Measuring and Managing Healthcare Supply and Demand in Real-Time.

Measuring the supply and demand for access to and wait-times for healthcare is key to managing healthcare services and allocating resources appropriately. Yet, few jurisdictions in distributed, socialized medicine settings have any way to do so. In this paper, we propose the requirements for a jurisdictional patient scheduling system that can measure key metrics, such as supply of and demand for regulated health care professional care, access to and wait times for care, real-time health system utilization and provide the data to compute patient journeys. The system is also capable of tracking new supply of providers and who does not have access to a primary care provider. Benefits, limitations and risks of the model are discussed.

VEuPathDB: the eukaryotic pathogen, vector and host bioinformatics resource center in 2023.

The Eukaryotic Pathogen, Vector and Host Informatics Resource (VEuPathDB, https://veupathdb.org) is a Bioinformatics Resource Center funded by the National Institutes of Health with additional funding from the Wellcome Trust. VEuPathDB supports >600 organisms that comprise invertebrate vectors, eukaryotic pathogens (protists and fungi) and relevant free-living or non-pathogenic species or hosts. Since 2004, VEuPathDB has analyzed omics data from the public domain using contemporary bioinformatic workflows, including orthology predictions via OrthoMCL, and integrated the analysis results with analysis tools, visualizations, and advanced search capabilities. The unique data mining platform coupled with >3000 pre-analyzed data sets facilitates the exploration of pertinent omics data in support of hypothesis driven research. Comparisons are easily made across data sets, data types and organisms. A Galaxy workspace offers the opportunity for the analysis of private large-scale datasets and for porting to VEuPathDB for comparisons with integrated data. The MapVEu tool provides a platform for exploration of spatially resolved data such as vector surveillance and insecticide resistance monitoring. To address the growing body of omics data and advances in laboratory techniques, VEuPathDB has added several new data types, searches and features, improved the Galaxy workspace environment, redesigned the MapVEu interface and updated the infrastructure to accommodate these changes.

Association of Race and Other Social Determinants of Health With HIV Pre-Exposure Prophylaxis Use: A County-Level Analysis Using the PrEP-to-Need Ratio.

Research is limited on the effect of racism and social determinants of health on HIV pre-exposure prophylaxis (PrEP) use. This study used the PrEP-to-Need Ratio (PNR), which measures PrEP prescriptions divided by HIV diagnoses in the county, to evaluate sufficient PrEP use. AIDSVu datasets were compared to county-level social determinants of health. Standardized regression coefficients (ß) were compared to identify strongest associations with PNR. Overall, factors including percent African American and percent uninsured had negative correlations with PNR, whereas median household income and severe housing cost burden had positive associations. Stratifying for population size, percent African American, percent uninsured, and severe housing cost burden were significant for low population areas, whereas median household income, percent in poverty, percent uninsured, and percent African American were significant for large populations. To reduce PrEP disparities, public health must develop strategies to reach those most in need, especially historically disadvantaged communities.

Transcranial Magnetic Stimulation for Posttraumatic Stress Disorder and Major Depression: Comparing Commonly Used Clinical Protocols.

Transcranial magnetic stimulation (TMS) is increasingly being used to treat posttraumatic stress disorder (PTSD) comorbid with major depressive disorder (MDD). Yet, identifying the most effective stimulation parameters remains an active area of research. We recently reported on the use of 5 Hz TMS to reduce PTSD and MDD symptoms. A recently developed form of TMS, intermittent theta burst stimulation (iTBS), appears noninferior for treating MDD. Because iTBS can be delivered in a fraction of the time, it provides significant logistical advantages; however, evaluations of whether iTBS provides comparable PTSD and MDD symptom reductions are lacking. We performed a retrospective chart review comparing clinical outcomes in veterans with PTSD and MDD who received iTBS (n = 10) with a matched cohort that received 5-Hz TMS (n = 10). Symptoms were evaluated using self-reported rating scales at baseline and every five treatments for up to 30 sessions. Both protocols were safe and reduced symptoms, ps < .001, but veterans who received iTBS reported poorer outcomes. These results were observed using mixed-model analyses, Group x Time interaction: p = .011, and effect sizes, where 5 Hz TMS demonstrated superior PTSD and MDD symptom improvement, ds = 1.81 and 1.51, respectively, versus iTBS, ds = 0.63 and 0.88, respectively. Data from prior controlled trials of iTBS, with increased stimulation exposure, have appeared to provide comparable clinical outcomes compared with 5 Hz TMS. Prospective and controlled comparisons are required; however, the present findings provide important information for clinicians using TMS to treat these commonly comorbid disorders.

