In pharmacoepidemiology, routinely collected data from electronic health records (including primary care databases, registries, and administrative healthcare claims) are a resource for research evaluating the real world effectiveness and safety of medicines. Currently available guidelines for the reporting of research using non-randomised, routinely collected data—specifically the REporting of studies Conducted using Observational Routinely collected health Data (RECORD) and the Strengthening the Reporting of OBservational studies in Epidemiology (STROBE) statements—do not capture the complexity of pharmacoepidemiological research. We have therefore extended the RECORD statement to include reporting guidelines specific to pharmacoepidemiological research (RECORD-PE). This article includes the RECORD-PE checklist (also available on www.record-statement.org) and explains each checklist item with examples of good reporting. We anticipate that increasing use of the RECORD-PE guidelines by researchers and endorsement and adherence by journal editors will improve the standards of reporting of pharmacoepidemiological research undertaken using routinely collected data. This improved transparency will benefit the research community, patient care, and ultimately improve public health.

PurposeReal‐world evidence (RWE) includes data from retrospective or prospective observational studies and observational registries and provides insights beyond those addressed by randomized controlled trials. RWE studies aim to improve health care decision making.MethodsThe International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and the International Society for Pharmacoepidemiology (ISPE) created a task force to make recommendations regarding good procedural practices that would enhance decision makers' confidence in evidence derived from RWD studies. Peer review by ISPOR/ISPE members and task force participants provided a consensus‐building iterative process for the topics and framing of recommendations.ResultsThe ISPOR/ISPE Task Force recommendations cover seven topics such as study registration, replicability, and stakeholder involvement in RWE studies. These recommendations, in concert with earlier recommendations about study methodology, provide a trustworthy foundation for the expanded use of RWE in health care decision making.ConclusionThe focus of these recommendations is good procedural practices for studies that test a specific hypothesis in a specific population. We recognize that some of the recommendations in this report may not be widely adopted without appropriate incentives from decision makers, journal editors, and other key stakeholders.

Purpose: Real-world evidence (RWE) includes data from retrospective or prospective observational studies and observational registries and provides insights beyond those addressed by randomized controlled trials. RWE studies aim to improve health care decision making. Methods: The International Society for Pharmacoeconomics and Outcomes Research (ISPOR)and the International Society for Pharmacoepidemiology (ISPE) created a task force to make recommendations regarding good procedural practices that would enhance decision makers' confidence in evidence derived from RWD studies. Peer review by ISPOR/ISPE members and task force participants provided a consensus-building iterative process for the topics and framing of recommendations.Results: The ISPOR/ISPE Task Force recommendations cover seven topics such as study registration, replicability, and stakeholder involvement in RWE studies. These recommendations, in concert with earlier recommendations about study methodology, provide a trustworthy foundation for the expanded use of RWE in health care decision making. Conclusion:The focus of these recommendations is good procedural practices for studies that test a specific hypothesis in a specific population. We recognize that some of the recommendations in this report may not be widely adopted without appropriate incentives from decision makers, journal editors, and other key stakeholders. KEYWORDScomparative effectiveness, decision making, guidelines, pharmacoepidemiology, real-world data, treatment effectivenessThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Abstract-The attraction, binding, and entry of monocytes into the vessel wall play an important role in atherogenesis. We have previously shown that minimally oxidized/modified LDL (MM-LDL), a pathogenically relevant lipoprotein, can activate human aortic endothelial cells (HAECs) to produce monocyte chemotactic activators. In the present study, we demonstrate that MM-LDL and oxidation products of 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine (PAPC) activate endothelial cells to synthesize monocyte chemotactic protein-1 (MCP-1) and interleukin-8 (IL-8). Several lines of evidence suggest that this activation is mediated by the lipid-dependent transcription factor peroxisome proliferatoractivated receptor ␣ (PPAR␣), the most abundant member of the PPAR family in HAECs.

