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1.
Lancet Infect Dis ; 2024 Apr 25.
Article in English | MEDLINE | ID: mdl-38679035

ABSTRACT

BACKGROUND: Dengue human infection models (DHIMs) are important tools to down-select dengue vaccine candidates and establish tetravalent efficacy before advanced clinical field trials. We aimed to provide data for the safety and immunogenicity of DHIM and evaluate dengue vaccine efficacy. METHODS: We performed an open-label, phase 1 trial at the University of Maryland (Baltimore, MD, USA). Eligible participants were healthy individuals aged 18-50 years who either previously received a tetravalent dengue purified inactivated vaccine prime followed by a live-attenuated vaccine boost (ie, the vaccinee group), or were unvaccinated flavivirus-naive participants (ie, the control group). Participants in the vaccinee group with detectable pre-challenge dengue virus-1 neutralising antibody titres and flavivirus-naive participants in the control group were inoculated with dengue virus-1 strain 45AZ5 in the deltoid region, 27-65 months following booster dosing. These participants were followed-up from days 4-16 following dengue virus-1 live virus human challenge, with daily real-time quantitative PCR specific to dengue virus-1 RNA detection, and dengue virus-1 solicited local and systemic adverse events were recorded. The primary outcomes were safety (ie, solicited local and systemic adverse events) and vaccine efficacy (ie, dengue virus-1 RNAaemia) following dengue challenge. This study is registered with ClinicalTrials.gov, number NCT04786457. FINDINGS: In January 2021, ten eligible participants were enrolled; of whom, six (60%) were in the vaccinee group and four (40%) were in the control group. Daily quantitative PCR detected dengue virus-1 RNA in nine (90%) of ten participants (five [83%] of six in the vaccinee group and all four [100%] in the control group). The mean onset of RNAaemia occurred on day 5 (SD 1·0) in the vaccinee group versus day 8 (1·5) in the control group (95% CI 1·1-4·9; p=0·007), with a trend towards reduced RNAaemia duration in the vaccinee group compared with the control group (8·2 days vs 10·5 days; 95% CI -0·08 to 4·68; p=0·056). Mild-to-moderate symptoms (nine [90%] of ten), leukopenia (eight [89%] of nine), and elevated aminotransferases (seven [78%] of nine) were commonly observed. Severe adverse events were detected only in the vaccinee group (fever ≥38·9°C in three [50%] of six, headache in one [17%], and transient grade 4 aspartate aminotransferase elevation in one [17%]). No deaths were reported. INTERPRETATION: Participants who had tetravalent dengue purified inactivated vaccine prime and live-attenuated vaccine boost were unprotected against dengue virus-1 infection and further showed increased clinical, immunological, and transcriptomic evidence for inflammation potentially mediated by pre-existing infection-enhancing antibodies. This study highlights the impact of small cohort, human challenge models studying dengue pathogenesis and downstream vaccine development. FUNDING: Military Infectious Disease Research Program and Medical Technology Enterprise Consortium and Advanced Technology International.

2.
Cell Rep ; 42(8): 112942, 2023 08 29.
Article in English | MEDLINE | ID: mdl-37561630

ABSTRACT

Zika virus (ZIKV) is an emerging pathogen that causes devastating congenital defects. The overlapping epidemiology and immunologic cross-reactivity between ZIKV and dengue virus (DENV) pose complex challenges to vaccine design, given the potential for antibody-dependent enhancement of disease. Therefore, classification of ZIKV-specific antibody targets is of notable value. From a ZIKV-infected rhesus macaque, we identify ZIKV-reactive B cells and isolate potent neutralizing monoclonal antibodies (mAbs) with no cross-reactivity to DENV. We group these mAbs into four distinct antigenic groups targeting ZIKV-specific cross-protomer epitopes on the envelope glycoprotein. Co-crystal structures of representative mAbs in complex with ZIKV envelope glycoprotein reveal envelope-dimer epitope and unique dimer-dimer epitope targeting. All four specificities are serologically identified in convalescent humans following ZIKV infection, and representative mAbs from all four groups protect against ZIKV replication in mice. These results provide key insights into ZIKV-specific antigenicity and have implications for ZIKV vaccine, diagnostic, and therapeutic development.


