Fluoride Varnish Research Articles

Efficacy of Different Fluoride Therapies on Hypersensitive Carious Lesions in Primary Teeth.

Background and Objectives: This prospective, comparative, double-cohort study aimed to compare the efficacy of silver diamine fluoride and potassium iodide (38% SDF+KI; Riva Star®) with sodium fluoride varnish (5% NaF; Duraphat®) in hypersensitive carious lesions in primary teeth to evaluate caries arrest and hypersensitivity relief. Materials and Methods: This study included thirty 2-5-year-olds (mean age = 3.67 ± 1.06 years; 16 males and 14 females) who required a desensitizing treatment for hypersensitive carious defects with visible dentin. A total of 15 of the participants were consecutively allocated to treatment with 5% NaF, and they were further compared to an equal number of participants treated with 38% SDF+KI solutions (n = 15). The treatments were performed following clinical evaluation of caries activity using the International Caries Classification and Management System (ICCMSTM) and the Bjørndal criteria (score of 0-9). Parental-reported hypersensitivity was evaluated using a visual analogue scale (0-10 = no to severe pain). Results: Clinical variables were evaluated at baseline and three months after treatment. Thereafter, a significant decline in hypersensitivity/pain led to lower final scores in the Riva Star® group (0.40 ± 1.12, p = 0.002) than in the Duraphat® group (1.40 ± 2.20, p = 0.004). The caries arrest effect was significantly higher in the Riva Star® group (86.7%) compared to the Duraphat® group three months after treatment (13.3%, p < 0.001). In both groups, there were no statistically significant differences in the children's behavior before, during, and after treatment. Conclusions: Ultimately, with both fluoride therapies reducing hypersensitivity/pain significantly, treatment with 38% SDF+KI was clearly more effective in caries arrest than 5% NaF varnish after a 3-month period.

Silver diamine fluoride with sodium fluoride varnish versus silver diamine fluoride in arresting early childhood caries: a 6-months follow up of a randomized field trial

BackgroundEarly childhood caries (ECC) is the most prevalent chronic health problem in young children, and it can be arrested using professionally applied fluoride such as Sodium fluoride (NaF) varnish and Silver Diamine Fluoride (SDF). This trial compared two interventions to arrest ECC lesions: 38% SDF combined with 5% NaF varnish versus 38% SDF and assessed whether the arrest rate was affected by baseline lesion severity measured by ICDAS.MethodsChildren aged ≤ 4 years from 4 nurseries in a rural area in Alexandria, Egypt joined the study in March 2022. They were included if they had at least one active carious lesion with ICDAS codes ≥ 3. They were randomized to receive either 38% SDF with 5% NaF varnish or 38% SDF alone. In both groups, the agents were applied at baseline and after 6 months on the caries lesions. NaF was additionally applied on all teeth in the oral cavity, and it was also applied after three months. The primary outcome was lesion arrest status after six months. Parents’ satisfaction with their children’s appearance was the secondary outcome. Pearson Chi-Square test was used for bivariate comparison and multi-level multiple logistic regression was used to assess the effect of the intervention on caries arrest controlling for confounders. The interaction between the intervention and baseline lesion severity (categorized into moderate and severe lesions) was assessed and the p value was calculated.ResultsThe study included 1606 lesions in 220 children, median (IQR) age = 48(9) months. The percentages of arrested lesions after the application of SDF + NaF and SDF only were 77.7% and 73.2% (p = 0.035). In multivariable analysis, SDF + NaF had significantly greater caries arrest effect than SDF alone (AOR = 2.12, p = 0.03) with significant difference (p = 0.03) between moderate (AOR = 4.10, p = 0.005) and advanced (AOR = 1.92, p = 0.08) lesions. Most parents were satisfied with their children’s appearance with no significant difference between groups (SDF + NaF = 84.5%, SDF = 78.18%, p = 0.23).ConclusionSDF + NaF had a higher arrest rate than SDF alone and this difference was significant in moderate but not advanced lesions. The findings have implications for the non-invasive management of ECC.Trial registrationThis trial was registered in the clinicaltrials.gov registry (#NCT05642494).

