bluuebunny/crossref_metadata_2025 huggingface dataset:
Improved RNA secondary structure and tertiary base-pairing prediction using evolutionary profile, mutational coupling and two-dimensional transfer learning
Authors: Singh Jaswinder , Paliwal Kuldip , Zhang Tongchuan , Singh Jaspreet , Litfin Thomas , Zhou Yaoqi
Published: March 2021

Motivation

The recent discovery of numerous non-coding RNAs (long non-coding RNAs, in particular) has transformed our perception about the roles of RNAs in living organisms. Our ability to understand them, however, is hampered by our inability to solve their secondary and tertiary structures in high resolution efficiently by existing experimental techniques. Computational prediction of RNA secondary structure, on the other hand, has received much-needed improvement, recently, through deep learning of a large approximate data, followed by transfer learning with gold-standard base-pairing structures from high-resolution 3-D structures. Here, we expand this single-sequence-based learning to the use of evolutionary profiles and mutational coupling.

Results

The new method allows large improvement not only in canonical base-pairs (RNA secondary structures) but more so in base-pairing associated with tertiary interactions such as pseudoknots, non-canonical and lone base-pairs. In particular, it is highly accurate for those RNAs of more than 1000 homologous sequences by achieving >0.8 F1-score (harmonic mean of sensitivity and precision) for 14/16 RNAs tested. The method can also significantly improve base-pairing prediction by incorporating artificial but functional homologous sequences generated from deep mutational scanning without any modification. The fully automatic method (publicly available as server and standalone software) should provide the scientific community a new powerful tool to capture not only the secondary structure but also tertiary base-pairing information for building three-dimensional models. It also highlights the future of accurately solving the base-pairing structure by using a large number of natural and/or artificial homologous sequences.

Availability and implementation

Standalone-version of SPOT-RNA2 is available at https://github.com/jaswindersingh2/SPOT-RNA2. Direct prediction can also be made at https://sparks-lab.org/server/spot-rna2/. The datasets used in this research can also be downloaded from the GITHUB and the webserver mentioned above.

Supplementary information

Supplementary data are available at Bioinformatics online.
HDL mediates reverse cholesterol transport from ram spermatozoa and induces hyperactivated motility
Authors: Bernecic Naomi C , de Graaf Simon P , Leahy Tamara , Gadella Bart M
Published: March 2021

Reverse cholesterol transport or cholesterol efflux is part of an extensive plasma membrane remodeling process in spermatozoa that is imperative for fertilization. For ram spermatozoa, sheep serum is well known to support in vitro fertilization (IVF), but knowledge of its explicit role is limited. Though, it is postulated to elicit cholesterol efflux owing to the presence of high-density lipoproteins (HDLs) that interact with transmembrane cholesterol transporters, such as adenosinetriphosphate (ATP)-binding cassette transporter A1 (ABCA1) and scavenger receptor class B, type I (SR-BI). In this study, we report that both sheep serum and HDLs were able to elicit cholesterol efflux alone by up to 20–40% (as measured by the boron dipyrromethene (BODIPY)-cholesterol assay). Furthermore, when the antagonists glibenclamide and valspodar were used to inhibit the function of ABCA1 and SR-BI or ABCA1 alone, respectively, cholesterol efflux was only marginally reduced (8–15%). Nevertheless, it is likely that in ram spermatozoa, a specific facilitated pathway of cholesterol efflux is involved in the interaction between cholesterol acceptors and transporters. Interestingly, exposure to HDLs also induced hyperactivated motility, another critical event required for successful fertilization. Taken together, this study details the first report of the dual action of HDLs on ram spermatozoa, providing both an insight into the intricacy of events leading up to fertilization in vivo as well as demonstrating the possible application of HDL supplementation in media for IVF.
Cybercrime is (often) boring: Infrastructure and alienation in a deviant subculture
Authors: Collier Ben , Clayton Richard , Hutchings Alice , Thomas Daniel
Published: March 2021

The boredom and alienation produced by capitalist societies and countervailing forces of attraction and excitement are at the heart of the subcultural account of crime. The underground hacker subculture is no exception, commonly represented as based around exciting, technically skilled practices and high-profile deviance. However, the illicit economy associated with these practices has become industrialized, developing shared infrastructures that facilitate the sale of illicit services rather than skilled technical work. We explore how this shift in the nature of work has shaped the culture and experiences of this subculture. Developing a novel concept—the ‘illicit infrastructure’—and drawing on an extensive analysis of empirical data from interviews and novel data sources such as forums and chat channels, we argue that as they industrialize, deviant subcultures can begin to replicate the division of labour, cultural tensions and conditions of alienation present in mainstream capitalist economies.
Monogenic mysteries unravel mitochondrial mechanisms
Authors: Rydning Siri Lynne , Wedding Iselin M
Published: March 2021

This scientific commentary refers to ‘Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia’, by Rebelo et al. (doi: 10.1093/brain/awab071).
Features of MOG required for recognition by patients with MOG antibody-associated disorders
Authors: Macrini Caterina , Gerhards Ramona , Winklmeier Stephan , Bergmann Lena , Mader Simone , Spadaro Melania , Vural Atay , Smolle Michaela , Hohlfeld Reinhard , Kümpfel Tania , Lichtenthaler Stefan F , Franquelim Henri G , Jenne Dieter , Meinl Edgar
Published: March 2021

