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In the present paper we investigated the effect of heterologous expression of a rat liver ketohexokinase in potato ( Solanum tuberosum L.) plants with the aim of investigating the role of fructose 1-phosphate in plant metabolism. Plants were generated that contained appreciable activity of ketohexokinase but did not accumulate fructose 1-phosphate. They were, however, characterised by a severe growth retardation and abnormal leaf development. Studies of 14CO 2 assimilation and metabolism, and of the levels of photosynthetic pigments, revealed that these lines exhibited restricted photosynthesis. Despite this fact, the levels of starch and soluble sugars remained relatively constant. Analysis of intermediates of starch and sucrose biosynthesis revealed large increases in the triose phosphate and fructose 1,6-bisphosphate pools but relatively unaltered levels of inorganic phosphate and 3-phosphoglycerate, and these lines were also characterised by an accumulation of glyceraldehyde. The transformants neither displayed consistent changes in the activities of Calvin cycle enzymes nor in enzymes of sucrose synthesis but displayed a metabolic profile partially reminiscent of that brought about by end-product limitation, but most likely caused by an inhibition of photosynthesis brought about by the accumulation of glyceraldehyde. Analysis of the metabolite contents in lamina and vein fractions of the leaf, and of the enzymes of carbohydrate oxidation indicate that the phloem-enriched veins of ketohexokinase-expressing leaves tend toward hypoxia and indicate a problem of phloem transport. [ABSTRACT FROM AUTHOR]

Background: Proteasome inhibitors are a novel class of compounds entering clinical trials as a method to increase tumour sensitivity to standard chemotherapy. This phase I/II trial was carried out to evaluate the combination of capecitabine and the proteasome inhibitor bortezomib in anthracycline and/or taxane-pretreated patients with metastatic breast cancer. Patients and methods: A total of 35 patients were treated with bortezomib (1.0–1.3 mg/m2 on days 1, 4, 8 and 11) and capecitabine (1500–2500 mg/m2 on days 1–14) in 3-week intervals for up to eight cycles. Results: The maximum tolerated doses (MTDs) were bortezomib 1.3 mg/m2 and capecitabine 2500 mg/m2. The treatment was generally well tolerated and associated with toxic effects that were consistent with the known side-effects of the individual agents. The intent-to-treat overall response rate was 15% and an additional 27% of patients had stable disease (SD). In the 20 patients treated at the MTD, the response rate was 15% and 40% had SD. Median time to progression and overall survival were 3.5 months [95% confidence interval (CI) 1.9–4.4] and 7.5 months (95% CI 5.6–14.6), respectively. Median duration of response was 4.4 months. Conclusion: The combination of bortezomib and capecitabine is well tolerated and has moderate antitumour activity in heavily pretreated patients. [ABSTRACT FROM AUTHOR]

