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1.
Vaccines (Basel) ; 10(11)2022 Nov 19.
Article in English | MEDLINE | ID: mdl-36423058

ABSTRACT

Pneumonia accounts for over 20% of deaths worldwide in children aged 1 to 5 years, disproportionately affecting lower- and middle-income countries. Effective, highly multivalent pneumococcal vaccines are available to decrease disease burden, with numerous new vaccines currently under development to serve a variety of worldwide markets. However, pneumococcal conjugate vaccines are among the hardest biologics to manufacture and characterize due to their complexity and heterogeneity. Current characterization methods are often inherently singleplex, requiring separate tests for each serotype present. In addition, identity and quantity are often determined with separate methods. We developed the VaxArray pneumococcal assay for applications in identity, quantity, and stability testing of pneumococcal polysaccharide and pneumococcal conjugate vaccines. The VaxArray pneumococcal assay has a time to result of less than 30 min and is an off-the-shelf multiplexed, microarray-based immunoassay kit that can identify and simultaneously quantify 23 pneumococcal polysaccharide serotypes common to many on-market and in-development vaccines. Here, we highlight the potential of the assay for identity testing by showing high reactivity and serotype specificity to a wide variety of native polysaccharides, CRM197-conjugated polysaccharides, and drug product. The assay also has vaccine-relevant lower limits of quantification in the low-to-mid ng/mL range and can be used for accurate quantification even in adjuvanted vaccines. Excellent correlation to the anthrone assay is demonstrated, with VaxArray resulting in significantly improved precision over this antiquated chemical method.

2.
Vaccines (Basel) ; 10(10)2022 Oct 12.
Article in English | MEDLINE | ID: mdl-36298569

ABSTRACT

The COVID-19 pandemic highlighted mRNA as a promising platform for vaccines and therapeutics. Many of the analytical tools used to characterize the critical quality attributes of mRNA are inherently singleplex and are not necessarily optimal from a labor and cost perspective. Here, we demonstrate the feasibility of a multiplexed platform (VaxArray) for efficient identity verification and concentration determination for both monovalent and multivalent mRNA formulations. A model system comprising mRNA constructs for influenza hemagglutinin and neuraminidase was used to characterize the analytical performance metrics for a VaxArray mRNA assay. The assay presented herein had a time to result of less than 2 h, required no PCR-based amplification nor extraction of mRNA from lipid nanoparticles, and exhibited high construct specificity that enabled application to the bivalent mixture. The sensitivity for influenza hemagglutinin and neuraminidase mRNA was sub-µg/mL, which is vaccine-relevant, and the average accuracy (%recovery of a check standard) and precision were 104 ± 2% and 9 ± 2%, respectively.

3.
J Immunol Methods ; 504: 113259, 2022 05.
Article in English | MEDLINE | ID: mdl-35314144

ABSTRACT

Next generation poliovirus vaccines are critical to reaching global poliovirus eradication goals. Recent efforts have focused on creating inactivated vaccines using attenuated Sabin strains that maintain patient safety benefits and immunogenicity of conventional inactivated vaccines while increasing manufacturing safety and lowering production costs, and on developing novel oral vaccines using modified Sabin strains that provide critical mucosal immunity but are further attenuated to minimize risk of reversion to neurovirulence. In addition, there is a push to improve the analytical tools for poliovirus vaccine characterization. Conventional and Sabin inactivated poliovirus vaccines typically rely on standard plate-based ELISA as in vitro D-antigen potency assays in combination with WHO international standards as calibrants. While widely utilized, the current D-antigen ELISA assays have a long time to result (up to 72 h), can suffer from lab-to-lab inconsistency due to non-standardized protocols and reagents, and are inherently singleplex. For D-antigen quantitation, we have developed the VaxArray Polio Assay Kit, a multiplexed, microarray-based immunoassay that uses poliovirus-specific human monoclonal antibodies currently under consideration as standardized reagents for characterizing inactivated Sabin and Salk vaccines. The VaxArray assay can simultaneously quantify all 3 poliovirus serotypes with a time to result of less than 3 h. Here we demonstrate that the assay has limits of quantification suitable for both bioprocess samples and final vaccines, excellent reproducibility and precision, and improved accuracy over an analogous plate-based ELISA. The assay is suitable for adjuvanted combination vaccines, as common vaccine additives and crude matrices do not interfere with quantification, and is intended as a high throughput, standardized quantitation tool to aid inactivated poliovirus vaccine manufacturers in streamlining vaccine development and manufacturing, aiding the global polio eradication effort.