Antibodies to myelin oligodendrocyte glycoprotein (MOG-Abs) define a distinct disease entity. Here we aimed to understand essential structural features of MOG required for recognition by autoantibodies from patients. We produced the N-terminal part of MOG in a conformationally correct form; this domain was insufficient to identify patients with MOG-Abs by ELISA even after site-directed binding. This was neither due to a lack of lipid embedding nor to a missing putative epitope at the C-terminus, which we confirmed to be an intracellular domain. When MOG was displayed on transfected cells, patients with MOG-Abs recognized full-length MOG much better than its N-terminal part with the first hydrophobic domain (P < 0.0001). Even antibodies affinity-purified with the extracellular part of MOG recognized full-length MOG better than the extracellular part of MOG after transfection. The second hydrophobic domain of MOG enhanced the recognition of the extracellular part of MOG by antibodies from patients as seen with truncated variants of MOG. We confirmed the pivotal role of the second hydrophobic domain by fusing the intracellular part of MOG from the evolutionary distant opossum to the human extracellular part; the chimeric construct restored the antibody binding completely. Further, we found that in contrast to 8-18C5, MOG-Abs from patients bound preferentially as F(ab′)2 rather than Fab. It was previously found that bivalent binding of human IgG1, the prominent isotype of MOG-Abs, requires that its target antigen is displayed at a distance of 13–16 nm. We found that, upon transfection, molecules of MOG did not interact so closely to induce a Förster resonance energy transfer signal, indicating that they are more than 6 nm apart. We propose that the intracellular part of MOG holds the monomers apart at a suitable distance for bivalent binding; this could explain why a cell-based assay is needed to identify MOG-Abs. Our finding that MOG-Abs from most patients require bivalent binding has implications for understanding the pathogenesis of MOG-Ab associated disorders. Since bivalently bound antibodies have been reported to only poorly bind C1q, we speculate that the pathogenicity of MOG-Abs is mostly mediated by other mechanisms than complement activation. Therefore, therapeutic inhibition of complement activation should be less efficient in MOG-Ab associated disorders than in patients with antibodies to aquaporin-4 .
Dravet syndrome-associated mutations inGABRA1,GABRB2andGABRG2define the genetic landscape of defects of GABAA receptors
Authors: Hernandez Ciria C , Tian XiaoJuan , Hu Ningning , Shen Wangzhen , Catron Mackenzie A , Yang Ying , Chen Jiaoyang , Jiang Yuwu , Zhang Yuehua , Macdonald Robert L
Published: March 2021

Dravet syndrome is a rare, catastrophic epileptic encephalopathy that begins in the first year of life, usually with febrile or afebrile hemiclonic or generalized tonic–clonic seizures followed by status epilepticus. De novo variants in genes that mediate synaptic transmission such as SCN1A and PCDH19 are often associated with Dravet syndrome. Recently, GABAA receptor subunit genes (GABRs) encoding α1 (GABRA1), β3 (GABRB3) and γ2 (GABRG2), but not β2 (GABRB2) or β1 (GABRB1), subunits are frequently associated with Dravet syndrome or Dravet syndrome-like phenotype. We performed next generation sequencing on 870 patients with Dravet syndrome and identified nine variants in three different GABRs. Interestingly, the variants were all in genes encoding the most common GABAA receptor, the α1β2γ2 receptor. Mutations in GABRA1 (c.644T>C, p. L215P; c.640C>T, p. R214C; c.859G>A; V287I; c.641G>A, p. R214H) and GABRG2 (c.269C>G, p. T90R; c.1025C>T, p. P342L) presented as de novo cases, while in GABRB2 two variants were de novo (c.992T>C, p. F331S; c.542A>T, p. Y181F) and one was autosomal dominant and inherited from the maternal side (c.990_992del, p.330_331del). We characterized the effects of these GABR variants on GABAA receptor biogenesis and channel function. We found that defects in receptor gating were the common deficiency of GABRA1 and GABRB2 Dravet syndrome variants, while mainly trafficking defects were found with the GABRG2 (c.269C>G, p. T90R) variant. It seems that variants in α1 and β2 subunits are less tolerated than in γ2 subunits, since variant α1 and β2 subunits express well but were functionally deficient. This suggests that all of these GABR variants are all targeting GABR genes that encode the assembled α1β2γ2 receptor, and regardless of which of the three subunits are mutated, variants in genes coding for α1, β2 and γ2 receptor subunits make them candidate causative genes in the pathogenesis of Dravet syndrome.
Design and simulation of a 1-GWp solar photovoltaic power station in Sudan
Authors: Abdalla Sohaib Nasr Mohamed , Özcan Hakan
Published: March 2021

Developing nations have a critical need to increase electricity supply. Sudan has much unrealized potential for generating solar energy, particularly in the northern region. This research study focuses on designing a 1-GW solar power station in northern Sudan using the PVsyst7.0 software program. To determine the appropriate location for the solar-energy station, 14 criteria were evaluated. This process is generic and suitable for use in any other country. The method for conducting cash-flow estimates and return on investment is illustrated in the economic evaluation. The city of Dongola, the capital of the northern state, was selected because of its high annual irradiance on a horizontal surface at ~2333.2 kWh/m2. The simulation results show that the annual optimum tilt angle of inclination for photovoltaic (PV) modules is 30°, the energy production is 1 979 259 MWh/yr and the average annual performance rate is 0.810. In addition, the electric power consumption per capita in Sudan is 269 kWh/yr, so the proposed solar power plant with 1 979 259 MWh/yr can provide energy to 7.4 million people per year annually and reduce carbon emissions by ~18 million tons of carbon dioxide per year. Economic calculations show that the levelized cost of electricity (LCOE) is $0.06/kWh, the discounted payback period is ~11 years and the net present value is $635 291 000. As a result, the proposed grid-connected PV solar plant is considered economically, technically and environmentally feasible in Sudan.
A case of Wolff–Parkinson–White syndrome in which two-dimensional speckle-tracking echocardiography was useful for identifying the location of the accessory atrioventricular pathway
Authors: Tanabe Junya , Watanabe Nobuhide , Yamaguchi Kazuto , Tanabe Kazuaki
Published: March 2021

Background

In Wolff–Parkinson–White (WPW) syndrome, accessory atrioventricular pathways (AP) result in abnormal pre-excitation around the atrioventricular annuli and produce a dyssynchronous contraction of cardiac chambers. Identification of the AP affects the outcome of catheter ablation.

