Faculty Bibliography

Methylene blue (MB) is a well-established antioxidant that has been shown to improve mitochondrial function in both in vitro and in vivo settings. Mitoquinone (MitoQ) is a selective antioxidant that specifically targets mitochondria and effectively reduces the accumulation of reactive oxygen species. To investigate the effect of long-term administration of MB on skeletal morphology, we administered MB to aged (18 months old) female C57BL/J6 mice, as well as to adult male and female mice with a genetically diverse background (UM-HET3). Additionally, we used MitoQ as an alternative approach to target mitochondrial oxidative stress during aging in adult female and male UM-HET3 mice. Although we observed some beneficial effects of MB and MitoQ in vitro, the administration of these compounds in vivo did not alter the progression of age-induced bone loss. Specifically, treating 18-month-old female mice with MB for 6 or 12 months did not have an effect on age-related bone loss. Similarly, long-term treatment with MB from 7 to 22 months or with MitoQ from 4 to 22 months of age did not affect the morphology of cortical bone at the mid-diaphysis of the femur, trabecular bone at the distal-metaphysis of the femur, or trabecular bone at the lumbar vertebra-5 in UM-HET3 mice. Based on our findings, it appears that long-term treatment with MB or MitoQ alone, as a means to reduce skeletal oxidative stress, is insufficient to inhibit age-associated bone loss. This supports the notion that interventions solely with antioxidants may not provide adequate protection against skeletal aging.

Background: Dental caries (tooth decay) is the world's most prevalent noncommunicable disease and can lead to pain, infection, and edentulism. Many children with caries lack access to traditional dental services. School-based caries prevention can increase access to care and reduce health inequities. Disruptions in school-based care due to pandemic control policies may result in children losing access to their primary dental care option. Methods: The CariedAway project was a school-based caries prevention program in operation from 2019 to 2023 in urban schools with a high proportion of low-income, minority students. Program operations were suspended for 2 years due to the COVID-19 pandemic. We estimated the prevalence of untreated decay, swelling, fistula, and pulpal involvement in participants at baseline and again after restrictions were lifted. Results: A total of 2998 children between the ages of 5 and 13 years were enrolled and received preventive care prior to pandemic shutdowns, and 1398 (47%) completed a follow-up observation after 2 years. At baseline, approximately 30% had untreated caries on any dentition, 11% of children presented with evidence of dental sealants, and no participants had swelling, fistula, or pulpal involvement. After 24 months, 12% of participants had swelling fistula, or pulpal involvement that was not treated during the pandemic period. Conclusion: There are considerable unmet dental needs in high-risk children that may be further exacerbated by a lack of access to care during disease outbreaks.

Growth hormone (GH) is a key mediator of skeletal growth. In humans, excess GH secretion due to pituitary adenoma, seen in patients with acromegaly, results in severe arthropathies. This study investigated the effects of long-term excess GH on the knee joint tissues. One year-old wild-type (WT) and bovine GH (bGH) transgenic mice were used as a model for excess GH. bGH mice showed increased sensitivity to mechanical and thermal stimuli, compared with WT mice. Micro-computed tomography analyses of the distal femur subchondral bone revealed significant reductions in trabecular thickness and significantly reduced bone mineral density of the tibial subchondral bone-plate that were associated with increased osteoclast activity in both male and female bGH compared with WT mice. bGH mice showed severe loss of matrix from the articular cartilage, osteophytosis, synovitis, and ectopic chondrogenesis. Articular cartilage loss in the bGH mice was associated with elevated markers of inflammation and chondrocyte hypertrophy. Finally, hyperplasia of synovial cells was associated with increased expression of Ki-67 and diminished p53 levels in the synovium of bGH mice. Unlike the low-grade inflammation seen in primary osteoarthritis, arthropathy caused by excess GH affects all joint tissues and triggers severe inflammatory response. Data of this study suggest that treatment of acromegalic arthropathy should involve inhibition of ectopic chondrogenesis and chondrocyte hypertrophy.

