A Real-world Toxicity Atlas Shows that Adverse Events of Combination Therapies Commonly Result in Additive Interactions.

PURPOSE: Combination therapies are a promising approach for improving cancer treatment, but it is challenging to predict their resulting adverse events in a real-world setting. EXPERIMENTAL DESIGN: We provide here a proof-of-concept study using 15 million patient records from the FDA Adverse Event Reporting System (FAERS). Complex adverse event frequencies of drugs or their combinations were visualized as heat maps onto a two-dimensional grid. Adverse event frequencies were shown as colors to assess the ratio between individual and combined drug effects. To capture these patterns, we trained a convolutional neural network (CNN) autoencoder using 7,300 single-drug heat maps. In addition, statistical synergy analyses were performed on the basis of BLISS independence or χ2 testing. RESULTS: The trained CNN model was able to decode patterns, showing that adverse events occur in global rather than isolated and unique patterns. Patterns were not likely to be attributed to disease symptoms given their relatively limited contribution to drug-associated adverse events. Pattern recognition was validated using trial data from ClinicalTrials.gov and drug combination data. We examined the adverse event interactions of 140 drug combinations known to be avoided in the clinic and found that near all of them showed additive rather than synergistic interactions, also when assessed statistically. CONCLUSIONS: Our study provides a framework for analyzing adverse events and suggests that adverse drug interactions commonly result in additive effects with a high level of overlap of adverse event patterns. These real-world insights may advance the implementation of new combination therapies in clinical practice.

Debulking different Corona (SARS-CoV-2 delta, omicron, OC43) and Influenza (H1N1, H3N2) virus strains by plant viral trap proteins in chewing gums to decrease infection and transmission.

Because oral transmission of SARS-CoV-2 is 3-5 orders of magnitude higher than nasal transmission, we investigated debulking of oral viruses using viral trap proteins (CTB-ACE2, FRIL) expressed in plant cells, delivered through the chewing gum. In omicron nasopharyngeal (NP) samples, the microbubble count (based on N-antigen) was significantly reduced by 20 µg of FRIL (p < 0.0001) and 0.925 µg of CTB-ACE2 (p = 0.0001). Among 20 delta or omicron NP samples, 17 had virus load reduced below the detection level of spike protein in the RAPID assay, after incubation with the CTB-ACE2 gum powder. A dose-dependent 50% plaque reduction with 50-100 ng FRIL or 600-800 µg FRIL gum against Influenza strains H1N1, H3N2, and Coronavirus HCoV-OC43 was observed with both purified FRIL, lablab bean powder or gum. In electron micrographs, large/densely packed clumps of overlapping influenza particles and FRIL protein were observed. Chewing simulator studies revealed that CTB-ACE2 release was time/dose-dependent and release was linear up to 20 min chewing. Phase I/II placebo-controlled, double-blinded clinical trial (IND 154897) is in progress to evaluate viral load in saliva before or after chewing CTB-ACE2/placebo gum. Collectively, this study advances the concept of chewing gum to deliver proteins to debulk oral viruses and decrease infection/transmission.

Diagnosis of Biofilm-Associated Peri-Implant Disease Using a Fluorescence-Based Approach.

Dental implants have become a routine component of daily dental practice and the demand for dental implants is expected to increase significantly in the future. Despite the high success rates of dental implants, failures do occur, resulting in discomfort, rampant destruction of the oral health, or painful and costly surgical replacement of a failed implant. Peri-implant diseases are inflammatory conditions affecting the soft/hard tissues surrounding a functional dental implant. Plenty of experimental evidence indicates that the accumulation of dental plaque at the soft tissue-implant interface and the subsequent local inflammatory response seems to be key in the pathogenesis of the peri-implant mucositis. Such peri-implant-soft tissue interface is less effective than natural teeth in resisting bacterial invasion, enhancing vulnerability to subsequent peri-implant disease. Furthermore, in certain individuals, it will progress to peri-implantitis, resulting in alveolar bone loss and implant failure. Although early diagnosis and accurate identification of risk factors are extremely important to effectively prevent peri-implant diseases, current systematic reviews revealed that a uniform classification and diagnostic methodology for peri-implantitis are lacking. Recent progress on fluorescence-based technology enabled rapid diagnosis of the disease and effective removal of plaques. Here, we briefly review biofilm-associated peri-implant diseases and propose a fluorescence-based approach for more accurate and objective diagnoses. A fluorescence-based diagnosis tool through headlights combined with special-filtered dental loupes may serve as a hands-free solution for both precise diagnosis and effective removal of plaque-biofilms.

