Searched for: in-biosketch:true
person:ru269
Prophage-encoded methyltransferase drives adaptation of community-acquired methicillin-resistant Staphylococcus aureus
Ulrich, Robert J; Podkowik, Magdalena; Tierce, Rebecca; Irnov, Irnov; Putzel, Gregory; Samhadaneh, Nora M; Lacey, Keenan A; Boff, Daiane; Morales, Sabrina M; Makita, Sohei; Karagounis, Theodora K; Zwack, Erin E; Zhou, Chunyi; Kim, Randie H; Drlica, Karl; Pironti, Alejandro; van Bakel, Harm; Torres, Victor J; Shopsin, Bo
We recently described the evolution of a community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) USA300 variant responsible for an outbreak of skin and soft tissue infections. Acquisition of a mosaic version of the Φ11 prophage (mΦ11) that increases skin abscess size was an early step in CA-MRSA adaptation that primed the successful spread of the clone. The present report shows how prophage mΦ11 exerts its effect on virulence for skin infection without encoding a known toxin or fitness genes. Abscess size and skin inflammation were associated with DNA methylase activity of an mΦ11-encoded adenine methyltransferase (designated pamA). pamA increased expression of fibronectin-binding protein A (fnbA; FnBPA), and inactivation of fnbA eliminated the effect of pamA on abscess virulence without affecting strains lacking pamA. Thus, fnbA is a pamA-specific virulence factor. Mechanistically, pamA was shown to promote biofilm formation in vivo in skin abscesses, a phenotype linked to FnBPA's role in biofilm formation. Collectively, these data reveal a critical mechanism-epigenetic regulation of staphylococcal gene expression-by which phage can regulate virulence to drive adaptive leaps by S. aureus.
PMID: 40700354
ISSN: 1558-8238
CID: 5901622
Quorum-sensing agr system of Staphylococcus aureus primes gene expression for protection from lethal oxidative stress
Podkowik, Magdalena; Perault, Andrew I; Putzel, Gregory; Pountain, Andrew; Kim, Jisun; DuMont, Ashley L; Zwack, Erin E; Ulrich, Robert J; Karagounis, Theodora K; Zhou, Chunyi; Haag, Andreas F; Shenderovich, Julia; Wasserman, Gregory A; Kwon, Junbeom; Chen, John; Richardson, Anthony R; Weiser, Jeffrey N; Nowosad, Carla R; Lun, Desmond S; Parker, Dane; Pironti, Alejandro; Zhao, Xilin; Drlica, Karl; Yanai, Itai; Torres, Victor J; Shopsin, Bo
The agr quorum-sensing system links Staphylococcus aureus metabolism to virulence, in part by increasing bacterial survival during exposure to lethal concentrations of H2O2, a crucial host defense against S. aureus. We now report that protection by agr surprisingly extends beyond post-exponential growth to the exit from stationary phase when the agr system is no longer turned on. Thus, agr can be considered a constitutive protective factor. Deletion of agr resulted in decreased ATP levels and growth, despite increased rates of respiration or fermentation at appropriate oxygen tensions, suggesting that Δagr cells undergo a shift towards a hyperactive metabolic state in response to diminished metabolic efficiency. As expected from increased respiratory gene expression, reactive oxygen species (ROS) accumulated more in the agr mutant than in wild-type cells, thereby explaining elevated susceptibility of Δagr strains to lethal H2O2 doses. Increased survival of wild-type agr cells during H2O2 exposure required sodA, which detoxifies superoxide. Additionally, pretreatment of S. aureus with respiration-reducing menadione protected Δagr cells from killing by H2O2. Thus, genetic deletion and pharmacologic experiments indicate that agr helps control endogenous ROS, thereby providing resilience against exogenous ROS. The long-lived 'memory' of agr-mediated protection, which is uncoupled from agr activation kinetics, increased hematogenous dissemination to certain tissues during sepsis in ROS-producing, wild-type mice but not ROS-deficient (Cybb
