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2. PP01.08 Circulating Genetically Abnormal Cells Predicts Risk of Lung Cancer in Individuals with Indeterminant Pulmonary Nodules

Author

Katchman, B.A., primary, Tahvilian, S., additional, Kuban, J.D., additional, Yankelevitz, D.F., additional, Leventon, D., additional, Henschke, C.I., additional, Zhu, J., additional, Baden, L., additional, Yip, R., additional, Hirsch, F.R., additional, Reed, R., additional, Brown, A., additional, Muldoon, A., additional, Trejo, M., additional, Donovan, M.J., additional, and Pagano, P.C., additional

Published
2023
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14. Identical and Nonidentical Twins: Risk and Factors Involved in Development of Islet Autoimmunity and Type 1 Diabetes

Author

Triolo, T.M., Fouts, A., Pyle, L., Yu, L., Gottlieb, P.A., Steck, A.K., Greenbaum, C.J., Atkinson, M., Baidal, D., Battaglia, M., Becker, D., Bingley, P., Bosi, E., Buckner, J., Clements, M., Colman, P., DiMeglio, L., Gitelman, S., Goland, R., Gottlieb, P., Herold, K., Knip, M., Krischer, J., Lernmark, A., Moore, W., Moran, A., Muir, A., Palmer, J., Peakman, M., Philipson, L., Raskin, P., Redondo, M., Rodriguez, H., Russell, W., Spain, L., Schatz, D.A., Sosenko, J., Wentworth, J., Wherrett, D., Wilson, D., Winter, W., Ziegler, A., Anderson, M., Antinozzi, P., Benoist, C., Blum, J., Bourcier, K., Chase, P., Clare-Salzler, M., Clynes, R., Eisenbarth, G., Fathman, C.G., Grave, G., Hering, B., Insel, R., Kaufman, F., Kay, T., Leschek, E., Mahon, J., Marks, J.B., Nanto-Salonen, K., Nepom, G., Orban, T., Parkman, R., Pescovitz, M., Peyman, J., Pugliese, A., Roep, B., Roncarolo, M., Savage, P., Simell, O., Sherwin, R., Siegelman, M., Skyler, J.S., Steck, A., Thomas, J., Trucco, M., Wagner, J., Krischer, J.P., Rafkin, L., Cowie, C., Foulkes, M., Krause-Steinrauf, H., Lachin, J.M., Malozowski, S., Ridge, J., Zafonte, S.J., Sosenko, J.M., Kenyon, N.S., Santiago, I., Bundy, B., Abbondondolo, M., Adams, T., Amado, D., Asif, I., Boonstra, M., Burroughs, C., Cuthbertson, D., Deemer, M., Eberhard, C., Fiske, S., Ford, J., Garmeson, J., Guillette, H., Geyer, S., Hays, B., Henderson, C., Henry, M., Heyman, K., Hsiao, B., Karges, C., Keaton, N., Kinderman, A., Law, P., Leinbach, A., Liu, S., Lloyd, J., Malloy, J., Maddox, K., Martin, J., Miller, J., Milliot, E., Moore, M., Muller, S., Nguyen, T., O'Donnell, R., Roberts, A., Sadler, K., Stavros, T., Tamura, R., Wood, K., Xu, P., Young, K., Alies, P., Badias, F., Baker, A., Bassi, M., Beam, C., Boulware, D., Bounmananh, L., Bream, S., Freeman, D., Gough, J., Ginem, J., Granger, M., Kieffer, M.H.M., Lane, P., Linton, C., Nallamshetty, L., Oduah, V., Parrimon, Y., Paulus, K., Pilger, J., Ramiro, J., Ritzie, A.L., Sharma, A., Shor, A., Song, X., Terry, A., Weinberger, J., Wootten, M., Harding, P., McDonough, S., Mcgee, P.F., Hess, K.O., Phoebus, D., Quinlan, S., Raiden, E., Batts, E., Buddy, C., Kirpatrick, K., Ramey, M., Shultz, A., Webb, C., Romesco, M., Fradkin, J., Aas, S., Blumberg, E., Beck, G., Brillon, D., Gubitosi-Klug, R., Laffel, L., Vigersky, R., Wallace, D., Braun, J., B. lo, Mitchell, H., Naji, A., Nerup, J., Orchard, T., Steffes, M., Tsiatis, A., Veatch, R., Zinman, B., Loechelt, B., Baden, L., Green, M., Weinberg, A., Marcovina, S., Palmer, J.P., Babu, S., Eisenbarth, G.S., Marks, J., Matheson, D., Gomez, D., McDonald, A., Pena, S., Pietropaolo, M., Shippy, K., Brown, T., Dove, A., Hammond, M., Hefty, D., Klein, J., Kuhns, K., Letlau, M., Lord, S., McCulloch-Olson, M., Miller, L., Odegard, J., Sachter, E., St Marie, M., Stickney, K., VanBuecken, D., Vellek, B., Webber, C., Allen, L., Bollyk, J., Hilderman, N., Ismail, H., Lamola, S., Sanda, S., Vendettuoli, H., Tridgell, D., Monzavi, R., Bock, M., Fisher, L., Halvorson, M., Jeandron, D., Kim, M., Wood, J., Geffner, M., Salazar, C., Cook, S., Freeby, M., Gallagher, M.P., Gandica, R., Greenberg, E., Kurland, A., Pollak, S., Wolk, A., Chan, M., Koplimae, L., Levine, E., Smith, K., Trast, J., Evans-Molina, C., Hufferd, R., Jagielo, B., Kruse, C., Patrick, V., Rigby, M., Spall, M., Swinney, K., Terrell, J., Christner, L., Ford, L., Lynch, S., Menendez, M., Merrill, P., and Pesc

