Great Britain transport, housing, and employment access datasets for small-area urban area analytics

This paper provides a brief description of three new forms of key datasets relevant to urban analytics studies namely: Transport, Housing and Employment Accessibility, covering Great Britain, developed by the Urban Big Data Centre (UBDC). Full details of the research related to this paper are contained in “Spatial urban data system: A cloud-enabled big data infrastructure for social and economic urban analytics” [1]. The transport Dataset contains public transport availability (PTA) indicators at both the stop/station and small-area levels (lower layer super output area (LSOA) and middle layer super output area (MSOA)). The employment dataset provides information on the number of people with access to employment within specific distances from each output area. The housing datasets contains quarterly house rent and sales prices aggregated at output area level (MSOA). The theoretical background for measuring the datasets at small area levels is also presented in this paper. Additionally, a variety of raw data used to produce some of the datasets (e.g. PTA) is also included to enable interested readers to reproduce them

1549TiP DeLLphi-303: Phase Ib first-line combination study of tarlatamab, a DLL3-targeting half-life extended bispecific T-cell engager (HLE BiTE®), with carboplatin, etoposide, and PD-L1 inhibition in extensive stage small cell lung cancer (ES-SCLC)

Background: The inhibitory Notch ligand, delta-like ligand 3 (DLL3), is a compelling therapeutic target due to its aberrant expression on the cell surface in most small cell lung cancer (SCLC). Tarlatamab (AMG 757) is a half-life extended bispecific T-cell engager (HLE BiTE®) molecule designed to specifically bind DLL3 on target cancer cells and CD3 on T cells, resulting in T cell-dependent killing of tumor cells. Data from an ongoing first-in-human monotherapy study show acceptable safety with evidence of tarlatamab efficacy in patients with relapsed/refractory SCLC (NCT03319940). Adding programmed death ligand 1 (PD-L1) inhibitors to first-line platinum chemotherapy is the emerging standard-of-care (SOC) in ES-SCLC and preclinical data suggests increased antitumor activity of BiTE molecules when combined with PD-1/PD-L1 inhibition or chemotherapy.1 These data support a clinical trial of tarlatamab combined with frontline carboplatin, etoposide, and PD-L1 inhibition in ES-SCLC. Trial design: This is a phase 1b, multicenter, open-label study evaluating tarlatamab in combination with first-line SOC chemo-immunotherapy in subjects with ES-SCLC. Tarlatamab will be evaluated in two separate settings: A) In combination with carboplatin, etoposide, and a PD-L1 inhibitor followed by maintenance cycles of tarlatamab plus PD-L1 inhibitor, and B) In combination with PD-L1 inhibitor following SOC chemo-immunotherapy as a maintenance only approach. Key eligibility criteria include patients with histologically or cytologically confirmed ES-SCLC with no prior systemic treatment (except as specified in protocol) and ECOG performance status ≤1. The primary objective is to evaluate the safety, tolerability, and determine the recommended phase 2 dose and/or maximum tolerated dose of tarlatamab in combination with PD-L1 inhibition with or without chemotherapy. Secondary endpoints are objective response rate, duration of response, disease control, progression-free survival, overall survival, and pharmacokinetics

Rapid Recapitulation of Nonalcoholic Steatohepatitis upon Loss of Host Cell Factor 1 Function in Mouse Hepatocytes

