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1. High-Resolution Mass Spectrometry for Human Exposomics: Expanding Chemical Space Coverage

Author: Lai, Yunjia, Koelmel, Jeremy P, Walker, Douglas I, Price, Elliott J, Papazian, Stefano, Manz, Katherine E, Castilla-Fernández, Delia, Bowden, John A, Nikiforov, Vladimir, David, Arthur, Bessonneau, Vincent, Amer, Bashar, Seethapathy, Suresh, Hu, Xin, Lin, Elizabeth Z, Jbebli, Akrem, McNeil, Brooklynn R, Barupal, Dinesh, Cerasa, Marina, Xie, Hongyu, Kalia, Vrinda, Nandakumar, Renu, Singh, Randolph, Tian, Zhenyu, Gao, Peng, Zhao, Yujia, Froment, Jean, Rostkowski, Pawel, Dubey, Saurabh, Coufalíková, Kateřina, Seličová, Hana, Hecht, Helge, Liu, Sheng, Udhani, Hanisha H, Restituito, Sophie, Tchou-Wong, Kam-Meng, Lu, Kun, Martin, Jonathan W, Warth, Benedikt, Pollitt, Krystal J Godri, Klánová, Jana, Fiehn, Oliver, Metz, Thomas O, Pennell, Kurt D, Jones, Dean P, and Miller, Gary W
Subjects: Medical Biochemistry and Metabolomics, Analytical Chemistry, Biomedical and Clinical Sciences, Chemical Sciences, Bioengineering, 2.5 Research design and methodologies (aetiology), Generic health relevance, Good Health and Well Being, Humans, Mass Spectrometry, Exposome, Metabolomics, Proteomics, Environmental Exposure, exposome, toxicants, high-resolutionmass spectrometry, chromatography, non-targetedanalysis, environmentalexposures, chemical space, metabolomics, environmental exposures, high-resolution mass spectrometry, non-targeted analysis, Environmental Sciences
Abstract: In the modern "omics" era, measurement of the human exposome is a critical missing link between genetic drivers and disease outcomes. High-resolution mass spectrometry (HRMS), routinely used in proteomics and metabolomics, has emerged as a leading technology to broadly profile chemical exposure agents and related biomolecules for accurate mass measurement, high sensitivity, rapid data acquisition, and increased resolution of chemical space. Non-targeted approaches are increasingly accessible, supporting a shift from conventional hypothesis-driven, quantitation-centric targeted analyses toward data-driven, hypothesis-generating chemical exposome-wide profiling. However, HRMS-based exposomics encounters unique challenges. New analytical and computational infrastructures are needed to expand the analysis coverage through streamlined, scalable, and harmonized workflows and data pipelines that permit longitudinal chemical exposome tracking, retrospective validation, and multi-omics integration for meaningful health-oriented inferences. In this article, we survey the literature on state-of-the-art HRMS-based technologies, review current analytical workflows and informatic pipelines, and provide an up-to-date reference on exposomic approaches for chemists, toxicologists, epidemiologists, care providers, and stakeholders in health sciences and medicine. We propose efforts to benchmark fit-for-purpose platforms for expanding coverage of chemical space, including gas/liquid chromatography-HRMS (GC-HRMS and LC-HRMS), and discuss opportunities, challenges, and strategies to advance the burgeoning field of the exposome.
Published: 2024

2. Results of the COVID-19 mental health international for the health professionals (COMET-HP) study: depression, suicidal tendencies and conspiracism.

Author: Fountoulakis, Konstantinos N, N. Karakatsoulis, Grigorios, Abraham, Seri, Adorjan, Kristina, Ahmed, Helal Uddin, Alarcón, Renato D, Arai, Kiyomi, Auwal, Sani Salihu, Bobes, Julio, Bobes-Bascaran, Teresa, Bourgin-Duchesnay, Julie, Bredicean, Cristina Ana, Bukelskis, Laurynas, Burkadze, Akaki, Cabrera Abud, Indira Indiana, Castilla-Puentes, Ruby, Cetkovich, Marcelo, Colon-Rivera, Hector, Corral, Ricardo, Cortez-Vergara, Carla, Crepin, Piirika, de Berardis, Domenico, Zamora Delgado, Sergio, de Lucena, David, de Sousa, Avinash, di Stefano, Ramona, Dodd, Seetal, Elek, Livia Priyanka, Elissa, Anna, Erdelyi-Hamza, Berta, Erzin, Gamze, Etchevers, Martin J, Falkai, Peter, Farcas, Adriana, Fedotov, Ilya, Filatova, Viktoriia, Fountoulakis, Nikolaos K, Frankova, Iryna, Franza, Francesco, Frias, Pedro, Galako, Tatiana, Garay, Cristian J, Garcia-Álvarez, Leticia, García-Portilla, Paz, Gonda, Xenia, Gondek, Tomasz M, Morera González, Daniela, Gould, Hilary, Grandinetti, Paolo, Grau, Arturo, Groudeva, Violeta, Hagin, Michal, Harada, Takayuki, Hasan, Tasdik M, Azreen Hashim, Nurul, Hilbig, Jan, Hossain, Sahadat, Iakimova, Rossitza, Ibrahim, Mona, Iftene, Felicia, Ignatenko, Yulia, Irarrazaval, Matias, Ismail, Zaliha, Ismayilova, Jamila, Jacobs, Asaf, Jakovljević, Miro, Jakšić, Nenad, Javed, Afzal, Yilmaz Kafali, Helin, Karia, Sagar, Kazakova, Olga, Khalifa, Doaa, Khaustova, Olena, Koh, Steve, Kopishinskaia, Svetlana, Kosenko, Korneliia, Koupidis, Sotirios A, Kovacs, Illes, Kulig, Barbara, Lalljee, Alisha, Liewig, Justine, Majid, Abdul, Malashonkova, Evgeniia, Malik, Khamelia, Iqbal Malik, Najma, Mammadzada, Gulay, Mandalia, Bilvesh, Marazziti, Donatella, Marčinko, Darko, Martinez, Stephanie, Matiekus, Eimantas, Mejia, Gabriela, Memon, Roha Saeed, Meza Martínez, Xarah Elenne, Mickevičiūtė, Dalia, Milev, Roumen, Mohammed, Muftau, Molina-López, Alejandro, and Morozov, Petr
Subjects: Anxiety, COVID-19, Conspiracy theories, Depression, Health professionals, Mental disorders, Mental health, Psychiatry, Suicidality, Humans, Female, Male, Mental Health, Suicidal Ideation, Health Personnel, Brain Disorders, Behavioral and Social Science, Serious Mental Illness, Mind and Body, Prevention, Good Health and Well Being, Clinical Sciences, Psychology, Cognitive Sciences
Abstract: IntroductionThe current study aimed to investigate the rates of anxiety, clinical depression, and suicidality and their changes in health professionals during the COVID-19 outbreak.Materials and methodsThe data came from the larger COMET-G study. The study sample includes 12,792 health professionals from 40 countries (62.40% women aged 39.76 ± 11.70; 36.81% men aged 35.91 ± 11.00 and 0.78% non-binary gender aged 35.15 ± 13.03). Distress and clinical depression were identified with the use of a previously developed cut-off and algorithm, respectively.Statistical analysisDescriptive statistics were calculated. Chi-square tests, multiple forward stepwise linear regression analyses, and Factorial Analysis of Variance (ANOVA) tested relations among variables.ResultsClinical depression was detected in 13.16% with male doctors and 'non-binary genders' having the lowest rates (7.89 and 5.88% respectively) and 'non-binary gender' nurses and administrative staff had the highest (37.50%); distress was present in 15.19%. A significant percentage reported a deterioration in mental state, family dynamics, and everyday lifestyle. Persons with a history of mental disorders had higher rates of current depression (24.64% vs. 9.62%; p
Published: 2023

3. Long-Term Assessment of Bone Regeneration in Nonunion Fractures Treated with Compression-Resistant Matrix and Recombinant Human Bone Morphogenetic Protein-2 in Dogs.

Author: Castilla, Andrea, Filliquist, Barbro, Spriet, Mathieu, Garcia, Tanya C, Arzi, Boaz, Chou, Po-Yen, and Kapatkin, Amy S
Subjects: Animals, Dogs, Humans, Fractures, Ununited, Dog Diseases, Transforming Growth Factor beta, Recombinant Proteins, Prospective Studies, Bone Regeneration, Fracture Healing, Fractures, Bone, Bone Morphogenetic Protein 2, Osteoporosis, Musculoskeletal, Bone morphogenetic protein 2, rhBMP-2, nonunion fracture, compression-resistant matrix, bone regeneration, Veterinary Sciences
Abstract: Objective The aim of this study was to assess bone density, bone architecture and clinical function of canine nonunion distal appendicular long bone fractures with a defect treated with fixation, compression-resistant matrix and recombinant human bone morphogenetic protein-2 (rhBMP-2).Study design Prospective cohort study with dogs at least 1-year post treatment. Computed tomography was performed and quantitative measurements from previous fracture sites were compared with measurements from contralateral limbs. Subjective evaluation included gait assessment and palpation.Results Six patients met the inclusion criteria. The rhBMP-2 treated bone exhibited higher density at the periphery and lower density in the centre, similar to the contralateral limb. All patients were weight bearing on the treated limb and all fractures were healed.Conclusion The rhBMP-2-treated bone underwent restoration of normal architecture and density. Acceptable limb function was present in all patients. The results of this study can serve as a basis for long-term response in treating nonunion fractures in veterinary patients.
Published: 2023

4. Temporal Improvements in COVID-19 Outcomes for Hospitalized Adults: A Post Hoc Observational Study of Remdesivir Group Participants in the Adaptive COVID-19 Treatment Trial

Author: Potter, Gail E, Bonnett, Tyler, Rubenstein, Kevin, Lindholm, David A, Rapaka, Rekha R, Doernberg, Sarah B, Lye, David C, Mularski, Richard A, Hynes, Noreen A, Kline, Susan, Paules, Catharine I, Wolfe, Cameron R, Frank, Maria G, Rouphael, Nadine G, Deye, Gregory A, Sweeney, Daniel A, Colombo, Rhonda E, Davey, Richard T, Mehta, Aneesh K, Whitaker, Jennifer A, Castro, Jose G, Amin, Alpesh N, Colombo, Christopher J, Levine, Corri B, Jain, Mamta K, Maves, Ryan C, Marconi, Vincent C, Grossberg, Robert, Hozayen, Sameh, Burgess, Timothy H, Atmar, Robert L, Ganesan, Anuradha, Gomez, Carlos A, Benson, Constance A, de Castilla, Diego Lopez, Ahuja, Neera, George, Sarah L, Nayak, Seema U, Cohen, Stuart H, Lalani, Tahaniyat, Short, William R, Erdmann, Nathaniel, Tomashek, Kay M, and Tebas, Pablo
Subjects: Biomedical and Clinical Sciences, Clinical Sciences, Prevention, Clinical Research, Rehabilitation, Complementary and Integrative Health, Clinical Trials and Supportive Activities, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Good Health and Well Being, Adult, Humans, Antiviral Agents, Clinical Trials, Phase III as Topic, Dexamethasone, Double-Blind Method, Randomized Controlled Trials as Topic, Treatment Outcome, COVID-19 Drug Treatment, Medical and Health Sciences, General & Internal Medicine, Clinical sciences
Abstract: BackgroundThe COVID-19 standard of care (SOC) evolved rapidly during 2020 and 2021, but its cumulative effect over time is unclear.ObjectiveTo evaluate whether recovery and mortality improved as SOC evolved, using data from ACTT (Adaptive COVID-19 Treatment Trial).DesignACTT is a series of phase 3, randomized, double-blind, placebo-controlled trials that evaluated COVID-19 therapeutics from February 2020 through May 2021. ACTT-1 compared remdesivir plus SOC to placebo plus SOC, and in ACTT-2 and ACTT-3, remdesivir plus SOC was the control group. This post hoc analysis compared recovery and mortality between these comparable sequential cohorts of patients who received remdesivir plus SOC, adjusting for baseline characteristics with propensity score weighting. The analysis was repeated for participants in ACTT-3 and ACTT-4 who received remdesivir plus dexamethasone plus SOC. Trends in SOC that could explain outcome improvements were analyzed. (ClinicalTrials.gov: NCT04280705 [ACTT-1], NCT04401579 [ACTT-2], NCT04492475 [ACTT-3], and NCT04640168 [ACTT-4]).Setting94 hospitals in 10 countries (86% U.S. participants).ParticipantsAdults hospitalized with COVID-19.InterventionSOC.Measurements28-day mortality and recovery.ResultsAlthough outcomes were better in ACTT-2 than in ACTT-1, adjusted hazard ratios (HRs) were close to 1 (HR for recovery, 1.04 [95% CI, 0.92 to 1.17]; HR for mortality, 0.90 [CI, 0.56 to 1.40]). Comparable patients were less likely to be intubated in ACTT-2 than in ACTT-1 (odds ratio, 0.75 [CI, 0.53 to 0.97]), and hydroxychloroquine use decreased. Outcomes improved from ACTT-2 to ACTT-3 (HR for recovery, 1.43 [CI, 1.24 to 1.64]; HR for mortality, 0.45 [CI, 0.21 to 0.97]). Potential explanatory factors (SOC trends, case surges, and variant trends) were similar between ACTT-2 and ACTT-3, except for increased dexamethasone use (11% to 77%). Outcomes were similar in ACTT-3 and ACTT-4. Antibiotic use decreased gradually across all stages.LimitationUnmeasured confounding.ConclusionChanges in patient composition explained improved outcomes from ACTT-1 to ACTT-2 but not from ACTT-2 to ACTT-3, suggesting improved SOC. These results support excluding nonconcurrent controls from analysis of platform trials in rapidly changing therapeutic areas.Primary funding sourceNational Institute of Allergy and Infectious Diseases.
Published: 2022

5. The effect of different degrees of lockdown and self-identified gender on anxiety, depression and suicidality during the COVID-19 pandemic: Data from the international COMET-G study.

Author: Fountoulakis, Konstantinos N, Karakatsoulis, Grigorios N, Abraham, Seri, Adorjan, Kristina, Ahmed, Helal Uddin, Alarcón, Renato D, Arai, Kiyomi, Auwal, Sani Salihu, Berk, Michael, Bjedov, Sarah, Bobes, Julio, Bobes-Bascaran, Teresa, Bourgin-Duchesnay, Julie, Bredicean, Cristina Ana, Bukelskis, Laurynas, Burkadze, Akaki, Abud, Indira Indiana Cabrera, Castilla-Puentes, Ruby, Cetkovich, Marcelo, Colon-Rivera, Hector, Corral, Ricardo, Cortez-Vergara, Carla, Crepin, Piirika, De Berardis, Domenico, Delgado, Sergio Zamora, De Lucena, David, De Sousa, Avinash, Stefano, Ramona Di, Dodd, Seetal, Elek, Livia Priyanka, Elissa, Anna, Erdelyi-Hamza, Berta, Erzin, Gamze, Etchevers, Martin J, Falkai, Peter, Farcas, Adriana, Fedotov, Ilya, Filatova, Viktoriia, Fountoulakis, Nikolaos K, Frankova, Iryna, Franza, Francesco, Frias, Pedro, Galako, Tatiana, Garay, Cristian J, Garcia-Álvarez, Leticia, García-Portilla, Maria Paz, Gonda, Xenia, Gondek, Tomasz M, González, Daniela Morera, Gould, Hilary, Grandinetti, Paolo, Grau, Arturo, Groudeva, Violeta, Hagin, Michal, Harada, Takayuki, Hasan, Tasdik M, Hashim, Nurul Azreen, Hilbig, Jan, Hossain, Sahadat, Iakimova, Rossitza, Ibrahim, Mona, Iftene, Felicia, Ignatenko, Yulia, Irarrazaval, Matias, Ismail, Zaliha, Ismayilova, Jamila, Jacobs, Asaf, Jakovljević, Miro, Jakšić, Nenad, Javed, Afzal, Kafali, Helin Yilmaz, Karia, Sagar, Kazakova, Olga, Khalifa, Doaa, Khaustova, Olena, Koh, Steve, Kopishinskaia, Svetlana, Kosenko, Korneliia, Koupidis, Sotirios A, Kovacs, Illes, Kulig, Barbara, Lalljee, Alisha, Liewig, Justine, Majid, Abdul, Malashonkova, Evgeniia, Malik, Khamelia, Malik, Najma Iqbal, Mammadzada, Gulay, Mandalia, Bilvesh, Marazziti, Donatella, Marčinko, Darko, Martinez, Stephanie, Matiekus, Eimantas, Mejia, Gabriela, Memon, Roha Saeed, Martínez, Xarah Elenne Meza, Mickevičiūtė, Dalia, Milev, Roumen, Mohammed, Muftau, and Molina-López, Alejandro
Subjects: Biomedical and Clinical Sciences, Clinical Sciences, Prevention, Mental Health, Depression, Brain Disorders, Serious Mental Illness, Mental health, Good Health and Well Being, Anxiety, COVID-19, Communicable Disease Control, Female, Humans, Male, Pandemics, Suicide, Suicidality, lockdown, anxiety, mental health history, Mental health, lockdown, anxiety, mental health history, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Clinical and health psychology
Abstract: IntroductionDuring the COVID-19 pandemic various degrees of lockdown were applied by countries around the world. It is considered that such measures have an adverse effect on mental health but the relationship of measure intensity with the mental health effect has not been thoroughly studied. Here we report data from the larger COMET-G study pertaining to this question.Material and methodsDuring the COVID-19 pandemic, data were gathered with an online questionnaire from 55,589 participants from 40 countries (64.85% females aged 35.80 ± 13.61; 34.05% males aged 34.90±13.29 and 1.10% other aged 31.64±13.15). Anxiety was measured with the STAI, depression with the CES-D and suicidality with the RASS. Distress and probable depression were identified with the use of a previously developed cut-off and algorithm respectively.Statistical analysisIt included the calculation of Relative Risk (RR), Factorial ANOVA and Multiple backwards stepwise linear regression analysis RESULTS: Approximately two-thirds were currently living under significant restrictions due to lockdown. For both males and females the risk to develop clinical depression correlated significantly with each and every level of increasing lockdown degree (RR 1.72 and 1.90 respectively). The combined lockdown and psychiatric history increased RR to 6.88 The overall relationship of lockdown with severity of depression, though significant was small.ConclusionsThe current study is the first which reports an almost linear relationship between lockdown degree and effect in mental health. Our findings, support previous suggestions concerning the need for a proactive targeted intervention to protect mental health more specifically in vulnerable groups.
Published: 2022

6. Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial.

Author: Wolfe, Cameron R, Tomashek, Kay M, Patterson, Thomas F, Gomez, Carlos A, Marconi, Vincent C, Jain, Mamta K, Yang, Otto O, Paules, Catharine I, Palacios, Guillermo M Ruiz, Grossberg, Robert, Harkins, Michelle S, Mularski, Richard A, Erdmann, Nathaniel, Sandkovsky, Uriel, Almasri, Eyad, Pineda, Justino Regalado, Dretler, Alexandra W, de Castilla, Diego Lopez, Branche, Angela R, Park, Pauline K, Mehta, Aneesh K, Short, William R, McLellan, Susan LF, Kline, Susan, Iovine, Nicole M, El Sahly, Hana M, Doernberg, Sarah B, Oh, Myoung-Don, Huprikar, Nikhil, Hohmann, Elizabeth, Kelley, Colleen F, Holodniy, Mark, Kim, Eu Suk, Sweeney, Daniel A, Finberg, Robert W, Grimes, Kevin A, Maves, Ryan C, Ko, Emily R, Engemann, John J, Taylor, Barbara S, Ponce, Philip O, Larson, LuAnn, Melendez, Dante Paolo, Seibert, Allan M, Rouphael, Nadine G, Strebe, Joslyn, Clark, Jesse L, Julian, Kathleen G, de Leon, Alfredo Ponce, Cardoso, Anabela, de Bono, Stephanie, Atmar, Robert L, Ganesan, Anuradha, Ferreira, Jennifer L, Green, Michelle, Makowski, Mat, Bonnett, Tyler, Beresnev, Tatiana, Ghazaryan, Varduhi, Dempsey, Walla, Nayak, Seema U, Dodd, Lori E, Beigel, John H, Kalil, Andre C, and ACTT-4 Study Group
Subjects: ACTT-4 Study Group, Humans, Oxygen, Sulfonamides, Azetidines, Pyrazoles, Purines, Dexamethasone, Treatment Outcome, Double-Blind Method, Adolescent, Adult, Middle Aged, Female, Male, SARS-CoV-2, COVID-19 Drug Treatment, Clinical Trials and Supportive Activities, Lung, Clinical Research, Prevention, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Good Health and Well Being, Clinical Sciences, Public Health and Health Services, Other Medical and Health Sciences
Abstract: BackgroundBaricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19.MethodsIn this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168.FindingsBetween Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012).InterpretationIn hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered.FundingNational Institute of Allergy and Infectious Diseases.
Published: 2022

7. Standards recommendations for the Earth BioGenome Project

Author: Lawniczak, Mara KN, Durbin, Richard, Flicek, Paul, Lindblad-Toh, Kerstin, Wei, Xiaofeng, Archibald, John M, Baker, William J, Belov, Katherine, Blaxter, Mark L, Bonet, Tomas Marques, Childers, Anna K, Coddington, Jonathan A, Crandall, Keith A, Crawford, Andrew J, Davey, Robert P, Di Palma, Federica, Fang, Qi, Haerty, Wilfried, Hall, Neil, Hoff, Katharina J, Howe, Kerstin, Jarvis, Erich D, Johnson, Warren E, Johnson, Rebecca N, Kersey, Paul J, Liu, Xin, Lopez, Jose Victor, Myers, Eugene W, Pettersson, Olga Vinnere, Phillippy, Adam M, Poelchau, Monica F, Pruitt, Kim D, Rhie, Arang, Castilla-Rubio, Juan Carlos, Sahu, Sunil Kumar, Salmon, Nicholas A, Soltis, Pamela S, Swarbreck, David, Thibaud-Nissen, Françoise, Wang, Sibo, Wegrzyn, Jill L, Zhang, Guojie, Zhang, He, Lewin, Harris A, and Richards, Stephen
Subjects: Human Genome, Genetics, Animals, Base Sequence, Biodiversity, Eukaryota, Genomics, Humans, Reference Standards, Reference Values, Sequence Analysis, DNA, Earth BioGenome Project, genomics, ethics, genome assembly
Abstract: A global international initiative, such as the Earth BioGenome Project (EBP), requires both agreement and coordination on standards to ensure that the collective effort generates rapid progress toward its goals. To this end, the EBP initiated five technical standards committees comprising volunteer members from the global genomics scientific community: Sample Collection and Processing, Sequencing and Assembly, Annotation, Analysis, and IT and Informatics. The current versions of the resulting standards documents are available on the EBP website, with the recognition that opportunities, technologies, and challenges may improve or change in the future, requiring flexibility for the EBP to meet its goals. Here, we describe some highlights from the proposed standards, and areas where additional challenges will need to be met.
Published: 2022

8. Results of the COVID-19 mental health international for the general population (COMET-G) study

Author: Fountoulakis, Konstantinos N, Karakatsoulis, Grigorios, Abraham, Seri, Adorjan, Kristina, Ahmed, Helal Uddin, Alarcón, Renato D, Arai, Kiyomi, Auwal, Sani Salihu, Berk, Michael, Bjedov, Sarah, Bobes, Julio, Bobes-Bascaran, Teresa, Bourgin-Duchesnay, Julie, Bredicean, Cristina Ana, Bukelskis, Laurynas, Burkadze, Akaki, Abud, Indira Indiana Cabrera, Castilla-Puentes, Ruby, Cetkovich, Marcelo, Colon-Rivera, Hector, Corral, Ricardo, Cortez-Vergara, Carla, Crepin, Piirika, De Berardis, Domenico, Zamora Delgado, Sergio, De Lucena, David, De Sousa, Avinash, Stefano, Ramona Di, Dodd, Seetal, Elek, Livia Priyanka, Elissa, Anna, Erdelyi-Hamza, Berta, Erzin, Gamze, Etchevers, Martin J, Falkai, Peter, Farcas, Adriana, Fedotov, Ilya, Filatova, Viktoriia, Fountoulakis, Nikolaos K, Frankova, Iryna, Franza, Francesco, Frias, Pedro, Galako, Tatiana, Garay, Cristian J, Garcia-Álvarez, Leticia, García-Portilla, Maria Paz, Gonda, Xenia, Gondek, Tomasz M, González, Daniela Morera, Gould, Hilary, Grandinetti, Paolo, Grau, Arturo, Groudeva, Violeta, Hagin, Michal, Harada, Takayuki, Hasan, M Tasdik, Hashim, Nurul Azreen, Hilbig, Jan, Hossain, Sahadat, Iakimova, Rossitza, Ibrahim, Mona, Iftene, Felicia, Ignatenko, Yulia, Irarrazaval, Matias, Ismail, Zaliha, Ismayilova, Jamila, Jacobs, Asaf, Jakovljević, Miro, Jakšić, Nenad, Javed, Afzal, Kafali, Helin Yilmaz, Karia, Sagar, Kazakova, Olga, Khalifa, Doaa, Khaustova, Olena, Koh, Steve, Kopishinskaia, Svetlana, Kosenko, Korneliia, Koupidis, Sotirios A, Kovacs, Illes, Kulig, Barbara, Lalljee, Alisha, Liewig, Justine, Majid, Abdul, Malashonkova, Evgeniia, Malik, Khamelia, Malik, Najma Iqbal, Mammadzada, Gulay, Mandalia, Bilvesh, Marazziti, Donatella, Marčinko, Darko, Martinez, Stephanie, Matiekus, Eimantas, Mejia, Gabriela, Memon, Roha Saeed, Martínez, Xarah Elenne Meza, Mickevičiūtė, Dalia, Milev, Roumen, Mohammed, Muftau, and Molina-López, Alejandro
Subjects: Mind and Body, Mental Health, Brain Disorders, Serious Mental Illness, Prevention, Depression, Behavioral and Social Science, Mental health, Good Health and Well Being, Adult, Anxiety, COVID-19, Female, Global Burden of Disease, Humans, Male, Middle Aged, Pandemics, SARS-CoV-2, Stress, Psychological, Suicidal Ideation, Suicidality, Conspiracy theories, Mental disorders, Psychiatry, Medical and Health Sciences, Psychology and Cognitive Sciences
Abstract: IntroductionThere are few published empirical data on the effects of COVID-19 on mental health, and until now, there is no large international study.Material and methodsDuring the COVID-19 pandemic, an online questionnaire gathered data from 55,589 participants from 40 countries (64.85% females aged 35.80 ± 13.61; 34.05% males aged 34.90±13.29 and 1.10% other aged 31.64±13.15). Distress and probable depression were identified with the use of a previously developed cut-off and algorithm respectively.Statistical analysisDescriptive statistics were calculated. Chi-square tests, multiple forward stepwise linear regression analyses and Factorial Analysis of Variance (ANOVA) tested relations among variables.ResultsProbable depression was detected in 17.80% and distress in 16.71%. A significant percentage reported a deterioration in mental state, family dynamics and everyday lifestyle. Persons with a history of mental disorders had higher rates of current depression (31.82% vs. 13.07%). At least half of participants were accepting (at least to a moderate degree) a non-bizarre conspiracy. The highest Relative Risk (RR) to develop depression was associated with history of Bipolar disorder and self-harm/attempts (RR = 5.88). Suicidality was not increased in persons without a history of any mental disorder. Based on these results a model was developed.ConclusionsThe final model revealed multiple vulnerabilities and an interplay leading from simple anxiety to probable depression and suicidality through distress. This could be of practical utility since many of these factors are modifiable. Future research and interventions should specifically focus on them.
Published: 2022

9. Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, phase 3 trial

Author: Kalil, Andre C, Mehta, Aneesh K, Patterson, Thomas F, Erdmann, Nathaniel, Gomez, Carlos A, Jain, Mamta K, Wolfe, Cameron R, Ruiz-Palacios, Guillermo M, Kline, Susan, Pineda, Justino Regalado, Luetkemeyer, Anne F, Harkins, Michelle S, Jackson, Patrick EH, Iovine, Nicole M, Tapson, Victor F, Oh, Myoung-don, Whitaker, Jennifer A, Mularski, Richard A, Paules, Catharine I, Ince, Dilek, Takasaki, Jin, Sweeney, Daniel A, Sandkovsky, Uriel, Wyles, David L, Hohmann, Elizabeth, Grimes, Kevin A, Grossberg, Robert, Laguio-Vila, Maryrose, Lambert, Allison A, de Castilla, Diego Lopez, Kim, EuSuk, Larson, LuAnn, Wan, Claire R, Traenkner, Jessica J, Ponce, Philip O, Patterson, Jan E, Goepfert, Paul A, Sofarelli, Theresa A, Mocherla, Satish, Ko, Emily R, de Leon, Alfredo Ponce, Doernberg, Sarah B, Atmar, Robert L, Maves, Ryan C, Dangond, Fernando, Ferreira, Jennifer, Green, Michelle, Makowski, Mat, Bonnett, Tyler, Beresnev, Tatiana, Ghazaryan, Varduhi, Dempsey, Walla, Nayak, Seema U, Dodd, Lori, Tomashek, Kay M, Beigel, John H, members, ACTT-3 study group, Hewlett, Angela, Taylor, Barbara S, Bowling, Jason E, Serrano, Ruth C, Rouphael, Nadine G, Wiley, Zanthia, Phadke, Varun K, Certain, Laura, Imlay, Hannah N, Engemann, John J, Walter, Emmanuel B, Meisner, Jessica, Rajme, Sandra, Billings, Joanne, Kim, Hyun, Martinez-Orozco, Jose A, Felix, Nora Bautista, Elmor, Sammy T, Bristow, Laurel R, Mertz, Gregory, Sosa, Nestor, Bell, Taison D, West, Miranda J, Elie-Turenne, Marie-Carmelle, Grein, Jonathan, Sutterwala, Fayyaz, Choe, Pyoeng Gyun, Kang, Chang Kyung, Sahly, Hana M El, Rhie, Kevin S, Hussein, Rezhan H, Winokur, Patricia L, Mikami, Ayako, Saito, Sho, Benson, Constance A, McConnell, Kimberly, Berhe, Mezgebe, Dishner, Emma, Frank, Maria G, Sarcone, Ellen, Crouch, Pierre-Cedric B, Jang, Hannah, and Jilg, Nikolaus
Subjects: Rehabilitation, Clinical Trials and Supportive Activities, Lung, Clinical Research, Infectious Diseases, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Infection, Adenosine Monophosphate, Adult, Aged, Alanine, Antiviral Agents, Double-Blind Method, Female, Humans, Interferon beta-1a, Japan, Male, Mexico, Middle Aged, Oxygen, Oxygen Saturation, Republic of Korea, SARS-CoV-2, Singapore, Treatment Outcome, United States, COVID-19 Drug Treatment, ACTT-3 study group members, Clinical Sciences, Public Health and Health Services, Other Medical and Health Sciences
Abstract: BackgroundFunctional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19.MethodsWe did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 μg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04492475.FindingsBetween Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87-1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3-7%) in the interferon beta-1a plus remdesivir group and 3% (2-6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69-2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group.InterpretationInterferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo.FundingThe National Institute of Allergy and Infectious Diseases (USA).
Published: 2021

10. Remdesivir for the Treatment of Covid-19 — Final Report

Author: Beigel, John H, Tomashek, Kay M, Dodd, Lori E, Mehta, Aneesh K, Zingman, Barry S, Kalil, Andre C, Hohmann, Elizabeth, Chu, Helen Y, Luetkemeyer, Annie, Kline, Susan, Lopez de Castilla, Diego, Finberg, Robert W, Dierberg, Kerry, Tapson, Victor, Hsieh, Lanny, Patterson, Thomas F, Paredes, Roger, Sweeney, Daniel A, Short, William R, Touloumi, Giota, Lye, David Chien, Ohmagari, Norio, Oh, Myoung-Don, Ruiz-Palacios, Guillermo M, Benfield, Thomas, Fätkenheuer, Gerd, Kortepeter, Mark G, Atmar, Robert L, Creech, C Buddy, Lundgren, Jens, Babiker, Abdel G, Pett, Sarah, Neaton, James D, Burgess, Timothy H, Bonnett, Tyler, Green, Michelle, Makowski, Mat, Osinusi, Anu, Nayak, Seema, and Lane, H Clifford
Subjects: Biomedical and Clinical Sciences, Clinical Sciences, Infectious Diseases, Clinical Trials and Supportive Activities, Clinical Research, Rehabilitation, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Infection, Good Health and Well Being, Adenosine Monophosphate, Administration, Intravenous, Adult, Aged, Alanine, Antiviral Agents, Betacoronavirus, COVID-19, Coronavirus Infections, Double-Blind Method, Extracorporeal Membrane Oxygenation, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Oxygen Inhalation Therapy, Pandemics, Pneumonia, Viral, Respiration, Artificial, SARS-CoV-2, Time Factors, Young Adult, COVID-19 Drug Treatment, ACTT-1 Study Group Members, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract: BackgroundAlthough several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), no antiviral agents have yet been shown to be efficacious.MethodsWe conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only.ResultsA total of 1062 patients underwent randomization (with 541 assigned to remdesivir and 521 to placebo). Those who received remdesivir had a median recovery time of 10 days (95% confidence interval [CI], 9 to 11), as compared with 15 days (95% CI, 13 to 18) among those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; P
Published: 2020

11. Modulation of the endocrine transcriptional program by targeting histone modifiers of the H3K27me3 mark

Author: Fontcuberta-PiSunyer, Marta, Cervantes, Sara, Miquel, Eulàlia, Mora-Castilla, Sergio, Laurent, Louise C, Raya, Angel, Gomis, Ramon, and Gasa, Rosa
Subjects: Biochemistry and Cell Biology, Biological Sciences, Diabetes, Genetics, Metabolic and endocrine, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Chromatin, Diabetes Mellitus, Enhancer of Zeste Homolog 2 Protein, Epigenesis, Genetic, Gene Expression Regulation, Developmental, Gene Silencing, Humans, Insulin, Insulin Secretion, Insulin-Secreting Cells, Jumonji Domain-Containing Histone Demethylases, Lysine, Nerve Tissue Proteins, Organogenesis, Biochemistry & Molecular Biology, Developmental Biology, Biochemistry and cell biology
Abstract: Posttranscriptional modifications of histones constitute an epigenetic mechanism that is closely linked to both gene silencing and activation events. Trimethylation of Histone3 at lysine 27 (H3K27me3) is a repressive mark that associates with developmental gene regulation during differentiation programs. In the developing pancreas, expression of the transcription factor Neurogenin3 in multipotent progenitors initiates endocrine differentiation that culminates in the generation of all pancreatic islet cell lineages, including insulin-producing beta cells. Previously, we showed that Neurogenin3 promoted the removal of H3K27me3 marks at target gene promoters in vitro, suggesting a functional connection between this factor and regulators of this chromatin mark. In the present study, we aimed to specifically evaluate whether targeting the activity of these histone modifiers can be used to modulate pancreatic endocrine differentiation. Our data show that chemical inhibition of the H3K27me3 demethylases Jmjd3/Utx blunts Neurogenin3-dependent gene activation in vitro. Conversely, inhibition of the H3K27me3 methyltransferase Ezh2 enhances both the transactivation ability of Neurogenin3 in cultured cells and the formation of insulin-producing cells during directed differentiation from pluripotent cells. These results can help improve current protocols aimed at generating insulin-producing cells for beta cell replacement therapy in diabetes.
Published: 2018

12. Neural Stem Cells Derived from Human Parthenogenetic Stem Cells Engraft and Promote Recovery in a Nonhuman Primate Model of Parkinson's Disease

Author: Gonzalez, Rodolfo, Garitaonandia, Ibon, Poustovoitov, Maxim, Abramihina, Tatiana, McEntire, Caleb, Culp, Ben, Attwood, Jordan, Noskov, Alexander, Christiansen-Weber, Trudy, Khater, Marwa, Mora-Castilla, Sergio, To, Cuong, Crain, Andrew, Sherman, Glenn, Semechkin, Andrey, Laurent, Louise C, Elsworth, John D, Sladek, John, Snyder, Evan Y, Redmond, D Eugene, and Kern, Russell A
Subjects: Biological Sciences, Stem Cell Research - Embryonic - Human, Transplantation, Neurosciences, Aging, Parkinson's Disease, Brain Disorders, Regenerative Medicine, Stem Cell Research - Nonembryonic - Human, Stem Cell Research, Neurodegenerative, 5.2 Cellular and gene therapies, Development of treatments and therapeutic interventions, Neurological, Animals, Behavior, Animal, Brain, Cell Differentiation, Cells, Cultured, Chlorocebus aethiops, Cluster Analysis, Corpus Striatum, Disease Models, Animal, Dopamine, Dopaminergic Neurons, Female, Gene Expression Regulation, Gene Regulatory Networks, Humans, Immunohistochemistry, Karyotype, MPTP Poisoning, Male, Neural Stem Cells, Parthenogenesis, Recovery of Function, Parkinson's disease, Neural stem cells, Human parthenogenetic stem cells, Pluripotent stem cells, Cell therapy, Technology, Medical and Health Sciences, Neurology & Neurosurgery, Biological sciences
Abstract: Cell therapy has attracted considerable interest as a promising therapeutic alternative for patients with Parkinsons disease (PD). Clinical studies have shown that grafted fetal neural tissue can achieve considerable biochemical and clinical improvements in PD. However, the source of fetal tissue grafts is limited and ethically controversial. Human parthenogenetic stem cells offer a good alternative because they are derived from unfertilized oocytes without destroying potentially viable human embryos and can be used to generate an unlimited supply of neural cells for transplantation. We have previously reported that human parthenogenetic stem cell-derived neural stem cells (hpNSCs) successfully engraft, survive long term, and increase brain dopamine (DA) levels in rodent and nonhuman primate models of PD. Here we report the results of a 12-month transplantation study of hpNSCs in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned African green monkeys with moderate to severe clinical parkinsonian symptoms. The hpNSCs manufactured under current good manufacturing practice (cGMP) conditions were injected bilaterally into the striatum and substantia nigra of immunosuppressed monkeys. Transplantation of hpNSCs was safe and well tolerated by the animals with no dyskinesia, tumors, ectopic tissue formation, or other test article-related serious adverse events. We observed that hpNSCs promoted behavioral recovery; increased striatal DA concentration, fiber innervation, and number of dopaminergic neurons; and induced the expression of genes and pathways downregulated in PD compared to vehicle control animals. These results provide further evidence for the clinical translation of hpNSCs and support the approval of the worlds first pluripotent stem cell-based phase I/IIa study for the treatment of PD (Clinical Trial Identifier NCT02452723).
Published: 2016

13. p62/SQSTM1 by Binding to Vitamin D Receptor Inhibits Hepatic Stellate Cell Activity, Fibrosis, and Liver Cancer

Author: Duran, Angeles, Hernandez, Eloy D, Reina-Campos, Miguel, Castilla, Elias A, Subramaniam, Shankar, Raghunandan, Sindhu, Roberts, Lewis R, Kisseleva, Tatiana, Karin, Michael, Diaz-Meco, Maria T, and Moscat, Jorge
Subjects: Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Nutrition, Chronic Liver Disease and Cirrhosis, Digestive Diseases, Liver Cancer, Rare Diseases, Liver Disease, Cancer, Oral and gastrointestinal, Animals, HEK293 Cells, Hepatic Stellate Cells, Humans, Liver Cirrhosis, Liver Neoplasms, Mice, Mice, Knockout, Receptors, Calcitriol, Retinoid X Receptors, Sequestosome-1 Protein, Signal Transduction, fibrosis, hepatic stellate cells, hepatocellular carcinoma, inflammation, liver cancer, non-alcoholic steatohepatitis, nuclear receptors, p62, sequestosome-1, vitamin D receptor, Neurosciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract: Hepatic stellate cells (HSCs) play critical roles in liver fibrosis and hepatocellular carcinoma (HCC). Vitamin D receptor (VDR) activation in HSCs inhibits liver inflammation and fibrosis. We found that p62/SQSTM1, a protein upregulated in liver parenchymal cells but downregulated in HCC-associated HSCs, negatively controls HSC activation. Total body or HSC-specific p62 ablation potentiates HSCs and enhances inflammation, fibrosis, and HCC progression. p62 directly interacts with VDR and RXR promoting their heterodimerization, which is critical for VDR:RXR target gene recruitment. Loss of p62 in HSCs impairs the repression of fibrosis and inflammation by VDR agonists. This demonstrates that p62 is a negative regulator of liver inflammation and fibrosis through its ability to promote VDR signaling in HSCs, whose activation supports HCC.
Published: 2016

14. Miniaturization Technologies for Efficient Single-Cell Library Preparation for Next-Generation Sequencing

Author: Mora-Castilla, Sergio, To, Cuong, Vaezeslami, Soheila, Morey, Robert, Srinivasan, Srimeenakshi, Dumdie, Jennifer N, Cook-Andersen, Heidi, Jenkins, Joby, and Laurent, Louise C
Subjects: Medical Biotechnology, Biomedical and Clinical Sciences, Engineering, Biomedical Engineering, Biotechnology, Genetics, Stem Cell Research, Generic health relevance, Computational Biology, DNA, Complementary, Embryonic Stem Cells, High-Throughput Nucleotide Sequencing, Humans, Miniaturization, Single-Cell Analysis, miniaturization, single cell, library, scale-down, Medical biotechnology, Biomedical engineering
Abstract: As the cost of next-generation sequencing has decreased, library preparation costs have become a more significant proportion of the total cost, especially for high-throughput applications such as single-cell RNA profiling. Here, we have applied novel technologies to scale down reaction volumes for library preparation. Our system consisted of in vitro differentiated human embryonic stem cells representing two stages of pancreatic differentiation, for which we prepared multiple biological and technical replicates. We used the Fluidigm (San Francisco, CA) C1 single-cell Autoprep System for single-cell complementary DNA (cDNA) generation and an enzyme-based tagmentation system (Nextera XT; Illumina, San Diego, CA) with a nanoliter liquid handler (mosquito HTS; TTP Labtech, Royston, UK) for library preparation, reducing the reaction volume down to 2 µL and using as little as 20 pg of input cDNA. The resulting sequencing data were bioinformatically analyzed and correlated among the different library reaction volumes. Our results showed that decreasing the reaction volume did not interfere with the quality or the reproducibility of the sequencing data, and the transcriptional data from the scaled-down libraries allowed us to distinguish between single cells. Thus, we have developed a process to enable efficient and cost-effective high-throughput single-cell transcriptome sequencing.
Published: 2016

15. Nonsense-Mediated RNA Decay Influences Human Embryonic Stem Cell Fate

Author: Lou, Chih-Hong, Dumdie, Jennifer, Goetz, Alexandra, Shum, Eleen Y, Brafman, David, Liao, Xiaoyan, Mora-Castilla, Sergio, Ramaiah, Madhuvanthi, Cook-Andersen, Heidi, Laurent, Louise, and Wilkinson, Miles F
Subjects: Biochemistry and Cell Biology, Biological Sciences, Stem Cell Research, Stem Cell Research - Embryonic - Human, Regenerative Medicine, Genetics, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Bone Morphogenetic Protein 4, Cell Differentiation, Cell Line, Cell Lineage, Ectoderm, Endoderm, Gene Expression Profiling, Human Embryonic Stem Cells, Humans, Mesoderm, Nonsense Mediated mRNA Decay, Pluripotent Stem Cells, RNA Helicases, RNA, Messenger, Sequence Analysis, RNA, Signal Transduction, Trans-Activators, Transforming Growth Factor beta, Clinical Sciences, Biochemistry and cell biology
Abstract: Nonsense-mediated RNA decay (NMD) is a highly conserved pathway that selectively degrades specific subsets of RNA transcripts. Here, we provide evidence that NMD regulates early human developmental cell fate. We found that NMD factors tend to be expressed at higher levels in human pluripotent cells than in differentiated cells, raising the possibility that NMD must be downregulated to permit differentiation. Loss- and gain-of-function experiments in human embryonic stem cells (hESCs) demonstrated that, indeed, NMD downregulation is essential for efficient generation of definitive endoderm. RNA-seq analysis identified NMD target transcripts induced when NMD is suppressed in hESCs, including many encoding signaling components. This led us to test the role of TGF-β and BMP signaling, which we found NMD acts through to influence definitive endoderm versus mesoderm fate. Our results suggest that selective RNA decay is critical for specifying the developmental fate of specific human embryonic cell lineages.
Published: 2016

16. Stage-specific regulation of the WNT/β-catenin pathway enhances differentiation of hESCs into hepatocytes.

Author: Touboul, Thomas, Chen, Shujuan, To, Cuong C, Mora-Castilla, Sergio, Sabatini, Karen, Tukey, Robert H, and Laurent, Louise C
Subjects: Cells, Cultured, Hepatocytes, Humans, Cytochrome P-450 Enzyme System, Transforming Growth Factor beta, alpha-Fetoproteins, Cell Differentiation, beta Catenin, Receptors, Notch, Wnt Signaling Pathway, Human Embryonic Stem Cells, Serum Albumin, Human, Fetal hepatocyte, Functionality, Hepatoblast, Human embryonic stem cell, WNT/β-catenin, WNT/beta-catenin, Gastroenterology & Hepatology, Clinical Sciences, Public Health and Health Services
Abstract: Background & aimsHepatocytes differentiated from human embryonic stem cells (hESCs) have the potential to overcome the shortage of primary hepatocytes for clinical use and drug development. Many strategies for this process have been reported, but the functionality of the resulting cells is incomplete. We hypothesize that the functionality of hPSC-derived hepatocytes might be improved by making the differentiation method more similar to normal in vivo hepatic development.MethodsWe tested combinations of growth factors and small molecules targeting candidate signaling pathways culled from the literature to identify optimal conditions for differentiation of hESCs to hepatocytes, using qRT-PCR for stage-specific markers to identify the best conditions. Immunocytochemistry was then used to validate the selected conditions. Finally, induction of expression of metabolic enzymes in terminally differentiated cells was used to assess the functionality of the hESC-derived hepatocytes.ResultsOptimal differentiation of hESCs was attained using a 5-stage protocol. After initial induction of definitive endoderm (stage 1), we showed that inhibition of the WNT/β-catenin pathway during the 2nd and 3rd stages of differentiation was required to specify first posterior foregut, and then hepatic gut cells. In contrast, during the 4th stage of differentiation, we found that activation of the WNT/β-catenin pathway allowed generation of proliferative bipotent hepatoblasts, which then were efficiently differentiated into hepatocytes in the 5th stage by dual inhibition of TGF-β and NOTCH signaling.ConclusionHere, we show that stage-specific regulation of the WNT/β-catenin pathway results in improved differentiation of hESCs to functional hepatocytes.
Published: 2016

17. Standards in semen examination: publishing reproducible and reliable data based on high-quality methodology

Author: Lars Björndahl, Christopher L R Barratt, David Mortimer, Ashok Agarwal, Robert J Aitken, Juan G Alvarez, Natalie Aneck-Hahn, Stefan Arver, Elisabetta Baldi, Lluís Bassas, Florence Boitrelle, Riana Bornman, Douglas T Carrell, José A Castilla, Gerardo Cerezo Parra, Jerome H Check, Patricia S Cuasnicu, Sally Perreault Darney, Christiaan de Jager, Christopher J De Jonge, Joël R Drevet, Erma Z Drobnis, Stefan S Du Plessis, Michael L Eisenberg, Sandro C Esteves, Evangelini A Evgeni, Alberto Ferlin, Nicolas Garrido, Aleksander Giwercman, Ilse G F Goovaerts, Trine B Haugen, Ralf Henkel, Lars Henningsohn, Marie-Claude Hofmann, James M Hotaling, Piotr Jedrzejczak, Pierre Jouannet, Niels Jørgensen, Jackson C Kirkman Brown, Csilla Krausz, Maciej Kurpisz, Ulrik Kvist, Dolores J Lamb, Hagai Levine, Kate L Loveland, Robert I McLachlan, Ali Mahran, Liana Maree, Sarah Martins da Silva, Michael T Mbizvo, Andreas Meinhardt, Roelof Menkveld, Sharon T Mortimer, Sergey Moskovtsev, Charles H Muller, Maria José Munuce, Monica Muratori, Craig Niederberger, Cristian O’Flaherty, Rafael Oliva, Willem Ombelet, Allan A Pacey, Michael A Palladino, Ranjith Ramasamy, Liliana Ramos, Nathalie Rives, Eduardo Rs Roldan, Susan Rothmann, Denny Sakkas, Andrea Salonia, Maria Cristina Sánchez-Pozo, Rosanna Sapiro, Stefan Schlatt, Peter N Schlegel, Hans-Christian Schuppe, Rupin Shah, Niels E Skakkebæk, Katja Teerds, Igor Toskin, Herman Tournaye, Paul J Turek, Gerhard van der Horst, Monica Vazquez-Levin, Christina Wang, Alex Wetzels, Theodosia Zeginiadou, Armand Zini, Faculty of Medicine and Pharmacy, Clinical sciences, Biology of the Testis, Centre for Reproductive Medicine - Gynaecology, Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), CHU Rouen, Normandie Université (NU), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Neuroendocrine, Endocrine and Germinal Differentiation Communication (NorDic), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Björndahl, L, Barratt, Clr, Mortimer, D, Agarwal, A, Aitken, Rj, Alvarez, Jg, Aneck-Hahn, N, Arver, S, Baldi, E, Bassas, L, Boitrelle, F, Bornman, R, Carrell, Dt, Castilla, Ja, Cerezo Parra, G, Check, Jh, Cuasnicu, P, Darney, Sp, de Jager, C, De Jonge, Cj, Drevet, Jr, Drobnis, Ez, Du Plessis, S, Eisenberg, Ml, Esteves, Sc, Evgeni, Ea, Ferlin, A, Garrido, N, Giwercman, A, Goovaerts, Igf, Haugen, Tb, Henkel, R, Henningsohn, L, Hofmann, Mc, Hotaling, Jm, Jedrzejczak, P, Jouannet, P, Jørgensen, N, Kirkman Brown, Jc, Krausz, C, Kurpisz, M, Kvist, U, Lamb, Dj, Levine, H, Loveland, Kl, Mclachlan, Ri, Mahran, A, Maree, L, Martins da Silva, S, Mbizvo, Mt, Meinhardt, A, Menkveld, R, Mortimer, St, Moskovtsev, S, Muller, Ch, Munuce, Mj, Muratori, M, Niederberger, C, O'Flaherty, C, Oliva, R, Ombelet, W, Pacey, Aa, Palladino, Ma, Ramasamy, R, Ramos, L, Rives, N, Roldan, Er, Rothmann, S, Sakkas, D, Salonia, A, Sánchez-Pozo, Mc, Sapiro, R, Schlatt, S, Schlegel, Pn, Schuppe, Hc, Shah, R, Skakkebæk, Ne, Teerds, K, Toskin, I, Tournaye, H, Turek, Pj, van der Horst, G, Vazquez-Levin, M, Wang, C, Wetzels, A, Zeginiadou, T, Zini, A., Pacey, Allan/0000-0002-4387-8871, Arver, Stefan/0000-0002-2925-355X, Mortimer, David/0000-0002-0638-2893, Barratt, christopher/0000-0003-0062-9979, Kirkman-Brown, Jackson, C/0000-0003-2833-8970, Bjorndahl, Lars/0000-0002-4709-5807, Baldi, Elisabetta/0000-0003-1808-3097, Aitken, Robert John/0000-0002-9152-156X, Bjorndahl, Lars, Barratt, Christopher L. R., Mortimer, David, Agarwal, Ashok, Aitken, Robert J., Alvarez, Juan G., Aneck-Hahn, Natalie, Arver, Stefan, Baldi, Elisabetta, Bassas, Lluis, Boitrelle, Florence, Bornman, Riana, Carrell, Douglas T., Castilla, Jose A., Cerezo Parra, Gerardo, Check, Jerome H., Cuasnicu, Patricia S., Darney, Sally Perreault, de Jager, Christiaan, De Jonge, Christopher J., Drevet, Joel R., Drobnis, Erma Z., Du Plessis, Stefan S., Eisenberg, Michael L., Esteves, Sandro C., Evgeni, Evangelini A., Ferlin, Alberto, Garrido, Nicolas, Giwercman, Aleksander, Goovaerts, Ilse G. F., Haugen, Trine B., Henkel, Ralf, Henningsohn, Lars, Hofmann, Marie-Claude, Hotaling, James M., Jedrzejczak, Piotr, Jouannet, Pierre, Jorgensen, Niels, Brown, Jackson C. Kirkman, Krausz, Csilla, Kurpisz, Maciej, Kvist, Ulrik, Lamb, Dolores J., Levine, Hagai, Loveland, Kate L., McLachlan, Robert, I, Mahran, Ali, Maree, Liana, da Silva, Sarah Martins, Mbizvo, Michael T., Meinhardt, Andreas, Menkveld, Roelof, Mortimer, Sharon T., Moskovtsev, Sergey, Muller, Charles H., Jose Munuce, Maria, Muratori, Monica, Niederberger, Craig, O'Flaherty, Cristian, Oliva, Rafael, OMBELET, Willem, Pacey, Allan A., Palladino, Michael A., Ramasamy, Ranjith, Ramos, Liliana, Rives, Nathalie, Roldan, Eduardo Rs, Rothmann, Susan, Sakkas, Denny, Salonia, Andrea, Cristina Sanchez-Pozo, Maria, Sapiro, Rosanna, Schlatt, Stefan, Schlegel, Peter N., Schuppe, Hans-Christian, Shah, Rupin, Skakkebaek, Niels E., Teerds, Katja, Toskin, Igor, Tournaye, Herman, Turek, Paul J., van der Horst, Gerhard, Vazquez-Levin, Monica, Wang, Christina, Wetzels, Alex, Zeginiadou, Theodosia, and Zini, Armand
Subjects: Reproducitibility, [SDV]Life Sciences [q-bio], andrology, basic semen examination, journal requirements, laboratory training, patient security, quality control, reproducibility, reproductive medicine, science development, standardized laboratory procedures, Humans, Reproducibility of Results, Publishing, Semen, Semen Analysis, Andrology, Obstetrics & Reproductive Medicine, Biology, 11 Medical and Health Sciences, Reproductive Biology, Science & Technology, Rehabilitation, Obstetrics & Gynecology, Obstetrics and Gynecology, Reproductive Medicine, 16 Studies in Human Society, Human and Animal Physiology, Fysiologie van Mens en Dier, Human medicine, Life Sciences & Biomedicine
Abstract: Biomedical science is rapidly developing in terms of more transparency, openness and reproducibility of scientific publications. This is even more important for all studies that are based on results from basic semen examination. Recently two concordant documents have been published: the 6th edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen, and the International Standard ISO 23162:2021. With these tools, we propose that authors should be instructed to follow these laboratory methods in order to publish studies in peer-reviewed journals, preferable by using a checklist as suggested in an Appendix to this article.
Published: 2022
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18. Metabolic rescue in pluripotent cells from patients with mtDNA disease