Sodium glucose cotransporter-2 inhibitors (SGLT2is) promote urinary glucose excretion and decrease plasma glucose levels independent of insulin. Canagliflozin (CANA) is an SGLT2i, which is widely prescribed, to reduce cardiovascular complications, and as a second-line therapy after metformin in the treatment of type 2 diabetes mellitus. Despite the robust metabolic benefits, reductions in bone mineral density (BMD) and cortical fractures were reported for CANA-treated subjects. In collaboration with the National Institute on Aging (NIA)-sponsored Interventions Testing Program (ITP), we tested skeletal integrity of UM-HET3 mice fed control (137 mice) or CANA-containing diet (180 ppm, 156 mice) from 7 to 22 months of age. Micro-computed tomography (micro-CT) revealed that CANA treatment caused significant thinning of the femur mid-diaphyseal cortex in both male and female mice, did not affect trabecular bone architecture in the distal femur or the lumbar vertebra-5 in male mice, but was associated with thinning of the trabeculae at the distal femur in CANA-treated female mice. In male mice, CANA treatment is associated with significant reductions in cortical bone volumetric BMD by micro-CT, and by quantitative backscattered scanning electron microscopy. Raman microspectroscopy, taken at the femur mid-diaphyseal posterior cortex, showed significant reductions in the mineral/matrix ratio and an increased carbonate/phosphate ratio in CANA-treated male mice. These data were supported by thermogravimetric assay (TGA) showing significantly decreased mineral and increased carbonate content in CANA-treated male mice. Finally, the sintered remains of TGA were subjected to X-ray diffraction and showed significantly higher fraction of whitlockite, a calcium orthophosphate mineral, which has higher resorbability than hydroxyapatite. Overall, long-term CANA treatment compromised bone morphology and mineral composition of bones, which likely contribute to increased fracture risk seen with this drug.

OBJECTIVES/OBJECTIVE:Evidence for affordable and pragmatic programmes to address the burden of untreated tooth decay in children in low- and middle-income settings is limited. This study aimed to (1) assess the effect of a government-run, school-based daily group toothbrushing programme compared to standard school-based oral health education on the incidence of dental caries and odontogenic infections in Filipino children over a period of 3 years; and (2) assess the additional preventive effect of on-demand oral urgent treatment (OUT) and weekly fluoride gel application. METHODS:A cluster-randomized trial was conducted in Camiguin, Philippines. Schools in three regions were randomly assigned to one of three intervention groups: The Essential Health Care Programme (EHCP), which includes daily toothbrushing with fluoride toothpaste; EHCP plus twice-yearly access to on-demand urgent oral treatment (EHCP + OUT) and EHCP plus weekly application of high-concentrated fluoride gel (EHCP + Fluoride). Schools in a nearby province with a similar child population were selected as external concurrent control group. Clinical oral examinations were performed by calibrated dentists from a random sample of 682 seven-year-old students who were examined at baseline and over the following 3 years. Outcome variables were the number of decayed primary teeth, the number of decayed, missing and filled permanent teeth (DMFT) and surfaces (DMFS), and the number of permanent teeth with pulpal involvement, ulcerations, fistula or abscess (PUFA). Data were analysed using multilevel mixed-effects negative binomial regression. RESULTS:Three years after implementation, increments in dental caries and odontogenic infections in permanent teeth did not significantly differ between the EHCP and control group, yet the incidence of DMFT was lower by 22% in children receiving EHCP. Compared to controls, children receiving EHCP + Fluoride had a significantly lower increment of DMFT, DMFS and PUFA by 40%, 40% and 47%, respectively. Children receiving EHCP + OUT had lower incidence rates of DMFT and DMFS than control children by 23% and 28%, respectively. A lower incidence rate was also found for PUFA, but the effect was not statistically significant. CONCLUSIONS:Findings suggest that the weekly application of fluoride gel and urgent oral treatment, in addition to daily school-based toothbrushing with fluoride toothpaste, are realistic and effective strategies to lower the burden of dental caries in Filipino children. Implementation challenges may explain why no substantial caries-preventive benefits were demonstrated for school-based toothbrushing only. Intervention compliance should be considered in future programme implementation and evaluation research.