Subject(s)
Poliomyelitis , Poliovirus , Antibodies, Viral , Antigens, Viral , Enzyme-Linked Immunosorbent Assay , Humans , Poliomyelitis/diagnosis , Poliomyelitis/prevention & control , Poliovirus Vaccine, Inactivated , Poliovirus Vaccine, Oral , Reproducibility of Results , Vaccines, Inactivated
4.
Vaccine X ; 9: 100113, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34622199

ABSTRACT

Measles-containing vaccines (MCV), specifically vaccines against measles and rubella (MR), are extremely effective and critical for the eradication of measles and rubella diseases. In developed countries, vaccination rates are high and vaccines are readily available, but continued high prevalence of both diseases in developing countries and surges in measles deaths in recent years have highlighted the need to expand vaccination efforts. To meet demand for additional vaccines at a globally affordable price, it is highly desirable to streamline vaccine production thereby reducing cost and speeding up time to delivery. MR vaccine characterization currently relies on the 50% cell culture infectious dose (CCID50) assay, an endpoint assay with low reproducibility that requires 10-14 days to complete. For streamlining bioprocess analysis and improving measurement precision relative to CCID50, we developed the VaxArray Measles and Rubella assay kit, which is based on a multiplexed microarray immunoassay with a 5-hour time to result. Here we demonstrate vaccine-relevant sensitivity ranging from 345 to 800 IFU/mL up to 100,000 IFU/mL (infectious units per mL) and specificity that allows simultaneous analysis in bivalent vaccine samples. The assay is sensitive to antigen stability and has minimal interference from common vaccine additives. The assay exhibits high reproducibility and repeatability, with 15% CV, much lower than the typical 0.3 log10 error (∼65%) observed for the CCID50 assay. The intact protein concentration measured by VaxArray is reasonably correlated to, but not equivalent to, CCID50 infectivity measurements for harvest samples. However, the measured protein concentration exhibits equivalency to CCID50 for more purified samples, including concentrated virus pools and monovalent bulks, making the assay a useful new tool for same-day analysis of vaccine samples for bioprocess development, optimization, and monitoring.

5.
J Virol Methods ; 291: 114111, 2021 05.
Article in English | MEDLINE | ID: mdl-33640374

ABSTRACT

Rapid, sensitive, and precise multiplexed assays for serological analysis during candidate COVID-19 vaccine development would streamline clinical trials. The VaxArray Coronavirus (CoV) SeroAssay quantifies IgG antibody binding to 9 pandemic, potentially pandemic, and endemic human CoV spike antigens in 2 h with automated results analysis. IgG antibodies in serum bind to the CoV spike protein capture antigens printed in a microarray format and are labeled with a fluorescent anti-species IgG secondary label. The assay demonstrated excellent lower limits of quantification ranging from 0.3 to 2.0 ng/mL and linear dynamic ranges of 76 to 911-fold. Average precision of 11 % CV and accuracy (% recovery) of 92.5 % over all capture antigens were achieved over 216 replicates representing 3 days and 3 microarray lots. Clinical performance on 263 human serum samples (132 SARS-CoV-2 negatives and 131 positives based on donor-matched RT-PCR and/or date of collection) produced 98.5 % PPA and 100 % NPA.


Subject(s)
Antibodies, Viral/blood , Coronavirus Infections/diagnosis , Coronavirus/isolation & purification , Microarray Analysis/methods , Serologic Tests/methods , Antigens, Viral/immunology , COVID-19/diagnosis , COVID-19/immunology , COVID-19 Nucleic Acid Testing , COVID-19 Testing/methods , Coronavirus/immunology , Coronavirus Infections/immunology , Humans , Immunoassay/methods , Immunoglobulin G/blood , Reproducibility of Results , SARS-CoV-2/isolation & purification , Sensitivity and Specificity , Spike Glycoprotein, Coronavirus/immunology
6.
Influenza Other Respir Viruses ; 14(1): 55-60, 2020 01.
Article in English | MEDLINE | ID: mdl-31608599