Host-cell factor 1 (HCF-1), encoded by the ubiquitously expressed X-linked gene Hcfc1, is an epigenetic coregulator important for mouse development and cell proliferation, including during liver regeneration. We used a hepatocyte-specific inducible Hcfc1 knock-out allele (called Hcfc1 <sup>hepKO</sup> ), to induce HCF-1 loss in hepatocytes of hemizygous Hcfc1 <sup>hepKO/Y</sup> males by four days. In heterozygous Hcfc1 <sup>hepKO/+</sup> females, owing to random X-chromosome inactivation, upon Hcfc1 <sup>hepKO</sup> allele induction, a 50/50 mix of HCF-1 positive and negative hepatocyte clusters is engineered. The livers with Hcfc1 <sup>hepKO/Y</sup> hepatocytes displayed a 21-24-day terminal non-alcoholic fatty liver (NAFL) followed by non-alcoholic steatohepatitis (NASH) disease progression typical of severe NAFL disease (NAFLD). In contrast, in livers with heterozygous Hcfc1 <sup>hepKO/+</sup> hepatocytes, HCF-1-positive hepatocytes replaced HCF-1-negative hepatocytes and revealed only mild-NAFL development. Loss of HCF-1 led to loss of PGC1α protein, probably owing to its destabilization, and deregulation of gene expression particularly of genes involved in mitochondrial structure and function, likely explaining the severe Hcfc1 <sup>hepKO/Y</sup> liver pathology. Thus, HCF-1 is essential for hepatocyte function, likely playing both transcriptional and non-transcriptional roles. These genetically-engineered loss-of-HCF-1 mice can be used to study NASH as well as NAFLD resolution

Characterization of Leishmania donovani MCM4: Expression Patterns and Interaction with PCNA

Events leading to origin firing and fork elongation in eukaryotes involve several proteins which are mostly conserved across the various eukaryotic species. Nuclear DNA replication in trypanosomatids has thus far remained a largely uninvestigated area. While several eukaryotic replication protein orthologs have been annotated, many are missing, suggesting that novel replication mechanisms may apply in this group of organisms. Here, we characterize the expression of Leishmania donovani MCM4, and find that while it broadly resembles other eukaryotes, noteworthy differences exist. MCM4 is constitutively nuclear, signifying that, unlike what is seen in S.cerevisiae, varying subcellular localization of MCM4 is not a mode of replication regulation in Leishmania. Overexpression of MCM4 in Leishmania promastigotes causes progress through S phase faster than usual, implicating a role for MCM4 in the modulation of cell cycle progression. We find for the first time in eukaryotes, an interaction between any of the proteins of the MCM2-7 (MCM4) and PCNA. MCM4 colocalizes with PCNA in S phase cells, in keeping with the MCM2-7 complex being involved not only in replication initiation, but fork elongation as well. Analysis of a LdMCM4 mutant indicates that MCM4 interacts with PCNA via the PIP box motif of MCM4 - perhaps as an integral component of the MCM2-7 complex, although we have no direct evidence that MCM4 harboring a PIP box mutation can still functionally associate with the other members of the MCM2-7 complex- and the PIP box motif is important for cell survival and viability. In Leishmania, MCM4 may possibly help in recruiting PCNA to chromatin, a role assigned to MCM10 in other eukaryotes

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

O impacto, sobre estudantes brasileiros, de uma linguagem visual para aprender a aprender conjuntamente

Resumo Um dos temas mais importantes na aprendizagem colaborativa apoiada pelo computador é a autorregulação da aprendizagem sem o apoio de professores. A autorregulação da colaboração pode ser definida como o conjunto dos processos sociais que os alunos usam para coordenar o seu esforço conjunto em uma atividade. Este trabalho apresenta um estudo de caso brasileiro que examina o impacto da plataforma computacional Metafora para apoiar a regulação da colaboração entre os estudantes brasileiros. Nosso objetivo é investigar se o uso da linguagem visual Metafora ajuda os alunos a aprenderem a aprender em conjunto (learn to learn togueter – L2L2). L2L2 abrange o desenvolvimento da capacidade de coordenação da colaboração. Para perseguir esse objetivo, são fornecidas evidências de mecanismos de coordenação e as respostas emocionais subjacentes ao uso, pelos alunos, da ferramenta de planejamento Metafora. Os resultados deste estudo de caso demonstram que as interações dos alunos, ao usarem a ferramenta de planejamento Metafora, influenciaram o seu desenvolvimento de L2L2 de maneira natural e envolvente. A ferramenta de planejamento Metafora proporciona aos alunos um ambiente amigável para a regulação dos processos de grupo e tem potencial para modificar os pensamentos dos estudantes com respeito à coordenação de processos colaborativos

Pharmacokinetic-Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance.

Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies

Induction of autophagy by spermidine promotes longevity.

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