Subject(s)
Dengue Virus , Dengue , Viral Vaccines , Zika Virus Infection , Zika Virus , Humans , Animals , Mice , Antibodies, Neutralizing , Epitopes , Macaca mulatta , Antibodies, Viral , Antibodies, Monoclonal , Viral Vaccines/therapeutic use , Viral Envelope Proteins/chemistry
3.
EBioMedicine ; 94: 104683, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37413891

ABSTRACT

BACKGROUND: COVID-19 vaccines have been critical for protection against severe disease following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) but gaps remain in our understanding of the immune responses that contribute to controlling subclinical and mild infections. METHODS: Vaccinated, active-duty US military service members were enrolled in a non-interventional, minimal-risk, observational study starting in May, 2021. Clinical data, serum, and saliva samples were collected from study participants and were used to characterise the humoral immune responses to vaccination and to assess its impact on clinical and subclinical infections, as well as virologic outcomes of breakthrough infections (BTI) including viral load and infection duration. FINDINGS: The majority of VIRAMP participants had received the Pfizer COVID-19 vaccine and by January, 2022, N = 149 had a BTI. The median BTI duration (PCR+ days) was 4 days and the interquartile range was 1-8 days. Participants that were nucleocapsid seropositive prior to their BTI had significantly higher levels of binding and functional antibodies to the spike protein, shorter median duration of infections, and lower median peak viral loads compared to seronegative participants. Furthermore, levels of neutralising antibody, ACE2 blocking activity, and spike-specific IgA measured prior to BTI also correlated with the duration of infection. INTERPRETATION: We extended previous findings and demonstrate that a subset of vaccine-induced humoral immune responses, along with nucleocapsid serostatus are associated with control of SARS-CoV-2 breakthrough infections in the upper airways. FUNDING: This work was funded by the DoD Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND) in collaboration with the Defense Health Agency (DHA) COVID-19 funding initiative for the VIRAMP study.


Subject(s)
COVID-19 , Military Personnel , Humans , COVID-19 Vaccines , SARS-CoV-2 , Immunity, Humoral , Breakthrough Infections , Antibodies, Neutralizing , Antibodies, Viral , Vaccination
4.
Nature ; 615(7953): 678-686, 2023 03.
Article in English | MEDLINE | ID: mdl-36922586

ABSTRACT

Dengue is a major health threat and the number of symptomatic infections caused by the four dengue serotypes is estimated to be 96 million1 with annually around 10,000 deaths2. However, no antiviral drugs are available for the treatment or prophylaxis of dengue. We recently described the interaction between non-structural proteins NS3 and NS4B as a promising target for the development of pan-serotype dengue virus (DENV) inhibitors3. Here we present JNJ-1802-a highly potent DENV inhibitor that blocks the NS3-NS4B interaction within the viral replication complex. JNJ-1802 exerts picomolar to low nanomolar in vitro antiviral activity, a high barrier to resistance and potent in vivo efficacy in mice against infection with any of the four DENV serotypes. Finally, we demonstrate that the small-molecule inhibitor JNJ-1802 is highly effective against viral infection with DENV-1 or DENV-2 in non-human primates. JNJ-1802 has successfully completed a phase I first-in-human clinical study in healthy volunteers and was found to be safe and well tolerated4. These findings support the further clinical development of JNJ-1802, a first-in-class antiviral agent against dengue, which is now progressing in clinical studies for the prevention and treatment of dengue.


Subject(s)
Antiviral Agents , Dengue Virus , Dengue , Primates , Viral Nonstructural Proteins , Animals , Humans , Mice , Antiviral Agents/adverse effects , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Clinical Trials, Phase I as Topic , Dengue/drug therapy , Dengue/prevention & control , Dengue/virology , Dengue Virus/classification , Dengue Virus/drug effects , Dose-Response Relationship, Drug , Drug Resistance, Viral , In Vitro Techniques , Molecular Targeted Therapy , Primates/virology , Protein Binding/drug effects , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/metabolism , Virus Replication
5.
Front Immunol ; 12: 777672, 2021.
Article in English | MEDLINE | ID: mdl-34899736

ABSTRACT

Dengue virus (DENV) is a prevalent human pathogen, infecting approximately 400 million individuals per year and causing symptomatic disease in approximately 100 million. A distinct feature of dengue is the increased risk for severe disease in some individuals with preexisting DENV-specific immunity. One proposed mechanism for this phenomenon is antibody-dependent enhancement (ADE), in which poorly-neutralizing IgG antibodies from a prior infection opsonize DENV to increase infection of Fc gamma receptor-bearing cells. While IgM and IgG are the most commonly studied DENV-reactive antibody isotypes, our group and others have described the induction of DENV-specific serum IgA responses during dengue. We hypothesized that monomeric IgA would be able to neutralize DENV without the possibility of ADE. To test this, we synthesized IgG and IgA versions of two different DENV-reactive monoclonal antibodies. We demonstrate that isotype-switching does not affect the antigen binding and neutralization properties of the two mAbs. We show that DENV-reactive IgG, but not IgA, mediates ADE in Fc gamma receptor-positive K562 cells. Furthermore, we show that IgA potently antagonizes the ADE activity of IgG. These results suggest that levels of DENV-reactive IgA induced by DENV infection might regulate the overall IgG mediated ADE activity of DENV-immune plasma in vivo, and may serve as a predictor of disease risk.


