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2.3. Statistical Analysis | EVENTS | For this analysis, data were pooled within treatment types (combined dupilumab 200 and 300 mg q2w and combined matched placebo groups). Annualized severe exacerbation rates over the 52-week treatment period were assessed using a negative binomial model, with the total number of events with onset from randomization up to visit 18 or the last contact date (whichever came earlier) as the response variable. The pooled treatment groups, age, region (pooled country), baseline eosinophil strata, baseline ICS dose level, and the number of severe exacerbation events within 1 year prior to the study were included in the model as covariates and the log-transformed standardized observation duration as an offset variable. Change from baseline in FEV | PMC10602700 | |
3. Results | PMC10602700 | |||
3.1. Baseline Characteristics | In total, 1,582 patients were included in the current analysis. Patients' mean age was similar across the analysis subgroups; however, a higher proportion of adolescents were included in the subgroups with low neutrophil counts (<4,000 cells/Overall, median (95% CI) blood neutrophil counts in the QUEST ITT population were 4,050 cells/ | PMC10602700 | ||
3.2. Annualized Severe Exacerbation Rates | Over the 52-week treatment period, significantly lower ( | PMC10602700 | ||
3.3. Change from Baseline in Prebronchodilator FEV | Significantly greater improvements ( | PMC10602700 | ||
3.4. Regression Analysis of Severe Exacerbations and Change from Baseline in Prebronchodilator FEV | exacerbations | REGRESSION | Regression analysis indicated that dupilumab reduced severe exacerbations and improved prebronchodilator FEV | PMC10602700 |
3.5. Safety | SAEs, injection-site reaction, neutropenia | VIRAL UPPER RESPIRATORY TRACT INFECTIONS, NEUTROPENIA | In the primary analysis of QUEST, the overall rates of TEAEs were similar in the combined placebo (83.1%) and dupilumab (81.0%) groups (SAEs, 8.4% and 8.2%, respectively). The most frequent AE occurring in ≥5% of patients and at higher rates among patients who received dupilumab was injection-site reaction (16.8% of patients in combined dupilumab vs. 7.9% in combined placebo groups). Viral upper respiratory tract infections (URTI) were the next most frequent AE in all groups [In patients with and without neutropenia, as analyzed here, overall rates of TEAEs and SAEs also were similar between dupilumab and placebo (Tables | PMC10602700 |
4. Discussion | inflammation, asthma | INFLAMMATION, ASTHMA | In this To our knowledge, this is the first analysis that describes the efficacy of a biologic that targets underlying type 2 inflammation by baseline neutrophil count in patients with asthma. Within the spectrum of asthma, elevated neutrophils can occur with or without type 2 inflammation. In a cluster analysis of patients in the SARP program, type 2 asthma patients with severe asthma who had the poorest lung function, frequent hospitalization, and uncontrolled symptoms despite high-dose oral corticosteroid use also had elevated blood neutrophils [One limitation of the current analysis is that it was performed | PMC10602700 |
5. Conclusions | asthma | ASTHMA | In summary, type 2 asthma comprises a spectrum of heterogeneity that includes patients with and without elevated blood neutrophils. Treatment with dupilumab resulted in consistent improvements in lung function in patients with uncontrolled, moderate-to-severe asthma across the type 2 spectrum, irrespective of mixed heterogeneity as described by blood neutrophil levels. Comparable responses were observed in patients with blood eosinophils ≥ 300 cells/ | PMC10602700 |
Acknowledgments | The authors thank Benjamin Ortiz for his contributions to the development of the manuscript. Research sponsored by Sanofi and Regeneron Pharmaceuticals Inc. ClinicalTrials.gov Identifier: | PMC10602700 | ||