Easy to apply fluoride varnish

Easy to apply fluoride varnish

The Patient Protection and Affordable Care Act and Pediatric Medical Clinicians’ Application of Fluoride Varnish

Fluoride varnish reduces children's tooth decay, yet few clinicians provide it. Most state Medicaid programs have covered this service during medical visits for children aged 1 to 5 years, but private insurers began covering it only in 2015 due to the Patient Protection and Affordable Care Act (ACA) mandate that they cover a set of recommended preventive services without cost-sharing. Evidence on clinicians' behavior change postmandate is limited. To examine monthly changes in fluoride varnish applications among pediatric clinicians following the ACA mandate. Using all-payer claims data from Massachusetts, this cohort study applied an interrupted time-series approach with linear regression models comparing changes in monthly clinician-level outcomes before and after the mandate. Participants included clinicians who billed at least 5 well-child visits for patients aged 1 to 5 years and were observed at least once premandate. Adjusted for clinician fixed effects, models were assessed overall and separately for clinicians categorized by their monthly share of well-child visits paid by private insurers before the mandate: mostly private (>66% of visits paid by private insurers), mostly public (<33% of visits paid by private insurers), or mixed (33%-66% of visits paid by private insurers) insurance types. Analysis was performed from June 1, 2022, to July 31, 2023. Preenactment and postenactment of the ACA mandate for private insurers to cover fluoride varnish applications without cost-sharing. Clinician-month measures of whether fluoride varnish was provided during at least 1 well-child visit and the share of such visits, analyzed separately for clinicians who did and did not apply fluoride varnish premandate. The sample included 2405 clinicians, with 107 841 clinician-months. Premandate, 10.48% of the visits included fluoride varnish applications. Two years postmandate, the likelihood of ever applying fluoride varnish was 13.64 (95% CI, 10.97-16.32) percentage points higher. For clinicians providing fluoride varnish premandate, the share of visits with fluoride varnish increased by 9.22 (95% CI, 5.41-13.02) percentage points. This increase was observed in clinicians who treated children with insurance that was mostly mixed and mostly private; no substantial change was observed among those treating children with mostly public insurance. In this cohort study of pediatric primary care clinicians, an association between the ACA mandate and an increase in fluoride varnish application was observed, especially among clinicians primarily treating privately insured patients and those applying it premandate. However, application remains infrequent, suggesting persistent barriers.

Fluoridated orthodontic adhesives: Implications of release and recharge and their impact on shear bond strength in demineralized tooth surfaces.

This study measured fluoride release from a light-cured orthodontic adhesive resin (Vega type) at three time intervals (one day, one week, and one month), investigated the rechargeability of the resin, and assessed its impact on shear bond strength in demineralized tooth surfaces. This study used 30 recently extracted upper premolar teeth to explore the effects of fluoride release over specific time intervals. The teeth underwent demineralization and were categorized into groups based on time intervals: one day, one week, and one month. Subgroups within each interval underwent fluoride recharging through fluoride varnish application. Fluoride release and shear bond strength were assessed after etching with phosphoric acid gel, applying the orthodontic adhesive, and curing. The samples were stored in deionized water. Fluoride quantification used a selective electrode, while shear bond strength assessment employed a universal testing machine. Finally, statistical analysis of the data was performed using SPSS 22. The study found that after one month, the adhesive had the highest fluoride release and shear bond strength mean values. There were significant differences in fluoride release and shear bond strength between the various groups studied. The application of fluoride varnish around the orthodontic bracket resulted in a positive effect on the shear bond strength of the bracket.

Efficacy of different remineralizing agents on primary teeth exposed to therapeutic gamma radiation: An in vitro randomized control study