Author: Ma, Hong, Folmes, Clifford DL, Wu, Jun, Morey, Robert, Mora-Castilla, Sergio, Ocampo, Alejandro, Ma, Li, Poulton, Joanna, Wang, Xinjian, Ahmed, Riffat, Kang, Eunju, Lee, Yeonmi, Hayama, Tomonari, Li, Ying, Van Dyken, Crystal, Gutierrez, Nuria Marti, Tippner-Hedges, Rebecca, Koski, Amy, Mitalipov, Nargiz, Amato, Paula, Wolf, Don P, Huang, Taosheng, Terzic, Andre, Laurent, Louise C, Belmonte, Juan Carlos Izpisua, and Mitalipov, Shoukhrat
Subjects: Stem Cell Research, Neurodegenerative, Stem Cell Research - Induced Pluripotent Stem Cell - Non-Human, Stem Cell Research - Induced Pluripotent Stem Cell, Genetics, Aetiology, 2.1 Biological and endogenous factors, Adenosine Triphosphate, Animals, Cell Line, DNA, Mitochondrial, Embryo, Mammalian, Fibroblasts, Gene Expression Profiling, Haplotypes, Humans, Induced Pluripotent Stem Cells, Leigh Disease, Mice, Mitochondria, Mitochondrial Diseases, Mitochondrial Encephalomyopathies, Mutation, Nuclear Transfer Techniques, Nucleotides, Oxygen Consumption, Polymorphism, Single Nucleotide, Sequence Analysis, RNA, Skin, General Science & Technology
Abstract: Mitochondria have a major role in energy production via oxidative phosphorylation, which is dependent on the expression of critical genes encoded by mitochondrial (mt)DNA. Mutations in mtDNA can cause fatal or severely debilitating disorders with limited treatment options. Clinical manifestations vary based on mutation type and heteroplasmy (that is, the relative levels of mutant and wild-type mtDNA within each cell). Here we generated genetically corrected pluripotent stem cells (PSCs) from patients with mtDNA disease. Multiple induced pluripotent stem (iPS) cell lines were derived from patients with common heteroplasmic mutations including 3243A>G, causing mitochondrial encephalomyopathy and stroke-like episodes (MELAS), and 8993T>G and 13513G>A, implicated in Leigh syndrome. Isogenic MELAS and Leigh syndrome iPS cell lines were generated containing exclusively wild-type or mutant mtDNA through spontaneous segregation of heteroplasmic mtDNA in proliferating fibroblasts. Furthermore, somatic cell nuclear transfer (SCNT) enabled replacement of mutant mtDNA from homoplasmic 8993T>G fibroblasts to generate corrected Leigh-NT1 PSCs. Although Leigh-NT1 PSCs contained donor oocyte wild-type mtDNA (human haplotype D4a) that differed from Leigh syndrome patient haplotype (F1a) at a total of 47 nucleotide sites, Leigh-NT1 cells displayed transcriptomic profiles similar to those in embryo-derived PSCs carrying wild-type mtDNA, indicative of normal nuclear-to-mitochondrial interactions. Moreover, genetically rescued patient PSCs displayed normal metabolic function compared to impaired oxygen consumption and ATP production observed in mutant cells. We conclude that both reprogramming approaches offer complementary strategies for derivation of PSCs containing exclusively wild-type mtDNA, through spontaneous segregation of heteroplasmic mtDNA in individual iPS cell lines or mitochondrial replacement by SCNT in homoplasmic mtDNA-based disease.
Published: 2015

19. Tolerance of human embryonic stem cell derived islet progenitor cells to vitrification-relevant solutions

Author: Lahmy, Reyhaneh, Bolyukh, Vladimir F, Castilla, Sergio Mora, Laurent, Louise C, Katkov, Igor I, and Itkin-Ansari, Pamela
Subjects: Medical Biotechnology, Biomedical and Clinical Sciences, Diabetes, Stem Cell Research, Stem Cell Research - Embryonic - Human, Transplantation, Regenerative Medicine, Basic Helix-Loop-Helix Transcription Factors, Cell Survival, Cryopreservation, Cryoprotective Agents, Dimethyl Sulfoxide, Ethylene Glycol, Freezing, Glycerol, Homeodomain Proteins, Human Embryonic Stem Cells, Humans, Islets of Langerhans, Nerve Tissue Proteins, Propylene Glycol, Solutions, Sucrose, Trans-Activators, Transcription Factors, Vitrification, Osmotic tolerance, Toxicity, Insulin progenitors, Macroencapsulation, Beta-cells, Biochemistry and Cell Biology, Medical Physiology, Biochemistry & Molecular Biology, Animal production, Medical physiology
Abstract: We have previously shown that human embryonic stem cell derived islet progenitors (hESC-IPs), encapsulated inside an immunoprotective device, mature in vivo and ameliorate diabetes in mice. The ability to cryopreserve hESC-IPs preloaded in these devices would enhance consistency and portability, but traditional 'slow freezing' methods did not work well for cells encapsulated in the device. Vitrification is an attractive alternative cryopreservation approach. To assess the tolerance of hESC-IPs to vitrification relevant conditions, we here are reporting cell survival following excursions in tonicity, exposure to fifteen 40% v/v combinations of 4 cryoprotectants, and varied methods for addition and elution. We find that 78% survival is achieved using a protocol in which cells are abruptly (in one step) exposed to a solution containing 10% v/v each dimethyl sulfoxide, propylene glycol, ethylene glycol, and glycerol on ice, and eluted step-wise with DPBS+0.5M sucrose at 37°C. Importantly, the hESC-IPs also maintain expression of the critical islet progenitor markers PDX-1, NKX6.1, NGN3 and NEURO-D1. Thus, hESC-IPs exhibit robust tolerance to exposure to vitrification solutions in relevant conditions.
Published: 2015