PMID: 38687677
ISSN: 2050-084x
CID: 5729302
Author Correction: Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials
Axfors, Cathrine; Schmitt, Andreas M; Janiaud, Perrine; Van't Hooft, Janneke; Abd-Elsalam, Sherief; Abdo, Ehab F; Abella, Benjamin S; Akram, Javed; Amaravadi, Ravi K; Angus, Derek C; Arabi, Yaseen M; Azhar, Shehnoor; Baden, Lindsey R; Baker, Arthur W; Belkhir, Leila; Benfield, Thomas; Berrevoets, Marvin A H; Chen, Cheng-Pin; Chen, Tsung-Chia; Cheng, Shu-Hsing; Cheng, Chien-Yu; Chung, Wei-Sheng; Cohen, Yehuda Z; Cowan, Lisa N; Dalgard, Olav; de Almeida E Val, Fernando F; de Lacerda, Marcus V G; de Melo, Gisely C; Derde, Lennie; Dubee, Vincent; Elfakir, Anissa; Gordon, Anthony C; Hernandez-Cardenas, Carmen M; Hills, Thomas; Hoepelman, Andy I M; Huang, Yi-Wen; Igau, Bruno; Jin, Ronghua; Jurado-Camacho, Felipe; Khan, Khalid S; Kremsner, Peter G; Kreuels, Benno; Kuo, Cheng-Yu; Le, Thuy; Lin, Yi-Chun; Lin, Wu-Pu; Lin, Tse-Hung; Lyngbakken, Magnus Nakrem; McArthur, Colin; McVerry, Bryan J; Meza-Meneses, Patricia; Monteiro, Wuelton M; Morpeth, Susan C; Mourad, Ahmad; Mulligan, Mark J; Murthy, Srinivas; Naggie, Susanna; Narayanasamy, Shanti; Nichol, Alistair; Novack, Lewis A; O'Brien, Sean M; Okeke, Nwora Lance; Perez, Léna; Perez-Padilla, Rogelio; Perrin, Laurent; Remigio-Luna, Arantxa; Rivera-Martinez, Norma E; Rockhold, Frank W; Rodriguez-Llamazares, Sebastian; Rolfe, Robert; Rosa, Rossana; Røsjø, Helge; Sampaio, Vanderson S; Seto, Todd B; Shahzad, Muhammad; Soliman, Shaimaa; Stout, Jason E; Thirion-Romero, Ireri; Troxel, Andrea B; Tseng, Ting-Yu; Turner, Nicholas A; Ulrich, Robert J; Walsh, Stephen R; Webb, Steve A; Weehuizen, Jesper M; Velinova, Maria; Wong, Hon-Lai; Wrenn, Rebekah; Zampieri, Fernando G; Zhong, Wu; Moher, David; Goodman, Steven N; Ioannidis, John P A; Hemkens, Lars G
PMID: 38316844
ISSN: 2041-1723
CID: 5632832
mRNA COVID-19 vaccine elicits potent adaptive immune response without the acute inflammation of SARS-CoV-2 infection
Ivanova, Ellie N; Shwetar, Jasmine; Devlin, Joseph C; Buus, Terkild B; Gray-Gaillard, Sophie; Koide, Akiko; Cornelius, Amber; Samanovic, Marie I; Herrera, Alberto; Mimitou, Eleni P; Zhang, Chenzhen; Karmacharya, Trishala; Desvignes, Ludovic; Ødum, Niels; Smibert, Peter; Ulrich, Robert J; Mulligan, Mark J; Koide, Shohei; Ruggles, Kelly V; Herati, Ramin S; Koralov, Sergei B
SARS-CoV-2 infection and vaccination elicit potent immune responses. Our study presents a comprehensive multimodal single-cell analysis of blood from COVID-19 patients and healthy volunteers receiving the SARS-CoV-2 vaccine and booster. We profiled immune responses via transcriptional analysis and lymphocyte repertoire reconstruction. COVID-19 patients displayed an enhanced interferon signature and cytotoxic gene upregulation, absent in vaccine recipients. B and T cell repertoire analysis revealed clonal expansion among effector cells in COVID-19 patients and memory cells in vaccine recipients. Furthermore, while clonal αβ T cell responses were observed in both COVID-19 patients and vaccine recipients, expansion of clonal γδ T cells was found only in infected individuals. Our dataset enables side-by-side comparison of immune responses to infection versus vaccination, including clonal B and T cell responses. Our comparative analysis shows that vaccination induces a robust, durable clonal B and T cell responses, without the severe inflammation associated with infection.