Subject(s)
Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antibody-Dependent Enhancement , Dengue Virus/immunology , Dengue/immunology , Immunoglobulin A/immunology , Immunoglobulin G/immunology , Opsonization , Animals , Antibodies, Monoclonal/metabolism , Antibodies, Neutralizing/metabolism , Antibodies, Viral/metabolism , Antibody Specificity , Chlorocebus aethiops , Dengue/metabolism , Dengue/virology , Dengue Virus/metabolism , Dengue Virus/pathogenicity , Host-Pathogen Interactions , Humans , Immunity, Humoral , Immunoglobulin A/metabolism , Immunoglobulin Class Switching , Immunoglobulin G/metabolism , K562 Cells , Vero Cells
6.
Sci Adv ; 7(42): eabg4084, 2021 Oct 15.
Article in English | MEDLINE | ID: mdl-34652943

ABSTRACT

Dengue virus (DENV) is a worldwide health burden, and a safe vaccine is needed. Neutralizing antibodies bind to quaternary epitopes on DENV envelope (E) protein homodimers. However, recombinantly expressed soluble E proteins are monomers under vaccination conditions and do not present these quaternary epitopes, partly explaining their limited success as vaccine antigens. Using molecular modeling, we found DENV2 E protein mutations that induce dimerization at low concentrations (<100 pM) and enhance production yield by more than 50-fold. Cross-dimer epitope antibodies bind to the stabilized dimers, and a crystal structure resembles the wild-type (WT) E protein bound to a dimer epitope antibody. Mice immunized with the stabilized dimers developed antibodies that bind to E dimers and not monomers and elicited higher levels of DENV2-neutralizing antibodies compared to mice immunized with WT E antigen. Our findings demonstrate the feasibility of using structure-based design to produce subunit vaccines for dengue and other flaviviruses.

7.
Sci Rep ; 11(1): 10823, 2021 05 24.
Article in English | MEDLINE | ID: mdl-34031504

ABSTRACT

Natural dengue virus (DENV) infections occur by mosquito bite but how the inoculation route affects the humoral immune response is unknown. We serologically profiled 20 non-human primates (NHP) from a prior study of DENV1 infection where animals were inoculated by mosquito (N = 10) or subcutaneous injection (N = 10). Using a comprehensive, densely tiled and highly redundant pan-flavivirus programmable phage library containing 91,562 overlapping 62 amino acid peptides, we produced a high-resolution map of linear peptide sequences enriched during DENV seroconversion. Profiles in mosquito-inoculated and subcutaneously-inoculated animals were similar up to 90 days after primary infection, but diverged at 1 year with differences in sero-reactivity in the Envelope (E; residues 215-406; p < 0.08), and Nonstructural-3 (NS3; residues 549-615; p < 0.05) proteins in mosquito-inoculated versus subcutaneously-inoculated animals. Within the E protein, residues 339-384 in domain III accounted for > 99% of the observed sero-reactivity difference. Antibody breadth did not vary by mode of inoculation. The differential reactivity to E domain III seen by phage display validated orthogonally by ELISA, but did not correlate with late neutralization titers. Serological profiling of humoral immune responses to DENV infection in NHP by programmable phage display demonstrated durable differences in sero-reactivity by route of inoculation.


Subject(s)
Culicidae/virology , Dengue Virus/immunology , Dengue/immunology , Viral Envelope Proteins/immunology , Viral Nonstructural Proteins/immunology , Animals , Antibodies, Neutralizing/blood , Cell Surface Display Techniques , Dengue/blood , Dengue/veterinary , Epitopes/analysis , Immunity, Humoral , Macaca mulatta , Protein Domains , Seroconversion , Viral Envelope Proteins/chemistry , Viral Nonstructural Proteins/chemistry
8.
NPJ Vaccines ; 6(1): 77, 2021 May 21.
Article in English | MEDLINE | ID: mdl-34021159

ABSTRACT

Antibody-dependent enhancement (ADE) is suspected to influence dengue virus (DENV) infection, but the role ADE plays in vaccination strategies incorporating live attenuated virus components is less clear. Using a heterologous prime-boost strategy in rhesus macaques, we examine the effect of priming with DENV purified inactivated vaccines (PIVs) on a tetravalent live attenuated vaccine (LAV). Sera exhibited low-level neutralizing antibodies (NAb) post PIV priming, yet moderate to high in vitro ADE activity. Following LAV administration, the PIV primed groups exhibited DENV-2 LAV peak viremias up to 1,176-fold higher than the mock primed group, and peak viremia correlated with in vitro ADE. Furthermore, PIV primed groups had more balanced and higher DENV-1-4 NAb seroconversion and titers than the mock primed group following LAV administration. These results have implications for the development of effective DENV vaccine prime-boost strategies and for our understanding of the role played by ADE in modulating DENV replication.

