Extreme creep resistance in a microstructurally stable nanocrystalline alloy.

Nanocrystalline metals, with a mean grain size of less than 100 nanometres, have greater room-temperature strength than their coarse-grained equivalents, in part owing to a large reduction in grain size. However, this high strength generally comes with substantial losses in other mechanical properties, such as creep resistance, which limits their practical utility; for example, creep rates in nanocrystalline copper are about four orders of magnitude higher than those in typical coarse-grained copper. The degradation of creep resistance in nanocrystalline materials is in part due to an increase in the volume fraction of grain boundaries, which lack long-range crystalline order and lead to processes such as diffusional creep, sliding and rotation. Here we show that nanocrystalline copper-tantalum alloys possess an unprecedented combination of properties: high strength combined with extremely high-temperature creep resistance, while maintaining mechanical and thermal stability. Precursory work on this family of immiscible alloys has previously highlighted their thermo-mechanical stability and strength, which has motivated their study under more extreme conditions, such as creep. We find a steady-state creep rate of less than 10(-6) per second-six to eight orders of magnitude lower than most nanocrystalline metals-at various temperatures between 0.5 and 0.64 times the melting temperature of the matrix (1,356 kelvin) under an applied stress ranging from 0.85 per cent to 1.2 per cent of the shear modulus. The unusual combination of properties in our nanocrystalline alloy is achieved via a processing route that creates distinct nanoclusters of atoms that pin grain boundaries within the alloy. This pinning improves the kinetic stability of the grains by increasing the energy barrier for grain-boundary sliding and rotation and by inhibiting grain coarsening, under extremely long-term creep conditions. Our processing approach should enable the development of microstructurally stable structural alloys with high strength and creep resistance for various high-temperature applications, including in the aerospace, naval, civilian infrastructure and energy sectors.

Recommendations for rosacea diagnosis, classification and management: update from the global ROSacea COnsensus 2019 panel.

BACKGROUND: A transition from a subtyping to a phenotyping approach in rosacea is underway, allowing individual patient management according to presenting features instead of categorization by predefined subtypes. The ROSacea COnsensus (ROSCO) 2017 recommendations further support this transition and align with guidance from other working groups. OBJECTIVES: To update and extend previous global ROSCO recommendations in line with the latest research and continue supporting uptake of the phenotype approach in rosacea through clinical tool development. METHODS: Nineteen dermatologists and two ophthalmologists used a modified Delphi approach to reach consensus on statements pertaining to critical aspects of rosacea diagnosis, classification and management. Voting was electronic and blinded. RESULTS: Delphi statements on which the panel achieved consensus of ≥ 75% voting 'Agree' or 'Strongly agree' are presented. The panel recommends discussing disease burden with patients during consultations, using four questions to assist conversations. The primary treatment objective should be achievement of complete clearance, owing to previously established clinical benefits for patients. Cutaneous and ocular features are defined. Treatments have been reassessed in line with recent evidence and the prior treatment algorithm updated. Combination therapy is recommended to benefit patients with multiple features. Ongoing monitoring and dialogue should take place between physician and patients, covering defined factors to maximize outcomes. A prototype clinical tool (Rosacea Tracker) and patient case studies have been developed from consensus statements. CONCLUSIONS: The current survey updates previous recommendations as a basis for local guideline development and provides clinical tools to facilitate a phenotype approach in practice and improve rosacea patient management. What's already known about this topic? A transition to a phenotype approach in rosacea is underway and is being recommended by multiple working groups. New research has become available since the previous ROSCO consensus, necessitating an update and extension of recommendations. What does this study add? We offer updated global recommendations for clinical practice that account for recent research, to continue supporting the transition to a phenotype approach in rosacea. We present prototype clinical tools to facilitate use of the phenotype approach in practice and improve management of patients with rosacea.

Patient perceptions of clear/almost clear skin in moderate-to-severe plaque psoriasis: results of the Clear About Psoriasis worldwide survey.

