bluuebunny/crossref_metadata_2025 huggingface dataset:
Cyclin F drives proliferation through SCF-dependent degradation of the retinoblastoma-like tumor suppressor p130/RBL2
Authors: Enrico Taylor P. , Stallaert Wayne , Wick Elizaveta T. , Ngoi Peter , Rubin Seth M. , Brown Nicholas G. , Purvis Jeremy E. , Emanuele Michael J.
Published: April 2021

Cell cycle gene expression programs fuel proliferation and are dysregulated in many cancers. The retinoblastoma-family proteins, RB, p130/RBL2 and p107/RBL1, coordinately repress cell cycle gene expression, inhibiting proliferation and suppressing tumorigenesis. Ubiquitin-dependent protein degradation is essential to cell cycle control, and numerous proliferative regulators, tumor suppressors, and oncoproteins are ubiquitinated. However, little is known about the role of ubiquitin signaling in controlling RB-family proteins. A systems genetics analysis of several hundred CRISPR/Cas9 loss-of-function screens suggested the potential regulation of the RB-network by cyclin F, a substrate recognition receptor for the SCF family of E3 ligases. We demonstrate that RBL2/p130 is a direct substrate of SCFcyclin F. We map a cyclin F regulatory site to a flexible linker in the p130 pocket domain, and show that this site mediates binding, stability, and ubiquitination. Expression of a non-degradable p130 represses cell cycle gene expression and strongly reduces proliferation. These data suggest that SCFcyclin Fplays a key role in the CDK-RB network and raises the possibility that aberrant p130 degradation could dysregulate the cell cycle in human cancers.
Updates to data versions and analytic methods influence the reproducibility of results from epigenome-wide association studies
Authors: Lussier Alexandre A. , Zhu Yiwen , Smith Brooke J. , Simpkin Andrew J. , Smith Andrew D.A.C. , Suderman Matthew J. , Walton Esther , Ressler Kerry J. , Dunn Erin C.
Published: April 2021

Introduction

Biomedical research has grown increasingly cooperative, with several large consortia compiling and sharing epigenomic data. Since data are typically preprocessed by consortia prior to distribution, the implementation of new pipelines can lead to different versions of the same dataset. Analytic frameworks also constantly evolve to incorporate cutting-edge methods and shifting best practices. However, it remains unknown how differences in data and analytic versions alter the results of epigenome-wide analyses, which has broad implications for the replicability of epigenetic associations. Thus, we assessed the impact of these changes using a subsample of the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort.

Methods

We analyzed two versions of DNA methylation data, processed using separate preprocessing and analytic pipelines, to examine associations between childhood adversity and prenatal smoking exposure on DNA methylation at age 7. We performed two sets of analyses: (1) epigenome-wide association studies (EWAS); (2) Structured Life Course Modeling Approach (SLCMA), a two-stage method that models time-dependent effects. We also compared results from the SLCMA using more recent methodological recommendations.

Results

Differences between ALSPAC data versions impacted both EWAS and SLCMA analyses, yielding different sets of associations at conventional p-value thresholds. However, the magnitude and direction of associations was generally consistent between data versions, regardless of significance thresholds. Updating the SLCMA analytic version similarly altered top associations, but time-dependent effects remained concordant.

Conclusions

Changes to data and analytic versions influenced the results of epigenome-wide studies, particularly when using p-value thresholds as reference points for successful replication and stability.
The Great Deceiver: miR-2392’s Hidden Role in Driving SARS-CoV-2 Infection
Authors: McDonald J. Tyson , Enguita Francisco Javier , Taylor Deanne , Griffin Robert J. , Priebe Waldemar , Emmett Mark R. , Sajadi Mohammad M. , Harris Anthony D. , Clement Jean , Dybas Joseph M. , Aykin-Burns Nukhet , Guarnieri Joseph W. , Singh Larry N. , Grabham Peter , Baylin Stephen B. , Yousey Aliza , Pearson Andrea N. , Corry Peter M. , Saravia-Butler Amanda , Aunins Thomas R. , Sharma Sadhana , Nagpal Prashant , Meydan Cem , Foox Jonathan , Mozsary Christopher , Cerqueira Bianca , Zaksas Viktorija , Singh Urminder , Wurtele Eve Syrkin , Costes Sylvain V. , Davanzo Gustavo Gastão , Galeano Diego , Paccanaro Alberto , Meinig Suzanne L. , Hagan Robert S. , Bowman Natalie M ,   UNC COVID-19 Pathobiology Consortium, Wolfgang Matthew C. , Altinok Selin , Sapoval Nicolae , Treangen Todd J. , Moraes-Vieira Pedro M. , Vanderburg Charles , Wallace Douglas C. , Schisler Jonathan , Mason Christopher E. , Chatterjee Anushree , Meller Robert , Beheshti Afshin
Published: April 2021

MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provides an exciting avenue towards antiviral therapeutics. From patient transcriptomic data, we have discovered a circulating miRNA, miR-2392, that is directly involved with SARS-CoV-2 machinery during host infection. Specifically, we show that miR-2392 is key in driving downstream suppression of mitochondrial gene expression, increasing inflammation, glycolysis, and hypoxia as well as promoting many symptoms associated with COVID-19 infection. We demonstrate miR-2392 is present in the blood and urine of COVID-19 positive patients, but not detected in COVID-19 negative patients. These findings indicate the potential for developing a novel, minimally invasive, COVID-19 detection method. Lastly, usingin vitrohuman andin vivohamster models, we have developed a novel miRNA-based antiviral therapeutic that targets miR-2392, significantly reduces SARS-CoV-2 viability in hamsters and may potentially inhibit a COVID-19 disease state in humans.
Limiting factors for queen conch (Lobatus gigas) reproduction: A simulation-based evaluation
Authors: Farmer Nicholas A. , Doerr Jennifer C.
Published: April 2021

