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Background: This study sought to evaluate the safety, efficacy, and resource utilization of a pilot outpatient surgery program for total hip arthroplasty compared to traditional inpatient total hip arthroplasty performed via the posterolateral approach. Methods: A cohort of 68 patients from two sites were enrolled in a regional pilot project for outpatient total hip arthroplasty (THA) and matched 1:1 against a cohort of patients undergoing routine inpatient THA. Data was extracted retrospectively from patient and hospital charts including adverse events (AE), readmission within 90 days, emergency room (ER) visits, patient calls, patient-reported outcome measures, length of stay, and multiple surgical variables. Results: The outpatient group had a mean hospital stay of 13 hours, whereas the inpatient group had a mean of 58 hours (p<0.001). Three outpatients and four inpatients experienced post-op complications. Three inpatients and one outpatient visited the ER within 8 weeks of surgery. No difference in pre-operative hemoglobin (p = 0.210), or surgical blood loss (p = 0.550) was found between study groups. There was no difference found between groups regarding Oxford-12 Hip Score improvement, nor satisfaction at six months, one and two years (p>0.125). Conclusion: This study demonstrates that outpatient THA using the posterolateral approach is as safe and effective as inpatient THA for overall healthy and carefully screened patients, based on the low rate of AEs observed and similar patient outcomes reported. Significantly reduced time in hospital demonstrates the reduced healthcare resources associated with outpatient THA. [ABSTRACT FROM AUTHOR]

Objectives: Urinary biochemistry is used to detect and monitor conditions associated with recurrent kidney stones. There are no predictive machine learning (ML) tools for kidney stone type or recurrence. We therefore aimed to build and validate ML models for these outcomes using age, gender, 24-hour urine biochemistry, and stone composition. Materials and Methods: Data from three cohorts were used, Southampton, United Kingdom (n = 3013), Newcastle, United Kingdom (n = 5984), and Bern, Switzerland (n = 794). Of these 3130 had available 24-hour urine biochemistry measurements (calcium, oxalate, urate [Ur], pH, volume), and 1684 had clinical data on kidney stone recurrence. Predictive ML models were built for stone type (n = 5 models) and recurrence (n = 7 models) using the UK data, and externally validated with the Swiss data. Three sets of models were built using complete cases, multiple imputation, and oversampling techniques. Results: For kidney stone type one model (extreme gradient boosting [XGBoost] built using oversampled data) was able to effectively discriminate between calcium oxalate, calcium phosphate, and Ur on both internal and external validation. For stone recurrence, none of the models were able to discriminate between recurrent and nonrecurrent stone formers. Conclusions: Kidney stone recurrence cannot be accurately predicted using modeling tools built using specific 24-hour urinary biochemistry values alone. A single model was able to differentiate between stone types. Further studies to delineate accurate predictive tools should be undertaken using both known and novel risk factors, including radiomics and genomics. [ABSTRACT FROM AUTHOR]

Specialist housing for older people is an important welfare service and integral part of the housing offer in many countries. An extensive evidence base details the relative merits of different modes of provision, but little light has been cast on the forces shaping provision and the interests served. Drawing on a new model of demand and supply of specialist provision in England at the local authority level, this study addresses this lacuna. Two key contributions are made to knowledge and understanding. First, the uneven landscape of specialist housing provision is charted and the extent to which this maps onto need is revealed. Second, this condition is explained by situating specialist housing within wider debates about the reimagining of housing systems driven by the neoliberal transformation of housing politics, and recognising that these processes can have uneven effects embedded in the nature of places. [ABSTRACT FROM AUTHOR]

Stabilization of amyloidogenic immunoglobulin light chains (LCs) by binding of small molecule "kinetic stabilizers" is under development as a novel treatment for light chain amyloidosis. From a high‐throughput screen, we previously identified 16 full‐length (FL) LC stabilizers from five distinct chemotypes. We then obtained structural biological information on two classes of hits, coumarins and hydantoins, revealing that both chemotypes bind to a pocket at the VL−VL interface of the FL LC dimer. Here, we report crystal structures of three screening hits from two other chemotypes, diaryl hydrazones and sulfones, in complex with an amyloidogenic FL LC. While two of these hits bind to the previously identified pocket, one diaryl hydrazone binds to a different pocket bisected by the C2 symmetry axis of the dimer. These data further expand on the FL LC stabilizer‐binding surface that could be used in design of more potent FL LC aggregation inhibitors. [ABSTRACT FROM AUTHOR]

Understanding how SARS-CoV-2 evades neutralizing antibodies is crucial for the development of therapeutic antibodies and universal vaccines. In this issue of Structure , Patel et al. elucidate mechanisms of SARS-CoV-2 escape from two major antibody classes. Cryoelectron microscopy (cryo-EM) structures of these antibodies with the SARS-CoV-2 spike formed the basis of their findings. [ABSTRACT FROM AUTHOR]

