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1. Protein Dose-Sparing Effect of AS01B Adjuvant in a Randomized Preventive HIV Vaccine Trial of ALVAC-HIV (vCP2438) and Adjuvanted Bivalent Subtype C gp120.

Author

Chirenje, Zvavahera, Laher, Fatima, Dintwe, One, Muyoyeta, Monde, deCamp, Allan, He, Zonglin, Grunenberg, Nicole, Laher Omar, Faatima, Seaton, Kelly, Polakowski, Laura, Woodward Davis, Amanda, Maganga, Lucas, Baden, Lindsey, Mayer, Kenneth, Kalams, Spyros, Keefer, Michael, Edupuganti, Srilatha, Rodriguez, Benigno, Frank, Ian, Scott, Hyman, Stranix-Chibanda, Lynda, Gurunathan, Sanjay, Koutsoukos, Marguerite, Van Der Meeren, Olivier, DiazGranados, Carlos, Paez, Carmen, Andersen-Nissen, Erica, Kublin, James, Corey, Lawrence, Ferrari, Guido, Tomaras, Georgia, and McElrath, M

Subjects
HIV, adjuvant, dose, vaccine, Humans, Female, Adjuvants, Immunologic, AIDS Vaccines, Adult, Male, Young Adult, HIV Infections, HIV Envelope Protein gp120, Adolescent, Double-Blind Method, HIV Antibodies, Squalene, Polysorbates, HIV-1, Viral Vaccines
Abstract

BACKGROUND: HVTN 120 is a phase 1/2a randomized double-blind placebo-controlled human immunodeficiency virus (HIV) vaccine trial that evaluated the safety and immunogenicity of ALVAC-HIV (vCP2438) and MF59- or AS01B-adjuvanted bivalent subtype C gp120 Env protein at 2 dose levels in healthy HIV-uninfected adults. METHODS: Participants received ALVAC-HIV (vCP2438) alone or placebo at months 0 and 1. At months 3 and 6, participants received either placebo, ALVAC-HIV (vCP2438) with 200 μg of bivalent subtype C gp120 adjuvanted with MF59 or AS01B, or ALVAC-HIV (vCP2438) with 40 μg of bivalent subtype C gp120 adjuvanted with AS01B. Primary outcomes were safety and immune responses. RESULTS: We enrolled 160 participants, 55% women, 18-40 years old (median age 24 years) of whom 150 received vaccine and 10 placebo. Vaccines were generally safe and well tolerated. At months 6.5 and 12, CD4+ T-cell response rates and magnitudes were higher in the AS01B-adjuvanted groups than in the MF59-adjuvanted group. At month 12, HIV-specific Env-gp120 binding antibody response magnitudes in the 40 μg gp120/AS01B group were higher than in either of the 200 μg gp120 groups. CONCLUSIONS: The 40 μg dose gp120/AS01B regimen elicited the highest CD4+ T-cell and binding antibody responses. Clinical Trials Registration . NCT03122223.

Published
2024

2. Worldwide Disparities in Recovery of Cardiac Testing 1 Year Into COVID-19.

Author

Einstein, Andrew, Hirschfeld, Cole, Williams, Michelle, Vitola, Joao, Better, Nathan, Villines, Todd, Cerci, Rodrigo, Shaw, Leslee, Choi, Andrew, Dorbala, Sharmila, Karthikeyan, Ganesan, Lu, Bin, Sinitsyn, Valentin, Ansheles, Alexey, Kudo, Takashi, Bucciarelli-Ducci, Chiara, Nørgaard, Bjarne, Maurovich-Horvat, Pál, Campisi, Roxana, Milan, Elisa, Louw, Lizette, Allam, Adel, Bhatia, Mona, Sewanan, Lorenzo, Malkovskiy, Eli, Cohen, Yosef, Randazzo, Michael, Narula, Jagat, Morozova, Olga, Pascual, Thomas, Pynda, Yaroslav, Dondi, Maurizio, and Paez, Diana

Subjects
COVID-19, cardiac testing, cardiovascular disease, coronavirus, global health, COVID-19, Delivery of Health Care, Health Personnel, Humans, Pandemics, Surveys and Questionnaires
Abstract

BACKGROUND: The extent to which health care systems have adapted to the COVID-19 pandemic to provide necessary cardiac diagnostic services is unknown. OBJECTIVES: The aim of this study was to determine the impact of the pandemic on cardiac testing practices, volumes and types of diagnostic services, and perceived psychological stress to health care providers worldwide. METHODS: The International Atomic Energy Agency conducted a worldwide survey assessing alterations from baseline in cardiovascular diagnostic care at the pandemics onset and 1 year later. Multivariable regression was used to determine factors associated with procedure volume recovery. RESULTS: Surveys were submitted from 669 centers in 107 countries. Worldwide reduction in cardiac procedure volumes of 64% from March 2019 to April 2020 recovered by April 2021 in high- and upper middle-income countries (recovery rates of 108% and 99%) but remained depressed in lower middle- and low-income countries (46% and 30% recovery). Although stress testing was used 12% less frequently in 2021 than in 2019, coronary computed tomographic angiography was used 14% more, a trend also seen for other advanced cardiac imaging modalities (positron emission tomography and magnetic resonance; 22%-25% increases). Pandemic-related psychological stress was estimated to have affected nearly 40% of staff, impacting patient care at 78% of sites. In multivariable regression, only lower-income status and physicians psychological stress were significant in predicting recovery of cardiac testing. CONCLUSIONS: Cardiac diagnostic testing has yet to recover to prepandemic levels in lower-income countries. Worldwide, the decrease in standard stress testing is offset by greater use of advanced cardiac imaging modalities. Pandemic-related psychological stress among providers is widespread and associated with poor recovery of cardiac testing.

Published
2022

3. Successful Treatment of Disseminated Disease Due to Highly Resistant Aspergillus calidoustus with a Novel Antifungal Therapy

Author

Camargo, Jose F, Jabr, Ra’ed, Anderson, Anthony D, Lekakis, Lazaros, Diaz-Paez, Meilin, Briski, Laurence M, Raja, Mohammed, Morris, Michele I, Komanduri, Krishna V, and Pereira, Denise

Subjects
Microbiology, Biological Sciences, Biomedical and Clinical Sciences, Clinical Sciences, Prevention, Vaccine Related, Transplantation, Antimicrobial Resistance, Emerging Infectious Diseases, Infectious Diseases, Rare Diseases, Stem Cell Research, Infection, Antifungal Agents, Aspergillosis, Aspergillus, Hematopoietic Stem Cell Transplantation, Humans, APX001, Aspergillus calidoustus, hematopoietic cell transplant, Medical Microbiology, Pharmacology and Pharmaceutical Sciences, Medical microbiology, Pharmacology and pharmaceutical sciences
Abstract

Invasive aspergillosis is the most common invasive mold infection following a hematopoietic cell transplant. Widespread use of antifungal prophylaxis has led to the increasing incidence of cryptic Aspergillus species. Aspergillus calidoustus is one of those emerging species and is notorious for multidrug resistance to antifungals. Here, we report a case of disseminated A. calidoustus infection in a hematopoietic stem cell transplant recipient who was successfully treated with combination therapy that included a novel antifungal.

Published
2022

4. Combined Single Cell Transcriptome and Surface Epitope Profiling Identifies Potential Biomarkers of Psoriatic Arthritis and Facilitates Diagnosis via Machine Learning

Author

Liu, Jared, Kumar, Sugandh, Hong, Julie, Huang, Zhi-Ming, Paez, Diana, Castillo, Maria, Calvo, Maria, Chang, Hsin-Wen, Cummins, Daniel D, Chung, Mimi, Yeroushalmi, Samuel, Bartholomew, Erin, Hakimi, Marwa, Ye, Chun Jimmie, Bhutani, Tina, Matloubian, Mehrdad, Gensler, Lianne S, and Liao, Wilson

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Machine Learning and Artificial Intelligence, Genetics, Prevention, Psoriasis, Rare Diseases, Autoimmune Disease, Clinical Research, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Inflammatory and immune system, Arthritis, Psoriatic, Biomarkers, Epitopes, Humans, Machine Learning, Transcriptome, psoriatic arthritis, psoriasis, CITE-seq, machine learning, diagnostic test, single cell, Immunology, Medical Microbiology, Biochemistry and cell biology
Abstract

Early diagnosis of psoriatic arthritis (PSA) is important for successful therapeutic intervention but currently remains challenging due, in part, to the scarcity of non-invasive biomarkers. In this study, we performed single cell profiling of transcriptome and cell surface protein expression to compare the peripheral blood immunocyte populations of individuals with PSA, individuals with cutaneous psoriasis (PSO) alone, and healthy individuals. We identified genes and proteins differentially expressed between PSA, PSO, and healthy subjects across 30 immune cell types and observed that some cell types, as well as specific phenotypic subsets of cells, differed in abundance between these cohorts. Cell type-specific gene and protein expression differences between PSA, PSO, and healthy groups, along with 200 previously published genetic risk factors for PSA, were further used to perform machine learning classification, with the best models achieving AUROC ≥ 0.87 when either classifying subjects among the three groups or specifically distinguishing PSA from PSO. Our findings thus expand the repertoire of gene, protein, and cellular biomarkers relevant to PSA and demonstrate the utility of machine learning-based diagnostics for this disease.

Published
2022

5. Single Cell Transcriptome and Surface Epitope Analysis of Ankylosing Spondylitis Facilitates Disease Classification by Machine Learning

Author

Alber, Samuel, Kumar, Sugandh, Liu, Jared, Huang, Zhi-Ming, Paez, Diana, Hong, Julie, Chang, Hsin-Wen, Bhutani, Tina, Gensler, Lianne S, and Liao, Wilson

Subjects
Biomedical and Clinical Sciences, Immunology, Genetics, Machine Learning and Artificial Intelligence, 2.1 Biological and endogenous factors, Inflammatory and immune system, Epitopes, Humans, Leukocytes, Mononuclear, Machine Learning, Spondylitis, Ankylosing, Transcriptome, ankylosing spondylitis, spondyloarthritis, single cell sequencing, CITE-seq, genomics, machine learning, Medical Microbiology, Biochemistry and cell biology
Abstract

Ankylosing spondylitis (AS) is an immune-mediated inflammatory disorder that primarily affects the axial skeleton, especially the sacroiliac joints and spine. This results in chronic back pain and, in extreme cases, ankylosis of the spine. Despite its debilitating effects, the pathogenesis of AS remains to be further elucidated. This study used single cell CITE-seq technology to analyze peripheral blood mononuclear cells (PBMCs) in AS and in healthy controls. We identified a number of molecular features associated with AS. CD52 was found to be overexpressed in both RNA and surface protein expression across several cell types in patients with AS. CD16+ monocytes overexpressed TNFSF10 and IL-18Rα in AS, while CD8+ TEM cells and natural killer cells overexpressed genes linked with cytotoxicity, including GZMH, GZMB, and NKG7. Tregs underexpressed CD39 in AS, suggesting reduced functionality. We identified an overrepresented NK cell subset in AS that overexpressed CD16, CD161, and CD38, as well as cytotoxic genes and pathways. Finally, we developed machine learning models derived from CITE-seq data for the classification of AS and achieved an Area Under the Receiver Operating Characteristic (AUROC) curve of > 0.95. In summary, CITE-seq identification of AS-associated genes and surface proteins in specific cell subsets informs our understanding of pathogenesis and potential new therapeutic targets, while providing new approaches for diagnosis via machine learning.

Published
2022

6. Impact of COVID-19 on Cardiovascular Testing in the United States Versus the Rest of the World

Author

Hirschfeld, Cole B, Shaw, Leslee J, Williams, Michelle C, Lahey, Ryan, Villines, Todd C, Dorbala, Sharmila, Choi, Andrew D, Shah, Nishant R, Bluemke, David A, Berman, Daniel S, Blankstein, Ron, Ferencik, Maros, Narula, Jagat, Winchester, David, Malkovskiy, Eli, Goebel, Benjamin, Randazzo, Michael J, Lopez-Mattei, Juan, Parwani, Purvi, Vitola, Joao V, Cerci, Rodrigo J, Better, Nathan, Raggi, Paolo, Lu, Bin, Sergienko, Vladimir, Sinitsyn, Valentin, Kudo, Takashi, Nørgaard, Bjarne Linde, Maurovich-Horvat, Pál, Cohen, Yosef A, Pascual, Thomas NB, Pynda, Yaroslav, Dondi, Maurizio, Paez, Diana, Einstein, Andrew J, Cerci, Rodrigo, Hinterleitner, Gerd, Lu, Yao, Morozova, Olga, Xu, Zhuoran, Cohen, Yosef, Randazzo, Michael, Choi, Andrew, Nasery, Mohammad Nawaz, Goda, Artan, Shirka, Ervina, Benlabgaa, Rabie, Bouyoucef, Salah, Medjahedi, Abdelkader, Nailli, Qais, Agolti, Mariela, Aguero, Roberto Nicolas, del Carmen Alak, Maria, Alberguina, Lucia Graciela, Arroñada, Guillermo, Astesiano, Andrea, Astesiano, Alfredo, Norton, Carolina Bas, Benteo, Pablo, Blanco, Juan, Bonelli, Juan Manuel, Bustos, Jose Javier, Cabrejas, Raul, Cachero, Jorge, Campisi, Roxana, Canderoli, Alejandro, Carames, Silvia, Carrascosa, Patrícia, Castro, Ricardo, Cendoya, Oscar, Cognigni, Luciano Martin, Collaud, Carlos, Cortes, Claudia, Courtis, Javier, Cragnolino, Daniel, Daicz, Mariana, De La Vega, Alejandro, De Maria, Silvia Teresa, Del Riego, Horacio, Dettori, Fernando, Deviggiano, Alejandro, and Dragonetti, Laura

Subjects
Heart Disease, Clinical Research, Health Services, Prevention, Aging, Cardiovascular, Good Health and Well Being, COVID-19, COVID-19 Testing, Humans, Pandemics, Predictive Value of Tests, SARS-CoV-2, United States, cardiovascular disease, cardiovascular imaging, coronavirus, diagnostic cardiovascular procedure, INCAPS-COVID Investigators Group, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Cardiovascular System & Hematology
Abstract

ObjectivesThis study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-U.S. institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic.BackgroundThe COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality.MethodsData were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States.ResultsReductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p

Published
2021

7. Sex Differences in the Association of Cigarette Craving with Insula Structure

Author

Diaz, Maylen Perez, Pochon, Jean-Baptiste, Ghahremani, Dara G, Dean, Andy C, Faulkner, Paul, Petersen, Nicole, Tyndale, Rachel F, Donis, Andrea, Paez, Diana, Cahuantzi, Citlaly, Hellemann, Gerhard S, and London, Edythe D

Subjects
Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Tobacco, Clinical Research, Behavioral and Social Science, Substance Misuse, Tobacco Smoke and Health, Neurosciences, Brain Disorders, Prevention, Drug Abuse (NIDA only), Good Health and Well Being, Adolescent, Adult, Cigarette Smoking, Craving, Female, Humans, Insular Cortex, Magnetic Resonance Imaging, Male, Sex Characteristics, Tobacco Use Disorder, Young Adult, insula, nicotine dependence, sex differences, smoking, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundCigarette craving, which can negatively impact smoking cessation, is reportedly stronger in women than in men when they initiate abstinence from smoking. Identifying approaches to counteract craving in people of different sexes may facilitate the development of personalized treatments for Tobacco Use Disorder, which disproportionately affects women. Because cigarette craving is associated with nicotine dependence and structure of the insula, this study addressed whether a person's sex influences these associations.MethodsThe research participants (n = 99, 48 women) reported daily cigarette smoking and provided self-reports of nicotine dependence. After overnight abstinence from smoking, they underwent structural magnetic resonance imaging scanning to determine cortical thickness of the left and right anterior circular insular sulcus, and self-rated their cigarette craving before and after their first cigarette of the day.ResultsWomen reported stronger craving than men irrespective of smoking condition (i.e., pre- and post-smoking) (P = .048), and smoking reduced craving irrespective of sex (P

Published
2021

8. Impact of COVID-19 on the imaging diagnosis of cardiac disease in Europe.

Author

Williams, Michelle Claire, Shaw, Leslee, Hirschfeld, Cole B, Maurovich-Horvat, Pal, Nørgaard, Bjarne L, Pontone, Gianluca, Jimenez-Heffernan, Amelia, Sinitsyn, Valentin, Sergienko, Vladimir, Ansheles, Alexey, Bax, Jeroen J, Buechel, Ronny, Milan, Elisa, Slart, Riemer HJA, Nicol, Edward, Bucciarelli-Ducci, Chiara, Pynda, Yaroslav, Better, Nathan, Cerci, Rodrigo, Dorbala, Sharmila, Raggi, Paolo, Villines, Todd C, Vitola, Joao, Malkovskiy, Eli, Goebel, Benjamin, Cohen, Yosef, Randazzo, Michael, Pascual, Thomas NB, Dondi, Maurizio, Paez, Diana, Einstein, Andrew J, and INCAPS COVID Investigators Group

Subjects
INCAPS COVID Investigators Group, Humans, Heart Diseases, Health Care Surveys, Predictive Value of Tests, Europe, Healthcare Disparities, Cardiac Imaging Techniques, Practice Patterns, Physicians', Cardiologists, COVID-19, cardiac imaging techniques, coronary artery disease, Cardiovascular
Abstract

We aimed to explore the impact of the COVID-19 pandemic on cardiac diagnostic testing and practice and to assess its impact in different regions in Europe. The online survey organised by the International Atomic Energy Agency Division of Human Health collected information on changes in cardiac imaging procedural volumes between March 2019 and March/April 2020. Data were collected from 909 centres in 108 countries. Centres in Northern and Southern Europe were more likely to cancel all outpatient activities compared with Western and Eastern Europe. There was a greater reduction in total procedure volumes in Europe compared with the rest of the world in March 2020 (45% vs 41%, p=0.003), with a more marked reduction in Southern Europe (58%), but by April 2020 this was similar in Europe and the rest of the world (69% vs 63%, p=0.261). Regional variations were apparent between imaging modalities, but the largest reductions were in Southern Europe for nearly all modalities. In March 2020, location in Southern Europe was the only independent predictor of the reduction in procedure volume. However, in April 2020, lower gross domestic product and higher COVID-19 deaths were the only independent predictors. The first wave of the COVID-19 pandemic had a significant impact on care of patients with cardiac disease, with substantial regional variations in Europe. This has potential long-term implications for patients and plans are required to enable the diagnosis of non-COVID-19 conditions during the ongoing pandemic.

Published
2021

9. A global metagenomic map of urban microbiomes and antimicrobial resistance

Author

Danko, David, Bezdan, Daniela, Afshin, Evan E, Ahsanuddin, Sofia, Bhattacharya, Chandrima, Butler, Daniel J, Chng, Kern Rei, Donnellan, Daisy, Hecht, Jochen, Jackson, Katelyn, Kuchin, Katerina, Karasikov, Mikhail, Lyons, Abigail, Mak, Lauren, Meleshko, Dmitry, Mustafa, Harun, Mutai, Beth, Neches, Russell Y, Ng, Amanda, Nikolayeva, Olga, Nikolayeva, Tatyana, Png, Eileen, Ryon, Krista A, Sanchez, Jorge L, Shaaban, Heba, Sierra, Maria A, Thomas, Dominique, Young, Ben, Abudayyeh, Omar O, Alicea, Josue, Bhattacharyya, Malay, Blekhman, Ran, Castro-Nallar, Eduardo, Cañas, Ana M, Chatziefthimiou, Aspassia D, Crawford, Robert W, De Filippis, Francesca, Deng, Youping, Desnues, Christelle, Dias-Neto, Emmanuel, Dybwad, Marius, Elhaik, Eran, Ercolini, Danilo, Frolova, Alina, Gankin, Dennis, Gootenberg, Jonathan S, Graf, Alexandra B, Green, David C, Hajirasouliha, Iman, Hastings, Jaden JA, Hernandez, Mark, Iraola, Gregorio, Jang, Soojin, Kahles, Andre, Kelly, Frank J, Knights, Kaymisha, Kyrpides, Nikos C, Łabaj, Paweł P, Lee, Patrick KH, Leung, Marcus HY, Ljungdahl, Per O, Mason-Buck, Gabriella, McGrath, Ken, Meydan, Cem, Mongodin, Emmanuel F, Moraes, Milton Ozorio, Nagarajan, Niranjan, Nieto-Caballero, Marina, Noushmehr, Houtan, Oliveira, Manuela, Ossowski, Stephan, Osuolale, Olayinka O, Özcan, Orhan, Paez-Espino, David, Rascovan, Nicolás, Richard, Hugues, Rätsch, Gunnar, Schriml, Lynn M, Semmler, Torsten, Sezerman, Osman U, Shi, Leming, Shi, Tieliu, Siam, Rania, Song, Le Huu, Suzuki, Haruo, Court, Denise Syndercombe, Tighe, Scott W, Tong, Xinzhao, Udekwu, Klas I, Ugalde, Juan A, Valentine, Brandon, Vassilev, Dimitar I, Vayndorf, Elena M, Velavan, Thirumalaisamy P, Wu, Jun, Zambrano, María M, Zhu, Jifeng, Zhu, Sibo, Mason, Christopher E, and Consortium, The International MetaSUB

Subjects
Microbiology, Biological Sciences, Genetics, Infectious Diseases, Emerging Infectious Diseases, Antimicrobial Resistance, Infection, Biodiversity, Databases, Genetic, Drug Resistance, Bacterial, Humans, Metagenomics, Microbiota, Urban Population, International MetaSUB Consortium, AMR, BGC, NGS, antimicrobial resistance, built Environment, de novo assembly, global health, metagenome, microbiome, shotgun sequencing, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

We present a global atlas of 4,728 metagenomic samples from mass-transit systems in 60 cities over 3 years, representing the first systematic, worldwide catalog of the urban microbial ecosystem. This atlas provides an annotated, geospatial profile of microbial strains, functional characteristics, antimicrobial resistance (AMR) markers, and genetic elements, including 10,928 viruses, 1,302 bacteria, 2 archaea, and 838,532 CRISPR arrays not found in reference databases. We identified 4,246 known species of urban microorganisms and a consistent set of 31 species found in 97% of samples that were distinct from human commensal organisms. Profiles of AMR genes varied widely in type and density across cities. Cities showed distinct microbial taxonomic signatures that were driven by climate and geographic differences. These results constitute a high-resolution global metagenomic atlas that enables discovery of organisms and genes, highlights potential public health and forensic applications, and provides a culture-independent view of AMR burden in cities.

Published
2021

10. A genomic catalog of Earth’s microbiomes

Author

Nayfach, Stephen, Roux, Simon, Seshadri, Rekha, Udwary, Daniel, Varghese, Neha, Schulz, Frederik, Wu, Dongying, Paez-Espino, David, Chen, I-Min, Huntemann, Marcel, Palaniappan, Krishna, Ladau, Joshua, Mukherjee, Supratim, Reddy, TBK, Nielsen, Torben, Kirton, Edward, Faria, José P, Edirisinghe, Janaka N, Henry, Christopher S, Jungbluth, Sean P, Chivian, Dylan, Dehal, Paramvir, Wood-Charlson, Elisha M, Arkin, Adam P, Tringe, Susannah G, Visel, Axel, Woyke, Tanja, Mouncey, Nigel J, Ivanova, Natalia N, Kyrpides, Nikos C, and Eloe-Fadrosh, Emiley A

Subjects
Climate Change Impacts and Adaptation, Biological Sciences, Ecology, Microbiology, Environmental Sciences, Human Genome, Genetics, Air Microbiology, Animals, Archaea, Bacteria, Catalogs as Topic, Ecosystem, Humans, Metabolomics, Metagenome, Metagenomics, Phylogeny, Soil Microbiology, Viruses, Water Microbiology, IMG/M Data Consortium
Abstract

The reconstruction of bacterial and archaeal genomes from shotgun metagenomes has enabled insights into the ecology and evolution of environmental and host-associated microbiomes. Here we applied this approach to >10,000 metagenomes collected from diverse habitats covering all of Earth's continents and oceans, including metagenomes from human and animal hosts, engineered environments, and natural and agricultural soils, to capture extant microbial, metabolic and functional potential. This comprehensive catalog includes 52,515 metagenome-assembled genomes representing 12,556 novel candidate species-level operational taxonomic units spanning 135 phyla. The catalog expands the known phylogenetic diversity of bacteria and archaea by 44% and is broadly available for streamlined comparative analyses, interactive exploration, metabolic modeling and bulk download. We demonstrate the utility of this collection for understanding secondary-metabolite biosynthetic potential and for resolving thousands of new host linkages to uncultivated viruses. This resource underscores the value of genome-centric approaches for revealing genomic properties of uncultivated microorganisms that affect ecosystem processes.

Published
2021

11. Ligamentum Teres Transfer During Medial Open Reduction in Patients with Developmental Dysplasia of the Hip.

Author

Paez, Conner, Badrinath, Raghav, Holt, Joshua, Bomar, James D, Mubarak, Scott J, Upasani, Vidyadhar V, and Wenger, Dennis R

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Pain Research, Clinical Research, Chronic Pain, Digestive Diseases, Developmental Dysplasia of the Hip, Hip Dislocation, Congenital, Hip Joint, Humans, Infant, Retrospective Studies, Round Ligaments, Treatment Outcome, ddh, developmental dysplasia of the hip, ligamentum teres reconstruction, ligamentum teres transfer, medial open reduction
Abstract

BackgroundThe ligamentum teres (LT) is believed to have a number of functions, including a role in hip stability, nociception, proprioception, vascular supply to the femoral head, and synovial fluid circulation. The LT is often excised in the process of performing a medial open reduction (MOR) of the hip. We sought to conduct a retrospective review of hips undergoing a MOR for dislocated infantile developmental dysplasia of the hip (DDH) to compare clinical and radiographic outcomes for patients with and without LT reconstruction.MethodsWe performed a retrospective review of 38 hips treated with MOR with or without LT reconstruction with minimum two-year follow-up. Radiographic outcomes were determined using the Severin score. Information regarding avascular necrosis (AVN), concomitant surgical procedures, repeat dislocation, subsequent surgery, limp, pain, and range of motion symmetry was recorded.ResultsEighteen hips that underwent MOR with LT reconstruction were compared to 20 hips that underwent MOR without LT reconstruction. Mean follow up for this cohort was 70.1 months (median: 61.8; Range: 24.2 to 182.2 months). The group with LT reconstruction had an 11% rate of AVN, the group without LT reconstruction had a 15% rate of AVN (p=1.0) No hips in either group re-dislocated or had pain at final follow up. Two hips (5%) had a limp at most recent follow up, all were in the group that did not receive a LT reconstruction (p=0.488). Three hips (17%) in the LT reconstruction group and one hip (5%) in the other group had asymmetrical hip range of motion at final follow up (p=0.328).ConclusionThis study offers preliminary data to suggest that ligamentum teres reconstruction is a safe procedure that can minimize the risk for subluxation or re-dislocation that can occur within the post reduction hip spica cast. Although in this study, the patients who did not have LT reconstruction had a similar re-dislocation rate, we believe that ligamentum teres preservation is a useful adjunct to medial open reduction, especially in centers that may only treat occasional cases or have less experience in applying an excellent hip spica cast.Level of Evidence: III.