Comorbid conditions are a risk for osteonecrosis of the jaw unrelated to antiresorptive therapy.

OBJECTIVE: Osteonecrosis of the jaw (ONJ) is commonly associated with antiresorptive therapy. There have been numerous reports of ONJ unrelated to antiresorptive therapy (ONJuat), confounding risk assessment. This study aimed to determine if ONJuat is associated with one or more particular comorbidities. STUDY DESIGN: This was a retrospective case-control study of patients with ONJuat and delayed healing (DH). Each case was matched for patient age and gender, as well as location of ONJuat or DH lesion to a control patient who had a history of dentoalveolar surgery with uneventful healing and no history of antiresorptive therapy. Comorbidity data included medical conditions and smoking. RESULTS: Of the 92 patients identified, 67 (73%) met the criteria for ONJuat and 25 (27%) for DH. The most common trigger for ONJ and DH was extraction (50%). The presence of any comorbidity (i.e., at least 1) was more prevalent in ONJuat than among controls (P = .04), and there were more comorbidities in patients with ONJuat and DH than in controls [M(SD) = 1.94 (1.2) and 2.0 (1.3) vs 1.26 (0.89); both P < .001]. CONCLUSIONS: ONJ and DH are not limited to patients with a history of antiresorptive therapy. More comorbidities may signal increased risk for ONJuat and DH.

Non-antibacterial tetracycline formulations: host-modulators in the treatment of periodontitis and relevant systemic diseases.

Traditionally, the dental profession has primarily treated periodontitis using a mechanical/surgical, rather than a pharmaceutical, approach. However, based on experiments several decades ago which demonstrated that tetracyclines, unexpectedly, inhibit collagen- and bone-destructive mammalian-derived enzymes (e.g. the collagenases), and through non-antibiotic mechanisms, the concept of host-modulation therapy (HMT) was developed. Accordingly, two drug-development strategies evolved: (i) the development of non-antimicrobial formulations of doxycycline; and (ii) the chemical modification of tetracyclines to eliminate their antibiotic activity but retain (or even enhance) their anti-collagenase properties. Regarding the latter, these chemically modified tetracyclines (CMTs) showed efficacy in vitro, in animal models of periodontal (and relevant systemic) disease, and in preliminary clinical trials on patients with Kaposi's sarcoma (however, at the high doses used, photosensitivity was a significant side-effect). In the first strategy, subantimicrobial-dose doxycycline (SDD) demonstrated safety and efficacy in human clinical trials and was approved by the U S Food and Drug Administration (U S FDA) and in other countries for the treatment of periodontitis (20 mg, twice daily, i.e. once every 12 hours) adjunctive to scaling and root planing, and for chronic inflammatory skin diseases (40-mg sustained-release 'beads'). SDD also showed efficacy in patients with systemic diseases relevant to periodontitis, including diabetes mellitus and arthritis, and in postmenopausal women with local and systemic bone loss. Importantly, long-term administration of SDD, of up to 2 years, in clinical trials did not produce antibiotic side-effects. SDD (and in the future, new HMTs, such as low-dose CMT-3, resolvins and chemically modified curcumins) may shift the paradigm of periodontal therapy from a predominantly surgical approach to the greater use of medicinal/pharmacologic strategies, ultimately to benefit larger numbers of patients.

The potential for glycemic control monitoring and screening for diabetes at dental visits using oral blood.

OBJECTIVES: We examined the potential for glycemic control monitoring and screening for diabetes in a dental setting among adults (n = 408) with or at risk for diabetes. METHODS: In 2013 and 2014, we performed hemoglobin A1c (HbA1c) tests on dried blood samples of gingival crevicular blood and compared these with paired "gold-standard" HbA1c tests with dried finger-stick blood samples in New York City dental clinic patients. We examined differences in sociodemographics and diabetes-related risk and health care characteristics for 3 groups of at-risk patients. RESULTS: About half of the study sample had elevated HbA1c values in the combined prediabetes and diabetes ranges, with approximately one fourth of those in the diabetes range. With a correlation of 0.991 between gingival crevicular and finger-stick blood HbA1c, measures of concurrence between the tests were extremely high for both elevated HbA1c and diabetes-range HbA1c levels. Persons already diagnosed with diabetes and undiagnosed persons aged 45 years or older could especially benefit from HbA1c testing at dental visits. CONCLUSIONS: Gingival crevicular blood collected at the dental visit can be used to screen for diabetes and monitor glycemic control for many at-risk patients.