ABSTRACT

BACKGROUND: Global influenza surveillance in humans and animals is a critical component of pandemic preparedness. The FluChip-8G Insight assay was developed to subtype both seasonal and potentially pandemic influenza viruses in a single assay with a same day result. FluChip-8G Insight uses whole gene segment RT-PCR-based amplification to provide robustness against genetic drift and subsequent microarray detection with artificial neural network-based data interpretation. OBJECTIVES: The objective of this study was to verify and validate the performance of the FluChip-8G Insight assay for the detection and positive identification of human and animal origin non-seasonal influenza A specimens. METHODS: We evaluated the ability of the FluChip-8G Insight technology to type and HA and NA subtype a sample set consisting of 297 results from 180 unique non-seasonal influenza A strains (49 unique subtypes). RESULTS: FluChip-8G Insight demonstrated a positive percent agreement ≥93% for 5 targeted HA and 5 targeted NA subtypes except for H9 (88%), and negative percent agreement exceeding 95% for all targeted subtypes. CONCLUSIONS: The FluChip-8G Insight neural network-based algorithm used for virus identification performed well over a data set of 297 naïve sample results, and can be easily updated to improve performance on emerging strains without changing the underlying assay chemistry.


Subject(s)
Hemagglutinin Glycoproteins, Influenza Virus/genetics , Influenza A virus/isolation & purification , Influenza, Human/virology , Neuraminidase/genetics , Reverse Transcriptase Polymerase Chain Reaction/methods , Viral Proteins/genetics , DNA Primers/genetics , Humans , Influenza A virus/classification , Influenza A virus/genetics , Influenza, Human/diagnosis , Influenza, Human/epidemiology , Pandemics , United States/epidemiology
7.
J Clin Virol ; 118: 20-27, 2019 09.
Article in English | MEDLINE | ID: mdl-31382226

ABSTRACT

BACKGROUND: The FluChip-8G Influenza A+B Assay is a multiplexed influenza RT-PCR and microarray-based assay with same day turnaround time, developed to subtype seasonal A viruses (H1N1pdm2009 and H3N2), distinguish B viruses as Yamagata or Victoria lineage, and is the only FDA cleared assay capable of positive identification of a wide variety of A subtypes as "non-seasonal" A viruses from human nasal specimens. OBJECTIVE: To evaluate clinical performance of the FluChip-8G Influenza A+B Assay for detection of seasonal influenza viruses in nasal and nasopharyngeal swab specimens, and to evaluate performance for detection of non-seasonal influenza viruses using contrived samples. STUDY DESIGN: For seasonal viruses, a multisite study of the FluChip-8G Influenza A+B Assay using prospectively and retrospectively collected nasal and nasopharyngeal swabs was performed using the FDA-cleared CDC Human Flu Dx Panel as the comparator assay. For non-seasonal viruses, testing was performed at a single site using contrived samples from 100 unique non-seasonal strains representing 41 subtypes. RESULTS: Sensitivity (95% CI) and specificity (95% CI) for each target group, respectively, from results of 1689 clinical specimens were: seasonal H1N1pdm2009: 96.4% (87.9-99.0), 99.3% (98.8-99.6), seasonal H3N2: 91.8% (87.7-94.7), 99.7% (99.2-99.9), Influenza B Victoria: 100% (94.0-100.0), 99.9% (99.6-100.0), and Influenza B Yamagata: 95.6% (89.2-98.3), 99.9% (99.6-100.0). The sensitivity and specificity from contrived influenza A non-seasonal viruses was determined to be 99.0% (94.6-99.8) and 100% (96.7-100.0). CONCLUSION: The FluChip-8G Influenza A+B Assay has robust sensitivity and specificity for detecting and identifying all target virus groups, including non-seasonal influenza A, with same day results.


Subject(s)
Genotyping Techniques/methods , Influenza A virus/isolation & purification , Influenza B virus/isolation & purification , Influenza, Human/diagnosis , Microarray Analysis/methods , Molecular Diagnostic Techniques/methods , Reverse Transcriptase Polymerase Chain Reaction/methods , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Influenza A virus/classification , Influenza A virus/genetics , Influenza B virus/classification , Influenza B virus/genetics , Male , Middle Aged , Nasal Cavity/virology , Nasopharynx/virology , Prospective Studies , Retrospective Studies , Sensitivity and Specificity , Young Adult
8.
J Virol Methods ; 273: 113686, 2019 11.
Article in English | MEDLINE | ID: mdl-31271790