IMPORTANCE:Dental caries is the most common global childhood disease. To control caries, the Centers for Disease Control and Prevention recommends school-based caries prevention, and the World Health Organization lists glass ionomer cement and silver diamine fluoride as essential medicines for oral disease. OBJECTIVE:To determine the noninferiority of silver diamine fluoride with fluoride varnish vs traditional glass ionomer sealants with fluoride varnish after 2 years when provided to children via a school-based health care program. DESIGN, SETTING, AND PARTICIPANTS:The CariedAway study is an ongoing single-blind, cluster randomized, noninferiority trial conducted between February 1, 2019, and June 1, 2023, among 2998 children in 47 New York City primary schools. Children aged 5 to 13 years of any race and ethnicity were recruited from block-randomized schools. Inclusion criteria for schools were a student population of at least 50% Hispanic or Latino or Latina ethnicity and/or Black race and at least 80% of students receiving free or reduced-cost lunch. Statistical analysis is reported through March 2022. INTERVENTIONS:Children received a single application of silver diamine fluoride with fluoride varnish or an active comparator of glass ionomer sealants and atraumatic restorations with fluoride varnish. MAIN OUTCOMES AND MEASURES:Primary outcomes were caries arrest and incidence after a 2-year follow-up, assessed using mixed-effects multilevel models and clustered 2-sample proportion tests. The noninferiority margin was 10%. Intention-to-treat analysis was performed using multiple imputation. RESULTS:A total of 2998 children (1566 girls [52.2%]; mean [SD] age at baseline, 6.6 [1.2] years; 1397 Hispanic or Latino or Latina children [46.6%]; 874 [29.2%] with untreated dental caries) were recruited and treated from September 16, 2019, to March 12, 2020. Follow-up observations were completed for 1398 children from June 7, 2021, to March 2, 2022. The mean (SE) proportion of children with arrested caries was 0.56 (0.04) after experimental treatment and 0.46 (0.04) after control treatment (difference, -0.11; 95% CI, -0.22 to 0.01). The mean (SE) proportion of patients without new caries was 0.81 (0.02) after experimental treatment and 0.82 (0.02) after control treatment (difference, 0.01; 95% CI, -0.04 to 0.06). Analysis of imputed data for the full sample did not deviate from per-protocol analyses. There were no adverse events. CONCLUSIONS AND RELEVANCE:In this randomized clinical trial, silver diamine fluoride with fluoride varnish was noninferior to sealants and atraumatic restorations with fluoride varnish for caries arrest and prevention. Results may support the use of silver diamine fluoride as an arresting and preventive agent in school-based oral health programs. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT03442309.

AIM/UNASSIGNED:The aim of this study was to digitally measure the dimensional changes in an irreversible hydrocolloid impression material (alginate) resulting from varying storage times under optimal storage conditions. MATERIALS AND METHODS/UNASSIGNED:A single type V dental stone control cast was used to make 25 alginate impressions using perforated stock trays. The impressions were randomly assigned into five groups of five samples each (n=5 per group) with varying storage times: Group 1, poured at 15 minutes; Group 2, poured at one hour; Group 3, poured at 24 hours (one day); Group 4, poured at 72 hours (three days); Group 5, poured at 168 hours (seven days). All impressions were stored in sealed Ziploc® plastic bags with a wet paper towel (100% relative humidity) at room temperature and stored according to the assigned group storage times. All impressions were poured in type V dental stone according to the manufacturer's instructions. The casts were scanned with a digital 3D desktop scanner and saved as electronic stereolithography (.stl) files. Each .stl file of the scanned casts were superimposed on the .stl file of the control cast using Geomagic® Control X™ software. Three preselected fixed comparison measuring points (CMP) on each cast were compared to the control cast. Point one (CMP1) was on the midfacial surface of central incisor. Point two (CMP2) and point three (CMP3) were on the mesiobuccal proximal marginal ridge areas of third molars. The discrepancies between the files at each point were analysed with colour maps, and quantified (Table 1). The tolerance was set at ±10μm. CMP scores were analysed using one-way analysis of variance (ANOVA) and Kruskal-Wallis (K-W) non-parametric H tests. RESULTS/UNASSIGNED:= 3.62, p = 0.46). CONCLUSIONS/UNASSIGNED:Under optimal storage conditions, there were no significant dimensional changes in casts poured from alginate up to seven days.