Induction of HIV-1-specific mucosal immune responses following intramuscular recombinant adenovirus serotype 26 HIV-1 vaccination of humans.

BACKGROUND: Defining mucosal immune responses and inflammation to candidate human immunodeficiency virus type 1 (HIV-1) vaccines represents a current research priority for the HIV-1 vaccine field. In particular, it is unclear whether intramuscular immunization can elicit immune responses at mucosal surfaces in humans. METHODS: In this double-blind, randomized, placebo-controlled clinical trial, we evaluated systemic and mucosal immune responses to a candidate adenovirus serotype 26 (Ad26) vectored HIV-1 envelop (Env) vaccine in baseline Ad26-seronegative and Ad26-seropositive healthy volunteers. Systematic mucosal sampling with rectal Weck-Cel sponges and rectal biopsies were performed. RESULTS: Intramuscular immunization elicited both systemic and mucosal Env-specific humoral and cellular immune responses in the majority of subjects. Individuals with preexisting Ad26-specific neutralizing antibodies had vaccine-elicited immune responses comparable to those of subjects who were Ad26 seronegative. We also observed no increase in activated total or vector-specific mucosal CD4+ T lymphocytes following vaccination by either histopathology or flow cytometry. CONCLUSIONS: These data demonstrate that a single intramuscular administration of this Ad26-vectored HIV-1 Env vaccine elicited both systemic and mucosal immune responses in humans. Induction of antigen-specific humoral and cellular mucosal immunity was not accompanied by a detectable increase in mucosal inflammation. CLINICAL TRIALS REGISTRATION: NCT01103687.

Interprofessional education between dentistry and nursing: the NYU experience.

In 2005, New York University Colleges of Dentistry and Nursing formed an organizational partnership to create a unique model of interprofessional education, research, service and practice. This paper describes the first eight years of experience, from the early reaction of the public to the partnership, to examples of success and past and current challenges.

First-in-human evaluation of a hexon chimeric adenovirus vector expressing HIV-1 Env (IPCAVD 002).

BACKGROUND: We report the first-in-human safety and immunogenicity assessment of a prototype hexon chimeric adenovirus (Ad) serotype 5 (Ad5) vector containing the hexon hypervariable regions of Ad serotype 48 (Ad48) and expressing human immunodeficiency virus (HIV) type 1 EnvA. METHODS: Forty-eight Ad5 and Ad48 seronegative, HIV-uninfected subjects were enrolled in a randomized, double-blind, placebo-controlled, dose escalation phase 1 study. Four groups of 12 subjects received 10(9) to 10(11) viral particles (vp) of the Ad5HVR48.EnvA.01 vaccine (n = 10 per group) or placebo (n = 2 per group) at week 0 or weeks 0, 4, and 24. Safety and immunogenicity were assessed. RESULTS: Self-limited reactogenicity was observed after the initial immunization in the highest (10(11) vp) dose group. Responses in vaccinees included Ad48 neutralizing antibody (nAb) titers higher than Ad5 nAb titers, EnvA-specific enzyme-linked immunosorbent assay titers, and EnvA-specific enzyme-linked immunospot assay responses, and these responses generally persisted at week 52. At week 28 in the 10(9), 10(10), and 10(11) vp 3-dose groups, geometric mean EnvA enzyme-linked immunosorbent assay titers were 5721, 10 929, and 3420, respectively, and Ad48 nAb titers were a median of 1.7-fold higher than for Ad5. CONCLUSIONS: Ad5HVR48.ENVA.01 was safe, well tolerated, and immunogenic at all doses tested. Vector-elicited nAb responses were greater for Ad48 than Ad5, confirming that Ad-specific nAbs in humans are primarily, but not exclusively, directed against the hexon hypervariable regions. Clinical Trials Registration. NCT00695877.

