Laboratory realization of relativistic pair-plasma beams.

Relativistic electron-positron plasmas are ubiquitous in extreme astrophysical environments such as black-hole and neutron-star magnetospheres, where accretion-powered jets and pulsar winds are expected to be enriched with electron-positron pairs. Their role in the dynamics of such environments is in many cases believed to be fundamental, but their behavior differs significantly from typical electron-ion plasmas due to the matter-antimatter symmetry of the charged components. So far, our experimental inability to produce large yields of positrons in quasi-neutral beams has restricted the understanding of electron-positron pair plasmas to simple numerical and analytical studies, which are rather limited. We present the first experimental results confirming the generation of high-density, quasi-neutral, relativistic electron-positron pair beams using the 440 GeV/c beam at CERN's Super Proton Synchrotron (SPS) accelerator. Monte Carlo simulations agree well with the experimental data and show that the characteristic scales necessary for collective plasma behavior, such as the Debye length and the collisionless skin depth, are exceeded by the measured size of the produced pair beams. Our work opens up the possibility of directly probing the microphysics of pair plasmas beyond quasi-linear evolution into regimes that are challenging to simulate or measure via astronomical observations.

Efficacy of standard- vs reduced-dose insulin for treatment of hyperkalemia: A quasi-experiment.

PURPOSE: Hyperkalemia more commonly affects patients with a glomerular filtration rate of less than 60 mL/min. Using intravenous (IV) insulin to shift potassium intracellularly may cause hypoglycemia, requiring additional treatment or longer hospitalization. Literature on insulin dosing in this context is limited, with one previous study indicating that 5 units of IV insulin might be as effective and result in less hypoglycemia than the standard dose of 10 units of IV insulin. The hyperkalemia treatment pathway at our institution was revised in May 2018 to include a reduced-dose option (5 units of insulin) for patients with end-stage renal disease. This study aimed to compare the prevalence of hypoglycemia between patients who received standard-dose vs reduced-dose IV insulin. METHODS: This single-center, retrospective, quasi-experimental study evaluated the impact of revision of the hyperkalemia treatment pathway by assessing rates of hypoglycemia during the 6 months before and after implementation of the revised pathway. The primary endpoint was prevalence of hypoglycemia, defined as a blood glucose level of less than or equal to 70 mg/dL. RESULTS: There was no statistically significant difference in the occurrence of hypoglycemia when comparing the pre- and postimplementation groups (36 [17.7%] patients vs 34 [18.7%] patients; P = 0.7924). The postimplementation group had a statistically significant lower reduction in potassium levels after treatment than the preimplementation group (mean [interquartile range], -0.9 [-1.3, -0.5] mEq/L vs -0.6 [-1.2, -0.2] mEq/L; P = 0.0095). Baseline potassium levels were similar between the groups. CONCLUSION: Administration of reduced-dose IV insulin for treatment of hyperkalemia was significantly less effective in lowering serum potassium levels and did not decrease prevalence of hypoglycemia. When accounting for potential confounders, the only variable that was associated with hypoglycemia was pretreatment glucose level.

Scalable radiotherapy data curation infrastructure for deep-learning based autosegmentation of organs-at-risk: A case study in head and neck cancer.

In this era of patient-centered, outcomes-driven and adaptive radiotherapy, deep learning is now being successfully applied to tackle imaging-related workflow bottlenecks such as autosegmentation and dose planning. These applications typically require supervised learning approaches enabled by relatively large, curated radiotherapy datasets which are highly reflective of the contemporary standard of care. However, little has been previously published describing technical infrastructure, recommendations, methods or standards for radiotherapy dataset curation in a holistic fashion. Our radiation oncology department has recently embarked on a large-scale project in partnership with an external partner to develop deep-learning-based tools to assist with our radiotherapy workflow, beginning with autosegmentation of organs-at-risk. This project will require thousands of carefully curated radiotherapy datasets comprising all body sites we routinely treat with radiotherapy. Given such a large project scope, we have approached the need for dataset curation rigorously, with an aim towards building infrastructure that is compatible with efficiency, automation and scalability. Focusing on our first use-case pertaining to head and neck cancer, we describe our developed infrastructure and novel methods applied to radiotherapy dataset curation, inclusive of personnel and workflow organization, dataset selection, expert organ-at-risk segmentation, quality assurance, patient de-identification, data archival and transfer. Over the course of approximately 13 months, our expert multidisciplinary team generated 490 curated head and neck radiotherapy datasets. This task required approximately 6000 human-expert hours in total (not including planning and infrastructure development time). This infrastructure continues to evolve and will support ongoing and future project efforts.

Observations of pressure anisotropy effects within semi-collisional magnetized plasma bubbles.

Magnetized plasma interactions are ubiquitous in astrophysical and laboratory plasmas. Various physical effects have been shown to be important within colliding plasma flows influenced by opposing magnetic fields, however, experimental verification of the mechanisms within the interaction region has remained elusive. Here we discuss a laser-plasma experiment whereby experimental results verify that Biermann battery generated magnetic fields are advected by Nernst flows and anisotropic pressure effects dominate these flows in a reconnection region. These fields are mapped using time-resolved proton probing in multiple directions. Various experimental, modelling and analytical techniques demonstrate the importance of anisotropic pressure in semi-collisional, high-ß plasmas, causing a reduction in the magnitude of the reconnecting fields when compared to resistive processes. Anisotropic pressure dynamics are crucial in collisionless plasmas, but are often neglected in collisional plasmas. We show pressure anisotropy to be essential in maintaining the interaction layer, redistributing magnetic fields even for semi-collisional, high energy density physics (HEDP) regimes.

An effective CTL peptide vaccine for Ebola Zaire Based on Survivors' CD8+ targeting of a particular nucleocapsid protein epitope with potential implications for COVID-19 vaccine design.

The 2013-2016 West Africa EBOV epidemic was the biggest EBOV outbreak to date. An analysis of virus-specific CD8+ T-cell immunity in 30 survivors showed that 26 of those individuals had a CD8+ response to at least one EBOV protein. The dominant response (25/26 subjects) was specific to the EBOV nucleocapsid protein (NP). It has been suggested that epitopes on the EBOV NP could form an important part of an effective T-cell vaccine for Ebola Zaire. We show that a 9-amino-acid peptide NP44-52 (YQVNNLEEI) located in a conserved region of EBOV NP provides protection against morbidity and mortality after mouse adapted EBOV challenge. A single vaccination in a C57BL/6 mouse using an adjuvanted microsphere peptide vaccine formulation containing NP44-52 is enough to confer immunity in mice. Our work suggests that a peptide vaccine based on CD8+ T-cell immunity in EBOV survivors is conceptually sound and feasible. Nucleocapsid proteins within SARS-CoV-2 contain multiple Class I epitopes with predicted HLA restrictions consistent with broad population coverage. A similar approach to a CTL vaccine design may be possible for that virus.

Role of the COOH-terminal nonhelical tailpiece in the assembly of a vertebrate nonmuscle myosin rod.

A short nonhelical sequence at the COOH-terminus of vertebrate nonmuscle myosin has been shown to enhance myosin filament assembly. We have analyzed the role of this sequence in chicken intestinal epithelial brush border myosin, using protein engineering/site-directed mutagenesis. Clones encoding the rod region of this myosin were isolated and sequenced. They were truncated at various restriction sites and expressed in Escherichia coli, yielding a series of mutant myosin rods with or without the COOH-terminal tailpiece and with serial deletions from their NH2-termini. Deletion of the 35 residue COOH-terminal nonhelical tailpiece was sufficient to increase the critical concentration for myosin rod assembly by 50-fold (at 150 mM NaCl, pH 7.5), whereas NH2-terminal deletions had only minor effects. The only exception was the longest NH2-terminal deletion, which reduced the rod to 119 amino acids and rendered it assembly incompetent. The COOH-terminal tailpiece could be reduced by 15 amino acids and it still efficiently promoted assembly. We also found that the tailpiece promoted assembly of both filaments and segments; assemblies which have different molecular overlaps. Rod fragments carrying the COOH-terminal tailpiece did not promote the assembly of COOH-terminally deleted material when the two were mixed together. The tailpiece sequence thus has profound effects on assembly, yet it is apparently unstructured and can be bisected without affecting its function. Taken together these observations suggest that the nonhelical tailpiece may act sterically to block an otherwise dominant but unproductive molecular interaction in the self assembly process and does not, as has been previously thought, bind to a specific target site(s) on a neighboring molecule.