20. Effects of hospital facilities on patient outcomes after cancer surgery

Author: Knight, Sr, Chu, K, Lapitan, Mc, Dare, Aj, Pius, R, Shaw, Ca, Drake, Tm, Norman, L, Ademuyiwa, Ao, Adisa, Ao, Aguilera, Ml, Al-Saqqa, Sw, Al-Slaibi, I, Bhangu, A, Biccard, Bm, Brocklehurst, P, Costas-Chavarri, A, Elhadi, M, Fairfield, Cj, Fitzgerald, Je, Ghosh, D, Glasbey, J, Henegouwen, Miv, Ingabire, Jca, Kingham, Tp, Lawani, I, Lieske, B, Lilford, R, Martin, J, Mclean, Ka, Moore, R, Morton, D, Nepogodiev, D, Ntirenganya, F, Pata, F, Pinkney, T, Stephen, R Knight, Catherine, A Shaw, Riinu, Pius, Thomas, M Drake, Lisa, Norman, Adesoji, O Ademuyiwa, Adewale, O Adisa, Maria Lorena Aguilera, Sara, W Al-Saqqa, Ibrahim, Al-Slaibi, Aneel, Bhangu, Bruce, M Biccard, Peter, Brocklehurst, Ainhoa, Costas-Chavarri, Kathryn, Chu, Anna, Dare, Muhammed, Elhadi, Cameron, J Fairfield, J Edward Fitzgerald, Dhruv, Ghosh, James, Glasbey, Mark, I van Berge Henegouwen, C Allen Ingabire, J, T Peter Kingham, Marie Carmela Lapitan, Ismaïl, Lawani, Bettina, Lieske, Richard, Lilford, Janet, Martin, Kenneth, A McLean, Rachel, Moore, Dion, Morton, Dmitri, Nepogodiev, Faustin, Ntirenganya, Francesco, Pata, Thomas, Pinkney, Ahmad Uzair Qureshi, Antonio Ramos-De la Medina, Aya, Riad, Hosni Khairy Salem, Joana, Simões, Richard, Spence, Neil, Smart, Stephen, Tabiri, Hannah, Thomas, Thomas, G Weiser, Malcolm, West, John, Whitaker, Ewen, M Harrison, Arben, Gjata, Maria Marta Modolo, Sebastian, King, Erick, Chan, Sayeda Nazmun Nahar, Ade, Waterman, Dominique, Vervoort, Alemayehu Ginbo Bedada, Bernardo De Azevedo, Ana Gabriela Figueiredo, Manol, Sokolov, Venerand, Barendegere, Gerald, Ekwen, Arnav, Agarwal, Qinyang, Liu, Juan Camilo Correa, Kalisya Luc Malemo, Jacques, Bake, Jakov, Mihanovic, Kamila, Kunčarová, Julius, Orhalmi, Hosni, Salem, Jyri, Teras, Aristotelis, Kechagias, Alexis, P Arnaud, Judith, Lindert, Vasileios, Kalles, Maria-Lorena, Aguilera-Arevalo, Gustavo, Recinos, Zsolt, Baranyai, Basant, Kumar, Harish Neelamraju Lakshmi, Sanoop Koshy Zachariah, Philip, Alexander, Sunil Kumar Venkatappa, Pramesh, C, Radhian, Amandito, Christina, Fleming, Luca, Ansaloni, Gianluca, Pellino, Ahmed, M Altibi, Ibrahim, Nour, Intisar, Hamdun, Ali, M Ghellai, Donatas, Venskutonis, Tomas, Poskus, Justas, Zilinskas, Precious, Malemia, Yong Yong Tew, Elaine, Borg, Sarah, Ellul, Fatima Zahraa Wafqui, David, W Borowski, Anne Sophie van Dalen, Cameron, Wells, Harissou, Adamou, Adesoji, Ademuyiwa, Adewale, Adisa, Kjetil, Søreide, Sara Al Saqqa, Osaid, Alser, Haya, Tahboub, Helmut Alfredo Segovia Lohse, Sebastian Shu Yip, Piotr, Major, António Sampaio Soares, Matei Razvan Bratu, Andrey, Litvin, Armen, Vardanyan, Ahmad, Gudal, Naif, Albati, Jovan, Juloski, Miran, Rems, Sarah, Rayne, Stephanie Van Straten, Yoshan, Moodley, Irene Ortega Vázquez, Jaime, Ruiz-Tovar, Kithsiri Janakantha Senanayake, Sujeewa Priyantha Bandara Thalgaspitiya, Omer Abdelbagi Omer, Anmar, Homeida, Yucel, Cengiz, Daniel, Clerc, Muhammad, Alshaar, Hanen, Bouaziz, Yuksel, Altinel, Matthew, Doe, Maryna, Freigofer, Ella, Teasdale, Rakan, Kabariti, Joshua Michael Clements, Stephen Richard Knight, Ahsan, Ashfaq, Ijeoma, Azodo, Gabriela, Wagner, Ivan, Trostchansky, Mayaba, Maimbo, David, Linyama, Helidon, Nina, Amanda, Zeko, Claudio Gabriel Fermani, Santiago, Villalobos, Federico, Carballo, Pablo, Farina, Sebastian, Guckenheimer, Marilla, Dickfos, Ankit, Ajmera, Chester, Chong, Ralph, Gourlay, Sikandar, Hussaini, Yi Jia Lee, Adeeb, Majid, Peter, Martin, Rebecca, Miles, Owen James Morris, Jamie, Phua, William, Ridley, Tarunpreet, Saluja, Ryan Renxin Tan, Jen, Teh, Anna, Wells, Bharti, Arora, Qaasim, Dollie, Debbie, Ho, Yanru, Ma, Omattage Mahasha Perera, Anthony, Truong, Amanda Caroline Dawson, Bryan, Lim, Upuli, Pahalawatta, Jacqueline, Phan, Xiao-Ming Sarah Woon-Shoo-Tong, Andrea, Yeoh, Lillian, Charman, Andrew, Drane, Sharon, Laura, Charmaine Chu Wen Lo, Amy, Mozes, Rita, Poon, Hao Han Tan, Ellen, Wall, Prakshi, Chopra, Jasmine De Giovanni, Bal, Dhital, Brian, Draganic, Alexander, Duller, Jonathan, Gani, Yao Kuan Goh, Jun Young Jeong, Brendan, Mcmanus, Prakash, Nagappan, Peter, Pockney, Anya, Rugendyke, Mahsa, Sarrami, Stephen, Smith, Vanessa, Wills, Hsu Ven Wong, Geoffrey, Ye, Geoffrey, Zhang, Ethan, Brooker, Daniel, Feng, Bonnie, Lau, Carlin, Ngai, Sarah, Birks, David, Gyorki, Jaime Otero de Pablos, Ali, Abbosh, Chris, Gillespie, Ahmed, Mahmoud, Bianca, Kwan, Joshua, Lawson, Andrea, Warwick, Janne, Bingham, Andrew, J Cockbain, Nagendra Naidu Dudi-Venkata, Jordan, Ellaby-Hall, Ben, Finlay, Emily, Humphries, Jade, Pisaniello, Monique, Pisaniello, Salma, Salih, Tarik, Sammour, Haidar Hadri Abd Wahab, April De Silva, Nicola, Hayward, Kartik, Iyer, Guy, Maddern, Gian Andrea Prevost, Naga, Annapureddy, Krishna Pranathi Settipalli, Jeremy, Yeo, Lucy, Hempenstall, Lily, Pham, Shaun, Purcell, Cherry, Talavera, Ashish, I Vaska, Gurpreet, Chaggar, Phillip, Chrapko, Annelise, Cocco, Sarah Michelle Crystal Jade Coulter-Nile, Grahame, Ctercteko, James, French, Houchen, Gong, Martijn, Gosselink, Thuvarahan, Jegathees, Ivan, Jin, Michelle, Kalachov, Kathryn, Kiefhaber, Katherine, Lee, Jason, Luong, Steven, Phan, Henry, Pleass, Kelly, Veale, Zhi, Zeng, Angela, Au, Ashe, Debiasio, Idy, Deng, Jananee, Myooran, Amrita, Nair, Peter, Stewart, Anton, Stift, Lukas Walter Unger, Kerstin, Wimmer, Nabila, Ahmed, Syed, Hasan, Saber, Rahman, Margaret, O'Shea, Greg, Padmore, Adrian, Peters, Pietro, Perduca, Guenda, Pulcina, Nicolas, Tinton, Frederic, Buxant, Elsa, Dabin, Giulia, Garofalo, Francis, Dossou, Freddy Houehanou Rodrigue Gnangnon, Yacoubou Imorou Souaibou, Pako, Motlaleselelo, Omphile, Tlhomelang, Igor Lima Buarque, Gustavo Mendonça Ataíde Gomes, Aldo Vieira Barros, Ilia, Batashki, Nikolai, Damianov, Vladislav, Stoyanov, Dragomir, Dardanov, Svilen, Maslyankov, Plamen, Petkov, George, Todorov, Evgeni, Zhivkov, Aygulya, Akisheva, Miguel Angel Castilla Moreno, Geno, Genov, Ivelina, Ilieva, Tsvetomir, Ivanov, Martin, Karamanliev, Azhar, Khan, Emil, Mitkov, Tsanko, Yotsov, Boyko, Atanasov, Nikolay, Belev, Mihail, Slavchev, Carlos, Nsengiyumva, Elgan, Jones, Simon, Stock, Steve, Kyota, James, Brown, Tresor Mabanza, K, Lemery Nigo Samuel, Chidi, Otuneme, Ngwang, Prosper, Franklin, Umenze, Marylise, Boutros, Natasha, Caminsky, Sinziana, Dumitra, Richard, Garfinkle, Dominique, Morency, Ebram, Salama, Alexander, Banks, Lorenzo, Ferri, Haitian, He, Amit, Katz, Alexander Sender Liberman, Sarkis, Meterissian, Allison, Pang, Elena, Parvez, Usmaan, Hameed, Fahima, Osman, Sangita, Sequeira, Natalie, Coburn, Alisha, Jaffer, Paul, Karanicolas, Matthew, Mosseler, Reilly, Musselman, Xinyuan, Liu, Ching Wan Yip, Juan Sebastian Garces-Otero, Carolina, Guzman, Sebastian, Sierra, Andres Uribe Valencia, Paulo Andrés Cabrera Rivera, Saul, Camelo, Andrea, Gonzalez, Alejandro, González-Orozco, Manuel Santiago Mosquera Paz, Carlos J- Perez Rivera, Felipe, Gonzalez, Andres, Isaza-Restrepo, Laura, Nino-Torres, Natalia Arias Madrid, Maria Clara Mendoza Arango, Justin, Tsandiraki, Damir, Jemendžić, Branislav, Kocman, Oliver, Šuman, Renata, Canic, Darko, Jurišić, Ivana, Karakas, Ana Krizanovic Rupcic, Vlatka, Pitlovic, Josip, Samardžić, Mario, Kopljar, Ivan, Bacic, Edgar, Domini, Robert, Karlo, Danijela, Miljanić, Andrea, Simic, Mariam, Ahmed, Majdi Al Nassrallah, Rabiya, Altaf, Talal, Amjad, Ruba, Eltoum, Heba, Haidar, Alhassan, Hassan, Omar, Khalil, Marwan, Qasem, Rommel, Ramesh, Gautham, Sajith, Maham, Wisal, Jan, Žatecký, Michele, Bujda, Katerina, Jirankova, Ales, Paclik, Aya, Abdallah, Mariam Abdulgawad Almogy, Esraa Ayman El-Sawy, Ahmed Moustafa ElFayoumy, Nourhan, Elghareeb, Nourhan Ahmed Esmat, Ahmed, Fadel, Abdullah, Habater, Heba, Hamdy, Amr, Hefni, Marwa, Kamal, Norhan Mohamed Abobakr, Ahmed, Sayed, Nancy, Shaker, Ehab, Taha, Hoda, Tharwat, Omar, Zakaria, Ibrahem, Abdelmotaleb, Ali, Al-Dhufri, Hamza, S Al-Himyari, Enas El Sheikh, Asmaa, Eldmaty, Aya, Elkhalawy, Ahmed, M Elkhashen, Kithara, Magdy, Safa, Mostafa, Habib Doutoum Sadia, Mohamed 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Fawzy, Hgag, Mohamed, Ibrahim, Mahmoud, Morsy, Mohamed Reda Loaloa, Ahmed, Refaat, Hadeer, Samir, Fatma, Shahien, Mohamed, Sobhy, Fathy, Sroor, Esraa, Abdellatif, Marina, Adel, Amr Abdelghani Afifi, Eman, Afifi, Marco, Antaky, Amr, Dawoud, Naira El Zoghby, Amira, El-Remaily, Ali Abdelazez Elzanfaly, Ahmed, Gadallah, Fatma Alzahraa Gamal, Omar, Hashem, Shrouk Medhat Youssef, Aliaa Muhammad Attyah, Malak, Munir, Omar, Shazly, Esraa, Taha, Karim, Wilson, Sawsan, Adel, Asmaa, Ali, Esraa, Eid, Esraa, Elhelow, Marwa, Elmahdy, Bassant, Elshatby, Amany Hossam El-Din Zakaria, Ahmad, Hossny, Eman, Ibrahim, Ahmed, M Yonis, Maram, Metwalli, Basant, Yousry, Esraa, Zid, Mina, A Yacoub, Ahmed, Abdelhakim, Nervana, Abouelsoad, Mo'Min, Alkhatib, Ahmed, Ashraf, Alaa, Ashraf, Yasmin, Elazab, Mahmoud, Elfanty, Osama, Elkabir, Mai, Elsayed, Ahmed, Elshimy, Hager, Elsobky, John, Eskander, Ahmed, Gad, Ward, Hamsho, Noura Khaled Abdelwahed, Menna, Magdy, Dalia, Moharam, Abeer, Osama, Shereen, Ramadan, Radwa, Roum, Taqwa, Sayed, Tarneem, Shehada, Ahmed Mohy Zidan, Khalid, Abbas, Amr, Ali, Mohamed, Attia, Mohamed, Balata, Ayman El Nakeeb, Mohamed Ibrahim Elsayed Elewaily, Ahmed, Elfallal, Hossam, Elfeki, Ahmed, Elkhadragy, Sameh, Emile, Helmy, Ezzat, Hasnaa, Hosni, Islam, Mansour, Waleed, Omar, Gehad, Othman, Kareem, Sadek, Mostafa, Shalaby, Noura, Shehab-Eldeen, Rawda Anas Khalifa, Helmy, Badr, Mostafa, Eldeep, Ahmed, Eldeep, Amany Eldoseuky Mohammed, Salwa, Khallaf, Eman Magdy Hegazy, Rokia, Mahmoud, Pola, Mikhail, Mahmoud, Morsi, Sara, Mowafy, Dina, Raafat, Amina, Safy, Marwa, Sera, Ahmed Shible Sera, Mostafa Salim Mohamed AbdAllah, Muhammad, Abdelkader, Abdulrahman Osama Abdou, Ahmedgaber, Ahmed, Shireen, Gaafar, Fatma Ibrahim Negm, Mina, Lapic, Ahmed, Maher, Hagar, Mahmoud, Ahmed, Mostafa, Mohamed, Samir, Fatma, Samy, Nourhan, Semeda, Hind, I Shalaby, Alaa, El-Taweel, Ahmed Galal Elnagar, Ahmed Gamal Hemidan, Mohamed, Hussein, Ahmed, A Kandil, Moawad, Mf, Ayat Allah Nasser Hamamah, Mostafa, Soliman, Mohamed, Abdelkhalek, Noura Abdelmaksoud Tawakel, Ahmed Mohamed Abdelwahed, Alrawy, Abdou, Khalid, Atallah, Mohammed Yasser Elsherbeny, Eman, Emara, Mohamed, Hamdy, Omar, Hamdy, Amira, Haron, Salma, Ismail, Islam Hany Metwally, Nihal Mohamed Hamed Elgaml, Ahmed, Nassar, Basel, Refky, Mirna, Sadek, Mahmoud, Saleh, Asmaa, Yunes, Mai, Zakaria, Mohammed, Zuhdy, Notila, Fayed, Mohammed Mustafa Hassan Mohammed, Sander, Kütner, Priit, Melnik, Indrek, Seire, Toomas, Ümarik, Eppu, Ainoa, Verner, Eerola, Hanna, Koppatz, Laura, Koskenvuo, Ville, Sallinen, Sini, Takala, Jevgeni, Katunin, Arto, Turunen, Niki, Christou, Muriel, Mathonnet, Vincent, Lavoue, Krystel Nyangoh Timoh, Lucie, Soulabaille, Romain, Lesourd, Aude, Merdrignac, Laurent, Sulpice, Benoît, André, Elodie, Chantalat, Charlotte, Vaysse, Bertrand, Dousset, Sebastien, Gaujoux, Gregory, Martin, Octavian, Clonda, Domantas, Juodis, Klaus, Kienle, Andras, Mravik, Samuel, Palmer, Gabor, Szabadhegyi, Anita Eseenam Agbeko, Solomon, Gyabaah, Frank Enoch Gyamfi, Nuhu, Naabo, Atta Owusu Senior, Joseph, Yorke, Frank, Owusu, Francis, Abantanga, Theophilus Teddy Kojo Anyomih, Abdul-Jalilu Mohammed Muntaka, Emmanuel Owusu Abem, Mohammed, Sheriff, Paul, M Wondoh, Dimitrios, Balalis, Dimitrios, Korkolis, Georgios, Gkiokas, Eirini, Pantiora, Theodosios, Theodosopoulos, Argyrios, Ioannidis, Konstantinos, Konstantinidis, Sofia, Konstantinidou, Nikolaos, Machairas, Anna, Paspala, Anastasia, Prodromidou, Christos, Chouliaras, Konstantinos, Papadopoulos, Ioannis, Baloyiannis, Ioannis, Mamaloudis, George, Tzovaras, Ioanna, Akrida, Maria-Ioanna, Argentou, Stylianos, Germanos, Evangelos, Iliopoulos, Ioannis, Maroulis, George, Skroubis, George, Theofanis, Christos, Chatzakis, Orestis, Ioannidis, Lydia, Loutzidou, Panagiotis, Karathanasis, Nikolaos, Michalopoulos, Charalampos, Theodoropoulos, Dimitrios, Theodorou, Tania, Triantafyllou, Zoe, Garoufalia, Natasha, Hasemaki, Michalis, Kontos, Gregory, Kouraklis, Stylianos, Kykalos, Theodore, Liakakos, Eustratia, Mpaili, Alexandros, Papalampros, Dimitrios, Schizas, Athanasios, Syllaios, Ekaterini Christina Tampaki, Antonios, Tsimpoukelis, Maria Ioanna Antonopoulou, Eirini, Deskou, Dimitrios, K Manatakis, Dimitrios, Papageorgiou, Menelaos, Zoulamoglou, Christos, Anthoulakis, Michalis, Margaritis, Nikolaos, Nikoloudis, Veronica, Campo, André, Ceballos, Mario-Andrés, Flores, Waleska, Giron, Donghyun, Ko, Gabriel, Martinez, Verónica Rivera Lara, Nataly, Rueda, Andres, Sanchez, Jorge Carlos Guillermo Tejeda Garrido, Alvaro Eduardo Alvarez Rivera, Elvis Benjamin Bamaca Ixcajoc, Lilian Elizabeth Barreda Zelaya, Patricia, Chacòn-Herrera, Ligia Margarita Corea Ruiz, Guillermo, Echeverria-Davila, Mario, Garcia, Danilo, García, Edgar Fernando Gutiérrez Mayen, Noriega, José, Nery, Mazariegos, Diego, Méndez, Michael Paniagua Espinoza, David, Bardos, Marton, Benke, Kristof, Illes, Balint András Kokas, Réka, Szabó, Akhila, Appukuttan, Anjitha, Asok, D K, Vijaykumar, 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Nastaran, Barati, Manoochehr, Karami, Hamidreza, Khorshidi, Homa, Naderifar, Mazin, A Abdulla, Maggie, Coleman, Ronan, J Doherty, Rob, Hannon, Brenda, Murphy, Aine, Stakelum, Des, Winter, Lylas, Aljohmani, Richard, Farnan, Yeshey, Seldon, Tanna, Tan, Shriya, Varghese, Mohammad, Alherz, Muaaz, Ather, Mohammad, Bajilan, Vivien, Graziadei, Isobel, Pilkington, Omar, Quidwai, Paul, Ridgway, Haaris, Shiwani, Abd Al-Rahman Tahir, Eimear, Blunnie, Daniel, Burke, Niall, Kennedy, Kate, Macdonagh, Maeve, O'Neill, Siobhan, Rooney, Giuseppe, Falco, Guglielmo, Ferrari, Simone, Mele, Gabriela Elisa Nita, Lara, Ugoletti, Maurizio, Zizzo, Gianmaria, Confalonieri, Giovanni, Pesenti, Fulvio, Tagliabue, Gianluca, Baronio, Deborah, Ongaro, Giacomo, Pata, Bruno, Compagnoni, Renato, Salvadori, Lucio, Taglietti, Nicola, D'Alessandro, Pierpaolo Di Lascio, Giovanni, Pascale, Luca, Bortolasi, Tommaso, Campagnaro, Massimo, Carlini, Giorgio, Lisi, Davide, Lombardi, Corrado, Pedrazzani, Domenico, Spoletini, Giulia, Turri, Paola, Violi, Donato Francesco Altomare, Fabrizio, Aquilino, Nicola, Musa, Vincenzo, Papagni, Arcangelo, Picciariello, Leonardo, Vincenti, Dario, Andreotti, Savino, Occhionorelli, Matteo, Tondo, Stefano Maria Massimiliano Basso, Paolo, Ubiali, Riccardo, Cirelli, Marco Enrico Mario Maino, Guglielmo Niccolò Piozzi, Emanuele, Picone, Rosa, Scaramuzzo, Giovanni, Sinibaldi, Alfonso, Amendola, Lorenzo, Anastasio, Luigi, Bucci, Emanuele, Caruso, Antonio, Castaldi, Sara Di Maso, Vincenza Paola Dinuzzi, Giovanni, Esposito, Maria, Gaudiello, Mariano Cesare Giglio, Paola Antonella Greco, Gaetano, Luglio, Andrea, Manfreda, Ester, Marra, Federica, Mastella, Gianluca, Pagano, Roberto, Peltrini, Vincenzo, Pepe, Michele, Sacco, Viviana, Sollazzo, Giovanni, Spiezio, Ettore, Cianchetti, Nunzia, Menduni, Michele Maria Carvello, Francesca Di Candido, Antonino, Spinelli, Fabio, Corsi, Luca, Sorrentino, Fabio, Marino, Emanuele Luigi Giuseppe Asti, Luigi, Bonavina, Emanuele, Rausa, Martina, Asta, 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Julius Ng We Yong, Kandasami Palayan, Chi Xuan Sam, Phuah Siow Jin, Jeremy Tan Ern Hwei, Yita Tang, Alvin Zubin Ter, Michael Pak-Kai Wong, Andee Dzulkarnaen Zakaria, Zaidi Zakaria, Fitjerald Henry, Thyivya Kalaiselvan, Muhammad Fairuz Shah Abd Karim, Mohamed Rezal Abdul Aziz, Nora Abdul Aziz, Tak Loon Khong, Peng Choong Lau, Hiong Chin Lim, April Camilla Roslani, Jonathan Chen Ken Seak, Sui-Weng Wong, Lai Fen Wong, Leow Yeen Chin, Mercy Chinemerem Anyanwu, Elaine Borg, Zachary Busuttil, Thomas Calleja, Kurt Lee Chircop, Ruth Cutajar, Andrew Michael Dimech, Sarah Ellul, Joseph Galea, Kiara Gascon Perai, Ruth Gatt, Lisa Kelman, Elizabeth Micallef, Favour Nwolu, Kim Sammut, Joanna Thompson, Sean Warwicker, Matthew Zammit, Fernando Cordera, Efraín Cruz González, Jorge Sánchez-García, Francisco José Barbosa Camacho, Francisco Javier Barrera López, Carlos Jose Zuloaga Fernandez Del Valle, Eric Acosta, Iván Romarico González Espinoza, Perla Moreno, Ana Olivia Cortes-Flores, Clotilde Fuentes Orozco, Alejandro Gonzalez Ojeda, Samantha Corro Díaz González, Laura Martinez, Antonio Ramos-De la Medina, Bonifacio Mosqueda Amador, Armando Novoa, Dennet Arturo Olazo Espejo, Alejandro Jimenez, Federico Lopez Rosales, Elva Gabriela Vanoye, Luis Alberto Garcia Gonzalez, Roberto Carlos Miranda-Ackerman, Manuel Solano-Genesta, Alethia Alvarez-Cano, Hector Hugo Romero-Garza, Heriberto Medina-Franco, Lorelí Mejía-Fernández, Noel Salgado-Nesme, Omar Vergara-Fernandez, Guadalupe Montserrat Gutiérrez-Mota, Francisco Xavier Hernandez Vera, Anabella Llantada Lopez, Gilberto Morgan Villela, Felipe de Jesus Ramirez Padilla, Walezka Tapia Marin, Mónica Martínez Maldonado, Ramses Sánchez Suárez, José Manuel Troche, Chaymae Benyaiche, Oumaima Outani, Souadka Amine, Amine Benkabbou, Anass Mohammed Majbar, Raouf Mohsine, Ali Rafik, Thida Oung, Moe Moe Tin, David W Borowski, Philipp Plarre, David W Borowski, Philipp Plarre, Anna Alberga, Nina Sluiter, Jurriaan Tuynman, Robin Blok, Didem Cömert, Roel Hompes, Marianne Kalff, Merel Elisabeth Stellingwerf, Pieter Tanis, Mark van Berge Henegouwen, Elise Maria van Praag, Daan Wisselink, Michael Gerhards, Josephine Lopes Cardozo, Emma Westerduin, Joske de Jonge, Aaw van Geloven, Kaz van Schilt, Frank den Boer, Simone Stoots, Stijn Vlek, Jamie Adams, Ibrahim S Al-Busaidi, Gabrielle Budd, Seung Il Choi, Michael Jen Jie Chu, Anurag Ganugapati, Lucy McKinstry, Rebecca Pascoe, Simon Richards, Kenrick Rosser, Annie Stevenson, Rebecca White, Shebani Farik, Jin Kwun, Ahmed Murad, Sarah Cowan, Timothy Hall, Michael Hayton, Laminou Malam Sani, Souleymane Oumarou Garba, Harissou Adamou, Ibrahim Amadou Magagi, Oumarou Habou, Halima Aliyu, Muhammad Daniyan, Tunde T Sholadoye, Lawal Abdullahi, Lofty-John Anyanwu, Aminu Mohammad Mohammad, Abubakar Bala Muhammad, Abdurrahman Abba Sheshe, Ibrahim Suleiman, Alaba Adesina, Ajibola Awolowo, Clement Onuoha, Omotayo Salami, Ogechukwu Taiwo, Agboola Taiwo, Stephen Kache, Jerry Godfrey Makama, Danjuma Sale, Olajide Abiola, Akinlabi Ajao, Anthony Ajiboye, Amarachukwu Etonyeaku, Julius Olaogun, Ademola Adebanjo, Opeoluwa Adesanya, Michael Olatunji Afolayan, Olanrewaju Balogun, Ayomide Makanjuola, Samuel Nwokocha, Rufus Wale Ojewola, Thomas Olagboyega Olajide, Adewale Aderounmu, Abdul-Rashid Adesunkanmi, Adewale Adisa, Augustine Agbakwuru, Adeleke Akeem Aderogba, Olusegun Isaac Alatise, Olukayode Arowolo, Oladejo Lawal, Tajudeen Mohammed, Chinedu Ndegbu, Olalekan Olasehinde, Funmilola Wuraola, Akinbolaji Akinkuolie, Amarachukwu Etonyeaku, Arinzechukwu Mosanya, Omobolaji Ayandipo, Peter Elemile, Taiwo Akeem Lawal, Samuel Ali Sani, Stephen Garba, Rebecca Hauwa Sani, Samson Olori, Henry Onyebuashi, Ifeanyi Umoke, Adedire Adenuga, Ademola Adeyeye, Olufemi Habeeb, Bashir Lawal, Abdulrasheed Nasir, Eirik Kjus Aahlin, Didrik Kjønås, Elisabeth Myrseth, Jibran Abbasy, Abdul Alvi, Omair Saleem, Asma Afzal, Anam Nazir, Muhammad Farooq, Ayesha Liaqat, Syed Asghar Naqi, Ali Raza, Muzna Sarfraz, Muhammad Sarwar, Muntaha Banglani, Ambreen Munir, Rahmat Sehrish, Bushra Ayub, Raza Sayyed, Amna Altaf, Saima Ayub, Ahmad Uzair Qureshi, Komal Saeed, Bilal Syed, Sana Amir Akbar, Abdul Wahid Anwer, Ruqayya Naheed Khan, Amina Iqbal Khan, Shahid Khattak, Sameen Mohtasham, Muhammad Asad Parvaiz, Aamir Ali Syed, Abdul Basit Ansari, Noman Shahzad, Tanwir Khaliq, Isbah Rashid, Shahzad Hussain Waqar, Hasan Abu Al-Saleem, Amjad Abu Alqumboz, Mohammad Alqadi, Adham Amro, Rawan Assa, Eman Awesat, Rawan Ayyad, Mohammed Hammad, Ayat Haymony, Bassel Hijazi, Bara Hmeidat, Rowaa Lahaseh, Aseel Qawasmi, Alaa Rajabi, Mohammed Shehada, Sundus Shkokani, Yasmine Yaghi, Nadine Yaghi, Mohammad AlZohour, Mohammad Farid, Yousef Mahmoud Habes, Wesam Juba, Yanal Nubani, Abdelrahman Rabee, Mohammad Sa'deh, Saeed Abed, Iyad Al Basos, Mohammad Alswerki, Dina Ashour, Israa Awad, Samar Diab, Alaa El Jamassi, Sahar El-Kahlout, Somaya Elhout, Ahmed N K Hajjaj, Doaa Hasanain, Baraa Nabil Hajjaj, Mohammed Obaid, Eman Saikaly, Ahmed Salhi, Hiba Al-Tammam, Murad Almasri, Muath Baniowda, Doha Beshtawi, Ali Horoub, Rami Misk, Bayan Mohammad, Rami Qasrawi, Tasnim Sholi, Samar Abu-Nimeh, Abrar Abu-Srour, Sadi A Abukhalaf, Samer Adawi, Barah Alsalameh, Kholoud Ayesh, Muawiyah Elqadi, Ahmad Hammouri, Fatima Karim Mustafa, Natalie Marzouqa, Shatha Melhem, Dima Miqdad, Balqees Mohamad, Mhammed Rawhi, Ayman B Abu Ahammala, Ahmed Abu Ataya, Israa Abu Jayyab, Samar Al-Shwaikh, Othman Alagha, Mohammed Alasttal, Haneen Awadallah, Mahmood Elblbessy, Jehad Fares, Akram Jarbou, Ibtisam Mahfouz, Moath A Albahnasawi, Asmaa' Abo Mahadi, Hasan Abuelhatal, Ayham Abuelqomboz, Abdelrahman Almoqayyad, Abdallah Alwali, Reem Balaawi, Mahmoud Hamouda, Mohammed Humeid, Abdullah Jedyan, Tasneem Mahmoud Abu Hamam, Ghadeer Matar, Ali Salem, Tahani Samra, Nureddin Shaheen, Karam Shihada, Ayoob A Nemer, Mahmoud Abu Al Amrain, Abdulwhhab Abu Alamrain, Najlaa Abu Jamie, Mohammed R Abu-Rous, Nada Alfarra, Mohammed AlTaweel, Noor Alwhaidi, Ramadan Hamed, Bader Saqqa, Ahmad Shaheen, Dana Aljaber, Loay Aljaberi, Malak Alwaheidi, Assef Jawaada, Hani Khaldi, Rami Qahoush, Jalil Qari, Rana Saadeh, Ahlam Salim, Aseel Yacoub, Abbas Abbas, Rana Abu Shua'ib, Baraa Abu Zainah, Mahmoud AbuSirrees, Basheer Babaa, Ola Barhoush, Asef Belal Qadomi, Laith Daraghmeh, Reema Haji, Alaa Khatatbeh, Lana Khatib, Salsabeel Qarariah, Yara Quzmar, Khalil Safadi, Roqaya Salameh, Mohammad Hassan, Shifaa Herzallah, Loai Massad, Ahmed Nazzal, Ranin Nazzal, Dennis Escobar, Gustavo Miguel Machain V, Agustin Rodriguez Gonzalez, Jorge Emerson Chachaima Mar, Nathaly Olga Chinchihualpa Paredes, Vicente Cuba, Walter Lopez, Maria Milagros Niquen Jimenez, Nestor Alberto Sanchez Bartra, Olenka Sapallanay Ojeda, Diego Sequeiros, Andrea Toscano Pacheco, María Vergara, Sol Abarca, Rodrigo Alcorta, Giuliano Borda-Luque, Ivan Edward Eusebio Zegarra, Claudia Luján López, Mirella Marrufo, Cinthya Mogrovejo, Andrea Nomura, Yamile Rodríguez Angeles, Maitza Rosario Vidal Meza, Gabriela Zavala, José Neiser Castillo Arrascue, Jomara Caroline Hidrogo Cabrera, José Julio Mariano Larrea Vera, Miguel Osorio, Edgar Alcides Ylatoma Díaz, Mark Anthony Fontanilla, Joseph Roy Fuentes, Anna Leah Salazar, Genieve Dominguez, Marc Paul Lopez, Shiela Macalindong, Mark Augustine Onglao, Arjel Ramirez, Marie Dione Sacdalan, Mayou Martin Tampo, Gemma Leonora Uy, Jeremiah Mangahas, Kenneth Yabut, Joannes Paul Cañete, Bernalynn Eris Cansana, Ernes John Castro, Maria Kaiserin Lipana, Manuel Francisco Roxas, Vlu Jean Zara, Maciej Chroł, Paula Franczak, Michał Orłowski, Piotr Budzyński, Andrzej Budzyński, Pawel Bury, Agata Czerwińska, Jadwiga Dworak, Jacek Dziedzic, Michał Kisielewski, Jan Kulawik, Anna Lasek, Piotr Major, Piotr Małczak, Marcin Migaczewski, Michał Pędziwiatr, Magdalena Pisarska, Dorota Radkowiak, Mateusz Rubinkiewicz, Anna Rzepa, Tomasz Skoczylas, Maciej Stanek, Katarzyna Truszkiewicz, Mateusz Wierdak, Marek Winiarski, Piotr Zarzycki, Anna Zub-Pokrowiecka, Piotr Kowalewski, Rafał Roszkowski, Maciej Walędziak, Miguel Tomé, Sara Patrocinio, Ines Guerreiro, Filipe Almeida, Xavier de Sousa, Nuno Monteiro, Maria Teresa Costa Santos, Daniela de Oliveira, Marta Lopes Serra, Daniela Morgado, Christian Neves, Ana Carolina Oliveira, Alice Pimentel, Sofia Silva, Márcia Carvalho, Lúcia Carvalho, Joana Magalhães, Leonor Matos, Tânia Monteiro, Carlota Ramos, Vanessa Santos, José Barbosa, Jose Costa-Maia, Vítor Devezas, Ana Fareleira, Cristina Fernandes, Diana Gonçalves, Henrique Mora, Marina Morais, Fabiana Silva de Sousa, Sara Catarino Santos, Ana Logrado, André Tojal, Edgar Amorim, Miguel F Cunha, Ana Fazenda, João Pedro Melo Neves, Inês Isabel Sampaio da Nóvoa Gomes Miguel, Diogo Veiga, José Azevedo, Hugo Cardoso Louro, Mariana Leite, José Azevedo, Maria Bairos Menezes, Bárbara Gama, Diana Brito, Marta Cristina Cruz Martins, André Graça E Magalhães, Ana Catarina Longras, Rita Lourenço, Diana Matos, Luis Castro, Filipa Policarpo, Joana Romano, Mariana Leite, Cristina Monteiro, Diogo Pinto, Marina Duarte, Sónia Fortuna Martins, Mariline Oliveira, Diogo Galvão, Lisandra Martins, Anaisa Silva, Viorel Taranu, Bárbara Vieira, Jessica Neves, Simone Oliveira, Hugo Ribeiro, Margarida Cinza, Rosa Felix, Arnaldo Machado, Joana Oliveira, Joana Patrício, Rita Pedroso de Lima, Mário Pereira, Miguel Rocha Melo, Cristina Velez, Alberto Abreu da Silva, Mariana Claro, Daniel Costa Santos, Andreia Ferreira, Hugo Capote, Daniela Rosado, Filipa Taré, Oriana Nogueira, Miguel Ângelo, José Miguel Baiao, Andreia Guimarães, João Marques, Miguel Nico Albano, Marta Silva, Ana Valente da Costa, Teresa Vieira Caroço, Sara Almeida Braga, Ines Capunge, Marta Fragoso, João Guimarães, Bruno Pinto, João Ribeiro, Miguel Angel, Guilherme Fialho, Monica Guerrero, Filipa Campos Costa, Diogo Cardoso, Vasco Cardoso, Magda Alves, Inês Estalagem, Tiago Louro, Cláudia Marques, Rita Martelo, Miguel Morgado, Rita Canotilho, Ana Margarida Correia, Pedro 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Noor, Reantha Pillay, Leandi Steynfaardt, Lucía González González, José Miguel Marín Santos, Paula Martín-Borregón, Javier Martínez Caballero, Cristina Nevado García, Pastora Rodriguez Fraga, Gonzalo De Castro Parga, Maria Pilar Fernández Veiga, Lucía Garrido López, Hugo Infante Pino, Irene Lages Cal, Marta López Otero, Manuel Nogueira Sixto, Marta Paniagua García Señorans, Laura Rodríguez Fernández, Alejandro Ruano Poblador, Erika Rufo Crespo, Raquel Sanchez-Santos, Vincenzo Vigorita, Ester Alonso Batanero, Dorisme Asnel, Isabel Cifrian Canales, Elisa Contreras Saiz, Irene De Santiago Alvarez, Tamara Díaz Vico, Sebastian Fernandez Arias, Daniel Fernández Martínez, Carmen García Bernardo, Luis Joaquín García Flórez, Carmen Garcia Gutierrez, Manuel García Munar, Carlos Alberto Márquez Zorrilla Molina, Marta Merayo, José Luis Michi Campos, Maria Moreno Gijon, Jorge L Otero-Diez, Jose Luis Rodicio Miravalles, Lorena Solar-Garcia, Aida Suárez Sánchez, Nuria Truan, Cristina Alejandre 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A., De Silva, K., Ekpete, O., Haque, S., Henderson, S., Ibrahim, B., Jayasinghe, T., Livie, J., Mailley, K., Nair, G., Tan, D., Baggaley, C., Dawidziuk, A., Szyszka, B., Barter, C., Gandhi, N., Hassell, K., Hitchin, S., Kelsall, J., Nagy, E., Nessa, A., Whisker, L., Yanni, F., Ali, M., Arora, D., Hediwattege, S., Kumarasinghe, N., Rathore, M., Tennakoon, A., Ali Ahmad, S. M., Bajomo, O., Nadira, F., Celentano, V., Griffiths, E., Karri, R. S., Mak, J. K. C., Pipe, M., Bhatti, M. I., Rabie, M., Boyle, C., Hamilton, D., Mihuna, A., Ng, J. C. K., Nicholson, G., Oliwa, A., Pearson, R., Rose, A., Yong, S. Q., Boereboom, C., Hanna, M., Walter, C., Greensmith, T. S., Mitchell, R., Monaghan, E., Crawford, J., Moug, S., Blackwell, J., Boyd-Carson, H., Herrod, P., Al-Allaf, O., Beattie, M., Bullock, C., Burman, S., Clark, G., Flamey, N., Flannery, O., Harding, A., Kodiatt, B., Lawday, S., Mahapatra, S., Mukundu Nagesh, N., Ng, M., Rye, D., Yoong, A., Clark, L., Deans, C., Edirisooriya, M., Carrington, E. V., Wong, T. L. E., Yusuf, B., Chamberlain, C., Duke, K., Kmiotek, E., Botes, A., Condie, N., Schrire, T., Shah, R., Thomas-Jones, I., Yates, C., Anthony, N., Matthews, E., Sahnan, K., Tankel, J., Tucker, S., Winter Beatty, J., Ziprin, P., Duggan, W., Kantartzi, A., Sridhar, S., Khaw, R. A., Srivastava, P., Underwood, C., Alves do Canto Brum, H., Chopra, S., Davis, L., Hughes, R., Tulley, J., Alberts, J., Athisayaraj, T., Olugbemi, M., Ahmad, K., Chan, C., Chapman, G., Fleming, H., Fox, B., Grewar, J., Hulse, K., Rutherford, D., Sinead, M., Speake, D., Vaughan-Shaw, P. G., Christodoulides, N., Kudhail, S., Welch, M., Husaini, S. M., Lambracos, S., Anyanwu, C., Suresh, R., Thomas, J. S., Gleeson, E., Platoff, R., Saif, A., Enumah, Z., Etchill, E., Gabre-Kidan, A., Bernstein, M., Carrano, F. M., Connors, J., Lynn, P., Melis, M., Newman, E., Foster, D. S., Perrone, K., Titan, A., Ahmad, S., Bafford, A. C. M. D., Dal Molin, M., Hanna, N., Zafar, S. N., Hemmila, M., Napolitano, L., Wong, J. J., Chandler, J., Wood, L., Wren, S., Ottesen, T., You, L., Yu, K., Arcienega Yanez, M. D. P., Ferreira Fernandes, M., Gonzalez, D., Cubas, S., Gonzalez, M. C., Zubiaurre, V., Demolin, R., Giroff, N., Sciuto, P., Campos, M., Rodriguez Cantera, G., Deepika, G., Simuchimba, E., Bulaya, A., Chibuye, C., Chirengendure, B., Kabale, M. -R., Kabongo, K., Munthali, J., Mweso, O., Pikiti, F., Otieno, J., Lai, L. T., Blackman, B., Subramaniam, S., Karim, R., Kok, N., Lee, Y. D., Ali, S., Sinha, A., Corrigan, R., Barnes, N., Wong, F., Dennis, G., Jedamzik, J., Phillips, E., Piette, W., Van hentenryck, M., Koco, H., Lawani, S., Kassa, M. W., Santos Bezerra, T., Gribnev, P., Dimitrov, D., Krastev, P., Oum, S., Bonghaseh, D. T., Al Farsi, M., Alsharqawi, N., Acevedo, V., Castillo Barbosa, A. C., Giron, F., Leon Rodriguez, J. P., Kucan, D., Rosko, D., Barsic, N., Zupan, D., Hegazi, A., Truncikova, V., Fryba, V., Mohamed, M., Nagi, A., Rashad Temerik, A., Elshawy, M. E., Mahmoud, M. I., Anwar, M., Rageh, T., Elmokadem, A., Gaballa, K., Teppo, S., Pengerma, P., Ballouhey, Q., Bergeat, D., Weyl, A., Hain, E., Gyedu, A., Yenli, E., Osei-Poku, D., Rompou, V. -A., Zoikas, A., Gaitanidis, A., Koukis, G., Perivoliotis, K., Tavlas, P., Galanos-Demiris, K., Zografos, G., Karavokyros, I., Xanthopoulou, G., Iordanidou, E., Ayau, F., Garcia, A., Damjan, P., Wason, D., B L, A., Rangganata, E., Kamath, P., O'Connor, D. B., Pinto, M., Perrone, F., Tropeano, F. P., Troilo, F., Bossi, D., Scala, D., Pulitano, L., Carella, M., Pietrabissa, A., Gori, A., Giraudo, G., De Simone, V., Russo, A. A., Braccio, B., Al-Taher, R., Athamneh, S., Parker, A., Sawiee, A., Kattia, A., Tababa, O., Shaeeb, Z., Syminas, V., Jurgaitis, J., Damuleviciene, G., Svagzdys, S., Razafimanjato, N. N. M., Chieng Loo, L., Tiong, I. C., Wan Muhmad, W. F., Vijeyan, H., Li Ying, T., Grech, G., Arrangoiz, R., Jimenez Ley, V. B., Arizpe, D., Lagunes Lara, E., Castro Lopez, E. V., Eaazim, J., Gordinou de Gouberville, M., Bastiaenen, V., Rottier, S., Nahab, F., Ji, M. Y., Seyoji, M., Nwachukwu, C., Emeghara, O., Muhammed, S. E., Idowu, A., Sowemimo, O., Ogundoyin, O., Akande, O., Lott, A., Nadeem, M., Laghari, A. A., Loya, A., Mushtaq, H., Abdullah, M. T., Abuhilal, B., Atawneh, M., Hamdan, H., Alhabil, B., Srour, A., Mousa, I., Da Silva Medina, L., Bartosiak, K., Ferreira, P., Francisco, V., Lemos, R., Frutuoso, L., Fernandes, S., Fonseca, T., Pereira, J., Rachadell, J., Torre, A., Madeira Martins, F., Carvalho, A. C., Rodrigues Ferreira, J., Ribeiro da Silva, B., Devesa, H., Vieira, A., Monica, I., Amaro, M., Sousa, D., Reia, M., Louro, J., Martins, A., Dominguez, J., Santos, I., Freitas Oliveira, N. M., Pereira, J. C., Silva-Vaz, P., Freire, L., Escrevente, R., Negoita, V. M., Shakhmatov, D., Nezerwa, Y., Radulovic, R., Obery, G., Viljoen, F., Mendes, T., Suarez, A., Moncada, E., Fernandez-Hevia, M., Curtis Martinez, C., Gil Garcia, J. M., Gonzalez Zunzarren, M., Idris, T., Eklov, K., Grahn, O., Amin, L., Blomqvist, M., Ajani, C., Kraus, R., Seeger, N., Willemin, M., Rayya, F., Ayash, M., Msouti, R., Kannas, I., Abazid, E., Esper, A., Slim, S., Kavcar, A. S., Aytac, E., Dural, A. C., Ilker, A., Eray, I. C., Kurnaz, E., Altiner, S., Tepe, M. D., Sahin, C., Savli, E., Innocent, A., Babirye, L., Diachenko, A., Hordoskiy, V., Curry, H., Chau, C. Y. C., Robertson, H., Lennon, H., Loi, L., Kirkham, E., Mccann, C., Watts, D., Gurung, B., Wilson, M., Tribedi, T., Garofalo, E., Zahra, B., Macdonald, S., Daniels, I., Ng, N., Khosla, S., Olivier, J., Yue, S. Y. P., Suresh, G., Wellington, J., Lorejo, E., Mossaad, M., Crutcher, M., Alimi, M., Baiu, I., Abdou, H., Conway, A., Peck, C., Perdomo Perez, M. A., Zulu, S., Nakazwe, M., Burger, S., Davies, J., Donaldson, R., Ede, C., Garden, O. J., Lesetedi, C., Mabedi, C., Magill, L., Makinde Alakaloko, F., Makupe, A., Monahan, M., Mulira, S., Muller, E., Musowoyo, J., Olory-Togbe, J. L., Roberts, T., Smith, M., Tayler, V., Windsor, J., Yepez, R., Sundar, S., Runigamugabo, E., Verjee, A., Chen, J., Daya, L., El Aroussi, N., Farina, V., Gnintedeme Olivier, T., Gonzales Nacarino, M., Hammani, A., Honjo, S., Jacobs, R., Kimura, H., Nkoronko, M., Oscullo Yepez, J. J., Pin Hung, W., Raj, A., Romani Pozo, A., Rommaneh, M., Sassamela Fabiano, S. C., Shiroma Gago, C. M., Srinivas, A., Sung, C. -Y., Tai, A., Valle Aranda, Y. C., Venturini, S., Wilguens Lartigue, J., Public and occupational health, AMS - Sports, APH - Health Behaviors & Chronic Diseases, CCA - Cancer Treatment and quality of life, Amsterdam Gastroenterology Endocrinology Metabolism, Cancer Center Amsterdam, and Albarella, Sara
Subjects: global surgery, hospitals, humans, income, neoplasms, postoperative period, poverty, prospective studies, no keywords listed, General Medicine, Prospective Studie, Hospital, Settore MED/18 - Chirurgia Generale, outcome, Hospitals, Humans, Income, Neoplasms, surgery, Postoperative Period, Poverty, Prospective Studies, cancer surgery, Human, hospital facilities
Abstract: © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide. Methods: A multimethods analysis was performed as part of the GlobalSurg 3 study—a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital. Findings: Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3·85 [95% CI 2·58–5·75]; p
Published: 2022
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21. Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis.

