Author: "A. Valentini" / Topic: humans - Searchworks@Jio Institute Digital Library Search Results

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3,112 results on '"A. Valentini"'

1. An ontology-based knowledge graph for representing interactions involving RNA molecules

Author: Cavalleri, Emanuele, Cabri, Alberto, Soto-Gomez, Mauricio, Bonfitto, Sara, Perlasca, Paolo, Gliozzo, Jessica, Callahan, Tiffany J, Reese, Justin, Robinson, Peter N, Casiraghi, Elena, Valentini, Giorgio, and Mesiti, Marco
Subjects: Biological Sciences, Bioinformatics and Computational Biology, Genetics, Networking and Information Technology R&D (NITRD), RNA, Humans, Biological Ontologies
Abstract: The "RNA world" represents a novel frontier for the study of fundamental biological processes and human diseases and is paving the way for the development of new drugs tailored to each patient's biomolecular characteristics. Although scientific data about coding and non-coding RNA molecules are constantly produced and available from public repositories, they are scattered across different databases and a centralized, uniform, and semantically consistent representation of the "RNA world" is still lacking. We propose RNA-KG, a knowledge graph (KG) encompassing biological knowledge about RNAs gathered from more than 60 public databases, integrating functional relationships with genes, proteins, and chemicals and ontologically grounded biomedical concepts. To develop RNA-KG, we first identified, pre-processed, and characterized each data source; next, we built a meta-graph that provides an ontological description of the KG by representing all the bio-molecular entities and medical concepts of interest in this domain, as well as the types of interactions connecting them. Finally, we leveraged an instance-based semantically abstracted knowledge model to specify the ontological alignment according to which RNA-KG was generated. RNA-KG can be downloaded in different formats and also queried by a SPARQL endpoint. A thorough topological analysis of the resulting heterogeneous graph provides further insights into the characteristics of the "RNA world". RNA-KG can be both directly explored and visualized, and/or analyzed by applying computational methods to infer bio-medical knowledge from its heterogeneous nodes and edges. The resource can be easily updated with new experimental data, and specific views of the overall KG can be extracted according to the bio-medical problem to be studied.
Published: 2024

2. Association of post-COVID phenotypic manifestations with new-onset psychiatric disease

Author: Coleman, Ben, Casiraghi, Elena, Callahan, Tiffany J, Blau, Hannah, Chan, Lauren E, Laraway, Bryan, Clark, Kevin B, Re’em, Yochai, Gersing, Ken R, Wilkins, Kenneth J, Harris, Nomi L, Valentini, Giorgio, Haendel, Melissa A, Reese, Justin T, and Robinson, Peter N
Subjects: Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Infectious Diseases, Coronaviruses, Prevention, Emerging Infectious Diseases, Mental Health, Minority Health, Clinical Research, Coronaviruses Disparities and At-Risk Populations, Brain Disorders, 2.4 Surveillance and distribution, Good Health and Well Being, Humans, COVID-19, Male, Female, Mental Disorders, Middle Aged, Adult, Retrospective Studies, SARS-CoV-2, Aged, Phenotype, Post-Acute COVID-19 Syndrome, Comorbidity, Electronic Health Records, Young Adult, Risk Factors, Adolescent, Public Health and Health Services, Psychology, Clinical sciences, Biological psychology
Abstract: Acute COVID-19 infection can be followed by diverse clinical manifestations referred to as Post Acute Sequelae of SARS-CoV2 Infection (PASC). Studies have shown an increased risk of being diagnosed with new-onset psychiatric disease following a diagnosis of acute COVID-19. However, it was unclear whether non-psychiatric PASC-associated manifestations (PASC-AMs) are associated with an increased risk of new-onset psychiatric disease following COVID-19. A retrospective electronic health record (EHR) cohort study of 2,391,006 individuals with acute COVID-19 was performed to evaluate whether non-psychiatric PASC-AMs are associated with new-onset psychiatric disease. Data were obtained from the National COVID Cohort Collaborative (N3C), which has EHR data from 76 clinical organizations. EHR codes were mapped to 151 non-psychiatric PASC-AMs recorded 28-120 days following SARS-CoV-2 diagnosis and before diagnosis of new-onset psychiatric disease. Association of newly diagnosed psychiatric disease with age, sex, race, pre-existing comorbidities, and PASC-AMs in seven categories was assessed by logistic regression. There were significant associations between a diagnosis of any psychiatric disease and five categories of PASC-AMs with odds ratios highest for neurological, cardiovascular, and constitutional PASC-AMs with odds ratios of 1.31, 1.29, and 1.23 respectively. Secondary analysis revealed that the proportions of 50 individual clinical features significantly differed between patients diagnosed with different psychiatric diseases. Our study provides evidence for association between non-psychiatric PASC-AMs and the incidence of newly diagnosed psychiatric disease. Significant associations were found for features related to multiple organ systems. This information could prove useful in understanding risk stratification for new-onset psychiatric disease following COVID-19. Prospective studies are needed to corroborate these findings.
Published: 2024

3. Generalisable long COVID subtypes: Findings from the NIH N3C and RECOVER programmes

Author: Reese, Justin T, Blau, Hannah, Casiraghi, Elena, Bergquist, Timothy, Loomba, Johanna J, Callahan, Tiffany J, Laraway, Bryan, Antonescu, Corneliu, Coleman, Ben, Gargano, Michael, Wilkins, Kenneth J, Cappelletti, Luca, Fontana, Tommaso, Ammar, Nariman, Antony, Blessy, Murali, TM, Caufield, J Harry, Karlebach, Guy, McMurry, Julie A, Williams, Andrew, Moffitt, Richard, Banerjee, Jineta, Solomonides, Anthony E, Davis, Hannah, Kostka, Kristin, Valentini, Giorgio, Sahner, David, Chute, Christopher G, Madlock-Brown, Charisse, Haendel, Melissa A, Robinson, Peter N, Consortium, N3C, Spratt, Heidi, Visweswaran, Shyam, Flack, Joseph Eugene, Yoo, Yun Jae, Gabriel, Davera, Alexander, G Caleb, Mehta, Hemalkumar B, Liu, Feifan, Miller, Robert T, Wong, Rachel, Hill, Elaine L, Consortium, RECOVER, Thorpe, Lorna E, and Divers, Jasmin
Subjects: Biomedical and Clinical Sciences, Clinical Sciences, Infectious Diseases, Precision Medicine, Coronaviruses, Emerging Infectious Diseases, Machine Learning and Artificial Intelligence, Networking and Information Technology R&D (NITRD), Good Health and Well Being, Humans, COVID-19, Disease Progression, Post-Acute COVID-19 Syndrome, SARS-CoV-2, N3C Consortium, RECOVER Consortium, Human Phenotype Ontology, Long COVID, Machine learning, Precision medicine, Semantic similarity, Public Health and Health Services, Clinical sciences, Epidemiology
Abstract: BackgroundStratification of patients with post-acute sequelae of SARS-CoV-2 infection (PASC, or long COVID) would allow precision clinical management strategies. However, long COVID is incompletely understood and characterised by a wide range of manifestations that are difficult to analyse computationally. Additionally, the generalisability of machine learning classification of COVID-19 clinical outcomes has rarely been tested.MethodsWe present a method for computationally modelling PASC phenotype data based on electronic healthcare records (EHRs) and for assessing pairwise phenotypic similarity between patients using semantic similarity. Our approach defines a nonlinear similarity function that maps from a feature space of phenotypic abnormalities to a matrix of pairwise patient similarity that can be clustered using unsupervised machine learning.FindingsWe found six clusters of PASC patients, each with distinct profiles of phenotypic abnormalities, including clusters with distinct pulmonary, neuropsychiatric, and cardiovascular abnormalities, and a cluster associated with broad, severe manifestations and increased mortality. There was significant association of cluster membership with a range of pre-existing conditions and measures of severity during acute COVID-19. We assigned new patients from other healthcare centres to clusters by maximum semantic similarity to the original patients, and showed that the clusters were generalisable across different hospital systems. The increased mortality rate originally identified in one cluster was consistently observed in patients assigned to that cluster in other hospital systems.InterpretationSemantic phenotypic clustering provides a foundation for assigning patients to stratified subgroups for natural history or therapy studies on PASC.FundingNIH (TR002306/OT2HL161847-01/OD011883/HG010860), U.S.D.O.E. (DE-AC02-05CH11231), Donald A. Roux Family Fund at Jackson Laboratory, Marsico Family at CU Anschutz.
Published: 2023

4. Metformin is associated with reduced COVID-19 severity in patients with prediabetes

Author: Chan, Lauren E, Casiraghi, Elena, Laraway, Bryan, Coleman, Ben, Blau, Hannah, Zaman, Adnin, Harris, Nomi L, Wilkins, Kenneth, Antony, Blessy, Gargano, Michael, Valentini, Giorgio, Sahner, David, Haendel, Melissa, Robinson, Peter N, Bramante, Carolyn, Reese, Justin, and consortium, on behalf of the N3C
Subjects: Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Good Health and Well Being, Female, Humans, Metformin, Retrospective Studies, COVID-19, Prediabetic State, Polycystic Ovary Syndrome, Hypoglycemic Agents, Thyroxine, N3C consortium, Glycemia, Polycystic ovary syndrome, Prediabetes, Public Health and Health Services, Psychology, Endocrinology & Metabolism, Clinical sciences, Public health, Clinical and health psychology
Abstract: AimsStudies suggest that metformin is associated with reduced COVID-19 severity in individuals with diabetes compared to other antihyperglycemics. We assessed if metformin is associated with reduced incidence of severe COVID-19 for patients with prediabetes or polycystic ovary syndrome (PCOS), common diseases that increase the risk of severe COVID-19.MethodsThis observational, retrospective study utilized EHR data from 52 hospitals for COVID-19 patients with PCOS or prediabetes treated with metformin or levothyroxine/ondansetron (controls). After balancing via inverse probability score weighting, associations with COVID-19 severity were assessed by logistic regression.ResultsIn the prediabetes cohort, when compared to levothyroxine, metformin was associated with a significantly lower incidence of COVID-19 with "mild-ED" or worse (OR [95% CI]: 0.636, [0.455-0.888]) and "moderate" or worse severity (0.493 [0.339-0.718]). Compared to ondansetron, metformin was associated with lower incidence of "mild-ED" or worse severity (0.039 [0.026-0.057]), "moderate" or worse (0.045 [0.03-0.069]), "severe" or worse (0.183 [0.077-0.431]), and "mortality/hospice" (0.223 [0.071-0.694]). For PCOS, metformin showed no significant differences in severity compared to levothyroxine, but was associated with a significantly lower incidence of "mild-ED" or worse (0.101 [0.061-0.166]), and "moderate" or worse (0.094 [0.049-0.18]) COVID-19 outcome compared to ondansetron.ConclusionsMetformin use is associated with less severe COVID-19 in patients with prediabetes or PCOS.
Published: 2022

5. NSAID use and clinical outcomes in COVID-19 patients: a 38-center retrospective cohort study

Author: Reese, Justin T, Coleman, Ben, Chan, Lauren, Blau, Hannah, Callahan, Tiffany J, Cappelletti, Luca, Fontana, Tommaso, Bradwell, Katie R, Harris, Nomi L, Casiraghi, Elena, Valentini, Giorgio, Karlebach, Guy, Deer, Rachel, McMurry, Julie A, Haendel, Melissa A, Chute, Christopher G, Pfaff, Emily, Moffitt, Richard, Spratt, Heidi, Singh, Jasvinder A, Mungall, Christopher J, Williams, Andrew E, and Robinson, Peter N
Subjects: Microbiology, Biological Sciences, Emerging Infectious Diseases, Coronaviruses, Lung, Infectious Diseases, Kidney Disease, Good Health and Well Being, Acute Kidney Injury, Anti-Inflammatory Agents, Non-Steroidal, COVID-19, COVID-19 Testing, Cohort Studies, Humans, Pandemics, Retrospective Studies, NSAIDs, Cyclooxygenase inhibitors, Observational study, Medical Microbiology, Virology
Abstract: BackgroundNon-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to reduce pain, fever, and inflammation but have been associated with complications in community-acquired pneumonia. Observations shortly after the start of the COVID-19 pandemic in 2020 suggested that ibuprofen was associated with an increased risk of adverse events in COVID-19 patients, but subsequent observational studies failed to demonstrate increased risk and in one case showed reduced risk associated with NSAID use.MethodsA 38-center retrospective cohort study was performed that leveraged the harmonized, high-granularity electronic health record data of the National COVID Cohort Collaborative. A propensity-matched cohort of 19,746 COVID-19 inpatients was constructed by matching cases (treated with NSAIDs at the time of admission) and 19,746 controls (not treated) from 857,061 patients with COVID-19 available for analysis. The primary outcome of interest was COVID-19 severity in hospitalized patients, which was classified as: moderate, severe, or mortality/hospice. Secondary outcomes were acute kidney injury (AKI), extracorporeal membrane oxygenation (ECMO), invasive ventilation, and all-cause mortality at any time following COVID-19 diagnosis.ResultsLogistic regression showed that NSAID use was not associated with increased COVID-19 severity (OR: 0.57 95% CI: 0.53-0.61). Analysis of secondary outcomes using logistic regression showed that NSAID use was not associated with increased risk of all-cause mortality (OR 0.51 95% CI: 0.47-0.56), invasive ventilation (OR: 0.59 95% CI: 0.55-0.64), AKI (OR: 0.67 95% CI: 0.63-0.72), or ECMO (OR: 0.51 95% CI: 0.36-0.7). In contrast, the odds ratios indicate reduced risk of these outcomes, but our quantitative bias analysis showed E-values of between 1.9 and 3.3 for these associations, indicating that comparatively weak or moderate confounder associations could explain away the observed associations.ConclusionsStudy interpretation is limited by the observational design. Recording of NSAID use may have been incomplete. Our study demonstrates that NSAID use is not associated with increased COVID-19 severity, all-cause mortality, invasive ventilation, AKI, or ECMO in COVID-19 inpatients. A conservative interpretation in light of the quantitative bias analysis is that there is no evidence that NSAID use is associated with risk of increased severity or the other measured outcomes. Our results confirm and extend analogous findings in previous observational studies using a large cohort of patients drawn from 38 centers in a nationally representative multicenter database.
Published: 2022

6. Crenigacestat blocking notch pathway reduces liver fibrosis in the surrounding ecosystem of intrahepatic CCA viaTGF-β inhibition

Author: Mancarella, Serena, Gigante, Isabella, Serino, Grazia, Pizzuto, Elena, Dituri, Francesco, Valentini, Maria F, Wang, Jingxiao, Chen, Xin, Armentano, Raffaele, Calvisi, Diego F, and Giannelli, Gianluigi
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Digestive Diseases, Rare Diseases, Liver Cancer, Liver Disease, Humans, Transforming Growth Factor beta1, Ecosystem, Cholangiocarcinoma, Liver, Bile Duct Neoplasms, Bile Ducts, Intrahepatic, Fibrosis, Tumor Microenvironment, Tissue microenvironment, Liver fibrosis, Tumor stroma crosstalk, Crenigacestat, Smad2, Oncology and carcinogenesis
Abstract: BackgroundIntrahepatic cholangiocarcinoma (iCCA) is a highly malignant tumor characterized by an intensive desmoplastic reaction due to the exaggerated presence of the extracellular (ECM) matrix components. Liver fibroblasts close to the tumor, activated by transforming growth factor (TGF)-β1 and expressing high levels of α-smooth muscle actin (α-SMA), become cancer-associated fibroblasts (CAFs). CAFs are deputed to produce and secrete ECM components and crosstalk with cancer cells favoring tumor progression and resistance to therapy. Overexpression of Notch signaling is implicated in CCA development and growth. The study aimed to determine the effectiveness of the Notch inhibitor, Crenigacestat, on the surrounding microenvironment of iCCA.MethodsWe investigated Crenigacestat's effectiveness in a PDX model of iCCA and human primary culture of CAFs isolated from patients with iCCA.ResultsIn silico analysis of transcriptomic profiling from PDX iCCA tissues treated with Crenigacestat highlighted "liver fibrosis" as one of the most modulated pathways. In the iCCA PDX model, Crenigacestat treatment significantly (p
Published: 2022

7. The Deep Genome Project

Author: Lloyd, KC Kent, Adams, David J, Baynam, Gareth, Beaudet, Arthur L, Bosch, Fatima, Boycott, Kym M, Braun, Robert E, Caulfield, Mark, Cohn, Ronald, Dickinson, Mary E, Dobbie, Michael S, Flenniken, Ann M, Flicek, Paul, Galande, Sanjeev, Gao, Xiang, Grobler, Anne, Heaney, Jason D, Herault, Yann, de Angelis, Martin Hrabě, Lupski, James R, Lyonnet, Stanislas, Mallon, Ann-Marie, Mammano, Fabio, MacRae, Calum A, McInnes, Roderick, McKerlie, Colin, Meehan, Terrence F, Murray, Stephen A, Nutter, Lauryl MJ, Obata, Yuichi, Parkinson, Helen, Pepper, Michael S, Sedlacek, Radislav, Seong, Je Kyung, Shiroishi, Toshihiko, Smedley, Damian, Tocchini-Valentini, Glauco, Valle, David, Wang, Chi-Kuang Leo, Wells, Sara, White, Jacqueline, Wurst, Wolfgang, Xu, Ying, and Brown, Steve DM
Subjects: Animals, Genes, Genome, Humans, Mice, Mutation, Phenotype, Proteins, Environmental Sciences, Biological Sciences, Information and Computing Sciences, Bioinformatics
Published: 2020

8. The Image Biomarker Standardization Initiative: Standardized Quantitative Radiomics for High-Throughput Image-based Phenotyping

Author: Zwanenburg, Alex, Vallières, Martin, Abdalah, Mahmoud A, Aerts, Hugo JWL, Andrearczyk, Vincent, Apte, Aditya, Ashrafinia, Saeed, Bakas, Spyridon, Beukinga, Roelof J, Boellaard, Ronald, Bogowicz, Marta, Boldrini, Luca, Buvat, Irène, Cook, Gary JR, Davatzikos, Christos, Depeursinge, Adrien, Desseroit, Marie-Charlotte, Dinapoli, Nicola, Dinh, Cuong Viet, Echegaray, Sebastian, El Naqa, Issam, Fedorov, Andriy Y, Gatta, Roberto, Gillies, Robert J, Goh, Vicky, Götz, Michael, Guckenberger, Matthias, Ha, Sung Min, Hatt, Mathieu, Isensee, Fabian, Lambin, Philippe, Leger, Stefan, Leijenaar, Ralph TH, Lenkowicz, Jacopo, Lippert, Fiona, Losnegård, Are, Maier-Hein, Klaus H, Morin, Olivier, Müller, Henning, Napel, Sandy, Nioche, Christophe, Orlhac, Fanny, Pati, Sarthak, Pfaehler, Elisabeth AG, Rahmim, Arman, Rao, Arvind UK, Scherer, Jonas, Siddique, Muhammad Musib, Sijtsema, Nanna M, Socarras Fernandez, Jairo, Spezi, Emiliano, Steenbakkers, Roel JHM, Tanadini-Lang, Stephanie, Thorwarth, Daniela, Troost, Esther GC, Upadhaya, Taman, Valentini, Vincenzo, van Dijk, Lisanne V, van Griethuysen, Joost, van Velden, Floris HP, Whybra, Philip, Richter, Christian, and Löck, Steffen
Subjects: Biomedical Imaging, Cancer, Bioengineering, Clinical Trials and Supportive Activities, Clinical Research, Good Health and Well Being, Biomarkers, Calibration, Fluorodeoxyglucose F18, Humans, Image Processing, Computer-Assisted, Lung Neoplasms, Magnetic Resonance Imaging, Phantoms, Imaging, Phenotype, Positron-Emission Tomography, Radiopharmaceuticals, Reproducibility of Results, Sarcoma, Software, Tomography, X-Ray Computed, Medical and Health Sciences, Nuclear Medicine & Medical Imaging
Abstract: Background Radiomic features may quantify characteristics present in medical imaging. However, the lack of standardized definitions and validated reference values have hampered clinical use. Purpose To standardize a set of 174 radiomic features. Materials and Methods Radiomic features were assessed in three phases. In phase I, 487 features were derived from the basic set of 174 features. Twenty-five research teams with unique radiomics software implementations computed feature values directly from a digital phantom, without any additional image processing. In phase II, 15 teams computed values for 1347 derived features using a CT image of a patient with lung cancer and predefined image processing configurations. In both phases, consensus among the teams on the validity of tentative reference values was measured through the frequency of the modal value and classified as follows: less than three matches, weak; three to five matches, moderate; six to nine matches, strong; 10 or more matches, very strong. In the final phase (phase III), a public data set of multimodality images (CT, fluorine 18 fluorodeoxyglucose PET, and T1-weighted MRI) from 51 patients with soft-tissue sarcoma was used to prospectively assess reproducibility of standardized features. Results Consensus on reference values was initially weak for 232 of 302 features (76.8%) at phase I and 703 of 1075 features (65.4%) at phase II. At the final iteration, weak consensus remained for only two of 487 features (0.4%) at phase I and 19 of 1347 features (1.4%) at phase II. Strong or better consensus was achieved for 463 of 487 features (95.1%) at phase I and 1220 of 1347 features (90.6%) at phase II. Overall, 169 of 174 features were standardized in the first two phases. In the final validation phase (phase III), most of the 169 standardized features could be excellently reproduced (166 with CT; 164 with PET; and 164 with MRI). Conclusion A set of 169 radiomics features was standardized, which enabled verification and calibration of different radiomics software. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Kuhl and Truhn in this issue.
Published: 2020

9. Soft windowing application to improve analysis of high-throughput phenotyping data

Author: Haselimashhadi, Hamed, Mason, Jeremy C, Munoz-Fuentes, Violeta, López-Gómez, Federico, Babalola, Kolawole, Acar, Elif F, Kumar, Vivek, White, Jacqui, Flenniken, Ann M, King, Ruairidh, Straiton, Ewan, Seavitt, John Richard, Gaspero, Angelina, Garza, Arturo, Christianson, Audrey E, Hsu, Chih-Wei, Reynolds, Corey L, Lanza, Denise G, Lorenzo, Isabel, Green, Jennie R, Gallegos, Juan J, Bohat, Ritu, Samaco, Rodney C, Veeraragavan, Surabi, Kim, Jong Kyoung, Miller, Gregor, Fuchs, Helmult, Garrett, Lillian, Becker, Lore, Kang, Yeon Kyung, Clary, David, Cho, Soo Young, Tamura, Masaru, Tanaka, Nobuhiko, Soo, Kyung Dong, Bezginov, Alexandr, About, Ghina Bou, Champy, Marie-France, Vasseur, Laurent, Leblanc, Sophie, Meziane, Hamid, Selloum, Mohammed, Reilly, Patrick T, Spielmann, Nadine, Maier, Holger, Gailus-Durner, Valerie, Sorg, Tania, Hiroshi, Masuya, Yuichi, Obata, Heaney, Jason D, Dickinson, Mary E, Wolfgang, Wurst, Tocchini-Valentini, Glauco P, Lloyd, Kevin C Kent, McKerlie, Colin, Seong, Je Kyung, Yann, Herault, de Angelis, Martin Hrabé, Brown, Steve DM, Smedley, Damian, Flicek, Paul, Mallon, Ann-Marie, Parkinson, Helen, and Meehan, Terrence F
Subjects: Biological Sciences, Genetics, Animals, Genetic Association Studies, Humans, Mice, Phenotype, Population Health, Software, Mathematical Sciences, Information and Computing Sciences, Bioinformatics, Biological sciences, Information and computing sciences, Mathematical sciences
Abstract: MotivationHigh-throughput phenomic projects generate complex data from small treatment and large control groups that increase the power of the analyses but introduce variation over time. A method is needed to utlize a set of temporally local controls that maximizes analytic power while minimizing noise from unspecified environmental factors.ResultsHere we introduce 'soft windowing', a methodological approach that selects a window of time that includes the most appropriate controls for analysis. Using phenotype data from the International Mouse Phenotyping Consortium (IMPC), adaptive windows were applied such that control data collected proximally to mutants were assigned the maximal weight, while data collected earlier or later had less weight. We applied this method to IMPC data and compared the results with those obtained from a standard non-windowed approach. Validation was performed using a resampling approach in which we demonstrate a 10% reduction of false positives from 2.5 million analyses. We applied the method to our production analysis pipeline that establishes genotype-phenotype associations by comparing mutant versus control data. We report an increase of 30% in significant P-values, as well as linkage to 106 versus 99 disease models via phenotype overlap with the soft-windowed and non-windowed approaches, respectively, from a set of 2082 mutant mouse lines. Our method is generalizable and can benefit large-scale human phenomic projects such as the UK Biobank and the All of Us resources.Availability and implementationThe method is freely available in the R package SmoothWin, available on CRAN http://CRAN.R-project.org/package=SmoothWin.Supplementary informationSupplementary data are available at Bioinformatics online.
Published: 2020