PMID: 38213787
ISSN: 2589-0042
CID: 5755392
Discrete immune response signature to SARS-CoV-2 mRNA vaccination versus infection
Ivanova, Ellie N; Devlin, Joseph C; Buus, Terkild B; Koide, Akiko; Cornelius, Amber; Samanovic, Marie I; Herrera, Alberto; Zhang, Chenzhen; Desvignes, Ludovic; Odum, Niels; Ulrich, Robert; Mulligan, Mark J; Koide, Shohei; Ruggles, Kelly V; Herati, Ramin S; Koralov, Sergei B
Both SARS-CoV-2 infection and vaccination elicit potent immune responses. A number of studies have described immune responses to SARS-CoV-2 infection. However, beyond antibody production, immune responses to COVID-19 vaccines remain largely uncharacterized. Here, we performed multimodal single-cell sequencing on peripheral blood of patients with acute COVID-19 and healthy volunteers before and after receiving the SARS-CoV-2 BNT162b2 mRNA vaccine to compare the immune responses elicited by the virus and by this vaccine. Phenotypic and transcriptional profiling of immune cells, coupled with reconstruction of the B and T cell antigen receptor rearrangement of individual lymphocytes, enabled us to characterize and compare the host responses to the virus and to defined viral antigens. While both infection and vaccination induced robust innate and adaptive immune responses, our analysis revealed significant qualitative differences between the two types of immune challenges. In COVID-19 patients, immune responses were characterized by a highly augmented interferon response which was largely absent in vaccine recipients. Increased interferon signaling likely contributed to the observed dramatic upregulation of cytotoxic genes in the peripheral T cells and innate-like lymphocytes in patients but not in immunized subjects. Analysis of B and T cell receptor repertoires revealed that while the majority of clonal B and T cells in COVID-19 patients were effector cells, in vaccine recipients clonally expanded cells were primarily circulating memory cells. Importantly, the divergence in immune subsets engaged, the transcriptional differences in key immune populations, and the differences in maturation of adaptive immune cells revealed by our analysis have far-ranging implications for immunity to this novel pathogen.
PMCID:8077568
PMID: 33907755
ISSN: n/a
CID: 4852132
Limits to Gauge Coupling in the Dark Sector Set by the Nonobservation of Instanton-Induced Decay of Super-Heavy Dark Matter in the Pierre Auger Observatory Data
Abreu, P; Aglietta, M; Albury, J M; Allekotte, I; Almeida Cheminant, K; Almela, A; Aloisio, R; Alvarez-Muñiz, J; Alves Batista, R; Ammerman Yebra, J; Anastasi, G A; Anchordoqui, L; Andrada, B; Andringa, S; Aramo, C; Araújo Ferreira, P R; Arnone, E; Arteaga Velázquez, J C; Asorey, H; Assis, P; Avila, G; Avocone, E; Badescu, A M; Bakalova, A; Balaceanu, A; Barbato, F; Bellido, J A; Berat, C; Bertaina, M E; Bhatta, G; Biermann, P L; Binet, V; Bismark, K; Bister, T; Biteau, J; Blazek, J; Bleve, C; Blümer, J; Boháčová, M; Boncioli, D; Bonifazi, C; Bonneau Arbeletche, L; Borodai, N; Botti, A M; Brack, J; Bretz, T; Brichetto Orchera, P G; Briechle, F L; Buchholz, P; Bueno, A; Buitink, S; Buscemi, M; Büsken, M; Caballero-Mora, K S; Caccianiga, L; Canfora, F; Caracas, I; Caruso, R; Castellina, A; Catalani, F; Cataldi, G; Cazon, L; Cerda, M; Chinellato, J A; Chudoba, J; Chytka, L; Clay, R W; Cobos Cerutti, A C; Colalillo, R; Coleman, A; Coluccia, M R; Conceição, R; Condorelli, A; Consolati, G; Contreras, F; Convenga, F; Correia Dos Santos, D; Covault, C E; Dasso, S; Daumiller, K; Dawson, B R; Day, J A; de Almeida, R M; de Jesús, J; de Jong, S J; de Mello Neto, J R T; De Mitri, I; de Oliveira, J; de Oliveira Franco, D; de Palma, F; de Souza, V; De