BackgroundTherapeutic radiation-induced caries is a major side effect. Dental and oral heath are adversely affected by the direct effects of radiotherapy. Preventive procedures are preferred to reinforce dental tissue resistance against radiation damage. ObjectiveResearch aim is to test the impact of different remineralizing protocols on the mineral content of deciduous enamel exposed to a therapeutic dose of gamma radiation. MethodsThirty deciduous enamel specimens were divided randomly into three experimental categories based on the type of remineralizing agent used. Group I (gamma irradiated teeth, then painted with fluoride varnish), Group II (gamma irradiated teeth, then treated with bioactive glass) and Group III (gamma irradiated teeth, and then treated with a diode laser 980 nm). Prepared specimens were assessed for mineral content by environmental Energy Dispersive X-ray Analysis. SEM photomicrographs were performed simultaneously. Results were investigated concerning pre- and post-irradiation values difference. The paired-samples t-test was performed to compare the atomic and weight percentages of the selected elements obtained from the samples in the control groups before and after therapeutic radiation. One-way analysis of variance and post hoc Tukey tests were used to compare between the categories regarding weight and atomic percentages. ResultsCalcium/Phosphorus (Ca/P) ratio and Fluoride content decreased significantly after radiotherapy. Fluoride content significantly increased after remineralizing agents' application with the greatest increase in Bioactive glass group followed by fluoride varnish (F.varnish) group and the least increase was in diode laser group. Significant increase in Ca/P ratio in bioactive glass group followed by insignificant increase in F.varnish group (I) with the least increase noticed in the Diode laser group. ConclusionTherapeutic radiation caused marked decrease in enamel mineral content. However, the reminralizing agents applied have an improving effect on the caused damage.

Dentinomimetics and cementomimetics of Moringa oleifera leaves extract

To evaluate the biomimetic remineralization capabilities of Moringa oleifera leaves (MOL) extract on coronal dentin and acellular cementum, two different concentrations (50 and 200 mg/ml) of MOL extract loaded in plain varnish (M1 and M2 groups respectively) were compared to fluoride varnish (FL group) and native surface (C group). Eighty sound premolar teeth were collected. Forty teeth (10 teeth in each group) were used for coronal dentin testing while the other forty (10 teeth in each group) were used for acellular cementum testing. Teeth in M1, M2, and FL groups were etched for 30 s and then received the specific varnish treatment. All samples were immersed in artificial saliva for 14 days and then collected, dried, and examined by scanning electron microscopy and energy dispersive X-ray spectroscopy (EDX). Histologically, FL group showed mineral deposition as discrete vesicular granules of various sizes on the surface of both coronal dentin and acellular cementum. Mineral deposition only occurred on some DTs openings while opened tubules remained. The surface of the acellular cementum revealed regular grooves, micro-fissures, and cracks. In the M1 and M2 groups, mineral deposition appeared as a homogenous continuous layer on coronal dentin and acellular cementum. Only a few DTs and cementum fissures were not filled completely. In L.S. sections of the coronal one-third, the DTs appeared almost sealed with varying lengths of mineral deposition. EDX results statistical analysis showed that the M2 group had the highest phosphate ions (P−) and calcium ions (Ca+2) at%. MOL has an extraordinary effect on the remineralization of coronal dentin and acellular cementum. It would have a promising ability to control dentinal hypersensitivity and formation of biomimetic cementum tissue.

Effect of fluoride varnishes on oral bacteria of preschool children with cavitated and non-cavitated carious lesions: randomized clinical trial

We compare the effect of calcium and phosphate-containing sodium fluoride (NaF) varnishes to conventional NaF varnish on S. mutans and L. fermentum counts. 3–4 years old children were grouped according to their caries status (n = 45 each): caries-free, with non-cavitated and with cavitated lesions. Each group was randomly subdivided (n = 15 each) into: Group 1- 5% NaF, Group 2- 5% NaF with tricalcium phosphate, Group 3- 5% NaF with casein phosphopeptide- amorphous calcium phosphate. Biofilm and saliva were collected to quantify microorganisms at baseline (T1) and 24-months (T2). Differences between groups were compared using Kruskal–Wallis test, followed by Dunn-Bonferroni post-test, at 0.0167 α-level. Significant difference was found for percentage of children with detectable biofilm L. fermentum (p = 0.013) at T1 and salivary S. mutans (p = 0.011) at T2. Percentage of children increased from T1 to T2 in Group 2 with salivary S. mutans (p = 0.007), salivary L. fermentum (p = 0.035), and biofilm L. fermentum (p = 0.019) and in Group 3 with salivary L. fermentum (p = 0.035). Bacterial change was not significant in both samples of intervention groups, except increase in salivary S. mutans (p = 0.038) in Group 3. Both calcium- and phosphate-containing NaF varnishes demonstrated similar antibacterial effect on S. mutans and L. fermentum compared to conventional NaF varnish.