10. Human and mouse essentiality screens as a resource for disease gene discovery

Author: Cacheiro, Pilar, Muñoz-Fuentes, Violeta, Murray, Stephen A, Dickinson, Mary E, Bucan, Maja, Nutter, Lauryl MJ, Peterson, Kevin A, Haselimashhadi, Hamed, Flenniken, Ann M, Morgan, Hugh, Westerberg, Henrik, Konopka, Tomasz, Hsu, Chih-Wei, Christiansen, Audrey, Lanza, Denise G, Beaudet, Arthur L, Heaney, Jason D, Fuchs, Helmut, Gailus-Durner, Valerie, Sorg, Tania, Prochazka, Jan, Novosadova, Vendula, Lelliott, Christopher J, Wardle-Jones, Hannah, Wells, Sara, Teboul, Lydia, Cater, Heather, Stewart, Michelle, Hough, Tertius, Wurst, Wolfgang, Sedlacek, Radislav, Adams, David J, Seavitt, John R, Tocchini-Valentini, Glauco, Mammano, Fabio, Braun, Robert E, McKerlie, Colin, Herault, Yann, de Angelis, Martin Hrabě, Mallon, Ann-Marie, Lloyd, KC Kent, Brown, Steve DM, Parkinson, Helen, Meehan, Terrence F, and Smedley, Damian
Subjects: Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Biotechnology, Human Genome, Prevention, 2.1 Biological and endogenous factors, Aetiology, Generic health relevance, Good Health and Well Being, Animals, Disease, Genes, Essential, Genetic Association Studies, Genomics, Humans, Mice, Mice, Knockout, Genomics England Research Consortium, International Mouse Phenotyping Consortium
Abstract: The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery.
Published: 2020

11. The CAFA challenge reports improved protein function prediction and new functional annotations for hundreds of genes through experimental screens

Author: Zhou, Naihui, Jiang, Yuxiang, Bergquist, Timothy R, Lee, Alexandra J, Kacsoh, Balint Z, Crocker, Alex W, Lewis, Kimberley A, Georghiou, George, Nguyen, Huy N, Hamid, Md Nafiz, Davis, Larry, Dogan, Tunca, Atalay, Volkan, Rifaioglu, Ahmet S, Dalkıran, Alperen, Cetin Atalay, Rengul, Zhang, Chengxin, Hurto, Rebecca L, Freddolino, Peter L, Zhang, Yang, Bhat, Prajwal, Supek, Fran, Fernández, José M, Gemovic, Branislava, Perovic, Vladimir R, Davidović, Radoslav S, Sumonja, Neven, Veljkovic, Nevena, Asgari, Ehsaneddin, Mofrad, Mohammad RK, Profiti, Giuseppe, Savojardo, Castrense, Martelli, Pier Luigi, Casadio, Rita, Boecker, Florian, Schoof, Heiko, Kahanda, Indika, Thurlby, Natalie, McHardy, Alice C, Renaux, Alexandre, Saidi, Rabie, Gough, Julian, Freitas, Alex A, Antczak, Magdalena, Fabris, Fabio, Wass, Mark N, Hou, Jie, Cheng, Jianlin, Wang, Zheng, Romero, Alfonso E, Paccanaro, Alberto, Yang, Haixuan, Goldberg, Tatyana, Zhao, Chenguang, Holm, Liisa, Törönen, Petri, Medlar, Alan J, Zosa, Elaine, Borukhov, Itamar, Novikov, Ilya, Wilkins, Angela, Lichtarge, Olivier, Chi, Po-Han, Tseng, Wei-Cheng, Linial, Michal, Rose, Peter W, Dessimoz, Christophe, Vidulin, Vedrana, Dzeroski, Saso, Sillitoe, Ian, Das, Sayoni, Lees, Jonathan Gill, Jones, David T, Wan, Cen, Cozzetto, Domenico, Fa, Rui, Torres, Mateo, Warwick Vesztrocy, Alex, Rodriguez, Jose Manuel, Tress, Michael L, Frasca, Marco, Notaro, Marco, Grossi, Giuliano, Petrini, Alessandro, Re, Matteo, Valentini, Giorgio, Mesiti, Marco, Roche, Daniel B, Reeb, Jonas, Ritchie, David W, Aridhi, Sabeur, Alborzi, Seyed Ziaeddin, Devignes, Marie-Dominique, Koo, Da Chen Emily, Bonneau, Richard, Gligorijević, Vladimir, Barot, Meet, Fang, Hai, Toppo, Stefano, and Lavezzo, Enrico
Subjects: Human Genome, Networking and Information Technology R&D (NITRD), Genetics, Generic health relevance, Animals, Biofilms, Candida albicans, Drosophila melanogaster, Genome, Bacterial, Genome, Fungal, Humans, Locomotion, Memory, Long-Term, Molecular Sequence Annotation, Pseudomonas aeruginosa, Protein function prediction, Long-term memory, Biofilm, Critical assessment, Community challenge, Environmental Sciences, Biological Sciences, Information and Computing Sciences, Bioinformatics
Abstract: BackgroundThe Critical Assessment of Functional Annotation (CAFA) is an ongoing, global, community-driven effort to evaluate and improve the computational annotation of protein function.ResultsHere, we report on the results of the third CAFA challenge, CAFA3, that featured an expanded analysis over the previous CAFA rounds, both in terms of volume of data analyzed and the types of analysis performed. In a novel and major new development, computational predictions and assessment goals drove some of the experimental assays, resulting in new functional annotations for more than 1000 genes. Specifically, we performed experimental whole-genome mutation screening in Candida albicans and Pseudomonas aureginosa genomes, which provided us with genome-wide experimental data for genes associated with biofilm formation and motility. We further performed targeted assays on selected genes in Drosophila melanogaster, which we suspected of being involved in long-term memory.ConclusionWe conclude that while predictions of the molecular function and biological process annotations have slightly improved over time, those of the cellular component have not. Term-centric prediction of experimental annotations remains equally challenging; although the performance of the top methods is significantly better than the expectations set by baseline methods in C. albicans and D. melanogaster, it leaves considerable room and need for improvement. Finally, we report that the CAFA community now involves a broad range of participants with expertise in bioinformatics, biological experimentation, biocuration, and bio-ontologies, working together to improve functional annotation, computational function prediction, and our ability to manage big data in the era of large experimental screens.
Published: 2019

12. Identification of genetic elements in metabolism by high-throughput mouse phenotyping

Author: Rozman, Jan, Rathkolb, Birgit, Oestereicher, Manuela A, Schütt, Christine, Ravindranath, Aakash Chavan, Leuchtenberger, Stefanie, Sharma, Sapna, Kistler, Martin, Willershäuser, Monja, Brommage, Robert, Meehan, Terrence F, Mason, Jeremy, Haselimashhadi, Hamed, IMPC Consortium, Hough, Tertius, Mallon, Ann-Marie, Wells, Sara, Santos, Luis, Lelliott, Christopher J, White, Jacqueline K, Sorg, Tania, Champy, Marie-France, Bower, Lynette R, Reynolds, Corey L, Flenniken, Ann M, Murray, Stephen A, Nutter, Lauryl MJ, Svenson, Karen L, West, David, Tocchini-Valentini, Glauco P, Beaudet, Arthur L, Bosch, Fatima, Braun, Robert B, Dobbie, Michael S, Gao, Xiang, Herault, Yann, Moshiri, Ala, Moore, Bret A, Kent Lloyd, KC, McKerlie, Colin, Masuya, Hiroshi, Tanaka, Nobuhiko, Flicek, Paul, Parkinson, Helen E, Sedlacek, Radislav, Seong, Je Kyung, Wang, Chi-Kuang Leo, Moore, Mark, Brown, Steve D, Tschöp, Matthias H, Wurst, Wolfgang, Klingenspor, Martin, Wolf, Eckhard, Beckers, Johannes, Machicao, Fausto, Peter, Andreas, Staiger, Harald, Häring, Hans-Ulrich, Grallert, Harald, Campillos, Monica, Maier, Holger, Fuchs, Helmut, Gailus-Durner, Valerie, Werner, Thomas, and Hrabe de Angelis, Martin
Subjects: Biochemistry and Cell Biology, Bioinformatics and Computational Biology, Genetics, Biological Sciences, Human Genome, Nutrition, 2.1 Biological and endogenous factors, Generic health relevance, Animals, Area Under Curve, Basal Metabolism, Blood Glucose, Body Weight, Diabetes Mellitus, Type 2, Gene Regulatory Networks, Genome-Wide Association Study, High-Throughput Screening Assays, Humans, Metabolic Diseases, Mice, Mice, Knockout, Obesity, Oxygen Consumption, Phenotype, Triglycerides, IMPC Consortium
Abstract: Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome.
Published: 2018

13. Disease model discovery from 3,328 gene knockouts by The International Mouse Phenotyping Consortium.

Author: Meehan, Terrence F, Conte, Nathalie, West, David B, Jacobsen, Julius O, Mason, Jeremy, Warren, Jonathan, Chen, Chao-Kung, Tudose, Ilinca, Relac, Mike, Matthews, Peter, Karp, Natasha, Santos, Luis, Fiegel, Tanja, Ring, Natalie, Westerberg, Henrik, Greenaway, Simon, Sneddon, Duncan, Morgan, Hugh, Codner, Gemma F, Stewart, Michelle E, Brown, James, Horner, Neil, International Mouse Phenotyping Consortium, Haendel, Melissa, Washington, Nicole, Mungall, Christopher J, Reynolds, Corey L, Gallegos, Juan, Gailus-Durner, Valerie, Sorg, Tania, Pavlovic, Guillaume, Bower, Lynette R, Moore, Mark, Morse, Iva, Gao, Xiang, Tocchini-Valentini, Glauco P, Obata, Yuichi, Cho, Soo Young, Seong, Je Kyung, Seavitt, John, Beaudet, Arthur L, Dickinson, Mary E, Herault, Yann, Wurst, Wolfgang, de Angelis, Martin Hrabe, Lloyd, KC Kent, Flenniken, Ann M, Nutter, Lauryl MJ, Newbigging, Susan, McKerlie, Colin, Justice, Monica J, Murray, Stephen A, Svenson, Karen L, Braun, Robert E, White, Jacqueline K, Bradley, Allan, Flicek, Paul, Wells, Sara, Skarnes, William C, Adams, David J, Parkinson, Helen, Mallon, Ann-Marie, Brown, Steve DM, and Smedley, Damian
Subjects: International Mouse Phenotyping Consortium, Animals, Mice, Knockout, Humans, Mice, Genetic Diseases, Inborn, Disease Models, Animal, Genetic Predisposition to Disease, Phenotype, Female, Male, Gene Knockout Techniques, Knockout, Genetic Diseases, Inborn, Disease Models, Animal, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract: Although next-generation sequencing has revolutionized the ability to associate variants with human diseases, diagnostic rates and development of new therapies are still limited by a lack of knowledge of the functions and pathobiological mechanisms of most genes. To address this challenge, the International Mouse Phenotyping Consortium is creating a genome- and phenome-wide catalog of gene function by characterizing new knockout-mouse strains across diverse biological systems through a broad set of standardized phenotyping tests. All mice will be readily available to the biomedical community. Analyzing the first 3,328 genes identified models for 360 diseases, including the first models, to our knowledge, for type C Bernard-Soulier, Bardet-Biedl-5 and Gordon Holmes syndromes. 90% of our phenotype annotations were novel, providing functional evidence for 1,092 genes and candidates in genetically uncharacterized diseases including arrhythmogenic right ventricular dysplasia 3. Finally, we describe our role in variant functional validation with The 100,000 Genomes Project and others.
Published: 2017

14. High-throughput discovery of novel developmental phenotypes.

Author: Dickinson, Mary E, Flenniken, Ann M, Ji, Xiao, Teboul, Lydia, Wong, Michael D, White, Jacqueline K, Meehan, Terrence F, Weninger, Wolfgang J, Westerberg, Henrik, Adissu, Hibret, Baker, Candice N, Bower, Lynette, Brown, James M, Caddle, L Brianna, Chiani, Francesco, Clary, Dave, Cleak, James, Daly, Mark J, Denegre, James M, Doe, Brendan, Dolan, Mary E, Edie, Sarah M, Fuchs, Helmut, Gailus-Durner, Valerie, Galli, Antonella, Gambadoro, Alessia, Gallegos, Juan, Guo, Shiying, Horner, Neil R, Hsu, Chih-Wei, Johnson, Sara J, Kalaga, Sowmya, Keith, Lance C, Lanoue, Louise, Lawson, Thomas N, Lek, Monkol, Mark, Manuel, Marschall, Susan, Mason, Jeremy, McElwee, Melissa L, Newbigging, Susan, Nutter, Lauryl MJ, Peterson, Kevin A, Ramirez-Solis, Ramiro, Rowland, Douglas J, Ryder, Edward, Samocha, Kaitlin E, Seavitt, John R, Selloum, Mohammed, Szoke-Kovacs, Zsombor, Tamura, Masaru, Trainor, Amanda G, Tudose, Ilinca, Wakana, Shigeharu, Warren, Jonathan, Wendling, Olivia, West, David B, Wong, Leeyean, Yoshiki, Atsushi, International Mouse Phenotyping Consortium, Jackson Laboratory, Infrastructure Nationale PHENOMIN, Institut Clinique de la Souris (ICS), Charles River Laboratories, MRC Harwell, Toronto Centre for Phenogenomics, Wellcome Trust Sanger Institute, RIKEN BioResource Center, MacArthur, Daniel G, Tocchini-Valentini, Glauco P, Gao, Xiang, Flicek, Paul, Bradley, Allan, Skarnes, William C, Justice, Monica J, Parkinson, Helen E, Moore, Mark, Wells, Sara, Braun, Robert E, Svenson, Karen L, de Angelis, Martin Hrabe, Herault, Yann, Mohun, Tim, Mallon, Ann-Marie, Henkelman, R Mark, Brown, Steve DM, Adams, David J, Lloyd, KC Kent, McKerlie, Colin, Beaudet, Arthur L, Bućan, Maja, and Murray, Stephen A
Subjects: International Mouse Phenotyping Consortium, Jackson Laboratory, Infrastructure Nationale PHENOMIN, Institut Clinique de la Souris, Charles River Laboratories, MRC Harwell, Toronto Centre for Phenogenomics, Wellcome Trust Sanger Institute, RIKEN BioResource Center, Animals, Mice, Inbred C57BL, Mice, Knockout, Humans, Mice, Disease, Imaging, Three-Dimensional, Conserved Sequence, Sequence Homology, Phenotype, Penetrance, Mutation, Polymorphism, Single Nucleotide, Genes, Essential, Genes, Lethal, Embryo, Mammalian, Genome-Wide Association Study, High-Throughput Screening Assays, Biotechnology, Human Genome, Pediatric, Congenital Structural Anomalies, Genetics, 2.1 Biological and endogenous factors, General Science & Technology
Abstract: Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.
Published: 2016

15. A Whole-Genome Analysis Framework for Effective Identification of Pathogenic Regulatory Variants in Mendelian Disease.

Author: Smedley, Damian, Schubach, Max, Jacobsen, Julius OB, Köhler, Sebastian, Zemojtel, Tomasz, Spielmann, Malte, Jäger, Marten, Hochheiser, Harry, Washington, Nicole L, McMurry, Julie A, Haendel, Melissa A, Mungall, Christopher J, Lewis, Suzanna E, Groza, Tudor, Valentini, Giorgio, and Robinson, Peter N
Subjects: Humans, Genetic Diseases, Inborn, Gene Frequency, Phenotype, Mutation, Point Mutation, Open Reading Frames, Genome, Human, Algorithms, Genome-Wide Association Study, Machine Learning, Genetic Diseases, Inborn, Genome, Human, Genetics & Heredity, Biological Sciences, Medical and Health Sciences
Abstract: The interpretation of non-coding variants still constitutes a major challenge in the application of whole-genome sequencing in Mendelian disease, especially for single-nucleotide and other small non-coding variants. Here we present Genomiser, an analysis framework that is able not only to score the relevance of variation in the non-coding genome, but also to associate regulatory variants to specific Mendelian diseases. Genomiser scores variants through either existing methods such as CADD or a bespoke machine learning method and combines these with allele frequency, regulatory sequences, chromosomal topological domains, and phenotypic relevance to discover variants associated to specific Mendelian disorders. Overall, Genomiser is able to identify causal regulatory variants as the top candidate in 77% of simulated whole genomes, allowing effective detection and discovery of regulatory variants in Mendelian disease.
Published: 2016

16. Evidence for a Negative Cooperativity between eIF5A and eEF2 on Binding to the Ribosome.

Author: Rossi, Danuza, Barbosa, Natalia M, Galvão, Fabio C, Boldrin, Paulo EG, Hershey, John WB, Zanelli, Cleslei F, Fraser, Christopher S, and Valentini, Sandro R
Subjects: Hela Cells, Ribosomes, Humans, Peptide Elongation Factor 2, Lysine, RNA-Binding Proteins, Peptide Initiation Factors, Cell Proliferation, Protein Biosynthesis, Up-Regulation, Protein Binding, Mutation, HeLa Cells, General Science & Technology
Abstract: eIF5A is the only protein known to contain the essential and unique amino acid residue hypusine. eIF5A functions in both translation initiation due to its stimulation of methionyl-puromycin synthesis and translation elongation, being highly required for peptide-bound formation of specific ribosome stalling sequences such as poly-proline. The functional interaction between eIF5A, tRNA, and eEF2 on the surface of the ribosome is further clarified herein. Fluorescence anisotropy assays were performed to determine the affinity of eIF5A to different ribosomal complexes and reveal its interaction exclusively and directly with the 60S ribosomal subunit in a hypusine-dependent manner (Ki60S-eIF5A-Hyp = 16 nM, Ki60S-eIF5A-Lys = 385 nM). A 3-fold increase in eIF5A affinity to the 80S is observed upon charged-tRNAiMet binding, indicating positive cooperativity between P-site tRNA binding and eIF5A binding to the ribosome. Previously identified conditional mutants of yeast eIF5A, eIF5AQ22H/L93F and eIF5AK56A, display a significant decrease in ribosome binding affinity. Binding affinity between ribosome and eIF5A-wild type or mutants eIF5AK56A, but not eIF5AQ22H/L93F, is impaired in the presence of eEF2 by 4-fold, consistent with negative cooperativity between eEF2 and eIF5A binding to the ribosome. Interestingly, high-copy eEF2 is toxic only to eIF5AQ22H/L93F and causes translation elongation defects in this mutant. These results suggest that binding of eEF2 to the ribosome alters its conformation, resulting in a weakened affinity of eIF5A and impairment of this interplay compromises cell growth due to translation elongation defects.
Published: 2016

17. Volumetric Intensity-Modulated Arc Stereotactic Radiosurgery Boost in Oligometastatic Patients with Spine Metastases: a Dose-escalation Study

Author: Deodato, Francesco, Pezzulla, D., Cilla, Savino, Ferro, M., Giannini, R., Romano, C., Boccardi, M., Buwenge, M., Valentini, Vincenzo, Morganti, Alessio Giuseppe, and Macchia, Gabriella
Subjects: Male, Adult, Aged, 80 and over, Spinal Neoplasms, Breast Neoplasms, Middle Aged, Radiosurgery, Magnetic Resonance Imaging, spinal metastases, volumetric arc radiotherapy, stereotactic body radiotherapy, Oncology, Humans, Female, Radiology, Nuclear Medicine and imaging, Radiotherapy, Intensity-Modulated, Radiotherapy, Conformal, Tomography, X-Ray Computed, Oligometastases, vertebral compression fracture, Settore MED/36 - DIAGNOSTICA PER IMMAGINI E RADIOTERAPIA, Aged
Abstract: To report the final results of a dose-escalation study of volumetric intensity-modulated arc stereotactic radiosurgery (VMAT-SRS) boost after three-dimensional conformal radiation therapy in patients with spine metastases.Oligometastatic cancer patients bearing up to five synchronous metastases (visceral or bone, including vertebral ones) and candidates for surgery or radiosurgery were considered for inclusion. 25 Gy was delivered in 10 daily fractions (2 weeks) to the metastatic lesion, affected vertebrae and adjacent ones (one cranial and one caudal vertebra). Sequentially, the dose to spinal metastases was progressively increased (8 Gy, 10 Gy, 12 Gy) in the patient cohorts. Dose-limiting toxicities were defined as any treatment-related non-hematologic acute adverse effects rated as grade ≥3 or any acute haematological toxicity rated as ≥ 4 by the Radiation Therapy Oncology Group scale.Fifty-two lesions accounting for 40 consecutive patients (male/female: 29/11; median age: 71 years; range 40-85) were treated from April 2011 to September 2020. Most patients had a primary prostate (65.0%) or breast cancer (22.5%). Thirty-two patients received 8 Gy VMAT-SRS boost (total BEDA 12 Gy spine metastasis SRS boost following 25 Gy to the affected and adjacent vertebrae was feasible with an excellent local control rate and toxicity profile.
Published: 2023
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18. Contrast-Enhanced Mammography Versus MRI in the Evaluation of Neoadjuvant Therapy Response in Patients With Breast Cancer: A Prospective Study

Author: Daniela Bernardi, Giulia Vatteroni, Alessandra Acquaviva, Marvi Valentini, Vincenzo Sabatino, Isabella Bolengo, Marco Pellegrini, Carmine Fantò, and Rubina M. Trimboli
Subjects: Adult, Carcinoma, Intraductal, Noninfiltrating, Humans, Female, Breast Neoplasms, Radiology, Nuclear Medicine and imaging, Prospective Studies, General Medicine, Middle Aged, Magnetic Resonance Imaging, Neoadjuvant Therapy, Mammography
Published: 2022
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19. Estimated Global Proportions of Individuals with Persistent Fatigue, Cognitive, and Respiratory Symptom Clusters Following Symptomatic COVID-19 in 2020 and 2021