Aim: The study aimed to synthesize evidence comparing task‐shifting interventions led by general practice nurses and mental health specialists in improving mental health outcomes of adults in primary care. Design This study used a systematic review of randomized controlled trials. Data Sources: Articles from the databases CINAHL, MEDLINE, APA PsycInfo, PubMed, EMBASE, Cochrane EBM Reviews, Web of Science Core Collection, and ProQuest Dissertation and Thesis published between 2000 and 2020 were included. Review Methods: The review was arranged based on the Cochrane Collaboration guidelines and reported using the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA). Results: Twelve articles met the eligibility criteria. Eight studies revealed that nurse‐led intervention was significantly superior to its comparator. The review identified three major themes: training and supervision, single and collaborative care and psychosocial treatments. Conclusion: Nurses could be temporarily employed to provide mental health services in the absence of mental health specialists as long as appropriate training and supervision was provided. This finding should be interpreted with caution due to the high risk of bias in the studies reviewed and the limited generalisability of their findings. Summary statement: What is already known about this topic? The shortage of psychiatrists and other mental health professionals has been causing treatment gaps in mental health care, not only in developing countries but also in developed countries.Task‐shifting or task‐sharing is one of the most promising strategies in addressing the treatment gap, but the involvement of nurses in this strategy is barely studied. What this paper adds? This paper explores the effect of task‐shifting and task‐sharing interventions led by general practice nurses for adults with mental disorders in primary care and found that nurses could deliver psychosocial interventions normally delivered by mental health specialists with at least the same quality provided they received proper training and supervision.This paper presented a theoretical framework of task‐shifting. The implications of this paper: In the absence of mental health services in primary care, general practice nurses could be temporarily employed to fill the vacancies.However, appropriate training and supervision are required before the programme is started to make sure that the nurses are adequately prepared to undertake the new roles in practice.The implementation of task‐shifting and task‐sharing requires a well‐planned and gradual implementation strategy to avoid burnout and workplace‐related distress in the target health workers. [ABSTRACT FROM AUTHOR]

The COVID‐19 pandemic has caused an unprecedented health crisis and economic burden worldwide. Its etiological agent SARS‐CoV‐2, a new virus in the coronavirus family, has infected hundreds of millions of people worldwide. SARS‐CoV‐2 has evolved over the past 2 years to increase its transmissibility as well as to evade the immunity established by previous infection and vaccination. Nevertheless, strong immune responses can be elicited by viral infection and vaccination, which have proved to be protective against the emergence of variants, particularly with respect to hospitalization or severe disease. Here, we review our current understanding of how the virus enters the host cell and how our immune system is able to defend against cell entry and infection. Neutralizing antibodies are a major component of our immune defense and have been extensively studied for SARS‐CoV‐2 and its variants. Structures of these neutralizing antibodies have provided valuable insights into epitopes that are protective against the original ancestral virus and the variants that have emerged. The molecular characterization of neutralizing epitopes as well as epitope conservation and resistance are important for design of next‐generation vaccines and antibody therapeutics. [ABSTRACT FROM AUTHOR]

The ascomycete fungus Microdochium nivale is one of the most damaging pathogens of cool season turfgrass. Prevention of and recovery from infection is costly to many sports facilities each year. In recent years, use of many chemical plant protectants has been restricted and turfgrass managers have increasingly sought alternative measures for disease control. The use of phosphite has been shown to be effective in reducing M. nivale disease symptoms in Agrostis stolonifera and Poa annua. The aim of this research was to assess initial defence responses in M. nivale‐infected turfgrass, specifically total phenolic content and hydrogen peroxide generation, to determine the effect phosphite treatment has on these responses and on suppression of symptoms. Phenolic compounds and H2O2 are shown to be components of host responses. Phosphite treatment led to enhanced accumulations of total phenolic content, and when applied sequentially or singly to greenhouse plants, it led to significant reductions in M. nivale disease symptoms compared to phosphate‐treated plants or controls. H2O2 extractions indicated that while phosphite treatment increased H2O2 generation compared to controls, the effect was no different to the responses in phosphate‐treated plants. [ABSTRACT FROM AUTHOR]

Phosphate (PO43-, Pi) is the sole phosphorus (P) containing compound utilized for plant growth, leading to the widespread use of Pi containing fertilizers. An alternative form of P, phosphite (PO33-, Phi) has increasingly been used in many crop systems, including amenity turfgrass, not only as a nutrient source but also as a pesticide and biostimulant. There are, however, conflicting reports of the efficacy and benefits of Phi as a source of P. This study was conducted to determine the rate of uptake, translocation and fate of Phi when applied as a foliar treatment to amenity turfgrass, and to assess its role as a source of P nutrition, determining the effect Phi treatments have on turfgrass growth, P deficiency responses, tissue and soil P accumulations. Analysis of Phi treated turfgrass using High Performance Ion Chromatography determined that Phi is rapidly taken up and translocated, that sequential Phi treatments lead to cumulative increases in meristematic tissues, an increase in soil P levels and no in planta conversion to Pi. In P sufficient rootzones (> 35 ppm), foliar applied Phi increased biomass in shoot, crowns, and roots, but also led to a reduction in root to shoot ratios. In phosphorus deficient rootzones (< 5 ppm), foliar applied Phi led to growth reductions in leaf, crown and root, and repression of P deficiency responses. [ABSTRACT FROM AUTHOR]

• A cyclic ion mobility (cIMS) device resolved synthetic sulfated tyrosine metabolites. • Calculated collision cross section data aided sulfation site determination. • The combination of cIMS and MS enabled the identification of isomeric metabolites. • In human urine a single isoform of tyrosine sulfate was detected and identified. • dopamine sulfate was also detected and identified in this human urine sample. Ion mobility (IM) separations, especially when combined with mass spectrometry, offer the opportunity for the rapid analysis and characterization of mixtures. However, the limited resolution afforded by many IM systems means that in practice applications may be limited. Here we have employed an IM separation on a high-resolution cyclic IM device with MS/MS to separate and characterize mixtures of sulfated isomers of tyrosine and associated metabolites containing multiple sulfated isoforms present in reaction mixtures. The cIMS device allowed ions, not resolved using a single pass, to be subjected to multiple passes, enabling the resolution of those with similar collision cross sections (CCS). Predicted single pass CCS values calculated for the isomers likely to be present in these mixtures showed only small differences between them, ranging between of between 0.1 – 0.7 % depending on structure. These small differences highlight the high degree of mobility resolution required for separating the isomers. Experimentally different isoforms of tyrosine sulfate and sulfated tyrosine metabolites could be sufficiently resolved via multipass separations (3–35 passes). This degree of separation provided resolving powers of up to 384 CCS/ΔCCS for sulfated dopamine which enabled good MS/MS spectra to be generated. In human urine the presence of a single sulfated form of tyrosine was detected and identified as the O-sulfate after 3 passes based on the synthetic standard. Of the other tyrosine-related sulfates for which synthetic standards had been prepared only dopamine sulfate was detected in this sample. [ABSTRACT FROM AUTHOR]