Author: Valencia, Tania, Kim, Ji Young, Abu-Baker, Shadi, Moscat-Pardos, Jorge, Ahn, Christopher S, Reina-Campos, Miguel, Duran, Angeles, Castilla, Elias A, Metallo, Christian M, Diaz-Meco, Maria T, and Moscat, Jorge
Subjects: Cell Line, Tumor, Fibroblasts, Stromal Cells, Animals, Mice, Inbred C57BL, Mice, Knockout, Humans, Mice, Prostatic Intraepithelial Neoplasia, Prostatic Neoplasms, Cell Transformation, Neoplastic, Neoplasm Invasiveness, Prostatic Hyperplasia, Inflammation, Multiprotein Complexes, Glucose, Amino Acids, Adaptor Proteins, Signal Transducing, Proto-Oncogene Proteins c-myc, Heat-Shock Proteins, Inflammation Mediators, Interleukin-6, Coculture Techniques, Transfection, Cell Communication, Signal Transduction, RNA Interference, Energy Metabolism, Oxidative Stress, Time Factors, Male, PTEN Phosphohydrolase, HEK293 Cells, TOR Serine-Threonine Kinases, Tumor Microenvironment, Sequestosome-1 Protein, Mechanistic Target of Rapamycin Complex 1, Oncology & Carcinogenesis, Oncology and Carcinogenesis, Neurosciences
Abstract: The tumor microenvironment plays a critical role in cancer progression, but the precise mechanisms by which stromal cells influence the epithelium are poorly understood. Here we show that p62 levels were reduced in the stroma of several tumors and that its loss in the tumor microenvironment or stromal fibroblasts resulted in increased tumorigenesis of epithelial prostate cancer cells. The mechanism involves the regulation of cellular redox through an mTORC1/c-Myc pathway of stromal glucose and amino acid metabolism, resulting in increased stromal IL-6 production, which is required for tumor promotion in the epithelial compartment. Thus, p62 is an anti-inflammatory tumor suppressor that acts through the modulation of metabolism in the tumor stroma.
Published: 2014

22. Temporal Improvements in COVID-19 Outcomes for Hospitalized Adults: A Post Hoc Observational Study of Remdesivir Group Participants in the Adaptive COVID-19 Treatment Trial

Author: Gail E. Potter, Tyler Bonnett, Kevin Rubenstein, David A. Lindholm, Rekha R. Rapaka, Sarah B. Doernberg, David C. Lye, Richard A. Mularski, Noreen A. Hynes, Susan Kline, Catharine I. Paules, Cameron R. Wolfe, Maria G. Frank, Nadine G. Rouphael, Gregory A. Deye, Daniel A. Sweeney, Rhonda E. Colombo, Richard T. Davey, Aneesh K. Mehta, Jennifer A. Whitaker, Jose G. Castro, Alpesh N. Amin, Christopher J. Colombo, Corri B. Levine, Mamta K. Jain, Ryan C. Maves, Vincent C. Marconi, Robert Grossberg, Sameh Hozayen, Timothy H. Burgess, Robert L. Atmar, Anuradha Ganesan, Carlos A. Gomez, Constance A. Benson, Diego Lopez de Castilla, Neera Ahuja, Sarah L. George, Seema U. Nayak, Stuart H. Cohen, Tahaniyat Lalani, William R. Short, Nathaniel Erdmann, Kay M. Tomashek, and Pablo Tebas
Subjects: Adult, Prevention, Clinical Trials and Supportive Activities, Rehabilitation, Evaluation of treatments and therapeutic interventions, General Medicine, Antiviral Agents, Medical and Health Sciences, Dexamethasone, COVID-19 Drug Treatment, Phase III as Topic, Treatment Outcome, Good Health and Well Being, Clinical Trials, Phase III as Topic, Double-Blind Method, Clinical Research, 6.1 Pharmaceuticals, General & Internal Medicine, Complementary and Integrative Health, Internal Medicine, Humans, Clinical Trials, Randomized Controlled Trials as Topic
Abstract: BackgroundThe COVID-19 standard of care (SOC) evolved rapidly during 2020 and 2021, but its cumulative effect over time is unclear.ObjectiveTo evaluate whether recovery and mortality improved as SOC evolved, using data from ACTT (Adaptive COVID-19 Treatment Trial).DesignACTT is a series of phase 3, randomized, double-blind, placebo-controlled trials that evaluated COVID-19 therapeutics from February 2020 through May 2021. ACTT-1 compared remdesivir plus SOC to placebo plus SOC, and in ACTT-2 and ACTT-3, remdesivir plus SOC was the control group. This post hoc analysis compared recovery and mortality between these comparable sequential cohorts of patients who received remdesivir plus SOC, adjusting for baseline characteristics with propensity score weighting. The analysis was repeated for participants in ACTT-3 and ACTT-4 who received remdesivir plus dexamethasone plus SOC. Trends in SOC that could explain outcome improvements were analyzed. (ClinicalTrials.gov: NCT04280705 [ACTT-1], NCT04401579 [ACTT-2], NCT04492475 [ACTT-3], and NCT04640168 [ACTT-4]).Setting94 hospitals in 10 countries (86% U.S. participants).ParticipantsAdults hospitalized with COVID-19.InterventionSOC.Measurements28-day mortality and recovery.ResultsAlthough outcomes were better in ACTT-2 than in ACTT-1, adjusted hazard ratios (HRs) were close to 1 (HR for recovery, 1.04 [95% CI, 0.92 to 1.17]; HR for mortality, 0.90 [CI, 0.56 to 1.40]). Comparable patients were less likely to be intubated in ACTT-2 than in ACTT-1 (odds ratio, 0.75 [CI, 0.53 to 0.97]), and hydroxychloroquine use decreased. Outcomes improved from ACTT-2 to ACTT-3 (HR for recovery, 1.43 [CI, 1.24 to 1.64]; HR for mortality, 0.45 [CI, 0.21 to 0.97]). Potential explanatory factors (SOC trends, case surges, and variant trends) were similar between ACTT-2 and ACTT-3, except for increased dexamethasone use (11% to 77%). Outcomes were similar in ACTT-3 and ACTT-4. Antibiotic use decreased gradually across all stages.LimitationUnmeasured confounding.ConclusionChanges in patient composition explained improved outcomes from ACTT-1 to ACTT-2 but not from ACTT-2 to ACTT-3, suggesting improved SOC. These results support excluding nonconcurrent controls from analysis of platform trials in rapidly changing therapeutic areas.Primary funding sourceNational Institute of Allergy and Infectious Diseases.
Published: 2022
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23. Combination of SABR With Anti-PD-1 in Oligoprogressive Non-Small Cell Lung Cancer and Melanoma: Results of a Prospective Multicenter Observational Study

Author: Rodolfo Chicas-Sett, Juan Zafra, Delvys Rodriguez-Abreu, Juan Castilla-Martinez, Gretel Benitez, Barbara Salas, Samuel Hernandez, Marta Lloret, Juan Luis Onieva, Isabel Barragan, and Pedro C. Lara
Subjects: Cancer Research, Lung Neoplasms, Nivolumab, Treatment Outcome, Radiation, Oncology, Carcinoma, Non-Small-Cell Lung, Humans, Radiology, Nuclear Medicine and imaging, Prospective Studies, Melanoma
Abstract: The percentage of patients with metastatic non-small cell lung cancer (NSCLC) and melanoma who benefit from anti-programmed cell death protein 1 (anti-PD-1) is low owing to resistance mechanisms. SABR has a role in oligoprogressive disease and can improve responses to anti-PD-1. This multicenter prospective observational study aimed to determine whether concomitant anti-PD-1 and SABR to oligoprogressive sites enhance tumor response in metastatic NSCLC and melanoma.Patients with metastatic NSCLC or melanoma in progression to anti-PD-1 but continuing the same line owing to clinical benefit were referred for palliative SABR. All patients received concomitant pembrolizumab or nivolumab and SABR to 1 to 5 lesions, maintaining anti-PD-1 until further progression, unacceptable toxicity, or medical/patient decision. Objective response rate-complete responses and partial responses-was evaluated during all follow-up according to Response Evaluation Criteria in Solid Tumors 1.1. The abscopal response was evaluated 8 weeks after SABR as a ≥30% reduction in 1 to 2 predefined nonirradiated lesions.Of the 61 patients enrolled, 50 could be analyzed. With a median follow-up of 32.8 months, objective response rate was 42% (30% complete responses and 12% partial responses). Median progression-free survival was 14.2 months (95% confidence interval, 6.9-29 months). Median overall survival since SABR was 37.4 months (95% confidence interval, 22.9 months-not reached). Abscopal response was 65%, evaluated in 40 patients who fulfilled the criteria.Combined anti-PD-1 and SABR in oligoprogressive metastatic NSCLC or melanoma can achieve high rates of response and extend the clinical benefit of immunotherapy by delaying further progression and a new systemic therapy. This approach should be assessed in larger randomized trials.
Published: 2022
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24. Family styles and quality of life in adolescents with bronchial asthma: The important role of self‐esteem and perceived threat of the disease

Author: Marián Pérez-Marín, Inmaculada Montoya Castilla, and Selene Valero-Moreno
Subjects: Male, Pulmonary and Respiratory Medicine, Adolescent, Health Status, Surveys and Questionnaires, Pediatrics, Perinatology and Child Health, Quality of Life, Humans, Female, Child, Self Concept, Asthma
Abstract: Analyze the relationship between family styles and quality of life (QoL) in adolescents with bronchial asthma and study the influence of self-esteem as a protective factor and threat perception as a risk factor.Family styles, QoL, perceived threat of the disease, and self-esteem were assessed in a total of 150 adolescents diagnosed with bronchial asthma with ages ranging from 12 to 16 years (M = 13.28; SD = 1.29), 60.7% being male. Descriptive statistics and mean comparisons were conducted according to the level of self-esteem. Relationships between variables were also studied using Pearson's correlations, and finally, the mediating role of self-esteem and the perceived threat of the disease was assessed using PROCESS.Adolescents shown healthy family characteristics (high scores on affect and parental mood and low scores on psychological control) and high scores on QoL. Thirty-five percent of adolescents showed low self-esteem and a tendency to underestimate the disease. There are existing relationships between family styles and QoL; thus, healthy family characteristics (affection, parental mood, autonomy promotion) were positively associated with QoL, while psychological control was negatively associated with QoL. Disease threat and self-esteem mediated the relationship between family styles and adolescent QoL. Disease threat was negatively, and self-esteem was positively associated with QoL.Self-esteem and family support are protective factors for the well-being of adolescents with bronchial asthma; however, the high perceived threat of the disease can have negative consequences for the adolescent's health and negatively impact their QoL.
Published: 2022
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25. Bidirectional intimate partner violence: Evidence from a list experiment in Kenya

Author: Carolina Castilla and David M. A. Murphy
Subjects: Male, Sexual Partners, Risk Factors, Health Policy, Prevalence, Humans, Intimate Partner Violence, Female, Violence, Kenya
Abstract: Intimate Partner Violence (IPV) continues to be a major public health concern that can both respond to economic policies and affect economic outcomes. Few studies regarding IPV, however, take a gender inclusive approach towards its identification. Using a sample of both men and women from rural Kenya, we are the first, to our knowledge, to conduct a list experiment with cohabiting married couples to identify the prevalence of physical violence on both men and women. We find that 14 percent of respondents agree with the statement "my spouse regularly hits me". In contrast to other survey evidence that uses direct elicitation, we find no differences in the prevalence of male-to-female and female-to-male violence. We provide supporting evidence that bidirectional IPV accounts for the lack of gender differences. A complete understanding of the typology of IPV can be crucial for policies seeking IPV reduction.
Published: 2022
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26. Cross-cultural validation of the Worries about COVID-19 and its consequences Scale (W-COV) in adolescents and young people

Author: Estefanía Mónaco, Konstanze Schoeps, Selene Valero-Moreno, Jesús Castro-Calvo, Inmaculada Montoya-Castilla, Constanza del Rosario, Fernanda Coello, Sebastián Herrera, Ángela Trujillo, Fernando Riveros Munevar, and Nancy Alejandra Amador Esparza
Subjects: Adult, Cross-Cultural Comparison, Male, Adolescent, Psychometrics, COVID-19, Reproducibility of Results, Anxiety, Young Adult, Cross-Sectional Studies, Surveys and Questionnaires, Quality of Life, Humans, Female, Pshychiatric Mental Health
Abstract: The pandemic context presents remarkable psychological challenges for adolescents and young adults. The aim of the present work was to construct and study the psychometric properties of a scale in Spanish language (W-COV) to measure their worries related to the pandemic. Participants were 5559 people aged between 14 and 25 years old (M = 19.05; SD = 3.28). Self-report data were collected using a cross-sectional and cross-cultural design. Participants were from 5 Spanish-speaking countries. Instruments were W-COV to assess worries about COVID-19 and its consequences; DASS-21 for anxiety, depression and stress; and SWLS for life satisfaction. Exploratory, confirmatory and multi-group factor analyses were conducted to determine the factorial structure of the W-COV and its measurement invariance (configural, metric, scalar and error variance). Correlational and regression analyses were also performed to study convergent and predictive validity. The results suggest that W-COV presents a bifactorial structure: (1) a general factor of worries about COVID-19; and (2) three different factors: worries about health, economic and psychosocial consequences from COVID-19. The internal reliability indices Cronbach's α and Omega were adequate. With respect to the invariance results, the instrument can be used interchangeably in the five countries considered, in both genders and in two different age groups (12-17 and 18-25). Regarding validity, W-COV factors were positively associated with anxiety, depression and stress, and negatively predicted life satisfaction. In conclusion, W-COV is a reliable and valid instrument for researchers and health care professionals to assess the psychological impact of the pandemic on mental health of young Ibero-Americans.
Published: 2022
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27. Clinical characteristics of patients with Mycoplasma pneumoniae infection

Author: Ana Isabel, Álvaro Varela, Aitziber, Aguinaga Pérez, Ana, Navascués Ortega, Jesús, Castilla, and Carmen, Ezpeleta Baquedano
Subjects: Community-Acquired Infections, Adolescent, Child, Preschool, Pneumonia, Mycoplasma, Humans, Macrolides, Child, Anti-Bacterial Agents, Mycoplasma pneumoniae, Retrospective Studies
Abstract: To describe the characteristics of patients diagnosed with Mycoplasma pneumoniae infection.A retrospective study of clinical and epidemiological characteristics of acute infections by M. pneumoniae confirmed by PCR was carried out in the Navarra Health Service (Spain) in 2014-2018.M. pneumoniae infection was confirmed in 9.5% of analyzed patients. Among 123 confirmed cases, 65% were 5-14 years old, 21.1%lt;5 years old, and 13.8% were ≥14 years old. Pneumonia was radiologically confirmed in 83.7% of cases, and 22.0% presented extra-respiratory manifestations. A total of 44.7% of cases required hospitalization. Bilateral pneumonia, asthmatic crisis and extra-respiratory manifestations were associated to higher risk of hospitalization (81.3, 72.2 and 66.7%, respectively). Microbiological targeted treatment was monotherapy with macrolides in 60.2% of cases and combined with other antibiotics in 13.0%.M. pneumoniae was the cause of acute respiratory infection affecting mainly to children younger than 14 years old and frequently required hospitalization.
Published: 2022
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28. Age and sex impact on visuospatial working memory (VSWM), mental rotation, and cognitive strategies during navigation

Author: Alexander Castilla, Alain Berthoz, Djordje Urukalo, Mohamed Zaoui, Anaick Perrochon, and Téo Kronovsek
Subjects: Male, Aging, Young Adult, Cognition, Memory, Short-Term, Space Perception, General Neuroscience, Humans, Female, General Medicine, Aged
Abstract: This study assessed the impact of sex and typical aging on visuospatial working memory (VSWM), mental rotations, and navigational strategies using behavioral information. Fifty healthy participants regrouped in older (OA) and young adults (YA) performed the Walking Corsi test (WalCT) and the Redrawn Mental Rotation Test (MRT) to explore mental rotation abilities. We recorded kinematic data such as locomotion trajectories, and spatial orientations during navigation. We created a new method of data analysis for the WalCT performances and compared it with the classical approach. This original method allowed us to identify cognitive strategies based on errors analysis. Our data suggested that VSWM and mental rotation capacities in locomotion were modulated by age (YA scored higher than OA), and sex (Young Adult Males (YA-M) having higher performance than Young Adult Females (YA-F). We observed a preferential use of cognitive strategies related to sex; YA-F relied more on egocentric strategies whereas YA-M relied more on allocentric strategies. The preferential use of cognitive strategies in the YA group was not observed in the OA group producing more random errors per sequence. The results suggest the effects that age and sex have on VSWM, cognitive strategies, and mental rotation during navigation and highlight the importance of navigational strategies training.
Published: 2022
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29. A real-world comparison of tisagenlecleucel and axicabtagene ciloleucel CAR T cells in relapsed or refractory diffuse large B cell lymphoma

Author: Emmanuel Bachy, Steven Le Gouill, Roberta Di Blasi, Pierre Sesques, Guillaume Manson, Guillaume Cartron, David Beauvais, Louise Roulin, François Xavier Gros, Marie Thérèse Rubio, Pierre Bories, Jacques Olivier Bay, Cristina Castilla Llorente, Sylvain Choquet, René-Olivier Casasnovas, Mohamad Mohty, Stéphanie Guidez, Magalie Joris, Michaël Loschi, Sylvain Carras, Julie Abraham, Adrien Chauchet, Laurianne Drieu La Rochelle, Bénédicte Deau-Fischer, Olivier Hermine, Thomas Gastinne, Jean Jacques Tudesq, Elodie Gat, Florence Broussais, Catherine Thieblemont, Roch Houot, Franck Morschhauser, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 (GRITA), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, CHU Lille, Centre Hospitalier Régional Universitaire [Lille] [CHRU Lille], and Groupe de Recherche sur les formes Injectables et les Technologies Associées (GRITA) - ULR 7365
Subjects: Biological Products, Receptors, Chimeric Antigen, T-Lymphocytes, [SDV]Life Sciences [q-bio], Antigens, CD19, Clinical Studies as Topic, Humans, Lymphoma, Large B-Cell, Diffuse, General Medicine, Cytokine Release Syndrome, Immunotherapy, Adoptive, General Biochemistry, Genetics and Molecular Biology, Retrospective Studies
Abstract: Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) have both demonstrated impressive clinical activity in relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL). In this study, we analyzed the outcome of 809 patients with R/R DLBCL after two or more previous lines of treatment who had a commercial chimeric antigen receptor (CAR) T cells order for axi-cel or tisa-cel and were registered in the retrospective French DESCAR-T registry study (NCT04328298). After 1:1 propensity score matching (n = 418), the best overall response rate/complete response rate (ORR/CRR) was 80%/60% versus 66%/42% for patients treated with axi-cel compared to tisa-cel, respectively (P P = 0.0003). Overall survival (OS) was also significantly improved after axi-cel infusion compared to after tisa-cel infusion (1-year OS 63.5% versus 48.8%; HR = 0.63; 95% CI, 0.45–0.88; P = 0.0072). Similar findings were observed using the inverse probability of treatment weighting statistical approach. Grade 1–2 cytokine release syndrome was significantly more frequent with axi-cel than with tisa-cel, but no significant difference was observed for grade ≥3. Regarding immune effector cell-associated neurotoxicity syndrome (ICANS), both grade 1–2 and grade ≥3 ICANS were significantly more frequent with axi-cel than with tisa-cel. In conclusion, our matched comparison study supports a higher efficacy and also a higher toxicity of axi-cel compared to tisa-cel in the third or more treatment line for R/R DLBCL.
Published: 2022
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30. Advancing in Schaaf-Yang syndrome pathophysiology: from bedside to subcellular analyses of truncated MAGEL2

Author: Laura Castilla-Vallmanya, Mónica Centeno-Pla, Mercedes Serrano, Héctor Franco-Valls, Raúl Martínez-Cabrera, Aina Prat-Planas, Elena Rojano, Juan A G Ranea, Pedro Seoane, Clara Oliva, Abraham J Paredes-Fuentes, Gemma Marfany, Rafael Artuch, Daniel Grinberg, Raquel Rabionet, Susanna Balcells, and Roser Urreizti
Subjects: nervous system diseases, Síndromes, Trastorns del metabolisme, Syndromes, Proteins, Errors congènits del metabolisme, Inborn errors of metabolism, Síndrome de Prader-Willi, Phenotype, Disorders of metabolism, disease management, Mutation, central nervous system diseases, gene expression, Genetics, Humans, Prader-Willi syndrome, clinical genetics, Biomarkers, Genetics (clinical)
Abstract: BackgroundSchaaf-Yang syndrome (SYS) is caused by truncating mutations inMAGEL2, mapping to the Prader-Willi region (15q11-q13), with an observed phenotype partially overlapping that of Prader-Willi syndrome. MAGEL2 plays a role in retrograde transport and protein recycling regulation. Our aim is to contribute to the characterisation of SYS pathophysiology at clinical, genetic and molecular levels.MethodsWe performed an extensive phenotypic and mutational revision of previously reported patients with SYS. We analysed the secretion levels of amyloid-β 1–40 peptide (Aβ1-40) and performed targeted metabolomic and transcriptomic profiles in fibroblasts of patients with SYS (n=7) compared with controls (n=11). We also transfected cell lines with vectors encoding wild-type (WT) or mutated MAGEL2 to assess stability and subcellular localisation of the truncated protein.ResultsFunctional studies show significantly decreased levels of secreted Aβ1-40and intracellular glutamine in SYS fibroblasts compared with WT. We also identified 132 differentially expressed genes, including non-coding RNAs (ncRNAs) such asHOTAIR, and many of them related to developmental processes and mitotic mechanisms. The truncated form of MAGEL2 displayed a stability similar to the WT but it was significantly switched to the nucleus, compared with a mainly cytoplasmic distribution of the WT MAGEL2. Based on the updated knowledge, we offer guidelines for the clinical management of patients with SYS.ConclusionA truncated MAGEL2 protein is stable and localises mainly in the nucleus, where it might exert a pathogenic neomorphic effect. Aβ1-40secretion levels andHOTAIRmRNA levels might be promising biomarkers for SYS. Our findings may improve SYS understanding and clinical management.
Published: 2022
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31. Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial

Author: Cameron R Wolfe, Kay M Tomashek, Thomas F Patterson, Carlos A Gomez, Vincent C Marconi, Mamta K Jain, Otto O Yang, Catharine I Paules, Guillermo M Ruiz Palacios, Robert Grossberg, Michelle S Harkins, Richard A Mularski, Nathaniel Erdmann, Uriel Sandkovsky, Eyad Almasri, Justino Regalado Pineda, Alexandra W Dretler, Diego Lopez de Castilla, Angela R Branche, Pauline K Park, Aneesh K Mehta, William R Short, Susan L F McLellan, Susan Kline, Nicole M Iovine, Hana M El Sahly, Sarah B Doernberg, Myoung-don Oh, Nikhil Huprikar, Elizabeth Hohmann, Colleen F Kelley, Mark Holodniy, Eu Suk Kim, Daniel A Sweeney, Robert W Finberg, Kevin A Grimes, Ryan C Maves, Emily R Ko, John J Engemann, Barbara S Taylor, Philip O Ponce, LuAnn Larson, Dante Paolo Melendez, Allan M Seibert, Nadine G Rouphael, Joslyn Strebe, Jesse L Clark, Kathleen G Julian, Alfredo Ponce de Leon, Anabela Cardoso, Stephanie de Bono, Robert L Atmar, Anuradha Ganesan, Jennifer L Ferreira, Michelle Green, Mat Makowski, Tyler Bonnett, Tatiana Beresnev, Varduhi Ghazaryan, Walla Dempsey, Seema U Nayak, Lori E Dodd, John H Beigel, Andre C Kalil, Lana Wahid, Emmanuel B. Walter, Akhila G. Belur, Grace Dreyer, Jan E. Patterson, Jason E. Bowling, Danielle O. Dixon, Angela Hewlett, Robert Odrobina, Jakrapun Pupaibool, Satish Mocherla, Suzana Lazarte, Meilani Cayabyab, Rezhan H. Hussein, Reshma R. Golamari, Kaleigh L. Krill, Sandra Rajme, Paul F. Riska, Barry S. Zingman, Gregory Mertz, Nestor Sosa, Paul A. Goepfert, Mezgebe Berhe, Emma Dishner, Mohamed Fayed, Kinsley Hubel, José Arturo Martinez-Orozco, Nora Bautista Felix, Sammy T. Elmor, Amer Ryan Bechnak, Youssef Saklawi, Jason W. Van Winkle, Diego F. Zea, Maryrose Laguio-Vila, Edward E. Walsh, Ann R. Falsey, Karen Carvajal, Robert C. Hyzy, Sinan Hanna, Norman Olbrich, Jessica J. Traenkner, Colleen S. Kraft, Pablo Tebas, Jillian T Baron, Corri Levine, Joy Nock, Joanne Billings, Hyun Kim, Marie-Carmelle Elie-Turenne, Jennifer A. Whitaker, Anne F. Luetkemeyer, Jay Dwyer, Emma Bainbridge, Pyoeng Gyun Choe, Chang Kyung Kang, Nikolaus Jilg, Valeria D Cantos, Divya R. Bhamidipati, Srinivasa Nithin Gopalsamy, Aarthi Chary, Jongtak Jung, Kyoung-Ho Song, Hong Bin Kim, Constance A. Benson, Kimberly McConnell, Jennifer P. Wang, Mireya Wessolossky, Katherine Perez, Taryn A Eubank, Catherine Berjohn, Gregory C. Utz, Patrick E.H. Jackson, Taison D. Bell, Heather M. Haughey, Abeer Moanna, Sushma Cribbs, Telisha Harrison, Christopher J. Colombo, Christina Schofield, Rhonda E. Colombo, Victor F. Tapson, Jonathan Grein, Fayyaz Sutterwala, Dilek Ince, Patricia L. Winokur, Monica Fung, Hannah Jang, David Wyles, Maria G. Frank, Ellen Sarcone, Henry Neumann, Anand Viswanathan, Sarah Hochman, Mark Mulligan, Benjamin Eckhardt, Ellie Carmody, Neera Ahuja, Kari Nadeau, David Svec, Jeffrey C. Macaraeg, Lee Morrow, Dave Quimby, Mary Bessesen, Lindsay Nicholson, Jill Adams, Princy Kumar, Allison A. Lambert, Henry Arguinchona, Radica Z. Alicic, Sho Saito, Norio Ohmagari, Ayako Mikami, David Chien Lye, Tau Hong Lee, Po Ying Chia, Lanny Hsieh, Alpesh N. Amin, Miki Watanabe, Keith A. Candiotti, Jose G. Castro, Maria A. Antor, Tida Lee, Tahaniyat Lalani, Richard M. Novak, Andrea Wendrow, Scott A. Borgetti, Sarah L. George, Daniel F. Hoft, James D. Brien, Stuart H. Cohen, George R. Thompson, Melony Chakrabarty, Faheem Guirgis, Richard T. Davey, Jocelyn Voell, Jeffrey R. Strich, David A. Lindholm, Katrin Mende, Trevor R. Wellington, Rekha R. Rapaka, Jennifer S. Husson, Andrea R. Levine, Seow Yen Tan, Humaira Shafi, Jaime M F Chien, David C. Hostler, Jordanna M. Hostler, Brian T. Shahan, David H. Adams, Anu Osinusi, Huyen Cao, Timothy H. Burgess, Julia Rozman, Kevin K. Chung, Christina Nieuwoudt, Jill A. El-Khorazaty, Heather Hill, Stephanie Pettibone, Nikki Gettinger, Theresa Engel, Teri Lewis, Jing Wang, Gregory A. Deye, Effie Nomicos, Rhonda Pikaart-Tautges, Mohamed Elsafy, Robert Jurao, Hyung Koo, Michael Proschan, Tammy Yokum, Janice Arega, and Ruth Florese
Subjects: Adult, Male, Pulmonary and Respiratory Medicine, ACTT-4 Study Group, Adolescent, Clinical Trials and Supportive Activities, Clinical Sciences, Dexamethasone, Double-Blind Method, Clinical Research, Humans, Lung, Sulfonamides, Other Medical and Health Sciences, SARS-CoV-2, Prevention, Evaluation of treatments and therapeutic interventions, Middle Aged, COVID-19 Drug Treatment, Oxygen, Good Health and Well Being, Treatment Outcome, Purines, 6.1 Pharmaceuticals, Public Health and Health Services, Azetidines, Pyrazoles, Female
Abstract: BackgroundBaricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19.MethodsIn this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168.FindingsBetween Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012).InterpretationIn hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered.FundingNational Institute of Allergy and Infectious Diseases.
Published: 2022
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32. Need for head and neck repositioning to restore electrophysiological signal changes at positioning for cervical myelopathy surgery