ABSTRACT

BACKGROUND: Influenza causes a significant annual disease burden, with characterization of the infecting virus important in clinical and public health settings. Rapid immunoassays are fast but insensitive, whereas real-time RT-PCR is sensitive but susceptible to genetic mutations and often requires multiple serial assays. The FluChip-8G Influenza A+B Assay provides type and subtype/lineage identification of influenza A and B, including non-seasonal A viruses, in a single microarray-based assay with same day turnaround time. OBJECTIVE: To evaluate key analytical performance characteristics of the FluChip-8G Influenza A+B Assay. STUDY DESIGN: Analytical sensitivity, cross-reactivity, and multi-site reproducibility were evaluated. RESULTS: The limit of detection (LOD) for the FluChip-8G influenza A+B Assay ranged from 5.8 × 102-1.5 × 105 genome copies/mL, with most samples ∼2 × 103 genome copies/mL (∼160 genome copies/reaction). Fifty two (52) additional strains were correctly identified near the LOD, demonstrating robust reactivity. Two variant viruses (H1N1v and H3N2v) resulted in dual identification as both "non-seasonal influenza A" and A/H1N1pdm09. No reproducible cross-reactivity was observed for the 34 organisms tested, however, challenges with internal control inhibition due to crude growth matrix were observed. Lastly, samples tested near the LOD showed high reproducibility (97.0% (95% CI 94.7-98.7)) regardless of operator, site, reagent lot, or testing day. CONCLUSION: The FluChip-8G Influenza A+B Assay is an effective new method for detecting and identifying both seasonal and non-seasonal influenza viruses, as revealed by good sensitivity and robust reactivity to 52 unique strains of influenza virus. In addition, the lack of cross-reactivity to non-influenza pathogens and high lab-to-lab reproducibility highlight the analytical performance of the assay as an alternative to real-time RT-PCR and sequencing-based assays. Clinical validation of the technology in a multi-site clinical study is the subject of a separate investigation.


Subject(s)
Influenza A virus/genetics , Influenza B virus/genetics , Influenza, Human/classification , Influenza, Human/diagnosis , Microarray Analysis/standards , Cross Reactions , Genome, Viral , Humans , Influenza A virus/classification , Influenza, Human/virology , Limit of Detection , Microarray Analysis/methods , Nose/virology , Reproducibility of Results , Sensitivity and Specificity
9.
Tob Prev Cessat ; 5: 44, 2019.
Article in English | MEDLINE | ID: mdl-32411906

ABSTRACT

INTRODUCTION: Quit and Win programs (Q&W) have been shown to improve smoking cessation rates by offering potential rewards to encourage smoking cessation. However, few studies have combined Q&W with intensive smoking cessation programs including behavioral counseling and pharmacotherapy, or studied Q&W in underserved, minority populations. This study was conducted to assess the impact on smoking cessation rates of adding a Q&W to intensive smoking cessation therapy in a largely underserved, minority population. METHODS: This was a single-center, prospective, open-label controlled study. Current smokers received pharmacist-led behavioral counseling and smoking cessation pharmacotherapy. Intervention group patients who successfully quit (verified by self-report and exhaled carbon monoxide) at 1 month and 3 months post-quit date were entered into a draw for $1000. The control group received the same smoking cessation services, but without a monetary incentive. RESULTS: Enrollment was 111 patients (N=85 in the intervention group), made up of predominantly underserved (82% had annual household income <$25000), minority (69.1%), and female (58%) patients. Groups were similar except the intervention group had lower educational and income levels, while the control group was more likely to smoke more than 1 pack per day. Quit rates at 3 months were 27% and 19% in the intervention and control groups, respectively (p=0.22). Female gender (OR=2.84; p=0.04) and Fagerström score (OR=0.71; p<0.01) were significant predictors of quitting. CONCLUSIONS: The addition of Q&W to intensive smoking cessation services increased clinic referrals and numerically improved cessation rates, although this difference was not statistically significant, possibly due to high attrition of the study.

10.
Int J Pharm ; 553(1-2): 57-64, 2018 Dec 20.
Article in English | MEDLINE | ID: mdl-30268850

ABSTRACT

The objective of this work is to use phage display libraries as a screening tool to identify peptides that facilitate transport across the mucus barrier. Mucus is a complex selective barrier to particles and molecules, limiting penetration to the epithelial surface of mucosal tissues. In mucus-associated diseases such as cystic fibrosis (CF), mucus has increased viscoelasticity and a higher concentration of covalent and non-covalent physical entanglements compared to healthy tissues, which greatly hinders permeability and transport of drugs and particles across the mucosae for therapeutic delivery. Treatment of CF lung diseases and associated infections must overcome this abnormal mucosal barrier. Critical bottlenecks hindering effective drug penetration remain and while recent studies have shown hydrophilic, net-neutral charge polymers can improve the transport of nanoparticles and minimize interactions with mucus, there is a dearth of alternative carriers available. We hypothesized that the screening of a phage peptide library against a CF mucus model would lead to the identification of phage-displayed peptide sequences able to improve transport in mucus. These combinatorial libraries possess a large diversity of peptide-based formulations (108-109) to achieve unprecedented screening for potential mucus-penetrating peptides. Here, phage clones displaying discovered peptides were shown to have up to 2.6-fold enhanced diffusivity in the CF mucus model. In addition, we demonstrate reduced binding affinities to mucin compared to wild-type control. These findings suggest that phage display libraries can be used as a strategy to improve transmucosal delivery.