• A generic mobile phase has been developed for metabolomic and lipidomic separations • Isopropyl alcohol was replaced by acetonitrile as the organic modifier for lipidomics • Lipidomics on a phenyl-hexyl column increased peak capacity (58 %) and detection (61 %) • RPLC on a C8 stationary phase was used for moderately polar-nonpolar analytes • Polar metabolites were separated by HILIC on an amide stationary phase The untargeted global profiling of endogenous metabolites and lipids has the potential to increase knowledge and understanding in many areas of biology. LC-MS/MS is a key technology for such analyses however, several different LC methodologies, using different mobile phase compositions, are required to cover the diversity in polarity and analyte structure encountered in biological samples. Most notably many lipid screening methods make use of isopropanol (IPA) as a major component of mobile phases employed for comprehensive lipidomic profiling. In order to increase laboratory efficiency, and minimize opportunities for errors, a suite of methods, based on a single acetonitrile (ACN)-aqueous buffer mobile phase combination, has been developed. This mobile phase can be used for hydrophobic interaction liquid chromatography on an amide stationary phase (for polar analytes), reversed-phase (RP) LC analysis on a C8 stationary phase (for moderately polar-non-polar compounds) and RPLC using a CSH phenyl-hexyl bonded column (for lipids). All of these sub 10 minute separations had good throughput and reproducibility with CV's of analyte response <25 % whilst eliminating the need for complex mobile phase preparation and the use of IPA as an organic modifier for lipidomics. Advantages of removing IPA and replacing it with the ACN-based method were a 58 % increase in peak capacity for lipids, with improved resolution for the di- and triglycerides and cholesterol esters compared to current methods. Compared to the IPA-containing solvent system the ACN-based mobile phase also resulted in a 61 % increase in lipid feature detection. The utility of this "universal" mobile phase approach was demonstrated by its application to a rat toxicology study investigating the consequences of methapyrilene administration through on the endogenous metabolite profiles of plasma and urine. Methapyrilene and its metabolites were also profiled in these samples. [ABSTRACT FROM AUTHOR]

Fifty years ago, the first landmark structures of antibodies heralded the dawn of structural immunology. Momentum then started to build toward understanding how antibodies could recognize the vast universe of potential antigens and how antibody-combining sites could be tailored to engage antigens with high specificity and affinity through recombination of germline genes (V, D, J) and somatic mutation. Equivalent groundbreaking structures in the cellular immune system appeared some 15 to 20 years later and illustrated how processed protein antigens in the form of peptides are presented by MHC molecules to T cell receptors. Structures of antigen receptors in the innate immune system then explained their inherent specificity for particular microbial antigens including lipids, carbohydrates, nucleic acids, small molecules, and specific proteins. These two sides of the immune system act immediately (innate) to particular microbial antigens or evolve (adaptive) to attain high specificity and affinity to a much wider range of antigens. We also include examples of other key receptors in the immune system (cytokine receptors) that regulate immunity and inflammation. Furthermore, these antigen receptors use a limited set of protein folds to accomplish their various immunological roles. The other main players are the antigens themselves. We focus on surface glycoproteins in enveloped viruses including SARS-CoV-2 that enable entry and egress into host cells and are targets for the antibody response. This review covers what we have learned over the past half century about the structural basis of the immune response to microbial pathogens and how that information can be utilized to design vaccines and therapeutics. [ABSTRACT FROM AUTHOR]

• Immunofocusing as a strategy for structure-based vaccine design. • Structure-based vaccine design for RSV F, influenza HA, HIV-1 Env. • Structure-based vaccine design translated into the clinic. The recent explosion of atomic-level structures of glycoproteins that comprise the surface antigens of human enveloped viruses, such as RSV, influenza, and HIV, provide tremendous opportunities for rational, structure-based vaccine design. Several concepts in structure-based vaccine design have been put into practice and are are well along preclinical and clinical implementation. Testing of these designed immunogens will provide key insights into the ability to induce the desired immune responses, namely neutralizing antibodies. Many of these immunogens in human clinical trials represent only the first wave of designs and will likely require continued tweaking and elaboration to achieve the ultimate goal of enhanced breadth and potency. Considerable effort is now being invested in germline targeting, epitope focusing, and improved immune presentation such as multivalent nanoparticle incorporation. This review highlights some of the recent advances in these areas as we prepare for the next generation of immunogens for subsequent rounds of iterative vaccine development. [ABSTRACT FROM AUTHOR]