Queen conch are among the most economically, socially, and culturally important fishery resources in the Caribbean. Despite a multitude of fisheries management measures enacted across the region, populations are depleted and failing to recover. It is believed that queen conch are highly susceptible to depensatory processes, impacting reproductive success and contributing to the lack of recovery. We developed a model of reproductive dynamics to evaluate how variations in biological factors such as population density, movement speeds, movement restrictions, rest periods between mating events, sexual facilitation, and perception of conspecifics affect reproductive success and overall reproductive output. We compared simulation results to empirical observations of mating and spawning frequencies from conch populations in the central Bahamas and Florida Keys. Our results confirm that low probability of mate finding associated with decreased population density is the primary driver behind observed breeding behavior in the field, although additional factors also play important roles. In particular, sexual facilitation and perception of conspecifics may explain observed lack of mating at low densities and differences between mating frequencies in the central Bahamas and Florida Keys, respectively. Our simulations suggest densities greater than 200 adults/ha are needed for high levels of spawning output, supporting the suggestion that effective management strategies for queen conch should aim to protect high-density reproductive aggregations and critical breeding habitats.
Small Extracellular Vesicles Secreted by Region-specific Astrocytes Ameliorate the Mitochondrial Function in a Cellular Model of Parkinson’s Disease
Authors: Leggio Loredana , L’Episcopo Francesca , Magrì Andrea , Ulloa-Navas María José , Paternò Greta , Vivarelli Silvia , Bastos Carlos A. P. , Tirolo Cataldo , Testa Nunzio , Caniglia Salvatore , Risiglione Pierpaolo , Pappalardo Fabrizio , Faria Nuno , Peruzzotti-Jametti Luca , Pluchino Stefano , García-Verdugo José Manuel , Messina Angela , Marchetti Bianca , Iraci Nunzio
Published: April 2021

Extracellular vesicles (EVs) are emerging as powerful players in cell-to-cell communication both in health and diseased brain. In Parkinson’s disease (PD) – characterized by selective dopaminergic (DAergic) neuron death in ventral midbrain (VMB) and degeneration of DAergic terminals in striatum (STR) – astrocytes (AS) exert dual harmful/protective functions. When activated by chemokine CCL3, AS promote a robust DAergic neuroprotection both in cellular and pre-clinical models of PD, with mechanisms not fully elucidated. Here we used a combination of techniques to characterize AS-EVs derived from VMB and STR, and investigated their potential to exert neuroprotection. First, we show that: (i) AS of both regions secrete small EVs of ~100 nm; (ii) VMB-AS release more EVs per cell than STR-AS under basal conditions; and (iii) only VMB-AS respond to CCL3 by producing more EVs, suggesting differential AS-EV secretion rate according to PD brain region. Next, addressing AS-EV potential against oxidative stress and mitochondrial toxicity, we found that AS-EVs, especially CCL3-AS-EVs, fully counteract H2O2-induced caspase-3 activation. Furthermore, using high resolution respirometry, we demonstrated that AS-EVs rescue the neuronal mitochondrial complex I function impaired by MPP+, with VMB-AS-EVs fully restoring ATP production in MPP+-injured neurons, highlighting a regional diversity of AS-EVs with neuroprotective implications for PD.
Jasmonate inhibits adventitious root initiation through transcriptional repression ofCKX1and activation ofRAP2.6Ltranscription factor in Arabidopsis
Authors: Dob Asma , Lakehal Abdellah , Novak Ondrej , Bellini Catherine
Published: April 2021

Adventitious rooting is ade novoorganogenesis process that enables plants to propagate clonally and cope with environmental stresses. Adventitious root initiation (ARI) is controlled by interconnected transcriptional and hormonal networks, but there is little knowledge of the genetic and molecular programs orchestrating these networks. Thus, we have applied genome-wide transcriptome profiling to elucidate the profound transcriptional reprogramming events preceding ARI. These reprogramming events are associated with downregulation of cytokinin (CK) signaling and response genes, which could be triggers for ARI. Interestingly, we found that CK free-base content declined during ARI, due to downregulation ofde novoCK biosynthesis and upregulation of CK inactivation pathways. We also found that MYC2-dependent jasmonate (JA) signaling inhibits ARI by downregulating expression of theCYTOKININ OXIDASE/DEHYDROGENASE1gene. We also demonstrated that JA and CK synergistically activate expression ofRELATED to APETALA2.6 LIKE(RAP2.6L) transcription factor, and constitutive expression of this transcription factor strongly inhibits ARI. Collectively, our findings reveal that previously unknown genetic interactions between JA and CK play key roles in ARI
Exquisite Sensitivity to Dual BRG1/BRM ATPase Inhibitors Reveals Broad SWI/SNF Dependencies in Acute Myeloid Leukemia
Authors: Rago Florencia , Rodrigues Lindsey Ulkus , Bonney Megan , Sprouffske Kathleen , Kurth Esther , Elliott GiNell , Ambrose Jessi , Aspesi Peter , Oborski Justin , Chen Julie T. , McDonald E. Robert , Mapa Felipa A , Ruddy David A. , Kauffmann Audrey , Abrams Tinya , Bhang Hyo-eun C. , Jagani Zainab
Published: April 2021

