Author: "Joannes A" / Topic: medicine.disease - Searchworks@Jio Institute Digital Library Search Results

337 results on '"Joannes A"'

1. Sporadic facial angiofibroma and sporadic angiomyolipoma mimicking tuberous sclerosis complex

Author: Katarzyna Klonowska, Joannes M. Grevelink, Aaron R. Thorner, David J. Kwiatkowski, and Elizabeth A. Thiele
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, Pathology, medicine.medical_specialty, Angiomyolipoma, Genetic counseling, Angiofibroma, medicine.disease_cause, Tuberous Sclerosis Complex 1 Protein, Tuberous sclerosis, Tuberous Sclerosis, Tuberous Sclerosis Complex 2 Protein, Genetics, medicine, Humans, Genetics (clinical), Genetic testing, Mutation, Massive parallel sequencing, medicine.diagnostic_test, business.industry, Tumor Suppressor Proteins, medicine.disease, Kidney Neoplasms, Leukemia, Myeloid, Acute, medicine.anatomical_structure, TSC1, TSC2, business
Abstract: Tuberous sclerosis complex (TSC) is a genetic syndrome due to mutations in either TSC1 or TSC2, leading to the development of hamartomatous tumours at multiple body sites, including facial skin (facial angiofibroma (FAF)), brain (cortical tubers) and kidney (angiomyolipoma (AML)). In this report, we describe an individual with minimal TSC clinical features, who had ‘no mutation identified’ (NMI) by prior genetic testing in a clinical laboratory. Our massively parallel sequencing (MPS) analysis of multiple samples from different body sites and tumours (including blood, saliva, normal skin, AML and FAF) revealed an extraordinary situation in which FAF and AML had completely independent inactivating biallelic variants in TSC2, not present in other matched samples. This suggests that the two different lesions (AML and FAF) are not due to the same underlying germline or mosaic mutation, rather both are likely sporadic events. This case demonstrates the relevance of thorough clinical examination, high-coverage MPS of multiple tumours and matched normal tissues, and appropriate genetic counselling for individuals with marginal TSC features and possible TSC1 or TSC2 mosaicism.
Published: 2021
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2. Cytoplasmic DDX3 as prognosticator in male breast cancer

Author: Inne H.M. Borel Rinkes, Venu Raman, Cathy B. Moelans, Lenny Verkooijen, Elsken van der Wall, Marilot C. T. Batenburg, Quirine F. Manson, Carmen C. van der Pol, and Paulus Joannes van Diest
Subjects: Male, 0301 basic medicine, Oncology, Cytoplasm, Multivariate analysis, Gene Expression, Cohort Studies, DEAD-box RNA Helicases, 0302 clinical medicine, Netherlands, Univariate analysis, General Medicine, Middle Aged, Prognosis, Immunohistochemistry, RNA Helicase A, Progression-Free Survival, Gene Expression Regulation, Neoplastic, Receptors, Androgen, 030220 oncology & carcinogenesis, Male breast cancer, Biomarker (medicine), Original Article, Adult, medicine.medical_specialty, Breast Neoplasms, Disease-Free Survival, Breast Neoplasms, Male, Pathology and Forensic Medicine, 03 medical and health sciences, DDX3, Internal medicine, medicine, Humans, Molecular Biology, Aged, Retrospective Studies, Cell Nucleus, business.industry, Retrospective cohort study, Oncogenes, Biomarker, Cell Biology, medicine.disease, Androgen receptor, 030104 developmental biology, Transcriptome, business
Abstract: Male breast cancer (MBC) is a rare disease. Due to its rarity, treatment is still directed by data mainly extrapolated from female breast cancer (FBC) treatment, despite the fact that it has recently become clear that MBC has its own molecular characteristics. DDX3 is a RNA helicase with tumor suppressor and oncogenic potential that was described as a prognosticator in FBC and can be targeted by small molecule inhibitors of DDX3. The aim of this study was to evaluate if DDX3 is a useful prognosticator for MBC patients. Nuclear as well as cytoplasmic DDX3 expression was studied by immunohistochemistry in a Dutch retrospective cohort of 106 MBC patients. Differences in 10-year survival by DDX3 expression were analyzed using log-rank test. The association between clinicopathologic variables, DDX3 expression, and survival was tested in uni- and multivariate Cox-regression analysis. High cytoplasmic DDX3 was associated with high androgen receptor (AR) expression while low nuclear DDX3 was associated with negative lymph node status. Nuclear and cytoplasmic DDX3 were not associated with each other. In a univariate analysis, high cytoplasmic DDX3 (p = 0.045) was significantly associated with better 10-year overall survival. In multivariate analyses, cytoplasmic DDX3 had independent prognostic value (p = 0.017). In conclusion, cytoplasmic DDX3 expression seems to be a useful prognosticator in MBC, as high cytoplasmic DDX3 indicated better 10-year survival.
Published: 2021
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3. Tuberculosis (TB) in pregnancy – A review

Author: Ngozi Orazulike, Jai Bhagwan Sharma, Odidika Ugochukwu Joannes Umeora, and Sangeeta Sharma
Subjects: Drug, Pediatrics, medicine.medical_specialty, Tuberculosis, media_common.quotation_subject, Antitubercular Agents, Pregnancy, Tuberculosis, Multidrug-Resistant, Isoniazid, medicine, Humans, Medical nutrition therapy, Tuberculosis, Pulmonary, Ethambutol, media_common, business.industry, Infant, Newborn, Obstetrics and Gynecology, Pyrazinamide, medicine.disease, Reproductive Medicine, Female, business, Rifampicin, medicine.drug
Abstract: Tuberculosis (TB) is a common infectious pathology especially in low-income countries, which may complicate pregnancy. Although pulmonary TB is more common in pregnancy than extra pulmonary TB (EPTB), EPTB is becoming more common especially in those living with human deficiency virus (HIV) co infection or have other comorbidities. The diagnosis of TB may be delayed in pregnancy due to the masking of its symptoms by those of pregnancy. If diagnosed and treated on time both pulmonary TB and EPTB are associated with excellent maternal and perinatal outcome. If, however, there is delay in diagnosis and treatment then there could be adverse maternal and fetal consequences like preterm labour, fetal growth restriction and even stillbirths. Similarly severe forms of TB like disseminated disease (miliary TB) or multi drug resistant TB (MDR TB) are associated with poor outcome. Diagnosis and management is same as in non-pregnant patients. Both drug sensitive pulmonary TB and EPTB are treated with four drugs (isoniazid, rifampicin, pyrazinamide and ethambutol) orally daily for 2 months followed by three drugs (isoniazid, rifampicin and ethambutol) orally daily for 4 months. Drug resistant TB is treated with second line drugs with caution, as some of these drugs are teratogenic. Optimum antenatal care and nutrition therapy along with anti-tuberculosis drugs provide for optimum maternal and perinatal outcome. This review discusses maternal and perinatal outcomes, diagnosis and management of pulmonary TB and extrapulmonary TB as well as perinatal tuberculosis.
Published: 2021
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4. Biomarker testing and mutation prevalence in metastatic colorectal cancer patients in five European countries using a large oncology database

Author: Patrick Cheung, Julien Taieb, Victoria Banks, George Kafatos, Kimberly Lowe, Fil Manuguid, Peter Burdon, Caroline Anger, Joannes H. J. M. van Krieken, and David Neasham
Subjects: Adult, Male, Proto-Oncogene Proteins B-raf, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Databases, Factual, Colorectal cancer, Medical Oncology, computer.software_genre, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, medicine, Humans, Genetic Testing, Precision Medicine, neoplasms, Aged, Retrospective Studies, Aged, 80 and over, Database, business.industry, Microsatellite instability, General Medicine, Middle Aged, Prognosis, medicine.disease, digestive system diseases, Europe, Clinical Practice, 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, Mutation (genetic algorithm), ras Proteins, Biomarker (medicine), Female, Microsatellite Instability, Colorectal Neoplasms, business, computer
Abstract: Background: The literature on biomarker testing for metastatic colorectal cancer (mCRC) in Europe is scarce. This study aimed to estimate the percentage of mCRC patients from five European countries tested for biomarkers over time. Materials & methods: An oncology database was retrospectively analyzed; evaluated biomarkers were RAS, BRAF and microsatellite instability (MSI). The patients were drug treated during 2018 and tested for relevant biomarkers in 2013–2018. Results: RAS testing was conducted in >90% of mCRC patients from 2014 onwards. BRAF testing increased from 31% of mCRC patients in 2013 to 67% in 2018. MSI testing increased from 10 to 41%. There was no notable trend over time for RAS and BRAF mutation or MSI-high prevalence. Conclusion: Biomarker testing among patients diagnosed with mCRC was increased over time. This study demonstrates the quick uptake of biomarker testing in clinical practice. These findings are significant as biomarker-based drugs are becoming more common.
Published: 2021
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5. Multiple Myeloma Minimal Residual Disease Detection: Targeted Mass Spectrometry in Blood vs Next-Generation Sequencing in Bone Marrow

Author: Alain J. van Gool, Irma Joosten, Pieter Langerhorst, Yolanda B. de Rijke, Marina Zajec, Martijn M. VanDuijn, Theo M. Luider, Jolein Gloerich, Hélène Caillon, Jill Corre, Somayya Noori, Thomas Dejoie, and Joannes F M Jacobs
Subjects: medicine.medical_specialty, Neoplasm, Residual, Myeloma protein, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], Concordance, Clinical Biochemistry, Gastroenterology, Mass Spectrometry, Analytical Chemistry, Bone Marrow, hemic and lymphatic diseases, Internal medicine, medicine, Humans, Progression-free survival, Multiple myeloma, business.industry, Biochemistry (medical), High-Throughput Nucleotide Sequencing, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], medicine.disease, Minimal residual disease, body regions, Clinical trial, medicine.anatomical_structure, Targeted mass spectrometry, Bone marrow, business, Multiple Myeloma, Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5]
Abstract: Background Minimal residual disease (MRD) status assessed on bone marrow aspirates is a major prognostic biomarker in multiple myeloma (MM). In this study we evaluated blood-based targeted mass spectrometry (MS-MRD) as a sensitive, minimally invasive alternative to measure MM disease activity. Methods Therapy response of 41 MM patients in the IFM-2009 clinical trial (NCT01191060) was assessed with MS-MRD on frozen sera and compared to routine state-of-the-art monoclonal protein (M-protein) diagnostics and next-generation sequencing (NGS-MRD) at 2 time points. Results In all 41 patients we were able to identify clonotypic M-protein-specific peptides and perform serum-based MS-MRD measurements. MS-MRD is significantly more sensitive to detect M-protein compared to either electrophoretic M-protein diagnostics or serum free light chain analysis. The concordance between NGS-MRD and MS-MRD status in 81 paired bone marrow/sera samples was 79%. The 50% progression-free survival (PFS) was identical (49 months) for patients who were either NGS-positive or MS-positive directly after maintenance treatment. The 50% PFS was 69 and 89 months for NGS-negative and MS-negative patients, respectively. The longest 50% PFS (96 months) was observed in patients who were MRD-negative for both methods. MS-MRD relapse during maintenance treatment was significantly correlated to poor PFS (P Conclusions Our data indicate proof-of-principle that MS-MRD evaluation in blood is a feasible, patient friendly alternative to NGS-MRD assessed on bone marrow. Clinical validation of the prognostic value of MS-MRD and its complementary value in MRD-evaluation of patients with MM is warranted in an independent larger cohort.
Published: 2021

6. TNF-α and IL-10 Control CXCL13 Expression in Human Macrophages

Author: Laurent Vernhet, Francisco Llamas-Gutierrez, Stéphane Jouneau, Valérie Lecureur, Audrey Joannes, Roselyne Viel, Lutz Wollin, Nessrine Bellamri, Bertrand De Latour, Claudie Morzadec, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), H2P2 - Histo Pathologie Hight Precision (H2P2), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Boehringer Ingelheim Pharma GmbH & Co. KG, Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Jonchère, Laurent
Subjects: Male, Chemokine, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], Immunology, Gene Expression, Neogenesis, stat, 03 medical and health sciences, Idiopathic pulmonary fibrosis, 0302 clinical medicine, Macrophages, Alveolar, Humans, Immunology and Allergy, Medicine, CXCL13, Lung, Aged, Janus Kinases, 030304 developmental biology, 0303 health sciences, biology, Tumor Necrosis Factor-alpha, business.industry, CD68, Macrophages, NF-kappa B, Interstitial lung disease, respiratory system, biology.organism_classification, medicine.disease, Chemokine CXCL13, Idiopathic Pulmonary Fibrosis, Interleukin-10, respiratory tract diseases, 3. Good health, [SDV] Life Sciences [q-bio], STAT Transcription Factors, Interleukin 10, biology.protein, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Lung Diseases, Interstitial, business, Signal Transduction, 030215 immunology
Abstract: The chemokine CXCL13 controls the normal organization of secondary lymphoid tissues and the neogenesis of ectopic lymphoid structures in nonlymphoid organs, particularly the lungs. The progression and severity of idiopathic pulmonary fibrosis (IPF), a fatal and irreversible interstitial lung disease, is predicted by the circulating blood concentrations of CXCL13. Although CXCL13 is produced by pulmonary tissues, it has not been determined which cells are involved. This study examines CXCL13 production by lung tissue macrophages from patients with IPF and the signaling pathways controlling CXCL13 gene expression in human alveolar macrophages (AM) and monocyte-derived macrophages (MoDM). CXCL13 is found in CD68- and CD206-positive AM from patients with IPF, and the CXCL13 gene is induced in these macrophages and MoDM when they are stimulated with LPS. We found that TNF-α and IL-10 control optimal CXCL13 gene expression in MoDM and possibly in AM by activating the NF-κB and JAK/STAT pathways, respectively. We also found that blood TNF-α and CXCL13 concentrations are significantly correlated in patients with IPF, suggesting that TNF-α contributes to CXCL13 production in humans. In conclusion, the results of this study demonstrate that AM from patients with IPF produces CXCL13 and that the NF-κB and JAK/STAT pathways are required to induce the expression of this major chemokine.
Published: 2020
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7. Clone-directed therapy for proliferative glomerulonephritis with monoclonal immunoglobulin depositions: is it always necessary?

Author: Monique C. Minnema, Alferso C. Abrahams, Rob C M van Kruijsdijk, Maarten Limper, Tri Q. Nguyen, and Joannes F M Jacobs
Subjects: Adult, Nephrology, medicine.medical_specialty, Glomerulonephritis, Membranoproliferative, Myeloma protein, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], Kidney Glomerulus, 030232 urology & nephrology, Clone (cell biology), Case Report, Disease, Plasma cell, 03 medical and health sciences, Glomerulonephritis, MGRS, 0302 clinical medicine, Internal medicine, Gammopathy, medicine, Humans, Adverse effect, business.industry, Proliferative glomerulonephritis with monoclonal immunoglobulin deposits, Antibodies, Monoclonal, M-protein, Middle Aged, medicine.disease, Clone Cells, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, Monoclonal gammopathy of renal significance, Female, business
Abstract: Monoclonal gammopathy of renal significance (MGRS) encompasses a group of disorders in which a monoclonal immunoglobulin (M-protein) secreted by a B-cell or plasma cell clone causes renal disease. Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a form of MGRS where M-protein is deposited in the glomerulus. Although evidence is limited, the current consensus is that therapy for PGNMID should be directed against the underlying clone. However, it is conceivable that there is heterogeneity in the renal prognosis of PGNMID and that not all patients have need for clone-directed therapy. Here, we report two cases of PGNMID with IgM-kappa gammopathy. In one case of a 53-year-old woman the glomerulonephritis resolved without clone-directed therapy. In the other case of a 34-year-old woman clone-directed therapy was discontinued due to adverse effects. Although no hematological response was achieved, the PGNMID resolved. In both cases there are no signs of a recurrent glomerulonephritis in over 3 years of follow-up. Here, we review the literature and suggest that some PGNMID patients have a favorable renal prognosis in whom clone-directed therapy can be withheld or postponed. Further research is warranted to yield predictors to identify these patients and to better understand the disease course of PGNMID.
Published: 2020
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8. Abstract P1-19-29: An integrated safety analysis of talazoparib monotherapy from five clinical trials (phase 1-3) in advanced cancers

Author: Jennifer K. Litton, Zev A. Wainberg, Johann S. de Bono, Hope S. Rugo, Akos Czibere, Silvana Lanzalone, Nicholas C. Turner, Liza DeAnnuntis, Miguel Martín, Lida A. Mina, Sara A. Hurvitz, Joannes Ettl, Tiziana Usari, Henri Roché, and Mohamed Elmeliegy
Subjects: Cancer Research, medicine.medical_specialty, Chemotherapy, Anemia, Nausea, business.industry, medicine.medical_treatment, Neutropenia, medicine.disease, Gastroenterology, Oncology, Internal medicine, Vomiting, medicine, Absolute neutrophil count, medicine.symptom, Adverse effect, business, Cause of death
Abstract: Background: Talazoparib is a potent oral inhibitor of poly(ADP-ribose) polymerase (PARP) 1 and 2, which significantly improved progression-free survival versus standard-of-care chemotherapy in patients with HER2-negative advanced breast cancer (ABC; locally advanced/metastatic breast cancer) and a germline BRCA1/2 mutation (gBRCA1/2mut) in the Phase 3 EMBRACA trial (Litton J, et al. N Engl J Med. 2018;379:753-763). An integrated analysis of five clinical trials (Phase 1-3) in multiple tumor types was performed to evaluate the safety of talazoparib administered at 1 mg/day (d). Methods: Data were pooled from the ongoing Phase 3 randomized EMBRACA trial in HER2-negative gBRCA1/2mut ABC (NCT01945775), the Phase 2 non-randomized ABRAZO trial in gBRCA1/2mut ABC (NCT02034916), the Phase 1 trial in advanced/recurrent solid tumors (NCT01286987), the Phase 1 cardiac repolarization trial in advanced solid tumors (NCT03042910), and an ongoing open-label extension trial (NCT02921919). Results: 494 patients who received talazoparib 1 mg/d were included (Table). The most common all-grade adverse drug reactions (≥20%) with talazoparib were ANEMIA (includes preferred terms: anemia, decreased hemoglobin, decreased hematocrit; 49.6%), fatigue (47.6%), nausea (44.3%), NEUTROPENIA (neutropenia, decreased neutrophil count; 30.2%), THROMBOCYTOPENIA (thrombocytopenia, decreased platelet count; 29.6%), headache (26.5%), diarrhea (22.7%), alopecia (22.3%; Grade 1, 20.6%; Grade 2, 1.6%), vomiting (22.3%), and decreased appetite (20.2%). Grade 3/4 toxicities (≥10%) with talazoparib were ANEMIA (35.2%), NEUTROPENIA (17.4%), and THROMBOCYTOPENIA (16.8%). Overall 24 patients (4.9%) died within 30 days after the last dose of study drug; the most common cause of death was disease progression (13 patients; 2.6%). Other causes of death were reported in 1 patient each (cerebral hemorrhage, dyspnea, lung infection, lung metastases, respiratory failure, suspected veno-occlusive liver disease, and worsening of neurological symptoms); cause of death was not reported for 4 patients. The most common treatment-related serious adverse event was anemia (4.3%). Median duration of talazoparib exposure was 5.4 months (range, 0.0-61.1). Median relative dose intensity (defined as actual-dose intensity/planned-dose intensity) was 92.8%. Dosing interruptions due to TEAEs were reported for 48.6% of patients receiving talazoparib; median duration of dosing interruption due to TEAEs was 8.0 days (range, 1.0-121.0). Hematologic TEAEs (≥5%) associated with dose modification (interruption or reduction) included anemia (33.0%), neutropenia (15.8%), thrombocytopenia (13.4%), and decreased platelet count (5.9%); non-hematologic TEAEs (≥2%) associated with dose modification included fatigue (4.3%), vomiting (2.6%), and nausea (2.0%). Only 18 patients (3.6%) permanently discontinued due to a TEAE (anemia, 3 patients [0.6%]; other events, 1 patient each [0.2%]). Conclusions: Talazoparib monotherapy at 1 mg/d was generally well tolerated with few patients permanently discontinuing talazoparib due to AEs. Common toxicities were primarily hematologic and were manageable through dosing modifications and/or standard supportive care. Funding: Pfizer Inc. Table Summary of TEAEsPhase 3 EMBRACA trialOpen-label trialsTalazoparibTalazoparib mg/dTalazoparib 1 mg/d1 mg/d populationbTalazoparibPCTABRAZONCT01286987NCT03042910OLEaTotalN=286N=126N=83N=77N=37N=46N=494Any TEAE282 (98.6)123 (97.6)81 (97.6)75 (97.4)28 (75.7)39 (84.8)484 (98.0)Grade 3 or 4 TEAE193 (67.5)80 (63.5)54 (65.1)52 (67.5)9 (24.3)21 (45.7)326 (66.0)Treatment-related Grade 3 or 4 TEAE159 (55.6)61 (48.4)48 (57.8)36 (46.8)3 (8.1)14 (30.4)260 (52.6)SAE91 (31.8)37 (29.4)23 (27.7)27 (35.1)3 (8.1)14 (30.4)156 (31.6)Treatment-related SAE26 (9.1)11 (8.7)11 (13.3)3 (3.9)1 (2.7)1 (2.2)42 (8.5)TEAE primary reason for permanent discontinuation13 (4.5)7 (5.6)3 (3.6)002 (4.3)18 (3.6)TEAE associated with dose modification190 (66.4)75 (59.5)55 (66.3)46 (59.7)4 (10.8)15 (32.6)308 (62.3)All data are number (%) of patients; d, day; OLE, open-label extension; PCT, physician’s choice of chemotherapy; SAE, serious adverse event; TEAE, treatment-emergent adverse event;aInitiated treatment with talazoparib; monotherapy (1 mg/d) in either the originating or the extension trial;b35 patients who initiated talazoparib 1 mg/d in two of the trials and continued in the OLE are counted only once in the total number of patients Citation Format: Joannes Ettl, Jennifer Litton, Hope S. Rugo, Lida Mina, Miguel Martin, Nicholas Turner, Henri Roché, Zev Wainberg, Johann de Bono, Tiziana Usari, Mohamed Elmeliegy, Silvana Lanzalone, Akos Czibere, Liza DeAnnuntis, Sara A. Hurvitz. An integrated safety analysis of talazoparib monotherapy from five clinical trials (phase 1-3) in advanced cancers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-29.
Published: 2020
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9. Holy Apparition or Hyper-Religiosity

Author: Hetty Zock, Joannes W. Renes, Hanneke Muthert, Arjan W. Braam, Eva Ouwehand, and Comparative Study of Religion
Subjects: Sociology and Political Science, Social Psychology, Bipolar disorder, Religiousness, 050109 social psychology, Religiosity, 03 medical and health sciences, Cross-cultural psychology, 0302 clinical medicine, Quality of life (healthcare), Religious, RELEVANCE, QUALITY-OF-LIFE, Religious experience, BELIEFS, SCHIZOPHRENIA, medicine, 0501 psychology and cognitive sciences, Applied Psychology, Explanatory models, VALUES, 05 social sciences, Religious studies, medicine.disease, Mental health, 030227 psychiatry, CANADA, spiritual experiences, Spiritual development, PSYCHIATRIC-INPATIENTS, Psychology, OUTPATIENTS, MENTAL-HEALTH, Clinical psychology, Qualitative research
Abstract: One point that emerges from qualitative research on religion and bipolar disorder (BD) is the problem patients with BD experience in distinguishing between genuine religious experiences and hyper-religiosity. However, clinical practice does not obviously address communication about differences in explanatory models for illness experiences. The aim of the current study is first to estimate the frequencies of different types of explanations (medical versus religious) for experiences perceived as religious and related to BD, second to explore how these types relate to diagnosis and religiousness, and third to explore the frequency of expectation of treatment for religiosity. In total, 196 adult patients at a specialist outpatient center for BD in the Netherlands completed a questionnaire consisting of seven types of explanations for religious experiences and several items on religiousness. Of the participants who had had religious experiences (66%), 46% viewed the experiences as ‘part of spiritual development’ and 42% as ‘both spiritual and pathological,’ 31% reported ‘keeping distance from such experiences,’ and 15% viewed them as ‘only pathological.’ Measures of religiousness were positively associated with ‘part of spiritual development’ and negatively associated with ‘keeping distance from the experiences’ and ‘only pathological.’ Half of the sample viewed religiosity as an important topic in treatment. It can be hypothesized that strength of religiousness may help people to integrate destabilizing experiences related to BD into their spiritual development. However, the ambiguity of strong religious involvement in BD necessitates careful exploration of the subject in clinical practice.
Published: 2020
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10. Prevalence of hypophosphatemia in the ICU – Results of an international one-day point prevalence survey

Author: Viana Marina Verçoza, Simpson Shannon, Pereira Fernando, Rosenfeld Ricardo, Jaber Samir, Michael P Casaer, Krol Tim, Joannes-Boyau Olivier, Mette M. Berger, Fumeaux Thierry, Cheng Meisy Pérez, Reintam Blaser Annika, Pérez Gema, Karu Inga, Martinez-Alejos Roberto, A. Reintam-Blaser, Duska Frantisek, Jain Nikilesh, Alberts Erna, Samat Noryani, M. Berger Mette, Deepak Swarna, Gurjar Mohan, Jan Gunst, Kuhn Karl Friedrich, Laube Marcus, Stefan J. Schaller, Pfortmuller Carmen, Jung Veronika, Gunst Jan, Jammer Ib, Kursat Gundogan, Grand Hubert, Joel Starkopf, Keryakos Hesham Kamal Habeeb, Morris Andrew Conway, Malbrain Manu, O. Appelberg, Straka Kelly, Perez Marie-Helene, Kleger Gian-Reto, Besch Guillaume, Manrique Ezequiel, Fodor Patricia, Ichai Carole, Launey Yoann, Nicolas Mongardon, Constantin Jean-Michel, O. Joannes-Boyau, Fuest Kristina, J. Schaller Stefan, Jamme Matthieu, Marrel Julien, Van Zanten Arthur, Casaer Michael, Huq Shihan, M.E. de Man Angelique, C. Ichai, Szakmany Tamas, Tamme Kadri, Heyer Laurent, Besançon Bodolea Costel, Islam Motiul, Arroyo Abel, and Pahuja Madhu
Subjects: 0301 basic medicine, Point prevalence survey, Adult, medicine.medical_specialty, Icu patients, Monitoring, Adolescent, Hypophosphatemia, Critical Care and Intensive Care Medicine, Nutrition and Dietetics, 030209 endocrinology & metabolism, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Electrolyte, medicine, Prevalence, Humans, Icu stay, Critically ill, Child, Nutrition, Aged, Aged, 80 and over, Repletion, 030109 nutrition & dietetics, business.industry, Organ dysfunction, Middle Aged, medicine.disease, Blood phosphate, Unexpected finding, Intensive Care Units, Plasma phosphate, Cross-Sectional Studies, Emergency medicine, medicine.symptom, business, Standard operating procedure
Abstract: BACKGROUND & AIMS: Hypophosphatemia (HypoP) is associated with organ dysfunction and mortality. Despite its potential severe consequences, HypoP remains poorly characterized in terms of real prevalence and timing of onset. The primary objective was to determine the prevalence of HypoP defined as blood phosphate
Published: 2021

11. Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries

Author: Stephen R Knight, Catherine A Shaw, Riinu Pius, Thomas M Drake, Lisa Norman, Adesoji O Ademuyiwa, Adewale O Adisa, Maria Lorena Aguilera, Sara W Al-Saqqa, Ibrahim Al-Slaibi, Aneel Bhangu, Bruce M Biccard, Peter Brocklehurst, Ainhoa Costas-Chavarri, Kathryn Chu, Anna Dare, Muhammed Elhadi, Cameron J Fairfield, J Edward Fitzgerald, Dhruv Ghosh, James Glasbey, Mark I. van Berge Henegouwen, J.C. Allen Ingabire, T Peter Kingham, Marie Carmela Lapitan, Ismaïl Lawani, Bettina Lieske, Richard Lilford, Janet Martin, Kenneth A McLean, Rachel Moore, Dion Morton, Dmitri Nepogodiev, Faustin Ntirenganya, Francesco Pata, Thomas Pinkney, Ahmad Uzair Qureshi, Antonio Ramos-De la Medina, Aya Riad, Hosni Khairy Salem, Joana Simões, Richard Spence, Neil Smart, Stephen Tabiri, Hannah Thomas, Thomas G Weiser, Malcolm West, John Whitaker, Ewen M Harrison, Arben Gjata, Maria Marta Modolo, Sebastian King, Erick Chan, Sayeda Nazmun Nahar, Ade Waterman, Dominique Vervoort, Alemayehu Ginbo Bedada, Bernardo De Azevedo, Ana Gabriela Figueiredo, Manol Sokolov, Venerand Barendegere, Gerald Ekwen, Arnav Agarwal, Qinyang Liu, Juan Camilo Correa, Kalisya Luc Malemo, Jacques Bake, Jakov Mihanovic, Kamila Kuncarová, Julius Orhalmi, Hosni Salem, Jyri Teras, Aristotelis Kechagias, Alexis P Arnaud, Judith Lindert, Vasileios Kalles, Maria-Lorena Aguilera-Arevalo, Gustavo Recinos, Zsolt Baranyai, Basant Kumar, Harish Neelamraju Lakshmi, Sanoop Koshy Zachariah, Philip Alexander, Sunil Kumar Venkatappa, C Pramesh, Radhian Amandito, Christina Fleming, Luca Ansaloni, Gianluca Pellino, Ahmed M. Altibi, Ibrahim Nour, Intisar Hamdun, Ali M. Ghellai, Donatas Venskutonis, Tomas Poskus, Justas Zilinskas, Precious Malemia, Yong Yong Tew, Elaine Borg, Sarah Ellul, fatima Zahraa Wafqui, David W Borowski, Anne Sophie van Dalen, Cameron Wells, Harissou Adamou, Adesoji Ademuyiwa, Adewale Adisa, Kjetil Søreide, Sara Al Saqqa, Osaid Alser, Haya Tahboub, Helmut Alfredo Segovia Lohse, Sebastian Shu Yip, Piotr Major, António Sampaio Soares, Matei Razvan Bratu, Andrey Litvin, Armen Vardanyan, JC Allen Ingabire, Ahmad Gudal, Naif Albati, Jovan Juloski, Miran Rems, Sarah Rayne, Stephanie Van Straten, Yoshan Moodley, Irene Ortega Vázquez, Jaime Ruiz-Tovar, Kithsiri Janakantha Senanayake, Sujeewa Priyantha Bandara Thalgaspitiya, Omer Abdelbagi Omer, Anmar Homeida, Yucel Cengiz, Daniel Clerc, Muhammad Alshaar, Hanen Bouaziz, Yuksel Altinel, Matthew Doe, Maryna Freigofer, Ella Teasdale, Rakan Kabariti, Joshua Michael Clements, Stephen Richard Knight, Ahsan Ashfaq, Ijeoma Azodo, Gabriela Wagner, Ivan Trostchansky, Mayaba Maimbo, David Linyama, Helidon Nina, Amanda Zeko, Claudio Gabriel Fermani, Santiago Villalobos, Federico Carballo, Pablo Farina, Sebastian Guckenheimer, Marilla Dickfos, Ankit Ajmera, Chester Chong, Ralph Gourlay, Sikandar Hussaini, Yi Jia Lee, Adeeb Majid, Peter Martin, Rebecca Miles, Owen James Morris, Jamie Phua, William Ridley, Tarunpreet Saluja, Ryan Renxin Tan, Jen Teh, Anna Wells, Bharti Arora, Qaasim Dollie, Debbie Ho, Yanru Ma, Omattage Mahasha Perera, Anthony Truong, Amanda Caroline Dawson, Bryan Lim, Upuli Pahalawatta, Jacqueline Phan, Xiao-Ming Sarah Woon-Shoo-Tong, Andrea Yeoh, Lillian Charman, Andrew Drane, Sharon Laura, Charmaine Chu Wen Lo, Amy Mozes, Rita Poon, Hao Han Tan, Ellen Wall, Prakshi Chopra, Jasmine De Giovanni, Bal Dhital, Brian Draganic, Alexander Duller, Jonathan Gani, Yao Kuan Goh, Jun Young Jeong, Brendan McManus, Prakash Nagappan, Peter Pockney, Anya Rugendyke, Mahsa Sarrami, Stephen Smith, Vanessa Wills, Hsu Ven Wong, Geoffrey Ye, Geoffrey Zhang, Ethan Brooker, Daniel Feng, Bonnie Lau, Carlin Ngai, Sarah Birks, David Gyorki, Jaime Otero de Pablos, Ali Abbosh, Chris Gillespie, Ahmed Mahmoud, Bianca Kwan, Joshua Lawson, Andrea Warwick, Janne Bingham, Andrew J Cockbain, Nagendra Naidu Dudi-Venkata, Jordan Ellaby-Hall, Ben Finlay, Emily Humphries, Jade Pisaniello, Monique Pisaniello, Salma Salih, Tarik Sammour, Haidar Hadri Abd Wahab, April De Silva, Nicola Hayward, Kartik Iyer, Guy Maddern, Gian Andrea Prevost, Naga Annapureddy, Krishna Pranathi Settipalli, Jeremy Yeo, Lucy Hempenstall, Lily Pham, Shaun Purcell, Cherry Talavera, Ashish I Vaska, Gurpreet Chaggar, Phillip Chrapko, Annelise Cocco, Sarah Michelle Crystal Jade Coulter-Nile, Grahame Ctercteko, James French, Houchen Gong, Martijn Gosselink, Thuvarahan Jegathees, Ivan Jin, Michelle Kalachov, Kathryn Kiefhaber, Katherine Lee, Jason Luong, Steven Phan, Henry Pleass, Kelly Veale, Zhi Zeng, Angela Au, Ashe DeBiasio, Idy Deng, Jananee Myooran, Amrita Nair, Peter Stewart, Anton Stift, Lukas Walter Unger, Kerstin Wimmer, Nabila Ahmed, Syed Hasan, Saber Rahman, Margaret O'Shea, Greg Padmore, Adrian Peters, Pietro Perduca, Guenda Pulcina, Nicolas Tinton, Frederic Buxant, Elsa Dabin, Giulia Garofalo, Francis Dossou, Freddy Houehanou Rodrigue Gnangnon, Yacoubou Imorou Souaibou, Pako Motlaleselelo, Omphile Tlhomelang, Igor Lima Buarque, Gustavo Mendonça Ataíde Gomes, Aldo Vieira Barros, Ilia Batashki, Nikolai Damianov, Vladislav Stoyanov, Dragomir Dardanov, Svilen Maslyankov, Plamen Petkov, George Todorov, Evgeni Zhivkov, Aygulya Akisheva, Miguel Angel Castilla Moreno, Geno Genov, Ivelina Ilieva, Tsvetomir Ivanov, Martin Karamanliev, Azhar Khan, Emil Mitkov, Tsanko Yotsov, Boyko Atanasov, Nikolay Belev, Mihail Slavchev, Carlos Nsengiyumva, Elgan Jones, Simon Stock, Steve Kyota, James Brown, Tresor Mabanza K., Lemery Nigo Samuel, Chidi Otuneme, Ngwang Prosper, Franklin Umenze, Marylise Boutros, Natasha Caminsky, Sinziana Dumitra, Richard Garfinkle, Dominique Morency, Ebram Salama, Alexander Banks, Lorenzo Ferri, Haitian He, Amit Katz, Alexander Sender Liberman, Sarkis Meterissian, Allison Pang, Elena Parvez, Usmaan Hameed, Fahima Osman, Sangita Sequeira, Natalie Coburn, Alisha Jaffer, Paul Karanicolas, Matthew Mosseler, Reilly Musselman, Xinyuan Liu, Ching Wan Yip, Juan Sebastian Garces-Otero, Carolina Guzman, Sebastian Sierra, Andres Uribe Valencia, Paulo Andrés Cabrera Rivera, Saul Camelo, Andrea Gonzalez, Alejandro González-Orozco, Manuel Santiago Mosquera Paz, Carlos J- Perez Rivera, Felipe Gonzalez, Andres Isaza-Restrepo, Laura Nino- Torres, Natalia Arias Madrid, Maria Clara Mendoza Arango, Justin Tsandiraki, Damir Jemendžic, Branislav Kocman, Oliver Šuman, Renata Canic, Darko Jurišic, Ivana Karakas, Ana Krizanovic Rupcic, Vlatka Pitlovic, Josip Samardžic, Mario Kopljar, Ivan Bacic, Edgar Domini, Robert Karlo, Danijela Miljanic, Andrea Simic, Mariam Ahmed, Majdi Al Nassrallah, Rabiya Altaf, Talal Amjad, Ruba Eltoum, Heba Haidar, Alhassan Hassan, Omar Khalil, Marwan Qasem, Rommel Ramesh, Gautham Sajith, Maham Wisal, Jan Žatecký, Michele Bujda, Katerina Jirankova, Ales Paclik, Aya Abdallah, Mariam Abdulgawad Almogy, Esraa Ayman El-sawy, Ahmed Moustafa ElFayoumy, Nourhan Elghareeb, Nourhan Ahmed Esmat, Ahmed Fadel, Abdullah Habater, Heba Hamdy, Amr Hefni, Marwa Kamal, Norhan Mohamed Abobakr, Ahmed Sayed, Nancy Shaker, Ehab Taha, Hoda Tharwat, Omar Zakaria, Ibrahem Abdelmotaleb, Ali Al-Dhufri, Hamza S. Al-Himyari, Enas El sheikh, Asmaa Eldmaty, Aya Elkhalawy, Ahmed M.Elkhashen, Kithara Magdy, Safa Mostafa, Habib Doutoum Sadia, Mohamed mahmoud Saleh, Dina Samir, Mohamed Yahia Mohamed Ali, Mahmoud A. Nassar, Samar Abdelhady, Aly Abdelrazek, Israa Abdelsalam, Aya El-Sawy, Eman Essam, Mohamed Gadelkarim, Khaled Ghaly, Mohamed Hassabalnaby, Rana Masarani, Nourhan Mohamed Shaaban, Ahmed Sabry, Menatalla Salem, Nourhan Akram Soliman, Diaaaldin Zahran, Moustafa Ramadan Abou El.soud, Esraa Tarek Badr, Hala Borham, Nehal Elmeslemany, Mohammad Elsayed, Fawzia Elsherif, Sara Eslam, Gehad Gaber, Sondos Ibrahim, Yara Kamh, Abdelrahman Mahmoud, Shimaa gamal Mohamed, Eman Morshedy, Cinderella Omar, Fatima Salem Soliman, Shaza Abdelkawy, Naglaa Abdelmohsen, Mahmoud Abdelshakour, Ahmed Dahy, Norhan Gamal, Mohammed Gamal, Ahmad Hasan, Helal Hetta, Nehad Mousa, Mohamed Omar, Somia Rabie, Mahmoud Saad, Bakeer Saleh, Marwa Sayed Mohamed, Muhammad Shawqi, Heba Abdelhady Mousa, Mostafa Alnoury, Mohamed Elbealawy, Ahmed Elshafey, Muhammad Essam Ibrahim El Desouki Muhammad Ahmed, Mennatullah Ghonaim, Fawzy Hgag, Mohamed Ibrahim, Mahmoud Morsy, Mohamed Reda Loaloa, Ahmed Refaat, Hadeer Samir, Fatma Shahien, Mohamed Sobhy, Fathy Sroor, Esraa Abdellatif, Marina Adel, Amr Abdelghani Afifi, Eman Afifi, Marco Antaky, Amr Dawoud, Naira El Zoghby, Amira El-remaily, Ali Abdelazez Elzanfaly, Ahmed Gadallah, Fatma Alzahraa Gamal, Omar Hashem, Shrouk Medhat Youssef, Aliaa Muhammad Attyah, Malak Munir, Omar Shazly, Esraa Taha, Karim Wilson, Sawsan Adel, Asmaa Ali, Esraa Eid, Esraa Elhelow, Marwa Elmahdy, Bassant Elshatby, Amany Hossam el-din Zakaria, Ahmad Hossny, Eman Ibrahim, Ahmed M.Yonis, Maram Metwalli, Basant Yousry, Esraa Zid, Mina A Yacoub, Ahmed Abdelhakim, Nervana Abouelsoad, Mo'min Alkhatib, Ahmed Ashraf, Alaa Ashraf, Yasmin Elazab, Mahmoud Elfanty, Osama Elkabir, Mai Elsayed, Ahmed Elshimy, Hager Elsobky, John Eskander, Ahmed Gad, Ward Hamsho, Noura Khaled Abdelwahed, Menna Magdy, Dalia Moharam, Abeer Osama, Shereen Ramadan, Radwa Roum, Taqwa Sayed, Tarneem Shehada, Ahmed Mohy Zidan, Khalid Abbas, Amr Ali, Mohamed Attia, Mohamed Balata, Ayman El Nakeeb, Mohamed Ibrahim Elsayed Elewaily, Ahmed Elfallal, Hossam Elfeki, Ahmed Elkhadragy, Sameh Emile, Helmy Ezzat, Hasnaa Hosni, Islam Mansour, Waleed Omar, Gehad Othman, Kareem Sadek, Mostafa Shalaby, Noura Shehab-Eldeen, Rawda Anas khalifa, Helmy Badr, Mostafa Eldeep, Ahmed Eldeep, Amany Eldoseuky mohammed, Salwa Khallaf, Eman Magdy Hegazy, Rokia Mahmoud, Pola Mikhail, Mahmoud Morsi, Sara Mowafy, Dina Raafat, Amina Safy, Marwa Sera, Ahmed shible Sera, Mostafa Salim Mohamed AbdAllah, Muhammad Abdelkader, Abdulrahman Osama Abdou, Ahmedgaber Ahmed, Shireen Gaafar, Fatma Ibrahim negm, Mina Lapic, Ahmed Maher, Hagar Mahmoud, Ahmed Mostafa, Mohamed Samir, Fatma Samy, Nourhan Semeda, Hind I. Shalaby, Alaa El-taweel, Ahmed Galal Elnagar, Ahmed Gamal Hemidan, Mohamed Hussein, Ahmed.A. Kandil, Mf Moawad, Ayat Allah Nasser Hamamah, Mostafa Soliman, Mohamed Abdelkhalek, Noura Abdelmaksoud Tawakel, Ahmed Mohamed Abdelwahed, Alrawy Abdou, Khalid Atallah, Mohammed Yasser Elsherbeny, Eman Emara, Mohamed Hamdy, Omar Hamdy, Amira Haron, Salma Ismail, Islam Hany Metwally, Nihal Mohamed Hamed Elgaml, Ahmed Nassar, Basel Refky, Mirna Sadek, Mahmoud Saleh, Asmaa Yunes, Mai Zakaria, Mohammed Zuhdy, Notila Fayed, Mohammed Mustafa Hassan Mohammed, Sander Kütner, Priit Melnik, Indrek Seire, Toomas Ümarik, Eppu Ainoa, Verner Eerola, Hanna Koppatz, Laura Koskenvuo, Ville Sallinen, Sini Takala, Jevgeni Katunin, Arto Turunen, Niki Christou, Muriel Mathonnet, Vincent Lavoue, Krystel Nyangoh Timoh, Lucie Soulabaille, Romain Lesourd, Aude Merdrignac, Laurent Sulpice, Benoît André, Elodie Chantalat, Charlotte Vaysse, Bertrand Dousset, Sebastien Gaujoux, Gregory Martin, Octavian Clonda, Domantas Juodis, Klaus Kienle, Andras Mravik, Samuel Palmer, Gabor Szabadhegyi, Anita Eseenam Agbeko, Solomon Gyabaah, Frank Enoch Gyamfi, Nuhu Naabo, Atta Owusu senior, Joseph Yorke, Frank Owusu, Francis Abantanga, Theophilus Teddy Kojo Anyomih, Abdul-Jalilu Mohammed Muntaka, Emmanuel Owusu Abem, Mohammed Sheriff, Paul M. Wondoh, Dimitrios Balalis, Dimitrios Korkolis, Georgios Gkiokas, Eirini Pantiora, Theodosios Theodosopoulos, Argyrios Ioannidis, Konstantinos Konstantinidis, Sofia Konstantinidou, Nikolaos Machairas, Anna Paspala, Anastasia Prodromidou, Christos Chouliaras, Konstantinos Papadopoulos, Ioannis Baloyiannis, Ioannis Mamaloudis, George Tzovaras, Ioanna Akrida, Maria-Ioanna Argentou, Stylianos Germanos, Evangelos Iliopoulos, Ioannis Maroulis, George Skroubis, George Theofanis, Christos Chatzakis, Orestis Ioannidis, Lydia Loutzidou, Panagiotis Karathanasis, Nikolaos Michalopoulos, Charalampos Theodoropoulos, Dimitrios Theodorou, Tania Triantafyllou, Zoe Garoufalia, Natasha Hasemaki, Michalis Kontos, Gregory Kouraklis, Stylianos Kykalos, Theodore Liakakos, Eustratia Mpaili, Alexandros Papalampros, Dimitrios Schizas, Athanasios Syllaios, Ekaterini Christina Tampaki, Antonios Tsimpoukelis, Maria Ioanna Antonopoulou, Eirini Deskou, Dimitrios K. Manatakis, Dimitrios Papageorgiou, Menelaos Zoulamoglou, Christos Anthoulakis, Michalis Margaritis, Nikolaos Nikoloudis, Veronica Campo, André Ceballos, Mario-Andrés Flores, Waleska Giron, Donghyun Ko, Gabriel Martinez, Verónica Rivera Lara, Nataly Rueda, Andres Sanchez, Jorge Carlos Guillermo Tejeda Garrido, Alvaro Eduardo Alvarez Rivera, Elvis Benjamin Bamaca Ixcajoc, Lilian Elizabeth Barreda Zelaya, Patricia Chacòn-Herrera, Ligia Margarita Corea Ruiz, Guillermo Echeverria-Davila, Mario Garcia, Danilo García, Edgar Fernando Gutiérrez Mayen, Noriega José, Nery Mazariegos, Diego Méndez, Michael Paniagua Espinoza, David Bardos, Marton Benke, Kristof Illes, Balint András Kokas, Réka Szabó, Akhila Appukuttan, Anjitha Asok, Vijaykumar D.k, Kapil Malik, Praveen Ravishankaran, Ritesh Tapkire, Guru Moorthy, Joyner Abraham, Ramesh Muthuvel, John Alapatt, Abhay Kattepur, Nizamudheen Pareekutty, Mebanshanbor Garod, Caleb Harris, Cliff Wanniang, Ashish Gupta, Deepak Nehra, Sanjeev Parshad, Rajgopal Acharya, Rajendra Badwe, Manish Bhandare, Urvashi Jain, Karishma Kirti, Nita Nair, Shailesh Shrikhande, Purvi Thakkar, Premkumar Anandan, Archana C S, Arun Holenarasipur Narasannaiah, Tejaswi Jagarlamudi, Rashmi M R, Mallikarjuna Manangi, Abhishek Raghavendra, K. Seshagiri Rao, Vinay S, Vinay Sajjan, Aneesh Shenoy, Santhosh Shivashankar Chikkanayakanahalli, Kavya Tharanath, Sushmita V, Peter Adidharma, Raksheeth Agarwal, Phebe Anggita Gultom, Ghafur Rasyid Arifin, Matthew Billy, Zatira Elfizri, Alessa Fahira, Devi Felicia, Triana Hardianti Gunardi, Nadya Johanna, Nadia Rahmadiani Nugrahadi, Sonar Soni Panigoro, Siti Rahmayanti, Retta Catherina Sihotang, Santi Yuanita Brata, Hadi Winoto, Nastaran Barati, Manoochehr Karami, Hamidreza Khorshidi, Homa Naderifar, Mazin A. Abdulla, Maggie Coleman, Ronan J Doherty, Rob Hannon, Brenda Murphy, Aine Stakelum, Des Winter, Lylas Aljohmani, Richard Farnan, Yeshey Seldon, Tanna Tan, Shriya Varghese, Mohammad Alherz, Muaaz Ather, Mohammad Bajilan, Vivien Graziadei, Isobel Pilkington, Omar Quidwai, Paul Ridgway, Haaris Shiwani, Abd al-Rahman Tahir, Eimear Blunnie, Daniel Burke, Niall Kennedy, Kate Macdonagh, Maeve O'Neill, Siobhan Rooney, Giuseppe Falco, Guglielmo Ferrari, Simone Mele, Gabriela Elisa Nita, Lara Ugoletti, Maurizio Zizzo, Gianmaria Confalonieri, Giovanni Pesenti, Fulvio Tagliabue, Gianluca Baronio, Deborah Ongaro, Giacomo Pata, Bruno Compagnoni, Renato Salvadori, Lucio Taglietti, Nicola D'Alessandro, Pierpaolo Di Lascio, Giovanni Pascale, Luca Bortolasi, Tommaso Campagnaro, Massimo Carlini, Giorgio Lisi, Davide Lombardi, Corrado Pedrazzani, Domenico Spoletini, Giulia Turri, Paola Violi, Donato Francesco Altomare, Fabrizio Aquilino, Nicola Musa, Vincenzo Papagni, Arcangelo Picciariello, Leonardo Vincenti, Dario Andreotti, Savino Occhionorelli, Matteo Tondo, Stefano Maria Massimiliano. Basso, Riccardo Cirelli, Marco Enrico Mario Maino, Guglielmo Niccolò Piozzi, Emanuele Picone, Rosa Scaramuzzo, Giovanni Sinibaldi, Alfonso Amendola, Lorenzo Anastasio, Luigi Bucci, Emanuele Caruso, Antonio Castaldi, Sara Di Maso, Vincenza Paola Dinuzzi, Giovanni Esposito, Maria Gaudiello, Mariano Cesare Giglio, Paola Antonella Greco, Gaetano Luglio, Andrea Manfreda, Ester Marra, Federica Mastella, Gianluca Pagano, Roberto Peltrini, Vincenzo Pepe, Michele Sacco, Viviana Sollazzo, Giovanni Spiezio, Ettore Cianchetti, Nunzia Menduni, Michele Maria Carvello, Francesca Di Candido, Antonino Spinelli, Fabio Corsi, Luca Sorrentino, Fabio Marino, Emanuele Luigi Giuseppe Asti, Luigi Bonavina, Emanuele Rausa, Martina Asta, Andrea Belli, Francesco Bianco, Carmela Cervone, Paolo Delrio, Armando Falato, Andrea Fares Bucci, Rita Guarino, Ugo Pace, Daniela Rega, Emilia De Luca, Gaetano Gallo, Giuseppe Sammarco, Giuseppe Sena, Giuseppina Vescio, Letizia Santandrea, Giampaolo Ugolini, Davide Zattoni, Nicola Chetta, Gaetano Logrieco, Serafino Vanella, Gianluca Garulli, Nicola Zanini, Andrea Bondurri, Francesco Cammarata, Francesco Colombo, Diego Foschi, Giulia Maria Beatrice Lamperti, Anna Maffioli, Gianluca Matteo Sampietro, Al'ona Yakushkina, Gloria Zaffaroni, Enrico Cicuttin, Maria Grazia Sibilla, Harmony Impellizzeri, Marco Inama, Gianluigi Moretto, Sylvie Mochet, Elisa Ponte, Antonella Usai, Stefano Mancini, Andrea Sagnotta, Luigi Solinas, Elisa Bolzonaro, Nicolò Tamini, Gianluca Curletti, Raffaele Galleano, Michele Malerba, Sofia Campanella, Gianfranco Cocorullo, Francesco Colli, Paolino De Marco, Nicolò Falco, Tommaso Fontana, Leonel jospin Kamdem Mambou, Antonella La Brocca, Leo Licari, Brenda Randisi, Giovanna Rizzo, Giulia Rotolo, Giuseppe Salamone, Roberta Tutino, Paolina Venturelli, Stefano Malabarba, Alessandro Sgrò, Ivan Vella, Bruno Cirillo, Daniele Crocetti, Giorgio De Toma, Pierfrancesco Lapolla, Andrea Mingoli, Paolo Sapienza, Angela Belvedere, Stefania Bianchini, Margherita Binetti, Arianna Birindelli, Valeria Tonini, Mauro Podda, Fabio Pulighe, Michele De Rosa, Lorenzo Bono, Felice Borghi, Paolo Geretto, Maria Carmela Giuffrida, Corrado Lauro, Alessandra Marano, Luca Pellegrino, Paola Salusso, Diego Sasia, Michela Campanelli, Alberto Realis Luc, Mario Trompetto, Roberto Cardia, Nicola Cillara, Antonio Nicola Giordano, Antonio Costanzo, Mario Alessandro Giovilli, Luca Turati, Silvestro Canonico, Guido Sciaudone, Francesco Selvaggi, Lucio Selvaggi, Nader Albsoul, Ahmad AlBsoul, Ala'a Aldeen Alkhatib, Osama Alsallaq, Justin Z. Amarin, Rami Ayoub, Isam Bsisu, M S El Muhtaseb, Mohammad Jabaiti, Jamal Melhem, Yasmeen Z. Qwaider, Mohammad Hasan Salameh, Ahmad Suleihat, Haya H. Suradi, Mohammad Alammarin, Almoutuz Aljaafreh, Mohammad Bani hani, Zeina Bani hani, Farah Bani Hani, Toqa Fahmawee, Shadi Hamouri, Cyrine Katanani, Ra'fat Tawalbeh, Tamara Tawalbeh, Hassan Zawahrah, Mohamad K. Abou Chaar, Lana Abusalem, Mahmoud Al-Masri, Hani Al-Najjar, Lutfi Barghuthi, Zahra Ahmed, Adnan Maulana, Omar Ngotho, Charbel Kamau, Aruyaru Stanley Mwenda, Fridah Bosire, Elizabeth Mwachiro, Robert Parker, Ian Simel, Kimutai Sylvester, Abdulmunem Ahmed Mustafa Althini, Sofian Elbarouni, Aya Elseed Elbeshina, Ahmed Gwea, Ans Malek, Wedad Albashir Masoud Farag, Abdulwahab Abdalei, Abu Baker Abdel Malik, Areej Abo-khammash, Ma'aly Abuhlaiga, Nour Adnan, Marwa Albaggar, Asma Alfitory, Asma Aljanfi, Fakhruddin Almuzghi, Zohoor Altumei, Fatima Alzabti, Hana Ashoushan, Mohamed Assalhi, Joma Azzubia, Sondos Bnhameida, Malik Delhen, Houssein Elshafei, Hana Elteir, Fatima Esbaga, Abdel Aziz Gobbi, Fatma Hamouda, Hamdan Hilan, Rania Ismail, Fieruz Jebran, Muataz Kasbour, Galia Maderi, Saja Mohammad, Burooj Mohammed, Habib Murtadi, Hamassat Mustafa, Mohamed Rajab, Sarah Trenba, Mariam Wafaa, Eman Al Sagheir, Alabas Almigheerbi, Ahmed Alzahaf, Sumayyah Ghayth Bahroun, Najah Ben Dallah, Mahmoud Elshaibani, Haitem Eswaye, Maha Karar, Samah Omar, Eman Younes, Maha Younes, Dafer Zreeg, Saleh Abujamra, Firas Ashour, Mala Elgammudi, Wesal Omar F. Aljadidi, Enas Saddouh, Randa Sharif, Aya Alabuzidi, AbdulMawlay Alwerfally, Sarra Aribi, Fatma Bibas, Taha Elfaituri, Yasmine Elhajjaji, Ala Khaled, Wegdan Khalil, Tesneem Layas, Enas Soula, Ahmed Tarek, Muad fathi khalleefah Abu hallalah, Hazem Abdelkarem Ahmed, Tagwa Alsharef, Abdulsalam Ali Ben Saoud, Tasnim El Gharmoul, Ahmed Elhadi, Safa Elrais, Abdulhalim Shebani, Heba Zarti, Asaid Zeiton, Marijus Ambrazevicius, Nerijus Kaselis, Migle Stakyte, Oleg Aliosin, Agne Cizauskaite, Sarunas Dailidenas, Vitalijus Eismontas, Migle Kybransiene, Vitalija Nutautiene, Narimantas Samalavicius, Dainius Simcikas, Algirdas Slepavicius, Albinas Tamosiunas, Nerijus Ubartas, Paulius Zeromskas, Saulius Bradulskis, Edvinas Dainius, Juozas Juocas, Egle Kubiliute, Juozas Kutkevicius, Aurimas Opolskis, Audrius Parseliunas, Andrejus Subocius, Egle Virbickaite, Diana Zuikyte, Algirdas Bogusevicius, Kristina Buzaite, Daiva Cepuliene, Ieva Cesleviciene, Vaidotas Cesna, Jolanta Gribauskaite, Povilas Ignatavicius, Mantas Jokubauskas, Monika Liugailaite, Ernest Margelis, Ruta Mazelyte, Lina Pankratjevaite, Matas Pažusis, Agne Rackeviciute, Justina Saladyte, Monika Škimelyte, Vygintas Šlenfuktas, Monika Sudeikyte, Algimantas Tamelis, Tomas Vanagas, Žygimantas Žumbakys, Aivaras Atkociunas, Audrius Dulskas, Justas Kuliavas, Justas Birutis, Sigitas Paškevicius, Mindaugas Šatkauskas, Donatas Danys, Matas Jakubauskas, Lina Jakubauskiene, Marius Kryzauskas, Vytautas Lipnickas, Gabija Makunaite, Fanjandrainy Rasoaherinomenjanahary, Herizo Rasolofonarivo, Luc Hervé Samison, Bitiel Banda, Vanessa Msosa, Ahmad Imran Ahmad Izzuddin, Andre Das, Ying Yee Gan, Tan Shong Sheng, Jia yng Siaw, Mohd Fadliyazid Ab Rahim, Dyg Zahratul Hamrak Abang Jamari, Nurfariza Che Husin, Muhd Yusairi Kamarulzaman, Yi Ping Lim, Nil Amri Mohamed Kamil, Mohd Razeen Mohd Hassan, Saidah Mohd Sahid, Johari Mustafa, Elaine Hui Been Ng, Wan Khamizar Wan Khazim, Ng Chang Ern, P.g. Lingeshan, Syariz Ezuan Sulaiman, Sue Ean Ang, Muhammad Navid Bin Mohamad Sithik, Yih Jeng Cheong, Mahadevan Deva Tata, Law Jia Xian, Aravinthan Kadravello, I-Ern Koh, Li-Yen Ng, Yuki Julius Ng We Yong, Kandasami Palayan, Chi Xuan Sam, Phuah Siow Jin, Jeremy Tan Ern Hwei, Yita Tang, Alvin Zubin Ter, Michael Pak-Kai Wong, Andee Dzulkarnaen Zakaria, Zaidi Zakaria, Fitjerald Henry, Thyivya Kalaiselvan, Muhammad Fairuz Shah Abd Karim, Mohamed Rezal Abdul Aziz, Nora Abdul Aziz, Tak Loon Khong, Peng Choong Lau, Hiong Chin Lim, April Camilla Roslani, Jonathan Chen Ken Seak, Sui-Weng Wong, Lai Fen Wong, Leow Yeen Chin, Mercy Chinemerem Anyanwu, Zachary Busuttil, Thomas Calleja, Kurt Lee Chircop, Ruth Cutajar, Andrew Michael Dimech, Joseph Galea, Kiara Gascon Perai, Ruth Gatt, Lisa Kelman, Elizabeth Micallef, Favour Nwolu, Kim Sammut, Joanna Thompson, Sean Warwicker, Matthew Zammit, Fernando Cordera, Efraín Cruz González, Jorge Sánchez-García, Francisco José Barbosa Camacho, Francisco Javier Barrera López, Carlos Jose Zuloaga Fernandez del Valle, Eric Acosta, Iván Romarico González Espinoza, Perla Moreno, Ana Olivia Cortes-Flores, Clotilde Fuentes Orozco, Alejandro Gonzalez Ojeda, Samantha Corro Díaz González, Laura Martinez, Bonifacio Mosqueda Amador, Armando Novoa, Dennet Arturo Olazo Espejo, Alejandro Jimenez, Federico Lopez Rosales, Elva Gabriela Vanoye, Luis Alberto Garcia Gonzalez, Roberto Carlos Miranda-Ackerman, Manuel Solano-Genesta, Alethia Alvarez-Cano, Hector Hugo Romero-Garza, Heriberto Medina-Franco, Lorelí Mejía-Fernández, Noel Salgado-Nesme, Omar Vergara-Fernandez, Guadalupe Montserrat Gutiérrez-Mota, Francisco Xavier Hernandez Vera, Anabella Llantada Lopez, Gilberto Morgan Villela, Felipe de Jesus Ramirez Padilla, Walezka Tapia Marin, Mónica Martínez Maldonado, Ramses Sánchez Suárez, José Manuel Troche, Chaymae Benyaiche, Oumaima Outani, Souadka Amine, Amine Benkabbou, Anass Mohammed Majbar, Raouf Mohsine, Ali Rafik, Thida Oung, Moe Moe Tin, Philipp Plarre, Anna Alberga, Nina Sluiter, Jurriaan Tuynman, Robin Blok, Didem Cömert, Roel Hompes, Marianne Kalff, Merel Elisabeth Stellingwerf, Pieter Tanis, Mark van Berge Henegouwen, Elise Maria van Praag, Daan Wisselink, Michael Gerhards, Josephine Lopes Cardozo, Emma Westerduin, Joske de Jonge, Aaw van Geloven, Kaz van Schilt, Frank den Boer, Simone Stoots, Stijn Vlek, Jamie Adams, Ibrahim S. Al-Busaidi, Gabrielle Budd, Seung il Choi, Michael Jen Jie Chu, Anurag Ganugapati, Lucy McKinstry, Rebecca Pascoe, Simon Richards, Kenrick Rosser, Annie Stevenson, Rebecca White, Shebani Farik, Jin Kwun, Ahmed Murad, Sarah Cowan, Timothy Hall, Michael Hayton, Laminou Malam Sani, Souleymane Oumarou Garba, Ibrahim Amadou Magagi, Oumarou Habou, Halima Aliyu, Muhammad Daniyan, Tunde T. Sholadoye, Lawal Abdullahi, Lofty-John Anyanwu, Aminu Mohammad Mohammad, Abubakar Bala Muhammad, Abdurrahman Abba Sheshe, Ibrahim Suleiman, Alaba Adesina, Ajibola Awolowo, Clement Onuoha, Omotayo Salami, Ogechukwu Taiwo, Agboola Taiwo, Stephen Kache, Jerry Godfrey Makama, Danjuma Sale, Olajide Abiola, Akinlabi Ajao, Anthony Ajiboye, Amarachukwu Etonyeaku, Julius Olaogun, Ademola Adebanjo, Opeoluwa Adesanya, Michael Olatunji Afolayan, Olanrewaju Balogun, Ayomide Makanjuola, Samuel Nwokocha, Rufus Wale Ojewola, Thomas Olagboyega Olajide, Adewale Aderounmu, Abdul-Rashid Adesunkanmi, Augustine Agbakwuru, Adeleke Akeem Aderogba, Olusegun Isaac Alatise, Olukayode Arowolo, Oladejo Lawal, Tajudeen Mohammed, Chinedu Ndegbu, Olalekan Olasehinde, Funmilola Wuraola, Akinbolaji Akinkuolie, Arinzechukwu Mosanya, Omobolaji Ayandipo, Peter Elemile, Taiwo Akeem Lawal, Samuel Ali SANI, Stephen Garba, Rebecca Hauwa SANI, Samson Olori, Henry Onyebuashi, Ifeanyi Umoke, Adedire Adenuga, Ademola Adeyeye, Olufemi Habeeb, Bashir Lawal, Abdulrasheed Nasir, Eirik Kjus Aahlin, Didrik Kjønås, Elisabeth Myrseth, Jibran Abbasy, Abdul Alvi, Omair Saleem, Asma Afzal, Anam Nazir, Muhammad Farooq, Ayesha Liaqat, Syed Asghar Naqi, Ali Raza, Muzna Sarfraz, Muhammad Sarwar, Muntaha Banglani, Ambreen Munir, Rahmat Sehrish, Bushra Ayub, Raza Sayyed, Amna Altaf, Saima Ayub, Komal Saeed, Bilal Syed, Sana Amir Akbar, Abdul Wahid Anwer, Ruqayya Naheed Khan, Amina Iqbal Khan, Shahid Khattak, Sameen Mohtasham, Muhammad Asad Parvaiz, Aamir Ali Syed, Abdul Basit Ansari, Noman Shahzad, Tanwir Khaliq, Isbah Rashid, Shahzad Hussain Waqar, Hasan Abu Al-saleem, Amjad Abu Alqumboz, Mohammad Alqadi, Adham Amro, Rawan Assa, Eman Awesat, Rawan Ayyad, Mohammed Hammad, Ayat Haymony, Bassel Hijazi, Bara Hmeidat, Rowaa Lahaseh, Aseel Qawasmi, Alaa Rajabi, Mohammed Shehada, Sundus Shkokani, Yasmine Yaghi, Nadine Yaghi, Mohammad AlZohour, Mohammad Farid, Yousef Mahmoud Habes, Wesam Juba, Yanal Nubani, Abdelrahman Rabee, Mohammad Sa'deh, Saeed Abed, Iyad Al basos, Mohammad Alswerki, Dina Ashour, Israa Awad, Samar Diab, Alaa El Jamassi, Sahar El-Kahlout, Somaya Elhout, Ahmed N K Hajjaj, Doaa Hasanain, Baraa Nabil hajjaj, Mohammed Obaid, Eman Saikaly, Ahmed Salhi, Hiba Al-Tammam, Murad Almasri, Muath Baniowda, Doha Beshtawi, Ali Horoub, Rami Misk, Bayan Mohammad, Rami Qasrawi, Tasnim Sholi, Samar Abu-Nimeh, Abrar Abu-srour, Sadi A. Abukhalaf, Samer Adawi, Barah Alsalameh, Kholoud Ayesh, Muawiyah Elqadi, Ahmad Hammouri, Fatima Karim Mustafa, Natalie Marzouqa, Shatha Melhem, Dima Miqdad, Balqees Mohamad, Mhammed Rawhi, Ayman B. Abu Ahammala, Ahmed Abu Ataya, Israa Abu Jayyab, Samar Al-Shwaikh, Othman Alagha, Mohammed Alasttal, Haneen Awadallah, Mahmood Elblbessy, Jehad Fares, Akram Jarbou, Ibtisam Mahfouz, Moath A. Albahnasawi, Asmaa' Abo mahadi, Hasan Abuelhatal, Ayham Abuelqomboz, Abdelrahman Almoqayyad, Abdallah Alwali, Reem Balaawi, Mahmoud Hamouda, Mohammed Humeid, Abdullah Jedyan, Tasneem Mahmoud Abu hamam, Ghadeer Matar, Ali Salem, Tahani Samra, Nureddin Shaheen, Karam Shihada, Ayoob A.Nemer, Mahmoud Abu Al Amrain, Abdulwhhab Abu Alamrain, Najlaa Abu Jamie, Mohammed R. Abu-Rous, Nada Alfarra, Mohammed AlTaweel, Noor Alwhaidi, Ramadan Hamed, Bader Saqqa, Ahmad Shaheen, Dana Aljaber, Loay Aljaberi, Malak Alwaheidi, Assef Jawaada, Hani Khaldi, Rami Qahoush, Jalil Qari, Rana Saadeh, Ahlam Salim, Aseel Yacoub, Abbas Abbas, Rana Abu shua`ib, Baraa Abu Zainah, Mahmoud AbuSirrees, Basheer Babaa, Ola Barhoush, Asef Belal qadomi, Laith Daraghmeh, Reema Haji, Alaa Khatatbeh, Lana Khatib, Salsabeel Qarariah, Yara Quzmar, Khalil Safadi, Roqaya Salameh, Mohammad Hassan, Shifaa Herzallah, Loai Massad, Ahmed Nazzal, Ranin Nazzal, Dennis Escobar, Gustavo Miguel Machain V, Agustin Rodriguez Gonzalez, Jorge Emerson Chachaima Mar, Nathaly Olga Chinchihualpa Paredes, Vicente Cuba, Walter Lopez, Maria Milagros Niquen Jimenez, Nestor Alberto Sanchez Bartra, Olenka Sapallanay Ojeda, Diego Sequeiros, Andrea Toscano Pacheco, María Vergara, Sol Abarca, Rodrigo Alcorta, Giuliano Borda-Luque, Ivan Edward Eusebio Zegarra, Claudia Luján López, Mirella Marrufo, Cinthya Mogrovejo, Andrea Nomura, Yamile Rodríguez Angeles, Maitza Rosario Vidal Meza, Gabriela Zavala, José Neiser Castillo Arrascue, Jomara Caroline Hidrogo Cabrera, José Julio Mariano Larrea vera, Miguel Osorio, Edgar Alcides Ylatoma Díaz, Mark Anthony Fontanilla, Joseph Roy Fuentes, Anna Leah Salazar, Genieve Dominguez, Marc Paul Lopez, Shiela Macalindong, Mark Augustine Onglao, Arjel Ramirez, Marie Dione Sacdalan, Mayou Martin Tampo, Gemma Leonora Uy, Jeremiah Mangahas, Kenneth Yabut, Joannes Paul Cañete, Bernalynn Eris Cansana, Ernes John Castro, Maria Kaiserin Lipana, Manuel Francisco Roxas, Vlu Jean Zara, Maciej Chrol, Paula Franczak, Michal Orlowski, Piotr Budzynski, Andrzej Budzynski, Pawel Bury, Agata Czerwinska, Jadwiga Dworak, Jacek Dziedzic, Michal Kisielewski, Jan Kulawik, Anna Lasek, Piotr Malczak, Marcin Migaczewski, Michal Pedziwiatr, Magdalena Pisarska, Dorota Radkowiak, Mateusz Rubinkiewicz, Anna Rzepa, Tomasz Skoczylas, Maciej Stanek, Katarzyna Truszkiewicz, Mateusz Wierdak, Marek Winiarski, Piotr Zarzycki, Anna Zub-Pokrowiecka, Piotr Kowalewski, Rafal Roszkowski, Maciej Waledziak, Miguel Tomé, Sara Patrocinio, Ines Guerreiro, Filipe Almeida, Xavier de Sousa, Nuno Monteiro, Maria Teresa Costa Santos, Daniela de Oliveira, Marta Lopes Serra, Daniela Morgado, Christian Neves, Ana Carolina Oliveira, Alice Pimentel, Sofia Silva, Márcia Carvalho, Lúcia Carvalho, Joana Magalhães, Leonor Matos, Tânia Monteiro, Carlota Ramos, Vanessa Santos, José Barbosa, Jose Costa-Maia, Vítor Devezas, Ana Fareleira, Cristina Fernandes, Diana Gonçalves, Henrique Mora, Marina Morais, Fabiana Silva de Sousa, Sara Catarino Santos, Ana Logrado, André Tojal, Edgar Amorim, Miguel F. Cunha, Ana Fazenda, João Pedro Melo Neves, Inês Isabel Sampaio da Nóvoa Gomes Miguel, Diogo Veiga, José Azevedo, Hugo Cardoso Louro, Mariana Leite, Maria Bairos Menezes, Bárbara Gama, Diana Brito, Marta Cristina Cruz Martins, André Graça e Magalhães, Ana Catarina Longras, Rita Lourenço, Diana Matos, Luis Castro, Filipa Policarpo, Joana Romano, Cristina Monteiro, Diogo Pinto, Marina Duarte, Sónia Fortuna Martins, Mariline Oliveira, Diogo Galvão, Lisandra Martins, Anaisa Silva, Viorel Taranu, Bárbara Vieira, Jessica Neves, Simone Oliveira, Hugo Ribeiro, Margarida Cinza, Rosa Felix, Arnaldo Machado, Joana Oliveira, Joana Patrício, Rita Pedroso de Lima, Mário Pereira, Miguel Rocha Melo, Cristina Velez, Alberto Abreu da Silva, Mariana Claro, Daniel Costa Santos, Andreia Ferreira, Hugo Capote, Daniela Rosado, Filipa Taré, Oriana Nogueira, Miguel Ângelo, José Miguel Baiao, Andreia Guimarães, João Marques, Miguel Nico Albano, Marta Silva, Ana Valente da Costa, Teresa Vieira Caroço, Sara Almeida Braga, Ines Capunge, Marta Fragoso, João Guimarães, Bruno Pinto, João Ribeiro, Miguel Angel, Guilherme Fialho, Monica Guerrero, Filipa Campos Costa, Diogo Cardoso, Vasco Cardoso, Magda Alves, Inês Estalagem, Tiago Louro, Cláudia Marques, Rita Martelo, Miguel Morgado, Rita Canotilho, Ana Margarida Correia, Pedro Martins, Mariana Peyroteo, João Gomes, Rita Monteiro, Manuela Romano, Daniela Macedo Alves, Rita Peixoto, Catarina Quintela, Maria João Jervis, Débora Melo, André Pacheco, Valter Paixão, Vera Pedro, Joana Pimenta, João Pimenta de Castro, Ana Rocha, Mircea Beuran, Cezar Ciubotaru, Bogdan Diaconescu, Sorin Hostiuc, Ionut Negoi, Bogdan Stoica, NA NA, Evgeny Anokhin, Georgy Kuznetsov, Giorgi Oganezov, Fedor Paramzin, Ekaterina Romanova, Valeryan Rutkovskii, Vasilii Rutkovskii, Mikhail Shushval, Mikhail Zabiyaka, Khasan Dzhumabaev, Valerii Ivanov, Zaman Mamedli, Sergey Achkasov, Artem Balkarov, Elnur Nabiev, Marat Nagudov, Evgeny Rybakov, Karina Saifutdinova, Oleg Sushkov, Lule Joseph, Isaac Ndayishimiye, Ntirenganya Faustin, Alphonse Zeta Mutabazi, Jean Paul Mvukiyehe, Vizir J.P Nsengimana, Carine Uwakunda, Mohammad Monir Abbas, Nouf Akeel, Murad Aljiffry, Kholoud Awaji, Ali Farsi, Ghader Jamjoum, Ahmad Khoja, Ashraf Maghrabi, Nadim Malibary, Mohammed Nassif, Abdulaziz Saleem, Abdullah Sultan, Wail Tashkandi, Hanaa Tashkandi, Nora Trabulsi, Mouhamadou Bachir Ba, Adja Coumba Diallo, Abdourahmane Ndong, Vladica Cuk, Uroš Jankovic, Sharon Zhiling Koh, Frederick Koh, Kuok Chung Lee, Kai Yin Lee, Sean Lee, Wei Qi Leong, Su Ann Lui, Prajwala Prakash, Jan Grosek, Gregor Norcic, Ales Tomazic, Nicolas Fitchat, Robert Jaich, Devorah Wineberg, Modise Zacharia Koto, Daniella Baiocchi, Damian Clarke, Christina Johanna Steenkamp, Sharon Bannister, Adam Boutall, Galya Chinnery, Anna Coccia, Angela Dell, Parveen Karjiker, Christo Kloppers, Nicholas Loxton, Tumi Mabogoane, Francois Malherbe, Eugenio Panieri, Shreya Rayamajhi, Tirsa van Wyngaard, Claire Warden, T E Madiba, Nivashen Pillay, Savannah Brooks, Charlise Kruger, Lisa Hannah Van Der Merwe, Ferhana Gool, Maahir Kariem, Heather Bougard, Nazmie Kariem, Fazlin Noor, Reantha Pillay, Leandi Steynfaardt, Lucía González González, José Miguel Marín Santos, Paula Martín-Borregón, Javier Martínez Caballero, Cristina Nevado García, Pastora Rodriguez Fraga, Gonzalo De Castro Parga, Maria Pilar Fernández Veiga, Lucía Garrido López, Hugo Infante Pino, Irene Lages Cal, Marta López Otero, Manuel Nogueira Sixto, Marta Paniagua García Señorans, Laura Rodríguez Fernández, Alejandro Ruano Poblador, Erika Rufo Crespo, Raquel Sanchez-Santos, Vincenzo Vigorita, Ester Alonso Batanero, Dorisme Asnel, Isabel Cifrian Canales, Elisa Contreras Saiz, Irene De Santiago Alvarez, Tamara Díaz Vico, Sebastian Fernandez Arias, Daniel Fernández Martínez, Carmen García Bernardo, Luis Joaquín García Flórez, Carmen