Abbreviations | ASTHMA | Adverse eventFractional exhaled nitric oxideForced expiratory volume in 1 sInhaled corticosteroidIntention-to-treatInterleukin-4/interleukin-13Least squaresParts per billionEvery 2 weeksSerious adverse eventSevere Asthma Research Program. | PMC10602700 | |
Data Availability | Qualified researchers may request access to patient level data and related study documents, including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized, and study documents will be redacted to protect the privacy of our trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: | PMC10602700 | ||
Additional Points | PMC10602700 | |||
Ethical Approval | The study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonisation Good Clinical Practice guideline, and applicable regulatory requirements. An independent data and safety monitoring committee conducted blinded monitoring of patient safety data. The local institutional review board or ethics committee at each study center oversaw trial conduct and documentation. | PMC10602700 | ||
Consent | All patients or their parents/guardians, provided written informed consent before participating in the trial. | PMC10602700 | ||
Conflicts of Interest | HANSEN | E. R. Bleecker reports clinical trials from AstraZeneca, Boehringer Ingelheim, Genentech, MedImmune, Novartis, Regeneron Pharmaceuticals Inc., and Sanofi Genzyme through his employer, Wake Forest School of Medicine and University of Arizona; and personal fees (paid consultant) from ALK-Abelló, AstraZeneca, GlaxoSmithKline, MedImmune, Novartis, Regeneron Pharmaceuticals Inc., Sanofi Genzyme, and Teva. R. A. Panettieri has no conflicts of interest to disclose. N. L. Lugogo has received clinical trial funding from AstraZeneca, Genentech, GlaxoSmithKline, and Sanofi; and is an advisory board member and consultant for AstraZeneca, Genentech, GlaxoSmithKline, Novartis, Regeneron Pharmaceuticals Inc., Sanofi, and Teva. J. Corren reports research grants (consultant) from AstraZeneca, Genentech, Novartis, Regeneron Pharmaceuticals Inc., and Sanofi; and speaker fees from AstraZeneca, Genentech, and Novartis. N. Daizadeh is a former employee of Sanofi and may hold stock and/or stock options in the company. J. A. Jacob-Nara, P. J. Rowe, T. J. Ferro, and C. N. Hansen are employees of Sanofi, and may hold stock and/or stock options in the company. Y. Deniz, A, Khodzhayev, and X. Soler are employees and shareholders of Regeneron Pharmaceuticals Inc. | PMC10602700 | |
Authors' Contributions | RAP | ND, JAJN, YD, PJR, AK, XS, TJF, and CNH contributed to study concept and design. ERB, RAP, NLL, and JC acquired data. ND conducted the statistical analyses on the data. All authors participated in the interpretation of the data, provided critical feedback, final approval for submission, and took responsibility for the accuracy, completeness, and protocol adherence of data and analyses. All investigators had confidentiality agreements with the sponsors. | PMC10602700 | |
Supplementary Materials | SAEs | Table S1: Treatment-emergent AEs and SAEs in patients with <1,500 neutrophils/Click here for additional data file.Distribution of baseline neutrophil counts in patients in the ITT population and in those with blood eosinophils ≥ 150 cells/Annualized severe exacerbation rates over the treatment period in patients with elevated type 2 biomarkers with or without elevated neutrophil counts at baseline. CI = confidence interval; FeNO = fractional exhaled nitric oxide; neutr = neutrophils; ppb = parts per billion; q2w = every 2 weeks. Change from baseline in prebronchodilator FEV(a–d) Change in annualized severe exacerbation rates over the treatment period and change from baseline in prebronchodilator FEVBaseline characteristics for patients with elevated type 2 biomarkers with or without elevated neutrophil counts at baseline.