BACKGROUND: Therapeutic advances have made the achievement of clear/almost clear skin possible for many patients with moderate-to-severe plaque psoriasis. OBJECTIVE: To determine patient perceptions of the impact of psoriasis and of attaining clear/almost clear skin. METHODS: Global survey of patients with moderate-to-severe psoriasis. RESULTS: A total of 8338 patients from 31 countries participated. The majority (57%) had not achieved self-assessed clear/almost clear skin with their current therapy, and 56% of those who had not met this goal believed it would be impossible to do so. Among the patients who had clear/almost clear skin, 73% had not initiated their current treatment until >1 year after psoriasis diagnosis, and 28% had to wait >5 years. Eighty-four percent of all respondents experienced discrimination and/or humiliation due to psoriasis, and many reported negative effects on work, intimate relationships, sleep and mental health. Patients without clear/almost clear skin reported that such achievement would open new possibilities, such as swimming (58%), a wider choice of clothing (40%), and meeting new people (26%). A limitation of this study, as with any survey-based research, is that selection and recall bias may have been present. Additionally, respondent definitions of clear/almost clear skin were subjective and may have varied. CONCLUSION: Despite the importance of clear/almost clear skin to psoriasis patients, most are still not achieving it, and many are unaware it is possible.

Biosimilars for psoriasis: worldwide overview of regulatory guidelines, uptake and implications for dermatology clinical practice.

The introduction of biological drugs for the treatment of patients with psoriasis has revolutionized treatment paradigms and enabled numerous patients to achieve disease control with an acceptable safety profile. However, the high cost of biologics limits access to these medications for the majority of patients worldwide. In recent years, the introduction of biosimilars for inflammatory diseases has become a fast evolving field. The future use of biosimilars offers the potential for decreased cost and increased access to biologics for patients with psoriasis. For approval of biosimilars, different regulatory agencies use highly variable methods for definition, production, approval, marketing and postmarketing surveillance. Due to potential interchangeability between biologics and biosimilars, traceability and pharmacovigilance are required to collect accurate data about adverse events in patients with psoriasis; spontaneous reporting, registries and use of 'big data' should facilitate this process on a global basis. The current article describes biosimilar regulatory guidelines and examples of biosimilar uptake in clinical practice in several countries around the world. As it is apparent that biological therapy treatment decisions may become more physician independent, the International Psoriasis Council recommends that dermatologists should take an active role in the development of biosimilar prescribing policies with their respective healthcare settings and government agencies.

Biosimilars for psoriasis: clinical studies to determine similarity.

Biosimilars are drugs that are similar, but not identical, to originator biologics. Preclinical analytical studies are required to show similarity on a molecular and structural level, but efficacy and safety studies in humans are essential to determining biosimilarity. In this review, written by members of the International Psoriasis Council, we discuss how biosimilars are evaluated in a clinical setting, with emphasis on extrapolation of indication, interchangeability and optimal clinical trial design.

Updating the diagnosis, classification and assessment of rosacea: recommendations from the global ROSacea COnsensus (ROSCO) panel.

BACKGROUND: Rosacea is currently diagnosed by consensus-defined primary and secondary features and managed by subtype. However, individual features (phenotypes) can span multiple subtypes, which has implications for clinical practice and research. Adopting a phenotype-led approach may facilitate patient-centred management. OBJECTIVES: To advance clinical practice by obtaining international consensus to establish a phenotype-led rosacea diagnosis and classification scheme with global representation. METHODS: Seventeen dermatologists and three ophthalmologists used a modified Delphi approach to reach consensus on statements pertaining to critical aspects of rosacea diagnosis, classification and severity evaluation. All voting was electronic and blinded. RESULTS: Consensus was achieved for transitioning to a phenotype-based approach to rosacea diagnosis and classification. The following two features were independently considered diagnostic for rosacea: (i) persistent, centrofacial erythema associated with periodic intensification; and (ii) phymatous changes. Flushing, telangiectasia, inflammatory lesions and ocular manifestations were not considered to be individually diagnostic. The panel reached agreement on dimensions for phenotype severity measures and established the importance of assessing the patient burden of rosacea. CONCLUSIONS: The panel recommended an approach for diagnosis and classification of rosacea based on disease phenotype.