Subject(s)
Cystic Fibrosis/drug therapy , Mucus/metabolism , Peptide Library , Peptides/chemistry , Animals , Biological Transport , Drug Carriers/chemistry , Drug Carriers/metabolism , Mucins/metabolism , Peptides/metabolism , Swine
12.
MMWR Morb Mortal Wkly Rep ; 67(3): 91-96, 2018 Jan 26.
Article in English | MEDLINE | ID: mdl-29370151

ABSTRACT

Zika virus infection during pregnancy can cause serious birth defects, including microcephaly and brain abnormalities (1). Population-based birth defects surveillance systems are critical to monitor all infants and fetuses with birth defects potentially related to Zika virus infection, regardless of known exposure or laboratory evidence of Zika virus infection during pregnancy. CDC analyzed data from 15 U.S. jurisdictions conducting population-based surveillance for birth defects potentially related to Zika virus infection.* Jurisdictions were stratified into the following three groups: those with 1) documented local transmission of Zika virus during 2016; 2) one or more cases of confirmed, symptomatic, travel-associated Zika virus disease reported to CDC per 100,000 residents; and 3) less than one case of confirmed, symptomatic, travel-associated Zika virus disease reported to CDC per 100,000 residents. A total of 2,962 infants and fetuses (3.0 per 1,000 live births; 95% confidence interval [CI] = 2.9-3.2) (2) met the case definition.† In areas with local transmission there was a non-statistically significant increase in total birth defects potentially related to Zika virus infection from 2.8 cases per 1,000 live births in the first half of 2016 to 3.0 cases in the second half (p = 0.10). However, when neural tube defects and other early brain malformations (NTDs)§ were excluded, the prevalence of birth defects strongly linked to congenital Zika virus infection increased significantly, from 2.0 cases per 1,000 live births in the first half of 2016 to 2.4 cases in the second half, an increase of 29 more cases than expected (p = 0.009). These findings underscore the importance of surveillance for birth defects potentially related to Zika virus infection and the need for continued monitoring in areas at risk for Zika.


Subject(s)
Congenital Abnormalities/epidemiology , Congenital Abnormalities/virology , Population Surveillance , Zika Virus Infection/complications , Female , Humans , Infant , Infant, Newborn , Pregnancy , Pregnancy Complications, Infectious/virology , Prevalence , Puerto Rico/epidemiology , United States/epidemiology
13.
JAMA Surg ; 152(1): 42-47, 2017 01 01.
Article in English | MEDLINE | ID: mdl-27603225

ABSTRACT

Importance: There are an increasing number of veterans in the United States, and the current delay and wait times prevent Veterans Affairs institutions from fully meeting the needs of current and former service members. Concrete strategies to improve throughput at these facilities have been sparse. Objective: To identify whether lean processes can be used to improve wait times for surgical procedures in Veterans Affairs hospitals. Design, Setting, and Participants: Databases in the Veterans Integrated Service Network 11 Data Warehouse, Veterans Health Administration Support Service Center, and Veterans Information Systems and Technology Architecture/Dynamic Host Configuration Protocol were queried to assess changes in wait times for elective general surgical procedures and clinical volume before, during, and after implementation of lean processes over 3 fiscal years (FYs) at a tertiary care Veterans Affairs medical center. All patients evaluated by the general surgery department through outpatient clinics, clinical video teleconferencing, and e-consultations from October 2011 through September 2014 were included. Patients evaluated through the emergency department or as inpatient consults were excluded. Exposures: The surgery service and systems redesign service held a value stream analysis in FY 2013, culminating in multiple rapid process improvement workshops. Multidisciplinary teams identified systemic inefficiencies and strategies to improve interdepartmental and patient communication to reduce canceled consultations and cases, diagnostic rework, and no-shows. High-priority triage with enhanced operating room flexibility was instituted to reduce scheduling wait times. General surgery department pilot projects were then implemented mid-FY 2013. Main Outcomes and Measures: Planned outcome measures included wait time, clinic and telehealth volume, number of no-shows, and operative volume. Paired t tests were used to identify differences in outcome measures after the institution of reforms. Results: Following rapid process improvement workshop project rollouts, mean (SD) patient wait times for elective general surgical procedures decreased from 33.4 (8.3) days in FY 2012 to 26.0 (9.5) days in FY 2013 (P = .02). In FY 2014, mean (SD) wait times were half the value of the previous FY at 12.0 (2.1) days (P = .07). This was a 3-fold decrease from wait times in FY 2012 (P = .02). Operative volume increased from 931 patients in FY 2012 to 1090 in FY 2013 and 1072 in FY 2014. Combined clinic, telehealth, and e-consultation encounters increased from 3131 in FY 2012 to 3460 in FY 2013 and 3517 in FY 2014, while the number of no-shows decreased from 366 in FY 2012 to 227 in FY 2014 (P = .02). Conclusions and Relevance: Improvement in the overall surgical patient experience can stem from multidisciplinary collaboration among systems redesign personnel, clinicians, and surgical staff to reduce systemic inefficiencies. Monitoring and follow-up of system efficiency measures and the employment of lean practices and process improvements can have positive short- and long-term effects on wait times, clinical throughput, and patient care and satisfaction.


