this study were to investigate predictive factors in the development of DM by comparing a homogenous group of DTC patients with and without DM, and to illustrate the overall and disease‐specific survival (DSS) rates of DTC patients presenting with DM.

Methods

A matched case–control study of patients with DTC and DM was undertaken. The study group comprised a consecutive series of cases with DM treated in the period 1968–2014. Patients with DM at initial presentation were identified (DTC‐DM group). A control group of patients without DM were matched based on age, gender, tumour size and histological subtype. The primary outcome measures were overall and disease‐free survival. Secondary outcome measures were lymph node involvement (LNI), extra‐thyroidal extension (ETE) of tumour and presence of BRAFV600E mutation identified on immunohistochemistry.

Results

A total of 2547 patients with DTC were reviewed and of these 83 (3.26%) had DM at initial presentation. At 5 and 10 years, the overall survival rates for DTC‐DM patients were 89.6% and 64%, respectively. The 5 and 10 year DSS rates for DTC‐DM cases were 90.2% and 67.3%, respectively. When compared to the DTC group, the DTC‐DM group had significantly higher rates of ETE (63% vs. 29.5%,P< 0.0001) and LNI (32.5% vs. 18.8%,P= 0.044). Among patients with papillary thyroid cancer (PTC), the presence of BRAFV600E mutation was significantly associated with DM (62.2% vs. 36.8%,P= 0.028).

Conclusion

ETE, LNI and BRAFV600E mutation in PTC are significant predictors for the development of distant metastatic disease.
Dexamethasone use and mortality in hospitalized patients with coronavirus disease 2019: A multicentre retrospective observational study
Authors: Hoertel Nicolas , Sánchez‐Rico Marina , Vernet Raphaël , Beeker Nathanaël , Neuraz Antoine , Alvarado Jesús M. , Daniel Christel , Paris Nicolas , Gramfort Alexandre , Lemaitre Guillaume , Salamanca Elisa , Bernaux Mélodie , Bellamine Ali , Burgun Anita , Limosin Frédéric ,   AP‐HP/Université de Paris/INSERM Covid‐19 research collaboration and AP‐HP Covid CDR Initiative
Published: February 2021

Aims

To examine the association between dexamethasone use and mortality among patients hospitalized for COVID‐19.

Methods

We examined the association between dexamethasone use and mortality at AP‐HP Greater Paris University hospitals. Study baseline was defined as the date of hospital admission. The primary endpoint was time to death. We compared this endpoint between patients who received dexamethasone and those who did not in time‐to‐event analyses adjusted for patient characteristics (such as age, sex and comorbidity) and clinical and biological markers of clinical severity of COVID‐19, and stratified by the need for respiratory support, i.e. mechanical ventilation or oxygen. The primary analysis was a multivariable Cox regression model.

Results

Of 12 217 adult patients hospitalized with a positive COVID‐19 reverse transcriptase–polymerase chain reaction test, 171 (1.4%) received dexamethasone orally or by intravenous perfusion during the visit. Among patients who required respiratory support, the end‐point occurred in 10/63 (15.9%) patients who received dexamethasone and 298/1129 (26.4%) patients who did not. In this group, there was a significant association between dexamethasone use and reduced mortality in the primary analysis (hazard ratio, 0.46; 95% confidence interval 0.22–0.96, P = .039). Among patients who did not require respiratory support, there was no significant association between dexamethasone use and the endpoint.

Conclusions

In this multicentre observational study, dexamethasone use administered either orally or by intravenous injection at a cumulative dose between 60 mg and 150 mg was associated with reduced mortality among patients with COVID‐19 requiring respiratory support.
Radioimmunotherapy with an 211At‐labeled anti–tissue factor antibody protected by sodium ascorbate
Authors: Takashima Hiroki , Koga Yoshikatsu , Manabe Shino , Ohnuki Kazunobu , Tsumura Ryo , Anzai Takahiro , Iwata Nozomi , Wang Yang , Yokokita Takuya , Komori Yukiko , Mori Daiki , Usuda Sachiko , Haba Hiromitsu , Fujii Hirofumi , Matsumura Yasuhiro , Yasunaga Masahiro
Published: February 2021