Various subunits of mammalian SWI/SNF chromatin remodeling complexes display loss-of-function mutations characteristic of tumor suppressors in different cancers, but an additional role for SWI/SNF supporting cell survival in distinct cancer contexts is emerging. In particular, genetic dependence on the catalytic subunit BRG1/SMARCA4 has been observed in acute myeloid leukemia (AML), yet the feasibility of direct therapeutic targeting of SWI/SNF catalytic activity in leukemia remains unknown. Here, we evaluated the activity of dual BRG1/BRM ATPase inhibitors across a genetically diverse panel of cancer cell lines and observed that hematopoietic cancer cell lines were among the most sensitive compared to other lineages. This result was striking in comparison to data from pooled short hairpin RNA screens, which showed that only a subset of leukemia cell lines display sensitivity to BRG1 knockdown. We demonstrate that combined genetic knockdown of BRG1 and BRM is required to recapitulate the effects of dual inhibitors, suggesting that SWI/SNF dependency in human leukemia extends beyond a predominantly BRG1-driven mechanism. Through gene expression and chromatin accessibility studies, we show that the dual inhibitors act at genomic loci associated with oncogenic transcription factors, and observe a downregulation of leukemic pathway genes includingMYC, a well-established target of BRG1 activity in AML. Overall, small molecule inhibition of BRG1/BRM induced common transcriptional responses across leukemia models resulting in a spectrum of cellular phenotypes. Our studies reveal the breadth of SWI/SNF dependency and support targeting SWI/SNF catalytic function as a potential therapeutic strategy in AML.
Annual dynamics ofZymoseptoria triticipopulations in wheat cultivar mixtures: a compromise between the efficiency and durability of a recently broken-down resistance gene?
Authors: Orellana-Torrejon Carolina , Vidal Tiphaine , Boixel Anne-Lise , Gélisse Sandrine , Saint-Jean Sébastien , Frédéric Suffert
Published: April 2021

Cultivar mixtures slow polycyclic epidemics but may also affect the evolution of pathogen populations by diversifying the selection pressures exerted by their plant hosts at field scale. We compared the dynamics of natural populations of the fungal pathogenZymoseptoria triticiin pure stands and in three binary mixtures of wheat cultivars (one susceptible cultivar and one cultivar carrying the recently broken-downStb16qgene) over two annual field epidemics. We combined analyses of population ‘size’ based on disease severity, and of population ‘composition’ based on changes in the frequency of virulence againstStb16qin seedling assays with more than 3000 strains. Disease reductions were observed in mixtures late in the epidemic, at the whole canopy scale and on both cultivars, suggesting the existence of a reciprocal ‘protective’ effect. The three cultivar proportions in the mixtures (0.25, 0.5 and 0.75) modulated the decrease in (i) the size of the pathogen population relative to the two pure stands, (ii) the size of the virulent subpopulation, and (iii) the frequency of virulence relative to the pure stand of the cultivar carryingStb16q. Our findings suggest that optimal proportions may differ slightly between the three indicators considered. We argued potential trade-offs that should be taken into account when deploying a resistance gene in cultivar mixtures: between the dual objectives ‘efficacy’ and ‘durability’, and between the ‘size’ and ‘frequency’ of the virulent subpopulation. Based on current knowledge, it remains unclear whether virulent subpopulation size or frequency has the largest influence on interepidemic virulence transmission.
A Computational and Biochemical Study of -1 Ribosomal Frameshifting in Human mRNAs
Authors: Zhou Xia , Huang Xiaolan , Du Zhihua
Published: April 2021

−1 programmed ribosomal frameshifting (−1 PRF) is a translational recoding mechanism used by many viral and cellular mRNAs. −1 PRF occurs at a heptanucleotide slippery sequence and is stimulated by a downstream RNA structure, most often in the form of a pseudoknot. The utilization of −1 PRF to produce proteins encoded by the −1 reading frame is wide-spread in RNA viruses, but relatively rare in cellular mRNAs. In human, only three such cases of −1 PRF events have been reported, all involving retroviral-like genes and protein products. To evaluate the extent of −1 PRF utilization in the human transcriptome, we have developed a computational scheme for identifying putative pseudoknot-dependent −1 PRF events and applied the method to a collection of 43,191 human mRNAs in the NCBI RefSeq database. In addition to the three reported cases, our study identified more than two dozen putative −1 PRF cases. The genes involved in these cases are genuine cellular genes without a viral origin. Moreover, in more than half of these cases, the frameshift site locates far upstream (>250 nt) from the stop codon of the 0 reading frame, which is nonviral-like. Using dual luciferase assays in HEK293T cells, we confirmed that the −1 PRF signals in the mRNAs of CDK5R2 and SEMA6C are functional in inducing efficient frameshifting. Our findings have significant implications in expanding the repertoire of the −1 PRF phenomenon and the protein-coding capacity of the human transcriptome.
Generalization of Cortical MOSTest Genome-Wide Associations Within and Across Samples
Authors: Loughnan Robert J. , Shadrin Alexey A. , Frei Oleksandr , van der Meer Dennis , Zhao Weiqi , Palmer Clare E. , Thompson Wesley K. , Makowski Carolina , Jernigan Terry L. , Andreassen Ole A. , Fan Chun Chieh , Dale Anders M.
Published: April 2021