9.
PLoS Pathog ; 17(1): e1009240, 2021 01.
Article in English | MEDLINE | ID: mdl-33513191

ABSTRACT

Dengue human infection studies present an opportunity to address many longstanding questions in the field of flavivirus biology. However, limited data are available on how the immunological and transcriptional response elicited by an attenuated challenge virus compares to that associated with a wild-type DENV infection. To determine the kinetic transcriptional signature associated with experimental primary DENV-1 infection and to assess how closely this profile correlates with the transcriptional signature accompanying natural primary DENV-1 infection, we utilized scRNAseq to analyze PBMC from individuals enrolled in a DENV-1 human challenge study and from individuals experiencing a natural primary DENV-1 infection. While both experimental and natural primary DENV-1 infection resulted in overlapping patterns of inflammatory gene upregulation, natural primary DENV-1 infection was accompanied with a more pronounced suppression in gene products associated with protein translation and mitochondrial function, principally in monocytes. This suggests that the immune response elicited by experimental and natural primary DENV infection are similar, but that natural primary DENV-1 infection has a more pronounced impact on basic cellular processes to induce a multi-layered anti-viral state.


Subject(s)
Dengue Virus/immunology , Dengue/immunology , Gene Expression Regulation , Animals , Cell Line , Dengue/virology , Humans , Immunity/genetics , Inflammation/genetics , Inflammation/virology , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/virology , Sequence Analysis, RNA , Single-Cell Analysis
10.
EBioMedicine ; 54: 102733, 2020 Apr.
Article in English | MEDLINE | ID: mdl-32315970

ABSTRACT

Antibody-mediated humoral immunity is thought to play a central role in mediating the immunopathogenesis of acute DENV infection, but limited data are available on the diversity, specificity, and functionality of the antibody response at the molecular level elicited by primary or secondary DENV infection. In order to close this functional gap in our understanding of DENV-specific humoral immunity, we utilized high-throughput single cell RNA sequencing to investigate B cells circulating in both primary and secondary natural DENV infections. We captured full-length paired immunoglobulin receptor sequence data from 9,027 B cells from a total of 6 subjects, including 2,717 plasmablasts. In addition to IgG and IgM class-switched cells, we unexpectedly found a high proportion of the DENV-elicited plasmablasts expressing IgA, principally in individuals with primary DENV infections. These IgA class-switched cells were extensively hypermutated even in individuals with a serologically confirmed primary DENV infection. Utilizing a combination of conventional biochemical assays and high-throughput shotgun mutagenesis, we determined that DENV-reactive IgA class-switched antibodies represent a significant fraction of DENV-reactive Igs generated in response to DENV infection, and that they exhibit a comparable epitope specificity to DENV-reactive IgG antibodies. These results provide insight into the molecular-level diversity of DENV-elicited humoral immunity and identify a heretofore unappreciated IgA plasmablast response to DENV infection.


Subject(s)
B-Lymphocytes/immunology , Dengue/immunology , Immunoglobulins/genetics , B-Lymphocytes/cytology , Cells, Cultured , Dengue/genetics , Humans , Immunity, Humoral , Immunoglobulins/metabolism , RNA-Seq , Single-Cell Analysis , Transcriptome
11.
PLoS Negl Trop Dis ; 14(4): e0008191, 2020 04.
Article in English | MEDLINE | ID: mdl-32267846