Author: Antonio Montalvo-Afonso, Francisco Isidro-Mesa, Elena Araus-Galdós, Vicente Martín-Velasco, José Manuel Castilla-Díez, Antonio Rodríguez-Salazar, Pedro David Delgado-López, and Javier Martín-Alonso
Subjects: Male, medicine.medical_specialty, medicine.medical_treatment, Electromyography, Spinal Cord Diseases, 03 medical and health sciences, Myelopathy, 0302 clinical medicine, Evoked Potentials, Somatosensory, medicine, Humans, Head and neck, medicine.diagnostic_test, business.industry, Incidence (epidemiology), Laminectomy, General Medicine, Middle Aged, Evoked Potentials, Motor, medicine.disease, Surgery, Electrophysiology, Cohort, Female, Neurology (clinical), Anterior approach, business, 030217 neurology & neurosurgery
Abstract: Objective To evaluate the incidence of significant intraoperative electrophysiological signal changes during surgical positioning, and to assess the effectiveness of head and neck repositioning on the restoration of signals, among patients undergoing surgery for cervical myelopathy. Material and methods We used multimodal intraoperative monitoring (somatosensory [SEP] and motor evoked potentials [MEP] and spontaneous electromyography) before and after patients’ positioning in a consecutive cohort of 103 patients operated for symptomatic cervical myelopathy. Significant changes were defined as > 50% attenuation in amplitude or > 10% increase in latency of SEP, or abolishment or 50–80% attenuation of MEP. Results Out of 103 patients (34.9% female, median age 54.5 years) 88 underwent laminectomy (85.4%) and 15 (14.6%) anterior approach. At the time of positioning, signal alterations occurred in 44 patients (42.7%), yet only 11 patients (10.7%) showed alarming changes. Immediate neck repositioning of these resulted in complete (n = 6) or partial (n = 4) restoration of potentials, yielding no postoperative deficits. The patient in which signals could not be restored after repositioning resulted in added postoperative deficit. The accuracy (true positives plus true negatives) of monitoring to detect new neurological deficits was 99.0% (102/103) for the entire cohort, and 100% (11/11) for those showing significant changes at the moment of positioning. Overall, only 1 patient, with non-significant SEP attenuation, experienced a new postoperative deficit, yielding a 0.97% rate of false negatives. Conclusion Among patients undergoing surgery for cervical myelopathy, 10.7% showed alarming electrophysiological signal changes at the time of positioning. Immediate repositioning of the neck resulted in near always restoration of potentials and avoidance of added neurological damage. Complete or partial restoration of potentials after repositioning yielded no postoperative deficits.
Published: 2022
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33. Analysis of Psychological Symptoms Following Disclosure of Amyloid-Positron Emission Tomography Imaging Results to Adults With Subjective Cognitive Decline

Author: Caprioglio, Camilla, Ribaldi, Federica, Visser, Leonie N. C., Minguillon, Carolina, Collij, Lyduine E., Grau-Rivera, Oriol, Zeyen, Philip, Molinuevo, José Luis, Gispert, Juan Domingo, Garibotto, Valentina, Moro, Christian, Walker, Zuzana, Edison, Paul, Demonet, Jean-François, Barkhof, Frederik, Scheltens, Philip, Alves, Isadora Lopes, Gismondi, Rossella, Farrar, Gill, Stephens, Andrew W., Jessen, Frank, Frisoni, Giovanni B., Altomare, Daniele, Abdelnour, Carla, Aguilera, Nuria, Aksman, Leon, Alarcón-Martín, Emilio, Alegret, Montse, Alonso-Lana, Silvia, Andersen, Pia, Arab, Majd, Aspö, Malin, Bader, Ilona, Bader, Ilse, Banton, Nigel, Barnes, Rodrigo, Barrie, Dawn, Battle, Mark, Belén Collado, Ana, Bellet, Julie, Berkhof, Johannes, Biger, Marine, Birck, Cindy, Bischof, Gerard, Boada, Mercè, Boellaard, Ronald, Bogdanovic, Nenad, Bollack, Ariane, Bombois, Stéphanie, Borg, Stefan, Borjesson-Hanson, Anne, Boskov, Vladimir, Boutantin, Justine, Boutoleau-Bretonniere, Claire, Bouwman, Femke, Breuilh, Laetitia, Bringman, Eva, Brunel, Baptiste, Bucci, Marco, Buckley, Chris, Buendía, Mar, Bullich, Santi, Calvet, Anna, Cañada, Laia, Cañada, Marta, Cardoso, Jorge, Carlier, Jasmine, Carre, Elise, Carrie, Isabelle, Cassagnaud, Pascaline, Cassol, Emmanuelle, Castilla-Martí, Miguel, Cazalon, Elodie, Chaarriau, Tiphaine, Chaigeau, Rachel, Chalmers, Taylor, Clerc, Marie-Thérèse, Clerigue, Montserrat, Cognat, Emmanuel, Coll, Nina, Collij, Lyduine E, Connely, Peter, Cordier, Elodie, Costes, Corine, Coulange, Camille, Courtemanche, Hélène, Creisson, Eric, Crinquette, Charlotte, Cuevas, Rosario, Cufi, Marie-Noëlle, Dardenne, Sophie, de Arriba, Maria, de Costa Luis, Casper, de Gier, Yvonne, de Verbizier Lonjon, Delphine, Dekker, Veronique, Dekyndt, Bérengère, Delbeuck, Xavier, Delrieu, Julien, Deramecourt, Vincent, Desclaux, Françoise, Diaz, Carlos, Diego, Susana, Djafar, Mehdi, Dölle, Britta, Doull, Laura, Dricot, Laurence, Drzezga, Alexander, Dubois, Bruno, Dumont, Julien, Dumur, Jean, Dumurgier, Julien, Dvorak, Martin, Ecay, Mirian, Escher, Claus, Estanga, Ainara, Esteban, Ester, Fanjaud, Guy, Fauria, Karine, Felez Sanchez, Marta, Feukam Talla, Patrick, Ford, Lisa, Frisoni, Giovanni B, Fuster, David, Gabelle, Audrey, Gaubert, Sinead, Gauci, Cédric, Geldhof, Christine, Georges, Jean, Ghika, Joseph, González, Elena, Goovaerts, Valerie, Goulart, Denis Mariano, Grasselli, Caroline, Gray, Katherine, Greensmith, Martin, Grozn, Laure, Guillemaud, Céline, Gunn, Fiona, Guntur Ramkumar, Prasad, Hagman, Göran, Hansseuw, Bernard, Heeman, Fiona, Hendriks, Janine, Himmelmann, Jakob, Hitzel, Anne, Hives, Florent, Hoenig, Merle, Hourrègue, Claire, Hudson, Justine, Huguet, Jordi, Ibarria, Marta, Iidow, Ifrah, Indart, Sandrine, Ingala, Silvia, Ivanoiu, Adrian, Jacquemont, Charlotte, Jelic, Vesna, Jiao, Jieqing, Jofresa, Sara, Jonsson, Cathrine, Kaliukhovich, Dzmitry, Kern, Silke, Kivipelto, Miia, Knezevic, Iva, Kuchcinski, Grégory, Laforce, Manon, Lafuente, Asunción, Lala, Françoise, Lammertsma, Adriaan, Lax, Michelle, Lebouvier, Thibaud, Lee, Ho-Yun, Lee, Lean, Leeuwis, Annebet, Lefort, Amandine, Legrand, Jean-François, Leroy, Mélanie, Lesoil Markowski, Constance, Levy, Marcel, Lhommel , Renaud, Lopes, Renaud, Lopes Alves, Isadora, Lorenzini, Luigi, Lorette, Adrien, Luckett, Emma, Lundin, Marie, Mackowiak, Marie-Anne, Malotaux, Vincent, Manber, Richard, Manyakov, Nikolay, Markiewicz, Pawel, Marne, Paula, Marquié, Marta, Martín, Elvira, Martínez, Joan, Martinez Lage, Pablo, Mastenbroek, Sophie E, Maureille, Aurélien, Meersmans, Karen, Mett, Anja, Milne, Joseph, Minguillón, Carolina, Modat, Marc, Montrreal, Laura, Müller, Theresa, Muniz, Graciela, Mutsarts, Henk Jan, Nilsson, Ted, Ninerola, Aida, Nordberg, Agneta, Novaes, Wilse, Nuno Carmelo Pires Silva, Joao, Operto, Greg, Orellana, Adela, Ousset, Pierre-Jean, Outteryck, Olivier, Pallardy, Amandine, Palombit, Alessandro, Pancho, Ana, Pappon, Martin, Paquet, Claire, Pariente, Jérémie, Pasquier, Florence, Payoux, Pierre, Peaker, Harry, Pelejà, Esther, Pennetier, Delphine, Pérez-Cordón, Alba, Perissinotti, Andrés, Perrenoud, Matthieu Paul, Petit, Sandrine, Petyt, Grégory, Pfeil, Julia, Pirotte, Blanche, Pla, Sandra, Plaza Wuthrich, Sonia, Poitrine, Lea, Pollet, Marianne, Poncelet, Jean-Benoit, Prior, John, Pruvo, Jean-Pierre, Putallaz, Pauline, Queneau, Mathieu, Quenon , Lisa, Rădoi, Andreea, Rafiq, Marie, Ramage, Fiona, Ramis, Maribel, Reinwald, Michael, Rios, Gonzalo, Ritchie, Craig, Rodriguez, Elena, Rollin, Adeline, Rouaud, Olivier, Sacuiu, Simona, Saint-Aubert, Laure, Sala, Arianna, Salabert, Anne-Sophie, Saldias, Jon, Salvadó, Gemma, Sanabria, Angela, Sannemann, Lena, Sastre, Nathalie, Savina, Daniela, Savitcheva, Irina, Schaeverbeke, Jolien, Schildermans, Carine, Schmidt, Mark, Schöll, Michael, Schuermans, Jeroen, Semah, Franck, Shekari, Mahnaz, Skoog, Ingmar, Sotolongo-Grau, Oscar, Stephens, Andrew, Stewart, Tiffany, Stutzmann, Jennyfer, Tait, Murray, Tárraga, Lluis, Tartari, Juan Pablo, Tysen-backstrom, Ann-christine, Valero, Sergi, Vallez Garcia, David, van Berckel, Bart N M, van Essen, Martijn, Van Laere, Koen, van Leur, Jeroen, van Maurik, Ingrid S, Vandenberghe, Rik, Vellas, Bruno, Virolinen, Jukka, Visser, Pieter Jelle, Walles, Håkan, Wallin, Emilia, Whitelaw, Grant, Wimberley, Catriona, Win , Zarni, Wink, Alle Meije, Wolz, Robin, Woodside, John, Yaqub, Maqsood, Zettergren, Anna, Medical Psychology, APH - Personalized Medicine, APH - Quality of Care, Radiology and nuclear medicine, Amsterdam Neuroscience - Neurodegeneration, Amsterdam Neuroscience - Brain Imaging, Amsterdam Neuroscience - Neuroinfection & -inflammation, CCA - Cancer Treatment and quality of life, CCA - Imaging and biomarkers, Neurology, Dekyndt, Bérengère, Delbeuck, Xavier, Delrieu, Julien, Demonet, Jean-François, Deramecourt, Vincent, Desclaux, Françoise, Diaz, Carlos, Diego, Susana, Djafar, Mehdi, Dölle, Britta, Doull, Laura, Dricot, Laurence, Drzezga, Alexander, Dubois, Bruno, Dumont, Julien, Dumur, Jean, Dumurgier, Julien, Dvorak, Martin, Ecay, Mirian, Edison, Paul, Escher, Claus, Estanga, Ainara, Esteban, Ester, Fanjaud, Guy, Farrar, Gill, Fauria, Karine, Felez Sanchez, Marta, Feukam Talla, Patrick, Ford, Lisa, Frisoni, Giovanni B, Fuster, David, Gabelle, Audrey, Garibotto, Valentina, Gaubert, Sinead, Gauci, Cédric, Geldhof, Christine, Georges, Jean, Ghika, Joseph, Gismondi, Rossella, Gispert, Juan Domingo, González, Elena, Goovaerts, Valerie, Goulart, Denis Mariano, Grasselli, Caroline, Grau-Rivera, Oriol, Gray, Katherine, Greensmith, Martin, Grozn, Laure, Guillemaud, Céline, Gunn, Fiona, Guntur Ramkumar, Prasad, Hagman, Göran, Hansseuw, Bernard, Heeman, Fiona, Hendriks, Janine, Himmelmann, Jakob, Hitzel, Anne, Hives, Florent, Hoenig, Merle, Hourrègue, Claire, Hudson, Justine, Huguet, Jordi, Ibarria, Marta, Iidow, Ifrah, Indart, Sandrine, Ingala, Silvia, Ivanoiu, Adrian, Jacquemont, Charlotte, Jelic, Vesna, Jessen, Frank, Jiao, Jieqing, Jofresa, Sara, Jonsson, Cathrine, Kaliukhovich, Dzmitry, Kern, Silke, Kivipelto, Miia, Knezevic, Iva, Kuchcinski, Grégory, Laforce, Manon, Lafuente, Asunción, Lala, Françoise, Lammertsma, Adriaan, Lax, Michelle, Lebouvier, Thibaud, Lee, Ho-Yun, Lee, Lean, Leeuwis, Annebet, Lefort, Amandine, Legrand, Jean-François, Leroy, Mélanie, Lesoil Markowski, Constance, Levy, Marcel, Lhommel, Renaud, Lopes, Renaud, Lopes Alves, Isadora, Lorenzini, Luigi, Lorette, Adrien, Luckett, Emma, Lundin, Marie, Mackowiak, Marie-Anne, Malotaux, Vincent, Manber, Richard, Manyakov, Nikolay, Markiewicz, Pawel, Marne, Paula, Marquié, Marta, Martín, Elvira, Martínez, Joan, Martinez Lage, Pablo, Mastenbroek, Sophie E, Maureille, Aurélien, Meersmans, Karen, Mett, Anja, Milne, Joseph, Minguillón, Carolina, Modat, Marc, Molinuevo, José Luis, Montrreal, Laura, Moro, Christian, Müller, Theresa, Muniz, Graciela, Mutsarts, Henk Jan, Nilsson, Ted, Ninerola, Aida, Nordberg, Agneta, Novaes, Wilse, Nuno Carmelo Pires Silva, Joao, Operto, Greg, Orellana, Adela, Ousset, Pierre-Jean, Outteryck, Olivier, Pallardy, Amandine, Palombit, Alessandro, Pancho, Ana, Pappon, Martin, Paquet, Claire, Pariente, Jérémie, Pasquier, Florence, Payoux, Pierre, Peaker, Harry, Abdelnour, Carla, Pelejà, Esther, Pennetier, Delphine, Pérez-Cordón, Alba, Perissinotti, Andrés, Perrenoud, Matthieu Paul, Petit, Sandrine, Petyt, Grégory, Pfeil, Julia, Pirotte, Blanche, Pla, Sandra, Aguilera, Nuria, Plaza Wuthrich, Sonia, Poitrine, Lea, Pollet, Marianne, Poncelet, Jean-Benoit, Prior, John, Pruvo, Jean-Pierre, Putallaz, Pauline, Queneau, Mathieu, Quenon, Lisa, Rădoi, Andreea, Aksman, Leon, Rafiq, Marie, Ramage, Fiona, Ramis, Maribel, Reinwald, Michael, Rios, Gonzalo, Ritchie, Craig, Rodriguez, Elena, Rollin, Adeline, Rouaud, Olivier, Sacuiu, Simona, Alarcón-Martín, Emilio, Saint-Aubert, Laure, Sala, Arianna, Salabert, Anne-Sophie, Saldias, Jon, Salvadó, Gemma, Sanabria, Angela, Sannemann, Lena, Sastre, Nathalie, Savina, Daniela, Savitcheva, Irina, Alegret, Montse, Schaeverbeke, Jolien, Scheltens, Philip, Schildermans, Carine, Schmidt, Mark, Schöll, Michael, Schuermans, Jeroen, Semah, Franck, Shekari, Mahnaz, Skoog, Ingmar, Sotolongo-Grau, Oscar, Alonso-Lana, Silvia, Stephens, Andrew, Stewart, Tiffany, Stutzmann, Jennyfer, Tait, Murray, Tárraga, Lluis, Tartari, Juan Pablo, Tysen-Backstrom, Ann-Christine, Valero, Sergi, Vallez Garcia, David, van Berckel, Bart N M, Altomare, Daniele, van Essen, Martijn, Van Laere, Koen, van Leur, Jeroen, van Maurik, Ingrid S, Vandenberghe, Rik, Vellas, Bruno, Virolinen, Jukka, Visser, Pieter Jelle, Walker, Zuzana, Walles, Håkan, Andersen, Pia, Wallin, Emilia, Whitelaw, Grant, Wimberley, Catriona, Win, Zarni, Wink, Alle Meije, Wolz, Robin, Woodside, John, Yaqub, Maqsood, Zettergren, Anna, Zeyen, Philip, Arab, Majd, Aspö, Malin, Bader, Ilona, Bader, Ilse, Banton, Nigel, Barkhof, Frederik, Barnes, Rodrigo, Barrie, Dawn, Battle, Mark, Belén Collado, Ana, Bellet, Julie, Berkhof, Johannes, Biger, Marine, Birck, Cindy, Bischof, Gerard, Boada, Mercè, Boellaard, Ronald, Bogdanovic, Nenad, Bollack, Ariane, Bombois, Stéphanie, Borg, Stefan, Borjesson-Hanson, Anne, Boskov, Vladimir, Boutantin, Justine, Boutoleau-Bretonniere, Claire, Bouwman, Femke, Breuilh, Laetitia, Bringman, Eva, Brunel, Baptiste, Bucci, Marco, Buckley, Chris, Buendía, Mar, Bullich, Santi, Calvet, Anna, Cañada, Laia, Cañada, Marta, Caprioglio, Camilla, Cardoso, Jorge, Carlier, Jasmine, Carre, Elise, Carrie, Isabelle, Cassagnaud, Pascaline, Cassol, Emmanuelle, Castilla-Martí, Miguel, Cazalon, Elodie, Chaarriau, Tiphaine, Chaigeau, Rachel, Chalmers, Taylor, Clerc, Marie-Thérèse, Clerigue, Montserrat, Cognat, Emmanuel, Coll, Nina, Collij, Lyduine E, Connely, Peter, Cordier, Elodie, Costes, Corine, Coulange, Camille, Courtemanche, Hélène, Creisson, Eric, Crinquette, Charlotte, Cuevas, Rosario, Cufi, Marie-Noëlle, Dardenne, Sophie, de Arriba, Maria, de Costa Luis, Casper, de Gier, Yvonne, de Verbizier Lonjon, Delphine, and Dekker, Veronique
Subjects: Male, Adult, metabolism [Brain], Positron-Emission Tomography, diagnosis [Alzheimer Disease], diagnostic imaging [Cognitive Dysfunction], Humans, metabolism [Amyloid beta-Peptides], ddc:610, Prospective Studies, Disclosure, General Medicine, Aged
Abstract: ImportanceIndividuals who are amyloid-positive with subjective cognitive decline and clinical features increasing the likelihood of preclinical Alzheimer disease (SCD+) are at higher risk of developing dementia. Some individuals with SCD+ undergo amyloid-positron emission tomography (PET) as part of research studies and frequently wish to know their amyloid status; however, the disclosure of a positive amyloid-PET result might have psychological risks.ObjectiveTo assess the psychological outcomes of the amyloid-PET result disclosure in individuals with SCD+ and explore which variables are associated with a safer disclosure in individuals who are amyloid positive.Design, Setting, and ParticipantsThis prospective, multicenter study was conducted as part of The Amyloid Imaging to Prevent Alzheimer Disease Diagnostic and Patient Management Study (AMYPAD-DPMS) (recruitment period: from April 2018 to October 2020). The setting was 5 European memory clinics, and participants included patients with SCD+ who underwent amyloid-PET. Statistical analysis was performed from July to October 2022.ExposuresDisclosure of amyloid-PET result.Main Outcomes and MeasuresPsychological outcomes were defined as (1) disclosure related distress, assessed using the Impact of Event Scale–Revised (IES-R; scores of at least 33 indicate probable presence of posttraumatic stress disorder [PTSD]); and (2) anxiety and depression, assessed using the Hospital Anxiety and Depression scale (HADS; scores of at least 15 indicate probable presence of severe mood disorder symptoms).ResultsAfter disclosure, 27 patients with amyloid-positive SCD+ (median [IQR] age, 70 [66-74] years; gender: 14 men [52%]; median [IQR] education: 15 [13 to 17] years, median [IQR] Mini-Mental State Examination [MMSE] score, 29 [28 to 30]) had higher median (IQR) IES-R total score (10 [2 to 14] vs 0 [0 to 2]; P P P P P = .06) and Depression (–1.0 [–2.0 to 0.0] vs –1.0 [–3.0 to 0.0]; P = .46) deltas (score after disclosure – scores at baseline). In patients with amyloid-positive SCD+, despite the small sample size, higher education was associated with lower disclosure-related distress (ρ = –0.43; P = .02) whereas the presence of study partner was associated with higher disclosure-related distress (W = 7.5; P = .03). No participants with amyloid-positive SCD+ showed probable presence of PTSD or severe anxiety or depression symptoms at follow-up.Conclusions and RelevanceThe disclosure of a positive amyloid-PET result to patients with SCD+ was associated with a bigger psychological change, yet such change did not reach the threshold for clinical concern.
Published: 2023
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34. Lifting Velocity as a Predictor of the Maximum Number of Repetitions That Can Be Performed to Failure During the Prone Bench Pull Exercise

Author: Sergio Miras-Moreno, Alejandro Pérez-Castilla, and Amador García-Ramos
Subjects: Lifting, Weight Lifting, Humans, Reproducibility of Results, Resistance Training, Orthopedics and Sports Medicine, Physical Therapy, Sports Therapy and Rehabilitation, Muscle Strength, Muscle, Skeletal
Abstract: Objective: To explore (1) the goodness of fit of generalized and individualized relationships between the maximum number of repetitions performed to failure (RTF) and the fastest mean velocity and peak velocity of the sets (RTF–velocity relationships), (2) the between-sessions reliability of mean velocity and peak velocity values associated with different RTFs, and (3) whether the errors in the prediction of the RTF under fatigued and nonfatigued conditions differ between generalized and individualized RTF–velocity relationships. Methods: Twenty-three sport-science students performed 4 testing sessions with the prone bench pull exercise in a Smith machine: a 1-repetition-maximum [1RM] session, 2 identical sessions consisting of singles sets of RTF against 4 randomized loads (60%–70%–80%–90%1RM), and 1 session consisting of 4 sets of RTF against the 75%1RM. Results: Individualized RTF–velocity relationships presented a higher goodness of fit (r2 = .96–.97 vs .67–.70) and accuracy (absolute errors = 2.1–2.9 repetitions vs 2.8–4.3 repetitions) in the prediction of the RTF than generalized RTF–velocity relationships. The reliability of the velocity values associated with different RTFs was generally high (average within-subject coefficient of variation = 4.01% for mean velocity and 3.98% for peak velocity). The error in the prediction of the RTF increased by ~1 repetition under fatigue (ie, set 1 vs sets 2–4). Conclusions: Individualized RTF–velocity relationships can be used with acceptable precision and reliability to prescribe the loads associated with a given RTF during the match a specific XRM during the prone bench pull exercise, but a lower accuracy is expected in a fatigued state.
Published: 2022
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35. Limits of the precision in refractive results after cataract surgery