Genome-Wide Association studies have typically been limited to single phenotypes, given that high dimensional phenotypes incur a large multiple comparisons burden: ~1 million tests across the genome times the number of phenotypes. Recent work demonstrates that a Multivariate Omnibus Statistic Test (MOSTest) is well powered to discover genomic effects distributed across multiple phenotypes. Applied to cortical brain MRI morphology measures, MOSTest has resulted in a drastic improvement in power to discover loci when compared to established approaches (min-P). One question that arises is how well these discovered loci replicate in independent data. Here we perform 10 times cross validation within 35,644 individuals from UK Biobank for imaging measures of cortical area, thickness and sulcal depth (>1,000 dimensionality for each). By deploying a replication method that aggregates discovered effects distributed across multiple phenotypes, termed PolyVertex Score (PVS), we demonstrate a higher replication yield and comparable replication rate of discovered loci for MOSTest (# replicated loci: 348-845, replication rate: 94-95%) in independent data when compared with the established min-P approach (# replicated loci: 31-68, replication rate: 65-80%). An out-of-sample replication of discovered loci was conducted with a sample of 8,336 individuals from the Adolescent Brain Cognitive Development®(ABCD) study, who are on average 50 years younger than UK Biobank individuals. We observe a higher replication yield and comparable replication rate of MOSTest compared to min-P. This finding underscores the importance of using well-powered multivariate techniques for both discovery and replication of high dimensional phenotypes in Genome-Wide Association studies.
An ancient clade ofPenelope-like retroelements with permuted domains is present in the green lineage and protists, and dominates many invertebrate genomes
Authors: Craig Rory J. , Yushenova Irina A. , Rodriguez Fernando , Arkhipova Irina R.
Published: April 2021

Penelope-like elements (PLEs) are an enigmatic clade of retroelements whose reverse transcriptases (RTs) share a most recent common ancestor with telomerase RTs. The single ORF of canonical EN+ PLEs encodes RT and a C-terminal GIY-YIG endonuclease (EN) that enables intrachromosomal integration, while EN–PLEs lack endonuclease and are generally restricted to chromosome termini. EN+ PLEs have only been found in animals, except for one case of horizontal transfer to conifers, while EN–PLEs occur in several kingdoms. Here we report a new, deep-branching PLE clade with a permuted domain order, whereby an N-terminal GIY-YIG endonuclease is linked to a C-terminal RT by a short domain with a characteristic Zn-finger-like motif. These N-terminal EN+ PLEs share a structural organization, including pseudo-LTRs and complex tandem/inverted insertions, with canonical EN+ PLEs fromPenelope/Poseidon,NeptuneandNematisclades, and show insertion bias for microsatellites, but lack hammerhead ribozyme motifs. However, their phylogenetic distribution is much broader. TheNaiadclade is found in numerous invertebrate phyla, where they can reach tens of thousands of copies per genome.Naiadsin spiders and clams independently evolved to encode selenoproteins.Chlamys, which lack the CCHH motif universal to PLE endonucleases, occur in green algae, spike mosses (targeting ribosomal DNA) and the slime moldPhysarum. Unlike canonical PLEs, RTs of N-terminal EN+ PLEs contain the insertion-in-fingers domain, strengthening the link between PLEs and telomerases. Additionally, we describeHydra, a novel metazoan C-terminal EN+ clade. Overall, we conclude that PLE diversity, distribution and abundance is comparable to non-LTR and LTR-retrotransposons.
Quorum sensing signals from epibiont mediate the induction of bioactive peptides in mat-forming cyanobacteriaNostoc
Authors: Saha Subhasish , Bulzu Paul-Adrian , Urajová Petra , Mareš Jan , Konert Grzegorz , Câmara Manoel João , Macho Markéta , Ewe Daniela , Hrouzek Pavel , Masojídek Jiří , Ghai Rohit , Saurav Kumar
Published: April 2021

The regulation of oligopeptides production is essential in understanding their ecological role in complex microbial communities including harmful cyanobacterial blooms. The role of chemical communication between the cyanobacterium and the microbial community harboured as epibionts within its phycosphere is at an initial stage of research and little is understood about its specificity. Herein, we present insight into the role of a bacterial epibiont in regulating production of cyanobacterial oligopeptides microviridins, well-known elastase inhibitors with presumed anti-grazing effects, in an ecologically important cyanobacterial genusNostoc. Heterologous expression and identification of specific signal molecules from the epibiont suggest the role of a quorum sensing-based interaction. Further, physiological experiments show an increase in microviridin production without affecting cyanobacterial growth and photosynthetic activity. Simultaneously, oligopeptides presenting a selective inhibition pattern provide support for their specific function in response to the presence of cohabitant epibionts. Thus, the chemical interaction revealed in our study provides an example of an interspecies signalling pathway monitoring the bacterial flora around the cyanobacterial filaments and induction of intrinsic species-specific metabolic responses.

IMPORTANCE

The regulation of cyanopeptide production beyond microcystin is essential to understand their ecological role in complex microbial communities, e.g. harmful cyanobacterial blooms. The role of chemical communication between the cyanobacterium and the epibionts within its phycosphere is at an initial stage of research and little is understood about its specificity. The frequency of cyanopeptide occurrence also demonstrates the need to understand the contribution of cyanobacterial peptides to the overall biological impact of cyanopeptides on aquatic organisms and vertebrates including humans. Our results shed light on the epibiont control of cyanopeptide production via quorum sensing mechanisms and we posit that such mechanisms may be widespread in natural cyanobacterial bloom community regulation.
Detection of porcine enteric viruses (Kobuvirus, Mamastrovirus and Sapelovirus) in domestic pigs in Corsica, France
Authors: Capai Lisandru , Piorkowski Géraldine , Maestrini Oscar , Casabianca François , Masse Shirley , de Lamballerie Xavier , Charrel Rémi N. , Falchi Alessandra
Published: April 2021