ABSTRACT

Dengue virus (DENV) is transmitted by infectious mosquitoes during blood-feeding via saliva containing biologically-active proteins. Here, we examined the effect of varying DENV infection modality in rhesus macaques in order to improve the DENV nonhuman primate (NHP) challenge model. NHPs were exposed to DENV-1 via subcutaneous or intradermal inoculation of virus only, intradermal inoculation of virus and salivary gland extract, or infectious mosquito feeding. The infectious mosquito feeding group exhibited delayed onset of viremia, greater viral loads, and altered clinical and immune responses compared to other groups. After 15 months, NHPs in the subcutaneous and infectious mosquito feeding groups were re-exposed to either DENV-1 or DENV-2. Viral replication and neutralizing antibody following homologous challenge were suggestive of sterilizing immunity, whereas heterologous challenge resulted in productive, yet reduced, DENV-2 replication and boosted neutralizing antibody. These results show that a more transmission-relevant exposure modality resulted in viral replication closer to that observed in humans.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Dengue/immunology , Animals , Dengue/virology , Dengue Virus/physiology , Disease Models, Animal , Female , Kinetics , Macaca mulatta/immunology , Mosquito Vectors/virology , RNA, Viral/blood , Salivary Glands/virology , Vaccination , Viral Load , Viremia/prevention & control , Virus Replication
12.
Nat Med ; 26(2): 228-235, 2020 02.
Article in English | MEDLINE | ID: mdl-32015557

ABSTRACT

Zika virus (ZIKV) has caused significant disease, with widespread cases of neurological pathology and congenital neurologic defects. Rapid vaccine development has led to a number of candidates capable of eliciting potent ZIKV-neutralizing antibodies (reviewed in refs. 1-3). Despite advances in vaccine development, it remains unclear how ZIKV vaccination affects immune responses in humans with prior flavivirus immunity. Here we show that a single-dose immunization of ZIKV purified inactivated vaccine (ZPIV)4-7 in a dengue virus (DENV)-experienced human elicited potent cross-neutralizing antibodies to both ZIKV and DENV. Using a unique ZIKV virion-based sorting strategy, we isolated and characterized multiple antibodies, including one termed MZ4, which targets a novel site of vulnerability centered on the Envelope (E) domain I/III linker region and protects mice from viremia and viral dissemination following ZIKV or DENV-2 challenge. These data demonstrate that Zika vaccination in a DENV-experienced individual can boost pre-existing flavivirus immunity and elicit protective responses against both ZIKV and DENV. ZPIV vaccination in Puerto Rican individuals with prior flavivirus experience yielded similar cross-neutralizing potency after a single vaccination, highlighting the potential benefit of ZIKV vaccination in flavivirus-endemic areas.


Subject(s)
Dengue/immunology , Tissue Donors , Viral Vaccines/therapeutic use , Zika Virus Infection/immunology , Zika Virus Infection/prevention & control , Animals , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Chlorocebus aethiops , Cross Reactions , Dengue Virus , Epitope Mapping , Female , Flavivirus/metabolism , Humans , Immunoglobulin G/chemistry , Inhibitory Concentration 50 , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Protein Binding , Protein Domains , Vaccination , Vaccines, Inactivated/therapeutic use , Vero Cells , Viremia , Zika Virus
13.
J Prosthodont ; 29(2): 114-123, 2020 Feb.
Article in English | MEDLINE | ID: mdl-31893566

ABSTRACT

PURPOSE: In-laboratory assessment by laboratory technicians may offer insight to increase clinical success of dental crowns, and research in this area is lacking. MATERIALS AND METHODS: Dentists in the National Dental Practice-Based Research Network enrolled patients in a study about single-unit crowns; laboratory technicians evaluated the quality of tooth preparations and impressions. The primary outcome for each crown was clinical acceptability (CAC), as judged by the treating dentist. A secondary outcome was "Goodness of Fit (GOF)," a composite score of several aspects of clinical fit, also judged by the study dentist. A mixed-effects logistic regression was used to analyze associations between laboratory technician ratings and the CAC and GOF. RESULTS: Dentists (n = 205) evaluated 3731 crowns. Technicians ranked the marginal detail of impressions as good or excellent in 92% of cases; other aspects of the impression were ranked good or excellent 88% of the time. Regarding tooth preparation, about 90% of preparations were considered adequate (neither excessive nor inadequate reduction). Factors associated with higher CAC were more preparation taper, and use of optical imaging. Factors associated with better GOF were higher impression quality, greater occlusal reduction, more preparation taper, and optical imaging. CONCLUSIONS: Overall quality of preparations and impressions was very high, as evaluated by laboratory technicians. Several clinical parameters were associated with higher CAC and GOF. Clinicians who struggle with crown remakes might consider less conservative tooth preparation, as well as using digital impression technology.