Subject(s)
Elective Surgical Procedures/statistics & numerical data , General Surgery/organization & administration , Hospital Administration/methods , Surgery Department, Hospital/organization & administration , Total Quality Management , United States Department of Veterans Affairs/organization & administration , Appointments and Schedules , Efficiency, Organizational , General Surgery/statistics & numerical data , Humans , No-Show Patients/statistics & numerical data , Operating Rooms/organization & administration , Pilot Projects , Process Assessment, Health Care , Referral and Consultation/statistics & numerical data , Surgery Department, Hospital/statistics & numerical data , Telemedicine/statistics & numerical data , Time Factors , Triage/organization & administration , United States , Waiting Lists
14.
Vaccine ; 34(27): 3059-3067, 2016 06 08.
Article in English | MEDLINE | ID: mdl-27155490

ABSTRACT

Aluminum salts such as aluminum oxyhydroxide and aluminum hydroxyphosphate are commonly used human vaccine adjuvants. In an effort to improve the adjuvant activity of aluminum salts, we previously showed that the adjuvant activity of aluminum oxyhydroxide nanoparticles is significantly more potent than that of aluminum oxyhydroxide microparticles. The present study was designed to (i) understand the mechanism underlying the potent adjuvant activity of aluminum oxyhydroxide nanoparticles, relative to microparticles, and (ii) to test whether aluminum hydroxyphosphate nanoparticles have a more potent adjuvant activity than aluminum hydroxyphosphate microparticles as well. In human THP-1 myeloid cells, wild-type and NLRP3-deficient, both aluminum oxyhydroxide nanoparticles and microparticles stimulate the secretion of proinflammatory cytokine IL-1ß by activating NLRP3 inflammasome, although aluminum oxyhydroxide nanoparticles are more potent than microparticles, likely related to the higher uptake of the nanoparticles by the THP-1 cells than the microparticles. Aluminum hydroxyphosphate nanoparticles also have a more potent adjuvant activity than microparticles in helping a model antigen lysozyme to stimulate specific antibody response, again likely related to their stronger ability to activate the NLRP3 inflammasome.


Subject(s)
Adjuvants, Immunologic/pharmacology , Aluminum Compounds/pharmacology , Myeloid Cells/immunology , Nanoparticles/chemistry , Animals , Antibody Formation , Cell Line , Female , Humans , Inflammasomes/immunology , Interleukin-1beta/immunology , Mice, Inbred BALB C , NLR Family, Pyrin Domain-Containing 3 Protein/immunology
15.
Am J Prev Med ; 51(2): 206-215, 2016 08.
Article in English | MEDLINE | ID: mdl-27178884