Effects of topical fluoride on primary tooth enamel microhardness after diode laser treatment

ObjectivesTooth decay is controlled and prevented using fluorides. Specifically, a combination of laser irradiation and topical fluoride application can improve fluoride absorption. Although laser irradiation is recommended in traditional technology for caries prevention, little is known about the efficacy of caries-inhibiting laser diodes. Further, most studies have focused on permanent teeth. The objective of this study was to explore the effect of laser diode radiation mixed with topical fluoride on the enamel surface microhardness of primary teeth. Material and methodThe 60 primary teeth were divided into 60 plates. Baseline Vickers microhardness was established for each enamel surface. The samples were then divided into three groups. 4 % NaF varnish (group A) and 4 % NaF varnish using diode 2 and 3 W lasers (groups B and C, respectively). The final microhardness was measured and statistically evaluated using SPSS version 16. ANOVA was used to compare the means of the tested groups, which had a P-value of 0.05, indicating significance. ResultThe mean and standard deviation of microhardness for the different groups was tested. Group C (4 % NaF with a diode laser at 3 W) showed a higher average Vickers hardness (VHN) than Group B (4 % NaF with a diode laser at 2 W), whereas group A showed the lowest average VHN. There was a significant difference in microhardness between groups (P 0.05). ConclusionThis study explored the effect of laser mixed with topical fluoride on enamel surface microhardness of primary teeth. The use of a diode laser (Quanta System, Italy) with a fluoride varnish applied to the enamel surface has a greater effect on the resistance of the enamel to caries.

Evaluation of the effectiveness of prophylactic sealing of pits and fissures of permanent teeth with fissure sealants - umbrella review

BackgroundTooth decay is an infectious disease which, in its initial phase, leads to the formation of cavities in the teeth through decalcification of the enamel and local tissue destruction. In addition to proper oral hygiene, prophylactic sealing of fissures and cavities with a sealant is a method of preventing the development of caries. The aim of this study is to summarise the effectiveness of fissure sealing of permanent teeth with fissure sealants compared to other preventive methods or no intervention.MethodAn umbrella review was carried out to achieve the purpose of our study. Searches were performed in Medline (via PubMed), Embase (via OVID), and Cochrane Library databases. Quality assessment of the included studies was performed using the AMSTAR2 tool. In addition, a manual search for recommendations/clinical practice guidelines on dental prophylaxis was performed.Results204 publications were identified, of which 15 met the inclusion criteria. Based on the results of 3 systematic reviews, there was a statistically significant reduced odds of caries occurrence or development with prophylactic sealing of permanent teeth compared with no intervention – depending on the review and follow-up period odds ratio (OR) ranged from 0.06 [95%CI: (0.01–0.32)] to 0.28 [95%CI: (0.20–0.38)]. In the eight systematic reviews that analysed different sealants, there were no statistically significant differences between the types of materials used for prophylactic tooth sealing. For systematic reviews comparing the efficacy of fissure sealants with fluoride varnish, three reported no statistically significant difference in the efficacy of caries incidence, with only one systematic review based on 1 RCT finding a statistically significant difference in favour of fissure sealants.ConclusionCompared to the no intervention, dental sealing is an effective method for the prevention of dental caries. However, it is not possible to conclude conclusively which type of sealant and which of the available prophylactic methods is more effective in preventing caries.

Easy to apply fluoride varnish.

Easy to apply fluoride varnish.

The effectiveness of medical nurses in treating children with silver diamine fluoride in a school-based caries prevention program.

The sustainability of school-based oral health programs depends on the utilization of effective, efficient treatments and the availability of a trained clinical workforce. The objective of this study was to determine whether registered nurses are comparable to dental hygienists in the application and effectiveness of silver diamine fluoride (SDF) and fluoride varnish (FV) for the prevention of dental caries. CariedAway was a school-based study of SDF and FV versus dental sealants and atraumatic restorations. Within the SDF + FV arm, participants were treated by either a licensed dental hygienist or a registered nurse, both under the supervision of a paediatric dentist. Although initial treatment assignment in CariedAway was randomized, assignment to provider was not. The proportion of children who remained caries free after 2 years was assessed for non-inferiority using two-group proportion tests, adjusting for the clustering effect of schools. A total of 417 children with no untreated caries at baseline were analysed including 298 treated by hygienists and 119 by nurses. The proportion of children who remained caries free after 2 years was 0.81 and 0.80 for those treated by hygienists and nurses, respectively, for a difference of 0.01 (95% CI = -0.07, 0.098) and within the pre-determined non-inferiority margin. Nurses may be effective in treating children with silver diamine fluoride and other fluoride varnishes in school-based oral health programs.