| PMC10602700 | |
Background | Edited by: Abdullah Akpinar, Adnan Menderes University, TürkiyeReviewed by: Jane Rich, The University of Newcastle, Australia; Birgitta Dresp-Langley, Centre National de la Recherche Scientifique (CNRS), FranceContact with nature promotes wellbeing through diverse pathways, providing a potential way of supporting health especially in primary care, where patients commonly suffer from multimorbidity and poor general health. Social prescribing is a non-pharmaceutical approach for improving health as well as social inclusion. This field study explores and compares the effects of a nature-based and an exercise-based social prescribing scheme on mental wellbeing and sleep, in a primary care population. | PMC10520711 | ||
Methods | Primary care patients identified to benefit from a general improvement to their health were recruited by nurses, doctors, or social workers to this non-randomized, intention-to-treat, pilot field-study. Participants ( | PMC10520711 | ||
Results | Participants (mean age 57 years, 79% female) rated their general and mental health lower than the general population. Participation in the Nature-group resulted in improved mental wellbeing (change in WEMWBS by 3.15, | PMC10520711 | ||
Conclusion | We attest that even in areas surrounded by greenery, active interventions can further improve health in a primary care population, and that nature-based interventions are beneficial for those in poor health. | PMC10520711 | ||
Introduction | Managing and increasing accessible green spaces has been recommended as a potential way of improving public health (Studies exploring the effects of nature-based social prescribing are still uncommon (Healthier sleep is associated with better mental wellbeing (Our study aims to:explore and compare the effects of a nature-based social prescribing scheme and an exercise-based social prescribing scheme on mental wellbeing in a primary care population,analyze general and mental health outcomes as well as sleep characteristics in a primary care population participating in social prescribing schemes, andtest if the effects on mental wellbeing of two different social prescribing schemes are different based on participants general health or mental health status. | PMC10520711 | ||
Methodology and material | PMC10520711 | |||
Study design | COLD | This is a controlled pilot field-study on parallel groups in an intention-to-treat setting. Participants were recruited from the population using the Health and Social Service Centre of Sipoo and all live in the municipality of Sipoo. Although situated only 17 km from the city center of Helsinki, the capital of Finland, Sipoo is a rural area with abundant green and blue spaces. The population density is 65 persons/kmThe intervention program adapted in this study was developed during the Terveysmetsä (transl. Health Forest) project, a national network project established in 2014 (The Nature-group program included learning more about local outdoor areas and nature itself, the biotopes visited were chosen to provide varied nature experiences, including forests, farmland, lakes, and seashore. Accompanied by nature guides the group practiced simple sensory exercises that enhance contact with nature and its microbiome. A more detailed program is attached in The Sports-group participated in an exercise program and met weekly in community sports facilities. Exercise we define as a planned, structured, repetitive, and purposeful form of physical activity that aims to improve or maintain one or more components of physical fitness. The sports program was planned and executed by professional sports instructors in cooperation with health professionals and included both aerobic and anaerobic exercise as well as team sports. The content of the exercise program was planned according to current best practice and considering the participants physical ability. Details of the program are attached in The intensity and duration of the physical activity as well as the social interaction were designed to be as alike as possible in the compared groups. Both groups were offered a meal or snack during or after the session, with the aim of increasing cohesion. The intervention was free of charge, but travel expenses (mostly by car or bus, <10 km) were not covered. With a maximum of 20 participants the groups met 7 times during an 8-week period. Every session took place in a different location. This enabled the participants in the Nature-group to become familiar with the different outdoor areas, and the Sports-group to become familiar with local sports facilities. The planned activity level was modest, equaling approximately 2 km of walking at slow pace. The intervention started in 2018 and was planned to go on until 2020, including 160 participants equally distributed between the groups. The participants were considered to have fulfilled the program if they attended 5 or more sessions. Based