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, Concordance, Twins, Autoimmunity, 030209 endocrinology & metabolism, Type 2 diabetes, Environment, medicine.disease_cause, Islets of Langerhans, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Seroepidemiologic Studies, Diabetes mellitus, Internal medicine, Diseases in Twins, Twins, Dizygotic, Internal Medicine, medicine, Genetic predisposition, Humans, Insulin, Mass Screening, Genetic Predisposition to Disease, 030212 general & internal medicine, Child, Mass screening, Autoantibodies, Advanced and Specialized Nursing, Type 1 diabetes, Glutamate Decarboxylase, business.industry, Siblings, Autoantibody, Twins, Monozygotic, Predicting Diabetes Using Genetic Risk Scores, medicine.disease, Diabetes Mellitus, Type 1, Endocrinology, Child, Preschool, Disease Progression, Female, business
Abstract

OBJECTIVE There are variable reports of risk of concordance for progression to islet autoantibodies and type 1 diabetes in identical twins after one twin is diagnosed. We examined development of positive autoantibodies and type 1 diabetes and the effects of genetic factors and common environment on autoantibody positivity in identical twins, nonidentical twins, and full siblings. RESEARCH DESIGN AND METHODS Subjects from the TrialNet Pathway to Prevention Study (N = 48,026) were screened from 2004 to 2015 for islet autoantibodies (GAD antibody [GADA], insulinoma-associated antigen 2 [IA-2A], and autoantibodies against insulin [IAA]). Of these subjects, 17,226 (157 identical twins, 283 nonidentical twins, and 16,786 full siblings) were followed for autoantibody positivity or type 1 diabetes for a median of 2.1 years. RESULTS At screening, identical twins were more likely to have positive GADA, IA-2A, and IAA than nonidentical twins or full siblings (all P < 0.0001). Younger age, male sex, and genetic factors were significant factors for expression of IA-2A, IAA, one or more positive autoantibodies, and two or more positive autoantibodies (all P ≤ 0.03). Initially autoantibody-positive identical twins had a 69% risk of diabetes by 3 years compared with 1.5% for initially autoantibody-negative identical twins. In nonidentical twins, type 1 diabetes risk by 3 years was 72% for initially multiple autoantibody–positive, 13% for single autoantibody–positive, and 0% for initially autoantibody-negative nonidentical twins. Full siblings had a 3-year type 1 diabetes risk of 47% for multiple autoantibody–positive, 12% for single autoantibody–positive, and 0.5% for initially autoantibody-negative subjects. CONCLUSIONS Risk of type 1 diabetes at 3 years is high for initially multiple and single autoantibody–positive identical twins and multiple autoantibody–positive nonidentical twins. Genetic predisposition, age, and male sex are significant risk factors for development of positive autoantibodies in twins.

