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3. Positron emission tomography imaging of the sodium iodide symporter senses real-time energy stress in vivo

Author

Piotr Dzien, Agata Mackintosh, Gaurav Malviya, Emma Johnson, Dmitry Soloviev, Gavin Brown, Alejandro Huerta Uribe, Colin Nixon, Scott K. Lyons, Oliver Maddocks, Karen Blyth, and David Y. Lewis

Subjects
Positron emission tomography, Reporter genes, Metabolic sensor, Energy charge, 2-DG, Oligomycin A, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Tissue environment is critical in determining tumour metabolic vulnerability. However, in vivo drug testing is slow and waiting for tumour growth delay may not be the most appropriate endpoint for metabolic treatments. An in vivo method for measuring energy stress would rapidly determine tumour targeting in a physiologically relevant environment. The sodium-iodide symporter (NIS) is an imaging reporter gene whose protein product co-transports sodium and iodide, and positron emission tomography (PET) radiolabelled anions into the cell. Here, we show that PET imaging of NIS-mediated radiotracer uptake can rapidly visualise tumour energy stress within minutes following in vivo treatment. Methods We modified HEK293T human embryonic kidney cells, and A549 and H358 lung cancer cells to express transgenic NIS. Next, we subjected these cells and implanted tumours to drugs known to induce metabolic stress to observe the impact on NIS activity and energy charge. We used [18F]tetrafluoroborate positron emission tomography (PET) imaging to non-invasively image NIS activity in vivo. Results NIS activity was ablated by treating HEK293T cells in vitro, with the Na+/K+ ATPase inhibitor digoxin, confirming that radiotracer uptake was dependent on the sodium–potassium concentration gradient. NIS-mediated radiotracer uptake was significantly reduced (− 58.2%) following disruptions to ATP re-synthesis by combined glycolysis and oxidative phosphorylation inhibition in HEK293T cells and by oxidative phosphorylation inhibition (− 16.6%) in A549 cells in vitro. PET signal was significantly decreased (− 56.5%) within 90 min from the onset of treatment with IACS-010759, an oxidative phosphorylation inhibitor, in subcutaneous transgenic A549 tumours in vivo, showing that NIS could rapidly and sensitively detect energy stress non-invasively, before more widespread changes to phosphorylated AMP-activated protein kinase, phosphorylated pyruvate dehydrogenase, and GLUT1 were detectable. Conclusions NIS acts as a rapid metabolic sensor for drugs that lead to ATP depletion. PET imaging of NIS could facilitate in vivo testing of treatments targeting energetic pathways, determine drug potency, and expedite metabolic drug development.

Published
2023
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4. High molar activity [18F]tetrafluoroborate synthesis for sodium iodide symporter imaging by PET

Author

Dmitry Soloviev, Piotr Dzien, Agata Mackintosh, Gaurav Malviya, Gavin Brown, and David Lewis

Subjects
NIS, Reporter gene imaging, Tetrafluoroborate, Fluorine-18, Positron emission tomography, Sodium iodide symporter, Medical physics. Medical radiology. Nuclear medicine, R895-920, Therapeutics. Pharmacology, RM1-950
Abstract

Abstract Background Sodium iodide symporter (NIS) imaging by positron emission tomography (PET) is gaining traction in nuclear medicine, with an increasing number of human studies being published using fluorine-18 radiolabelled tetrafluoroborate ([18F]TFB). Clinical success of any radiotracer relies heavily on its accessibility, which in turn depends on the availability of robust radiolabelling procedures providing a radiotracer in large quantities and of high radiopharmaceutical quality. Results Here we publish an improved radiolabelling method and quality control procedures for high molar activity [18F]TFB. The use of ammonium hydroxide for [18F]fluoride elution, commercially available boron trifluoride-methanol complex dissolved in acetonitrile as precursor and removal of unreacted [18F]fluoride on Florisil solid-phase extraction cartridges resulted in the reliable production of [18F]TFB on SYNTHRA and TRACERLAB FXFN automated synthesizers with radiochemical yields in excess of 30%, radiochemical purities in excess of 98% and molar activities in the range of 34–217 GBq/µmol at the end of synthesis. PET scanning of a mouse lung tumour model carrying a NIS reporter gene rendered images of high quality and improved sensitivity. Conclusions A novel automated radiosynthesis procedure for [18F]tetrafluoroborate has been developed that provides the radiotracer with high molar activity, suitable for preclinical imaging of NIS reporter gene.

Published
2022
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5. Detecting disabilities in everyday life: evidence from a geriatric assessment

Author

Cornelius Dzien, Petra Unterberger, Paul Hofmarcher, Hannes Winner, and Monika Lechleitner

Subjects
Geriatric assessment, Functional limitations, Activities of daily living (ADL), Variable selection, Least absolute shrinkage and selection operator (LASSO), Receiver operating characteristic (ROC) analysis, Geriatrics, RC952-954.6
Abstract

Abstract Background The activities of daily living (ADL) score is a widely used index to establish the degree of independence from any help in everyday life situations. Measuring ADL accurately is time-consuming and costly. This paper presents a framework to approximate ADL via variables usually collected in comprehensive geriatric assessments. We show that the selected variables serve as good indicators in explaining the physical disabilities of older patients. Methods Our sample included information from a geriatric assessment of 326 patients aged between 64 and 99 years in a hospital in Tyrol, Austria. In addition to ADL, 23 variables reflecting the physical and mental status of these patients were recorded during the assessment. We performed least absolute shrinkage and selection operator (LASSO) to determine which of these variables had the highest impact on explaining ADL. Then, we used receiver operating characteristic (ROC) analysis and logistic regression techniques to validate our model performance. Finally, we calculated cut-off points for each of the selected variables to show the values at which ADL fall below a certain threshold. Results Mobility, urinary incontinence, nutritional status and cognitive function were most closely related to ADL and, therefore, to geriatric patients’ functional limitations. Jointly, the selected variables were able to detect neediness with high accuracy (area under the ROC curve (AUC) = 0.89 and 0.91, respectively). If a patient had a limitation in one of these variables, the probability of everyday life disability increased with a statistically significant factor between 2.4 (nutritional status, 95%-CI 1.5–3.9) and 15.1 (urinary incontinence, 95%-CI 3.6–63.4). Conclusions Our study highlights the most important impairments of everyday life to facilitate more efficient use of clinical resources, which in turn allows for more targeted treatment of geriatric patients. At the patient level, our approach enables early detection of functional limitations and timely indications of a possible need for assistance in everyday life.

Published
2022
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9. Hyperpolarized Amino Acid Derivatives as Multivalent Magnetic Resonance pH Sensor Molecules.

Author

Hundshammer, Christian, Düwel, Stephan, Ruseckas, David, Topping, Geoffrey, Dzien, Piotr, Müller, Christoph, Feuerecker, Benedikt, Hövener, Jan B, Haase, Axel, Schwaiger, Markus, Glaser, Steffen J, and Schilling, Franz

Subjects
amino acids, dissolution dynamic nuclear polarization, hyperpolarized, magnetic resonance spectroscopic imaging, nuclear magnetic resonance, pH sensors, Environmental Science and Management, Ecology, Analytical Chemistry, Distributed Computing, Electrical and Electronic Engineering
Abstract

pH is a tightly regulated physiological parameter that is often altered in diseased states like cancer. The development of biosensors that can be used to non-invasively image pH with hyperpolarized (HP) magnetic resonance spectroscopic imaging has therefore recently gained tremendous interest. However, most of the known HP-sensors have only individually and not comprehensively been analyzed for their biocompatibility, their pH sensitivity under physiological conditions, and the effects of chemical derivatization on their logarithmic acid dissociation constant (pKa). Proteinogenic amino acids are biocompatible, can be hyperpolarized and have at least two pH sensitive moieties. However, they do not exhibit a pH sensitivity in the physiologically relevant pH range. Here, we developed a systematic approach to tailor the pKa of molecules using modifications of carbon chain length and derivatization rendering these molecules interesting for pH biosensing. Notably, we identified several derivatives such as [1-13C]serine amide and [1-13C]-2,3-diaminopropionic acid as novel pH sensors. They bear several spin-1/2 nuclei (13C, 15N, 31P) with high sensitivity up to 4.8 ppm/pH and we show that 13C spins can be hyperpolarized with dissolution dynamic polarization (DNP). Our findings elucidate the molecular mechanisms of chemical shift pH sensors that might help to design tailored probes for specific pH in vivo imaging applications.