Rosacea treatment update: recommendations from the global ROSacea COnsensus (ROSCO) panel.

BACKGROUND: Rosacea is currently treated according to subtypes. As this does not adequately address the spectrum of clinical presentation (phenotypes), it has implications for patient management. The ROSacea COnsensus panel was established to address this issue. OBJECTIVES: To incorporate current best treatment evidence with clinical experience from an international expert panel and establish consensus to improve outcomes for patients with rosacea. METHODS: Seventeen dermatologists and three ophthalmologists reached consensus on critical aspects of rosacea treatment and management using a modified Delphi approach. The panel voted on statements using the responses 'strongly disagree', 'disagree', 'agree' or 'strongly agree'. Consensus was defined as ≥ 75% 'agree' or 'strongly agree'. All voting was electronic and blinded. RESULTS: The panel agreed on phenotype-based treatments for signs and symptoms presenting in individuals with rosacea. First-line treatments were identified for individual major features of transient and persistent erythema, inflammatory papules/pustules, telangiectasia and phyma, underpinned by general skincare measures. Multiple features in an individual patient can be simultaneously treated with multiple agents. If treatment is inadequate given appropriate duration, another first-line option or the addition of another first-line agent should be considered. Maintenance treatment depends on treatment modality and patient preferences. Ophthalmological referral for all but the mildest ocular features should be considered. Lid hygiene and artificial tears in addition to medications are used to treat ocular rosacea. CONCLUSIONS: Rosacea diagnosis and treatment should be based on clinical presentation. Consensus was achieved to support this approach for rosacea treatment strategies.

Mycobacterium tuberculosis CwsA interacts with CrgA and Wag31, and the CrgA-CwsA complex is involved in peptidoglycan synthesis and cell shape determination.

Bacterial cell division and cell wall synthesis are highly coordinated processes involving multiple proteins. Here, we show that Rv0008c, a novel small membrane protein from Mycobacterium tuberculosis, localizes to the poles and on membranes and shows an overall punctate localization throughout the cell. Furthermore, Rv0008c interacts with two proteins, CrgA and Wag31, implicated in peptidoglycan (PG) synthesis in mycobacteria. Deletion of the Rv0008c homolog in M. smegmatis, MSMEG_0023, caused bulged cell poles, formation of rounded cells, and defects in polar localization of Wag31 and cell wall synthesis, with cell wall synthesis measured by the incorporation of the [(14)C]N-acetylglucosamine cell wall precursor. The M. smegmatis MSMEG_0023 crgA double mutant strain showed severe defects in growth, viability, cell wall synthesis, cell shape, and the localization of the FtsZ, FtsI, and Wag31 proteins. The double mutant strain also exhibited increased autolytic activity in the presence of detergents. Because CrgA and Wag31 proteins interact with FtsI individually, we believe that regulated cell wall synthesis and cell shape maintenance require the concerted actions of the CrgA, Rv0008c, FtsI, and Wag31 proteins. We propose that, together, CrgA and Rv0008c, renamed CwsA for cell wall synthesis and cell shape protein A, play crucial roles in septal and polar PG synthesis and help coordinate these processes with the FtsZ-ring assembly in mycobacteria.

A Case Report of Severe Factor XI Deficiency during Cardiac Surgery: Less Can Be More.

Severe congenital Factor XI (FXI) deficiency (<20% normal activity) can be associated with significant bleeding disorders, and there has been great concern for severe bleeding following cardiac surgery requiring cardiopulmonary bypass (CPB) in this patient population. Over the past four decades remarkably different approaches to this problem have been taken, including the administration of blood volumes of fresh frozen plasma, administration of activated recombinant Factor VII, and diminutive administration of heparin. We describe a case wherein the patient was assessed in the perioperative period with a point-of-care, viscoelastic hemostasis device (ROTEM), with changes in the intrinsic/Factor XII-dependent coagulation pathway determined before, during, and after CPB. Fresh frozen plasma was administered in small amounts (5−7.5 mL/kg) just before surgery began and just before cessation of CPB. Administering fresh frozen plasma to the patient to nearly normalize in vitro ROTEM hemostasis values at times when hemostasis was needed resulted in no important bleeding occurring or need of further transfusion of other blood products. In conclusion, by using small amounts of fresh frozen plasma guided by ROTEM, an evidenced-based, precision medicine approach resulted in optimized patient care and outcome.