on previous studies in similar populations, we emphasized a 25% drop-out. The intervention was completed twice a year (spring and autumn) during the years of 2018 and 2019 which causes some variance as Finland is a northern country with dark, and commonly cold winters. The COVID-19 epidemic in 2020 hindered the group interventions reducing the total number of participants. A Nature-group was organized in autumn 2020, but its data is not included in this study due to the contrasting general circumstances. A separate qualitative follow-up study was conducted in 2022 (It was possible to participate the intervention without being part of the study. Participants in the study signed an informed consent form allowing the use of data and giving permission to recontact. Participants were free to withdraw from the study at any time without giving a reason, and this did not interfere with their care in any way. The study was approved by the coordinating Ethical Committee of Helsinki and Uusimaa Hospital District (HUS/3520/2017) and study permission was granted by the municipality (7.2.2018). All data is anonymized and stored at the Finnish Institute for Health and Welfare (THL). | PMC10520711 | |
Methodology | Our main outcome is the self-assessed mental wellbeing. Secondarily, we also analyze self-reported and device-based sleep. A flow-chart of the assessments is displayed in Flowchart of intervention. | PMC10520711 | ||
Questionnaire | Self-assessed mental wellbeing was measured with the 14-item Warwick-Edinburgh Mental Well-Being Scale (WEMWBS). The questionnaire also included demographic information (gender, age) and 6 additional questions (Q1–Q6) rated on a Likert-like scale: 1 (little/bad/badly) to 5 (much/good/well). Personal preference was measured in Q1 (The WEMWB scale was developed to assess positive mental wellbeing ( | PMC10520711 | ||
Accelerometer measurements of sleep | Each participant was provided with a wrist worn accelerometer | PMC10520711 | ||
Statistical analyses | REGRESSION | We created groups for self-reported health outcomes, where scores of 1 to 3 were regarded as poor health and scores of 4 and 5 as good health. Data were tested for normality. The differences between the Nature-and Sports-groups as well as between the categorial groups were assessed using Student’s The changes in WEMWBS, Q1–Q6 scores and accelerometer data were analyzed using either dependent t-test or Wilcoxon signed-rank test, depending on the distribution of data. Answers of Q1–Q6, gender, age, group, and season were further used as covariates in univariate regression models analyzing factors which may explain the changes in the WEMWBS sleep outcomes. The statistical analyses were performed using IBM SPSS Statistics, version 27, software. | PMC10520711 | |
General health | At baseline, only 26% of the participants considered themselves in good general health on the 1-to-5 scale (mean 2.97, SD 0.93), 20% felt their physical ability was good (mean 2.77, SD 0.92) and 44% rated their mental health as good (mean 3.31, SD 0.94). Following the intervention, the perceived health improved (mean change 0.4, 95% CI 0.21 to 0.59, The descriptive data and the change in outcomes following the intervention are presented in Perceived health, mental wellbeing and sleep at baseline for all participants and mean change within groups after intervention Baseline information includes all participants, the groups did not differ at baseline.ᵝ (score 4-5) *T-test and Warwick-Edinburgh Mental Well-Being. Bold values indicates statistical significance. | PMC10520711 | ||
Mental wellbeing | The change in mental wellbeing using the WEMWBS score was our primary outcome, we analyzed the impact participation in the interventions had on the whole group, as well as considering the Nature-group and Sports-group separately. The compared groups did not differ at baseline, both groups were normally distributed although at endpoint the range was bigger in the Nature-group (Change in positive mental wellbeing.Measured on the Warwick-Edinburgh Mental Well-Being Scale (WEMWBS). Bold values indicates statistical significance. | PMC10520711 | ||
Differences in mental wellbeing by general and mental health status | An important finding is that the participants with poor perceived health had less improvement, or even a reduction, in mental wellbeing compared to those considering their health good. Results are presented in Illustrates change in WEMWBS score depending on The pattern is similar regarding perceived mental health, and here, there was a difference depending on perceived health in both groups. In the Nature-group, those in poor mental health ( | PMC10520711 | ||
