319 results on '"Raphael, Simon"'
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2. Interlaboratory comparison of a multiplex immunoassay that measures human serum IgG antibodies against six-group B streptococcus polysaccharides
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Kirsty Le Doare, Michelle A. Gaylord, Annaliesa S. Anderson, Nick Andrews, Carol J. Baker, Shanna Bolcen, Arif Felek, Peter C. Giardina, Christopher D. Grube, Tom Hall, Bassam Hallis, Alane Izu, Shabir A. Madhi, Pete Maniatis, Mary Matheson, Fatme Mawas, Andrew McKeen, Julia Rhodes, Bailey Alston, Palak Patel, Stephanie Schrag, Raphael Simon, Charles Y. Tan, Stephen Taylor, Gaurav Kwatra, and Andrew Gorringe
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Group B streptococcus ,maternal ,neonatal ,correlate of protection ,vaccines ,Immunologic diseases. Allergy ,RC581-607 ,Therapeutics. Pharmacology ,RM1-950 - Abstract
ABSTRACTMeasurement of IgG antibodies against group B streptococcus (GBS) capsular polysaccharide (CPS) by use of a standardized and internationally accepted multiplex immunoassay is important for the evaluation of candidate maternal GBS vaccines in order to compare results across studies. A standardized assay is also required if serocorrelates of protection against invasive GBS disease are to be established in infant sera for the six predominant GBS serotypes since it would permit the comparison of results across the six serotypes. We undertook an interlaboratory study across five laboratories that used standardized assay reagents and protocols with a panel of 44 human sera to measure IgG antibodies against GBS CPS serotypes Ia, Ib, II, III, IV, and V. The within-laboratory intermediate precision, which included factors like the lot of coated beads, laboratory analyst, and day, was generally below 20% relative standard deviation (RSD) for all six serotypes, across all five laboratories. The cross-laboratory reproducibility was
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- 2024
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3. Preclinical validation of an Escherichia coli O-antigen glycoconjugate for the prevention of serotype O1 invasive disease
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Laurent Chorro, Duston Ndreu, Axay Patel, Srinivas Kodali, Zhenghui Li, David Keeney, Kaushik Dutta, Aniruddha Sasmal, Arthur Illenberger, C. Lynn Torres, Rosalind Pan, Natalie C. Silmon de Monerri, Ling Chu, Raphael Simon, Annaliesa S. Anderson, and Robert G. K. Donald
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O-antigen ,Escherichia coli ,glycoconjugate vaccine ,K1 capsule ,Microbiology ,QR1-502 - Abstract
ABSTRACT A US collection of invasive Escherichia coli serotype O1 bloodstream infection (BSI) isolates were assessed for genotypic and phenotypic diversity as the basis for designing a broadly protective O-antigen vaccine. Eighty percent of the BSI isolate serotype O1 strains were genotypically ST95 O1:K1:H7. The carbohydrate repeat unit structure of the O1a subtype was conserved in the three strains tested representing core genome multi-locus sequence types (MLST) sequence types ST95, ST38, and ST59. A long-chain O1a CRM197 lattice glycoconjugate antigen was generated using oxidized polysaccharide and reductive amination chemistry. Two ST95 strains were investigated for use in opsonophagocytic assays (OPA) with immune sera from vaccinated animals and in murine lethal challenge models. Both strains were susceptible to OPA killing with O1a glycoconjugate post-immune sera. One of these, a neonatal sepsis strain, was found to be highly lethal in the murine challenge model for which virulence was shown to be dependent on the presence of the K1 capsule. Mice immunized with the O1a glycoconjugate were protected from challenges with this strain or a second, genotypically related, and similarly virulent neonatal isolate. This long-chain O1a CRM197 lattice glycoconjugate shows promise as a component of a multi-valent vaccine to prevent invasive E. coli infections.IMPORTANCEThe Escherichia coli serotype O1 O-antigen serogroup is a common cause of invasive bloodstream infections (BSI) in populations at risk such as newborns and the elderly. Sequencing of US BSI isolates and structural analysis of O polysaccharide antigens purified from strains that are representative of genotypic sub-groups confirmed the relevance of the O1a subtype as a vaccine antigen. O polysaccharide was purified from a strain engineered to produce long-chain O1a O-antigen and was chemically conjugated to CRM197 carrier protein. The resulting glycoconjugate elicited functional antibodies and was protective in mice against lethal challenges with virulent K1-encapsulated O1a isolates.
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- 2024
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4. Fit-for-Purpose Ki-67 Immunohistochemistry Assays for Breast Cancer
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Torlakovic, Emina E., Baniak, Nick, Barnes, Penny J., Chancey, Keith, Chen, Liam, Cheung, Carol, Clairefond, Sylvie, Cutz, Jean-Claude, Faragalla, Hala, Gravel, Denis H., Dakin Hache, Kelly, Iyengar, Pratibha, Komel, Michael, Kos, Zuzana, Lacroix-Triki, Magali, Marolt, Monna J., Mrkonjic, Miralem, Mulligan, Anna Marie, Nofech-Mozes, Sharon, Park, Paul C., Plotkin, Anna, Raphael, Simon, Rees, Henrike, Seno, H Rommel, Thai, Duc-Vinh, Troxell, Megan L., Varma, Sonal, Wang, Gang, Wang, Tao, Wehrli, Bret, and Bigras, Gilbert
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- 2024
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5. Calibration of a serum reference standard for Group B streptococcal polysaccharide conjugate vaccine development using surface plasmon resonance
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Alexandre Esadze, Christopher D. Grube, Sabine Wellnitz, Suddham Singh, Ha H. Nguyen, Michelle A. Gaylord, Aiping Zhu, Alexey Gribenko, Charles Y. Tan, Annaliesa S. Anderson, and Raphael Simon
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Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Group B streptococcus (GBS) is a leading cause of neonatal morbidity and mortality worldwide. Development of a maternal vaccine to protect newborns through placentally transferred antibody is considered feasible based on the well-established relationship between anti-GBS capsular polysaccharide (CPS) IgG levels at birth and reduced risk of neonatal invasive GBS. An accurately calibrated serum reference standard that can be used to measure anti-CPS concentrations is critical for estimation of protective antibody levels across serotypes and potential vaccine performance. For this, precise weight-based measurement of anti-CPS IgG in sera is required. Here, we report an improved approach for determining serum anti-CPS IgG levels using surface plasmon resonance with monoclonal antibody standards, coupled with a direct Luminex-based immunoassay. This technique was used to quantify serotype-specific anti-CPS IgG levels in a human serum reference pool derived from subjects immunized with an investigational six-valent GBS glycoconjugate vaccine.
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- 2023
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6. Systematic Review and Meta-analysis of Lyme Disease Data and Seropositivity for Borrelia burgdorferi, China, 2005‒2020
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James H. Stark, Xiuyan Li, Ji Chun Zhang, Leah Burn, Srinivas R. Valluri, Jiaxin Liang, Kaijie Pan, Mark A. Fletcher, Raphael Simon, Luis Jodar, and Bradford D. Gessner
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Lyme disease ,Borrelia burgdorferi ,tick-borne diseases ,vector-borne infections ,epidemiology ,seroepidemiologic studies ,Medicine ,Infectious and parasitic diseases ,RC109-216 - Abstract
Since its initial identification in 1986, Lyme disease has been clinically diagnosed in 29 provinces in China; however, national incidence data are lacking. To summarize Lyme disease seropositivity data among persons across China, we conducted a systematic literature review of Chinese- and English-language journal articles published during 2005‒2020. According to 72 estimates that measured IgG by using a diagnostic enzyme-linked assay (EIA) alone, the seropositivity point prevalence with a fixed-effects model was 9.1%. A more conservative 2-tier testing approach of EIA plus a confirmatory Western immunoblot (16 estimates) yielded seropositivity 1.8%. Seropositivity by EIA for high-risk exposure populations was 10.0% and for low-risk exposure populations was 4.5%; seropositivity was highest in the northeastern and western provinces. Our analysis confirms Lyme disease prevalence, measured by seropositivity, in many Chinese provinces and populations at risk. This information can be used to focus prevention measures in provinces where seropositivity is high.
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- 2022
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7. A bibliometric analysis of orthogeriatric care: top 50 articles
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Bastian, Johannes Dominik, Meier, Malin Kristin, Ernst, Raphael Simon, Gieger, Jochen, and Stuck, Andreas Ernst
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- 2022
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8. Complementary measurement of nontyphoidal Salmonella-specific IgG and IgA antibodies in oral fluid and serum
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Sean C. Elias, Esther Muthumbi, Alfred Mwanzu, Perpetual Wanjiku, Agnes Mutiso, Raphael Simon, and Calman A. MacLennan
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Nontyphoidal ,Oral fluid ,IgG ,IgA ,O-Antigen ,Flagellin ,Science (General) ,Q1-390 ,Social sciences (General) ,H1-99 - Abstract
Objectives: Immuno-epidemiological studies of orally acquired, enteric pathogens such as nontyphoidal Salmonella (NTS) often focus on serological measures of immunity, ignoring potentially relevant oral mucosal responses. In this study we sought to assess the levels and detectability of both oral fluid and serum IgG and IgA to NTS antigens, in endemic and non-endemic populations. Methods: IgG and IgA antibodies specific for Salmonella Typhimurium and Salmonella Enteritidis O antigen and phase 1 flagellin were assessed using Enzyme Linked Immunosorbent Assay (ELISA). Paired oral fluid and serum samples were collected from groups of 50 UK adults, Kenyan adults and Kenyan infants. Additionally, oral fluid alone was collected from 304 Kenyan individuals across a range of ages. Results: Antigen-specific IgG and IgA was detectable in the oral fluid of both adults and infants. Oral fluid antibody increased with age, peaking in adulthood for both IgG and IgA but a separate peak was also observed for IgA in infants. Oral fluid and serum responses correlated for IgG but not IgA. Despite standardised collection the relationship between oral fluid volume and antibody levels varied with age and country of origin. Conclusions: Measurement of NTS-specific oral fluid antibody can be used to complement measurement of serum antibody. For IgA in particular, oral fluid may offer insights into how protective immunity to NTS changes as individuals transition with age, from maternal to acquired systemic and mucosal immunity. This may prove useful in helping to guide future vaccine design.