Subject(s)
Laboratory Personnel , Tooth , Crowns , Dental Impression Technique , Dental Prosthesis Design , Dentists , Humans
14.
J Prosthet Dent ; 123(5): 701-709, 2020 May.
Article in English | MEDLINE | ID: mdl-31590974

ABSTRACT

STATEMENT OF PROBLEM: The definitive impression for a single-unit crown involves many material and technique factors that may affect the success of the crown. PURPOSE: The purpose of this prospective cohort study was to determine whether impression technique (tray selection), impression material, or tissue displacement technique are associated with the clinical acceptability of the crown (CAC). MATERIAL AND METHODS: Dentists in the National Dental Practice-Based Research Network documented details of the preparation, impression, and delivery of 3730 consecutive single-unit crowns. Mixed-effects logistic regression analyses were performed to evaluate associations between impression techniques and materials and the CAC and to assess associations between the presence of a subgingival margin with the displacement technique and the outcome variables CAC and number of impressions required. RESULTS: Of the 3730 crowns, 3589 (96.2%) were deemed clinically acceptable. A significant difference in the CAC was found with different impression techniques (P<.001) and different impression materials (P<.001). The percentage of the CAC for digital scans was 99.5%, 95.8% for dual-arch trays, 95.2% for quadrant trays, and 94.0% for complete-arch impression trays. Although no statistically significant difference was found in the CAC produced with dual-arch trays without both mesial and distal contacts, crowns fabricated under these conditions were less likely to achieve excellent occlusion. The percentage of the CAC for digital scans was 99.5%, 97.0% for polyether impressions, 95.5% for polyvinyl siloxane impressions, and 90.5% for other impression materials. Accounting for the location of the margin, the use of a dual-cord displacement technique was significantly associated with lower rates of requiring more than 1 impression (P=.015, odds ratio=1.43). CONCLUSIONS: Dual-arch trays produced clinically acceptable crowns; however, if the prepared tooth was unbounded, the occlusal fit was more likely to have been compromised. Digital scans produced a slightly higher rate of CAC than conventional impression materials. The use of a dual-cord technique was associated with a decreased need to remake impressions when the margins were subgingival.


Subject(s)
Dental Impression Technique , Tooth , Crowns , Dental Impression Materials , Models, Dental , Prospective Studies
15.
J Am Dent Assoc ; 150(6): 522-530, 2019 06.
Article in English | MEDLINE | ID: mdl-31030937

ABSTRACT

BACKGROUND: In this article, the authors present clinical factors associated with the type of cement practitioners use for restoration of single-unit crowns. METHODS: A total of 202 dentists in The National Dental Practice-Based Research Network recorded clinical details (including cement type) used for 3,468 single-unit crowns. The authors classified crowns as bonded if the dentist used a resin cement. The authors used mixed-model logistic regression to assess the associations between various clinical factors and the dentist's decision to bond. RESULTS: A total of 38.1% of crowns were bonded, and 61.9% were nonbonded; 39.1% (79 of 202) of dentists never bonded a crown, and 20.3% (41 of 202) of dentists bonded every crown in the study. Crowns with excessive occlusal reduction (as judged by laboratory technicians) were more likely to be bonded (P = .02); however, there was no association with bonding and excessive taper (P = .15) or axial reduction (P = .08). Crowns were more likely to be bonded if they were fabricated from leucite-reinforced glass ceramic (76.5%) or lithium disilicate (70.8%) than if they were fabricated from layered zirconia (38.8%), full-contour zirconia (30.1%), full metal (14.7%), or porcelain-fused-to-metal (13.8%) (P < .01) restorative material. There was no significant association between choice to bond and crown margin location (P = .35). Crowns in the anterior maxilla were more likely to be bonded (P < .01). CONCLUSIONS: Excessive occlusal tooth preparation, anterior location of a crown, and the use of glass ceramic crowns were associated significantly with the decision to bond. PRACTICAL IMPLICATIONS: In this study, the authors identified factors significantly associated with the clinical decision made by practicing dentists when selecting a cement for restoration of single-unit crowns.


Subject(s)
Crowns , Dental Cements , Dental Materials , Dental Porcelain , Dental Prosthesis Design , Dental Stress Analysis , Glass Ionomer Cements , Materials Testing , Resin Cements
16.
PLoS Negl Trop Dis ; 13(1): e0007060, 2019 01.
Article in English | MEDLINE | ID: mdl-30682026