Author: D, Romero Valero, J, Escolano Serrano, C E, Monera Lucas, G, Castilla Martínez, and J J, Martínez Toldos
Subjects: Cornea, Lenses, Intraocular, Biometry, Lens Implantation, Intraocular, Visual Acuity, Humans, General Medicine, Cataract
Abstract: In order to improve refractive results in cataract surgery with an intraocular lens implant, it is important to know the sources of error as well as the limit of this process. Therefore, the objective of the present work is to approximate the theoretical limit in the precision in the refractive result after cataract surgery with the currently available means and to assess the impact of different sources of error in this process.We conducted a search of the literature to determine the variability provided by each component of the process. Based on the Barrett Universal-II formula, we performed an error propagation analysis. The theoretical limit was defined as the situation in which the refractive result is only affected by the variability in the parameters introduced in the formula, the tolerance of the intraocular lens and the subjective refraction.The main contributors to the error were (1) intraoperative and postoperative variability variables not considered by the formulas (49.33%), (2) postoperative subjective refraction (38.29%), (3) mean keratometry (5.98%) and (4) the variability in the labelling of the power of the intraocular lens (5.09%). The theoretical limit obtained for the intraocular lens calculation with the means available today was 91.9% of the eyes between ±0.50D.We found a theoretical limit for the intraocular lens calculation of 91.9% of the eyes between ±0.50D. Approaching the precision limit described in the study requires the use of optical biometrics and state-of-the-art formulas, a reproducible surgical technique, and the compensation of systematic errors by adjusting constants.
Published: 2022
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36. Vitrectomy with subretinal tissue plasminogen activator (r-TPA) and intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) for submacular hemorrhages treatment: Retrospective analysis of 22 cases

Author: A, Herranz Cabarcos, M J, Quiroz Quiroga, I, Alarcón Valero, M, Castilla Martí, V, Pospoki, and D, Vilaplana Blanch
Subjects: Male, Macular Degeneration, Vascular Endothelial Growth Factors, Tissue Plasminogen Activator, Vitrectomy, Intravitreal Injections, Visual Acuity, Humans, Retinal Hemorrhage, Female, General Medicine, Retrospective Studies
Abstract: Macular hemorrhages are a severe complication of other retinal pathologies, such as age-related macular degeneration (AMD) or macroaneurysms. Their therapeutic approach is not standardized, and can vary from observation to surgical treatment.Retrospective analysis of 22 cases of macular hemorrhage, treated with vitrectomy associated to subretinal rTPA and intravitreal anti-VEGF over a period of 5 years.22 eyes of 22 patients were included, of which 12 (52%) were women. The mean age at diagnosis was 84.4 years. 13 patients were pseudophakic (54.1%) and 19 (86.36%) had previous ophthalmological comorbidities. The etiology of the macular hemorrhage was AMD in 19 patients (86.36%). The mean of best VA corrected at diagnosis was 24.55 (Early Treatment Diabetic Retinopathy Study score -ETDRS), with a statistically significant improvement to 36.78 3 months after surgery (p = 0.011). With an average of 23.5 months of follow-up, no differences in prognosis associated with the etiology or size of the hemorrhage were observed.The treatment of macular hemorrhages by vitrectomy, subretinal rTPA and antiVEGF improves the visual prognosis of affected patients.
Published: 2022
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37. Pilot phase results of a prospective, randomized controlled trial of narrowband ultraviolet B phototherapy in hospitalized <scp>COVID</scp> ‐19 patients

Author: Frank H, Lau, Catherine E, Powell, Giacomo, Adonecchi, Denise M, Danos, Andrew R, DiNardo, Robert J, Chugden, Peter, Wolf, and Carmen F, Castilla
Subjects: Treatment Outcome, COVID-19, Humans, Ultraviolet Therapy, Prospective Studies, Dermatology, Phototherapy, Molecular Biology, Biochemistry
Abstract: COVID-19 morbidity and mortality are driven by poor immune regulation. Narrowband ultraviolet B (NB-UVB) phototherapy is standard of care in a number of immune-dysregulated diseases. To assess the efficacy of NB-UVB phototherapy for improving COVID-19 outcomes in high-risk, hospitalized, we developed the Adaptive Photo-Protection Trial. This is a multi-center, prospective, double-blinded, randomized, placebo-controlled trial. The pilot phase results are reported here. Consecutive patients admitted with a positive COVID-19 PCR were screened for eligibility. Enrolled subjects were computer randomized 1:1 to NB-UVB or placebo phototherapy. Subjects were treated daily with escalating doses on 27% of their body surface area for up to 8 consecutive days. Primary outcomes were safety and efficacy, defined as persistent or painful erythema and 28-day mortality. Comparisons were made via non-parametric exact tests. Patients in treatment (n = 15) and placebo (n = 15) arms had similar demographics. No adverse events occurred. Twenty eight-day mortality was 13.3% in treatment vs. 33.3% in placebo arms (p = 0.39). NB-UVB phototherapy in hospitalized COVID-19 patients was safe. Decreased mortality was observed in treated patients but this was statistically non-significant. Given its low-cost, scalability, and adjunctive nature, NB-UVB has the potential to improve COVID-19 outcomes. Continuation of this trial is warranted.
Published: 2022
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38. Teachers' Response to Stress, Anxiety and Depression During <scp>COVID</scp> ‐19 Lockdown: What Have We Learned From the Pandemic?

Author: Laura Lacomba‐Trejo, Konstanze Schoeps, Selene Valero‐Moreno, Constanza del Rosario, and Inmaculada Montoya‐Castilla
Subjects: Male, Philosophy, Cross-Sectional Studies, Depression, Communicable Disease Control, Public Health, Environmental and Occupational Health, COVID-19, Humans, Female, Anxiety, Pandemics, Education
Abstract: As a result of national lockdown due to the COVID-19 outbreak, teachers were forced to suspend their classes and replace them with online teaching and home schooling. Additional stressors such as competing family responsibility have increased their worries and mental health problems. The aim of this study was to determine the impact of COVID-19-related worries on teachers' emotional symptoms, considering the mediating role of several protective factors.A total of 614 Chilean teachers (94.60% women) participated in this study using a cross-sectional design and incidental sampling method. Self-report data was collected assessing emotional symptoms, COVID-19-related worries, life satisfaction, affect balance, and resilience. Descriptive analyses, Pearson's correlations, hierarchical regressions, and mediation models were conducted.The results indicated that emotional symptoms were associated with prepandemic physical and mental health problems, higher levels of worries and negative affect, as well as lower levels of life satisfaction and resilience. Results from the mediation models showed that the negative impact of COVID-19-related worries on emotional symptoms was alleviated by affect balance and resilience.These findings highlight the importance of addressing the risk and protective factors for teachers' mental health during exceptional situations such as the ongoing pandemic.
Published: 2022
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39. Confirmatory Factor Analysis of the Transgender Knowledge, Attitudes, and Beliefs (T-KAB) Scale for the Mexican Population

Author: Ana Fresán, Tecelli Domínguez-Martínez, María Fernanda Castilla-Peón, Rebeca Robles, Omar Hernández, Tania Vélez, and Carolina Muñoz
Subjects: Adult, Male, Health Knowledge, Attitudes, Practice, Psychometrics, Arts and Humanities (miscellaneous), Surveys and Questionnaires, Humans, Reproducibility of Results, Female, Factor Analysis, Statistical, Transgender Persons, General Psychology
Abstract: Transphobia is a result of the widespread lack of knowledge among the general population, together with prejudice based on irrational fear and hatred, of those who do not fit the dominant, socially established gender categories. Little is known about transgender-related knowledge, attitudes, and beliefs among the Mexican population, due to the lack of reliable, valid Spanish-language instruments. This study presents a Spanish translation of the Transgender Knowledge, Attitudes, and Beliefs (T-KAB) Scale and examines its psychometric properties for the Mexican population. A cohort of 501 adult subjects, 337 (67.3%) women and 161 (32.1%) men, drawn from the general population, answered the T-KAB in an anonymous online survey. A confirmatory factor analysis (CFA) and internal consistency measure were used to determine whether its dimensions were reliable and valid for use in a Mexican Spanish language and cultural context. A CFA including the three original dimensions proposed and excluding one item from the T-KAB Scale showed appropriate goodness of fit indices (χ
Published: 2022
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40. Mortality from esophagectomy for esophageal cancer across low, middle, and high-income countries: An international cohort study

Author: Kamarajah, Sk, Nepogodiev, D, Bekele, A, Cecconello, I, Evans, Rpt, Guner, A, Gossage, Ja, Harustiak, T, Hodson, J, Isik, A, Kidane, B, Leon-Takahashi, Am, Mahendran, Ha, Negoi, I, Okonta, Ke, Rosero, G, Sayyed, Rh, Singh, P, Takeda, Fr, van Hillegersberg, R, Vohra, Rs, White, Re, Griffiths, Ea, Alderson, D, Bundred, J, Gossage, J, Jefferies, B, Mckay, S, Mohamed, I, Siaw-Acheampong, K, Vohra, R, Wanigasooriya, K, Whitehouse, T, Gjata, A, Moreno, Ji, Guevara, Cr, Kechagias, A, Gockel, I, Kennedy, A, Da Roit, A, Bagajevas, A, Azagra, Js, Mejia-Fernandez, L, Wijnhoven, Bpl, El Kafsi, J, Sousa, M, Sampaio, As, Blanco, R, Wallner, B, Schneider, Pm, Hsu, Pk, Gananadha, S, Wills, V, Devadas, M, Duong, C, Talbot, M, Hii, Mw, Jacobs, R, Andreollo, Na, Johnston, B, Darling, G, Isaza-Restrepo, A, Arias-Amezquita, F, Raptis, D, Gaedcke, J, Reim, D, Izbicki, J, Egberts, Jh, Dikinis, S, Kjaer, Dw, Larsen, Mh, Achiam, Mp, Saarnio, J, Theodorou, D, Liakakos, T, Korkolis, Dp, Robb, Wb, Collins, C, Murphy, T, Reynolds, J, Tonini, V, Migliore, M, Bonavina, L, Valmasoni, M, Bardini, R, Weindelmayer, J, Terashima, M, Alghunaim, E, Elhadi, M, Medina-Franco, H, Lau, Pc, Heisterkamp, J, Rosman, C, Beban, G, Babor, R, Gordon, A, Rossaak, Ji, Pal, Kmi, Qureshi, Au, Naqi, Sa, Syed, Aa, Barbosa, J, Vicente, Cs, Leite, J, Freire, J, Casaca, R, Costa, Rct, Scurtu, Rr, Mogoanta, Ss, Bolca, C, Constantinoiu, S, Sekhniaidze, D, Bjelovic, M, Jby, So, Gacevski, G, Loureiro, C, Pera, M, Bianchi, A, Moreno, Gm, Fernandez, Jm, Carrera, Mst, Vallve-Bernal, M, Pascual, Mac, Elmahi, S, Halldestam, I, Hedberg, J, Monig, S, Gutknecht, S, Tez, M, Tirnaksiz, Mb, Colak, E, Sevinc, B, Hindmarsh, A, Khan, I, Khoo, D, Byrom, R, Gokhale, J, Wilkerson, P, Jain, P, Chan, D, Robertson, K, Iftikhar, S, Skipworth, R, Forshaw, M, Higgs, S, Nijjar, R, Viswanath, Yks, Turner, P, Dexter, S, Boddy, A, Allum, Wh, Oglesby, S, Cheong, E, Beardsmore, D, Maynard, N, Berrisford, R, Mercer, S, Puigt, S, Melhadot, R, Kelty, C, Underwood, T, Dawas, K, Lewis, W, Al-Bahrani, A, Bryce, G, Thomas, M, Arndt, At, Palazzo, F, Meguid, Ra, Fergusson, J, Beenen, E, Mosse, C, Salim, J, Cheah, S, Wright, T, Cerdeira, Mp, Mcquillan, P, Richardson, M, Liem, H, Spillane, J, Yacob, M, Albadawi, F, Thorpe, T, Dingle, A, Cabalag, C, Loi, K, Fisher, Om, Ward, S, Read, M, Johnson, M, Bassari, R, Bui, H, Sallum, Raa, da Rocha, Jrm, Lopes, Lr, Tercioti, V, Coelho, Jd, Ferrer, Jap, Buduhan, G, Tan, L, Srinathan, S, Shea, P, Yeung, J, Allison, F, Carroll, P, Vargas-Barato, F, Gonzalez, F, Ortega, J, Nino-Torres, L, Beltran-Garcia, Tc, Castilla, L, Pineda, M, Bastidas, A, Gomez-Mayorga, J, Cortes, N, Cetares, C, Caceres, S, Duarte, S, Pazdro, A, Snajdauf, M, Faltova, H, Sevcikova, M, Mortensen, Pb, Katballe, N, Ingemann, T, Morten, B, Kruhlikava, I, Ainswort, Ap, Stilling, Nm, Eckardt, J, Holm, J, Thorsteinsson, M, Siemsen, M, Brandt, B, Nega, B, Teferra, E, Tizazu, A, Kauppila, Jh, Koivukangas, V, Merilainen, S, Gruetzmann, R, Krautz, C, Weber, G, Golcher, H, Emons, G, Azizian, A, Ebeling, M, Niebisch, S, Kreuser, N, Albanese, G, Hesse, J, Volovnik, L, Boecher, U, Reeh, M, Triantafyllou, S, Schizas, D, Michalinos, A, Mpali, E, Mpoura, M, Charalabopoulos, A, Manatakis, Dk, Balalis, D, Bolger, J, Baban, C, Mastrosimone, A, Mcanena, O, Quinn, A, Suilleabhain, Cbo, Hennessy, Mm, Ivanovski, I, Khizer, H, Ravi, N, Donlon, N, Cervellera, M, Vaccari, S, Bianchini, S, Sartarelli, L, Asti, E, Bernardi, D, Merigliano, S, Provenzano, L, Scarpa, M, Saadeh, L, Salmaso, B, De Manzoni, G, Giacopuzzi, S, La Mendola, R, De Pasqual, Ca, Tsubosa, Y, Niihara, M, Irino, T, Makuuchi, R, Ishii, K, Mwachiro, M, Fekadu, A, Odera, A, Mwachiro, E, Alshehab, D, Ahmed, Ha, Shebani, Ao, Elhadi, A, Elnagar, Fa, Elnagar, Hf, Makkai-Popa, St, Wong, Lf, Tan, Yr, Thannimalai, S, Ca, Ho, Pang, Ws, Tan, Jh, Basave, Hnl, Cortes-Gonzalez, R, Lagarde, Sm, van Lanschot, Jjb, Cords, C, Jansen, Wa, Martijnse, I, Matthijsen, R, Bouwense, S, Klarenbeek, B, Verstegen, M, van Workum, F, Ruurda, Jp, van der Sluis, Pc, de Maat, M, Evenett, N, Johnston, P, Patel, R, Maccormick, A, Young, M, Smith, B, Ekwunife, C, Memon, Ah, Shaikh, K, Wajid, A, Khalil, N, Haris, M, Mirza, Zu, Qudus, Sba, Sarwar, Mz, Shehzadi, A, Raza, A, Jhanzaib, Mh, Farmanali, J, Zakir, Z, Shakeel, O, Nasir, I, Khattak, S, Baig, M, Noor, Ma, Ahmed, Hh, Naeem, A, Pinho, Ac, da Silva, R, Bernardes, A, Campos, Jc, Matos, H, Braga, T, Monteiro, C, Ramos, P, Cabral, F, Gomes, Mp, Martins, Pc, Correia, Am, Videira, Jf, Ciuce, C, Drasovean, R, Apostu, R, Paitici, S, Racu, Ae, Obleaga, Cv, Beuran, M, Stoica, B, Ciubotaru, C, Negoita, V, Cordos, I, Birla, Rd, Predescu, D, Hoara, Pa, Tomsa, R, Shneider, V, Agasiev, M, Ganjara, I, Gunjic, D, Veselinovic, M, Babic, T, Chin, Ts, Shabbir, A, Kim, G, Crnjac, A, Samo, H, Del Val, Id, Leturio, S, Ramon, Jm, Dal Cero, M, Rifa, S, Rico, M, Pomar, Ap, Corcoles, Jam, Miravalles, Jlr, Pais, Sa, Turienzo, Sa, Alvarezt, Ls, Alvarez, Ls, Campos, Pv, Rendo, Ag, Garcia, Ss, Santos, Epg, Martinez, Et, Fernandez, Dm, Magadan, Ac, Concepcion, Mv, Diaz, Lc, Rosat, Ra, Perez, Sle, Bailon, Cm, Tinoco, Cc, Bhojwani, Ec, Sanchez, Dp, Ahmed, Me, Dzhendov, T, Lindberg, F, Rutegard, M, Sundbom, M, Mickael, C, Colucci, N, Schnider, A, Er, S, Kurnaz, E, Turkyilmaz, S, Turkyilmaz, A, Yildirim, R, Baki, Be, Akkapulu, N, Karahan, O, Damburaci, N, Hardwickt, R, Safranek, P, Sujendran, V, Bennett, J, Afzal, Z, Shrotri, M, Chan, B, Exarchou, K, Gilbert, T, Amalesh, T, Mukherjee, D, Mukherjee, S, Wiggins, Th, Kennedy, R, Mccain, S, Harris, A, Dobson, G, Davies, N, Wilson, I, Mayo, D, Bennett, D, Young, R, Manby, P, Blencowe, N, Schiller, M, Byrne, B, Mitton, D, Wong, V, Elshaer, A, Cowen, M, Menon, V, Tan, Lc, Mclaughlin, E, Koshy, R, Sharp, C, Brewer, H, Das, N, Cox, M, Al Khyatt, W, Worku, D, Iqbal, R, Walls, L, Mcgregor, R, Fullarton, G, Macdonald, A, Mackay, C, Craig, C, Dwerryhouse, S, Hornby, S, Jaunoo, S, Wadley, M, Baker, C, Saad, M, Kelly, M, Davies, A, Di Maggio, F, Mistry, P, Singhal, R, Tucker, O, Kapoulas, S, Powell-Brett, S, Davis, P, Bromley, G, Watson, L, Verma, R, Ward, J, Shetty, V, Ball, C, Pursnani, K, Sarela, A, Sue, Lh, Mehta, S, Hayden, J, To, N, Palser, T, Hunter, D, Supramaniam, K, Butt, Z, Ahmed, A, Kumar, S, Chaudry, A, Moussa, O, Kordzadeh, A, Lorenzi, B, Wilson, M, Patil, P, Noaman, I, Willem, J, Bouras, G, Evans, R, Singh, M, Warrilow, H, Ahmad, A, Tewari, N, Yanni, F, Couch, J, Theophilidou, E, Reilly, Jj, van Boxel, G, Akbari, K, Zanotti, D, Sgromo, B, Sanders, G, Wheatley, T, Ariyarathenam, A, Reece-Smith, A, Humphreys, L, Choh, C, Carter, N, Knight, B, Pucher, P, Athanasiou, A, Tan, B, Abdulrahman, M, Vickers, J, Akhtar, K, Chaparala, R, Brown, R, Alasmar, Mma, Ackroyd, R, Patel, K, Tamhankar, A, Wyman, A, Walker, R, Grace, B, Abbassi, N, Slim, N, Ioannidi, L, Blackshaw, G, Havard, T, Escofet, X, Powell, A, Owera, A, Rashid, F, Jambulingam, P, Padickakudi, J, Ben-Younes, H, Mccormack, K, Makey, Ia, Karush, Mk, Seder, Cw, Liptay, Mj, Chmielewski, G, Rosato, El, Berger, Ac, Zheng, R, Okolo, E, Singh, A, Scott, Cd, Weyant, Mj, Mitchell, Jd, Moenig, Stefan Paul, Kamarajah S.K., Nepogodiev D., Bekele A., Cecconello I., Evans R.P.T., Guner A., Gossage J.A., Harustiak T., Hodson J., Isik A., Kidane B., Leon-Takahashi A.M., Mahendran H.A., Negoi I., Okonta K.E., Rosero G., Sayyed R.H., Singh P., Takeda F.R., van Hillegersberg R., Vohra R.S., White R.E., Griffiths E.A., Alderson D., Bundred J., Gossage J., Jefferies B., McKay S., Mohamed I., Siaw- Acheampong K., Vohra R., Wanigasooriya K., Whitehouse T., Gjata A., Moreno J.I., Guevara C.R., Kechagias A., Gockel I., Kennedy A., Da Roit A., Bagajevas A., Azagra J.S., Mejia-Fernandez L., Wijnhoven B.P.L., El Kafsi J., Sousa M., Sampaio A.S., Blanco R., Wallner B., Schneider P.M., Hsu P.K., Gananadha S., Wills V., Devadas M., Duong C., Talbot M., Hii M.W., Jacobs R., Andreollo N.A., Johnston B., Darling G., Isaza-Restrepo A., Arias- Amezquita F., Raptis D., Gaedcke J., Reim D., Izbicki J., Egberts J.H., Dikinis S., Kjaer D.W., Larsen M.H., Achiam M.P., Saarnio J., Theodorou D., Liakakos T., Korkolis D.P., Robb W.B., Collins C., Murphy T., Reynolds J., Tonini V., Migliore M., Bonavina L., Valmasoni M., Bardini R., Weindelmayer J., Terashima M., Alghunaim E., Elhadi M., Medina-Franco H., Lau P.C., Heisterkamp J., Rosman C., Beban G., Babor R., Gordon A., Rossaak J.I., Pal K.M.I., Qureshi A.U., Naqi S.A., Syed A.A., Barbosa J., Vicente C.S., Leite J., Freire J., Casaca R., Costa R.C.T., Scurtu R.R., Mogoanta S.S., Bolca C., Constantinoiu S., Sekhniaidze D., Bjelovic M., So J.B.Y., Gacevski G., Loureiro C., Pera M., Bianchi A., Moreno G.M., Martin Fernandez J., Trugeda Carrera M.S., Vallve-Bernal M., Citores Pascual M.A., Elmahi S., Halldestam I., Hedberg J., Monig S., Gutknecht S., Tez M., Tirnaksiz M.B., Colak E., Sevinc B., Hindmarsh A., Khan I., Khoo D., Byrom R., Gokhale J., Wilkerson P., Jain P., Chan D., Robertson K., Iftikhar S., Skipworth R., Forshaw M., Higgs S., Nijjar R., Viswanath Y.K.S., Turner P., Dexter S., Boddy A., Allum W.H., Oglesby S., Cheong E., Beardsmore D., Maynard N., Berrisford R., Mercer S., Puig S., Melhado R., Kelty C., Underwood T., Dawas K., Lewis W., Al-Bahrani A., Bryce G., Thomas M., Arndt A.T., Palazzo F., Meguid R.A., Fergusson J., Beenen E., Mosse C., Salim J., Cheah S., Wright T., Cerdeira M.P., McQuillan P., Richardson M., Liem H., Spillane J., Yacob M., Albadawi F., Thorpe T., Dingle A., Cabalag C., Loi K., Fisher O.M., Ward S., Read M., Johnson M., Bassari R., Bui H., Sallum R.A.A., da Rocha J.R.M., Lopes L.R., Tercioti V., Coelho J.D., Ferrer J.A.P., Buduhan G., Tan L., Srinathan S., Shea P., Yeung J., Allison F., Carroll P., Vargas-Barato F., Gonzalez F., Ortega J., Nino-Torres L., Beltran-Garcia T.C., Castilla L., Pineda M., Bastidas A., Gomez-Mayorga J., Cortes N., Cetares C., Caceres S., Duarte S., Pazdro A., Snajdauf M., Faltova H., Sevcikova M., Mortensen P.B., Katballe N., Ingemann T., Morten B., Kruhlikava I., Ainswort A.P., Stilling N.M., Eckardt J., Holm J., Thorsteinsson M., Siemsen M., Brandt B., Nega B., Teferra E., Tizazu A., Kauppila J.H., Koivukangas V., Merilainen S., Gruetzmann R., Krautz C., Weber G., Golcher H., Emons G., Azizian A., Ebeling M., Niebisch S., Kreuser N., Albanese G., Hesse J., Volovnik L., Boecher U., Reeh M., Triantafyllou S., Schizas D., Michalinos A., Mpali E., Mpoura M., Charalabopoulos A., Manatakis D.K., Balalis D., Bolger J., Baban C., Mastrosimone A., McAnena O., Quinn A., O Suilleabhain C.B., Hennessy M.M., Ivanovski I., Khizer H., Ravi N., Donlon N., Cervellera M., Vaccari S., Bianchini S., Sartarelli L., Asti E., Bernardi D., Merigliano S., Provenzano L., Scarpa M., Saadeh L., Salmaso B., De Manzoni G., Giacopuzzi S., La Mendola R., De Pasqual C.A., Tsubosa Y., Niihara M., Irino T., Makuuchi R., Ishii K., Mwachiro M., Fekadu A., Odera A., Mwachiro E., AlShehab D., Ahmed H.A., Shebani A.O., Elhadi A., Elnagar F.A., Elnagar H.F., Makkai-Popa S.T., Wong L.F., Tan Y.R., Thannimalai S., Ho C.A., Pang W.S., Tan J.H., Basave H.N.L., Cortes-Gonzalez R., Lagarde S.M., van Lanschot J.J.B., Cords C., Jansen W.A., Martijnse I., Matthijsen R., Bouwense S., Klarenbeek B., Verstegen M., van Workum F., Ruurda J.P., van der Sluis P.C., de Maat M., Evenett N., Johnston P., Patel R., MacCormick A., Young M., Smith B., Ekwunife C., Memon A.H., Shaikh K., Wajid A., Khalil N., Haris M., Mirza Z.U., Qudus S.B.A., Sarwar M.Z., Shehzadi A., Raza A., Jhanzaib M.H., Farmanali J., Zakir Z., Shakeel O., Nasir I., Khattak S., Baig M., Noor M.A., Ahmed H.H., Naeem A., Pinho A.C., da Silva R., Bernardes A., Campos J.C., Matos H., Braga T., Monteiro C., Ramos P., Cabral F., Gomes M.P., Martins P.C., Correia A.M., Videira J.F., Ciuce C., Drasovean R., Apostu R., Paitici S., Racu A.E., Obleaga C.V., Beuran M., Stoica B., Ciubotaru C., Negoita V., Cordos I., Birla R.D., Predescu D., Hoara P.A., Tomsa R., Shneider V., Agasiev M., Ganjara I., Gunjic D., Veselinovic M., Babic T., Chin T.S., Shabbir A., Kim G., Crnjac A., Samo H., Diez del Val I., Leturio S., Ramon J.M., Dal Cero M., Rifa S., Rico M., Pagan Pomar A., Martinez Corcoles J.A., Rodicio Miravalles J.L., Pais S.A., Turienzo S.A., Alvarez L.S., Campos P.V., Rendo A.G., Garcia S.S., Santos E.P.G., Martinez E.T., Fernandez D.M., Magadan A.C., Concepcion M.V., Diaz L.C., Rosat R.A., Perez S.L., Bailon C.M., Tinoco C.C., Choolani Bhojwani E., Sanchez D.P., Ahmed M.E., Dzhendov T., Lindberg F., Rutegard M., Sundbom M., Mickael C., Colucci N., Schnider A., Er S., Kurnaz E., Turkyilmaz S., Turkyilmaz A., Yildirim R., Baki B.E., Akkapulu N., Karahan O., Damburaci N., Hardwick R., Safranek P., Sujendran V., Bennett J., Afzal Z., Shrotri M., Chan B., Exarchou K., Gilbert T., Amalesh T., Mukherjee D., Mukherjee S., Wiggins T.H., Kennedy R., McCain S., Harris A., Dobson G., Davies N., Wilson I., Mayo D., Bennett D., Young R., Manby P., Blencowe N., Schiller M., Byrne B., Mitton D., Wong V., Elshaer A., Cowen M., Menon V., Tan L.C., McLaughlin E., Koshy R., Sharp C., Brewer H., Das N., Cox M., Al Khyatt W., Worku D., Iqbal R., Walls L., McGregor R., Fullarton G., Macdonald A., MacKay C., Craig C., Dwerryhouse S., Hornby S., Jaunoo S., Wadley M., Baker C., Saad M., Kelly M., Davies A., Di Maggio F., Mistry P., Singhal R., Tucker O., Kapoulas S., Powell-Brett S., Davis P., Bromley G., Watson L., Verma R., Ward J., Shetty V., Ball C., Pursnani K., Sarela A., Sue L.H., Mehta S., Hayden J., To N., Palser T., Hunter D., Supramaniam K., Butt Z., Ahmed A., Kumar S., Chaudry A., Moussa O., Kordzadeh A., Lorenzi B., Wilson M., Patil P., Noaman I., Willem J., Bouras G., Evans R., Singh M., Warrilow H., Ahmad A., Tewari N., Yanni F., Couch J., Theophilidou E., Reilly J.J., van Boxel G., Akbari K., Zanotti D., Sgromo B., Sanders G., Wheatley T., Ariyarathenam A., Reece-Smith A., Humphreys L., Choh C., Carter N., Knight B., Pucher P., Athanasiou A., Tan B., Abdulrahman M., Vickers J., Akhtar K., Chaparala R., Brown R., Alasmar M.M.A., Ackroyd R., Patel K., Tamhankar A., Wyman A., Walker R., Grace B., Abbassi N., Slim N., Ioannidi L., Blackshaw G., Havard T., Escofet X., Powell A., Owera A., Rashid F., Jambulingam P., Padickakudi J., Ben-Younes H., Mccormack K., Makey I.A., Karush M.K., Seder C.W., Liptay M.J., Chmielewski G., Rosato E.L., Berger A.C., Zheng R., Okolo E., Singh A., Scott C.D., Weyant M.J., Mitchell J.D., and Surgery
Subjects: Male, Esophageal Neoplasms, SURGERY, IMPACT, medicine.medical_treatment, Tumours of the digestive tract Radboud Institute for Health Sciences [Radboudumc 14], 0302 clinical medicine, FAILURE, Postoperative Period, Prospective Studies, 030212 general & internal medicine, Prospective cohort study, Generalized estimating equation, COMPLICATIONS, ddc:617, Anastomosis, Surgical, General Medicine, Middle Aged, Esophageal cancer, Reconstructive and regenerative medicine Radboud Institute for Molecular Life Sciences [Radboudumc 10], HOSPITAL VOLUME, Oncology, Esophagectomy, 030220 oncology & carcinogenesis, Anastomotic leak, Global surgery, Postoperative mortality, Female, Cohort study, Adult, medicine.medical_specialty, Necrosis, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Esophagus, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, Developing Countries, Aged, business.industry, Developed Countries, Cancer, Odds ratio, GLOBAL BURDEN, RESCUE, medicine.disease, Confidence interval, Surgery, business
Abstract: Background: No evidence currently exists characterising global outcomes following major cancer surgery, including esophageal cancer. Therefore, this study aimed to characterise impact of high income countries (HIC) versus low and middle income countries (LMIC) on the outcomes following esophagectomy for esophageal cancer.Method: This international multi-center prospective study across 137 hospitals in 41 countries included patients who underwent an esophagectomy for esophageal cancer, with 90-day follow-up. The main explanatory variable was country income, defined according to the World Bank Data classification. The primary outcome was 90-day postoperative mortality, and secondary outcomes were composite leaks (anastomotic leak or conduit necrosis) and major complications (Clavien-Dindo Grade III - V). Multivariable generalized estimating equation models were used to produce adjusted odds ratios (ORs) and 95% confidence intervals (CI95%).Results: Between April 2018 to December 2018, 2247 patients were included. Patients from HIC were more significantly older, with higher ASA grade, and more advanced tumors. Patients from LMIC had almost three-fold increase in 90-day mortality, compared to HIC (9.4% vs 3.7%, p < 0.001). On adjusted analysis, LMIC were independently associated with higher 90-day mortality (OR: 2.31, CI95%: 1.17-4.55, p = 0.015). However, LMIC were not independently associated with higher rates of anastomotic leaks (OR: 1.06, CI95%: 0.57-1.99, p = 0.9) or major complications (OR: 0.85, CI95%: 0.54-1.32, p = 0.5), compared to HIC.Conclusion: Resections in LMIC were independently associated with higher 90-day postoperative mortality, likely reflecting a failure to rescue of these patients following esophagectomy, despite similar composite anastomotic leaks and major complication rates to HIC. These findings warrant further research, to identify potential issues and solutions to improve global outcomes following esophagectomy for cancer.
Published: 2021
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41. Effect of perceived stress, concern about hypoglycaemia and level of knowledge of management of the disease on glycaemic control in type 1 diabetes mellitus