Garcia Gutierrez, Manuel García Munar, Carlos Alberto Márquez Zorrilla Molina, Marta Merayo, José Luis Michi Campos, Maria Moreno Gijon, Jorge L. Otero-Diez, Jose Luis Rodicio Miravalles, Lorena Solar-Garcia, Aida Suárez Sánchez, Nuria Truan, Cristina Alejandre Villalobos, Yurena Caballero Díaz, Marta Jimenez, Dacil Montesdeoca, Antonio Navarro-Sánchez, Victor Vega, Juan Beltrán de Heredia, Zahira Gómez, Carlos Jezieniecki, Ana Patricia Legido Morán, Mario Montes-Manrique, Mario Rodriguez-Lopez, María Ruiz Soriano, Jeancarlos Trujillo Díaz, Andrea Vazquez Fernandez, Nuria Argudo, Miguel Pera, Laia Torrent Jansà, Melody García Domínguez, Ignacio Goded, Marta Roldón Golet, Issa Talal El-Abur, Alejandra Utrilla Fornals, Vanesa Zambrana Campos, Maria Del Mar Aguilar Martinez, Marina Bosch, Luis García-Catalá, Luis Sánchez-Guillén, Eva Artigau, Nuria Gomez Romeu, David Julià Bergkvist, Beatriz Espina Perez, Olga Morató, Carles Olona, Beatriz Diéguez, Alexander Forero-Torres, Manuel Losada, Segundo Gomez-Abril, Paula Gonzálvez, Rosario Martinez, Sergio Navarro Martínez, Carmen Payá-Llorente, Álvaro Pérez Rubio, Sandra Santarrufina Martinez, Juan Carlos Sebastián Tomás, Ramon Trullenque Juan, Alberto Gegúndez Simón, Paloma Maté, Maria Isabel Prieto-Nieto, Ines Rubio-Perez, Aitor Urbieta, Marina Vicario Bravo, David Abelló, Matteo Frasson, Alvaro Garcia-Granero, Alfredo Abad Gurumeta, Ane Abad-Motos, Elena Lucena-de Pablo, Beatriz Nozal, Javier Ripollés-Melchor, Rut Salvachúa, Esther Ferrero, Luis Garcia-Sancho Tellez, Antonio L. Picardo, Jose Alberto Rojo López, Laura Patricia Zorrilla Matilla, Carmen Cagigas Fernandez, Sonia Castanedo Bezanilla, José Estevez Tesouro, Maria Jose Fernandez-Diaz, Juan García Cardo, Marcos Gomez Ruiz, Erik Gonzalez-Tolaretxipi, Jaime Jimeno Fraile, Cristobal Poch, Montserrat Rodriguez-Aguirre, Noemí Troche Pesqueira, Maria Soledad Trugeda-Carrera, Javier de la Torre, Ruth Blanco-Colino, Eloy Espin-Basany, Martin Espinosa-Bravo, Clara Morales Comas, Eduardo Reyes Afonso, Joaquín Rivero Déniz, Christian Siso Raber, Mireia Verdaguer Tremolosa, Pramodh Chandrasinghe, Sumudu Kumarage, Nimeshi Wijekoon Arachchilage, Ahmed Abdalla Ahmed Elkamel, Mohammed A. Adam, Nina Blomme, Anders Thorell, Fredrik Wogensen, Andreas Älgå, Dhirar Ansarei, Fuat Celebioglu, Göran Heinius, Linda Nigard, Emil Pieniowski, Sandra Ahlqvist, Ida Björklund, Andreas Frånberg, Martina Håkansson, Karin Adamo, Oskar Franklin, Malin Sund, Rebecca Wiberg, Yvette Andersson, Abbas Chabok, Maziar Nikberg, Alexander Kugelberg, Claudia Canonica, Dimitrios Christoforidis, Fabrizio Fasolini, Paolo Gaffuri, Mauro Giuliani, Francesco Meani, Sotirios Georgios Popeskou, Silvia Pozza, Wiebke Wandschneider, Lorenz Peterer, Lukas Werner Widmer, Bernd Zimmermann, Panagiotis Bakoleas, Iris Chanousi, Lydia Charalampidou, Lukasz Filip Grochola, Franziska Heid, Sotirios Ntaoulas, Michail Outos, Georgios Peros, Hanna Podolska-Skoczek, Katharina Beate Reinisch, Christian Zielasek, Nicolas Demartines, Jérôme Gilgien, Amaniel Kefleyesus, Pénélope St-Amour, Arnaud Toussaint, Maryam Alhimyar, Bayan Alsaid, Amr Alyafi, Ahmad Alkhaledi, Basel Kouz, Ahmad Omarain, Yusra Al-Sabbagh, Haya Alkhatib, Samer Sara, Ahmad Alhaj, Aghyad Danial, Lama Kadoura, Sarah Maa Albared, Yamen Monawar, Louei Nahas, Barook Abd, Ahmad Saad, Habib Wakkaf, Hatem Bouzaiene, Montassar Ghalleb, Elif Akaydin, Ata Cem Akbaba, Onur Atakul, Ege Baltaci, Sevval Besli, Gökçen Burgu, Ulukan Cenal, Cansu de Muijnck, Hasan Can Demirkaya, Alper Dogruoz, Zeynep Ipek Gezer, Yasemin Gündogdu, Merve Kara, Hasan Kürsad Korkmaz, Gökalp Kagan Kurtoglu, Volkan Ozben, Berk Baris Ozmen, Ahmet Murat Pektas, Eda Kübra Sel, Nilüfer Yenidünya, Fuat Baris Bengur, Berke Mustafa Oral, Tahir Koray Yozgatli, Seymur Abdullayev, Mehmet Emin Gunes, Nuri Alper Sahbaz, Tuba Banaz, Kübra Kargici, Omer Faruk Kuyumcu, Erkan Yanikoglu, Merve Yesilsancak, Duygu Yilmaz, Melik Kagan Aktas, Ahmet Rencuzogullari, Arda Isik, Sezai Leventoglu, Ali Yalçinkaya, Osman Yüksel, Mustafa U Kalayci, Yasin Kara, Inanc Samil Sarici, Alp Akin, Gökçe nur Alemdag, Ekin Arslan, Bahadir Emre Baki, Muhammed Selim Bodur, Adnan Calik, Bahar Candas Altinbas, Irem Cihanyurdu, Oguz Erkul, Burak Gül, Ali Guner, Beyza Köse, Anil Semiz, Sule Sevim, Serkan Tayar, Kadir Tomas, Ozan yavuz Tüfek, Serdar Türkyilmaz, Mehmet Ulusahin, Arif Usta, Reyyan Yildirim, Sertaç Ata Güler, Ozan Can Tatar, Ecenur Varol, Busenur Kirimtay, Muhammed Uysal, Alp Yildiz, Emin Kose, Ahmet Burak Ciftci, Elif Çolak, Huseyin Eraslan, Gultekin Ozan Kucuk, Kürsat Yemez, Herman Lule, Mumbere Bienfait, Emmanuel Bua, Noella Okalany, Maksym Basarab, Oleksii Bielosludtsev, Kateryna Kolhanova, Kateryna Perepelytsia, Kateryna Romanukha, Dmytro Savenkov, Stanislav Siryi, Maksym Tereshchenko, Nezamai Viacheslav, Anton Volovetskyi, Andrey Kebkalo, Yegor Tryliskyy, Volodimir Tyselskiy, Eilidh Bruce, Bing Lun Chow, Emma Iddles, Sarah McGuckin, Nicola Newall, George Ramsay, Parivrudh Sharma, Caitlin Stewart, Jeremy Wong, Abdul Badran, Michael Bath, Fanny Belais, Eman Butt, Kaustuv Joshi, Milan Kapur, Mike Shaw, Adam Townson, Christopher Yee Khang Williams, Timothy Gray, Robert Greig, Mansoor Husain, Elspeth Murray, Ahmed Mustafa, Ashar Asif, Arya Gokul, Max Shah, Mabel Temisanren Akitikori, Alexandros Charalabopoulos, Sophie Davidson, Sinead McNally, Shamil Rupani, Fatema Juma, Sarah Catherine Mills, Laura Muirhead, Kate Sellars, Una Walsh, Oliver Warren, Alice Chambers, Richard Hunt, Stephen Boyce, Hannah Cornwall, Isabel Tol, Eleftherios Orestis Argyriou, Nicola Eardley, Meical Povey, Joanna M S Aithie, Ahmer Irfan, Mari-Claire McGuigan, Robert Starr, Craig Russell Warren, Jess Archibald, Georgia Kirby, Ivan Kisyov, Chun Kheng Khoo, Rachel Lee, Dana Photiou, Rowan Davis, Uday Prasad, P Zichu Yang, Jonathan Bird, Edmund Leung, Virginia Summerour, Chelise Currow, Jianshen Kiam, Gerald Jack Soon Tan, Anitha Muthusami, Ibifunke Pegba-Otemolu, Tomas Urbonas, Joseph Nunoo-Mensah, Edgaras Smolskas, Alex Boddy, Gianpiero Gravante, David Hunter, David Andrew, Amanda Koh, Amari Thompson, Lawrence Adams, Hollie A Clements, Kasun De Silva, Ogbonnia Ekpete, Seraj Haque, Scott Henderson, Bilal Ibrahim, Thummini Jayasinghe, Jennifer Livie, Keir Mailley, Gopikrishnan Nair, Daniel Tan, Caitlin Baggaley, Aleksander Dawidziuk, Bartosz Szyszka, Charlotte Barter, Nirav Gandhi, Karen Hassell, Samantha Hitchin, Jennett Kelsall, Eva Nagy, Ashrafun Nessa, Lisa Whisker, Fady Yanni, Mahmoud Ali, Deeksha Arora, Sunanda Hediwattege, Navam Kumarasinghe, Munir Rathore, Athula Tennakoon, Syed Mustafa Ali Ahmad, Oreoluwa Bajomo, Fahema Nadira, Valerio Celentano, Ewen Griffiths, Rama Santhosh Karri, Jason Kei Chak Mak, Michelle Pipe, Muhammad Iqbal Bhatti, Mohamed Rabie, Connor Boyle, David Hamilton, Aishath Mihuna, James Chean Khun Ng, Gary Nicholson, Agata Oliwa, Robert Pearson, Anna Rose, Shun Qi Yong, Catherine Boereboom, Michael Hanna, Catherine Walter, Thomas Samuel Greensmith, Rachel Mitchell, Eimear Monaghan, James Crawford, Susan Moug, James Blackwell, Hannah Boyd-Carson, Philip Herrod, Omar Al-Allaf, Miriam Beattie, Cameron Bullock, Shivang Burman, Gemma Clark, Nicolas Flamey, Oliver Flannery, Alexander Harding, Ben Kodiatt, Samuel Lawday, Shivani Mahapatra, Navin Mukundu Nagesh, Michael Ng, Dupinderjit Rye, Andrel Yoong, Laura Clark, Chris Deans, Monisha Edirisooriya, Emma Victoria Carrington, Tsz Lun Ernest Wong, Baasil Yusuf, Carla Chamberlain, Kathryn Duke, Elizabeth Kmiotek, Azel Botes, Natalie Condie, Timothy Schrire, Reena Shah, Iolo Thomas-Jones, Charlotte Yates, Natasha Anthony, Edward Matthews, Kapil Sahnan, James Tankel, Sally Tucker, Jasmine Winter Beatty, Paul Ziprin, William Duggan, Anastasia Kantartzi, Shruthi Sridhar, Rachel Alys Khaw, Prakhar Srivastava, Charlotte Underwood, Homero Alves do Canto Brum, Sharat Chopra, Laura Davis, Rebecca Hughes, Joshua Tulley, Justin Alberts, Thomas Athisayaraj, Mojolaoluwa Olugbemi, Kasim Ahmad, Claudia Chan, Gavin Chapman, Hannah Fleming, Benjamin Fox, Julia Grewar, Kate Hulse, Duncan Rutherford, Mackay Sinead, Scott Smith, Doug Speake, Peter G Vaughan-Shaw, Natasha Christodoulides, Simrit 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A., Abu shua'ib R., Abu Zainah B., AbuSirrees M., Babaa B., Barhoush O., Belal qadomi A., Daraghmeh L., Haji R., Khatatbeh A., Khatib L., Qarariah S., Quzmar Y., Safadi K., Salameh R., Hassan M., Herzallah S., Massad L., Nazzal A., Nazzal R., Escobar D., Machain V G.M., Rodriguez Gonzalez A., Chachaima Mar J.E., Chinchihualpa Paredes N.O., Cuba V., Lopez W., Niquen Jimenez M.M., Sanchez Bartra N.A., Sapallanay Ojeda O., Sequeiros D., Toscano Pacheco A., Vergara M., Abarca S., Alcorta R., Borda-Luque G., Eusebio Zegarra I.E., Lujan Lopez C., Marrufo M., Mogrovejo C., Nomura A., Rodriguez Angeles Y., Vidal Meza M.R., Zavala G., Castillo Arrascue J.N., Hidrogo Cabrera J.C., Larrea vera J.J.M., Osorio M., Ylatoma Diaz E.A., Fontanilla M.A., Fuentes J.R., Salazar A.L., Dominguez G., Lopez M.P., Macalindong S., Onglao M.A., Ramirez A., Sacdalan M.D., Tampo M.M., Uy G.L., Mangahas J., Yabut K., Canete J.P., Cansana B.E., Castro E.J., Lipana M.K., Roxas M.F., Zara V.J., Chrol M., Franczak P., 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Adam M., Blomme N., Thorell A., Wogensen F., Alga A., Ansarei D., Celebioglu F., Heinius G., Nigard L., Pieniowski E., Ahlqvist S., Bjorklund I., Franberg A., Hakansson M., Adamo K., Franklin O., Sund M., Wiberg R., Andersson Y., Chabok A., Nikberg M., Kugelberg A., Canonica C., Christoforidis D., Fasolini F., Gaffuri P., Giuliani M., Meani F., Popeskou S.G., Pozza S., Wandschneider W., Peterer L., Widmer L.W., Zimmermann B., Bakoleas P., Chanousi I., Charalampidou L., Grochola L.F., Heid F., Ntaoulas S., Outos M., Peros G., Podolska-Skoczek H., Reinisch K.B., Zielasek C., Demartines N., Gilgien J., Kefleyesus A., St-Amour P., Toussaint A., Alhimyar M., Alsaid B., Alyafi A., Alkhaledi A., Kouz B., Omarain A., Al-Sabbagh Y., Alkhatib H., Sara S., Alhaj A., Danial A., Kadoura L., Maa Albared S., Monawar Y., Nahas L., Abd B., Saad A., Wakkaf H., Bouzaiene H., Ghalleb M., Akaydin E., Akbaba A.C., Atakul O., Baltaci E., Besli S., Burgu G., Cenal U., de Muijnck C., Demirkaya H.C., Dogruoz A., Gezer Z.I., Gundogdu Y., Kara M., Korkmaz H.K., Kurtoglu G.K., Ozben V., Ozmen B.B., Pektas A.M., Sel E.K., Yenidunya N., Bengur F.B., Oral B.M., Yozgatli T.K., Abdullayev S., Gunes M.E., Sahbaz N.A., Banaz T., Kargici K., Kuyumcu O.F., Yanikoglu E., Yesilsancak M., Yilmaz D., Aktas M.K., Rencuzogullari A., Isik A., Leventoglu S., Yalcinkaya A., Yuksel O., Kalayci M.U., Kara Y., Sarici I.S., Akin A., Alemdag G.N., Arslan E., Baki B.E., Bodur M.S., Calik A., Candas Altinbas B., Cihanyurdu I., Erkul O., Gul B., Guner A., Kose B., Semiz A., Sevim S., Tayar S., Tomas K., Tufek O.Y., Turkyilmaz S., Ulusahin M., Usta A., Yildirim R., Guler S.A., Tatar O.C., Varol E., Kirimtay B., Uysal M., Yildiz A., Kose E., Ciftci A.B., Colak E., Eraslan H., Kucuk G.O., Yemez K., Lule H., Bienfait M., Bua E., Okalany N., Basarab M., Bielosludtsev O., Kolhanova K., Perepelytsia K., Romanukha K., Savenkov D., Siryi S., Tereshchenko M., Viacheslav N., Volovetskyi A., Kebkalo A., Tryliskyy Y., Tyselskiy V., Bruce E., Chow B.L., Iddles E., McGuckin S., Newall N., Ramsay G., Sharma P., Stewart C., Wong J., Badran A., Bath M., Belais F., Butt E., Joshi K., Kapur M., Shaw M., Townson A., Williams C.Y.K., Gray T., Greig R., Husain M., Murray E., Mustafa A., Asif A., Gokul A., Shah M., Akitikori M.T., Charalabopoulos A., Davidson S., McNally S., Rupani S., Juma F., Mills S.C., Muirhead L., Sellars K., Walsh U., Warren O., Chambers A., Hunt R., Boyce S., Cornwall H., Tol I., Argyriou E.O., Eardley N., Povey M., Aithie J.M.S., Irfan A., McGuigan M.-C., Starr R., Warren C.R., Archibald J., Kirby G., Kisyov I., Khoo C.K., Lee R., Photiou D., Davis R., Prasad U., Yang P.Z., Bird J., Leung E., Summerour V., Currow C., Kiam J., Tan G.J.S., Muthusami A., Pegba-Otemolu I., Urbonas T., Nunoo-Mensah J., Smolskas E., Boddy A., Gravante G., Hunter D., Andrew D., Koh A., Thompson A., Adams L., Clements H.A., De Silva K., Ekpete O., Haque S., Henderson S., Ibrahim B., Jayasinghe T., Livie J., Mailley K., Nair G., Tan D., Baggaley C., Dawidziuk A., Szyszka B., Barter C., Gandhi N., Hassell K., Hitchin S., Kelsall J., Nagy E., Nessa A., Whisker L., Yanni F., Ali M., Arora D., Hediwattege S., Kumarasinghe N., Rathore M., Tennakoon A., Ali Ahmad S.M., Bajomo O., Nadira F., Celentano V., Griffiths E., Karri R.S., Mak J.K.C., Pipe M., Bhatti M.I., Rabie M., Boyle C., Hamilton D., Mihuna A., Ng J.C.K., Nicholson G., Oliwa A., Pearson R., Rose A., Yong S.Q., Boereboom C., Hanna M., Walter C., Greensmith T.S., Mitchell R., Monaghan E., Crawford J., Moug S., Blackwell J., Boyd-Carson H., Herrod P., Al-Allaf O., Beattie M., Bullock C., Burman S., Clark G., Flamey N., Flannery O., Harding A., Kodiatt B., Lawday S., Mahapatra S., Mukundu Nagesh N., Ng M., Rye D., Yoong A., Clark L., Deans C., Edirisooriya M., Carrington E.V., Wong T.L.E., Yusuf B., Chamberlain C., Duke K., Kmiotek E., Botes A., Condie N., Schrire T., Shah R., Thomas-Jones I., Yates C., Anthony N., Matthews E., Sahnan K., Tankel J., Tucker S., Winter Beatty J., Ziprin P., Duggan W., Kantartzi A., Sridhar S., Khaw R.A., Srivastava P., Underwood C., Alves do Canto Brum H., Chopra S., Davis L., Hughes R., Tulley J., Alberts J., Athisayaraj T., Olugbemi M., Ahmad K., Chan C., Chapman G., Fleming H., Fox B., Grewar J., Hulse K., Rutherford D., Sinead M., Speake D., Vaughan-Shaw P.G., Christodoulides N., Kudhail S., Welch M., Husaini S.M., Lambracos S., Anyanwu C., Suresh R., Thomas J.S., Gleeson E., Platoff R., Saif A., Enumah Z., Etchill E., Gabre-Kidan A., Bernstein M., Carrano F.M., Connors J., Lynn P., Melis M., Newman E., Foster D.S., Perrone K., Titan A., Ahmad S., Bafford A.C.M.D., Dal Molin M., Hanna N., Zafar S.N., Hemmila M., Napolitano L., Wong J.J., Chandler J., Wood L., Wren S., Ottesen T., You L., Yu K., Arcienega Yanez M.D.P., Ferreira Fernandes M., Gonzalez D., Cubas S., Gonzalez M.C., Zubiaurre V., Demolin R., Giroff N., Sciuto P., Campos M., Rodriguez Cantera G., Deepika G., Simuchimba E., Bulaya A., Chibuye C., Chirengendure B., Kabale M.-R., Kabongo K., Munthali J., Mweso O., Pikiti F., Otieno J., Lai L.T., Blackman B., Subramaniam S., Karim R., Kok N., Lee Y.D., Ali S., Sinha A., Corrigan R., Barnes N., Wong F., Dennis G., Jedamzik J., Phillips E., Piette W., Van hentenryck M., Koco H., Lawani S., Kassa M.W., Santos Bezerra T., Gribnev P., Dimitrov D., Krastev P., Oum S., Bonghaseh D.T., Al Farsi M., Alsharqawi N., Acevedo V., Castillo Barbosa A.C., Giron F., Leon Rodriguez J.P., Kucan D., Rosko D., Barsic N., Zupan D., Hegazi A., Truncikova V., Fryba V., Mohamed M., Nagi A., Rashad Temerik A., Elshawy M.E., Mahmoud M.I., Anwar M., Rageh T., Elmokadem A., Gaballa K., Teppo S., Pengerma P., Ballouhey Q., Bergeat D., Weyl A., Hain E., Gyedu A., Yenli E., Osei-Poku D., Rompou V.-A., Zoikas A., Gaitanidis A., Koukis G., Perivoliotis K., Tavlas P., Galanos-Demiris K., Zografos G., Karavokyros I., Xanthopoulou G., Iordanidou E., Ayau F., Garcia A., Damjan P., Wason D., B L A., Rangganata E., Kamath P., O'Connor D.B., Pinto M., Perrone F., Tropeano F.P., Troilo F., Bossi D., Scala D., Pulitano L., Carella M., Pietrabissa A., Gori A., Giraudo G., De Simone V., Russo A.A., Braccio B., Al-Taher R., Athamneh S., Parker A., Sawiee A., Kattia A., Tababa O., Shaeeb Z., Syminas V., Jurgaitis J., Damuleviciene G., Svagzdys S., Razafimanjato N.N.M., Chieng Loo L., Tiong I.C., Wan Muhmad W.F., Vijeyan H., Li Ying T., Grech G., Arrangoiz R., Jimenez Ley V.B., Arizpe D., Lagunes Lara E., Castro Lopez E.V., Eaazim J., Gordinou de Gouberville M., Bastiaenen V., Rottier S., Nahab F., Ji M.Y., Seyoji M., Nwachukwu C., Emeghara O., Muhammed S.E., Idowu A., Sowemimo O., Ogundoyin O., Akande O., Lott A., Nadeem M., Laghari A.A., Loya A., Mushtaq H., Abdullah M.T., Abuhilal B., Atawneh M., Hamdan H., Alhabil B., Srour A., Mousa I., Da Silva Medina L., Bartosiak K., Ferreira P., Francisco V., Lemos R., Frutuoso L., Fernandes S., Fonseca T., Pereira J., Rachadell J., Torre A., Madeira Martins F., Carvalho A.C., Rodrigues Ferreira J., Ribeiro da Silva B., Devesa H., Vieira A., Monica I., Amaro M., Sousa D., Reia M., Louro J., Martins A., Dominguez J., Santos I., Freitas Oliveira N.M., Pereira J.C., Silva-Vaz P., Freire L., Escrevente R., Negoita V.M., Shakhmatov D., Nezerwa Y., Radulovic R., Obery G., Viljoen F., Mendes T., Suarez A., Moncada E., Fernandez-Hevia M., Curtis Martinez C., Gil Garcia J.M., Gonzalez Zunzarren M., Idris T., Eklov K., Grahn O., Amin L., Blomqvist M., Ajani C., Kraus R., Seeger N., Willemin M., Rayya F., Ayash M., Msouti R., Kannas I., Abazid E., Esper A., Slim S., Kavcar A.S., Aytac E., Dural A.C., Ilker A., Eray I.C., Kurnaz E., Altiner S., Tepe M.D., Sahin C., Savli E., Innocent A., Babirye L., Diachenko A., Hordoskiy V., Curry H., Chau C.Y.C., Robertson H., Lennon H., Loi L., Kirkham E., McCann C., Watts D., Gurung B., Wilson M., Tribedi T., Garofalo E., Zahra B., MacDonald S., Daniels I., Ng N., Khosla S., Olivier J., Yue 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V., Ye, G., Zhang, G., Brooker, E., Feng, D., Lau, B., Ngai, C., Birks, S., Gyorki, D., Otero de Pablos, J., Abbosh, A., Gillespie, C., Mahmoud, A., Kwan, B., Lawson, J., Warwick, A., Bingham, J., Cockbain, A. J., Dudi-Venkata, N. N., Ellaby-Hall, J., Finlay, B., Humphries, E., Pisaniello, J., Pisaniello, M., Salih, S., Sammour, T., Abd Wahab, H. H., De Silva, A., Hayward, N., Iyer, K., Maddern, G., Prevost, G. A., Annapureddy, N., Settipalli, K. P., Yeo, J., Hempenstall, L., Pham, L., Purcell, S., Talavera, C., Vaska, A. I., Chaggar, G., Chrapko, P., Cocco, A., Coulter-Nile, S. M. C. J., Ctercteko, G., French, J., Gong, H., Gosselink, M., Jegathees, T., Jin, I., Kalachov, M., Kiefhaber, K., Lee, K., Luong, J., Phan, S., Pleass, H., Veale, K., Zeng, Z., Au, A., Debiasio, A., Deng, I., Myooran, J., Nair, A., Stewart, P., Stift, A., Unger, L. W., Wimmer, K., Ahmed, N., Hasan, S., Rahman, S., O'Shea, M., Padmore, G., Peters, A., Perduca, P., Pulcina, G., Tinton, N., Buxant, F., Dabin, E., Garofalo, G., Dossou, F., Gnangnon, F. H. R., Imorou Souaibou, Y., Motlaleselelo, P., Tlhomelang, O., Lima Buarque, I., Mendonca Ataide Gomes, G., Vieira Barros, A., Batashki, I., Damianov, N., Stoyanov, V., Dardanov, D., Maslyankov, S., Petkov, P., Todorov, G., Zhivkov, E., Akisheva, A., Castilla Moreno, M. A., Genov, G., Ilieva, I., Ivanov, T., Karamanliev, M., Khan, A., Mitkov, E., Yotsov, T., Atanasov, B., Belev, N., Slavchev, M., Nsengiyumva, C., Jones, E., Stock, S., Kyota, S., Brown, J., Mabanza, K. T., Nigo Samuel, L., Otuneme, C., Prosper, N., Umenze, F., Boutros, M., Caminsky, N., Dumitra, S., Garfinkle, R., Morency, D., Salama, E., Banks, A., Ferri, L., He, H., Katz, A., Liberman, A. 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A., Fadel, A., Habater, A., Hamdy, H., Hefni, A., Kamal, M., Mohamed Abobakr, N., Sayed, A., Shaker, N., Taha, E., Tharwat, H., Zakaria, O., Abdelmotaleb, I., Al-Dhufri, A., Al-Himyari, H. S., El sheikh, E., Eldmaty, A., Elkhalawy, A., M. Elkhashen, A., Magdy, K., Mostafa, S., Sadia, H. D., Saleh, M. M., Samir, D., Yahia Mohamed Ali, M., A. Nassar, M., Abdelhady, S., Abdelrazek, A., Abdelsalam, I., El-Sawy, A., Essam, E., Gadelkarim, M., Ghaly, K., Hassabalnaby, M., Masarani, R., Mohamed Shaaban, N., Sabry, A., Salem, M., Soliman, N. A., Zahran, D., Abou, El. soud M. R., Badr, E. T., Borham, H., Elmeslemany, N., Elsayed, M., Elsherif, F., Eslam, S., Gaber, G., Ibrahim, S., Kamh, Y., Mohamed, S. G., Morshedy, E., Omar, C., Salem Soliman, F., Abdelkawy, S., Abdelmohsen, N., Abdelshakour, M., Dahy, A., Gamal, N., Gamal, M., Hasan, A., Hetta, H., Mousa, N., Omar, M., Rabie, S., Saad, M., Saleh, B., Sayed Mohamed, M., Shawqi, M., Abdelhady Mousa, H., Alnoury, M., Elbealawy, M., Elshafey, A., Essam Ibrahim El Desouki Muhammad Ahmed, M., Ghonaim, M., Hgag, F., Ibrahim, M., Morsy, M., Reda Loaloa, M., Refaat, A., Samir, H., Shahien, F., Sobhy, M., Sroor, F., Abdellatif, E., Adel, M., Afifi, A. A., Afifi, E., Antaky, M., Dawoud, A., El Zoghby, N., El-remaily, A., Elzanfaly, A. A., Gadallah, A., Gamal, F. A., Hashem, O., Medhat Youssef, S., Muhammad Attyah, A., Munir, M., Shazly, O., Wilson, K., Adel, S., Ali, A., Eid, E., Elhelow, E., Elmahdy, M., Elshatby, B., Hossam el-din Zakaria, A., Hossny, A., Ibrahim, E., M. 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I., Veiga, D., Azevedo, J., Cardoso Louro, H., Leite, M., Bairos Menezes, M., Gama, B., Brito, D., Cruz Martins, M. C., Graca e Magalhaes, A., Longras, A. C., Lourenco, R., Matos, D., Castro, L., Policarpo, F., Romano, J., Monteiro, C., Pinto, D., Duarte, M., Fortuna Martins, S., Oliveira, M., Galvao, D., Martins, L., Silva, A., Taranu, V., Vieira, B., Neves, J., Oliveira, S., Ribeiro, H., Cinza, M., Felix, R., Machado, A., Oliveira, J., Patricio, J., Pedroso de Lima, R., Pereira, M., Rocha Melo, M., Velez, C., Abreu da Silva, A., Claro, M., Costa Santos, D., Ferreira, A., Capote, H., Rosado, D., Tare, F., Nogueira, O., Angelo, M., Baiao, J. M., Guimaraes, A., Marques, J., Nico Albano, M., Silva, M., Valente da Costa, A., Vieira Caroco, T., Almeida Braga, S., Capunge, I., Fragoso, M., Guimaraes, J., Pinto, B., Ribeiro, J., Angel, M., Fialho, G., Guerrero, M., Campos Costa, F., Cardoso, D., Cardoso, V., Alves, M., Estalagem, I., Louro, T., Marques, C., Martelo, R., Morgado, M., Canotilho, R., Correia, A. M., Martins, P., Peyroteo, M., Gomes, J., Monteiro, R., Romano, M., Alves, D. M., Peixoto, R., Quintela, C., Jervis, M. J., Melo, D., Pacheco, A., Paixao, V., Pedro, V., Pimenta, J., Pimenta de Castro, J., Rocha, A., Beuran, M., Ciubotaru, C., Diaconescu, B., Hostiuc, S., Negoi, I., Stoica, B., Na, N. A., Anokhin, E., Kuznetsov, G., Oganezov, G., Paramzin, F., Romanova, E., Rutkovskii, V., Shushval, M., Zabiyaka, M., Dzhumabaev, K., Ivanov, V., Mamedli, Z., Achkasov, S., Balkarov, A., Nabiev, E., Nagudov, M., Rybakov, E., Saifutdinova, K., Sushkov, O., Joseph, L., Ndayishimiye, I., Faustin, N., Mutabazi, A. 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Townson, Adam, Williams, Christopher Yee Khang, Gray, Timothy, Greig, Robert, Husain, Mansoor, Murray, Elspeth, Mustafa, Ahmed, Asif, Ashar, Gokul, Arya, Shah, Max, Akitikori, Mabel Temisanren, Charalabopoulos, Alexandros, Davidson, Sophie, McNally, Sinead, Rupani, Shamil, Juma, Fatema, Mills, Sarah Catherine, Muirhead, Laura, Sellars, Kate, Walsh, Una, Warren, Oliver, Chambers, Alice, Hunt, Richard, Boyce, Stephen, Cornwall, Hannah, Tol, Isabel, Argyriou, Eleftherios Orestis, Eardley, Nicola, Povey, Meical, Aithie, Joanna M S, Irfan, Ahmer, McGuigan, Mari-Claire, Starr, Robert, Warren, Craig Russell, Archibald, Jess, Kirby, Georgia, Kisyov, Ivan, Khoo, Chun Kheng, Lee, Rachel, Photiou, Dana, Davis, Rowan, Prasad, Uday, Yang, P Zichu, Bird, Jonathan, Leung, Edmund, Summerour, Virginia, Currow, Chelise, Kiam, Jianshen, Tan, Gerald Jack Soon, Muthusami, Anitha, Pegba-Otemolu, Ibifunke, Urbonas, Tomas, Nunoo-Mensah, Joseph, Smolskas, Edgaras, Boddy, Alex, Gravante, Gianpiero, Hunter, David, Andrew, David, Koh, Amanda, Thompson, Amari, Adams, Lawrence, Clements, Hollie A, De Silva, Kasun, Ekpete, Ogbonnia, Haque, Seraj, Henderson, Scott, Ibrahim, Bilal, Jayasinghe, Thummini, Livie, Jennifer, Mailley, Keir, Nair, Gopikrishnan, Tan, Daniel, Baggaley, Caitlin, Dawidziuk, Aleksander, Szyszka, Bartosz, Barter, Charlotte, Gandhi, Nirav, Hassell, Karen, Hitchin, Samantha, Kelsall, Jennett, Nagy, Eva, Nessa, Ashrafun, Whisker, Lisa, Yanni, Fady, Ali, Mahmoud, Arora, Deeksha, Hediwattege, Sunanda, Kumarasinghe, Navam, Rathore, Munir, Tennakoon, Athula, Ali Ahmad, Syed Mustafa, Bajomo, Oreoluwa, Nadira, Fahema, Celentano, Valerio, Griffiths, Ewen, Karri, Rama Santhosh, Mak, Jason Kei Chak, Pipe, Michelle, Bhatti, Muhammad Iqbal, Rabie, Mohamed, Boyle, Connor, Hamilton, David, Mihuna, Aishath, Ng, James Chean Khun, Nicholson, Gary, Oliwa, Agata, Pearson, Robert, Rose, Anna, Yong, Shun Qi, Boereboom, Catherine, Hanna, Michael, Walter, Catherine, Greensmith, Thomas Samuel, Mitchell, Rachel, Monaghan, Eimear, Crawford, James, Moug, Susan, Blackwell, James, Boyd-Carson, Hannah, Herrod, Philip, Al-Allaf, Omar, Beattie, Miriam, Bullock, Cameron, Burman, Shivang, Clark, Gemma, Flamey, Nicolas, Flannery, Oliver, Harding, Alexander, Kodiatt, Ben, Lawday, Samuel, Mahapatra, Shivani, Mukundu Nagesh, Navin, Ng, Michael, Rye, Dupinderjit, Yoong, Andrel, Clark, Laura, Deans, Chris, Edirisooriya, Monisha, Carrington, Emma Victoria, Wong, Tsz Lun Ernest, Yusuf, Baasil, Chamberlain, Carla, Duke, Kathryn, Kmiotek, Elizabeth, Botes, Azel, Condie, Natalie, Schrire, Timothy, Shah, Reena, Thomas-Jones, Iolo, Yates, Charlotte, Anthony, Natasha, Matthews, Edward, Sahnan, Kapil, Tankel, James, Tucker, Sally, Winter Beatty, Jasmine, Ziprin, Paul, Duggan, William, Kantartzi, Anastasia, Sridhar, Shruthi, Khaw, Rachel Alys, Srivastava, Prakhar, Underwood, Charlotte, Alves do Canto Brum, Homero, Chopra, Sharat, Davis, Laura, Hughes, Rebecca, Tulley, Joshua, Alberts, Justin, Athisayaraj, Thomas, Olugbemi, Mojolaoluwa, Ahmad, Kasim, Chan, Claudia, Chapman, Gavin, Fleming, Hannah, Fox, Benjamin, Grewar, Julia, Hulse, Kate, Rutherford, Duncan, Sinead, Mackay, Smith, Scott, Speake, Doug, Vaughan-Shaw, Peter G, Christodoulides, Natasha, Kudhail, Simrit, Welch, Matthew, Husaini, Syed Muhibullah, Lambracos, Simon, Anyanwu, Chikamuche, Suresh, Rishi, Thomas, Jimmy Scott, Gleeson, Elizabeth, Platoff, Rebecca, Saif, Areeba, Enumah, Zachary, Etchill, Eric, Gabre-Kidan, Alodia, Bernstein, Mitchell, Carrano, Francesco Maria, Connors, Joseph, Lynn, Patricio, Melis, Marcovalerio, Newman, Elliot, Foster, Deshka S, Perrone, Kenneth, Titan, Ashley, Ahmad, Sarwat, Bafford, Andrea Chao M D, Dal Molin, Marco, Hanna, Nader, Zafar, Syed Nabeel, Hemmila, Mark, Napolitano, Lena, Wong, Jane J, Chandler, Julia, Wood, Lauren, Wren, Sherry, Ottesen, Taylor, You, Lucia, Yu, Kristin, Arciénega Yañez, María Del Pilar, Ferreira Fernandes, Martin, González, Daniel, Cubas, Santiago, González, María Catalina, Zubiaurre, Vanessa, Demolin, Rodrigo, Giroff, Nicolas, Sciuto, Pablo, Campos, Maite, Rodríguez Cantera, Gabriela, Deepika, Garg, Simuchimba, Elliot, Bulaya, Anadi, Chibuye, Chali, Chirengendure, Bright, Kabale, Mary-Rose, Kabongo, Kizito, Munthali, James, Mweso, Oliver, Pikiti, Francis, Otieno, James, Lai, Log Tung, Blackman, Brighid, Richards, Sophie, Subramaniam, Suren, Karim, Rafid, Kok, Nathan, Lee, Yanni Dion, Ali, Shabina, Sinha, Aanjaneya, Corrigan, Robert, Barnes, Nicole, Wong, Florence, Dennis, Grace, Jedamzik, Julia, Phillips, Emil, Piette, Wivine, Van Hentenryck, Marie, Koco, Houenoukpo, Lawani, Souliath, Kassa, Mamo Woldu, Santos Bezerra, Tainá, Gribnev, Petar, Dimitrov, Dobromir, Krastev, Panche, Oum, Sovannarith, Bonghaseh, Divine Tim, Al Farsi, Maryam, Alsharqawi, Nourah, Acevedo, Veronica, Castillo Barbosa, Andrea Carolina, Giron, Felipe, Leon Rodriguez, Jimmy Paul, Kucan, Darko, Rosko, Damir, Barsic, Neven, Župan, Domagoj, Hegazi, Amgad, Truncíková, Vendula, Fryba, Vladimir, Mohamed, Mostafa, Sultan, Ahmed, Nagi, Ahmed, Rashad Temerik, Abdallah, Elshawy, Mohamed Elemam, Mahmoud, Moustafa Ibrahim, Omar, Shrouk, Anwar, Mohamed, Rageh, Tarek, Elmokadem, Aya, Gaballa, Khaled, Teppo, Sandra, Turunen, Antti, Pengermä, Pasi, Ballouhey, Quentin, Bergeat, Damien, Weyl, Ariane, Hain, Elisabeth, Gyedu, Adam, Yenli, Edwin, Osei-Poku, Dorcas, Rompou, Vaia-Aliki, Zoikas, Athanasios, Gaitanidis, Apostolos, Koukis, Georgios, Perivoliotis, Konstantinos, Tavlas, Panagiotis, Galanos-Demiris, Konstantinos, Zografos, George, Karavokyros, Ioannis, Xanthopoulou, Georgia, Iordanidou, Eirini, Ayau, Fernanda, Garcia, Allan, Damján, Pekli, Wason, Deepender, B L, Ashika, Rangganata, Ervandy, Kamath, Prerna, O'Connor, Donal B, Pinto, Margherita, Perrone, Fabrizio, Tropeano, Francesca Paola, Troilo, Francesca, Bossi, Daniela, Scala, Dario, Pulitanò, Lucrezia, Carella, Marcella, Pietrabissa, Andrea, Gori, Alice, Giraudo, Giorgio, De Simone, Veronica, Russo, Alfio Alessandro, Braccio, Bartolomeo, Al-Taher, Raed, Athamneh, Sarah, Parker, Andrea, Sawiee, Adnan, Kattia, Amina, Salem, Malik, Tababa, Osama, Shaeeb, Zuhour, Syminas, Vilius, Jurgaitis, Jonas, Damuleviciene, Gyte, Svagzdys, Saulius, Poskus, Tomas, Razafimanjato, Narindra Njarasoa Mihaja, Chieng Loo, Ling, Tiong, Ing Ching, Wan Muhmad, Wan Farahiyah, Vijeyan, Harinthiran, Li Ying, Teoh, Grech, Gabriella, Arrangoiz, Rodrigo, Jimenez Ley, Vania Brickelia, Arizpe, Daniel, Lagunes Lara, Elizabeth, Castro López, Elizabeth Victoria, Eaazim, Jose, Gordinou de Gouberville, Marije, Bastiaenen, Vivian, Rottier, Simone, Nahab, Fouad, Ji, Maria Yeonhee, Seyoji, Mohammed, Nwachukwu, Callistus, Emeghara, Okechukwu, Muhammed, Sayyid Egbunu, Idowu, Ayodeji, Sowemimo, Olamiposi, Ogundoyin, Olakayode, Akande, Oluwatosin, Lott, Alexander, Nadeem, Maliha, Laghari, Ahsan Ali, Loya, Asif, Mushtaq, Hassan, Abdullah, Muhammad Tariq, Abuhilal, Baseel, Atawneh, Mohammad, Hamdan, Hamdan, Alhabil, Belal, Srour, Abedelrahman, Mousa, Ibrahim, Da Silva Medina, Luis, Bartosiak, Katarzyna, Ferreira, Pedro, Francisco, Vítor, Lemos, Ricardo, Frutuoso, Luísa, Fernandes, Sara, Fonseca, Telma, Pereira, Jorge, Rachadell, Juan, Torre, Ana, Madeira Martins, Filipe, Carvalho, Ana Cristina, Rodrigues Ferreira, Joana, Ribeiro da Silva, Bruno, Devesa, Helena, Vieira, Ana, Mónica, Inês, Amaro, Margarida, Sousa, Diogo, Reia, Marta, Louro, João, Martins, Ana, Dominguez, Joaquina, Santos, Inês, Freitas Oliveira, Nuno Miguel, Pereira, José Carlos, Silva-Vaz, Pedro, Freire, Ligia, Escrevente, Ricardo, Negoita, Valentina Madalina, Shakhmatov, Dmitry, Nezerwa, Yves, Radulovic, Radosav, Obery, Gareth, Viljoen, Francois, Mendes, Tome, Suarez, Antonio, Moncada, Enrique, Fernandez-Hevia, Maria, Curtis Martínez, Carolina, Gil Garcia, Julia Maria, González Zunzarren, Mariana, Idris, Tarig, Eklöv, Karolina, Grahn, Oskar, Amin, Leila, Blomqvist, Malin, Ajani, Costanza, Kraus, Rebecca, Seeger, Nico, Willemin, Melissa, Rayya, Fadi, Ayash, Mohammad, Msouti, Raneem, Kannas, Israa, Abazid, Eias, Esper, Asil, Slim, Skander, Kavcar, Akil Serdar, Aytac, Erman, Dural, Ahmet Cem, Ilker, Ayse, Eray, Ismail Cem, Kurnaz, Eray, Altiner, Saygin, Tepe, Mustafa Deniz, Sahin, Can, Savli, Evrim, Innocent, Aryon, Babirye, Lilian, Diachenko, Andrii, Hordoskiy, Vladislav, Curry, Heather, Chau, Charlene Yat Che, Robertson, Harry, Mahmoud, Arin, Lennon, Hannah, Loi, Lynette, Kirkham, Emily, McCann, Cameron, Watts, Daniel, Gurung, Binay, Wilson, Michael, Tribedi, Thomas, Garofalo, Eleonora, Zahra, Baryab, MacDonald, Scott, Daniels, Ian, Ng, Nathan, Khosla, Shivun, Olivier, James, Yue, Sum Yu Pansy, Suresh, Gayathri, Wellington, Jack, Lorejo, Emmanuel, Mossaad, Mafdi, Crutcher, Madison, Alimi, Marjan, Baiu, Ioana, Abdou, Hossam, Conway, Alison, Peck, Connor, Perdomo Perez, Mauro Andres, Zulu, Stanley, Nakazwe, Mildred, Burger, Sule, Davies, Justine, Donaldson, Rachel, Ede, Chikwendu, Garden, O James, Lesetedi, Chiapo, Mabedi, Charles, Magill, Laura, Makinde Alakaloko, Felix, Makupe, Alex, Monahan, Mark, Mulira, Soloman, Muller, Elmi, Musowoyo, Jospeh, Olory-Togbe, Jean Léon, Roberts, Tracey, Smith, Martin, Tayler, Viki, Windsor, John, Yepez, Raul, Sundar, Sudha, Runigamugabo, Emmy, Verjee, Azmina, Chen, José, Daya, Leonid, El Aroussi, Nouhaila, Farina, Valeria, Gnintedeme Olivier, Tchianze, Gonzales Nacarino, Mauricio, Hammani, Aamr, Honjo, Sarah, Jacobs, Rebecca, Kimura, Hitomi, Nkoronko, Mugisha, Oscullo Yepez, Jasson Javier, Pin Hung, Wei, Raj, Ankit, Romani Pozo, Alina, Rommaneh, Muna, Sassamela Fabiano, Samuel Chimbioputo, Shiroma Gago, Camila Milagros, Srinivas, Abhishekh, Sung, Chia-Yen, Tai, Aswan, Valle Aranda, Yener Cristyell, Venturini, Sara, and Wilguens Lartigue, Jean
Subjects: Pediatrics, Colorectal cancer, IMPACT, Disease, Colorectal Neoplasm, 030204 cardiovascular system & hematology, Cancer, surgery, postoperative mortality, 0302 clinical medicine, Postoperative Complications, Global health, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, General Medicine, DISEASES, Income, cancer surgery, Colorectal Neoplasms, Breast Neoplasm, Cohort study, Human, Adult, Developed Countrie, medicine.medical_specialty, Global surgery, General surgery, International multicentre study, Cancer surgery, Breast Neoplasms, Department of Error, NO, Developing Countrie, 03 medical and health sciences, Breast cancer, Stomach Neoplasms, medicine, Humans, Developing Countries, Neoplasm Staging, business.industry, Developed Countries, Odds ratio, CARE, medicine.disease, 3126 Surgery, anesthesiology, intensive care, radiology, Prospective Studie, Postoperative Complication, business
Abstract: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Background: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods: This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Findings: Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation: Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding: National Institute for Health Research Global Health Research Unit.
Published: 2021
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12. High mean arterial pressure target to improve sepsis-associated acute kidney injury in patients with prior hypertension: a feasibility study