Background: Mucopolysaccharidoses (MPSs) are rare congenital lysosomal storage disorders due to a deficiency of enzymes metabolising glycosaminoglycans, leading to their accumulation in tissues. This multisystem disease often requires surgical intervention, including valvular cardiac surgery. Adult MPSs have complex airways making anaesthesia risky. Methods: We report novel three-dimensional (3D) modelling airway assessments and multidisciplinary peri-operative airway management. Results: Five MPS adults underwent cardiac surgery at the national MPS cardiac centre (type I = 4, type II = 1; ages 20, 24, 33, 35, 37 years; two males, three females). All had complex airway abnormalities. Assessments involved examination, nasendoscopy, imaging, functional studies, 3D reconstruction, virtual endoscopy, virtual reality and simulation using computerised, physical modelling. Awake oral fibre-optic intubation was achieved via airway conduit. Staged extubation was performed on the first post-operative day under laryngo-tracheoscopic guidance. The post-operative period involved chest physiotherapy and occupational therapy. All patients had safe intubation, ventilation and extubation. Four had good cardiac surgical outcomes, one (MPS type I; age 35 years) was inoperable due to endocarditis. None had post-operative airway complications. Conclusions: Expertise from cardiovascular-heart team, multidisciplinary airway management, use of novel techniques is vital. Traditional airway assessments are insufficient, so ENT input, radiology and computerised methods to assess and simulate the airway in 3D by collaboration with clinical engineering is essential. [ABSTRACT FROM AUTHOR]

Novel pathogens can cause massive declines in populations, and even extirpation of hosts. But disease can also act as a selective pressure on survivors, driving the evolution of resistance or tolerance. Bat white-nose syndrome (WNS) is a rapidly spreading wildlife disease in North America. The fungus causing the disease invades skin tissues of hibernating bats, resulting in disruption of hibernation behavior, premature energy depletion, and subsequent death. We used whole-genome sequencing to investigate changes in allele frequencies within a population of Myotis lucifugus in eastern North America to search for genetic resistance to WNS. Our results show low FST values within the population across time, i.e., prior to WNS (Pre- WNS) compared to the population that has survived WNS (Post-WNS). However, when dividing the population with a geographical cut-off between the states of Pennsylvania and New York, a sharp increase in values on scaffold GL429776 is evident in the Post-WNS samples. Genes present in the diverged area are associated with thermoregulation and promotion of brown fat production. Thus, although WNS may not have subjected the entire M. lucifugus population to selective pressure, it may have selected for specific alleles in Pennsylvania through decreased gene flow within the population. However, the persistence of remnant subpopulations in the aftermath of WNS is likely due to multiple factors in bat life history. [ABSTRACT FROM AUTHOR]

Income-related housing allowances are used by most advanced welfare states to ensure that their citizens have access to decent accommodation at a price within their means. Surprisingly, comparing outcomes when the subsidy is paid to the claimant or direct to the landlord has attracted little attention, despite differences existing between countries. This paper uses data collected as part of the evaluation of the Direct Payment Demonstration Projects (DPDPs) in Great Britain to test the impact on rent collection and arrears of paying Housing Benefit to tenants, as oppose to the landlord direct. The DPDPs aimed to provide learning in readiness for the introduction of Universal Credit, which sees six separate benefits consolidated into one monthly payment made to the claimant. Using quasi-experimental rental account analysis techniques, the direct payment was found to have a significant negative effect on both rent collection and arrears. However, evidence suggested that the longer term impact may be smaller as tenants become more 'normalised' to having responsibility for paying their rent. These findings make an important contribution to the major theoretical debate on the effectiveness of using welfare policy to promote 'responsibilisation', which has become the dominant discourse since the mid-late 1990's. [ABSTRACT FROM AUTHOR]

Background: the risk of compassion fatigue in healthcare staff is real, especially when considering the current financial pressures. A course in compassion-based care (CBC) was delivered to mental health staff at a hospital in north-west England, with the intention of rehabilitating ward culture and, subsequently, improving patient experience. Aims: to explore staff experiences of participating in the CBC course. Methods: a qualitative study using semi-structured interviews with participants (n=12) was conducted. All staff attending the course were eligible and were invited to participate. Interview transcripts were thematically analysed. Findings: five themes characterising participant experience emerged from the data: meeting a need; creating the space; reorientation; prioritising self-care; and influencing team dynamics. Data overwhelmingly indicated the success of the CBC course. Conclusion: the CBC course appeared to have a profound effect on participants; it should be considered for further rollout and evaluation. [ABSTRACT FROM AUTHOR]

Concerned about the preservation of and access to documentary heritage, UNESCO established the Memory of the World program in 1992. As an operational program without formal legal basis, the program has involved an international advisory committee (IAC) of 14 experts appointed by the director-general. In its early years, the program, focused on documents at risk, set an ambitious agenda, addressing this priority and assessing emerging technologies for digitizing, disseminating, and reconstituting dispersed libraries and fonds in various media. Within a few years, the program changed direction and established an international register that emphasized globally significant materials. Through two and a half decades, the Memory of the World program has held a series of international conferences and has influenced the adoption of several key UNESCO policy instruments. In 2017, the advisory committee launched a comprehensive review, seeking to engage UNESCO in realizing the concept of "memory of the world." This article traces the evolution of the program, analyzing the interactions among the professions, the UNESCO secretariat, and more recently, diplomats. The earnest advice of the IAC has consistently been dominated by the themes of resources, visibility, and unmet potential. Intense political interest in decisions about including certain materials in the Register has highlighted the continuing power of the record in international issues. The Memory of the World program must now manage both professional and governmental interests - a balance normally established in UNESCO's structures by means of a formal convention adopted by member states. [ABSTRACT FROM AUTHOR]