Tissue factor (TF), the trigger protein of the extrinsic blood coagulation cascade, is abundantly expressed in various cancers including gastric cancer. Anti‐TF monoclonal antibodies (mAbs) capable of targeting cancers have been successfully applied to armed antibodies such as antibody‐drug conjugates (ADCs) and molecular imaging probes. We prepared an anti‐TF mAb, clone 1084, labeled with astatine‐211 (211At), as a promising alpha emitter for cancer treatment. Alpha particles are characterized by high linear energy transfer and a range of 50‐100 µm in tissue. Therefore, selective and efficient tumor accumulation of alpha emitters results in potent antitumor activities against cancer cells with minor effects on normal cells adjacent to the tumor. Although the 211At‐conjugated clone 1084 (211At‐anti‐TF mAb) was disrupted by an 211At‐induced radiochemical reaction, we demonstrated that astatinated anti‐TF mAbs eluted in 0.6% or 1.2% sodium ascorbate (SA) solution were protected from antibody denaturation, which contributed to the maintenance of cellular binding activities and cytocidal effects of this immunoconjugate. Although body weight loss was observed in mice administered a 1.2% SA solution, the loss was transient and the radioprotectant seemed to be tolerable in vivo. In a high TF–expressing gastric cancer xenograft model, 211At‐anti‐TF mAb in 1.2% SA exerted a significantly greater antitumor effect than nonprotected 211At‐anti‐TF mAb. Moreover, the antitumor activities of the protected immunoconjugate in gastric cancer xenograft models were dependent on the level of TF in cancer cells. These findings suggest the clinical availability of the radioprotectant and applicability of clone 1084 to 211At‐radioimmunotherapy.
Multipanel assay of 17 tumor‐associated antibodies for serological detection of stage 0/I breast cancer
Authors: Sumazaki Makoto , Ogata Hideaki , Nabeya Yoshihiro , Kuwajima Akiko , Hiwasa Takaki , Shimada Hideaki
Published: February 2021

Because the production of tumor‐associated antibodies (TAA) is a humoral immune response in cancer patients, serum autoantibodies may be detected even in patients with early‐stage tumors. Seventeen recombinant proteins with tags in Escherichia coli (p53, RalA, p90, NY‐ESO‐1, HSP70, c‐myc, galectin‐1, Sui1, KN‐HN‐1, HSP40, PrxVI, p62, cyclin B1, HCC‐22‐5, annexin II, HCA25a, and HER2) were applied as capturing antigens in sandwich ELISA to measure serum IgG levels. Sera from 73 healthy donors and 386 patients with breast cancer, including 182 stage 0/I patients, were evaluated using cutoff values for each TAA equal to the mean +3 SD of the serum levels of healthy controls. The positive TAA rates were relatively high for p53 (10%) and RalA (10%). The positive rates of all TAA of stage 0/I were similar to those of all patients. Even in the stage 0/I patients, 24% showed that two or more TAA were positive, and the positive rate of a five‐TAA combination assay was 37%. The positivity rate was significantly higher for the non–luminal type than for the luminal type (P = .003). Logistic analysis showed that seropositivity (positive for one or more TAA) in breast cancer patients was independent from any TNM factor or disease stage and was significantly associated with histological grade in the multivariate analysis (P = .007). TAA in breast cancer patients may be useful for early detection. However, seropositivity of breast cancer reflects the tumor characteristics but not the disease stage.
Single‐center utilization of donor‐derived cell‐free DNA testing in the management of heart transplant patients
Authors: Gondi Keerthi T. , Kao Andrew , Linard Jodie , Austin Bethany A. , Everley Mark P. , Fendler Timothy J. , Khumri Taiyeb , Lawhorn Stephanie L. , Magalski Anthony , Nassif Michael E. , Sperry Brett W. , Vodnala Deepthi , Borkon A. Michael
Published: February 2021

Background

Gene expression profiling (GEP) and donor‐derived cell‐free DNA (dd‐cfDNA) are useful in acute rejection (AR) surveillance in orthotopic heart transplant (OHT) patients. We report a single‐center experience of combined GEP and dd‐cfDNA testing for AR surveillance.

Methods

GEP and dd‐cfDNA are tested together starting at 2 months post‐OHT. After 6 months, combined testing was obtained before scheduled endomyocardial biopsy (EMB), and EMB was canceled with a negative dd‐cfDNA. This approach was compared to using a GEP‐only approach, where EMB was canceled with a negative GEP. We evaluated for frequency of EMB cancellation with dd‐cfDNA usage.

Results

A total of 153 OHT patients over a 13‐month period underwent 495 combined GEP/dd‐cfDNA tests. 82.2% of dd‐cfDNA tests were below threshold. Above threshold results identified high‐risk patients who developed AR. 378 combined tests ≥6 months post‐OHT resulted in cancellation of 83.9% EMBs as opposed to 71.2% with GEP surveillance alone. There were 2 acute cellular and 2 antibody‐mediated rejection episodes, and no significant AR ≥6 months.