Providing high-quality research training for veterinary pathologists in Europe.

Despite their key role in a wide range of fields relating to animal and public health, there is currently a lack of veterinary pathologists in Europe. In 1999, to help address the problem, the European College of Veterinary Pathologists (ECVP) and the European Society of Veterinary Pathology (ESVP) established a joint Education Committee. In this Special Article, Professor Anja Kipar and colleagues, all members of the committee, describe the ECVP/ESVP Summer Schools in Veterinary Pathology programme, which aims to provide high-quality research training for veterinary pathologists from all over Europe and beyond.

Would the introduction of the Index of Orthognathic Functional Treatment Need (IOFTN) affect referrals and acceptance of people for orthognathic treatment?

Introduction The Index of Orthognathic Functional Treatment Need (IOFTN) was developed to measure functional difficulties arising from malocclusions related to facial deformity. The IOFTN is not currently being used to determine suitability for orthognathic treatment, however, it is a useful aid for assessing and referring patients and takes into account functional and facial appearance. This paper aims to evaluate the potential impact of introduction of the IOFTN on the future provision of orthognathic services.Methods Two methods were used to consider the impact of the IOFTN on orthognathic provision. Firstly, a local retrospective audit was undertaken in Leeds Teaching Hospital NHS Trust involving thirty consecutively treated patients, for whom full records were retrieved. Data was collected using a standardised data caption form. Local standards were agreed concerning the need for treatment. Secondly, a systematic search of published studies was completed to assess evidence from across the UK.Results The audit standard, that is, 90% of patients treated with orthognathic surgery should be categorised as grade 4 (great need) or 5 (very great need) using the IOFTN, was fulfilled. The most common reason for seeking treatment related to dental and facial aesthetics and no patients were treated for speech or TMJ problems alone. The systematic review searches identified four suitable records for inclusion in the review, including two audits and two retrospective studies undertaken in secondary care settings across England and Scotland. These studies showed that at least 86% of all participants scored 4 or 5 using the IOFTN.Conclusions The findings from the audit and literature review indicate that referrals from general dentists and acceptance for orthognathic treatment in secondary care is unlikely to be significantly affected by introduction of the IOFTN. Referring dentists may find the IOFTN a useful prompt for determining whether people are suitable for orthognathic treatment.

Can dental registrants use the Index of Orthodontic Treatment Need accurately? Part 1: Knowledge of IOTN among dental registrants.

Aim To determine whether dental registrants can use the dental health component (DHC) and aesthetic component (AC) of the Index of Orthodontic Treatment Need (IOTN) 'accurately' to an acceptable level of agreement and diagnostic validity.Method Participants from six different registrant groups were asked to score the IOTN for 14 cases based on study models and photographs as well as completing a short questionnaire. Participants in the study were all recruited at study days and annual conferences. The main outcome measures include the different registrant groups IOTN scores compared to expert panel scores using kappa statistics. To assess for diagnostic validity, individual participants sensitivity and specificity scores were calculated.Result Overall, 229 registrants took part in the study. For the DHC the specialist orthodontist (SO), postgraduate orthodontic student (PGOS) and the qualified orthodontic therapist (QOT) groups achieved a mean kappa ≥0.60 indicating 'acceptable' agreement with the expert panel scores. The dental foundation trainee (DFT) and general dental practitioner (GDP) group achieved a mean kappa of 0.20 and 0.22 respectively indicating poor and fair agreement. The student orthodontic therapist (SOT) group achieved a mean kappa of 0.55 indicating moderate agreement. For the AC none of the registrant groups achieved an acceptable level of agreement with the mean kappa scores for the different groups ranging from kappa 0.13-0.21, indicating poor to fair agreement.Conclusion Overall agreement for the DHC was varied for the different registrant groups ranging from fair to substantial agreement. Registrants were better at applying the DHC compared to the AC with agreement ranging from poor to fair. More needs to done to help registrants use the IOTN more 'accurately'.

Can dental registrants use the Index of Orthodontic Treatment Need accurately? Part 2. Factors influencing knowledge of IOTN among dental registrants.