Published
2021

12. International Impact of COVID-19 on the Diagnosis of Heart Disease

Author

Einstein, Andrew J, Shaw, Leslee J, Hirschfeld, Cole, Williams, Michelle C, Villines, Todd C, Better, Nathan, Vitola, Joao V, Cerci, Rodrigo, Dorbala, Sharmila, Raggi, Paolo, Choi, Andrew D, Lu, Bin, Sinitsyn, Valentin, Sergienko, Vladimir, Kudo, Takashi, Nørgaard, Bjarne Linde, Maurovich-Horvat, Pál, Campisi, Roxana, Milan, Elisa, Louw, Lizette, Allam, Adel H, Bhatia, Mona, Malkovskiy, Eli, Goebel, Benjamin, Cohen, Yosef, Randazzo, Michael, Narula, Jagat, Pascual, Thomas NB, Pynda, Yaroslav, Dondi, Maurizio, Paez, Diana, Hinterleitner, Gerd, Lu, Yao, Morozova, Olga, Xu, Zhuoran, Lopez-Mattei, Juan, Parwani, Purvi, Nasery, Mohammad Nawaz, Goda, Artan, Shirka, Ervina, Benlabgaa, Rabie, Bouyoucef, Salah, Medjahedi, Abdelkader, Nailli, Qais, Agolti, Mariela, Aguero, Roberto Nicolas, del Carmen Alak, Maria, Alberguina, Lucia Graciela, Arroñada, Guillermo, Astesiano, Andrea, Astesiano, Alfredo, Norton, Carolina Bas, Benteo, Pablo, Blanco, Juan, Bonelli, Juan Manuel, Bustos, Jose Javier, Cabrejas, Raul, Cachero, Jorge, Canderoli, Alejandro, Carames, Silvia, Carrascosa, Patrícia, Castro, Ricardo, Cendoya, Oscar, Cognigni, Luciano Martin, Collaud, Carlos, Cortes, Claudia, Courtis, Javier, Cragnolino, Daniel, Daicz, Mariana, De La Vega, Alejandro, De Maria, Silvia Teresa, Del Riego, Horacio, Dettori, Fernando, Deviggiano, Alejandro, Dragonetti, Laura, Embon, Mario, Enriquez, Ruben Emilio, Ensinas, Jorge, Faccio, Fernando, Facello, Adolfo, Garofalo, Diego, Geronazzo, Ricardo, Gonza, Natalia, Gutierrez, Lucas, Guzzo, Miguel Angel, Hasbani, Victor, Huerin, Melina, Jäger, Victor, Lewkowicz, Julio Manuel, De Munaín, Maria Nieves A López, Lotti, Jose Maria, Marquez, Alejandra, Masoli, Osvaldo, Mastrovito, Edgardo, Mayoraz, Matias, Melado, Graciela Eva, Mele, Anibal, Merani, Maria Fernanda, Meretta, Alejandro Horacio, and Molteni, Susana

Subjects
Heart Disease, Biomedical Imaging, Clinical Research, Cardiovascular, Heart Disease - Coronary Heart Disease, Good Health and Well Being, COVID-19, Diagnostic Techniques, Cardiovascular, Global Health, Health Care Surveys, Heart Diseases, Humans, International Agencies, the, INCAPS COVID Investigators Group, cardiac testing, cardiovascular disease, coronavirus, global health, Cardiorespiratory Medicine and Haematology, Public Health and Health Services, Cardiovascular System & Hematology
Abstract

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has adversely affected diagnosis and treatment of noncommunicable diseases. Its effects on delivery of diagnostic care for cardiovascular disease, which remains the leading cause of death worldwide, have not been quantified.ObjectivesThe study sought to assess COVID-19's impact on global cardiovascular diagnostic procedural volumes and safety practices.MethodsThe International Atomic Energy Agency conducted a worldwide survey assessing alterations in cardiovascular procedure volumes and safety practices resulting from COVID-19. Noninvasive and invasive cardiac testing volumes were obtained from participating sites for March and April 2020 and compared with those from March 2019. Availability of personal protective equipment and pandemic-related testing practice changes were ascertained.ResultsSurveys were submitted from 909 inpatient and outpatient centers performing cardiac diagnostic procedures, in 108 countries. Procedure volumes decreased 42% from March 2019 to March 2020, and 64% from March 2019 to April 2020. Transthoracic echocardiography decreased by 59%, transesophageal echocardiography 76%, and stress tests 78%, which varied between stress modalities. Coronary angiography (invasive or computed tomography) decreased 55% (p

Published
2021

13. Patterns of Antiretroviral Therapy Use and Immunologic Profiles at Enrollment in the REPRIEVE Trial

Author

Fichtenbaum, Carl J, Ribaudo, Heather J, Leon-Cruz, Jorge, Overton, Edgar T, Zanni, Markella V, Malvestutto, Carlos D, Aberg, Judith A, Kileel, Emma M, Fitch, Kathleen V, Van Schalkwyk, Marije, Kumarasamy, Nagalingeswaran, Martinez, Esteban, Santos, Breno Riegel, Joseph, Yvetot, Lo, Janet, Siminski, Sue, Melbourne, Kathleen, Sponseller, Craig A, Desvigne-Nickens, Patrice, Bloomfield, Gerald S, Currier, Judith S, Hoffmann, Udo, Douglas, Pamela S, Grinspoon, Steven K, Curran, Adrian, Baranauskas, Adrienne, Wilkin, Aimee, Abrams-Downey, Alexandra J, Eckard, Allison Ross, Wurcel, Alysse G, González-Cordón, Ana, Paez, Armando, Sha, Beverly E, Santos, Breno, Yoshida, Carina Beppu, Rolle, Charlotte-Paige, Somboonwit, Charurut, Funk, Connie, Gómez-Ayerbe, Cristina, Frank, Cynthia, Nixon, Daniel E, Skiest, Daniel J, Choi, David, Mushatt, David M, Rial-Crestelo, David, Perez, Deborah K, Burke, Deirdre J, dos Santos, Desirée VG, Jayaweera, Dushyantha T, Gardner, Edward M, DeJesus, Edwin, Connick, Elizabeth, Lam, Emerline G, Hecker, Emily J, Kallas, Esper G, Waters, Evan, Rhame, Frank, Sattler, Fred R, Wang, Gary P, Enrile Seedhom, Helen May, Tavares, Isabel CF, Stapleton, Jack T, Bennet, Jaclyn, Brock, James B, Scott, James, Forcht, Janet, Lama, Javier R, Valencia, Javier, Brumfield, Jennifer K, Portilla, Joaquin, Kumar, Jonathan, Navarro, Jordi, Pinto, Jorge A, Castro, Jose G, Bernardino, Jose I, Casado, Jose L, Madruga, José Valdez, Baraiaetxaburu, Josu, Berenguer, Juan, Tashima, Karen T, Ho, Ken, Costa, Laura VL, Perez Latorre, Leire, Mohapi, Lerato, López-González, L, Fantry, Lori E, Domínguez-Domínguez, Lourdes, Martín-Carbonero, Luz, Cornelissen, Lynne M, Jain, Mamta K, Masiá, Mar, Lacerda, Marcus VG, Saumoy, Maria, Villalobos-Hernández, Marina, and Mall, Mark

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Sexually Transmitted Infections, HIV/AIDS, Clinical Trials and Supportive Activities, Clinical Research, Infectious Diseases, 6.1 Pharmaceuticals, Infection, Good Health and Well Being, Adult, Anti-Retroviral Agents, CD4 Lymphocyte Count, CD4-CD8 Ratio, Cross-Sectional Studies, Female, HIV Infections, Humans, Male, Middle Aged, Randomized Controlled Trials as Topic, HIV, statins, pitavastatin calcium, antiretroviral therapy, CD4 cell count, CD4/CD8 ratio, REPRIEVE, cardiovascular disease, REPRIEVE Investigators, Biological Sciences, Medical and Health Sciences, Microbiology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundPatterns of antiretroviral therapy (ART) use and immunologic correlates vary globally, and contemporary trends are not well described.MethodsThe REPRIEVE trial (Randomized Trial to Prevent Vascular Events in HIV) enrolled persons with human immunodeficiency virus (HIV) who were aged 40-75 years, receiving ART, and had low-to-moderate cardiovascular disease risk. ART use was summarized within Global Burden of Disease (GBD) super-regions, with adjusted linear and logistic regression analyses examining associations with immune parameters and key demographics.ResultsA total of 7770 participants were enrolled, with a median age of 50 years (interquartile range, 45-55 years); 31% were female, 43% were black or African American, 15% were Asian, 56% had a body mass index >25 (calculated as weight in kilograms divided by height in meters squared), and 49% were current or former smokers. The median CD4 T-cell count was 620/µL (interquartile range, 447-826/ µ L), and the median duration of prior ART use, 9.5 years (5.3-14.8) years. The most common ART regimens were nucleoside/nucleotide reverse-transcriptase inhibitor (NRTI) plus nonnucleoside reverse-transcriptase inhibitor (43%), NRTI plus integrase strand transfer inhibitor (25%), and NRTI plus protease inhibitor (19%). Entry ART varied by GBD region, with shifts during the trial enrollment period. In adjusted analyses, entry CD4 cell count and CD4/CD8 ratio were associated with GBD region, sex, entry regimen, duration of ART, and nadir CD4 cell count; CD4 and CD8 cell counts were also associated with body mass index and smoking status.ConclusionsThere were substantial variations in ART use by geographic region and over time, likely reflecting the local availability of specific medications, changes in treatment guidelines and provider/patient preferences. The analyses of CD4 cell counts and CD4/CD8 ratios may provide valuable insights regarding immune correlates and outcomes in people living with HIV.Clinical trials registrationNCT02344290.

Published
2020

14. Development and content validation of measures assessing adherence barriers and behaviors for use in clinical care

Author

Fredericksen, RJ, Yang, FM, Gibbons, LE, Edwards, TC, Brown, S, Fitzsimmons, E, Alperovitz-Bichell, K, Godfrey, M, Wang, A, Church, A, Gutierrez, C, Paez, E, Dant, L, Loo, S, Walcott, M, Mugavero, MJ, Mayer, KH, Mathews, WC, Patrick, DL, Crane, PK, and Crane, HM

Subjects
Health Services and Systems, Health Sciences, Clinical Trials and Supportive Activities, Prevention, Clinical Research, Behavioral and Social Science, 7.1 Individual care needs, Management of diseases and conditions, Good Health and Well Being, Adult, Chronic Disease, Female, HIV Infections, Humans, Male, Medication Adherence, Middle Aged, Self Report, Medication adherence, Patient-reported outcomes, Pharmacology and Pharmaceutical Sciences, Public Health and Health Services, Pharmacology & Pharmacy, Health services and systems, Public health
Abstract

BackgroundProviders are often unaware of poor adherence to prescribed medications for their patients with chronic diseases.ObjectiveTo develop brief, computer-administered patient-reported measures in English and Spanish assessing adherence behaviors and barriers. Design, Participants, and Main Measures: Item pools were constructed from existing measures of medication adherence behaviors and barriers, which informed development of a patient concept elicitation interview guide to identify medication adherence behavior and barrier-related concepts. Two hundred six patients either living with HIV (PLWH) or without were interviewed. Interviews were coded, concepts matched to item pool content, and new items were developed for novel concepts. A provider/investigator team highlighted clinically relevant items. Cognitive interviews were conducted with patients on final candidate items (n = 37). The instruments were administered to 2081 PLWH.Key resultsBehavioral themes from concept elicitation interviews included routines incorporating time of day, placement, visual cues, and intentionality to miss or skip doses. Barrier themes included health-related (e.g. depressed mood, feeling ill), attitudes/beliefs (e.g., need for medication), access (e.g., cost/insurance problems), and circumstantial barriers (e.g., lack of privacy, disruption of daily routine). The final instruments included 6 behavior items, and 1 barrier item with up to 23 response options. PLWH endorsed a mean (SD) of 3.5 (1.1) behaviors. The 201 PLWH who missed ≥2 doses in the previous week endorsed a mean (SD) of 3.1 (2.5) barriers. The intraclass correlation coefficient (ICC) for the numbers of behaviors endorsed in 61 PLWH after 4-16 days was 0.54 and for the number of barriers for the 20 PLWH with ≥2 missed doses the ICC was 0.89, representing fair and excellent test-retest reliability.ConclusionMeasures of medication adherence behaviors and barriers were developed for use with patients living with chronic diseases focusing on clinical relevance, brevity, and content validity for use in clinical care.

Published
2019

15. A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor

Author

Sin-Chan, Patrick, Mumal, Iqra, Suwal, Tannu, Ho, Ben, Fan, Xiaolian, Singh, Irtisha, Du, Yuchen, Lu, Mei, Patel, Neilket, Torchia, Jonathon, Popovski, Dean, Fouladi, Maryam, Guilhamon, Paul, Hansford, Jordan R, Leary, Sarah, Hoffman, Lindsey M, Levy, Jean M Mulcahy, Lassaletta, Alvaro, Solano-Paez, Palma, Rivas, Eloy, Reddy, Alyssa, Gillespie, G Yancey, Gupta, Nalin, Van Meter, Timothy E, Nakamura, Hideo, Wong, Tai-Tong, Ra, Young-Shin, Kim, Seung-Ki, Massimi, Luca, Grundy, Richard G, Fangusaro, Jason, Johnston, Donna, Chan, Jennifer, Lafay-Cousin, Lucie, Hwang, Eugene I, Wang, Yin, Catchpoole, Daniel, Michaud, Jean, Ellezam, Benjamin, Ramanujachar, Ramya, Lindsay, Holly, Taylor, Michael D, Hawkins, Cynthia E, Bouffet, Eric, Jabado, Nada, Singh, Sheila K, Kleinman, Claudia L, Barsyte-Lovejoy, Dalia, Li, Xiao-Nan, Dirks, Peter B, Lin, Charles Y, Mack, Stephen C, Rich, Jeremy N, and Huang, Annie

Subjects
Rare Diseases, Neurosciences, Cancer, Genetics, Biotechnology, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Biomarkers, Tumor, Brain Neoplasms, Cell Cycle, Cell Transformation, Neoplastic, Chromosomes, Human, Pair 19, Chromosomes, Human, Pair 2, DNA Copy Number Variations, Enhancer Elements, Genetic, Epigenesis, Genetic, Gene Expression Regulation, Gene Regulatory Networks, Genetic Association Studies, Genetic Predisposition to Disease, Humans, MicroRNAs, Models, Biological, Multigene Family, N-Myc Proto-Oncogene Protein, Neoplasms, Germ Cell and Embryonal, Oncogenes, RNA-Binding Proteins, C19MC, ETMR, LIN28A, MYCN, brain tumor, cell-cycle, epigenetics, microRNA, super-enhancer, therapeutics, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Embryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a C19MC-LIN28A-MYCN circuit fueled by multiple complex regulatory loops including an MYCN core transcriptional network and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. Our data show that this powerful oncogenic circuit, which entraps an early neural lineage network, is potently abrogated by bromodomain inhibitor JQ1, leading to ETMR cell death.

Published
2019

16. NMR metabolomics of cerebrospinal fluid differentiates inflammatory diseases of the central nervous system.

Author

French, Caitlin D, Willoughby, Rodney E, Pan, Amy, Wong, Susan J, Foley, John F, Wheat, L Joseph, Fernandez, Josefina, Encarnacion, Rafael, Ondrush, Joanne M, Fatteh, Naaz, Paez, Andres, David, Dan, Javaid, Waleed, Amzuta, Ioana G, Neilan, Anne M, Robbins, Gregory K, Brunner, Andrew M, Hu, William T, Mishchuk, Darya O, and Slupsky, Carolyn M

Subjects
Central Nervous System, Cerebrospinal Fluid, Humans, Central Nervous System Diseases, Magnetic Resonance Spectroscopy, Adolescent, Child, Child, Preschool, Female, Male, Metabolomics, Young Adult, Preschool, Biological Sciences, Medical And Health Sciences, Tropical Medicine, Medical and Health Sciences
Abstract

BACKGROUND:Myriad infectious and noninfectious causes of encephalomyelitis (EM) have similar clinical manifestations, presenting serious challenges to diagnosis and treatment. Metabolomics of cerebrospinal fluid (CSF) was explored as a method of differentiating among neurological diseases causing EM using a single CSF sample. METHODOLOGY/PRINCIPAL FINDINGS:1H NMR metabolomics was applied to CSF samples from 27 patients with a laboratory-confirmed disease, including Lyme disease or West Nile Virus meningoencephalitis, multiple sclerosis, rabies, or Histoplasma meningitis, and 25 controls. Cluster analyses distinguished samples by infection status and moderately by pathogen, with shared and differentiating metabolite patterns observed among diseases. CART analysis predicted infection status with 100% sensitivity and 93% specificity. CONCLUSIONS/SIGNIFICANCE:These preliminary results suggest the potential utility of CSF metabolomics as a rapid screening test to enhance diagnostic accuracies and improve patient outcomes.

Published
2018

17. Circumstances Surrounding High-risk Sexual Experiences Among Primary Care Patients Living With and Without HIV

Author

Fredericksen, Rob J, Walcott, M, Yang, FM, Gibbons, LE, Fitzsimmons, E, Brown, S, Mayer, KH, Edwards, TC, Loo, S, Gutierrez, C, Paez, E, Dant, L, Mathews, WC, Mugavero, MJ, Patrick, DL, Crane, PK, and Crane, HM

Subjects
Biomedical and Clinical Sciences, Health Services and Systems, Public Health, Clinical Sciences, Health Sciences, Paediatrics, Pediatric AIDS, Infectious Diseases, HIV/AIDS, Prevention, Pediatric, Clinical Research, Sexually Transmitted Infections, Behavioral and Social Science, 7.1 Individual care needs, Management of diseases and conditions, Infection, Good Health and Well Being, Adult, Female, HIV Infections, Humans, Male, Middle Aged, Primary Health Care, Risk Factors, Risk-Taking, Sexual Behavior, Substance-Related Disorders, General & Internal Medicine, Clinical sciences, Health services and systems, Public health
Abstract

IntroductionRates of sexually transmitted infection (STI) are rising in the USA, yet STI risk remains under-addressed by providers, even in HIV care, and with high-risk patients. We interviewed primary care patients living with and without HIV regarding circumstances surrounding sexual risk behavior to identify opportunities for providers to address and reduce STI risk.MethodsWe conducted semi-structured 1:1 interviews with patients living with and without HIV reporting ≥ 1 sex partner and varying STI exposure risk in the past 12 months from four geographically diverse US HIV and primary care clinics. We audio-recorded, transcribed, and coded interviews by circumstance type, using double-coding to ensure inter-coder reliability. We used Fisher's exact and T tests to determine associations with demographic/risk factors.ResultsPatients (n = 91) identified a mean of 3 of 11 circumstances. These included substance use (54%), desire for physical/emotional intimacy (48%), lack of HIV/STI status disclosure (44%), psychological drivers (i.e., coping, depression; 38%), personal dislike of condoms (22%), partner condom dislike/refusal (19%), receiving payment for sex (13%), and condom unavailability (9%). Higher proportions of those who were high STI-exposure risk patients, defined as those with ≥ 2 sex partners in the past 3 months reporting never or sometimes using condoms, reported disliking condoms (p = .006); higher proportions of the high-risk and moderate-risk (≥ 2 partners and condom use "most of the time") groups reported substance use as a circumstance (p = .04).ConclusionCircumstances surrounding perceived STI exposure risk were diverse, often overlapping, and dependent on internal, environmental, and partner-related factors and inadequate communication. Meaningful care-based interventions regarding HIV/STI transmission behavior must address the diversity and interplay of these factors.

Published
2018

18. Development and Content Validation of a Patient-Reported Sexual Risk Measure for Use in Primary Care

Author

Fredericksen, Rob J, Mayer, Kenneth H, Gibbons, Laura E, Edwards, Todd C, Yang, Frances M, Walcott, Melonie, Brown, Sharon, Dant, Lydia, Loo, Stephanie, Gutierrez, Cristina, Paez, Edgar, Fitzsimmons, Emma, Wu, Albert W, Mugavero, Michael J, Mathews, William C, Lober, William B, Kitahata, Mari M, Patrick, Donald L, Crane, Paul K, and Crane, Heidi M

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Health Sciences, Clinical Research, Infectious Diseases, Prevention, Pediatric AIDS, HIV/AIDS, Behavioral and Social Science, Sexually Transmitted Infections, Pediatric, Infection, Adult, Antiretroviral Therapy, Highly Active, Diagnosis, Computer-Assisted, Female, Gender Identity, HIV Infections, Humans, Interviews as Topic, Male, Middle Aged, Patient Reported Outcome Measures, Primary Health Care, Risk Assessment, Risk-Taking, Sexual Behavior, Sexual Partners, Terminology as Topic, United States, Unsafe Sex, sexual risk behavior measurement, patient-reported outcomes, General & Internal Medicine, Clinical sciences, Health services and systems, Public health
Abstract

BACKGROUND:Patient-provider sexual risk behavior discussions occur infrequently but may be facilitated by high-quality sexual risk screening tools. OBJECTIVE:To develop the Sexual Risk Behavior Inventory (SRBI), a brief computer-administered patient-reported measure. DESIGN:Qualitative item development/quantitative instrument validation. PARTICIPANTS:We developed SRBI items based on patient interviews (n = 128) at four geographically diverse US primary care clinics. Patients were diverse in gender identity, sex, sexual orientation, age, race/ethnicity, and HIV status. We compared sexual risk behavior identified by the SRBI and the Risk Assessment Battery (RAB) among patients (n = 422). APPROACH:We constructed an item pool based on validated measures of sexual risk, developed an in-depth interview guide based on pool content, and used interviews to elicit new sexual risk concepts. We coded concepts, matched them to item pool content, and developed new content where needed. A provider team evaluated item clinical relevance. We conducted cognitive interviews to assess item comprehensibility. We administered the SRBI and the RAB to patients. KEY RESULTS:Common, clinically relevant concepts in the SRBI included number of sex partners; partner HIV status; partner use of antiretroviral medication (ART)/pre-exposure prophylaxis (PrEP); and recent sex without barrier protection, direction of anal sex, and concern regarding HIV/STI exposure. While 90% reported inconsistent condom use on the RAB, same-day SRBI administration revealed that for over one third, all their partners were on ART/PrEP. CONCLUSION:The SRBI is a brief, skip-patterned, clinically relevant measure that ascertains sexual risk behavior across sex, sexual orientation, gender identity, partner HIV serostatus, and partner treatment status, furnishing providers with context to determine gradations of risk for HIV/STI.

Published
2018

19. Murine colitis reveals a disease-associated bacteriophage community

Author

Duerkop, Breck A, Kleiner, Manuel, Paez-Espino, David, Zhu, Wenhan, Bushnell, Brian, Hassell, Brian, Winter, Sebastian E, Kyrpides, Nikos C, and Hooper, Lora V

Subjects
Microbiology, Biological Sciences, Digestive Diseases, Inflammatory Bowel Disease, Crohn's Disease, Autoimmune Disease, 2.1 Biological and endogenous factors, Aetiology, Oral and gastrointestinal, Animals, Bacteriophages, Cells, Cultured, Colitis, Disease Models, Animal, Dysbiosis, Gastrointestinal Microbiome, Genome, Viral, Humans, Intestinal Mucosa, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Medical Microbiology
Abstract

The dysregulation of intestinal microbial communities is associated with inflammatory bowel diseases (IBD). Studies aimed at understanding the contribution of the microbiota to inflammatory diseases have primarily focused on bacteria, yet the intestine harbours a viral component dominated by prokaryotic viruses known as bacteriophages (phages). Phage numbers are elevated at the intestinal mucosal surface and phages increase in abundance during IBD, suggesting that phages play an unidentified role in IBD. We used a sequence-independent approach for the selection of viral contigs and then applied quantitative metagenomics to study intestinal phages in a mouse model of colitis. We discovered that during colitis the intestinal phage population is altered and transitions from an ordered state to a stochastic dysbiosis. We identified phages specific to pathobiotic hosts associated with intestinal disease, whose abundances are altered during colitis. Additionally, phage populations in healthy and diseased mice overlapped with phages from healthy humans and humans with IBD. Our findings indicate that intestinal phage communities are altered during inflammatory disease, establishing a platform for investigating phage involvement in IBD.

Published
2018

20. Investigation of recombination-intense viral groups and their genes in the Earth's virome.

Author

Meier-Kolthoff, Jan P, Uchiyama, Jumpei, Yahara, Hiroko, Paez-Espino, David, and Yahara, Koji

Subjects
Mouth, Humans, Bacteria, Viruses, Bacteriophages, DNA, Viral, Ecosystem, Biodiversity, Recombination, Genetic, Genome, Viral, Earth (Planet), Metagenome, Metagenomics, Host Specificity, Earth, Planet, Biotechnology, Genetics, Infection, DNA, Viral, Recombination, Genetic, Genome, Earth, Biochemistry and Cell Biology, Other Physical Sciences
Abstract

Bacteriophages (phages), or bacterial viruses, are the most abundant and diverse biological entities that impact the global ecosystem. Recent advances in metagenomics have revealed their rampant abundance in the biosphere. A fundamental aspect of bacteriophages that remains unexplored in metagenomic data is the process of recombination as a driving force in evolution that occurs among different viruses within the same bacterial host. Here, we systematically examined signatures of recombination in every gene from 211 species-level viral groups in a recently obtained dataset of the Earth's virome that contain corresponding information on the host bacterial species. Our study revealed that signatures of recombination are widespread (84%) among the diverse viral groups. We identified 25 recombination-intense viral groups, widely distributed across the viral taxonomy, and present in bacterial species living in the human oral cavity. We also revealed a significant inverse association between the recombination-intense viral groups and Type II restriction endonucleases, that could be effective in reducing recombination among phages in a cell. Furthermore, we identified recombination-intense genes that are significantly enriched for encoding phage morphogenesis proteins. Changes in the viral genomic sequence by recombination may be important to escape cleavage by the host bacterial immune systems.

Published
2018

21. Medication understanding among patients living with multiple chronic conditions: Implications for patient-reported measures of adherence

Author

Fredericksen, RJ, Gibbons, L, Brown, S, Edwards, TC, Yang, FM, Fitzsimmons, E, Alperovitz-Bichell, K, Godfrey, M, Wang, A, Church, A, Gutierrez, C, Paez, E, Dant, L, Loo, S, Walcott, M, Mugavero, MJ, Mayer, K, Mathews, WC, Patrick, DL, Crane, PK, and Crane, HM

Subjects
Health Services and Systems, Nursing, Health Sciences, Patient Safety, Clinical Research, Management of diseases and conditions, 7.1 Individual care needs, Adult, Aged, Female, HIV Infections, Health Literacy, Humans, Male, Medication Adherence, Middle Aged, Multiple Chronic Conditions, Primary Health Care, United States, Medication literacy, Health literacy, Medication adherence, Patient-reported outcomes, Multiple chronic conditions, Pharmacology and Pharmaceutical Sciences, Public Health and Health Services, Pharmacology & Pharmacy, Health services and systems, Public health
Abstract

BackgroundLow health literacy is associated with poor medication adherence and poor health outcomes. Limited understanding of prescribed medications may decrease validity of patient-reported adherence measures.ObjectivesTo assess knowledge of names and purposes of prescribed medications among patients with multiple chronic conditions.MethodsIndividual interviews were conducted with a convenience sample of patients from six U.S. primary care clinics. Participants (n = 57) were English and/or Spanish-speaking patients prescribed 3+ medications for chronic conditions, for which non-adherence may lead to disability or death. In individual interviews, patients were asked to name their medications, explain the purpose of each, and to explain how they distinguish them from one another. Interviews were audio recorded, transcribed, and coded; coded content was quantified by 1) whether or not the patient could name medications; 2) method of categorizing medications; 3) whether or not the purpose of the medication was understood. Descriptive statistics were compiled using Fisher's exact test to determine the relationship between patient knowledge and medication characteristics.ResultsThirty percent of patients could not name at least one of their medications; 19% did not know their purpose; 30% held misconceptions about the purpose of one or more medications. There was no significant difference in ability to name medications or state their medication's purpose between patients using medi-sets, pre-packaged rolls, or blister packs, and patients who stored pills in their original containers (p = 0.56 and p = 0.73, respectively), or across demographic groups (p = 0.085 to 0.767).ConclusionsMany patients demonstrated difficulty identifying the name and purpose of prescribed medications; this did not differ by demographic group or medication storage type. Patients may benefit from routine review of medications with their provider in order to improve health literacy, outcomes, and patient-reported adherence measurement.