ABSTRACT

INTRODUCTION: Excessive alcohol use exacerbates morbidity and mortality among hepatitis C virus (HCV)-infected people. The purpose of this study was to describe self-reported patterns of alcohol use and examine the association with HCV infection and other sociodemographic and health-related factors. METHODS: Data from 20,042 participants in the 2003-2010 National Health and Nutrition Examination Survey were analyzed in 2014. Estimates were derived for self-reported demographic characteristics, HCV-RNA (indicative of current HCV infection) status, and alcohol use at four levels: lifetime abstainers, former drinkers, non-excessive current drinkers, and excessive current drinkers. RESULTS: Former drinkers and excessive current drinkers had a higher prevalence of HCV infection (2.2% and 1.5%, respectively) than never or non-excessive current drinkers (0.4% and 0.9%, respectively). HCV-infected adults were estimated to ever drink five or more drinks/day almost every day at some time during their lifetime about 3.3 times more often (43.8% vs 13.7%, p<0.001) than those who were never infected with HCV. Controlling for age, sex, race/ethnicity, education, and having a usual source of health care, HCV infection was significantly associated with excessive current drinking (adjusted prevalence ratio, 1.3; 95% CI=1.1, 1.6) and former drinking (adjusted prevalence ratio, 1.3; 95% CI=1.1, 1.6). CONCLUSIONS: Chronic HCV infection is associated with both former and excessive current drinking. Public health HCV strategies should implement interventions with emphasis on alcohol abuse, which negatively impacts disease progression for HCV-infected individuals.


Subject(s)
Alcohol Drinking/epidemiology , Alcoholism , Hepatitis C, Chronic/epidemiology , Adult , Aged , Female , Hepacivirus/isolation & purification , Humans , Male , Middle Aged , Nutrition Surveys , Prevalence , United States/epidemiology
16.
J Proteome Res ; 14(10): 4394-401, 2015 Oct 02.
Article in English | MEDLINE | ID: mdl-26347193

ABSTRACT

An early-stage, population-wide biomarker for ovarian cancer (OVC) is essential to reverse its high mortality rate. Aberrant glycosylation by OVC has been reported, but studies have yet to identify an N-glycan with sufficiently high specificity. We curated a human biorepository of 82 case-control plasma samples, with 27%, 12%, 46%, and 15% falling across stages I-IV, respectively. For relative quantitation, glycans were analyzed by the individuality normalization when labeling with glycan hydrazide tags (INLIGHT) strategy for enhanced electrospray ionization, MS/MS analysis. Sixty-three glycan cancer burden ratios (GBRs), defined as the log10 ratio of the case-control extracted ion chromatogram abundances, were calculated above the limit of detection. The final GBR models, built using stepwise forward regression, included three significant terms: OVC stage, normalized mean GBR, and tag chemical purity; glycan class, fucosylation, or sialylation were not significant variables. After Bonferroni correction, seven N-glycans were identified as significant (p < 0.05), and after false discovery rate correction, an additional four glycans were determined to be significant (p < 0.05), with one borderline (p = 0.05). For all N-glycans, the vectors of the effects from stages II-IV were sequentially reversed, suggesting potential biological changes in OVC morphology or in host response.


Subject(s)
Biomarkers, Tumor/blood , Ovarian Neoplasms/blood , Ovarian Neoplasms/diagnosis , Polysaccharides/blood , Carbohydrate Sequence , Case-Control Studies , Chromatography, Liquid/methods , Female , Fucose/blood , Glycosylation , Humans , Hydrazines/chemistry , Molecular Sequence Data , Neoplasm Staging , Ovarian Neoplasms/pathology , Sialic Acids/blood , Staining and Labeling/methods , Tandem Mass Spectrometry/methods
17.
Surg Clin North Am ; 95(2): 237-54, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25814104

ABSTRACT

Postoperative pulmonary complications (PPCs) occur frequently among general surgical patients. The spectrum of illness is broad and includes preventable causes of morbidity and death. Careful preoperative evaluation can identify undiagnosed and undertreated illness and allow for preoperative intervention. Optimization of patient, surgical, and anesthetic factors is crucial in the prevention of PPCs.


Subject(s)
Lung Diseases/etiology , Lung Diseases/prevention & control , Perioperative Care , Postoperative Complications , Age Factors , Health Status , Humans , Risk Factors
18.
J Trauma Acute Care Surg ; 77(4): 635-9, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25250607