Case summary

We report a case of WPW syndrome and paroxysmal atrial fibrillation in a 65-year-old man. Wolff–Parkinson–White syndrome Type B was suspected from lead V1, but when two-dimensional speckle-tracking echocardiography (2D-STE) was performed, a decrease in regional strain was observed in the anterior basal wall of the left ventricle. We identified the earliest site of atrioventricular conduction, and improvement in the regional strain at the site of ablation was observed after successful AP ablation.

Discussion

Various echocardiographic techniques have been investigated as non-invasive alternatives for AP localization. Longitudinal 2D-STE accurately identified contractile abnormalities associated with the AP, allowing us to non-invasively estimate the localization of the AP in WPW syndrome.
The African Union’s Struggle Against ‘Unconstitutional Change of Government’: From a Moral Prescription to a Requirement under International Law?
Authors: de Wet Erika
Published: March 2021

In 1992 Thomas Franck proclaimed an emerging right to democratic governance in international law. With reference to developments in the Organization of American States (OAS) and the Commission on Security and Cooperation in Europe, he identified free and fair elections as the core benchmark of this right, possessing significant legitimacy in terms of its pedigree, determinacy, coherence and adherence. The current contribution examines Franck’s understanding of the right to democratic governance within the African context, notably in relation to those institutional developments that have occurred since the adoption of the Constitutive Act of the African Union (AU) in 2000. Specifically, the article assesses the benchmarks of the notion of ‘unconstitutional changes of government’ in Article 4(p) of the AU Constitutive Act and their inter-linkage with free and fair elections. In so doing, it critically questions the response of the AU to unconstitutional changes of government and its implications for the normative maturity of the benchmark in question. It places the analysis in a broader context by drawing some parallels with the current back-sliding in democratic governance that is occurring also within the Council of Europe (CoE) and the European Union.
Impact of diabetes on coronary severity and cardiovascular outcomes in patients with heterozygous familial hypercholesterolaemia
Authors: Liu Ming-Ming , Peng Jia , Guo Yuan-Lin , Wu Na-Qiong , Zhu Cheng-Gang , Gao Ying , Dong Qian , Li Jian-Jun
Published: March 2021

Aims

Type 2 diabetes mellitus (T2DM) is an independent risk factor for cardiovascular disease. However, the association between T2DM and coronary artery disease (CAD) in patients with heterozygous familial hypercholesterolaemia (HeFH) has not been thoroughly evaluated. Our study aimed to assess the effect of T2DM on CAD severity and hard cardiovascular endpoints in a HeFH cohort.

Methods and results

A total of 432 patients with HeFH with a molecular and/or clinical Dutch Lipid Clinic Network score ≥6 (definite and probable) were enrolled. Patients were divided into a T2DM group (n = 99) and a non-T2DM group (n = 333). The severity of coronary stenosis was assessed by the number of diseased vessels and Gensini, SYNTAX, and Jeopardy scores. Hard endpoints included a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiac death. Cox regression and Kaplan–Meier analyses were used to evaluate the effect of T2DM on hard cardiovascular endpoints. The prevalence of CAD was higher in patients with T2DM compared with those without (96.0% vs. 77.5%, respectively; P < 0.001). Patients with T2DM demonstrated a greater number of diseased vessels (P = 0.029) and more severe coronary lesions with high Gensini, SYNTAX, and Jeopardy score tertiles (P = 0.031, P = 0.001, and P = 0.024, respectively). During a median of 3.75 years up to a maximum of 9 years of follow-up, hard endpoints occurred in 13 of 99 patients with T2DM and 16 of 333 without T2DM at baseline. Compared with patients without T2DM, patients with T2DM were at a significantly greater risk of hard endpoints [multivariate adjusted hazard ratio (HR) 2.32, 95% confidence interval (CI) 1.02–4.84; P = 0.025]. Additionally, patients with T2DM and good glucose control (HbA1c < 7.0%) were at a lower risk of hard endpoints compared with those with poor glucose control (HbA1c ≥ 7.0%, HR 0.08, 95% CI 0.01–0.56; P = 0.011).

Conclusion

We conclude that T2DM is an independent predictor of CAD severity when assessed by number of diseased vessels, Gensini, SYNTAX, Jeopardy scores, and hard cardiovascular endpoints, suggesting that T2DM could be further used for risk stratification of patients with HeFH.
Multivariate genome-wide analysis of immunoglobulin G N-glycosylation identifies new loci pleiotropic with immune function
Authors: Shadrina Alexandra S , Zlobin Alexander S , Zaytseva Olga O , Klarić Lucija , Sharapov Sodbo Z , D Pakhomov Eugene , Perola Marcus , Esko Tonu , Hayward Caroline , Wilson James F , Lauc Gordan , Aulchenko Yurii S , Tsepilov Yakov A
Published: March 2021

