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Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs.
Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel.
Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy.
Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.
Elliptic flow from nuclear collisions is a hadronic observable sensitive to the early stages of system evolution. We report first results on elliptic flow of charged particles at midrapidity in Au+Au collisions at sqrt(s_NN)=130 GeV using the STAR TPC at RHIC. The elliptic flow signal, v_2, averaged over transverse momentum, reaches values of about 6% for relatively peripheral collisions and decreases for the more central collisions. This can be interpreted as the observation of a higher degree of thermalization than at lower collision energies. Pseudorapidity and transverse momentum dependence of elliptic flow are also presented.
Elliptic flow from nuclear collisions is a hadronic observable sensitive to the early stages of system evolution. We report first results on elliptic flow of charged particles at midrapidity in Au+Au collisions at sqrt[sNN] = 130 GeV using the STAR Time Projection Chamber at the Relativistic Heavy Ion Collider. The elliptic flow signal, v2, averaged over transverse momentum, reaches values of about 6% for relatively peripheral collisions and decreases for the more central collisions. This can be interpreted as the observation of a higher degree of thermalization than at lower collision energies. Pseudorapidity and transverse momentum dependence of elliptic flow are also presented.
A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.
Background: High reproducibility of LV mass and volume measurement from cine cardiovascular magnetic resonance (CMR) has been shown within single centers. However, the extent to which contours may vary from center to center, due to different training protocols, is unknown. We aimed to quantify sources of variation between many centers, and provide a multi-center consensus ground truth dataset for benchmarking automated processing tools and facilitating training for new readers in CMR analysis.
Methods: Seven independent expert readers, representing seven experienced CMR core laboratories, analyzed fifteen cine CMR data sets in accordance with their standard operating protocols and SCMR guidelines. Consensus contours were generated for each image according to a statistical optimization scheme that maximized contour placement agreement between readers.
Results: Reader-consensus agreement was better than inter-reader agreement (end-diastolic volume 14.7 ml vs 15.2–28.4 ml; end-systolic volume 13.2 ml vs 14.0–21.5 ml; LV mass 17.5 g vs 20.2–34.5 g; ejection fraction 4.2 % vs 4.6–7.5 %). Compared with consensus contours, readers were very consistent (small variability across cases within each reader), but bias varied between readers due to differences in contouring protocols at each center. Although larger contour differences were found at the apex and base, the main effect on volume was due to small but consistent differences in the position of the contours in all regions of the LV.
Conclusions: A multi-center consensus dataset was established for the purposes of benchmarking and training. Achieving consensus on contour drawing protocol between centers before analysis, or bias correction after analysis, is required when collating multi-center results.
In this meeting report, particularly addressing the topic of protection of the cardiovascular system from ischemia/reperfusion injury, highlights are presented that relate to conditioning strategies of the heart with respect to molecular mechanisms and outcome in patients’ cohorts, the influence of co-morbidities and medications, as well as the contribution of innate immune reactions in cardioprotection. Moreover, developmental or systems biology approaches bear great potential in systematically uncovering unexpected components involved in ischemia–reperfusion injury or heart regeneration. Based on the characterization of particular platelet integrins, mitochondrial redox-linked proteins, or lipid-diol compounds in cardiovascular diseases, their targeting by newly developed theranostics and technologies opens new avenues for diagnosis and therapy of myocardial infarction to improve the patients’ outcome.
Tolerizing CTL by sustained hepatic PD-L1 expression provides a new therapy spproach in mouse sepsis
(2019)
Cytotoxic T lymphocyte (CTL) activation contributes to liver damage during sepsis, but the mechanisms involved are largely unknown. Understanding the underlying principle will permit interference with CTL activation and thus, provide a new therapeutic option.
Methods: To elucidate the mechanism leading to CTL activation we used the Hepa1-6 cell line in vitro and the mouse model of in vivo polymicrobial sepsis, following cecal-ligation and -puncture (CLP) in wildtype, myeloid specific NOX-2, global NOX2 and NOX4 knockout mice, and their survival as a final readout. In this in vivo setting, we also determined hepatic mRNA and protein expression as well as clinical parameters of liver damage - aspartate- and alanine amino-transaminases. Hepatocyte specific overexpression of PD-L1 was achieved in vivo by adenoviral infection and transposon-based gene transfer using hydrodynamic injection.