Sleep | SE | Sleep quality and sleep duration was generally low in this population, only 31% felt they slept well. Mean time in bed assessed by accelerometers was only 5.4 h (SD 1.3) and mean sleep time 4.8 h (SD 1.2). 81% slept less than 6 h per night, usually considered as an insufficient amount of sleep. Accelerometer-based number of awakenings (NOFA) after sleep onset was 14 on average (SD 5) and mean time wake after sleep onset (WASO) was 34 min (SD 13). Sleep efficiency (SE) was 89% on average.Following the intervention, 61% (22 out of 36) of the participants in the Nature-group experienced a positive change in perceived sleep (z = −3.78, | PMC10520711 | |
Discussion | First, we address the third aim of this study, i.e., investigating the impacts of health status on the effects of the social prescribing interventions. Next, we discuss about implementation of the interventions, and finally, we discuss on the strengths and limitations of this study.As intended, participants in the study rated their health lower than the general population. Only 27% regarded their health as good or very good, with the corresponding figures being 62% for men and 63% for women responding to the Finnish population survey FinHealth 2017 ( | PMC10520711 | ||
Mental wellbeing | and reduced loneliness | The WEMWBS average of 48 is inferior to that of the general population. In the FinHealth 2017 survey, the average WEMWBS score in southern Finland was 52.8 (95% CI 52.3 to 53.3) (Improved mental health is associated with reduced mortality and mental illness (Social interaction and reduced loneliness are potential mediators for well-being ( | PMC10520711 | |
Sleep | Poor sleep surfaced as a clear finding, 81% slept less than 6 h per night and 70% of the participants also rated their sleep quality as poor. In the FinHealth 2017 study, the average self-reported sleep time was 7.4 h for adults aged over 30 years, with only 14% of the women and 16% of the men sleeping less than 6 h per night. Following the intervention, total sleep time improved in the Sports-group but decreased in the Nature-group. This change was close to significant and opposite to our expectation. Diminished sleep time was observed only in the participants with good self-rated health. Despite this accelerometer-based outcome, perceived sleep improved significantly in the Nature-group, with reduced time awake after sleep onset and reduced number of awakenings being likely explanations for the positive experience.Population studies have indicated that surrounding greenery has a positive impact on sleep duration ( | PMC10520711 | ||
Nature connectedness as a potential pathway to positive mental wellbeing | CARDIOVASCULAR DISEASE | Even though most of the study participants rated nature as very important at baseline, taking part in the Nature-group further strengthened this feeling. Experiencing interconnection with nature increases the motivation to protect and defend it, and the improved connection with nature also increases happiness and wellbeing (Contact with nature appears to be important to human health, since living close to green space has an inverse association with all-cause mortality, especially mortality due to cardiovascular disease (The restorative capacity of nature is commonly explained by (a) the stress recovery theory, which underlines that contact with nature promotes a positively toned mental state and activates the parasympathetic nervous system (High perceived stress increases reliance on primary care service (There is a knowledge gap regarding what role contact with nature has on an individual level, as personal preferences and cultural values influence how we experience nature and how willing we are to interconnect with it ( | PMC10520711 | |
Can nature-based social prescribing reduce inequality? | depressive, angina pectoris | DISEASE, CORONARY ATHEROSCLEROSIS | In a global context, Finns are healthy (Primary care patients seek help for various symptoms that may or may not be caused by a disease. General practitioners (GPs) are at the frontline in diagnosing medical conditions, but also familiar with the role that social and psychological factors play in wellbeing. One example is a recent Swedish cross-sectional study of a middle-aged general population concluding that angina pectoris symptoms, irrespective of degree of coronary atherosclerosis, are highly associated with stress and depressive symptoms, among other sociodemographic and psychological factors ( | PMC10520711 |