Oral Health Care Strategies in Rural Communities: A Case Study.

Dental caries affect 97% of the world's population during their lifetime. Early childhood caries are the number one chronic disease affecting young children, and it disproportionately affects children of low-income families. American Academy of Pediatrics recommends fluoridated toothpaste to all children starting at tooth eruption, regardless of caries risk. In addition, fluoride varnish is recommended in all children every 3 to 6 months from tooth emergence until they have an established dental home. The health disparities that are most apparent in the rural communities are inadequate prenatal care, low birth weight, cancer, chronic respiratory disease, heart disease, unintentional injury, and stroke. When it comes to oral health, water fluoridation is one of the most cost-effective strategies in preventing dental caries. The need for oral health education in physician assistant/associate (PA) programs is well documented. Implementation has largely been performed using interprofessional education. This article describes an interprofessional education program that teaches PA students to apply fluoride varnish so that they are practice-ready when they graduate and practice medicine.

Anti-inflammatory Activity and Cytotoxic Effect of Ginger and Rosemary-mediated Titanium Oxide Nanoparticles-based Dental Varnish

Anti-inflammatory Activity and Cytotoxic Effect of Ginger and Rosemary-mediated Titanium Oxide Nanoparticles-based Dental Varnish

The effect of silver nanoparticles in addition to sodium fluoride on remineralization of artificial root dentin caries.

Silver nanoparticle was developed to overcome the drawback of silver diamine fluoride. However, evidence is limited, especially in root caries. The aim of this study was to evaluate the remineralization effect of silver nanoparticles on root caries. Fifty-five root human dentin slices size 5 × 5 mm2 from patients aged over 60 years old were immersed in demineralized solution to create artificial caries. Specimens were allocated into five groups according to the remineralizing agents: silver diamine fluoride (SDF), silver nanoparticles solution (AgNPs), silver nanoparticle solution followed by sodium fluoride varnish (AgNPs+NaF), sodium fluoride varnish (NaF), and tap water. After 8 days of pH-cycling challenge, the microhardness test, lesion depth evaluation, dentin surface morphology, and elemental analysis were performed. Data was analysed using F-test One-way ANOVA followed by Tukey's post hoc test and paired T-test. All test groups demonstrated a significantly higher microhardness value and lower lesion depth compared with the control group. AgNPs+NaF and NaF-treated groups showed lower efficacy than SDF. Crystal precipitation was presented in all groups composed of silver. Addition of fluoride varnish did not benefit for silver nanoparticles in preventing further demineralization. SDF provides the highest effectiveness in elderly root carious dentin.

Barriers and Facilitators to Optimal Fluoride Varnish Application

ObjectiveNational guidelines recommend that all children under age six receive fluoride varnish (FV) in medical settings. However, application rates remain low. This study aimed to update understanding of barriers and facilitators to guideline concordant FV application. MethodsWe conducted virtual semi-structured interviews with a purposive sample (eg, FV application rates, geographic location, practice size and type) of pediatric primary care clinicians and medical assistants in Massachusetts between February 1 and June 30, 2022. The Consolidated Framework for Implementation Research (CFIR) served as the study’s theoretical framework and data were analyzed using a modified grounded theory approach. ResultsOf the 31 participants, 90% identified as White and 81% as female. Major themes, which linked to four CFIR domains, included: variation in perceived adequacy of reimbursement; differences in FV application across practice types; variation in processes, protocols, and priorities; external accountability for quality of care; and potential levers for change. Important subthemes included challenges for small practices; role of quality measures in delivering guideline-concordant preventive oral health care; and desire for preventive care coordination with dentists. ConclusionsThis study suggests that potential barriers and facilitators to guideline concordant FV application exist at multiple levels that may warrant further study. Examples include testing the effectiveness of quality measures for FV application and testing strategies for implementing consistent processes and protocols for improving FV application rates.