Amoebiasis is the third-most common cause of mortality worldwide from a parasitic disease. Although the primary etiological agent of amoebiasis is the obligate human parasite Entamoeba histolytica, other members of the genus Entamoeba can infect humans and may be pathogenic. Here, we present the first annotated reference genome for Entamoeba moshkovskii, a species that has been associated with human infections, and compare the genomes of E. moshkovskii, E. histolytica, the human commensal Entamoeba dispar, and the nonhuman pathogen Entamoeba invadens. Gene clustering and phylogenetic analyses show differences in expansion and contraction of families of proteins associated with host or bacterial interactions. They intimate the importance to parasitic Entamoeba species of surface-bound proteins involved in adhesion to extracellular membranes, such as the Gal/GalNAc lectin and members of the BspA and Ariel1 families. Furthermore, E. dispar is the only one of the four species to lack a functional copy of the key virulence factor cysteine protease CP-A5, whereas the gene's presence in E. moshkovskii is consistent with the species' potentially pathogenic nature. Entamoeba moshkovskii was found to be more diverse than E. histolytica across all sequence classes. The former is ∼200 times more diverse than latter, with the four E. moshkovskii strains tested having a most recent common ancestor nearly 500 times more ancient than the tested E. histolytica strains. A four-haplotype test indicates that these E. moshkovskii strains are not the same species and should be regarded as a species complex. [ABSTRACT FROM AUTHOR]

This paper integrates more than 50 years of geological, geochemical and environmental research relevant to the Pb content of soils in Mt Isa to clarify the role of soil as a potential pathway for Pb exposure to local residents. Most of Mt Isa is underlain by thin residual soils that formed by weathering of the Proterozoic Mt Isa Group (MIG). The MIG contains carbonate and volcaniclastic sedimentary rocks largely derived from contemporaneous and earlier cycles of igneous activity and minor detritus from an Archean basement. The upper part of the MIG contains stratiform Pb ore deposits that are about 1650 Ma old. Deformation and erosion have exposed these rocks to weathering and soil forming processes several times since the Proterozoic, with the current landform developing over the last 20 Ma. Soil formation has generally depleted Pb from the subsoil and enriched the top soil. Pb has been widely distributed to the northwest and north of the city in wind-blown dust and water runoff from outcrops of oxidised ore for millions of years. Additional Pb emissions from smelting commenced at Mt Isa in 1931. Most of the urban area receives 50–100 mg/m 2 /yr of Pb from dust deposition and some of this is resuspended or washed away. Additional Pb in mine waste rock and contaminated river sand was brought into the residential area as fill or for sandpits. The Mt Isa community is exposed to Pb in air at levels regulated to minimise health effects of inhalation and ingestion. The observed Pb levels in air generally correlate with distance from the mine but not with the distribution of children with elevated blood Pb levels. Geological evidence of anomalous soil Pb derived from underlying layers of mineralised rock may partly explain the observed blood Pb distribution. [ABSTRACT FROM AUTHOR]

The influenza virus hemagglutinin (HA) glycoprotein mediates receptor binding and membrane fusion during viral entry in host cells. Blocking these key steps in viral infection has applications for development of novel antiinfluenza therapeutics as well as vaccines. However, the lack of structural information on how small molecules can gain a foothold in the small, shallow receptor-binding site (RBS) has hindered drug design against this important target on the viral pathogen. Here, we report on the serendipitous crystallization-based discovery of a small-molecule N-cyclohexyltaurine, commonly known as the buffering agent CHES, that is able to bind to both group-1 and group-2 HAs of influenza A viruses. X-ray structural characterization of group-1 H5N1 A/Vietnam/1203/2004 (H5/Viet) and group-2 H3N2 A/Hong Kong/1/1968 (H3/HK68) HAs at 2.0-Å and 2.57-Å resolution, respectively, revealed that N-cyclohexyltaurine binds to the heart of the conserved HA RBS. N-cyclohexyltaurine mimics the binding mode of the natural receptor sialic acid and RBS-targeting bnAbs through formation of similar hydrogen bonds and CH-π interactions with the HA. In H3/HK68, N-cyclohexyltaurine also binds to a conserved pocket in the stem region, thereby exhibiting a dual-binding mode in group-2 HAs. These long-awaited structural insights into RBS recognition by a noncarbohydrate-based small molecule enhance our knowledge of how to target this important functional site and can serve as a template to guide the development of novel broad-spectrum small-molecule therapeutics against influenza virus. [ABSTRACT FROM AUTHOR]

Housing subsidies are used by developed welfare states to ensure their citizens can access decent and affordable housing. This paper assesses the relative importance of individual and area level factors on the degree to which private sector landlords were affected by changes to Local Housing Allowance (LHA) in the UK. The changes were part of the government's package of measures to reform LHA and reduce the welfare benefit bill. Multi-level modelling techniques have been applied to a longitudinal survey of 788 private sector landlords who had LHA tenants in 19 Local Authorities across GB. The analysis shows that whilst landlords were affected by reforms, area effects were not as pronounced as anticipated. In general, landlords were equally affected regardless of where they operate. The findings suggest tenants in the most affected areas have absorbed increases in their rent shortfall signifying income was not the overriding determinant of demand. [ABSTRACT FROM AUTHOR]

The need for rapid and efficient high throughput metabolic phenotyping (metabotyping) in metabolomic/metabonomic studies often requires compromises to be made between analytical speed and metabolome coverage. Here the effect of column length (150, 75 and 30 mm) and gradient duration (15, 7.5 and 3 min respectively) on the number of features detected when untargeted metabolic profiling of human urine using reversed-phase gradient ultra performance chromatography with, and without, ion mobility spectrometry, has been examined. As would be expected, reducing column length from 150 to 30 mm, and gradient duration, from 15 to 3 min, resulted in a reduction in peak capacity from 311 to 63 and a similar reduction in the number of features detected from over ca. 16,000 to ca. 6500. Under the same chromatographic conditions employing UPLC/IMS/MS to provide an additional orthogonal separation resulted in an increase in the number of MS features detected to nearly 20,000 and ca. 7500 for the 150 mm and the 30 mm columns respectively. Based on this limited study the potential of LC/IMS/MS as a tool for improving throughput and increasing metabolome coverage clearly merits further in depth study. [ABSTRACT FROM AUTHOR]