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- 2023
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9. The relationship of weather with daily physical activity and the time spent out of home in older adults from Germany – the ActiFE study
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Klimek, Matthias, Peter, Raphael Simon, Denkinger, Michael, Dallmeier, Dhayana, Rapp, Kilian, Rothenbacher, Dietrich, and Klenk, Jochen
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- 2022
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10. Distribution of serotypes and antibiotic resistance of invasive Pseudomonas aeruginosa in a multi-country collection
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Shamima Nasrin, Nicolas Hegerle, Shaichi Sen, Joseph Nkeze, Sunil Sen, Jasnehta Permala-Booth, Myeongjin Choi, James Sinclair, Milagritos D. Tapia, J. Kristie Johnson, Samba O. Sow, Joshua T. Thaden, Vance G. Fowler, Karen A. Krogfelt, Annelie Brauner, Efthymia Protonotariou, Eirini Christaki, Yuichiro Shindo, Andrea L. Kwa, Sadia Shakoor, Ashika Singh-Moodley, Olga Perovic, Jan Jacobs, Octavie Lunguya, Raphael Simon, Alan S. Cross, and Sharon M. Tennant
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Pseudomonas ,Serotype ,Flagellin ,Multidrug resistance ,Microbiology ,QR1-502 - Abstract
Abstract Background Pseudomonas aeruginosa is an opportunistic pathogen that causes a wide range of acute and chronic infections and is frequently associated with healthcare-associated infections. Because of its ability to rapidly acquire resistance to antibiotics, P. aeruginosa infections are difficult to treat. Alternative strategies, such as a vaccine, are needed to prevent infections. We collected a total of 413 P. aeruginosa isolates from the blood and cerebrospinal fluid of patients from 10 countries located on 4 continents during 2005–2017 and characterized these isolates to inform vaccine development efforts. We determined the diversity and distribution of O antigen and flagellin types and antibiotic susceptibility of the invasive P. aeruginosa. We used an antibody-based agglutination assay and PCR for O antigen typing and PCR for flagellin typing. We determined antibiotic susceptibility using the Kirby-Bauer disk diffusion method. Results Of the 413 isolates, 314 (95%) were typed by an antibody-based agglutination assay or PCR (n = 99). Among the 20 serotypes of P. aeruginosa, the most common serotypes were O1, O2, O3, O4, O5, O6, O8, O9, O10 and O11; a vaccine that targets these 10 serotypes would confer protection against more than 80% of invasive P. aeruginosa infections. The most common flagellin type among 386 isolates was FlaB (41%). Resistance to aztreonam (56%) was most common, followed by levofloxacin (42%). We also found that 22% of strains were non-susceptible to meropenem and piperacillin-tazobactam. Ninety-nine (27%) of our collected isolates were resistant to multiple antibiotics. Isolates with FlaA2 flagellin were more commonly multidrug resistant (p = 0.04). Conclusions Vaccines targeting common O antigens and two flagellin antigens, FlaB and FlaA2, would offer an excellent strategy to prevent P. aeruginosa invasive infections.
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- 2022
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11. Effect of Secular Trend, Age, and Length of Follow-up on Optimum Body Mass Index From 1985 Through 2015 in a Large Austrian Cohort
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Raphael Simon Peter, Bernhard Föger, Hans Concin, and Gabriele Nagel
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bmi ,mortality ,age ,secular trend ,length of follow-up ,Medicine (General) ,R5-920 - Abstract
Background: Obesity and its health consequences will dominate health care systems in many countries during the next decades. However, the body mass index (BMI) optimum in relation to all-cause mortality is still a matter of debate. Material and Methods: Data of the Vorarlberg Health Monitoring & Prevention Program (VHM&PP, 1985–2005) and data provided by the Main Association of Austrian Social Security Institutions (MAASSI, 2005–2015) were analyzed. Information was available on age, sex, smoking status, measured height and weight, and mortality. Generalized additive models were used to model mortality as a function of BMI, calendar time, age, and follow-up. Results: In MAASSI (N = 282,216, 46.0% men), men and women were on average 2.7 years older than in VHM&PP (N = 185,361, 46.1% men). Average BMI was slightly higher in men (26.1 vs 25.7 kg/m2) but not in women (24.6 vs 24.7 kg/m2). We found an interactive effect of age and follow-up on the BMI optimum. Over age 35 years in men and 55 years in women, the BMI optimum decreased with length of follow-up. While keeping covariates fixed, BMI optimum increased slightly between 1985 and 2015 in men and women, 24.9 (95% CI, 23.9–25.9) to 26.4 (95% CI, 25.3–27.3), and 22.4 (95% CI, 21.7–23.1) to 23.3 (95% CI, 22.6–24.5) kg/m2, respectively. Conclusion: Age and length of follow-up have a pronounced effect on the BMI associated with the lowest all-cause mortality. After controlling for age and length of follow-up, the BMI optimum increased slightly over 30 years in this large study sample.
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- 2021
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12. Comparison of wait times across the breast cancer treatment pathway among screened women undergoing organized breast assessment versus usual care
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Blackmore, Kristina M., Weerasinghe, Ashini, Holloway, Claire M. B., Majpruz, Vicky, Mirea, Lucia, O’Malley, Frances P., Harris, Cathy Paroschy, Hendry, Ashley, Hey, Amanda, Kornecki, Anat, Lougheed, George, Maier, Barbara-Anne, Marchand, Patricia, McCready, David, Rand, Carol, Raphael, Simon, Segal-Nadler, Roanne, Sehgal, Neelu, Muradali, Derek, and Chiarelli, Anna M.
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- 2019
13. Advances towards licensure of a maternal vaccine for the prevention of invasive group B streptococcus disease in infants: a discussion of different approaches
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Judith Absalon, Raphael Simon, David Radley, Peter C. Giardina, Kenneth Koury, Kathrin U. Jansen, and Annaliesa S. Anderson
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gbs ,invasive disease ,infants ,iap ,capsular polysaccharide ,conjugate vaccine ,maternal immunization ,serocorrelate ,Immunologic diseases. Allergy ,RC581-607 ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Group B streptococcus (Streptococcus agalactiae, GBS) is an important cause of life-threatening disease in newborns. Pregnant women colonized with GBS can transmit the bacteria to the developing fetus, as well as to their neonates during or after delivery where infection can lead to sepsis, meningitis, pneumonia, or/and death. While intrapartum antibiotic prophylaxis (IAP) is the standard of care for prevention of invasive GBS disease in some countries, even in such settings a substantial residual burden of disease remains. A GBS vaccine administered during pregnancy could potentially address this important unmet medical need and provide an adjunct or alternative to IAP for the prevention of invasive GBS disease in neonates. A hurdle for vaccine development has been relatively low disease rates making efficacy studies difficult. Given the well-accepted inverse relationship between anti-GBS capsular polysaccharide antibody titers at birth and risk of disease, licensure using serological criteria as a surrogate biomarker represents a promising approach to accelerate the availability of a GBS vaccine.
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- 2022
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14. The impact of organized breast assessment on survival by stage for screened women diagnosed with invasive breast cancer
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Smith, Courtney R., Chiarelli, Anna M., Holloway, Claire MB., Mirea, Lucia, O'Malley, Frances P., Blackmore, Kristina M., Pandya, Anjali, Majpruz, Vicky, Harris, Cathy Paroschy, Hendry, Ashley, Hey, Amanda, Kornecki, Anat, Lougheed, George, Maier, Barbara-Anne, Marchand, Patricia, McCready, David, Rand, Carol, Raphael, Simon, Segal-Nadler, Roanne, Sehgal, Neelu, and Muradali, Derek
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- 2018
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15. Progress towards the development of Klebsiella vaccines
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Myeongjin Choi, Sharon M Tennant, Raphael Simon, and Alan S Cross
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klebsiella pneumoniae ,antimicrobial resistance ,vaccine ,conjugate vaccine ,o polysaccharide ,capsular polysaccharide ,maps vaccine ,Internal medicine ,RC31-1245 - Abstract
Introduction: Klebsiella pneumoniae (KP) are a leading cause of healthcare-associated infections. The dramatic increase in microbial resistance to third-generation cephalosporin and carbapenem ‘front line’ antimicrobial agents and the paucity of new antimicrobials have left clinicians with few therapeutic options and resulted in increased morbidity and mortality. Vaccines may reduce the incidence of infections thereby reducing the necessity for antimicrobials and are not subject to antimicrobial resistance mechanisms. Areas covered: We review whole cell, subunit, capsular polysaccharide (CPS), O polysaccharide (OPS) and conjugate vaccines against KP infection, as well as alternative KP vaccine platforms. Expert opinion: Vaccine-induced antibodies to KP CPS have been protective in preclinical studies, but the number of CPS types (>77) makes vaccines against this virulence factor less feasible. Since four OPS serotypes account of ~80% of invasive KP infections and anti-OPS antibodies are also protective in preclinical studies, both OPS-based conjugate and multiple antigen presenting system (MAPS) vaccines are in active development. Vaccines based on other KP virulence factors, such as outer membrane proteins, type 3 fimbriae (MrkA) and siderophores are at earlier stages of development. Novel strategies for the clinical testing of KP vaccines need to be developed.