ABSTRACT

BACKGROUND: The diagnosis of osteoporosis is important in the care of elderly patients at risk of trauma. While pelvis computed tomography (CT) is accurate in the measurement of bone mineral density, axial skull CT has not previously been evaluated for this purpose. This study investigated whether data from axial skull CT scans can screen for osteoporosis. METHODS: Bone density measurements were derived from digital analysis of routine scans of the head and pelvis using quantitative CT. The study took place from October 2010 to November 2011 at a medium-sized community hospital. The first study phase included patients older than 18 years who had both a head and a pelvis CT scan within 30 days. The known diagnostic value for osteoporosis on pelvis CT scans was used to derive a diagnostic value for head CT. The second study phase included adult trauma patients who underwent noncontrast head CT during an initial trauma evaluation. A subgroup analysis was performed during Phase II on patients older than 65 years to identify the incidence of fracture as it is affected by age and bone mineral density. RESULTS: Our data demonstrated that head CT was able to identify osteoporosis with a sensitivity of 0.70, a specificity of 0.81, and an accuracy of 0.76 compared with pelvic CT. Of 261 trauma patients, 54% had bone disease based on axial skull CT criteria. Patients older than 65 years with a positive screen result for osteoporosis on head CT were twice as likely to have a fracture. CONCLUSION: Analysis of data from head CT scans has the potential to provide a useful screen for osteoporosis. Adding this analysis to CT scans performed for elderly trauma patients could result in improved diagnosis and treatment of osteoporosis. LEVEL OF EVIDENCE: Diagnostic study, level II.


Subject(s)
Osteoporosis/diagnosis , Skull/diagnostic imaging , Tomography, X-Ray Computed/methods , Adult , Aged , Aged, 80 and over , Bone Density , Female , Humans , Middle Aged , Osteoporotic Fractures/epidemiology , Prospective Studies
19.
J Pain Res ; 6: 755-63, 2013.
Article in English | MEDLINE | ID: mdl-24357937

ABSTRACT

Lumbar radiculopathy pain represents a major public health problem, with few effective long-term treatments. Preclinical neuropathic and postsurgical pain studies implicate the kinase adenosine monophosphate activated kinase (AMPK) as a potential pharmacological target for the treatment of chronic pain conditions. Metformin, which acts via AMPK, is a safe and clinically available drug used in the treatment of diabetes. Despite the strong preclinical rationale, the utility of metformin as a potential pain therapeutic has not yet been studied in humans. Our objective was to assess whether metformin is associated with decreased lumbar radiculopathy pain, in a retrospective chart review. We completed a retrospective chart review of patients who sought care from a university pain specialist for lumbar radiculopathy between 2008 and 2011. Patients on metformin at the time of visit to a university pain specialist were compared with patients who were not on metformin. We compared the pain outcomes in 46 patients on metformin and 94 patients not taking metformin therapy. The major finding was that metformin use was associated with a decrease in the mean of "pain now," by -1.85 (confidence interval: -3.6 to -0.08) on a 0-10 visual analog scale, using a matched propensity scoring analysis and confirmed using a Bayesian analysis, with a significant mean decrease of -1.36 (credible interval: -2.6 to -0.03). Additionally, patients on metformin showed a non-statistically significant trend toward decreased pain on a variety of other pain descriptors. Our proof-of-concept findings suggest that metformin use is associated with a decrease in lumbar radiculopathy pain, providing a rational for larger retrospective trials in different pain populations and for prospective trials, to test the effectiveness of metformin in reducing neuropathic pain.

20.
J Am Soc Mass Spectrom ; 24(9): 1376-84, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23860851

ABSTRACT

The Individuality Normalization when Labeling with Isotopic Glycan Hydrazide Tags (INLIGHT) strategy for the sample preparation, data analysis, and relative quantification of N-linked glycans is presented. Glycans are derivatized with either natural (L) or stable-isotope labeled (H) hydrazide reagents and analyzed using reversed phase liquid chromatography coupled online to a Q Exactive mass spectrometer. A simple glycan ladder, maltodextrin, is first used to demonstrate the relative quantification strategy in samples with negligible analytical and biological variability. It is shown that after a molecular weight correction attributable to isotopic overlap and a post-acquisition normalization of the data to account for any systematic bias, a plot of the experimental H:L ratio versus the calculated H:L ratio exhibits a correlation of unity for maltodextrin samples mixed in different ratios. We also demonstrate that the INLIGHT approach can quantify species over four orders of magnitude in ion abundance. The INLIGHT strategy is further demonstrated in pooled human plasma, where it is shown that the post-acquisition normalization is more effective than using a single spiked-in internal standard. Finally, changes in glycosylation are able to be detected in complex biological matrices, when spiked with a glycoprotein. The ability to spike in a glycoprotein and detect change at the glycan level validates both the sample preparation and data analysis strategy, making INLIGHT an invaluable relative quantification strategy for the field of glycomics.


Subject(s)
Glycomics/methods , Isotope Labeling/methods , Mass Spectrometry/methods , Polysaccharides/analysis , Chromatography, Reverse-Phase , Glycoproteins/chemistry , Glycosylation , Humans , Plasma/chemistry , Polysaccharides/isolation & purification
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