Author: Wulf Hanson, Sarah, Abbafati, Cristiana, Aerts, Joachim G, Al-Aly, Ziyad, Ashbaugh, Charlie, Ballouz, Tala, Blyuss, Oleg, Bobkova, Polina, Bonsel, Gouke, Borzakova, Svetlana, Buonsenso, Danilo, Butnaru, Denis, Carter, Austin, Chu, Helen, De Rose, Cristina, Diab, Mohamed Mustafa, Ekbom, Emil, El Tantawi, Maha, Fomin, Victor, Frithiof, Robert, Gamirova, Aysylu, Glybochko, Petr V, Haagsma, Juanita A, Haghjooy Javanmard, Shaghayegh, Hamilton, Erin B, Harris, Gabrielle, Heijenbrok-Kal, Majanka H, Helbok, Raimund, Hellemons, Merel E, Hillus, David, Huijts, Susanne M, Hultström, Michael, Jassat, Waasila, Kurth, Florian, Larsson, Ing-Marie, Lipcsey, Miklós, Liu, Chelsea, Loflin, Callan D, Malinovschi, Andrei, Mao, Wenhui, Mazankova, Lyudmila, Mcculloch, Denise, Menges, Dominik, Mohammadifard, Noushin, Munblit, Daniel, Nekliudov, Nikita A, Ogbuoji, Osondu, Osmanov, Ismail M, Peñalvo, José L, Petersen, Maria Skaalum, Puhan, Milo A, Rahman, Mujibur, Rass, Verena, Reinig, Nickolas, Ribbers, Gerard M, Ricchiuto, Antonia, Rubertsson, Sten, Samitova, Elmira, Sarrafzadegan, Nizal, Shikhaleva, Anastasia, Simpson, Kyle E, Sinatti, Dario, Soriano, Joan B, Spiridonova, Ekaterina, Steinbeis, Fridolin, Svistunov, Andrey A, Valentini, Piero, van de Water, Brittney J, van den Berg-Emons, Rita, Wallin, Ewa, Witzenrath, Martin, Yifan, Wu, Hanzhang, Xu, Zoller, Thomas, Adolph, Christopher, Albright, James, Amlag, Joanne O, Aravkin, Aleksandr Y, Bang-Jensen, Bree L, Bisignano, Catherine, Castellano, Rachel, Castro, Emma, Chakrabarti, Suman, Collins, James K, Dai, Xiaochen, Daoud, Farah, Dapper, Carolyn, Deen, Amanda, Duncan, Bruce B, Erickson, Megan, Ewald, Samuel B, Ferrari, Alize J, Flaxman, Abraham D, Fullman, Nancy, Gamkrelidze, Amiran, Giles, John R, Guo, Gaorui, Hay, Simon I, Jiawei, He, Helak, Monika, Hulland, Erin N, Kereselidze, Maia, Krohn, Kris J, Lazzar-Atwood, Alice, Lindstrom, Akiaja, Lozano, Rafael, Malta, Deborah Carvalho, Månsson, Johan, Mantilla Herrera, Ana M, Mokdad, Ali H, Monasta, Lorenzo, Nomura, Shuhei, Pasovic, Maja, Pigott, David M, Reiner, Robert C, Reinke, Grace, Ribeiro, Antonio Luiz P, Santomauro, Damian Francesco, Sholokhov, Aleksei, Spurlock, Emma Elizabeth, Walcott, Rebecca, Walker, Ally, Wiysonge, Charles Shey, Zheng, Peng, Bettger, Janet Prvu, Murray, Christopher J L, Vos, Theo, Pulmonary Medicine, Public Health, and Rehabilitation Medicine
Subjects: Adult, Male, Internationality, long covid, Adolescent, Pain, Global Health, Cov-2, proportion of polpulation, Young Adult, Post-Acute COVID-19 Syndrome, Humans, Child, Fatigue, Original Investigation, Aged, SARS-CoV-2, Mood Disorders, COVID-19, Bayes Theorem, Syndrome, General Medicine, Middle Aged, Child, Preschool, Female, Cognition Disorders, Respiratory Insufficiency
Abstract: ImportanceSome individuals experience persistent symptoms after initial symptomatic SARS-CoV-2 infection (often referred to as Long COVID).ObjectiveTo estimate the proportion of males and females with COVID-19, younger or older than 20 years of age, who had Long COVID symptoms in 2020 and 2021 and their Long COVID symptom duration.Design, Setting, and ParticipantsBayesian meta-regression and pooling of 54 studies and 2 medical record databases with data for 1.2 million individuals (from 22 countries) who had symptomatic SARS-CoV-2 infection. Of the 54 studies, 44 were published and 10 were collaborating cohorts (conducted in Austria, the Faroe Islands, Germany, Iran, Italy, the Netherlands, Russia, Sweden, Switzerland, and the US). The participant data were derived from the 44 published studies (10 501 hospitalized individuals and 42 891 nonhospitalized individuals), the 10 collaborating cohort studies (10 526 and 1906), and the 2 US electronic medical record databases (250 928 and 846 046). Data collection spanned March 2020 to January 2022.ExposuresSymptomatic SARS-CoV-2 infection.Main Outcomes and MeasuresProportion of individuals with at least 1 of the 3 self-reported Long COVID symptom clusters (persistent fatigue with bodily pain or mood swings; cognitive problems; or ongoing respiratory problems) 3 months after SARS-CoV-2 infection in 2020 and 2021, estimated separately for hospitalized and nonhospitalized individuals aged 20 years or older by sex and for both sexes of nonhospitalized individuals younger than 20 years of age.ResultsA total of 1.2 million individuals who had symptomatic SARS-CoV-2 infection were included (mean age, 4-66 years; males, 26%-88%). In the modeled estimates, 6.2% (95% uncertainty interval [UI], 2.4%-13.3%) of individuals who had symptomatic SARS-CoV-2 infection experienced at least 1 of the 3 Long COVID symptom clusters in 2020 and 2021, including 3.2% (95% UI, 0.6%-10.0%) for persistent fatigue with bodily pain or mood swings, 3.7% (95% UI, 0.9%-9.6%) for ongoing respiratory problems, and 2.2% (95% UI, 0.3%-7.6%) for cognitive problems after adjusting for health status before COVID-19, comprising an estimated 51.0% (95% UI, 16.9%-92.4%), 60.4% (95% UI, 18.9%-89.1%), and 35.4% (95% UI, 9.4%-75.1%), respectively, of Long COVID cases. The Long COVID symptom clusters were more common in women aged 20 years or older (10.6% [95% UI, 4.3%-22.2%]) 3 months after symptomatic SARS-CoV-2 infection than in men aged 20 years or older (5.4% [95% UI, 2.2%-11.7%]). Both sexes younger than 20 years of age were estimated to be affected in 2.8% (95% UI, 0.9%-7.0%) of symptomatic SARS-CoV-2 infections. The estimated mean Long COVID symptom cluster duration was 9.0 months (95% UI, 7.0-12.0 months) among hospitalized individuals and 4.0 months (95% UI, 3.6-4.6 months) among nonhospitalized individuals. Among individuals with Long COVID symptoms 3 months after symptomatic SARS-CoV-2 infection, an estimated 15.1% (95% UI, 10.3%-21.1%) continued to experience symptoms at 12 months.Conclusions and RelevanceThis study presents modeled estimates of the proportion of individuals with at least 1 of 3 self-reported Long COVID symptom clusters (persistent fatigue with bodily pain or mood swings; cognitive problems; or ongoing respiratory problems) 3 months after symptomatic SARS-CoV-2 infection.
Published: 2022

20. When to test for COVID-19 using real-time reverse transcriptase polymerase chain reaction: a systematic review

Author: Paula Gabrielli dos Santos, Helena Cristina Valentini Speggiorin Vieira, Vinícius Wietholter, João Pedro Gallina, Thomás Ranquetat Andrade, Daniel Rodrigo Marinowic, Gabriele Goulart Zanirati, and Jaderson Costa da Costa
Subjects: Microbiology (medical), COVID-19 Testing, Infectious Diseases, Clinical Laboratory Techniques, Reverse Transcriptase Polymerase Chain Reaction, COVID-19, Humans, RNA-Directed DNA Polymerase, Prospective Studies, General Medicine, Middle Aged, Real-Time Polymerase Chain Reaction, Retrospective Studies
Abstract: The aim of this study was to evaluate the time in days between symptom onset and first positive real-time reverse transcriptase polymerase chain reaction (RT-PCR) result for COVID-19.This systematic review was conducted in the MEDLINE (PubMed), Embase, and Scopus databases using the following descriptors: "COVID-19", "SARS-CoV-2", "coronavirus", "RT-PCR", "real time PCR", and "diagnosis".The included studies were conducted in 31 different countries and reported on a total of 6831 patients. The median age of the participants was 49.95 years. The three most common symptoms were fever, cough, and dyspnea, which affected 4012 (58.68%), 3192 (46.69%), and 2009 patients (29.38%), respectively. Among the 90 included studies, 13 were prospective cohorts, 15 were retrospective cohorts, 36 were case reports, 20 were case series, and six were cross-sectional studies. The overall mean time between symptom onset and positive test result was 6.72 days. Fourteen articles were analyzed separately for the temporal profile of RT-PCR test results; the best performance was on days 22-24, when 98% of test results were positive.These findings corroborate the RT-PCR COVID-19 testing practices of some health units. In addition, the most frequently described symptoms of these patients can be considered the initial symptoms of infection and used in decision-making about RT-PCR testing.
Published: 2022
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21. Complete Percutaneous Revascularization in Patients Aged ≥85 Years With Acute Coronary Syndrome and Multivessel Coronary Artery Disease

Author: Marcello Marino, Simonluca Digiacomo, Michele Cacucci, Antonio Catanoso, Paolo Valentini, and Maurizio Landolina
Subjects: Percutaneous Coronary Intervention, Time Factors, Treatment Outcome, Myocardial Infarction, Humans, Coronary Artery Disease, Acute Coronary Syndrome, Coronary Angiography, Cardiology and Cardiovascular Medicine, Aged
Abstract: Multivessel coronary disease is frequent in older patients who underwent coronary angiography for acute coronary syndrome. Whether a complete revascularization or a culprit-only approach is preferable in these patients is still debated. We included consecutive patients aged ≥85 years, presenting with acute coronary syndrome and showing multivessel coronary disease at coronary angiography. Patients were grouped according to complete (residual SYNTAX score [RSS] 0 to 8) or incomplete (RSSgt;8) revascularization. Primary end point was the rate of major adverse cardiovascular events (MACEs, the composite of cardiovascular death, re-myocardial infarction [re-MI], clinically driven percutaneous coronary intervention, and rehospitalization because of cardiac disease) at 2 years follow-up. A total of 166 patients met the criteria for enrollment; 108 patients had a final RSS 0 to 8 (complete revascularization) and 58 patients had a final RSSgt;8 (incomplete revascularization). The rate of MACE was reduced in patients who underwent complete revascularization (35.2% vs 51.7%, p = 0.039, adjusted hazard ratio 0.60, 95% confidence interval 0.37 to 0.98, p = 0.04), a difference mainly driven by a reduction in re-MI (8.3% vs 19.0%, p = 0.045), clinically driven percutaneous coronary intervention (2.8% vs 19.0%, plt;0.001), and rehospitalization for cardiac disease (9.3% vs 24.1%, p = 0.009). Other independent predictors of MACE were active malignancy, previous MI, left ventricle ejection fractionlt;35% (increasing risk of events), and radial access (reducing risk of events). In conclusion, in patients aged ≥85 years, a complete revascularization is associated with a better prognosis, especially in terms of nonfatal events.
Published: 2022
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22. Association between contralateral background parenchymal enhancement on MRI and outcome in patients with unilateral invasive breast cancer receiving neoadjuvant chemotherapy

Author: Rossella Rella, Enida Bufi, Paolo Belli, Anna Rita Scrofani, Federica Petta, Alberto Borghetti, Fabio Marazzi, Vincenzo Valentini, and Riccardo Manfredi
Subjects: Adult, Radiological and Ultrasound Technology, Breast Neoplasms, General Medicine, Middle Aged, Magnetic Resonance Imaging, Neoadjuvant Therapy, Young Adult, Ki-67 Antigen, Humans, Female, Radiology, Nuclear Medicine and imaging, Mastectomy, Aged, Retrospective Studies
Abstract: The purpose of this study was to retrospectively investigate whether background parenchymal enhancement (BPE) of the contralateral breast on magnetic resonance imaging (MRI) is associated with clinical outcomes in patients with unilateral invasive breast cancer receiving neoadjuvant chemotherapy (NAC).A total of 228 women (47.6 years ± 10 [SD]; range: 24-74 years) with invasive breast cancer who underwent NAC between 2005 and 2013 were included. All included patients underwent breast MRI before and after NAC. Quantitative semiautomated analysis of BPE of the contralateral healthy breast was performed. The enhancement level on baseline MRI (baseline BPE) and on MRI after chemotherapy (final BPE) and the change in enhancement rate between baseline MRI and final MRI were recorded. Cox regression was used to test associations between BPE variables, patient and tumor characteristics, overall survival (OS) and disease-free survival (DFS). Subgroup analyses based on menopausal status and immunohistochemical subtypes were performed.Median follow-up was 92 months. Multivariable analysis revealed that Ki-67 level (P = 0.026) and receipt of mastectomy (P = 0.015) were independent variables associated with OS while Ki-67 level (P = 0.010) and post-NAC pathological node categorization (P = 0.027) were independent variables associated with DFS. BPE was not associated with OS (P = 0.500, 0.546 and 0.712 for baseline BPE, final BPE and BPE change, respectively) or with DFS (P = 0.568, 0.412 and 0.327, respectively).BPE of the contralateral breast on MRI may have limited prognostic value in patients with breast cancer treated with NAC.
Published: 2022
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23. Characteristics and outcomes of an international cohort of 600 000 hospitalized patients with COVID-19