Vito, E; Del Popolo, A; Del Río, M; Deligny, O; Deval, L; di Matteo, A; Dobre, M; Dobrigkeit, C; D'Olivo, J C; Domingues Mendes, L M; Dos Anjos, R C; Dova, M T; Ebr, J; Engel, R; Epicoco, I; Erdmann, M; Escobar, C O; Etchegoyen, A; Falcke, H; Farmer, J; Farrar, G; Fauth, A C; Fazzini, N; Feldbusch, F; Fenu, F; Fick, B; Figueira, J M; Filipčič, A; Fitoussi, T; Fodran, T; Fujii, T; Fuster, A; Galea, C; Galelli, C; García, B; Garcia Vegas, A L; Gemmeke, H; Gesualdi, F; Gherghel-Lascu, A; Ghia, P L; Giaccari, U; Giammarchi, M; Glombitza, J; Gobbi, F; Gollan, F; Golup, G; Gómez Berisso, M; Gómez Vitale, P F; Gongora, J P; González, J M; González, N; Goos, I; Góra, D; Gorgi, A; Gottowik, M; Grubb, T D; Guarino, F; Guedes, G P; Guido, E; Hahn, S; Hamal, P; Hampel, M R; Hansen, P; Harari, D; Harvey, V M; Haungs, A; Hebbeker, T; Heck, D; Hill, G C; Hojvat, C; Hörandel, J R; Horvath, P; Hrabovský, M; Huege, T; Insolia, A; Isar, P G; Janecek, P; Johnsen, J A; Jurysek, J; Kääpä, A; Kampert, K H; Keilhauer, B; Khakurdikar, A; Kizakke Covilakam, V V; Klages, H O; Kleifges, M; Kleinfeller, J; Knapp, F; Kunka, N; Lago, B L; Langner, N; Leigui de Oliveira, M A; Lenok, V; Letessier-Selvon, A; Lhenry-Yvon, I; Lo Presti, D; Lopes, L; López, R; Lu, L; Luce, Q; Lundquist, J P; Machado Payeras, A; Mancarella, G; Mandat, D; Manning, B C; Manshanden, J; Mantsch, P; Marafico, S; Mariani, F M; Mariazzi, A G; Mariş, I C; Marsella, G; Martello, D; Martinelli, S; Martínez Bravo, O; Mastrodicasa, M; Mathes, H J; Matthews, J; Matthiae, G; Mayotte, E; Mayotte, S; Mazur, P O; Medina-Tanco, G; Melo, D; Menshikov, A; Michal, S; Micheletti, M I; Miramonti, L; Mollerach, S; Montanet, F; Morejon, L; Morello, C; Mostafá, M; Müller, A L; Muller, M A; Mulrey, K; Mussa, R; Muzio, M; Namasaka, W M; Nasr-Esfahani, A; Nellen, L; Nicora, G; Niculescu-Oglinzanu, M; Niechciol, M; Nitz, D; Norwood, I; Nosek, D; Novotny, V; Nožka, L; Nucita, A; Núñez, L A; Oliveira, C; Palatka, M; Pallotta, J; Papenbreer, P; Parente, G; Parra, A; Pawlowsky, J; Pech, M; Pękala, J; Pelayo, R; Peña-Rodriguez, J; Pereira Martins, E E; Perez Armand, J; Pérez Bertolli, C; Perrone, L; Petrera, S; Petrucci, C; Pierog, T; Pimenta, M; Pirronello, V; Platino, M; Pont, B; Pothast, M; Privitera, P; Prouza, M; Puyleart, A; Querchfeld, S; Rautenberg, J; Ravignani, D; Reininghaus, M; Ridky, J; Riehn, F; Risse, M; Rizi, V; Rodrigues de Carvalho, W; Rodriguez Rojo, J; Roncoroni, M J; Rossoni, S; Roth, M; Roulet, E; Rovero, A C; Ruehl, P; Saftoiu, A; Saharan, M; Salamida, F; Salazar, H; Salina, G; Sanabria Gomez, J D; Sánchez, F; Santos, E M; Santos, E; Sarazin, F; Sarmento, R; Sarmiento-Cano, C; Sato, R; Savina, P; Schäfer, C M; Scherini, V; Schieler, H; Schimassek, M; Schimp, M; Schlüter, F; Schmidt, D; Scholten, O; Schoorlemmer, H; Schovánek, P; Schröder, F G; Schulte, J; Schulz, T; Sciutto, S J; Scornavacche, M; Segreto, A; Sehgal, S; Shellard, R C; Sigl, G; Silli, G; Sima, O; Smau, R; Šmída, R; Sommers, P; Soriano, J F; Squartini, R; Stadelmaier, M; Stanca, D; Stanič, S; Stasielak, J; Stassi, P; Streich, A; Suárez-Durán, M; Sudholz, T; Suomijärvi, T; Supanitsky, A D; Szadkowski, Z; Tapia, A; Taricco, C; Timmermans, C; Tkachenko, O; Tobiska, P; Todero Peixoto, C J; Tomé, B; Torrès, Z; Travaini, A; Travnicek, P; Trimarelli, C; Tueros, M; Ulrich, R; Unger, M; Vaclavek, L; Vacula, M; Valdés Galicia, J F; Valore, L; Varela, E; Vásquez-Ramírez, A; Veberič, D; Ventura, C; Vergara Quispe, I D; Verzi, V; Vicha, J; Vink, J; Vorobiov, S; Wahlberg, H; Watanabe, C; Watson, A A; Weindl, A; Wiencke, L; Wilczyński, H; Wittkowski, D; Wundheiler, B; Yushkov, A; Zapparrata, O; Zas, E; Zavrtanik, D; Zavrtanik, M; Zehrer, L; ,