The N-glycosylation of immunoglobulin G (IgG) affects its structure and function. It has been demonstrated that IgG N-glycosylation patterns are inherited as complex quantitative traits. Genome-wide association studies identified loci harboring genes encoding enzymes directly involved in protein glycosylation as well as loci likely to be involved in regulation of glycosylation biochemical pathways. Many of these loci could be linked to immune functions and risk of inflammatory and autoimmune diseases. The aim of the present study was to discover and replicate new loci associated with IgG N-glycosylation and to investigate possible pleiotropic effects of these loci onto immune function and the risk of inflammatory and autoimmune diseases. We conducted a multivariate genome-wide association analysis of 23 IgG N-glycosylation traits measured in 8090 individuals of European ancestry. The discovery stage was followed up by replication in 3147 people and in silico functional analysis. Our study increased the total number of replicated loci from 22 to 29. For the discovered loci, we suggest a number of genes potentially involved in the control of IgG N-glycosylation. Among the new loci, two (near RNF168 and TNFRSF13B) were previously implicated in rare immune deficiencies and were associated with levels of circulating immunoglobulins. For one new locus (near AP5B1/OVOL1), we demonstrated a potential pleiotropic effect on the risk of asthma. Our findings underline an important link between IgG N-glycosylation and immune function and provide new clues to understanding their interplay.
Exploring pharmacists’ views surrounding conscientious objection to abortion and implications in practice
Authors: Maxwell Clare , McKendrick Jane , Hanlon Claire , Penson Peter , Fleming Valerie
Published: March 2021

Background

General Pharmaceutical Council standards (UK) state ‘pharmacy professionals have the right to practise in line with their religion, personal values or beliefs as long as they …make sure that person-centred care is not compromised’, indicating a potential conflict for pharmacists who wish to exercise their right to conscientious objection (CO) to abortion while maintaining a duty of care to their patients.

Objective

The objective of this study was to explore pharmacists’ views of conscientious objection to abortion and whether this included the supply of EC and the impact on practice.

Method

Eighteen UK pharmacists were interviewed using semistructured interviews. Interviews were transcribed verbatim, imported into NVivo11 and analysed using thematic analysis.

Key findings

Five themes were identified: beliefs as to what constitutes abortion, influences on beliefs, conflicts of conscience, accommodating conscience and professional obligations. Views were polarised in relation to the role of emergency contraception (EC) as an abortifacient. Religion was often viewed as the reason underpinning CO to abortion. Conflicts in relation to CO to abortion included the role of referral and EC and employability for objectors. Some pharmacists viewed their role of providing patient choice as incompatible with the right of CO to abortion.

Conclusions

This study shows the conflicts and challenges surrounding CO to abortion in professional pharmacy practice. While the majority of pharmacists believe CO to abortion should and could be accommodated, this can prove challenging in certain working environments, both in relation to ensuring a duty of care to patients is upheld and due to the ongoing debate concerning EC and whether it has a definitive role in abortion or not.
Common general surgical never events: analysis of NHS England never event data
Authors: Omar Islam , Singhal Rishi , Wilson Michael , Parmar Chetan , Khan Omar , Mahawar Kamal
Published: March 2021

Background

There is little available data on common general surgical never events (NEs). Lack of this information may have affected our attempts to reduce the incidence of these potentially serious clinical incidents.

Objectives

The purpose of this study was to identify common general surgical NEs from the data held by the National Health Service (NHS) England.

Methods

We analysed the NHS England NE data from April 2012 to February 2020 to identify common general surgical NEs.

Results

There was a total of 797 general surgical NEs identified under three main categories such as wrong-site surgery (n = 427; 53.58%), retained items post-procedure (n = 355; 44.54%) and wrong implant/prosthesis (n = 15; 1.88%). We identified a total of 56 common general surgical themes—25 each in the wrong-site surgery and retained foreign body categories and six in wrong implants category.

Wrong skin condition surgery was the commonest wrong-site surgery (n = 117; 27.4%). There were 18 wrong-side chest drains (4.2%) and 18 (4.2%) wrong-side angioplasty/angiograms. There were seven (1.6%) instances of confusion in pilonidal/perianal/perineal surgeries and six (1.4%) instances of biopsy of the cervix rather than the colon or rectum.

Retained surgical swabs were the most common retained items (n = 165; 46.5%). There were 28 (7.9%) laparoscopic retrieval bags with or without the specimen, 26 (7.3%) chest drain guide wires, 26 (7.3%) surgical needles and 9 (2.5%) surgical drains. Wrong stents were the most common (n = 9; 60%) wrong implants followed by wrong breast implants (n = 2; 13.3%).