Many enteric viruses are found in pig farms around the world and can cause death of animals or important production losses for breeders. Among the wide spectrum of enteric viral species, porcine Sapelovirus (PSV), porcine Kobuvirus (PKoV) and porcine Astrovirus (PAstV) are frequently found in pig feces. In this study we investigated sixteen pig farms in Corsica, France, to evaluate the circulation of three enteric viruses (PKoV, PAstV-1 and PSV). In addition to the three viruses studied by RT–qPCR (908 pig feces samples), 26 stool samples were tested using the Next Generation Sequencing method (NGS). Our results showed viral RNA detection rates (i) of 62.0% [58.7–65.1] (n = 563/908) for PSV, (ii) of 44.8% [41.5–48.1] (n = 407/908) for PKoV and (iii) of 8.6% [6.8–10.6] (n = 78/908) for PAstV-1. Significant differences were observed for all three viruses according to age (P-value = 2.4e–13 for PAstV-1; 2.4e–12 for PKoV and 0.005 for PSV). The type of breeding was significantly associated with RNA detection only for PAstV-1 (P-value = 9.6e–6). Among the 26 samples tested with NGS method, consensus sequences corresponding to 10 different species of virus were obtained This study provides first insight on the presence of three common porcine enteric viruses in France. We also showed that they are frequently encountered in pigs born and bred in Corsica, which demonstrates endemic local circulation.

Importance

This study provides important information in the comprehension of the epidemiology of different viruses circulating in swine farms. We have shown the great diversity of viruses that could be present in extensive farms. Moreover, to our knowledge, this is the first detection of these different viruses in France. So far, this study has to be considered as a first step in the study of enteric viruses in Corsican pig farms.
Aspartate in the intestine: dual service as anaerobic electron acceptor and nitrogen source
Authors: Conway Tyrrell
Published: April 2021

Fumarate was previously known to serve as an anaerobic electron acceptor by E. coli when colonizing the mammalian intestine, but the source of that fumarate was elusive. In this issue, Unden and coworkers demonstrate that l‐aspartic acid is the source of fumarate that drives anaerobic respiration by colonized E. coli (Schubert et al., 2021). Moreover, Schubert et al., establish that E. coli is able to grow anaerobically by using aspartate as a sole source of nitrogen. These groundbreaking findings indicate that a single amino acid – aspartate – supports anaerobic respiration and acquisition of nitrogen by E. coli in the intestine.
Social status, political priorities and unequal representation
Authors: TRABER DENISE , HÄNNI MIRIAM , GIGER NATHALIE , BREUNIG CHRISTIAN
Published: April 2021

Researchers on inequalities in representation debate about whether governments represent the preferences of the rich better than those of less affluent citizens. We argue that problems of high‐ and low‐status citizens are treated differently already at the agenda‐setting stage. If affluent and less affluent citizens have different priorities about which issues should be tackled by government, then these divergent group priorities explain why government favours high‐ over low‐status citizens. Due to different levels of visibility, resources and social ties, governments pay more attention to what high‐status citizens consider important in their legislative agenda and pay less attention to the issues of low‐status citizens. We combined three types of data for our research design. First, we extracted the policy priorities (most important issues) for all status groups from Eurobarometer data between 2002 and 2016 for 10 European countries and matched this information with data on policy outcomes from the Comparative Agendas Project. We then strengthen our results using a focused comparison of three single country studies over longer time series. We show that a priority gap exists and has representational consequences. Our analysis has important implications for the understanding of the unequal representation of status groups as it sheds light on an important, yet so far unexplored, aspect of the political process. Since the misrepresentation of political agendas occurs at the very beginning of the policy‐making process, the consequences are potentially even more severe than for the unequal treatment of preferences.
Pediatric opioid fatalities: What can we learn for prevention?
Authors: Bishop‐Freeman Sandra C. , Young Kerry A. , Aurelius Michelle B. , Hudson Jason S.
Published: April 2021

The aim of this study was to highlight 19 cases investigated by the North Carolina Office of the Chief Medical Examiner over the last 12 years involving accidental or undetermined manner of death opioid ingestions leading to fatalities in young children. These pediatric ingestions have closely mirrored the opioid epidemic in adults transitioning from prescription medications to illicit drugs including fentanyl and fentanyl analogues. Unlike a typical adult ingestion for purposes of self‐harm or pleasure, poisonings in toddlers and infants are usually the result of curiosity, exploration, a decreased sense of danger, or imitation of adult or older sibling behavior. Eleven of the decedents were between the ages of 8 and 24 months. Among the cases were 12 prescription opioid exposure deaths and 7 illicit drug poisonings. A majority of the decedents were found unresponsive in an unkept home and/or in unsafe sleeping spaces with easy access to drugs or drug materials, which stresses the importance of safe pediatric sleeping conditions. After a complete pathological investigation, several of the cases had physical or scene evidence demonstrating that foil, plastic, or paper small enough to be ingested can contain enough potent opioid to cause death. Details from the toxicological investigation are included for each case to provide postmortem whole blood drug concentrations for forensic practitioners. Accidental pediatric poisonings are preventable. Risk reduction through improving awareness and education of the dangers of opioids is a key factor in mitigating these tragedies.
Unusual cutaneous presentation in a corrosive acid ingestion
Authors: Mittal Chaitanya , Gupta Vaibhav , Meshram Vikas P. , Kanchan Tanuj , Setia Puneet , Bharti Jyotsna Naresh , Sarangi Sujata , Malik Shaloo
Published: April 2021