Aim To understand the frequency of use and training of IOTN amongst dental registrants working in primary and secondary care. To ascertain which factors influence 'accuracy' of IOTN amongst dental registrants.Method Participants were asked to complete a short questionnaire at the same time as scoring the IOTN for 14 cases. The questionnaire was developed by the authors of this study to understand registrants' place of work, frequency of use of IOTN and training undertaken in IOTN. Multiple linear regression analysis was used to reveal which predictor factors best described a registrant's knowledge of IOTN.Results The mean kappa scores were the highest for participants working in secondary care (K = 0.68) when compared to those solely working in primary care. The SO and GDP groups were found to be the groups with the largest proportion of participants using IOTN on a daily basis. Only the participants that used the IOTN everyday achieved an acceptable mean DHC K >0.60. There is an increasing trend of mean DHC kappa scores evident with increasing frequency of use of IOTN. All participants had received training in the use of IOTN with the majority (n = 181/229) having their last episode of training within the last five years. The majority of the training received in IOTN was classified as being verifiable (n = 154/229) with the remainder classifying their training as non-verifiable. Two predictor variables were found to have a significant influence on the DHC kappa scores, which included registrant group and place of work. Only one of the predictor variables had a statistically significant influence on the AC kappa scores, which was the type of CPD, with participants who had received non-verifiable CPD having a lower kappa scores.Conclusion Place of work, frequency of use of IOTN and registrant group were the main factors which were found to influence accuracy of use of IOTN. This study has highlighted a need for greater support in terms of resources, training and tools to help dental registrants use the IOTN more accurately to an acceptable level.

Orthodontic therapists - has their introduction affected outcomes?

Objective To assess the effect of the introduction of orthodontic therapists (OTs) on the quality of orthodontic treatment outcomes in two specialist orthodontic practices in the UK.Study design Retrospective cross sectional observational study.Setting Multi-centre evaluation at two specialist orthodontic practices in Yorkshire. Data collection was carried out during 2014.Materials and methods The treatment undertaken by three specialist orthodontic clinicians (A, B and C) was evaluated at two time points. The first time point (T1) was before the introduction of OTs when the specialist orthodontic clinicians were solo operators. The second time point (T2) followed the introduction of OTs. Patients at T2 had their treatment planned by a specialist orthodontist and were seen for care by both the orthodontist and an OT who had been qualified for a minimum of three years. A sample size of 30 orthodontic patients per clinician at each time point was chosen. Included participants had completed a course of fixed appliance therapy. They were consecutively selected from cases that had been completed in the specified time frame for each clinician.Main outcome measures The quality of treatment was assessed objectively using the quantitative Peer Assessment Rating index (PAR index). Data extracted from the specialist practice databases also allowed conclusions to be drawn about the length of treatment time and number of appointments in each treatment group.Results and conclusions There appears to have been no change in orthodontic treatment outcomes following the introduction of supervised OTs at two specialist orthodontic practices.

Effects of 0.5% Timolol Maleate Ophthalmic Solution on Heart Rate and Selected Echocardiographic Indices in Apparently Healthy Cats.

BACKGROUND: Echocardiographic assessment of diastolic function is challenging in cats, partially because of transmitral flow pattern fusion associated with high heart rates. With heart rate (HR) reduction, transmitral flow waveforms separate, allowing identification of diastolic dysfunction. Timolol, an ophthalmic, nonselective beta-blocker used in glaucoma is safe and transiently decreases HR in clinical trials. HYPOTHESIS: Administration of timolol ophthalmic solution decreases HR and facilitates echocardiographic assessment of diastolic function in cats without inducing clinically relevant adverse effects. ANIMALS: Twenty-five apparently healthy cats. METHODS: Electrocardiograms and echocardiograms including transmitral flow patterns were evaluated before and 20 minutes after ocular administration of 1 drop of timolol 0.5% solution. Twenty cats underwent treatment with timolol, and 5 different cats served as untreated controls to evaluate the effects of acclimation to the hospital environment on HR. RESULTS: Acclimation to the hospital had no effect on HR in control cats. After timolol administration, a significant median HR reduction of 25 bpm was observed (P < .0001). Timolol had no effect on E/A ratio in cats without E/A fusion (7/20, P = .44). Of the 13 cats with E and A waves that were fused before timolol application, separation of these waves was identified in 8 cats (62%) after timolol treatment. No bradyarrhythmias were noted after timolol administration, but 2 cats had first-degree atrioventricular block. Timolol resulted in resolution of dynamic outflow tract obstruction in 6 of 6 cats. CONCLUSIONS AND CLINICAL IMPORTANCE: Ocular administration of timolol safely decreases HR in cats and could facilitate assessment of diastolic function.