Conclusion

This study found 56 common general surgical NEs. This information is not available to surgeons around the world. Increased awareness of these common themes of NEs may allow for the adoption of more effective and specific safeguards and ultimately help reduce their incidence.
The potential impact of the COVID-19 pandemic on global antimicrobial and biocide resistance: an AMR Insights global perspective
Authors: Ansari Shamshul , Hays John P , Kemp Andrew , Okechukwu Raymond , Murugaiyan Jayaseelan , Ekwanzala Mutshiene Deogratias , Ruiz Alvarez Maria Josefina , Paul-Satyaseela Maneesh , Iwu Chidozie Declan , Balleste-Delpierre Clara , Septimus Ed , Mugisha Lawrence , Fadare Joseph , Chaudhuri Susmita , Chibabhai Vindana , Wadanamby J M Rohini W W , Daoud Ziad , Xiao Yonghong , Parkunan Thulasiraman , Khalaf Yara , M’Ikanatha Nkuchia M , van Dongen Maarten B M ,   Global AMR Insights Ambassador Network, Barkema Herman W , Strathdee Steffanie , Benyeogor Emmanuel , Ighodalo Uzairue Leonard , Prasad Kurcheti Pani , M Carlos , Gu Yoshiaki , Essack Sabiha , de Silva Dilan , Vellinga Akke , Mommtaz Ghannam Wagih , Tsoho Najib Auwal , Sakeena M H F , Ilenwabor Rhoda , Shetty Dhanuraj (Raj) , Ayebare Arnold , Traore Zoumana Isaac , Henry Ola , Kiran Amritanjali , Ilenwabor Rhoda , Toro Luisa Fernanda , Smail Adil , Amulele Anne , Founou Luria Leslie , Sawant Prathamesh S , Buregyeya Esther , Castro-Sanchez Enrique , Moreno-Morales Javier , Izadjoo Mina , Gori Andrea , Goff Debra , Blocker Arielle , Forte Giovanna , Tahir Muhammad Farooq , Diggle Mathew , Chakraborty Dipanjan , Asamoah Anita E , Aberi Humphrey
Published: March 2021

The COVID-19 pandemic presents a serious public health challenge in all countries. However, repercussions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections on future global health are still being investigated, including the pandemic’s potential effect on the emergence and spread of global antimicrobial resistance (AMR). Critically ill COVID-19 patients may develop severe complications, which may predispose patients to infection with nosocomial bacterial and/or fungal pathogens, requiring the extensive use of antibiotics. However, antibiotics may also be inappropriately used in milder cases of COVID-19 infection. Further, concerns such as increased biocide use, antimicrobial stewardship/infection control, AMR awareness, the need for diagnostics (including rapid and point-of-care diagnostics) and the usefulness of vaccination could all be components shaping the influence of the COVID-19 pandemic. In this publication, the authors present a brief overview of the COVID-19 pandemic and associated issues that could influence the pandemic’s effect on global AMR.
Single-center Experience with Venous Thromboembolism Prophylaxis for Obese Burn Patients
Authors: McKinzie Brian P , Nizamani Rabia , Jones Samuel , King Booker , Williams Felicia N
Published: March 2021

Burn injured patients are at high risk of thromboembolic complications. Morbid obesity further increases this risk. Our objective was to evaluate the efficacy of enoxaparin dosed 40 mg twice daily in achieving prophylactic plasma anti-Xa levels in obese burn patients.

A retrospective chart review from November 2018 until September 2019 identified patients who were either ≥100 kg or had a body mass index ≥30 kg/m2 and initiated on enoxaparin 40 mg twice daily for venous thromboembolism prophylaxis. Patients were ≥18 yr of age and received ≥3 sequential doses of enoxaparin with appropriately timed peak plasma anti-Xa levels to monitor efficacy.

One hundred forty-eight patients were screened with 43 patients included for analysis. Forty-two percent of the patients did not reach target peak plasma anti-Xa levels (0.2–0.5 IU/ml) on enoxaparin 40 mg twice daily. Patients who did not meet prophylactic target levels were more likely to be male (P < 0.05) and have an increased mean body weight (129 ± 24 kg vs 110 ± 16 kg, P < 0.05). Thirteen out of 18 patients received dosage adjustments with subsequent anti-Xa levels available for follow-up assessment, of which an additional six patients required further dosage adjustment to meet prophylactic goals.

Current utilization of a fixed 40 mg twice daily regimen of enoxaparin for venous thromboembolism (VTE) is inadequate to meet target prophylactic peak plasma anti-Xa levels in the obese burn patient population. Dose adjusting enoxaparin to target anti-Xa levels to reduce VTE rates in obese burn patients should be further evaluated.
The underground life of homeodomain-leucine zipper transcription factors
Authors: Perotti María Florencia , Arce Agustín Lucas , Chan Raquel Lía
Published: March 2021

Roots are the anchorage organs of plants, responsible for water and nutrient uptake, exhibiting high plasticity. Root architecture is driven by the interactions of biomolecules, including transcription factors and hormones that are crucial players regulating root plasticity. Multiple transcription factor families are involved in root development; some, such as ARFs and LBDs, have been well characterized, whereas others remain less well investigated. In this review, we synthesize the current knowledge about the involvement of the large family of homeodomain-leucine zipper (HD-Zip) transcription factors in root development. This family is divided into four subfamilies (I–IV), mainly according to structural features, such as additional motifs aside from HD-Zip, as well as their size, gene structure, and expression patterns. We explored and analyzed public databases and the scientific literature regarding HD-Zip transcription factors in Arabidopsis and other species. Most members of the four HD-Zip subfamilies are expressed in specific cell types and several individuals from each group have assigned functions in root development. Notably, a high proportion of the studied proteins are part of intricate regulation pathways involved in primary and lateral root growth and development.
Motivation to engage in crowdsourcing: Towards the synthetic psychological–sociological model
Authors: Daugavietis Jānis
Published: March 2021