Published
2018

10. Multi-scale in vivo imaging of tumour development using a germline conditional triple-reporter system

Author

Lewis, David, primary, Dzien, Piotr, additional, Iraolagoitia, Ximena Raffo, additional, May, Stephanie, additional, Stevenson, David, additional, McGarry, Lynn, additional, Soloviev, Dmitry, additional, Brown, Gavin, additional, Nixon, Colin, additional, Kapeni, Chrysa, additional, Roche, Maike De La, additional, Blyth, Karen, additional, Lyons, Scott, additional, Bird, Thomas, additional, Strathdee, Douglas, additional, Fruhwirth, Gilbert, additional, and Carlin, Leo, additional

Published
2024
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16. Coregulation Analysis of Mechanistic Biomarkers in Autosomal Dominant Polycystic Kidney Disease

Author

Johannes Leierer, Paul Perco, Benedikt Hofer, Susanne Eder, Alexander Dzien, Julia Kerschbaum, Michael Rudnicki, and Gert Mayer

Subjects
autosomal dominant polycystic kidney disease, mechanistic biomarkers, EGFR signaling, angiogenesis, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disorder leading to deterioration of kidney function and end stage kidney disease (ESKD). A number of molecular processes are dysregulated in ADPKD but the exact mechanism of disease progression is not fully understood. We measured protein biomarkers being linked to ADPKD-associated molecular processes via ELISA in urine and serum in a cohort of ADPKD patients as well as age, gender and eGFR matched CKD patients and healthy controls. ANOVA and t-tests were used to determine differences between cohorts. Spearman correlation coefficient analysis was performed to assess coregulation patterns of individual biomarkers and renal function. Urinary epidermal growth factor (EGF) and serum apelin (APLN) levels were significantly downregulated in ADPKD patients. Serum vascular endothelial growth factor alpha (VEGFA) and urinary angiotensinogen (AGT) were significantly upregulated in ADPKD patients as compared with healthy controls. Arginine vasopressin (AVP) was significantly upregulated in ADPKD patients as compared with CKD patients. Serum VEGFA and VIM concentrations were positively correlated and urinary EGF levels were negatively correlated with urinary AGT levels. Urinary EGF and AGT levels were furthermore significantly associated with estimated glomerular filtration rate (eGFR) in ADPKD patients. In summary, altered protein concentrations in body fluids of ADPKD patients were found for the mechanistic markers EGF, APLN, VEGFA, AGT, AVP, and VIM. In particular, the connection between EGF and AGT during progression of ADPKD warrants further investigation.

Published
2021
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18. Fat-Free Mass and Fasting Glucose Values in Patients with and without Statin Therapy Assigned to Age Groups between 75 Years

Author

Alexander Dzien, Hannes Winner, Engelbert Theurl, Christine Dzien-Bischinger, and Monika Lechleitner

Subjects
Fat-free mass, Aging, Statin, Nutrition. Foods and food supply, TX341-641, Nutritional diseases. Deficiency diseases, RC620-627
Abstract

Objective: The aging-associated changes in body composition result in an increased cardiometabolic risk. A tremendous reduction of cardiovascular morbidity and mortality can be obtained by statin therapy. Statins are well tolerated, with myopathy as the most serious negative side effect. Some recently published studies indicate that the incidence of type 2 diabetes might be increased during intensified statin therapy. The aim of our study was to investigate whether statin therapy has an influence on the aging-associated changes in fat-free mass (FFM). Methods: A total of 3,280 persons attending a medical outdoor center between January 2005 and July 2011 were assigned to 3 age groups from 75 years. Clinical data, body mass index (BMI), and body composition were evaluated in the different age groups in patients with and without statin therapy. To analyze the impact of statin use on FFM, we regressed a patient's FFM on an interaction term between statin use and age and other control variables. Results: Aging was associated with a decrease in BMI and FFM, while fat mass continuously increased up to the age of >75 years. This was paralleled by a continuous increase in fasting glucose levels in patients with and without statin therapy. The loss of FFM between the age group 75 years was more pronounced in statin-treated patients (10.88%) than in non-statin users (8.47%). Creatine phosphokinase values revealed a decrease of 7.77 U/l between the age groups 75 years in non-statin users and of 14.75 U/l in statin users. Statistical analysis indicated that the effect of statin therapy on FFM is more pronounced in younger than in older patients. Conclusions: Patients under statin therapy seem to be more vulnerable to the aging-associated lowering of FFM. Diagnostic procedures and interventions to prevent a loss of muscle mass might be of particular advantage in elderly patients under statin therapy.

Published
2013
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19. High molar activity [

Author

Dmitry, Soloviev, Piotr, Dzien, Agata, Mackintosh, Gaurav, Malviya, Gavin, Brown, and David, Lewis

Abstract

Sodium iodide symporter (NIS) imaging by positron emission tomography (PET) is gaining traction in nuclear medicine, with an increasing number of human studies being published using fluorine-18 radiolabelled tetrafluoroborate ([Here we publish an improved radiolabelling method and quality control procedures for high molar activity [A novel automated radiosynthesis procedure for [

Published
2022

20. Positron emission tomography imaging of the sodium iodide symporter senses real-time energy stress in vivo

Author

Piotr Dzien, Agata Mackintosh, Gaurav Malviya, Emma Johnson, Dmitry Soloviev, Gavin Brown, Alejandro Huerta Uribe, Colin Nixon, Scott K. Lyons, Oliver Maddocks, Karen Blyth, and David Y. Lewis

Abstract

Background: Tissue environment is critical in determining tumour metabolic vulnerability. However, in vivo drug testing is slow and waiting for tumour growth delay may not be the most appropriate endpoint for metabolic treatments. An in vivo method for measuring energy stress would rapidly determine tumour targeting in a physiologically relevant environment. The sodium-iodide symporter (NIS) is an imaging reporter gene whose protein product co-transports sodium and iodide, and positron emission tomography (PET) radiolabelled anions into the cell. Here, we show that PET imaging of NIS-mediated radiotracer uptake can rapidly visualise tumour energy stress within minutes following in vivo treatment. Methods: We modified HEK293T human embryonic kidney cells and A549 lung cancer cells to express transgenic. We treated cells and implanted tumours with drugs that caused metabolic stress to determine the effects in NIS activity and energy charge. We used [18F]tetrafluoroborate positron emission tomography (PET) imaging to non-invasively image NIS activity in vivo. Results: NIS activity was ablated by treating HEK293T cells in vitro, with the Na+/K+ ATPase inhibitor digoxin, confirming that radiotracer uptake was dependent on the sodium-potassium concentration gradient. NIS-mediated radiotracer uptake was significantly reduced (-58.2%) following disruptions to ATP re-synthesis by combined glycolysis and oxidative phosphorylation inhibition in HEK293T cells and by oxidative phosphorylation inhibition (16.6%) in A549 cells in vitro. PET signal was significantly decreased (-56.5%) within 90 minutes from the onset of treatment with IACS-010759, an oxidative phosphorylation inhibitor, in subcutaneous transgenic A549 tumours in vivo, showing that NIS could rapidly and sensitively detect energy stress non-invasively, before more widespread changes to phosphorylated AMP-activated protein kinase, phosphorylated pyruvate dehydrogenase and GLUT1 were detectable. Conclusions: NIS acts as a rapid metabolic sensor for drugs that lead to ATP depletion. PET imaging of NIS could facilitate in vivo testing of treatments targeting energetic pathways, determine drug potency and expedite metabolic drug development.