VEuPathDB: the eukaryotic pathogen, vector and host bioinformatics resource center.

The Eukaryotic Pathogen, Vector and Host Informatics Resource (VEuPathDB, https://veupathdb.org) represents the 2019 merger of VectorBase with the EuPathDB projects. As a Bioinformatics Resource Center funded by the National Institutes of Health, with additional support from the Welllcome Trust, VEuPathDB supports >500 organisms comprising invertebrate vectors, eukaryotic pathogens (protists and fungi) and relevant free-living or non-pathogenic species or hosts. Designed to empower researchers with access to Omics data and bioinformatic analyses, VEuPathDB projects integrate >1700 pre-analysed datasets (and associated metadata) with advanced search capabilities, visualizations, and analysis tools in a graphic interface. Diverse data types are analysed with standardized workflows including an in-house OrthoMCL algorithm for predicting orthology. Comparisons are easily made across datasets, data types and organisms in this unique data mining platform. A new site-wide search facilitates access for both experienced and novice users. Upgraded infrastructure and workflows support numerous updates to the web interface, tools, searches and strategies, and Galaxy workspace where users can privately analyse their own data. Forthcoming upgrades include cloud-ready application architecture, expanded support for the Galaxy workspace, tools for interrogating host-pathogen interactions, and improved interactions with affiliated databases (ClinEpiDB, MicrobiomeDB) and other scientific resources, and increased interoperability with the Bacterial & Viral BRC.

EuPathDB: the eukaryotic pathogen genomics database resource.

The Eukaryotic Pathogen Genomics Database Resource (EuPathDB, http://eupathdb.org) is a collection of databases covering 170+ eukaryotic pathogens (protists & fungi), along with relevant free-living and non-pathogenic species, and select pathogen hosts. To facilitate the discovery of meaningful biological relationships, the databases couple preconfigured searches with visualization and analysis tools for comprehensive data mining via intuitive graphical interfaces and APIs. All data are analyzed with the same workflows, including creation of gene orthology profiles, so data are easily compared across data sets, data types and organisms. EuPathDB is updated with numerous new analysis tools, features, data sets and data types. New tools include GO, metabolic pathway and word enrichment analyses plus an online workspace for analysis of personal, non-public, large-scale data. Expanded data content is mostly genomic and functional genomic data while new data types include protein microarray, metabolic pathways, compounds, quantitative proteomics, copy number variation, and polysomal transcriptomics. New features include consistent categorization of searches, data sets and genome browser tracks; redesigned gene pages; effective integration of alternative transcripts; and a EuPathDB Galaxy instance for private analyses of a user's data. Forthcoming upgrades include user workspaces for private integration of data with existing EuPathDB data and improved integration and presentation of host-pathogen interactions.

Nonviral methods for inducing pluripotency to cells.

The concept of inducing pluripotency to adult somatic cells by introducing reprogramming factors to them is one that has recently emerged, gained widespread acclaim and garnered much attention among the scientific community. The idea that cells can be reprogrammed, and are not unidirectionally defined opens many avenues for study. With their clear potential for use in the clinic, these reprogrammed cells stand to have a huge impact in regenerative medicine. This realization did not occur overnight but is, however, the product of many decades worth of advancements in researching this area. It was a combination of such research that led to the development of induced pluripotent stem cells as we know it today. This review delivers a brief insight in to the roots of iPS research and focuses on succinctly describing current nonviral methods of inducing pluripotency using plasmid vectors, small molecules and chemicals, and RNAs.

EuPathDB: the eukaryotic pathogen database.

EuPathDB (http://eupathdb.org) resources include 11 databases supporting eukaryotic pathogen genomic and functional genomic data, isolate data and phylogenomics. EuPathDB resources are built using the same infrastructure and provide a sophisticated search strategy system enabling complex interrogations of underlying data. Recent advances in EuPathDB resources include the design and implementation of a new data loading workflow, a new database supporting Piroplasmida (i.e. Babesia and Theileria), the addition of large amounts of new data and data types and the incorporation of new analysis tools. New data include genome sequences and annotation, strand-specific RNA-seq data, splice junction predictions (based on RNA-seq), phosphoproteomic data, high-throughput phenotyping data, single nucleotide polymorphism data based on high-throughput sequencing (HTS) and expression quantitative trait loci data. New analysis tools enable users to search for DNA motifs and define genes based on their genomic colocation, view results from searches graphically (i.e. genes mapped to chromosomes or isolates displayed on a map) and analyze data from columns in result tables (word cloud and histogram summaries of column content). The manuscript herein describes updates to EuPathDB since the previous report published in NAR in 2010.