Author: Alexandre Ouattara, Jean Ripoche, Sébastien Rubin, Gauthier Bouche, Antoine Dewitte, Gilles Hilbert, Aurore Labat, Pierre-Antoine Duvignaud, Christian Combe, Didier Gruson, Alexandre Boyer, Olivier Joannes-Boyau, Immunology from Concept and Experiments to Translation (ImmunoConcept), Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), CHU Bordeaux [Bordeaux], Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Bioingénierie tissulaire (BIOTIS), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)
Subjects: medicine.medical_specialty, Mean arterial pressure, Fractional excretion of sodium, Urology, Renal function, 030204 cardiovascular system & hematology, Critical Care and Intensive Care Medicine, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Urine sodium, Norepinephrine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Septic shock, Intensive care, medicine, 10. No inequality, Creatinine, RC86-88.9, business.industry, Research, Acute kidney injury, Medical emergencies. Critical care. Intensive care. First aid, 030208 emergency & critical care medicine, medicine.disease, chemistry, Blood pressure, Urine osmolality, Kidney concentrating ability, business
Abstract: Background The optimal mean arterial pressure (MAP) in cases of septic shock is still a matter of debate in patients with prior hypertension. An MAP between 75 and 85 mmHg can improve glomerular filtration rate (GFR) but its effect on tubular function is unknown. We assessed the effects of high MAP level on glomerular and tubular renal function in two intensive care units of a teaching hospital. Inclusion criteria were patients with a history of chronic hypertension and developing AKI in the first 24 h of septic shock. Data were collected during two 6 h periods of MAP regimen administered consecutively after haemodynamic stabilisation in an order depending on the patient's admission unit: a high-target period (80–85 mmHg) and a low-target period (65–70 mmHg). The primary endpoint was the creatinine clearance (CrCl) calculated from urine and serum samples at the end of each MAP period by the UV/P formula. Results 26 patients were included. Higher urine output (+0.2 (95%:0, 0.4) mL/kg/h; P = 0.04), urine sodium (+6 (95% CI 0.2, 13) mmol/L; P = 0.04) and lower serum creatinine (− 10 (95% CI − 17, − 3) µmol/L; P = 0.03) were observed during the high-MAP period as compared to the low-MAP period, resulting in a higher CrCl (+25 (95% CI 11, 39) mL/mn; P = 0.002). The urine creatinine, urine–plasma creatinine ratio, urine osmolality, fractional excretion of sodium and urea showed no significant variation. The KDIGO stage at inclusion only interacted with serum creatinine variation and low level of sodium excretion at inclusion did not interact with these results. Conclusions In the early stage of sepsis-associated AKI, a high-MAP target in patients with a history of hypertension was associated with a higher CrCl, but did not affect the kidneys' ability to concentrate urine, which may reflect no effect on tubular function.
Published: 2021
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13. Illness perceptions as an independent predictor of chronic low back pain and pain-related disability: a prospective cohort study