Instantons, which are nonperturbative solutions to Yang-Mills equations, provide a signal for the occurrence of quantum tunneling between distinct classes of vacua. They can give rise to decays of particles otherwise forbidden. Using data collected at the Pierre Auger Observatory, we search for signatures of such instanton-induced processes that would be suggestive of super-heavy particles decaying in the Galactic halo. These particles could have been produced during the post-inflationary epoch and match the relic abundance of dark matter inferred today. The nonobservation of the signatures searched for allows us to derive a bound on the reduced coupling constant of gauge interactions in the dark sector: α_{X}≲0.09, for 10^{9}≲M_{X}/GeV<10^{19}. Conversely, we obtain that, for instance, a reduced coupling constant α_{X}=0.09 excludes masses M_{X}≳3×10^{13} GeV. In the context of dark matter production from gravitational interactions alone, we illustrate how these bounds are complementary to those obtained on the Hubble rate at the end of inflation from the nonobservation of tensor modes in the cosmological microwave background.
PMID: 36827568
ISSN: 1079-7114
CID: 5911432
Hydroxychloroquine/chloroquine for the treatment of hospitalized patients with COVID-19: An individual participant data meta-analysis
Di Stefano, Leon; Ogburn, Elizabeth L; Ram, Malathi; Scharfstein, Daniel O; Li, Tianjing; Khanal, Preeti; Baksh, Sheriza N; McBee, Nichol; Gruber, Joshua; Gildea, Marianne R; Clark, Megan R; Goldenberg, Neil A; Bennani, Yussef; Brown, Samuel M; Buckel, Whitney R; Clement, Meredith E; Mulligan, Mark J; O'Halloran, Jane A; Rauseo, Adriana M; Self, Wesley H; Semler, Matthew W; Seto, Todd; Stout, Jason E; Ulrich, Robert J; Victory, Jennifer; Bierer, Barbara E; Hanley, Daniel F; Freilich, Daniel
BACKGROUND:Results from observational studies and randomized clinical trials (RCTs) have led to the consensus that hydroxychloroquine (HCQ) and chloroquine (CQ) are not effective for COVID-19 prevention or treatment. Pooling individual participant data, including unanalyzed data from trials terminated early, enables more detailed investigation of the efficacy and safety of HCQ/CQ among subgroups of hospitalized patients. METHODS:We searched ClinicalTrials.gov in May and June 2020 for US-based RCTs evaluating HCQ/CQ in hospitalized COVID-19 patients in which the outcomes defined in this study were recorded or could be extrapolated. The primary outcome was a 7-point ordinal scale measured between day 28 and 35 post enrollment; comparisons used proportional odds ratios. Harmonized de-identified data were collected via a common template spreadsheet sent to each principal investigator. The data were analyzed by fitting a prespecified Bayesian ordinal regression model and standardizing the resulting predictions. RESULTS:Eight of 19 trials met eligibility criteria and agreed to participate. Patient-level data were available from 770 participants (412 HCQ/CQ vs 358 control). Baseline characteristics were similar between groups. We did not find evidence of a difference in COVID-19 ordinal scores between days 28 and 35 post-enrollment in the pooled patient population (odds ratio, 0.97; 95% credible interval, 0.76-1.24; higher favors HCQ/CQ), and found no convincing evidence of meaningful treatment effect heterogeneity among prespecified subgroups. Adverse event and serious adverse event rates were numerically higher with HCQ/CQ vs control (0.39 vs 0.29 and 0.13 vs 0.09 per patient, respectively). CONCLUSIONS:The findings of this individual participant data meta-analysis reinforce those of individual RCTs that HCQ/CQ is not efficacious for treatment of COVID-19 in hospitalized patients.