Sequence comparison of putative regulatory DNA of the 5' flanking region of the myeloperoxidase gene in normal and leukemic bone marrow cells.

Myeloperoxidase (MPO) is an enzyme which is exclusively expressed in immature myeloid cells with downregulation of gene expression occurring during granulocytic maturation. Levels of MPO RNA, protein, and enzyme activity differ, usually in a concordant fashion, among the various classes of acute leukemia and among different cases within a particular class. One portion of the gene thought to be involved in regulation of MPO expression is the proximal 5' flanking region. To determine if mutations in this putatively regulatory region of the MPO gene might be responsible for some of the differences in level of MPO expression among different cases or classes of acute leukemia, we compared the nucleotide sequence of this part of the gene from 16 patients with acute leukemia, with DNA from normal human bone marrow cells and selected other neoplasms and cell lines. The sequence of this regulatory region was found to be identical in cases of acute myeloid leukemia (AML) with tha of normal DNA except for a dA to dG transition in the Alu region, 463 bases upstream from the transcription start site. This base substitution was seen in almost all cases of AML studied, regardless of the level of MPO which they expressed. It was absent from normal human DNA obtained from various tissues, and cases of acute and chronic lymphocytic leukemia, carcinoma of lung, and most cell lines examined. The base substitution was also absent in a remission blood sample from one of the cases which showed the dA to dG transition in leukemic marrow, suggesting that the base substitution is a mutation rather than a polymorphism. Our results suggest that mutations in promoter or enhancer DNA are not an important cause of the differences in level of MPO gene expression seen among different cases or different classes of AML. However, the base substitution we have detected could potentially serve as a useful marker for detection of residual disease in patients with AML following treatment.

'Who does what' in the orthodontic workforce.

The contraction of the economy in the United Kingdom and constraints on the National Health Service (NHS) together with new opportunities for the delivery of orthodontic treatment has resulted in an increasing number of dental personnel across the different registrant groups. This article focuses on the changes that have taken place in the orthodontic workforce over the past decade. Although others help deliver orthodontic services such as material suppliers, treatment coordinators and those involved in marketing, this article will restrict itself to informing the reader specifically about which dental registrants are doing what at the clinical interface. How health professionals have developed their skills to undertake the role they play within the team and possible threats arising because of these changes are also discussed.

Who needs orthodontic treatment? Who gets it? And who wants it?

As the health and expectations of the UK population improve, demand for orthodontic treatment is increasing. This article will examine who actually needs orthodontic treatment and who is currently receiving it, while also providing an opinion on the the risks versus benefits in providing demand-led treatment.

Mother-to-child discordance in HLA-G exon 2 is associated with a reduced risk of perinatal HIV-1 transmission.

Definitive genetic parameters correlating with mother-to-child transmission (MCT) of HIV have not been fully established. We screened for the potential correlation between HLA-G variants and MCT, in a cohort of mother-child pairs. Discordance in exon 2 of HLA-G was significantly more common among non-transmitting (93%) than transmitting mother-child pairs (40%). Our results suggest that mother-child pairs both carrying the identical mutation in HLA-G exon 2 may be at higher risk of MCT of HIV-1.

Electrode cuff-induced changes in DNA and PDGF gene expression in the rat carotid artery.