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- 2019
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16. Deletions in guaBA and htrA but not clpX or rfaL constitute a live-attenuated vaccine strain of Salmonella Newport to protect against serogroup C2-C3 Salmonella in mice
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Fabien J. Fuche, Jennifer A. Jones, Girish Ramachandran, Ellen E. Higginson, Raphael Simon, and Sharon M. Tennant
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salmonella ,serogroup c2-c3 ,newport ,vaccine ,mouse model ,Immunologic diseases. Allergy ,RC581-607 ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Non-typhoidal Salmonella (NTS) are a leading cause of foodborne infections worldwide, and serogroups B, C1, C2-C3 and D are the most common serogroups associated with human disease. While live vaccine candidates that protect against S. Typhimurium (serogroup B) and S. Enteritidis (serogroup D) have been described by us and others, far less effort has been directed towards vaccines that target either serogroup C1 or C2-C3 Salmonella. Here we describe a Salmonella Newport-based live-attenuated vaccine (serogroup C2-C3). Deletion of the genes clpX or rfaL, previously used in live vaccines to attenuate S. Typhimurium and/or S. Enteritidis, failed to attenuate S. Newport. However, we found that deletion of either guaBA or htrA raised the 50% lethal dose of S. Newport in an intraperitoneal infection model in BALB/c mice. Our live-attenuated vaccine candidate CVD 1966 (S. Newport ΔguaBA ΔhtrA) elicited strong antibody responses against COPS, flagellin and outer membrane proteins when administered intraperitoneally or orally. Following lethal challenge with the parental virulent strain of S. Newport, we observed vaccine efficacies of 53% for immunization via the intraperitoneal route and 47% for immunization via the oral route. Following intraperiteonal immunization, the vaccine also significantly reduced the bacterial burden of challenge organisms in the liver and spleen. Interestingly, reducing the LPS chain length by deleting rfaL did not induce a stronger immune response towards surface antigens, and failed to elicit any protection against lethal homologous challenge. In conclusion, we have developed a live-attenuated Salmonella serogroup C2-C3 vaccine that we are further evaluating.
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- 2019
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17. Immunogenicity and protective efficacy against Salmonella C2-C3 infection in mice immunized with a glycoconjugate of S. Newport Core-O polysaccharide linked to the homologous serovar FliC protein
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Ofir Schuster, Khandra T. Sears, Girish Ramachandran, Fabien J. Fuche, Brittany Curtis, Sharon M. Tennant, and Raphael Simon
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o polysaccharide ,flagellin ,vaccine ,salmonella ,group c ,conjugate ,Immunologic diseases. Allergy ,RC581-607 ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Nontyphoidal Salmonella (NTS) are important human enteric pathogens globally. Among the different serovars associated with human NTS disease, S. Newport (a serogroup C2-C3 Salmonella) accounts for a measurable proportion of cases. However, to date there are no licensed human NTS vaccines. NTS lipopolysaccharide-associated O polysaccharides are virulence factors and protective antigens in animal models. As isolated molecules, bacterial polysaccharides are generally poorly immunogenic, a limitation overcome by conjugation to a protein carrier. We report herein the development of a candidate serogroup C2-C3 glycoconjugate vaccine based on S. Newport Core-O polysaccharide (COPS) and phase 1 flagellin (FliC). S. Newport COPS and FliC were purified from genetically engineered reagent strains, and conjugated at the polysaccharide reducing end to FliC protein lysines with thioether chemistry. S. Newport COPS:FliC immunization in mice improved anti-polysaccharide immune responses, generated high anti-FliC IgG titers, and mediated robust protection against challenge with both the homologous serovar as well another serogroup C2-C3 serovar (S. Muenchen). Analyses of S. Newport COPS:FliC induced sera found that the anti-COPS IgG antibodies were specific for serogroup C2-C3 lipopolysaccharide, and could promote bactericidal killing by complement and uptake into phagocytes. These preclinical studies establish the protective capacity of serogroup C2-C3 OPS glycoconjugates, and provide a path forward for the development of a multivalent Salmonella vaccine for humans that includes serogroup C2-C3.
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- 2019
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18. Long-term low-level ambient air pollution exposure and risk of lung cancer – A pooled analysis of 7 European cohorts
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Ulla Arthur Hvidtfeldt, Gianluca Severi, Zorana Jovanovic Andersen, Richard Atkinson, Mariska Bauwelinck, Tom Bellander, Marie-Christine Boutron-Ruault, Jørgen Brandt, Bert Brunekreef, Giulia Cesaroni, Jie Chen, Hans Concin, Francesco Forastiere, Carla H. van Gils, John Gulliver, Ole Hertel, Gerard Hoek, Barbara Hoffmann, Kees de Hoogh, Nicole Janssen, Karl-Heinz Jöckel, Jeanette Therming Jørgensen, Klea Katsouyanni, Matthias Ketzel, Jochem O. Klompmaker, Norun Hjertager Krog, Alois Lang, Karin Leander, Shuo Liu, Petter L.S. Ljungman, Patrik K.E. Magnusson, Amar Jayant Mehta, Gabriele Nagel, Bente Oftedal, Göran Pershagen, Raphael Simon Peter, Annette Peters, Matteo Renzi, Debora Rizzuto, Sophia Rodopoulou, Evangelia Samoli, Per Everhard Schwarze, Torben Sigsgaard, Mette Kildevæld Simonsen, Massimo Stafoggia, Maciek Strak, Danielle Vienneau, Gudrun Weinmayr, Kathrin Wolf, Ole Raaschou-Nielsen, and Daniela Fecht
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Air pollution ,Lung cancer incidence ,Particulate matter ,Dose response relationship ,Environmental sciences ,GE1-350 - Abstract
Background/aim: Ambient air pollution has been associated with lung cancer, but the shape of the exposure-response function - especially at low exposure levels - is not well described. The aim of this study was to address the relationship between long-term low-level air pollution exposure and lung cancer incidence. Methods: The “Effects of Low-level Air Pollution: a Study in Europe” (ELAPSE) collaboration pools seven cohorts from across Europe. We developed hybrid models combining air pollution monitoring, land use data, satellite observations, and dispersion model estimates for nitrogen dioxide (NO2), fine particulate matter (PM2.5), black carbon (BC), and ozone (O3) to assign exposure to cohort participants’ residential addresses in 100 m by 100 m grids. We applied stratified Cox proportional hazards models, adjusting for potential confounders (age, sex, calendar year, marital status, smoking, body mass index, employment status, and neighborhood-level socio-economic status). We fitted linear models, linear models in subsets, Shape-Constrained Health Impact Functions (SCHIF), and natural cubic spline models to assess the shape of the association between air pollution and lung cancer at concentrations below existing standards and guidelines. Results: The analyses included 307,550 cohort participants. During a mean follow-up of 18.1 years, 3956 incident lung cancer cases occurred. Median (Q1, Q3) annual (2010) exposure levels of NO2, PM2.5, BC and O3 (warm season) were 24.2 µg/m3 (19.5, 29.7), 15.4 µg/m3 (12.8, 17.3), 1.6 10−5m−1 (1.3, 1.8), and 86.6 µg/m3 (78.5, 92.9), respectively. We observed a higher risk for lung cancer with higher exposure to PM2.5 (HR: 1.13, 95% CI: 1.05, 1.23 per 5 µg/m3). This association was robust to adjustment for other pollutants. The SCHIF, spline and subset analyses suggested a linear or supra-linear association with no evidence of a threshold. In subset analyses, risk estimates were clearly elevated for the subset of subjects with exposure below the EU limit value of 25 µg/m3. We did not observe associations between NO2, BC or O3 and lung cancer incidence. Conclusions: Long-term ambient PM2.5 exposure is associated with lung cancer incidence even at concentrations below current EU limit values and possibly WHO Air Quality Guidelines.
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- 2021
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19. Fibroepithelial lesions of the breast: a comprehensive morphological and outcome analysis of a large series
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Slodkowska, Elzbieta, Nofech-Mozes, Sharon, Xu, Bin, Parra-Herran, Carlos, Lu, Fang-I, Raphael, Simon, Zubovits, Judit, and Hanna, Wedad
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- 2018
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20. Metabolic factors and hip fracture risk in a large Austrian cohort study
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Erlangga Dominic, Wolfgang Brozek, Raphael Simon Peter, Ella Fromm, Hanno Ulmer, Kilian Rapp, Hans Concin, and Gabriele Nagel
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Metabolic syndrome ,Hip fractures ,Body mass index ,Serum cholesterol ,Triglycerides ,Vorarlberg Health Monitoring and Prevention Program ,Diseases of the musculoskeletal system ,RC925-935 - Abstract
To explore the association of incident hip fractures with metabolic syndrome (MetS) and its single components, we designed a prospective cohort study of hip fracture incidence among 117,053 participants of a population-based health surveillance program in Vorarlberg, the westernmost Austrian province. Incident hip fractures were recorded between 5 and 10 years after inclusion at baseline from 2003 to 2009. Applying Cox proportional hazard models for each MetS component and for a composite z-score for MetS, hazards for fracture were estimated in quintiles, as continuous z-score variables, and as pathological cut off values. Mean age was 50.1 ± 15.6 years at baseline, 5–10 years after which 947 incident hip fractures occurred. An association of a higher composite MetS score with decreased hip fracture risk was observed in women (HR 0.80, 95%-CI 0.88–0.96, p
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- 2020
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21. The Diversity of Lipopolysaccharide (O) and Capsular Polysaccharide (K) Antigens of Invasive Klebsiella pneumoniae in a Multi-Country Collection
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Myeongjin Choi, Nicolas Hegerle, Joseph Nkeze, Shaichi Sen, Sanchita Jamindar, Shamima Nasrin, Sunil Sen, Jasnehta Permala-Booth, James Sinclair, Milagritos D. Tapia, J. Kristie Johnson, Sylla Mamadou, Joshua T. Thaden, Vance G. Fowler, Ana Aguilar, Enrique Terán, Dominique Decre, Florence Morel, Karen Angeliki Krogfelt, Annelie Brauner, Efthymia Protonotariou, Eirini Christaki, Yuichiro Shindo, Yi-Tsung Lin, Andrea L. Kwa, Sadia Shakoor, Ashika Singh-Moodley, Olga Perovic, Jan Jacobs, Octavie Lunguya, Raphael Simon, Alan S. Cross, and Sharon M. Tennant
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Klebsiella pneumoniae ,multidrug resistance ,vaccine ,O antigen ,K antigen ,Microbiology ,QR1-502 - Abstract
Klebsiella pneumoniae is a common cause of sepsis and is particularly associated with healthcare-associated infections. New strategies are needed to prevent or treat infections due to the emergence of multi-drug resistant K. pneumoniae. The goal of this study was to determine the diversity and distribution of O (lipopolysaccharide) and K (capsular polysaccharide) antigens on a large (>500) global collection of K. pneumoniae strains isolated from blood to inform vaccine development efforts. A total of 645 K. pneumoniae isolates were collected from the blood of patients in 13 countries during 2005–2017. Antibiotic susceptibility was determined using the Kirby-Bauer disk diffusion method. O antigen types including the presence of modified O galactan types were determined by PCR. K types were determined by multiplex PCR and wzi capsular typing. Sequence types of isolates were determined by multilocus sequence typing (MLST) targeting seven housekeeping genes. Among 591 isolates tested for antimicrobial resistance, we observed that 19.3% of isolates were non-susceptible to carbapenems and 62.1% of isolates were multidrug resistant (from as low as 16% in Sweden to 94% in Pakistan). Among 645 isolates, four serotypes, O1, O2, O3, and O5, accounted for 90.1% of K. pneumoniae strains. Serotype O1 was associated with multidrug resistance. Fifty percent of 199 tested O1 and O2 strains were gmlABC-positive, indicating the presence of the modified polysaccharide subunit D-galactan III. The most common K type was K2 by both multiplex PCR and wzi capsular typing. Of 39 strains tested by MLST, 36 strains were assigned to 26 known sequence types of which ST14, ST25, and ST258 were the most common. Given the limited number of O antigen types, diverse K antigen types and the high multidrug resistance, we believe that an O antigen-based vaccine would offer an excellent prophylactic strategy to prevent K. pneumoniae invasive infection.
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- 2020
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22. Regional variation of care dependency after hip fracture in Germany: A retrospective cohort study using health insurance claims data.
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Claudia Schulz, Gisela Büchele, Raphael Simon Peter, Dietrich Rothenbacher, Patrick Roigk, Kilian Rapp, Katrin Christiane Reber, and Hans-Helmut König
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Medicine ,Science - Abstract
OBJECTIVE:To investigate variation of care dependency after hip fracture across German regions based on the assessment by the German statutory long-term care insurance. DATA SOURCES/STUDY SETTING:Patient-level statutory health and long-term care insurance claims data from 2009-2011 and official statistical data from Germany. STUDY DESIGN:We performed a retrospective cohort study. Investigated multinomial outcome categories were increase in care dependency (new onset or a higher care dependency than pre-fracture), no change as reference and death as competing risk in the quarterly period following hip fracture (follow-up 3 months). Regional variation was operationalized with the variance of regional-level random intercepts based on generalized linear mixed models. We adjusted for patient and regional characteristics. PRINCIPAL FINDINGS:The study included 122,887 hip fracture patients in 95 German postal code regions. Crude outcomes were 30.87% increase in care dependency and 14.35% death. Results indicated modest variation on regional level. Male sex, increasing age, increasing comorbidity, pertrochanteric and subtrochanteric fracture site compared to femoral neck, time from hospital admission to surgery of 3 or more days, as well as increasing inpatient length of stay, non-participation in rehabilitation and regions with lower hospital density were positively associated with an increase in care dependency. CONCLUSIONS:Several characteristics on patient and regional level associated with the outcome were identified. Variation in the increase in care dependency after hip fracture appeared to be attributable primarily to patient characteristics. Variation on regional level was only modest.
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- 2020
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23. Relationship between cardiac biomarker concentrations and long-term mortality in subjects with osteoarthritis.
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Martin Rehm, Gisela Büchele, Raphael Simon Peter, Rolf Erwin Brenner, Klaus-Peter Günther, Hermann Brenner, Wolfgang Koenig, and Dietrich Rothenbacher
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Medicine ,Science - Abstract
Osteoarthritis (OA) is associated with adverse cardio-metabolic features. N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponins T and I (hs-cTnT and hs-cTnI) are well-characterized cardiac markers and provide prognostic information. The objective was to assess the association of cardiac biomarker concentrations with long-term mortality in subjects with OA. In a cohort of 679 OA subjects, undergoing hip or knee replacement during 1995/1996, cardiac biomarkers were measured and subjects were followed over 20 years. During a median follow-up of 18.4 years, 332 (48.9%) subjects died. Median of hs-cTnT, hs-cTnI, and NT-proBNP at baseline was 3.2 ng/L, 3.9 ng/L, and 96.8 ng/L. The top quartile of NT-proBNP was associated with increased risk of mortality (Hazard Ratio (HR) 1.79, 95% confidence interval (CI) 1.17-2.73) after adjustment for covariates including troponins (hs-cTnT HR 1.30 (95% CI 0.90-1.89), hs-cTnI HR 1.32 (95% CI 0.87-2.00) for top category). When biomarker associations were evaluated as continuous variables, only NT-proBNP (HR per log-unit increment 1.34, 95% CI 1.16-1.54) and hs-cTnI (HR 1.38, 95% CI 1.11-1.72) showed robust results. Elevated cardiac biomarker concentrations predicted an increased risk of long-term mortality and strongest for NT-proBNP and hs-cTnI. These results might help to identify subjects at risk and target preventive efforts early.
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- 2020
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24. Life course body mass index and risk and prognosis of amyotrophic lateral sclerosis: results from the ALS registry Swabia
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Peter, Raphael Simon, Rosenbohm, Angela, Dupuis, Luc, Brehme, Torben, Kassubek, Jan, Rothenbacher, Dietrich, Nagel, Gabriele, and Ludolph, Albert Christian
- Published
- 2017
25. Understanding Mortality of Femoral Fractures Following Low-Impact Trauma in Persons With and Without Care Need
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Bluhmki, Tobias, Peter, Raphael Simon, Rapp, Kilian, König, Hans-Helmut, Becker, Clemens, Lindlbauer, Ivonne, Rothenbacher, Dietrich, Beyersmann, Jan, and Büchele, Gisela
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- 2017
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26. Intrinsic B cell TLR-BCR linked coengagement induces class-switched, hypermutated, neutralizing antibody responses in absence of T cells
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Carlos E. Rivera, Yulai Zhou, Daniel P. Chupp, Hui Yan, Amanda D. Fisher, Raphael Simon, Hong Zan, Zhenming Xu, and Paolo Casali
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Lipopolysaccharides ,T-Lymphocytes ,Antibodies ,Vaccine Related ,Mice ,Rare Diseases ,Biodefense ,Receptors ,Escherichia coli ,Animals ,Vaccine Related (AIDS) ,Neutralizing ,Multidisciplinary ,Prevention ,Inflammatory and immune system ,B-Cell ,Toll-Like Receptor 4 ,Toll-Like Receptor 5 ,Infectious Diseases ,Emerging Infectious Diseases ,Good Health and Well Being ,Antigen ,Antibody Formation ,Immunization ,Digestive Diseases ,Flagellin ,Biotechnology - Abstract
Maturation of antibody responses entails somatic hypermutation (SHM), class-switch DNA recombination (CSR), plasma cell differentiation, and generation of memory B cells, and it is thought to require T cell help. We showed that B cell Toll-like receptor 4 (TLR4)–B cell receptor (BCR) (receptor for antigen) coengagement by 4-hydroxy-3-nitrophenyl acetyl (NP)–lipopolysaccharide (LPS) ( Escherichia coli lipid A polysaccharide O-antigen) or TLR5-BCR coengagement by Salmonella flagellin induces mature antibody responses to NP and flagellin in Tcr β −/− Tcr δ −/− and NSG/B mice. TLR-BCR coengagement required linkage of TLR and BCR ligands, “linked coengagement.” This induced B cell CSR/SHM, germinal center–like differentiation, clonal expansion, intraconal diversification, plasma cell differentiation, and an anamnestic antibody response. In Tcr β −/− Tcr δ −/− mice, linked coengagement of TLR4-BCR by LPS or TLR5-BCR by flagellin induced protective antibodies against E. coli or Salmonella Typhimurium. Our findings unveiled a critical role of B cell TLRs in inducing neutralizing antibody responses, including those to microbial pathogens, without T cell help.
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- 2023
27. Conformational Heterogeneity of the HIV Envelope Glycan Shield
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Mingjun Yang, Jing Huang, Raphael Simon, Lai-Xi Wang, and Alexander D. MacKerell
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Medicine ,Science - Abstract
Abstract To better understand the conformational properties of the glycan shield covering the surface of the HIV gp120/gp41 envelope (Env) trimer, and how the glycan shield impacts the accessibility of the underlying protein surface, we performed enhanced sampling molecular dynamics (MD) simulations of a model glycosylated HIV Env protein and related systems. Our simulation studies revealed a conformationally heterogeneous glycan shield with a network of glycan-glycan interactions more extensive than those observed to date. We found that partial preorganization of the glycans potentially favors binding by established broadly neutralizing antibodies; omission of several specific glycans could increase the accessibility of other glycans or regions of the protein surface to antibody or CD4 receptor binding; the number of glycans that can potentially interact with known antibodies is larger than that observed in experimental studies; and specific glycan conformations can maximize or minimize interactions with individual antibodies. More broadly, the enhanced sampling MD simulations described here provide a valuable tool to guide the engineering of specific Env glycoforms for HIV vaccine design.
- Published
- 2017
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28. Sources of heterogeneity in studies of the BMI-mortality association
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Raphael Simon Peter
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Body mass index ,Mortality ,Heterogeneity ,Medicine (General) ,R5-920 - Abstract
Background: To date, the amount of heterogeneity among studies of the body mass index-mortality association attributable to differences in the age distribution and length of follow-up has not been quantified. Therefore, we wanted to quantify the amount of heterogeneity attributable to age and follow-up in results of studies on the body mass index-mortality relation. Methods: We used optima of the body mass index mortality association reported for 30 populations and performed meta-regression to estimate the amount of heterogeneity attributable to sex, ethnicity, mean age at baseline, percentage smokers, and length of follow-up. Results: Ethnicity as single factor accounted for 36% (95% CI, 11–56%) of heterogeneity. Mean age and length of follow-up had an interactive effect and together accounted for 56% (95% CI, 24–74%) of the remaining heterogeneity. Sex did not significantly contribute to the heterogeneity, after controlling for ethnicity, age, and length of follow-up. Conclusions: A considerable amount of heterogeneity in studies of the body mass index-mortality association is attributable to ethnicity, age, and length of follow-up.
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- 2017
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29. Maternal Antibodies Elicited by Immunization With an O- Polysaccharide Glycoconjugate Vaccine Protect Infant Mice Against Lethal Salmonella Typhimurium Infection
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Scott M. Baliban, Brittany Curtis, Mohammed N. Amin, Myron Mike Levine, Marcela F. Pasetti, and Raphael Simon
- Subjects
Salmonella ,polysaccharide ,flagellin ,glycoconjugate ,vaccine ,antibody ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Non-typhoidal Salmonella (NTS) are a leading cause of pediatric invasive bacterial infections in sub-Saharan Africa with high associated case fatality rates in children under 5 years old. We have developed glycoconjugate vaccines consisting of the lipid A-removed surface polysaccharide of NTS, core and O-polysaccharide (COPS), and the flagellar monomer protein (FliC) from the homologous serovar as the carrier. We previously established that COPS:FliC was immunogenic and protective in mice immunized as adults or infants; however, the brief period of murine infancy precluded the evaluation of protection against invasive NTS (iNTS) disease in early life. In the present study, we used a mouse model of maternal immunization to investigate transmission of S. Typhimurium COPS:FliC-induced maternal antibodies and protection against lethal iNTS challenge in infant mice. We found that vaccinated dams developed high levels of COPS- and FliC-specific IgG, which were transferred to their offspring. Sera from both vaccinated mothers and their litters mediated complement-dependent bactericidal activity in-vitro. Passively immunized 2-week old infant mice born to vaccinated mothers were fully protected from challenge with an S. Typhimurium blood isolate from sub-Saharan Africa. The pre-clinical findings reported herein demonstrate that anti-COPS:FliC antibodies induced by vaccination are sufficient for protection of murine infants against experimental S. Typhimurium infection. By underscoring the protective role of antibody, our results suggest that maintaining an adequate titer of protective anti-Salmonella antibodies during early life, either through pediatric or maternal COPS:FliC vaccination, may reduce iNTS disease in young children in sub-Saharan Africa.
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- 2019
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30. Epidemiologic research topics in Germany: a keyword network analysis of 2014 DGEpi conference presentations
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Peter, Raphael Simon, Brehme, Torben, Völzke, Henry, Muche, Rainer, Rothenbacher, Dietrich, and Büchele, Gisela
- Published
- 2016
31. The Economic Cost of Thyroid Cancer in France and the Corresponding Share Associated With Treatment of Overdiagnosed Cases
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Mengmeng Li, Filip Meheus, Stephanie Polazzi, Patricia Delafosse, Françoise Borson-Chazot, Arnaud Seigneurin, Raphael Simon, Jean-Damien Combes, Luigino Dal Maso, Marc Colonna, Antoine Duclos, and Salvatore Vaccarella
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Health Policy ,Public Health, Environmental and Occupational Health - Published
- 2023
32. Refinement of a Live Attenuated Salmonella enterica Serovar Newport Vaccine with Improved Safety
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Shamima Nasrin, Fabien J. Fuche, Khandra T. Sears, Jennifer A. Jones, Myron M. Levine, Raphael Simon, and Sharon M. Tennant
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Salmonella ,vaccine ,live ,attenuated ,Newport ,Muenchen ,Medicine - Abstract
Non-typhoidal Salmonella (NTS) is a major cause of gastroenteritis and is responsible for approximately 93 million cases annually. In healthy individuals, gastroenteritis caused by NTS is usually self-limiting, however, NTS can cause severe invasive disease in immunocompromised patients. Very little research has been directed towards development of vaccines against Salmonella serogroups O:6,7 or O:8. We have constructed a live attenuated serogroup O:8 vaccine, CVD 1979, by deleting guaBA, htrA, and aroA from the genome of S. Newport. We have shown that the candidate vaccine is well tolerated in mice and elicits serum immunoglobulin G (IgG) antibodies against core O-polysaccharide (COPS) when administered orally. Immunized mice were challenged intraperitoneally with wild-type S. Newport and bacterial burden in the liver and spleen was found to be significantly reduced in the livers of immunized mice compared to control mice. We also observed moderate vaccine efficacy (45%) against lethal challenge with the serogroup O:8 serovar, S. Muenchen, but low vaccine efficacy (28%) following lethal challenge with a serogroup O:6,7 serovar, S. Virchow. In vitro, we have shown that antibodies generated by CVD 1979 only recognize lipopolysaccharide (LPS) from serogroup O:8 but not serogroup O:6,7 serovars, and that they mediate opsonophagocytic antibody (OPA) activity against serogroup O:8 but not serogroup O:6,7 serovars. We also showed that OPA activity can be blocked by pre-incubating the antisera with serogroup O:8 lipopolysaccharide. Taken together, our data demonstrate that we have constructed a well-tolerated, effective live attenuated S. Newport vaccine which elicits functional antibodies against serogroup O:8 but not O:6,7 serovars.
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- 2021
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33. Association of clinical outcome assessments of mobility capacity and incident disability in community-dwelling older adults - a systematic review and meta-analysis
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Braun, Tobias, primary, Thiel, Christian, additional, Peter, Raphael Simon, additional, Bahns, Carolin, additional, Büchele, Gisela, additional, Rapp, Kilian, additional, Becker, Clemens, additional, and Grüneberg, Christian, additional
- Published
- 2022
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34. Effect of Secular Trend, Age, and Length of Follow-up on Optimum Body Mass Index From 1985 Through 2015 in a Large Austrian Cohort
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Peter, Raphael Simon, Föger, Bernhard, Concin, Hans, and Nagel, Gabriele
- Subjects
Adult ,Male ,Medicine (General) ,length of follow-up ,mortality ,Body Mass Index ,Cohort Studies ,bmi ,secular trend ,R5-920 ,age ,Risk Factors ,Others ,Austria ,Humans ,Original Article ,Female ,Obesity ,Follow-Up Studies - Abstract
Background: Obesity and its health consequences will dominate health care systems in many countries during the next decades. However, the body mass index (BMI) optimum in relation to all-cause mortality is still a matter of debate. Material and Methods: Data of the Vorarlberg Health Monitoring & Prevention Program (VHM&PP, 1985–2005) and data provided by the Main Association of Austrian Social Security Institutions (MAASSI, 2005–2015) were analyzed. Information was available on age, sex, smoking status, measured height and weight, and mortality. Generalized additive models were used to model mortality as a function of BMI, calendar time, age, and follow-up. Results: In MAASSI (N = 282,216, 46.0% men), men and women were on average 2.7 years older than in VHM&PP (N = 185,361, 46.1% men). Average BMI was slightly higher in men (26.1 vs 25.7 kg/m2) but not in women (24.6 vs 24.7 kg/m2). We found an interactive effect of age and follow-up on the BMI optimum. Over age 35 years in men and 55 years in women, the BMI optimum decreased with length of follow-up. While keeping covariates fixed, BMI optimum increased slightly between 1985 and 2015 in men and women, 24.9 (95% CI, 23.9–25.9) to 26.4 (95% CI, 25.3–27.3), and 22.4 (95% CI, 21.7–23.1) to 23.3 (95% CI, 22.6–24.5) kg/m2, respectively. Conclusion: Age and length of follow-up have a pronounced effect on the BMI associated with the lowest all-cause mortality. After controlling for age and length of follow-up, the BMI optimum increased slightly over 30 years in this large study sample.
- Published
- 2021
35. A Nonlethal Full-Thickness Flame Burn Produces a Seroma Beneath the Forming Eschar, Thereby Promoting Pseudomonas aeruginosa Sepsis in Mice
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Alan S. Cross, Adrienne R Kambouris, Kerri Lopez, Jessica C Allen, Gideon Wolf, Scott M Baliban, Jerod Brammer, Raphael Simon, Myeongjin Choi, Gary Fiskum, Wei Chao, Nevil J. Singh, and Catriona Miller
- Subjects
Chemokine ,Soft Tissue Injuries ,Secondary infection ,Eschar ,medicine.disease_cause ,Proinflammatory cytokine ,Sepsis ,Mice ,Immune system ,Animals ,Humans ,Medicine ,Pseudomonas Infections ,biology ,business.industry ,Pseudomonas aeruginosa ,Rehabilitation ,medicine.disease ,Disease Models, Animal ,Seroma ,Immunology ,Emergency Medicine ,biology.protein ,Surgery ,medicine.symptom ,Burns ,business - Abstract
The World Health Organization estimates ~180,000 deaths occur annually from burn-related injuries. Many victims who survive the initial burn trauma succumb to bacterial infections that lead to sepsis during treatment. Although advancements in burn care continue to improve in high-income countries due to their burn centers and advanced research, low and middle-income countries continue to see high frequencies of burn injuries and burn-related deaths due to secondary infections. Bacterial-derived sepsis is the most life-threatening danger for people that survive burn injuries. Here we provide evidence for the first time that a subeschar seroma forms postburn even in the absence of infection in mice. The seroma fills with a volume estimated at 500 µL of fluid, 25% of the blood supply, free of red blood cells. The seroma fluid supports robust Pseudomonas aeruginosa (PA) growth and contains inflammatory cytokines and chemokines, which recruit immature neutrophils and monocytes to the seroma in the absence of endothelial breakdown. These immune cells fail to contain PA expansion and dissemination. This recruitment of monocytes and immature neutrophils may result in sequestering these critical immune cells away from other tissues during a pivotal time during bacterial dissemination, promoting PA-mediated sepsis.
- Published
- 2021
36. 2134. A Phase 2 Study to Evaluate the Safety, Tolerability, and Immunogenicity of a Booster Dose of a Group B Streptococcus 6-Valent Polysaccharide Conjugate Vaccine (GBS6)
- Author
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Babalwa Jongihlati, Nathan Segall, Stanley Block, James Peterson, Judith Absalon, Samantha Munson, Yasmin Sanchez-Pearson, Raphael Simon, Natalie Silmon de Monerri, David Radley, Emily A Gomme, Michelle Gaylord, William C Gruber, Kathrin U Jansen, Daniel A Scott, and Annaliesa S Anderson
- Subjects
Infectious Diseases ,Oncology - Abstract
Background Group B streptococcus (GBS) is a leading cause of invasive bacterial infections in young infants and pregnant women. Pfizer is developing a hexavalent GBS vaccine (GBS6) as a maternal vaccine to prevent invasive GBS disease due to the 6 most prevalent serotypes in young infants. We previously reported Phase 1 safety and immunogenicity data for GBS6. There is precedent for repeat doses of vaccines to augment or sustain circulating antibodies available for placental transfer with each pregnancy; thus, data to inform GBS6 booster strategies were required. Methods This was a Phase 2 open-label extension study to evaluate the safety and immunogenicity of a booster dose of GBS6 (20 μg capsular polysaccharide (CPS)/serotype/dose) with or without AlPO4, given ∼2 years after primary vaccination in 151 healthy nonpregnant adults. Sera taken before and 1-month postbooster were assessed for anti-CPS IgG using a direct Luminex immunoassay. Participants recorded solicited local and systemic events for 14 days after vaccination and unsolicited safety events through 6 months after vaccination. Immunogenicity time points from the Phase 1 study are referred to as primary dose. Results Immunogenicity results For all serotypes, serotype-specific IgG geometric mean concentrations (GMCs) remained elevated compared to baseline at the prebooster time point and were higher 1-month postbooster than 1 month post primary. The 1-month postbooster IgG GMCs were 10- to 59-fold higher than at the prebooster time point. There were similar responses between the 2 formulations. Safety and tolerability results The most frequently reported local reaction was mild to moderate pain at the injection site. Greater pain was associated with AlPO4 formulation. The most frequently reported systemic events were mild to moderate headache and fatigue. The frequency of adverse events was low. Figure 1Antibody Response Line Plot of IgG GMCs by Vaccine Group - All SerotypesFigure 2.Reverse Cumulative Distribution Curves (RCDCs) for IgG 1 Month After Primary and Booster Vaccination, by Vaccine Group – All SerotypesFigure 3.IgG Geometric Mean Fold Rises (GMFRs) at 1 Month Postbooster Vaccination Conclusion A booster dose of GBS6 given ∼2 years after a primary dose to healthy nonpregnant adults was safe and elicited robust immune responses that were also consistently higher than after primary dose. This study suggests that repeat vaccination with GBS6 may confer additional benefit in pregnant women in subsequent pregnancies. Disclosures Babalwa Jongihlati, MD, MBA, Pfizer: Stocks/Bonds Judith Absalon, MD, MPH, Pfizer: Stocks/Bonds Samantha Munson, MPH, MBA, Pfizer: Stocks/Bonds Yasmin Sanchez-Pearson, PhD, Pfizer: Stocks/Bonds Raphael Simon, PhD, Pfizer: Stocks/Bonds Natalie Silmon de Monerri, PhD, Pfizer: Stocks/Bonds David Radley, MS, Pfizer: Employee|Pfizer: Stocks/Bonds Emily A. Gomme, Ph.D., Pfizer: Stocks/Bonds Michelle Gaylord, PhD, Pfizer: Stocks/Bonds William C. Gruber, MD, Pfizer, Inc.: Salary|Pfizer, Inc.: Stocks/Bonds Kathrin U. Jansen, PhD, Pfizer: Stocks/Bonds Daniel A. Scott, MD, Pfizer: Employee|Pfizer: Stocks/Bonds Annaliesa S. Anderson, PhD, Pfizer: Stocks/Bonds.
- Published
- 2022
37. Growth Differentiation Factor-15 as a Potent Predictor of Long-Term Mortality among Subjects with Osteoarthritis
- Author
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Natalie Arnold, Martin Rehm, Gisela Büchele, Raphael Simon Peter, Rolf Erwin Brenner, Klaus-Peter Günther, Hermann Brenner, Wolfgang Koenig, and Dietrich Rothenbacher
- Subjects
growth differentiation factor-15 ,total mortality ,osteoarthritis ,prognosis ,Medicine - Abstract
Background: Subjects with osteoarthritis (OA) are at increased risk for cardiovascular (CV) and all-cause mortality. Whether biomarkers improve outcome prediction in these patients remains to be elucidated. We investigated the association between growth differentiation factor 15 (GDF-15), a novel stress-responsive cytokine, and long-term all-cause mortality among OA patients. Methods: Within the Ulm Osteoarthritis Study, GDF-15 has been measured in the serum of 636 subjects, who underwent hip or knee arthroplasty between 1995 and 1996 (median age 65 years). Results: During a median follow-up of 19.7 years, a total of 402 deaths occurred. GDF-15 was inversely associated with walking distance. Compared to the bottom quartile (Q), subjects within the top quartile of GDF-15 demonstrated a 2.69-fold increased risk of dying (hazard ratio (HR) (95% confidence interval (CI)) 2.69 (1.82–3.96) adjusted for age, sex, BMI, smoking status, localization of OA, diabetes, maximum walking distance, total cholesterol, and cystatin C. Further adjustment for NT-proBNP, troponin I, and hs-C-reactive protein did not change the results appreciably (HR (95%CI) 1.56 (1.07–2.28); 1.75 (1.21–2.55); 2.32 (1.55–3.47) for Q2, Q3, and Q4 respectively, p for trend < 0.001). Conclusions: In subjects with OA, GDF-15 represents a potent predictor of decreased survival over >20 years, independently of conventional CV risk factors, renal, cardiac, and inflammatory biomarkers as well as walking disability, previously associated with increased mortality and lower extremity OA.
- Published
- 2020
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38. The Gathering Storm: Is Untreatable Typhoid Fever on the Way?
- Author
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Myron M. Levine and Raphael Simon
- Subjects
ceftriaxone resistance ,chloramphenicol ,typhoid fever ,Microbiology ,QR1-502 - Abstract
ABSTRACT Klemm et al. (mBio 9:e00105-18, 2018, https://doi.org/10.1128/mBio.00105-18) present comprehensive antibiotic sensitivity patterns and genomic sequence data on Salmonella enterica serovar Typhi blood culture isolates from typhoid fever cases during an epidemic in Pakistan. Microbiologic and genomic data pinpoint the identities and locations of the antimicrobial resistance genes and the outbreak strain’s lineage. They propose that Salmonella enterica serovar Typhi be added to the list of bacterial pathogens of public health importance that have become extensively drug resistant (XDR). This paper portends possible dire scenarios for typhoid fever control if XDR strains disseminate globally. Since the outbreak strain is of the H58 haplotype, known for its ability to spread worldwide and displace endemic S. Typhi, this concern is well-founded. The report of Klemm et al. forewarns the global community to address control of typhoid fever more aggressively through prevention, should therapeutic options disappear. This Commentary frames the Klemm et al. findings within a historic perspective.
- Published
- 2018
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39. Immunogenicity and efficacy following sequential parenterally-administered doses of Salmonella Enteritidis COPS:FliC glycoconjugates in infant and adult mice.
- Author
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Scott M Baliban, Brittany Curtis, Deanna Toema, Sharon M Tennant, Myron M Levine, Marcela F Pasetti, and Raphael Simon
- Subjects
Arctic medicine. Tropical medicine ,RC955-962 ,Public aspects of medicine ,RA1-1270 - Abstract
In sub-Saharan Africa, invasive nontyphoidal Salmonella (iNTS) infections with serovars S. Enteritidis, S. Typhimurium and I 4,[5],12:i:- are widespread in children < 5 years old. Development of an efficacious vaccine would provide an important public health tool to prevent iNTS disease in this population. Glycoconjugates of S. Enteritidis core and O-polysaccharide (COPS) coupled to the homologous serovar phase 1 flagellin protein (FliC) were previously shown to be immunogenic and protected adult mice against death following challenge with a virulent Malian S. Enteritidis blood isolate. This study extends these observations to immunization of mice in early life and also assesses protection with partial and full regimens. Anti-COPS and anti-FliC serum IgG titers were assessed in infant and adult mice after immunization with 1, 2 or 3 doses of S. Enteritidis COPS:FliC alone or co-formulated with aluminum hydroxide or monophosphoryl lipid A (MPL) adjuvants. S. Enteritidis COPS:FliC was immunogenic in both age groups, although the immune responses were quantitatively lower in infants. Kinetics of antibody production were similar for the native and adjuvanted formulations after three doses; conjugates formulated with MPL elicited significantly increased anti-COPS IgG titers in adult but not infant mice. Nevertheless, robust protection against S. Enteritidis challenge was seen for all three formulations when three doses were given either during infancy or as adults. We further found that significant protection could be achieved with two COPS:FliC doses, despite elicitation of modest serum anti-COPS IgG antibody titers. These findings guide potential immunization strategies that may be translated to develop a human pediatric iNTS vaccine for sub-Saharan Africa.
- Published
- 2018
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40. Development of a broad spectrum glycoconjugate vaccine to prevent wound and disseminated infections with Klebsiella pneumoniae and Pseudomonas aeruginosa.
- Author
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Nicolas Hegerle, Myeongjin Choi, James Sinclair, Mohammed N Amin, Morgane Ollivault-Shiflett, Brittany Curtis, Rachel S Laufer, Surekha Shridhar, Jerod Brammer, Franklin R Toapanta, Ian Alan Holder, Marcela F Pasetti, Andrew Lees, Sharon M Tennant, Alan S Cross, and Raphael Simon
- Subjects
Medicine ,Science - Abstract
Klebsiella pneumoniae (KP) and Pseudomonas aeruginosa (PA) are important human pathogens that are associated with a range of infection types, including wound and disseminated infections. Treatment has been complicated by rising rates of antimicrobial resistance. Immunoprophylactic strategies are not constrained by antimicrobial resistance mechanisms. Vaccines against these organisms would be important public health tools, yet they are not available. KP surface O polysaccharides (OPS) are protective antigens in animal models of infection. Similarly, PA flagellin (Fla), the major subunit of the flagellar filament, is required for virulence and is a target of protective antibodies in animal models. We report herein the development of a combined KP and PA glycoconjugate vaccine comprised of the four most common KP OPS types associated with human infections (O1, O2, O3, O5), chemically linked to the two Fla types of PA (FlaA, FlaB). Conjugation of KP OPS to PA Fla enhanced anti-polysaccharide immune responses and produced a formulation that generated antibody titers to the four KP OPS types and both PA Fla antigens in rabbits. Passive transfer of vaccine-induced rabbit antisera reduced the bacterial burden and protected mice against fatal intravenous KP infection. Mice passively transferred with conjugate-induced antisera were also protected against PA infection after thermal injury with a FlaB-expressing isolate, but not a FlaA isolate. Taken together, these promising preclinical results provide important proof-of-concept for a broad spectrum human vaccine to prevent KP and PA infections.
- Published
- 2018
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41. Longitudinal study of body mass index, dyslipidemia, hyperglycemia, and hypertension in 60,000 men and women in Sweden and Austria.
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Mieke Van Hemelrijck, Hanno Ulmer, Gabriele Nagel, Raphael Simon Peter, Josef Fritz, Robin Myte, Bethany van Guelpen, Bernhard Föger, Hans Concin, Christel Häggström, Pär Stattin, and Tanja Stocks
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Medicine ,Science - Abstract
BACKGROUND:Obesity is suggested to underlie development of other metabolic aberrations, but longitudinal relationships between metabolic factors at various ages has not been studied in detail. METHODS:Data from 27,379 men and 32,275 women with in total 122,940 health examinations in the Västerbotten Intervention Project, Sweden and the Vorarlberg Health Monitoring and Prevention Programme, Austria were used to investigate body mass index (BMI), mid-blood pressure, and fasting levels of glucose, triglycerides, and total cholesterol at baseline in relation to 10-year changes of these factors and weight. We included paired examinations performed 10±2 years apart and used them for longitudinal analysis with linear regression of changes between the ages 30 and 40, 40 and 50, or 50 and 60 years. RESULTS:Higher levels of BMI were associated with increases in glucose and mid-blood pressure as well as triglycerides levels, and, to a lesser extent, decreases in cholesterol levels. For instance, per 5 kg/m2 higher BMI at age 40, glucose at age 50 increased by 0.24 mmol/l (95%CI: 0.22-0.26) and mid-blood pressure increased by 1.54 mm Hg (95%CI: 1.35-1.74). The strongest association observed was between BMI at age 30 and mid-blood pressure, which was 2.12 mm Hg (95% CI: 1.79-2.45) increase over ten years per 5 kg/m2 higher BMI level. This association was observed at an age when blood pressure levels on average remained stable. Other associations than those with BMI at baseline were much weaker. However, triglyceride levels were associated with future glucose changes among individuals with elevated BMI, particularly in the two older age groups. CONCLUSION:BMI was most indicative of long-term changes in metabolic factors, and the strongest impact was observed for increases in blood pressure between 30 and 40 years of age. Our study supports that lifestyle interventions preventing metabolic aberrations should focus on avoiding weight increases.
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- 2018
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42. Health-economic evaluation of collaborative orthogeriatric care for patients with a hip fracture in Germany: a retrospective cohort study using health and long-term care insurance claims data
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Raphael Simon Peter, Gisela Büchele, Clemens Becker, Ulrich Liener, Dietrich Rothenbacher, Christian Brettschneider, Kilian Rapp, Claudia Schulz, and Hans-Helmut König
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medicine.medical_specialty ,Cost effectiveness ,Cost-Benefit Analysis ,Economics, Econometrics and Finance (miscellaneous) ,Orthogeriatric co-management ,03 medical and health sciences ,Insurance, Long-Term Care ,0302 clinical medicine ,Health care ,medicine ,Humans ,030212 general & internal medicine ,Long-term care insurance ,health care economics and organizations ,Aged ,Retrospective Studies ,Original Paper ,030222 orthopedics ,Hip fracture ,Health economics ,Hip Fractures ,business.industry ,Health Policy ,Public health ,Retrospective cohort study ,Health Care Costs ,medicine.disease ,Entropy balancing ,Economic evaluation ,Emergency medicine ,Cost-effectiveness ,Quality-Adjusted Life Years ,business - Abstract
Background Evidence suggests benefits of orthogeriatric co-management (OGCM) for hip fracture patients. Yet, evidence on cost-effectiveness is limited and based on small datasets. The aim of our study was to conduct an economic evaluation of the German OGCM for geriatric hip fracture patients. Methods This retrospective cohort study was based on German health and long-term care insurance data. Individuals were 80 years and older, sustained a hip fracture in 2014, and were treated in hospitals providing OGCM (OGCM group) or standard care (control group). Health care costs from payer and societal perspective, life years gained (LYG) and cost-effectiveness were investigated within 1 year. We applied weighted gamma and two-part models, and entropy balancing to account for the lack of randomisation. We calculated incremental cost-effectiveness ratios (ICER) and employed the net-benefit approach to construct cost-effectiveness acceptability curves. Results 14,005 patients were treated in OGCM, and 10,512 in standard care hospitals. Total average health care costs per patient were higher in the OGCM group: €1181.53 (p p Conclusion Survival improved in hospitals providing OGCM. Costs were found to increase, driven by inpatient and long-term care. The cost-effectiveness depends on the willingness-to-pay. The ICER is likely to improve with a longer follow-up.
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- 2021
43. Development of a glycoconjugate vaccine to prevent invasive Salmonella Typhimurium infections in sub-Saharan Africa.
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Scott M Baliban, Mingjun Yang, Girish Ramachandran, Brittany Curtis, Surekha Shridhar, Rachel S Laufer, Jin Y Wang, John Van Druff, Ellen E Higginson, Nicolas Hegerle, Kristen M Varney, James E Galen, Sharon M Tennant, Andrew Lees, Alexander D MacKerell, Myron M Levine, and Raphael Simon
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Arctic medicine. Tropical medicine ,RC955-962 ,Public aspects of medicine ,RA1-1270 - Abstract
Invasive infections associated with non-typhoidal Salmonella (NTS) serovars Enteritidis (SE), Typhimurium (STm) and monophasic variant 1,4,[5],12:i:- are a major health problem in infants and young children in sub-Saharan Africa, and currently, there are no approved human NTS vaccines. NTS O-polysaccharides and flagellin proteins are protective antigens in animal models of invasive NTS infection. Conjugates of SE core and O-polysaccharide (COPS) chemically linked to SE flagellin have enhanced the anti-COPS immune response and protected mice against fatal challenge with a Malian SE blood isolate. We report herein the development of a STm glycoconjugate vaccine comprised of STm COPS conjugated to the homologous serovar phase 1 flagellin protein (FliC) with assessment of the role of COPS O-acetyls for functional immunity. Sun-type COPS conjugates linked through the polysaccharide reducing end to FliC were more immunogenic and protective in mice challenged with a Malian STm blood isolate than multipoint lattice conjugates (>95% vaccine efficacy [VE] versus 30-43% VE). Immunization with de-O-acetylated STm-COPS conjugated to CRM197 provided significant but reduced protection against STm challenge compared to mice immunized with native STm-COPS:CRM197 (63-74% VE versus 100% VE). Although OPS O-acetyls were highly immunogenic, post-vaccination sera that contained various O-acetyl epitope-specific antibody profiles displayed similar in vitro bactericidal activity when equivalent titers of anti-COPS IgG were assayed. In-silico molecular modeling further indicated that STm OPS forms a single dominant conformation, irrespective of O-acetylation, in which O-acetyls extend outward and are highly solvent exposed. These preclinical results establish important quality attributes for an STm vaccine that could be co-formulated with an SE-COPS:FliC glycoconjugate as a bivalent NTS vaccine for use in sub-Saharan Africa.
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- 2017
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44. Modeling the Potential for Vaccination to Diminish the Burden of Invasive Non-typhoidal Salmonella Disease in Young Children in Mali, West Africa.
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Kristin Bornstein, Laura Hungerford, David Hartley, John D Sorkin, Milagritos D Tapia, Samba O Sow, Uma Onwuchekwa, Raphael Simon, Sharon M Tennant, and Myron M Levine
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Arctic medicine. Tropical medicine ,RC955-962 ,Public aspects of medicine ,RA1-1270 - Abstract
BACKGROUND:In sub-Saharan Africa, systematic surveillance of young children with suspected invasive bacterial disease (e.g., septicemia, meningitis) has revealed non-typhoidal Salmonella (NTS) to be a major pathogen exhibiting high case fatality (~20%). Where infant vaccination against Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae has been introduced to prevent invasive disease caused by these pathogens, as in Bamako, Mali, their burden has decreased markedly. In parallel, NTS has become the predominant invasive bacterial pathogen in children aged
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- 2017
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45. Cryptosporidium hominis gene catalog: a resource for the selection of novel Cryptosporidium vaccine candidates.
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Olukemi O. Ifeonu, Raphael Simon, Sharon M. Tennant, Abhineet S. Sheoran, Maria C. Daly, Victor Felix, Jessica C. Kissinger, Giovanni Widmer, Myron M. Levine, Saul Tzipori, and Joana C. Silva
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- 2016
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46. The .NET Contract Wizard: Adding Design by Contract to Languages Other than Eiffel.
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Karine Arnout and Raphael Simon
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- 2001
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47. Association of clinical outcome assessments of mobility capacity and incident disability in community-dwelling older adults - a systematic review and meta-analysis
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Tobias Braun, Christian Thiel, Raphael Simon Peter, Carolin Bahns, Gisela Büchele, Kilian Rapp, Clemens Becker, and Christian Grüneberg
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Aging ,Neurology ,Time and Motion Studies ,Outcome Assessment, Health Care ,Humans ,Independent Living ,Longitudinal Studies ,Postural Balance ,Molecular Biology ,Biochemistry ,Aged ,Biotechnology - Abstract
IMPORTANCEThe predictive value of common performance-based outcome assessments of mobility capacity on incident disability in activities of daily living in community-dwelling older adults remains uncertain.OBJECTIVETo synthesize all available research on the association between mobility capacity and incident disability in non-disabled older adults.DATA SOURCESMEDLINE, EMBASE and CINAHL databases were searched without any limits or restrictions.STUDY SELECTIONPublished reports of longitudinal cohort studies that estimated a direct association between baseline mobility capacity, assessed with a standardized outcome assessment, and subsequent development of disability, including initially non-disabled older adults.DATA EXTRACTION AND SYNTHESISData extraction was completed by independent pairs of reviewers. The risk of bias was assessed using the Quality in Prognosis Studies (QUIPS) tool. Random-effect models were used to explore the objective. The certainty of evidence was assessed using GRADE.MAIN OUTCOME AND MEASURESThe main outcome measures were the pooled relative risks (RR) per one conventional unit per mobility assessment for incident disability in activities of daily living.RESULTSA total of 40 reports were included, evaluating 85,515 and 78,379 participants at baseline and follow-up, respectively (median mean age: 74.6 years). The median disability rate at follow-up was 12.0% (IQR: 5.4%–23.3%). The overall risk of bias was judged as low, moderate and high in 6 (15%), 6 (15%), and 28 (70%) reports, respectively.For usual and fast gait speed, the RR per -0.1 m/s was 1.23 (95% CI: 1.18–1.28; 26,638 participants) and 1.28 (95% CI: 1.19–1.38; 8,161 participants), respectively. Each point decrease in Short Physical Performance Battery score increased the risk of incident disability by 30% (RR = 1.30, 95% CI: 1.23– 1.38; 9,183 participants). The RR of incident disability by each second increase in Timed Up and Go test and Chair Rise Test performance was 1.15 (95% CI: 1.09–1.21; 30,426 participants) and 1.07 (95% CI: 1.04–1.10; 9,450 participants), respectively.CONCLUSIONS AND RELEVANCEAmong community-dwelling non-disabled older adults, a poor mobility capacity is a potent modifiable risk factor for incident disability. Mobility impairment should be mandated as a quality indicator of health for older people.Key PointsQUESTIONWhat are the associations between clinical outcome assessments of mobility capacity and incident disability in community-dwelling older adults?FINDINGSIn this systematic review and meta-analysis that included 40 reports and data of 85,515 older adults, the risk ratios of incident disability on activities of daily living were 1.23, 1.30, 1.15, and 1.07 for usual gait speed, Short Physical Performance Battery, Timed Up and Go test, and Chair Rise Test, respectively, per one conventional unit.MEANINGCommon assessments of mobility capacity may help identify older people at risk of incident disability and should be routinely established in regular health examinations.
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- 2022
48. The relationship of weather with daily physical activity and the time spent out of home in older adults from Germany – the ActiFE study
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Matthias, Klimek, Raphael Simon, Peter, Michael, Denkinger, Dhayana, Dallmeier, Kilian, Rapp, Dietrich, Rothenbacher, Jochen, Klenk, and R, Peter
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Geriatrics and Gerontology - Abstract
Background There is a need for a comprehensive evaluation of the associations between varieties of weather conditions on the time spent out-of-home (TOH) and on walking duration (WD) among older adults. We aim to investigate the extent to which various weather parameters (temperature, solar radiation, sunshine duration, humidity, windspeed, and rain) determine daily WD the TOH in older adults. Methods The ActiFE (Activity and Function in Older People in Ulm) study is a prospective study of participants aged 65 years or older who wore an accelerometer and kept a movement diary in up to three temporally separated waves from 2009 to 2018 for a duration up to seven days per wave (up to three weeks in summary). We used weather data from a weather station near the participants‘ homes. Age-adjusted and gender-stratified generalized mixed models were used to predict WD and TOH (with 95% confidence interval (CI)) within and between weather categories. Generalized additive models were computed for the single predictions at the weather quartile boundaries. Cubic splines (with 95% pointwise confidence bands (CB)) visualized the continuous course of the weather values. Results Higher temperatures, solar radiation and more hours of sunshine, led to an increase in WD and TOH, while higher precipitation, humidities and windspeeds led to a decrease. Women had in general higher WD and TOH times than men. Conclusions Our data suggest that weather parameters have a considerable influence on PA and TOH. Future analyses and interpretation of PA data should therefore account for weather parameters.
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- 2022
49. Additional file 1 of The relationship of weather with daily physical activity and the time spent out of home in older adults from Germany ��� the ActiFE study
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Klimek, Matthias, Peter, Raphael Simon, Denkinger, Michael, Dallmeier, Dhayana, Rapp, Kilian, Rothenbacher, Dietrich, and Klenk, Jochen
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Additional file 1: Table A.1. Association between the weather parameter values calculated by Spearman���s rank correlation coefficients. Table A.2. Regression coefficients (95% confidence interval (CI)) and explained variance (adjusted for sex and age) for mutually adjusted model of WD and TOH with weather parameters. Table A.3. Prediction of walking duration and time out-of-home for weather quartile boundary values for women. Table A.4. Prediction of walking duration and time out-of-home for weather quartile boundary values for men
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- 2022
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50. Measuring Non-Typhoidal Salmonella Specific Antibodies in Oral Fluid as a Non-Invasive Alternative to Serum
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Sean Christopher Elias, Esther Muthumbi, Alfred Mwanzu, Perpetual Wanjiku, Agnes Mutiso, Raphael Simon, and Calman MacLennan
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History ,Polymers and Plastics ,Business and International Management ,Industrial and Manufacturing Engineering - Published
- 2022
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