The relationship between smoking and periodontal disease. Review of literature and case report.

Cigarette smoking has been associated with tooth loss from periodontal disease for a long time. Smoking cessation has been shown to reverse these effects. The purpose of this paper is to review the current literature regarding the possible mechanisms for destruction of the periodontium caused by smoking and to present a protocol for the implementation of a smoking cessation program at New York University College of Dentistry.

First-in-human evaluation of the safety and immunogenicity of a recombinant adenovirus serotype 26 HIV-1 Env vaccine (IPCAVD 001).

BACKGROUND: We report the first-in-human safety and immunogenicity assessment of a prototype Ad26 vector-based human immunodeficiency virus (HIV) vaccine in humans. METHODS: Sixty Ad26-seronegative, healthy, HIV-uninfected subjects were enrolled in a randomized, double-blinded, placebo-controlled, dose-escalation phase 1 study. Five groups of 12 subjects received 10(9)-10(11) vp of the Ad26-EnvA vaccine (N = 10/group) or placebo (N = 2/group) at weeks 0 and 24 or weeks 0, 4, and 24. Safety and immunogenicity were assessed. RESULTS: Self-limited reactogenicity was observed after the initial immunization at the highest (10(11) vp) dose. No product-related SAEs were observed. All subjects who received the Ad26-EnvA vaccine developed Ad26 NAb titers, EnvA-specific enzyme-linked immunosorbent assays (ELISA) titers, and EnvA-specific enzyme-linked immunospot assays (ELISPOT) responses. These responses persisted at week 52. At week 28 in the 10(9), 10(10), 10(11) vp 3-dose and the 10(10) and 5 × 10(10) vp 2-dose groups, geometric mean EnvA ELISA titers were 6113, 12 470, 8545, 3470, and 9655 and mean EnvA ELISPOT responses were 397, 178, 736, 196, and 1311 SFC/10(6) peripheral blood mononuclear cells, respectively. CONCLUSION: This Ad26 vectored vaccine was generally safe and immunogenic at all doses tested. Reactogenicity was minimal with doses of 5 × 10(10) vp or less. Ad26 is a promising new vaccine vector for HIV-1. CLINICAL TRIALS REGISTRATION: NCT00618605.

Implementing tobacco use treatment guidelines in public health dental clinics in New York City.

In this study we evaluated the effect of a multicomponent intervention to implement the Public Health Service (PHS) guideline Treating Tobacco Use and Dependence in six randomly selected dental clinics in New York University's College of Dentistry. The main outcome measure-provider adherence to tobacco use treatment guidelines-was assessed by auditing a random selection of patient charts pre (698) and post (641) intervention. The intervention components included a chart reminder and referral system, free nicotine replacement therapy (NRT), and provider training and feedback. The results showed that rates of screening for tobacco use did not change between pre and post test chart audits. However, providers were significantly more likely to offer advice (28.4 percent pre, 49 percent post), assess readiness to quit (17.8 percent pre, 29.9 percent post), and offer assistance (6.5 percent pre and 15.6 percent post) in the post test period. Increases in NRT distribution were associated with booster training sessions but declined in the time periods between those trainings. Research is needed to further define sustainable strategies for implementing tobacco use treatment in dental clinics. The results of this study suggest the feasibility and effectiveness of using a tailored multicomponent approach to implement tobacco use treatment guidelines in dental clinics.

Safety and immunogenicity of HCV E1E2 vaccine adjuvanted with MF59 administered to healthy adults.

BACKGROUND: Hepatitis C virus (HCV) causes chronic liver disease that often leads to cirrhosis and hepatocellular carcinoma. In animal studies, chimpanzees were protected against chronic infection following experimental challenge with either homologous or heterologous HCV genotype 1a strains which predominate in the USA and Canada. We describe the first in humans clinical trial of this prophylactic HCV vaccine. METHODS: HCV E1E2 adjuvanted with MF59C.1 (an oil-in-water emulsion) was given at 3 different dosages on day 0 and weeks 4, 24 and 48 in a phase 1, placebo-controlled, dose escalation trial to healthy HCV-negative adults. RESULTS: There was no significant difference in the proportion of subjects reporting adverse events across the groups. Following vaccination subjects developed antibodies detectable by ELISA, CD81 neutralization and VSV/HCV pseudotype neutralization. There were no significant differences between vaccine groups in the number of responders and geometric mean titers for each of the three assays. All subjects developed lymphocyte proliferation responses to E1E2 and an inverse response to increasing amounts of antigen was noted. CONCLUSIONS: The vaccine was safe and generally well-tolerated at each of the 3 dosage levels and induced antibody and lymphoproliferative responses. A larger study to further evaluate safety and immunogenicity is warranted.

