German primary care data collection projects: a scoping review.

BACKGROUND: The widespread use of electronic health records (EHRs) has led to a growing number of large routine primary care data collection projects globally, making these records a valuable resource for health services and epidemiological and clinical research. This scoping review aims to comprehensively assess and compare strengths and limitations of all German primary care data collection projects and relevant research publications that extract data directly from practice management systems (PMS). METHODS: A literature search was conducted in the electronic databases in May 2021 and in June 2022. The search string included terms related to general practice, routine data, and Germany. The retrieved studies were classified as applied studies and methodological studies, and categorised by type of research, subject area, sample of publications, disease category, or main medication analysed. RESULTS: A total of 962 references were identified, with 241 studies included from six German projects in which databases are populated by EHRs from PMS. The projects exhibited significant heterogeneity in terms of size, data collection methods, and variables collected. The majority of the applied studies (n = 205, 85%) originated from one database with a primary focus on pharmacoepidemiological topics (n = 127, 52%) including prescription patterns (n = 68, 28%) and studies about treatment outcomes, compliance, and treatment effectiveness (n = 34, 14%). Epidemiological studies (n = 77, 32%) mainly focused on incidence and prevalence studies (n = 41, 17%) and risk and comorbidity analysis studies (n = 31, 12%). Only 10% (n = 23) of studies were in the field of health services research, such as hospitalisation. CONCLUSION: The development and durability of primary care data collection projects in Germany is hindered by insufficient public funding, technical issues of data extraction, and strict data protection regulations. There is a need for further research and collaboration to improve the usability of EHRs for health services and research.

PD-1 signaling uncovers a pathogenic subset of T cells in inflammatory arthritis.

BACKGROUND: PD-1 is an immune checkpoint on T cells, and interventions to block this receptor result in T cell activation and enhanced immune response to tumors and pathogens. Reciprocally, despite a decade of research, approaches to treat autoimmunity with PD-1 agonists have only had limited successful. To resolve this, new methods must be developed to augment PD-1 function beyond engaging the receptor. METHODS: We conducted a flow cytometry analysis of T cells isolated from the peripheral blood and synovial fluid of patients with rheumatoid arthritis. In addition, we performed a genome-wide CRISPR/Cas9 screen to identify genes associated with PD-1 signaling. We further analyzed genes involved in PD-1 signaling using publicly available bulk and single-cell RNA sequencing datasets. RESULTS: Our screen confirmed known regulators in proximal PD-1 signaling and, importantly, identified an additional 1112 unique genes related to PD-1 ability to inhibit T cell functions. These genes were strongly associated with the response of cancer patients to PD-1 blockades and with high tumor immune dysfunction and exclusion scores, confirming their role downstream of PD-1. Functional annotation revealed that the most significant genes uncovered were those associated with known immune regulation processes. Remarkably, these genes were considerably downregulated in T cells isolated from patients with inflammatory arthritis, supporting their overall inhibitory functions. A study of rheumatoid arthritis single-cell RNA sequencing data demonstrated that five genes, KLRG1, CRTAM, SLAMF7, PTPN2, and KLRD1, were downregulated in activated and effector T cells isolated from synovial fluids. Backgating these genes to canonical cytotoxic T cell signatures revealed PD-1+ HLA-DRHIGH KLRG1LOW T cells as a novel inflammatory subset of T cells. CONCLUSIONS: We concluded that PD-1+ HLA-DRHIGH KLRG1LOW T cells are a potential target for future PD-1 agonists to treat inflammatory diseases. Our study uncovers new genes associated with PD-1 downstream functions and, therefore, provides a comprehensive resource for additional studies that are much needed to characterize the role of PD-1 in the synovial subset of T cells.

PD-1 signaling uncovers a pathogenic subset of T cells in inflammatory arthritis.

Background: PD-1 is an immune checkpoint on T cells and interventions to block this receptor result in T cell activation and enhanced immune response to tumors. Paired to that, and despite a decade of research, approaches to treat autoimmunity with PD-1 agonists still need to be more successful. To resolve this, new methods must be developed to augment PD-1 function beyond engaging the receptor. Methods: We conducted a flow cytometry analysis of T cells isolated from the peripheral blood and synovial fluid of patients with rheumatoid arthritis. In addition, we performed a genome-wide CRISPR/Cas9 screen to identify genes associated with PD-1 signaling. We further analyzed genes involved in PD-1 signaling using publicly available bulk and single-cell RNA sequencing datasets. Results: Our screen confirmed known regulators in proximal PD-1 signaling and, importantly, found an additional 1,112 unique genes related to PD-1 ability to inhibit T cell functions. These genes were strongly associated with the response of cancer patients to PD-1 blockades and with high tumor immune dysfunction and exclusion scores, confirming their role downstream of PD-1. Functional annotation revealed that more significant genes uncovered were those associated with known immune regulation processes. Remarkably, these genes were considerably downregulated in T cells isolated from patients with inflammatory arthritis, supporting their overall inhibitory functions. A study of rheumatoid arthritis single-cell RNA sequencing data demonstrated that five genes, KLRG1, CRTAM, SLAMF7, PTPN2, and KLRD1, were downregulated in activated and effector T cells isolated from synovial fluids. Back-gating these genes to canonical cytotoxic T cell signatures revealed PD-1 + HLA-DR HIGH KLRG LOW T cells as a novel inflammatory subset of T cells. Conclusion: We concluded that PD-1 + HLA-DR HIGH KLRG LOW T cells are a potential target for future PD-1 agonists to treat inflammatory diseases. Our study uncovers new genes associated with PD-1 downstream functions and, therefore, provides a comprehensive resource for additional studies that are much needed to characterize the role of PD-1 in the synovial subset of T cells.

SHP2 Targets ITK Downstream of PD-1 to Inhibit T Cell Function.

PD-1 is a critical therapeutic target in cancer immunotherapy and antibodies blocking PD-1 are approved for multiple types of malignancies. The phosphatase SHP2 is the main effector mediating PD-1 downstream signaling and accordingly attempts have been made to target this enzyme as an alternative approach to treat immunogenic tumors. Unfortunately, small molecule inhibitors of SHP2 do not work as expected, suggesting that the role of SHP2 in T cells is more complex than initially hypothesized. To better understand the perplexing role of SHP2 in T cells, we performed interactome mapping of SAP, an adapter protein that is associated with SHP2 downstream signaling. Using genetic and pharmacological approaches, we discovered that SHP2 dephosphorylates ITK specifically downstream of PD-1 and that this event was associated with PD-1 inhibitory cellular functions. This study suggests that ITK is a unique target in this pathway, and since ITK is a SHP2-dependent specific mediator of PD-1 signaling, the combination of ITK inhibitors with PD-1 blockade may improve upon PD-1 monotherapy in the treatment of cancer.