Author: Kartsonaki, Christiana, Baillie, J Kenneth, Barrio, Noelia García, Baruch, Joaquín, Beane, Abigail, Blumberg, Lucille, Bozza, Fernando, Broadley, Tessa, Burrell, Aidan, Carson, Gail, Citarella, Barbara Wanjiru, Dagens, Andrew, Dankwa, Emmanuelle A, Donnelly, Christl A, Dunning, Jake, Elotmani, Loubna, Escher, Martina, Farshait, Nataly, Goffard, Jean-Christophe, Gonçalves, Bronner P, Hall, Matthew, Hashmi, Madiha, Sim Lim Heng, Benedict, Ho, Antonia, Jassat, Waasila, Pedrera Jiménez, Miguel, Laouenan, Cedric, Lissauer, Samantha, Martin-Loeches, Ignacio, Mentré, France, Merson, Laura, Morton, Ben, Munblit, Daniel, Nekliudov, Nikita A, Nichol, Alistair D, Singh Oinam, Budha Charan, Ong, David, Panda, Prasan Kumar, Petrovic, Michele, Pritchard, Mark G, Ramakrishnan, Nagarajan, Ramos, Grazielle Viana, Roger, Claire, Sandulescu, Oana, Semple, Malcolm G, Sharma, Pratima, Sigfrid, Louise, Somers, Emily C, Streinu-Cercel, Anca, Taccone, Fabio, Vecham, Pavan Kumar, Kumar Tirupakuzhi Vijayaraghavan, Bharath, Wei, Jia, Wils, Evert-Jan, Ci Wong, Xin, Horby, Peter, Rojek, Amanda, Olliaro, Piero L, ISARIC Clinical Characterisation Group: Ali Abbas, Sheryl Ann Abdukahil, Nurul Najmee Abdulkadir, Ryuzo Abe, Laurent Abel, Lara Absil, Subhash Acharya, Andrew Acker, Elisabeth Adam, Diana Adrião, Saleh Al Ageel, Shakeel Ahmed, Kate Ainscough, Eka Airlangga, Tharwat Aisa, Ali Ait Hssain, Younes Ait Tamlihat, Takako Akimoto, Ernita Akmal, Eman Al Qasim, Razi Alalqam, Angela Alberti, Tala Al-Dabbous, Senthilkumar Alegesan, Cynthia Alegre, Marta Alessi, Beatrice Alex, Kévin Alexandre, Abdulrahman Al-Fares, Huda Alfoudri, Imran Ali, Adam Ali, Naseem Ali Shah, Kazali Enagnon Alidjnou, Jeffrey Aliudin, Qabas Alkhafajee, Clotilde Allavena, Nathalie Allou, Aneela Altaf, João Alves, Rita Alves, João Melo Alves, Maria Amaral, Nur Amira, Phoebe Ampaw, Roberto Andini, Claire Andréjak, Andrea Angheben, François Angoulvant, Séverine Ansart, Sivanesen Anthonidass, Massimo Antonelli, Carlos Alexandre Antunes de Brito, Ardiyan Apriyana, Yaseen Arabi, Irene Aragao, Francisco Arancibia, Carolline Araujo, Antonio Arcadipane, Patrick Archambault, Lukas Arenz, Jean-Benoît Arlet, Christel Arnold-Day, Lovkesh Arora, Rakesh Arora, Elise Artaud-Macari, Diptesh Aryal, Angel Asensio, Muhammad Ashraf, Namra Asif, Mohammad Asim, Jean Baptiste Assie, Amirul Asyraf, Anika Atique, A M Udara Lakshan Attanyake, Johann Auchabie, Hugues Aumaitre, Adrien Auvet, Laurène Azemar, Cecile Azoulay, Benjamin Bach, Delphine Bachelet, Claudine Badr, Nadia Baig, J Kevin Baird, Erica Bak, Agamemnon Bakakos, Nazreen Abu Bakar, Andriy Bal, Mohanaprasanth Balakrishnan, Valeria Balan, Firouzé Bani-Sadr, Renata Barbalho, Nicholas Yuri Barbosa, Wendy S Barclay, Saef Umar Barnett, Michaela Barnikel, Helena Barrasa, Audrey Barrelet, Cleide Barrigoto, Marie Bartoli, Mustehan Bashir, Romain Basmaci, Muhammad Fadhli Hassin Basri, Denise Battaglini, Jules Bauer, Diego Fernando Bautista Rincon, Denisse Bazan Dow, Alexandra Bedossa, Ker Hong Bee, Husna Begum, Sylvie Behilill, Albertus Beishuizen, Aleksandr Beljantsev, David Bellemare, Anna Beltrame, Beatriz Amorim Beltrão, Marine Beluze, Nicolas Benech, Lionel Eric Benjiman, Dehbia Benkerrou, Suzanne Bennett, Luís Bento, Jan-Erik Berdal, Delphine Bergeaud, Hazel Bergin, José Luis Bernal Sobrino, Giulia Bertoli, Lorenzo Bertolino, Simon Bessis, Sybille Bevilcaqua, Karine Bezulier, Amar Bhatt, Krishna Bhavsar, Claudia Bianco, Farah Nadiah Bidin, Moirangthem Bikram Singh, Felwa Bin Humaid, Mohd Nazlin Bin Kamarudin, François Bissuel, Patrick Biston, Laurent Bitker, Jonathan Bitton, Pablo Blanco-Schweizer, Catherine Blier, Frank Bloos, Mathieu Blot, Filomena Boccia, Laetitia Bodenes, Alice Bogaarts, Debby Bogaert, Anne-Hélène Boivin, Pierre-Adrien Bolze, François Bompart, Aurelius Bonfasius, Diogo Borges, Raphaël Borie, Hans Martin Bosse, Elisabeth Botelho-Nevers, Lila Bouadma, Olivier Bouchaud, Sabelline Bouchez, Dounia Bouhmani, Damien Bouhour, Kévin Bouiller, Laurence Bouillet, Camile Bouisse, Anne-Sophie Boureau, John Bourke, Maude Bouscambert, Aurore Bousquet, Jason Bouziotis, Bianca Boxma, Marielle Boyer-Besseyre, Maria Boylan, Axelle Braconnier, Cynthia Braga, Timo Brandenburger, Filipa Brás Monteiro, Luca Brazzi, Patrick Breen, Dorothy Breen, Kathy Brickell, Shaunagh Browne, Alex Browne, Nicolas Brozzi, Marjolein Brusse-Keizer, Nina Buchtele, Christian Buesaquillo, Polina Bugaeva, Marielle Buisson, Danilo Buonsenso, Erlina Burhan, Ingrid G Bustos, Denis Butnaru, André Cabie, Susana Cabral, Eder Caceres, Cyril Cadoz, Mia Callahan, Kate Calligy, Jose Andres Calvache, João Camões, Valentine Campana, Paul Campbell, Josie Campisi, Cecilia Canepa, Mireia Cantero, Pauline Caraux-Paz, Sheila Cárcel, Chiara Simona Cardellino, Sofia Cardoso, Filipe Cardoso, Filipa Cardoso, Nelson Cardoso, Simone Carelli, Nicolas Carlier, Thierry Carmoi, Gayle Carney, Inês Carqueja, Marie-Christine Carret, François Martin Carrier, Ida Carroll, Maire-Laure Casanova, Mariana Cascão, Siobhan Casey, José Casimiro, Bailey Cassandra, Silvia Castañeda, Nidyanara Castanheira, Guylaine Castor-Alexandre, Henry Castrillón, Ivo Castro, Ana Catarino, François-Xavier Catherine, Paolo Cattaneo, Roberta Cavalin, Giulio Giovanni Cavalli, Alexandros Cavayas, Adrian Ceccato, Minerva Cervantes-Gonzalez, Anissa Chair, Catherine Chakveatze, Adrienne Chan, Meera Chand, Christelle Chantalat Auger, Jean-Marc Chapplain, Julie Chas, Allegra Chatterjee, Mobin Chaudry, Jonathan Samuel Chávez Iñiguez, Anjellica Chen, Yih-Sharng Chen, Matthew Pellan Cheng, Antoine Cheret, Thibault Chiarabini, Julian Chica, Suresh Kumar Chidambaram, Leong Chin Tho, Catherine Chirouze, Davide Chiumello, Sung-Min Cho, Bernard Cholley, Marie-Charlotte Chopin, Ting Soo Chow, Yock Ping Chow, Hiu Jian Chua, Jonathan Chua, Jose Pedro Cidade, José Miguel Cisneros Herreros, Anna Ciullo, Jennifer Clarke, Emma Clarke, Rolando Claure-Del Granado, Sara Clohisey, Perren J Cobb, Cassidy Codan, Caitriona Cody, Alexandra Coelho, Megan Coles, Gwenhaël Colin, Michael Collins, Sebastiano Maria Colombo, Pamela Combs, Marie Connor, Anne Conrad, Sofía Contreras, Elaine Conway, Graham S Cooke, Mary Copland, Hugues Cordel, Amanda Corley, Sabine Cornelis, Alexander Daniel Cornet, Arianne Joy Corpuz, Andrea Cortegiani, Grégory Corvaisier, Emma Costigan, Camille Couffignal, Sandrine Couffin-Cadiergues, Roxane Courtois, Stéphanie Cousse, Rachel Cregan, Charles Crepy D'Orleans, Cosimo Cristella, Sabine Croonen, Gloria Crowl, Jonathan Crump, Claudina Cruz, Juan Luis Cruz Berm, Jaime Cruz Rojo, Marc Csete, Ailbhe Cullen, Matthew Cummings, Gerard Curley, Elodie Curlier, Colleen Curran, Paula Custodio, Ana da Silva Filipe, Charlene Da Silveira, Al-Awwab Dabaliz, Darren Dahly, Heidi Dalton, Jo Dalton, Seamus Daly, Nick Daneman, Corinne Daniel, Jorge Dantas, Frédérick D'Aragon, Menno de Jong, Gillian de Loughry, Diego de Mendoza, Etienne De Montmollin, Rafael Freitas de Oliveira França, Ana Isabel de Pinho Oliveira, Rosanna De Rosa, Cristina De Rose, Thushan de Silva, Peter de Vries, Jillian Deacon, David Dean, Alexa Debard, Marie-Pierre Debray, Nathalie DeCastro, William Dechert, Lauren Deconninck, Romain Decours, Eve Defous, Isabelle Delacroix, Eric Delaveuve, Karen Delavigne, Nathalie M Delfos, Ionna Deligiannis, Andrea Dell'Amore, Christelle Delmas, Pierre Delobel, Corine Delsing, Elisa Demonchy, Emmanuelle Denis, Dominique Deplanque, Pieter Depuydt, Mehul Desai, Diane Descamps, Mathilde Desvallées, Santi Dewayanti, Pathik Dhanger, Alpha Diallo, Sylvain Diamantis, André Dias, Juan Jose Diaz, Priscila Diaz, Rodrigo Diaz, Kévin Didier, Jean-Luc Diehl, Wim Dieperink, Jérôme Dimet, Vincent Dinot, Fara Diop, Alphonsine Diouf, Yael Dishon, Félix Djossou, Annemarie B Docherty, Helen Doherty, Arjen M Dondorp, Andy Dong, Maria Donnelly, Sean Donohue, Yoann Donohue, Chloe Donohue, Peter Doran, Céline Dorival, Eric D'Ortenzio, James Joshua Douglas, Renee Douma, Nathalie Dournon, Triona Downer, Joanne Downey, Mark Downing, Tom Drake, Aoife Driscoll, Murray Dryden, Claudio Duarte Fonseca, Vincent Dubee, François Dubos, Alexandre Ducancelle, Toni Duculan, Susanne Dudman, Abhijit Duggal, Paul Dunand, Mathilde Duplaix, Emanuele Durante-Mangoni, Lucian Durham, Bertrand Dussol, Juliette Duthoit, Xavier Duval, Anne Margarita Dyrhol-Riise, Sim Choon Ean, Marco Echeverria-Villalobos, Siobhan Egan, Carla Eira, Mohammed El Sanharawi, Subbarao Elapavaluru, Brigitte Elharrar, Jacobien Ellerbroek, Philippine Eloy, Tarek Elshazly, Iqbal Elyazar, Isabelle Enderle, Tomoyuki Endo, Chan Chee Eng, Ilka Engelmann, Vincent Enouf, Olivier Epaulard, Mariano Esperatti, Hélène Esperou, Marina Esposito-Farese, João Estevão, Manuel Etienne, Nadia Ettalhaoui, Anna Greti Everding, Mirjam Evers, Marc Fabre, Isabelle Fabre, Amna Faheem, Arabella Fahy, Cameron J Fairfield, Zul Fakar, Komal Fareed, Pedro Faria, Ahmed Farooq, Hanan Fateena, Arie Zainul Fatoni, Karine Faure, Raphaël Favory, Mohamed Fayed, Niamh Feely, Laura Feeney, Jorge Fernandes, Marília Andreia Fernandes, Susana Fernandes, François-Xavier Ferrand, Eglantine Ferrand Devouge, Joana Ferrão, Mário Ferraz, Sílvia Ferreira, Isabel Ferreira, Benigno Ferreira, Ricard Ferrer-Roca, Nicolas Ferriere, Céline Ficko, Claudia Figueiredo-Mello, William Finlayson, Juan Fiorda, Thomas Flament, Clara Flateau, Tom Fletcher, Letizia Lucia Florio, Deirdre Flynn, Claire Foley, Jean Foley, Victor Fomin, Tatiana Fonseca, Patricia Fontela, Simon Forsyth, Denise Foster, Giuseppe Foti, Erwan Fourn, Robert A Fowler, Marianne Fraher, Diego Franch-Llasat, John F Fraser, Christophe Fraser, Marcela Vieira Freire, Ana Freitas Ribeiro, Caren Friedrich, Ricardo Fritz, Stéphanie Fry, Nora Fuentes, Masahiro Fukuda, G Argin, Valérie Gaborieau, Rostane Gaci, Massimo Gagliardi, Jean-Charles Gagnard, Amandine Gagneux-Brunon, Sérgio Gaião, Linda Gail Skeie, Phil Gallagher, Carrol Gamble, Yasmin Gani, Arthur Garan, Rebekha Garcia, Julia Garcia-Diaz, Esteban Garcia-Gallo, Navya Garimella, Denis Garot, Valérie Garrait, Basanta Gauli, Nathalie Gault, Aisling Gavin, Anatoliy Gavrylov, Alexandre Gaymard, Johannes Gebauer, Eva Geraud, Louis Gerbaud Morlaes, Nuno Germano, Praveen Kumar Ghisulal, Jade Ghosn, Marco Giani, Jess Gibson, Tristan Gigante, Morgane Gilg, Elaine Gilroy, Guillermo Giordano, Michelle Girvan, Valérie Gissot, Daniel Glikman, Petr Glybochko, Eric Gnall, Geraldine Goco, François Goehringer, Siri Goepel, Jin Yi Goh, Jonathan Golob, Rui Gomes, Kyle Gomez, Joan Gómez-Junyent, Marie Gominet, Alicia Gonzalez, Patricia Gordon, Isabelle Gorenne, Laure Goubert, Cécile Goujard, Tiphaine Goulenok, Margarite Grable, Jeronimo Graf, Edward Wilson Grandin, Pascal Granier, Giacomo Grasselli, Christopher A Green, Courtney Greene, William Greenhalf, Segolène Greffe, Domenico Luca Grieco, Matthew Griffee, Fiona Griffiths, Ioana Grigoras, Albert Groenendijk, Anja Grosse Lordemann, Heidi Gruner, Yusing Gu, Jérémie Guedj, Martin Guego, Dewi Guellec, Anne-Marie Guerguerian, Daniela Guerreiro, Romain Guery, Anne Guillaumot, Laurent Guilleminault, Maisa Guimarães de Castro, Thomas Guimard, Marieke Haalboom, Daniel Haber, Hannah Habraken, Ali Hachemi, Amy Hackmann, Nadir Hadri, Fakhir Haidri, Sheeba Hakak, Adam Hall, Sophie Halpin, Jawad Hameed, Ansley Hamer, Raph L Hamers, Rebecca Hamidfar, Terese Hammond, Lim Yuen Han, Rashan Haniffa, Kok Wei Hao, Hayley Hardwick, Ewen M Harrison, Janet Harrison, Samuel Bernard Ekow Harrison, Alan Hartman, Mohd Shahnaz Hasan, Junaid Hashmi, Muhammad Hayat, Ailbhe Hayes, Leanne Hays, Jan Heerman, Lars Heggelund, Ross Hendry, Martina Hennessy, Aquiles Henriquez-Trujillo, Maxime Hentzien, Jaime Hernandez-Montfort, Andrew Hershey, Liv Hesstvedt, Astarini Hidayah, Eibhilin Higgins, Dawn Higgins, Rupert Higgins, Rita Hinchion, Samuel Hinton, Hiroaki Hiraiwa, Haider Hirkani, Hikombo Hitoto, Yi Bin Ho, Alexandre Hoctin, Isabelle Hoffmann, Wei Han Hoh, Oscar Hoiting, Rebecca Holt, Jan Cato Holter, Juan Pablo Horcajada, Koji Hoshino, Ikram Houas, Catherine L Hough, Stuart Houltham, Jimmy Ming-Yang Hsu, Jean-Sébastien Hulot, Stella Huo, Abby Hurd, Iqbal Hussain, Samreen Ijaz, Hajnal-Gabriela Illes, Patrick Imbert, Mohammad Imran, Rana Imran Sikander, Aftab Imtiaz, Hugo Inácio, Carmen Infante Dominguez, Yun Sii Ing, Elias Iosifidis, Mariachiara Ippolito, Sarah Isgett, Tiago Isidoro, Nadiah Ismail, Margaux Isnard, Junji Itai, Daniel Ivulich, Danielle Jaafar, Salma Jaafoura, Julien Jabot, Clare Jackson, Nina Jamieson, Victoria Janes, Pierre Jaquet, Coline Jaud-Fischer, Stéphane Jaureguiberry, Jeffrey Javidfar, Denise Jaworsky, Florence Jego, Anilawati Mat Jelani, Synne Jenum, Ruth Jimbo-Sotomayor, Ong Yiaw Joe, Ruth N Jorge García, Cédric Joseph, Mark Joseph, Swosti Joshi, Mercé Jourdain, Philippe Jouvet, Hanna Jung, Anna Jung, Dafsah Juzar, Ouifiya Kafif, Florentia Kaguelidou, Neerusha Kaisbain, Thavamany Kaleesvran, Sabina Kali, Alina Kalicinska, Smaragdi Kalomoiri, Muhammad Aisar Ayadi Kamaluddin, Zul Amali Che Kamaruddin, Nadiah Kamarudin, Paul Kambiya, Kavita Kamineni, Darshana Hewa Kandamby, Chris Kandel, Kong Yeow Kang, Darakhshan Kanwal, Pratap Karpayah, Todd Karsies, Daisuke Kasugai, Anant Kataria, Kevin Katz, Aasmine Kaur, Christy Kay, Hannah Keane, Seán Keating, Pulak Kedia, Claire Kelly, Yvelynne Kelly, Andrea Kelly, Niamh Kelly, Aoife Kelly, Sadie Kelly, Maeve Kelsey, Ryan Kennedy, Kalynn Kennon, Maeve Kernan, Younes Kerroumi, Sharma Keshav, Imrana Khalid, Osama Khalid, Antoine Khalil, Coralie Khan, Irfan Khan, Quratul Ain Khan, Sushil Khanal, Abid Khatak, Amin Khawaja, Krish Kherajani, Michelle E Kho, Saye Khoo, Ryan Khoo, Denisa Khoo, Nasir Khoso, Khor How Kiat, Yuri Kida, Peter Kiiza, Beathe Kiland Granerud, Anders Benjamin Kildal, Jae Burm Kim, Antoine Kimmoun, Detlef Kindgen-Milles, Alexander King, Nobuya Kitamura, Paul Klenerman, Rob Klont, Gry Kloumann Bekken, Stephen R Knight, Robin Kobbe, Chamira Kodippily, Malte Kohns Vasconcelos, Sabin Koirala, Mamoru Komatsu, Caroline Kosgei, Arsène Kpangon, Karolina Krawczyk, Vinothini Krishnan, Sudhir Krishnan, Oksana Kruglova, Deepali Kumar, Ganesh Kumar, Mukesh Kumar, Dinesh Kuriakose, Ethan Kurtzman, Demetrios Kutsogiannis, Galyna Kutsyna, Konstantinos Kyriakoulis, Marie Lachatre, Marie Lacoste, John G Laffey, Marie Lagrange, Fabrice Laine, Olivier Lairez, Sanjay Lakhey, Antonio Lalueza, Marc Lambert, François Lamontagne, Marie Langelot-Richard, Vincent Langlois, Eka Yudha Lantang, Marina Lanza, Cédric Laouénan, Samira Laribi, Delphine Lariviere, Stéphane Lasry, Sakshi Lath, Naveed Latif, Odile Launay, Didier Laureillard, Yoan Lavie-Badie, Andy Law, Teresa Lawrence, Cassie Lawrence, Minh Le, Clément Le Bihan, Cyril Le Bris, Georges Le Falher, Lucie Le Fevre, Quentin Le Hingrat, Marion Le Maréchal, Soizic Le Mestre, Gwenaël Le Moal, Vincent Le Moing, Hervé Le Nagard, Paul Le Turnier, Ema Leal, Marta Leal Santos, Todd C Lee, James Lee, Jennifer Lee, Heng Gee Lee, Biing Horng Lee, Yi Lin Lee, Su Hwan Lee, Gary Leeming, Laurent Lefebvre, Bénédicte Lefebvre, Benjamin Lefevre, Sylvie LeGac, Jean-Daniel Lelievre, François Lellouche, Adrien Lemaignen, Véronique Lemee, Anthony Lemeur, Gretchen Lemmink, Ha Sha Lene, Jenny Lennon, Rafael León, Marc Leone, Michela Leone, Quentin Lepiller, François-Xavier Lescure, Olivier Lesens, Mathieu Lesouhaitier, Amy Lester-Grant, Bruno Levy, Yves Levy, Claire Levy-Marchal, Katarzyna Lewandowska, Erwan L'Her, Gianluigi Li Bassi, Janet Liang, Ali Liaquat, Geoffrey Liegeon, Wei Shen Lim, Kah Chuan Lim, Chantre Lima, Lim Lina, Bruno Lina, Andreas Lind, Maja Katherine Lingad, Guillaume Lingas, Sylvie Lion-Daolio, Keibun Liu, Marine Livrozet, Patricia Lizotte, Antonio Loforte, Navy Lolong, Leong Chee Loon, Diogo Lopes, Dalia Lopez-Colon, Jose W Lopez-Revilla, Anthony L Loschner, Paul Loubet, Bouchra Loufti, Guillame Louis, Silvia Lourenco, Lara Lovelace-Macon, Lee Lee Low, Marije Lowik, Jia Shyi Loy, Jean Christophe Lucet, Carlos Lumbreras Bermejo, Carlos M Luna, Olguta Lungu, Liem Luong, Nestor Luque, Dominique Luton, Nilar Lwin, Ruth Lyons, Olavi Maasikas, Oryane Mabiala, Moïse Machado, Gabriel Macheda, Hashmi Madiha, Guillermo Maestro de la Calle, Rafael Mahieu, Sophie Mahy, Ana Raquel Maia, Lars S Maier, Mylène Maillet, Thomas Maitre, Maximilian Malfertheiner, Nadia Malik, Paddy Mallon, Fernando Maltez, Denis Malvy, Victoria Manda, Laurent Mandelbrot, Frank Manetta, Julie Mankikian, Edmund Manning, Aldric Manuel, Ceila Maria Sant Ana Malaque, Flávio Marino, Daniel Marino, Samuel Markowicz, Charbel Maroun Eid, Ana Marques, Catherine Marquis, Brian Marsh, Laura Marsh, Megan Marshal, John Marshall, Celina Turchi Martelli, Dori-Ann Martin, Emily Martin, Guillaume Martin-Blondel, Martin Martinot, Alejandro Martin-Quiros, João Martins, Ana Martins, Nuno Martins, Caroline Martins Rego, Gennaro Martucci, Olga Martynenko, Eva Miranda Marwali, Marsilla Marzukie, David Maslove, Sabina Mason, Sobia Masood, Basri Mat Nor, Moshe Matan, Meghena Mathew, Daniel Mathieu, Mathieu Mattei, Romans Matulevics, Laurence Maulin, Michael Maxwell, Javier Maynar, Thierry Mazzoni, Natalie Mc Evoy, Lisa Mc Sweeney, Colin McArthur, Anne McCarthy, Aine McCarthy, Colin McCloskey, Rachael McConnochie, Sherry McDermott, Sarah E McDonald, Aine McElroy, Samuel McElwee, Victoria McEneany, Allison McGeer, Chris McKay, Johnny McKeown, Kenneth A McLean, Paul McNally, Bairbre McNicholas, Elaine McPartlan, Edel Meaney, Cécile Mear-Passard, Maggie Mechlin, Maqsood Meher, Omar Mehkri, Ferruccio Mele, Luis Melo, Kashif Memon, Joao Joao Mendes, Ogechukwu Menkiti, Kusum Menon, Alexander J Mentzer, Emmanuelle Mercier, Noémie Mercier, Antoine Merckx, Mayka Mergeay-Fabre, Blake Mergler, António Mesquita, Roberta Meta, Osama Metwally, Agnès Meybeck, Dan Meyer, Alison M Meynert, Vanina Meysonnier, Amina Meziane, Mehdi Mezidi, Céline Michelanglei, Isabelle Michelet, Efstathia Mihelis, Vladislav Mihnovit, Hugo Miranda-Maldonado, Nor Arisah Misnan, Tahira Jamal Mohamed, Nik Nur Eliza Mohamed, Asma Moin, David Molina, Elena Molinos, Brenda Molloy, Mary Mone, Agostinho Monteiro, Claudia Montes, Giorgia Montrucchio, Shona C Moore, Sarah Moore, Lina Morales Cely, Lucia Moro, Catherine Motherway, Ana Motos, Hugo Mouquet, Clara Mouton Perrot, Julien Moyet, Caroline Mudara, Aisha Kalsoom Mufti, Ng Yong Muh, Dzawani Muhamad, Jimmy Mullaert, Fredrik Müller, Karl Erik Müller, Syed Muneeb, Nadeem Munir, Laveena Munshi, Aisling Murphy, Lorna Murphy, Marlène Murris, Srinivas Murthy, Himed Musaab, Himasha Muvindi, Gugapriyaa Muyandy, Dimitra Melia Myrodia, Farah Nadia Mohd-Hanafiah, Dave Nagpal, Alex Nagrebetsky, Mangala Narasimhan, Nageswaran Narayanan, Rashid Nasim Khan, Alasdair Nazerali-Maitland, Nadège Neant, Holger Neb, Erni Nelwan, Raul Neto, Emily Neumann, Pauline Yeung Ng, Wing Yiu Ng, Anthony Nghi, Duc Nguyen, Orna Ni Choileain, Niamh Ni Leathlobhair, Prompak Nitayavardhana, Stephanie Nonas, Nurul Amani Mohd Noordin, Marion Noret, Nurul Faten Izzati Norharizam, Lisa Norman, Alessandra Notari, Mahdad Noursadeghi, Karolina Nowicka, Adam Nowinski, Saad Nseir, Jose I Nunez, Nurnaningsih Nurnaningsih, Dwi Utomo Nusantara, Elsa Nyamankolly, Fionnuala O Brien, Annmarie O Callaghan, Annmarie O'Callaghan, Giovanna Occhipinti, Derbrenn OConnor, Max O'Donnell, Tawnya Ogston, Takayuki Ogura, Tak-Hyuk Oh, Sophie O'Halloran, Katie O'Hearn, Shinichiro Ohshimo, Agnieszka Oldakowska, João Oliveira, Larissa Oliveira, Jee Yan Ong, Wilna Oosthuyzen, Anne Opavsky, Peter Openshaw, Saijad Orakzai, Claudia Milena Orozco-Chamorro, Jamel Ortoleva, Javier Osatnik, Linda O'Shea, Miriam O'Sullivan, Siti Zubaidah Othman, Nadia Ouamara, Rachida Ouissa, Eric Oziol, Maïder Pagadoy, Justine Pages, Mario Palacios, Amanda Palacios, Massimo Palmarini, Giovanna Panarello, Hem Paneru, Lai Hui Pang, Mauro Panigada, Nathalie Pansu, Aurélie Papadopoulos, Rachael Parke, Melissa Parker, Briseida Parra, Taha Pasha, Jérémie Pasquier, Bruno Pastene, Fabian Patauner, Drashti Patel, Mohan Dass Pathmanathan, Luís Patrão, Patricia Patricio, Juliette Patrier, Lisa Patterson, Rajyabardhan Pattnaik, Mical Paul, Christelle Paul, Jorge Paulos, William A Paxton, Jean-François Payen, Kalaiarasu Peariasamy, Giles J Peek, Florent Peelman, Nathan Peiffer-Smadja, Vincent Peigne, Mare Pejkovska, Paolo Pelosi, Ithan D Peltan, Rui Pereira, Daniel Perez, Luis Periel, Thomas Perpoint, Antonio Pesenti, Vincent Pestre, Lenka Petrou, Ventzislava Petrov-Sanchez, Frank Olav Pettersen, Gilles Peytavin, Scott Pharand, Michael Piagnerelli, Walter Picard, Olivier Picone, Maria de Piero, Carola Pierobon, Djura Piersma, Carlos Pimentel, Raquel Pinto, Catarina Pires, Isabelle Pironneau, Lionel Piroth, Ayodhia Pitaloka, Riinu Pius, Laurent Plantier, Hon Shen Png, Julien Poissy, Ryadh Pokeerbux, Maria Pokorska-Spiewak, Sergio Poli, Georgios Pollakis, Diane Ponscarme, Jolanta Popielska, Diego Bastos Porto, Andra-Maris Post, Douwe F Postma, Pedro Povoa, Diana Póvoas, Jeff Powis, Sofia Prapa, Sébastien Preau, Christian Prebensen, Jean-Charles Preiser, Anton Prinssen, Gamage Dona Dilanthi Priyadarshani, Lucia Proença, Sravya Pudota, Oriane Puéchal, Bambang Pujo Semedi, Mathew Pulicken, Gregory Purcell, Luisa Quesada, Vilmaris Quinones-Cardona, Víctor Quirós González, Else Quist-Paulsen, Mohammed Quraishi, Maia Rabaa, Christian Rabaud, Ebenezer Rabindrarajan, Aldo Rafael, Marie Rafiq, Gabrielle Ragazzo, Mutia Rahardjani, Rozanah Abd Rahman, Ahmad Kashfi Haji Ab Rahman, Arsalan Rahutullah, Fernando Rainieri, Giri Shan Rajahram, Pratheema Ramachandran, Ahmad Afiq Ramli, Blandine Rammaert, Asim Rana, Rajavardhan Rangappa, Ritika Ranjan, Christophe Rapp, Aasiyah Rashan, Thalha Rashan, Ghulam Rasheed, Menaldi Rasmin, Indrek Rätsep, Cornelius Rau, Tharmini Ravi, Ali Raza, Andre Real, Stanislas Rebaudet, Sarah Redl, Brenda Reeve, Attaur Rehman, Liadain Reid, Dag Henrik Reikvam, Renato Reis, Jordi Rello, Jonathan Remppis, Martine Remy, Hongru Ren, Hanna Renk, Anne-Sophie Resseguier, Matthieu Revest, Oleksa Rewa, Luis Felipe Reyes, Tiago Reyes, Maria Ines Ribeiro, Antonia Ricchiuto, David Richardson, Denise Richardson, Laurent Richier, Siti Nurul Atikah Ahmad Ridzuan, Jordi Riera, Ana L Rios, Asgar Rishu, Patrick Rispal, Karine Risso, Maria Angelica Rivera Nuñez, Nicholas Rizer, Chiara Robba, André Roberto, Stephanie Roberts, David L Robertson, Olivier Robineau, Ferran Roche-Campo, Paola Rodari, Simão Rodeia, Bernhard Roessler, Pierre-Marie Roger, Emmanuel Roilides, Juliette Romaru, Roberto Roncon-Albuquerque, Mélanie Roriz, Manuel Rosa-Calatrava, Michael Rose, Dorothea Rosenberger, Nurul Hidayah Mohammad Roslan, Andrea Rossanese, Matteo Rossetti, Bénédicte Rossignol, Patrick Rossignol, Stella Rousset, Carine Roy, Benoît Roze, Desy Rusmawatiningtyas, Clark D Russell, Maria Ryan, Maeve Ryan, Steffi Ryckaert, Aleksander Rygh Holten, Isabela Saba, Sairah Sadaf, Musharaf Sadat, Valla Sahraei, Maximilien Saint-Gilles, Pranya Sakiyalak, Nawal Salahuddin, Leonardo Salazar, Jodat Saleem, Gabriele Sales, Stéphane Sallaberry, Charlotte Salmon Gandonniere, Hélène Salvator, Olivier Sanchez, Angel Sanchez-Miralles, Vanessa Sancho-Shimizu, Gyan Sandhu, Zulfiqar Sandhu, Pierre-François Sandrine, Marlene Santos, Shirley Sarfo-Mensah, Bruno Sarmento Banheiro, Iam Claire E Sarmiento, Benjamine Sarton, Ankana Satya, Sree Satyapriya, Rumaisah Satyawati, Egle Saviciute, Parthena Savvidou, Yen Tsen Saw, Justin Schaffer, Tjard Schermer, Arnaud Scherpereel, Marion Schneider, Stephan Schroll, Michael Schwameis, Gary Schwartz, Brendan Scicluna, Janet T Scott, James Scott-Brown, Nicholas Sedillot, Tamara Seitz, Jaganathan Selvanayagam, Mageswari Selvarajoo, Caroline Semaille, Rasidah Bt Senian, Eric Senneville, Claudia Sepulveda, Filipa Sequeira, Tânia Sequeira, Ary Serpa Neto, Pablo Serrano Balazote, Ellen Shadowitz, Syamin Asyraf Shahidan, Mohammad Shamsah, Anuraj Shankar, Shaikh Sharjeel, Catherine A Shaw, Victoria Shaw, Ashraf Sheharyar, Rohan Shetty, Rajesh Mohan Shetty, Haixia Shi, Nisreen Shiban, Mohiuddin Shiekh, Nobuaki Shime, Hiroaki Shimizu, Keiki Shimizu, Sally Shrapnel, Pramesh Sundar Shrestha, Shubha Kalyan Shrestha, Hoi Ping Shum, Nassima Si Mohammed, Ng Yong Siang, Jeanne Sibiude, Atif Siddiqui, Piret Sillaots, Catarina Silva, Rogério Silva, Maria Joao Silva, Wai Ching Sin, Dario Sinatti, Punam Singh, Budha Charan Singh, Pompini Agustina Sitompul, Karisha Sivam, Vegard Skogen, Sue Smith, Benjamin Smood, Coilin Smyth, Michelle Smyth, Morgane Snacken, Dominic So, Tze Vee Soh, Joshua Solomon, Tom Solomon, Agnès Sommet, Rima Song, Tae Song, Jack Song Chia, Michael Sonntagbauer, Azlan Mat Soom, Alberto Sotto, Edouard Soum, Marta Sousa, Ana Chora Sousa, Maria Sousa Uva, Vicente Souza-Dantas, Alexandra Sperry, Elisabetta Spinuzza, B P Sanka Ruwan Sri Darshana, Shiranee Sriskandan, Sarah Stabler, Thomas Staudinger, Stephanie-Susanne Stecher, Trude Steinsvik, Ymkje Stienstra, Birgitte Stiksrud, Eva Stolz, Amy Stone, Adrian Streinu-Cercel, David Stuart, Ami Stuart, Decy Subekti, Gabriel Suen, Jacky Y Suen, Asfia Sultana, Charlotte Summers, Dubravka Supic, Deepashankari Suppiah, Magdalena Surovcová, Suwarti Suwarti, Andrey Svistunov, Sarah Syahrin, Konstantinos Syrigos, Jaques Sztajnbok, Konstanty Szuldrzynski, Shirin Tabrizi, Lysa Tagherset, Shahdattul Mawarni Taib, Ewa Talarek, Sara Taleb, Jelmer Talsma, Renaud Tamisier, Maria Lawrensia Tampubolon, Kim Keat Tan, Yan Chyi Tan, Taku Tanaka, Hiroyuki Tanaka, Hayato Taniguchi, Huda Taqdees, Arshad Taqi, Coralie Tardivon, Pierre Tattevin, M Azhari Taufik, Hassan Tawfik, Richard S Tedder, Tze Yuan Tee, João Teixeira, Sofia Tejada, Marie-Capucine Tellier, Sze Kye Teoh, Vanessa Teotonio, François Téoulé, Pleun Terpstra, Olivier Terrier, Nicolas Terzi, Hubert Tessier-Grenier, Adrian Tey, Alif Adlan Mohd Thabit, Anand Thakur, Zhang Duan Tham, Suvintheran Thangavelu, Vincent Thibault, Simon-Djamel Thiberville, Benoît Thill, Jananee Thirumanickam, Shaun Thompson, Emma C Thomson, David Thomson, Surain Raaj Thanga Thurai, Ryan S Thwaites, Paul Tierney, Vadim Tieroshyn, Peter S Timashev, Jean-François Timsit, Noémie Tissot, Jordan Zhien Yang Toh, Maria Toki, Kristian Tonby, Sia Loong Tonnii, Margarida Torres, Antoni Torres, Rosario Maria Torres Santos-Olmo, Hernando Torres-Zevallos, Michael Towers, Tony Trapani, Théo Treoux, Cécile Tromeur, Ioannis Trontzas, Tiffany Trouillon, Jeanne Truong, Christelle Tual, Sarah Tubiana, Helen Tuite, Jean-Marie Turmel, Lance C W Turtle, Anders Tveita, Pawel Twardowski, Makoto Uchiyama, P G Ishara Udayanga, Andrew Udy, Roman Ullrich, Alberto Uribe, Asad Usman, Timothy M Uyeki, Cristinava Vajdovics, Piero Valentini, Luís Val-Flores, Amélie Valran, Stijn Van de Velde, Marcel van den Berge, Machteld Van der Feltz, Job van der Palen, Paul van der Valk, Nicky Van Der Vekens, Peter Van der Voort, Sylvie Van Der Werf, Laura van Gulik, Jarne Van Hattem, Carolien van Netten, 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Munblit, Daniel, Nekliudov, Nikita A, Nichol, Alistair D, Singh Oinam, Budha Charan, Ong, David, Panda, Prasan Kumar, Petrovic, Michele, Pritchard, Mark G, Ramakrishnan, Nagarajan, Ramos, Grazielle Viana, Roger, Claire, Sandulescu, Oana, Semple, Malcolm G, Sharma, Pratima, Sigfrid, Louise, Somers, Emily C, Streinu-Cercel, Anca, Taccone, Fabio, Vecham, Pavan Kumar, Kumar Tirupakuzhi Vijayaraghavan, Bharath, Wei, Jia, Wils, Evert-Jan, Ci Wong, Xin, Horby, Peter, Rojek, Amanda, Olliaro, Piero L, ISARIC Clinical Characterisation Group: Ali Abbas, Sheryl Ann Abdukahil, Nurul Najmee Abdulkadir, Ryuzo Abe, Laurent Abel, Lara Absil, Subhash Acharya, Andrew Acker, Elisabeth Adam, Diana Adrião, Saleh Al Ageel, Shakeel Ahmed, Kate Ainscough, Eka Airlangga, Tharwat Aisa, Ali Ait Hssain, Younes Ait Tamlihat, Takako Akimoto, Ernita Akmal, Eman Al Qasim, Razi Alalqam, Angela Alberti, Tala Al-Dabbous, Senthilkumar Alegesan, Cynthia Alegre, Marta Alessi, Beatrice Alex, Kévin Alexandre, Abdulrahman 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Bakar, Andriy Bal, Mohanaprasanth Balakrishnan, Valeria Balan, Firouzé Bani-Sadr, Renata Barbalho, Nicholas Yuri Barbosa, Wendy S Barclay, Saef Umar Barnett, Michaela Barnikel, Helena Barrasa, Audrey Barrelet, Cleide Barrigoto, Marie Bartoli, Mustehan Bashir, Romain Basmaci, Muhammad Fadhli Hassin Basri, Denise Battaglini, Jules Bauer, Diego Fernando Bautista Rincon, Denisse Bazan Dow, Alexandra Bedossa, Ker Hong Bee, Husna Begum, Sylvie Behilill, Albertus Beishuizen, Aleksandr Beljantsev, David Bellemare, Anna Beltrame, Beatriz Amorim Beltrão, Marine Beluze, Nicolas Benech, Lionel Eric Benjiman, Dehbia Benkerrou, Suzanne Bennett, Luís Bento, Jan-Erik Berdal, Delphine Bergeaud, Hazel Bergin, José Luis Bernal Sobrino, Giulia Bertoli, Lorenzo Bertolino, Simon Bessis, Sybille Bevilcaqua, Karine Bezulier, Amar Bhatt, Krishna Bhavsar, Claudia Bianco, Farah Nadiah Bidin, Moirangthem Bikram Singh, Felwa Bin Humaid, Mohd Nazlin Bin Kamarudin, François Bissuel, Patrick Biston, Laurent Bitker, 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Antoine Cheret, Thibault Chiarabini, Julian Chica, Suresh Kumar Chidambaram, Leong Chin Tho, Catherine Chirouze, Davide Chiumello, Sung-Min Cho, Bernard Cholley, Marie-Charlotte Chopin, Ting Soo Chow, Yock Ping Chow, Hiu Jian Chua, Jonathan Chua, Jose Pedro Cidade, José Miguel Cisneros Herreros, Anna Ciullo, Jennifer Clarke, Emma Clarke, Rolando Claure-Del Granado, Sara Clohisey, Perren J Cobb, Cassidy Codan, Caitriona Cody, Alexandra Coelho, Megan Coles, Gwenhaël Colin, Michael Collins, Sebastiano Maria Colombo, Pamela Combs, Marie Connor, Anne Conrad, Sofía Contreras, Elaine Conway, Graham S Cooke, Mary Copland, Hugues Cordel, Amanda Corley, Sabine Cornelis, Alexander Daniel Cornet, Arianne Joy Corpuz, Andrea Cortegiani, Grégory Corvaisier, Emma Costigan, Camille Couffignal, Sandrine Couffin-Cadiergues, Roxane Courtois, Stéphanie Cousse, Rachel Cregan, Charles Crepy D'Orleans, Cosimo Cristella, Sabine Croonen, Gloria Crowl, Jonathan Crump, Claudina Cruz, Juan Luis Cruz Berm, Jaime Cruz Rojo, Marc Csete, Ailbhe Cullen, Matthew Cummings, Gerard Curley, Elodie Curlier, Colleen Curran, Paula Custodio, Ana da Silva Filipe, Charlene Da Silveira, Al-Awwab Dabaliz, Darren Dahly, Heidi Dalton, Jo Dalton, Seamus Daly, Nick Daneman, Corinne Daniel, Jorge Dantas, Frédérick D'Aragon, Menno de Jong, Gillian de Loughry, Diego de Mendoza, Etienne De Montmollin, Rafael Freitas de Oliveira França, Ana Isabel de Pinho Oliveira, Rosanna De Rosa, Cristina De Rose, Thushan de Silva, Peter de Vries, Jillian Deacon, David Dean, Alexa Debard, Marie-Pierre Debray, Nathalie DeCastro, William Dechert, Lauren Deconninck, Romain Decours, Eve Defous, Isabelle Delacroix, Eric Delaveuve, Karen Delavigne, Nathalie M Delfos, Ionna Deligiannis, Andrea Dell'Amore, Christelle Delmas, Pierre Delobel, Corine Delsing, Elisa Demonchy, Emmanuelle Denis, Dominique Deplanque, Pieter Depuydt, Mehul Desai, Diane Descamps, Mathilde Desvallées, Santi Dewayanti, Pathik Dhanger, Alpha Diallo, Sylvain Diamantis, André Dias, Juan Jose Diaz, Priscila Diaz, Rodrigo Diaz, Kévin Didier, Jean-Luc Diehl, Wim Dieperink, Jérôme Dimet, Vincent Dinot, Fara Diop, Alphonsine Diouf, Yael Dishon, Félix Djossou, Annemarie B Docherty, Helen Doherty, Arjen M Dondorp, Andy Dong, Maria Donnelly, Sean Donohue, Yoann Donohue, Chloe Donohue, Peter Doran, Céline Dorival, Eric D'Ortenzio, James Joshua Douglas, Renee Douma, Nathalie Dournon, Triona Downer, Joanne Downey, Mark Downing, Tom Drake, Aoife Driscoll, Murray Dryden, Murray Dryden, Claudio Duarte Fonseca, Vincent Dubee, François Dubos, Alexandre Ducancelle, Toni Duculan, Susanne Dudman, Abhijit Duggal, Paul Dunand, Mathilde Duplaix, Emanuele Durante-Mangoni, Lucian Durham, Bertrand Dussol, Juliette Duthoit, Xavier Duval, Anne Margarita Dyrhol-Riise, Sim Choon Ean, Marco Echeverria-Villalobos, Siobhan Egan, Carla Eira, Mohammed El Sanharawi, Subbarao Elapavaluru, Brigitte Elharrar, Jacobien Ellerbroek, Philippine Eloy, Tarek Elshazly, Iqbal Elyazar, Isabelle Enderle, Tomoyuki Endo, Chan Chee Eng, Ilka Engelmann, Vincent Enouf, Olivier Epaulard, Mariano Esperatti, Hélène Esperou, Marina Esposito-Farese, João Estevão, Manuel Etienne, Nadia Ettalhaoui, Anna Greti Everding, Mirjam Evers, Marc Fabre, Isabelle Fabre, Amna Faheem, Arabella Fahy, Cameron J Fairfield, Zul Fakar, Komal Fareed, Pedro Faria, Ahmed Farooq, Hanan Fateena, Arie Zainul Fatoni, Karine Faure, Raphaël Favory, Mohamed Fayed, Niamh Feely, Laura Feeney, Jorge Fernandes, Marília Andreia Fernandes, Susana Fernandes, François-Xavier Ferrand, Eglantine Ferrand Devouge, Joana Ferrão, Mário Ferraz, Sílvia Ferreira, Isabel Ferreira, Benigno Ferreira, Ricard Ferrer-Roca, Nicolas Ferriere, Céline Ficko, Claudia Figueiredo-Mello, William Finlayson, Juan Fiorda, Thomas Flament, Clara Flateau, Tom Fletcher, Letizia Lucia Florio, Deirdre Flynn, Claire Foley, Jean Foley, Victor Fomin, Tatiana Fonseca, Patricia Fontela, Simon Forsyth, Denise Foster, Giuseppe Foti, Erwan Fourn, Robert A Fowler, Marianne Fraher, Diego Franch-Llasat, John F Fraser, Christophe Fraser, Marcela Vieira Freire, Ana Freitas Ribeiro, Caren Friedrich, Ricardo Fritz, Stéphanie Fry, Nora Fuentes, Masahiro Fukuda, G Argin, Valérie Gaborieau, Rostane Gaci, Massimo Gagliardi, Jean-Charles Gagnard, Amandine Gagneux-Brunon, Sérgio Gaião, Linda Gail Skeie, Phil Gallagher, Carrol Gamble, Yasmin Gani, Arthur Garan, Rebekha Garcia, Julia Garcia-Diaz, Esteban Garcia-Gallo, Navya Garimella, Denis Garot, Valérie Garrait, Basanta Gauli, Nathalie Gault, Aisling Gavin, Anatoliy Gavrylov, Alexandre Gaymard, Johannes Gebauer, Eva Geraud, Louis Gerbaud Morlaes, Nuno Germano, Praveen Kumar Ghisulal, Jade Ghosn, Marco Giani, Jess Gibson, Tristan Gigante, Morgane Gilg, Elaine Gilroy, Guillermo Giordano, Michelle Girvan, Valérie Gissot, Daniel Glikman, Petr Glybochko, Eric Gnall, Geraldine Goco, François Goehringer, Siri Goepel, Jin Yi Goh, Jonathan Golob, Rui Gomes, Kyle Gomez, Joan Gómez-Junyent, Marie Gominet, Alicia Gonzalez, Patricia Gordon, Isabelle Gorenne, Laure Goubert, Cécile Goujard, Tiphaine Goulenok, Margarite Grable, Jeronimo Graf, Edward Wilson Grandin, Pascal Granier, Giacomo Grasselli, Christopher A Green, Courtney Greene, William Greenhalf, Segolène Greffe, Domenico Luca Grieco, Matthew Griffee, Fiona Griffiths, Ioana Grigoras, Albert Groenendijk, Anja Grosse Lordemann, Heidi Gruner, Yusing Gu, Jérémie Guedj, Martin Guego, Dewi Guellec, Anne-Marie Guerguerian, Daniela Guerreiro, Romain Guery, Anne Guillaumot, Laurent Guilleminault, Maisa Guimarães de Castro, Thomas Guimard, Marieke Haalboom, Daniel Haber, Hannah Habraken, Ali Hachemi, Amy Hackmann, Nadir Hadri, Fakhir Haidri, Sheeba Hakak, Adam Hall, Sophie Halpin, Jawad Hameed, Ansley Hamer, Raph L Hamers, Rebecca Hamidfar, Terese Hammond, Lim Yuen Han, Rashan Haniffa, Kok Wei Hao, Hayley Hardwick, Ewen M Harrison, Janet Harrison, Samuel Bernard Ekow Harrison, Alan Hartman, Mohd Shahnaz Hasan, Junaid Hashmi, Muhammad Hayat, Ailbhe Hayes, Leanne Hays, Jan Heerman, Lars Heggelund, Ross Hendry, Martina Hennessy, Aquiles Henriquez-Trujillo, Maxime Hentzien, Jaime Hernandez-Montfort, Andrew Hershey, Liv Hesstvedt, Astarini Hidayah, Eibhilin Higgins, Dawn Higgins, Rupert Higgins, Rita Hinchion, Samuel Hinton, Hiroaki Hiraiwa, Haider Hirkani, Hikombo Hitoto, Yi Bin Ho, Alexandre Hoctin, Isabelle Hoffmann, Wei Han Hoh, Oscar Hoiting, Rebecca Holt, Jan Cato Holter, Juan Pablo Horcajada, Koji Hoshino, Ikram Houas, Catherine L Hough, Stuart Houltham, Jimmy Ming-Yang Hsu, Jean-Sébastien Hulot, Stella Huo, Abby Hurd, Iqbal Hussain, Samreen Ijaz, Hajnal-Gabriela Illes, Patrick Imbert, Mohammad Imran, Rana Imran Sikander, Aftab Imtiaz, Hugo Inácio, Carmen Infante Dominguez, Yun Sii Ing, Elias Iosifidis, Mariachiara Ippolito, Sarah Isgett, Tiago Isidoro, Nadiah Ismail, Margaux Isnard, Junji Itai, Daniel Ivulich, Danielle Jaafar, Salma Jaafoura, Julien Jabot, Clare Jackson, Nina Jamieson, Victoria Janes, Pierre Jaquet, Coline Jaud-Fischer, Stéphane Jaureguiberry, Jeffrey Javidfar, Denise Jaworsky, Florence Jego, Anilawati Mat Jelani, Synne Jenum, Ruth Jimbo-Sotomayor, Ong Yiaw Joe, Ruth N Jorge García, Cédric Joseph, Mark Joseph, Swosti Joshi, Mercé Jourdain, Philippe Jouvet, Hanna Jung, Anna Jung, Dafsah Juzar, Ouifiya Kafif, Florentia Kaguelidou, Neerusha Kaisbain, Thavamany Kaleesvran, Sabina Kali, Alina Kalicinska, Smaragdi Kalomoiri, Muhammad Aisar Ayadi Kamaluddin, Zul Amali Che Kamaruddin, Nadiah Kamarudin, Paul Kambiya, Kavita Kamineni, Darshana Hewa Kandamby, Chris Kandel, Kong Yeow Kang, Darakhshan Kanwal, Pratap Karpayah, Todd Karsies, Daisuke Kasugai, Anant Kataria, Kevin Katz, Aasmine Kaur, Christy Kay, Hannah Keane, Seán Keating, Pulak Kedia, Claire Kelly, Yvelynne Kelly, Andrea Kelly, Niamh Kelly, Aoife Kelly, Sadie Kelly, Maeve Kelsey, Ryan Kennedy, Kalynn Kennon, Maeve Kernan, Younes Kerroumi, Sharma Keshav, Imrana Khalid, Osama Khalid, Antoine Khalil, Coralie Khan, Irfan Khan, Quratul Ain Khan, Sushil Khanal, Abid Khatak, Amin Khawaja, Krish Kherajani, Michelle E Kho, Saye Khoo, Ryan Khoo, Denisa Khoo, Nasir Khoso, Khor How Kiat, Yuri Kida, Peter Kiiza, Beathe Kiland Granerud, Anders Benjamin Kildal, Jae Burm Kim, Antoine Kimmoun, Detlef Kindgen-Milles, Alexander King, Nobuya Kitamura, Paul Klenerman, Rob Klont, Gry Kloumann Bekken, Stephen R Knight, Robin Kobbe, Chamira Kodippily, Malte Kohns Vasconcelos, Sabin Koirala, Mamoru Komatsu, Caroline Kosgei, Arsène Kpangon, Karolina Krawczyk, Vinothini Krishnan, Sudhir Krishnan, Oksana Kruglova, Deepali Kumar, Ganesh Kumar, Mukesh Kumar, Dinesh Kuriakose, Ethan Kurtzman, Demetrios Kutsogiannis, Galyna Kutsyna, Konstantinos Kyriakoulis, Marie Lachatre, Marie Lacoste, John G Laffey, Marie Lagrange, Fabrice Laine, Olivier Lairez, Sanjay Lakhey, Antonio Lalueza, Marc Lambert, François Lamontagne, Marie Langelot-Richard, Vincent Langlois, Eka Yudha Lantang, Marina Lanza, Cédric Laouénan, Samira Laribi, Delphine 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Gilles Peytavin, Scott Pharand, Michael Piagnerelli, Walter Picard, Olivier Picone, Maria de Piero, Carola Pierobon, Djura Piersma, Carlos Pimentel, Raquel Pinto, Catarina Pires, Isabelle Pironneau, Lionel Piroth, Ayodhia Pitaloka, Riinu Pius, Laurent Plantier, Hon Shen Png, Julien Poissy, Ryadh Pokeerbux, Maria Pokorska-Spiewak, Sergio Poli, Georgios Pollakis, Diane Ponscarme, Jolanta Popielska, Diego Bastos Porto, Andra-Maris Post, Douwe F Postma, Pedro Povoa, Diana Póvoas, Jeff Powis, Sofia Prapa, Sébastien Preau, Christian Prebensen, Jean-Charles Preiser, Anton Prinssen, Gamage Dona Dilanthi Priyadarshani, Lucia Proença, Sravya Pudota, Oriane Puéchal, Bambang Pujo Semedi, Mathew Pulicken, Gregory Purcell, Luisa Quesada, Vilmaris Quinones-Cardona, Víctor Quirós González, Else Quist-Paulsen, Mohammed Quraishi, Maia Rabaa, Christian Rabaud, Ebenezer Rabindrarajan, Aldo Rafael, Marie Rafiq, Gabrielle Ragazzo, Mutia Rahardjani, Rozanah Abd Rahman, Ahmad Kashfi Haji Ab Rahman, Arsalan 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Wahab, Noor Hidayu Wahab, Nadirah Abdul Wahid, Marina Wainstein, Wan Fadzlina Wan Muhd Shukeri, Chih-Hsien Wang, Steve Webb, Katharina Weil, Tan Pei Wen, Sanne Wesselius, T Eoin West, Murray Wham, Bryan Whelan, Nicole White, Paul Henri Wicky, Aurélie Wiedemann, Surya Otto Wijaya, Keith Wille, Suzette Willems, Virginie Williams, Calvin Wong, Yew Sing Wong, Teck Fung Wong, Natalie Wright, Gan Ee Xian, Lim Saio Xian, Kuan Pei Xuan, Ioannis Xynogalas, Siti Rohani Binti Mohd Yakop, Masaki Yamazaki, Yazdan Yazdanpanah, Nicholas Yee Liang Hing, Cécile Yelnik, Chian Hui Yeoh, Stephanie Yerkovich, Toshiki Yokoyama, Hodane Yonis, Obada Yousif, Saptadi Yuliarto, Akram Zaaqoq, Marion Zabbe, Kai Zacharowski, Masliza Zahid, Maram Zahran, Nor Zaila Binti Zaidan, Maria Zambon, Miguel Zambrano, Alberto Zanella, Konrad Zawadka, Nurul Zaynah, Hiba Zayyad, Alexander Zoufaly, David Zucman, University of Oxford, Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, CHU Pontchaillou [Rennes], ARN régulateurs bactériens et médecine (BRM), Université de Rennes (UR)-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 ), This work was made possible by the UK Foreign, Commonwealth and Development Office, Wellcome (215091/Z/18/Z, 205228/Z/16/Z, 220757/Z/20/Z), Bill & Melinda Gates Foundation (OPP1209135), UK Medical Research Council Clinical Research Training Fellowship (MR/V001671/1), the philanthropic support of the donors to the University of Oxford’s COVID-19 Research Response Fund, CIHR Coronavirus Rapid Research Funding Opportunity (OV2170359) and the co-ordination in Canada by Sunnybrook Research Institute, endorsement of the Irish Critical Care—Clinical Trials Group, co-ordination in Ireland by the Irish Critical Care—Clinical Trials Network at University College Dublin and funding by the Health Research Board of Ireland (CTN-2014–12), the Rapid European COVID-19 Emergency Response research (RECOVER) (H2020 project 101003589) and European Clinical Research Alliance on Infectious Diseases (ECRAID) (965313), the COVID clinical management team, AIIMS, Rishikesh, India, the COVID-19 Clinical Management team, Manipal Hospital Whitefield, Bengaluru, India, Cambridge NIHR Biomedical Research Centre, the dedication and hard work of the Groote Schuur Hospital Covid ICU Team, support by the Groote Schuur nursing and University of Cape Town registrar bodies co-ordinated by the Division of Critical Care at the University of Cape Town, the Liverpool School of Tropical Medicine and the University of Oxford, the dedication and hard work of the Norwegian SARS-CoV-2 study team, the Research Council of Norway (grant no. 312780) and a philanthropic donation from Vivaldi Invest A/S owned by Jon Stephenson von Tetzchner, Imperial NIHR Biomedical Research Centre, the Comprehensive Local Research Networks of which PJMO is an NIHR Senior Investigator (NIHR201385), Innovative Medicines Initiative Joint Undertaking under Grant Agreement No. 115523 COMBACTE, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007– 2013) and EFPIA companies, in-kind contribution, the French COVID cohort (NCT04262921) is sponsored by INSERM and is funded by the REACTing (REsearch & ACtion emergING infectious diseases) consortium and by a grant of the French Ministry of Health (PHRC n 20–0424), Stiftungsfonds zur Förderung der Bekämpfung der Tuberkulose und anderer Lungenkrankheiten of the City of Vienna (project no. APCOV22BGM), Italian Ministry of Health ‘Fondi Ricerca corrente–L1P6’ to IRCCS Ospedale Sacro Cuore–Don Calabria, Australian Department of Health grant (3273191), Gender Equity Strategic Fund at University of Queensland, Artificial Intelligence for Pandemics (A14PAN) at University of Queensland, the Australian Research Council Centre of Excellence for Engineered Quantum Systems (EQUS, CE170100009), the Prince Charles Hospital Foundation, Australia, grants from Instituto de Salud Carlos III, Ministerio de Ciencia, Spain, Brazil, National Council for Scientific and Technological Development (scholarship no. 303953/2018–7), the Firland Foundation, Shoreline, Washington, USA, a grant from foundation Bevordering Onderzoek Franciscus, the South Eastern Norway Health Authority and the Research Council of Norway, and preparedness work conducted by the Short PeRiod IncideNce sTudy of Severe Acute Respiratory Infection. Data and Material provision was supported by grants from the National Institute for Health Research (NIHR, award CO-CIN-01), the Medical Research Council (MRC, and grant MC_PC_19059) and by the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with PHE (award no. 200907), NIHR HPRU in Respiratory Infections at Imperial College London with PHE (award no. 200927), Liverpool Experimental Cancer Medicine Centre (grant no. C18616/A25153), NIHR Biomedical Research Centre at Imperial College London (award no. IS-BRC-1215–20013) and NIHR Clinical Research Network providing infrastructure support.
Subjects: Male, Epidemiology, MESH: Hospitalization, MESH: Proportional Hazards Models, MESH: Risk Factors, Risk Factors, MESH: Child, cohort study, MESH: COVID-19, Humans, MESH: SARS-CoV-2, Child, Proportional Hazards Models, MESH: Humans, MESH: Middle Aged, SARS-CoV-2, COVID-19, risk of death, General Medicine, Middle Aged, co-morbidities, symptoms, treatments, MESH: Male, Hospitalization, Intensive Care Units, MESH: Intensive Care Units, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, COVID-19/therapy
Abstract: Background We describe demographic features, treatments and clinical outcomes in the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) COVID-19 cohort, one of the world's largest international, standardized data sets concerning hospitalized patients. Methods The data set analysed includes COVID-19 patients hospitalized between January 2020 and January 2022 in 52 countries. We investigated how symptoms on admission, co-morbidities, risk factors and treatments varied by age, sex and other characteristics. We used Cox regression models to investigate associations between demographics, symptoms, co-morbidities and other factors with risk of death, admission to an intensive care unit (ICU) and invasive mechanical ventilation (IMV). Results Data were available for 689 572 patients with laboratory-confirmed (91.1%) or clinically diagnosed (8.9%) SARS-CoV-2 infection from 52 countries. Age [adjusted hazard ratio per 10 years 1.49 (95% CI 1.48, 1.49)] and male sex [1.23 (1.21, 1.24)] were associated with a higher risk of death. Rates of admission to an ICU and use of IMV increased with age up to age 60 years then dropped. Symptoms, co-morbidities and treatments varied by age and had varied associations with clinical outcomes. The case-fatality ratio varied by country partly due to differences in the clinical characteristics of recruited patients and was on average 21.5%. Conclusions Age was the strongest determinant of risk of death, with a ∼30-fold difference between the oldest and youngest groups; each of the co-morbidities included was associated with up to an almost 2-fold increase in risk. Smoking and obesity were also associated with a higher risk of death. The size of our international database and the standardized data collection method make this study a comprehensive international description of COVID-19 clinical features. Our findings may inform strategies that involve prioritization of patients hospitalized with COVID-19 who have a higher risk of death.
Published: 2023
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24. Diagnostic issues faced by a rare disease healthcare network during Covid-19 outbreak: data from the Campania Rare Disease Registry