The cariogenic dental biofilm: good, bad or just something to control?

This paper discusses the role of dental biofilm and adjunctive therapies in the management of dental caries. Dental biofilm is a site of bacterial proliferation and growth, in addition to being a location of acid production. It also serves as a reservoir for calcium exchange between the tooth and saliva. The salivary pellicle, a protein-rich biofilm layer, regulates the reaction between tooth surface, saliva and erosive acids. The protective effects of this pellicle on enamel are well established. However, understanding the effects of the pellicle/biofilm interaction in protecting dentin from erosive conditions requires further research. Saliva interacts with the biofilm, and is important in reducing the cariogenic effects of dental plaque as acidogenic bacteria consume fermentable carbohydrates producing acids that may result in tooth demineralization. Adequate supplies of healthy saliva can provide ingredients for successful remineralization. Strategies for managing the cariogenic biofilm are discussed with emphasis on the effectiveness of over-the-counter (OTC) products. However, since many toothpaste components have been altered recently, new clinical trials may be required for true validation of product effectiveness. A new generation of calcium-based remineralizing technologies may offer the ability to reverse the effects of demineralization. Nevertheless, remineralization is a microscopic subsurface phenomenon, and it will not macroscopically replace tooth structure lost in a cavitated lesion. Optimal management of cavitations requires early detection. This, coupled with advances in adhesive restorative materials and microsurgical technique, will allow the tooth to be restored with minimal destruction to nearby healthy tissue.

Pilot study: digital subtraction radiography as a tool to assess alveolar bone changes in periodontitis patients under treatment with subantimicrobial doses of doxycycline.

BACKGROUND: Subtle changes in marginal alveolar bone level can be demonstrated using digital subtraction of sequential radiographs. OBJECTIVE: We aimed to evaluate the practical application of geometrically corrected digital subtraction in a clinical study of alveolar bone response to a drug previously shown to inhibit alveolar bone loss. STUDY DESIGN: Selected periapical radiographs were acquired with projective standardization of patients with clinical marginal alveolar bone loss. Subsequently, patients received a 6-month regimen of subantimicrobial doxycycline or placebo. Standardized radiographs of the same alveolar regions were acquired after 3 and 6 months, and baseline radiographs were subtracted from these images. RESULTS: Blinded digital subtraction analysis indicated various levels of marginal bone gain in 3 of the 6 patients in the experimental group, whereas in 3 of the 5 placebo patients the method showed bone loss. CONCLUSION: These results suggest that geometrically corrected digital subtraction possibly agrees with clinical predictors of bone loss severity.

Subantimicrobial-dose doxycycline modulates gingival crevicular fluid biomarkers of periodontitis in postmenopausal osteopenic women.

BACKGROUND: We recently demonstrated that a 2-year subantimicrobial-dose doxycycline (SDD) regimen (double-masked, placebo-controlled clinical trial) in postmenopausal (PM) women exhibiting mild systemic bone loss (osteopenia) and local bone loss (periodontitis) reduced the progression of periodontal attachment loss (intent-to-treat analysis) and the severity of gingival inflammation and alveolar bone loss (subgroups) without producing antibiotic side effects. We now describe SDD effects on biomarkers of collagen degradation and bone resorption in the gingival crevicular fluid (GCF) of the same vulnerable subjects. METHODS: GCF was collected from SDD- and placebo-treated PM subjects (n=64 each) at the baseline and 1- and 2-year appointments; the volume was determined; and the samples were analyzed for collagenase activity (using a synthetic peptide as substrate), relative levels of three genetically distinct collagenases (Western blot), a type-1 collagen breakdown product/bone resorption marker (a carboxyterminal telopeptide cross-link fragment of type I collagen [ICTP]; radioimmunoassay), and interleukin-1beta (enzyme-linked immunosorbent assay). Statistical analyses were performed using generalized estimating equations; primary analyses were intent-to-treat. RESULTS: Collagenase activity was significantly reduced by SDD treatment relative to placebo based on intent-to-treat (P=0.01). ICTP showed a similar pattern of change during SDD treatment, and GCF collagenase activity and ICTP were positively correlated at all time periods (P<0.001). Matrix metalloproteinase (MMP)-8 accounted for approximately 80% of total collagenase in GCF, with much less MMP-1 and -13, and SDD reduced the odds of elevated MMP-8 by 60% compared to placebo (P=0.006). CONCLUSION: These observations support the therapeutic potential of long-term SDD therapy to reduce periodontal collagen breakdown and alveolar bone resorption in PM women; effects on serum biomarkers of systemic bone loss in these subjects are being analyzed.