Published
2019
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17. Efficacy of the mRNA-1273 SARS-CoV-2 Vaccine at Completion of Blinded Phase.

Author

El Sahly, H. M., Baden, L. R., Essink, B., Doblecki-Lewis, S., Martin, J. M., Anderson, E. J., Campbell, T. B., Clark, J., Jackson, L. A., Fichtenbaum, C. J., Zervos, M., Rankin, B., Eder, F., Feldman, G., Kennelly, C., Han-Conrad, L., Levin, M., Neuzil, K. M., Corey, L., and Gilbert, P.

Abstract

Background: At interim analysis in a phase 3, observer-blinded, placebo-controlled clinical trial, the mRNA-1273 vaccine showed 94.1% efficacy in preventing coronavirus disease 2019 (Covid-19). After emergency use of the vaccine was authorized, the protocol was amended to include an open-label phase. Final analyses of efficacy and safety data from the blinded phase of the trial are reported.Methods: We enrolled volunteers who were at high risk for Covid-19 or its complications; participants were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo, 28 days apart, at 99 centers across the United States. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The data cutoff date was March 26, 2021.Results: The trial enrolled 30,415 participants; 15,209 were assigned to receive the mRNA-1273 vaccine, and 15,206 to receive placebo. More than 96% of participants received both injections, 2.3% had evidence of SARS-CoV-2 infection at baseline, and the median follow-up was 5.3 months in the blinded phase. Vaccine efficacy in preventing Covid-19 illness was 93.2% (95% confidence interval [CI], 91.0 to 94.8), with 55 confirmed cases in the mRNA-1273 group (9.6 per 1000 person-years; 95% CI, 7.2 to 12.5) and 744 in the placebo group (136.6 per 1000 person-years; 95% CI, 127.0 to 146.8). The efficacy in preventing severe disease was 98.2% (95% CI, 92.8 to 99.6), with 2 cases in the mRNA-1273 group and 106 in the placebo group, and the efficacy in preventing asymptomatic infection starting 14 days after the second injection was 63.0% (95% CI, 56.6 to 68.5), with 214 cases in the mRNA-1273 group and 498 in the placebo group. Vaccine efficacy was consistent across ethnic and racial groups, age groups, and participants with coexisting conditions. No safety concerns were identified.Conclusions: The mRNA-1273 vaccine continued to be efficacious in preventing Covid-19 illness and severe disease at more than 5 months, with an acceptable safety profile, and protection against asymptomatic infection was observed. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.). [ABSTRACT FROM AUTHOR]

Published
2021
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18. Autonomy as both challenge and development in clinical education

Author

Fredholm, A., Savin-Baden, Maggi, Henningsohn, L., Silén, C., and M. Savin-Baden, L. Henningsohnc, C. Silén

Subjects
LB2300, business.industry, media_common.quotation_subject, education, Professional development, Open learning, R1, Experiential learning, Education, Narrative inquiry, Health care, Pedagogy, Active learning, Autodidacticism, LB2361, Psychology, business, Autonomy, media_common
Abstract

This study examines autonomy in learning, related to medical and health care students perception of learning and development in clinical education. An understanding of the ways in which students learning and professional development is facilitated by autonomy, and a qualitative different understanding of the concept is vital for future development of learning and teaching strategies in medical and health care education. Self-directed learning and management of the learning process have been, and still are, stressed within health care and medical education, thus paying less interest to internal processes of learning involving responsibility and independence. The aim of the study was to investigate the relationship between autonomy in learning and narratives of personal challenge and development in the context of student experiences in clinical education. The study was undertaken using narrative inquiry. Findings consist of four themes; Dependence of the clinical supervisor, Feelings of ambivalence, Professional becoming and Need for authenticity. Through our analysis of findings we suggest that autonomy should be regarded as something that develops in relation to others and not as a merely individual phenomenon and that an authentic clinical situation enhances students' experiences of autonomy.

Published
2015
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19. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine.

Author

Baden, L. R., Sahly, H. M. El, Essink, B., Kotloff, K., Frey, S., Novak, R., Diemert, D., Spector, S. A., Rouphael, N., Creech, C. B., McGettigan, J., Khetan, S., Segall, N., Solis, J., Brosz, A., Fierro, C., Schwartz, H., Neuzil, K., Corey, L., and Gilbert, P.