This article is aimed at analysis of user participation in web-based crowdsourcing projects in the digital humanities (DH) field, with a focus on what motivates these volunteers.1 The first aim of the article is a critical analysis of models of motivators for involvement offered to date. The analysis is based on a review of DH crowdsourcing literature, as a result of which there is an indication of shortcomings of the psychological data-driven approach that has dominated thus far. The second aim of the article is to offer a new model that synthesizes the psychological-motivation approach with a sociological one. Applying Pierre Bourdieu’s Theory of Capital, the motivation model created by the psychological self-determination theory (SDT) is supplemented with capital dimensions and specific types of capital. The new model is empirically tested, utilizing specific data collected in the course of a crowdsourcing project, specifically, volunteers’ online survey. The conclusion states that the model synthesized using the psychological and sociological approach preserves the main SDT category scale (intrinsic–extrinsic), at the same time, the sociological capital categories implemented therein permit for making more concrete the psychological scale’s ‘intermediate phase’ (internalized extrinsic motivations) that had been amorphous up to that point, rendering the motivation model more coherent and readily applied.
Diabetes Mellitus and Tuberculosis Treatment Outcomes in Pune, India
Authors: Mave Vidya , Gaikwad Sanjay , Barthwal Madhusudan , Chandanwale Ajay , Lokhande Rahul , Kadam Dileep , Dharmshale Sujata , Bharadwaj Renu , Kagal Anju , Pradhan Neeta , Deshmukh Sona , Atre Sachin , Sahasrabudhe Tushar , Meshram Shailesh , Kakrani Arjun , Kulkarni Vandana , Raskar Swapnil , Suryavanshi Nishi , Kornfeld Hardy , Dooley Kelly E , Chon Sandy , Gupte Akshay , Gupta Amita , Gupte Nikhil , Golub Jonathan E
Published: March 2021

Background

Diabetes mellitus (DM) increases the risk of tuberculosis (TB) disease. Knowledge of the impact of DM on TB treatment outcomes is primarily based on retrospective studies.

Methods

We conducted a prospective cohort study of new pulmonary TB patients with and without DM (TB-DM and TB only) in India. The association of DM with a composite unfavorable TB treatment outcome (failure, recurrence, mortality) over 18 months was determined, and the effect of DM on all-cause mortality and early mortality (death during TB treatment) was assessed.

Results

Of 799 participants, 574 (72%) had TB only and 225 (28%) had TB-DM. The proportion of patients with DM who experienced the composite outcome was 20%, as compared with 21% for TB-only participants (adjusted hazard ratio [aHR], 1.13; 95% CI, 0.75–1.70). Mortality was higher in participants with DM (10% vs 7%), and early mortality was substantially higher among patients with DM (aHR, 4.36; 95% CI, 1.62–11.76).

Conclusions

DM was associated with early mortality in this prospective cohort study, but overall unfavorable outcomes were similar to participants without DM. Interventions to reduce mortality during TB treatment among people with TB-DM are needed.
Factors associated with longitudinal change of meniscal extrusion in overweight women without clinical signs of osteoarthritis
Authors: van der Voet Jan A , Wesselius Daan , Zhang Fan , Vroegindeweij Dammis , Oei Edwin H , Bierma-Zeinstra Sita M A , Englund Martin , Runhaar Jos
Published: March 2021

Objectives

To identify variables associated with longitudinal change in meniscal extrusion, which might be used as possible targets for knee osteoarthritis (KOA) prevention.

Methods

In a high-risk population of middle-aged overweight women, meniscal extrusion was assessed with magnetic resonance imaging (1.5 T, coronal proton density, in-plane resolution 0.5 mm2, Sante DICOM Editor) at baseline and after 30 months. Outcomes were the absolute change in medial and lateral extrusion (mm) and relative change in extrusion (%). Based upon literature, 11 factors were hypothesized to be associated with longitudinal change. Generalized estimating equations were used to model the effect on meniscal change (P <0.05).

Results

In total, 677 knees of 343 women were available for analysis, with a mean age of 55.7 years (+/−3.2) and a mean BMI of 32.3 kg/m2 (+/−4.2). The greatest change in meniscal extrusion appeared medially with incident meniscal tear (4.4%; absolute 0.9 mm (95% CI: 0.3, 1.5; P =0.004); relative 14.5% (4.4, 24.7; 0.005)). Varus malalignment was associated with an increase of medial extrusion of 0.6 mm (37.6%; 0.1, 1.0; 0.009). A 5 kg/m2 higher baseline BMI was associated with absolute and relative increase of medial extrusion of 0.2 mm and 2.96% (0.1, 0.3; <0.001 and 1.3, 4.8; 0.002). Less explicit but significant changes in extrusion appeared with longitudinal change in BMI.

Conclusion

Meniscal tears, varus malalignment and BMI were significantly associated with change in meniscal extrusion in middle-aged overweight women, providing viable therapeutic targets to prevent or reduce extrusion and thereby decelerate KOA development.
The Changing Virulence of Stripe Rust in Canada from 1984 to 2017
Authors: Ghanbarnia Kaveh , Gourlie Ryan , Amundsen Eric , Aboukhaddour Reem
Published: March 2021

Stripe rust, caused by the fungal pathogen Puccinia striiformis f. sp. tritici, is an important wheat disease worldwide. In this study, the P. striiformis f. sp. tritici population in Canada, representing a time period from 1984 to 2017, was analyzed for virulence diversity and geographical distribution. Virulence of 140 P. striiformis f. sp. tritici isolates was evaluated on 17 near-isogenic wheat lines in the ‘Avocet S’ background, each containing a single resistance gene along with an 18th line ‘Tyee’. Seedlings were inoculated with a urediniospore/talc mixture and infection types were evaluated on a scale of 0 to 9. In total, 89 races were identified with various combinations of defeated Yr genes. Clear changes in pathogen virulence have been observed through time that are confirmed by clustering algorithms. The results showed that the tested P. striiformis f. sp. tritici isolates remained avirulent on Yr1, Yr5, and Yr15, and have very low frequency of virulence on Yr76, but had high frequencies of virulence on Yr6, Yr7, Yr8, Yr9, Yr17, Yr43, Yr44, YrTr1, and YrExp2. P. striiformis f. sp. tritici virulence spiked on Yr7, Yr8, and Yr9 for the first time in 2000, and on Yr10 and Yr27 in 2010. Overall, the predominant races in Canada were very similar to those reported in the United States (PSTv-37, PSTv-41, and PSTv-52), which indicates long-distance migration of P. striiformis f. sp. tritici from the United States to Canada. Sixty-four races had unique virulence combinations that had not been previously reported in the United States, which suggested that evolution of virulence/avirulence for host resistance by mutation at local scale, is possible. Analysis of diversity between Canadian isolates and races from the United States since 2010 showed that the P. striiformis f. sp. tritici population in western Canada is similar to that in the western states of the United States, and that the population in eastern Canada is similar to the eastern and/or central regions of the United States, supporting the hypothesis that specific P. striiformis f. sp. tritici populations in North America travel through different wind trajectories.
The selective serotonin reuptake inhibitors enhance the cytotoxicity of sorafenib in hepatocellular carcinoma cells
Authors: Zhang Huan , Xu Huanji , Tang Qiulin , Bi Feng
Published: March 2021