Characterization of CrgA, a new partner of the Mycobacterium tuberculosis peptidoglycan polymerization complexes.

The role(s) in cell division of the Mycobacterium tuberculosis Rv0011c gene product, a homolog of the Streptomyces CrgA protein that is responsible for coordinating growth and cytokinesis in sporogenic aerial hyphae, is largely unknown. We show that an enhanced cyan fluorescent protein-M. tuberculosis CrgA (ECFP-CrgA(MT)) fusion protein is localized to the cell membrane, midcell, and cell pole regions in Mycobacterium smegmatis. Furthermore, the ECFP-CrgA(MT) fusion protein colocalized with FtsZ-enhanced yellow fluorescent protein (EYFP) in M. smegmatis. Bacterial two-hybrid assays indicated strong interactions of M. tuberculosis CrgA with FtsZ, FtsQ, and the class B penicillin-binding proteins, FtsI (PBPB) and PBPA. The midcell localization of CrgA(MT) was severely compromised under conditions of FtsZ depletion, which indicated that CrgA localizes to the midcell region after assembly of the FtsZ ring. M. tuberculosis cells with reduced CrgA levels were elongated and grew more slowly than wild-type cells, which indicated defects in cell division, whereas CrgA overproduction did not show growth defects. A M. smegmatis ΔcrgA strain exhibited a bulged cell morphology, elongated cells with a chain-like phenotype, cells with polar bulbous structures, and a modest growth defect. FtsZ and FtsI levels were not affected in cells producing altered levels of CrgA. Septal and membrane localization of GFP-FtsI was enhanced by CrgA overproduction and was diminished in a ΔcrgA strain, which indicates that one role of CrgA is to promote and/or stabilize FtsI localization. Overall, these data indicate that CrgA is a novel member of the cell division complex in mycobacteria and possibly facilitates septum formation.

Anomalous mechanical behavior of nanocrystalline binary alloys under extreme conditions.

Fundamentally, material flow stress increases exponentially at deformation rates exceeding, typically, ~103 s-1, resulting in brittle failure. The origin of such behavior derives from the dislocation motion causing non-Arrhenius deformation at higher strain rates due to drag forces from phonon interactions. Here, we discover that this assumption is prevented from manifesting when microstructural length is stabilized at an extremely fine size (nanoscale regime). This divergent strain-rate-insensitive behavior is attributed to a unique microstructure that alters the average dislocation velocity, and distance traveled, preventing/delaying dislocation interaction with phonons until higher strain rates than observed in known systems; thus enabling constant flow-stress response even at extreme conditions. Previously, these extreme loading conditions were unattainable in nanocrystalline materials due to thermal and mechanical instability of their microstructures; thus, these anomalies have never been observed in any other material. Finally, the unique stability leads to high-temperature strength maintained up to 80% of the melting point (~1356 K).

Selenocysteine tRNA[Ser]Sec gene is ubiquitous within the animal kingdom.

Recently, a mammalian tRNA which was previously designated as an opal suppressor seryl-tRNA and phosphoseryl-tRNA was shown to be a selenocysteyl-tRNA (B. J. Lee, P. J. Worland, J. N. Davis, T. C. Stadtman, and D. Hatfield, J. Biol. Chem. 264:9724-9727, 1989). Hence, this tRNA is now designated as selenocysteyl-tRNA[Ser]Sec, and its function is twofold, to serve as (i) a carrier molecule upon which selenocysteine is biosynthesized and (ii) as a donor of selenocysteine, which is the 21st naturally occurring amino acid of protein, to the nascent polypeptide chain in response to specific UGA codons. In the present study, the selenocysteine tRNA gene was sequenced from Xenopus laevis, Drosophila melanogaster, and Caenorhabditis elegans. The tRNA product of this gene was also identified within the seryl-tRNA population of a number of higher and lower animals, and the human tRNA[Ser]Sec gene was used as a probe to identify homologous sequences within genomic DNAs of organisms throughout the animal kingdom. The studies showed that the tRNA[Ser]Sec gene has undergone evolutionary change and that it is ubiquitous in the animal kingdom. Further, we conclude that selenocysteine-containing proteins, as well as the use of UGA as a codon for selenocysteine, are far more widespread in nature than previously thought.