Published
2022

22. Positron emission tomography imaging of the sodium iodide symporter senses real-time energy stress in vivo

Author

Dzien, Piotr, primary, Mackintosh, Agata, additional, Malviya, Gaurav, additional, Johnson, Emma, additional, Soloviev, Dmitry, additional, Brown, Gavin, additional, Uribe, Alejandro Huerta, additional, Nixon, Colin, additional, Lyons, Scott K., additional, Maddocks, Oliver, additional, Blyth, Karen, additional, and Lewis, David Y., additional

Published
2022
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23. Human jackstone arms show a protein-rich, X-ray lucent core, suggesting that proteins drive their rapid and linear growth

Author

Ronald S. Boris, Michael S. Borofsky, Cornelius Dzien, Victor Hugo Canela, James E. Lingeman, Sharon B. Bledsoe, James C. Williams, and Tarek M. El-Achkar

Subjects
Morphology (linguistics), Calcium Oxalate, X-Rays, Urology, 030232 urology & nephrology, Shell (structure), Calcium oxalate, X-ray, A protein, X-Ray Microtomography, Anatomy, Article, Core (optical fiber), Kidney Calculi, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, chemistry, Arm, Humans, Linear growth, Micro ct
Abstract

Jackstone calculi, having arms that extend out from the body of the stone, were first described over a century ago, but this morphology of stones has been little studied. We examined 98 jackstones from 50 different patient specimens using micro-computed tomography (micro CT) and infrared (IR) spectroscopy. Micro CT showed that jackstone arms consisted of an X-ray lucent core within each arm. This X-ray lucent core frequently showed sporadic, thin layers of apatite arranged transversely to the axis of the arm. The shells of the jackstones were always composed of calcium oxalate (CaOx), and with the monohydrate form the majority or sole mineral. Study of layering in the shell regions by micro CT showed that growth lines extended from the body of the stone out onto jack arms and that the thickness of the shell covering of jack arms often thinned with distance from the stone body, suggesting that the arms grew at a faster radial rate than did the stone body. Histological cross-sections of decalcified jackstone arms showed the core to be more highly autofluorescent than was the CaOx shell, and immunohistochemistry showed the core to be enriched in Tamm-Horsfall protein. We hypothesize that the protein-rich core of a jack arm might preferentially bind more protein from the urine and resist deposition of CaOx, such that the arm grows in a linear manner and at a faster rate than the bulk of the stone. This hypothesis thus predicts an enrichment of certain urine proteins in the core of the jack arm, a theory that is testable by appropriate analysis.

Published
2021

24. Effect of Zn(II) on pramlintide: structural kink, fibril formation, antifungal activity

Author

Dorota Dudek, Emilia Dzien, Joanna Watly, Agnieszka Matera-Witkiewicz, Aleksandra Mikolajczyk, Agata Hajda, Joanna Olesiak-Banska, and Magdalena Rowinska-Zyrek

Abstract

The antimicrobial properties of amylin, a polypeptide secreted by the pancreas, are far less known than its antidiabetic function. Among the studied amylin analogues, the coordination of zinc(II) enhances the antifungal properties of pramlintide, a non-fibrillating therapeutic analogue of amylin; binding at the N-terminal amino group and His18 imidazole, it induces a kink in the peptide structure, which, in turn, triggers a fibrillization process of the complex, resulting in an amyloid structure most likely responsible for the disruption of the fungal cell.

Published
2022

26. Detecting disabilities in everyday life: evidence from a geriatric assessment

Author

Petra Unterberger, Cornelius Dzien, Paul Hofmarcher, Hannes Winner, and Monika Lechleitner

Subjects
Aged, 80 and over, Urinary Incontinence, ROC Curve, Activities of Daily Living, Humans, Disabled Persons, Geriatrics and Gerontology, Geriatric Assessment, Aged
Abstract

BackgroundThe activities of daily living (ADL) score is a widely used index to establish the degree of independence from any help in everyday life situations. Measuring ADL accurately is time-consuming and costly. This paper presents a framework to approximate ADL via variables usually collected in comprehensive geriatric assessments. We show that the selected variables serve as good indicators in explaining the physical disabilities of older patients.MethodsOur sample included information from a geriatric assessment of 326 patients aged between 64 and 99 years in a hospital in Tyrol, Austria. In addition to ADL, 23 variables reflecting the physical and mental status of these patients were recorded during the assessment. We performed least absolute shrinkage and selection operator (LASSO) to determine which of these variables had the highest impact on explaining ADL. Then, we used receiver operating characteristic (ROC) analysis and logistic regression techniques to validate our model performance. Finally, we calculated cut-off points for each of the selected variables to show the values at which ADL fall below a certain threshold.ResultsMobility, urinary incontinence, nutritional status and cognitive function were most closely related to ADL and, therefore, to geriatric patients’ functional limitations. Jointly, the selected variables were able to detect neediness with high accuracy (area under the ROC curve (AUC) = 0.89 and 0.91, respectively). If a patient had a limitation in one of these variables, the probability of everyday life disability increased with a statistically significant factor between 2.4 (nutritional status, 95%-CI 1.5–3.9) and 15.1 (urinary incontinence, 95%-CI 3.6–63.4).ConclusionsOur study highlights the most important impairments of everyday life to facilitate more efficient use of clinical resources, which in turn allows for more targeted treatment of geriatric patients. At the patient level, our approach enables early detection of functional limitations and timely indications of a possible need for assistance in everyday life.

Published
2022

27. Will the COVID-19 pandemic slow down in the Northern hemisphere by the onset of summer? An epidemiological hypothesis

Author

Günter Weiss, Hannes Winner, Christine Dzien-Bischinger, Monika Lechleitner, and Alexander Dzien

Subjects
0301 basic medicine, Microbiology (medical), medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Epidemiology, Pneumonia, Viral, 030106 microbiology, Primary care, Global Health, Betacoronavirus, 03 medical and health sciences, 0302 clinical medicine, Pandemic, medicine, Global health, Humans, Registries, 030212 general & internal medicine, Pandemics, Respiratory Tract Infections, Respiratory viral infection, SARS-CoV-2, Cold season, Brief Report, Temperature, Northern Hemisphere, COVID-19, Outbreak, Seasonality, General Medicine, Influenza, Infectious Diseases, Geography, Seasons, Coronavirus Infections, Demography
Abstract

The COVID-19 pandemic has affected most countries of the world. As corona viruses are highly prevalent in the cold season, the question remains whether or not the pandemic will improve with increasing temperatures in the Northern hemisphere. We use data from a primary care registry of almost 15,000 patients over 20 years to retrieve information on viral respiratory infection outbreaks. Our analysis suggests that the severity of the pandemic will be softened by the seasonal change to summer.

Published
2020

28. Health-Related Quality of Life and Family Functioning of Primary Caregivers of Children with Menkes Disease.

Author

Rozensztrauch, Anna, Dzien, Izabela, and Śmigiel, Robert

Subjects
*QUALITY of life, *JUVENILE diseases, *PHYSICAL mobility, *FAMILIES, *EPILEPSY
Abstract

Background: Menkes disease (MD; OMIM #309400) is a progressive neurodegeneration that results from abnormalities in the copper metabolism which are already present before birth. It is an extremely rare condition. The study was conducted to assess the quality of life of children with MD syndrome and the impact of the disease on family functioning. Methods: A cross-sectional questionnaire survey was used. The subjects were 16 parents of children with MD. The method used was the Paediatric Quality of Life Inventory and the PedsQL Family Impact Module and the author's own questionnaire. Results: Quality of life (QOL) was 29.14 (SD = 14.73), with the lowest for physical functioning (M = 10.55; SD = 10.26) and highest for emotional functioning (M = 48.13; SD = 29.43). The highest score was on the family relationships domain (M = 56.25, SD = 20.38) and the cognitive functioning domain (M = 50.00, SD = 19.24) and the lowest was on the daily activities' domain (M = 32.29, SD = 20.38) and the physical functioning domain (M = 39.84, SD = 14.90). The analysis did not show statistically significant relationships between age (p = 0.193) and the number of epileptic seizures a week (p = 0.641) and the overall QOL of the children studied. No statistically significant relationships were found between treatment with copper histidine and the overall QOL of the children (p = 0.914) and in physical functioning (p = 0.927), emotional functioning (p = 0.706), and social functioning (p = 0.751). The presence of comorbidities did not have an influence on the overall QOL. Conclusions: MD has a moderate impact on the functioning of the families of the affected children. The age of the child, number of epileptic seizures a week, feeding method (oral feeding or feeding via a PEG tube), and treatment with copper histidine do not have a significant impact on the QOL of children with MD. [ABSTRACT FROM AUTHOR]

Published
2023
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30. Covid-19 screening: are forehead temperature measurements during cold outdoor temperatures really helpful?