Influenza virus evolves rapidly to constantly escape from natural immunity. Most humoral immune responses to influenza virus target the hemagglutinin (HA) glycoprotein, which is the major antigen on the surface of the virus. The HA is composed of a globular head domain for receptor binding and a stem domain for membrane fusion. The major antigenic sites of HA are located in the globular head subdomain, which is highly tolerant of amino acid substitutions and continual addition of glycosylation sites. Nonetheless, the evolution of the receptor-binding site and the stem region on HA is severely constrained by their functional roles in engaging the host receptor and in mediating membrane fusion, respectively. Here, we review how broadly neutralizing antibodies (bnAbs) exploit these evolutionary constraints to protect against diverse influenza strains. We also discuss the emerging role of other epitopes that are conserved only in subsets of viruses. This rapidly increasing knowledge of the evolutionary biology, immunology, structural biology, and virology of influenza virus is invaluable for development and design of more universal influenza vaccines and novel therapeutics. [ABSTRACT FROM AUTHOR]

The broad-spectrum antiviral drug Arbidol shows efficacy against influenza viruses by targeting the hemagglutinin (HA) fusion machinery. However, the structural basis of the mechanism underlying fusion inhibition by Arbidol has remained obscure, thereby hindering its further development as a specific and optimized influenza therapeutic. We determined crystal structures of Arbidol in complex with influenza virus HA from pandemic 1968 H3N2 and recent 2013 H7N9 viruses. Arbidol binds in a hydrophobic cavity in the HA trimer stem at the interface between two protomers. This cavity is distal to the conserved epitope targeted by broadly neutralizing stem antibodies and is ∼16 Å from the fusion peptide. Arbidol primarily makes hydrophobic interactions with the binding site but also induces some conformational rearrangements to form a network of inter- and intraprotomer salt bridges. By functioning as molecular glue, Arbidol stabilizes the prefusion conformation of HA that inhibits the large conformational rearrangements associated with membrane fusion in the low pH of the endosome. This unique binding mode compared with the small-molecule inhibitors of other class I fusion proteins enhances our understanding of how small molecules can function as fusion inhibitors and guides the development of broad-spectrum therapeutics against influenza virus. [ABSTRACT FROM AUTHOR]

Structure determination of the HIV-1 envelope glycoprotein (Env) presented a number of challenges, but several high-resolution structures have now become available. In 2013, cryo- EM and x-ray structures of soluble, cleaved SOSIP Env trimers from the clade A BG505 strain provided the first glimpses into the Env trimer fold as well as more the variable regions. A recent cryo- EM structure of a native full-length trimer without any stabilizing mutations had the same core structure, but revealed new insights and features. A more comprehensive and higher resolution understanding of the glycan shield has also emerged, enabling a more complete representation of the Env glycoprotein structure. Complexes of Env trimers with broadly neutralizing antibodies have surprisingly illustrated that most of the Env surface can be targeted in natural infection and that the neutralizing epitopes are almost all composed of both peptide and glycan components. These structures have also provided further evidence of the inherent plasticity of Env and how antibodies can exploit this flexibility by perturbing or even stabilizing the trimer to facilitate neutralization. These breakthroughs have stimulated further design and stabilization of Env trimers as well as other platforms to generate trimers that now span multiple subtypes. These Env trimers when used as immunogens, have led to the first vaccine-induced neutralizing antibodies for structural and functional analyses. [ABSTRACT FROM AUTHOR]

• Methods and techniques in planar chromatography (TLC/HPTLC) are reviewed. • The advantages and limitations of planar chromatography are revisited. • New developments in bioautography for "effect testing" are highlighted. • Advances in the detection/identification analytes by TLC/MS are described. • Future directions in the development and use of planar chromatography are considered. Planar chromatography, in the form of thin-layer or high-performance thin-layer chromatography (TLC, HPTLC), continues to provide a robust and widely used separation technique. It is unrivaled as a simple and rapid qualitative method for mixture analysis, or for finding bioactive components in mixtures. The format of TLC/HPTLC also provides a unique method for preserving the separation, enabling further investigation of components of interest (including quantification/structure determination) separated in both time and space from the original analysis. The current practice of planar chromatography and areas of development of the technology are reviewed and promising future directions in the use of TLC/HPTLC are outlined. [ABSTRACT FROM AUTHOR]

The National Health and Medical Research Council recently reported that there were not enough high-quality studies to conclude that associations between health effects and blood lead levels <10 μg/dL were caused by lead. It identified uncontrolled confounding, measurement error and other potential causal factors as common weaknesses. This paper supports those findings with evidence of uncontrolled confounding by parental education, intelligence or household management from several papers. It suggests that inappropriate statistical tests and aggregation of data representing different exposure routes partly explain why confounding has been overlooked. Inadequate correction of confounding has contributed to incorrect conclusions regarding causality at low levels of lead. Linear or log-linear regression models have tended to mask any threshold. While the effects of higher levels of lead exposure are not disputed, overestimation of health effects at low lead exposures has significant implications for policy-makers endeavouring to protect public health through cost-effective regulations. [ABSTRACT FROM PUBLISHER]