PMCID:9521809
PMID: 36173983
ISSN: 1932-6203
CID: 5334472
Author Correction: Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials
Axfors, Cathrine; Schmitt, Andreas M; Janiaud, Perrine; Van't Hooft, Janneke; Abd-Elsalam, Sherief; Abdo, Ehab F; Abella, Benjamin S; Akram, Javed; Amaravadi, Ravi K; Angus, Derek C; Arabi, Yaseen M; Azhar, Shehnoor; Baden, Lindsey R; Baker, Arthur W; Belkhir, Leila; Benfield, Thomas; Berrevoets, Marvin A H; Chen, Cheng-Pin; Chen, Tsung-Chia; Cheng, Shu-Hsing; Cheng, Chien-Yu; Chung, Wei-Sheng; Cohen, Yehuda Z; Cowan, Lisa N; Dalgard, Olav; de Almeida E Val, Fernando F; de Lacerda, Marcus V G; de Melo, Gisely C; Derde, Lennie; Dubee, Vincent; Elfakir, Anissa; Gordon, Anthony C; Hernandez-Cardenas, Carmen M; Hills, Thomas; Hoepelman, Andy I M; Huang, Yi-Wen; Igau, Bruno; Jin, Ronghua; Jurado-Camacho, Felipe; Khan, Khalid S; Kremsner, Peter G; Kreuels, Benno; Kuo, Cheng-Yu; Le, Thuy; Lin, Yi-Chun; Lin, Wu-Pu; Lin, Tse-Hung; Lyngbakken, Magnus Nakrem; McArthur, Colin; McVerry, Bryan J; Meza-Meneses, Patricia; Monteiro, Wuelton M; Morpeth, Susan C; Mourad, Ahmad; Mulligan, Mark J; Murthy, Srinivas; Naggie, Susanna; Narayanasamy, Shanti; Nichol, Alistair; Novack, Lewis A; O'Brien, Sean M; Okeke, Nwora Lance; Perez, Léna; Perez-Padilla, Rogelio; Perrin, Laurent; Remigio-Luna, Arantxa; Rivera-Martinez, Norma E; Rockhold, Frank W; Rodriguez-Llamazares, Sebastian; Rolfe, Robert; Rosa, Rossana; Røsjø, Helge; Sampaio, Vanderson S; Seto, Todd B; Shahzad, Muhammad; Soliman, Shaimaa; Stout, Jason E; Thirion-Romero, Ireri; Troxel, Andrea B; Tseng, Ting-Yu; Turner, Nicholas A; Ulrich, Robert J; Walsh, Stephen R; Webb, Steve A; Weehuizen, Jesper M; Velinova, Maria; Wong, Hon-Lai; Wrenn, Rebekah; Zampieri, Fernando G; Zhong, Wu; Moher, David; Goodman, Steven N; Ioannidis, John P A; Hemkens, Lars G
PMID: 33990619
ISSN: 2041-1723
CID: 4876372
Measurement of the Fluctuations in the Number of Muons in Extensive Air Showers with the Pierre Auger Observatory
Aab, A; Abreu, P; Aglietta, M; Albury, J M; Allekotte, I; Almela, A; Alvarez-Muñiz, J; Alves Batista, R; Anastasi, G A; Anchordoqui, L; Andrada, B; Andringa, S; Aramo, C; Araújo Ferreira, P R; Asorey, H; Assis, P; Avila, G; Badescu, A M; Bakalova, A; Balaceanu, A; Barbato, F; Barreira Luz, R J; Becker, K H; Bellido, J A; Berat, C; Bertaina, M E; Bertou, X; Biermann, P L; Bister, T; Biteau, J; Blazek, J; Bleve, C; Boháčová, M; Boncioli, D; Bonifazi, C; Bonneau Arbeletche, L; Borodai, N; Botti, A M; Brack, J; Bretz, T; Briechle, F L; Buchholz, P; Bueno, A; Buitink, S; Buscemi, M; Caballero-Mora, K S; Caccianiga, L; Cancio, A; Canfora, F; Caracas, I; Carceller, J M; Caruso, R; Castellina, A; Catalani, F; Cataldi, G; Cazon, L; Cerda, M; Chinellato, J A; Choi, K; Chudoba, J; Chytka, L; Clay, R W; Cobos Cerutti, A C; Colalillo, R; Coleman, A; Coluccia, M R; Conceição, R; Condorelli, A; Consolati, G; Contreras, F; Convenga, F; Covault, C E; Dasso, S; Daumiller, K; Dawson, B R; Day, J A; de Almeida, R M; de Jesús, J; de Jong, S J; De Mauro, G; de Mello Neto, J R T; De Mitri, I; de Oliveira, J; de