Author

Wolfgang Halder, Hannes Winner, Monika Lechleitner, and Cornelius Dzien

Subjects
Complete data, Coronavirus disease 2019 (COVID-19), Acclimatization, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Infrared thermometer, Entrance screening, 030204 cardiovascular system & hematology, Body Temperature, 03 medical and health sciences, 0302 clinical medicine, Animal science, Forehead temperature, Humans, Medicine, Forehead, 030212 general & internal medicine, Temperature control, SARS-CoV-2, business.industry, Spring season, Temperature, COVID-19, General Medicine, Hospitals, Low outdoor temperatures, medicine.anatomical_structure, Fever screening, Original Article, business
Abstract

Summary Background Body temperature control is a frequently used screening test for infectious diseases, such as Covid-19 (Sars-CoV-2). We used this procedure to test the body temperature of staff members in a hospital in Tyrol (Austria), where the Covid-19 disease occurred in March 2020. The hospital is located in a mountain area at 995 m above sea level with low outdoor temperatures during early spring season. Under these conditions, we analyzed whether forehead temperature control offers a sufficient screening tool for infectious diseases. Methods Forehead temperature of 101 healthy male and female employees was measured with an infrared thermometer directly after entering the hospital (0 min), followed by further controls after 1 min, 3 min, 5 min and 60 min. We also tracked the outside temperature and the temperature at the entrance hall of the hospital. Results Complete data of body temperature were available for 46 female and 46 male study participants. The average forehead temperature measured directly after entrance to the hospital was the lowest (0 min) 33.17 ± 1.45 °C, and increased constantly to 34.90 ± 1.49 °C after 1 min, 35.77 ± 1.10 °C after 3 min, 36.08 ± 0.79 °C after 5 min, and 36.6 ± 0.24 °C after 60 min. The outside temperature ranged between −5.5 °C and 0 °C, the indoor temperature had a constant value of 20.5 °C. Conclusion Our results indicate that forehead infrared temperature control is not an appropriate tool to screen for infectious disease directly at the entrance of a building, at least during early spring season with cold outdoor temperatures.

Published
2020

32. Health-Related Quality of Life and Family Functioning of Primary Caregivers of Children with Menkes Disease

Author

Anna Rozensztrauch, Izabela Dzien, and Robert Śmigiel

Subjects
quality of life, rare disease, Menkes disease, General Medicine, family impact
Abstract

Background: Menkes disease (MD; OMIM #309400) is a progressive neurodegeneration that results from abnormalities in the copper metabolism which are already present before birth. It is an extremely rare condition. The study was conducted to assess the quality of life of children with MD syndrome and the impact of the disease on family functioning. Methods: A cross-sectional questionnaire survey was used. The subjects were 16 parents of children with MD. The method used was the Paediatric Quality of Life Inventory and the PedsQL Family Impact Module and the author’s own questionnaire. Results: Quality of life (QOL) was 29.14 (SD = 14.73), with the lowest for physical functioning (M = 10.55; SD = 10.26) and highest for emotional functioning (M = 48.13; SD = 29.43). The highest score was on the family relationships domain (M = 56.25, SD = 20.38) and the cognitive functioning domain (M = 50.00, SD = 19.24) and the lowest was on the daily activities’ domain (M = 32.29, SD = 20.38) and the physical functioning domain (M = 39.84, SD = 14.90). The analysis did not show statistically significant relationships between age (p = 0.193) and the number of epileptic seizures a week (p = 0.641) and the overall QOL of the children studied. No statistically significant relationships were found between treatment with copper histidine and the overall QOL of the children (p = 0.914) and in physical functioning (p = 0.927), emotional functioning (p = 0.706), and social functioning (p = 0.751). The presence of comorbidities did not have an influence on the overall QOL. Conclusions: MD has a moderate impact on the functioning of the families of the affected children. The age of the child, number of epileptic seizures a week, feeding method (oral feeding or feeding via a PEG tube), and treatment with copper histidine do not have a significant impact on the QOL of children with MD.

Published
2023

33. High cardiorespiratory fitness is more beneficial in pre-diabetic men than women

Author

Hannes Gatterer, Hanno Ulmer, Alexander Dzien, Matthias Somavilla, and Martin Burtscher

Subjects
Fitness Level, Impaired Fasting Glucose, Impaired Glucose Tolerance, Gender, Diabetes, Medicine (General), R5-920
Abstract

OBJECTIVES: To investigate gender-specific relationships between cardiorespiratory fitness and factors that predict the development of diabetes and to identify the risk factors that predict fasting plasma glucose and 2-hour plasma glucose levels. INTRODUCTION: Different risk factors (e.g., low cardiorespiratory fitness) may cause elevated plasma glucose levels in men compared to women. Therefore, gender-specific analyses are needed. METHODS: Cardiorespiratory fitness (maximal power output achieved during a standard cycle ergometry test), resting blood pressure, total serum cholesterol, high-density lipoprotein cholesterol and triglyceride levels were measured in 32 pre-diabetic men (mean age: 57.2 + 6.8 years; mean body mass index (BMI): 28.5 + 3.0 kg/m²) and 40 pre-diabetic women (mean age: 55.0 + 7.3 years, mean BMI: 30.4+5.7 kg/m²). A stepwise regression with backward variable selection was performed to construct models that predict 2-hour and fasting plasma glucose levels. RESULTS: Maximal power output was inversely related to the 2-hour plasma glucose level in the entire group (r= -0.237, p

Published
2011
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34. Hyperpolarized Amino Acid Derivatives as Multivalent Magnetic Resonance pH Sensor Molecules

Author

Christian Hundshammer, Stephan Düwel, David Ruseckas, Geoffrey Topping, Piotr Dzien, Christoph Müller, Benedikt Feuerecker, Jan B. Hövener, Axel Haase, Markus Schwaiger, Steffen J. Glaser, and Franz Schilling

Subjects
pH sensors, hyperpolarized, dissolution dynamic nuclear polarization, magnetic resonance spectroscopic imaging, nuclear magnetic resonance, amino acids, Chemical technology, TP1-1185
Abstract

pH is a tightly regulated physiological parameter that is often altered in diseased states like cancer. The development of biosensors that can be used to non-invasively image pH with hyperpolarized (HP) magnetic resonance spectroscopic imaging has therefore recently gained tremendous interest. However, most of the known HP-sensors have only individually and not comprehensively been analyzed for their biocompatibility, their pH sensitivity under physiological conditions, and the effects of chemical derivatization on their logarithmic acid dissociation constant (pKa). Proteinogenic amino acids are biocompatible, can be hyperpolarized and have at least two pH sensitive moieties. However, they do not exhibit a pH sensitivity in the physiologically relevant pH range. Here, we developed a systematic approach to tailor the pKa of molecules using modifications of carbon chain length and derivatization rendering these molecules interesting for pH biosensing. Notably, we identified several derivatives such as [1-13C]serine amide and [1-13C]-2,3-diaminopropionic acid as novel pH sensors. They bear several spin-1/2 nuclei (13C, 15N, 31P) with high sensitivity up to 4.8 ppm/pH and we show that 13C spins can be hyperpolarized with dissolution dynamic polarization (DNP). Our findings elucidate the molecular mechanisms of chemical shift pH sensors that might help to design tailored probes for specific pH in vivo imaging applications.

Published
2018
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38. High molar activity [18F]tetrafluoroborate synthesis for sodium iodide symporter imaging by PET.