Sertraline and fluoxetine are the two most commonly used selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression. Accumulating evidence has revealed that SSRIs can reduce the risk of hepatocellular carcinoma (HCC), but their therapeutic effects in HCC have not yet been elucidated. Previous studies have reported that sertraline and fluoxetine can suppress the growth of gastric carcinoma, melanoma and nonsmall cell lung cancers by inhibiting the mammalian target rapamycin (mTOR) activity. In this study, we found that sertraline and fluoxetine blocked the protein kinase B (AKT)/mTOR pathway and suppressed the growth of HCC cells in vitro, in xenografts and in diethylnitrosamine/carbon tetrachloride (DEN/CCL4)-induced primary liver mouse model. Sertraline and fluoxetine can synergize with sorafenib, the first approved standard therapy for advanced HCC, to inhibit the viability of HCC cells in vitro and in vivo. In addition, the combination of sorafenib and SSRIs synergistically inhibited the effects of the AKT/mTOR pathway. These results reveal novel therapeutic effects of a combination of SSRIs and sorafenib in HCC.
OFFICE MANAGEMENT OF OZURDEX IMPLANT DISLOCATION INTO THE ANTERIOR CHAMBER
Authors: Ahuja Abhimanyu S. , Jaraki Jude A. , Halperin Lawrence S.
Published: March 2021

Purpose:

To describe a novel office procedure that permits the repositioning of an Ozurdex implant from the anterior chamber back into the vitreous cavity.

Methods:

Description of an office technique for Ozurdex repositioning using a 30-gauge needle.

Results:

In both cases, the Ozurdex implant was successfully returned to the vitreous cavity. In Case 1, the patient's visual acuities 1 and 2 weeks after this were 20/70 and 20/40, respectively, and had no further complications. In Case 2, the patient returned 1 week later, with the implant remaining posterior and a visual acuity of 20/40.

Conclusion:

The success of this novel technique in these cases demonstrates the potential to avoid a surgical procedure in the event of Ozurdex implant migration to the anterior chamber, while at the same time allowing the Ozurdex implant to remain effective in the eye.
Sports Medicine Physician Decision-Making, Practice Changes, and Mental Health During the Early Phase of the SARS-CoV-2 Global Pandemic
Authors: Cushman Daniel M. , Teramoto Masaru , Babu Ashwin , Olafsen Nathan , Onishi Kentaro , Asay Alexandra , McCormick Zachary L.
Published: March 2021

Objective:

The SARS-CoV-2 pandemic has had a profound effect on the healthcare system. This study aimed to identify its effects on sports medicine physicians during the early phase of this pandemic.

Design:

Survey study.

Setting:

Sports medicine providers.

Participants:

Physician members of the American Medical Society for Sports Medicine were surveyed between March 25 and April 4, 2020. A total of 810 responses were obtained from 2437 physicians who viewed the survey.

Interventions:

The survey consisted of questions examining demographics, prepandemic practice patterns, anxiety and depression screening, and new beliefs and behaviors following government-based medical policy changes resulting from the pandemic.

Main Outcome Measures:

Changes in clinical volume and treatment practices, Patient Health Questionnaire (PHQ-4).

Results:

The mean in-person clinic visits reduced to 17.9%, telephone visits to 24.4%, telemedicine (video) visits to 21.8%, and procedural visits to 13.8% of prepandemic practice volume. The mean PHQ-4 scores for physicians were 2.38 ± 2.40. Clinic and procedural volumes were reduced less by male physicians, as well as more experienced physicians, nonphysical medicine and rehabilitation training background, in government or private practice, and in the Southern region of the United States (P < 0.05). Physicians were more likely to reduce their anti-inflammatory (37.8% decreasing vs 6.8% increasing, P < 0.001) and opioid (10.5% vs 6.8%, P = 0.003) prescriptions rather than increase.

Conclusions:

During the early phase of the SARS-COV-2 pandemic sports medicine physicians reported reducing in-person evaluation, management, and procedure volume by over 80%. Multiple demographic and geographic factors were associated with practice volume changes.
Readiness to Provide Medications for Addiction Treatment in HIV Clinics: A Multisite Mixed-Methods Formative Evaluation
Authors: Edelman E. Jennifer , Gan Geliang , Dziura James , Esserman Denise , Morford Kenneth L. , Porter Elizabeth , Chan Philip A. , Cornman Deborah H. , Oldfield Benjamin J. , Yager Jessica E. , Muvvala Srinivas B. , Fiellin David A.
Published: March 2021

Background:

We sought to characterize readiness, barriers to, and facilitators of providing medications for addiction treatment (MAT) in HIV clinics.