Author: Carmen Grau‐Del Valle, José Francisco Marco‐Expósito, Neus Bosch‐Sierra, Begoña Zaragoza‐Villena, Eva Solá, Inmaculada Montoya‐Castilla, Carlos Morillas, and Celia Bañuls
Subjects: Adult, Glycated Hemoglobin, Diabetes Mellitus, Type 1, Cross-Sectional Studies, Humans, Hypoglycemic Agents, Insulin, Glycemic Control, General Medicine, Hypoglycemia, Stress, Psychological, General Nursing
Abstract: To evaluate perceived stress, concern about hypoglycaemia and the level of knowledge of management of the disease in patients with type 1 diabetes mellitus and their relationship with glycaemic control, gender and age.Perceived stress and concern about hypoglycaemia are significant obstacles to achieving adequate glycaemic control in patients with type 1 diabetes mellitus, and notably influence management of the disease itself.A cross-sectional study was carried out in 193 adult patients with type 1 diabetes mellitus. Study quality was scored using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist for cohort studies. Glycaemic control was evaluated by number and type of hypoglycaemic event and glycosylated haemoglobin. Questionnaires about hypoglycaemia concern (HFS II), perceived stress (PSS), unrecognised hypoglycaemia (Clarke Test) and level of knowledge of the disease were completed.Perceived stress was significantly associated with glycosylated haemoglobin (p 0.001) and concern about hypoglycaemia (p 0.037). With respect to level of knowledge, we observed that an advanced level was associated with lower glycosylated haemoglobin (p 0.001), number (p 0.001) and type (p 0.001) of hypoglycaemic episode, and less perceived stress (p = 0.006). In addition, age was negatively correlated with perceived stress (p 0.030) and positively correlated with the number of unrecognised hypoglycaemic episodes (p 0.002), which was associated, in turn, with a higher number of daily glycaemia tests (p 0.037) and concern about hypoglycaemia (p 0.006).In type 1 diabetes mellitus, perceived stress can negatively influence glycaemic control and concern about hypoglycaemia, and level of knowledge about the condition has a bearing on glycosylated haemoglobin levels, perceived stress and number and type of hypoglycaemic events. In addition, higher age is associated with more frequent unrecognised hypoglycaemic events.It is essential to identify and address the psychological needs of patients with type 1 diabetes mellitus with the aim of achieving an adequate management of the disease itself and generating a change in future intervention strategies.
Published: 2022
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42. Macular optical coherence tomography for screening of pathology prior to cataract surgery: An approach based on tele-evaluation

Author: A. Herranz-Cabarcos, Z. Vega-López, O. Salas-Fandos, MJ Quiroz-Quiroga, P. Burgos-Fernández, P. Martí-Rodrigo, M. Castilla-Marti, V. Poposki, and AR. Martínez-Palmer
Subjects: Ophthalmology, genetic structures, Humans, Epiretinal Membrane, Cataract Extraction, Prospective Studies, sense organs, General Medicine, Cataract, Tomography, Optical Coherence, eye diseases
Abstract: Background To assess the benefit of macular spectral-domain optical coherence tomography (SD-OCT) as a part of the routinary preoperative study of patients undergoing cataract surgery. Methods A prospective single-center study study was performed. Consecutive patients with normal biomicroscopic funduscopy, moderate cataract and no history of ophthalmological pathologies were enrolled. All patients underwent macular SD-OCT. The obtained images were analysed by a general ophthalmologist and two retina specialists. Incidence of macular pathology and its relation to age and comorbidities were assessed. Results Eight-hundred and thirty-six eyes of 419 patients were enrolled in this study. All images were analysed telematically by a general ophthalmologist. Forty-nine eyes were excluded due to insufficient quality of the obtained images. Abnormal images were observed in 156 eyes (18.6%), including age-related macular degeneration in 68 (8.2%), epiretinal membrane (ERM) in 67 (8.0%), cystoid macular edema in 3 eyes (0.4%), among others. Diagnostics with severe impact on patient visual prognosis were observed in 16 eyes (3.82%) from 12 patients. The relationship between incidence of macular pathologies and age or comorbidities was not statistically significant. To assess accuracy of the first observer, images were subsequently analysed by two retinologists. The kappa index of concordance was 0.80 and 0.85. Conclusions Implementing a systematic macular SD-OCT as a preoperative test prior to cataract surgery would improve quality of postoperative visual prognosis information. A general ophthalmologist would be suitable to screen for pathology through macular OCT images.
Published: 2022
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43. Inhibitors of the p38 cell signaling pathway as antiviral compounds against Junín virus

Author: Jesús Emanuel Brunetti, Verónica Mara Quintana, Luis Alberto Scolaro, and Viviana Castilla
Subjects: HEK293 Cells, Junin virus, Virology, Chlorocebus aethiops, Animals, Humans, General Medicine, Virus Replication, Antiviral Agents, Vero Cells, HeLa Cells, Signal Transduction
Abstract: In the present study, we analyzed the modulation of p38 cell signaling by Junín virus (JUNV) and evaluated the antiviral activity of p38 inhibitors against JUNV. While JUNV induced a progressive activation of p38 throughout the infection in Vero cells, a partial downregulation of p38 phosphorylation was observed in HEK293 and HeLa cells. The compounds SB203580 and SB202190, which are selective inhibitors of p38, significantly reduced viral protein expression and viral yield in the cell lines examined, indicating that the p38 signaling pathway might be a promising antiviral target against JUNV infection.
Published: 2022
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44. Load-Velocity Relationship Variables to Assess the Maximal Neuromuscular Capacities During the Back-Squat Exercise

Author: Zeki AKYILDIZ, Deniz Şentürk, Ivan Jukic, Amador García-Ramos, Alejandro Pérez-Castilla, and Danica Janićijević
Subjects: Male, Posture, Exercise Test, Humans, Reproducibility of Results, Resistance Training, Physical Therapy, Sports Therapy and Rehabilitation, Orthopedics and Sports Medicine, Muscle Strength, Current Research, Exercise Therapy
Abstract: Background: The relationship between the external load lifted and movement velocity can be modeled by a simple linear regression, and the variables derived from the load-velocity (L-V) relationship were recently used to estimate the maximal neuromuscular capacities during 2 variants of the back-squat exercise. Hypothesis: The L-V relationship variables will be highly reliable and will be highly associated with the traditional tests commonly used to evaluate the maximal force and power. Study Design: Twenty-four male wrestlers performed 5 testing sessions (a 1-repetition maximum [1RM] session, and 4 experimental sessions [2 with the concentric-only back-squat and 2 with the eccentric-concentric back-squat]). Each experimental session consisted of performing 3 repetitions against 5 loads (45%-55%-65%-75%-85% of the 1RM), followed by single 1RM attempts. Level of Evidence: Level 3. Methods: Individual L-V relationships were modeled from the mean velocity collected under all loading conditions from which the following 3 variables were calculated: load-axis intercept ( L0), velocity-axis intercept ( v0), and area under the line ( Aline = L0· v0/2). The back-squat 1RM strength and the maximum power determined as the apex of the power-velocity relationship ( Pmax) were also determined as traditional measures of maximal force and power capacities, respectively. Results: The between-session reliability was high for the Aline (coefficient of variation [CV] range = 2.58%-4.37%; intraclass correlation coefficient [ICC] range = 0.98-0.99) and generally acceptable for L0 and v0 (CV range = 5.08%-9.01%; ICC range = 0.45-0.96). Regarding the concurrent validity, the correlations were very large between L0 and the 1RM strength ( rrange = 0.87-0.88) and nearly perfect between Aline and Pmax ( r = 0.98-0.99). Conclusion: The load-velocity relationship variables can be obtained with a high reliability ( L0, v0, and Aline) and validity ( L0 and Aline) during the back-squat exercise. Clinical Relevance: The load-velocity relationship modeling represents a quick and simple procedure to estimate the maximal neuromuscular capacities of lower-body muscles.
Published: 2022
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45. Blood β-Synuclein and Neurofilament Light Chain During the Course of Prion Disease

Author: Steffen Halbgebauer, Samir Abu-Rumeileh, Patrick Oeckl, Petra Steinacker, Francesco Roselli, Diana Wiesner, Angela Mammana, Michael Beekes, Izaro Kortazar-Zubizarreta, Guiomar Perez de Nanclares, Sabina Capellari, Armin Giese, Joaquin Castilla, Albert C. Ludolph, Dana Žáková, Piero Parchi, and Markus Otto
Subjects: beta-Synuclein, Neurofilament Proteins, animal diseases, mental disorders, Intermediate Filaments, Humans, Neurology (clinical), Biomarkers, Creutzfeldt-Jakob Syndrome, Prion Diseases, nervous system diseases
Abstract: Background and ObjectivesFor early diagnosis and disease monitoring of neurodegenerative diseases (NDs), reliable blood biomarkers are needed. Elevated levels of neurofilament light chain protein (NfL), an axonal damage marker, have been described across different NDs, with highest values in prion diseases and amyotrophic lateral sclerosis (ALS). Synaptic degeneration is a common early feature in most NDs and seems to precede neuronal degeneration in prion disease. However, synaptic markers in blood are still missing. Here, we investigated whether the brain-specific protein β-synuclein might be a suitable blood biomarker for early diagnosis and evaluation of synaptic integrity in prion disease.MethodsWe analyzed blood β-synuclein with a newly established digital ELISA and NfL with a single-molecule array in samples obtained from human participants and prion and ALS animal models. Furthermore, β-synuclein was investigated in brain tissue of individuals with Creutzfeldt-Jakob disease (CJD) and controls.ResultsWe investigated 308 patients, including 129 cases with prion disease, 8 presymptomatic PRNP variation carriers, 60 with ALS, 68 with other ND, and 43 control patients. In CJD symptomatic cases, β-synuclein and NfL were markedly increased compared to all other diagnostic groups (p < 0.001). In the large majority of presymptomatic PRNP variation carriers, β-synuclein and NfL levels were within normal ranges. In prion disease animal models, β-synuclein and NfL displayed normal levels in the presymptomatic phase with a sudden elevation at disease onset and a plateau in the symptomatic phase. In contrast to NfL, β-synuclein was not elevated in either symptomatic patients with ALS or an ALS animal model. In the discrimination between prion disease and all other groups, β-synuclein (area under the curve 0.97, 95% CI 0.94–0.99, p < 0.001) was superior to NfL (area under the curve 0.91, 95% CI 0.88–0.94, p < 0.001). In addition, brain tissue β-synuclein showed significantly reduced levels in patients with CJD compared to control patients (p < 0.001).DiscussionBlood β-synuclein was significantly elevated in patients with CJD, reflecting ongoing synaptic damage, and showed good discriminative characteristics. We therefore propose it as a candidate blood marker for early diagnosis and monitoring of synaptic integrity in prion disease.Classification of EvidenceThis study provides Class III evidence that serum β-synuclein concentration accurately distinguishes patients with symptomatic CJD from controls.
Published: 2022
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46. Comprehensive management of risk factors in peripheral vascular disease. Expert consensus

Author: Pilar Caridad Morata Barrado, Carlos Guijarro Herraiz, Jorge Jesús Martín Cañuelo, J.F. Merino-Torres, Cristina Tejera Pérez, María Ángeles Martínez López, Teresa Rama Martínez, Sergio Cinza-Sanjurjo, Mª Dolores Aicart Bort, C. Brotons, Vicente Pascual Fuster, Emilio Ortega, Tomás Ripoll Vera, Carmen Peinado Adiego, Alberto Cordero, Carlos Jericó Alba, Luis Castilla-Guerra, Francisco Valls-Roca, Pablo Antonio Toledo Frías, Rosa María Sánchez-Hernández, Antonio Pérez Pérez, Ángel Brea Hernando, Juan Girbés Borrás, Miguel Ángel Prieto Díaz, J.M. Mostaza, María Soledad Navas de Solís, Elisa Velasco Valdazo, Estíbaliz Jarauta Simón, Juan Carlos Ferrer García, José Manuel Ruiz Palomar, Francisco M. Morales-Pérez, Julio Sánchez Álvarez, Javier de Juan Bagudá, Núria Muñoz Rivas, Elías Delgado, Manuel Frías Vargas, Ovidio Muñiz Grijalvo, Esther Doiz Artázcoz, Pedro Valdivielso, Adriana Saltijeral Cerezo, Rebeca Reyes García, Manuel Rodríguez Piñero, Beatriz Jiménez Muñoz, Luis Leiva Hernando, Enrique Rodilla Sala, Alfonso Barquilla García, Jose Daniel Mosquera Lozano, Carlos Santos Altozano, Antonio Miguel Hernández Martínez, Alejandro Berenguel Senén, Manuel Gargallo Fernández, María Gloria Cánovas Molina, Julio Antonio Carbayo Herencia, Ignacio Párraga Martínez, Elena Iborra Ortega, Aurora García Lerín, Vicente Ignacio Arrarte Esteban, Vivencio Barrios, Jose Polo García, Manuel Antonio Botana López, Ruth Sánchez Ortiga, Manuel Suárez Tembra, Miguel Brito Banfiel, Ángel Carlos Matía Cubillo, José María Cepeda Rodrigo, Daniel Escribano Pardo, P. Beato, M. Comellas, Inés Gil Gil, R. Campuzano, Martín Ruiz Ortiz, Víctor Rodríguez Sáenz de Buruaga, Agustín Blanco Echevarría, Rosario Lorente Calvo, José Manuel Comas Samper, Sergio Hevia, Natalia de la Fuente, Juan Cosin Sales, Rafael Vidal-Pérez, Virginia Bellido Castañeda, N. Plana, Amelia Carro, Carlos Lahoz, Magdalena León Mazorra, Sergio Martínez Hervas, Maria Seoane Vicente, Melina Vega de Ceniga, M. Antonia Pérez Lázaro, Sergio Jansen Chaparro, Antonio Ruiz García, Isabel Ayala Vigueras, Miren Morillas Bueno, Esther Merino Lanza, Andrés Galarza Tapia, Marta Casañas Martínez, Daiana Ibarretxe Gerediaga, María Durán Martínez, José Antonio Rubio, Óscar Moreno-Pérez, Andrés García León, Luis Estallo Laliena, Eduardo Carrasco Carrasco, Vicente Pallarés-Carratalá, Alberto Zamora Cervantes, Javier Escalada, Juan Carlos Obaya Rebollar, Mercedes Guerra Requena, José Antonio Quindimil Vázquez, Pedro J. Pinés Corrales, Carlos Escobar Cervantes, Lisardo García-Martín, Albert Clarà, Jose María Fernández Rodriguez-Lacin, Miguel Turégano Yedro, Francisco Javier Félix Redondo, Luis Masmiquel, Jacinto Fernández Pardo, Laura Calsina Juscafresa, María Eugenia López Valverde, Eva María Pereira López, Fátima Almagro Múgica, and Agustín Medina Falcón
Subjects: medicine.medical_specialty, Consensus, Vascular disease, business.industry, Arterial disease, Delphi method, Expert consensus, General Medicine, Disease, medicine.disease, Quit smoking, Peripheral Arterial Disease, Risk Factors, Multidisciplinary approach, Diabetes Mellitus, medicine, Humans, Ankle Brachial Index, Medical prescription, Intensive care medicine, business
Abstract: There is currently a degree of divergence among the main clinical practice guidelines on the management of risk factors for peripheral arterial disease (PAD). This project aims to gain understanding of the management of PAD risk factors in clinical practice and to reach a multidisciplinary consensus on the strategies to be followed in order to optimize its identification, treatment, and follow-up.A multidisciplinary consensus following the Delphi methodology.Professionals (n = 130) with extensive experience in PAD participated in this consultation. The results suggest that in order to optimize the control of risk factors, efforts should be aimed at: (1) promoting the involvement and awareness of all specialists in the identification of and screening for the disease; (2) guaranteeing the possibility of evaluating the ankle-brachial index (ABI) in all the medical specialties involved; (3) promoting strategies for patients to quit smoking through the use of drugs, programs, or referrals to specialized units; (4) promoting an appropriate Mediterranean-based diet and the prescription of daily exercise; (5) raising awareness of the importance of ensuring LDL cholesterol values below 70 mg/dL, especially in symptomatic but also in asymptomatic patients (55 mg/dL following the publication of the ESC/EAS guide); (6) recommending the use of antiplatelet therapy in asymptomatic patients with diabetes mellitus (DM) and/or a pathological ABI; and (7) protocolizing the annual evaluation of ABI in high-risk patients.This document presents the 22 agreed-upon strategies which are intended to help professionals optimize multidisciplinary management of PAD risk factors.
Published: 2022
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47. The Vital Role of CHWs During the COVID-19 Pandemic within the South Texas Communities

Author: Pamela Recto, Jose Zapata, Eduardo Gandara, Andrea Moreno-Vasquez, Annette Zavala Idar, Martha Castilla, Ludivina Hernandez, Melissa Flores, Juana Escareno, Cynthia Castillo, Vicky Morales, and Janna Lesser
Subjects: Community Health Workers, Rural Population, COVID-19, Humans, Pshychiatric Mental Health, Pandemics, Texas, Qualitative Research
Published: 2022
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48. Improved post-stroke spontaneous recovery by astrocytic extracellular vesicles

Author: Aura N. Campero-Romero, Nigel H. Greig, Luis Concha, Berenice N. Bernal-Vicente, Augusto Cesar Poot-Hernandez, Ricardo A. Santana-Martínez, Martha L. Escobar, Isaac Ponce, Araceli Martínez-Moreno, Axayacatl Morales-Guadarrama, Esteban Urrieta, Perla Moreno-Castilla, Yessica Heras-Romero, Luis B. Tovar-y-Romo, and Ruth Rincon-Heredia
Subjects: Confocal, Spontaneous recovery, Ischemia, Corpus callosum, Extracellular vesicles, Extracellular Vesicles, Basal (phylogenetics), Drug Discovery, Genetics, medicine, Animals, Humans, In patient, Molecular Biology, Stroke, Pharmacology, medicine.diagnostic_test, Chemistry, Magnetic resonance imaging, Recovery of Function, medicine.disease, Magnetic Resonance Imaging, Axons, Microvesicles, Rats, Disease Models, Animal, Astrocytes, Post stroke, Molecular Medicine, Original Article, Neuroscience
Abstract: Spontaneous recovery after a stroke accounts for a major part of the neurological recovery in patients. However limited, the spontaneous recovery is mechanistically driven by axonal restorative processes for which several molecular cues have been previously described. We report the acceleration of spontaneous recovery in a preclinical model of ischemia/reperfusion in rats via a single intracerebroventricular administration of extracellular vesicles released from primary cortical astrocytes. We used MRI, confocal and multiphoton microscopy to correlate the structural remodeling of the corpus callosum and striatocortical circuits with neurological performance over 21 days. We also evaluated the functionality of the corpus callosum by repetitive recordings of compound action potentials to show that the recovery facilitated by astrocytic extracellular vesicles was both anatomical and functional. Our data provide compelling evidence that astrocytes can hasten the basal recovery that naturally occurs post-stroke through the release of cellular mediators contained in extracellular vesicles.
Published: 2022
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49. Network Meta-Analysis for Single-Case Design Studies: An Illustration

Author: Ana Barbosa Mendes, Laleh Jamshidi, Wim Van den Noortgate, and Belén Fernández-Castilla
Subjects: Health Policy, Network Meta-Analysis, Humans
Abstract: Single-case designs (SCDs) are used to evaluate the effects of interventions on individual participants. By repeatedly measuring participants under different conditions, SCD studies focus on individual effects rather than on group summaries. The main limitation of SCDs remains its generalisability to wider populations, reducing the relevance of their findings for practice and policy making. With this limitation in mind, methodological developments for synthesising SCD data from different studies that investigate the same research question have intensified in the past decades (e.g. multilevel modelling). However, these techniques are restricted to comparing two interventions at a time and can only incorporate evidence from studies that directly compare the two treatments of interest. These limitations could be addressed by using network meta-analysis that incorporates both direct and indirect evidence to simultaneously compare multiple interventions. Despite its potential, network meta-analytical techniques have yet to be applied to SCD data. Thus, in this paper, we argue that network meta-analysis can be a valuable tool to synthesise SCD data. We demonstrate the use of network meta-analysis in SCD data using a real dataset, and we conclude by reflecting on the challenges that SCD researchers might face when applying network meta-analysis methods to their data.
Published: 2022
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50. Probability of high-risk genetic matching with oocyte and semen donors: complete gene analysis or genotyping test?

Author: Marta Molina Romero, Alberto Yoldi Chaure, Miguel Gañán Parra, Purificación Navas Bastida, José Luis del Pico Sánchez, Ángel Vaquero Argüelles, Paloma de la Fuente Vaquero, Juan Pablo Ramírez López, and José Antonio Castilla Alcalá
Subjects: Genotype, Oocyte Donation, Reproductive Medicine, Oocytes, Genetics, Humans, Obstetrics and Gynecology, Genetic Testing, General Medicine, Tissue Donors, Genetics (clinical), Probability, Developmental Biology
Abstract: PURPOSE: To estimate the probability of high-risk genetic matching when assisted reproductive techniques (ART) are applied with double gamete donation, following an NGS carrier test based on a complete study of the genes concerned. We then determine the results that would have been obtained if the genotyping tests most widely used in Spanish gamete banks had been applied. METHODS: In this descriptive observational study, 1818 gamete donors were characterised by NGS. The pathogenic variants detected were analysed to estimate the probability of high-risk genetic matching and to determine the results that would have been obtained if the three most commonly used genotyping tests in ART had been applied. RESULTS: The probability of high-risk genetic matching with gamete donation, screened by NGS and complete gene analysis, was 5.5%, versus the 0.6–2.7% that would have been obtained with the genotyping test. A total of 1741 variants were detected, including 607 different variants, of which only 22.6% would have been detected by all three genotyping tests considered and 44.7% of which would not have been detected by any of these tests. CONCLUSION: Our study highlights the considerable heterogeneity of the genotyping tests, which present significant differences in their ability to detect pathogenic variants. The complete study of the genes by NGS considerably reduces reproductive risks when genetic matching is performed with gamete donors. Accordingly, we recommend that carrier screening in gamete donors be carried out using NGS and a complete study with nontargeted analysis of the variants of the screened genes. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10815-021-02381-0.
Published: 2022
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