The scientific focus of the DRFZ's Programme Area Epidemiology and Health Services Research is, on the one hand, investigating the health care situation of people with rheumatic diseases in Germany, including its deficits, progress and trends. On the other hand, an essential goal is to uncover risk factors for unfavourable disease trajectories, but also protective factors, through the long-term observation of disease courses in large cohorts. With the approval of innovative, targeted therapies at the beginning of this millennium, the question of the real-world safety and effectiveness of the various anti-rheumatic therapies became a key issue for doctors and patients. The biologics registers have developed into central instruments of the programme area, which enable questions on comparative drug safety, but also on therapy effectiveness and risk reduction through effective therapy, to be answered in a robust manner.In this article, selected results of epidemiological research at the DRFZ are presented. The overall goal of the research was and is to contribute to improving the quality of life of children and adults with rheumatic and musculoskeletal diseases. This is the purpose of clinical-evaluative health services research as well as the acquisition of knowledge that supports effective, individualised therapy. Large, long-term patient cohorts and a stable network with clinical rheumatologists and those affected have proven to be indispensable instruments., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Differences in the distribution of individual-level clinical risk factors across regions do not fully explain the observed global disparities in COVID-19 outcomes. We aimed to investigate the associations between environmental and societal factors and country-level variations in mortality attributed to COVID-19 among people with rheumatic disease globally., Methods: In this observational study, we derived individual-level data on adults (aged 18-99 years) with rheumatic disease and a confirmed status of their highest COVID-19 severity level from the COVID-19 Global Rheumatology Alliance (GRA) registry, collected between March 12, 2020, and Aug 27, 2021. Environmental and societal factors were obtained from publicly available sources. The primary endpoint was mortality attributed to COVID-19. We used a multivariable logistic regression to evaluate independent associations between environmental and societal factors and death, after controlling for individual-level risk factors. We used a series of nested mixed-effects models to establish whether environmental and societal factors sufficiently explained country-level variations in death., Findings: 14 044 patients from 23 countries were included in the analyses. 10 178 (72·5%) individuals were female and 3866 (27·5%) were male, with a mean age of 54·4 years (SD 15·6). Air pollution (odds ratio 1·10 per 10 μg/m 3 [95% CI 1·01-1·17]; p=0·0105), proportion of the population aged 65 years or older (1·19 per 1% increase [1·10-1·30]; p<0·0001), and population mobility (1·03 per 1% increase in number of visits to grocery and pharmacy stores [1·02-1·05]; p<0·0001 and 1·02 per 1% increase in number of visits to workplaces [1·00-1·03]; p=0·032) were independently associated with higher odds of mortality. Number of hospital beds (0·94 per 1-unit increase per 1000 people [0·88-1·00]; p=0·046), human development index (0·65 per 0·1-unit increase [0·44-0·96]; p=0·032), government response stringency (0·83 per 10-unit increase in containment index [0·74-0·93]; p=0·0018), as well as follow-up time (0·78 per month [0·69-0·88]; p<0·0001) were independently associated with lower odds of mortality. These factors sufficiently explained country-level variations in death attributable to COVID-19 (intraclass correlation coefficient 1·2% [0·1-9·5]; p=0·14)., Interpretation: Our findings highlight the importance of environmental and societal factors as potential explanations of the observed regional disparities in COVID-19 outcomes among people with rheumatic disease and lay foundation for a new research agenda to address these disparities., Funding: American College of Rheumatology and European Alliance of Associations for Rheumatology., Competing Interests: MID reports research support from Pfizer for unrelated work. AS reports grants from a consortium of 13 companies (AbbVie, Bristol Myers Squibb, Celltrion, Fresenius Kabi, Lilly, Mylan, Hexal, Merck, Pfizer, Roche, Samsung, Sanofi-Aventis, and UCB) supporting the German RABBIT register, and personal fees from lectures for AbbVie, Merck, Roche, Bristol Myers Squibb, and Pfizer, outside of the submitted work. EFM reports that the Portuguese League Against Rheumatic Diseases received support for specific activities: grants from Abbvie, Novartis, Janssen-Cilag, Lilly Portugal, Sanofi, Grünenthal SA, Merck, Celgene, Medac, Pharmakern, the Global Alliance for Patient Access; grants and non-financial support from Pfizer; and non-financial support from Grünenthal GmbH, outside of the submitted work. KLH reports receiving speaker fees from Abbvie and grant income from Bristol Myers Squibb, UCB, and Pfizer, unrelated to this work. KLH is also supported by the National Institute for Health Research (NIHR) Manchester Biomedical Research Centre. LG reports research grants from Amgen, Galapagos, Janssen, Lilly, Pfizer, Sandoz, and Sanofi; and consulting fees from AbbVie, Amgen, Bristol Myers Squibb, Biogen, Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, Samsung Bioepis, Sanofi-Aventis, and UCB, all unrelated to this work. LC has not received fees or personal grants from any laboratory, but her institute works by contract for laboratories among other institutions, such as Abbvie Spain, Eisai, Gebro Pharma, Merck Sharp & Dohme España, SA Pharma, Novartis Farmaceutica, Pfizer, Roche Farma, Sanofi, Aventis, Astellas Pharma, Actelion Pharmaceuticals España, Grünenthal GmbH, and UCB Pharma. JAS has performed consultancy for AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, and Optum, unrelated to this work. LW has received consulting or speaking fees from Aurinia Pharma, outside of the submitted work. MFU-G reports grant or research support from Jannsen and Pfizer, unrelated to this work. The Swedish Rheumatology Quality Register, with LL as register holder, has agreements with Abbvie, Amgen, Eli Lilly, Gilead, Novartis, Pfizer, Sanofi, Sobi, and UCB for register data analyses, unrelated to this work. CR has received consulting or speaker fees from Abbvie, Amgen, AstraZeneca, BMS, Biogen, Eli Lilly, Glenmark, GlaxoSmithKline, Merck, Mylan, and Pfizer; and grants from Biogen, Lilly, and Nordic Pharma, all unrelated to this work. MJS has received speaker fees from Abbvie, AstraZeneca, Novartis, and Pfizer. AR has received speaker fees from Janssen, Pfizer, and Novartis. GP-E reports reports personal consulting fees, speaking fees, or both from Pfizer, GlaxoSmithKline, Janssen, Sandoz, and Sanofi, outside of the submitted work. PCR reports personal consulting fees, speaking fees, or both from Abbvie, Eli Lilly, Janssen, Novartis, Pfizer, and UCB; and travel assistance from Roche. PMM has received consulting fees, speaker fees, or both from Abbvie, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche, and UCB, unrelated to this work. PMM is supported by the NIHR University College London Hospitals Biomedical Research Centre. ES is a Board Member of the Canadian Arthritis Patient Alliance, a patient-run, volunteer-based organisation whose activities are largely supported by independent grants from pharmaceutical companies. JWL has received research funding from Pfizer, outside of the submitted work. JSH is supported by grants from the Rheumatology Research Foundation and has salary support from the Childhood Arthritis and Rheumatology Research Alliance. JSH has performed consulting for Novartis, Sobi, and Biogen, unrelated to this work. PS reports honorarium for doing social media for American College of Rheumatology journals. RG reports personal fees, speaking fees, or both from Abbvie, Janssen, Novartis, Pfizer, and Cornerstones; and travel assistance from Pfizer. SB reports non-branded consulting fees for AbbVie, Horizon, and Novartis; and is employed by Pfizer. ZSW reports grant support from Bristol Myers Squibb and Principia–Sanofi; and performed consultancy for Viela Bio and MedPace, outside of the submitted work. ZSW's work is supported by grants from the National Institutes of Health. JY has performed consulting for Eli Lilly, Pfizer, Aurinia, and AstraZeneca, outside of the submitted work. All other authors declare no competing interests., (Published by Elsevier Ltd.)