Published
2018

22. Cultivation and sequencing of rumen microbiome members from the Hungate1000 Collection

Author

Seshadri, Rekha, Leahy, Sinead C, Attwood, Graeme T, Teh, Koon Hoong, Lambie, Suzanne C, Cookson, Adrian L, Eloe-Fadrosh, Emiley A, Pavlopoulos, Georgios A, Hadjithomas, Michalis, Varghese, Neha J, Paez-Espino, David, Perry, Rechelle, Henderson, Gemma, Creevey, Christopher J, Terrapon, Nicolas, Lapebie, Pascal, Drula, Elodie, Lombard, Vincent, Rubin, Edward, Kyrpides, Nikos C, Henrissat, Bernard, Woyke, Tanja, Ivanova, Natalia N, and Kelly, William J

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Human Genome, Cancer, Microbiome, Cancer Genomics, Genetics, Animals, Archaea, Bacteria, Biofuels, Gastrointestinal Microbiome, Humans, Lignin, Microbiota, Rumen, Hungate1000 project collaborators
Abstract

Productivity of ruminant livestock depends on the rumen microbiota, which ferment indigestible plant polysaccharides into nutrients used for growth. Understanding the functions carried out by the rumen microbiota is important for reducing greenhouse gas production by ruminants and for developing biofuels from lignocellulose. We present 410 cultured bacteria and archaea, together with their reference genomes, representing every cultivated rumen-associated archaeal and bacterial family. We evaluate polysaccharide degradation, short-chain fatty acid production and methanogenesis pathways, and assign specific taxa to functions. A total of 336 organisms were present in available rumen metagenomic data sets, and 134 were present in human gut microbiome data sets. Comparison with the human microbiome revealed rumen-specific enrichment for genes encoding de novo synthesis of vitamin B12, ongoing evolution by gene loss and potential vertical inheritance of the rumen microbiome based on underrepresentation of markers of environmental stress. We estimate that our Hungate genome resource represents ∼75% of the genus-level bacterial and archaeal taxa present in the rumen.

Published
2018

23. Validity assessment of the PROMIS fatigue domain among people living with HIV

Author

Gibbons, LE, Fredericksen, R, Batey, DS, Dant, L, Edwards, TC, Mayer, KH, Mathews, WC, Morales, LS, Mugavero, MJ, Yang, FM, Paez, E, Kitahata, MM, Patrick, DL, Crane, HM, Crane, PK, and for the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS)

Subjects
Prevention, HIV/AIDS, Infectious Diseases, Clinical Research, Good Health and Well Being, Adult, Aged, Aged, 80 and over, Cross-Sectional Studies, Diagnostic Tests, Routine, Fatigue, Female, HIV Infections, Humans, Longitudinal Studies, Male, Middle Aged, Psychometrics, Young Adult, Bioengineering, HIV, PROMIS, Validity, Measurement, Patient burden, Centers for AIDS Research Network of Integrated Clinical Systems, Immunology, Virology
Abstract

PurposeTo evaluate psychometric characteristics and cross-sectional and longitudinal validity of the 7-item PROMIS® Fatigue Short Form and additional fatigue items among people living with HIV (PLWH) in a nationally distributed network of clinics collecting patient reported data at the time of routine clinical care.MethodsCross-sectional and longitudinal fatigue data were collected from September 2012 through April 2013 across clinics participating in the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS). We analyzed data regarding psychometric characteristics including simulated computerized adaptive testing and differential item functioning, and regarding associations with clinical characteristics.ResultsWe analyzed data from 1597 PLWH. Fatigue was common in this cohort. Scores from the PROMIS® Fatigue Short Form and from the item bank had acceptable psychometric characteristics and strong evidence for validity, but neither performed better than shorter instruments already integrated in CNICS.ConclusionsThe PROMIS® Fatigue Item Bank is a valid approach to measuring fatigue in clinical care settings among PLWH, but in our analyses did not perform better than instruments associated with less respondent burden.

Published
2017

24. A thermostable Cas9 with increased lifetime in human plasma.

Author

Harrington, Lucas B, Paez-Espino, David, Staahl, Brett T, Chen, Janice S, Ma, Enbo, Kyrpides, Nikos C, and Doudna, Jennifer A

Subjects
Humans, Endonucleases, Bacterial Proteins, Ribonucleoproteins, Protein Engineering, Enzyme Stability, Models, Molecular, Hot Temperature, Geobacillus stearothermophilus, CRISPR-Cas Systems, Gene Editing, CRISPR-Associated Protein 9, Emerging Infectious Diseases
Abstract

CRISPR-Cas9 is a powerful technology that has enabled genome editing in a wide range of species. However, the currently developed Cas9 homologs all originate from mesophilic bacteria, making them susceptible to degradation and unsuitable for applications requiring cleavage at elevated temperatures. Here, we show that the Cas9 protein from the thermophilic bacterium Geobacillus stearothermophilus (GeoCas9) catalyzes RNA-guided DNA cleavage at elevated temperatures. GeoCas9 is active at temperatures up to 70 °C, compared to 45 °C for Streptococcus pyogenes Cas9 (SpyCas9), which expands the temperature range for CRISPR-Cas9 applications. We also found that GeoCas9 is an effective tool for editing mammalian genomes when delivered as a ribonucleoprotein (RNP) complex. Together with an increased lifetime in human plasma, the thermostable GeoCas9 provides the foundation for improved RNP delivery in vivo and expands the temperature range of CRISPR-Cas9.

Published
2017

25. Uncovering Earth's virome.

Author

Paez-Espino, David, Eloe-Fadrosh, Emiley A, Pavlopoulos, Georgios A, Thomas, Alex D, Huntemann, Marcel, Mikhailova, Natalia, Rubin, Edward, Ivanova, Natalia N, and Kyrpides, Nikos C

Subjects
Animals, Humans, Viruses, Bacteriophages, DNA, Viral, RNA, Transfer, Sequence Analysis, Ecosystem, Biodiversity, Phylogeny, Genes, Viral, Genome, Viral, Earth (Planet), Host-Pathogen Interactions, Metagenome, Metagenomics, Host Specificity, Phylogeography, Aquatic Organisms, Clustered Regularly Interspaced Short Palindromic Repeats, Datasets as Topic, Earth, Planet, DNA, Viral, RNA, Transfer, Genes, Genome, Earth, Planet, Genetics, Biodefense, Vaccine Related, Prevention, Infectious Diseases, Emerging Infectious Diseases, 2.2 Factors relating to physical environment, Infection, General Science & Technology
Abstract

Viruses are the most abundant biological entities on Earth, but challenges in detecting, isolating, and classifying unknown viruses have prevented exhaustive surveys of the global virome. Here we analysed over 5 Tb of metagenomic sequence data from 3,042 geographically diverse samples to assess the global distribution, phylogenetic diversity, and host specificity of viruses. We discovered over 125,000 partial DNA viral genomes, including the largest phage yet identified, and increased the number of known viral genes by 16-fold. Half of the predicted partial viral genomes were clustered into genetically distinct groups, most of which included genes unrelated to those in known viruses. Using CRISPR spacers and transfer RNA matches to link viral groups to microbial host(s), we doubled the number of microbial phyla known to be infected by viruses, and identified viruses that can infect organisms from different phyla. Analysis of viral distribution across diverse ecosystems revealed strong habitat-type specificity for the vast majority of viruses, but also identified some cosmopolitan groups. Our results highlight an extensive global viral diversity and provide detailed insight into viral habitat distribution and host–virus interactions.

Published
2016

26. STAT3-mediated astrogliosis protects myelin development in neonatal brain injury.

Author

Nobuta, Hiroko, Ghiani, Cristina A, Paez, Pablo M, Spreuer, Vilma, Dong, Hongmei, Korsak, Rose A, Manukyan, Armine, Li, Jiaxi, Vinters, Harry V, Huang, Eric J, Rowitch, David H, Sofroniew, Michael V, Campagnoni, Anthony T, de Vellis, Jean, and Waschek, James A

Subjects
Astrocytes, Myelin Sheath, Cells, Cultured, Stem Cells, Animals, Mice, Inbred C57BL, Animals, Newborn, Mice, Knockout, Humans, Mice, Brain Injuries, Disease Models, Animal, Postmortem Changes, Gliosis, Benzamides, Dioxoles, Glial Fibrillary Acidic Protein, Lipopolysaccharides, Receptors, Transforming Growth Factor beta, Culture Media, Conditioned, Enzyme-Linked Immunosorbent Assay, Age Factors, Signal Transduction, Cell Differentiation, Cell Proliferation, Gene Expression Regulation, Developmental, Infant, Infant, Newborn, Female, Male, STAT3 Transcription Factor, Smad2 Protein, Transforming Growth Factor beta1, Infant Mortality, Preterm, Low Birth Weight and Health of the Newborn, Pediatric, Perinatal Period - Conditions Originating in Perinatal Period, Physical Injury - Accidents and Adverse Effects, Neurosciences, Neurodegenerative, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Neurological, Clinical Sciences, Neurology & Neurosurgery
Abstract

ObjectivePathological findings in neonatal brain injury associated with preterm birth include focal and/or diffuse white matter injury (WMI). Despite the heterogeneous nature of this condition, reactive astrogliosis and microgliosis are frequently observed. Thus, molecular mechanisms by which glia activation contribute to WMI were investigated.MethodsPostmortem brains of neonatal brain injury were investigated to identify molecular features of reactive astrocytes. The contribution of astrogliosis to WMI was further tested in a mouse model in genetically engineered mice.ResultsActivated STAT3 signaling in reactive astrocytes was found to be a common feature in postmortem brains of neonatal brain injury. In a mouse model of neonatal WMI, conditional deletion of STAT3 in astrocytes resulted in exacerbated WMI, which was associated with delayed maturation of oligodendrocytes. Mechanistically, the delay occurred in association with overexpression of transforming growth factor (TGF)β-1 in microglia, which in healthy controls decreased with myelin maturation in an age-dependent manner. TGFβ-1 directly and dose-dependently inhibited the maturation of purified oligodendrocyte progenitors, and pharmacological inhibition of TGFβ-1 signaling in vivo reversed the delay in myelin development. Factors secreted from STAT3-deficient astrocytes promoted elevated TGFβ-1 production in cultured microglia compared to wild-type astrocytes.InterpretationThese results suggest that myelin development is regulated by a mechanism involving crosstalk between microglia and oligodendrocyte progenitors. Reactive astrocytes may modify this signaling in a STAT3-dependent manner, preventing the pathological expression of TGFβ-1 in microglia and the impairment of oligodendrocyte maturation.

Published
2012

27. Role of mesenchymal stromal cells derivatives in diabetic foot ulcers: a controlled randomized phase 1/2 clinical trial

Author

Martha L. Arango-Rodríguez, Víctor Alfonso Solarte-David, Silvia M. Becerra-Bayona, Eduardo Callegari, Maria D. Paez, Claudia L. Sossa, Miguel Enrique Ochoa Vera, Ligia C. Mateus, Sergio Eduardo serrano, Andrea K. Ardila-Roa, and Lady T. Giratá Viviescas

Subjects
Proteomics, Wound Healing, Cancer Research, Transplantation, Immunology, Bone Marrow Cells, Mesenchymal Stem Cells, Cell Biology, Diabetic Foot, Oncology, Diabetes Mellitus, Humans, Immunology and Allergy, Genetics (clinical)
Abstract

Diabetes-related foot complications have been identified as the most common isolated cause of morbidity among patients with diabetes and the leading cause of amputation. Therefore, new strategies to stimulate skin regeneration may provide a novel therapeutic approach to reduce non-healing ulcer disease. Recently, we demonstrated in proof-of-concept in humans that administration of allogeneic bone marrow mesenchymal stromal cellss derivatives (allo-hBM-MSCDs) is effective in a similar way to the use of allogeneic bone marrow mesenchymal stromal cellss (allo-hBM-MSCs) in grade 2 diabetic foot ulcers (DFUs).To assess the safety and efficacy profile of the allo-hBM-MSCDs relative to the conventional approach (PolyMen® dressing) in 1/2 clinical trial phases in patients with grade 1 and 2 DFUs.In the present study, we used 2 doses of allo-hBM-MSCDs (1 mL) or 1 dose of allo-hBM-MSCs (1 × 106 cells) intradermally injected around wounds and assessed their safety and effectiveness, relative to the conventional approach (PolyMem dressing). Allo-hBM-MSCDs and allo-hBM-MSCs were produced in a certified Good Manufacturing Practice-type Laboratory. Patients with grade 1 and 2 DFUs were randomized to receive allo-hBM-MSCDs (n=12), allo-hBM-MSCs (n=6) or conventional treatment (PolyMem dressing) (n=10). The wound-healing process was macroscopically evaluated until the complete closure of the ulcers.No adverse events were reported. Patients with grade 1 and 2 DFUs treated with either allo-hBM-MSCDs or allo-hBM-MSCs, achieved greater percentages of wound closure, enhanced skin regeneration in shorter times and a greater ulcer-free survival relative to the patients who received conventional treatment. Finally, through proteomic analysis, we elucidated the proteins and growth factors that are secreted by allo-hBM-MSCs and relevant to the wound-healing process. In addition, by combining proteomics with Gene Ontology analysis, we comprehensively classified secreted proteins on both biological process and molecular function.In this phase 1/2 trial, our cumulative results suggest that 2 doses of allo-hBM-MSCDs combined with a wound dressing are a safe and effective treatment for grade 1 and 2 DFUs.

Published
2022
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28. The NALCN channel regulates metastasis and nonmalignant cell dissemination

Author

Rahrmann, Eric P, Shorthouse, David, Jassim, Amir, Hu, Linda P, Ortiz, Mariaestela, Mahler-Araujo, Betania, Vogel, Peter, Paez-Ribes, Marta, Fatemi, Atefeh, Hannon, Gregory J, Iyer, Radhika, Blundon, Jay A, Lourenço, Filipe C, Kay, Jonathan, Nazarian, Rosalynn M, Hall, Benjamin A, Zakharenko, Stanislav S, Winton, Douglas J, Zhu, Liqin, Gilbertson, Richard J, Shorthouse, David [0000-0002-3207-3584], Vogel, Peter [0000-0002-7535-0545], Hannon, Gregory J [0000-0003-4021-3898], Lourenço, Filipe C [0000-0002-9655-2488], Kay, Jonathan [0000-0002-8970-4260], Hall, Benjamin A [0000-0003-0355-2946], Zakharenko, Stanislav S [0000-0001-8115-202X], Winton, Douglas J [0000-0001-6067-7927], Zhu, Liqin [0000-0002-2346-150X], Gilbertson, Richard J [0000-0001-7539-9472], and Apollo - University of Cambridge Repository

Subjects
Mice, Neoplasms, Genetics, Humans, Animals, Membrane Proteins, Ion Channels
Abstract

Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289, Funder: American Lebanese Syrian Associated Charities (ALSAC); doi: https://doi.org/10.13039/100012524, Funder: U.S. Department of Health & Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute (National Cancer Institute Division of Cancer Epidemiology and Genetics); doi: https://doi.org/10.13039/100011541, Funder: U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI); doi: https://doi.org/10.13039/100000054, Funder: RCUK | MRC | Medical Research Foundation; doi: https://doi.org/10.13039/501100009187, We identify the sodium leak channel non-selective protein (NALCN) as a key regulator of cancer metastasis and nonmalignant cell dissemination. Among 10,022 human cancers, NALCN loss-of-function mutations were enriched in gastric and colorectal cancers. Deletion of Nalcn from gastric, intestinal or pancreatic adenocarcinomas in mice did not alter tumor incidence, but markedly increased the number of circulating tumor cells (CTCs) and metastases. Treatment of these mice with gadolinium-a NALCN channel blocker-similarly increased CTCs and metastases. Deletion of Nalcn from mice that lacked oncogenic mutations and never developed cancer caused shedding of epithelial cells into the blood at levels equivalent to those seen in tumor-bearing animals. These cells trafficked to distant organs to form normal structures including lung epithelium, and kidney glomeruli and tubules. Thus, NALCN regulates cell shedding from solid tissues independent of cancer, divorcing this process from tumorigenesis and unmasking a potential new target for antimetastatic therapies.

Published
2022
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29. Sentinel Lymph Node Methods in Breast Cancer

Author

Francesco Giammarile, Sergi Vidal-Sicart, Diana Paez, Olivier Pellet, Estrada-Lobato Enrique, Miriam Mikhail-Lette, Olga Morozova, Navarro Marulanda Maria Camila, Rodríguez Sanchez Diana Ivonne, Roberto C. Delgado Bolton, Renato A. Valdés Olmos, and Giuliano Mariani

Subjects
Sentinel Lymph Node Biopsy, Axilla, Humans, Breast Neoplasms, Female, Radiology, Nuclear Medicine and imaging, Sentinel Lymph Node, Neoplasm Staging
Abstract

Breast cancer is the most frequent cancer diagnosed in women worldwide. Accurate lymph node staging is essential for both prognosis (of early-stage disease) and treatment (for regional control of disease) in patients with breast cancer. The sentinel lymph nodes are the regional nodes that directly drain lymph from the primary tumor. No imaging modality is accurate enough to detect lymph node metastases when a primary breast cancer is at an early stage (I or II), but sentinel lymph node biopsy is a highly reliable method for screening axillary nodes and for identifying metastatic (including micro-metastatic) disease in regional lymph nodes. Despite the widespread use of sentinel lymph node biopsy for early-stage breast cancer, relevant variations have been described regarding practical aspects of the procedure, and some variability has initially been reported regarding the rates of intraoperative sentinel lymph node identification and of false-negative findings, most likely because of differences in the size of the populations being investigated and in lymphatic mapping techniques. Nevertheless, using adequate learning curves and once a multidisciplinary team is experienced with the procedure, improved levels of accuracy are achieved.

Published
2022
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30. Reactogenicity of the Messenger <scp>RNA SARS</scp> – <scp>CoV</scp> ‐2 Vaccines Associated With Immunogenicity in Patients With Autoimmune and Inflammatory Disease

Author

Monica M. Yang, Kimberly E. Taylor, Diana Paez, Alex Carividi, Emanuel Demissie, Niti Pawar, Alia A. El‐Qunni, Lily E. McMorrow, Rebecca E. Schriefer, Katherine Huang, Baylee Kinnett, Michael Klebert, Alem Haile, Jane A. O'Halloran, Rachel M. Presti, Wooseob Kim, Ali H. Ellebedy, Matthew A. Ciorba, Michael A. Paley, Parakkal Deepak, Alfred H. J. Kim, Patricia Katz, Mehrdad Matloubian, Mary Nakamura, and Lianne S. Gensler

Subjects
COVID-19 Vaccines, Rheumatology, SARS-CoV-2, Humans, COVID-19, RNA, Messenger, Myalgia, Antibodies, Viral, Fatigue
Abstract

Little is known regarding the reactogenicity and related SARS-CoV-2 vaccine response in patients with chronic inflammatory disease (CID). Our objective was to characterize the adverse event profile of CID patients following SARS-CoV-2 vaccination and understand the relationship between reactogenicity and immunogenicity of SARS-CoV-2 vaccines.CID patients and healthy controls eligible to receive messenger RNA (mRNA) SARS-CoV-2 vaccines participated in 3 study visits (pre-vaccine, after dose 1, and after dose 2) in which blood and clinical data were collected. Assessment of adverse events were solicited within 7 days of receiving each dose. Serum anti-SARS-CoV-2 spike IgG ± antibody titers were quantified following vaccination. Statistical analysis was performed utilizing mixed models and tobit regressions, with adjustment for covariates.The present study included 441 participants (322 CID patients and 119 control subjects). Compared to controls, CID patients reported greater symptom severity after dose 1 (P = 0.0001), including more myalgia and fatigue (P 0.05). For immunogenicity, a higher symptom severity after dose 1 and a higher number of symptoms after dose 2 was associated with higher antibody titers (P ≤ 0.05). Each increase of 1 symptom was associated with a 15.1% increase in antibody titer. Symptom association was strongest with site pain after dose 1 (105%; P = 0.03) and fatigue after dose 2 (113%; P = 0.004).Patients with CID have a distinct reactogenicity profile following SARS-CoV-2 vaccination compared to controls. Furthermore, there is an association between increased reactogenicity and increased vaccine response. This finding may speak to the more variable immunogenicity in CID patients and may be an important indicator of vaccine response to the novel SARS-CoV-2 vaccines.

Published
2022
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31. Rehabilitation versus surgical reconstruction for non-acute anterior cruciate ligament injury (ACL SNNAP): a pragmatic randomised controlled trial

Author

David J Beard, Loretta Davies, Jonathan A Cook, Jamie Stokes, Jose Leal, Heidi Fletcher, Simon Abram, Katie Chegwin, Akiko Greshon, William Jackson, Nicholas Bottomley, Matt Dodd, Henry Bourke, Beverly A Shirkey, Arsenio Paez, Sarah E Lamb, Karen Barker, Michael Phillips, Mark Brown, Vanessa Lythe, Burhan Mirza, Andrew Carr, Paul Monk, Carlos Morgado Areia, Sean O'Leary, Fares Haddad, Chris Wilson, Andrew Price, Richard Emsley, George Peat, Martyn Snow, Marion Campbell, Tessa Howell, Hilary Johnson, Stephen McDonnell, Thomas Pinkney, Mark Williams, Helen Campbell, Jackie Davies, Jiyang Li, Christina Bagg, Laura Haywood, Anne Nicholson, Joanne Riches, Sean Symons, Mark Vertue, Louay Al Mouazzen, Rachel Bray, Damian Clark, James Coulthard, Tim Holland, Nick Howells, Andrew Jones, Richard Kapur, Alastair Kiszely, Harry Krishnan, Karen MacDonald-Taylor, Jon Manara, James Murray, Corina Negrut, Vishai Pai, Andrew Porteous, Sven Putnis, James Robinson, Shav Rupasinghe, Veenesh Selvaratnam, James Smith, Nick Smith, Jarrad Stevens, Clare Taylor, Anthony Theodorides, Niraj Vetharajan, Helen Vint, Lucy Young, Susan Bullock, Rebecca Cook, Alexander Dodds, Amanda Freeman-Hicks, Paula Hillout, Thomas Cornell, Abbie Coutts, Suzy Dean, Nicki Devooght-Johnson, Emma Ferrell, Eve Fletcher, Chrissie Hall, Benjamin Kent, Sandra Kessly, Robin Kincaid, Mohamed Lazizi, Ahmed Mostafa, Toby Nisbett, Tim Powell, Peter Riddlestone, Andrew Roberton, Jessica Summers, Lucy Whitbread, Belinda Wroath, Emma Fenlon, Andrew Hall, Helen Jeffrey, Raghuram Thonse, Debra Dunne, Andy Metcalfe, Kerri McGowan, Simon Middleton, Feisal Shah, Tim Spalding, Charlie Marie Suddens, Tamar Sweed, Joanna Teuke, Peter Thompson, David Wright, Justine Amero, Emma Brown, Hugh Chissell, Andrea Croucher, Gareth Dickinson, Catherine Hawkes-Blackburn, Alice Peacocke, Graham Smith, Carol Snipe, Kim Dearnley, Reza Mayahi, Barry Andrews, Massimo Barcelona, Hazel Giles, Abdulkerim Gokturk, Paul Harnett, Katie Jeeves, Joyce Kadunyi, Sheena Mendoza, Ines Reichert, Marta Santamaria, Harshinder Virdee, Sanjeev Anand, Nayef Aslam-Pervez, Stephen Draycott, Faye Howarth, Irfan Jina, Niall Maher, Denise Ross, Lindsey Worstenholme, Abdul Baig, Arun Bhaskaran, Daniel Banks, Tracy Brear, Carla Christie, Laura Cowen, Jack Davis, Ross Dixey, Colin Esler, Amirah Essop-Adam, Christina Haines, Linzy Houchen-Wolloff, Husein Varachia, Richard Wood, Glaxy Gray, Jessica Nichols, Alice Panes, Susan Partridge, Lawrie Rogerson, Pankaj Sharma, David Triggs, Ian Venables, Danielle Wilcock, Sarah Buckley, Thelma Darian, Elizabeth Denis, Jo Duncan, Charlotte Hirst, James Newman, Fern Richardson, Jon Smith, Megan Adcode, Megan Cottingham, Eliza Foster, Andrew Kelly, Niamh McKay, Jane Rewbury, Alison Whitcher, James Williams, Esther Zebracki, Llinos Davies, Jayadeep Jayachandran, Alison Tardivel, Victoria Whitehead, Martha Batting, Amy Bond, Marc Deakin, Christopher Dodd, Alison Hudak, Samantha Hynes, Luke Jones, Gail Lang, David McKenna, Susan Morris, Clare Scott-Dempster, Adam Sykes, Iason Vichos, Simon Wood, Rupert Clifton, Stephanie Diaz, Craig Hendy, Nishil Modi, Brendan O'Mahony, Susan O'Sullivan, Nicola Parker, Mira Pecheva, Rowan Rumonovic, Emma McLoughlin, Jeremy Rushbrook, Anna Thornhill, Valerie Parkinson, Rafael Sales, Katja Van De Snepscheut-Jones, David Wilcock, Daniel Wright, Joanna Allison, Simon Baker, Kate Beesley, Gill Ferrari, Benedict Lankester, Alison Lewis, Joanne Lyons, Jamie O'Callaghan, Sarah Sutcliffe, Dianne Wood, Emily Bannister, Chloe Brown, Debbie Burden, Terence Campbell, Emma Craig, Rashmi Easow, Julie Foxton, Alexandra Hazlerigg, Chethan Jayabev, Rosie Murdoch, Georgie Parsons, Harry Brown, Paula Carvelli, Rugaia Montaser, Ali Pepper, Sinduja Sivarajan, Oliver Templeton-Ward, Eva Wilson, Julie Cronin, Sarah Diment, Victoria King, Katharine Shean, Leonidas Vachtsevanos, Katharine Wilcocks, Ben Wilson, Paul McNestry, Joanna Ollerenshaw, James Stoddard, Paul Sutton, Sanjay Anand, Judith Bell, Albert Chikate, Diane Daniel, Timothy Davies, Tom Finnigan, Antonio Frasquet-Garcia, Susan Hopkins, Sharon Kerrison, Angela McGowan, David Sands Johnson, Lara Smith, Philip Turner, Helen Wilkinson, Lynne Allsop, Deborah Anthony, Rebecca Boulton, Sarah Brown, Vikram Desai, Mandy Gill, Cheryl Heeley, Sushrut Kulkarni, Wayne Lovegrove, Dominic Nash, Terri Ann Sewell, Sarah Shelton, Katie Slack, James Cartwright, Lynda Connor, Andrew Davies, Caroline Davies, Glyn Gainard, Dave Graham-Woollard, Carl Murphy, Leanne Quinn, Caradog Thomas, Jenny Travers, Marie Williams, Amanda Bell, Sunny Deo, Katharine Francis, Tracy Jackson, Laura McCafferty, Basalingappa Navadgi, Karan Plank, Venkat Satish, Claire Thelwall, Rachel Knight, Rahul Patel, Bruce Paton, Ashutosh Acharya, Utuman Aland, Miltiades Areirobulos, Pascal de Feyter, Lisa Ditchfield, Hafiz Iqbaz, Daniel Massey, Gareth Stables, Sarah Appleby, Michael Brown, Sarah Cable, Alexander Damen, Joana Da Rocha, Louise Foster, Elizabeth Hamilton, Catriona Hatton, Cassie Honeywell, Kunal Kulkarni, Lucy Markham, Haadiya Mohammed, John O'Grady, Yogesh Joshi, Heather Mclintock, Tania Morgan, Jane Stockport, Pranshu Agrawal, Jo Armstrong, Shannon Briggs, Ben Coupe, Anne Evans, Rob Gilbert, Sandra Latham, and Aslam Mohammed

Subjects
RD32, Treatment Outcome, Anterior Cruciate Ligament Reconstruction, Knee Joint, Anterior Cruciate Ligament Injuries, RM930, Humans, Knee Injuries, General Medicine, R1, RD, State Medicine
Abstract

Background: Anterior cruciate ligament (ACL) rupture is a common debilitating injury that can cause instability of the knee. We aimed to investigate the best management strategy between reconstructive surgery and non-surgical treatment for patients with a non-acute ACL injury and persistent symptoms of instability. Methods: We did a pragmatic, multicentre, superiority, randomised controlled trial in 29 secondary care National Health Service orthopaedic units in the UK. Patients with symptomatic knee problems (instability) consistent with an ACL injury were eligible. We excluded patients with meniscal pathology with characteristics that indicate immediate surgery. Patients were randomly assigned (1:1) by computer to either surgery (reconstruction) or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment), stratified by site and baseline Knee Injury and Osteoarthritis Outcome Score—4 domain version (KOOS4). This management design represented normal practice. The primary outcome was KOOS4 at 18 months after randomisation. The principal analyses were intention-to-treat based, with KOOS4 results analysed using linear regression. This trial is registered with ISRCTN, ISRCTN10110685, and ClinicalTrials.gov, NCT02980367. Findings: Between Feb 1, 2017, and April 12, 2020, we recruited 316 patients. 156 (49%) participants were randomly assigned to the surgical reconstruction group and 160 (51%) to the rehabilitation group. Mean KOOS4 at 18 months was 73·0 (SD 18·3) in the surgical group and 64·6 (21·6) in the rehabilitation group. The adjusted mean difference was 7·9 (95% CI 2·5–13·2; p=0·0053) in favour of surgical management. 65 (41%) of 160 patients allocated to rehabilitation underwent subsequent surgery according to protocol within 18 months. 43 (28%) of 156 patients allocated to surgery did not receive their allocated treatment. We found no differences between groups in the proportion of intervention-related complications. Interpretation: Surgical reconstruction as a management strategy for patients with non-acute ACL injury with persistent symptoms of instability was clinically superior and more cost-effective in comparison with rehabilitation management. Funding: The UK National Institute for Health Research Health Technology Assessment Programme.