Cost-effectiveness Analysis of Stereotactic Radiosurgery Alone Versus Stereotactic Radiosurgery with Upfront Whole Brain Radiation Therapy for Brain Metastases.

AIMS: Stereotactic radiosurgery (SRS) alone or upfront whole brain radiation therapy (WBRT) plus SRS are the most commonly used treatment options for one to three brain oligometastases. The most recent randomised clinical trial result comparing SRS alone with upfront WBRT plus SRS (NCCTG N0574) has favoured SRS alone for neurocognitive function, whereas treatment options remain controversial in terms of cognitive decline and local control. The aim of this study was to conduct a cost-effectiveness analysis of these two competing treatments. MATERIALS AND METHODS: A Markov model was constructed for patients treated with SRS alone or SRS plus upfront WBRT based on largely randomised clinical trials. Costs were based on 2016 Medicare reimbursement. Strategies were compared using the incremental cost-effectiveness ratio (ICER) and effectiveness was measured in quality-adjusted life years (QALYs). One-way and probabilistic sensitivity analyses were carried out. Strategies were evaluated from the healthcare payer's perspective with a willingness-to-pay threshold of $100 000 per QALY gained. RESULTS: In the base case analysis, the median survival was 9 months for both arms. SRS alone resulted in an ICER of $9917 per QALY gained. In one-way sensitivity analyses, results were most sensitive to variation in cognitive decline rates for both groups and median survival rates, but the SRS alone remained cost-effective for most parameter ranges. CONCLUSIONS: Based on the current available evidence, SRS alone was found to be cost-effective for patients with one to three brain metastases compared with upfront WBRT plus SRS.

Cytomegalovirus infection inducing flare of Behcet's disease with possible recurrence of glomerulonephritis after renal transplantation.

We present a case of young male with end-stage renal disease due to type III membranoproliferative glomerulonephritis (GN) and clinical features consistent with Behcet's disease (BD). He developed flare of BD 3 months after deceased donor renal transplantation following cytomegalovirus infection, in the form of oral and genital ulcers. He also had GN characterized by mild mesangial proliferation, neutrophilic infiltration and subepithelial, mesangial and intramembranous electron dense deposits, which could possibly be attributed to recurrence of renal disease due to BD. The clinical flare of BD was treated with colchicine with good response.

Characterization of the functional replication origin of Mycobacterium tuberculosis.

The gene order in the 5kb Mycobacterium tuberculosis dnaA region is rnpA, rpmH, dnaA, dnaN and recF. We show that M. tuberculosis DNA fragment containing the dnaA-dnaN intergenic region functioned as oriC, i.e., allowed autonomous replication to otherwise nonreplicative plasmids, in M. tuberculosis H37Ra (H37Ra), avirulent strain of M. tuberculosis, and in Mycobacterium bovis BCG (BCG), a closely related, slowly growing mycobacterial strain. Removal of Escherichia coli plasmid replication origin (ColE1) from the M. tuberculosis oriC plasmids did not abolish their ability to function as oriC, confirming that the autonomous replication activity of these plasmids is due to the presence of the DNA fragment containing the dnaA-dnaN intergenic region. Deletion analyses revealed that the minimal oriC DNA fragment is 814bp. The copy number of M. tuberculosis oriC plasmids containing ColE1 ori relative to chromosomal oriC is one and the 5' flanking region of minimal oriC contains features that support stable autonomous replication. The M. tuberculosis oriC did not function in rapidly growing mycobacterial species such as M. smegmatis. M. smegmatis oriC functioned only in M. fortuitum, but not in any of the slowly growing mycobacterial species such as M. tuberculosis and BCG. Together these data suggest that the replication initiation mechanisms in the slowly growing Mycobacteria are similar and probably different from those in the rapidly growing Mycobacteria and vice versa.