Low current (0.25, 3 mA) stimulation through a miniature electrode cuff encased around the carotid artery of the rat was used to induce intimal hyperplasia, an important feature of the atherosclerotic plaque and a phenomenon limiting the long term success of angioplasty. Compared to contralateral unstimulated arteries, 11-14 days of daily transmural stimulation of cuffed arteries (20 min period) significantly increased the amount of extracted DNA (diphenylamine colorimetric assay). Low current (0.25 mA) was as effective as 3 mA in producing an increase in extractable DNA. The cuff alone without applied current also stimulated an increase in DNA content but to a smaller degree than in arteries receiving current. Infusion of a calcium channel antagonist, diltiazem, at a dose which achieved therapeutic drug levels, significantly reduced the amount of electrode cuff-induced DNA content but had no effect on the increase in DNA induced by the presence of the cuff without applied current. Gene expression of PDGF-A chain, PDGF-B chain and PDGF-beta receptor (beta r) (Northern analysis of extracted carotid RNA) increased within 4 h after electrical stimulation with 3 mA. Lower current (0.25 mA) and the presence of the cuff also enhanced PDGF gene expression but with a delayed onset of several days. The pattern of gene expression for PDGF ligands and beta r during the 11-14 days of stimulation differed, but each remained above contralateral control levels. It is concluded that the continued coexpression of PDGF and one of its receptors may contribute to induced hyperplastic changes.

Humans with OKT4-epitope deficiency have a single nucleotide base change in the CD4 gene, resulting in substitution of TRP240 for ARG240.

The OKT4 epitope of the CD4 cell-surface protein has been shown to be polymorphic in white, black, and Japanese populations. The variable phenotypic expression is due to an alteration of the OKT4 epitope, since those persons lacking reactivity with OKT4 monoclonal antibody (mAb) are reactive with OKT4A-F mAb as well as other mAb specific for CD4. To determine the nature of this polymorphism at the gene level, we sequenced polymerase chain reaction-amplified genomic DNA containing the CD4-V3 and -V4 exons from American black subjects who are OKT4-normal, OKT4-negative heterozygous, or OKT4-negative homozygous. Comparison of the sequences revealed that the two CD4 exons are identical except for a cytosine-to-thymidine transition occurring at nucleotide position 868. This alters the first codon position of mino acid 240 and results in a tryptophan residue replacing an arginine residue. The change was also found in white and Japanese persons who are OKT4-negative.

A novel DRB1 allele in DR2-positive American blacks.

Class II D region antigens of the major histocompatibility complex are naturally occurring dimeric proteins found on the surface of lymphoid cells. In most haplotypes at least two of the polymorphic beta chains are associated with a nonpolymorphic alpha chain. The allelic variation of these proteins lies in the first domain of the expressed protein. At present, there are four known DRB genes. DRB1 encodes for the classical DR 1, 3, 4, 5, etc., specificities. DRB3 and DRB4 encode the four supertypic specificities of DRw52 and the single phenotype of DRw53, respectively. Two DRB genes are expressed in human leukocyte antigen DR2-positive individuals. While DRB1 is the more polymorphic gene in most haplotypes, in DR2 haplotypes it appears that DRB5 encodes the polymorphic DR beta chain and the DRB1 encodes a nonpolymorphic beta chain. We attempted to further define the diversity of this region by direct dideoxynucleotide sequencing of polymerase-chain-reaction-amplified genomic DNA. We identified a novel DRB1 allele in DR2-positive individuals that was only observed in the American blacks sampled. This allele may code for a black specific class II antigen.

Production of a novel viral suppressive activity associated with resistance to infection among female sex workers exposed to HIV type 1.

To investigate mechanisms of natural resistance to human immunodeficiency virus type 1 (HIV-1), we obtained blood samples from eight women who remained HIV-1 negative after > 3 years of high-risk sex work in Chiang Rai, Thailand. CD4+ T lymphocytes from these highly exposed, persistently seronegative (HEPS) women were readily infectable in vitro with HIV-1 subtypes B and E. Autologous CD8+ cell suppression of both HIV-1 subtypes was evident in HEPS infection cultures, but to an extent also observed in cultures from non-HIV-exposed individuals. Furthermore, production of beta-chemokines was not enhanced in HEPS cultures. However, HEPS cultures displayed significantly enhanced production of a soluble activity that suppressed postintegrated HIV-1 replication. This activity was the unique product of CD4+ T cell and monocyte cocultures. Therefore, although HEPS individuals are apparently susceptible to infection, the production of a postintegrated HIV-1 suppressive activity during monocyte-T cell interactions might protect against the establishment of infection by limiting viral dissemination.