Published
2022
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32. Worldwide Disparities in Recovery of Cardiac Testing 1 Year Into COVID-19

Author

Andrew J. Einstein, Cole Hirschfeld, Michelle C. Williams, Joao V. Vitola, Nathan Better, Todd C. Villines, Rodrigo Cerci, Leslee J. Shaw, Andrew D. Choi, Sharmila Dorbala, Ganesan Karthikeyan, Bin Lu, Valentin Sinitsyn, Alexey A. Ansheles, Takashi Kudo, Chiara Bucciarelli-Ducci, Bjarne Linde Nørgaard, Pál Maurovich-Horvat, Roxana Campisi, Elisa Milan, Lizette Louw, Adel H. Allam, Mona Bhatia, Lorenzo Sewanan, Eli Malkovskiy, Yosef Cohen, Michael Randazzo, Jagat Narula, Olga Morozova, Thomas N.B. Pascual, Yaroslav Pynda, Maurizio Dondi, Diana Paez, Gerd Hinterleitner, Yao Lu, Zhuoran Xu, Cole B. Hirschfeld, Ikenna Erinne, Mrinali Shetty, Andrew Choi, Juan Lopez-Mattei, Purvi Parwani, Artan Goda, Ervina Shirka, Salah Bouyoucef, Lydia Chelghoum, Farouk Mansouri, Abdelkader Medjahedi, Qais Naili, Mokhtar Ridouh, Diego Alasia, Lucia Alberghina, Natalia Aramayo, Diego Buchara, Franco Gabriel Busso, Jose Javier Bustos Rivadero, Jorge Camilletti, Hugo Campanelli, Ricardo Belisario Castro, Mariana Daicz, Horacio del Riego, Laura Dragonetti, Diego Echazarreta, Juan Erriest, Fernando Faccio, Adolfo Facello, Hugo Gallegos, Ricardo Geronazzo, Horacio Glait, Victor Hasbani, Victor Jäger, Julio Manuel Lewkowicz, Jose Lotti, Neiva Maciel, Osvaldo Masoli, Edgardo Mastrovito, Maria Medus, Maria Fernanda Merani, Susana Molteni, Marcos Montecinos, Gustavo Parisi, Claudio Pereyra Sueldo, Diego Perez de Arenaza, Luis Quintana, Alejandro Radzinschi, Marcela Redruello, Marina Rodríguez, Horacio Rojas, Arturo Romero Acuña, Daniel Schere, Sonia Traverso, Gustavo Vazquez, Susana Zeffiro, Mari Sakanyan, Scott Beuzeville, Raef Boktor, Michael Crowley, D'Arne Downie, Girish Dwivedi, Barry Elison, Omar Farouque, Kim Jasper, Subodh Joshi, Joseph Lee, Kenneth Lee, Elaine Lui, Peter Mcconachie, Joanne Meaker, Dee Nandurkar, Johanne Neill, Edward O'Rourke, Patricia O'Sullivan, George Pandos, Manuja Premaratne, David Prior, Natalie Rutherford, Connor Saunders, Kim Taubman, Andrew Tauro, Andrew Taylor, James Theuerle, Paul Thomas, Jonathan Tow, Anthony Upton, Shankar Vamadevan, Victor Wayne, Eva Alina Wegner, David Wong, John Younger, Dietrich Beitzke, Gudrun Feuchtner, Oliver Sommer, Konrad Weiss, Natallia Maroz-Vadalazhskaya, Uladzimir Tserakhau, Filip Homans, Caroline M. Van De Heyning, Raúl Araujo, Valentina Soldat-Stankovic, Sinisa Stankovic, Augusto Almeida, Carlos Anselmi, Guilherme S.A. Azevedo, Marcio Sommer Bittencourt, Diego Bromfman Pianta, Estevan Cabeda, Lara Carreira, Igor Coelho, Fernando de Amorim Fernandes, Andrea de Lorenzo, Roberta Delgado, Fernanda Erthal, Fabio Fernandes, Juliano Fernandes, Thiago Ferreira de Souza, Murilo Foppa, Wilson Furlan Matos Alves, Cibele Gontijo, Ilan Gottlieb, Gabriel Grossman, Maria Helena Albernaz Siqueira, Cesar Higa Nomura, Katia Hiromoto Koga, Ronaldo Lima, Rafael Lopes, Hugo Humberto Marçal Filho, Paulo Masiero, Luiz Mastrocola, Maria Eduarda Menezes de Siqueira, Claudio Mesquita, Danilo Naves, Filipe Penna, Ibraim Pinto, Thércio Rocha, Juliana Leal Rocha, Alfredo Rodrigues, Leila Salioni, Adelina Sanches, Marcelo Santos, Leonardo Sara Da Silva, Paulo Schvartzman, Cristina Sebastião Matushita, Tiago Senra, Marcelo Silva, Carlos Eduardo Soares, Bernardo Spiro, Carlos Eduardo Suaide Silva, Rafael Torres, Guilherme Urpia Monte, Andrea Vilela, Alexandre Volney Villa, Joao Vitola, Themissa Voss, Roberto Waltrick, Marcello Zapparoli, Hamid Naseer, Marina Garcheva-Tsacheva, Tiémégna Florence Ouattara, Sarameth Thou, Soley Varoeun, Gad Abikhzer, Rob Beanlands, Michael Chetrit, Dominique Dabreo, Carole Dennie, Matthias Friedrich, Mohmmed Nassoh Hafez, Kate Hanneman, Robert Miller, Anastasia Oikonomou, Idan Roifman, Gary Small, Vikas Tandon, Adwait Trivedi, James White, Katherine Zukotynski, Rita Alay, Carmen Concha, Teresa Massardo, Pedro Abad, Kelly Anzola, Harold Arturo, Luis Benitez, Alberto Cadena, Carlos Caicedo Zamudio, Antonio Calderón, Claudia T. Gutierrez Villamil, Claudia Jaimes, Juan L. Londono, Nelson Lopez, Sonia Merlano-Gaitan, Ramon Murgieitio-Cabrera, Manuel Valencia, Damiana Vergel, Alejandro Zuluaga Santamaria, Felix Solis, Tonci Batinic, Maja Franceschi, Maja Hrabak Paar, Marina Prpic, Cuba: Juan Felipe Batista, Lazaro Omar Cabrera, Amalia Peix, Yamilé Peña, Luis Manuel Rochela Vázquez, Ioannis Ntalas, Milan Kaminek, Vladimir Kincl, Otto Lang, Jawdat Abdulla, Morten Bøttcher, Martin Busk, Uka Geisler, Lars C. Gormsen, Nicolaj Hansson, Søren Hess, Jens Hove, Lars Thorbjoern Jensen, Magnus T. Jensen, Kristian Hay Kragholm, Bjarne L. Nørgaard, Kristian Øvrehus, Jan Rasmussen, Niels Peter Rønnow Sand, Hanne Sondergaard, Tomas Zaremba, Herwin Speckter, Nelson Amores, Mayra Sanchez Velez, Taghreed Abd Alrahman, Sherif Abd Elsamad, Alia Abdelfattah, Adel Allam, Sameh Elkaffas, Mona Hassan, Elshaymaa Hussein, Ahmed Ibrahim, Ahmed Kandeel, Mohamed Mandour Ali, Mahmoud Shaaban, Camila Flores, Verónica Vanesa Gómez Leiva, Anita Liiver, Martti Larikka, Valtteri Uusitalo, Denis Agostini, Clothilde Berger, Matthieu Dietz, Fabien Hyafil, Mickaël Ohana, Kevin Prigent, Hamza Regaieg, Laure Sarda-Mantel, Darach O. 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Karim, Mady Doucoure, Luise Reichmuth, Anthony Samuel, Mohamed Lemine Dieng, Ambedhkar Shantaram Naojee, Estrella Aguilera Hernandez, Cesar Rene Alducin Tellez, Erick Alexánderson-Rosas, Erika Barragan, Manuel Cabada, Daniel Calderón, Isabel Carvajal-Juarez, José Esparza, Manlio Gerardo Gama-Moreno, Virginia Garcia Quinto, Nelsy Coromoto Gonzalez, Mary Carmen Herrera-Zarza, Aloha Meave, Jesus Gregorio Medina Verdugo, Gabriela Melendez, Rafael Humberto Morales Murguia, Carlos Salvador Navarro Quiroz, Mario Ornelas, Andres Preciado-Anaya, Oscar Ulises Preciado-Gutiérrez, Adriana Puente, Aristóteles Ramírez Salazar, Sandra Graciela Rosales Uvera, Sandra Rosales-Uvera, Jose Antonio Serna Macias, Lilia Sierra-Galan, Lilia M. 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Aaysha Cader, Raihan Hussain, Saidur Rahman Khan, Tapati Mandal, Faria Nasreen, Yunqiang An, Dianbo Cao, Lianggeng Gong, Yang Hou, Chongfu Jia, Tao Li, Caiying Li, Hui Liu, Wenya Liu, Jinkang Liu, Ming-Yen Ng, Heshui Shi, Chunxiang Tang, Ximing Wang, Zhaoqian Wang, Yining Wang, Jiang Wu, Yan Yi, Li Yuan, Tong Zhang, Longjiang Zhang, Edith Chavez, Carlos Cruz, Christian Llontop, Rosanna Morales, Paz Abrihan, Asela Bustos-Barroso, Michele Duldulao-Ogbac, Christopher Eduarte, Jerry Obaldo, Alvin Quinon, Belinda San Juan, Carlo Joe San Juan, Marie Rhiamar Sauler-Gomez, Mila Uy, Magdalena Kostkiewicz, Jolanta Kunikowska, Anna Teresinska, Tomasz Urbanik, Nuno Bettencourt, Ricardo Fontes-Carvalho, Cristina Gavina, Lino Gonçalves, Filipe Macedo, Nuno Moreno, Carla Sousa, Ana Teresa Timoteo, Maria João Vidigal, Mahmoud Al Heidous, Subramaniyan Ramanathan, Samer Arnous, Said Aytani, Angela Byrne, Tadhg Gleeson, David Kerins, Julie O'Brien, Ji-In Bang, Henry Bom, Miju Cheon, Gi Jeong Cheon, Sang-Geon Cho, Chae Moon Hong, Yong Hyu Jeong, Won Jun Kang, Yeon-Koo Kang, Ji-Young Kim, So Won Oh, Young So, Ho-Chun Song, Kyoung Sook Won, Soo Woong Yoo, Irena Mitevska, Marija Vavlukis, Barbara Gužic Salobir, Monika Štalc, Theodora Benedek, Marian Pop, Claudiu Stan, Alexey Ansheles, Olga Dariy, Nina Gagarina, Irina Itskovich, Anatoliy Karalkin, Alexander Kokov, Gulya Marina, Ekaterina Migunova, Viktor Pospelov, Daria Ryzhkova, Guzaliya Sayfullina, Vladimir Sergienko, Irina Shurupova, Margarita Vakhromeeva, Nailia Valiullina, Konstantin Zavadovsky, Kirill Zhuravlev, Rami Abazid, Turki Al Garni, Mirvat Alasnag, Ahmed Aljizeeri, Hamid Amer, Ahmad Amro, Hesham Hamdy, Osama Smettei, Dragana Sobic Saranovic, Marina Vlajkovic, Felix Keng, Jason See, Zuzana Berecova, Jana Polakova Mistinova, Osayande Evbuomwan, Nerisha Govender, Jonathan Hack, Bawinile Hadebe, Khanyisile Hlongwa, Mitchell Kaplan, Hoosen Lakhi, Katarina Milos, Moshe Modiselle, Stuart More, Ntanganedzeni Muambadzi, Leonie Scholtz, Manuel Barreiro-Perez, Isabel Blanco, Jordi Broncano, Alicia Camarero, Irene Casáns-Tormo, Javier De Haro, Albert Flotats, Elia García, Ceferino Gutierrez Mendiguchia, Amelia Jimenez-Heffernan, Ruben Leta, Javier Lopez Diaz, Luis Lumbreras Vega, Ana Manovel-Sánchez, Amparo Martinez Monzonis, Bianca Patrut, Virginia Pubul, Ricardo Ruano Perez, Nahla Zeidan, Damayanthi Nanayakkara, Ahmed Suliman, Henrik Engblom, Mustafa Murtadha, Ellen Ostenfeld, Magnus Simonsson, Hatem Alkadhi, Ronny Ralf Buechel, Peter Burger, Christoph Gräni, Christel Kamani, Nadine Kawel-Böhm, Bernd Klaeser, Robert Manka, John Prior, Tawika Kaewchur, Benjapa Khiewvan, Arpakorn Kositwattanarerk, Sirianong Namwongprom, Tanyaluck Thientunyakit, Haluk Burcak Sayman, Mahmut Yüksel, Mugisha Julius Sebikali, Emmy Okello, Pavlo Korol, Iryna Noverko, Maryna Satyr, Tahir Ahmad, Khaled Alfakih, Ivo Andrade, Susan Buckingham, Anda Bularga, John-Paul Carpenter, Graham Cole, David Cusack, Sarojini David, Patrick Davis, Timothy Fairbairn, Arjun Ghosh, Prasad Guntur Ramkumar, Mark Hamilton, Faisal Haque, Benjamin Hudson, Annette Johnstone, V.J. Karthikeyan, Mike Kay, Mohammad Ali Khan, Jamie Kitt, Chen Sheng Low, Elisa Mcalindon, David Mccreavy, Brian Morrissey, Manish Motwani, Dilip Na, Edward Nicol, Dilip Patel, Jonathan Rodrigues, Chris Rofe, Rebecca Schofield, Thomas Semple, Azeem Sheikh, Apurva Sinha, Deepak Subedi, William Topping, Katherine Tweed, Stephen Richard Underwood, Jonathan Weir-Mccall, Hamed Zuhairy, Taimur Abbasi, Shady Abohashem, Sandra Abramson, Mouaz Al-Mallah, Mohan Ashok Kumar, Mallory Balmer-Swain, Daniel Berman, Adam Bernheim, Sabha Bhatti, Robert Biederman, Erik Bieging, Scott Bingham, Stephen Bloom, Sean Blue, Andressa Borges, Kelley Branch, Paco Bravo, Sujatha Buddhe, Matthew Budoff, Renée Bullock-Palmer, Michael Cahill, Candace Candela, Jane Cao, Saurav Chatterjee, Yiannis Chatzizisis, Nita Ray Chaudhuri, Michael Cheezum, Anjali Chelliah, Tiffany Chen, Marcus Chen, Lu Chen, Aalap Chokshi, Jina Chung, Sorin Danciu, William DeSisto, Michael Dilorenzo, Rami Doukky, William Duvall, Maros Ferencik, Cameron Foster, Anthon Fuisz, Michael Gannon, David German, Myron Gerson, Jeffrey Geske, Fadi Hage, Agha Haider, Sofia Haider, Yasmin Hamirani, Karen Hassen, Robert Hendel, Jacqueline Henkel, Stephen Horgan, Mark Hyun, Rajesh Janardhanan, Scott Jerome, Dinesh Kalra, David Kassop, Mona Kinkhabwala, George Kinzfogl, Bernard Koch, Lynne Koweek, Joseph Krepp, Younghoon Kwon, Jay Layer, John Lesser, Steve Leung, Bernadette Lisske, Kathleen Magurany, Jeremy Markowitz, Brenda Mccullough, Azita Moalemi, Chanan Moffitt, Juan Montanez, Warren Moore, Shamil Morayati, Mahmud Mossa-Basha, Zorana Mrsic, Venkatesh Murthy, Prashant Nagpal, Katarina Nelson, Prabhjot Nijjar, Rupal O’Quinn, Edward Passen, Toral Patel, Pravin Patil, Amit Pursnani, Nancy Quachang, Mark Rabbat, Pragya Ranjan, Patricia Rodriguez Lozano, Mary Schemmer, Rebecca Seifried, Nishant Shah, Amee Shah, Sujata Shanbhag, Gaurav Sharma, Robert Skotnicki, Michael Sobczak, Prem Soman, Vincent Sorrell, Monvadi Srichai, Jim Streeter, Leah Strickland, Suliman Suliman, Naghmeh Tebyanian, Dustin Thomas, Randall Thompson, Seth Uretsky, Srikanth Vallurupalli, Marian Vandyck-Acquah, Vikas Verma, Todd Villines, Joseph Weinstein, David Wolinsky, Karolina Zareba, Michael Zgaljardic, Mario Beretta, Rodolfo Ferrando, Miguel Kapitan, Fernando Mut, Omoa Djuraev, Gulnora Rozikhodjaeva, Luisa Vera, Binh Duong Duc, Xuan Canh Nguyen, Phuoc Minh Hiep Nguyen, Translational Immunology Groningen (TRIGR), Cardiovascular Centre (CVC), ​Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Molecular Pharmacology, Drug Design, Einstein, A, Hirschfeld, C, Williams, M, Vitola, J, Better, N, Villines, T, Cerci, R, Shaw, L, Choi, A, Dorbala, S, Karthikeyan, G, Lu, B, Sinitsyn, V, Ansheles, A, Kudo, T, Bucciarelli-Ducci, C, Norgaard, B, Maurovich-Horvat, P, Campisi, R, Milan, E, Louw, L, Allam, A, Bhatia, M, Sewanan, L, Malkovskiy, E, Cohen, Y, Randazzo, M, Narula, J, Morozova, O, Pascual, T, Pynda, Y, Dondi, M, 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Rutherford, N, Saunders, C, Taubman, K, Tauro, A, Taylor, A, Theuerle, J, Thomas, P, Tow, J, Upton, A, Vamadevan, S, Wayne, V, Wegner, E, Wong, D, Younger, J, Beitzke, D, Feuchtner, G, Sommer, O, Weiss, K, Maroz-Vadalazhskaya, N, Tserakhau, U, Homans, F, Van De Heyning, C, Araujo, R, Soldat-Stankovic, V, Stankovic, S, Almeida, A, Anselmi, C, Azevedo, G, Bittencourt, M, Pianta, D, Cabeda, E, Carreira, L, Coelho, I, de Amorim Fernandes, F, de Lorenzo, A, Delgado, R, Erthal, F, Fernandes, F, Fernandes, J, Ferreira de Souza, T, Foppa, M, Matos Alves, W, Gontijo, C, Gottlieb, I, Grossman, G, Albernaz Siqueira, M, Nomura, C, Koga, K, Lima, R, Lopes, R, Marcal Filho, H, Masiero, P, Mastrocola, L, Menezes de Siqueira, M, Mesquita, C, Naves, D, Penna, F, Pinto, I, Rocha, T, Rocha, J, Rodrigues, A, Salioni, L, Sanches, A, Santos, M, Da Silva, L, Schvartzman, P, Matushita, C, Senra, T, Silva, M, Soares, C, Spiro, B, Suaide Silva, C, Torres, R, Monte, G, Vilela, A, Villa, A, Voss, T, Waltrick, R, 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Ornelas, M, Preciado-Anaya, A, Preciado-Gutierrez, O, Puente, A, Salazar, A, Rosales Uvera, S, Rosales-Uvera, S, Serna Macias, J, Sierra-Galan, L, Tirado Alderete, J, Vallejo, E, Faraggi, M, Sereegotov, E, Ben Rais, N, Alaoui, N, Kyiphyu, T, Oo, S, Win, S, Zar, H, Ghimire, R, Neupane, M, Glaudemans, A, Slart, R, Verschure, D, Allen, B, Edmond, J, Mckenzie, C, Tie, S, Van Pelt, N, Worthington, K, Young, C, Soli, I, Kana, S, Onubogu, U, Sani, M, Braten, A, Jorgensen, A, Vassbotn, H, Al Dhuhli, H, Jawa, Z, Tag, N, Fatima, S, Imran, M, Younis, M, Saadullah, M, Malo, Y, Lenturut-Katal, D, Castillo, M, Ortellado, J, Akhter, A, Cader, F, Hussain, R, Khan, S, Mandal, T, Nasreen, F, An, Y, Cao, D, Gong, L, Hou, Y, Jia, C, Li, T, Li, C, Liu, H, Liu, W, Liu, J, Ng, M, Shi, H, Tang, C, Wang, X, Wang, Z, Wang, Y, Wu, J, Yi, Y, Yuan, L, Zhang, T, Zhang, L, Chavez, E, Cruz, C, Llontop, C, Morales, R, Abrihan, P, Bustos-Barroso, A, Duldulao-Ogbac, M, Eduarte, C, Obaldo, J, Quinon, A, San Juan, B, San Juan, C, Sauler-Gomez, M, Uy, M, Kostkiewicz, M, Kunikowska, J, Teresinska, A, Urbanik, T, Bettencourt, N, Fontes-Carvalho, R, Gavina, C, Goncalves, L, Macedo, F, Moreno, N, Sousa, C, Timoteo, A, Vidigal, M, Al Heidous, M, Ramanathan, S, Arnous, S, Aytani, S, Byrne, A, Gleeson, T, Kerins, D, O'Brien, J, Bang, J, Bom, H, Cheon, M, Cheon, G, Cho, S, Hong, C, Jeong, Y, Kang, W, Kang, Y, Kim, J, Oh, S, So, Y, Song, H, Won, K, Yoo, S, Mitevska, I, Vavlukis, M, Salobir, B, Stalc, M, Benedek, T, Pop, M, Stan, C, Dariy, O, Gagarina, N, Itskovich, I, Karalkin, A, Kokov, A, Marina, G, Migunova, E, Pospelov, V, Ryzhkova, D, Sayfullina, G, Sergienko, V, Shurupova, I, Vakhromeeva, M, Valiullina, N, Zavadovsky, K, Zhuravlev, K, Abazid, R, Al Garni, T, Alasnag, M, Aljizeeri, A, Amer, H, Amro, A, Hamdy, H, Smettei, O, Saranovic, D, Vlajkovic, M, Keng, F, See, J, Berecova, Z, Mistinova, J, Evbuomwan, O, Govender, N, Hack, J, Hadebe, B, Hlongwa, K, Kaplan, M, Lakhi, H, Milos, K, Modiselle, M, More, S, Muambadzi, N, Scholtz, L, Barreiro-Perez, M, Blanco, I, Broncano, J, Camarero, A, Casans-Tormo, I, De Haro, J, Flotats, A, Garcia, E, Mendiguchia, C, Jimenez-Heffernan, A, Leta, R, Diaz, J, Vega, L, Manovel-Sanchez, A, Monzonis, A, Patrut, B, Pubul, V, Perez, R, Zeidan, N, Nanayakkara, D, Suliman, A, Engblom, H, Murtadha, M, Ostenfeld, E, Simonsson, M, Alkadhi, H, Buechel, R, Burger, P, Grani, C, Kamani, C, Kawel-Bohm, N, Klaeser, B, Manka, R, Prior, J, Kaewchur, T, Khiewvan, B, Kositwattanarerk, A, Namwongprom, S, Thientunyakit, T, Sayman, H, Yuksel, M, Sebikali, M, Okello, E, Korol, P, Noverko, I, Satyr, M, Ahmad, T, Alfakih, K, Andrade, I, Buckingham, S, Bularga, A, Carpenter, J, Cole, G, Cusack, D, David, S, Davis, P, Fairbairn, T, Ghosh, A, Ramkumar, P, Hamilton, M, Haque, F, Hudson, B, Johnstone, A, Karthikeyan, V, Kay, M, Khan, M, Kitt, J, Low, C, Mcalindon, E, Mccreavy, D, Morrissey, B, Motwani, M, Na, D, Nicol, E, Patel, D, Rodrigues, J, Rofe, C, Schofield, R, Semple, T, Sheikh, A, Sinha, A, Subedi, D, Topping, W, Tweed, K, Underwood, S, Weir-Mccall, J, Zuhairy, H, Abbasi, T, Abohashem, S, Abramson, S, Al-Mallah, M, Kumar, M, Balmer-Swain, M, Berman, D, Bernheim, A, Bhatti, S, Biederman, R, Bieging, E, Bingham, S, Bloom, S, Blue, S, Borges, A, Branch, K, Bravo, P, Buddhe, S, Budoff, M, Bullock-Palmer, R, Cahill, M, Candela, C, Cao, J, Chatterjee, S, Chatzizisis, Y, Chaudhuri, N, Cheezum, M, Chelliah, A, Chen, T, Chen, M, Chen, L, Chokshi, A, Chung, J, Danciu, S, Desisto, W, Dilorenzo, M, Doukky, R, Duvall, W, Ferencik, M, Foster, C, Fuisz, A, Gannon, M, German, D, Gerson, M, Geske, J, Hage, F, Haider, A, Haider, S, Hamirani, Y, Hassen, K, Hendel, R, Henkel, J, Horgan, S, Hyun, M, Janardhanan, R, Jerome, S, Kalra, D, Kassop, D, Kinkhabwala, M, Kinzfogl, G, Koch, B, Koweek, L, Krepp, J, Kwon, Y, Layer, J, Lesser, J, Leung, S, Lisske, B, Magurany, K, Markowitz, J, Mccullough, B, Moalemi, A, Moffitt, C, Montanez, J, Moore, W, Morayati, S, Mossa-Basha, M, Mrsic, Z, Murthy, V, Nagpal, P, Nelson, K, Nijjar, P, O'Quinn, R, Passen, E, Patil, P, Pursnani, A, Quachang, N, Rabbat, M, Ranjan, P, Lozano, P, Schemmer, M, Seifried, R, Shah, N, Shah, A, Shanbhag, S, Sharma, G, Skotnicki, R, Sobczak, M, Soman, P, Sorrell, V, Srichai, M, Streeter, J, Strickland, L, Suliman, S, Tebyanian, N, Thomas, D, Thompson, R, Uretsky, S, Vallurupalli, S, Vandyck-Acquah, M, Verma, V, Weinstein, J, Wolinsky, D, Zareba, K, Zgaljardic, M, Beretta, M, Ferrando, R, Kapitan, M, Mut, F, Djuraev, O, Rozikhodjaeva, G, Vera, L, Duc, B, Nguyen, X, Hiep Nguyen, P, Einstein, Andrew J, Hirschfeld, Cole, Williams, Michelle C, Vitola, Joao V, Better, Nathan, Villines, Todd C, Cerci, Rodrigo, Shaw, Leslee J, Choi, Andrew D, Dorbala, Sharmila, Karthikeyan, Ganesan, Lu, Bin, Sinitsyn, Valentin, Ansheles, Alexey A, Kudo, Takashi, Bucciarelli-Ducci, Chiara, Nørgaard, Bjarne Linde, Maurovich-Horvat, Pál, Campisi, Roxana, Milan, Elisa, Louw, Lizette, Allam, Adel H, Bhatia, Mona, Sewanan, Lorenzo, Malkovskiy, Eli, Cohen, Yosef, Randazzo, Michael, Narula, Jagat, Morozova, Olga, Pascual, Thomas N B, Pynda, Yaroslav, Dondi, Maurizio, Paez, Diana, and Cuocolo, Alberto

Subjects
cardiac testing, Health Personnel, delivery of health care, coronavirus, COVID-19, global health, 610 Medicine & health, cardiovascular disease, health personnel, humans, pandemics, surveys and questionnaires, coronaviru, Surveys and Questionnaires, Humans, Cardiology and Cardiovascular Medicine, Delivery of Health Care, Pandemics, COVID-19/epidemiology
Abstract

BACKGROUND: The extent to which health care systems have adapted to the COVID-19 pandemic to provide necessary cardiac diagnostic services is unknown.OBJECTIVES: The aim of this study was to determine the impact of the pandemic on cardiac testing practices, volumes and types of diagnostic services, and perceived psychological stress to health care providers worldwide.METHODS: The International Atomic Energy Agency conducted a worldwide survey assessing alterations from baseline in cardiovascular diagnostic care at the pandemic's onset and 1 year later. Multivariable regression was used to determine factors associated with procedure volume recovery.RESULTS: Surveys were submitted from 669 centers in 107 countries. Worldwide reduction in cardiac procedure volumes of 64% from March 2019 to April 2020 recovered by April 2021 in high- and upper middle-income countries (recovery rates of 108% and 99%) but remained depressed in lower middle- and low-income countries (46% and 30% recovery). Although stress testing was used 12% less frequently in 2021 than in 2019, coronary computed tomographic angiography was used 14% more, a trend also seen for other advanced cardiac imaging modalities (positron emission tomography and magnetic resonance; 22%-25% increases). Pandemic-related psychological stress was estimated to have affected nearly 40% of staff, impacting patient care at 78% of sites. In multivariable regression, only lower-income status and physicians' psychological stress were significant in predicting recovery of cardiac testing.CONCLUSIONS: Cardiac diagnostic testing has yet to recover to prepandemic levels in lower-income countries. Worldwide, the decrease in standard stress testing is offset by greater use of advanced cardiac imaging modalities. Pandemic-related psychological stress among providers is widespread and associated with poor recovery of cardiac testing.