Oliveira Franco, D; de Souza, V; De Vito, E; Debatin, J; Del Río, M; Deligny, O; Dembinski, H; Dhital, N; Di Matteo, A; Dobrigkeit, C; D'Olivo, J C; Dos Anjos, R C; Dova, M T; Ebr, J; Engel, R; Epicoco, I; Erdmann, M; Escobar, C O; Etchegoyen, A; Falcke, H; Farmer, J; Farrar, G; Fauth, A C; Fazzini, N; Feldbusch, F; Fenu, F; Fick, B; Figueira, J M; Filipčič, A; Fodran, T; Freire, M M; Fujii, T; Fuster, A; Galea, C; Galelli, C; García, B; Garcia Vegas, A L; Gemmeke, H; Gesualdi, F; Gherghel-Lascu, A; Ghia, P L; Giaccari, U; Giammarchi, M; Giller, M; Glombitza, J; Gobbi, F; Gollan, F; Golup, G; Gómez Berisso, M; Gómez Vitale, P F; Gongora, J P; González, N; Goos, I; Góra, D; Gorgi, A; Gottowik, M; Grubb, T D; Guarino, F; Guedes, G P; Guido, E; Hahn, S; Halliday, R; Hampel, M R; Hansen, P; Harari, D; Harvey, V M; Haungs, A; Hebbeker, T; Heck, D; Hill, G C; Hojvat, C; Hörandel, J R; Horvath, P; Hrabovský, M; Huege, T; Hulsman, J; Insolia, A; Isar, P G; Johnsen, J A; Jurysek, J; Kääpä, A; Kampert, K H; Keilhauer, B; Kemp, J; Klages, H O; Kleifges, M; Kleinfeller, J; Köpke, M; Kukec Mezek, G; Lago, B L; LaHurd, D; Lang, R G; Langner, N; Leigui de Oliveira, M A; Lenok, V; Letessier-Selvon, A; Lhenry-Yvon, I; Lo Presti, D; Lopes, L; López, R; Lorek, R; Luce, Q; Lucero, A; Lundquist, J P; Machado Payeras, A; Mancarella, G; Mandat, D; Manning, B C; Manshanden, J; Mantsch, P; Marafico, S; Mariazzi, A G; Mariş, I C; Marsella, G; Martello, D; Martinez, H; Martínez Bravo, O; Mastrodicasa, M; Mathes, H J; Matthews, J; Matthiae, G; Mayotte, E; Mazur, P O; Medina-Tanco, G; Melo, D; Menshikov, A; Merenda, K-D; Michal, S; Micheletti, M I; Miramonti, L; Mollerach, S; Montanet, F; Morello, C; Mostafá, M; Müller, A L; Muller, M A; Mulrey, K; Mussa, R; Muzio, M; Namasaka, W M; Nellen, L; Niculescu-Oglinzanu, M; Niechciol, M; Nitz, D; Nosek, D; Novotny, V; Nožka, L; Nucita, A; Núñez, L A; Palatka, M; Pallotta, J; Papenbreer, P; Parente, G; Parra, A; Pech, M; Pedreira, F; Pȩkala, J; Pelayo, R; Peña-Rodriguez, J; Perez Armand, J; Perlin, M; Perrone, L; Petrera, S; Pierog, T; Pimenta, M; Pirronello, V; Platino, M; Pont, B; Pothast, M; Privitera, P; Prouza, M; Puyleart, A; Querchfeld, S; Rautenberg, J; Ravignani, D; Reininghaus, M; Ridky, J; Riehn, F; Risse, M; Ristori, P; Rizi, V; Rodrigues de Carvalho, W; Rodriguez Rojo, J; Roncoroni, M J; Roth, M; Roulet, E; Rovero, A C; Ruehl, P; Saffi, S J; Saftoiu, A; Salamida, F; Salazar, H; Salina, G; Sanabria Gomez, J D; Sánchez, F; Santos, E M; Santos, E; Sarazin, F; Sarmento, R; Sarmiento-Cano, C; Sato, R; Savina, P; Schäfer, C M; Scherini, V; Schieler, H; Schimassek, M; Schimp, M; Schlüter, F; Schmidt, D; Scholten, O; Schovánek, P; Schröder, F G; Schröder, S; Schulte, J; Sciutto, S J; Scornavacche, M; Shellard, R C; Sigl, G; Silli, G; Sima, O; Šmída, R; Sommers, P; Soriano, J F; Souchard, J; Squartini, R; Stadelmaier, M; Stanca, D; Stanič, S; Stasielak, J; Stassi, P; Streich, A; Suárez-Durán, M; Sudholz, T; Suomijärvi, T; Supanitsky, A D; Šupík, J; Szadkowski, Z; Taboada, A; Tapia, A; Timmermans, C; Tkachenko, O; Tobiska, P; Todero