Strengths and limitations | ADVERSE EVENTS, ADVERSE EFFECTS, DISEASE | This is a non-randomized pilot study in a real life, primary care setting and should be interpretated as such. Some aspects can be regarded both as strengths and limitations. First, inclusion was not based on a specific disease or diagnosis, but a common need for general health improvement. This strategic choice is based on the knowledge that primary care patients seek help for various health problems and symptoms, and frequent attenders commonly suffer from symptoms that might not be due to a specific diagnosis (Second, some methodological limitations need to be noted. All participants live in an area with abundant green and blue spaces, therefore, it is likely that the participants in the Sports-group also spent active time outdoors. Sleep was assessed by wrist-worn accelerometers that are considered acceptable for use in population studies or community-based interventions, and they compare rather well with polysomnography, which is considered the gold standard measure of sleep (Third, the follow-up time is short. The social restrictions following the outbreak of the COVID-19 pandemic ended this study early, therefore, we were able to recruit approximately half of the planned number of participants. A six-month follow-up questionnaire was initially planned, but as the COVID-19 pandemic occupied professionals, it simply was not possible to fulfill this part of the study. Also, we were not able to analyze how participation in the intervention affected the use of health care services. Research in primary care faces pragmatic challenges and needs stronger structure in Finland. Digital tools could facilitate communication between participants and instructors as well as providing a platform for follow-up when developing social prescribing programs. However, consideration of the target groups’ ability to use technical devices is important. The national Sustainable Growth Program in Finland is part of the NextGenerationEU program, aiming to support growth that is ecologically, socially and economically sustainable (Fourth, this was not a randomized controlled trial. The concept of Health Forest started out as a trial, and the study protocol evolved from these experiences. As the project had gained public interest before the study, positive perception may impact the results in favor of the Nature-group, also among the referring health professionals. Even so, the activities for the Sports-group were planned carefully to represent the current best practice. Primary care clients committed to both social prescribing schemes, and no adverse effects nor adverse events occurred. We found no difference in season, and this being found the Nature-groups can be organized all year round also in Nordic countries. Based on the encouraging results we hope to see more preventive projects utilizing nature and research addressing how nature can be used as a treatment. In future research, the use of cluster randomization is a way to provide a more robust study design. In bigger studies, inclusion of health data such as diagnosis and medication could help us understand more about the conditions to which nature-based social prescribing is best of help, and by including information health metrics we might also learn whether nature-based interventions can reduce demand on health and social service.The programs used in this study can be adapted to different target groups and locations, and we consider the practical approach as the biggest strength of this field-study. | PMC10520711 | |
Conclusion | Our results support the increasing understanding that nature-based interventions have a positive effect on mental wellbeing in primary care patients. In green surroundings, prescribed nature-based interventions or group exercise can improve perceived health and ability to function. Improved mental health and positive mental wellbeing was observed only in the Nature-group. Based on the observed differences in improved mental wellbeing depending on perceived health, we would recommend either sports or nature-activity for those initially feeling healthy, and nature-based intervention especially for those rating their health as poor. | PMC10520711 | ||
Data availability statement | The datasets presented in this article are not readily available because according to the research permission all data is anonymised and stored at the Finnish Institute for Health and Welfare. Data can be shared with a specific request from the institute, but not be shared by the researchers. Requests to access the datasets should be directed to research professor TP, | PMC10520711 | ||
Ethics statement | The studies involving human participants were reviewed and approved by Ethical Committee of Helsinki and Uusimaa Hospital District (HUS/3520/2017) and study permission was granted by the municipality of Sipoo (7.2.2018). The patients/participants provided their written informed consent to participate in this study. This study was registered as a clinical trial ( | PMC10520711 | ||
Author contributions | MH | TP, MH, AP, and AM: conceptualization, methodology, and planning. AK, TP, AP, and HW: literature review. HW: preparation of accelerometer data. AK and TP: statistical analysis. AK: writing—original draft preparation. AK, TP, MH, and AP: writing—review and editing. TP: supervision and owner of data. All authors contributed to the article and approved the submitted version. | PMC10520711 | |