Published
2022
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33. Reporting guideline for the early-stage clinical evaluation of decision support systems driven by artificial intelligence

Author

Vasey, Baptiste, Nagendran, Myura, Campbell, Bruce, Clifton, David A, Collins, Gary S., Denaxas, Spiros, Denniston, Alastair K., Faes, Livia, Geerts, Bart, Ibrahim, Mudathir, Liu, Xiaoxuan, Mateen, Bilal A., Mathur, Piyush, Mccradden, Melissa D., Morgan, Lauren, Ordish, Johan, Rogers, Campbell, Saria, Suchi, Ting, Daniel S. W., Watkinson, Peter, Weber, Wim, Wheatstone, Peter, Mcculloch, Peter, Lee, Aaron Y., Fraser, Alan G., Connell, Ali, Vira, Alykhan, Esteva, Andre, Althouse, Andrew D., Beam, Andrew L., de Hond, Anne, Boulesteix, Anne-Laure, Bradlow, Anthony, Ercole, Ari, Paez, Arsenio, Tsanas, Athanasios, Kirby, Barry, Glocker, Ben, Velardo, Carmelo, Park, Chang Min, Hehakaya, Charisma, Baber, Chris, Paton, Chris, Johner, Christian, Kelly, Christopher J., Vincent, Christopher J., Yau, Christopher, Mcgenity, Clare, Gatsonis, Constantine, Faivre-Finn, Corinne, Simon, Crispin, Sent, Danielle, Bzdok, Danilo, Treanor, Darren, Clifton, David A., Wong, David C., Steiner, David F., Higgins, David, Benson, Dawn, O’Regan, Declan P., Gunasekaran, Dinesh V., Danks, Dominic, Neri, Emanuele, Kyrimi, Evangelia, Schwendicke, Falk, Magrabi, Farah, Ives, Frances, Rademakers, Frank E., Fowler, George E., Frau, Giuseppe, Hogg, H. D. Jeffry, Marcus, Hani J., Chan, Heang-Ping, Xiang, Henry, Mcintyre, Hugh F., Harvey, Hugh, Kim, Hyungjin, Habli, Ibrahim, Fackler, James C., Shaw, James, Higham, Janet, Wohlgemut, Jared M., Chong, Jaron, Bibault, Jean-Emmanuel, Cohen, Jérémie F., Kers, Jesper, Morley, Jessica, Krois, Joachim, Monteiro, Joao, Horovitz, Joel, Fletcher, John, Taylor, Jonathan, Yoon, Jung Hyun, Singh, Karandeep, Moons, Karel G. M., Karpathakis, Kassandra, Catchpole, Ken, Hood, Kerenza, Balaskas, Konstantinos, Kamnitsas, Konstantinos, Militello, Laura, Wynants, Laure, Oakden-Rayner, Lauren, Lovat, Laurence B., Smits, Luc J. M., Hinske, Ludwig C., Elzarrad, M. Khair, van Smeden, Maarten, Giavina-Bianchi, Mara, Daley, Mark, Sendak, Mark P., Sujan, Mark, Rovers, Maroeska, Decamp, Matthew, Woodward, Matthew, Komorowski, Matthieu, Marsden, Max, Mackintosh, Maxine, Abramoff, Michael D., de la Hoz, Miguel Ángel Armengol, Hambidge, Neale, Daly, Neil, Peek, Niels, Redfern, Oliver, Ahmad, Omer F., Bossuyt, Patrick M., Keane, Pearse A., Ferreira, Pedro N. P., Schnell-Inderst, Petra, Mascagni, Pietro, Dasgupta, Prokar, Guan, Pujun, Barnett, Rachel, Kader, Rawen, Chopra, Reena, Mann, Ritse M., Sarkar, Rupa, Mäenpää, Saana M., Finlayson, Samuel G., Vollam, Sarah, Vollmer, Sebastian J., Park, Seong Ho, Laher, Shakir, Joshi, Shalmali, van der Meijden, Siri L., Shelmerdine, Susan C., Tan, Tien-En, Stocker, Tom J. W., Giannini, Valentina, Madai, Vince I., Newcombe, Virginia, Wei Yan, Ng, Rogers, Wendy A., Ogallo, William, Park, Yoonyoung, and Perkins, Zane B.

Subjects
Research Report, Consensus, Artificial Intelligence, Research Design, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Immunology, Humans, General Medicine, DECIDE-AI expert group, General Biochemistry, Genetics and Molecular Biology, 11 Medical and Health Sciences, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Checklist
Abstract

A growing number of artificial intelligence (AI)-based clinical decision support systems are showing promising performance in preclinical, in silico evaluation, but few have yet demonstrated real benefit to patient care. Early-stage clinical evaluation is important to assess an AI system’s actual clinical performance at small scale, ensure its safety, evaluate the human factors surrounding its use and pave the way to further large-scale trials. However, the reporting of these early studies remains inadequate. The present statement provides a multi-stakeholder, consensus-based reporting guideline for the Developmental and Exploratory Clinical Investigations of DEcision support systems driven by Artificial Intelligence (DECIDE-AI). We conducted a two-round, modified Delphi process to collect and analyze expert opinion on the reporting of early clinical evaluation of AI systems. Experts were recruited from 20 pre-defined stakeholder categories. The final composition and wording of the guideline was determined at a virtual consensus meeting. The checklist and the Explanation & Elaboration (E&E) sections were refined based on feedback from a qualitative evaluation process. In total, 123 experts participated in the first round of Delphi, 138 in the second round, 16 in the consensus meeting and 16 in the qualitative evaluation. The DECIDE-AI reporting guideline comprises 17 AI-specific reporting items (made of 28 subitems) and ten generic reporting items, with an E&E paragraph provided for each. Through consultation and consensus with a range of stakeholders, we developed a guideline comprising key items that should be reported in early-stage clinical studies of AI-based decision support systems in healthcare. By providing an actionable checklist of minimal reporting items, the DECIDE-AI guideline will facilitate the appraisal of these studies and replicability of their findings.

Published
2022
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34. An Exploratory Study to Investigate the Utility of Clinical Screening for Neurodegenerative Disease in Age-Related Eye Disease Research

Author

Victoria S, Pelak, Yosbelkys Martin, Paez, Jennifer L, Patnaik, Samantha K, Holden, Prem S, Subramanian, Marc T, Mathias, Naresh, Mandava, and Anne M, Lynch

Subjects
Male, Retinal Ganglion Cells, Macular Degeneration, Ophthalmology, Quality of Life, Visual Acuity, Humans, Female, Neurodegenerative Diseases, Neurology (clinical), Tomography, Optical Coherence, Aged
Abstract

Unrecognized neurodegenerative diseases (NDD) in age-related eye disease research studies have the potential to confound vision-specific quality of life and retinal optical coherence tomography (OCT) outcome measures. The aim of this exploratory study was to investigate relationships between NDD screening tools and visual outcome measures in a small cohort of controls from the Colorado Age-Related Macular Degeneration Registry (CO-AMD), to consider the utility of future studies.Twenty-nine controls from the CO-AMD were screened using the Montreal Cognitive Assessment (MoCA), a Colorado Parkinsonian Checklist, and the Lewy Body Composite Risk Score. Univariate and multivariable linear regression modeling was used to assess associations between screening tools and the National Eye Institute Visual Function Questionnaire-25 (VFQ-25) and macular OCT outcome measures, and t tests were used to evaluate outcome measure differences between those with normal vs abnormal MoCA scores.One patient withdrew. The average age was 72.8 years, and 68% were female patients. Ten participants (36%) had abnormal MoCA scores, and their VFQ-25 scores were only 1 point less and not statistically different than those with normal MoCA scores. Macular OCT volumes and thicknesses for retinal nerve fiber layer (RNFL) and retinal ganglion cell layer were consistently and moderately lower for those with abnormal MoCA scores, and a positive association between MoCA and macular RNFL volume was observed, although differences and regression were not significant. Parkinson screening tests were abnormal for only 4 participants and were not associated with OCT or VFQ-25 measures by regression modeling.Given the degree and direction of observed differences, further investigation is warranted regarding the relationship between cognitive screening tools and macular OCT measures in age-related eye disease research, but future investigations regarding the relationship between NDD screening tools and VFQ-25 seem unwarranted.

Published
2022
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35. Predictive and Therapeutic Implications of a Novel PLCγ1/SHP2-Driven Mechanism of Cetuximab Resistance in Metastatic Colorectal Cancer

Author

Raquel Cruz-Duarte, Cátia Rebelo de Almeida, Magda Negrão, Afonso Fernandes, Paula Borralho, Daniel Sobral, Lina M. Gallego-Paez, Daniel Machado, João Gramaça, José Vílchez, Ana T. Xavier, Miguel Godinho Ferreira, Ana R. Miranda, Helder Mansinho, Maria J. Brito, Teresa R. Pacheco, Catarina Abreu, Ana Lucia-Costa, André Mansinho, Rita Fior, Luís Costa, Marta Martins, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Champalimaud Foundation [Lisbon, Portugal], Instituto de Medicina Molecular (iMM), Faculdade de Medicina [Lisboa], Universidade de Lisboa (ULISBOA)-Universidade de Lisboa (ULISBOA), Repositório da Universidade de Lisboa, UCIBIO - Applied Molecular Biosciences Unit, and DCV - Departamento de Ciências da Vida

Subjects
Cancer Research, Phospholipase C gamma, Rectal Neoplasms, Cetuximab, Protein Tyrosine Phosphatase, Non-Receptor Type 11, [SDV.CAN]Life Sciences [q-bio]/Cancer, digestive system diseases, 3. Good health, ErbB Receptors, Proto-Oncogene Proteins p21(ras), SDG 3 - Good Health and Well-being, Oncology, Antineoplastic Combined Chemotherapy Protocols, Colonic Neoplasms, Mutation, Animals, Humans, Colorectal Neoplasms, neoplasms, Zebrafish, ComputingMilieux_MISCELLANEOUS, Retrospective Studies
Abstract

© 2022 The Authors; Published by the American Association for Cancer Research. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 International (CC BY-NC-ND), Purpose: Cetuximab is an EGFR-targeted therapy approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC). However, about 60% of these patients show innate resistance to cetuximab. To increase cetuximab efficacy, it is crucial to successfully identify responder patients, as well as to develop new therapeutic approaches to overcome cetuximab resistance. Experimental design: We evaluated the value of EGFR effector phospholipase C gamma 1 (PLCγ1) in predicting cetuximab responses, by analyzing progression-free survival (PFS) of a multicentric retrospective cohort of 94 treated patients with mCRC (log-rank test and Cox regression model). Furthermore, we used in vitro and zebrafish xenotransplant models to identify and target the mechanism behind PLCγ1-mediated resistance to cetuximab. Results: In this study, levels of PLCγ1 were found increased in RAS WT tumors and were able to predict cetuximab responses in clinical samples and in vitro and in vivo models. Mechanistically, PLCγ1 expression was found to bypass cetuximab-dependent EGFR inhibition by activating ERK and AKT pathways. This novel resistance mechanism involves a noncatalytic role of PLCγ1 SH2 tandem domains in the propagation of downstream signaling via SH2-containing protein tyrosine phosphatase 2 (SHP2). Accordingly, SHP2 inhibition sensitizes PLCγ1-resistant cells to cetuximab. Conclusions: Our discoveries reveal the potential of PLCγ1 as a predictive biomarker for cetuximab responses and suggest an alternative therapeutic approach to circumvent PLCγ1-mediated resistance to cetuximab in patients with RAS WT mCRC. In this way, this work contributes to the development of novel strategies in the medical management and treatment of patients with mCRC., M. Martins' research was supported by Liga Portuguesa Contra o Cancro (LPCC): Terry Fox Fundation; Investigador FCT- Fundação para a Ciência e Technologia (IF/00409/2014) and IMM Bridge grant; RC-D research was supported by Fundação para a Ciência e Technologia (SFRH/BD/139138/2018). A. Fernandes was supported by LPCC-IMM BIOBANK; R. Fior was supported by Champalimaud Foundation and L. Costa was supported by Merck Serono.

Published
2022
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36. Emerging strategies for beta cell transplantation to treat diabetes

Author

Jesus Paez-Mayorga, Izeia Lukin, Dwaine Emerich, Paul de Vos, Gorka Orive, and Alessandro Grattoni

Subjects
Pharmacology, Islets of Langerhans, Diabetes Mellitus, Type 1, Islets of Langerhans Transplantation, Humans, Insulin, Toxicology
Abstract

Beta cell replacement has emerged as an attractive therapeutic alternative to traditional exogenous insulin administration for management of type 1 diabetes (T1D). Beta cells deliver insulin dynamically based on individual glycometabolic requirements, providing glycemic control while significantly reducing patient burden. Although transplantation into the portal circulation is clinically available, poor engraftment, low cell survival, and immune rejection have sparked investigation of alternative strategies for beta cell transplantation. In this review, we focus on current micro- and macroencapsulation technologies for beta cell transplantation and evaluate their advantages and challenges. Specifically, we comment on recent methods to ameliorate graft hypoxia including enhanced vascularization, reduction of pericapsular fibrotic overgrowth (PFO), and oxygen supplementation. We also discuss emerging beta cell-sourcing strategies to overcome donor shortage and provide insight into potential approaches to address outstanding challenges in the field.

Published
2022
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37. Improved Confidence in a Confirmatory Stage by Application of Item-Based Pharmacometrics Model: Illustration with a Phase III Active Comparator-Controlled Trial in COPD Patients

Author

Carolina Llanos-Paez, Claire Ambery, Shuying Yang, Misba Beerahee, Elodie L. Plan, and Mats O. Karlsson

Subjects
Pharmacology, mixed model repeated measures, Organic Chemistry, item response theory, non-linear mixed effect model, Pharmaceutical Science, Farmaceutiska vetenskaper, chronic obstructive pulmonary disease, Bronchodilator Agents, Pharmaceutical Sciences, Pulmonary Disease, Chronic Obstructive, patient-reported outcomes, Administration, Inhalation, Humans, Molecular Medicine, Pharmacology (medical), Patient Reported Outcome Measures, Biotechnology
Abstract

Purpose The current study aimed to illustrate how a non-linear mixed effect (NLME) model-based analysis may improve confidence in a Phase III trial through more precise estimates of the drug effect. Methods The FULFIL clinical trial was a Phase III study that compared 24 weeks of once daily inhaled triple therapy with twice daily inhaled dual therapy in patients with chronic obstructive pulmonary disease (COPD). Patient reported outcome data, obtained by using The Evaluating Respiratory Symptoms in COPD (E-RS:COPD) questionnaire, from the FULFIL study were analyzed using an NLME item-based response theory model (IRT). The change from baseline (CFB) in E-RS:COPD total score over 4-week intervals for each treatment arm was obtained using the IRT and compared with published results obtained with a mixed model repeated measures (MMRM) analysis. Results The IRT included a graded response model characterizing item parameters and a Weibull function combined with an offset function to describe the COPD symptoms-time course in patients receiving either triple therapy (n = 907) or dual therapy (n = 894). The IRT improved precision of the estimated drug effect compared to MMRM, resulting in a sample size of at least 3.64 times larger for the MMRM analysis to achieve the IRT precision in the CFB estimate. Conclusion This study shows the advantage of IRT over MMRM with a direct comparison of the same primary endpoint for the two analyses using the same observed clinical trial data, resulting in an increased confidence in Phase III.

Published
2022
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38. Meds to Beds: A Quality Improvement Approach to Optimizing the Discharge Medication Process for Pediatric Patients

Author

Shivali Choxi, Alexander F. Glick, Lauren Z Foster, Juan Betancur Paez, Dante Toscano, Joanna Tracy, and Rebecca E. Rosenberg

Subjects
medicine.medical_specialty, Quality management, Leadership and Management, business.industry, Communication, Psychological intervention, Pharmacy, medicine.disease, Quality Improvement, Patient Discharge, Workflow, Electronic health record, Acute care, medicine, Electronic Health Records, Humans, Medical emergency, Medical prescription, Child, business, Process Measures
Abstract

Background Using an on-site pharmacy or medication to bedside (MTB) program allows patients to obtain prescriptions and education before discharge, potentially improving adherence and preventing harm. The aim of this project was to improve discharge processes for pediatric acute care patients by increasing the proportion of oral antibiotics (1) prescribed to the on-site pharmacy from 15% to 70% and (2) delivered to bedside from 0% to 50%. Methods The Model for Improvement was used to iteratively implement interventions: increased on-site pharmacy capabilities, MTB program creation and streamlined enrollment, and secure electronic health record (EHR) messaging between clinicians and pharmacy staff regarding prescriptions. Process measures were proportion of antibiotics prescribed to the on-site pharmacy and delivered to bedside. Outcomes included surveys of family satisfaction with discharge medication education and discharge medication–related safety reports. Discharged before noon (DBN) was the balancing measure. Aims were analyzed using statistical process control charts and chi-square tests. Results A total of 1,908 antibiotics were prescribed over 28-months. On-site pharmacy prescriptions increased from 15% to 46% after pharmacy capabilities increased, then to 86% after MTB program launch, optimized workflow, and initiation of EHR messaging. Bedside medication delivery increased from 0% to 58% with these interventions. Family satisfaction with discharge medication education and frequency of discharge medication–related safety reports was not significantly different pre- and postintervention. DBN varied throughout the study. Conclusion Through clinician and pharmacy staff partnership, this initiative increased on-site pharmacy use and discharge antibiotics delivered to bedside. Key interventions included increased pharmacy capabilities, MTB program with streamlined workflow, and EHR–based communication.

Published
2022
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39. Gut bless you: The microbiota-gut-brain axis in irritable bowel syndrome

Author

Eline Margrete Randulff Hillestad, Aina van der Meeren, Bharat Halandur Nagaraja, Ben René Bjørsvik, Noman Haleem, Alfonso Benitez-Paez, Yolanda Sanz, Trygve Hausken, Gülen Arslan Lied, Arvid Lundervold, Birgitte Berentsen, Ministerio de Ciencia e Innovación (España), European Commission, and Norwegian Research Council

Subjects
Microbiota, Gastroenterology, Big data analysis, Review, General Medicine, Fecal Microbiota Transplantation, Microbiota-gut-brain axis, digestive system, Gastrointestinal Microbiome, Irritable Bowel Syndrome, Neurogastroenterology, stomatognathic diseases, fluids and secretions, Structural and functional magnetic resonance imaging, Brain-Gut Axis, Machine learning, Humans
Abstract

Irritable bowel syndrome (IBS) is a common clinical label for medically unexplained gastrointestinal symptoms, recently described as a disturbance of the microbiota-gut-brain axis. Despite decades of research, the pathophysiology of this highly heterogeneous disorder remains elusive. However, a dramatic change in the understanding of the underlying pathophysiological mechanisms surfaced when the importance of gut microbiota protruded the scientific picture. Are we getting any closer to understanding IBS' etiology, or are we drowning in unspecific, conflicting data because we possess limited tools to unravel the cluster of secrets our gut microbiota is concealing? In this comprehensive review we are discussing some of the major important features of IBS and their interaction with gut microbiota, clinical microbiota-altering treatment such as the low FODMAP diet and fecal microbiota transplantation, neuroimaging and methods in microbiota analyses, and current and future challenges with big data analysis in IBS., Supported by the Spanish Ministry of Science and Innovation (MICINN, Spain), No. AGL2017-88801-P (to Sanz Y); the Miguel Server grant from the Spanish "Carlos III" Health Institute (ISCIII), No. CP19/00132 (to Benitez-Paez A); The Norwegian Research Council (Funding Post-doc Position for Bharath Halandur Nagaraja), No. FRIMEDBIO276010; and Helse Vest’s Research Funding, No. HV912243; and ERC H2020-MSCA-IF-2019, No. 895219 (to Haleem N).

Published
2022
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40. Luciferin-Bioinspired Click Ligation Enables Hydrogel Platforms with Fine-Tunable Properties for 3D Cell Culture

Author

Minye Jin, Gülistan Koçer, and Julieta I. Paez

Subjects
Molecular Structure, Surface Properties, Luciferins, Materials Testing, Humans, Biocompatible Materials, Cell Culture Techniques, Three Dimensional, Hydrogels, General Materials Science, Particle Size, Cells, Cultured
Abstract

There is an increasing interest in coupling reactions for cross-linking of cell-encapsulating hydrogels under biocompatible, chemoselective, and tunable conditions. Inspired by the biosynthesis of luciferins in fireflies, here we exploit the cyanobenzothiazole-cysteine (CBT-Cys) click ligation to develop polyethylene glycol hydrogels as tunable scaffolds for cell encapsulation. Taking advantage of the chemoselectivity and versatility of CBT-Cys ligation, a highly flexible gel platform is reported here. We demonstrate luciferin-inspired hydrogels with important advantages for cell encapsulation applications: (i) gel precursors derived from inexpensive reagents and with good stability in aqueous solution (4 weeks), (ii) adjustable gel mechanics within physiological ranges (

Published
2022
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41. Coats Disease in 9 Patients: A Hispanic Case Series

Author

Maximiliano Barrera-Sánchez, Rosa E. Martinez-Muñoz, Raul E. Ruiz-Lozano, Catharina Busch, Juan Homar Paez-Garza, and Patricio J. Rodriguez-Valdes

Subjects
Male, Ophthalmology, Laser Coagulation, Retinal Detachment, Humans, Infant, Retinal Telangiectasis, Female, Hispanic or Latino, Follow-Up Studies, Retrospective Studies
Abstract

To describe demographic and clinical characteristics, treatment, and visual prognosis of Coats disease in Hispanic patients.A retrospective chart review was performed on nine patients (ten eyes) diagnosed with Coats disease in our two clinical centrers from 2004 - 2017.Mean age at diagnosis was 5.5 years (range 1 - 12 years) and mean follow-up time was 48 months (range 9 - 108 months). Eight patients (89%) were male and had unilateral disease and one (11%) female patient had bilateral disease. In 40% of the cases, patients were asymptomatic. Visual acuity at first presentation was worse than hand motion in 60% of the eyes. Half of the eyes (5/10 eyes, 50%) had exudative retinal detachment (≥ stage IIIA). Vascular ablation with cryotherapy combined with retinal photocoagulation was the most frequent therapeutic approach (40%). Despite anatomical success at 6 months in 100% of the treated eyes, visual outcome at 1 year of treatment was poor (worse than 20/200) in 70% of the cases.In our case series, patients were mostly asymptomatic on presentation, with severe stages of Coats disease. Even with anatomical success after surgical treatment in all treated cases, long-term visual prognosis remained very limited.Beschreibung der demografischen und klinischen Charakteristika, der Behandlung und Prognose bei Morbus Coats in hispanischen Patienten.Retrospektive Observationsstudie von Patienten mit Morbus Coats, die zwischen 2004 und 2017 in unseren 2 spezialisierten Augenkliniken vorstellig waren.Das mittlere Alter bei Erstdiagnose betrug 5,5 Jahre (Range: 1 – 12 Jahre) und die mittlere Nachbeobachtungszeit betrug 48 Monate (Range: 9 – 108 Monate). Acht Patienten (89%) waren männlich und hatten eine einseitige Erkrankung. Eine weibliche Patientin (11%) präsentierte eine bilaterale Erkrankung. In 40% der Fälle waren die Patienten asymptomatisch. Der Visus beim ersten Besuch war bei 60% der Augen eine Handbewegung oder schlechter. Die Hälfte der Patienten (5/10 Augen, 50%) zeigten bei Erstdiagnose bereits eine exsudative Netzhautablösung (≥ Stadium IIIA). Die Kryotherapie in Kombination mit einer Photokoagulation der Netzhaut war der häufigste therapeutische Ansatz (40%). Trotz eines anatomischen Erfolgs nach 6 Monaten in 100% der behandelten Augen blieb der Visus in 70% der behandelten Augen auch nach 1 Jahr weiterhin schlecht ( 20/200 Snellen = 0,1 Dezimal).In unserer Fallserie waren die meisten Patienten trotz bereits fortgeschrittenem Erkrankungsstadium bei Erstdiagnose asymptomatisch. Auch mit erfolgreicher chirurgischer Intervention blieb die langfristige Visusprognose in vielen Fällen sehr reduziert.