This essay works toward three goals. First, it lays some groundwork for researching prophetic literature as a source for ancient Judean historical thought. Prophetic literature reveals a great deal about how ancient Judeans thought about and with their past, as it was represented in their literary repertoire. Second, it examines Isaiah 40-48, to see how this sort of second-order thinking about the past is on display in a particular passage of text. And third, it draws some preliminary conclusions about historical thought in this text and how it relates to historical thinking evident in other Judean literature. [ABSTRACT FROM AUTHOR]

Halloysite with tubular morphology is formed in a wide range of geological environments from the alteration of various rock types. Intrusive acidic coarse-grained rocks, such as granites, pegmatites and anorthosite, with large potash and sodic feldspars contents, are subsequently altered to kaolinite, halloysite and other clay minerals by weathering or shallow hydrothermal fluid activity. Processing to separate the halloysite-kaolinite fraction from the altered host rock provides a product which can be used as a paper filler and in ceramics and fibreglass, among other uses, with various deposits in Brazil, China, Thailand and elsewhere. In the Kerikeri-Matauri Bay district of Northland, North Island, New Zealand, volcanic alkali rhyolite was extruded as domes and cooled rapidly with fine-grained feldspar subsequently altered to halloysite. The IMERYS plant in Matauri Bay separates the clay from the quartz-cristobalite matrix with an ∼20% yield of halloysite. The principal market is for high-quality porcelain and bone china that require low levels of Fe2O3 and TiO2. Deposits with high levels of halloysite occur in China, Turkey and the USA. The Dragon mine in Utah, USA was recently reopened by Applied Minerals Inc. and now produces halloysite from zones of up to 100% white halloysite. Smaller occurrences of tubular halloysite are mined in China, Turkey and elsewhere from masses of comparatively pure clay that appear to have crystallized directly from solutions in which Al and Si were soluble. [ABSTRACT FROM AUTHOR]

Mice that have been genetically humanized for proteins involved in drug metabolism and toxicity and mice engrafted with human hepatocytes are emerging and promising in vivo models for an improved prediction of the pharmacokinetic, drug–drug interaction and safety characteristics of compounds in humans. The specific advantages and disadvantages of these models should be carefully considered when using them for studies in drug discovery and development. Here, an overview on the corresponding genetically humanized and chimeric liver humanized mouse models described to date is provided and illustrated with examples of their utility in drug metabolism and toxicity studies. We compare the strength and weaknesses of the two different approaches, give guidance for the selection of the appropriate model for various applications and discuss future trends and perspectives. [ABSTRACT FROM AUTHOR]

Objectives We report the diagnostic validity of a selection algorithm for identifying epilepsy cases. Study design and setting Retrospective validation study of International Classification of Diseases 10th Revision Australian Modification (ICD-10AM)-coded hospital records and pharmaceutical data sampled from 300 consecutive potential epilepsy-coded cases and 300 randomly chosen cases without epilepsy from 3/7/2012 to 10/7/2013. Two epilepsy specialists independently validated the diagnosis of epilepsy. A multivariable logistic regression model was fitted to identify the optimum coding algorithm for epilepsy and was internally validated. Results One hundred fifty-eight out of three hundred (52.6%) epilepsy-coded records and 0/300 (0%) nonepilepsy records were confirmed to have epilepsy. The kappa for interrater agreement was 0.89 (95% CI = 0.81–0.97). The model utilizing epilepsy (G40), status epilepticus (G41) and ≥ 1 antiepileptic drug (AED) conferred the highest positive predictive value of 81.4% (95% CI = 73.1–87.9) and a specificity of 99.9% (95% CI = 99.9–100.0). The area under the receiver operating curve was 0.90 (95% CI = 0.88–0.93). Conclusion When combined with pharmaceutical data, the precision of case identification for epilepsy data linkage design was considerably improved and could provide considerable potential for efficient and reasonably accurate case ascertainment in epidemiological studies. [ABSTRACT FROM AUTHOR]

• The analysis of B vitamins by UPLC-ESI-MS/MS, including phosphorylated and non-phosphorylated B vitamers, was significantly improved by the Hybrid Surface Technology. • The major improvements include increased sensitivity, elimination of carry-over, and better peak shape. • The positive impacts were observed not only in the initial use stage, but also in the normal use stage. • The hybrid surface technology provides a generic, effective, and robust solution to mitigate the metal analyte adsorption in LC. Recently, a novel hybrid surface technology (HST) has been developed to mitigate metal analyte adsorption in liquid chromatography. The HST provides a hybrid organic–inorganic surface on the metal fluidic path, from injection to detector and including the column frits and wall, to mitigate the interaction between analytes and metals. Here the impact of the HST on the analysis of B group vitamins using liquid chromatography coupled with electrospray tandem mass spectrometry (LC-ESI-MS/MS) has been evaluated. Significant improvements in analyte intensity, limit of quantification (LOQ), carry-over, and peak shape were observed using an LC-ESI-MS/MS system and column that incorporated the HST. The key observed improvements include a 3–10 times increase in sensitivity (providing a lower LOQ) for riboflavin, thiamine, nicotinamide, FMN, PLP, and 5MTHF, no carry-over, and a more symmetrical peak for thiamine. When applied to the analysis of B group vitamins in energy drinks and B vitamin dietary supplement samples, the HST system demonstrated excellent accuracy and repeatability. [ABSTRACT FROM AUTHOR]

The HIV-1 envelope glycoprotein (Env) trimer is responsible for receptor recognition and viral fusion with CD4 + T cells, and is the sole target for neutralizing antibodies. Thus, understanding its molecular architecture is of significant interest. However, the Env trimer has proved to be a challenging target for 3D structure determination. Recent electron microscopy (EM) and X-ray structures have at last enabled us to decipher the structural complexity and unique features of the Env trimer, and how it is recognized by an ever-expanding arsenal of potent broadly neutralizing antibodies. We describe our current knowledge of the Env trimer structure in the context of exciting recent developments in the identification and characterization of HIV broadly neutralizing antibodies. [ABSTRACT FROM AUTHOR]