Subjects
*COVID-19, *SARS-CoV-2, *DRUG efficacy, *COVID-19 vaccines, *INTRAMUSCULAR injections, *REVERSE genetics, *IMMUNIZATION of children
Abstract

BACKGROUND Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle-encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome corona- virus 2 (SARS-CoV-2), the virus that causes Covid-19. METHODS This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 jug) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2. RESULTS The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person- years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA- 1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; PcO.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient re- actogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups. CONCLUSIONS The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. [ABSTRACT FROM AUTHOR]

Published
2021
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20. Effect of Oral Insulin on Prevention of Diabetes in Relatives of Patients With Type 1 Diabetes A Randomized Clinical Trial

Author

Greenbaum, C., Atkinson, M., Baidal, D., Battaglia, M., Bingley, P., Bosi, E., Buckner, J., Clements, M., Colman, P., DiMeglio, L., Evans-Molina, C., Gitelman, S., Goland, R., Gottlieb, P., Herold, K., Knip, M., Krischer, J., Lernmark, A., Moore, W., Moran, A., Muir, A., Palmer, J., Peakman, M., Philipson, L., Raskin, P., Redondo, M., Rodriguez, H., Russell, W., Spain, L., Schatz, D.A., Sosenko, J., Wherrett, D., Wilson, D., Winter, W., Ziegler, A., Anderson, M., Antinozzi, P., Benoist, C., Blum, J., Bourcier, K., Chase, P., Clare-Salzler, M., Clynes, R., Cowie, C., Eisenbarth, G., Fathman, C.G., Grave, G., Harrison, L., Hering, B., Insel, R., Jordan, S., Kaufman, F., Kay, T., Kenyon, N., Klines, R., Lachin, J., Leschek, E., Mahon, J., Marks, J.B., Monzavi, R., Nanto-Salonen, K., Nepom, G., Orban, T., Parkman, R., Pescovitz, M., Peyman, J., Pugliese, A., Ridge, J., Roep, B., Roncarolo, M., Savage, P., Simell, O., Sherwin, R., Siegelman, M., Skyler, J.S., Thomas, J., Trucco, M., Wagner, J., Greenbaum, C.J., Krischer, J.P., Rafkin, L., Foulkes, M., Krause-Steinrauf, H., Lachin, J.M., Malozowski, S., Zafonte, S.J., Kenyon, N.S., Santiago, I., Bundy, B., Abbondondolo, M., Adams, T., Asif, D.A.I., Boonstra, M., Boulware, D., Burroughs, C., Cuthbertson, D., Eberhard, C., Fiske, S., Ford, J., Garmeson, J., Guillette, H., Geyer, S., Hays, B., Henderson, C., Henry, M., Heyman, K., Hsiao, B., Karges, C., Kinderman, A., Lane, L., Leinbach, A., Liu, S., Lloyd, J