Published
2021
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42. Impact of COVID-19 on Cardiovascular Testing in the United States Versus the Rest of the World

Author

Hirschfeld, Cole B., Shaw, Leslee J., Williams, Michelle C., Lahey, Ryan, Villines, Todd C., Dorbala, Sharmila, Choi, Andrew D., Shah, Nishant R., Bluemke, David A., Berman, Daniel S., Blankstein, Ron, Ferencik, Maros, Narula, Jagat, Winchester, David, Malkovskiy, Eli, Goebel, Benjamin, Randazzo, Michael J., Lopez-Mattei, Juan, Parwani, Purvi, Vitola, Joao V., Cerci, Rodrigo J., Better, Nathan, Raggi, Paolo, Lu, Bin, Sergienko, Vladimir, Sinitsyn, Valentin, Kudo, Takashi, Nørgaard, Bjarne Linde, Maurovich-Horvat, Pál, Cohen, Yosef A., Pascual, Thomas N. B., Pynda, Yaroslav, Dondi, Maurizio, Paez, Diana, Einstein, Andrew J., Cerci, Rodrigo, Hinterleitner, Gerd, Lu, Yao, Morozova, Olga, Xu, Zhuoran, Cohen, Yosef, Randazzo, Michael, Choi, Andrew, Nasery, Mohammad Nawaz, Goda, Artan, Shirka, Ervina, Benlabgaa, Rabie, Bouyoucef, Salah, Medjahedi, Abdelkader, Nailli, Qais, Agolti, Mariela, Aguero, Roberto Nicolas, Alak, Maria del Carmen, Alberguina, Lucia Graciela, Arroñada, Guillermo, Astesiano, Andrea, Astesiano, Alfredo, Norton, Carolina Bas, Benteo, Pablo, Blanco, Juan, Bonelli, Juan Manuel, Bustos, Jose Javier, Cabrejas, Raul, Cachero, Jorge, Campisi, Roxana, Canderoli, Alejandro, Carames, Silvia, Carrascosa, Patrícia, Castro, Ricardo, Cendoya, Oscar, Cognigni, Luciano Martin, Collaud, Carlos, Cortes, Claudia, Courtis, Javier, Cragnolino, Daniel, Daicz, Mariana, De La Vega, Alejandro, De Maria, Silvia Teresa, Del Riego, Horacio, Dettori, Fernando, Deviggiano, Alejandro, Dragonetti, Laura, Embon, Mario, Enriquez, Ruben Emilio, Ensinas, Jorge, Faccio, Fernando, Facello, Adolfo, Garofalo, Diego, Geronazzo, Ricardo, Gonza, Natalia, Gutierrez, Lucas, Guzzo, Miguel Angel, Hasbani, Victor, Huerin, Melina, Jäger, Victor, Lewkowicz, Julio Manuel, Nieves A López De Munaín, Maria, Lotti, Jose Maria, Marquez, Alejandra, Masoli, Osvaldo, Masoli, Osvaldo Horacio, Mastrovito, Edgardo, Mayoraz, Matias, Melado, Graciela Eva, Mele, Anibal, Merani, Maria Fernanda, Meretta, Alejandro Horacio, Molteni, Susana, Montecinos, Marcos, Noguera, Eduardo, Novoa, Carlos, Sueldo, Claudio Pereyra, Ascani, Sebastian Perez, Pollono, Pablo, Pujol, Maria Paula, Radzinschi, Alejandro, Raimondi, Gustavo, Redruello, Marcela, Rodríguez, Marina, Rodríguez, Matías, Romero, Romina Lorena, Acuña, Arturo Romero, Rovaletti, Federico, San Miguel, Lucas, Solari, Lucrecia, Strada, Bruno, Traverso, Sonia, Traverzo, Sonia Simona, Espeche, Maria del Huerto Velazquez, Weihmuller, Juan Sebastian, Wolcan, Juan, Zeffiro, Susana, Sakanyan, Mari, Beuzeville, Scott, Boktor, Raef, Butler, Patrick, Calcott, Jennifer, Carr, Loretta, Chan, Virgil, Chao, Charles, Chong, Woon, Dobson, Mark, Downie, D'Arne, Dwivedi, Girish, Elison, Barry, Engela, Jean, Francis, Roslyn, Gaikwad, Anand, Basavaraj, Ashok Gangasandra, Goodwin, Bruce, Greenough, Robert, Hamilton-Craig, Christian, Hsieh, Victar, Joshi, Subodh, Lederer, Karin, Lee, Kenneth, Lee, Joseph, Magnussen, John, Mai, Nghi, Mander, Gordon, Murton, Fiona, Nandurkar, Dee, Neill, Johanne, O'Rourke, Edward, O'Sullivan, Patricia, Pandos, George, Pathmaraj, Kunthi, Pitman, Alexander, Poulter, Rohan, Premaratne, Manuja, Prior, David, Ridley, Lloyd, Rutherford, Natalie, Salehi, Hamid, Saunders, Connor, Scarlett, Luke, Seneviratne, Sujith, Shetty, Deepa, Shrestha, Ganesh, Shulman, Jonathan, Solanki, Vijay, Stanton, Tony, Stuart, Murch, Stubbs, Michael, Swainson, Ian, Taubman, Kim, Taylor, Andrew, Thomas, Paul, Unger, Steven, Upton, Anthony, Vamadevan, Shankar, Van Gaal, William, Verjans, Johan, Voutnis, Demetrius, Wayne, Victor, Wilson, Peter, Wong, David, Wong, Kirby, Younger, John, Feuchtner, Gudrun, Mirzaei, Siroos, Weiss, Konrad, Maroz-Vadalazhskaya, Natallia, Gheysens, Olivier, Homans, Filip, Moreno-Reyes, Rodrigo, Pasquet, Agnès, Roelants, Veronique, Van De Heyning, Caroline M., Ríos, Raúl Araujo, Soldat-Stankovic, Valentina, Stankovic, Sinisa, Albernaz Siqueira, Maria Helena, Almeida, Augusto, Alves Togni, Paulo Henrique, Andrade, Jose Henrique, Andrade, Luciana, Anselmi, Carlos, Araújo, Roberta, Azevedo, Guilherme, Bezerra, Sabbrina, Biancardi, Rodrigo, Grossman, Gabriel Blacher, Brandão, Simone, Pianta, Diego Bromfman, Carreira, Lara, Castro, Bruno, Chang, Tien, Cunali, Fernando, Cury, Roberto, Dantas, Roberto, de Amorim Fernandes, Fernando, De Lorenzo, Andrea, De Macedo Filho, Robson, Erthal, Fernanda, Fernandes, Fabio, Fernandes, Juliano, De Souza, Thiago Ferreira, Alves, Wilson Furlan, Ghini, Bruno, Goncalves, Luiz, Gottlieb, Ilan, Hadlich, Marcelo, Kameoka, Vinícius, Lima, Ronaldo, Lima, Adna, Lopes, Rafael Willain, Machado e Silva, Ricardo, Magalhães, Tiago, Silva, Fábio Martins, Mastrocola, Luiz Eduardo, Medeiros, Fábio, Meneghetti, José Claudio, Naue, Vania, Naves, Danilo, Nolasco, Roberto, Nomura, Cesar, Oliveira, Joao Bruno, Paixao, Eduardo, De Carvalho, Filipe Penna, Pinto, Ibraim, Possetti, Priscila, Quinta, Mayra, Nogueira Ramos, Rodrigo Rizzo, Rocha, Ricardo, Rodrigues, Alfredo, Rodrigues, Carlos, Romantini, Leila, Sanches, Adelina, Santana, Sara, Sara da Silva, Leonardo, Schvartzman, Paulo, Matushita, Cristina Sebastião, Senra, Tiago, Shiozaki, Afonso, Menezes de Siqueira, Maria Eduarda, Siqueira, Cristiano, Smanio, Paola, Soares, Carlos Eduardo, Junior, José Soares, Bittencourt, Marcio Sommer, Spiro, Bernardo, Mesquita, Cláudio Tinoco, Torreao, Jorge, Torres, Rafael, Uellendahl, Marly, Monte, Guilherme Urpia, Veríssimo, Otávia, Cabeda, Estevan Vieira, Pedras, Felipe Villela, Waltrick, Roberto, Zapparoli, Marcello, Naseer, Hamid, Garcheva-Tsacheva, Marina, Kostadinova, Irena, Theng, Youdaline, Abikhzer, Gad, Barette, Rene, Chow, Benjamin, Dabreo, Dominique, Friedrich, Matthias, Garg, Ria, Hafez, Mohammed Nassoh, Johnson, Chris, Kiess, Marla, Leipsic, Jonathon, Leung, Eugene, Miller, Robert, Oikonomou, Anastasia, Probst, Stephan, Roifman, Idan, Small, Gary, Tandon, Vikas, Trivedi, Adwait, White, James, Zukotynski, Katherine, Canessa, Jose, Muñoz, Gabriel Castro, Concha, Carmen, Hidalgo, Pablo, Lovera, Cesar, Massardo, Teresa, Vargas, Luis Salazar, Abad, Pedro, Arturo, Harold, Ayala, Sandra, Benitez, Luis, Cadena, Alberto, Caicedo, Carlos, Moncayo, Antonio Calderón, Gomez, Sharon, Gutierrez Villamil, Claudia T., Jaimes, Claudia, Londoño, Juan, Londoño Blair, Juan Luis, Pabon, Luz, Pineda, Mauricio, Rojas, Juan Carlos, Ruiz, Diego, Escobar, Manuel Valencia, Vasquez, Andres, Vergel, Damiana, Zuluaga, Alejandro, Gamboa, Isabel Berrocal, Castro, Gabriel, González, Ulises, Baric, Ana, Batinic, Tonci, Franceschi, Maja, Paar, Maja Hrabak, Jukic, Mladen, Medakovic, Petar, Persic, Viktor, Prpic, Marina, Punda, Ante, Batista, Juan Felipe, Gómez Lauchy, Juan Manuel, Gutierrez, Yamile Marcos, Menéndez, Rayner, Peix, Amalia, Rochela, Luis, Panagidis, Christoforos, Petrou, Ioannis, Engelmann, Vaclav, Kaminek, Milan, Kincl, Vladimír, Lang, Otto, Simanek, Milan, Abdulla, Jawdat, Bøttcher, Morten, Christensen, Mette, Gormsen, Lars Christian, Hasbak, Philip, Hess, Søren, Holdgaard, Paw, Johansen, Allan, Kyhl, Kasper, Norgaard, Bjarne Linde, Øvrehus, Kristian Altern, Rønnow Sand, Niels Peter, Steffensen, Rolf, Thomassen, Anders, Zerahn, Bo, Perez, Alfredo, Escorza Velez, Giovanni Alejandro, Velez, Mayra Sanchez, Abdel Aziz, Islam Shawky, Abougabal, Mahasen, Ahmed, Taghreed, Allam, Adel, Asfour, Ahmed, Hassan, Mona, Hassan, Alia, Ibrahim, Ahmed, Kaffas, Sameh, Kandeel, Ahmed, Ali, Mohamed Mandour, Mansy, Ahmad, Maurice, Hany, Nabil, Sherif, Shaaban, Mahmoud, Flores, Ana Camila, Poksi, Anne, Knuuti, Juhani, Kokkonen, Velipekka, Larikka, Martti, Uusitalo, Valtteri, Bailly, Matthieu, Burg, Samuel, Deux, Jean-François, Habouzit, Vincent, Hyafil, Fabien, Lairez, Olivier, Proffit, Franck, Regaieg, Hamza, Sarda-Mantel, Laure, Tacher, Vania, Schneider, Roman P., Ayetey, Harold, Angelidis, George, Archontaki, Aikaterini, Chatziioannou, Sofia, Datseris, Ioannis, Fragkaki, Christina, Georgoulias, Panagiotis, Koukouraki, Sophia, Koutelou, Maria, Kyrozi, Eleni, Repasos, Evangelos, Stavrou, Petros, Valsamaki, Pipitsa, Gonzalez, Carla, Gutierrez, Goleat, Maldonado, Alejandro, Buga, Klara, Garai, Ildiko, Schmidt, Erzsébet, Szilveszter, Balint, Várady, Edit, Banthia, Nilesh, Bhagat, Jinendra Kumar, Bhargava, Rishi, Bhat, Vivek, Bhatia, Mona, Choudhury, Partha, Chowdekar, Vijay Sai, Irodi, Aparna, Jain, Shashank, Joseph, Elizabeth, Kumar, Sukriti, Girijanandan Mahapatra, Prof Dr, Mitra, Deepanjan, Mittal, Bhagwant Rai, Ozair, Ahmad, Patel, Chetan, Patel, Tapan, Patel, Ravi, Patel, Shivani, Saxena, Sudhir, Sengupta, Shantanu, Singh, Santosh, Singh, Bhanupriya, Sood, Ashwani, Verma, Atul, Affandi, Erwin, Alam Edison, Padma Savenadia, Gunawan, Gani, Hapkido, Habusari, Hidayat, Basuki, Huda, Aulia, Mukti, Anggoro Praja, Prawiro, Djoko, Soeriadi, Erwin Affandi, Syawaluddin, Hilman, Albadr, Amjed, Assadi, Majid, Emami, Farshad, Houshmand, Golnaz, Maleki, Majid, Rostami, Maryam Tajik, Zakavi, Seyed Rasoul, Zaid, Eed Abu, Agranovich, Svetlana, Arnson, Yoav, Bar-Shalom, Rachel, Frenkel, Alex, Knafo, Galit, Lugassi, Rachel, Maor Moalem, Israel Shlomo, Mor, Maya, Muskal, Noam, Ranser, Sara, Shalev, Aryeh, Albano, Domenico, Alongi, Pierpaolo, Arnone, Gaspare, Bagatin, Elisa, Baldari, Sergio, Bauckneht, Matteo, Bertelli, Paolo, Bianco, Francesco, Bonfiglioli, Rachele, Boni, Roberto, Bruno, Andrea, Bruno, Isabella, Busnardo, Elena, Califaretti, Elena, Camoni, Luca, Carnevale, Aldo, Casoni, Roberta, Cavallo, Armando Ugo, Cavenaghi, Giorgio, Chierichetti, Franca, Chiocchi, Marcello, Cittanti, Corrado, Colletta, Mauro, Conti, Umberto, Cossu, Alberto, Cuocolo, Alberto, Cuzzocrea, Marco, De Rimini, Maria Luisa, De Vincentis, Giuseppe, Del Giudice, Eleonora, Del Torto, Alberico, Della Tommasina, Veronica, Durmo, Rexhep, Erba, Paola Anna, Evangelista, Laura, Faletti, Riccardo, Faragasso, Evelina, Farsad, Mohsen, Ferro, Paola, Florimonte, Luigia, Frantellizzi, Viviana, Fringuelli, Fabio Massimo, Gatti, Marco, Gaudiano, Angela, Gimelli, Alessia, Giubbini, Raffaele, Giuffrida, Francesca, Ialuna, Salvatore, Laudicella, Riccardo, Leccisotti, Lucia, Leva, Lucia, Liga, Riccardo, Liguori, Carlo, Longo, Giampiero, Maffione, Margherita, Mancini, Maria Elisabetta, Marcassa, Claudio, Milan, Elisa, Nardi, Barbara, Pacella, Sara, Pepe, Giovanna, Pontone, Gianluca, Pulizzi, Sabina, Quartuccio, Natale, Rampin, Lucia, Ricci, Fabrizio, Rossini, Pierluigi, Rubini, Giuseppe, Russo, Vincenzo, Sacchetti, Gian Mauro, Sambuceti, Gianmario, Scarano, Massimo, Sciagrà, Roberto, Sperandio, Massimiliano, Stefanelli, Antonella, Ventroni, Guido, Zoboli, Stefania, Baugh, Dainia, Chambers, Duane, Madu, Ernest, Nunura, Felix, Asano, Hiroshi, Chimura, Chimura Misato, Fujimoto, Shinichiro, Fujisue, Koichiro, Fukunaga, Tomohisa, Fukushima, Yoshimitsu, Fukuyama, Kae, Hashimoto, Jun, Ichikawa, Yasutaka, Iguchi, Nobuo, Imai, Masamichi, Inaki, Anri, Ishimura, Hayato, Isobe, Satoshi, Kadokami, Toshiaki, Kato, Takao, Kumita, Shinichiro, Maruno, Hirotaka, Mataki, Hiroyuki, Miyagawa, Masao, Morimoto, Ryota, Moroi, Masao, Nagamachi, Shigeki, Nakajima, Kenichi, Nakata, Tomoaki, Nakazato, Ryo, Nanasato, Mamoru, Naya, Masanao, Norikane, Takashi, Ohta, Yasutoshi, Okayama, Satoshi, Okizaki, Atsutaka, Otomi, Yoichi, Otsuka, Hideki, Saito, Masaki, Sakata, Sakata Yasushi, Sarai, Masayoshi, Sato, Daisuke, Shiraishi, Shinya, Suwa, Yoshinobu, Takanami, Kentaro, Takehana, Kazuya, Taki, Junichi, Tamaki, Nagara, Taniguchi, Yasuyo, Teragawa, Hiroki, Tomizawa, Nobuo, Tsujita, Kenichi, Umeji, Kyoko, Wakabayashi, Yasushi, Yamada, Shinichiro, Yamazaki, Shinya, Yoneyama, Tatsuya, Rawashdeh, Mohammad, Batyrkhanov, Daultai, Dautov, Tairkhan, Makhdomi, Khalid, Ombati, Kevin, Alkandari, Faridah, Garashi, Masoud, Coie, Tchoyoson Lim, Rajvong, Sonexay, Kalinin, Artem, Kalnina, Marika, Haidar, Mohamad, Komiagiene, Renata, Kviecinskiene, Giedre, Mataciunas, Mindaugas, Vajauskas, Donatas, Picard, Christian, Karim, Noor Khairiah A., Reichmuth, Luise, Samuel, Anthony, Allarakha, Mohammad Aaftaab, Naojee, Ambedhkar Shantaram, Alexanderson-Rosas, Erick, Barragan, Erika, González-Montecinos, Alejandro Becerril, Cabada, Manuel, Rodriguez, Daniel Calderon, Carvajal-Juarez, Isabel, Cortés, Violeta, Cortés, Filiberto, De La Peña, Erasmo, Gama-Moreno, Manlio, González, Luis, Ramírez, Nelsy Gonzalez, Jiménez-Santos, Moisés, Matos, Luis, Monroy, Edgar, Morelos, Martha, Ornelas, Mario, Ortga Ramirez, Jose Alberto, Preciado-Anaya, Andrés, Preciado-Gutiérrez, Óscar Ulises, Barragan, Adriana Puente, Rosales Uvera, Sandra Graciela, Sandoval, Sigelinda, Tomas, Miguel Santaularia, Sierra-Galan, Lilia M., Siu, Silvia, Vallejo, Enrique, Valles, Mario, Faraggi, Marc, Sereegotov, Erdenechimeg, Ilic, Srdja, Ben-Rais, Nozha, Alaoui, Nadia Ismaili, Taleb, Sara, Myo, Khin Pa, Thu, Phyo Si, Ghimire, Ram Kumar, Rajbanshi, Bijoy, Barneveld, Peter, Glaudemans, Andor, Habets, Jesse, Koopmans, Klaas Pieter, Manders, Jeroen, Pool, Stefan, Scholte, Arthur, Scholtens, Asbjørn, Slart, Riemer, Thimister, Paul, Van Asperen, Erik-Jan, Veltman, Niels, Verschure, Derk, Wagenaar, Nils, Edmond, John, Ellis, Chris, Johnson, Kerryanne, Keenan, Ross, Hua, Shaw, Occleshaw, Christopher, Sasse, Alexander, To, Andrew, Van Pelt, Niels, Young, Calum, Cuadra, Teresa, Roque Vanegas, Hector Bladimir, Soli, Idrissa Adamou, Issoufou, Djibrillou Moussa, Ayodele, Tolulope, Madu, Chibuzo, Onimode, Yetunde, Efros-Monsen, Elen, Forsdahl, Signe Helene, Hildre Dimmen, Jenni-Mari, Jørgensen, Arve, Krohn, Isabel, Løvhaugen, Pål, Bråten, Anders Tjellaug, Al Dhuhli, Humoud, Al Kindi, Faiza, Al-Bulushi, Naeema, Jawa, Zabah, Tag, Naima, Afzal, Muhammad Shehzad, Fatima, Shazia, Younis, Muhammad Numair, Riaz, Musab, Saadullah, Mohammad, Herrera, Yariela, Lenturut-Katal, Dora, Vázquez, Manuel Castillo, Ortellado, José, Akhter, Afroza, Cao, Dianbo, Cheung, Stephen, Dai, Xu, Gong, Lianggeng, Han, Dan, Hou, Yang, Li, Caiying, Li, Tao, Li, Dong, Li, Sijin, Liu, Jinkang, Liu, Hui, Ng, Ming Yen, Sun, Kai, Tang, Gongshun, Wang, Jian, Wang, Ximing, Wang, Zhao-Qian, Wang, Yining, Wang, Yifan, Wu, Jiang, Wu, Zhifang, Xia, Liming, Xiao, Jiangxi, Xu, Lei, Yang, Youyou, Yin, Wu, Yu, Jianqun, Yuan, Li, Zhang, Tong, Zhang, Longjiang, Zhang, Yong-Gao, Zhang, Xiaoli, Zhu, Li, Alfaro, Ana, Abrihan, Paz, Barroso, Asela, Cruz, Eric, Gomez, Marie Rhiamar, Magboo, Vincent Peter, Medina, John Michael, Obaldo, Jerry, Pastrana, Davidson, Pawhay, Christian Michael, Quinon, Alvin, Tang, Jeanelle Margareth, Tecson, Bettina, Uson, Kristine Joy, Uy, Mila, Kostkiewicz, Magdalena, Kunikowska, Jolanta, Bettencourt, Nuno, Cantinho, Guilhermina, Ferreira, Antonio, Syed, Ghulam, Arnous, Samer, Atyani, Said, Byrne, Angela, Gleeson, Tadhg, Kerins, David, Meehan, Conor, Murphy, David, Murphy, Mark, Murray, John, O'Brien, Julie, Bang, Ji-In, Bom, Henry, Cho, Sang-Geon, Hong, Chae Moon, Jang, Su Jin, Jeong, Yong Hyu, Kang, Won Jun, Kim, Ji-Young, Lee, Jaetae, Namgung, Chang Kyeong, So, Young, Won, Kyoung Sook, Majstorov, Venjamin, Vavlukis, Marija, Salobir, Barbara Gužic, Štalc, Monika, Benedek, Theodora, Benedek, Imre, Mititelu, Raluca, Stan, Claudiu Adrian, Ansheles, Alexey, Dariy, Olga, Drozdova, Olga, Gagarina, Nina, Gulyaev, Vsevolod Milyevich, Itskovich, Irina, Karalkin, Anatoly, Kokov, Alexander, Migunova, Ekaterina, Pospelov, Viktor, Ryzhkova, Daria, Saifullina, Guzaliya, Sazonova, Svetlana, Shurupova, Irina, Trifonova, Tatjana, Ussov, Wladimir Yurievich, Vakhromeeva, Margarita, Valiullina, Nailya, Zavadovsky, Konstantin, Zhuravlev, Kirill, Alasnag, Mirvat, Okarvi, Subhani, Saranovic, Dragana Sobic, Keng, Felix, Jason See, Jia Hao, Sekar, Ramkumar, Yew, Min Sen, Vondrak, Andrej, Bejai, Shereen, Bennie, George, Bester, Ria, Engelbrecht, Gerrit, Evbuomwan, Osayande, Gongxeka, Harlem, Vuuren, Magritha Jv, Kaplan, Mitchell, Khushica, Purbhoo, Lakhi, Hoosen, Louw, Lizette, Malan, Nico, Milos, Katarina, Modiselle, Moshe, More, Stuart, Naidoo, Mathava, Scholtz, Leonie, Vangu, Mboyo, Aguadé-Bruix, Santiago, Blanco, Isabel, Cabrera, Antonio, Camarero, Alicia, Casáns-Tormo, Irene, Cuellar-Calabria, Hug, Flotats, Albert, Fuentes Cañamero, Maria Eugenia, García, María Elia, Jimenez-Heffernan, Amelia, Leta, Rubén, Diaz, Javier Lopez, Lumbreras, Luis, Marquez-Cabeza, Juan Javier, Martin, Francisco, Martinez de Alegria, Anxo, Medina, Francisco, Canal, Maria Pedrera, Peiro, Virginia, Pubul-Nuñez, Virginia, Rayo Madrid, Juan Ignacio, Rey, Cristina Rodríguez, Perez, Ricardo Ruano, Ruiz, Joaquín, Hernández, Gertrudis Sabatel, Sevilla, Ana, Zeidán, Nahla, Nanayakkara, Damayanthi, Udugama, Chandraguptha, Simonsson, Magnus, Alkadhi, Hatem, Buechel, Ronny Ralf, Burger, Peter, Ceriani, Luca, De Boeck, Bart, Gräni, Christoph, Juillet de Saint Lager Lucas, Alix, Kamani, Christel H., Kawel-Boehm, Nadine, Manka, Robert, Prior, John O., Rominger, Axel, Vallée, Jean-Paul, Khiewvan, Benjapa, Premprabha, Teerapon, Thientunyakit, Tanyaluck, Sellem, Ali, Kir, Kemal Metin, Sayman, Haluk, Sebikali, Mugisha Julius, Muyinda, Zerida, Kmetyuk, Yaroslav, Korol, Pavlo, Mykhalchenko, Olena, Pliatsek, Volodymyr, Satyr, Maryna, Albalooshi, Batool, Ahmed Hassan, Mohamed Ismail, Anderson, Jill, Bedi, Punit, Biggans, Thomas, Bularga, Anda, Bull, Russell, Burgul, Rajesh, Carpenter, John-Paul, Coles, Duncan, Cusack, David, Deshpande, Aparna, Dougan, John, Fairbairn, Timothy, Farrugia, Alexia, Gopalan, Deepa, Gummow, Alistair, Ramkumar, Prasad Guntur, Hamilton, Mark, Harbinson, Mark, Hartley, Thomas, Hudson, Benjamin, Joshi, Nikhil, Kay, Michael, Kelion, Andrew, Khokhar, Azhar, Kitt, Jamie, Lee, Ken, Low, Chen, Mak, Sze Mun, Marousa, Ntouskou, Martin, Jon, Mcalindon, Elisa, Menezes, Leon, Morgan-Hughes, Gareth, Moss, Alastair, Murray, Anthony, Nicol, Edward, Patel, Dilip, Peebles, Charles, Pugliese, Francesca, Luis Rodrigues, Jonathan Carl, Rofe, Christopher, Sabharwal, Nikant, Schofield, Rebecca, Semple, Thomas, Sharma, Naveen, Strouhal, Peter, Subedi, Deepak, Topping, William, Tweed, Katharine, Weir-Mccall, Jonathan, Abbara, Suhny, Abbasi, Taimur, Abbott, Brian, Abohashem, Shady, Abramson, Sandra, Al-Abboud, Tarek, Al-Mallah, Mouaz, Almousalli, Omar, Ananthasubramaniam, Karthikeyan, Kumar, Mohan Ashok, Askew, Jeffrey, Attanasio, Lea, Balmer-Swain, Mallory, Bayer, Richard R., Bernheim, Adam, Bhatti, Sabha, Bieging, Erik, Bloom, Stephen, Blue, Sean, Bluemke, David, Borges, Andressa, Branch, Kelley, Bravo, Paco, Brothers, Jessica, Budoff, Matthew, Bullock-Palmer, Renée, Burandt, Angela, Burke, Floyd W., Bush, Kelvin, Candela, Candace, Capasso, Elizabeth, Cavalcante, Joao, Chang, Donald, Chatterjee, Saurav, Chatzizisis, Yiannis, Cheezum, Michael, Chen, Tiffany, Chen, Jennifer, Chen, Marcus, Clarcq, James, Cordero, Ayreen, Crim, Matthew, Danciu, Sorin, Decter, Bruce, Dhruva, Nimish, Doherty, Neil, Doukky, Rami, Dunbar, Anjori, Duvall, William, Edwards, Rachael, Esquitin, Kerry, Farah, Husam, Fentanes, Emilio, Fisher, Daniel, Fitzpatrick, Daniel, Foster, Cameron, Fuisz, Tony, Gannon, Michael, Gastner, Lori, Gerson, Myron, Ghoshhajra, Brian, Goldberg, Alan, Goldner, Brian, Gonzalez, Jorge, Gore, Rosco, Gracia-López, Sandra, Hage, Fadi, Haider, Agha, Haider, Sofia, Hamirani, Yasmin, Hassen, Karen, Hatfield, Mallory, Hawkins, Carolyn, Hawthorne, Katie, Heath, Nicholas, Hendel, Robert, Hernandez, Phillip, Hill, Gregory, Horgan, Stephen, Huffman, Jeff, Hurwitz, Lynne, Iskandrian, Ami, Janardhanan, Rajesh, Jellis, Christine, Jerome, Scott, Kalra, Dinesh, Kaviratne, Summanther, Kay, Fernando, Kelly, Faith, Khalique, Omar, Kinkhabwala, Mona, Iii, George Kinzfogl, Kircher, Jacqueline, Kirkbride, Rachael, Kontos, Michael, Kottam, Anupama, Krepp, Joseph, Layer, Jay, Lee, Steven H., Leppo, Jeffrey, Lesser, John, Leung, Steve, Lewin, Howard, Litmanovich, Diana, Liu, Yiyan, Magurany, Kathleen, Markowitz, Jeremy, Marn, Amanda, Matis, Stephen E., Mckenna, Michael, Mcrae, Tony, Mendoza, Fernando, Merhige, Michael, Min, David, Moffitt, Chanan, Moncher, Karen, Moore, Warren, Morayati, Shamil, Morris, Michael, Mossa-Basha, Mahmud, Mrsic, Zorana, Murthy, Venkatesh, Nagpal, Prashant, Napier, Kyle, Nelson, Katarina, Nijjar, Prabhjot, Osman, Medhat, Passen, Edward, Patel, Amit, Patil, Pravin, Paul, Ryan, Phillips, Lawrence, Polsani, Venkateshwar, Poludasu, Rajaram, Pomerantz, Brian, Porter, Thomas, Prentice, Ryan, Pursnani, Amit, Rabbat, Mark, Ramamurti, Suresh, Rich, Florence, Luna, Hiram Rivera, Robinson, Austin, Robles, Kim, Rodríguez, Cesar, Rorie, Mark, Rumberger, John, Russell, Raymond, Sabra, Philip, Sadler, Diego, Schemmer, Mary, Schoepf, U. Joseph, Shah, Samir, Shah, Nishant, Shanbhag, Sujata, Sharma, Gaurav, Shayani, Steven, Shirani, Jamshid, Shivaram, Pushpa, Sigman, Steven, Simon, Mitch, Slim, Ahmad, Smith, David, Smith, Alexandra, Soman, Prem, Sood, Aditya, Srichai-Parsia, Monvadi Barbara, Streeter, James, T, Albert, Tawakol, Ahmed, Thomas, Dustin, Thompson, Randall, Torbet, Tara, Trinidad, Desiree, Ullery, Shawn, Unzek, Samuel, Uretsky, Seth, Vallurupalli, Srikanth, Verma, Vikas, Waller, Alfonso, Wang, Ellen, Ward, Parker, Weissman, Gaby, Wesbey, George, White, Kelly, Wolinsky, David, Yost, Sandra, Zgaljardic, Michael, Alonso, Omar, Beretta, Mario, Ferrando, Rodolfo, Kapitan, Miguel, Mut, Fernando, Djuraev, Omoa, Rozikhodjaeva, Gulnora, Le Ngoc, Ha, Mai, Son Hong, Nguyen, Xuan Canh, Hirschfeld, Cole B., Shaw, Leslee J., Williams, Michelle C., Lahey, Ryan, Villines, Todd