Corrosive digestive tract injuries are considered to be a source of morbidity and mortality worldwide. The cases of acid ingestion in Forensic Medicine practice are not infrequent. Corrosive ingestion usually presents with injuries over the face, oropharynx, esophagus, and gastrointestinal tract. We report a case of a 65‐year‐old woman who was brought to the emergency department with a history of ingestion of toilet cleaner at her home. Following this, she developed blackish‐brown discoloration over the abdomen. The patient survived for less than one day. An autopsy confirmed the perforation of the stomach and small intestine. 500 ml of blackish fluid was present in the peritoneal cavity which resulted in corrosive peritonitis. The chemical examiner's report showed corrosive mixtures comprising sulfate, nitrate, and chloride ions in the peritoneal contents. This case report highlights atypical cutaneous presentation over the abdomen following corrosive acid ingestion, which has not been reported previously. The possible explanation for this cutaneous manifestation was corrosive effects of the underlying viscera due to its close proximation to the abdominal wall and presence of minimal intra‐abdominal fat. A direct physical connection between perforation and cutaneous findings was not identified. The case emphasizes the need for a comprehensive approach in managing such cases, analyzing ingested material, and following standard autopsy protocols in case of death.
Persistent and Transient Inefficiency of Australian States and Territories in Providing Public Hospital Services: An Application of Bayesian Stochastic Finite Mixture Frontier Analysis
Authors: Andrews Antony , Temoso Omphile , Kimpton Sean
Published: April 2021

Current literature on public hospital efficiency in Australia only reveals information on how efficient public hospitals are in the short run. The presence of persistent technical inefficiency arising from long‐term systemic problems and government‐related regulatory constraints does not appear to have been addressed. Using the aggregated hospital panel data for the period 2002–2018 on eight Australian states and territories, this study incorporates the measure of both transient and persistent technical inefficiency while controlling for unobserved heterogeneity to obtain a more precise measure of technical efficiency. This study’s findings estimate the national average transient efficiency to be 0.96. In contrast, the national average persistent efficiency is estimated to be 0.83. Further, Queensland (0.67), Victoria (0.66) and New South Wales (0.60) posted the lowest overall technical efficiency driven by the high level of persistent inefficiency. On the other hand, Northern Territory (0.96), Australian Capital Territory (0.95) and Tasmania (0.95) are the top performers. This study’s findings call on policy‐makers and regulators to disclose hospital‐level data to researchers to gain further insight into the causes of persistence in inefficiency, especially among bigger states, which will help formulate more targeted policy interventions.
Infectious disease phylodynamics with occurrence data
Authors: Featherstone Leo A. , Di Giallonardo Francesca , Holmes Edward C. , Vaughan Timothy G. , Duchêne Sebastián
Published: April 2021

Phylodynamic models use pathogen genome sequence data to infer epidemiological dynamics. With the increasing genomic surveillance of pathogens, especially during the SARS‐CoV‐2 pandemic, new practical questions about their use are emerging.

One such question focuses on the inclusion of un‐sequenced case occurrence data alongside sequenced data to improve phylodynamic analyses. This approach can be particularly valuable if sequencing efforts vary over time.

Using simulations, we demonstrate that birth–death phylodynamic models can employ occurrence data to eliminate bias in estimates of the basic reproductive number due to misspecification of the sampling process. In contrast, the coalescent exponential model is robust to such sampling biases, but in the absence of a sampling model it cannot exploit occurrence data. Subsequent analysis of the SARS‐CoV‐2 epidemic in the northwest USA supports these results.

We conclude that occurrence data are a valuable source of information in combination with birth–death models. These data should be used to bolster phylodynamic analyses of infectious diseases and other rapidly spreading species in the future.
Severe mental illness is associated with increased mortality and severe course of COVID‐19
Authors: Barcella Carlo Alberto , Polcwiartek Christoffer , Mohr Grimur Høgnason , Hodges Gethin , Søndergaard Kathrine , Niels Bang Casper , Andersen Mikkel Porsborg , Fosbøl Emil , Køber Lars , Schou Morten , Torp‐Pedersen Christian , Kessing Lars Vedel , Gislason Gunnar , Kragholm Kristian
Published: April 2021

Objective

Psychiatric disorders have been associated with unfavourable outcome following respiratory infections. Whether this also applies to coronavirus disease 2019 (COVID‐19) has been scarcely investigated.

Methods

Using the Danish administrative databases, we identified all patients with a positive real‐time reverse transcription‐polymerase chain reaction test for COVID‐19 in Denmark up to and including 2 January 2021. Multivariable cox regression was used to calculate 30‐day absolute risk and average risk ratio (ARR) for the composite end point of death from any cause and severe COVID‐19 associated with psychiatric disorders, defined using both hospital diagnoses and redemption of psychotropic drugs.

Results

We included 144,321 patients with COVID‐19. Compared with patients without psychiatric disorders, the standardized ARR of the composite outcome was significantly increased for patients with severe mental illness including schizophrenia spectrum disorders 2.43 (95% confidence interval [CI], 1.79–3.07), bipolar disorder 2.11 (95% CI, 1.25–2.97), unipolar depression 1.70 (95% CI, 1.38–2.02), and for patients who redeemed psychotropic drugs 1.70 (95% CI, 1.48–1.92). No association was found for patients with other psychiatric disorders 1.13 (95% CI, 0.86–1.38). Similar results were seen with the outcomes of death or severe COVID‐19.