Author: Limongelli G, Iucolano S, Monda E, Elefante P, De Stasio C, Lubrano I, Caiazza M, Mazzella M, Fimiani F, Galdo M, De Marchi G, Esposito M, Rubino M, Cirillo A, Fusco A, Esposito A, Trama U, Esposito S, Scarano G, Sepe J, Andria G, Orlando V, Menditto E, Chiodini P, Campania Rare Disease, Iolascon A, Franzese A, Sanduzzi Zamparelli A, Tessitore A, Romano A, Venosa A, Nunzia Olivieri A, Bianco A, La Manna A, Cerbone AM, Spasiano A, Agnese Stanziola A, Colao A, De Bellis A, Gambale A, Toriello A, Tufano A, Ciampa A, Maria Risitano A, Pisani A, Russo A, Volpe A, De Martino B, Amato B, De Fusco C, Piscopo C, Selleri C, Tucci C, Pignata C, Cioffi D, Melis D, Pasquali D, De Brasi D, Spitaleri D, Russo D, Martellotta D, De Michele E, Varricchio E, Miraglia Del Giudice E, Coscioni E, Cimino E, Pane F, Tranfa F, Pollio F, Lonardo F, Nuzzi F, Simonelli F, Trojsi F, Habetswallner F, Valentini G, Cerbone G, Parenti G, Tedeschi G, Capasso G, Battista Rossi G, Gaglione G, Sarnelli G, Argenziano G, Bellastella G, De Michele G, Fiorentino G, Spadaro G, Scala I, Santoro L, Zeppa L, Auricchio L, Elio Adinolfi L, Alessio M, Amitrano M, Savanelli MC, Russo MG, Ferrucci MG, Carbone MT, Pellecchia MT, Salerno M, Melone M, Del Donno M, Vitale M, Triggiani M, Della Monica M, Lo Presti M, Tenuta M, Mignogna MD, Schiavulli M, Zacchia M, Brunetti-Pierri N, Iovino P, Moscato P, Iandoli R, Scarpa R, Russo R, Troisi S, Sbordone S, Perrotta S, Fecarotta S, Sampaolo S, Cicalese V., Limongelli, Giuseppe, Iucolano, Stefano, Monda, Emanuele, Elefante, Pasquale, De Stasio, Chiara, Lubrano, Imma, Caiazza, Martina, Mazzella, Marialuisa, Fimiani, Fabio, Galdo, Maria, De Marchi, Giulia, Esposito, Martina, Rubino, Marta, Cirillo, Annapaola, Fusco, Adelaide, Esposito, Augusto, Trama, Ugo, Esposito, Salvatore, Scarano, Gioacchino, Sepe, Joseph, Andria, Generoso, Orlando, Valentina, Menditto, Enrica, Chiodini, Paolo, Iolascon, Achille, Franzese, Adriana, Sanduzzi Zamparelli, Alessandro, Tessitore, Alessandro, Romano, Alfonso, Venosa, Alfredo, Nunzia Olivieri, Alma, Bianco, Andrea, La Manna, Angela, Cerbone, Anna Maria, Spasiano, Anna, Agnese Stanziola, Anna, Colao, Annamaria, De Bellis, Annamaria, Gambale, Antonella, Toriello, Antonella, Tufano, Antonella, Ciampa, Antonio, Maria Risitano, Antonio, Pisani, Antonio, Russo, Antonio, Volpe, Antonio, De Martino, Bernardo, Amato, Bruno, De Fusco, Carmela, Piscopo, Carmelo, Selleri, Carmine, Tucci, Celeste, Pignata, Claudio, Cioffi, Daniela, Melis, Daniela, Pasquali, Daniela, De Brasi, Daniele, Spitaleri, Daniele, De Brasi, Davide, Russo, Domenico, Martellotta, Donata, De Michele, Elisa, Varricchio, Elziario, Miraglia Del Giudice, Emanuele, Coscioni, Enrico, Cimino, Ernesto, Pane, Fabrizio, Tranfa, Fausto, Pollio, Filiberto, Lonardo, Fortunato, Nuzzi, Francesca, Simonelli, Francesca, Trojsi, Francesca, Habetswallner, Francesco, Valentini, Gabriele, Cerbone, Gaetana, Parenti, Giancarlo, Tedeschi, Gioacchino, Capasso, Giovambattista, Battista Rossi, Giovanni, Gaglione, Giovanni, Sarnelli, Giovanni, Argenziano, Giuseppe, Bellastella, Giuseppe, De Michele, Giuseppe, Fiorentino, Giuseppe, Spadaro, Giuseppe, Scala, Iri, Santoro, Lucio, Zeppa, Lucio, Auricchio, Luigi, Elio Adinolfi, Luigi, Alessio, Maria, Amitrano, Maria, Savanelli, Maria Cristina, Russo, Maria Giovanna, Ferrucci, Maria Grazia, Carbone, Maria Teresa, Pellecchia, Maria Teresa, Salerno, Mariacarolina, Melone, Marina, Del Donno, Mario, Vitale, Mario, Triggiani, Massimo, Della Monica, Matteo, Lo Presti, Maurizio, Tenuta, Maurizio, Mignogna, Michele Davide, Schiavulli, Michele, Zacchia, Miriam, Brunetti-Pierri, Nicola, Iovino, Paola, Moscato, Paolo, Iandoli, Raffaele, Scarpa, Raffaele, Russo, Romualdo, Troisi, Salvatore, Sbordone, Sandro, Perrotta, Silverio, Fecarotta, Simona, Sampaolo, Simone, Cicalese, Virgilio, Limongelli, G, Iucolano, S, Monda, E, Elefante, P, De Stasio, C, Lubrano, I, Caiazza, M, Mazzella, M, Fimiani, F, Galdo, M, De Marchi, G, Esposito, M, Rubino, M, Cirillo, A, Fusco, A, Esposito, A, Trama, U, Esposito, S, Scarano, G, Sepe, J, Andria, G, Orlando, V, Menditto, E, Chiodini, P, Campania Rare, Disease, Iolascon, A, Franzese, A, Sanduzzi Zamparelli, A, Tessitore, A, Romano, A, Venosa, A, Nunzia Olivieri, A, Bianco, A, La Manna, A, Cerbone, Am, Spasiano, A, Agnese Stanziola, A, Colao, A, De Bellis, A, Gambale, A, Toriello, A, Tufano, A, Ciampa, A, Maria Risitano, A, Pisani, A, Russo, A, Volpe, A, De Martino, B, Amato, B, De Fusco, C, Piscopo, C, Selleri, C, Tucci, C, Pignata, C, Cioffi, D, Melis, D, Pasquali, D, De Brasi, D, Spitaleri, D, Russo, D, Martellotta, D, De Michele, E, Varricchio, E, Miraglia Del Giudice, E, Coscioni, E, Cimino, E, Pane, F, Tranfa, F, Pollio, F, Lonardo, F, Nuzzi, F, Simonelli, F, Trojsi, F, Habetswallner, F, Valentini, G, Cerbone, G, Parenti, G, Tedeschi, G, Capasso, G, Battista Rossi, G, Gaglione, G, Sarnelli, G, Argenziano, G, Bellastella, G, De Michele, G, Fiorentino, G, Spadaro, G, Scala, I, Santoro, L, Zeppa, L, Auricchio, L, Elio Adinolfi, L, Alessio, M, Amitrano, M, Savanelli, Mc, Russo, Mg, Ferrucci, Mg, Carbone, Mt, Pellecchia, Mt, Salerno, M, Melone, M, Del Donno, M, Vitale, M, Triggiani, M, Della Monica, M, Lo Presti, M, Tenuta, M, Mignogna, Md, Schiavulli, M, Zacchia, M, Brunetti-Pierri, N, Iovino, P, Moscato, P, Iandoli, R, Scarpa, R, Russo, R, Troisi, S, Sbordone, S, Perrotta, S, Fecarotta, S, Sampaolo, S, and Cicalese, V.
Subjects: Pediatrics, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Home therapy, rare diseases, 030204 cardiovascular system & hematology, Campania region, Covid-19, Italy, patient registry, Disease Outbreaks, 03 medical and health sciences, COVID-19 Testing, 0302 clinical medicine, Pandemic, Health care, medicine, Retrospective analysis, Humans, AcademicSubjects/MED00860, Registries, 030212 general & internal medicine, Medical diagnosis, Pandemics, Retrospective Studies, business.industry, Public Health, Environmental and Occupational Health, Outbreak, General Medicine, Original Article, business, Delivery of Health Care, Rare disease
Abstract: Background The aims of this study were: to investigate the capacity of the rare disease healthcare network in Campania to diagnose patients with rare diseases during the outbreak of Covid-19; and to shed light on problematic diagnoses during this period. Methods To describe the impact of the Covid-19 pandemic on the diagnosis of patients with rare diseases, a retrospective analysis of the Campania Region Rare Disease Registry was performed. A tailored questionnaire was sent to rare disease experts to investigate major issues during the emergency period. Results Prevalence of new diagnoses of rare disease in March and April 2020 was significantly lower than in 2019 (117 versus 317, P Conclusions This study describes the effects of the Covid-19 outbreak on the diagnosis of rare disease in a single Italian region and investigates potential issues of diagnosis and management during this period.
Published: 2021
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25. Prevention of recurrent respiratory infections