Author

Soloviev, Dmitry, Dzien, Piotr, Mackintosh, Agata, Malviya, Gaurav, Brown, Gavin, and Lewis, David

Subjects
*SODIUM iodide, *TETRAFLUOROBORATES, *SOLID phase extraction, *POSITRON emission tomography, *REPORTER genes, *RADIOCHEMICAL purification, *RADIOACTIVE tracers
Abstract

Background: Sodium iodide symporter (NIS) imaging by positron emission tomography (PET) is gaining traction in nuclear medicine, with an increasing number of human studies being published using fluorine-18 radiolabelled tetrafluoroborate ([18F]TFB). Clinical success of any radiotracer relies heavily on its accessibility, which in turn depends on the availability of robust radiolabelling procedures providing a radiotracer in large quantities and of high radiopharmaceutical quality. Results: Here we publish an improved radiolabelling method and quality control procedures for high molar activity [18F]TFB. The use of ammonium hydroxide for [18F]fluoride elution, commercially available boron trifluoride-methanol complex dissolved in acetonitrile as precursor and removal of unreacted [18F]fluoride on Florisil solid-phase extraction cartridges resulted in the reliable production of [18F]TFB on SYNTHRA and TRACERLAB FXFN automated synthesizers with radiochemical yields in excess of 30%, radiochemical purities in excess of 98% and molar activities in the range of 34–217 GBq/µmol at the end of synthesis. PET scanning of a mouse lung tumour model carrying a NIS reporter gene rendered images of high quality and improved sensitivity. Conclusions: A novel automated radiosynthesis procedure for [18F]tetrafluoroborate has been developed that provides the radiotracer with high molar activity, suitable for preclinical imaging of NIS reporter gene. [ABSTRACT FROM AUTHOR]

Published
2022
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39. Intra-individual variability of eGFR trajectories in early diabetic kidney disease and lack of performance of prognostic biomarkers

Author

Patrick B. Mark, László Rosivall, Hannes Winner, Sara Denicolò, Gert Mayer, Julia Kerschbaum, Hiddo J.L. Heerspink, Christine Dzien-Bischinger, Alexander Dzien, Andrzej Wiecek, Susanne Eder, Michael Rudnicki, Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), and Groningen Kidney Center (GKC)

Subjects
Oncology, medicine.medical_specialty, Population, 030232 urology & nephrology, lcsh:Medicine, Renal function, 030209 endocrinology & metabolism, Type 2 diabetes, Disease, Article, 03 medical and health sciences, Medical research, 0302 clinical medicine, Risk Factors, Internal medicine, Albuminuria, Humans, Medicine, Diabetic Nephropathies, Prospective Studies, lcsh:Science, Prospective cohort study, education, education.field_of_study, Multidisciplinary, business.industry, Surrogate endpoint, lcsh:R, medicine.disease, Diabetes Mellitus, Type 2, Nephrology, Disease Progression, lcsh:Q, medicine.symptom, business, Biomarkers, Glomerular Filtration Rate, Kidney disease
Abstract

Studies reporting on biomarkers aiming to predict adverse renal outcomes in patients with type 2 diabetes and kidney disease (DKD) conventionally define a surrogate endpoint either as a percentage of decrease of eGFR (e.g. ≥ 30%) or an absolute decline (e.g. ≥ 5 ml/min/year). The application of those study results in clinical practise however relies on the assumption of a linear and intra-individually stable progression of DKD. We studied 860 patients of the PROVALID study and 178 of an independent population with a relatively preserved eGFR at baseline and at least 5 years of follow up. Individuals with a detrimental prognosis were identified using various thresholds of a percentage or absolute decline of eGFR after each year of follow up. Next, we determined how many of the patients met the same criteria at other points in time. Interindividual eGFR decline was highly variable but in addition intra-individual eGFR trajectories also were frequently non-linear. For example, of all subjects reaching an endpoint defined as a decrease of eGFR by ≥ 30% between baseline and 3 years of follow up, only 60.3 and 45.2% lost at least the same amount between baseline and year 4 or 5. The results were similar when only patients on stable medication or subpopulations based on baseline eGFR or albuminuria status were analyzed or an eGFR decline of ≥ 5 ml/min/1.73m2/year was used. Identification of reliable biomarkers predicting adverse prognosis is a strong clinical need given the large interindividual variability of DKD progression. However, it is conceptually challenging in early DKD because of non-linear intra-individual eGFR trajectories. As a result, the performance of a prognostic biomarker may be accurate after a specific time of follow-up in a single population only.

Published
2020

41. Coregulation Analysis of Mechanistic Biomarkers in Autosomal Dominant Polycystic Kidney Disease

Author

Paul Perco, Alexander Dzien, Gert Mayer, Julia Kerschbaum, Benedikt Hofer, Michael A. Rudnicki, Susanne Eder, and Johannes Leierer

Subjects
0301 basic medicine, Male, Vascular Endothelial Growth Factor A, 030232 urology & nephrology, Angiotensinogen, urologic and male genital diseases, chemistry.chemical_compound, angiogenesis, 0302 clinical medicine, Epidermal growth factor, Medicine, Biology (General), Spectroscopy, Aged, 80 and over, autosomal dominant polycystic kidney disease, General Medicine, Middle Aged, Polycystic Kidney, Autosomal Dominant, female genital diseases and pregnancy complications, Computer Science Applications, Apelin, Vascular endothelial growth factor, Vascular endothelial growth factor A, Chemistry, Female, EGFR signaling, Adult, medicine.medical_specialty, QH301-705.5, Urinary system, Autosomal dominant polycystic kidney disease, Renal function, Catalysis, Article, Inorganic Chemistry, 03 medical and health sciences, mechanistic biomarkers, Internal medicine, Humans, Physical and Theoretical Chemistry, Molecular Biology, QD1-999, Aged, Epidermal Growth Factor, business.industry, urogenital system, Organic Chemistry, medicine.disease, Arginine Vasopressin, 030104 developmental biology, Endocrinology, chemistry, Kidney disorder, business, Biomarkers
Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disorder leading to deterioration of kidney function and end stage kidney disease (ESKD). A number of molecular processes are dysregulated in ADPKD but the exact mechanism of disease progression is not fully understood. We measured protein biomarkers being linked to ADPKD-associated molecular processes via ELISA in urine and serum in a cohort of ADPKD patients as well as age, gender and eGFR matched CKD patients and healthy controls. ANOVA and t-tests were used to determine differences between cohorts. Spearman correlation coefficient analysis was performed to assess coregulation patterns of individual biomarkers and renal function. Urinary epidermal growth factor (EGF) and serum apelin (APLN) levels were significantly downregulated in ADPKD patients. Serum vascular endothelial growth factor alpha (VEGFA) and urinary angiotensinogen (AGT) were significantly upregulated in ADPKD patients as compared with healthy controls. Arginine vasopressin (AVP) was significantly upregulated in ADPKD patients as compared with CKD patients. Serum VEGFA and VIM concentrations were positively correlated and urinary EGF levels were negatively correlated with urinary AGT levels. Urinary EGF and AGT levels were furthermore significantly associated with estimated glomerular filtration rate (eGFR) in ADPKD patients. In summary, altered protein concentrations in body fluids of ADPKD patients were found for the mechanistic markers EGF, APLN, VEGFA, AGT, AVP, and VIM. In particular, the connection between EGF and AGT during progression of ADPKD warrants further investigation.

Published
2021
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44. Glycogen synthase kinase 3 protein kinase activity is frequently elevated in human non-small cell lung carcinoma and supports tumour cell proliferation.