Among the different psychiatric subgroups, patients with schizophrenia spectrum disorders had the highest 30‐day absolute risk for the composite outcome 3.1% (95% CI, 2.3–3.9%), death 1.2% (95% CI, 0.4–2.0%) and severe COVID‐19 2.7% (95% CI, 1.9–3.6%).

Conclusion

Schizophrenia spectrum disorders, bipolar disorder, unipolar depression and psychotropic drug redemption are associated with unfavourable outcomes in patients with COVID‐19.
Trends in Australian dental prescribing of antibiotics: 2005–2016
Authors: Walsh LJ , Ford PJ , McGuire T , van Driel M , Hollingworth SA
Published: April 2021

Background

Prescribing of antibiotics by dentists for surgical prophylaxis or as an adjunct to managing dental infections is a substantial part of the overall landscape for prescribed antibiotics in health care settings.

Methods

We explored trends in the antibiotic prescribing patterns of Australian dentists over the 12‐year period, 2005–2016. We obtained data on dispensed prescriptions of antibiotics from registered dentists subsidized on the Pharmaceutical Benefits Scheme.

Results

Australian dentists were responsible for almost 7 million dispensed prescriptions of antibiotics over 12 years; an average of 24 prescriptions per year per dentist. The most commonly prescribed antibiotic was amoxicillin, followed by amoxicillin + clavulanic acid and metronidazole. These top three antibiotics constituted more than 80% of all antibiotics prescribed and their use increased dramatically over time. There was a large increase in the prescribing of broad‐spectrum antibiotics over time, most of which occurred from 2011 to 2016.

Conclusions

Excessive prescribing of broad‐spectrum antibiotics runs contrary to national antimicrobial stewardship (AMS) initiatives and guidelines. Multifaceted educational strategies are essential to align prescribing with current best practice. High‐level evidence to inform clear guidelines on antibiotic prescribing in dental infections, with audit and feedback, should reduce the inappropriate use of antibiotics in dentistry.
Dissemination of EAACI food allergy guidelines using a flexible, practical, whole school allergy awareness toolkit
Authors: Higgs Jennette , Styles Kathryn , Bowyer Sarah , Warner Amena , Dunn Galvin Audrey
Published: April 2021

Background

Essential training for emergency adrenaline auto‐injector administration alone provides an inadequate safeguard in school environments. Recent UK deaths have reinforced the urgency for embedding whole school (WS) allergy awareness to minimise risk. We documented the development of a practical, flexible WS Food Allergy Awareness Toolkit for UK secondary schools.

Methods

We used a multidisciplinary participatory action research methodology, involving successive modification and retesting of a pragmatic toolkit in 3 case study schools. A School Allergy Action Group drives WS risk assessment, helping schools gradually implement best practice policy in line with their particular needs. Additional schools self‐piloted the resulting toolkit with only remote monitoring. School surveys, based on EAACI guidelines were developed to identify priorities and assess change.

Results

Effectiveness of the resulting process toolkit, now available online, was independently demonstrated via pre/post‐intervention questionnaires from 24/10 pupils with food allergy (FA) and 97/6 pupils without FA, respectively. Pearson correlational analysis showed strong negative relationships between Food Allergy Quality of Life Questionnaire (FAQLQ) at T0 and School Support (SS) at T0 (r = −0.8, P<0.01), and between SS and Self‐Efficacy (SE) (r = 0.73, P<0.05). Mean FAQLQ scores improved between T0 (3.3) and T1 (2.5). SE improved for those with FA (mean difference = 1.0). In those without FA, SE (mean difference = 0.9) and Attitudes and Knowledge (mean difference = 0.7) also improved.

Conclusions

Full stakeholder involvement in toolkit development encourages usage and, therefore, improves WS community awareness; reduces risk of reactions; fosters a more accepting societal attitude and empowers pupils with/without allergies to self‐manage effectively.
Laparoscopic sigmoidectomy with splenic flexure mobilization for colon cancer in situs inversus totalis: Preoperative assessment and preparation
Authors: Kudo Takuya , Matsuda Takeru , Urakawa Naoki , Hasegawa Hiroshi , Kanaji Shingo , Yamashita Kimihiro , Oshikiri Taro , Kakeji Yoshihiro
Published: April 2021

Situs inversus totalis (SIT) is a rare condition in which the internal organ's position is a mirror image of normal anatomy. Although several investigators reported laparoscopic surgery for colorectal cancer in patients with SIT, it is considered difficult even for an experienced surgeon because of the mirror position. We show a case report of laparoscopic sigmoidectomy with the splenic flexure mobilization (SFM) procedure in SIT. A 79‐year‐old woman with SIT was referred to our hospital for a locally advanced sigmoid cancer (cT3N1M0, cStageIIIB). We safely performed the laparoscopic sigmoidectomy with SFM, as shown in detail below. No postoperative complication occurred, and the patient is in good health with no recurrences 30 months after surgery, as of the writing this report. We propose three critical points; checking the CT angiography to understand the anatomy; using flip‐horizontal video of “normal” laparoscopic sigmoidectomy to confirm an unfamiliar situation; adding the epigastric trocar to make SFM procedures safe and comfortable.
Attitude change after a curriculum on the science and philosophy of well‐being and happiness for high school students: A classroom‐randomized trial
Authors: Desan Paul H. , Setton Mark K. , Holzer Allison A. , Young Kevin C. , Sun Yan , He Fei , Li Baosong , Weinstein Andrea J. , Yu Xiaoling
Published: April 2021

Background

Multiple interventions have been tested to promote well‐being in high school students, often focusing on depression prevention.

Aims

To test the impact of a one‐semester active learning curriculum covering the modern science and philosophy of well‐being and happiness on attitudinal measures related to the curriculum and standard measures of depression and well‐being.