Author: Emiel van Trijffel, Martijn S Stenneberg, Ronald W Kan, Michiel F. Reneman, Joannes M. Hallegraeff, Extremities Pain and Disability (EXPAND), Physiotherapy, Human Physiology and Anatomy, and Experimental Anatomy
Subjects: 030506 rehabilitation, medicine.medical_specialty, Psychological intervention, Physical Therapy, Sports Therapy and Rehabilitation, Illness perceptions, Disability Evaluation, 03 medical and health sciences, 0302 clinical medicine, Humans, Medicine, Disabled Persons, Prospective Studies, 030212 general & internal medicine, Prospective cohort study, physiotherapy, risk, Referred pain, business.industry, Chronic pain, Infant, Prognosis, medicine.disease, Low back pain, Chronic low back pain, Child, Preschool, Physical therapy, Perception, Chronic Pain, medicine.symptom, 0305 other medical science, business, Low Back Pain, Cohort study
Abstract: OBJECTIVES: To investigate whether illness perceptions, measured with the Brief Illness Perception Questionnaire, are an independent predictor of chronic low back pain and pain-related disability at 12 weeks.DESIGN: A prospective, observational cohort study.SETTING: 26 outpatient primary care physiotherapy practices throughout the Netherlands.PARTICIPANTS: Acute nonspecific low back pain patients between the age of 18 and 60 years, with or without radiating pain, and a pain-free episode of at least three months before onset.INTERVENTIONS: Standard physiotherapy care according to Dutch clinical practice guidelines.OUTCOME MEASURE: Chronic low back pain defined as pain ≥3/10 on the Numeric Pain Rating Scale and as pain-related disability ≥19/70 on the Pain Disability Index measured after 12 weeks.RESULTS: Two hundred and four people with acute nonspecific low back pain completed both assessments. In the multivariable analyses, adjusted for pain intensity, disability, duration, radiating pain, depressed mood, associations of illness perceptions were OR 1.04 (95% CI: 1.01 to 1.08) for pain and 1.04 (95% CI: 0.99 to 1.09) for pain-related disability.CONCLUSIONS: Illness perceptions independently predicted chronic low back pain but not pain-related disability at 12 weeks. The added predictive value of illness perceptions was relatively low.
Published: 2021

14. Broad Bands Observed in Serum Electrophoresis Should Not Be Taken Lightly

Author: Laurens Nieuwenhuizen, Matthieu C J Bosman, Dirk L Bakkeren, Rachel H P Schreurs, and Joannes F M Jacobs
Subjects: 0301 basic medicine, Antiserum, biology, medicine.diagnostic_test, Chemistry, Myeloma protein, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], Biochemistry (medical), Clinical Biochemistry, 030204 cardiovascular system & hematology, Immunoglobulin light chain, medicine.disease, Molecular biology, Hemolysis, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Polyclonal antibodies, Serum protein electrophoresis, biology.protein, medicine, Hemoglobin, Densitometry
Abstract: A 78-year-old woman was referred to our hospital for further investigation of a bicytopenia. She had a history of rheumatoid arthritis and Sjogren syndrome for which she was treated with methotrexate and etanercept. She had no complaints, and during physical examination, no lymphadenopathy, masses, or visceromegaly was found. Hematologic evaluation showed the following results: hemoglobin, 9.7 g/dL (reference, 12.1–16.1 g/dL); white blood cells, 1.6 × 109/L (reference, 4.0–10.0 × 109/L); and thrombocytes, 156 × 109/L (reference 150–400 × 109/L). A peripheral blood smear did not show blasts or dysplastic features of the white blood cells. The patient had normal ferritin, vitamin B12, and folic acid concentrations without evidence of hemolysis. Serum protein electrophoresis (SPE)4 and immunofixation electrophoresis (IFE) with pentavalent antiserum were performed as M-protein screening. Both techniques demonstrated a broad band in the β/γ region (Fig. 1A). Further IFE analysis, shown in Fig. 1B, identified the abnormal pattern as a broad IgG band (blue brackets) with no corresponding light chain band (red brackets). These data suggested the presence of an IgG heavy chain M protein (γ-HC). Capillary electrophoresis (CE) combined with immunosubtraction (IS) analysis (Fig. 1C) confirmed that the abnormal pattern was caused by a γ-HC. IgG-IS (Fig. 1D) illustrated that the γ region consisted of polyclonal IgG-κ and IgG-λ (green). The β2 region largely consisted of IgG not associated with light chains (γ-HC, represented in red), and the remaining fraction (blue) was a combination of polyclonal IgA, polyclonal IgG, and nonimmunoglobulins. Fig. 1. Laboratory findings associated with γ-HC. (A), SPE and the corresponding densitometry scan show an abnormal broad band bridging the β/γ region. The same abnormal dense region is observed in the pentavalent screen. (B), IFE analysis demonstrates that the abnormal dense region corresponds to IgG (blue brackets) and has no …
Published: 2019
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15. Clonotypic Features of Rearranged Immunoglobulin Genes Yield Personalized Biomarkers for Minimal Residual Disease Monitoring in Multiple Myeloma

Author: Joannes F M Jacobs, Pieter Langerhorst, Martijn M. VanDuijn, Alain J. van Gool, Arie B. Brinkman, Jolein Gloerich, Hans J. C. T. Wessels, Irma Joosten, Patricia J. T. A. Groenen, Blanca Scheijen, and Neurology
Subjects: 0301 basic medicine, Immunoglobulin gene, Neoplasm, Residual, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], Clinical Biochemistry, Population, Computational biology, Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], Plasma cell, Biology, Flow cytometry, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, education, Multiple myeloma, education.field_of_study, Genes, Immunoglobulin, medicine.diagnostic_test, Biochemistry (medical), Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], medicine.disease, Minimal residual disease, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Disease Progression, biology.protein, Antibody, Multiple Myeloma, Peptides, Clone (B-cell biology), Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5], Biomarkers
Abstract: Background Due to improved treatment, more patients with multiple myeloma (MM) reach a state of minimal residual disease (MRD). Different strategies for MM MRD monitoring include flow cytometry, allele-specific oligonucleotide–quantitative PCR, next-generation sequencing, and mass spectrometry (MS). The last 3 methods rely on the presence and the stability of a unique immunoglobulin fingerprint derived from the clonal plasma cell population. For MS-MRD monitoring it is imperative that MS-compatible clonotypic M-protein peptides are identified. To support implementation of molecular MRD techniques, we studied the presence and stability of these clonotypic features in the CoMMpass database. Methods An analysis pipeline based on MiXCR and HIGH-VQUEST was constructed to identify clonal molecular fingerprints and their clonotypic peptides based on transcriptomic datasets. To determine the stability of the clonal fingerprints, we compared the clonal fingerprints during disease progression for each patient. Results The analysis pipeline to establish the clonal fingerprint and MS-suitable clonotypic peptides was successfully validated in MM cell lines. In a cohort of 609 patients with MM, we demonstrated that the most abundant clone harbored a unique clonal molecular fingerprint and that multiple unique clonotypic peptides compatible with MS measurements could be identified for all patients. Furthermore, the clonal immunoglobulin gene fingerprints of both the light and heavy chain remained stable during MM disease progression. Conclusions Our data support the use of the clonal immunoglobulin gene fingerprints in patients with MM as a suitable MRD target for MS-MRD analyses.
Published: 2021

16. The use of host cell DNA methylation analysis in the detection and management of women with advanced cervical intraepithelial neoplasia: A review

Author: Christophorus Joannes Lambertus Maria Meijer, Renske D.M. Steenbergen, Wieke W. Kremer, Daniëlle A M Heideman, and Gemma G. Kenter
Subjects: Oncology, Carcinogenesis, cervical cancer screening, Uterine Cervical Neoplasms, Cervix Uteri, Review Article, medicine.disease_cause, Screening programme, 0302 clinical medicine, Obstetrics and gynaecology, Methylation analysis, human papillomavirus, Papillomaviridae, Early Detection of Cancer, Colposcopy, Cervical cancer, education.field_of_study, 030219 obstetrics & reproductive medicine, Cervical screening, DNA methylation, medicine.diagnostic_test, HPV infection, Obstetrics and Gynecology, General Medicine, Methylation, Middle Aged, female genital diseases and pregnancy complications, Genetic Techniques, Female, Misoprostol, Adult, medicine.medical_specialty, Population, Reviews, cervical intraepithelial neoplasia, Cervical intraepithelial neoplasia, 03 medical and health sciences, Internal medicine, Uterine Myomectomy, medicine, Humans, education, business.industry, Papillomavirus Infections, medicine.disease, Uterine Cervical Dysplasia, DNA, Viral, Triage, business
Abstract: This paper briefly reviews the role of hypermethylation of host cell genes in cervical carcinogenesis and discusses potential clinical applications of methylation analysis in the management of high‐risk HPV (hrHPV) ‐positive women. We argue that methylation assays can be used: 1. for primary triage of hrHPV‐positive women to detect cervical cancer and advanced cervical intraepithelial neoplasia (CIN); 2. as secondary triage for women with minor cytological abnormalities to identify those with the highest risk of CIN3 or worse; 3. as exit test for women leaving the screening programme to identify cervical cancer and advanced CIN; and 4. to support management of CIN. Tweetable abstract This paper discusses potential clinical applications of DNA methylation analysis in the management of women with a high‐risk HPV infection., Tweetable abstract This paper discusses potential clinical applications of DNA methylation analysis in the management of women with a high‐risk HPV infection.
Published: 2021
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17. Research trends in gestational diabetes mellitus in Southeast Asia: A bibliometric analysis (1975-2020)

Author: Mary Nadine Alessandra R. Uy, Inah Marie C. Aquino, Joanne Jennifer E. Tan, Elizabeth P. Pacheco, Joannes Luke B. Asis, and Ourlad Alzeus G. Tantengco
Subjects: Bibliometric analysis, business.industry, Endocrinology, Diabetes and Metabolism, Psychological intervention, Scopus, General Medicine, Bibliometrics, medicine.disease, Databases, Bibliographic, Southeast asia, Gestational diabetes, Diabetes, Gestational, Citation analysis, Pregnancy, Environmental health, Internal Medicine, Medicine, Humans, Female, business, Productivity, Asia, Southeastern
Abstract: Aims To determine the characteristics and trends of published articles in the field of gestational diabetes mellitus (GDM) in Southeast Asia (SEA) through a bibliometric analysis. Methods Systematic review of literature on GDM in SEA countries was performed using the Ovid MEDLINE®, Scopus, and WPRIM databases between 1975 and 2020. All published studies on GDM conducted in or published by authors from any SEA country were included in our analysis. Bibliometric information was obtained from Scopus and bibliometrics diagrams were created using VOSviewer software. Results A total of 322 articles were obtained in this study. The number of publications showed an upward trend starting 2011. The country with the greatest number of publications was Malaysia while The National University of Singapore was the most productive institution in GDM research in SEA. The focus of GDM research in SEA were on the prevalence, prevention, diagnosis, and pregnancy outcomes. GDP, research expenditure, and researchers per million people were positively correlated with research productivity and impact in GDM research in SEA. Conclusions This is the first bibliometric analysis on GDM in SEA countries. GDM research in SEA continued to increase in the past years but still lagged behind that of other regions. The SEA countries should consider increasing support for research to produce substantial research that can serve as basis for evidence-based and locally applicable GDM interventions.
Published: 2021

18. Identification of Paired-related Homeobox Protein 1 as a key mesenchymal transcription factor in Idiopathic Pulmonary Fibrosis

Author: Bernard Mari, L. Deneuville, Mada Ghanem, Hervé Mal, E. Fortas, Antoine Froidure, A. Vadel, K. Schirduan, Bruno Crestani, Pierre Mordant, A. Joannes, Arnaud Mailleux, A. Maurac, Madeleine Jaillet, Meline Homps-Legrand, Emmeline Marchal-Duval, L. Giersch, Martina Korfei, Andreas Günther, Aurélien Justet, C.M. Mounier, Aurélie Cazes, and F. Jaschinski
Subjects: biology, medicine.medical_treatment, respiratory system, medicine.disease, Bleomycin, respiratory tract diseases, Idiopathic pulmonary fibrosis, chemistry.chemical_compound, Cytokine, Downregulation and upregulation, chemistry, Fibrosis, medicine, biology.protein, Cancer research, Homeobox, Transcription factor, Platelet-derived growth factor receptor
Abstract: Matrix remodeling is a salient feature of idiopathic pulmonary fibrosis (IPF). Targeting cells driving matrix production and remodeling could be a promising avenue for IPF treatment. Analysis of public transcriptomic database identified paired-related homeobox protein-1 (PRRX1) as an upregulated mesenchymal transcription factor (TF) in IPF. We confirmed that PRRX1 isoforms were upregulated in IPF lung tissue and strongly expressed by lung fibroblasts. In vitro, PRRX1 expression was up-regulated by cues associated with proliferative and anti-fibrotic properties in lung fibroblasts, while IPF fibroblast-derived matrix increased PRRX1 TFs expression in a PDGFR dependent manner in control ones. Meanwhile, signals promoting myofibroblastic differentiation decreased PRRX1 TF. We demonstrated that PRRX1 inhibition decreased fibroblast proliferation by downregulating the expression of S phase cyclins. PRRX1 inhibition also impacted TGF-{beta} driven myofibroblastic differentiation by inhibiting SMAD2/3 phosphorylation through phosphatase PPM1A upregulation and TGFBR2 downregulation, leading to a TGF-{beta} response global decrease. Finally, targeted inhibition of Prrx1 TFs attenuated fibrotic remodeling both in vivo with intra-tracheal antisense oligonucleotides in the bleomycin mice model of lung fibrosis and ex vivo using mouse and Human precision-cut lung slices stimulated with fibrosis cytokine cocktail. Altogether, our results identified PRRX1 as a mesenchymal transcription factor driving myofibroblastic phenotype and lung fibrogenesis. Brief SummaryInhibition of a single fibroblast-associated transcription factor, namely paired-related homeobox protein 1, is sufficient to dampen lung fibrogenesis.
Published: 2021
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19. Referring patients with chronic kidney disease back to primary care: a criteria-based analysis in outpatient renal clinics

Author: Marcus Antonius Gerard Jan ten Dam, Marcus Matheus Hendrik Hermans, Jacobus Franciscus Maria Wetzels, Davy Gerda Hermina Antoin van Dam, Carola van Dipten, Wilhelmus Joannes Carolus de Grauw, Nynke Scherpbier-de Haan, and Willem Jan Jozef Assendelft
Subjects: Nephrology, Retrospective cohort study, Adult, Male, medicine.medical_specialty, Referral, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Ambulatory Care Facilities, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], Patient satisfaction, All institutes and research themes of the Radboud University Medical Center, Risk Factors, Internal medicine, Chronic kidney disease, medicine, Outpatient clinic, Back referral, Humans, Renal Insufficiency, Chronic, Referral and Consultation, Aged, Retrospective Studies, Aged, 80 and over, Shared care, Primary Health Care, business.industry, Research, Middle Aged, medicine.disease, Primary care, Comorbidity, Diseases of the genitourinary system. Urology, Emergency medicine, Female, RC870-923, Renal disorders Radboud Institute for Health Sciences [Radboudumc 11], business, Kidney disease, Glomerular Filtration Rate
Abstract: Background The increased demand for nephrology care for patients with chronic kidney disease (CKD) necessitates a critical review of the need for secondary care facilities and the possibilities for referral back to primary care. This study aimed to evaluate the characteristics and numbers of patients who could potentially be referred back to primary care, using predefined criteria developed by nephrologists and general practitioners. Method We organised a consensus meeting with eight nephrologists and two general practitioners to define the back referral (BR) criteria, and performed a retrospective cohort study reviewing records from patients under nephrologist care in three hospitals. Results We reached a consensus about the BR criteria. Overall, 78 of the 300 patients (26%) in the outpatient clinics met the BR criteria. The characteristics of the patients who met the BR criteria were: 56.4% male, a median age of 70, an average of 3.0 outpatients visits per year, and a mean estimated glomerular filtration rate of 46 ml/min/1,73m2. Hypertension was present in 67.9% of this group, while 27.3% had diabetes and 16.9% had cancer. The patients who could be referred back represented all CKD stages except stage G5. The most common stage (16%) was G3bA2 (eGFR 30 ≤ 44 and ACR 3 ≤ 30). Conclusion A substantial proportion of patients were eligible for referral back to primary care. These patients often have a comorbidity, such as hypertension or diabetes. Future research should focus on generalisability of the BR criteria, the feasibility of actual implementation of the back referral, follow-up assessments of renal function and patient satisfaction.
Published: 2021