Author

Emma E Vincent, Douglas J E Elder, Linda O'Flaherty, Olivier E Pardo, Piotr Dzien, Lois Phillips, Carys Morgan, Joya Pawade, Margaret T May, Muhammad Sohail, Martin R Hetzel, Michael J Seckl, and Jeremy M Tavaré

Subjects
Medicine, Science
Abstract

Glycogen synthase kinase 3 (GSK3) is a central regulator of cellular metabolism, development and growth. GSK3 activity was thought to oppose tumourigenesis, yet recent studies indicate that it may support tumour growth in some cancer types including in non-small cell lung carcinoma (NSCLC). We examined the undefined role of GSK3 protein kinase activity in tissue from human NSCLC.The expression and protein kinase activity of GSK3 was determined in 29 fresh frozen samples of human NSCLC and patient-matched normal lung tissue by quantitative immunoassay and western blotting for the phosphorylation of three distinct GSK3 substrates in situ (glycogen synthase, RelA and CRMP-2). The proliferation and sensitivity to the small-molecule GSK3 inhibitor; CHIR99021, of NSCLC cell lines (Hcc193, H1975, PC9 and A549) and non-neoplastic type II pneumocytes was further assessed in adherent culture.Expression and protein kinase activity of GSK3 was elevated in 41% of human NSCLC samples when compared to patient-matched control tissue. Phosphorylation of GSK3α/β at the inhibitory S21/9 residue was a poor biomarker for activity in tumour samples. The GSK3 inhibitor, CHIR99021 dose-dependently reduced the proliferation of three NSCLC cell lines yet was ineffective against type II pneumocytes.NSCLC tumours with elevated GSK3 protein kinase activity may have evolved dependence on the kinase for sustained growth. Our results provide further important rationale for exploring the use of GSK3 inhibitors in treating NSCLC.

Published
2014
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48. Prevalence of diabetic and impact on cardiovascular events and mortality in patients with chronic coronary syndromes, across multiple geographical regions and ethnicities