The CD19 protein is expressed on the surface of all B-lymphoid cells with the exception of terminally differentiated plasma cells and has been implicated as a signal-transducing receptor in the control of proliferation and differentiation. Here we demonstrate complete correlation between the expression pattern of the CD19 gene and the B-cell-specific transcription factor BSAP in a large panel of B-lymphoid cell lines. The human CD19 gene has been cloned, and several BSAP-binding sites have been mapped by in vitro protein-DNA binding studies. In particular, a high-affinity BSAP-binding site instead of a TATA sequence is located in the -30 promoter region upstream of a cluster of heterogeneous transcription start sites. Moreover, this site is occupied by BSAP in vivo in a CD19-expressing B-cell line but not in plasma or HeLa cells. This high-affinity site has been conserved in the promoters of both human and mouse CD19 genes and was furthermore shown to confer B-cell specificity to a f-globin reporter gene in transient transfection experiments. In addition, BSAP was found to be the only abundant DNA-binding activity of B-cell nuclear extracts that interacts with the CD19 promoter. Together, this evidence strongly implicates BSAP in the regulation of the CD19 gene.The differentiation of B lymphocytes from progenitor cells to immunoglobulin-secreting plasma cells is a multistep process which is characterized by the sequential expression of specific cell surface markers involved in cell-cell interaction and signal transduction (29). Among them is the B-cellspecific antigen CD19. This protein is expressed throughout B-cell ontogeny from the early progenitor cell up to the mature B-cell stage and is lost from the cell surface only at the terminal stages of B-cell differentiation. The CD19 molecule is present on both normal and malignant B-lymphoid cells and hence is the most reliable diagnostic surface marker of the human B-cell lineage (23, 35). The CD19 gene codes for a 95-kDa protein with two extracellular immunoglobulinlike domains, a short transmembrane region, and a large cytoplasmic tail (33,34,38). These features suggest that the CD19 protein is a membrane receptor involved in signal transduction of B lymphocytes. No natural ligand for CD19 is as yet known; instead, monoclonal anti-CD19 antibodies have been used to study the physiological function of the CD19 molecule. In agreement with the receptor hypothesis, antibody binding leads to rapid internalization of CD19 (7,35) and to mobilization of free intracellular calcium ions (17,27,35). CD19 antibodies strongly inhibit proliferation of resting mature B cells in response to stimulation with antiimmunoglobulin M (IgM) antibodies (11,27,35 (14).Regulation of B-cell-specific gene expression is brought about by several distinct transcription factors (reference 3 and references therein). One of them is the B-cell lineagespecific activator protein (BSAP). We have identified this transcription factor as a mammalian homolog of the sea urchin protein TSAP, which is res...

PurposeDefining a study population and creating an analytic dataset from longitudinal healthcare databases involves many decisions. Our objective was to catalogue scientific decisions underpinning study execution that should be reported to facilitate replication and enable assessment of validity of studies conducted in large healthcare databases.MethodsWe reviewed key investigator decisions required to operate a sample of macros and software tools designed to create and analyze analytic cohorts from longitudinal streams of healthcare data. A panel of academic, regulatory, and industry experts in healthcare database analytics discussed and added to this list.ConclusionEvidence generated from large healthcare encounter and reimbursement databases is increasingly being sought by decision‐makers. Varied terminology is used around the world for the same concepts. Agreeing on terminology and which parameters from a large catalogue are the most essential to report for replicable research would improve transparency and facilitate assessment of validity. At a minimum, reporting for a database study should provide clarity regarding operational definitions for key temporal anchors and their relation to each other when creating the analytic dataset, accompanied by an attrition table and a design diagram.A substantial improvement in reproducibility, rigor and confidence in real world evidence generated from healthcare databases could be achieved with greater transparency about operational study parameters used to create analytic datasets from longitudinal healthcare databases.

Increased expression of vascular cell adhesion molecule 1 (VCAM1) is associated with a variety of chronic inflammatory conditions, making its expression and function a target for therapeutic intervention. We have recently identified CAM741, a derivative of a fungus-derived cyclopeptolide that acts as a selective inhibitor of VCAM1 synthesis in endothelial cells. Here we show that the compound represses the biosynthesis of VCAM1 in cells by blocking the process of cotranslational translocation, which is dependent on the signal peptide of VCAM1. CAM741 does not inhibit targeting of the VCAM1 nascent chains to the translocon channel but prevents translocation to the luminal side of the endoplasmic reticulum (ER), through a process that involves the translocon component Sec61beta. Consequently, the VCAM1 precursor protein is synthesized towards the cytosolic compartment of the cells, where it is degraded. Our results indicate that the inhibition of cotranslational translocation with low-molecular-mass compounds, using specificity conferred by signal peptides, can modulate the biosynthesis of certain secreted and/or membrane proteins. In addition, they highlight cotranslational translocation at the ER membrane as a potential target for drug discovery.

The scientific community and decision-makers are increasingly concerned about transparency and reproducibility of epidemiologic studies using longitudinal healthcare databases. We explored the extent to which published pharmacoepidemiologic studies using commercially available databases could be reproduced by other investigators. We identified a nonsystematic sample of 38 descriptive or comparative safety/effectiveness cohort studies. Seven studies were excluded from reproduction, five because of violation of fundamental design principles, and two because of grossly inadequate reporting. In the remaining studies, >1,000 patient characteristics and measures of association were reproduced with a high degree of accuracy (median differences between original and reproduction <2% and <0.1). An essential component of transparent and reproducible research with healthcare databases is more complete reporting of study implementation. Once reproducibility is achieved, the conversation can be elevated to assess whether suboptimal design choices led to avoidable bias and whether findings are replicable in other data sources.