Abstract: In a recent ZAW article, Michael Chan argues that II Reg 25,27-30 alludes to Gen 40-41, and that this allusion provides a hermeneutical key for understanding the purpose of II Reg 25,27-30 in an Enneateuchal context: it points to an imminent exodus, a return from exile and a gathering of diaspora in the promised land. This article picks up where Chan left off, in order to flesh out some of the implications of his contribution. It argues that remembering exodus at the end of II Reg included hope, as Chan says, but also struggles and failure, punishment and death. Exodus is multivocal. Likewise, the end of II Reg contributes to a multivocal discourse concerning Davidic kingship, which included the end of Chronicles and prophetic literature. The diminution of Davidic kingship in II Reg 25,27-30 is balanced by other perspectives. The article concludes with an observation on the import of this multivocality for Yehudite social memory. Résumé: Dans un article récent de la ZAW, Michael Chan tente d'établir que II Rois 25,27-30 fait allusion à Gen. 40-41, et que cette relation offre une clé herméneutique pour la compréhension de cette péricope dans le contexte de l'Ennéateuque: celle-ci renvoie à un exode imminent, un retour de l'exil et un rassemblement de la diaspora en terre promise. Cette étude prend le relais de celle de Chan, afin d'élucider certaines implications de sa contribution. L'A. soutient que l'évocation de l'Exode à la fin de II Rois inclut l'espérance (comme Chan le dit), mais aussi les combats et les échecs, la punition et la mort. L'exode est polysémique. De la même manière, la fin de II Rois contribue à un discours polyvalent sur la royauté de David, auquel participent aussi la fin des Chroniques et la littérature prophétique. L'amoindrissement de la royauté davidique en II Rois 25,27-30 est compensé par d'autres perspectives. On note enfin l'importance de cette polysémie pour la mémoire collective de Juda. Zusammenfassung: In einem aktuellen ZAW-Aufsatz argumentiert Michael Chan, dass II Reg 25,27-30 auf Gen 40-41 anspielt, und dass diese Anspielung einen hermeneutischen Schlüssel für das Verständnis von II Reg 25,27-30 im Kontext des Enneateuch bereitstellt: Diese verweist auf einen nahe bevorstehenden Exodus, eine Rückkehr aus dem Exil und eine Sammlung der Diaspora im verheißenen Land. Dieser Artikel beginnt dort, wo Chan aufgehört hat, um einige der Konsequenzen seines Beitrags zu verdeutlichen. Es wird argumentiert, dass die Erinnerung an den Exodus am Ende von II Reg Hoffnung einschließt, wie Chan sagt, aber auch Kämpfe und Scheitern, Strafe und Tod. Der Exodus ist mehrdeutig. In ähnlicher Weise trägt das Ende von II Reg zu einem vielstimmigen Diskurs über das davidische Königtum bei, zu dem auch das Ende der Chronik und die prophetische Literatur gehören. Die Verkleinerung des davidischen Königtums in II Reg 25,27-30 wird durch andere Perspektiven ausbalanciert. Der Artikel schließt mit einer Beobachtung über die Bedeutung dieser Vielstimmigkeit für das kollektive Gedächtnis Jehuds. [ABSTRACT FROM AUTHOR]

This article presents a trial of three-, four- and five-choice multiple choice question papers and its impact on pharmacy and medical students. It discusses the characteristics of the students who participated in the trial, the differences in response time and test score reliability, and the difficulties in the selection of medical students for research projects.

Previous research has pointed to the role television can play in informing health practices and beliefs. Within the academic setting in particular, some educators have raised concerns about the influence of medical dramas on students. Less research, however, draws on the perspectives of students, and this study therefore explores medical students’ perceptions of medical practice and professionalism in popular medical television programmes. Qualitative data from surveys of Australian undergraduate medical students showed that students perceived professionalism in dichotomous ways, with three main themes: cure–care, where a doctor’s skill is either technical or interpersonal; work–leisure, where a doctor is either dedicated to work or personal life; and clinical–administration, where work is either direct patient care or administration. There continue to be imagined divisions between curing and caring for students, who express concerns about balancing work and leisure, and expectations that doctors should have little administrative work. Given students were able to identify these important contemporary issues around professionalism on television, there is pedagogical value in using popular images of the medical world in medical education. [ABSTRACT FROM PUBLISHER]

The article discusses how the Canadian Archives Summit and the expert panel launched by the Royal Society of Canada in 2013 reflect a deep concern on the key memory institutions and their roles and relationships in a technology-enabled, mobile and information-rich society. Topics discussed the summit's intention of ensuring that Canada's documentary heritage continues and advance public recognition of the documentary heritage as a source of enduring knowledge that is accessible to everyone.

The present review aims to critically discuss some of the major problems and limitations of LC-MS based metabolomics as experienced from an analytical chemistry standpoint. Metabolomics offers distinct advantages to a variety of life sciences. Continuous development of the field has been realised due to intensive efforts from a great many scientists from widely divergent backgrounds and research interests as demonstrated by the contents of this special issue. The aim of this commentary is to describe current hindrances to field's progress, (some unique to metabolomics, some common with other omics fields or with conventional targeted bioanalysis) to propose some potential solutions to overcome these constraints and to provide a future perspective for likely developments in the field. [ABSTRACT FROM AUTHOR]