Funding | This research was funded by the municipality of Sipoo and the Finnish Institute for Health and Welfare (THL) as well as the Child and Nature Foundation. AK has received research grants from HUS-erva, Perkléns stiftelse, and Finska Läkarsällskapet. Open access funded by Helsinki University Library. | PMC10520711 | ||
Conflict of interest | AP was an entrepreneur at Luonnontie, a company developing Health Forest models.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC10520711 | ||
Publisher’s note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.The authors thank the personnel at Health and Social Service Centre of Sipoo for planning the intervention, recruiting participants and being part of the study. Chief physician Anna Peitola helped making the study possible. Marko Leppänen paid an important part in planning and conducting the nature intervention. Elsi Haverinen and Hanna Elonheimo helped in managing the accelerometers and analyzing their data. | PMC10520711 | ||
Supplementary material | The Supplementary material for this article can be found online at: Click here for additional data file. | PMC10520711 | ||
References | PMC10520711 | |||
Subject terms | non-alcoholic fatty liver disease, NAFLD, non-alcoholic steatohepatitis, inflammation, fibrosis, liver disease, NASH | NON-ALCOHOLIC STEATOHEPATITIS, INFLAMMATION, LIVER FIBROSIS, FIBROSIS, LIVER DISEASE, NON-ALCOHOLIC FATTY LIVER DISEASE, COMPLICATIONS | Leukocyte telomere length (LTL) gets shorter with each cell division and is also sensitive to reactive oxygen species damage and inflammatory processes. Studies in adults with non-alcoholic fatty liver disease (NAFLD) have found that increased fibrosis but not ALT levels are associated with shorter LTL. Few pediatric studies have been conducted; as such, we sought to evaluate potential associations between LTL and liver disease and liver disease progression in pediatric patients. Using data from the Treatment of NAFLD in Children (TONIC) randomized controlled trial, we assessed the potential predictive relationship between LTL and liver disease progression based on two successive liver biopsies over 96 weeks. We assessed the potential relationship between LTL and child age, sex, and race/ethnicity and features of liver disease including components of histology. We subsequently evaluated predictors for improvement in non-alcoholic steatohepatitis (NASH) at 96 weeks including LTL. We also assessed predictors of lobular inflammation improvement at 96 weeks using multivariable models. Mean LTL at baseline was 1.33 ± 0.23 T/S. Increasing lobular and portal inflammation were associated with longer LTL. In multivariable models, greater lobular inflammation at baseline was associated with longer LTL (Coeff 0.03, 95% CI 0.006–0.13; p = 0.03). Longer LTL at baseline was associated with worsening lobular inflammation at 96 weeks (Coeff 2.41, 95% CI 0.78–4.04; p < 0.01). There was no association between liver fibrosis and LTL. The association between LTL and pediatric NASH does not parallel adults with no association between fibrosis stage and NASH. Conversely, longer LTL was associated with more lobular inflammation at baseline and increased lobular inflammation over the 96-week period. Longer LTL in children may indicate greater risk for future complications from NASH. | PMC10070244 |
Introduction | NAFLD, Obesity, Digestive, non-alcoholic steatohepatitis, macrovesicular steatosis, fatty liver, panacinar or periportal macrovesicular steatosis, inflammation, cirrhosis, fibrosis, lobular inflammation, abdominal obesity, NASH, portal lymphocytic inflammation, NAFL, Diabetes, NALFD | OBESITY, FATTY LIVER, NON-ALCOHOLIC STEATOHEPATITIS, INFLAMMATION, LIVER FIBROSIS, FIBROSIS, NON-ALCOHOLIC FATTY LIVER, NON-ALCOHOLIC FATTY LIVER DISEASE, CIRRHOSIS, KIDNEY DISEASES, INSULIN RESISTANCE, NON-ALCOHOLIC FATTY LIVER DISEASE, DIABETES, REGRESSION, METABOLIC SYNDROME | Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of fatty liver change, including non-alcoholic steatohepatitis (NASH), that can be considered to represent a hepatic manifestation of metabolic syndrome. Obesity, specifically abdominal obesity, and insulin resistance increase risk for NAFLD and NASH in children. NASH is defined by presence of > 5% macrovesicular steatosis, hepatocyte ballooning, and lobular inflammation and typically also has portal lymphocytic inflammation. This typical (type 1) pattern is observed in most adults, whereas in children an alternate (type 2) pattern, consisting of severe panacinar or periportal macrovesicular steatosis and portal-based fibrosis and inflammation is recognized. NALFD is an umbrella term that includes NASH and non-alcoholic fatty liver (NAFL), which has much lower risk for progression to liver fibrosis, cirrhosis, and eventual liver transplantation than NASH, though NAFL with lobular inflammation may confer some increased risk of fibrosis over NAFL without lobular inflammationFactors associated with fibrosis progression to cirrhosis and from NAFL to NASH are not well delineated, particularly in pediatric