20. The Treatment Gap in Osteoporosis

Author: Nazia Ayub, Malak Faraj, Sam Ghatan, Nicola Napoli, Joannes A. A. Reijers, and Ling Oei
Subjects: 0301 basic medicine, medicine.medical_specialty, Bone disease, Osteoporosis, Romosozumab, review, 030209 endocrinology & metabolism, 03 medical and health sciences, 0302 clinical medicine, pharmacological treatment, Teriparatide, Medicine, Raloxifene, Intensive care medicine, Bone mineral, treatment gap, business.industry, General Medicine, medicine.disease, osteoporosis, 030104 developmental biology, Denosumab, fracture, glucocorticoid, epidemiology, business, Osteonecrosis of the jaw, medicine.drug
Abstract: Worldwide, there are millions of people who have been diagnosed with osteoporosis, a bone disease that increases the risk of fracture due to low bone mineral density and deterioration of bone architecture. In the US alone, there are approximately ten million men and women diagnosed with osteoporosis and this number is still growing. Diagnosis is made by measuring bone mineral density. Medications used for the treatment of osteoporosis are bisphosphonates, denosumab, raloxifene, and teriparatide. Recently, romosozumab has been added as well. In recent years, a number of advances have been made in the field of diagnostic methods and the diverse treatment options for osteoporosis. Despite these advances and a growing incidence of osteoporosis, there is a large group being left undertreated or even untreated. This group of the under/untreated has been called the treatment gap. Concerns regarding rare side effects of the medications, such as osteonecrosis of the jaw, have been reported to be one of the many causes for the treatment gap. Also, this group seems not to be sufficiently informed of the major benefits of the treatment and the diversity in treatment options. Knowledge of these could be very helpful in improving compliance and hopefully reducing the gap. In this paper, we summarize recent evidence regarding the efficacy of the various treatment options, potential side effects, and the overall benefit of treatment.
Published: 2021
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21. Hypophosphatemia in critically ill adults and children - A systematic review

Author: Carole Ichai, Olivier Joannes-Boyau, Angelique de Man, Sonja Fruhwald, Jan Gunst, Stéphane Dauger, Mette M. Berger, Annika Reintam Blaser, Maria Helena Perez, Kadri Tamme, Carina Benstoem, Michael P Casaer, Jan Wernerman, Stefan J. Schaller, Joel Starkopf, Manu L N G Malbrain, Guillaume Besch, Michael Hiesmayr, ACS - Diabetes & metabolism, Intensive care medicine, ACS - Atherosclerosis & ischemic syndromes, Supporting clinical sciences, and Intensive Care
Subjects: 0301 basic medicine, Adult, medicine.medical_specialty, Hypophosphatemia, Critical Illness, MEDLINE, 030209 endocrinology & metabolism, Phosphate, CINAHL, Critical Care and Intensive Care Medicine, law.invention, Refeeding syndrome, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Intensive care, medicine, Prevalence, Humans, Intensive care medicine, Child, Outcome, 030109 nutrition & dietetics, Nutrition and Dietetics, business.industry, Retrospective cohort study, medicine.disease, Clinical research, outcome, Observational study, business, Critical illness
Abstract: BACKGROUND & AIMS: Phosphate is the main intracellular anion essential for numerous biological processes. Symptoms of hypophosphatemia are non-specific, yet potentially life-threatening. This systematic review process was initiated to gain a global insight into hypophosphatemia, associated morbidity and treatments. METHODS: A systematic review was conducted (PROSPERO CRD42020163191). Nine clinically relevant questions were generated, seven for adult and two for pediatric critically ill patients, and prevalence of hypophosphatemia was assessed in both groups. We identified trials through systematic searches of Medline, EMBASE, Scopus, Cochrane Central Register of Controlled Trials, CINAHL, and Web of Science. Quality assessment was performed using the Cochrane risk of bias tool for randomized controlled trials and the Newcastle-Ottawa Scale for observational studies. RESULTS: For all research questions, we identified 2727 titles in total, assessed 399 full texts, and retained 82 full texts for evidence synthesis, with 20 of them identified for several research questions. Only 3 randomized controlled trials were identified with two of them published only in abstract form, as well as 28 prospective and 31 retrospective studies, and 20 case reports. Relevant risk of bias regarding selection and comparability was identified for most of the studies. No meta-analysis could be performed. The prevalence of hypophosphatemia varied substantially in critically ill adults and children, but no study assessed consecutive admissions to intensive care. In both critically ill adults and children, several studies report that hypophosphatemia is associated with worse outcome (prolonged length of stay and the need for respiratory support, and higher mortality). However, there was insufficient evidence regarding the optimal threshold upon which hypophosphatemia becomes critical and requires treatment. We found no studies regarding the optimal frequency of phosphate measurements, and regarding the time window to correct hypophosphatemia. In adults, nutrient restriction on top of phosphate repletion in patients with refeeding syndrome may improve survival, although evidence is weak. CONCLUSIONS: Evidence on the definition, outcome and treatment of clinically relevant hypophosphatemia in critically ill adults and children is scarce and does not allow answering clinically relevant questions. High quality clinical research is crucial for the development of respective guidelines. ispartof: CLINICAL NUTRITION vol:40 issue:4 pages:1744-1754 ispartof: location:England status: published
Published: 2020
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22. Prevalence and risk factors for low back pain during pregnancy among women in Abakaliki, Nigeria

Author: Njoku Isaac Omoke, Love Chimezirim Okafor, Peace Ifeoma Amaraegbulam, and Odidika Ugochukwu Joannes Umeora
Subjects: Adult, medicine.medical_specialty, pregnancy women, Adolescent, Nigeria, Third trimester, Logistic regression, Young Adult, Pregnancy, Risk Factors, Surveys and Questionnaires, Prevalence, Medicine, Humans, Labour ward, Multivariable regression analysis, business.industry, Obstetrics, Previous pregnancy, Research, Postpartum Period, General Medicine, Middle Aged, medicine.disease, Low back pain, Pregnancy Complications, Cross-Sectional Studies, Female, University teaching, medicine.symptom, business, Low Back Pain
Abstract: Introduction low back pain (LBP) during pregnancy is an important health concern among women globally. The prevalence and risk factors for LBP in pregnancy vary from and within sub-regions and have implications in preventive and treatment strategies. In West African sub-region, there is scanty data on LBP during pregnancy. This study aimed to determine the prevalence and predisposing factors for LBP during pregnancy in this environment. Methods this was a cross-sectional study carried out among pregnant women admitted into the Labour Ward of Alex Ekwueme Federal University Teaching Hospital, Abakaliki, Nigeria over a period of 8 months. They were interviewed within 2 to 7 days postpartum with a questionnaire. Sociodemographic and obstetrics characteristics as well as LBP intensity, features and associated factors were evaluated. Significant factors for LBP that emerged from the univariable analysis were entered into multivariable regression analysis to evaluate the risk of each factor when adjusted to other factors. Results of the 478 women interviewed, 138 (28.9%) of them (95% CI 25.1-33.1) reported LBP in the index pregnancy. The onset of pain was predominantly in the third trimester and the mean pain intensity was 4.3 ± 1.36. In the univariable analysis, six factors were significantly associated with LBP. Logistic regression analysis identified LBP in previous pregnancy (aOR: 24.76, (95% CI 6.88-89.11); p< 0.001), macrosomia (aOR: 4.15(95% CI 2.05-8.42); p< 0.001) and absence of domestic help (aOR: 0.50(95% CI 0.31-0.82); p=0.006) as independent risk factors for LBP during pregnancy among the women. Conclusion in this study, LBP during pregnancy is within worldwide range and predominantly mild to moderate in intensity. The independent risk factors identified call for high priorities accorded to women with these factors in measures aimed at addressing LBP during pregnancy.
Published: 2020

23. Real-world experience with caplacizumab in the management of acute TTP

Author: Jun Yong, Hamish Lyall, Oliver Tomkins, Rebecca J Shaw, Louise Humphrey, Tina Dutt, Phillip L R Nicolson, William Thomas, Rachel Rayment, Matthew J Stubbs, Alexandros Rampotas, Gillian C. Lowe, Michael J R Desborough, Quentin A. Hill, Richard Gooding, Toby A. Eyre, Joost J. van Veen, John R. Grainger, Joanna Haughton, Maeve P. Crowley, Susan Rhodes, John Hanley, Cheng Hock Toh, Alice Taylor, Benjamin Bailiff, Muhammad Mohsin, Steven Lane, Nicole Priddee, Tanya Cranfield, Marie Scully, and Joannes Hermans
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, medicine.medical_treatment, Immunology, Thrombotic thrombocytopenic purpura, 030204 cardiovascular system & hematology, Biochemistry, law.invention, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Randomized controlled trial, Fibrinolytic Agents, law, Internal medicine, von Willebrand Factor, medicine, Intubation, media_common.cataloged_instance, Humans, European union, Young adult, Child, media_common, Aged, Aged, 80 and over, Purpura, Thrombotic Thrombocytopenic, business.industry, Disease Management, Cell Biology, Hematology, Middle Aged, Single-Domain Antibodies, medicine.disease, United Kingdom, Clinical trial, Treatment Outcome, 030220 oncology & carcinogenesis, Child, Preschool, Rituximab, Female, Caplacizumab, business, medicine.drug
Abstract: The cornerstone of life-saving therapy in immune-mediated thrombotic thrombocytopenic purpura (iTTP) has been plasma exchange (PEX) combined with immunomodulatory strategies. Caplacizumab, a novel anti–von Willebrand factor nanobody trialed in 2 multicenter randomized controlled trials (RCTs) leading to European Union and US Food and Drug Administration approval, has been available in the United Kingdom (UK) through a patient access scheme. Data were collected retrospectively from 2018 to 2020 for 85 patients (4 children) receiving caplacizumab from 22 UK hospitals. Patient characteristics and outcomes in the real-world clinical setting were compared with caplacizumab trial end points and historical outcomes in the precaplacizumab era. Eighty-four of 85 patients received steroid and rituximab alongside PEX; 26% required intubation. Median time to platelet count normalization (3 days), duration of PEX (7 days), and hospital stay (12 days) were comparable with RCT data. Median duration of PEX and time from PEX initiation to platelet count normalization were favorable compared with historical outcomes (P < .05). Thrombotic thrombocytopenic purpura (TTP) recurred in 5 of 85 patients; all had persistent ADAMTS13 activity < 5 IU/dL. Of 31 adverse events in 26 patients, 17 of 31 (55%) were bleeding episodes, and 5 of 31 (16%) were thrombotic events (2 unrelated to caplacizumab); mortality was 6% (5/85), with no deaths attributed to caplacizumab. In 4 of 5 deaths, caplacizumab was introduced >48 hours after PEX initiation (3-21 days). This real-world evidence represents the first and largest series of TTP patients, including pediatric patients, receiving caplacizumab outside of clinical trials. Representative of true clinical practice, the findings provide valuable information for clinicians treating TTP globally.
Published: 2020

24. Characterization of acute kidney injury in critically ill patients with severe coronavirus disease 2019

Author: Odile Pillet, Antoine Dewitte, Marie Lise Bats, Olivier Guisset, Claire Rigothier, Catherine Fleureau, Alexandre Boyer, Hadrien Rozé, Cédric Carrié, Renaud Prevel, Frédéric Vargas, Laurent Petit, Nahema Issa, Sandrine Dabernat, Sébastien Rubin, Antoine Garric, Olivier Joannes-Boyau, Charline Sazio, Hoang Nam Bui, Fabrice Camou, Didier Gruson, Christian Combe, Benjamin Clouzeau, Gaelle Mourissoux, Arthur Orieux, Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, CHU Bordeaux [Bordeaux], Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Admin, Oskar
Subjects: Glycosuria, medicine.medical_specialty, medicine.medical_treatment, critically ill patients, 030232 urology & nephrology, urologic and male genital diseases, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Gastroenterology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Interquartile range, Intensive care, Internal medicine, medicine, 030212 general & internal medicine, Renal replacement therapy, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Transplantation, Creatinine, urogenital system, business.industry, Acute kidney injury, COVID-19, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, acute tubular injury, female genital diseases and pregnancy complications, 3. Good health, acute kidney injury, chemistry, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Nephrology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, acute interstitial nephritis, Albuminuria, Original Article, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, medicine.symptom, business, renal replacement therapy, Kidney disease
Abstract: Background Coronavirus disease 2019 (COVID-19)-associated acute kidney injury (AKI) frequency, severity and characterization in critically ill patients has not been reported. Methods Single-centre cohort performed from 3 March 2020 to 14 April 2020 in four intensive care units in Bordeaux University Hospital, France. All patients with COVID-19 and pulmonary severity criteria were included. AKI was defined using Kidney Disease: Improving Global Outcomes (KDIGO) criteria. A systematic urinary analysis was performed. The incidence, severity, clinical presentation, biological characterization (transient versus persistent AKI; proteinuria, haematuria and glycosuria) and short-term outcomes were evaluated. Results Seventy-one patients were included, with basal serum creatinine (SCr) of 69 ± 21 µmol/L. At admission, AKI was present in 8/71 (11%) patients. Median [interquartile range (IQR)] follow-up was 17 (12–23) days. AKI developed in a total of 57/71 (80%) patients, with 35% Stage 1, 35% Stage 2 and 30% Stage 3 AKI; 10/57 (18%) required renal replacement therapy (RRT). Transient AKI was present in only 4/55 (7%) patients and persistent AKI was observed in 51/55 (93%). Patients with persistent AKI developed a median (IQR) urine protein/creatinine of 82 (54–140) (mg/mmol) with an albuminuria/proteinuria ratio of 0.23 ± 20, indicating predominant tubulointerstitial injury. Only two (4%) patients had glycosuria. At Day 7 after onset of AKI, six (11%) patients remained dependent on RRT, nine (16%) had SCr >200 µmol/L and four (7%) had died. Day 7 and Day 14 renal recovery occurred in 28% and 52%, respectively. Conclusion Severe COVID-19-associated AKI is frequent, persistent, severe and characterized by an almost exclusive tubulointerstitial injury without glycosuria.
Published: 2020
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25. Characterisation of Acute Kidney Injury in Critically Ill Patients with Severe Coronavirus Disease-2019 (COVID-19)

Author: Benjamin Clouzeau, Alexandre Boyer, Gaelle Mourissoux, Fabrice Camou, Laurent Petit, Antoine Dewitte, Claire Rigothier, Odile Pillet, Olivier Guisset, Antoine Garric, Olivier Joannes-Boyau, Hoang-Nam Bui, Christian Combe, Hadrien Rozé, Nahema Issa, Marie-Lise Bats, Frédéric Vargas, Renaud Prevel, Catherine Fleureau, Cédric Carrié, Didier Gruson, Charline Sazio, Sébastien Rubin, Sandrine Dabernat, and Arthur Orieux
Subjects: Glycosuria, Creatinine, medicine.medical_specialty, Proteinuria, urogenital system, business.industry, Urinary system, medicine.medical_treatment, Acute kidney injury, urologic and male genital diseases, medicine.disease, Gastroenterology, female genital diseases and pregnancy complications, chemistry.chemical_compound, chemistry, Intensive care, Internal medicine, Albuminuria, Medicine, Renal replacement therapy, medicine.symptom, business
Abstract: BackgroundCOVID-19-associated acute kidney injury frequency, severity and characterisation in critically ill patients has not been reported.MethodsSingle-center cohort performed from March 3, 2020, to April 14, 2020 in 4 intensive care units in Bordeaux University Hospital, France. All patients with COVID19 and pulmonary severity criteria were included. AKI was defined using KDIGO criteria. A systematic urinary analysis was performed. The incidence, severity, clinical presentation, biological characterisation (transient vs. persistent acute kidney injury; proteinuria, hematuria and glycosuria), and short-term outcomes was evaluated.Results71 patients were included, with basal serum creatinine of 69 ± 21 µmol/L. At admission, AKI was present in 8/71 (11%) patients. Median follow-up was 17 [12–23] days. AKI developed in a total of 57/71 (80%) patients with 35% Stage 1, 35% Stage 2, and 30% Stage 3 acute kidney injury; 10/57 (18%) required renal replacement therapy. Transient AKI was present in only 4/55 (7%) patients and persistent AKI was observed in 51/55 (93%). Patients with persistent AKI developed a median urine protein/creatinine of 82 [54–140] (mg/mmol) with an albuminuria/proteinuria ratio of 0.23 ± 20 indicating predominant tubulo-interstitial injury. Only 2 (4%) patients had glycosuria. At Day 7 onset of after AKI, six (11%) patients remained dependent on renal replacement therapy, nine (16%) had SCr > 200 µmol/L, and four (7%) died. Day 7 and day 14 renal recovery occurred in 28% and 52 % respectively.ConclusionCOVID-19-associated AKI is frequent, persistent severe and characterised by an almost exclusive tubulo-interstitial injury without glycosuria.
Published: 2020
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26. Trends in disease incidence and survival and their effect on mortality in Scotland: nationwide cohort study of linked hospital admission and death records 2001-2016

Author: Harry Campbell, James F. Wilson, Jon Minton, Peter K. Joshi, Joannes J Kerssens, Paul R. H. J. Timmers, Ian Grant, and Colin Fischbacher
Subjects: Adult, Male, medicine.medical_specialty, Heart disease, Population, Disease, Kaplan-Meier Estimate, Death Certificates, Secondary Care, Sex Factors, Cause of Death, Epidemiology, medicine, Humans, Mortality, education, Aged, Aged, 80 and over, education.field_of_study, business.industry, Public health, Incidence (epidemiology), Incidence, General Medicine, Middle Aged, medicine.disease, Health Surveys, Hospitalization, Scotland, Socioeconomic Factors, Infectious disease (medical specialty), Medicine, Female, epidemiology, Public Health, Morbidity, business, Cohort study, Demography
Abstract: ObjectivesIdentify causes and future trends underpinning Scottish mortality improvements and quantify the relative contributions of disease incidence and survival.DesignPopulation-based study.SettingLinked secondary care and mortality records across Scotland.Participants1 967 130 individuals born between 1905 and 1965 and resident in Scotland from 2001 to 2016.Main outcome measuresHospital admission rates and survival within 5 years postadmission for 28 diseases, stratified by sex and socioeconomic status.Results‘Influenza and pneumonia’, ‘Symptoms and signs involving circulatory and respiratory systems’ and ‘Malignant neoplasm of respiratory and intrathoracic organs’ were the hospital diagnosis groupings associated with most excess deaths, being both common and linked to high postadmission mortality. Using disease trends, we modelled a mean mortality HR of 0.737 (95% CI 0.730 to 0.745) from one decade of birth to the next, equivalent to a life extension of ~3 years per decade. This improvement was 61% (30%–93%) accounted for by improved disease survival after hospitalisation (principally cancer) with the remainder accounted for by lowered hospitalisation incidence (principally heart disease and cancer). In contrast, deteriorations in infectious disease incidence and survival increased mortality by 9% (~3.3 months per decade). Disease-driven mortality improvements were slightly greater for men than women (due to greater falls in disease incidence), and generally similar across socioeconomic deciles. We project mortality improvements will continue over the next decade but slow by 21% because much progress in disease survival has already been achieved.ConclusionMorbidity improvements broadly explain observed mortality improvements, with progress on prevention and treatment of heart disease and cancer contributing the most. The male–female health gaps are closing, but those between socioeconomic groups are not. Slowing improvements in morbidity may explain recent stalling in improvements of UK period life expectancies. However, these could be offset if we accelerate improvements in the diseases accounting for most deaths and counteract recent deteriorations in infectious disease.
Published: 2020
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27. Liver Iron Retention Estimated from Utilization of Oral and Intravenous Radioiron in Various Anemias and Hemochromatosis in Humans

Author: Richard van Wijk, Annelies J. Van Vuren, Joannes J.M. Marx, and Eduard J. van Beers
Subjects: 0301 basic medicine, Male, Administration, Oral, lcsh:Chemistry, 0302 clinical medicine, lcsh:QH301-705.5, iron 2, Spectroscopy, iron deficiency 5, Iron Radioisotopes, Anemia, Iron-Deficiency, Chemistry, Transferrin, General Medicine, Iron deficiency, Middle Aged, Computer Science Applications, medicine.anatomical_structure, Liver, 030220 oncology & carcinogenesis, Hereditary hemochromatosis, hereditary anemia 4, Administration, Intravenous, Female, Hemochromatosis, Adult, medicine.medical_specialty, Adolescent, Serum Albumin, Human, Anemia, Hemolytic, Congenital, Catalysis, Article, Inorganic Chemistry, 03 medical and health sciences, Young Adult, Internal medicine, medicine, Liver iron, Humans, In patient, NTBI 3, Physical and Theoretical Chemistry, Molecular Biology, Aged, Red Cell, Organic Chemistry, hemochromatosis 1, Albumin, medicine.disease, Red blood cell, 030104 developmental biology, Endocrinology, lcsh:Biology (General), lcsh:QD1-999, Case-Control Studies
Abstract: Patients with hereditary hemochromatosis and non-transfusion-dependent hereditary anemia develop predominantly liver iron-overload. We present a unique method allowing quantification of liver iron retention in humans during first-pass of 59Fe-labeled iron through the portal system, using standard ferrokinetic techniques measuring red cell iron uptake after oral and intravenous 59Fe administration. We present data from patients with iron deficiency (ID, N = 47), hereditary hemochromatosis (HH, N = 121) and non-transfusion-dependent hereditary anemia (HA, N = 40). Mean mucosal iron uptake and mucosal iron transfer (&plusmn, SD) were elevated in patients with HH (59 &plusmn, 18%, 80 &plusmn, 15% respectively), HA (65 &plusmn, 17%, 74 &plusmn, 18%) and ID (84 &plusmn, 14%, 94 &plusmn, 6%) compared to healthy controls (43 &plusmn, 19%, 64 &plusmn, 18%) (p &lt, 0.05) resulting in increased iron retention after 14 days compared to healthy controls in all groups (p &lt, 0.01). The fraction of retained iron utilized for red cell production was 0.37 &plusmn, 0.17 in untreated HA, 0.55 &plusmn, 0.20 in untreated HH and 0.99 &plusmn, 0.22 in ID (p &lt, 0.01). Interestingly, compared to red blood cell iron utilization after oral iron administration, red blood cell iron utilization was higher after injection of transferrin-bound iron in HA and HH. Liver iron retention was considerably higher in HH and HA compared to ID. We hypothesize that albumin serves as a scavenger of absorbed Fe(II) for delivering albumin-bound Fe(III) to hepatocytes.
Published: 2020
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28. An international multi-center serum protein electrophoresis accuracy and M-protein isotyping study. Part I: factors impacting limit of quantitation of serum protein electrophoresis

Author: David F. Keren, Jody L. Frinack, Katherine A Turner, Martina Zaninotto, Anna Caldini, Michael W Ettore, Stephen Bell, Galina Zemtsovskaja, Robert O. Fullinfaw, Gabriella Righetti, Sara Altinier, Maria Stella Graziani, Christopher R. McCudden, Katina Katakouzinos, Matthew Burke, Julio C. Delgado, Marie Therese Melki, Ronald A. Booth, Joannes F M Jacobs, Maria Alice V. Willrich, Jillian R Tate, Theo de Malmanche, and Giovanni Palladini
Subjects: Immunofixation, Accuracy and precision, monoclonal proteins, limit of quantitation, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], Clinical Biochemistry, Paraproteinemias, Antibodies, Monoclonal, Humanized, immunosubtraction, All institutes and research themes of the Radboud University Medical Center, Limit of Detection, medicine, Humans, Detection limit, Chromatography, biology, medicine.diagnostic_test, accuracy, Chemistry, Biochemistry (medical), immunofixation, Hypergammaglobulinemia, protein electrophoresis, Antibodies, Monoclonal, Reproducibility of Results, Gamma globulin, General Medicine, Gel electrophoresis of proteins, medicine.disease, Blood Protein Electrophoresis, Laboratories, Hospital, Immunoglobulin Isotypes, Myeloma Proteins, Serum protein electrophoresis, Monoclonal, biology.protein
Abstract: Background Serum protein electrophoresis (SPEP) is used to quantify the serum monoclonal component or M-protein, for diagnosis and monitoring of monoclonal gammopathies. Significant imprecision and inaccuracy pose challenges in reporting small M-proteins. Using therapeutic monoclonal antibody-spiked sera and a pooled beta-migrating M-protein, we aimed to assess SPEP limitations and variability across 16 laboratories in three continents. Methods Sera with normal, hypo- or hypergammaglobulinemia were spiked with daratumumab, Dara (cathodal migrating), or elotuzumab, Elo (central-gamma migrating), with concentrations from 0.125 to 10 g/L (n = 62) along with a beta-migrating sample (n = 9). Provided with total protein (reverse biuret, Siemens), laboratories blindly analyzed samples according to their SPEP and immunofixation (IFE) or immunosubtraction (ISUB) standard operating procedures. Sixteen laboratories reported the perpendicular drop (PD) method of gating the M-protein, while 10 used tangent skimming (TS). A mean percent recovery range of 80%–120% was set as acceptable. The inter-laboratory %CV was calculated. Results Gamma globulin background, migration pattern and concentration all affect the precision and accuracy of quantifying M-proteins by SPEP. As the background increases, imprecision increases and accuracy decreases leading to overestimation of M-protein quantitation especially evident in hypergamma samples, and more prominent with PD. Cathodal migrating M-proteins were associated with less imprecision and higher accuracy compared to central-gamma migrating M-proteins, which is attributed to the increased gamma background contribution in M-proteins migrating in the middle of the gamma fraction. There is greater imprecision and loss of accuracy at lower M-protein concentrations. Conclusions This study suggests that quantifying exceedingly low concentrations of M-proteins, although possible, may not yield adequate accuracy and precision between laboratories.
Published: 2020

29. Evolution of RAS testing over time: factors influencing mutation rates in metastatic colorectal cancer patients

Author: Kelly Dufraing, Cleo Keppens, Véronique Tack, Albert Gerrit Siebers, George Kafatos, Sabada Dube, Gaston Demonty, Kimberly Lowe, Leonie Ilse Kroeze, Marjolijn Ligtenberg, Nicola Normanno, Lien Tembuyser, Vander Borght Sara, Joannes Henricus van Krieken, and Elisabeth Marie C Dequeker
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Mutation rate, business.industry, Colorectal cancer, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], Gastroenterology, medicine.disease, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], medicine, business
Abstract: Aim: Correct identification of RAS gene variants is key for targeted treatment decisions in patients with metastatic colorectal cancer. Published RAS mutation rates differ and could be influenced by several factors including testing methods. This study aimed to describe the performance of laboratories to correctly identify RAS variants over time and to understand how RAS testing has evolved in Europe. Materials & methods: Misclassification and test failure rates were calculated and related to the used test methodology for 239 unique laboratories participating in external quality assessment for metastatic colorectal cancer between 2013 and 2018. In addition, 33 laboratories completed a survey aiming to obtain more details on their routine testing strategies, number of samples analyzed and RAS mutation rates between 2013 and 2017. Results: The mutation status was correctly analyzed in 96.1% (N = 5471) RAS and BRAF tests. A total of 4.6% (N = 2860) RAS tests included false-negative results. In 1.6% (N = 5562) RAS and BRAF tests, an analysis failure occurred. Misclassifications and technical failures both decreased between 2013 and 2018. The number of next-generation sequencing users increased from 6.9% (N = 130) in 2013 to 44.6% (N = 112) in 2018. Over time, more codons were included in the methodologies, yet 23.2% (N = 112) did not offer full RAS testing (exon 2, 3, 4) in 2018. Based on the survey the overall RAS mutation rate was estimated as 45.2% (N = 27,325). Conclusion: This is the largest observational study reporting RAS mutation rates to-date. There was no trend of RAS mutation rates over time despite having a clear shift to more sensitive tests and increased quality of testing. ispartof: Colorectal Cancer vol:9 issue:1 status: Published online
Published: 2020
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30. Optimizing continuous renal replacement therapy in the ICU