Results: We observed downregulation of PD-L1 on hepatocytes in the murine sepsis model. Adenoviral and transposon-based gene transfer to restore PD-L1 expression, significantly improved survival and reduced the release of liver damage, as PD-L1 is a co-receptor that negatively regulates T cell function. Similar protection was observed during pharmacological intervention using recombinant PD-L1-Fc. N-acetylcysteine blocked the downregulation of PD-L1 suggesting the involvement of reactive oxygen species. This was confirmed in vivo, as we observed significant upregulation of PD-L1 expression in NOX4 knockout mice, following sham operation, whereas its expression in global as well as myeloid lineage NOX2 knockout mice was comparable to that in the wild type animals. PD-L1 expression remained high following CLP only in total NOX2 knockouts, resulting in significantly reduced release of liver damage markers.
Conclusion: These results suggest that, contrary to common assumption, maintaining PD-L1 expression on hepatocytes improves liver damage and survival of mice during sepsis. We conclude that administering recombinant PD-L1 or inhibiting NOX2 activity might offer a new therapeutic option in sepsis.
Background: Evaluation of automated attenuation-based tube potential selection and its impact on image quality and radiation dose in CT (computed tomography) examinations for cancer staging.
Methods: A total of 110 (59 men, 51 women) patients underwent chest-abdomen-pelvis CT examinations; 55 using a fixed tube potential of 120 kV/current of 210 Reference mAs (using CareDose4D), and 55 using automated attenuation-based tube potential selection (CAREkV) also using a current of 210 Reference mAs. This evaluation was performed as a single-centre, observer-blinded retrospective analysis. Image quality was assessed by two readers in consensus. Attenuation, image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were measured or calculated for objective image evaluation. For the evaluation of radiation exposure, dose-length-product (DLP) values were compared and Size-specific dose estimates (SSDE) values were calculated.
Results: Diagnostic image quality was obtained from all patients. The median DLP (703.5 mGy · cm, range 390–2203 mGy · cm) was 7.9% lower when using the algorithm compared with the standard 120 kV protocol (median 756 mGy · cm, range 345–2267 mGy · cm). A reduction in potential to 100 kV occurred in 32 cases; therefore, these patients received significantly lower radiation exposure compared with the 120 kV protocol.
Conclusion: Automated attenuation-based tube potential selection produces good diagnostic image quality in chest-abdomen-pelvis CT and reduces the patient’s overall radiation dose by 7.9% compared to the standard 120 kV protocol.
Background: In Germany, patients receiving oral anticoagulation (OAC) are often treated by general practitioners (GPs), and large proportions of patients receive vitamin K antagonists (VKAs). The quality of OAC in German GP practices, differences between various practices, and improvement potential through implementation of case management, have not yet been investigated satisfactorily.
Based on results of a cluster-randomized controlled trial, we aimed to assess whether OAC quality can be improved, any variations between practices exist and determine practice- and patient-level factors.
Methods: The PICANT trial (2012–2015) was performed in 52 GP practices in Hesse, Germany. Adult patients with long-term indication for OAC received best practice case management in the intervention group. International normalized ratio (INR) values were recorded from anticoagulation passes. The Rosendaal method was used to calculate Time in Therapeutic Range (TTR) at patient level, and mean pooling to obtain center-specific TTR (cTTR) at practice level. The quality of OAC was assessed by TTR and cTTR. Linear model analyses were used to investigate associations between practice−/ patient-level factors and TTR.
Results: Inclusion of 736 patients (49.6% intervention and 50.4% control patients); 690 (93.8%) received phenprocoumon. Within 24 months, the TTR was 75.1% (SD 17.6) in the intervention versus 74.3% (SD 17.8) in the control group (p = 0.670). The cTTR averaged 75.1% (SD 6.5, range: 60.4 to 86.7%) in the intervention versus 74.3% (SD 7.2, range: 52.7 to 85.7%) in the control group (p = 0.668). At practice level, the TTR was significantly lower in practices with a male physician and certification in quality management. At patient level, the TTR was significantly higher in patients with moderate to high compliance, in men, and in patients that performed self-management. The TTR was significantly lower in patients with certain comorbidities, and who were hospitalized.
Conclusions: The intervention did not effectively improve OAC quality compared to routine care. Quality of INR control was generally good, but considerable variation existed between GP practices. The variability indicates optimization potential in some practices. The demonstrated association between patient-level factors and TTR highlights the importance of considering patient characteristics that may impede achieving high quality therapeutic outcomes.
Trial registration: ISRCTN registry, ISRCTN41847489, registered 27 February 2012.