Excess in growth hormone (GH) levels, seen in patients with acromegaly, is associated with increases in fractures. This happens despite wider bones and independent of bone mineral density. We used the bovine GH (bGH) transgenic mice, which show constitutive excess in GH and insulin-like growth factor 1 (IGF-1) in serum and tissues, to study how lifelong increases in GH and IGF-1 affect skeletal integrity. Additionally, we crossed the acid labile subunit (ALS) null (ALSKO) to the bGH mice to reduce serum IGF-1 levels. Our findings indicate sexually dimorphic effects of GH on cortical and trabecular bone. Male bGH mice showed enlarged cortical diameters, but with marrow cavity expansion and thin cortices as well as increased vascular porosity that were associated with reductions in diaphyseal strength and stiffness. In contrast, female bGH mice presented with significantly smaller-diameter diaphysis, with greater cortical bone thickness and with a slightly reduced tissue elastic modulus (by microindentation), ultimately resulting in overall stronger, stiffer bones. We found increases in C-terminal telopeptide of type 1 collagen and procollagen type 1 N propeptide in serum, independent of circulating IGF-1 levels, indicating increased bone remodeling with excess GH. Sexual dimorphism in response to excess GH was also observed in the trabecular bone compartment, particularly at the femur distal metaphysis. Female bGH mice preserved their trabecular architecture during aging, whereas trabecular bone volume in male bGH mice significantly reduced and was associated with thinning of the trabeculae. We conclude that pathological excess in GH results in sexually dimorphic changes in bone architecture and gains in bone mass that affect whole-bone mechanical properties, as well as sex-specific differences in bone material properties. © 2022 American Society for Bone and Mineral Research (ASBMR).

OBJECTIVE:Silver diamine fluoride (SDF) is a non-surgical treatment for the arrest and prevention of dental caries that results in irreversible black staining of dental decay. The objective of this study was to evaluate the short-term impact of SDF treatment on oral health-related quality of life (OHRQoL) relative to a standard package of glass ionomer sealants and atraumatic restorative treatment (ART) in children aged 5-13 years. METHODS:CariedAway is a pragmatic, longitudinal, cluster-randomized non-inferiority trial of non-surgical interventions for caries. Secondary study outcomes included OHRQoL and academic performance. Oral health-related quality of life was measured at each study visit using the Child Oral Health Impact Profile. Change in OHRQoL was assessed using linear regression and non-inferiority was determined using t tests. RESULTS:160 children with an average age of 8.7 years completed quality of life assessments. Untreated decay at baseline (approximately 25%) was associated with significantly worse OHRQoL and treatment in both groups resulted in incremental improvement: children receiving SDF improved their OHRQoL scores from 16.44 (SD = 11.12) to 14.62 (SD = 11.90), and those receiving traditional sealants and atraumatic restorations slightly improved from 16.65 (SD = 10.56) to 16.47 (SD = 11.09). Quality of life in children receiving silver diamine fluoride was non-inferior to those receiving sealants and ART at least 6 months post-treatment (mean difference = 1.85, 95% CI = - 2.10, 5.80), and change in OHRQoL did not depend on the severity of baseline decay. CONCLUSIONS:OHRQoL is related to untreated dental caries, and observed changes following SDF treatment were non-inferior relative to standard preventive therapies.

OBJECTIVE:Silver diamine fluoride (SDF) is an effective non-surgical treatment for dental caries which may also impact oral health-related quality of life (OHRQoL). The objective of this study was to conduct a network meta-analysis of SDF versus other standard of care therapies on OHRQoL. DATA SOURCES:Studies published in PubMed/MEDLINE, Scopus, or Web of Science through July 2021 with no date or language restrictions. STUDY SELECTION:Any randomized controlled trial, cohort, or case-control study that included silver diamine fluoride as either a single or combinative treatment for dental caries and a quantitatively measured outcome for oral health-related quality of life was included. DATA EXTRACTION AND SYNTHESIS:Potentially eligible studies were screened by two independent reviewers trained in conducting systematic reviews. Studies meeting inclusion criteria underwent a full-text review with data being extracted using a standardized form, including publication details, study methodology, outcomes, assessors, and sample information. Studies underwent a risk of bias assessment. Quantitative synthesis was performed using fixed effects meta-analysis and individual comparisons were assessed via network meta-analysis. MAIN OUTCOME(S) AND MEASURE(S):Oral health-related quality of life. RESULTS:19 articles were returned following search strategies. Following screening, ten studies were evaluated for full-text eligibility and five were retained for meta-analyses. Results across all treatments indicate no differences in OHRQoL when compared to SDF (SMD = -0.06, 95% CI = -0.20, 0.08). Direct and indirect estimates from network meta-analysis indicated that OHRQoL in children was not significantly different when treated with SDF versus atraumatic restorations (d = 0.02, 95% CI = -0.32, 0.36) or placebo (d = 0.03, 95% CI = -0.16, 0.22). CONCLUSIONS:Evidence from the literature consistently shows no discernible impact on OHRQoL across various non-surgical treatments for dental caries. Overall oral health-related quality of life may increase regardless of treatment protocol due to treatment of the underlying disease. Concerns over the staining of dental decay and oral mucosa resulting from treatment with silver diamine fluoride do not seem to affect OHRQoL.