Amplification and cloning of the Mycobacterium tuberculosis dnaA gene.

To identify and subsequently clone the gene encoding the DnaA protein, degenerate oligodeoxyribonucleotide (oligo) primers targeted against two highly conserved domains of the eubacterial DnaA were used to amplify a 780-bp DNA region spanning the two primers from genomic DNA preparations of Mycobacterium tuberculosis (Mt), M. bovis (Mb) and M. avium (Ma). Nucleotide (nt) sequences and deduced amino acid (aa) sequences of these fragments revealed homologies with each other and with the corresponding regions from other bacteria. Using an oligo specific to Mt dnaA as a probe, the Mt genomic DNA cosmid libraries propagated in Escherichia coli were screened and a cosmid DNA clone hybridizing with the oligo was identified. Furthermore, a 5-kb DNA fragment containing the Mt dnaA was subcloned into a pUC18 vector.

Base-base interactions in nucleic acids containing A-T base pairs. Structure of poly[d(A-T)].

The Watson-Crick type of base pairing is considered to be mandatory for the formation of duplex DNA. However, conformational calculations carried out in our laboratory, have shown that some combinations of backbone torsion angles and sugar pucker lead to duplexes with Hoogsteen type of base pairing also. Here we present the results of energy calculations performed on A-T containing doublet sequences in the D-form with both Hoogsteen and Watson-Crick type of base pairing and the 3 viable models for the A-T containing polynucleotide duplex poly[d(A-T)].

XYY chromosome anomaly and schizophrenia.

Sex chromosome anomalies have been associated with psychoses, and most of the evidence is linked to the presence of an additional X chromosome. We report a patient with XYY chromosome anomaly who developed schizophrenia.

In situ hybridization and immunocytochemistry for improved assessment of human immunodeficiency virus cultures.

The authors characterized the early intracellular events involved in human immunodeficiency virus (HIV) replication after in vitro inoculation into cultures of susceptible human T-cell lines and phytohemagglutinin-stimulated peripheral-blood mononuclear cells (PMCs). Within 24 hours of infection, in situ hybridization with HIV DNA probe detected cytoplasmic viral RNA. Viral core antigen was detected in infected cells over the subsequent two to ten days by means of an immunocytochemical assay employing monoclonal antibodies. Several days later, cell-free virus was detected by both reverse transcriptase assay and a p25gag antigen-capture assay. When these methods were applied to monitor cultures of ten sero-positive persons' PMCs, a similar progression of virus replication was apparent: cytoplasmic viral RNA was detected in infected PMCs by day 3, with the subsequent appearance of intracellular viral proteins (days 6-9) and cell-free virus (days 12-21). In situ hybridization and immunocytochemistry offer complementary, sensitive, and specific approaches for monitoring the early stages of acquired immune deficiency syndrome virus replication in vitro.

In vivo exposure to ultraviolet radiation enhances pathogenic effects of murine leukemia virus, LP-BM5, in murine acquired immunodeficiency syndrome.

LP-BM5 murine leukemia virus (MuLV) induces an immunodeficiency syndrome (MAIDS) in C57BL/6 mice which resembles immunological abnormalities observed in early stages of human AIDS. In our study, MAIDS virus-infected mice were exposed to low doses of ultraviolet radiation (UVR) before and after virus inoculation and compared with MAIDS-infected but not UVR-exposed mice. In all tested parameters (blood IgM levels; mitogenic responses to PHA, ConA, LPS and anti-mu; MLR; antigenic response to SRBC; enlargement and histopathologic changes of the spleen) we observed the same trend: changes due to MAIDS infection were more pronounced in the UVR-exposed group than in the unexposed group. Statistically significant differences between these two groups were seen for mitogenic responses at two different time points after virus inoculation. These results demonstrate that in vivo UVR exposure enhances the immunosuppressive effects of a retroviral infection. UVR exposure may affect the progression of AIDS in a similar manner.