Infant oral health education curriculum for medical, nursing, and social work trainees

Tooth decay is the most common chronic disease in children, and children often see their primary care practitioners more frequently than dentists (Adjaye-Gbewonyo and Black 2019-2020; National Center for Health Statistics 2019-2020). This Infant Oral Health Education Program included two online training sessions for trainees in social work, nursing, medicine, and dentistry. Trainees were assessed on anticipated changes to their practice related to children's oral health. During the first training session, trainees received a lecture on infant oral health, and then discussed a case study in interprofessional groups to reinforce the content. Trainees in medicine and nursing completed training to receive Medicaid reimbursement for performing preventive oral health services. The second training session was profession specific with tailored instructions in the form of videos, as well as a demonstration on fluoride varnish application. Of the 78 trainees (22 social work, 4 pediatric nurse practitioner, 38 pediatric medicine residents, and 14 pediatric dentistry residents), 91 % (n = 70) reported that they were introduced to at least one new health information resource or tool. Four-fifths of the eligible trainees (n = 16/20, 80 %) who completed the evaluation had fulfilled the State's requirements to receive Medicaid reimbursement for performing preventive oral health services. Three-fourths of trainees (n = 22/29, 75 %) reported that they are likely to promote children's oral health in future clinical practice. Trainees from all four professions provided positive feedback about the content.

Effectiveness of silver diamine fluoride versus sodium fluoride varnish combined with mother’s motivational interviewing for arresting early childhood caries: a randomized clinical trial

BackgroundSilver Diamine Fluoride (SDF) has gained attention as one of the minimally invasive modalities to manage ECC although it causes black staining of treated carious lesions. A possible affordable alternative may be Sodium Fluoride (NaF) varnish combined with good oral hygiene promoted by parental Motivational Interviewing (MI). The study compared the effectiveness of 38% SDF solution and 5% NaF varnish supported by parental MI in arresting ECC.Materials and methodsChildren aged ≤ 4 years old with at least one active carious lesion (ICDAS score ≥ 3) were randomly assigned to treatment by a single application of 38% SDF solution or a single application of 5% NaF varnish supported by two MI sessions for mothers at baseline and after three months. Chi-Squared test was used to compare groups and multilevel logistic regression analysis was used to assess the effect of the interventions on ECC arrest adjusting for confounders. The interaction between the type of intervention and baseline lesion severity, moderate (ICDAS 3/4) or advanced (ICDAS 5/6), was also assessed.ResultsThe study included 165 children with 949 active lesions. After 6 months, there were no significant differences between SDF and NaF/MI groups in overall caries arrest (63.7% and 58.1%, p = 0.08), and in moderate lesions (72.9% and 69.6%, p = 0.52). However, in advanced lesions, the arrest rate was significantly higher in the SDF than the NaF/ MI group (60.3% and 50.0%, P = 0.01). Multilevel multiple logistic regression showed no significant differences between the interventions (AOR = 1.56, P = 0.27) with significant interaction between the intervention and baseline lesion severity (p < 0.001). Moderate lesions treated with SDF (AOR = 3.69, P = 0.008) or NaF/MI (AOR = 3.32, P < 0.001) had significantly higher odds of arrest than advanced lesions treated with NaF/ MI with no difference between advanced lesions treated with SDF or NaF/ MI (AOR = 1.85, P = 0.155) in arrest rate.ConclusionNaF/ MI can be an alternative to SDF in arresting advanced and moderate ECC lesions without staining with stronger effect on moderate lesions (ICDAS 3/4).Trial registrationThe trial was retrospectively registered at clinicaltrial.gov registry (#NCT05761041) on 9/3/2023.

Remineralization Efficacy Of Gum Arabic Varnish Vs Fluoride Varnish And Cpp-Acp With Fluoride Based Varnish In Initial Carious Lesions Over 6 Months Follow Up: A Randomized Controlled Clinical Trial

Remineralization Efficacy Of Gum Arabic Varnish Vs Fluoride Varnish And Cpp-Acp With Fluoride Based Varnish In Initial Carious Lesions Over 6 Months Follow Up: A Randomized Controlled Clinical Trial

Evaluation of Caries Preventive Potential of Preventive Regimens Containing Herbal-Based or Fluoride-Based Toothpastes Versus Fluoride Varnish and Fluoride Toothpaste Only in High Caries Risk Patients: Randomized Clinical Trial

Evaluation of Caries Preventive Potential of Preventive Regimens Containing Herbal-Based or Fluoride-Based Toothpastes Versus Fluoride Varnish and Fluoride Toothpaste Only in High Caries Risk Patients: Randomized Clinical Trial