A human ubiquitin conjugating enzyme (E2)-HECT E3 ligase structure-function screen.

Here we describe a systematic structure-function analysis of the human ubiquitin (Ub) E2 conjugating proteins, consisting of the determination of 15 new high-resolution three-dimensional structures of E2 catalytic domains, and autoubiquitylation assays for 26 Ub-loading E2s screened against a panel of nine different HECT (homologous to E6-AP carboxyl terminus) E3 ligase domains. Integration of our structural and biochemical data revealed several E2 surface properties associated with Ub chain building activity; (1) net positive or neutral E2 charge, (2) an "acidic trough" located near the catalytic Cys, surrounded by an extensive basic region, and (3) similarity to the previously described HECT binding signature in UBE2L3 (UbcH7). Mass spectrometry was used to characterize the autoubiquitylation products of a number of functional E2-HECT pairs, and demonstrated that HECT domains from different subfamilies catalyze the formation of very different types of Ub chains, largely independent of the E2 in the reaction. Our data set represents the first comprehensive analysis of E2-HECT E3 interactions, and thus provides a framework for better understanding the molecular mechanisms of ubiquitylation.

The conserved CPH domains of Cul7 and PARC are protein-protein interaction modules that bind the tetramerization domain of p53.

Cul7 is a member of the Cullin Ring Ligase (CRL) family and is required for normal mouse development and cellular proliferation. Recently, a region of Cul7 that is highly conserved in the p53-associated, Parkin-like cytoplasmic protein PARC, was shown to bind p53 directly. Here we identify the CPH domains (conserved domain within Cul7, PARC, and HERC2 proteins) of both Cul7 and PARC as p53 interaction domains using size exclusion chromatography and NMR spectroscopy. We present the first structure of the evolutionarily conserved CPH domain and provide novel insight into the Cul7-p53 interaction. The NMR structure of the Cul7-CPH domain reveals a fold similar to peptide interaction modules such as the SH3, Tudor, and KOW domains. The p53 interaction surface of both Cul7 and PARC CPH domains was mapped to a conserved surface distinct from the analogous peptide-binding regions of SH3, KOW, and Tudor domains, suggesting a novel mode of interaction. The CPH domain interaction surface of p53 resides in the tetramerization domain and is formed by residues contributed by at least two subunits.

BioAfrica's HIV-1 proteomics resource: combining protein data with bioinformatics tools.

Most Internet online resources for investigating HIV biology contain either bioinformatics tools, protein information or sequence data. The objective of this study was to develop a comprehensive online proteomics resource that integrates bioinformatics with the latest information on HIV-1 protein structure, gene expression, post-transcriptional/post-translational modification, functional activity, and protein-macromolecule interactions. The BioAfrica HIV-1 Proteomics Resource http://bioafrica.mrc.ac.za/proteomics/index.html is a website that contains detailed information about the HIV-1 proteome and protease cleavage sites, as well as data-mining tools that can be used to manipulate and query protein sequence data, a BLAST tool for initiating structural analyses of HIV-1 proteins, and a proteomics tools directory. The Proteome section contains extensive data on each of 19 HIV-1 proteins, including their functional properties, a sample analysis of HIV-1HXB2, structural models and links to other online resources. The HIV-1 Protease Cleavage Sites section provides information on the position, subtype variation and genetic evolution of Gag, Gag-Pol and Nef cleavage sites. The HIV-1 Protein Data-mining Tool includes a set of 27 group M (subtypes A through K) reference sequences that can be used to assess the influence of genetic variation on immunological and functional domains of the protein. The BLAST Structure Tool identifies proteins with similar, experimentally determined topologies, and the Tools Directory provides a categorized list of websites and relevant software programs. This combined database and software repository is designed to facilitate the capture, retrieval and analysis of HIV-1 protein data, and to convert it into clinically useful information relating to the pathogenesis, transmission and therapeutic response of different HIV-1 variants. The HIV-1 Proteomics Resource is readily accessible through the BioAfrica website at: http://bioafrica.mrc.ac.za/proteomics/index.html.