Efficacy of sub-antimicrobial dose doxycycline in post-menopausal women: clinical outcomes.

AIMS: To determine the clinical efficacy of a 2-year continuous sub-antimicrobial dose doxycycline (SDD; 20 mg bid) in post-menopausal, osteopenic, oestrogen-deficient women on periodontal maintenance. MATERIALS AND METHODS: One-hundred and twenty-eight subjects were randomized to SDD (n=64) or placebo (n=64). Clinical measurements were performed at posterior interproximal sites at baseline and every 6 months during this 2-year randomized, double-blind, placebo-controlled clinical trial with adjunctive, no-cost 3-4-month periodontal maintenance. Statistical analyses of secondary outcomes from this clinical trial used Generalized Estimating Equations in primarily intent-to-treat analyses. RESULTS: For the placebo group, 3.4% of the sites showed improvement in clinical attachment levels (CAL) and 2.7% had progressive loss in CAL; for the SDD group, 5.0% of the sites showed an improvement in CAL and 2.2% had progressive loss in CAL. This difference (2.1% of sites) was more favourable in the SDD group than in the placebo [odds ratio (OR)=0.81 [corrected] 95% confidence interval (CI): 0.67-0.97, p=0.03] in these well-maintained patients, whereas probing depths, bleeding on probing and supragingival plaque did not differ significantly between groups (p>0.2). However, in exploratory subgroup analysis of non-smokers, SDD showed reduced bleeding versus placebo (27%versus 33%; p=0.05). In protocol-adherent subjects, the odds of bleeding were 34% lower for SDD (p=0.05). CONCLUSIONS: Analyses of secondary outcomes of this clinical trial indicated that SDD may be of benefit in reducing progressive attachment loss in post-menopausal females; additional research is needed to confirm these findings. Protocol registered at (ClinicalTrials.gov). Identifier:NCT00066027.

Subantimicrobial dose doxycycline effects on alveolar bone loss in post-menopausal women.

AIM: Determine the efficacy of 2-year continuous subantimicrobial dose doxycycline (SDD; 20 mg bid) on alveolar bone in post-menopausal osteopenic, oestrogen-deficient women undergoing periodontal maintenance in a 2-year double-blind, placebo-controlled, randomized clinical trial. MATERIAL AND METHODS: One-hundred and twenty-eight subjects randomized to SDD or placebo (n=64 each). Posterior vertical bite wings taken at baseline, 1 and 2 years for alveolar bone density (ABD), using radiographic absorptiometry (RA) and computer-assisted densitometric image analysis (CADIA), and alveolar bone height (ABH). Statistical analyses utilized generalized estimating equations; primary analyses were intent to treat (ITT). Results are presented as SDD versus placebo. RESULTS: Under ITT, there was no statistically significant effect of SDD on ABD loss (RA: p=0.8; CADIA: p=0.2) or ABH loss (p=0.2). Most sites (81-95%) were inactive. For subgroup analyses, mean CADIA was higher with SDD for non-smokers (p=0.05) and baseline probing depths > or =5 mm (p=0.003). SDD was associated with 29% lower odds of more progressive ABH loss in women >5 years post-menopausal (p=0.05) and 36% lower among protocol-adherent subjects (p=0.03). CONCLUSIONS: In post-menopausal osteopenic women with periodontitis, SDD did not differ overall from placebo. Based on exploratory subgroup analyses, additional research is needed to determine the usefulness of SDD in non-smokers, subjects >5 years post-menopausal and in deeper pockets. Protocol registered at (ClinicalTrials.gov). Identifier: NCT00066027.