Author

H Appeltants, C Boesch, I Cromarty, D Carretta, S Romanov, U Windstetter, F Mibach, Jens Refsgaard, S Lebedev, F Proietti, M Y Tamimi, M C Gamboa, M Novikova, E Prada, K H Sim, E Messas, E Zherlitsyna, A Kalampalikis, N Nevolina, N Trocan, J Cohen, G Szto, R Gilabert Gómez, M Omelchenko, A Pinzani, D Goodwin, J Umaran Sánchez, Kim Fox, S H Dong, K Kronberg, E Castillo Lueña, T Ignatieva, S Joubert, C Macchi, S Lee, S Eidelman, F Alizon, S Chandra, M Akbar, D M Colquhoun, G Yanes Bowden, J de Juan Baguda, M Sebastian, C Wernham, K Miedema, R La Greca, C Morton, B S Jheeta, A C Tran, T Q Do, O Rodrigues, J Yan, S H Kim, R Jurgaitienė, Jean-Claude Tardif, R Baleón, D Hay, V Hennebelle, F Fazekas, R Davies, P Gratia, L Sorodoc, S Y Wu, C Martínez Sánchez, L Lopes Antunes, T H T Pham, I Suliman, M J Gómez Martinez, A Pernat, S H Hur, M Alanazy, L Zhabina, M Stanley, J Rogers, Y J Kim, S Geffroy, L K Andersen, S Coman, V Pedrosa del Moral, Y Garaud, J Krupicka, O Dzhkha, C Paul, M Jeżewska, B Mahler Mioto, V Abduvalieva, P Morra, L Kucheryava, C La Rosa, B Chan, M Wrębiak-Trznadel, A Kozlowski, M Sharif, L López Barreiro, V Kolesnikov, M Lawrence, A Tucker, C Okawabata, B La Hay, E Sadauskienė, B K Nguyen, L Bui, A Said, M E Ruíz Esparza, R K Saran, M S C Ho, E Homs Espinach, J R Romo Santana, J Forte De Carvalho, I Pattison, H H Phan, L Baleeva, L Kisiel, A López Granados, C Raters, F Paganelli, R Haberl, A P T Wong, D Xu, R Jagathesan, L Grekhova, H Stursova, Q B Truong, P Raymond, Y Sosnova, N H Khong, J Zarauza Navarro, C Florescu, L Gorshkova, N Saaidin, E Gordillo Higuero, L Davin, I Budanova, C Lavicka, L Gruznykh, P Bogdański, A Dufka, I Arroja, H A R Tahir, G Wilson, G Kolios, S J Yoon, Simon Cattan, K Berdnik, A Serrano, B Sievers, A Rodríguez Almodóvar, L A Holden, F O'Reilly, D Verleyen, H Hafez, K Nehrig, S M Kang, S Berrisch-Rahmel, E Meyer-Michael, P Samama, L Soares, A K Nguyen, F Tuktarova, C Weytjens, E Sandoval Rodriguez, J Cheng, F M Villasenor, João Morais, B Sullivan, R Zimoląg, Albert V. Smith, S F Ding, J C Louchart, G Guardigli, R Furtak, P Azzolini, S Chushak, J L Delgado Prieto, S Kornienko, K K Sia, J H Shin, F Baylac Domengetroy, P Błaszczak, M Saade, N Černič-Šuligoj, K Coetzee, A Kadleckova, V Scollo, O Larina, R Pal, M M Singh, N Nosova, R Burns, B S Yoo, O Gukov, F Massari, V Antia, A Brattström, G Holt, M Scherbak, V Firastrau, Y J Li, E Mikhailova, L Machado Cesar, C García García, J Pjontek, C Everton Biglow, G Pes, C Brown, A Bumbu, S Felis, R Bosch, M Lazaro, Luigi Tavazzi, R Engel, I Romeo Castillejo, Y S Byun, F Matias, I Grushetskaya, C Mestre-Fernandes, T Kheliya, S Schlesingerova, G Theodorakis, I Tsamopoulos, R Pedretti, A Puente Barragán, M P Vo, B Lammens, T Carruthers, J S Bhatt, A Khodanov, N Pasechnaya, I Petrova, G Boutros, I A Khan, E Le Moal, D Garofalo, H R Malaterre, A Bahal, J F Martínez González, H N Dinh, N V Pham, C Barjhoux, I Gilmour, C Soriano Navarro, O D Chioncel, K Tóth, N Borodina, P Khanoyan, B Sevilla Toral, H H Kim, C M A Bui, C Dernedde, N Eliseeva, M Galinier, E Kosachek, M M Doohan, L Potapska, M Tennekoon, R Nourallah, L Perez De Isla, K H Chee, E Panova, D M Walker, G Glanowska, G Hua, A Silvestre, W Wang, Matthew A. Brown, B Luke, G Jarosiński, R Davis, S Cleron, C Liatas, I Orestis, M Dereń, J Sudnik, S X Zhou, J Fuertes Alonso, O Baranova, S Mingalaeva, T N Vo, K A Ngo, J A Rodríguez Fernández, R Ishmael, G Bode, K K Chan, G Al Radaideh, S Ramphall, H D Theron, V Montagud Saavedra, A Yusuf, G F Mazzanti Mignaqui, L Evtukhova, J Lorenc, D Beacock, O B Šlapikienė, F Alitto, J N Poujois, B Berzal Martín, M Felbermayer, V Mallamaci, T Spitsina, R Ramachandran, A Jánosi, V Dženkevičiūtė, S Gillam, V Joulie, G Esna Ashari, R Henry, E Durand, A Alam, V Fourchard, H Dreycopp, R Fressonnet, C Camossa, O Jerzykowska, M Castrucci, G Sinicropi, B K Goyal, V Vasylenko, R Grogono, M Partington, B Vaquette, R Blindt, Mª T Moreno Casquete, V Kukaleva, W Streb, P F Clavette, M Pérez Paredes, V Hadjiivanov, C Bundy, D E Manyari, A Wassef, J Kuchar, W Nisker, P S Bath, S Panpunnung, G H Choo, Datshana P Naidoo, Y Pavlova, R McManus, N Brand, E Davies, L Prunier, A Schenowitz, P Sternthal, T Sinotova, J Martínez Florez, R Sykulski, J Pinar Sopena, M Balbi, Y Pesant, D A Playford, C Villar Mariscal, F Redding Escalante, W Wongcharoen, O Grechishkina, A Girão, M Speth-Nitschke, K A Mahendran, A Bianco, A Vadavi, G Singh, L Petoin Peuch, L Sukhanova, A Y Y Fong, J L Vega Barbado, A Dzien, S Honorat, G Ansalone, G Kamensky, G McLaren, T B Kim, I Bratu, R Fillet, V Rogozhyna, L Nagy, M Malgina, M A Sheikh Abdul Kader, Z C Li, L Rotaru H Rus, D Adamczyk-Kot, J Estrella, S Serrano García, P Farto E Abreu, D Mescharekova, Su Thillai Vallal, P Seal, S Möller, A Cziráki, T T H Ta, S Davies, H Ge, M Arafah, M Ovize, A Olszewski, V Aboyans, C Roche, F Al Tamimi, L Popova, V Kazachkova, R Rennert, J Aubry, G Bourgeois, J Mackrell, F Al Kandari, N Reifart, J Bérubé, W H J Hutse, O Lysunets, I Butkuvienė, J Cotroneo, J Gdalia, J Dalle Mule, R Santos, B Singh, H Mohammed, A Birkenhagen, T Chiscaneanu, H Sullivan, Jacob A. Udell, N Bolotova, A Jankowska, M Skonieczny, B S K Ch'ng, O Aiyegbayo, S Ciaroni, N Lago, S R Coimbra, R Ellis, B K Koo, S Rostik, P Jacquier, A Conradie, N Biryukova, M Ayche, A Khripun, B Peperstraete, E Velasco Espejo-Saavedra, G Cunliffe, G Grollier, C Ceraulo, T L To, Q H Tran, M Anscombe, R Jordan, I Czuriga, P Haimes, R Ancín Viguiristi, H Q Zhang, C A Chételat, A Rafter, E Rinkūnienė, K Yang, W Gao, J Pearce, L C Fernández Léoz, L Gareeva, R Fernández Alvarez, G Verret, P Astrakhantseva, C M Chu, L Murphy, P A Do, J L Liu, A Clifford, K Woollard, N Dmitrieva, N Lousada, R Díaz Juárez, N Semenova, T Fesenko, F Henschel, R Amini, G Matuszewska, R Christodorescu, J Varaldi, S Varughese, V Lafarenko, A Ashford, J L Colomer Martín, S Assouline, H Noor Hasni, A Weatherup, T Forster, R Kaserbacher, I Caldwell, N Arabadzhi, Emmanuel Sorbets, A Rink, E C Rueda Calle, J M Stordeur, P West, V C Do, Béla Merkely, J Antunes, U Altmann, S Magheru, B Bachmann, W Parkar, M de los Reyes López, M Wazana, A Frattola, M Mospan, V Koval, E Giusti Rossi, J Vasconcelos, K B Do, A Ogorodnichuk, D Lighezan, G Mentz, J M Cherry, P Pouderou, M Moretti, C M Spinu, Emmanuelle Vidal-Petiot, N Kupstytė, P Jourdain, V Voronina, O Varezhnikova, S Williams, H AlFaleh, R Lew, P Hildebrant, J Drozd, G Muscio, T H Ashton, A Achilli, J Harinasuta, T Ghose, G Walawski, Y Arkhipova, M Alves Costa, B Day, A Suntinger, A Singh, P Sheringham, A Vázquez García, J Taggeselle, J T Dong, T H Goh, G Rojas, R Schultz, A Ballet, O Likhobabina, Z M Qian, S Sandoval Navarrete, D Manzi, S Langridge, W Haerer, C K Abdullah, L Hay, Á Herdade, A Gałuszka-Bilińska, F Biausque, V M Lai, D S Eccleston, L Nikolaeva, P Kalaras, J Martínez Redding, N P H Tran, B Wauer, Philippe Gabriel Steg, B Etcheverry, J Navarro Manchón, R Augarde, C Dixon, M Y Chen, J L Gleizes, S Pustovit, J L Farges, S Cox, G Manchet, K Shein, L Parker, C C Ang, O Sinyukova, V Veth, A Kurekhyan, N Cindea Nica, N Wittlich, J Al Yazeedi, A Pucheu, V Elliott, J Bories, K Alford, M F Ferrão E Vasconcelos, A Adamkiewicz-Piejko, R Cervenak, J F Beltrame, A Castro, L Safonova, G Koutsimpanis, C de Brito Vianna, R Wysocki, V Ginzburg, J Hernández Afonso, A Ihonor, O Golubeva, M Karachaliou, S Kleta, D d'Este, Gustavs Latkovskis, F Jäger, E Gamzatov, Y Kozhelenko, J Lippai, T T L Ong, S J Ge, A Hersi, K Kyd, S Mingam, V Yordanova, L Bardachenko, E Mozerova, S W Liu, J Zdrojewska, E Chung, M Leclair, M Nazir, S Zarechnova, A Rahman, M Sołtysiak, B Maguire, F Moreira Pinto, R Fathi, E Prieto Moriche, C Priftis, P Heno, N Sytilina, A Pladys, S Shimonenko, P Keller, J F Junior, G Amiel Oster Sauvinet, J P Kanner, L Tkachenko, J Dalal, A Liston, D Herrera Fernández, J L Bonnet, A Chirivella González, R P Shah, F A Reyes Cisneros, C Avgerinos, P Ravoala, V Albero Martínez, G Suarez, V Jouve, A Frankiewicz, A Lindsay, A De Meester, H Dau, M Pornin, J Álvarez Gil, J Murin, T Hodac, J J Gómez Barrado, Y J Wu, S Jean, P Hilti, A Dayani, R Steponėnienė, G A Somsen, H Zhang, J Moore, P Tarenidis, T H Nguyen, M Maliszewski, L Voloshyna, S Novo, A Phrommintikul, I Shanina, Roberto Ferrari, P Franklin, C Turner, W Boonyapisit, F Sepulcri, P Vandergoten, J Carvalho, J Halcox, V Rotenberger, J F Baril, M Turiel, P Shiels, P Painsipp, S Reis Monteiro, T Honsig, V Vivekaphirat, J Ardill, P Brodzicki, A Khalifa, H Audibert, T Wettstein, F Auhser, D Ezekiel, D Pella, E Simarro Martín-Ambrioso, H S Seo, J A Núñez Gamero, Gabriel Steg, M Orbán, S Bykovskaya, W Gadziński, N Rozkova, G H M Vawda, R A Motyer, B Limeres González, E Fernandez Valadez, Riyaz S. Patel, I Shaikh, E Ziak, A Estriga, P Dodemant, Dragos Vinereanu, W Miao, L Marullo, F MacNamara, S K Tan, N Giacomantonio, A Leherissier, H W Li, Arpana Agrawal, Y Moreau, F David, S K Ma, A N Jamaluddin, E Alegría Ezquerra, Scalzo, M C Ta, T T Nguyen, A Sudre, R Gupta, H Lagioia, M Haiba, P Kohan, M Szentivanyi, T Dmitrieva, N Vechtomova, C Vuille, R G Schena, P Navratil, O Tsygankov, L Saaby, P Lefebvre, S King Wong, S Maheas Morlet, N H Pham, P Bonnet, S Modi, L Gaspar, M Karlicek, S Pallie, H T Pham, S Abele, N Bizyaeva, L Facila Rubio, N Meneveau, G Poluyanova, J Calaça, S Orazi, M Emonts, A Yusufali, V Sprott, Z Vazhdaeva, M R Conte, E Bulakhova, K Giokoglu, E Page, E Kotova, G Maragoni, C Jerjes Sánchez, T Kiver, M Brunehaut Petaut, A Nagy, P Singer, Zs Sziegl, B Fontanet, S Strange, A Watson, J Föchterle, Janet A. Dunn, R Šlapikas, M Stikhurova, S Salimova, J Volmar, E Otero Chulian, S Hutchinson, R Koller, X Bonnaud, E Peris Domingo, F Marín Ortuño, E Galve Basilio, S Bongo, L Payot, C Miller, A Samothrakitis, L Silva Melchor, K Orzechowski, W Hofer, L V Nguyen, R Oliver, K T Jung, J Robb, D Sobczyk, J Muller, A Tomatti, M Gruchała, C Bradshaw, D Richmond, E Mineeva, E Smirnova, A Idrissi-Sbai, H Vial, R Balai, I Kiseleva, H Jones, M Gibbs, D Ohlmeyer, Y Al Wahshi, V d’Alessandro, S Pérez Ibiricu, V Zachos, A Chernozemova, D R Spink, J Schneider, A M Peset Cubero, M Irurita Latasa, M Migliore, G Perna, E Daniels, M H Tay, N Z Khiew, I Soin, F Bernasconi, T Garban, F Omardeen, O Rodina, L Kanagaratnam, I Blum-Decary, A Jaussi, D Romero Alvira, D Vermander, N Kanumilli, M A Romero Maldonado, M Fernández-Valls Gómez, H Tran, T P Nguyen, H Omar, R S Collette, B Kisjós, H Krause-Allmendinger, J Silva E Sá, H Topf, F Panetta, T C Do, G Roul, J Leso, A Lacroix, M Fic, C Hart, R Chan, L Lema, Y Polyanskaya, R Howlett, Lesley J. Burgess, X P Chen, Hywel C Williams, V T Le, N Gurianova, R Duchowska, V P Nair, D Mitropoulos, A Allcock, T T H Bui, M Golub, E Yakovenko, M Perry, F Belcastro, K Svolis, B H R Forge, F Fernández de la Cigoña, N Murga Eizagaechevarría, G Mariano Pêgo, V Mincheva, T N Nguyen, J Moyal, M Wei, H Vinhas, A Batalla Celorio, C Romero Menor, S Rahman, N Hassler jun, F Duclos, K Ladha, A Ordóñez España, B C Chang, R Cortés Sánchez, G Lafrance, I Mihailova, Y Riou, I Pashentseva, S Tantillo, U Casas Juarezy, Ian B. Wilkinson, MJuneja, Q L Liu, M Baquero Alonso, P Kirmond, A Stevens, T Bouvy, P Casas Giménez, G Kassianos, P Kohler, T Rundell, J A Romero Hinojosa, T Sagastagoitia Gorostiza, M A Bennouna, A Hourany, F Thoin, G Steurer, V Batushkin, L Kolevatova, A Földi, G Sabe-Affaki, J T M Geraedts, I Illushechkin, T Korotich, W Manlay, B Merian, G Morrison, Y Wang, G Solache, P Magnus, A Lugin, S Tereshko, Jorge Escobedo, D Sharp, A Thelemann, J Gold, M Catarino Carvalho, P Lang, B Hermellin, B Doucet, A Martín Santana, E Foltzer, J Mora Robles, A I Bakbak, G Stanciulescu, L Baurenski, O Demina, G Lalljie, N Shmakova, R Vicente Amato, N Q Nguyen, S Kimmel, J-M Grégoire, F Tumarov, R Cue Carpio, S Nikishina, A Mukhtar, J Rueda Soriano, M Gnädinger, Michal Tendera, P Raska, S Cicek-Hartvig, E Potapova, A Melero Pita, P Ormiston, L Pastor Torres, R Shaw, M S Chenniappan, T Guo, L Zharikova, R Amoretti, J Janssen, G Kositsina, S Rajendran, N Atamanchuk, V Plastiras, T Kiernan, M H Pham, V M J Jelinek, J Dalrymple, S Van de Walle, M Goethals, I Stelmakh, S Cantabrana Miguel, L Hurlock-Clarke, C Ferreyra Solorio, J Alcaravela, H H Chuang, C Statescu, T Ługowski, B G Vanhauwaert, E London, G Z Pan, Z Özkan-Rashed, F Fellous, O Fillipova, K Ashmak, L Sargento, N Starostina, J A Ortiz de Murua López, H Thomas, T Gerasimova, L H Gowdak, S Perings, E Gaxiola, K Walcher, O Pogrebna, T Stasiuk, J Bell P McNaught, J Upton, G Scott, P Rossi Sevillano, A Gillet, T K L Nguyen, L E Manautou, L Kardashevskaya, A B Syed, F Brumelot, E Il'ina, V Alekseenko, G Wehr, G Gerges, B Fitzgerald, M Castellari, I Bratishko, M Dorobantu, I O'Connor, M V Ivan, A Esenokova, M Z Abdul Wahab, S Sylivris, S S S Quek, P Buffet, L Thomas, S Darnes Soler, N Pelicano, B Truong, N Vyshnevaya, M Habab, J Moreira, S Z Lv, D Shukla, P Eavis, E Kryvenkova, S Hansone, S Tabet, M Adda, R Trambitas, L A Fernández Lázaro, M Basara, R Mažutavičius, B Roy, X Dreyfus, T Karaseva, R Tilluckdharry, K Królicka, A Rogowsky, 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M Baar, P Lafontaine, C O'Dong, I Petropoulos, B-M Altevogt, D Warden, T De Backer, G Miñana Escrivá, T L Mai, U Schlesinger-Irsch, M M Gomaa, E Moksyuta, M Drexler, P Monteiro, P Grooterhorst, J Moolman, P McAlavey, J O'Shea, L P Quinn, F Crespo, K Srinivasa Reddy, T Shokina, Ellen M. Schmidt, M H Jeong, K Denef, A Pleskof, I Takács, Y Tikhonov, O Ushakov, L Stevens, J Ezcurdia Sasieta, L Nkombua, O Henne Otero, J Y Fraboulet, D S Kim, G Hoh, A Tamm, M Sardon, G Chatzioakim, M A Ulecia Martínez, S Reymond, M Myint, G Proença, R Massabie, E Foster, H Dougall, Anjan Kumar Roy, C Franco Aranda, M Getman, E Filippova, C Aguiar, X D Pu, N Voronina, L L Chen, M Szulc, L Bayakhchan, M J Pinto Vaz, C Niederberger, N Vites, I Sen, Paul R. 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Subjects
medicine.medical_specialty, Cardiac & Cardiovascular Systems, Epidemiology, LONG-TERM, medicine.medical_treatment, Chronic coronary syndromes, Coronary Artery Disease, Revascularization, Ventricular Function, Left, GLUCOSE, MELLITUS, Risk Factors, Internal medicine, Diabetes mellitus, Diabetes Mellitus, Ethnicity, Prevalence, medicine, Humans, ARTERY-DISEASE, Myocardial infarction, Stroke, RISK, OUTCOMES, Ejection fraction, Science & Technology, business.industry, Proportional hazards model, CLARIFY Investigators, Hazard ratio, Diabetes, Stroke Volume, Geographical disparities, Syndrome, medicine.disease, MIDDLE-EAST, EUROPEAN-SOCIETY, Treatment Outcome, MYOCARDIAL-INFARCTION, Heart failure, CLARIFY registry, Cardiovascular System & Cardiology, HEART-FAILURE, Cardiology and Cardiovascular Medicine, business, Life Sciences & Biomedicine
Abstract