Sample

Subjects were first‐year students in an urban high school in Beijing, China (equivalent to US tenth grade).

Methods

Nine classrooms were randomly assigned to the intervention curriculum (n = 252), and nine classrooms were randomly assigned to a traditional psychology curriculum (n = 263). Students completed questionnaires pre‐ and post‐semester including a Positive Attitude Scale (PAS, concerning Relatedness, Competence, Autonomy, Gratitude, Calmness, Mindfulness, and Hope), Positive and Negative Affect Scale (PANAS), Centers for Epidemiological Studies Depression Scale (CES‐D), Life Satisfaction Scale (LS), Subjective Happiness Scale (SHS), Meaning in Life Questionnaire (MLQ), and a test of knowledge about well‐being (Knowledge Test, KT).

Results

In a hierarchical linear model, there were statistically significant intervention effects on six of the seven subscales of the PAS, on PANAS balance, and on the KT. CES‐D, LS, SHS, and MLQ were improved but not significantly so. Notable overall secular trends in measures of well‐being were observed, with a peak in September and nadir in April.

Conclusions

A one‐semester course for high school students regarding well‐being and happiness demonstrated significant changes in positive attitudes, affective balance, and knowledge about happiness. Circannual trends in well‐being measures over the academic year have implications for those designing school intervention studies.
Computational design and modeling of nanobodies toward SARS‐CoV‐2 receptor binding domain
Authors: Yang Jingyi , Zhang Zhao , Yang Fengyuan , Zhang Haiwei , Wu Haibo , Zhu Feng , Xue Weiwei
Published: April 2021

The ongoing pandemic of coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has become a global health concern and pose a serious threat to humanity. There is an urgent need for developing therapeutic drugs and (or) biologics to prevent the spread of the virus. The life cycle of SARS‐CoV‐2 shows that the virus enters host cells by first binding to angiotensin‐converting enzyme 2 (ACE2) through its spike protein receptor‐binding domain (RBD). Therefore, blocking the binding between of ACE2 and SARS‐CoV‐2 RBD can inhibit the virus infection in the host cells. In this study, by grafting the complementarity‐determining regions (CDRs) of developed SARS‐CoV, MERS‐CoVs specific neutralizing antibodies (nAbs) include monoclonal antibodies (mAbs) as well as SARS‐CoV‐2 mAbs onto a known stable nanobody (Nb) scaffold, and a total of 16 Nbs sequences were designed. Five Nbs, namely CS01, CS02, CS03, CS10, and CS16, were selected based on the free energy landscape of protein docking verified by the recently reported Nb‐RBD cocrystal structures. CS01, CS02, and CS03 occupied the ACE2 binding site of RBD, while CS10 and CS16 were proposed to inhibit the interaction between RBD and ACE2 through an allosteric mechanism. Based on the structures of the five Nbs in complex with RBD, seven brand‐new Nbs with enhanced binding affinities (CS02_RD01, CS03_RD01, CS03_RD02, CS03_RD03, CS03_RD04, CS16_RD01, and CS16_RD02) were generated by redesign of residues on the interface of the five Nbs contact with SARS‐CoV‐2 RBD. In addition, the identified “hot spots” on the interface of each complex provide useful information to understand the binding mechanism of designed Nbs to SARS‐CoV‐2 RBD. In sum, the predicted stabilities and high binding affinities of the 11 (re)designed Nbs indicating the potential of the developed computational framework in this work to design effective agents to block the infection of SARS‐CoV‐2.
A scoping review of pharmacy participation in dental and oral health care
Authors: Hu Jie , McMillan Sara S. , El‐Den Sarira , O'Reilly Claire L. , Collins Jack C. , Wheeler Amanda J.
Published: April 2021

Objectives

To explore the scope of dental and oral health care (DOHC) provided by the pharmacy profession and associated outcomes, and attitudes of pharmacy staff and other key stakeholders about pharmacy involvement in this context.

Methods

A scoping review of full‐text articles describing outcomes related to pharmacy staff/student involvement in, knowledge of or attitudes towards DOHC in any setting, and stakeholder perspectives was conducted. Articles written in English were searched for using PubMed, EMBASE, EBSCO, International Pharmaceutical Abstracts, Education Resources Information Centre, Web of Science, Google Scholar, and ProQuest for Dissertations and Theses. No date restrictions were used. Key outcomes were mapped: role and practice, knowledge and attitudes, and training and education.

Results

Seventy studies met the inclusion criteria: 49 were conducted in developed countries; 60 were quantitative in design; and 38 involved community pharmacy settings only. Pharmacists and pharmacy support staff commonly managed DOHC inquiries (n = 13), including the provision of advice and products with or without a further referral. Integrated pharmacist‐led services in dental settings (n = 4) showed improved prescribing and quality use of medicines but low community pharmacy referrals were identified in studies involving mystery shoppers with potential oral cancer (n = 7). DOHC promotion programmes delivered by pharmacy staff and collaborations with dentists were limited. There was interest from the pharmacy profession for a role in DOHC; however, knowledge gaps were reported and needs for further training identified. Consumer participant DOHC outcomes were not reported.

Conclusions

Community pharmacists and pharmacy staff were interested in an expanded role in DOHC; however, this scoping review identified lack of knowledge and sub‐optimal practice as potential barriers. Research on development, implementation and evaluation of DOHC‐related services and practice by pharmacy staff was scarce. Further evidence of consumer‐related oral health outcomes and their perceptions of the role of pharmacy is needed.