ABSTRACT

Zika virus (ZIKV) recently caused a pandemic complicated by Guillain-Barre syndrome (GBS) and birth defects. ZIKV is structurally similar to the dengue viruses (DENV) and in vitro studies suggest antibody dependent enhancement occurs in ZIKV infections preceded by DENV; however, the clinical significance of this remains unclear. We undertook a PRISMA-adherent systematic review of all current human and non-human primate (NHP) data to determine if prior infection with DENV, compared to DENV-naïve hosts, is associated with a greater risk of ZIKV clinical complications or greater ZIKV peak viremia in vivo. We identified 1146 studies in MEDLINE, EMBASE and the grey literature, of which five studies were eligible. One human study indicated no increase in the risk of GBS in ZIKV infections with prior DENV exposure. Two additional human studies showed a small increase in ZIKV viremia in those with prior DENV exposure; however, this was not statistically significant nor was it associated with an increase in clinical severity or adverse pregnancy outcomes. While no meta-analysis was possible using human data, a pooled analysis of the two NHP studies leveraging extended data provided only weak evidence of a 0.39 log10 GE/mL rise in ZIKV viremia in DENV experienced rhesus macaques compared to those with no DENV exposure (p = 0.22). Using a customized quality grading criteria, we further show that no existing published human studies have offered high quality measurement of both acute ZIKV and antecedent DENV infections. In conclusion, limited human and NHP studies indicate a small and non-statistically significant increase in ZIKV viremia in DENV-experienced versus DENV-naïve hosts; however, there is no evidence that even a possible small increase in ZIKV viremia would correlate with a change in ZIKV clinical phenotype. More data derived from larger sample sizes and improved sero-assays are needed to resolve this question, which has major relevance for clinical prognosis and vaccine design.


Subject(s)
Antibodies, Viral/immunology , Dengue Virus/immunology , Dengue/virology , Zika Virus Infection/virology , Zika Virus/immunology , Animals , Antibodies, Viral/blood , Dengue/blood , Dengue/complications , Dengue Virus/genetics , Guillain-Barre Syndrome/blood , Guillain-Barre Syndrome/complications , Guillain-Barre Syndrome/virology , Humans , MEDLINE , Macaca mulatta , Mice , Models, Animal , Viremia , Zika Virus/genetics , Zika Virus Infection/blood , Zika Virus Infection/complications
17.
J Prosthodont ; 28(2): 122-130, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30412320

ABSTRACT

PURPOSE: Some crowns returned from the laboratory are clinically unacceptable, and dentists must remake them. The objectives of this study were to: (1) quantify the remake rate of single-unit crowns; and (2) identify factors significantly associated with crown remakes and intraoral fit. MATERIALS AND METHODS: Dentists participating in the National Dental Practice-Based Research Network recruited patients needing crowns and documented fabrication techniques, patient characteristics, and outcomes. Crowns were considered clinically acceptable or rejected. Also, various aspects of the clinical fit of the crown were graded and categorized as 'Goodness of Fit (GOF).' Dentist and patient characteristics were tested statistically for associations with crown acceptability and GOF. RESULTS: More than 200 dentists participated in this study (N = 205) and evaluated 3750 single-unit crowns. The mean age (years) of patients receiving a crown was 55. The remake rate for crowns was 3.8%. The range of rejection rates among individual practitioners was 0% to 42%. Most clinicians (118, or 58%) did not reject any crowns; all rejections came from 42% of the clinicians (n = 87). The most common reasons for rejections were proximal misfit, marginal errors, and esthetic failures. Fewer years in practice was significantly associated with lower crown success rates and lower fit scores. GOF was also associated with practice busyness and patient insurance status, patient gender (dentists reported better fit for female patients), and patient ethnicity. CONCLUSIONS: The crown remake rate in this study was about 4%. Remakes and crown GOF were associated with certain dentist and practice characteristics.


Subject(s)
Crowns , Dental Prosthesis Design , Practice Patterns, Dentists'/statistics & numerical data , Decision Making , Esthetics, Dental , Female , Humans , Male , Middle Aged , Prospective Studies , Surveys and Questionnaires , United States
18.
J Prosthodont ; 27(9): 813-820, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30311319

ABSTRACT

PURPOSE: To: (1) determine which preparation techniques clinicians use in routine clinical practice for single-unit crown restorations; (2) test whether certain practice, dentist, and patient characteristics are significantly associated with these techniques. MATERIALS AND METHODS: Dentists in the National Dental Practice-Based Research Network participated in a questionnaire regarding preparation techniques, dental equipment used for single-unit crown preparations, scheduled chair time, occlusal clearance determination, location of finish lines, magnification during preparation, supplemental lighting, shade selection, use of intraoral photographs, and trimming dies. Survey responses were compared by dentist and practice characteristics using ANOVA. RESULTS: Of the 2132 eligible dentists, 1777 (83%) responded to the survey. The top two margin configuration choices for single-unit crown preparation for posterior crowns were chamfer/heavy chamfer (65%) and shoulder (23%). For anterior crowns, the most prevalent choices were the chamfer (54%) and the shoulder (37%) configurations. Regarding shade selection, a combination of dentist, assistant, and patient input was used to select anterior shades 59% of the time. Photographs are used to communicate shade selection with the laboratory in about half of esthetically demanding cases. The ideal finish line was located at the crest of gingival tissue for 49% of respondents; 29% preferred 1 mm below the crest; and 22% preferred the finish line above the crest of tissue. Average chair time scheduled for a crown preparation appointment was 76 ± 21 minutes. Practice and dentist characteristics were significantly associated with margin choice including practice type (p < 0.001), region (p < 0.001), and years since graduation (p < 0.001). CONCLUSIONS: Network dentists prefer chamfer/heavy chamfer margin designs, followed by shoulder preparations. These choices were related to practice and dentist characteristics.