., Malloy, J., Maddox, K., Martin, J., Miller, J., Moore, M., Muller, S., Nguyen, T., O'Donnell, R., Parker, M., Pereyra, M.J., Reed, N., Roberts, A., Sadler, K., Stavros, T., Tamura, R., Wood, K., Xu, P., Young, K., Alies, P., Badias, F., Baker, A., Bassi, M., Beam, C., Bounmananh, L., Bream, S., Deemer, M., Freeman, D., Gough, J., Ginem, J., Granger, M., Holloway, M., Kieffer, M., Lane, P., Law, P., Linton, C., Nallamshetty, L., Oduah, V., Parrimon, Y., Paulus, K., Pilger, J., Ramiro, J., Ritzie, A.Q.L., Sharma, A., Shor, A., Song, X.H., Terry, A., Weinberger, J., Wootten, M., Harding, M.F.P., McDonough, S., Mcgee, P.F., Hess, K.O., Phoebus, D., Quinlan, S., Raiden, E., Fradkin, J., Beck, G., Blumberg, E., Gubitosi-Klug, R., Laffel, L., Veatch, R., Wallace, D., Braun, J., Brillon, D., B. lo, Mitchell, H., Naji, A., Nerup, J., Orchard, T., Steffes, M., Tsiatis, A., Zinman, B., Loechelt, B., Baden, L., Green, M., Weinberg, A., Marcovina, S., Palmer, J.P., Yu, L.P., Shultz, A., Batts, E., Fitzpatrick, K., Ramey, M., Guerra, R., Webb, C., Caffey, F., Carr, L., Ergun-Longmire, B., Fenton, C., Giebner, D., Johnson, J., Maglionico, D., Marinelli, M., Martin, K., Minnozzi, E., Riley, W., Wilson, M., Gougeon, C., Ho, J., Huang, C., Pacaud, D., Virtanen, H., Craig, C., Ghatak, A., Henderson, T., Leyland, H., Padmore, K., Paul, P., Brickman, W., Halsey-Lyda, M., Petrie, P., Rizzo, D., Steuer, R., Suchyta, K., Torchen, L., Zimmerman, D., Bode, B., Dial, M., Gazaway, K., Hosey, R., Alkanani, A., Barker, J., Barr, M., Blau, A., Burdick, P., Burke, B., Chase, H., Drye, M., Escobar, E., Fitzgerald-Miller, L., Fouts, A., Gage, V., Gall, E., Goettle, H., Harris, S., Ketchum, K., King, M., Klingensmith, G., Lehr, D., Lehr, J., Lewis, L., Logsden-Sackett, N., Lykens, J., Maahs, D., Michels, A., Pelletier, S., Rihanek, M., Rodriguez, P., Schauwecker, A., Simmons, K., Smith, J., Steck, A., Tran, B., Tran, T., Wadwa, P., Wagner, R., Wright, H., Betancourt, J., Bui, V., DeSalvo, D., Gomez, D., Jake, K., Lynds, J., McCartney, T., McDonald, A., Pena, S., Pietropaolo, M., Greenbaum, C., Atkinson, M., Baidal, D., Battaglia, M., Becker, D., Bingley, P., Bosi, E., Buckner, J., Clements, M., Colman, P., Dimeglio, L., Evans-Molina, C., Gitelman, S., Goland, R., Gottlieb, P., Herold, K., Knip, M., Krischer, J., Lernmark, A., Moore, W., Moran, A., Muir, A., Palmer, J., Peakman, M., Philipson, L., Raskin, P., Redondo, M., Rodriguez, H., Russell, W., Spain, L., Schatz, D. A., Sosenko, J., Wherrett, D., Wilson, D., Winter, W., and Ziegler, A.