BackgroundIn contrast with the setting of acute myocardial infarction, there are limited data regarding the impact of diabetes mellitus on clinical outcomes in contemporary cohorts of patients with chronic coronary syndromes. We aimed to investigate the prevalence and prognostic impact of diabetes according to geographical regions and ethnicity.Methods and resultsCLARIFY is an observational registry of patients with chronic coronary syndromes, enrolled across 45 countries in Europe, Asia, America, Middle East, Australia, and Africa in 2009–2010, and followed up yearly for 5 years. Chronic coronary syndromes were defined by ≥1 of the following criteria: prior myocardial infarction, evidence of coronary stenosis >50%, proven symptomatic myocardial ischaemia, or prior revascularization procedure.Among 32 694 patients, 9502 (29%) had diabetes, with a regional prevalence ranging from below 20% in Northern Europe to ∼60% in the Gulf countries. In a multivariable-adjusted Cox proportional hazards model, diabetes was associated with increased risks for the primary outcome (cardiovascular death, myocardial infarction, or stroke) with an adjusted hazard ratio of 1.28 (95% confidence interval 1.18, 1.39) and for all secondary outcomes (all-cause and cardiovascular mortality, myocardial infarction, stroke, heart failure, and coronary revascularization). Differences on outcomes according to geography and ethnicity were modest.ConclusionIn patients with chronic coronary syndromes, diabetes is independently associated with mortality and cardiovascular events, including heart failure, which is not accounted by demographics, prior medical history, left ventricular ejection fraction, or use of secondary prevention medication. This is observed across multiple geographic regions and ethnicities, despite marked disparities in the prevalence of diabetes.ClinicalTrials identifierISRCTN43070564

Published
2021

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