A Probabilistic Approach to Automated Bidding in Alternative Auctions

This paper presents an approach to develop bidding agents that participate in multiple alternative auctions, with the goal of obtaining an item at the lowest price. The approach consists of a prediction method and a planning algorithm. The prediction method exploits the history of past auctions in order to build probability functions capturing the belief that a bid of a given price may win a given auction. The planning algorithm computes the lowest price, such that by sequentially bidding in a subset of the relevant auctions, the agent can obtain the item at that price with an acceptable probability. The approach addresses the case where the auctions are for substitutable items with different values. Experimental results are reported, showing that the approach increases the payoff of their users and the welfare of the market

Evaluating Patient Experience at a Novel Health Service for Aboriginal and Torres Strait Islander Prisoners: A Pilot Study

BackgroundThe Winnunga Alexander Maconochie Centre Health and Wellbeing Service (AMCHWS) is the first prison health service operated by an Aboriginal Community Controlled Health Organisation in Australia. This pilot study developed and implemented a patient experience survey to evaluate the novel model of healthcare delivered by the Winnunga AMCHWS to Aboriginal and Torres Strait Islander prisoners. MethodsPatients accessing the Winnunga AMCHWS between February and May 2020 were invited to participate in the study. Descriptive data were analysed and compiled for demographics, patient satisfaction, patient perception of care quality, cultural safety, and patient thoughts on the Winnunga AMCHWS. FindingsSixteen of 26 eligible patients participated in the survey (62% response rate). At least 75% of patients were satisfied with the waiting time to see staff at the Winnunga AMCHWS most or all of the time. All 16 patients reported that Winnunga AMCHWS staff always treated them with dignity and respect. Of 14 patients who identified as Aboriginal, nine felt that they were treated better by staff because of their Aboriginal identity while the other five felt their Aboriginal identity made no difference to their treatment by the staff. InterpretationThis patient experience survey of the Winnunga AMCHWS found that it has provided highly satisfactory, timely, respectful, and culturally safe care to patients. Due to the limitations of this study, continual evaluation of the Winnunga AMCHWS and future studies to evaluate the continuity of care, health, and re-offending rates of released patients are needed to fully evaluate the Winnunga AMCHWS model

Fixed lateral unicompartmental knee replacement is a reliable treatment for lateral compartment osteoarthritis after mobile-bearing medial unicompartmental replacement

Purpose: Lateral osteoarthritis following medial unicompartmental knee replacement (UKR) is usually treated with total knee replacement, however, lateral UKR is a less invasive option that preserves a well-functioning medial UKR. This study aimed to determine the 5-year outcome of the cemented Fixed Lateral Oxford UKR (FLO) when used for the treatment of severe lateral disease after medial Oxford unicompartmental knee replacement. Methods: Forty-four knees with lateral bone-on-bone osteoarthritis (n = 43) and avascular necrosis (n = 1) treated with the FLO following medial Oxford UKR were followed up prospectively. The Oxford Knee Score (OKS) and Tegner Activity Score (TAS) were collected pre- and post-operatively. Life-table analysis was used to determine survival rates. Results: The mean patient age at the time of FLO surgery was 74.4 years with a mean time of 12.1 years between the primary medial UKR and the conversion to a bi-UKR with a FLO. Mean follow-up of the FLO was 3.5 years. After FLO no intra-operative or medical complications, re-admissions, or mortality occurred. There was one reoperation in which a bearing was exchanged for a medial bearing dislocation. There were no revisions of the FLO, so the FLO survival rate at 5 years was 100% (24 at risk). The mean pre-operative OKS was 22, which significantly (p < 0.0001) improved to a mean of 42, 42, and 40 at 1, 2, and 5 years, respectively. The median TAS had a non-significant improvement from 2.5 (Range 0–8) pre-operatively to 2 (Range 1–6) at 5 years postoperatively. Conclusion: The FLO is a reliable treatment for lateral osteoarthritis following medial UKR. At 5 years there was a 100% survival of the FLO with a mean OKS of 40. Level of evidence: IV, Prospective Case Series

Improved microbubble (MB) Localisation Using Particle Detecting algorithm:Evaluation of Algorithm Performance for Different Beamforming Methods

International audienceThe performance of image analysis techniques (particle detection) on contrast enhanced ultrasound (CEUS) images could be enhanced by using it in combination with the right beamformer (BF). The current study investigates the best performing combination of a particle detecting algorithm (Kanoulas et al. 2019) with four beamformers (BFs), classical and adaptive. In a series of in silico experiments, adjacent MBs are placed in distances comparable to the lateral resolution limit, the CEUS images of the MBs were simulated in FieldII, and finally beamformed with the four methods. The images were processed with the MB detection algorithm and the results were evaluated by the true detections (TD), missed MBs, spurious detections, and localisation uncertainty (LU). For the smallest distances all methods deteriorate but the MV methods provided 4-12% more TD. For the intermediate distances the TD were comparable for all BFs but the adaptive methods provided lower LU. When a set of evaluation metrics is used, the adaptive methods provide marginally but systematically improved results which suggests that, under the appropriate imaging conditions, they could be used to enhance vessel mapping

Dynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation

The glucagon-like peptide-1 receptor (GLP-1R) has broad physiological roles and is a validated target for treatment of metabolic disorders. Despite recent advances in GLP-1R structure elucidation, detailed mechanistic understanding of how different peptides generate profound differences in G protein-mediated signalling is still lacking. Here we combine cryo-electron microscopy, molecular dynamics simulations, receptor mutagenesis and pharmacological assays, to interrogate the mechanism and consequences of GLP-1R binding to four peptide agonists; glucagon-like peptide-1, oxyntomodulin, exendin-4 and exendin-P5. These data reveal that distinctions in peptide N-terminal interactions and dynamics with the GLP-1R transmembrane domain are reciprocally associated with differences in the allosteric coupling to G proteins. In particular, transient interactions with residues at the base of the binding cavity correlate with enhanced kinetics for G protein activation, providing a rationale for differences in G protein-mediated signalling efficacy from distinct agonists

Activation of the GLP-1 receptor by a non-peptidic agonist

Class B G-protein-coupled receptors are major targets for the treatment of chronic diseases, including diabetes and obesity1. Structures of active receptors reveal peptide agonists engage deep within the receptor core, leading to an outward movement of extracellular loop 3 and the tops of transmembrane helices 6 and 7, an inward movement of transmembrane helix 1, reorganization of extracellular loop 2 and outward movement of the intracellular side of transmembrane helix 6, resulting in G-protein interaction and activation2,3,4,5,6. Here we solved the structure of a non-peptide agonist, TT-OAD2, bound to the glucagon-like peptide-1 (GLP-1) receptor. Our structure identified an unpredicted non-peptide agonist-binding pocket in which reorganization of extracellular loop 3 and transmembrane helices 6 and 7 manifests independently of direct ligand interaction within the deep transmembrane domain pocket. TT-OAD2 exhibits biased agonism, and kinetics of G-protein activation and signalling that are distinct from peptide agonists. Within the structure, TT-OAD2 protrudes beyond the receptor core to interact with the lipid or detergent, providing an explanation for the distinct activation kinetics that may contribute to the clinical efficacy of this compound series. This work alters our understanding of the events that drive the activation of class B receptors

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder

Glucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing and multiplex ligation-dependent probe amplification. Mutations in the SLC2A1 gene were detected in 54 patients (41%) and subsequently in three clinically affected family members. In these 57 patients we identified 49 different mutations, including six multiple exon deletions, six known mutations and 37 novel mutations (13 missense, five nonsense, 13 frame shift, four splice site and two translation initiation mutations). Clinical data were retrospectively collected from referring physicians by means of a questionnaire. Three different phenotypes were recognized: (i) the classical phenotype (84%), subdivided into early-onset (<2 years) (65%) and late-onset (18%); (ii) a non-classical phenotype, with mental retardation and movement disorder, without epilepsy (15%); and (iii) one adult case of glucose transporter-1 deficiency syndrome with minimal symptoms. Recognizing glucose transporter-1 deficiency syndrome is important, since a ketogenic diet was effective in most of the patients with epilepsy (86%) and also reduced movement disorders in 48% of the patients with a classical phenotype and 71% of the patients with a non-classical phenotype. The average delay in diagnosing classical glucose transporter-1 deficiency syndrome was 6.6 years (range 1 month-16 years). Cerebrospinal fluid glucose was below 2.5 mmol/l (range 0.9-2.4 mmol/l) in all patients and cerebrospinal fluid : blood glucose ratio was below 0.50 in all but one patient (range 0.19-0.52). Cerebrospinal fluid lactate was low to normal in all patients. Our relatively large series of 57 patients with glucose transporter-1 deficiency syndrome allowed us to identify correlations between genotype, phenotype and biochemical data. Type of mutation was related to the severity of mental retardation and the presence of complex movement disorders. Cerebrospinal fluid : blood glucose ratio was related to type of mutation and phenotype. In conclusion, a substantial number of the patients with glucose transporter-1 deficiency syndrome do not have epilepsy. Our study demonstrates that a lumbar puncture provides the diagnostic clue to glucose transporter-1 deficiency syndrome and can thereby dramatically reduce diagnostic delay to allow early start of the ketogenic die

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness