Last data update: May 06, 2024. (Total: 46732 publications since 2009)
Records 1-25 (of 25 Records) |
Query Trace: Ades E[original query] |
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Cardio-Oncology Rehabilitation to Manage Cardiovascular Outcomes in Cancer Patients and Survivors: A Scientific Statement From the American Heart Association
Gilchrist SC , Barac A , Ades PA , Alfano CM , Franklin BA , Jones LW , La Gerche A , Ligibel JA , Lopez G , Madan K , Oeffinger KC , Salamone J , Scott JM , Squires RW , Thomas RJ , Treat-Jacobson DJ , Wright JS , American Heart Association Exercise Cardiac Rehabilitation , and Secondary Prevention Committee of the Council on Clinical Cardiology , Council on Cardiovascular and Stroke Nursing , Council on Peripheral Vascular Disease . Circulation 2019 139 (21) e997-e1012 Cardiovascular disease is a competing cause of death in patients with cancer with early-stage disease. This elevated cardiovascular disease risk is thought to derive from both the direct effects of cancer therapies and the accumulation of risk factors such as hypertension, weight gain, cigarette smoking, and loss of cardiorespiratory fitness. Effective and viable strategies are needed to mitigate cardiovascular disease risk in this population; a multimodal model such as cardiac rehabilitation may be a potential solution. This statement from the American Heart Association provides an overview of the existing knowledge and rationale for the use of cardiac rehabilitation to provide structured exercise and ancillary services to cancer patients and survivors. This document introduces the concept of cardio-oncology rehabilitation, which includes identification of patients with cancer at high risk for cardiac dysfunction and a description of the cardiac rehabilitation infrastructure needed to address the unique exposures and complications related to cancer care. In this statement, we also discuss the need for future research to fully implement a multimodal model of cardiac rehabilitation for patients with cancer and to determine whether reimbursement of these services is clinically warranted. |
A Veterans' Healthcare Administration (VHA) antibiotic stewardship intervention to improve outpatient antibiotic use for acute respiratory infections: A cost-effectiveness analysis.
Yoo M , Madaras-Kelly K , Nevers M , Fleming-Dutra KE , Hersh AL , Ying J , Haaland B , Samore M , Nelson RE . Infect Control Hosp Epidemiol 2021 43 (10) 1-7 OBJECTIVES: The Core Elements of Outpatient Antibiotic Stewardship provides a framework to improve antibiotic use, but cost-effectiveness data on implementation of outpatient antibiotic stewardship interventions are limited. We evaluated the cost-effectiveness of Core Element implementation in the outpatient setting. METHODS: An economic simulation model from the health-system perspective was developed for patients presenting to outpatient settings with uncomplicated acute respiratory tract infections (ARI). Effectiveness was measured as quality-adjusted life years (QALYs). Cost and utility parameters for antibiotic treatment, adverse drug events (ADEs), and healthcare utilization were obtained from the literature. Probabilities for antibiotic treatment and appropriateness, ADEs, hospitalization, and return ARI visits were estimated from 16,712 and 51,275 patient visits in intervention and control sites during the pre- and post-implementation periods, respectively. Data for materials and labor to perform the stewardship activities were used to estimate intervention cost. We performed a one-way and probabilistic sensitivity analysis (PSA) using 1,000,000 second-order Monte Carlo simulations on input parameters. RESULTS: The proportion of ARI patient-visits with antibiotics prescribed in intervention sites was lower (62% vs 74%) and appropriate treatment higher (51% vs 41%) after implementation, compared to control sites. The estimated intervention cost over a 2-year period was $133,604 (2018 US dollars). The intervention had lower mean costs ($528 vs $565) and similar mean QALYs (0.869 vs 0.868) per patient compared to usual care. In the PSA, the intervention was dominant in 63% of iterations. CONCLUSIONS: Implementation of the CDC Core Elements in the outpatient setting was a cost-effective strategy. |
The Million Hearts Initiative: Catalyzing utilization of cardiac rehabilitation and accelerating implementation of new care models
Wall HK , Stolp H , Wright JS , Ritchey MD , Thomas RJ , Ades PA , Sperling LS . J Cardiopulm Rehabil Prev 2020 40 (5) 290-293 Million Hearts and partners have been committed to raising national cardiac rehabilitation participation rates to a goal of 70%. Quality improvement tools, resources, and surveillance models have been developed in support. Efforts to enhance research programs and collaborative initiatives have created momentum to accelerate implementation of new care models. |
Anticoagulation across care transitions: Identifying minimum data to maximize drug safety
Shehab N , Greenwald JL , Budnitz DS . Jt Comm J Qual Patient Saf 2018 44 (11) 627-629 Adverse drug events (ADEs) are one of the most common and costly causes of iatrogenic patient harm, and anticoagulants are the leading cause of acute, serious ADEs among hospitalized patients, long term care residents, and older outpatients.1–5 In the United States, hospitalization costs associated with anticoagulant ADEs have been estimated at more than $2.5 billion,6 and in 2016 more than $5 billion was spent on anticoagulants in Medicare Part D claims.7 Accordingly, reducing patient harm associated with anticoagulation has been a Joint Commission National Patient Safety Goal (NPSG.03.05.01) since 2008,8,9 is one of three main focus areas of the 2014 Department of Health and Human Services National Action Plan for Adverse Drug Event Prevention,10 and is a key component of the ongoing Centers for Medicare & Medicaid Services Quality Innovation Network and Hospital Improvement Innovation Network efforts to improve patient safety.11,12 An article, “Defining Minimum Necessary Anticoagulation-Related Communication at Discharge: Consensus of the Care Transitions Task Force of the New York State Anticoagulation Coalition,” in this issue of The Joint Commission Journal on Quality and Patient Safety, Triller and colleagues take another important step on the long road to achieving safer and more effective anticoagulation by proposing the core information that needs to be communicated among providers as patients treated with anticoagulants make the transition between health care settings.13 |
US emergency department visits for adverse drug events from antibiotics in children, 2011-2015
Lovegrove MC , Geller AI , Fleming-Dutra KE , Shehab N , Sapiano MRP , Budnitz DS . J Pediatric Infect Dis Soc 2018 8 (5) 384-391 Background: Antibiotics are among the most commonly prescribed medications for children; however, at least one-third of pediatric antibiotic prescriptions are unnecessary. National data on short-term antibiotic-related harms could inform efforts to reduce overprescribing and to supplement interventions that focus on the long-term benefits of reducing antibiotic resistance. Methods: Frequencies and rates of emergency department (ED) visits for antibiotic adverse drug events (ADEs) in children were estimated using adverse event data from the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project and retail pharmacy dispensing data from QuintilesIMS (2011-2015). Results: On the basis of 6542 surveillance cases, an estimated 69464 ED visits (95% confidence interval, 53488-85441) were made annually for antibiotic ADEs among children aged </=19 years from 2011 to 2015, which accounts for 46.2% of ED visits for ADEs that results from systemic medication. Two-fifths (40.7%) of ED visits for antibiotic ADEs involved a child aged </=2 years, and 86.1% involved an allergic reaction. Amoxicillin was the most commonly implicated antibiotic among children aged </=9 years. When we accounted for dispensed prescriptions, the rates of ED visits for antibiotic ADEs declined with increasing age for all antibiotics except sulfamethoxazole-trimethoprim. Amoxicillin had the highest rate of ED visits for antibiotic ADEs among children aged </=2 years, whereas sulfamethoxazole-trimethoprim resulted in the highest rate among children aged 10 to 19 years (29.9 and 24.2 ED visits per 10000 dispensed prescriptions, respectively). Conclusions: Antibiotic ADEs lead to many ED visits, particularly among young children. Communicating the risks of antibiotic ADEs could help reduce unnecessary prescribing. Prevention efforts could target pediatric patients who are at the greatest risk of harm. |
Update: Interim guidance for health care providers caring for pregnant women with possible Zika virus exposure - United States (including U.S. territories), July 2017
Oduyebo T , Polen KD , Walke HT , Reagan-Steiner S , Lathrop E , Rabe IB , Kuhnert-Tallman WL , Martin SW , Walker AT , Gregory CJ , Ades EW , Carroll DS , Rivera M , Perez-Padilla J , Gould C , Nemhauser JB , Ben Beard C , Harcourt JL , Viens L , Johansson M , Ellington SR , Petersen E , Smith LA , Reichard J , Munoz-Jordan J , Beach MJ , Rose DA , Barzilay E , Noonan-Smith M , Jamieson DJ , Zaki SR , Petersen LR , Honein MA , Meaney-Delman D . MMWR Morb Mortal Wkly Rep 2017 66 (29) 781-793 CDC has updated the interim guidance for U.S. health care providers caring for pregnant women with possible Zika virus exposure in response to 1) declining prevalence of Zika virus disease in the World Health Organization's Region of the Americas (Americas) and 2) emerging evidence indicating prolonged detection of Zika virus immunoglobulin M (IgM) antibodies. Zika virus cases were first reported in the Americas during 2015-2016; however, the incidence of Zika virus disease has since declined. As the prevalence of Zika virus disease declines, the likelihood of false-positive test results increases. In addition, emerging epidemiologic and laboratory data indicate that, as is the case with other flaviviruses, Zika virus IgM antibodies can persist beyond 12 weeks after infection. Therefore, IgM test results cannot always reliably distinguish between an infection that occurred during the current pregnancy and one that occurred before the current pregnancy, particularly for women with possible Zika virus exposure before the current pregnancy. These limitations should be considered when counseling pregnant women about the risks and benefits of testing for Zika virus infection during pregnancy. This updated guidance emphasizes a shared decision-making model for testing and screening pregnant women, one in which patients and providers work together to make decisions about testing and care plans based on patient preferences and values, clinical judgment, and a balanced assessment of risks and expected outcomes. |
Increasing cardiac rehabilitation participation from 20% to 70%: A road map from the Million Hearts Cardiac Rehabilitation Collaborative
Ades PA , Keteyian SJ , Wright JS , Hamm LF , Lui K , Newlin K , Shepard DS , Thomas RJ . Mayo Clin Proc 2016 92 (2) 234-242 The primary aim of the Million Hearts initiative is to prevent 1 million cardiovascular events over 5 years. Concordant with the Million Hearts' focus on achieving more than 70% performance in the "ABCS" of aspirin for those at risk, blood pressure control, cholesterol management, and smoking cessation, we outline the cardiovascular events that would be prevented and a road map to achieve more than 70% participation in cardiac rehabilitation (CR)/secondary prevention programs by the year 2022. Cardiac rehabilitation is a class Ia recommendation of the American Heart Association and the American College of Cardiology after myocardial infarction or coronary revascularization, promotes the ABCS along with lifestyle counseling and exercise, and is associated with decreased total mortality, cardiac mortality, and rehospitalizations. However, current participation rates for CR in the United States generally range from only 20% to 30%. This road map focuses on interventions, such as electronic medical record-based prompts and staffing liaisons that increase referrals of appropriate patients to CR, increase enrollment of appropriate individuals into CR, and increase adherence to longer-term CR. We also calculate that increasing CR participation from 20% to 70% would save 25,000 lives and prevent 180,000 hospitalizations annually in the United States. |
Augmented passive immunotherapy with P4 peptide improves phagocyte activity in severe sepsis
Morton B , Mitsi E , Pennington SH , Reine J , Wright AD , Parker R , Welters ID , Blakey JD , Rajam G , Ades EW , Ferreira DM , Wang D , Kadioglu A , Gordon SB . Shock 2016 46 (6) 635-641 INTRODUCTION: Antimicrobial resistance threatens to undermine treatment for severe infection; new therapeutic strategies are urgently needed. Pre-clinical work shows that augmented passive immunotherapy with P4 peptide increases phagocytic activity and shows promise as a novel therapeutic strategy. Our aim was to determine ex vivo P4 activity in a target population of patients admitted to critical care with severe infection. METHODS: We prospectively recruited UK critical care unit patients with severe sepsis and observed clinical course (≥3 months post discharge). Blood samples were taken in early (≤ 48hrs post-diagnosis, n = 54), latent (seven days post-diagnosis, n = 39) and convalescent (3-6 months post-diagnosis, n = 18) phases of disease. The primary outcome measure was killing of opsonised S.pneumoniae by neutrophils with and without P4 peptide stimulation. We also used a flow cytometric whole blood phagocytosis assay to determine phagocyte association and oxidation of intraphagosomal reporter beads. RESULTS: P4 peptide increased neutrophil killing of opsonised pneumococci by 8.6% (C.I. 6.35 - 10.76, p < 0.001) in all phases of sepsis, independent of infection source and microbiological status. This represented a 54.9% increase in bacterial killing compared to unstimulated neutrophils (15.6%) in early phase samples. Similarly, P4 peptide treatment significantly increased neutrophil and monocyte intraphagosomal reporter bead association and oxidation, independent of infection source. CONCLUSIONS: We have extended pre-clinical work to demonstrate that P4 peptide significantly increases phagocytosis and bacterial killing in samples from a target patient population with severe sepsis. This study supports the rationale for augmented passive immunotherapy as a therapeutic strategy in severe sepsis. |
Impact of sulfadoxine-pyrimethamine resistance on effectiveness of intermittent preventive therapy for malaria in pregnancy at clearing infections and preventing low birth weight
Desai M , Gutman J , Taylor SM , Wiegand RE , Khairallah C , Kayentao K , Ouma P , Coulibaly SO , Kalilani L , Mace KE , Arinaitwe E , Mathanga DP , Doumbo O , Otieno K , Edgar D , Chaluluka E , Kamuliwo M , Ades V , Skarbinski J , Shi YP , Magnussen P , Meshnick S , Ter Kuile FO . Clin Infect Dis 2015 62 (3) 323-333 BACKGROUND: Monitoring the effectiveness of intermittent preventive therapy in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is crucial owing to increasing SP resistance in sub-Saharan Africa. METHODS: Between 2009 and 2013, both the efficacy of IPTp-SP at clearing existing peripheral malaria infections and the effectiveness of IPTp-SP at reducing low birthweight (LBW) were assessed among HIV-negative participants in 8 sites in 6 countries. Sites were classified as high, medium or low resistance after measuring mutations conferring SP resistance. An individual-level prospective pooled analysis was conducted. RESULTS: Among 1,222 parasitaemic pregnant women, overall PCR-uncorrected and -corrected failure rates by day 42 were 21.3% and 10.0%, respectively (39.7% and 21.1% in high-resistance areas; 4.9% and 1.1% in low-resistance areas). Median time to recurrence decreased with increasing prevalence of Pfdhps-K540E. Among 6,099 women at delivery, each incremental dose of IPTp-SP was associated with a 22% reduction in the risk of LBW (prevalence ratio [PR]=0.78 [95% CI 0.69-0.88], p<0.001). This association was not modified by insecticide-treated net use or gravidity, and remained significant in areas with SP resistance (PR=0.81 [0.67-0.97], p=0.02). CONCLUSIONS: The efficacy of SP to clear peripheral parasites and prevent new infections during pregnancy is compromised in areas with >90% prevalence of Pfdhps-K540E. Nevertheless, in these high resistance areas, IPTp-SP use remains associated with increases in birthweight and maternal haemoglobin. The effectiveness of IPTp in eastern and southern Africa is threatened by further increases in SP-resistance and reinforces the need to evaluate alternative drugs and strategies for the control of malaria in pregnancy. |
A proteomic characterization of Bordetella pertussis clinical isolates associated with a California state pertussis outbreak
Williamson YM , Moura H , Whitmon J , Woolfitt AR , Schieltz DM , Rees JC , Guo S , Kirkham H , Bouck D , Ades EW , Tondella ML , Carlone GM , Sampson JS , Barr JR . Int J Proteomics 2015 2015 536537 Bordetella pertussis (Bp) is the etiologic agent of pertussis (whooping cough), a highly communicable infection. Although pertussis is vaccine preventable, in recent years there has been increased incidence, despite high vaccine coverage. Possible reasons for the rise in cases include the following: Bp strain adaptation, waning vaccine immunity, increased surveillance, and improved clinical diagnostics. A pertussis outbreak impacted California (USA) in 2010; children and preadolescents were the most affected but the burden of disease fell mainly on infants. To identify protein biomarkers associated with this pertussis outbreak, we report a whole cellular protein characterization of six Bp isolates plus the pertussis acellular vaccine strain Bp Tohama I (T), utilizing gel-free proteomics-based mass spectrometry (MS). MS/MS tryptic peptide detection and protein database searching combined with western blot analysis revealed three Bp isolates in this study had markedly reduced detection of pertactin (Prn), a subunit of pertussis acellular vaccines. Additionally, antibody affinity capture technologies were implemented using anti-Bp T rabbit polyclonal antisera and whole cellular proteins to identify putative immunogens. Proteome profiling could shed light on pathogenesis and potentially lay the foundation for reduced infection transmission strategies and improved clinical diagnostics. |
Emergency department visits by children and adolescents for antipsychotic drug adverse events
Hampton LM , Daubresse M , Chang HY , Alexander GC , Budnitz DS . JAMA Psychiatry 2015 72 (3) 292-4 The per capita number of outpatient visits in which an antipsychotic drug was supplied or prescribed increased approximately 660% among children and 380% among adolescents between the mid-1990s and the mid-2000s in the United States,1 prompting concerns about possible inappropriate prescribing. The most recent revisions to the DSM-5 were intended in part to decrease inappropriate child and adolescent antipsychotic drug use,2 and the American Psychiatric Association has warned against using antipsychotics as first-line therapy in children and adolescents for conditions other than psychotic disorders.3 To quantify acute harms from child and adolescent antipsychotic drug use, we estimated the numbers and rates of US emergency department (ED) visits and hospitalizations for adverse drug events (ADEs) from therapeutic use of antipsychotics and comparator psychotropic medications among children 10 years or younger and adolescents 11 to 18 years. |
Emergency department visits by adults for psychiatric medication adverse events
Hampton LM , Daubresse M , Chang HY , Alexander GC , Budnitz DS . JAMA Psychiatry 2014 71 (9) 1006-14 IMPORTANCE: In 2011, an estimated 26.8 million US adults used prescription medications for mental illness. OBJECTIVE: To estimate the numbers and rates of adverse drug event (ADE) emergency department (ED) visits involving psychiatric medications among US adults between January 1, 2009, and December 31, 2011. DESIGN AND SETTING: Descriptive analyses of active, nationally representative surveillance of ADE ED visits using the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance system and of drug prescribing during outpatient visits using the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey. PARTICIPANTS: Medical records from national probability samples of ED and outpatient visits by adults 19 years or older were reviewed and analyzed. EXPOSURES: Antidepressants, antipsychotics, lithium salts, sedatives and anxiolytics, and stimulants. MAIN OUTCOMES AND MEASURES: National estimates of ADE ED visits resulting from therapeutic psychiatric medication use and of psychiatric medication ADE ED visits per 10 000 outpatient visits at which psychiatric medications were prescribed. RESULTS: From 2009 through 2011, there were an estimated 89 094 (95% CI, 68 641-109 548) psychiatric medication ADE ED visits annually, with 19.3% (95% CI, 16.3%-22.2%) resulting in hospitalization and 49.4% (95% CI, 46.5%-52.4%) involving patients aged 19 to 44 years. Sedatives and anxiolytics, antidepressants, antipsychotics, lithium salts, and stimulants were implicated in an estimated 30 707 (95% CI, 23 406-38 008), 25 377 (95% CI, 19 051-31 704), 21 578 (95% CI, 16 599-26 557), 3620 (95% CI, 2311-4928), and 2779 (95% CI, 1764-3794) respective ADE ED visits annually. Antipsychotics and lithium salts were implicated in 11.7 (95% CI, 10.1-13.2) and 16.4 (95% CI, 13.0-19.9) ADE ED visits per 10 000 outpatient prescription visits, respectively, compared with 3.6 (95% CI, 3.2-4.1) for sedatives and anxiolytics, 2.9 (95% CI, 2.3-3.5) for stimulants, and 2.4 (95% CI, 2.1-2.7) for antidepressants. The commonly used sedative zolpidem tartrate was implicated in 11.5% (95% CI, 9.5%-13.4%) of all adult psychiatric medication ADE ED visits and in 21.0% (95% CI, 16.3%-25.7%) of visits involving adults 65 years or older, in both cases significantly more than any other psychiatric medication. CONCLUSIONS AND RELEVANCE: Psychiatric medications are implicated in many ADEs treated in US EDs. Efforts to reduce ADEs should include adults of all ages but might prioritize medications causing high numbers and rates of ED visits. |
Prediction and characterization of helper T-cell epitopes from pneumococcal surface adhesin A
Singh R , Gupta P , Sharma PK , Ades EW , Hollingshead SK , Singh S , Lillard JW . Immunology 2014 141 (4) 514-530 Pneumococcal surface adhesin A (PsaA) is a multifunctional lipoprotein known to bind nasopharyngeal epithelial cells, and is significantly involved in bacterial adherence and virulence. Identification of PsaA peptides that optimally bind human leucocyte antigen (HLA) and elicit a potent immune response would be of great importance to vaccine development. However, this is hindered by the multitude of HLA polymorphisms in humans. To identify the conserved immunodominant epitopes, we used an experimental dataset of 28 PsaA synthetic peptides and in silico methods to predict specific peptide-binding to HLA and murine MHC class II molecules. We also characterized spleen and cervical lymph node (CLN) -derived T helper (Th) lymphocyte cytokine responses to these peptides after Streptococcus pneumoniae strain EF3030 challenge in mice. Individual, yet overlapping, peptides 15 amino acids in length revealed residues of PsaA that consistently caused the highest interferon-gamma, interleukin-2 (IL-2), IL-5 and IL-17 responses and proliferation as well as moderate IL-10 and IL-4 responses by ex vivo re-stimulated splenic and CLN CD4+ T cells isolated from S. pneumoniae strain EF3030-challenged F1 (B6 x BALB/c) mice. In silico analysis revealed that peptides from PsaA may interact with a broad range of HLA-DP, -DQ and -DR alleles, due in part to regions lacking beta-turns and asparagine endopeptidase sites. These data suggest that Th cell peptides (7, 19, 20, 22, 23 and 24) screened for secondary structures and MHC class II peptide-binding affinities can elicit T helper cytokine and proliferative responses to PsaA peptides. |
Cough and cold medication adverse events after market withdrawal and labeling revision
Hampton LM , Nguyen DB , Edwards JR , Budnitz DS . Pediatrics 2013 132 (6) 1047-54 BACKGROUND: In October 2007, manufacturers voluntarily withdrew over-the-counter (OTC) infant cough and cold medications (CCMs) from the US market. A year later, manufacturers announced OTC CCM labeling would be revised to warn against OTC CCM use by children aged <4 years. We determined whether emergency department (ED) visits for CCM adverse drug events (ADEs) declined after these interventions. METHODS: We used National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance data from 2004 to 2011 to estimate the number of ED visits for CCM ADEs before and after each intervention. RESULTS: Among children aged <2 years, ED visits for CCM ADEs decreased from 4.1% of all ADE ED visits before the market withdrawal to 2.4% of all ADE visits afterward (difference in proportion: -1.7%, 95% confidence interval [CI]: -2.7% to -0.6%). Among children aged 2 to 3 years, ED visits for CCM ADEs decreased from 9.5% of all ADE ED visits before the labeling revision announcement to 6.5% of all ADE visits afterward (difference in proportion: -3.0%, 95% CI: -5.4% to -0.6%). Unsupervised ingestions accounted for 64.3% (95% CI: 51.1% to 77.5%) of CCM ADE ED visits involving children aged <2 years after the withdrawal and 88.8% (95% CI: 83.8% to 93.8%) of visits involving children aged 2 to 3 years after the labeling revision announcement. CONCLUSIONS: After a voluntary market withdrawal and labeling revision, ED visits for CCM ADEs declined among children aged <2 years and 2 to 3 years relative to ADE ED visits for all drugs. Interventions addressing unsupervised ingestions are needed to reduce CCM ADEs. |
Emergency department visits and hospitalizations for digoxin toxicity: United States, 2005-2010
See I , Shehab N , Kegler SR , Laskar SR , Budnitz DS . Circ Heart Fail 2013 7 (1) 28-34 BACKGROUND: Recent data on digoxin prescribing and adverse events are lacking but could help inform the management of digoxin in contemporary heart failure treatment. METHODS AND RESULTS: We determined nationally-representative numbers and rates of emergency department (ED) visits for digoxin toxicity in the United States using 2005-2010 reports from the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project and the National Ambulatory (and Hospital Ambulatory) Medical Care Surveys. Based on 441 cases, an estimated 5,156 (95% confidence interval [CI], 2,663-7,648) ED visits for digoxin toxicity occurred annually in the United States; over three-fourths (78.8% [95% CI, 73.5%-84.1%]) resulted in hospitalization. Serum digoxin level was ≥2.0 ng/mL for 95.8% (95% CI, 93.2%-98.4%) of estimated ED visits with levels reported (n=251 cases). The rate of ED visits per 10,000 outpatient prescription visits among patients ≥85 years was twice that of patients 40-84 years (rate ratio, 2.4 [95% CI, 1.2-5.0]); among females, the rate was twice that of males (rate ratio, 2.3 [95% CI, 1.1-4.7]). Digoxin toxicity accounted for an estimated 1.0% (95% CI, 0.6%-1.4%) of ED visits for all adverse drug events (ADEs) among patients ≥40 years, but an estimated 3.3% (95% CI, 2.3%-4.4%) of ED visits and 5.9% (95% CI, 4.0%-7.9%) of hospitalizations for all ADEs among patients ≥85 years. Estimated annual ED visits and hospitalizations remained relatively constant from 2005-2010. CONCLUSIONS: Digoxin toxicity is not declining; more careful prescribing to high-risk groups and improved monitoring of serum levels might be needed to reduce morbidity from outpatient digoxin use. |
P4-mediated antibody therapy in an acute model of invasive pneumococcal disease
Bangert M , Bricio-Moreno L , Gore S , Rajam G , Ades EW , Gordon SB , Kadioglu A . J Infect Dis 2012 205 (9) 1399-407 New treatments against severe bacterial infections are needed because the response to antibiotic treatment is slow in acute settings and is becoming less effective owing to the emergence of antibiotic-resistant pathogens. P4-mediated antibody therapy offers a unique treatment strategy that combines exogenous immunoglobulin with the immunoactivating peptide P4. In an acute model of pneumococcal disease, mice were infected with Streptococcus pneumoniae and treated intravenously or intranasally with P4 and intravenous immunoglobulin (IVIG). Survival of P4-IVIG-treated mice increased from 0% to 60% among those that received intravenous treatment and from 0% to 100% among those that received intranasal treatment. Importantly, intranasal administration of P4 at an early stage of infection prevented the onset of bacteremia and sepsis. Increased survival was associated with reduced bacterial burden in affected tissues and with recruitment and activation of professional phagocytes, as manifested by increased expression of Fc-gamma receptors. In vitro studies involving P4-stimulated alveolar, peritoneal, and J774.2 murine macrophages showed an increased ability of these immune cells to phagocytose pneumococci independent of capsule. The use of adjunct antibody therapies to treat infectious diseases shows promise. |
A gel-free proteomic-based method for the characterization of Bordetella pertussis clinical isolates
Williamson YM , Moura H , Simmons K , Whitmon J , Melnick N , Rees J , Woolfitt A , Schieltz DM , Tondella ML , Ades E , Sampson J , Carlone G , Barr JR . J Microbiol Methods 2012 90 (2) 119-33 Bordetella pertussis (Bp) is the etiologic agent of pertussis or whooping cough, a highly contagious respiratory disease occurring primarily in infants and young children. Although vaccine preventable, pertussis cases have increased over the years leading researchers to re-evaluate vaccine control strategies. Since bacterial outer membrane proteins, comprising the surfaceome, often play roles in pathogenesis and antibody-mediated immunity, three recent Bp circulating isolates were examined using proteomics to identify any potential changes in surface protein expression. Fractions enriched for outer membrane proteins were digested with trypsin and the peptides analyzed by nano liquid chromatography-electrospray ionization-mass spectrometry (nLC-ESI-MS), followed by database analysis to elucidate the surfaceomes of our three Bp isolates. Furthermore, a less labor intensive non-gel based antibody affinity capture technology in conjunction with MS was employed to assess each Bp strains' immunogenic outer membrane proteins. This novel technique is generally applicable allowing for the identification of immunogenic surface expressed proteins on pertussis and other pathogenic bacteria. |
Analysis of influenza viruses from patients clinically suspected of infection with an oseltamivir resistant virus during the 2009 pandemic in the United States.
Nguyen HT , Trujillo AA , Sheu TG , Levine M , Mishin VP , Shaw M , Ades EW , Klimov AI , Fry AM , Gubareva LV . Antiviral Res 2012 93 (3) 381-6 During the 2009 influenza pandemic, the Centers for Disease Control and Prevention provided antiviral susceptibility testing for patients infected with suspected drug-resistant viruses. Specimens from 72 patients admitted to an intensive care unit or with a severe immunocompromising condition, who failed to clinically improve after oseltamivir treatment, were accepted for testing. Respiratory specimens were tested for the presence of the oseltamivir resistance-conferring H275Y substitution in the neuraminidase (NA) by pyrosequencing. Virus isolates propagated in MDCK cells were tested in phenotypic NA inhibition (NI) assays using licensed NA inhibitors (NAIs), zanamivir and oseltamivir, and investigational NAIs, peramivir and laninamivir. Conventional sequencing and plaque purification were conducted on a subset of viruses. Pyrosequencing data were obtained for 87 specimens collected from 58 of the 72 (81%) patients. Of all patients, 27 (38%) had at least one specimen in which H275Y was detected. Analysis of sequential samples from nine patients revealed intra-treatment emergence of H275Y variant and a shift from wildtype-to-H275Y in quasispecies during oseltamivir therapy. A shift in the H275Y proportion was observed as a result of virus propagation in MDCK cells. Overall, the NI method was less sensitive than pyrosequencing in detecting the presence of H275Y variants in virus isolates. Using the NI method, isolates containing H275Y variant at 50% exhibited resistance to oseltamivir and peramivir, but retained full susceptibility to zanamivir. H275Y viruses recovered from two patients had an additional substitution I223K or I223R that conferred a 38-52- and 33-97-fold enhancement in oseltamivir- and peramivir-resistance, respectively. These viruses also showed decreased susceptibility to zanamivir and laninamivir. These data suggest that pyrosequencing is a powerful tool for timely detection of NAI resistant viruses and that NI assays are needed for comprehensive testing to detect novel resistance substitutions. |
A rapid method for capture and identification of immunogenic proteins in Bordetella pertussis enriched membranes fractions: a fast-track strategy applicable to other microorganisms
West R , Whitmon J , Williamson YM , Moura H , Nelson M , Melnick N , Tondella ML , Schieltz D , Rees J , Woolfitt AR , Barr JR , Ades EW , Carlone GM , Sampson JS . J Proteomics 2012 75 (6) 1966-72 Mass spectrometry (MS) coupled with 1-D and 2-D electrophoresis can be utilized to detect and identify immunogenic proteins, but these methods are laborious and time-consuming. We describe an alternative, simple, rapid gel-free strategy to identify multiple immunogenic proteins from Bordetella pertussis (Bp). It couples immunoprecipitation to nano liquid chromatography- tandem mass spectrometry (IP-nLC-MS/MS) and is significantly both time- and labor-saving. We developed a gel-free magnetic bead-based immunoprecipitation (IP) method using different NP-40/PBS concentrations in which solubilized proteins of Bp Tohama I membrane fractions were precipitated with polyclonal rabbit anti-Bp whole cell immune sera. Immune complexes were analyzed by MS and Scaffold analysis (>95% protein identification probability). Total immunoproteins identified were 50, 63 and 49 for 0.90%, 0.45% and 0.22% NP-40/PBS buffer concentrations respectively. Known Bp proteins identified included pertactin, serotype 2 fimbrial subunit and filamentous hemagglutinin. As proof of concept that this gel-free protein immunoprecipitation method enabled the capture of multiple immunogenic proteins, IP samples were also analyzed by SDS-PAGE and immunoblotting. Bypassing gels and subjecting immunoprecipitated proteins directly to MS is a simple and rapid antigen identification method with relatively high throughput. IP-nLC-MS/MS provides a novel alternative approach for current methods used for the identification of immunogenic proteins. |
Emergency department visits for antiviral adverse events during the 2009 H1N1 influenza pandemic
Lovegrove MC , Shehab N , Hales CM , Poneleit K , Crane E , Budnitz DS . Public Health Rep 2011 126 (3) 312-7 The 2009 pandemic influenza A (H1N1) outbreak was associated with an increased use of antiviral agents and highlighted the role of population-based monitoring for related adverse drug events (ADEs). An ongoing, nationally representative emergency department-based surveillance system was used to identify and characterize ADEs during the pandemic. Active surveillance for ADEs successfully provided timely, population-based data during the pandemic. Increases in antiviral ADEs paralleled increases in prescribing. Type and severity of ADEs were similar across all seasons. |
Immunotherapy with a combination of intravenous immune globulin and p4 peptide rescues mice from postinfluenza pneumococcal pneumonia
Weeks JN , Boyd KL , Rajam G , Ades EW , McCullers JA . Antimicrob Agents Chemother 2011 55 (5) 2276-81 Alternate therapies are needed for treatment of secondary bacterial pneumonia following influenza. The immunomodulatory peptide P4 has shown promise in mouse models of primary pneumococcal infection. Mice infected with influenza virus then challenged with Streptococcus pneumoniae were treated with a combination of P4 peptide and intravenous immune globulin. Survival was improved from 20% to 80% in treated mice relative to controls. Clinical cure correlated with increased clearance of bacteria and decreased lung consolidation. Greater trafficking of professional phagocytic cells to the site of pneumococcal infection coupled with enhanced opsonophagocytosis as manifest by decreased surface display of Fcgamma receptors on neutrophils and macrophages were associated with P4 peptide treatment. This suggests that the mechanism of action for improved clearance of bacteria engendered by P4 is through improved uptake by phagocytes mediated by IgG Fc - Fcgamma receptor interactions following antibody mediated opsonophagocytosis of bacteria. Antibody-based therapies, when coupled with immune modulators such as P4 peptide, may be an effective tool together with antibiotics in our armamentarium against severe pneumonia. |
P4 peptide therapy rescues aged mice from fatal pneumococcal sepsis
Rajam G , Bangert M , Hammons GM , Melnick N , Carlone GM , Sampson JS , Ades EW . Clin Vaccine Immunol 2010 17 (11) 1823-4 Many studies suggest that with aging, immune capabilities gradually diminish, leading to a decrease in antibody production, cytokines, and various effector cells (1-4). In this study, we examined the effects of an immune-enhancing peptide on aged mice. P4, a 28-amino-acid cationic peptide derived from pneumococcal surface adhesin A (PsaA), is a eukaryotic cellular activator (10). Previously, we demonstrated that the cellular activation properties of P4 can be utilized to rescue severely ill young mice from fatal pneumococcal infection in the presence of pathogen-specific antibodies and active complement (8, 12). While P4 therapy was used to rescue young Swiss Webster mice (6 to 10 weeks old), we questioned its effectiveness in aged mice (11 and 15 months old). | Intranasal inoculation of mice with Streptococcus pneumoniae WU2 (serotype 3) and P4 therapy were done using protocols previously described, with minor modifications (12). Eleven-month-old BALB/c (n = 20) and 15-month-old Swiss Webster mice (n = 20) were infected intranasally with S. pneumoniae WU2 (∼2.1 × 107 cells/mouse). Mice were monitored and visually scored twice daily for moribund characteristics as previously described (12). At 48 h postchallenge, 80% (16/20) were moribund. Moribund mice were divided into a control (n = 8) and a treatment group (n = 8). Two doses of P4 therapy with pathogen-specific antibody (intravenous immunoglobulin [IVIG]; Gamunex, Telecris, NC) and P4 were administered intravenously (postinfection) in the treatment group. Treated and untreated animals were monitored for 166 h, and the data computed for significant differences among various groups using a t test for paired samples for the means (MS Excel 2007). |
An augmented passive immune therapy to treat fulminant bacterial infections
Rajam G , Sampson J , Carlone GM , Ades EW . Recent Pat Antiinfect Drug Discov 2010 5 (2) 157-67 In the early 1900s, passive immunization/antibody therapy was used to treat a variety of human ailments such as hypoimmunoglobulinemia, cancer and infectious disease. The advent of antibiotic therapy had relegated this type of therapy obsolete for treatment of infectious diseases. Emergence of multi-drug resistant pathogens along with novel monoclonal antibody production techniques has rekindled the interest in passive immunization (PI). An increase in the number of monoclonal antibody patent applications in the recent past suggests a renewed commercial interest in PI. Despite these developments, antibody therapy for infectious diseases has limitations including the need for large or frequent dosages. P4, a 28-amino acid peptide is a multi-lineage cellular activator. P4, along with infectious disease (i.e. Pathogen) specific immunoglobulin, has been shown in vitro and in vivo in mice to potentiate innate immunity. This review will discuss the progress made in passive antibody therapy, the challenges still to be surmounted, and the potential expanded role of an immune-potentiating peptide (bio-molecule) in the quest to utilize and revitalize passive immunization. |
Mass spectrometric analysis of multiple pertussis toxins and toxoids
Williamson YM , Moura H , Schieltz D , Rees J , Woolfitt AR , Pirkle JL , Sampson JS , Tondella ML , Ades E , Carlone G , Barr JR . J Biomed Biotechnol 2010 2010 942365 Bordetella pertussis (Bp) is the causative agent of pertussis, a vaccine preventable disease occurring primarily in children. In recent years, there has been increased reporting of pertussis. Current pertussis vaccines are acellular and consist of Bp proteins including the major virulence factor pertussis toxin (Ptx), a 5-subunit exotoxin. Variation in Ptx subunit amino acid (AA) sequence could possibly affect the immune response. A blind comparative mass spectrometric (MS) analysis of commercially available Ptx as well as the chemically modified toxoid (Ptxd) from licensed vaccines was performed to assess peptide sequence and AA coverage variability as well as relative amounts of Ptx subunits. Qualitatively, there are similarities among the various sources based on AA percent coverages and MS/MS fragmentation profiles. Additionally, based on a label-free mass spectrometry-based quantification method there is differential relative abundance of the subunits among the sources. |
Concomitant administration of recombinant PsaA and PCV7 reduces Streptococcus pneumoniae serotype 19A colonization in a murine model
Whaley MJ , Sampson JS , Johnson SE , Rajam G , Stinson-Parks A , Holder P , Mauro E , Romero-Steiner S , Carlone GM , Ades EW . Vaccine 2010 28 (18) 3071-5 A murine colonization model was used to determine the effect of co-administering 7-valent polysaccharide-protein conjugate vaccine and pneumococcal surface adhesin A. Mice were challenged intranasally with either PCV7 serotypes, 4 or 14, or a non-PCV7 serotype, 19A. Post-challenge samples were evaluated for IgG antibody levels, opsonophagocytic activity, and nasopharyngeal colonization. No interference was observed between immune responses from the concomitant and individual immunizations. Concomitant immunizations reduced carriage for tested serotypes; largest reduction was observed for 19A. From these mouse studies, co-administering pneumococcal antigens appear to expand coverage and reduce colonization against a non-PCV7 serotype without inhibiting immunogenicity to other serotypes. |
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