Peixoto, C J; Tomé, B; Torralba Elipe, G; Travaini, A; Travnicek, P; Trimarelli, C; Trini, M; Tueros, M; Ulrich, R; Unger, M; Vaclavek, L; Vacula, M; Valdés Galicia, J F; Valiño, I; Valore, L; Varela, E; Varma K C, V; Vásquez-Ramírez, A; Veberič, D; Ventura, C; Vergara Quispe, I D; Verzi, V; Vicha, J; Vink, J; Vorobiov, S; Wahlberg, H; Watson, A A; Weber, M; Weindl, A; Wiencke, L; Wilczyński, H; Winchen, T; Wirtz, M; Wittkowski, D; Wundheiler, B; Yushkov, A; Zapparrata, O; Zas, E; Zavrtanik, D; Zavrtanik, M; Zehrer, L; Zepeda, A; ,
We present the first measurement of the fluctuations in the number of muons in extensive air showers produced by ultrahigh energy cosmic rays. We find that the measured fluctuations are in good agreement with predictions from air shower simulations. This observation provides new insights into the origin of the previously reported deficit of muons in air shower simulations and constrains models of hadronic interactions at ultrahigh energies. Our measurement is compatible with the muon deficit originating from small deviations in the predictions from hadronic interaction models of particle production that accumulate as the showers develop.
PMID: 33929235
ISSN: 1079-7114
CID: 5911002
Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials
Axfors, Cathrine; Schmitt, Andreas M; Janiaud, Perrine; Van't Hooft, Janneke; Abd-Elsalam, Sherief; Abdo, Ehab F; Abella, Benjamin S; Akram, Javed; Amaravadi, Ravi K; Angus, Derek C; Arabi, Yaseen M; Azhar, Shehnoor; Baden, Lindsey R; Baker, Arthur W; Belkhir, Leila; Benfield, Thomas; Berrevoets, Marvin A H; Chen, Cheng-Pin; Chen, Tsung-Chia; Cheng, Shu-Hsing; Cheng, Chien-Yu; Chung, Wei-Sheng; Cohen, Yehuda Z; Cowan, Lisa N; Dalgard, Olav; de Almeida E Val, Fernando F; de Lacerda, Marcus V G; de Melo, Gisely C; Derde, Lennie; Dubee, Vincent; Elfakir, Anissa; Gordon, Anthony C; Hernandez-Cardenas, Carmen M; Hills, Thomas; Hoepelman, Andy I M; Huang, Yi-Wen; Igau, Bruno; Jin, Ronghua; Jurado-Camacho, Felipe; Khan, Khalid S; Kremsner, Peter G; Kreuels, Benno; Kuo, Cheng-Yu; Le, Thuy; Lin, Yi-Chun; Lin, Wu-Pu; Lin, Tse-Hung; Lyngbakken, Magnus Nakrem; McArthur, Colin; McVerry, Bryan J; Meza-Meneses, Patricia; Monteiro, Wuelton M; Morpeth, Susan C; Mourad, Ahmad; Mulligan, Mark J; Murthy, Srinivas; Naggie, Susanna; Narayanasamy, Shanti; Nichol, Alistair; Novack, Lewis A; O'Brien, Sean M; Okeke, Nwora Lance; Perez, Léna; Perez-Padilla, Rogelio; Perrin, Laurent; Remigio-Luna, Arantxa; Rivera-Martinez, Norma E; Rockhold, Frank W; Rodriguez-Llamazares, Sebastian; Rolfe, Robert; Rosa, Rossana; Røsjø, Helge; Sampaio, Vanderson S; Seto, Todd B; Shehzad, Muhammad; Soliman, Shaimaa; Stout, Jason E; Thirion-Romero, Ireri; Troxel, Andrea B; Tseng, Ting-Yu; Turner, Nicholas A; Ulrich, Robert J; Walsh, Stephen R; Webb, Steve A; Weehuizen, Jesper M; Velinova, Maria; Wong, Hon-Lai; Wrenn, Rebekah; Zampieri, Fernando G; Zhong, Wu; Moher, David; Goodman, Steven N; Ioannidis, John P A; Hemkens, Lars G
Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.
PMID: 33859192
ISSN: 2041-1723
CID: 4846322