Author: Katia Perruccio, Giulia Trippella, Martina Ciarcià, Paolo Becherucci, Alberto Villani, Marco Zecca, Valeria Caldarelli, Sergio Bottero, Maria Laura Panatta, Diego Peroni, Giuseppe Di Mauro, Angela Pasinato, Lorenzo Pignataro, Sofia D’Elios, Diletta Valentini, Maurizio de Martino, Guido Morbin, Fabio Cardinale, Vito Leonardo Miniello, Massimo Pifferi, Luciana Indinnimeo, Luisa Galli, Marco Antonio Motisi, Francesca Santamaria, Gian Luigi Marseglia, Francesco Macrì, Chiara Tersigni, Anna Teresa Palamara, Michele Miraglia Del Giudice, Guido Castelli Gattinara, Paolo Biasci, Emanuela Sitzia, Renato Cutrera, Elena Chiappini, Andrea Lo Vecchio, Roberto Mattina, Daniele Ciofi, Claudio Vicini, Sandro Valentini, Paola Marchisio, Attilio Varricchio, Mattia Doria, Sara Torretta, Irene Trambusti, Andrea Novelli, Barbara Bortone, Giorgio Piacentini, Maria Carmen Verga, Sara Antonini, Chiappini, E., Santamaria, F., Marseglia, G. L., Marchisio, P., Galli, L., Cutrera, R., de Martino, M., Antonini, S., Becherucci, P., Biasci, P., Bortone, B., Bottero, S., Caldarelli, V., Cardinale, F., Gattinara, G. C., Ciarcia, M., Ciofi, D., D'Elios, S., Di Mauro, G., Doria, M., Indinnimeo, L., Lo Vecchio, A., Macri, F., Mattina, R., Miniello, V. L., del Giudice, M. M., Morbin, G., Motisi, M. A., Novelli, A., Palamara, A. T., Panatta, M. L., Pasinato, A., Peroni, D., Perruccio, K., Piacentini, G., Pifferi, M., Pignataro, L., Sitzia, E., Tersigni, C., Torretta, S., Trambusti, I., Trippella, G., Valentini, D., Valentini, S., Varricchio, A., Verga, M. C., Vicini, C., Zecca, M., and Villani, A.
Subjects: Pneumococcal Vaccine, Complementary Therapies, medicine.medical_specialty, Prebiotic, Review, Probiotic, Recurrent respiratory infection, Antioxidants, Adenoidectomy, Pneumococcal Vaccines, Adjuvants, Immunologic, Quality of life, Recurrence, medicine, Antibiotic Prophylaxi, Respiratory Tract Infection, Humans, Recurrent respiratory infections, Thiazolidine, Hyaluronic Acid, Child, Intensive care medicine, Respiratory Tract Infections, Children, Administration, Intranasal, Tonsillectomy, Maternal and child health, business.industry, Probiotics, Prevention, Vitamins, Antibiotic Prophylaxis, Settore MED/38, Complete resolution, Pyrrolidonecarboxylic Acid, Algorithm, Prebiotics, Immune system, Complementary Therapie, Influenza Vaccines, Resveratrol, Thiazolidines, Antioxidant, Influenza Vaccine, business, Algorithms, Human
Abstract: Recurrent respiratory infections (RRIs) are a common clinical condition in children, in fact about 25% of children under 1 year and 6% of children during the first 6 years of life have RRIs. In most cases, infections occur with mild clinical manifestations and the frequency of episodes tends to decrease over time with a complete resolution by 12 years of age. However, RRIs significantly reduce child and family quality of life and lead to significant medical and social costs. Despite the importance of this condition, there is currently no agreed definition of the term RRIs in the literature, especially concerning the frequency and type of infectious episodes to be considered. The aim of this consensus document is to propose an updated definition and provide recommendations with the intent of guiding the physician in the complex process of diagnosis, management and prevention of RRIs. Supplementary Information The online version contains supplementary material available at 10.1186/s13052-021-01150-0.
Published: 2021
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26. Evaluation of early regression index as response predictor in cervical cancer: A retrospective study on T2 and DWI MR images

Author: Davide Cusumano, Luca Russo, Benedetta Gui, Rosa Autorino, Luca Boldrini, Luca D'Erme, Salvatore Persiani, Francesco Catucci, Sara Broggi, Giulia Panza, Alessia Nardangeli, Maura Campitelli, Gabriella Ferrandina, Gabriella Macchia, Claudio Fiorino, Vincenzo Valentini, Giovanni Scambia, Riccardo Manfredi, and Maria Antonietta Gambacorta
Subjects: Radiomics, Rectal Neoplasms, Uterine Cervical Neoplasms, Chemoradiotherapy, Hematology, Cervical Cancer, Magnetic Resonance Imaging, Neoadjuvant Therapy, Diffusion Magnetic Resonance Imaging, Treatment Outcome, Oncology, Predictive model, Humans, Image-based biomarker, Female, Radiology, Nuclear Medicine and imaging, Retrospective Studies, Settore MED/36 - DIAGNOSTICA PER IMMAGINI E RADIOTERAPIA
Abstract: Early Regression Index (ERIA total of 88 patients affected by LACC (FIGO IB2-IVA) and treated with CRT were enrolled. An MRI protocol consisting in two acquisitions (T2-w and DWI) in two times (before treatment and at mid-therapy) was applied. Gross Tumor Volume (GTV) was delineated and ERIERIThis study identified ERI
Published: 2022
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27. Unexplained regression in Down syndrome: Management of 51 patients in an international patient database

Author: Stephanie L. Santoro, Nicole T. Baumer, Michelle Cornacchia, Catherine Franklin, Sarah J. Hart, Kelsey Haugen, Margaret A. Hojlo, Nora Horick, Priya S. Kishnani, Kavita Krell, Andrew McCormick, Anna L. Milliken, Nicolas M. Oreskovic, Katherine G. Pawlowski, Sabrina Sargado, Amy Torres, Diletta Valentini, Kishore Vellody, and Brian G. Skotko
Subjects: Young Adult, Treatment Outcome, Adolescent, Outcome Assessment, Health Care, Genetics, Humans, Immunoglobulins, Intravenous, Down Syndrome, Genetics (clinical)
Abstract: Research to guide clinicians in the management of the devastating regression which can affect adolescents and young adults with Down syndrome is limited. A multi-site, international, longitudinal cohort of individuals with a clinical diagnosis of Unexplained Regression in Down syndrome (URDS) was collated through seven Down syndrome clinics. Tiered medical evaluation, a 28-item core symptom list, and interim management are described naturalistically. Improvement-defined by the percentage of baseline function on a Parent-reported Functional Score, overall improvement in symptoms on a Clinician-administered Functional Assessment, or report of management type being associated with improvement-was analyzed. Improvement rates using ECT, IVIG, and others were compared. Across seven clinics, 51 patients with URDS had regression at age 17.6 years, on average, and showed an average 14.1 out of 28 symptoms. Longitudinal improvement in function was achieved in many patients and the medical management, types of treatment, and their impact on function are described. Management with intravenous immunoglobulin (IVIG) was significantly associated with higher rate of improvement in symptoms at the next visit (p = 0.001). Our longitudinal data demonstrates that URDS is treatable, with various forms of clinical management and has a variable course. The data suggests that IVIG may be an effective treatment in some individuals. Our description of the management approaches used in this cohort lays the groundwork for future research, such as development of standardized objective outcome measure and creation of a clinical practice guideline for URDS.
Published: 2022
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28. The role of gut dysbiosis-associated inflammation in heart failure

Author: Fabiane Valentini Francisqueti-Ferron, Erika Tiemi Nakandakare-Maia, Juliana Silva Siqueira, Artur Junio Togneri Ferron, Taynara Aparecida Vieira, Silméia Garcia Zanati Bazan, and Camila Renata Corrêa
Subjects: Heart Failure, Inflammation, Dysbiosis, Humans, General Medicine
Published: 2022
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29. Catheter salvage strategies in children with central venous catheter-related or -associated bloodstream infections: a systematic review and meta-analysis

Author: D, Buonsenso, G, Salerno, G, Sodero, F, Mariani, L, Pisapia, C, Gelormini, M, Di Nardo, P, Valentini, G, Scoppettuolo, and D G, Biasucci
Subjects: Microbiology (medical), Catheterization, Central Venous, CRBSI, Bacteremia, General Medicine, Antimicrobial lock therapy, Settore MED/38, Settore MED/17, Anti-Bacterial Agents, CLABSI, Infectious Diseases, Anti-Infective Agents, Paediatric, Catheter-Related Infections, Sepsis, Settore MED/41, Central venous catheter, Children, Central Venous Catheters, Humans, Child, Disinfectants
Abstract: Optimal management of central venous catheter-related, or -associated, bloodstream infections (CRBSI or CLABSI) in children is not established.To evaluate success of catheter salvage strategies in paediatric patients.Studies were retrieved from medical databases and article reference lists. Data were collected relating to clinical outcomes of two treatments: systemic antibiotics alone or in association with antimicrobial lock therapy (ALT). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated from a mixed logistic effects model. Heterogeneity was summarized using IFrom 345 identified publications, 19 met inclusion criteria (total of 914 attempted salvage strategies). To achieve successful catheter salvage, in CRBSI the addition of ALT was superior to systemic antibiotics alone (OR: -0.40; 95% CI: -1.41, 0.62): 77% (95% CI: 69, 85; IThe addition of an antimicrobial lock solution to systemic antibiotic may be beneficial for successful catheter salvage in paediatric patients with CRBSI, depending on aetiology, whereas no statistically significant difference between systemic antibiotic with or without addition of an antimicrobial lock solution was found regarding CLABSI.
Published: 2022
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30. Functional and structural characterization of the insertion region in the ligand binding domain of the vitamin D nuclear receptor

Author: Rochel, Natachu, Tocchini‐Valentini, Guiseppe, Egea, Pascal F, Juntunen, Kari, Garnier, Jean‐Marie, Vihko, Pirkko, and Moras, Dino
Subjects: Nutrition, Genetics, Amino Acid Sequence, Animals, COS Cells, Calcitriol, Humans, Ligands, Models, Molecular, Molecular Sequence Data, Protein Structure, Tertiary, Receptors, Calcitriol, Sequence Deletion, Sequence Homology, Amino Acid, Transcriptional Activation, Transfection, X-Ray Diffraction, nuclear receptor, VDR LBD, ligand binding, conformation, transactivation, Medicinal and Biomolecular Chemistry, Biochemistry and Cell Biology, Medical Biochemistry and Metabolomics, Biochemistry & Molecular Biology
Abstract: Vitamin D nuclear receptor mediates the genomic actions of the active form of vitamin D, 1,25(OH)2D3. This hormone is involved in calcium and phosphate metabolism and cell differentiation. Compared to other nuclear receptors, VDR presents a large insertion region at the N-terminal part of the ligand binding domain between helices H1 and H3, encoded by an additional exon. This region is poorly conserved in VDR in different species and is not well ordered as observed by secondary structure prediction. We engineered a VDR ligand binding domain mutant by removing this insertion region. Here we report its biochemical and biophysical characterization. The mutant protein exhibits the same ligand binding, dimerization with retinoid X receptor and transactivation properties as the wild-type VDR, suggesting that the insertion region does not affect these main functions. Solution studies by small angle X-ray scattering shows that the conformation in solution of the VDR mutant is similar to that observed in the crystal and that the insertion region in the VDR wild-type is not well ordered.
Published: 2001

31. Automated hybrid volumetric modulated arc therapy (HVMAT) for whole-breast irradiation with simultaneous integrated boost to lumpectomy area

Author: Gabriella Macchia, M. Boccardi, C. Romano, Alessio G. Morganti, Savino Cilla, Vittoria E. Morabito, Lidia Strigari, Milly Buwenge, Livia P. De Vivo, Vincenzo Valentini, Luca Indovina, Francesco Deodato, Cilla S., Romano C., Macchia G., Boccardi M., De Vivo L.P., Morabito V.E., Buwenge M., Strigari L., Indovina L., Valentini V., Deodato F., and Morganti A.G.
Subjects: Organs at Risk, Simultaneous integrated boost, medicine.medical_treatment, Dose accuracy, Breast Neoplasms, Mastectomy, Segmental, Imaging phantom, Automation, Whole Breast Irradiation, medicine, Humans, Radiology, Nuclear Medicine and imaging, Breast, Radiation treatment planning, business.industry, Radiotherapy Planning, Computer-Assisted, Autoplanning, Lumpectomy, Volumetric modulated arc therapy, Radiotherapy Dosage, Hybrid, Left breast, Simultaneously integrated boost, Oncology, Female, Radiotherapy, Intensity-Modulated, Nuclear medicine, business
Abstract: Purpose: To develop anautomated treatment planning approach for whole breast irradiation with simultaneous integrated boost using an automated hybrid VMAT class solution (HVMAT). Materials and methods: Twenty-five consecutive patients with left breast cancer received 50 Gy (2 Gy/fraction) to the whole breast and an additional simultaneous 10 Gy (2.4 Gy/fraction) to the tumor cavity. Ipsilateral lung, heart, and contralateral breast were contoured as main organs-at-risk. HVMAT plans were inversely optimized by combining two open fields with aVMAT semi-arc beam. Open fields were setup to include the whole breast with a2 cm flash region and to carry 80% of beams weight. HVMAT plans were compared with three tangential techniques: conventional wedged-field tangential plans (SWF), field-in-field forward planned tangential plans (FiF), and hybrid-IMRT plans (HMRT). Dosimetric differences among the plans were evaluated using Kruskal–Wallis one-way analysis of variance. Dose accuracy was validated using the PTW Octavius-4D phantom together with the 15002D-array. Results: No significant differences were found among the four techniques for both targets coverage. HVMAT plans showed consistently better PTVs dose contrast, conformity, and homogeneity (p < 0.001 for all metrics) and statistically significant reduction of high-dose breast irradiation. V55 and V60 decreased by 30.4, 26.1, and 20.8% (p < 0.05) and 12.3, 9.9, and 6.0% (p < 0.05) for SWF, FIF, and HMRT, respectively. Pretreatment dose verification reported agamma pass-rate greater than the acceptance threshold of 95% for all HVMAT plans. In addition, HVMAT reduced the time for full planning optimization to about 20 min. Conclusions: HVMAT plans resulted in superior target dose conformity and homogeneity compared to other tangential techniques. Due to fast planning time HVMAT can be applied for all patients, minimizing the impact on human or departmental resources.
Published: 2021
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32. AI Cardiac MRI Scar Analysis Aids Prediction of Major Arrhythmic Events in the Multicenter DERIVATE Registry