Setting:

Four HIV clinics in the northeastern United States.

Methods:

Mixed-methods formative evaluation conducted June 2017–February 2019. Surveys assessed readiness [visual analog scale, less ready (0–<7) vs. more ready (≥7–10)]; evidence and context ratings for MAT provision; and preferred addiction treatment model. A subset (n = 37) participated in focus groups.

Results:

Among 71 survey respondents (48% prescribers), the proportion more ready to provide addiction treatment medications varied across substances [tobacco (76%), opioid (61%), and alcohol (49%) treatment medications (P values < 0.05)]. Evidence subscale scores were higher for those more ready to provide tobacco [median (interquartile range) = 4.0 (4.0, 5.0) vs. 4.0 (3.0, 4.0), P = 0.008] treatment medications, but not significantly different for opioid [5.0 (4.0, 5.0) vs. 4.0 (4.0, 5.0), P = 0.11] and alcohol [4.0 (3.0, 5.0) vs. 4.0 (3.0, 4.0), P = 0.42] treatment medications. Median context subscale scores ranged from 3.3 to 4.0 and generally did not vary by readiness status (P values > 0.05). Most favored integrating MAT into HIV care but preferred models differed across substances. Barriers to MAT included identification of treatment-eligible patients, variable experiences with MAT and perceived medication complexity, perceived need for robust behavioral services, and inconsistent availability of on-site specialists. Facilitators included knowledge of adverse health consequences of opioid and tobacco use, local champions, focus on quality improvement, and multidisciplinary teamwork.

Conclusions:

Efforts to implement MAT in HIV clinics should address both gaps in perspectives regarding the evidence for MAT and contextual factors and may require substance-specific models.
Asymmetry, division of labour and the evolution of ageing in multicellular organisms
Authors: Pen Ido , Flatt Thomas
Published: March 2021

Between the 1930s and 1960s, evolutionary geneticists worked out the basic principles of why organisms age. Despite much progress in the evolutionary biology of ageing since that time, however, many puzzles remain. The perhaps most fundamental of these is the question of which organisms should exhibit senescence and which should not (or which should age rapidly and which should not). The evolutionary origin of ageing from a non-senescent state has been conceptually framed, for example, in terms of the separation between germ-line and soma, the distinction between parents and their offspring, and—in unicellular organisms—the unequal distribution of cellular damage at cell division. These ideas seem to be closely related to the concept of ‘division of labour' between reproduction and somatic maintenance. Here, we review these concepts and develop a toy model to explore the importance of such asymmetries for the evolution of senescence. We apply our model to the simplest case of a multicellular system: an organism consisting of two totipotent cells. Notably, we find that in organisms which reproduce symmetrically and partition damage equally, senescence is still able to evolve, contrary to previous claims. Our results might have some bearing on understanding the origin of the germ-line–soma separation and the evolution of senescence in multicellular organisms and in colonial species consisting of multiple types of individuals, such as, for example, eusocial insects with their different castes.

This article is part of the theme issue ‘Ageing and sociality: why, when and how does sociality change ageing patterns?'
Death happy: adaptive ageing and its evolution by kin selection in organisms with colonial ecology
Authors: Galimov Evgeniy R. , Gems David
Published: March 2021

Standard evolutionary theory, supported by mathematical modelling of outbred, dispersed populations predicts that ageing is not an adaptation. We recently argued that in clonal, viscous populations, programmed organismal death could promote fitness through social benefits and has, in some organisms (e.g.
Caenorhabditis elegans
), evolved to shorten lifespan. Here, we review previous adaptive death theory, including consumer sacrifice, biomass sacrifice and defensive sacrifice types of altruistic adaptive death. In addition, we discuss possible adaptive death in certain semelparous fish, coevolution of reproductive and adaptive death, and adaptive reproductive senescence in
C. elegans
. We also describe findings from recent tests for the existence of adaptive death in
C. elegans
using computer modelling. Such models have provided new insights into how trade-offs between fitness at the individual and colony levels mean that senescent changes can be selected traits. Exploring further the relationship between adaptive death and social interactions, we consider examples where adaptive death results more from action of kin than from self-destructive mechanisms and, to describe this, introduce the term adaptive killing of kin.

This article is part of the theme issue ‘Ageing and sociality: why, when and how does sociality change ageing patterns?’
The plasticity of lifespan in social insects
Authors: Heinze Jürgen , Giehr Julia
Published: March 2021

One of the central questions of ageing research is why lifespans of organisms differ so tremendously among related taxa and, even more surprising, among members of the same species. Social insects provide a particularly pronounced example for this. Here, we review previously published information on lifespan plasticity in social insects and provide new data on worker lifespan in the antCardiocondyla obscurior, which because of its relatively short lifespan is a convenient model to study ageing. We show that individual lifespan may vary within species with several reproductive and social traits, such as egg-laying rate, queen number, task, colony size and colony composition. For example, inCardiocondyla, highly fecund queens live longer than reproductively less active queens, and workers tend to live longer when transferred into a novel social environment or, as we show with new data, into small colonies. We hypothesize that this plasticity of lifespan serves to maximize the reproductive output of the colony as a whole and thus the inclusive fitness of all individuals. The underlying mechanisms that link the social environment or reproductive status with lifespan are currently unresolved. Several studies in honeybees and ants indicate an involvement of nutrient-sensing pathways, but the details appear to differ among species.

This article is part of the theme issue ‘Ageing and sociality: why, when and how does sociality change ageing patterns?'