Subject(s)
Crowns , Dental Prosthesis Design/methods , Dental Prosthesis Design/statistics & numerical data , Female , Humans , Male , Practice Patterns, Dentists'/statistics & numerical data , Surveys and Questionnaires , United States
19.
J Prosthodont ; 27(8): 722-732, 2018 Oct.
Article in English | MEDLINE | ID: mdl-28076661

ABSTRACT

PURPOSE: To: (1) determine which impression and gingival displacement techniques practitioners use for single-unit crowns on natural teeth; and (2) test whether certain dentist and practice characteristics are significantly associated with the use of these techniques. MATERIALS AND METHODS: Dentists participating in the National Dental Practice-Based Research Network were eligible for this survey study. The study used a questionnaire developed by clinicians, statisticians, laboratory technicians, and survey experts. The questionnaire was pretested via cognitive interviewing with a regionally diverse group of practitioners. The survey included questions regarding gingival displacement and impression techniques. Survey responses were compared by dentist and practice characteristics using ANOVA. RESULTS: The response rate was 1777 of 2132 eligible dentists (83%). Regarding gingival displacement, most clinicians reported using either a single cord (35%) or dual cord (35%) technique. About 16% of respondents preferred an injectable retraction technique. For making impressions, the most frequently used techniques and materials are: poly(vinyl siloxane), 77%; polyether, 12%; optical/digital, 9%. A dental auxiliary or assistant made the final impression 2% of the time. Regarding dual-arch impression trays, 23% of practitioners report they typically use a metal frame tray, 60% use a plastic frame, and 16% do not use a dual-arch tray. Clinicians using optical impression techniques were more likely to be private practice owners or associates. CONCLUSIONS: This study documents current techniques for gingival displacement and making impressions for crowns. Certain dentist and practice characteristics are significantly associated with these techniques.


Subject(s)
Crowns , Dental Impression Technique/statistics & numerical data , Practice Patterns, Dentists'/statistics & numerical data , Dental Prosthesis Design/statistics & numerical data , Female , Humans , Male , Surveys and Questionnaires , United States
20.
J Am Dent Assoc ; 148(11): 788-796.e4, 2017 11.
Article in English | MEDLINE | ID: mdl-28822536

ABSTRACT

BACKGROUND: Objectives were to determine the likelihood that a clinician accepts an impression for a single-unit crown and document crown remake rates. METHODS: The authors developed a questionnaire that asked dentists about techniques used to fabricate single-unit crowns. The authors showed dentists photographs of 4 impressions and asked them to accept or reject each impression. The authors correlated answers with dentist and practice characteristics. Other questions pertained to laboratory use and crown remake rates. RESULTS: The response rate was 83% (1,777 of 2,132 eligible dentists). Of the 4 impressions evaluated, 3 received consistent responses, with 85% agreement. One impression was more equivocal; 52% accepted the impression. The likelihood of accepting an impression was associated significantly with the clinician's sex, race, ethnicity, and practice busyness. Clinicians produced 18 crowns per month on average, and 9% used in-office milling. Most dentists (59%) reported a remake rate of less than 2%, whereas 17% reported a remake rate greater than 4%. Lower remake rates were associated significantly with more experienced clinicians, optical impressions, and not using dual-arch trays. CONCLUSIONS: Although dentists were largely consistent in their evaluation of impressions (> 85%), nonclinical factors were associated with whether an impression was accepted or rejected. Lower crown remake rates were associated with more experienced clinicians, optical impressions, and not using dual-arch trays. PRACTICAL IMPLICATIONS: These results provide a snapshot of clinical care considerations among a diverse group of dentists. Clinicians can compare their own remake rates and impression evaluation techniques with those in this sample when developing best practice protocols.


Subject(s)
Crowns , Dental Impression Technique/statistics & numerical data , Dental Prosthesis Design/statistics & numerical data , Practice Patterns, Dentists'/statistics & numerical data , Decision Making , Dental Impression Materials , Esthetics, Dental , Humans , Surveys and Questionnaires , United States
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