Author: Fahime Ghanbari, Thomas Joyce, Valentina Lorenzoni, Andrea I. Guaricci, Anna-Giulia Pavon, Laura Fusini, Daniele Andreini, Mark G. Rabbat, Giovanni Donato Aquaro, Raffaele Abete, Jan Bogaert, Giovanni Camastra, Samuela Carigi, Nazario Carrabba, Grazia Casavecchia, Stefano Censi, Gloria Cicala, Carlo N. De Cecco, Manuel De Lazzari, Gabriella Di Giovine, Mauro Di Roma, Marta Focardi, Nicola Gaibazzi, Annalaura Gismondi, Matteo Gravina, Chiara Lanzillo, Massimo Lombardi, Jordi Lozano-Torres, Ambra Masi, Claudio Moro, Giuseppe Muscogiuri, Alberto Nese, Silvia Pradella, Stefano Sbarbati, U. Joseph Schoepf, Adele Valentini, Gérard Crelier, Pier Giorgio Masci, Gianluca Pontone, Sebastian Kozerke, Juerg Schwitter, Institut Català de la Salut, [Ghanbari F] Cardiovascular Department, CMR Center, University Hospital Lausanne–CHUV, Lausanne, Switzerland. Faculty of Biology and Medicine, Lausanne University, UniL, Lausanne, Switzerland. [Joyce T] Institute for Biomedical Engineering, University and ETH Zurich, Zurich, Switzerland. [Lorenzoni V] Institute of Management, Scuola Superiore Sant’Anna, Pisa, Italy. [Guaricci AI] Institute of Cardiovascular Disease, Department of Emergency and Organ Transplantation, University Hospital Policlinico of Bari, Bari, Italy. [Pavon AG] Cardiovascular Department, CMR Center, University Hospital Lausanne–CHUV, Lausanne, Switzerland. [Fusini L] Centro Cardiologico Monzino IRCCS, Milan, Italy. Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy. [Lozano-Torres J] Servei de Cardiologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Centro de Investigación Biomédica en Red-CV, CIBER CV, Madrid, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: conceptos matemáticos::algoritmos::inteligencia artificial [FENÓMENOS Y PROCESOS], Male, Intel·ligència artificial, enfermedades cardiovasculares::enfermedades cardíacas::arritmias cardíacas [ENFERMEDADES], Mathematical Concepts::Algorithms::Artificial Intelligence [PHENOMENA AND PROCESSES], Arrítmia, Contrast Media, Magnetic Resonance Imaging, Cine, Stroke Volume, Gadolinium, Magnetic Resonance Imaging, Ventricular Function, Left, Cicatrix, Artificial Intelligence, Predictive Value of Tests, Diagnosis::Diagnostic Techniques and Procedures::Diagnostic Imaging::Tomography::Magnetic Resonance Imaging [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Imatgeria per ressonància magnètica, Humans, diagnóstico::técnicas y procedimientos diagnósticos::diagnóstico por imagen::tomografía::imagen por resonancia magnética [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Radiology, Nuclear Medicine and imaging, Registries, Cardiovascular Diseases::Heart Diseases::Arrhythmias, Cardiac [DISEASES], Aged, Retrospective Studies
Abstract: Background Scar burden with late gadolinium enhancement (LGE) cardiac MRI (CMR) predicts arrhythmic events in patients with postinfarction in single-center studies. However, LGE analysis requires experienced human observers, is time consuming, and introduces variability. Purpose To test whether postinfarct scar with LGE CMR can be quantified fully automatically by machines and to compare the ability of LGE CMR scar analyzed by humans and machines to predict arrhythmic events. Materials and Methods This study is a retrospective analysis of the multicenter, multivendor CarDiac MagnEtic Resonance for Primary Prevention Implantable CardioVerter DebrillAtor ThErapy (DERIVATE) registry. Patients with chronic heart failure, echocardiographic left ventricular ejection fraction (LVEF) of less than 50%, and LGE CMR were recruited (from January 2015 through December 2020). In the current study, only patients with ischemic cardiomyopathy were included. Quantification of total, dense, and nondense scars was carried out by two experienced readers or a Ternaus network, trained and tested with LGE images of 515 and 246 patients, respectively. Univariable and multivariable Cox analyses were used to assess patient and cardiac characteristics associated with a major adverse cardiac event (MACE). Area under the receiver operating characteristic curve (AUC) was used to compare model performances. Results In 761 patients (mean age, 65 years ± 11, 671 men), 83 MACEs occurred. With use of the testing group, univariable Cox-analysis found New York Heart Association class, left ventricle volume and/or function parameters (by echocardiography or CMR), guideline criterion (LVEF of ≤35% and New York Heart Association class II or III), and LGE scar analyzed by humans or the machine-learning algorithm as predictors of MACE. Machine-based dense or total scar conferred incremental value over the guideline criterion for the association with MACE (AUC: 0.68 vs 0.63, P = .02 and AUC: 0.67 vs 0.63, P = .01, respectively). Modeling with competing risks yielded for dense and total scar (AUC: 0.67 vs 0.61, P = .01 and AUC: 0.66 vs 0.61, P = .005, respectively). Conclusion In this analysis of the multicenter CarDiac MagnEtic Resonance for Primary Prevention Implantable CardioVerter DebrillAtor ThErapy (DERIVATE) registry, fully automatic machine learning-based late gadolinium enhancement analysis reliably quantifies myocardial scar mass and improves the current prediction model that uses guideline-based risk criteria for implantable cardioverter defibrillator implantation. ClinicalTrials.gov registration no.: NCT03352648 Published under a CC BY 4.0 license. Supplemental material is available for this article. ispartof: Radiology vol:307 issue:3 pages:e222239- ispartof: location:United States status: published
Published: 2023

33. Long-term outcomes of pediatric infections: from traditional infectious diseases to long Covid

Author: Buonsenso, D, Gennaro, LD, Rose, CD, Morello, R, D'Ilario, F, Zampino, G, Piazza, M, Boner, AL, Iraci, C, O'Connell, S, Cohen, VB, Esposito, S, Munblit, D, Reena, J, Sigfrid, L, and Valentini, P
Subjects: Microbiology (medical), Post-Acute COVID-19 Syndrome, Italy, SARS-CoV-2, COVID-19, Humans, Child, Communicable Diseases, Microbiology
Abstract: There is limited evidence available on the long-term impact of SARS-CoV-2 infection in children. In this article, the authors analyze the recent evidence on pediatric long Covid and lessons learnt from a pediatric post-Covid unit in Rome, Italy. To gain a better understanding of the concerns raised by parents and physicians in relation to the potential long-term consequences of this novel infection, it is important to recognize that long-term effect of a post-infectious disease is not a new phenomenon.The authors analyze the recent evidence on pediatric long Covid and lessons learnt from a pediatric post-Covid unit in Rome, Italy. Also, we analyze the long-term effects of other infectious diseases.
Published: 2022
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34. The importance of ventilatory thresholds to define aerobic exercise intensity in cardiac patients and healthy subjects

Author: Martin Halle, Marco Bonifazi, Marta Focardi, Matteo Cameli, Paul Dendale, Nicola Mochi, Francesca Valentini, Antonio Pagliaro, Francesca Anselmi, Dominique Hansen, Serafina Valente, Luna Cavigli, Flavio D'Ascenzi, Anselmi, Francesca, Cavigli, Luna, Pagliaro, Antonio, Valente, Serafina, Valentini, Francesca, Cameli, Matteo, Focardi, Marta, Mochi, Nicola, DENDALE, Paul, HANSEN, Dominique, Bonifazi, Marco, Halle, Martin, and D’ascenzi, Flavio
Subjects: Adult, Male, medicine.medical_specialty, Heart Diseases, exercise prescription, Physical Therapy, Sports Therapy and Rehabilitation, Ventricular Function, Left, ventilatory threshold, exercise intensity, Oxygen Consumption, Heart Rate, Internal medicine, Heart rate, cardiopulmonary exercise testing, lactate, Medicine, Aerobic exercise, Humans, Orthopedics and Sports Medicine, Prospective Studies, Exercise, biology, Athletes, business.industry, Healthy subjects, Original Articles, Middle Aged, biology.organism_classification, Intensity (physics), Echocardiography, Exercise intensity, Cardiology, Exercise Test, Physical Endurance, Regression Analysis, Original Article, Female, Sedentary Behavior, Exercise prescription, Ventilatory threshold, business, Pulmonary Ventilation
Abstract: Background Although structured exercise training is strongly recommended in cardiac patients, uncertainties exist about the methods for determining exercise intensity (EI) and their correspondence with effective EI obtained by ventilatory thresholds. We aimed to determine the first (VT1 ) and second ventilatory thresholds (VT2 ) in cardiac patients, sedentary subjects, and athletes comparing VT1 and VT2 with EI defined by recommendations. Methods We prospectively enrolled 350 subjects (mean age: 50.7±12.9 years; 167 cardiac patients, 150 healthy sedentary subjects, and 33 competitive endurance athletes). Each subject underwent ECG, echocardiography, and cardiopulmonary exercise testing. The percentages of peak VO2 , peak heart rate (HR), and HR reserve were obtained at VT1 and VT2 and compared with the EI definition proposed by the recommendations. Results VO2 at VT1 corresponded to high rather than moderate EI in 67.1% and 79.6% of cardiac patients, applying the definition of moderate exercise by the previous recommendations and the 2020 guidelines, respectively. Most cardiac patients had VO2 values at VT2 corresponding to very-high rather than high EI (59.9% and 50.3%, by previous recommendations and 2020 guidelines, respectively). A better correspondence between ventilatory thresholds and recommended EI domains was observed in healthy subjects and athletes (90% and 93.9%, respectively). Conclusions EI definition based on percentages of peak HR and peak VO2 may misclassify the effective EI, and the discrepancy between the individually determined and the recommended EI is particularly relevant in cardiac patients. A ventilatory threshold-based rather than a range-based approach is advisable to define an appropriate level of EI.
Published: 2021

35. Clinical spectrum time course in non-Asian patients positive for anti-MDA5 antibodies

Author: Lorenzo, Cavagna, Federica, Meloni, Alain, Meyer, Gianluca, Sambataro, Mirko, Belliato, Ellen De Langhe, Cavazzana, Ilaria, Nicolò, Pipitone, Konstantinos, Triantafyllias, Marta, Mosca, Simone, Barsotti, Giuseppe, Zampogna, Alessandro, Biglia, Giacomo, Emmi, Marianne De Visser, Anneke Van Der Kooi, Paola, Parronchi, Sandrine, Hirschi, Jose Antonio Pereira da Silva, Carlo Alberto Scirè, Federica, Furini, Margherita, Giannini, Olga Martinez Gonzalez, Laura, Damian, Yves, Piette, Vanessa, Smith, Antonio, Mera-Valera, Javier, Bachiller-Corral, Ivan Cabezas Rodriguez, Anahy, M Brandy-Garcia, François, Maurier, Julie, Perrin, Juan, Gonzalez-Moreno, Ulrich, Drott, Christiane, Delbruck, Andreas, Schwarting, Eugenio, Arrigoni, Gian Domenico Sebastiani, Annamaria, Iuliano, Carlotta, Nannini, Luca, Quartuccio, Ana, B Rodriguez Cambron, Maria, Á Blázquez Cañamero, Ignacio Villa Blanco, Giovanni, Cagnotto, Alberto, Pesci, Francesco, Luppi, Giulia, Dei, Fredeswinda Isabel Romero Bueno, Franceschini, Franco, Ilaria, Chiapparoli, Giovanni, Zanframundo, Sara, Lettieri, Ludovico De Stefano, Maurizio, Cutolo, Alessandro, Mathieu, Matteo, Piga, Sergio, Prieto-González, Maria Francisca Moraes-Fontes, Joao Eurico Fonseca, Vega, Jovani, Valeria, Riccieri, Alessandro, Santaniello, Stephen, Montfort, David, Bilocca, Gian Luca Erre, Elena, Bartoloni, Roberto, Gerli, M Cristina Monti, Hanns, M Lorenz, Domenico, Sambataro, Silvia Bellando Randone, Udo, Schneider, Claudia, Valenzuela, Raquel, Lopez-Mejias, Jose, Cifrian, Mayra, Mejia, Monserrat-Ixchel Gonzalez Perez, Sarah, Wendel, Marco, Fornaro, Giacomo De Luca, Giovanni, Orsolini, Maurizio, Rossini, Philippe, Dieude, Johannes, Knitza, Santos, Castañeda, Reinhard, E Voll, Jorge, Rojas-Serrano, Adele, Valentini, Carlo, Vancheri, Marco, Matucci-Cerinic, Eugen, Feist, Veronica, Codullo, Florenzo, Iannone, Jorg, H Distler, Carlomaurizio, Montecucco, Miguel, A Gonzalez-Gay, AENEAS collaborative group, Neurology, ANS - Neuroinfection & -inflammation, AII - Inflammatory diseases, EURO-NMD, Cavagna, L, Meloni, F, Meyer, A, Sambataro, G, Belliato, M, De Langhe, E, Cavazzana, I, Pipitone, N, Triantafyllias, K, Mosca, M, Barsotti, S, Zampogna, G, Biglia, A, Emmi, G, De Visser, M, Van Der Kooi, A, Parronchi, P, Hirschi, S, da Silva, J, Scire, C, Furini, F, Giannini, M, Martinez Gonzalez, O, Damian, L, Piette, Y, Smith, V, Mera-Valera, A, Bachiller-Corral, J, Cabezas Rodriguez, I, Brandy-Garcia, A, Maurier, F, Perrin, J, Gonzalez-Moreno, J, Drott, U, Delbruck, C, Schwarting, A, Arrigoni, E, Sebastiani, G, Iuliano, A, Nannini, C, Quartuccio, L, Rodriguez Cambron, A, Blazquez Canamero, M, Villa Blanco, I, Cagnotto, G, Pesci, A, Luppi, F, Dei, G, Romero Bueno, F, Franceschini, F, Chiapparoli, I, Zanframundo, G, Lettieri, S, De Stefano, L, Cutolo, M, Mathieu, A, Piga, M, Prieto-Gonzalez, S, Moraes-Fontes, M, Fonseca, J, Jovani, V, Riccieri, V, Santaniello, A, Montfort, S, Bilocca, D, Erre, G, Bartoloni, E, Gerli, R, Monti, M, Lorenz, H, Sambataro, D, Bellando Randone, S, Schneider, U, Valenzuela, C, Lopez-Mejias, R, Cifrian, J, Mejia, M, Gonzalez Perez, M, Wendel, S, Fornaro, M, De Luca, G, Orsolini, G, Rossini, M, Dieude, P, Knitza, J, Castaneda, S, Voll, R, Rojas-Serrano, J, Valentini, A, Vancheri, C, Matucci-Cerinic, M, Feist, E, Codullo, V, Iannone, F, Distler, J, Montecucco, C, Gonzalez-Gay, M, Repositório da Universidade de Lisboa, Cavagna, Lorenzo, Meloni, Federica, Meyer, Alain, Sambataro, Gianluca, Belliato, Mirko, De Langhe, Ellen, Cavazzana, Ilaria, Pipitone, Nicolò, Triantafyllias, Konstantino, Mosca, Marta, Barsotti, Simone, Zampogna, Giuseppe, Biglia, Alessandro, Emmi, Giacomo, De Visser, Marianne, Van Der Kooi, Anneke, Parronchi, Paola, Hirschi, Sandrine, da Silva, Jose Antonio Pereira, Scirè, Carlo Alberto, Furini, Federica, Giannini, Margherita, Martinez Gonzalez, Olga, Damian, Laura, Piette, Yve, Smith, Vanessa, Mera-Valera, Antonio, Bachiller-Corral, Javier, Cabezas Rodriguez, Ivan, Brandy-Garcia, Anahy M, Maurier, Françoi, Perrin, Julie, Gonzalez-Moreno, Juan, Drott, Ulrich, Delbruck, Christiane, Schwarting, Andrea, Arrigoni, Eugenio, Sebastiani, Gian Domenico, Iuliano, Annamaria, Nannini, Carlotta, Quartuccio, Luca, Rodriguez Cambron, Ana B, Blázquez Cañamero, Maria Á, Villa Blanco, Ignacio, Cagnotto, Giovanni, Pesci, Alberto, Luppi, Francesco, Dei, Giulia, Romero Bueno, Fredeswinda Isabel, Franceschini, Franco, Chiapparoli, Ilaria, Zanframundo, Giovanni, Lettieri, Sara, De Stefano, Ludovico, Cutolo, Maurizio, Mathieu, Alessandro, Piga, Matteo, Prieto-González, Sergio, Moraes-Fontes, Maria Francisca, Fonseca, Joao Eurico, Jovani, Vega, Riccieri, Valeria, Santaniello, Alessandro, Montfort, Stephen, Bilocca, David, Erre, Gian Luca, Bartoloni, Elena, Gerli, Roberto, Monti, M Cristina, Lorenz, Hanns M, Sambataro, Domenico, Bellando Randone, Silvia, Schneider, Udo, Valenzuela, Claudia, Lopez-Mejias, Raquel, Cifrian, Jose, Mejia, Mayra, Gonzalez Perez, Monserrat-Ixchel, Wendel, Sarah, Fornaro, Marco, De Luca, Giacomo, Orsolini, Giovanni, Rossini, Maurizio, Dieude, Philippe, Knitza, Johanne, Castañeda, Santo, Voll, Reinhard E, Rojas-Serrano, Jorge, Valentini, Adele, Vancheri, Carlo, Matucci-Cerinic, Marco, Feist, Eugen, Codullo, Veronica, Iannone, Florenzo, Distler, Jorg H, Montecucco, Carlomaurizio, and Gonzalez-Gay, Miguel A
Subjects: Lung Diseases, Interferon-Induced Helicase, IFIH1, rapidly progressive interstitial lung diseases, idiopathic inflammatory myopathies, idiopathic inflammatory myopathie, Immunology, Middle Aged, Prognosis, Dermatomyositis, rapidly progressive interstitial lung disease, Rheumatology, melanoma differentiation-associated protein 5 antibody, rapidly progressive interstitial lung diseases, idiopathic inflammatory myopathies, Humans, Immunology and Allergy, Female, Lung Diseases, Interstitial, Interferon-Induced Helicase, Interstitial, melanoma differentiation-associated protein 5 antibody, Autoantibodies, Retrospective Studies, IFIH1
Abstract: © Copyright Clinical and Experimental Rheumatology 2022., Objectives: To define the clinical spectrum time-course and prognosis of non-Asian patients positive for anti-MDA5 antibodies. Methods: We conducted a multicentre, international, retrospective cohort study. Results: 149 anti-MDA5 positive patients (median onset age 53 years, median disease duration 18 months), mainly females (100, 67%), were included. Dermatomyositis (64, 43%) and amyopathic dermatomyositis (47, 31%), were the main diagnosis; 15 patients (10%) were classified as interstitial pneumonia with autoimmune features (IPAF) and 7 (5%) as rheumatoid arthritis. The main clinical findings observed were myositis (84, 56%), interstitial lung disease (ILD) (108, 78%), skin lesions (111, 74%), and arthritis (76, 51%). The onset of these manifestations was not concomitant in 74 cases (50%). Of note, 32 (21.5%) patients were admitted to the intensive care unit for rapidly progressive-ILD, which occurred in median 2 months from lung involvement detection, in the majority of cases (28, 19%) despite previous immunosuppressive treatment. One-third of patients (47, 32% each) was ANA and anti-ENA antibodies negative and a similar percentage was anti-Ro52 kDa antibodies positive. Non-specific interstitial pneumonia (65, 60%), organising pneumonia (23, 21%), and usual interstitial pneumonia-like pattern (14, 13%) were the main ILD patterns observed. Twenty-six patients died (17%), 19 (13%) had a rapidly progressive-ILD. Conclusions: The clinical spectrum of the anti-MDA5 antibodies-related disease is heterogeneous. Rapidly-progressive ILD deeply impacts the prognosis also in non-Asian patients, occurring early during the disease course. Anti-MDA5 antibody positivity should be considered even when baseline autoimmune screening is negative, anti-Ro52 kDa antibodies are positive, and radiology findings show a NSIP pattern.
Published: 2022

36. SBI is uncommon in the absence of paediatricians' gut feeling and abnormal respiratory pattern

Author: Giorgio Cozzi, Antimo Tessitore, Manuela Giangreco, Paola Cogo, Elena Valentini, Simona Salis, Paola Pascolo, Egidio Barbi, Cozzi, Giorgio, Tessitore, Antimo, Giangreco, Manuela, Cogo, Paola, Valentini, Elena, Salis, Simona, Pascolo, Paola, and Barbi, Egidio
Subjects: Emergency department, Infant, General Medicine, Gut feeling, Bacterial Infections, Abnormal respiratory pattern, Severe bacterial infection, Paediatric patients, Italy, Child, Preschool, Pediatrics, Perinatology and Child Health, Humans, Paediatric patient, Prospective Studies, Pediatricians, Child, Emergency Service, Hospital
Abstract: According to the Italian national statistical institute, severe bacterial infections (SBI) in Italy are responsible for 1.7% of mortality under 5 years of age and their recognition is often challenging, especially in the first stages of the disease. We tried to estimate the prevalence of SBI in our target population and to identify signs and symptoms that could guide in the initial evaluation of a child with a possible SBI.We designed a prospective, multicentre study and enrolled patients aged 0-14 years at the first evaluation to the emergency department with an acute illness lasting a maximum of 5 days. The presence of variables suggestive of SBI was collected for every enrolled patient. One week after the enrolment, every patient was followed up by telephone.SBI is more likely to be detected with the 'gut feeling' in both univariate and multivariate models (univariate OR: 7.16, 95% CI: 4.08-12.56; multivariate OR: 5.34, 95% CI: 2.78-10.25), while abnormal breathing pattern resulted significative only in univariate model (OR 3.83, 95% CI: 1.98-7.40). Nevertheless, their associated sensitivity is low.SBI is uncommon in the absence of paediatricians' gut feeling and abnormal respiratory pattern.
Published: 2022

37. Clinical Impact of Pathologic Residual Tumor in Locally Advanced Cervical Cancer Patients Managed by Chemoradiotherapy Followed by Radical Surgery: A Large, Multicenter, Retrospective Study

Author: Alex Federico, Luigi Pedone Anchora, Valerio Gallotta, Francesco Fanfani, Francesco Cosentino, Luigi Carlo Turco, Nicolo’ Bizzarri, Francesco Legge, Elena Teodorico, Gabriella Macchia, Vincenzo Valentini, Giovanni Scambia, and Gabriella Ferrandina
Subjects: Neoplasm, Residual, Pathologic residual disease, cervical cancer, cervical cancer, Uterine Cervical Neoplasms, Chemoradiotherapy, Settore MED/40 - GINECOLOGIA E OSTETRICIA, Oncology, Lymphatic Metastasis, Humans, Lymph Node Excision, Female, Surgery, Pathologic residual disease, Lymph Nodes, Neoplasm Staging, Retrospective Studies
Abstract: Background Exclusive chemoradiation (E-CT/RT) represents the standard of treatment for locally advanced cervical cancer (LACC). Chemoradiation (CT/RT) followed by radical surgery (RS) may play a role for patients with a suboptimal response to CT/RT or in low-income countries with limited access to radiotherapy. Histologic assessment of residual tumor after CT/RT and RS allows accurate definition of prognostic categories. Methods Data on patients with FIGO stages 1B2 to 4A cervical cancer managed by CT/RT and RS from June 1996 to March 2020 were retrospectively analyzed. Pathologic response on the cervix was defined as complete (pCR), microscopic (persistent tumor foci ≤ 3 mm) (pmicroR), or macroscopic (persistent tumor foci > 3 mm) (pmacroR). Lymph node (LN) residual tumor was classified as absent or present. Results The 701 patients in this study underwent CT/RT and RS. Of the 701 patients, 293 (41.8%) had pCR, 188 (26.8%) had pmicroR, and 220 (31.4%) had pMacroR. Residual tumor was found in the pelvic lymph nodes of 66 (9.4%) patients and the aortic lymph nodes of 29 (4.1%) patients. The 5-year DFS and OS were respectively 86.6% and 92.5% in the pCR cases, 80.3% and 89.1% in the pmicroR cases, and 56.2% and 68.8% in the pmacroR cases. Among the patients with lymph node residual tumor, the 5-year DFS and OS were respectively 16.7% and 40% in the pCR cases, 35.4% and 53.3% in the pmicroR cases, and 31.7% and 31.1% in the pmacroR cases. Cervical residual tumor,, positive pelvic LNs, and positive aortic LNs were associated with worse DFS and OS in both the uni- and multivariate analyses. Conclusions Persistence of pathologic residual tumor on the cervix and LNs after CT/RT are reliable predictors of survival for LACC patients undergoing CT/RT and adjuvant surgery.
Published: 2022
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38. Validation plan of bone marrow collection, processing and distribution using the failure mode and effect analysis methodology: a technical report

Author: Martina Bartolo, Caterina Giovanna Valentini, Luciana Teofili, Simona Sica, Maria Bianchi, and Nicoletta Orlando
Subjects: validation plan, Risk analysis, Cancer Research, Process (engineering), Computer science, Immunology, bone marrow harvest, Risk Assessment, Consistency (database systems), Bone Marrow, allogeneic hematopoietic stem cell transplant, Humans, Immunology and Allergy, Operations management, Healthcare Failure Mode and Effect Analysis, Child, FMEA, Genetics (clinical), Accreditation, Transplantation, Bone Marrow Collection, bone marrow processing, Cell Biology, Tissue Donors, Settore MED/15 - MALATTIE DEL SANGUE, Oncology, Donation, Tissue and Organ Harvesting, Technical report, Failure mode and effects analysis
Abstract: Background aims Bone marrow (BM) is commonly used in the pediatric and adult setting as a source of hematopoietic stem cells (HSCs). The standards of the Joint Accreditation Committee of the International Society for Cell & Gene Therapy & European Society for Blood and Marrow Transplantation (JACIE) include specific requirements regarding BM collection, processing and distribution. To run this process, each transplant team develops a series of JACIE-compliant procedures, customizing them with regard to local settings and paths. Moreover, JACIE standards require that transplant teams validate and periodically revise their procedures to keep the entire process under control. In this article, the authors describe the methodology adopted in our center to fulfill the aforementioned JACIE requirements. Methods The authors developed a validation plan based on the failure mode and effect analysis (FMEA) methodology. According to the FMEA approach, the authors carefully revised activities and procedures connected to BM collection, processing and distribution at our institution. The entire process was initially divided into five main phases (assessment of donor eligibility, perioperative autologous blood donation, preparation of BM collection kit, BM harvesting and BM processing and distribution), comprising 17 subphases and 22 activities. Results For each activity, one or more failure modes were identified, for a total of 28 failure modes, and a risk priority number (RPN) was then assigned to each failure mode. Although many procedures were validated, others were subjected to substantial changes according to the RPN rating. Moreover, specific indicators were identified for subsequent monitoring to contain the risk of failure of steps emerging as critical at FMEA. Conclusions This is the first study describing use of the FMEA methodology within an HSC transplant program. Shaping the risk analysis based on local experience may be a trustworthy tool for identifying critical issues, directing strict monitoring of critical steps or even amending connected procedures. Overall, the FMEA approach enabled the authors to improve our process, checking its consistency over time.
Published: 2022
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39. Lineage-specific early complete donor chimerism and risk of relapse after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia

Author: Hannes Lindahl, Sofie Vonlanthen, Davide Valentini, Andreas T. Björklund, Mikael Sundin, Stephan Mielke, and Dan Hauzenberger
Subjects: Leukemia, Myeloid, Acute, Transplantation Chimera, Transplantation, Recurrence, Hematopoietic Stem Cell Transplantation, Graft vs Host Disease, Humans, Transplantation, Homologous, Hematology, Chimerism, Retrospective Studies
Abstract: Recipient–donor chimerism is routinely analyzed after allogeneic hematopoietic stem cell transplantation (HSCT) to monitor engraftment and graft rejection. For malignancies, chimerism can also be used to screen for disease relapse post-HSCT but methodology and interpretation of results are not standardized and likely depend on underlying diagnosis. We have implemented highly sensitive and accurate methodologies for chimerism analysis for the purpose of improving relapse prediction. Here, we report an exploratory retrospective analysis of clinical routine chimerism results from all 154 HSCTs for acute myeloid leukemia (AML) performed at our center during the years 2015–2020 with the aim of suggesting a clinically useful threshold at which risk of relapse is high. Relapse was not reliably predicted based on single elevated chimerism values obtained before time of overt relapse. However, early complete donor chimerism, here defined as recipient DNA + cells in any blood or bone marrow sample taken during the first 60 days after HSCT, correlated inversely with relapse during the observation time (log-rank test P = 0.033). We propose that achievement of complete chimerism determined early after HSCT using sensitive methods can be used for risk-stratification of AML patients.
Published: 2022
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40. Relationships between daily physical activity combinations and psychophysical health status of Italian breast cancer survivors

Author: Andrea Di Blasio, Giulia Di Dalmazi, Teresa Morano, Ines Bucci, Sara Verrocchio, Simona Grossi, Ettore Cianchetti, Pasquale Valentini, Lucia Cugusi, Stefano Gobbo, Marco Bergamin, Antonino Grassadonia, and Giorgio Napolitano
Subjects: Community and Home Care, health promotion, Health Status, mood, Health Policy, Public Health, Environmental and Occupational Health, Breast Neoplasms, body mass index, cortisol, Leisure time and activity, Cancer Survivors, Surveys and Questionnaires, Humans, cancer, Female, sleep, Exercise
Abstract: In breast cancer survivors (BCS), the contemporaneous increase of sedentary time and reduction of physical activity (PA) requires early attention because it has negative consequences for their health. Aims of the study were to investigate: a) the correlations between PA, sedentarism, and health-related measures; b) the association between different patterns of daily activity and health-related outcomes. Two hundred and nineteen BCS (50.98 ± 6.28) were selected for this study. Psychological, anthropometric, endocrine, sleeping, and both daily sedentary time and PA variables were considered. Sedentarism and PA have opposite correlations with anthropometric variables, anxiety, depression, morning salivary cortisol, and sleeping characteristics. The first favors pathological values and the latter favors normal values. Regression tree analysis showed the impact of different daily sedentary time and PA combinations on the investigated variables and allowed the individualization of their optimal combination for health. Our results could be useful to healthcare providers and BCS.
Published: 2022
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41. The association between appetite loss, frailty, and psychosocial factors in community-dwelling older adults adults

Author: Mariana Staut Zukeran, João Valentini Neto, Carla Vasconcelos Romanini, Silvana Vieira Bandeira Mingardi, Gabriela Cabett Cipolli, Ivan Aprahamian, and Sandra Maria Lima Ribeiro
Subjects: Cohort Studies, Cross-Sectional Studies, Nutrition and Dietetics, Frailty, Frail Elderly, Endocrinology, Diabetes and Metabolism, Appetite, Humans, Female, Independent Living, Middle Aged, Brazil, Aged
Abstract: Appetite loss (AL) in older adults can reduce energy and nutrient intake, increasing the risk of weight loss, sarcopenia, frailty, and ultimately, mortality. The identification of associated factors to AL is important to plan different interventions.To identify the association between appetite loss, frailty, and psychosocial factors in community-dwelling older adults.Cross-sectional analysis of the cohort study MiMiCS-FRAIL based in Jundiai City, São Paulo, Brazil. Patients 60+ years old were evaluated from January 2019 to August 2020. The AL (dependent variable) was evaluated through the SNAQ questionnaire; the independent variables were: frailty (identified by frailty index-36; FI-36) which is based on the accumulation of deficits; depressive symptoms (GDS scale); ethnicity, and years of formal schooling, both used as proxies of socioeconomic status. The associations were investigated using logistic regression models (crude and multiple).The final sample included 122 older adults, 58.2% of women, mean age of 71.7 years, 80.3% White, and low educational level (5.8 ± 4.3 years of formal schooling). We found 19.6% of the sample presenting AL. The final regression models showed independent and significant association between AL and age (OR = 1.11; 95%IC = 1.03-1.20; p 0.01), being non-White (OR = 6.47; 95%IC = 1.63-25.58; p 0.01), and presence of depressive symptoms (OR = 8.38; 95%IC = 2.31-30.47; p 0.01). However, years of formal schooling, gender, and FI-36 remained statistically non-significant in the model.Our data pointed to the presence of depressive symptoms and social variables as significant factors associated with AL. Further studies with more robust samples or longitudinal design will clarify some unanswered questions of our study.
Published: 2022
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42. Polympact: exploring functional relations among common human genetic variants

Author: Samuel Valentini, Francesco Gandolfi, Mattia Carolo, Davide Dalfovo, Lara Pozza, and Alessandro Romanel
Subjects: Genetics, Cluster Analysis, Humans, Human Genetics, Polymorphism, Single Nucleotide, Genome-Wide Association Study
Abstract: In the last years, many studies were able to identify associations between common genetic variants and complex diseases. However, the mechanistic biological links explaining these associations are still mostly unknown. Common variants are usually associated with a relatively small effect size, suggesting that interactions among multiple variants might be a major genetic component of complex diseases. Hence, elucidating the presence of functional relations among variants may be fundamental to identify putative variants’ interactions. To this aim, we developed Polympact, a web-based resource that allows to explore functional relations among human common variants by exploiting variants’ functional element landscape, their impact on transcription factor binding motifs, and their effect on transcript levels of protein-coding genes. Polympact characterizes over 18 million common variants and allows to explore putative relations by combining clustering analysis and innovative similarity and interaction network models. The properties of the network models were studied and the utility of Polympact was demonstrated by analysing the rich sets of Breast Cancer and Alzheimer's GWAS variants. We identified relations among multiple variants, suggesting putative interactions. Polympact is freely available at bcglab.cibio.unitn.it/polympact.
Published: 2022
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43. Transanal Endoscopic Microsurgery Versus Total Mesorectal Excision in ypT0-1 Rectal Cancer After Preoperative Radiochemotherapy: Postoperative Morbidity, Functional Results, and Long-term Oncologic Outcome

Author: Gianluca, Rizzo, Donato P, Pafundi, Francesco, Sionne, Giulia, Pietricola, Luca, D'Agostino, Maria A, Gambacorta, Vincenzo, Valentini, and Claudio, Coco
Subjects: Transanal Endoscopic Microsurgery, Rectal Neoplasms, Gastroenterology, Humans, General Medicine, Morbidity, Follow-Up Studies, Neoplasm Staging, Retrospective Studies
Abstract: In patients with locally advanced extraperitoneal rectal cancer, a multidisciplinary approach represents the standard treatment. However, considering the favorable prognosis in patients with major or complete response, radical surgery might represent overtreatment.This study aimed to evaluate postoperative short-term morbidity, functional outcome, and oncologic long-term outcome in patients with rectal cancer treated with local excision by transanal endoscopic microsurgery or radical surgery and to determine who achieved a complete or major pathological response (ypT0-1) after neoadjuvant treatment.This was a retrospective study.The study was conducted at a single center.Patients who had received neoadjuvant treatment by local excision with a major or complete pathological response at histological examination (transanal endoscopic microsurgery group) were compared to patients treated by radical surgery with the same pathological response (total mesorectal excision group).The interventions included local excision by transanal endoscopic microsurgery and radical surgery with total mesorectal excision.Postoperative short-term morbidity, functional outcome 1 year after surgery, and oncologic long-term outcome were measured.Ninety-three patients were included in the study (35 in the transanal endoscopic microsurgery group and 58 in the mesorectal excision group). In the total mesorectal excision group, a sphincter-saving approach was possible in 89.7% (vs 100%; p = 0.049); a protective temporary stoma was necessary in 74.1% of radical procedures (vs 0%; p0.001), and 13.8% of these became permanent. Short-term postoperative morbidity was lower after local excision (14.3% vs 46.6%; p = 0.002). One year after surgery, the transanal endoscopic microsurgery group recorded better evacuation and continence function than the total mesorectal excision group. Oncologic outcome was similar between the groups.This study had a retrospective design.If a major or complete pathological response occurs after neoadjuvant treatment, an organ-sparing approach by local excision seems to offer the same oncologic results as radical surgery, but it has a better postoperative morbidity rate and better functional results. See Video Abstract at http://links.lww.com/DCR/B901 .Microcirugía endoscópica transanal versus escisión total del mesorrecto en cáncer de recto ypT0-1 después de radioquimioterapia preoperatoria: morbilidad posoperatoria, resultados funcionales y resultado oncológico a largo plazo.En pacientes con cáncer rectal extraperitoneal localmente avanzado, un abordaje multidisciplinario con radioquimioterapia preoperatoria y cirugía con escisión total del mesorrecto representa el tratamiento estándar. En pacientes que obtienen una respuesta mayor o completa, la cirugía radical puede representar un sobretratamiento, considerando el pronóstico favorable de estos casos.Evaluar la morbilidad posoperatoria a corto plazo, el resultado funcional y el resultado oncológico a largo plazo en pacientes con cáncer de recto tratados con escisión local mediante microcirugía endoscópica transanal o mediante cirugía radical y que obtuvieron una respuesta patológica completa o mayor (ypT0-1) después del tratamiento neoadyuvante.Este fue un estudio retrospectivo.El estudio se realizó en un solo centro.El estudio se realizó en un solo centro.Se comparó a los pacientes tratados, tras tratamiento neoadyuvante (1996-2016), mediante escisión local con respuesta patológica mayor o completa al examen histológico (grupo de microcirugía endoscópica transanal), con los pacientes tratados mediante cirugía radical con la misma respuesta patológica (grupo de escisión mesorrectal total).Extirpación local mediante microcirugía endoscópica transanal y cirugía radical con escisión mesorrectal total.Morbilidad posoperatoria a corto plazo, resultado funcional a un año después de la cirugía (evaluado con una puntuación de evacuación y continencia) y resultado oncológico a largo plazo.Las limitaciones de este estudio incluyen su diseño retrospectivo.Si se produce una respuesta patológica mayor o completa después del tratamiento neoadyuvante, un abordaje con preservación de órganos mediante escisión local parece ofrecer los mismos resultados oncológicos que la cirugía radical, pero tiene una menor tasa de morbilidad postoperatoria y mejores resultados funcionales un año después de la cirugía. Consulte Video Resumen en http://links.lww.com/DCR/B901 . (Traducción-Dr. Felipe Bellolio ).
Published: 2022
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44. The Use of Scapular Bone Flaps During Head-and-Neck Reconstruction: Functional, Orthopedic, and Quality of Life Analyses of Flap-Harvest-Related Deficits

Author: Valentino Valentini, Giovanni Di Giacomo, Danilo Di Giorgio, Marco Delia Monaca, Paolo Priore, Luigi Piscitelli, and Andrea Battisti
Subjects: Adult, Male, General Medicine, Middle Aged, Plastic Surgery Procedures, Free Tissue Flaps, Scapula, Young Adult, Otorhinolaryngology, Quality of Life, Humans, Female, Surgery, Neck, Aged, Retrospective Studies
Abstract: The authors sought correlations between harvesting of the scapular bone tip free flap used for head-and-neck reconstruction and any shoulder function deficit, particularly at the level of the rotator cuff. The flap permits reconstruction of large and diverse regions of the head and neck, but long-term harvest morbidity has not been investigated extensively. The authors analyzed the clinical records of all patients who underwent head-and-neck reconstructions using free scapular tip flaps in our department over the past 5 years. The inclusion criteria were complete clinical and radiological documentation and follow-up for at least 12 months. Two populations, a surgical and control population, were analyzed. All patients in both populations underwent the simple shoulder test, an internationally validated self-administered test that highlights functional shoulder deficits, and 3 additional tests at orthopedic visits: the external rotation test, Patte test, and external rotation lag sign test. A head-and-neck cancer-specific questionnaire (University of Washington Quality of Life, version 4) was completed by the surgical patients. All statistical analyses were performed using Software IBM SPSS Statistics (IBM Corp., Armonk, NY).A total of 19 patients met the inclusion criteria: 11 males (57.8%) and 8 females (42.2%) of mean age 60.9 years (range 23-75 years). In addition, 20 age-and sex-matched volunteers with no history of shoulder pathology were evaluated in terms of shoulder functionality. The average score on the simple shoulder test was 10.55 in the healthy population versus 8.31 in the study population ( P0.001); in particular, shoulder strength differed between the groups. Similarly, the orthopedic examinations revealed clinically significant differences between the controls and patients on the Patte test and external rotation lag sign test (both P0.001), but not the external rotation test ( P0.001). The mean University of Washington Quality of Life was 73.39; most patients reported good quality of life (52.6%), followed by very good (15.7%).The free scapular bone tip flap is valuable for reconstruction of head-and-neck defects; the long and reliable vascularpedicle allows rapid patient mobilization. Morbidity was confined to small reductions in shoulder strength and external rotation, which do not affect quality of life.
Published: 2022
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45. Role of Chemoradiation in the Adjuvant Treatment of Radically Resected Pancreatic Cancer Patients: A Mono-Institutional Retrospective Analysis

Author: Gian Carlo Mattiucci, Lisa Salvatore, Andrea D’Aviero, Cinzia Bagalà, Maria Bensi, Francesco Mosè Castronovo, Francesco Cellini, Paola De Franco, Brunella Di Stefano, Gabriella Macchia, Valeria Masiello, Roberta Menghi, Giuseppe Quero, Sara Reina, Alessio Giuseppe Morganti, Sergio Alfieri, Giampaolo Tortora, and Vincenzo Valentini
Subjects: Pancreatic Neoplasms, Cancer Research, Oncology, Chemotherapy, Adjuvant, Humans, Chemoradiotherapy, Adjuvant, Fluorouracil, Hematology, Aged, Retrospective Studies
Abstract: Introduction: Pancreatic cancer (PC) represents an unfavorable prognosis condition, even in patients with resectable disease. The aim of this series was to investigate the role of treatment intensification with adjuvant chemoradiation (CRT) in radically resected PC patients. Methods: Data from PC patients who underwent radical surgery, adjuvant chemotherapy (CT), and CRT throughout a 20-year period were retrospectively collected. Actuarial local control (LC) and the overall survival (OS) were the primary endpoints, with disease-free survival and metastasis-free survival (MFS) representing secondary endpoints. Results: The analysis included 108 PC patients treated with adjuvant CRT and CT from January 2000 to August 2019. Median age was 66 years (range: 40–83), and all patients underwent radical surgical resection with adjuvant CT (88, 81.5%) plus concomitant CRT (101, 93.5%) or radiotherapy alone (7, 6.5%). The median dose delivered to the tumor bed was 50.4 Gy (range: 45–50.6 Gy), while median dose to regional lymphatic drainage stations was 39.6 Gy (range 39.6–45 Gy). Concomitant CT was a gemcitabine-based regimen in the vast majority of patients (87, 80.6%). Median follow-up time was 21 months; the 2- and 5-year LC rates were 75.8% and 59.1%, respectively. Perineural invasion at pathological assessment was found significantly associated with LC (p = 0.028). Median OS was 40 months with 2- and 5-year OS rates of 73.9% and 41.6%, respectively. Conclusions: The outcomes of this series suggest to investigate the possible impact of adding adjuvant CRT to CT in PC patients. Timing and combination of modern CRT with new systemic therapies need to be further investigated to personalize therapy and optimize clinical advantages.
Published: 2022
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46. A combined molecular dynamics simulation and DFT study on mercapto-benzamide inhibitors for the HIV NCp7 protein

Author: Enrico Pieroni, GIANCARLO CAPPELLINI, Roberto Cardia, and Maria Valentini
Subjects: Benzamides, HIV-1, Humans, General Physics and Astronomy, Capsid Proteins, HIV Infections, Molecular Dynamics Simulation, Physical and Theoretical Chemistry, gag Gene Products, Human Immunodeficiency Virus, Protein Binding
Abstract: Molecular dynamics and quantum simulations are performed to elucidate some aspects of the action mechanism of mercapto-benzamides, a proposed class of antivirals against HIV-1. These molecules act as prodrugs that, after modifications in the biological environment, are able to denature the HIV nucleocapsid protein 7, a metal binder protein, with two zinc finger motifs, vital for RNA maturation and viral replication. Despite their attractive features, these molecules and their biological target are not well understood. Simulations were performed to support a proposed action mechanism, based on the activation of mercapto-benzamides by acetylation, targeting a relatively rare protein hydrolyzed state, followed by
Published: 2022
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47. Donor cell-derived myelofibrosis relapse after allogeneic stem cell transplantation

Author: Patrizia Chiusolo, Nicoletta Orlando, Sabrina Giammarco, Monica Rossi, Elisabetta Metafuni, Salvatore Leotta, Giuseppe Milone, Caterina Giovanna Valentini, Maria Bianchi, Filippo Frioni, Claudio Pellegrino, Federica Sorà, Luigi Maria Larocca, Simona Sica, Andrea Bacigalupo, and Luciana Teofili
Subjects: relapse, Transplantation Conditioning, mesenchymal cells, myeloproliferative neoplasms, transplanattion, microenvironment, endothelial progenitor cells, Hematopoietic Stem Cell Transplantation, Graft vs Host Disease, Hematology, Tissue Donors, Settore MED/15 - MALATTIE DEL SANGUE, Primary Myelofibrosis, Recurrence, Humans
Published: 2023

48. Risk Factors for cognitive, motor and language development of preterm children in the first year of life

Author: Júlia Vicente Hass, Carolina Panceri, Renato Soibelmann Procianoy, Rita de Cássia Silveira, and Nadia Cristina Valentini
Subjects: Infant, Newborn, Infant, Preterm birth, Language Development, Child Development, Cognition, Risk Factors, Pediatrics, Perinatology and Child Health, Humans, Female, Developmental disability, Child, Child development, Infant, Premature
Abstract: Objective: To perform a longitudinal investigation of risk factors in premature infants’ cognitive, motor, and language development. Methods: Thirty-three preterm infants were assessed at 4, 8, and 12 months of corrected age, using the Bayley-III Scales. Parents completed questionnaires regarding development opportunities at home, parenting practices and knowledge. Results: Significant associations were found (1) at 4-months between cognitive scores and family income, variety of stimuli, availability of toys, parenting practices and knowledge; language and parenting practices; and motor skills and parenting practices; (2) at 8-months between cognitive score and length of stay in the Neonatal Intensive Care Unit (NICU), gestational age, birth weight, toys, and parenting knowledge; language and toys; and motor skills and toys and parenting knowledge; (3) at 12-months between cognitive scores and length of stay in the NICU, family income, breastfeeding, toys, and parenting knowledge; language and income and toys; and motor scores and length of stay in the NICU, gestational age, income, stimuli, toys, and parenting knowledge. Regression analyses indicated that: for (1) cognitive development, stimulus variety explained 72% of the model variance at 4 months of age; time at the NICU explained 67 and 43% at 8 and 12 months of age, respectively, and breastfeeding time explained 41% of the model variance at 12 months; (2) for language development, family income explained 42% of the model variance at 12 months; and for motor development (3), time at the NICU explained 80% of the model variance at 12 months. Conclusions: The development over the first year of life is not explained by the severity of birth conditions and associated morbidities only, but also by parenting practices.
Published: 2023

49. Single shot of intravenous iron in cardiac surgery: The ICARUS study

Author: Filippo Corsi, Annalisa Pasquini, Manuel Guerrera, Francesca Bevilacqua, Temistocle Taccheri, Maria Enrica Antoniucci, Maria Calabrese, Caterina Giovanna Valentini, Nicoletta Orlando, Martina Bartolo, Giorgio Cannetti, Claudio Pellegrino, Franco Cavaliere, and Luciana Teofili
Subjects: Settore MED/15 - MALATTIE DEL SANGUE, Anesthesiology and Pain Medicine, Iron, Patient blood management, Humans, Administration, Intravenous, Anemia, Iron Deficiencies, Cardiac Surgical Procedures, Cardiac surgery, Ferric carboxymaltose, Settore MED/22 - CHIRURGIA VASCOLARE, Retrospective Studies
Abstract: Iron deficiency (ID), with or without anemia, is commonly observed among patients scheduled for cardiac surgery. We investigated if screening ID in the immediate preoperative period and treating ID patients regardless of anemia could reduce perioperative transfusion requirements.This is an observational single-center propensity score-matched study including candidates to elective cardiac surgery prospectively and retrospectively enrolled. Prospectively enrolled patients were screened for ID at hospital admission: if ferritin was ≤100 μg/L or ≤ 300 μg/L with transferrin saturation index ≤20% they received intravenous ferric carboxymaltose, B12-vitamin, and folic acid. A retrospective series of patients not screened for ID and matched for gender, type of surgery, BMI, Goudie transfusion risk score, hemoglobin level, and red blood cell (RBC) indices, served as controls. The primary outcome was the proportion of patients requiring ≤1 packed RBC (pRBC) unit within day 7 or discharge The main secondary outcomes were intraoperative and postoperative pRBC transfusions, duration of hospitalization, and cost-effectiveness of ID screening and treatment.We included 479 prospective and 833 retrospective cases: 442 patients screened for ID and 442 matched controls with unknown iron status were analyzed. ID was observed in 196 patients (44.3%) and iron was administered 1 day (IQR 1-2) before surgery. Overall, 76.9% of patients in the prospective group and 69.7% of controls received ≤1 pRBC transfusion (p = 0.014). The risk for multiple transfusions was lower in patients screened for ID (OR 0.689, 95% CI 0.510-0.930). Despite similar Hb levels at day 7, patients in the prospective group received fewer postoperative pRBC transfusions (p 0.001) and had a shorter hospital length of stay (p 0.001). Globally, hospitalization costs were lower in patients screened and treated for ID.Short-term pre-operative iron therapy is associated with a reduction in postoperative transfusions in anemic and non-anemic ID cardiac surgery patients and has a favorable impact on hospitalization costs.NCT04744181.
Published: 2023

50. Multi-center validation of an artificial intelligence system for detection of COVID-19 on chest radiographs in symptomatic patients

Author: Michael D. Kuo, Keith W. H. Chiu, David S. Wang, Anna Rita Larici, Dmytro Poplavskiy, Adele Valentini, Alessandro Napoli, Andrea Borghesi, Guido Ligabue, Xin Hao B. Fang, Hing Ki C. Wong, Sailong Zhang, John R. Hunter, Abeer Mousa, Amato Infante, Lorenzo Elia, Salvatore Golemi, Leung Ho P. Yu, Christopher K. M. Hui, and Bradley J. Erickson
Subjects: Artificial intelligence, Public health, Deep Learning, Thoracic, Humans, COVID-19, Radiology, Radiography, Thoracic, Radiology, Nuclear Medicine and imaging, General Medicine, Tomography, X-Ray Computed, Retrospective Studies
Abstract: While chest radiograph (CXR) is the first-line imaging investigation in patients with respiratory symptoms, differentiating COVID-19 from other respiratory infections on CXR remains challenging. We developed and validated an AI system for COVID-19 detection on presenting CXR.A deep learning model (RadGenX), trained on 168,850 CXRs, was validated on a large international test set of presenting CXRs of symptomatic patients from 9 study sites (US, Italy, and Hong Kong SAR) and 2 public datasets from the US and Europe. Performance was measured by area under the receiver operator characteristic curve (AUC). Bootstrapped simulations were performed to assess performance across a range of potential COVID-19 disease prevalence values (3.33 to 33.3%). Comparison against international radiologists was performed on an independent test set of 852 cases.RadGenX achieved an AUC of 0.89 on 4-fold cross-validation and an AUC of 0.79 (95%CI 0.78-0.80) on an independent test cohort of 5,894 patients. Delong's test showed statistical differences in model performance across patients from different regions (p0.01), disease severity (p0.001), gender (p0.001), and age (p = 0.03). Prevalence simulations showed the negative predictive value increases from 86.1% at 33.3% prevalence, to greater than 98.5% at any prevalence below 4.5%. Compared with radiologists, McNemar's test showed the model has higher sensitivity (p0.001) but lower specificity (p0.001).An AI model that predicts COVID-19 infection on CXR in symptomatic patients was validated on a large international cohort providing valuable context on testing and performance expectations for AI systems that perform COVID-19 prediction on CXR.• An AI model developed using CXRs to detect COVID-19 was validated in a large multi-center cohort of 5,894 patients from 9 prospectively recruited sites and 2 public datasets. • Differences in AI model performance were seen across region, disease severity, gender, and age. • Prevalence simulations on the international test set demonstrate the model's NPV is greater than 98.5% at any prevalence below 4.5%.
Published: 2023

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