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Adolescent, medicine.medical_treatment, Administration, Oral, 030209 endocrinology & metabolism, Placebo, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Interquartile range, law, Internal medicine, Diabetes mellitus, medicine, Humans, Hypoglycemic Agents, Insulin, Family, Treatment Failure, Child, Original Investigation, Autoantibodies, Type 1 diabetes, Glucose tolerance test, medicine.diagnostic_test, business.industry, General Medicine, ta3121, Glucose Tolerance Test, medicine.disease, 030104 developmental biology, Diabetes Mellitus, Type 1, Child, Preschool, Cohort, Female, business, Follow-Up Studies
Abstract

Importance Type 1 diabetes requires major lifestyle changes and carries increased morbidity and mortality. Prevention or delay of diabetes would have major clinical effect. Objective To determine whether oral insulin delays onset of type 1 diabetes in autoantibody-positive relatives of patients with type 1 diabetes. Design, Setting, and Participants Between March 2, 2007, and December 21, 2015, relatives with at least 2 autoantibodies, including insulin autoantibodies and normal glucose tolerance, were enrolled in Canada, the United States, Australia, New Zealand, the United Kingdom, Italy, Sweden, Finland, and Germany. The main study group (n = 389) had first-phase insulin release on an intravenous glucose tolerance test that was higher than the threshold. The 55 patients in the secondary stratum 1 had an identical antibody profile as the main study group except they had first-phase insulin release that was lower than the threshold. Secondary strata 2 (n = 114) and strata 3 (n = 3) had different autoantibody profiles and first-phase insulin release threshold combinations. Follow-up continued through December 31, 2016. Interventions Randomization to receive 7.5 mg/d of oral insulin (n = 283) or placebo (n = 277), including participants in the main study group who received oral insulin (n = 203) or placebo (n = 186). Main Outcome and Measures The primary outcome was time to diabetes in the main study group. Significance was based on a 1-sided threshold of .05, and 1-sided 95% CIs are reported. Results Of a total of 560 randomized participants (median enrollment age, 8.2 years; interquartile range [IQR], 5.7-12.1 years; 170 boys [60%]; 90.7% white non-Hispanic; 57.6% with a sibling with type 1 diabetes), 550 completed the trial including 389 participants (median age, 8.4 years; 245 boys [63%]), 382 (96%) in the main study group. During a median follow-up of 2.7 years (IQR, 1.5-4.6 years) in the main study group, diabetes was diagnosed in 58 participants (28.5%) in the oral insulin group and 62 (33%) in the placebo group. Time to diabetes was not significantly different between the 2 groups (hazard ratio [HR], 0.87; 95% CI, 0-1.2;P = .21). In secondary stratum 1 (n = 55), diabetes was diagnosed in 13 participants (48.1%) in the oral insulin group and in 19 participants (70.3%) in the placebo group. The time to diabetes was significantly longer with oral insulin (HR, 0.45; 95% CI, 0-0.82;P = .006). The HR for time to diabetes for the between-group comparisons for the 116 participants in the other secondary stratum was 1.03 (95% CI, 0-2.11;P = .53) and for the entire cohort of 560 participants was 0.83 (95% CI, 0-1.07;P = .11), which were not significantly different. The most common adverse event was infection (n = 254), with 134 events in the oral insulin group and 120 events in the placebo group, but no significant study-related adverse events occurred. Conclusions and Relevance Among autoantibody-positive relatives of patients with type 1 diabetes, oral insulin at a dose of 7.5 mg/d, compared with placebo, did not delay or prevent the development of type 1 diabetes over 2.7 years. These findings do not support oral insulin as used in this study for diabetes prevention. Trial Registration clinicaltrials.gov Identifier:NCT00419562

Published
2017

22. Antigen-Specific Antibody Glycosylation Is Regulated via Vaccination

Author

Trkola, A, Mahan, AE, Jennewein, MF, Suscovich, T, Dionne, K, Tedesco, J, Chung, AW, Streeck, H, Pau, M, Schuitemaker, H, Francis, D, Fast, P, Laufer, D, Walker, BD, Baden, L, Barouch, DH, Alter, G, Trkola, A, Mahan, AE, Jennewein, MF, Suscovich, T, Dionne, K, Tedesco, J, Chung, AW, Streeck, H, Pau, M, Schuitemaker, H, Francis, D, Fast, P, Laufer, D, Walker, BD, Baden, L, Barouch, DH, and Alter, G

Abstract

Antibody effector functions, such as antibody-dependent cellular cytotoxicity, complement deposition, and antibody-dependent phagocytosis, play a critical role in immunity against multiple pathogens, particularly in the absence of neutralizing activity. Two modifications to the IgG constant domain (Fc domain) regulate antibody functionality: changes in antibody subclass and changes in a single N-linked glycan located in the CH2 domain of the IgG Fc. Together, these modifications provide a specific set of instructions to the innate immune system to direct the elimination of antibody-bound antigens. While it is clear that subclass selection is actively regulated during the course of natural infection, it is unclear whether antibody glycosylation can be tuned, in a signal-specific or pathogen-specific manner. Here, we show that antibody glycosylation is determined in an antigen- and pathogen-specific manner during HIV infection. Moreover, while dramatic differences exist in bulk IgG glycosylation among individuals in distinct geographical locations, immunization is able to overcome these differences and elicit antigen-specific antibodies with similar antibody glycosylation patterns. Additionally, distinct vaccine regimens induced different antigen-specific IgG glycosylation profiles, suggesting that antibody glycosylation is not only programmable but can be manipulated via the delivery of distinct inflammatory signals during B cell priming. These data strongly suggest that the immune system naturally drives antibody glycosylation in an antigen-specific manner and highlights a promising means by which next-generation therapeutics and vaccines can harness the antiviral activity of the innate immune system via directed alterations in antibody glycosylation in vivo. .