C., Dorbala, Sharmila, Choi, Andrew D., Shah, Nishant R., Bluemke, David A., Berman, Daniel S., Blankstein, Ron, Ferencik, Maro, Narula, Jagat, Winchester, David, Malkovskiy, Eli, Goebel, Benjamin, Randazzo, Michael J., Lopez-Mattei, Juan, Parwani, Purvi, Vitola, Joao V., Cerci, Rodrigo J., Better, Nathan, Raggi, Paolo, Lu, Bin, Sergienko, Vladimir, Sinitsyn, Valentin, Kudo, Takashi, Nørgaard, Bjarne Linde, Maurovich-Horvat, Pál, Cohen, Yosef A., Pascual, Thomas N. B., Pynda, Yaroslav, Dondi, Maurizio, Paez, Diana, Einstein, Andrew J., Cerci, Rodrigo, Hinterleitner, Gerd, Lu, Yao, Morozova, Olga, Xu, Zhuoran, Cohen, Yosef, Randazzo, Michael, Choi, Andrew, Nasery, Mohammad Nawaz, Goda, Artan, Shirka, Ervina, Benlabgaa, Rabie, Bouyoucef, Salah, Medjahedi, Abdelkader, Nailli, Qai, Agolti, Mariela, Aguero, Roberto Nicola, Alak, Maria del Carmen, Alberguina, Lucia Graciela, Arroñada, Guillermo, Astesiano, Andrea, Astesiano, Alfredo, Norton, Carolina Ba, Benteo, Pablo, Blanco, Juan, Bonelli, Juan Manuel, Bustos, Jose Javier, Cabrejas, Raul, Cachero, Jorge, Campisi, Roxana, Canderoli, Alejandro, Carames, Silvia, Carrascosa, Patrícia, Castro, Ricardo, Cendoya, Oscar, Cognigni, Luciano Martin, Collaud, Carlo, Cortes, Claudia, Courtis, Javier, Cragnolino, Daniel, Daicz, Mariana, De La Vega, Alejandro, De Maria, Silvia Teresa, Del Riego, Horacio, Dettori, Fernando, Deviggiano, Alejandro, Dragonetti, Laura, Embon, Mario, Enriquez, Ruben Emilio, Ensinas, Jorge, Faccio, Fernando, Facello, Adolfo, Garofalo, Diego, Geronazzo, Ricardo, Gonza, Natalia, Gutierrez, Luca, Guzzo, Miguel Angel, Hasbani, Victor, Huerin, Melina, Jäger, Victor, Lewkowicz, Julio Manuel, Nieves A López De Munaín, Maria, Lotti, Jose Maria, Marquez, Alejandra, Masoli, Osvaldo, Masoli, Osvaldo Horacio, Mastrovito, Edgardo, Mayoraz, Matia, Melado, Graciela Eva, Mele, Anibal, Merani, Maria Fernanda, Meretta, Alejandro Horacio, Molteni, Susana, Montecinos, Marco, Noguera, Eduardo, Novoa, Carlo, Sueldo, Claudio Pereyra, Ascani, Sebastian Perez, Pollono, Pablo, Pujol, Maria Paula, Radzinschi, Alejandro, Raimondi, Gustavo, Redruello, Marcela, Rodríguez, Marina, Rodríguez, Matía, Romero, Romina Lorena, Acuña, Arturo Romero, Rovaletti, Federico, San Miguel, Luca, Solari, Lucrecia, Strada, Bruno, Traverso, Sonia, Traverzo, Sonia Simona, Espeche, Maria del Huerto Velazquez, Weihmuller, Juan Sebastian, Wolcan, Juan, Zeffiro, Susana, Sakanyan, Mari, Beuzeville, Scott, Boktor, Raef, Butler, Patrick, Calcott, Jennifer, Carr, Loretta, Chan, Virgil, Chao, Charle, Chong, Woon, Dobson, Mark, Downie, D'Arne, Dwivedi, Girish, Elison, Barry, Engela, Jean, Francis, Roslyn, Gaikwad, Anand, Basavaraj, Ashok Gangasandra, Goodwin, Bruce, Greenough, Robert, Hamilton-Craig, Christian, Hsieh, Victar, Joshi, Subodh, Lederer, Karin, Lee, Kenneth, Lee, Joseph, Magnussen, John, Mai, Nghi, Mander, Gordon, Murton, Fiona, Nandurkar, Dee, Neill, Johanne, O'Rourke, Edward, O'Sullivan, Patricia, Pandos, George, Pathmaraj, Kunthi, Pitman, Alexander, Poulter, Rohan, Premaratne, Manuja, Prior, David, Ridley, Lloyd, Rutherford, Natalie, Salehi, Hamid, Saunders, Connor, Scarlett, Luke, Seneviratne, Sujith, Shetty, Deepa, Shrestha, Ganesh, Shulman, Jonathan, Solanki, Vijay, Stanton, Tony, Stuart, Murch, Stubbs, Michael, Swainson, Ian, Taubman, Kim, Taylor, Andrew, Thomas, Paul, Unger, Steven, Upton, Anthony, Vamadevan, Shankar, Van Gaal, William, Verjans, Johan, Voutnis, Demetriu, Wayne, Victor, Wilson, Peter, Wong, David, Wong, Kirby, Younger, John, Feuchtner, Gudrun, Mirzaei, Siroo, Weiss, Konrad, Maroz-Vadalazhskaya, Natallia, Gheysens, Olivier, Homans, Filip, Moreno-Reyes, Rodrigo, Pasquet, Agnè, Roelants, Veronique, Van De Heyning, Caroline M., Ríos, Raúl Araujo, Soldat-Stankovic, Valentina, Stankovic, Sinisa, Albernaz Siqueira, Maria Helena, Almeida, Augusto, Alves Togni, Paulo Henrique, Andrade, Jose Henrique, Andrade, Luciana, Anselmi, Carlo, Araújo, Roberta, Azevedo, Guilherme, Bezerra, Sabbrina, Biancardi, Rodrigo, Grossman, Gabriel Blacher, Brandão, Simone, Pianta, Diego Bromfman, Carreira, Lara, Castro, Bruno, Chang, Tien, Cunali, Fernando, Cury, Roberto, Dantas, Roberto, de Amorim Fernandes, Fernando, De Lorenzo, Andrea, De Macedo Filho, Robson, Erthal, Fernanda, Fernandes, Fabio, Fernandes, Juliano, De Souza, Thiago Ferreira, Alves, Wilson Furlan, Ghini, Bruno, Goncalves, Luiz, Gottlieb, Ilan, Hadlich, Marcelo, Kameoka, Viníciu, Lima, Ronaldo, Lima, Adna, Lopes, Rafael Willain, Machado e Silva, Ricardo, Magalhães, Tiago, Silva, Fábio Martin, Mastrocola, Luiz Eduardo, Medeiros, Fábio, Meneghetti, José Claudio, Naue, Vania, Naves, Danilo, Nolasco, Roberto, Nomura, Cesar, Oliveira, Joao Bruno, Paixao, Eduardo, De Carvalho, Filipe Penna, Pinto, Ibraim, Possetti, Priscila, Quinta, Mayra, Nogueira Ramos, Rodrigo Rizzo, Rocha, Ricardo, Rodrigues, Alfredo, Rodrigues, Carlo, Romantini, Leila, Sanches, Adelina, Santana, Sara, Sara da Silva, Leonardo, Schvartzman, Paulo, Matushita, Cristina Sebastião, Senra, Tiago, Shiozaki, Afonso, Menezes de Siqueira, Maria Eduarda, Siqueira, Cristiano, Smanio, Paola, Soares, Carlos Eduardo, Junior, José Soare, Bittencourt, Marcio Sommer, Spiro, Bernardo, Mesquita, Cláudio Tinoco, Torreao, Jorge, Torres, Rafael, Uellendahl, Marly, Monte, Guilherme Urpia, Veríssimo, Otávia, Cabeda, Estevan Vieira, Pedras, Felipe Villela, Waltrick, Roberto, Zapparoli, Marcello, Naseer, Hamid, Garcheva-Tsacheva, Marina, Kostadinova, Irena, Theng, Youdaline, Abikhzer, Gad, Barette, Rene, Chow, Benjamin, Dabreo, Dominique, Friedrich, Matthia, Garg, Ria, Hafez, Mohammed Nassoh, Johnson, Chri, Kiess, Marla, Leipsic, Jonathon, Leung, Eugene, Miller, Robert, Oikonomou, Anastasia, Probst, Stephan, Roifman, Idan, Small, Gary, Tandon, Vika, Trivedi, Adwait, White, Jame, Zukotynski, Katherine, Canessa, Jose, Muñoz, Gabriel Castro, Concha, Carmen, Hidalgo, Pablo, Lovera, Cesar, Massardo, Teresa, Vargas, Luis Salazar, Abad, Pedro, Arturo, Harold, Ayala, Sandra, Benitez, Lui, Cadena, Alberto, Caicedo, Carlo, Moncayo, Antonio Calderón, Gomez, Sharon, Gutierrez Villamil, Claudia T., Jaimes, Claudia, Londoño, Juan, Londoño Blair, Juan Lui, Pabon, Luz, Pineda, Mauricio, Rojas, Juan Carlo, Ruiz, Diego, Escobar, Manuel Valencia, Vasquez, Andre, Vergel, Damiana, Zuluaga, Alejandro, Gamboa, Isabel Berrocal, Castro, Gabriel, González, Ulise, Baric, Ana, Batinic, Tonci, Franceschi, Maja, Paar, Maja Hrabak, Jukic, Mladen, Medakovic, Petar, Persic, Viktor, Prpic, Marina, Punda, Ante, Batista, Juan Felipe, Gómez Lauchy, Juan Manuel, Gutierrez, Yamile Marco, Menéndez, Rayner, Peix, Amalia, Rochela, Lui, Panagidis, Christoforo, Petrou, Ioanni, Engelmann, Vaclav, Kaminek, Milan, Kincl, Vladimír, Lang, Otto, Simanek, Milan, Abdulla, Jawdat, Bøttcher, Morten, Christensen, Mette, Gormsen, Lars Christian, Hasbak, Philip, Hess, Søren, Holdgaard, Paw, Johansen, Allan, Kyhl, Kasper, Norgaard, Bjarne Linde, Øvrehus, Kristian Altern, Rønnow Sand, Niels Peter, Steffensen, Rolf, Thomassen, Ander, Zerahn, Bo, Perez, Alfredo, Escorza Velez, Giovanni Alejandro, Velez, Mayra Sanchez, Abdel Aziz, Islam Shawky, Abougabal, Mahasen, Ahmed, Taghreed, Allam, Adel, Asfour, Ahmed, Hassan, Mona, Hassan, Alia, Ibrahim, Ahmed, Kaffas, Sameh, Kandeel, Ahmed, Ali, Mohamed Mandour, Mansy, Ahmad, Maurice, Hany, Nabil, Sherif, Shaaban, Mahmoud, Flores, Ana Camila, Poksi, Anne, Knuuti, Juhani, Kokkonen, Velipekka, Larikka, Martti, Uusitalo, Valtteri, Bailly, Matthieu, Burg, Samuel, Deux, Jean-Françoi, Habouzit, Vincent, Hyafil, Fabien, Lairez, Olivier, Proffit, Franck, Regaieg, Hamza, Sarda-Mantel, Laure, Tacher, Vania, Schneider, Roman P., Ayetey, Harold, Angelidis, George, Archontaki, Aikaterini, Chatziioannou, Sofia, Datseris, Ioanni, Fragkaki, Christina, Georgoulias, Panagioti, Koukouraki, Sophia, Koutelou, Maria, Kyrozi, Eleni, Repasos, Evangelo, Stavrou, Petro, Valsamaki, Pipitsa, Gonzalez, Carla, Gutierrez, Goleat, Maldonado, Alejandro, Buga, Klara, Garai, Ildiko, Schmidt, Erzsébet, Szilveszter, Balint, Várady, Edit, Banthia, Nilesh, Bhagat, Jinendra Kumar, Bhargava, Rishi, Bhat, Vivek, Bhatia, Mona, Choudhury, Partha, Chowdekar, Vijay Sai, Irodi, Aparna, Jain, Shashank, Joseph, Elizabeth, Kumar, Sukriti, Girijanandan Mahapatra, Prof Dr, Mitra, Deepanjan, Mittal, Bhagwant Rai, Ozair, Ahmad, Patel, Chetan, Patel, Tapan, Patel, Ravi, Patel, Shivani, Saxena, Sudhir, Sengupta, Shantanu, Singh, Santosh, Singh, Bhanupriya, Sood, Ashwani, Verma, Atul, Affandi, Erwin, Alam, Edison, Padma, Savenadia, Gunawan, Gani, Hapkido, Habusari, Hidayat, Basuki, Huda, Aulia, Mukti, Anggoro Praja, Prawiro, Djoko, Soeriadi, Erwin Affandi, Syawaluddin, Hilman, Albadr, Amjed, Assadi, Majid, Emami, Farshad, Houshmand, Golnaz, Maleki, Majid, Rostami, Maryam Tajik, Zakavi, Seyed Rasoul, Zaid, Eed Abu, Agranovich, Svetlana, Arnson, Yoav, Bar-Shalom, Rachel, Frenkel, Alex, Knafo, Galit, Lugassi, Rachel, Maor Moalem, Israel Shlomo, Mor, Maya, Muskal, Noam, Ranser, Sara, Shalev, Aryeh, Albano, Domenico, Alongi, Pierpaolo, Arnone, Gaspare, Bagatin, Elisa, Baldari, Sergio, Bauckneht, Matteo, Bertelli, Paolo, Bianco, Francesco, Bonfiglioli, Rachele, Boni, Roberto, Bruno, Andrea, Bruno, Isabella, Busnardo, Elena, Califaretti, Elena, Camoni, Luca, Carnevale, Aldo, Casoni, Roberta, Cavallo, Armando Ugo, Cavenaghi, Giorgio, Chierichetti, Franca, Chiocchi, Marcello, Cittanti, Corrado, Colletta, Mauro, Conti, Umberto, Cossu, Alberto, Cuocolo, Alberto, Cuzzocrea, Marco, De Rimini, Maria Luisa, De Vincentis, Giuseppe, Del Giudice, Eleonora, Del Torto, Alberico, Della Tommasina, Veronica, Durmo, Rexhep, Erba, Paola Anna, Evangelista, Laura, Faletti, Riccardo, Faragasso, Evelina, Farsad, Mohsen, Ferro, Paola, Florimonte, Luigia, Frantellizzi, Viviana, Fringuelli, Fabio Massimo, Gatti, Marco, Gaudiano, Angela, Gimelli, Alessia, Giubbini, Raffaele, Giuffrida, Francesca, Ialuna, Salvatore, Laudicella, Riccardo, Leccisotti, Lucia, Leva, Lucia, Liga, Riccardo, Liguori, Carlo, Longo, Giampiero, Maffione, Margherita, Mancini, Maria Elisabetta, Marcassa, Claudio, Milan, Elisa, Nardi, Barbara, Pacella, Sara, Pepe, Giovanna, Pontone, Gianluca, Pulizzi, Sabina, Quartuccio, Natale, Rampin, Lucia, Ricci, Fabrizio, Rossini, Pierluigi, Rubini, Giuseppe, Russo, Vincenzo, Sacchetti, Gian Mauro, Sambuceti, Gianmario, Scarano, Massimo, Sciagrà, Roberto, Sperandio, Massimiliano, Stefanelli, Antonella, Ventroni, Guido, Zoboli, Stefania, Baugh, Dainia, Chambers, Duane, Madu, Ernest, Nunura, Felix, Asano, Hiroshi, Chimura, Chimura Misato, Fujimoto, Shinichiro, Fujisue, Koichiro, Fukunaga, Tomohisa, Fukushima, Yoshimitsu, Fukuyama, Kae, Hashimoto, Jun, Ichikawa, Yasutaka, Iguchi, Nobuo, Imai, Masamichi, Inaki, Anri, Ishimura, Hayato, Isobe, Satoshi, Kadokami, Toshiaki, Kato, Takao, Kumita, Shinichiro, Maruno, Hirotaka, Mataki, Hiroyuki, Miyagawa, Masao, Morimoto, Ryota, Moroi, Masao, Nagamachi, Shigeki, Nakajima, Kenichi, Nakata, Tomoaki, Nakazato, Ryo, Nanasato, Mamoru, Naya, Masanao, Norikane, Takashi, Ohta, Yasutoshi, Okayama, Satoshi, Okizaki, Atsutaka, Otomi, Yoichi, Otsuka, Hideki, Saito, Masaki, Sakata, Sakata Yasushi, Sarai, Masayoshi, Sato, Daisuke, Shiraishi, Shinya, Suwa, Yoshinobu, Takanami, Kentaro, Takehana, Kazuya, Taki, Junichi, Tamaki, Nagara, Taniguchi, Yasuyo, Teragawa, Hiroki, Tomizawa, Nobuo, Tsujita, Kenichi, Umeji, Kyoko, Wakabayashi, Yasushi, Yamada, Shinichiro, Yamazaki, Shinya, Yoneyama, Tatsuya, Rawashdeh, Mohammad, Batyrkhanov, Daultai, Dautov, Tairkhan, Makhdomi, Khalid, Ombati, Kevin, Alkandari, Faridah, Garashi, Masoud, Coie, Tchoyoson Lim, Rajvong, Sonexay, Kalinin, Artem, Kalnina, Marika, Haidar, Mohamad, Komiagiene, Renata, Kviecinskiene, Giedre, Mataciunas, Mindauga, Vajauskas, Donata, Picard, Christian, Karim, Noor Khairiah A., Reichmuth, Luise, Samuel, Anthony, Allarakha, Mohammad Aaftaab, Naojee, Ambedhkar Shantaram, Alexanderson-Rosas, Erick, Barragan, Erika, González-Montecinos, Alejandro Becerril, Cabada, Manuel, Rodriguez, Daniel Calderon, Carvajal-Juarez, Isabel, Cortés, Violeta, Cortés, Filiberto, De La Peña, Erasmo, Gama-Moreno, Manlio, González, Lui, Ramírez, Nelsy Gonzalez, Jiménez-Santos, Moisé, Matos, Lui, Monroy, Edgar, Morelos, Martha, Ornelas, Mario, Ortga Ramirez, Jose Alberto, Preciado-Anaya, André, Preciado-Gutiérrez, Óscar Ulise, Barragan, Adriana Puente, Rosales Uvera, Sandra Graciela, Sandoval, Sigelinda, Tomas, Miguel Santaularia, Sierra-Galan, Lilia M., Siu, Silvia, Vallejo, Enrique, Valles, Mario, Faraggi, Marc, Sereegotov, Erdenechimeg, Ilic, Srdja, Ben-Rais, Nozha, Alaoui, Nadia Ismaili, Taleb, Sara, Myo, Khin Pa, Thu, Phyo Si, Ghimire, Ram Kumar, Rajbanshi, Bijoy, Barneveld, Peter, Glaudemans, Andor, Habets, Jesse, Koopmans, Klaas Pieter, Manders, Jeroen, Pool, Stefan, Scholte, Arthur, Scholtens, Asbjørn, Slart, Riemer, Thimister, Paul, Van Asperen, Erik-Jan, Veltman, Niel, Verschure, Derk, Wagenaar, Nil, Edmond, John, Ellis, Chri, Johnson, Kerryanne, Keenan, Ro, Hua, Shaw, Occleshaw, Christopher, Sasse, Alexander, To, Andrew, Van Pelt, Niel, Young, Calum, Cuadra, Teresa, Roque Vanegas, Hector Bladimir, Soli, Idrissa Adamou, Issoufou, Djibrillou Moussa, Ayodele, Tolulope, Madu, Chibuzo, Onimode, Yetunde, Efros-Monsen, Elen, Forsdahl, Signe Helene, Hildre Dimmen, Jenni-Mari, Jørgensen, Arve, Krohn, Isabel, Løvhaugen, Pål, Bråten, Anders Tjellaug, Al Dhuhli, Humoud, Al Kindi, Faiza, Al-Bulushi, Naeema, Jawa, Zabah, Tag, Naima, Afzal, Muhammad Shehzad, Fatima, Shazia, Younis, Muhammad Numair, Riaz, Musab, Saadullah, Mohammad, Herrera, Yariela, Lenturut-Katal, Dora, Vázquez, Manuel Castillo, Ortellado, José, Akhter, Afroza, Cao, Dianbo, Cheung, Stephen, Dai, Xu, Gong, Lianggeng, Han, Dan, Hou, Yang, Li, Caiying, Li, Tao, Li, Dong, Li, Sijin, Liu, Jinkang, Liu, Hui, Ng, Ming Yen, Sun, Kai, Tang, Gongshun, Wang, Jian, Wang, Ximing, Wang, Zhao-Qian, Wang, Yining, Wang, Yifan, Wu, Jiang, Wu, Zhifang, Xia, Liming, Xiao, Jiangxi, Xu, Lei, Yang, Youyou, Yin, Wu, Yu, Jianqun, Yuan, Li, Zhang, Tong, Zhang, Longjiang, Zhang, Yong-Gao, Zhang, Xiaoli, Zhu, Li, Alfaro, Ana, Abrihan, Paz, Barroso, Asela, Cruz, Eric, Gomez, Marie Rhiamar, Magboo, Vincent Peter, Medina, John Michael, Obaldo, Jerry, Pastrana, Davidson, Pawhay, Christian Michael, Quinon, Alvin, Tang, Jeanelle Margareth, Tecson, Bettina, Uson, Kristine Joy, Uy, Mila, Kostkiewicz, Magdalena, Kunikowska, Jolanta, Bettencourt, Nuno, Cantinho, Guilhermina, Ferreira, Antonio, Syed, Ghulam, Arnous, Samer, Atyani, Said, Byrne, Angela, Gleeson, Tadhg, Kerins, David, Meehan, Conor, Murphy, David, Murphy, Mark, Murray, John, O'Brien, Julie, Bang, Ji-In, Bom, Henry, Cho, Sang-Geon, Hong, Chae Moon, Jang, Su Jin, Jeong, Yong Hyu, Kang, Won Jun, Kim, Ji-Young, Lee, Jaetae, Namgung, Chang Kyeong, So, Young, Won, Kyoung Sook, Majstorov, Venjamin, Vavlukis, Marija, Salobir, Barbara Gužic, Štalc, Monika, Benedek, Theodora, Benedek, Imre, Mititelu, Raluca, Stan, Claudiu Adrian, Ansheles, Alexey, Dariy, Olga, Drozdova, Olga, Gagarina, Nina, Gulyaev, Vsevolod Milyevich, Itskovich, Irina, Karalkin, Anatoly, Kokov, Alexander, Migunova, Ekaterina, Pospelov, Viktor, Ryzhkova, Daria, Saifullina, Guzaliya, Sazonova, Svetlana, Shurupova, Irina, Trifonova, Tatjana, Ussov, Wladimir Yurievich, Vakhromeeva, Margarita, Valiullina, Nailya, Zavadovsky, Konstantin, Zhuravlev, Kirill, Alasnag, Mirvat, Okarvi, Subhani, Saranovic, Dragana Sobic, Keng, Felix, Jason See, Jia Hao, Sekar, Ramkumar, Yew, Min Sen, Vondrak, Andrej, Bejai, Shereen, Bennie, George, Bester, Ria, Engelbrecht, Gerrit, Evbuomwan, Osayande, Gongxeka, Harlem, Vuuren, Magritha Jv, Kaplan, Mitchell, Khushica, Purbhoo, Lakhi, Hoosen, Louw, Lizette, Malan, Nico, Milos, Katarina, Modiselle, Moshe, More, Stuart, Naidoo, Mathava, Scholtz, Leonie, Vangu, Mboyo, Aguadé-Bruix, Santiago, Blanco, Isabel, Cabrera, Antonio, Camarero, Alicia, Casáns-Tormo, Irene, Cuellar-Calabria, Hug, Flotats, Albert, Fuentes Cañamero, Maria Eugenia, García, María Elia, Jimenez-Heffernan, Amelia, Leta, Rubén, Diaz, Javier Lopez, Lumbreras, Lui, Marquez-Cabeza, Juan Javier, Martin, Francisco, Martinez de Alegria, Anxo, Medina, Francisco, Canal, Maria Pedrera, Peiro, Virginia, Pubul-Nuñez, Virginia, Rayo Madrid, Juan Ignacio, Rey, Cristina Rodríguez, Perez, Ricardo Ruano, Ruiz, Joaquín, Hernández, Gertrudis Sabatel, Sevilla, Ana, Zeidán, Nahla, Nanayakkara, Damayanthi, Udugama, Chandraguptha, Simonsson, Magnu, Alkadhi, Hatem, Buechel, Ronny Ralf, Burger, Peter, Ceriani, Luca, De Boeck, Bart, Gräni, Christoph, Juillet de Saint Lager Lucas, Alix, Kamani, Christel H., Kawel-Boehm, Nadine, Manka, Robert, Prior, John O., Rominger, Axel, Vallée, Jean-Paul, Khiewvan, Benjapa, Premprabha, Teerapon, Thientunyakit, Tanyaluck, Sellem, Ali, Kir, Kemal Metin, Sayman, Haluk, Sebikali, Mugisha Juliu, Muyinda, Zerida, Kmetyuk, Yaroslav, Korol, Pavlo, Mykhalchenko, Olena, Pliatsek, Volodymyr, Satyr, Maryna, Albalooshi, Batool, Ahmed Hassan, Mohamed Ismail, Anderson, Jill, Bedi, Punit, Biggans, Thoma, Bularga, Anda, Bull, Russell, Burgul, Rajesh, Carpenter, John-Paul, Coles, Duncan, Cusack, David, Deshpande, Aparna, Dougan, John, Fairbairn, Timothy, Farrugia, Alexia, Gopalan, Deepa, Gummow, Alistair, Ramkumar, Prasad Guntur, Hamilton, Mark, Harbinson, Mark, Hartley, Thoma, Hudson, Benjamin, Joshi, Nikhil, Kay, Michael, Kelion, Andrew, Khokhar, Azhar, Kitt, Jamie, Lee, Ken, Low, Chen, Mak, Sze Mun, Marousa, Ntouskou, Martin, Jon, Mcalindon, Elisa, Menezes, Leon, Morgan-Hughes, Gareth, Moss, Alastair, Murray, Anthony, Nicol, Edward, Patel, Dilip, Peebles, Charle, Pugliese, Francesca, Luis Rodrigues, Jonathan Carl, Rofe, Christopher, Sabharwal, Nikant, Schofield, Rebecca, Semple, Thoma, Sharma, Naveen, Strouhal, Peter, Subedi, Deepak, Topping, William, Tweed, Katharine, Weir-Mccall, Jonathan, Abbara, Suhny, Abbasi, Taimur, Abbott, Brian, Abohashem, Shady, Abramson, Sandra, Al-Abboud, Tarek, Al-Mallah, Mouaz, Almousalli, Omar, Ananthasubramaniam, Karthikeyan, Kumar, Mohan Ashok, Askew, Jeffrey, Attanasio, Lea, Balmer-Swain, Mallory, Bayer, Richard R., Bernheim, Adam, Bhatti, Sabha, Bieging, Erik, Bloom, Stephen, Blue, Sean, Bluemke, David, Borges, Andressa, Branch, Kelley, Bravo, Paco, Brothers, Jessica, Budoff, Matthew, Bullock-Palmer, Renée, Burandt, Angela, Burke, Floyd W., Bush, Kelvin, Candela, Candace, Capasso, Elizabeth, Cavalcante, Joao, Chang, Donald, Chatterjee, Saurav, Chatzizisis, Yianni, Cheezum, Michael, Chen, Tiffany, Chen, Jennifer, Chen, Marcu, Clarcq, Jame, Cordero, Ayreen, Crim, Matthew, Danciu, Sorin, Decter, Bruce, Dhruva, Nimish, Doherty, Neil, Doukky, Rami, Dunbar, Anjori, Duvall, William, Edwards, Rachael, Esquitin, Kerry, Farah, Husam, Fentanes, Emilio, Fisher, Daniel, Fitzpatrick, Daniel, Foster, Cameron, Fuisz, Tony, Gannon, Michael, Gastner, Lori, Gerson, Myron, Ghoshhajra, Brian, Goldberg, Alan, Goldner, Brian, Gonzalez, Jorge, Gore, Rosco, Gracia-López, Sandra, Hage, Fadi, Haider, Agha, Haider, Sofia, Hamirani, Yasmin, Hassen, Karen, Hatfield, Mallory, Hawkins, Carolyn, Hawthorne, Katie, Heath, Nichola, Hendel, Robert, Hernandez, Phillip, Hill, Gregory, Horgan, Stephen, Huffman, Jeff, Hurwitz, Lynne, Iskandrian, Ami, Janardhanan, Rajesh, Jellis, Christine, Jerome, Scott, Kalra, Dinesh, Kaviratne, Summanther, Kay, Fernando, Kelly, Faith, Khalique, Omar, Kinkhabwala, Mona, Iii, George Kinzfogl, Kircher, Jacqueline, Kirkbride, Rachael, Kontos, Michael, Kottam, Anupama, Krepp, Joseph, Layer, Jay, Lee, Steven H., Leppo, Jeffrey, Lesser, John, Leung, Steve, Lewin, Howard, Litmanovich, Diana, Liu, Yiyan, Magurany, Kathleen, Markowitz, Jeremy, Marn, Amanda, Matis, Stephen E., Mckenna, Michael, Mcrae, Tony, Mendoza, Fernando, Merhige, Michael, Min, David, Moffitt, Chanan, Moncher, Karen, Moore, Warren, Morayati, Shamil, Morris, Michael, Mossa-Basha, Mahmud, Mrsic, Zorana, Murthy, Venkatesh, Nagpal, Prashant, Napier, Kyle, Nelson, Katarina, Nijjar, Prabhjot, Osman, Medhat, Passen, Edward, Patel, Amit, Patil, Pravin, Paul, Ryan, Phillips, Lawrence, Polsani, Venkateshwar, Poludasu, Rajaram, Pomerantz, Brian, Porter, Thoma, Prentice, Ryan, Pursnani, Amit, Rabbat, Mark, Ramamurti, Suresh, Rich, Florence, Luna, Hiram Rivera, Robinson, Austin, Robles, Kim, Rodríguez, Cesar, Rorie, Mark, Rumberger, John, Russell, Raymond, Sabra, Philip, Sadler, Diego, Schemmer, Mary, Schoepf, U. Joseph, Shah, Samir, Shah, Nishant, Shanbhag, Sujata, Sharma, Gaurav, Shayani, Steven, Shirani, Jamshid, Shivaram, Pushpa, Sigman, Steven, Simon, Mitch, Slim, Ahmad, Smith, David, Smith, Alexandra, Soman, Prem, Sood, Aditya, Srichai-Parsia, Monvadi Barbara, Streeter, Jame, T, Albert, Tawakol, Ahmed, Thomas, Dustin, Thompson, Randall, Torbet, Tara, Trinidad, Desiree, Ullery, Shawn, Unzek, Samuel, Uretsky, Seth, Vallurupalli, Srikanth, Verma, Vika, Waller, Alfonso, Wang, Ellen, Ward, Parker, Weissman, Gaby, Wesbey, George, White, Kelly, Wolinsky, David, Yost, Sandra, Zgaljardic, Michael, Alonso, Omar, Beretta, Mario, Ferrando, Rodolfo, Kapitan, Miguel, Mut, Fernando, Djuraev, Omoa, Rozikhodjaeva, Gulnora, Le Ngoc, Ha, Mai, Son Hong, Nguyen, Xuan Canh, Hirschfeld, C, Shaw, L, Williams, M, Lahey, R, Villines, T, Dorbala, S, Choi, A, Shah, N, Bluemke, D, Berman, D, Blankstein, R, Ferencik, M, Narula, J, Winchester, D, Malkovskiy, E, Goebel, B, Randazzo, M, Lopez-Mattei, J, Parwani, P, Vitola, J, Cerci, R, Better, N, Raggi, P, Lu, B, Sergienko, V, Sinitsyn, V, Kudo, T, Nørgaard, B, Maurovich-Horvat, P, Cohen, Y, Pascual, T, Pynda, Y, Dondi, M, Paez, D, Einstein, A, and Erba, P