Author: Lionel Velly, Olivier Joannes-Boyau, and Carole Ichai
Subjects: Critical Care, medicine.medical_treatment, 030232 urology & nephrology, MEDLINE, urologic and male genital diseases, Critical Care and Intensive Care Medicine, Session (web analytics), 03 medical and health sciences, 0302 clinical medicine, Clinical Protocols, Team strategy, medicine, Humans, Citrate anticoagulation, Renal replacement therapy, Simulation Training, business.industry, Anticoagulants, 030208 emergency & critical care medicine, Acute Kidney Injury, medicine.disease, female genital diseases and pregnancy complications, Renal Replacement Therapy, Intensive Care Units, Identification (information), Clinical Competence, Medical emergency, business
Abstract: Purpose of review The consideration of acute kidney injury, its incidence and its impact on the outcome of patients has grown continuously in recent years, leading to an increase in the use of renal replacement therapy (RRT) techniques. However, the successful conduct of RRT depends on the effectiveness of the entire team, doctors and nurses. It is therefore important to know the essential elements to be implemented in the ICU to ensure optimal RRT. Recent findings Recent studies show that the successful conduct of a RRT session requires a good knowledge of the principles of the technique, regular basic training, identification of experts, drafting clear and well followed protocols and good communication between the various stakeholders. In addition, the use of the latest advances, such as regional citrate anticoagulation, allows further optimization of therapy, only if, again, both physicians and nurses are properly trained and highly involved. Summary We now have a better understanding of the measures to be deployed to optimize RRT. Organization, training, evaluation and protocols are the key points of the team's efficiency for a safe and effective implementation of RRT.
Published: 2018
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31. A nationwide study on concordance with multimodal treatment guidelines in bipolar disorder

Author: Ralph Kupka, Willem A. Nolen, Eline J. Regeer, Adriaan W. Hoogendoorn, Joannes W. Renes, Psychiatry, APH - Mental Health, APH - Methodology, and Clinical Cognitive Neuropsychiatry Research Program (CCNP)
Subjects: medicine.medical_specialty, Bipolar I disorder, Concordance, medicine.medical_treatment, Population, Schizoaffective disorder, Guidelines, lcsh:RC321-571, 03 medical and health sciences, 0302 clinical medicine, ADHERENCE, I DISORDER, mental disorders, medicine, Psychoeducation, MANAGEMENT, Bipolar disorder, Psychiatry, education, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, POPULATION, education.field_of_study, business.industry, Research, lcsh:QP351-495, PHARMACOTHERAPY, Guideline, medicine.disease, DEPRESSION, 030227 psychiatry, Psychiatry and Mental health, Mood, lcsh:Neurophysiology and neuropsychology, Bipolar, PATTERNS, QUALITY-OF-CARE, business, 030217 neurology & neurosurgery
Abstract: Background: Most previous studies on concordance with treatment guidelines for bipolar disorder focused on pharmacotherapy. Few studies have included other treatment modalities. Aims: To study concordance with the Dutch guideline of various treatment modalities in outpatient treatment settings for patients with bipolar disorder and to identity factors associated with concordance. Methods: A nationwide non-interventional study using psychiatrists’ and patients’ surveys. Results: 839 patients with bipolar or schizoaffective disorder bipolar type were included. Concordance with the guideline was highest for participation of a psychiatrist in the treatment (98%) and for maintenance pharmacotherapy (96%), but lower for supportive treatment (73.5%), use of an emergency plan (70.6%), psychotherapy (52.2%), group psychoeducation (47.2%), and mood monitoring (47%). Presence of a written treatment plan, a more specialized treatment setting, more years of education, and diagnosis of bipolar I disorder versus bipolar II, bipolar NOS, or schizoaffective disorder were significantly associated with better concordance. Conclusion: In contrast to pharmacotherapy, psychosocial treatments are only implemented to a limited extend in everyday clinical practice in bipolar disorder. More effort is needed to implement non-pharmacological guideline recommendations for bipolar disorder.
Published: 2018
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32. Development of a Targeted Mass-Spectrometry Serum Assay To Quantify M-Protein in the Presence of Therapeutic Monoclonal Antibodies

Author: Marina Zajec, Martijn M. VanDuijn, Yolanda B. de Rijke, Theo M. Luider, Corrie M de Kat Angelino, Patricia J. T. A. Groenen, Joannes F M Jacobs, Christoph Stingl, Clinical Chemistry, and Neurology
Subjects: 0301 basic medicine, Neoplasm, Residual, medicine.drug_class, Myeloma protein, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], Gene Expression, Ipilimumab, Antineoplastic Agents, Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], Monoclonal antibody, Biochemistry, Sensitivity and Specificity, Mass Spectrometry, 03 medical and health sciences, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, medicine, Biomarkers, Tumor, Humans, Amino Acid Sequence, Multiple myeloma, business.industry, Daratumumab, Antibodies, Monoclonal, General Chemistry, medicine.disease, Minimal residual disease, 030104 developmental biology, Targeted mass spectrometry, Myeloma Proteins, Nivolumab, 030220 oncology & carcinogenesis, Isotope Labeling, Cancer research, Biological Assay, business, Multiple Myeloma, Peptides, Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5], medicine.drug
Abstract: M-protein diagnostics can be compromised for patients receiving therapeutic monoclonal antibodies as treatment in multiple myeloma. Conventional techniques are often not able to distinguish between M-proteins and therapeutic monoclonal antibodies administered to the patient. This may prevent correct response assessment and can lead to overtreatment. We have developed a serum-based targeted mass-spectrometry assay to detect M-proteins, even in the presence of three therapeutic monoclonal antibodies (daratumumab, ipilimumab, and nivolumab). This assay can target proteotypic M-protein peptides as well as unique peptides derived from therapeutic monoclonal antibodies. We address the sensitivity in M-protein diagnostics and show that our mass-spectrometry assay is more than two orders of magnitude more sensitive than conventional M-protein diagnostics. The use of stable isotope-labeled peptides allows absolute quantification of the M-protein and increases the potential of assay standardization across multiple laboratories. Finally, we discuss the position of mass-spectrometry assays in monitoring minimal residual disease in multiple myeloma, which is currently dominated by molecular techniques based on plasma cell assessment that requires invasive bone marrow aspirations or biopsies.
Published: 2018

33. Safety and dose-dependency of eptacog beta (activated) in a dose escalation study of non-bleeding congenital haemophilia A or B patients, with or without inhibitors

Author: Lisa N. Boggio, A. Bellon, J. B. Lawrence, Jasper Stevens, Matthijs Moerland, Michael Wang, Jonathan M. Ducore, J. Frieling, Jacobus Burggraaf, Mindy L. Simpson, and Joannes A. A. Reijers
Subjects: Adult, Male, medicine.medical_specialty, Metabolic Clearance Rate, Haemophilia A, Cmax, Factor VIIa, 030204 cardiovascular system & hematology, Pharmacology, Hemophilia A, Haemophilia, Dizziness, Hemophilia B, Gastroenterology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Internal medicine, medicine, Humans, Genetics (clinical), Factor IX, Dose-Response Relationship, Drug, biology, business.industry, Headache, Hematology, General Medicine, Middle Aged, medicine.disease, Recombinant Proteins, Coagulation, Recombinant factor VIIa, Area Under Curve, Pharmacodynamics, biology.protein, business, 030215 immunology, medicine.drug
Abstract: Introduction Varying initial doses of activated eptacog beta (recombinant human FVIIa, rhFVIIa) may provide therapeutic options when treating bleeding in patients with congenital haemophilia who have developed inhibitory antibodies to factor VIII (FVIII) or factor IX (FIX). This study evaluated escalated doses of a new rhFVIIa product as a prelude to selecting the doses for clinical efficacy evaluation in haemophilia patients. Aim To assess the safety, pharmacokinetics, and laboratory pharmacodynamics of 3 doses of rhFVIIa in non-bleeding patients with congenital haemophilia A or B with or without inhibitors. Methods Adult male patients (18-75 years old) with congenital haemophilia A or B (with or without inhibitors) received infusions of rhFVIIa at doses of 25, 75 or 225 μg/kg body weight. Ten patients were treated at each dose level, and each patient received 2 different dose levels. Descriptive methods were used to analyse the data. Results Administration of rhFVIIa at all doses was well tolerated. Pharmacokinetic analyses showed that peak FVIIa plasma levels (Cmax) were approximately proportional to dose and correlated well with peak thrombin generation. Total AUC0-inf also was approximately dose proportional. Clot formation and duration correlated with FVIIa activity. Repeat doses did not produce an immunological response. Conclusion In the first dose-escalation study of rhFVIIa to support product registration, eptacog beta at doses of 25, 75, and 225 μg/kg was pharmacodynamically active and well tolerated in non-bleeding patients with congenital haemophilia A or B.
Published: 2017
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34. Pregnancy

Author: Joannes J Kerssens, Robert S. Lindsay, Graham P. Leese, Rachael Wood, Scott M. Nelson, Helen M. Colhoun, Sarah H. Wild, S. T. Mackin, and Sam Philip
Subjects: Pediatrics, medicine.medical_specialty, Pregnancy, Endocrinology, business.industry, Endocrinology, Diabetes and Metabolism, Diabetes mellitus, Internal Medicine, medicine, Observational study, Outcome data, medicine.disease, business
Published: 2018
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35. Report of the first AKI Round Table meeting: an initiative of the ESICM AKI Section

Author: Alexander Zarbock, Michael Joannidis, Lui G. Forni, Marlies Ostermann, Antoine G. Schneider, Eric Hoste, Thomas Rimmelé, I Bobek, Olivier Joannes-Boyau, John R. Prowle, Matthieu Legrand, M van Dam, and Michael Darmon
Subjects: Nephrology, medicine.medical_specialty, Kidney Disease, medicine.medical_treatment, Clinical Sciences, 030232 urology & nephrology, MEDLINE, Renal and urogenital, ACUTE KIDNEY INJURY, BLOOD-PRESSURE, PROGRESSION, Critical Care and Intensive Care Medicine, urologic and male genital diseases, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, Internal medicine, Epidemiology, medicine, Medicine and Health Sciences, Renal replacement therapy, Intensive care medicine, RISK, business.industry, RENAL REPLACEMENT THERAPY, lcsh:Medical emergencies. Critical care. Intensive care. First aid, Acute kidney injury, Methodology, 030208 emergency & critical care medicine, lcsh:RC86-88.9, RECOVERY, medicine.disease, Intensive care unit, female genital diseases and pregnancy complications, Systematic review, Observational study, business, CRITICALLY-ILL PATIENTS
Abstract: Purpose Critical Care Nephrology is an emerging sub-specialty of Critical Care. Despite increasing awareness about the serious impact of acute kidney injury (AKI) and renal replacement therapy (RRT), important knowledge gaps persist. This report represents a summary of a 1-day meeting of the AKI section of the European Society of Intensive Care Medicine (ESICM) identifying priorities for future AKI research. Methods International Members of the AKI section of the ESICM were selected and allocated to one of three subgroups: “AKI diagnosis and evaluation”, “Medical management of AKI” and “Renal Replacement Therapy for AKI.” Using a modified Delphi methodology, each group identified knowledge gaps and developed potential proposals for future collaborative research. Results The following key research projects were developed: Systematic reviews: (a) epidemiology of AKI with stratification by patient cohorts and diagnostic criteria; (b) role of higher blood pressure targets in patients with hypertension admitted to the Intensive Care Unit, and (c) specific clearance characteristics of different modalities of continuous renal replacement therapy (CRRT). Observational studies: (a) epidemiology of critically ill patients according to AKI duration, and (b) current clinical practice of CRRT. Intervention studies:( a) Comparison of different blood pressure targets in critically ill patients with hypertension, and (b) comparison of clearance of solutes with various molecular weights between different CRRT modalities. Conclusion Consensus was reached on a future research agenda for the AKI section of the ESICM.
Published: 2019

36. Reference ranges of the Sebia free light chain ratio in patients with chronic kidney disease

Author: Joannes F M Jacobs and Laurence Lutteri
Subjects: 030213 general clinical medicine, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], Clinical Biochemistry, 030204 cardiovascular system & hematology, Immunoglobulin lambda-Chains, Immunoglobulin light chain, Immunoglobulin kappa-Chains, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Reference Values, medicine, Humans, In patient, Renal Insufficiency, Chronic, Immunoassay, Creatinine, medicine.diagnostic_test, Chemistry, Biochemistry (medical), General Medicine, medicine.disease, Free Light Chain, Molecular biology, Immunoglobulin Light Chains, Kidney disease
Abstract: Item does not contain fulltext
Published: 2018

37. Pharmacokinetics and pharmacodynamics of anti-infective agents during continuous veno-venous hemofiltration in critically ill patients: Lessons learned from an ancillary study of the IVOIRE trial

Author: Julien Coquin, Herbert D. Spapen, Antoine Dewitte, Marie-Claude Saux, Catherine Fleureau, Jason A. Roberts, Alexandre Ouattara, Sebastien Redant, Paul Perez, Luc Kugener, Dominique Breilh, Hadrien Rozé, David De Bels, Olivier Joannes-Boyau, Patrick M. Honore, Jean Baptiste Gordien, Rachid Attou, Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Centre Hospitalier Universitaire Brugmann [Bruxelles] (CHU), University of Queensland [Brisbane], Vrije Universiteit Brussel (VUB), IVOIRE study group, INSERM, U1034, Supporting clinical sciences, Intensive Care, and Internal Medicine Specializations
Subjects: 0301 basic medicine, medicine.medical_specialty, medicine.medical_treatment, [SDV]Life Sciences [q-bio], 030106 microbiology, high volume hemofiltration, antibiotics, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Internal medicine, Intensive care, Hemofiltration, Sieving coefficient, continuous veno-venous hemofiltration, Internal Medicine, medicine, pharmacodynamics, Medicine(all), business.industry, Septic shock, Acute kidney injury, 030208 emergency & critical care medicine, Antimicrobial, medicine.disease, [SDV] Life Sciences [q-bio], antibiotic dosage, Article RECHERCHE, Pharmacodynamics, Anesthesia, septic shock, Original Article, business, pharmacokinetics
Abstract: Background Hemofiltration rate, changes in blood and ultrafiltration flow, and discrepancies between the prescribed and administered doses strongly influence pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobial agents during continuous veno-venous hemofiltration (CVVH) in critically ill patients. Methods Ancillary data were from the prospective multicenter IVOIRE (hIgh VOlume in Intensive caRE) study. High volume (HV, 70 mL/kg/h) was at random compared with standard volume (SV, 35 mL/kg/h) CVVH in septic shock patients with acute kidney injury (AKI). PK/PD parameters for all antimicrobial agents used in each patient were studied during five days. Results Antimicrobial treatment met efficacy targets for both percentage of time above the minimal inhibitory concentration and inhibitory quotient. A significant correlation was observed between the ultrafiltration flow and total systemic clearance (Spearman test: P < 0.005) and between CVVH clearance and drug elimination half-life (Spearman test: P < 0.005). All agents were easily filtered. Mean sieving coefficient ranged from 38.7% to 96.7%. Mean elimination half-life of all agents was significantly shorter during HV-CVVH (from 1.29 to 28.54 h) than during SV-CVVH (from 1.51 to 33.85 h) (P < 0.05). Conclusions This study confirms that CVVH influences the PK/PD behavior of most antimicrobial agents. Antimicrobial elimination was directly correlated with convection rate. Current antimicrobial dose recommendations will expose patients to underdosing and increase the risk for treatment failure and development of resistance. Dose recommendations are proposed for some major antibiotic and antifungal treatments in patients receiving at least 25 mL/kg/h CVVH.
Published: 2019
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38. Major depressive disorder is associated with changes in a cluster of serum and urine biomarkers

Author: Edwin R. van den Heuvel, Eduard Antonius Joannes Arnoldussen, Johannes S. Kamphuis, Anna C. Muller Kobold, Robert A. Schoevers, Leandra J M Boonman-de Winter, Erin M van Buel, Paul G.M. Luiten, Lambertus F J Timmers, Hans C. Klein, Mattheus F A Veerman, Dirk van Rumpt, Ulrich L. M. Eisel, Anatoliy V. Gladkevich, Marcus J M Meddens, Fokko J. Bosker, Willem C Bohlmeijer, Johan A. den Boer, Eisel lab, Stochastic Studies and Statistics, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Perceptual and Cognitive Neuroscience (PCN), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Stochastic Operations Research, Eindhoven MedTech Innovation Center, and Statistics
Subjects: Oncology, Adult, Male, medicine.medical_specialty, Urine, Major depressive disorder, Disease cluster, SDG 3 – Goede gezondheid en welzijn, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, 030212 general & internal medicine, Permutation analysis, Depression (differential diagnoses), Depressive Disorder, Major, Receiver operating characteristic, business.industry, Area under the curve, Middle Aged, medicine.disease, Biomarker panel, Psychiatry and Mental health, Clinical Psychology, Urine biomarkers, ROC Curve, Area Under Curve, Case-Control Studies, Biomarker (medicine), ELISA, Female, business, 030217 neurology & neurosurgery, Algorithms, Biomarkers
Abstract: Major Depressive Disorder (MDD) is a heterogeneous disorder with a considerable symptomatic overlap with other psychiatric and somatic disorders. This study aims at providing evidence for association of a set of serum and urine biomarkers with MDD. We analyzed urine and serum samples of 40 MDD patients and 47 age- and sex-matched controls using 40 potential MDD biomarkers (21 serum biomarkers and 19 urine biomarkers). All participants were of Caucasian origin. We developed an algorithm to combine the heterogeneity at biomarker level. This method enabled the identification of correlating biomarkers based on differences in variation and distribution between groups, combined the outcome of the selected biomarkers, and calculated depression probability scores (the "bio depression score"). Phenotype permutation analysis showed a significant discrimination between MDD and euthymic (control) subjects for biomarkers in urine (P
Published: 2019
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39. Arsenic trioxyde inhibits the functions on lung fibroblasts derived from patients with idiopathic pulmonary fibrosis

Author: Maela Duclos, Francisco Llamas Gutierrez, Laurent Vernhet, Bertrand De Latour, Audrey Joannes, Stéphane Jouneau, Claudie Morzadec, Nessrine Bellamri, Stefan-Lutz Wollin, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), CHU Pontchaillou [Rennes], Boehringer Ingelheim Pharma GmbH & Co. KG, and Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Lung, business.industry, [SDV]Life Sciences [q-bio], Treatments, Idiopathic pulmonary fibrosis, Pirfenidone, respiratory system, medicine.disease, Bleomycin, respiratory tract diseases, 3. Good health, chemistry.chemical_compound, medicine.anatomical_structure, chemistry, Pulmonary fibrosis, Cancer research, medicine, Nintedanib, Experimental approaches, Viability assay, Arsenic trioxide, business, ComputingMilieux_MISCELLANEOUS, medicine.drug
Abstract: Nintedanib and pirfenidone have been approved for the treatment of idiopathic pulmonary fibrosis (IPF). Both drugs were shown to reduce but not to stop disease progression. Hence the medical need is still high for new effective anti-fibrotic molecules. Arsenic trioxide (ATO), a safe and effective drug used in cancer therapy, decreased pulmonary fibrosis induced by bleomycin in mice. In order to specify the anti-fibrotic properties of ATO, we investigated its effects on main functions of human lung fibroblasts (HLFs). IPF and control HLFs were derived from lung biopsies isolated from patients with IPF or without intertitial lung disease. After pre-treatment with ATO (0.01-1 μM) and stimulation with PDGF-BB (50 ng/ml) or TGF-β1 (1 ng/ml), proliferation, migration and differentiation of HLFs were assessed as well as the cell stress response triggered by ATO. The metalloid did not affect cell viability but it significantly decreased, in a concentration-dependent manner, the proliferation and migration of control and IPF HLFs induced by PDGF-BB. ATO also prevented the up-regulation of α-SMA, Collagen-1 and p-SMAD3 protein levels in TGF-β1-stimulated HLFs. The metalloid effects were associated with stabilization of the transcription factor NRF2 and induction of the antioxidant proteins NQO1 and HO-1 that emphases the stress response developed by ATO-treated HLFs. In conclusions, our results demonstrate that, in vitro, ATO concentrations, in the range of arsenic plasmatic levels measured in patients treated with standard dosing, counteracts the detrimental functions of IPF HLFs. ATO may thus be taken into consideration as a new therapeutic option for IPF treatment.
Published: 2019
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40. Improvements in the incidence and survival of cancer and cardiovascular but not infectious disease have driven recent mortality improvements in Scotland: nationwide cohort study of linked hospital admission and death records 2001-2016

Author: Peter K. Joshi, Paul R. H. J. Timmers, Harry Campbell, Jon Minton, James F. Wilson, Joannes J Kerssens, Colin Fischbacher, and Ian Grant
Subjects: education.field_of_study, Heart disease, business.industry, Incidence (epidemiology), Population, Hazard ratio, Disease, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Infectious disease (medical specialty), Life expectancy, Medicine, 030212 general & internal medicine, education, business, 030217 neurology & neurosurgery, Demography, Cohort study
Abstract: ObjectivesTo identify the causes and future trends underpinning improvements in life expectancy in Scotland and quantify the relative contributions of disease incidence and survival.DesignPopulation-based study.SettingLinked secondary care and mortality records across Scotland.Participants1,967,130 individuals born between 1905 and 1965, and resident in Scotland throughout 2001–2016.Main outcome measuresHospital admission rates and survival in the five years following admission for 28 diseases, stratified by sex and socioeconomic status.ResultsThe five hospital admission diagnoses associated with the greatest burden of death subsequent to admission were “Influenza and pneumonia”, “Symptoms and signs involving the circulatory and respiratory systems”, “Malignant neoplasm of respiratory and intrathoracic organs”, “Symptoms and signs involving the digestive system and abdomen”, and “General symptoms and signs”. Using disease trends, we modelled a mean mortality hazard ratio of 0.737 (95% CI 0.730–0.745) across decades of birth, equivalent to a life extension of ∼3 years per decade. This improvement was 61% (30%–93%) accounted for by improvements in disease survival after hospitalisation (principally cancer) with the remainder accounted for by a fall in hospitalisation incidence (principally heart disease and cancer). In contrast, deteriorations in the incidence and survival of infectious diseases reduced mortality improvements by 9% (∼3.3 months per decade). Overall, health-driven mortality improvements were slightly greater for men than women (due to greater falls in disease incidence), and generally similar across socioeconomic deciles. We project mortality improvements will continue over the next decade but will slow down by 21% because much of the progress in disease survival has already been achieved.ConclusionMorbidity improvements broadly explain observed improvements in overall mortality, with progress on the prevention and treatment of heart disease and cancer making the most significant contributions. The gaps between men and women’s morbidity and mortality are closing, but the gap between socioeconomic groups is not. A slowing trend in improvements in morbidity may explain the stalling in improvements of period life expectancies observed in recent studies in the UK. However, our modelled slowing of improvements could be offset if we achieve even faster improvements in the major diseases contributing to the burden of death, or if we improve prevention and survival of diseases which have deteriorated recently, such as infectious disease, in the future.Summary boxWhat is already known on this topicLong term improvements in Scottish mortality have slowed down recently, while life expectancy inequalities between socioeconomic classes are increasing.Deaths attributed to ischaemic heart disease and stroke in Scotland have declined in the last two decades.What this study addsGains in life expectancy can largely be attributed to improvements in cancer survival and falls in incidence of cancer and cardiovascular disease.The hospitalisation rate and survival of several infectious diseases have deteriorated, and for urinary infections, this decline has been more rapid in more socioeconomically deprived classes.Improvements in morbidity are projected to slow down, with much progress in survival of heart disease and cancer already achieved, and align with the recently observed slow-down in mortality improvements.
Published: 2019
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41. Genetic risk score has added value over initial clinical grading stage in predicting disease progression in age-related macular degeneration

Author: Joannes M. M. Groenewoud, Thomas J. Heesterbeek, Clara I. Sánchez, Carel B. Hoyng, Bart Liefers, Eiko K. de Jong, Tunde Peto, Ilhan Erkin Acar, Anneke I. den Hollander, Daniel Pauleikhoff, and Hans W. Hense
Subjects: Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Genetic testing, genetic structures, Epidemiology, Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13], lcsh:Medicine, Drusen, Predictive markers, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Article, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, Geographic Atrophy, Internal medicine, Added value, medicine, Humans, Genetic Predisposition to Disease, Prospective Studies, Genetic risk, Prospective cohort study, lcsh:Science, Grading (tumors), Aged, Multidisciplinary, business.industry, Macular degeneration, Disease progression, lcsh:R, fungi, medicine.disease, Choroidal Neovascularization, eye diseases, Clinical trial, 030104 developmental biology, Disease Progression, Female, lcsh:Q, Medical imaging, sense organs, business, 030217 neurology & neurosurgery
Abstract: Several prediction models for progression of age-related macular degeneration (AMD) have been developed, but the added value of using genetic information in those models in addition to clinical characteristics is ambiguous. In this prospective cohort study, we explored the added value of genetics using a genetic risk score (GRS) based on 52 AMD-associated variants, in addition to the clinical severity grading at baseline as quantified by validated drusen detection software, to predict disease progression in 177 AMD patients after 6.5 years follow-up. The GRS was strongly associated with the drusen coverage at baseline (P 2 increased from 0.46 to 0.56. This improvement by the GRS was predominantly seen in patients with a drusen coverage
Published: 2019
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42. A cure for septic AKI: Why not keep the dream alive?