Conclusion

Routine dd‐cfDNA testing alongside GEP testing yielded a significant reduction in EMB volume by re‐classifying GEP (+) patients into a lower risk group, without reduction in AR detection. The addition of dd‐cfDNA identified patients at higher risk for AR.
Virtual screening FDA approved drugs against multiple targets of SARS‐CoV‐2
Authors: Liang Hualou , Zhao Liang , Gong Xiajing , Hu Meng , Wang Hongbin
Published: February 2021

The outbreak of the novel coronavirus severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2), the causative agent of coronavirus disease 2019 (COVID‐19) respiratory disease, led to a global pandemic with high morbidity and mortality. Despite frenzied efforts in therapeutic development, there are currently no effective drugs for treatment, nor are there vaccines for its prevention. Drug repurposing, representing as an effective drug discovery strategy from existing drugs, is one of the most practical treatment options against the outbreak. In this study, we present a novel strategy for in silico molecular modeling screening for potential drugs that may interact with multiple main proteins of SARS‐CoV‐2. Targeting multiple viral proteins is a novel drug discovery concept in that it enables the potential drugs to act on different stages of the virus’ life cycle, thereby potentially maximizing the drug potency. We screened 2631 US Food and Drug Administration (FDA)‐approved small molecules against 4 key proteins of SARS‐CoV‐2 that are known as attractive targets for antiviral drug development. In total, we identified 29 drugs that could actively interact with 2 or more target proteins, with 5 drugs (avapritinib, bictegravir, ziprasidone, capmatinib, and pexidartinib) being common candidates for all 4 key host proteins and 3 of them possessing the desirable molecular properties. By overlaying docked positions of drug candidates onto individual host proteins, it has been further confirmed that the binding site conformations are conserved. The drugs identified in our screening provide potential guidance for experimental confirmation, such as in vitro molecular assays and in vivo animal testing, as well as incorporation into ongoing clinical studies.
Pre‐operative diagnosis of a Brunner's gland hamartoma by endoscopic ultrasound‐guided fine needle aspiration
Authors: Cotton James , Bavi Prashant , Ghorab Zeina , James Paul , Stefano Serra , Schwock Joerg , Ko Hyang Mi
Published: February 2021

This case describes characteristic golden‐yellow mucin in Brunner’s gland hamartoma diagnosed by EUS‐FNA pre‐operatively and demonstrates the value of immunohistochemical mucin profiles in supporting the diagnosis.
Heterogeneous long‐term trajectories of glycaemic control in type 1 diabetes
Authors: Miller Rachel G. , Orchard Trevor J. , Onengut‐Gumuscu Suna , Chen Wei‐Min , Rich Stephen S. , Costacou Tina
Published: February 2021

Aims

We aimed to identify long‐term HbA1c trajectories and examine associated characteristics in an observational, childhood‐onset (<17 years) type 1 diabetes cohort.

Methods

Data are from the Epidemiology of Diabetes Complications study, comprising 405 participants with ≥2 of seven possible HbA1c measurements over follow‐up (1988–2013) and available DNA (baseline mean diabetes duration 21 years, 53% men). HbA1c trajectories were estimated using latent class growth models. Baseline and change in participant characteristics were compared across trajectories.

Results

Five HbA1c trajectories were identified: low (51%), intermediate stable (22%), improved (19%), high stable (6%), and worsened (2%; not included in analyses). Age, diabetes duration, diabetes onset age, and sex did not differ across trajectories. Characteristics did not differ significantly between intermediate stable and low trajectories at baseline, though albumin excretion rate (AER, p = 0.0002) and estimated glomerular filtration rate (eGFR, p = 0.001) worsened slightly more in intermediate stable over time. Improved and high stable trajectories had higher baseline LDL‐c (p = 0.002 and 0.003, respectively). Improved trajectory increased median self‐monitoring of blood glucose from <1 to 3.5 times/day (p < 0.0001) and had larger LDL‐c improvement (p = 0.004) but greater worsening of AER (p < 0.0001) and eGFR (p < 0.0001) than low. The A allele of rs12970134 (near MC4R) was associated with improved (p = 0.0003) or high stable (p = 0.001) HbA1c trajectory, both patterns with high baseline HbA1c.

Conclusions

Long‐term HbA1c trajectories were primarily associated with modifiable factors in this type 1 diabetes cohort. The intermediate stable pattern had a risk factor profile that suggests some protection against adverse metabolic effects of chronic hyperglycaemia, warranting further study.