Subjects
Aging, Coronavirus disease 2019 (COVID-19), Clinical Sciences, coronavirus, Disease, 030204 cardiovascular system & hematology, Cardiorespiratory Medicine and Haematology, Cardiovascular, 030218 nuclear medicine & medical imaging, NO, 03 medical and health sciences, 0302 clinical medicine, COVID-19 Testing, Cardiovascular procedures, Predictive Value of Tests, cardiovascular disease, Clinical Research, Environmental health, INCAPS-COVID Investigators Group, Pandemic, Volume reduction, Medicine, Humans, Radiology, Nuclear Medicine and imaging, cardiovascular imaging, diagnostic cardiovascular procedure, Pandemics, business.industry, SARS-CoV-2, Prevention, COVID-19, Health Services, United States/epidemiology, United States, Invasive coronary angiography, coronaviru, Heart Disease, Good Health and Well Being, MYOCARDIAL-INFARCTION, Cardiovascular System & Hematology, Predictive value of tests, HOSPITAL ADMISSIONS, Cardiology and Cardiovascular Medicine, Early phase, business
Abstract

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-U.S. institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection.

Published
2021
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43. Delegation of Work Within a Patient-Centered Medical Home

Author

Bonnie J. Wakefield, Michelle A. Lampman, Monica B. Paez, Amany Farag, Heidi Ferguson, and Greg L. Stewart

Subjects
Patient Care Team, United States Department of Veterans Affairs, Primary Health Care, Leadership and Management, Patient-Centered Care, Surveys and Questionnaires, Humans, General Medicine, United States
Abstract

The aim of this study was to analyze the perceptions of core team members implementing patient-centered medical home (PCMH) within the Veterans Health Administration regarding delegation of work.Significant overlap exists in the performance of work tasks among PCMH team members (primary care providers, RNs, clinical associates, clerks), and scant literature exists on appropriate delegation within PCMH teams.This study conducted used a quantitative and qualitative analysis of 4254 respondents to a 2018 survey.Primary care providers rely heavily on team members, and nurses report being relied upon at high levels. Lack of role clarity and a perceived need for a team leader were concerns voiced by participants.Findings indicated a need for clear guidance on roles and responsibilities within the team. Patient-centered medical home team members need information about the scope of practice of each professional group to allow providers to function at the top of their scope of practice and ensure effective delegation.

Published
2022

44. Non-prescribed antibiotic dispensing practices for symptoms of urinary tract infection in community pharmacies and accredited drug dispensing outlets in Tanzania : a simulated clients approach

Author

Pendo M. Ndaki, Martha F. Mushi, Joseph R. Mwanga, Eveline T. Konje, Stella Mugassa, Msilikale W. Manyiri, Stanley M. Mwita, Nyanda E. Ntinginya, Blandina T. Mmbaga, Katherine Keenan, Wilber Sabiiti, Mike Kesby, Fernando Benitez-Paez, Alison Sandeman, Matthew T. G. Holden, Stephen E. Mshana, Medical Research Council, University of St Andrews. School of Geography & Sustainable Development, University of St Andrews. School of Medicine, University of St Andrews. Infection and Global Health Division, University of St Andrews. Geographies of Sustainability, Society, Inequalities and Possibilities, University of St Andrews. Biomedical Sciences Research Complex, and University of St Andrews. St Andrews Bioinformatics Unit

Subjects
Male, Pharmacies, MCC, Antibiotic resistance, Antibiotic, NDAS, Azithromycin, Tanzania, Prescription, Anti-Bacterial Agents, Cross-Sectional Studies, Pharmaceutical Preparations, Urinary Tract Infections, Humans, Female, Family Practice, Dispensing practice
Abstract

Background Antibiotic dispensing without prescription is a major determinant of the emergence of Antimicrobial Resistance (AMR) which has impact on population health and cost of healthcare delivery. This study used simulated clients describing UTI like symptoms to explore compliance with regulation, variations in dispensing practices and drug recommendation, and quality of seller-client interaction on the basis of the gender of the client and the type of drug outlets in three regions in Tanzania. Method A total of 672 Accredited Drug Dispensing Outlets (ADDOs) and community pharmacies were visited by mystery clients (MCs). The study was conducted in three regions of Tanzania namely Kilimanjaro (180, 26.79%), Mbeya (169, 25.15%) and Mwanza (323, 48.07%) in March–May 2020. During data collection, information was captured using epicollect5 software before being analyzed using Stata version 13. Results Overall, 89.43% (CI: 86.87–91.55%) of drug sellers recommended antibiotics to clients who described UTI like symptoms but held no prescription and 58.93% were willing to sell less than the minimum recommended course. Female clients were more likely than male to be asked if they were taking other medications (27.2% vs 9.8%), or had seen a doctor (27.8% vs 14.7%), and more likely to be advised to consult a doctor (21.6% vs 9.0%); pharmacies addressed these issues more often than ADDOs (17.7% vs 13.2, 23.9% vs 16.6%, 17.7 vs 10.9% respectively). Sellers recommended 32 different drugs to treat the same set of symptoms, only 7 appear in the Tanzanian Standard Treatment Guidelines as recommended for UTI and 30% were 2nd and 3rd line drugs. ADDO sellers recommended 31 drug types (including 2nd and 3rd line) but had permission to stock only 3 (1st line) drugs. The most commonly suggested antibiotics were Azithromycin (35.4%) and ciprofloxacin (20.5%). Azithromycin was suggested more often in pharmacies (40.8%) than in ADDOs (34.4%) and more often to male clients (36.0%) than female (33.1%). Conclusion These findings support the need for urgent action to ensure existing regulations are adhered to and to promote the continuing professional development of drug sellers at all outlet levels to ensure compliance with regulation, high quality service and better antibiotic stewardship.

Published
2022

45. Prostate cancer castrate resistant progression usage of non-canonical androgen receptor signaling and ketone body fuel

Author

Juan Bizzotto, John C. Araujo, Anh Hoang, Nora M. Navone, Ximing Tang, Valeria Antico-Arciuch, Sofia Lage-Vickers, Alejandra Paez, Geraldine Gueron, Estefania Labanca, Maria Gabriela Raso, Mark Titus, Nicolas Anselmino, Christopher J. Logothetis, Pablo Sanchis, Peter Shepherd, Jun Yang, Elba Vazquez, Eleni Efstathiou, and Javier Cotignola

Subjects
Male, Cancer Research, medicine.drug_class, Context (language use), Ketone Bodies, Biology, urologic and male genital diseases, Article, Androgen deprivation therapy, Mice, Prostate cancer, chemistry.chemical_compound, Cell Line, Tumor, Genetics, medicine, Animals, Humans, Molecular Biology, OXCT1, Cancer, ACAT1, Fatty Acids, Androgen Antagonists, medicine.disease, Androgen, Cancer metabolism, Gene Expression Regulation, Neoplastic, Androgen receptor, Prostatic Neoplasms, Castration-Resistant, Castration, chemistry, Receptors, Androgen, Disease Progression, Cancer research, Neoplasm Transplantation, Signal Transduction
Abstract

Prostate cancer (PCa) that progresses after androgen deprivation therapy (ADT) remains incurable. The underlying mechanisms that account for the ultimate emergence of resistance to ADT, progressing to castrate-resistant prostate cancer (CRPC), include those that reactivate androgen receptor (AR), or those that are entirely independent or cooperate with androgen signaling to underlie PCa progression. The intricacy of metabolic pathways associated with PCa progression spurred us to develop a metabolism-centric analysis to assess the metabolic shift occurring in PCa that progresses with low AR expression. We used PCa patient-derived xenografts (PDXs) to assess the metabolic changes after castration of tumor-bearing mice and subsequently confirmed main findings in human donor tumor that progressed after ADT. We found that relapsed tumors had a significant increase in fatty acids and ketone body (KB) content compared with baseline. We confirmed that critical ketolytic enzymes (ACAT1, OXCT1, BDH1) were dysregulated after castrate-resistant progression. Further, these enzymes are increased in the human donor tissue after progressing to ADT. In an in silico approach, increased ACAT1, OXCT1, BDH1 expression was also observed for a subset of PCa patients that relapsed with low AR and ERG (ETS-related gene) expression. Further, expression of these factors was also associated with decreased time to biochemical relapse and decreased progression-free survival. Our studies reveal the key metabolites fueling castration resistant progression in the context of a partial or complete loss of AR dependence.

Published
2021
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46. Bilateral hyperplasia of choroid plexus with severe CSF production: a case report and review of the glymphatic system

Author

Ezequiel Garcia-Ballestas, Gabriel Campos, Osvaldo Koller, Maximiliano Paez-Nova, Luis Rafael Moscote-Salazar, Sergio Valenzuela, and Karem Andaur

Subjects
Plexus, medicine.medical_specialty, Pathology, Hyperplasia, business.industry, Infant, General Medicine, medicine.disease, Pathophysiology, Cerebral Ventricles, Hydrocephalus, Cerebrospinal fluid, Choroid Plexus, Pediatrics, Perinatology and Child Health, Ascites, medicine, Humans, Choroid plexus, Glymphatic system, Neurology (clinical), Neurosurgery, medicine.symptom, business, Glymphatic System
Abstract

An important feature of hydrocephalus is the alteration of the cerebral spinal fluid (CSF) homeostasis. New insights in the understanding of production, secretion, and absorption of CSF, along with the discovery of the glymphatic system (GS), can be useful for a better understanding and treatment of hydrocephalus in disorders with CSF overproduction. A 1-year-old patient was diagnosed with communicating hydrocephalus; ventricle peritoneal shunt (VPS) is installed and ascites developed. VPS is exposed, yielding volumes of 1000-1200ml/day CSF per day. MRI is performed showing generalized choroidal plexus hyperplasia. Bilateral endoscopic coagulation of thechoroid plexus was performed in 2 stages (CPC) however the high rate of CSF production persisted, needing a bilateral plexectomy through septostomy, which finally decreased the CSF outflow. New knowledge about the CSF physiology will help to propose better treatment depending on the cause of the hydrocephalus. The GS is becoming an additional reason to better study and develop new therapies focused of the modulation of alternative CSF reabsorption. Despite the current knowledge about hydrocephalus, we remain without a complete understanding of the pathophysiology of this condition. GS could be more important than conventional concept of reabsorption of CSF in the arachnoid villi, therefore GS could be a new key point, which will guide future investigations.

Published
2021
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47. Analytical and clinical evaluation of a heat shock SARS-CoV-2 detection method without RNA extraction for N and E genes RT-qPCR

Author

Doménica de Mora, Angel S. Rodriguez, Michelle Paez, Miguel Angel Garcia-Bereguiain, Manuel Gonzalez, Maritza Olmedo, Byron Freire-Paspuel, Alfredo Bruno, Alberto Orlando, Martha Judith Sánchez, Jennifer Romero, and Maria Belen Paredes-Espinosa

Subjects
0301 basic medicine, Microbiology (medical), Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 030106 microbiology, Infectious and parasitic diseases, RC109-216, Real-Time Polymerase Chain Reaction, Sensitivity and Specificity, Article, 03 medical and health sciences, 0302 clinical medicine, COVID-19 Testing, medicine, Humans, Viral rna, 030212 general & internal medicine, Gene, Pandemics, business.industry, SARS-CoV-2, RT-qPCR, Clinical performance, COVID-19, General Medicine, RNA extraction free, Virology, Infectious Diseases, Heat shock, Shock (circulatory), RNA, Viral, RNA extraction, medicine.symptom, business, Clinical evaluation, Heat-Shock Response
Abstract

Background The COVID-19 pandemic has caused significant supply shortages worldwide for SARS-CoV-2 molecular diagnosis, like RNA extraction kits. Objective The aim of our study was to evaluate the clinical performance and analytical sensitivity of a simple SARS-CoV-2 diagnosis protocol based on heat shock without RNA extraction using both "CDC" (N gene) and "Charite" (E gene) RT-qPCR protocols. Results 1,036 nasopharyngeal samples, 543 of them SARS-CoV-2 positive, were analyzed. The heat shock method correctly identified 68.8% (232/337) and 89.4% (202/226) of SARS-CoV-2 positive samples for N gene and E gene, respectively. Analytical sensitivity was assessed for heat shock method using the CDC RT-qPCR protocol, obtaining sensitivity values of 98.6%, 93.3% and 84.8% for limit of detection of 100.000, 50.000 and 20.000 viral RNA copies/mL of sample. Conclusions Our findings show that a simple heat shock SARS-CoV-2 RT-qPCR diagnosis method without RNA extraction is a reliable alternative for potentially infectious SARS-CoV-2 positive patients at the time of testing. This affordable protocol can help overcome the cost and supply shortages for SARS-CoV-2 diagnosis, especially in developing countries. In Ecuador, it has been used already by laboratories in the public health system for more than 100.000 specimens.

Published
2021

48. Metagenomic compendium of 189,680 DNA viruses from the human gut microbiome

Author

Stephen Nayfach, David Paez-Espino, Nikos C. Kyrpides, Philip Hugenholtz, Amy D Proal, Hila Sberro, Ami S. Bhatt, Michael A. Fischbach, Lee Call, Soo Jen Low, and Natalia Ivanova

Subjects
Resource, Microbiology (medical), Bacteroidia, Viral protein, viruses, Immunology, Genome, Viral, Biology, medicine.disease_cause, Applied Microbiology and Biotechnology, Microbiology, Genome, CRISPR Spacers, Virus, Feces, Viral Proteins, 03 medical and health sciences, 0302 clinical medicine, Catalogs as Topic, Genetics, medicine, Humans, Bacteriophages, Human virome, Microbiome, Data mining, Phylogeny, 030304 developmental biology, 0303 health sciences, Bacteria, DNA Viruses, Genetic Variation, Cell Biology, biology.organism_classification, Archaea, Gastrointestinal Microbiome, Metagenomics, DNA, Viral, 030217 neurology & neurosurgery
Abstract

Bacteriophages have important roles in the ecology of the human gut microbiome but are under-represented in reference databases. To address this problem, we assembled the Metagenomic Gut Virus catalogue that comprises 189,680 viral genomes from 11,810 publicly available human stool metagenomes. Over 75% of genomes represent double-stranded DNA phages that infect members of the Bacteroidia and Clostridia classes. Based on sequence clustering we identified 54,118 candidate viral species, 92% of which were not found in existing databases. The Metagenomic Gut Virus catalogue improves detection of viruses in stool metagenomes and accounts for nearly 40% of CRISPR spacers found in human gut Bacteria and Archaea. We also produced a catalogue of 459,375 viral protein clusters to explore the functional potential of the gut virome. This revealed tens of thousands of diversity-generating retroelements, which use error-prone reverse transcription to mutate target genes and may be involved in the molecular arms race between phages and their bacterial hosts., Almost 190,000 draft-quality DNA virus genomes are recovered by mining more than 11,000 deposited human stool metagenomes to improve resources for understanding the human gut virome.

Published
2021
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49. Changes in the global impact of COVID-19 on nuclear medicine departments during 2020: an international follow-up survey

Author

Pilar Orellana, Yaroslav Pynda, Maria C. Navarro-Marulanda, Enrique Estrada L., Ken Herrmann, Gopinath Gnanasegaran, Francesco Giammarile, Noura El-Haj, Miriam Mikhail, Lutz S. Freudenberg, Roberto C. Delgado Bolton, Sobhan Vinjamuri, Olga Morozova, Diana Paez, Olivier Pellet, and Partha S. Choudhury

Subjects
Coronavirus disease 2019 (COVID-19), SARS-CoV-2, business.industry, Atomic energy, Specific time, Medizin, International survey, COVID-19, General Medicine, Geography, Surveys and Questionnaires, Nuclear medicine, Pandemic, Humans, Survey data collection, Original Article, Global impact, Radiology, Nuclear Medicine and imaging, Survey, business, Regional differences, Follow up survey, Follow-Up Studies
Abstract

Aim As a follow-up to the international survey conducted by the International Atomic Energy Agency (IAEA) in April 2020, this survey aims to provide a situational snapshot of the COVID-19 impact on nuclear medicine services worldwide, 1 year later. The survey was designed to determine the impact of the pandemic at two specific time points: June and October 2020, and compare them to the previously collected data. Materials and methods A web-based questionnaire, in the same format as the April 2020 survey was disseminated to nuclear medicine facilities worldwide. Survey data was collected using a secure software platform hosted by the IAEA; it was made available for 6 weeks, from November 23 to December 31, 2020. Results From 505 replies received from 96 countries, data was extracted from 355 questionnaires (of which 338 were fully completed). The responses came from centres across varying regions of the world and with heterogeneous income distributions. Regional differences and challenges across the world were identified and analysed. Globally, the volume of nuclear medicine procedures decreased by 73.3% in June 2020 and 56.9% in October 2020. Among the nuclear medicine procedures, oncological PET studies showed less of a decline in utilization compared to conventional nuclear medicine, particularly nuclear cardiology. The negative impact was also significantly less pronounced in high-income countries. A trend towards a gradual return to the pre-COVID-19 situation of the supply chains of radioisotopes, generators, and other essential materials was evident. Conclusion The year 2020 has a significant decrease in nuclear medicine diagnostic and therapeutic procedures as a result of the pandemic-related challenges. In June, the global decline recorded in the survey was greater than in October when the situation began to show improvement. However, the total number of procedures remained below those recorded in April 2020 and fell to less than half of the volumes normally carried out pre-pandemic.

Published
2021
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50. Impact of COVID-19 on Nuclear Medicine Departments in Africa and Latin America

Author

Pilar Orellana, Yaroslav Pynda, Noura El-Haj, Miriam Mikhail, Enrique Estrada Lobato, Olivier Pellet, Olga Morozova, Francesco Giammarile, Roberto C. Delgado Bolton, and Diana Paez

Subjects
2019-20 coronavirus outbreak, Latin Americans, Coronavirus disease 2019 (COVID-19), IPC, Infection Prevention and Control, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), MEDLINE, IAEA, International Atomic Energy Agency, PET, Positron Emission Tomography, Article, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, PPE, Personal Protective Equipment, LMIC, Lower-Middle-Income Countries, IRIS, International Research Integration System, Agency (sociology), Pandemic, Medicine, Humans, Radiology, Nuclear Medicine and imaging, CNM, Conventional Nuclear Medicine, Pandemics, business.industry, SARS-CoV-2, Atomic energy, COVID-19, LIC, Low-Income Countries, HIC, High-Income Countries, Latin America, 030220 oncology & carcinogenesis, COVID-19, Coronavirus Disease 2019, UMIC, Upper-Middle-Income Countries, WHO, World Health Organisation, Nuclear Medicine, Nuclear medicine, business
Abstract

The International Atomic Energy Agency (IAEA) conducted a survey to determine the impact of the COVID-19 pandemic on nuclear medicine services worldwide at two specific time-points: June and October 2020. In this paper, we describe the impact of COVID-19 on nuclear medicine departments in Africa (19 countries, 41 centers) and Latin America (15 countries, 83 centers) obtained from the survey. Respectively in Africa and Latin America, the volume of nuclear medicine procedures decreased by 69% and 79% in June 2020 and 44% and 67% in October 2020. Among the nuclear medicine procedures, oncological PET studies showed less of a decline in utilization compared to conventional nuclear medicine studies. A gradual trend towards a return to the pre-COVID-19 status of the supply chains of radioisotopes, generators, and other essential materials was evident. Overall, in 2020, the pandemic-related challenges resulted in significant decrease in nuclear medicine diagnostic and therapeutic procedures in Africa and Latin America. The impact was more pronounced in Latin America than in Africa. The current COVID-19 pandemic poses many challenges for the practice of nuclear medicine. If adequately prepared, departments can continue to deliver their essential services, while mitigating the risk for patients and staff. This requires adapting the SOPs, as quickly as possible, to meet the new requirements.

Published
2021

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