This review article summarizes the current projects and perspectives of rheumatological healthcare research in the program area epidemiology of the German Rheumatism Research Center. Health services research is conducted with the help of various data sources. In addition to the classical rheumatological disease registers, health insurance data and population-related cohorts are increasingly being used for analyses. From data collection and monitoring to analysis algorithms, digital applications will change the healthcare research over the coming years. Collaborative analyses with national and international cooperation partners, including biomarkers, complete the research fields in the program area epidemiology. The digitalization of research projects is a central component that will further change health services research in the coming decade.

Over the past 28 years the German Rheumatism Research Center in Berlin has initiated various epidemiological studies in which data on patients with inflammatory rheumatic diseases are collected nationwide and multicentric. The spectrum ranges from rheumatoid arthritis and spondylarthritis to connective tissue diseases and rheumatic diseases in childhood. Based on the respective scientific question, studies of different types were established. The German National Databases for adults and children annually collect cross-sectional data to map the care of patients. In two inception cohorts, adults with early arthritis and patients with juvenile idiopathic arthritis are investigated from disease onset. The long-term observational cohorts/registries RABBIT, RABBIT-SpA and JuMBO focus on the long-term efficacy and safety of biologic drugs and other targeted treatments. Rhekiss investigates women with inflammatory rheumatic diseases when trying to become pregnant, during pregnancy and postpartum. This article highlights each of these observational studies with its characteristics as well as national and international collaborations.

Background: The treatment of axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) has changed enormously in recent years due to market authorization of a number of new biologicals with different modes of action and the increasing use of biosimilars. Real-world data on long-term safety and efficacy under routine daily conditions is not yet sufficient. Therefore, the German Rheumatism Research Center has initiated a new cohort study covering axSpA and PsA., Objective: Presentation of initial results from the new register RABBIT-SpA, which was started in May 2017., Material and Methods: This is a prospective longitudinal cohort study with a similar study design to the German biologics register RABBIT. Patients can be included at the start of a new treatment either in the so-called index drug group or in the comparison group (conventional systemic treatment, including non-steroidal anti-inflammatory drugs, NSAID). Follow-up per patient should be at least 5 years and preferably 10 years. The RABBIT-SpA uses a web-based documentation system., Results: Up to mid-December 2018 a total of 514 axSpA patients had been documented in RABBIT-SpA, 410 with an index drug and 104 with conventional treatment. There are differences between these treatment groups, e. g. in the duration of the disease and in parameters of disease activity. It is also noticeable that in axSpA patients, approximately 5 years lie between the onset of the symptoms and confirmation of the diagnosis. Of the 355 PsA patients, 265 were included with an index drug and 90 with conventional treatment. Of the PsA patients 86% have a dominant peripheral manifestation. The average number of pressure tender joints is 8 and the average number of swollen joints is 4., Conclusion: The online register RABBIT-SpA is well-received by the participating rheumatological institutions. The electronic recording of patient data can be carried out in a reasonable time. Participation in the RABBIT-SpA is open to new rheumatological institutions at any time.