Author: Antoine-Guillaume Schneider, Thibault Michel, and Olivier Joannes-Boyau
Subjects: Creatinine, medicine.medical_specialty, business.industry, MEDLINE, Acute kidney injury, General Medicine, Acute Kidney Injury, Critical Care and Intensive Care Medicine, medicine.disease, Alkaline Phosphatase, Sepsis, chemistry.chemical_compound, Anesthesiology and Pain Medicine, chemistry, Internal medicine, medicine, Alkaline phosphatase, Humans, business, Original Investigation
Abstract: IMPORTANCE: Sepsis-associated acute kidney injury (AKI) adversely affects long-term kidney outcomes and survival. Administration of the detoxifying enzyme alkaline phosphatase may improve kidney function and survival. OBJECTIVE: To determine the optimal therapeutic dose, effect on kidney function, and adverse effects of a human recombinant alkaline phosphatase in patients who are critically ill with sepsis-associated AKI. DESIGN, SETTING, AND PARTICIPANTS: The STOP-AKI trial was an international (53 recruiting sites), randomized, double-blind, placebo-controlled, dose-finding, adaptive phase 2a/2b study in 301 adult patients admitted to the intensive care unit with a diagnosis of sepsis and AKI. Patients were enrolled between December 2014 and May 2017, and follow-up was conducted for 90 days. The final date of follow-up was August 14, 2017. INTERVENTIONS: In the intention-to-treat analysis, in part 1 of the trial, patients were randomized to receive recombinant alkaline phosphatase in a dosage of 0.4 mg/kg (n = 31), 0.8 mg/kg (n = 32), or 1.6 mg/kg (n = 29) or placebo (n = 30), once daily for 3 days, to establish the optimal dose. The optimal dose was identified as 1.6 mg/kg based on modeling approaches and adverse events. In part 2, 1.6 mg/kg (n = 82) was compared with placebo (n = 86). MAIN OUTCOMES AND MEASURES: The primary end point was the time-corrected area under the curve of the endogenous creatinine clearance for days 1 through 7, divided by 7 to provide a mean daily creatinine clearance (AUC(1-7) ECC). Incidence of fatal and nonfatal (serious) adverse events ([S]AEs) was also determined. RESULTS: Overall, 301 patients were enrolled (men, 70.7%; median age, 67 years [interquartile range {IQR}, 59-73]). From day 1 to day 7, median ECC increased from 26.0 mL/min (IQR, 8.8 to 59.5) to 65.4 mL/min (IQR, 26.7 to 115.4) in the recombinant alkaline phosphatase 1.6-mg/kg group vs from 35.9 mL/min (IQR, 12.2 to 82.9) to 61.9 mL/min (IQR, 22.7 to 115.2) in the placebo group (absolute difference, 9.5 mL/min [95% CI, −23.9 to 25.5]; P = .47). Fatal adverse events occurred in 26.3% of patients in the 0.4-mg/kg recombinant alkaline phosphatase group; 17.1% in the 0.8-mg/kg group, 17.4% in the 1.6-mg/kg group, and 29.5% in the placebo group. Rates of nonfatal SAEs were 21.0% for the 0.4-mg/kg recombinant alkaline phosphatase group, 14.3% for the 0.8-mg/kg group, 25.7% for the 1.6-mg/kg group, and 20.5% for the placebo group. CONCLUSIONS AND RELEVANCE: Among patients who were critically ill with sepsis-associated acute kidney injury, human recombinant alkaline phosphatase compared with placebo did not significantly improve short-term kidney function. Further research is necessary to assess other clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02182440
Published: 2019

43. Effect of a Recombinant Human Soluble Thrombomodulin on Mortality in Patients With Sepsis-Associated Coagulopathy: The SCARLET Randomized Clinical Trial

Author: Vincent, Jean-Louis, Francois, Bruno, Zabolotskikh, Igor, Daga, Mradul Kumar, Lascarrou, Jean-Baptiste, Kirov, Mikhail Y., Pettila, Ville, Wittebole, Xavier, Meziani, Ferhat, Mercier, Emmanuelle, Lobo, Suzana M., Barie, Philip S., Crowther, Mark, Esmon, Charles T., Fareed, Jawed, Gando, Satoshi, Gorelick, Kenneth J., Levi, Marcel, Mira, Jean-Paul, Opal, Steven M., Parrillo, Joseph, Russell, James A., Saito, Hidehiko, Tsuruta, Kazuhisa, Sakai, Takumi, Fineberg, David, Bertuzzi, Romina, Bellomo, Rinaldo, Chapman, Marianne, Ernest, David, Fletcher, Jason, French, Craig, Gowardman, John, Shehabi, Yahya, Venkatesh, Bala, Walsham, James, Vij, Sanjiv, Chochrad, Didier, Creteur, Jacques, Devriendt, Jacques, Dive, Alain-Michel, Dugernier, Thierry, Foret, Frederic, Hoste, Eric, Jorens, Philippe, Simon, Marc, Spapen, Herbert, Dias, Fernando, Freire, Antonio, Lobo, Suzana Margarth, Simeonov, Georgi, Stefanov, Chavdar, Aslanian, Pierre, Berthiaume, Luc, Martin, Claudio, Chittock, Dean, Dhar, Anil, Doig, Christopher, Jones, Gwynne, Hall, Richard, Boyd, John, Shin, Phil, Wood, Gordon, Zarychanski, Ryan, Quinteros, Guillermo Agamenon, Gasparovic, Vladimir, Husedzinovic, Ino, Balik, Martin, Burget, Ivo, Dlouhy, Pavel, Pachl, Jan, Karlsson, Sari, Laru-Sompa, Raili, Parviainen, Ilkka, Ruokone, Esko, Skrifvars, Markus, Bohe, Julien, Dellamonica, Jean, Duguet, Alexandre, Durand-Gasselin, Jacques, Fiancette, Maud, Joannes-Boyau, Olivier, Lefrant, Jean-Yves, Mercat, Alain, Nseir, Saad, Quenot, Jean-Pierre, Reignier, Jean, Schwebel, Carole, Marx, Gernot, Zacharowski, Kai, Armaganidis, Apostolos, Komnos, Apostolos, Fejer, Csaba, Appajigol, Jayaprakash, Behera, Sarat Kumar, ChandraShekhar, Shivprasad, Chowdhury, Sanmay, D'costa, Pradeep Micheal, Gupta, Hari Shankar Shivkumar, Iyer, Shivakumar, Khan, Zafer A., Mehta, Minesh, Murthy, Sudharshan, Sahu, Sambit, Tewari, Reshma, Bar-Lavie, Yaron, Bregman, Gennady, Cohen, Jonathan, Eden, Arie, Einav-Bromiker, Sharon, Jakobson, Daniel, Nimrod, Adi, Beishuizen, Albertus, Gerritsen, Richard, Pickkers, Peter, Rozendaal, Wim, Schoonderbeek, F. J., Spoelstra-de Man, Angelique, van Zanten, Arthur R. H., Zijlstra, Jan G., Freebairn, Ross, Henderson, Seton, McArthur, Colin, Young, Paul, Mayorga, Manuel Jesus, Agafina, Alina S., Bubnova, Natalia, Gritsan, Alexey, Kameneva, Evgenia, Katasonov, Sergey P., Khasanova, Nina M., Kruberg, Lilly, Kulabukhov, Vladimir V., Lebedinskii, Konstantin, Spesivtsev, Yuri A., Rankovic, Zarko, Hong, Sang Bum, Kim, Min-Ja, Suh, Gee Young, Yoo, Chul-Gyu, Raventos, Antonio Artigas, Ferrer, Ricard, Vazquez, Rita Galeiras, Hernandez, Marianela, Piacentini, Enrique, Rodriguez Oviedo, Alejandro Hugo, Garcia, Miguel Sanchez, Chan, Ming-Cheng, Cheng, Kuo-Chen, Yu, Chong-Jen, Eddleston, Jane, Smith, Fang Gao, MacNaughton, Peter, Welters, Ingeborg, Allen, Karen, Bochicchio, Grant, Carlson, Richard, Eaton, Stephanie, Fink, Ryan, Gianatiempo, Carmine, Kapoor, Rajat, Kinasewitz, Gary, Koura, Firas, Krell, Kenneth, Martin, Niels, Nepal, Santosh, Pastores, Stephen M., Peltan, Ithan, Pullman, John, Seibert, Allan, Smith, Jason, Tennenberg, Steven, Wilhelm, Andrew, Zeno, Brian, Allton, Pam, Carruthers, David, Matsuki, Osamu, Kayanoki, Toshihiko, UCL - SSS/IREC/MEDA - Pôle de médecine aiguë, UCL - (MGD) Services des soins intensifs, Intensive care medicine, ACS - Atherosclerosis & ischemic syndromes, ACS - Diabetes & metabolism, UCL - (SLuc) Service de soins intensifs, Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), and SCARLET Trial Grp
Subjects: Male, medicine.medical_specialty, Thrombomodulin, COAGULATION, PROTEIN, Placebo, 01 natural sciences, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, Intensive care, Cause of Death, Sepsis, medicine, Clinical endpoint, Coagulopathy, Humans, 030212 general & internal medicine, International Normalized Ratio, Treatment Failure, 0101 mathematics, Infusions, Intravenous, Original Investigation, Aged, business.industry, Mortality rate, 010102 general mathematics, Anticoagulants, General Medicine, Disseminated Intravascular Coagulation, Blood Coagulation Disorders, Middle Aged, medicine.disease, Recombinant Proteins, 3. Good health, Injections, Intravenous, Female, Human medicine, business, Packed red blood cells
Abstract: IMPORTANCE Previous research suggested that soluble human recombinant thrombomodulin may reduce mortality among patients with sepsis-associated coagulopathy.OBJECTIVE To determine the effect of human recombinant thrombomodulin vs placebo on 28-day all-cause mortality among patients with sepsis-associated coagulopathy.DESIGN, SETTING, AND PARTICIPANTS The SCARLET trial was a randomized, double-blind, placebo-controlled, multinational, multicenter phase 3 study conducted in intensive care units at 159 sites in 26 countries. All adult patients admitted to one of the participating intensive care units between October 2012 and March 2018 with sepsis-associated coagulopathy and concomitant cardiovascular and/or respiratory failure, defined as an international normalized ratio greater than 1.40 without other known etiology and a platelet count in the range of 30 to 150 x 10(9)/L or a greater than 30% decrease in platelet count within 24 hours, were considered for inclusion. The final date of follow-up was February 28, 2019.INTERVENTIONS Patients with sepsis-associated coagulopathy were randomized and treated with an intravenous bolus or a 15-minute infusion of thrombomodulin (0.06mg/kg/d [maximum, 6mg/d]; n=-395) or matching placebo (n=-405) once daily for 6 days.MAIN OUTCOME AND MEASURES The primary end pointwas 28-day all-cause mortality.RESULTS Among 816 randomized patients, 800 (mean age, 60.7 years; 437 [54.6%] men) completed the study and were included in the full analysis set. In these patients, the 28-day all-cause mortality rate was not statistically significantly different between the thrombomodulin group and the placebo group (106 of 395 patients [26.8%] vs 119 of 405 patients [29.4%], respectively; P=-.32). The absolute risk difference was 2.55%(95% CI, -3.68% to 8.77%). The incidence of serious major bleeding adverse events (defined as any intracranial hemorrhage; life-threatening bleeding; or bleeding event classified as serious by the investigator, with administration of at least 1440mL [typically 6 units] of packed red blood cells over 2 consecutive days) was 23 of 396 patients (5.8%) in the thrombomodulin group and 16 of 404 (4.0%) in the placebo group.CONCLUSIONS AND RELEVANCE Among patients with sepsis-associated coagulopathy, administration of a human recombinant thrombomodulin, compared with placebo, did not significantly reduce 28-day all-cause mortality.TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01598831
Published: 2019
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44. Metabolomics in serum of patients with non-advanced age-related macular degeneration reveals aberrations in the glutamine pathway

Author: Kersten, Eveline, Dammeier, Sascha, Ajana, Soufiane, Groenewoud, Joannes M.M., Codrea, Marius, Klose, Franziska, Lechanteur, Yara T., Fauser, Sascha, Ueffing, Marius, Delcourt, Cécile, Hoyng, Carel B., de Jong, Eiko, Den Hollander, Anneke I., Arango-Gonzalez, Blanca, Arndt, Verena, Bhatia, Vaibhav, Bhatta-Charya, Shomi S., Biarnés, Marc, Borrell, Anna, Bühren, Sebastian, Calado, Sofia M., Colijn, Johanna M., Cougnard-Grégoire, Audrey, De la Cerda, Berta, Del-Court, Cécile, Diaz-Corrales, F. J., Diether, Sigrid, Emri, Eszter, Ender-Mann, Tanja, Ferraro, Lucia, Garcia, Míriam, Heesterbeek, Thomas J., Honisch, Sabina, Iacone, Roberto, Kilger, Ellen, Klaver, Caroline C.W., Langen, Hanno, Lengyel, Imre, Luthert, Phil, Maugeais, Cyrille, Meester-Smoor, Magda, Merle, Benedicte, Monés, Jordi, Nogoceke, Everson, Peto, Tunde, Pool, Fran, Rodríguez, Eduardo, Bartz-Schmidt, Karl Ulrich, Verzijden, Timo, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ophthalmology, and Epidemiology
Subjects: 0301 basic medicine, genetic structures, Metabolite, Glutamine, Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13], Disease, Bioinformatics, Biochemistry, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], chemistry.chemical_compound, Macular Degeneration, 0302 clinical medicine, Medicine and Health Sciences, Metabolites, Geriatric Ophthalmology, Amino Acids, Multidisciplinary, Agricultural and Biological Sciences(all), Organic Compounds, Retinal Degeneration, Acidic Amino Acids, Discriminant Analysis, Neurochemistry, Neurotransmitters, Middle Aged, 3. Good health, Chemistry, Physical Sciences, Biomarker (medicine), Medicine, Retinal Disorders, Female, Metabolic Pathways, Glutamate, Metabolic Networks and Pathways, Research Article, Science, 03 medical and health sciences, Metabolomics, Age related, medicine, Humans, Least-Squares Analysis, General, Nutrition, Aged, Glutaminolysis, business.industry, Biochemistry, Genetics and Molecular Biology(all), Organic Chemistry, Chemical Compounds, Biology and Life Sciences, Proteins, Macular degeneration, medicine.disease, eye diseases, Diet, Ophthalmology, 030104 developmental biology, Metabolism, chemistry, Geriatrics, Macular Disorders, 030221 ophthalmology & optometry, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, sense organs, business, Biomarkers, Neuroscience
Abstract: Contains fulltext : 205500.pdf (Publisher’s version ) (Open Access) Age-related macular degeneration (AMD) is a common, progressive multifactorial vision-threatening disease and many genetic and environmental risk factors have been identified. The risk of AMD is influenced by lifestyle and diet, which may be reflected by an altered metabolic profile. Therefore, measurements of metabolites could identify biomarkers for AMD, and could aid in identifying high-risk individuals. Hypothesis-free technologies such as metabolomics have a great potential to uncover biomarkers or pathways that contribute to disease pathophysiology. To date, only a limited number of metabolomic studies have been performed in AMD. Here, we aim to contribute to the discovery of novel biomarkers and metabolic pathways for AMD using a targeted metabolomics approach of 188 metabolites. This study focuses on non-advanced AMD, since there is a need for biomarkers for the early stages of disease before severe visual loss has occurred. Targeted metabolomics was performed in 72 patients with early or intermediate AMD and 72 control individuals, and metabolites predictive for AMD were identified by a sparse partial least squares discriminant analysis. In our cohort, we identified four metabolite variables that were most predictive for early and intermediate stages of AMD. Increased glutamine and phosphatidylcholine diacyl C28:1 levels were detected in non-advanced AMD cases compared to controls, while the rate of glutaminolysis and the glutamine to glutamate ratio were reduced in non-advanced AMD. The association of glutamine with non-advanced AMD corroborates a recent report demonstrating an elevated glutamine level in early AMD using a different metabolomics technique. In conclusion, this study indicates that metabolomics is a suitable method for the discovery of biomarker candidates for AMD. In the future, larger metabolomics studies could add to the discovery of novel biomarkers in yet unknown AMD pathways and expand our insights in AMD pathophysiology.
Published: 2019
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45. Cytokine removal in human septic shock : where are we and where are we going?

Author: Eric Hoste, Olivier Joannes-Boyau, Rita Jacobs, Manu L N G Malbrain, Patrick M. Honore, Zsolt Molnár, Lui G. Forni, Supporting clinical sciences, Faculty of Medicine and Pharmacy, and Intensive Care
Subjects: medicine.medical_specialty, DAMPS, HIGH-VOLUME, POLYMYXIN-B HEMOPERFUSION, medicine.medical_treatment, Immune modulation, Blood purification, Modified delphi, Review, Cartridges, Critical Care and Intensive Care Medicine, Sepsis, Cytosorb, 03 medical and health sciences, SHORT-TERM SURVIVAL, 0302 clinical medicine, Septic shock, medicine, Medicine and Health Sciences, Intensive care medicine, IN-VIVO, Executive summary, PAMPS, business.industry, MORTALITY, lcsh:Medical emergencies. Critical care. Intensive care. First aid, 030208 emergency & critical care medicine, lcsh:RC86-88.9, Continuous haemofiltration, medicine.disease, INTENSIVE-CARE UNITS, DR EXPRESSION, SEVERE SEPSIS, Cytokine, 030228 respiratory system, Haemoperfusion, Cytokines, Narrative review, business, CRITICALLY-ILL PATIENTS, Sorbents
Abstract: Although improving, the mortality from septic shock still remains high despite increased international awareness. As a consequence, much effort has focused on alternative treatment strategies in an effort to improve outcomes. The application of blood purification therapies to improve immune homeostasis has been suggested as one such method, but these approaches, such as high-volume continuous haemofiltration or cytokine and/or endotoxin removal, have enjoyed little success to date. More recently, the use of sorbent technologies has attracted much attention. These adsorbers are highly effective at removing inflammatory mediators, in particular, cytokines, from the bloodstream. This narrative review is the executive summary of meetings held throughout the 6th International Fluid Academy Days in Antwerp, Belgium (Nov 23–25, 2017), focusing on the current understanding regarding the use of such adsorbers in humans with septic shock. We followed a modified Delphi approach involving a combination of evidence appraisal together with expert opinion in order to achieve recommendations for practice and, importantly, future research.
Published: 2019

46. Amino acids and vitamins status during continuous renal replacement therapy: An ancillary prospective observational study of a randomised control trial

Author: Catherine Fleureau, Olivier Joannes-Boyau, Antoine Dewitte, Alexandre Ouattara, Isabelle Redonnet-Vernhet, Mette M. Berger, Patrick M. Honore, Samir Mesli, Walter Picard, and Antoine G. Schneider
Subjects: medicine.medical_specialty, Continuous Renal Replacement Therapy, Critical Illness, medicine.medical_treatment, Critical Care and Intensive Care Medicine, Gastroenterology, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, medicine, Humans, Prospective Studies, 030212 general & internal medicine, Renal replacement therapy, Amino Acids, Wasting, Septic shock, business.industry, 030208 emergency & critical care medicine, Vitamins, General Medicine, Acute Kidney Injury, medicine.disease, Micronutrient, Renal Replacement Therapy, Glutamine, Anesthesiology and Pain Medicine, Parenteral nutrition, Lean body mass, medicine.symptom, business
Abstract: Background Continuous renal replacement therapy (CRRT) is associated with micronutrients loss. Current recommendations are to administer 1–1.5 g/kg/day of proteins during CRRT. We aim to evaluate the net effect of CRRT on amino acids (AA), vitamins A and C (Vit A, Vit C) levels. Methods This is a prospective observational study embedded within a randomised controlled trial comparing two CRRT doses in patients with septic shock. CRRT was provided in continuous veno-venous haemofiltration mode at a dose of either 35 ml/kg/h or 70 ml/kg/h. All patients received parenteral nutrition with standard trace elements and vitamins (protein intake 1 g/kg/d). We measured serum levels of glutamine, valine and alanine as well as Vit A and Vit C upon randomisation, study day four and eight. In addition, we measured a larger panel of AA in a subset of 11 patients. Results We included 30 patients (17 allocated to 70 ml/kg/h and 13 to 35 ml/kg/h CRRT). Before CRRT initiation, mean plasma levels of glutamine and valine, Vit A and Vit C were low. CRRT was not associated with any significant change in AA levels except for a decrease in cystein. It was associated with an increase in Vit A and a decrease in Vit C levels. CRRT dose had no impact on those nutrients blood levels. Conclusions Irrespective of dose, CRRT was associated with a decrease in cysteine and Vit C and an increase in Vit A with no significant change in other AA. Further studies should focus on lean mass wasting during CRRT.
Published: 2021
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47. Hospitalization costs and estimates of direct and indirect economic losses due to injury sustained in road traffic crashes: Results from a one-year cohort study in three European countries (The REHABILAID project)

Author: Vangelis Kotsyfos, Joannes Chliaoutakis, Maria Papadakaki, Marco von der Geest, Dietmar Otte, Chiara Orsi, Türker Özkan, Ottavia Eleonora Ferraro, Georgia Tzamalouka, Timo Lajunen, Maria-Aggeliki Stamouli, and Anna Morandi
Subjects: 050210 logistics & transportation, business.industry, 05 social sciences, Poison control, Critical Care and Intensive Care Medicine, medicine.disease, Intensive care unit, Suicide prevention, Occupational safety and health, law.invention, 03 medical and health sciences, Indirect costs, 0302 clinical medicine, law, Intensive care, 0502 economics and business, Injury prevention, Emergency Medicine, Medicine, Surgery, 030212 general & internal medicine, Medical emergency, business, Cohort study
Abstract: Introduction The financial cost of injuries sustained in road traffic crashes is high for victims, families and national budgets, but there is limited information on the cost of injury from the victims’ perspective, especially in terms of the hard-to-reach multi-trauma patient population such as those admitted to the intensive care units of hospitals. Materials and methods The current study received funding by the European Commission Directorate-General Mobility and Transport. It is a prospective, prevalence-based, cost-of-illness study. Participants admitted in the intensive care units of seven public hospitals in Greece, Germany and Italy because of injuries from road traffic crashes, during one year, were enrolled in the study. Patients were followed-up for one year after the intensive care unit admission to report emerging direct and indirect costs related to their injury. Results A total of 120 people were enrolled. Males, those aged 25–49, motorcyclists and those severely injured (Maximum Abbreviated Injury Scale (MAIS) 3+) with highest severity located at the central part of the body, accounted for the highest percentages of both the direct and indirect injury costs. The highest average direct costs were for females, those aged 50–64, pedestrians and those slightly injured (MAIS 1 or 2) with highest severity at the central region of the body. Males, patients aged 25–49, car passengers and truck drivers as well as those slightly injured (MAIS 1 or 2) with highest severity at multiple locations were over-represented in the average indirect costs. Conclusions Those groups that account for a high percentage of injury costs should be targeted in health policy initiatives.
Published: 2016
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48. Biomarkers in critical illness: have we made progress?

Author: Willem Boer, Olivier Joannes-Boyau, Rita Jacobs, Herbert D. Spapen, Viola Van Gorp, Inne Hendrickx, Jouke De Regt, Patrick M. Honore, Elisabeth De Waele, Supporting clinical sciences, Internal Medicine Specializations, Faculty of Medicine and Pharmacy, Research Group Critical Care and Cerebral Resuscitation, and Intensive Care
Subjects: ARDS, medicine.medical_specialty, International Journal of Nephrology and Renovascular Disease, Review, 03 medical and health sciences, 0302 clinical medicine, Sepsis, medicine, 030212 general & internal medicine, Intensive care medicine, Medicine(all), Critically ill, business.industry, Organ dysfunction, Acute kidney injury, Translational medicine, biomarkers, 030208 emergency & critical care medicine, Acute Kidney Injury, medicine.disease, Surgery, Nephrology, Critical illness, Biomarker (medicine), medicine.symptom, business
Abstract: Patrick M Honore,1 Rita Jacobs,1 Inne Hendrickx,1 Elisabeth De Waele,1 Viola Van Gorp,1 Olivier Joannes-Boyau,2 Jouke De Regt,1 Willem Boer,3 Herbert D Spapen1 1Intensive Care Unit, Universitair Ziekenhuis Brussel, VUB University, Brussels, Belgium; 2Intensive Care Unit, Hopital Haut Leveque, University of Bordeaux 2, Bordeaux, France; 3Intensive Care Unit, Ziekenhuis Oost-Limburg, Genk, Belgium Abstract: Biomarkers have emerged as exemplary key players in translational medicine. Many have been assessed for timely recognition, early treatment, and adequate follow-up for a variety of pathologies. Biomarker sensitivity has improved considerably over the last years but specificity remains poor, in particular when two “marker-sensitive” conditions overlap in one patient. Biomarker research holds an enormous potential for diagnostic and prognostic purposes in postoperative and critically ill patients who present varying degrees of inflammation, infection, and concomitant (sub)acute organ dysfunction or failure. Despite a remarkable progress in development and testing, biomarkers are not yet ready for routine use at the bedside. Keywords: biomarkers, acute kidney injury, sepsis, ARDS
Published: 2016
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49. A genetic variant in NRP1 is associated with worse response to ranibizumab treatment in neovascular age-related macular degeneration

Author: Amer Omar, Sascha Fauser, Joannes M. M. Groenewoud, Laura Lorés-Motta, Philipp S. Muether, Anneke I. den Hollander, Robert K. Koenekoop, Carel B. Hoyng, Eiko K. de Jong, Freekje van Asten, John C. Chen, and Dzenita Smailhodzic
Subjects: Male, 0301 basic medicine, Oncology, Visual acuity, Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13], Sensory disorders Radboud Institute for Health Sciences [Radboudumc 12], Angiogenesis Inhibitors, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], 0302 clinical medicine, Genotype, antiangiogenic drugs, General Pharmacology, Toxicology and Pharmaceutics, Genetics (clinical), Aged, 80 and over, personalized medicine, single-nucleotide polymorphism, 3. Good health, Treatment Outcome, Cohort, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Molecular Medicine, Female, medicine.symptom, lucentis, medicine.drug, medicine.medical_specialty, Single-nucleotide polymorphism, pathologic neovascularization, Polymorphism, Single Nucleotide, Loading dose, 03 medical and health sciences, Ranibizumab, Internal medicine, Genetic variation, Genetics, medicine, Humans, age-related macular degeneration, Molecular Biology, Aged, business.industry, Original Articles, choroid neovascularization, Macular degeneration, medicine.disease, Vascular Endothelial Growth Factor Receptor-2, Neuropilin-1, 030104 developmental biology, Wet Macular Degeneration, 030221 ophthalmology & optometry, business
Abstract: Supplemental Digital Content is available in the text., Objective The aim of the study was to investigate the role of single-nucleotide polymorphisms (SNPs) located in the neuropilin-1 (NRP1) gene in treatment response to antivascular endothelial growth factor (VEGF) therapy for neovascular age-related macular degeneration (nvAMD). Methods Four SNPs in the NRP1 gene (rs2229935, rs2247383, rs2070296, and rs2804495) were genotyped in a study cohort of 377 nvAMD patients who received the loading dose of three monthly ranibizumab injections. Treatment response was assessed as the change in visual acuity after three monthly loading injections compared with baseline. Results SNP rs2070296 was associated with change in visual acuity after 3 months of treatment. Patients carrying the GA or AA genotypes performed significantly worse than individuals carrying the GG genotype (P=0.01). A cumulative effect of rs2070296 in the NRP1 gene and rs4576072 located in the VEGF receptor 2 (VEGFR2 or KDR) gene, previously associated with treatment response, was observed. Patients carrying two risk alleles performed significantly worse than patients carrying zero or one risk allele (P=0.03), and patients with more than two risk alleles responded even worse to the therapy (P=3×10–3). The combined effect of these two SNPs on the response was also seen after 6 and 12 months of treatment. Conclusion This study suggests that genetic variation in NRP1, a key molecule in VEGFA-driven neovascularization, influences treatment response to ranibizumab in nvAMD patients. The results of this study may be used to generate prediction models for treatment response, which in the future may help tailor medical care to individual needs.
Published: 2016
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50. Abstract DDT02-04: A novel PRMT5 inhibitor with potent in vitro and in vivo activity in preclinical lung cancer models

Author: Dushen Chetty, Matthew V. Lorenzi, Sylvie Laquerre, Gaston Stanislas Marcella Diels, Edward C. Lawson, Carol Yanovich, Italo Poggesi, Ivan Somers, Dana Gaffney, Wim Bert Griet Schepens, Hillary Millar, Weimei Sun, Tongfei Wu, Lijs Beke, Viellevoye Marcel, Marc Du Jardin, Petra Vinken, Erika van Heerde, Tinne Verhulst, James P. Edwards, Dirk Brehmer, Barbara Herkert, Geert Mannens, Vineet Pande, Alain Philippe Poncelet, Christopher Moy, An Boeckx, Marc Parade, Thomas Nys, Jan-Willem Thuring, Lieven Meerpoel, and Joannes T. M. Linders
Subjects: 0301 basic medicine, Cancer Research, Methyltransferase, business.industry, Protein arginine methyltransferase 5, Methylation, medicine.disease_cause, medicine.disease, In vitro, 03 medical and health sciences, 030104 developmental biology, Oncology, In vivo, Cancer research, medicine, Cytotoxic T cell, Carcinogenesis, business, Lung cancer
Abstract: PRMT5 is a type II methyltransferase that specifically adds methyl groups to arginine as a long-lasting post-translational modification. The PRMT5/MEP50 complex regulates a plethora of cellular processes, such as epigenetics and splicing, which are notable events involved in tumorigenesis. Although not frequently mutated or amplified in tumors, elevated PRMT5 protein levels in lung and hematologic cancers are correlated with poorer survival. The PRMT5 inhibitor JNJ-64619178 has been selected as a clinical candidate based on its high selectivity and potency (subnanomolar range) under different in vitro and cellular conditions, paired with favorable pharmacokinetics and safety properties. JNJ-64619178 binds into the SAM binding pocket and reaches the substrate binding pocket to inhibit PRMT5/MEP50 function in a time-dependent manner. Broad cell line panel profiling of JNJ-64619178 revealed a wide range of sensitivity, which is indicative of a genomic dependency instead of a general cytotoxic on-target consequence of PRMT5 inhibition. Further investigations indicate a synthetic lethal correlation between PRMT5 inhibition and key cancer driver pathways. JNJ-64619178, dosed orally (10 mg/kg, every day), showed selective and efficient blockage of the methylation of SMD1/3 proteins, which are crucial components of the spliceosome and substrates of PRMT5/MEP50. JNJ-64619178 also demonstrated tumor regression in a biomarker-driven human small cell lung cancer xenograft model (NCI-H1048) and prolonged tumor growth inhibition after dosing cessation. In rodent and nonrodent toxicology studies, a tolerated dose of JNJ-64619178 has been identified, with the observed toxicity consistent with on-target activity. In summary, JNJ-64619178 has a favorable preclinical package that supports clinical testing in patients diagnosed with lung cancer and hematologic malignancies. Citation Format: Dirk Brehmer, Tongfei Wu, Geert Mannens, Lijs Beke, Petra Vinken, Dana Gaffney, Weimei Sun, Vineet Pande, Jan-Willem Thuring, Hillary Millar, Italo Poggesi, Ivan Somers, An Boeckx, Marc Parade, Erika van Heerde, Thomas Nys, Carol Yanovich, Barbara Herkert, Tinne Verhulst, Marc Du Jardin, Lieven Meerpoel, Christopher Moy, Gaston Diels, Marcel Viellevoye, Wim Schepens, Alain Poncelet, Joannes T. Linders, Edward C. Lawson, James P. Edwards, Dushen Chetty, Sylvie Laquerre, Matthew V. Lorenzi. A novel PRMT5 inhibitor with potent in vitro and in vivo activity in preclinical lung cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr DDT02-04. doi:10.1158/1538-7445.AM2017-DDT02-04
Published: 2017
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