Published
2016

23. Correction: Antigen-Specific Antibody Glycosylation Is Regulated via Vaccination.

Author

Mahan, AE, Jennewein, MF, Suscovich, T, Dionne, K, Tedesco, J, Chung, AW, Streeck, H, Pau, M, Schuitemaker, H, Francis, D, Fast, P, Laufer, D, Walker, BD, Baden, L, Barouch, DH, Alter, G, Mahan, AE, Jennewein, MF, Suscovich, T, Dionne, K, Tedesco, J, Chung, AW, Streeck, H, Pau, M, Schuitemaker, H, Francis, D, Fast, P, Laufer, D, Walker, BD, Baden, L, Barouch, DH, and Alter, G

Abstract

[This corrects the article DOI: 10.1371/journal.ppat.1005456.].

Published
2016

25. Improved detection of invasive pulmonary aspergillosis arising during leukemia treatment using a panel of host response proteins and fungal antigens

Author

Brasier, AR, Zhao, Y, Spratt, HM, Wiktorowicz, JE, Ju, H, Wheat, LJ, Baden, L, Stafford, S, Wu, Z, Issa, N, Caliendo, AM, Denning, DW, Soman, K, Clancy, CJ, Nguyen, MH, Sugrue, MW, Alexander, BD, Wingard, JR, Brasier, AR, Zhao, Y, Spratt, HM, Wiktorowicz, JE, Ju, H, Wheat, LJ, Baden, L, Stafford, S, Wu, Z, Issa, N, Caliendo, AM, Denning, DW, Soman, K, Clancy, CJ, Nguyen, MH, Sugrue, MW, Alexander, BD, and Wingard, JR

Abstract

Invasive pulmonary aspergillosis (IPA) is an opportunistic fungal infection in patients undergoing chemotherapy for hematological malignancy, hematopoietic stem cell transplant, or other forms of immunosuppression. In this group, Aspergillus infections account for the majority of deaths due to mold pathogens. Although early detection is associated with improved outcomes, current diagnostic regimens lack sensitivity and specificity. Patients undergoing chemotherapy, stem cell transplantation and lung transplantation were enrolled in a multi-site prospective observational trial. Proven and probable IPA cases and matched controls were subjected to discovery proteomics analyses using a biofluid analysis platform, fractionating plasma into reproducible protein and peptide pools. From 556 spots identified by 2D gel electrophoresis, 66 differentially expressed post-translationally modified plasma proteins were identified in the leukemic subgroup only. This protein group was rich in complement components, acute-phase reactants and coagulation factors. Low molecular weight peptides corresponding to abundant plasma proteins were identified. A candidate marker panel of host response (9 plasma proteins, 4 peptides), fungal polysaccharides (galactomannan), and cell wall components (β-D glucan) were selected by statistical filtering for patients with leukemia as a primary underlying diagnosis. Quantitative measurements were developed to qualify the differential expression of the candidate host response proteins using selective reaction monitoring mass spectrometry assays, and then applied to a separate cohort of 57 patients with leukemia. In this verification cohort, a machine learning ensemble-based algorithm, generalized pathseeker (GPS) produced a greater case classification accuracy than galactomannan (GM) or host proteins alone. In conclusion, Integration of host response proteins with GM improves the diagnostic detection of probable IPA in patients undergoing treatment for

Published
2015

45. The relationship of the U wave to the 10-year incidence of myocardial infarction.

Author

Sparrow, D, Weiss, S T, Thomas, H E, Rosner, B, and Baden, L

Abstract

The relationship between the baseline electrocardiogram and 10-year incidence of myocardial infarction was examined in a cohort of 1013 men. The men were participants in the Normative Aging Study, a longitudinal study of aging initiated in 1963 at the Veterans Administration Outpatient Clinic in Boston, Massachusetts. Absence of the U wave among these men yielded a relative risk estimate of myocardial infarction of 2.7 as compared to men with a U wave present (95% confidence interval, 1.4-5.2). This association persisted when standard coronary risk factors (cholesterol, blood pressure, and cigarette smoking) were taken into consideration in a multivariate analysis. The results support the conclusion that an abnormality in the electrocardiogram considered to be of little importance indicates an increased risk of myocardial infarction independent of known coronary risk factors.

Published
1983
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