patients. Furthermore, NASH in children may manifest with a type 1 or type 2 pattern, or show transition from one type to another (typically from type 2 to type 1), particularly in older children and adolescentsRecent studies have focused on the potential role of telomeres, the non-coding DNA sequences that protect chromosomes from damage and degradation, specifically hepatocyte telomeres as playing a potential role in the process of liver aging that is associated with NAFLD, specifically NASH and fibrosis processesUsing data collected from the National Institute of Diabetes and Digestive and Kidney Diseases sponsored Treatment of Non-alcoholic Fatty Liver Disease in Children Trial (TONIC) (NCT00063635), we evaluated the relationship between leukocyte telomere length (LTL) in children with NAFLD and NASH in TONIC. We additionally assessed the potential role of LTL as a predictive biomarker of NASH progression and regression using data points from this trial over 96 weeks of follow-up. As there was detailed liver biopsy characteristics on each child at two time points, we sought to understand the role that LTL might be play to help elucidate the process of NAFLD progression in children. | PMC10070244 |
Methods | NAFLD, NASH, muscle antibody, autoimmune hepatitis | AUTOIMMUNE HEPATITIS, EVENT, INSULIN RESISTANCE, LIVER | The Treatment of NAFLD in Children Trial (TONIC) was a NIH sponsored randomized, double-blind, placebo-controlled trial that was conducted at 10 research centers in the US with 173 patients (age 8–17) with biopsy confirmed NAFLD to assess the impact of vitamin E (400 IU twice daily) compared with 500 mg metformin twice daily versus placebo over 96 weeks (ClinicalTrials.gov identifier: NCT00063635, 03/07/2003). The primary outcome was reduction in serum alanine aminotransferase (ALT) levelsAs part of the TONIC trial, whole blood was collected from children to collect DNA samples for potential genetic testing. DNA was extracted using the Qiagen Autopure LS DNA extractors using PUREGENE reagents using a modified salting out procedure. DNA was rehydrated by incubating at 56 °C for 1 h in a shaking incubator and placed on orbital shakers for 36–48 h prior to stock transfer. In the event a sample had a 260/280 ratio less than 1.7 (indicative of protein contamination), it was re-precipitated to improve its purity. DNA extraction was performed as soon as samples were received by the lab. Samples that were processed for DNA extraction and passed quality control were assigned storage locations by RUCDR STARLIMS in a − 80 °C freezer until LTL assay.Liver biopsies were obtained at study entry and subsequently after 96 weeks of therapy for all children enrolled in the TONIC trial. For all biopsies, the NASH Clinical Research Network (CRN) recommended a 16-gauge biopsy needle and a specimen length of at least 1.5 cm. The liver tissue was prepared locally for light microscopy with stains including hematoxylin and eosin, Masson’s trichrome and iron stain. All slides were sent to the data coordinating center for central reading by the study pathologistsAt baseline and 96 weeks of follow-up liver function tests and biomarkers of metabolic health including lipids and insulin resistance were also evaluated in the children. Anthropometrics including body mass index (BMI) and waist circumference were also assessed. Additionally, at baseline, autoantibodies associated with autoimmune hepatitis were assessed including anti-nuclear antibody (ANA), anti-smooth muscle antibody (ASMA) and anti-mitochondrial antibody (AMA). | PMC10070244 |
Leukocyte telomere length analysis | Extracted DNA was shipped in batch to the Blackburn Telomere Lab at the University of California, San Francisco. The telomere qPCR primers were tel1b [5′-CGGTTT(GTTTGG)5GTT-3′], used at a final concentration of 100 nM, and tel2b [5′-GGCTTG(CCTTAC)5CCT-3′], used at a final concentration of 900 nM. The single-copy gene (human beta-globin) qPCR primers were hbg1 [5′-GCTTCTGACACAACTGTGTTCACTAGC-3′], used at a final concentration of 300 nM, and hbg2 [5′-CACCAACTTCATCCACGTTCACC-3′], used at a final concentration of 700 nM. The final reaction mix consisted of the following: 20 mM Tris-hydrochloride, pH 8.4; 50 mM potassium chloride; 200 μM each deoxyribonucleotide triphosphate; 1% dimethyl sulfoxide; 0.4 × SYBR green I; 22 ng The thermal profile for telomere (T) consisted of denaturing at 96 °C for 1 min followed by 30 cycles of denaturing at 96 °C for 1 s and annealing or extension at 54 °C for 60 s with fluorescence data collection. The thermal profile for a single copy gene (S) consisted of denaturing at 96 °C for 1 min followed by 8 cycles of denaturing at 95 °C for 15 s, annealing at 58 °C for 1 s, and extension at 72 °C for 20 s, followed by 35 cycles of denaturing at 96 °C for 1 s, annealing at 58 °C for 1 s, extension at 72 °C for 20 s, and holding at 83 °C for 5 s with data collection. The T/S ratio for each sample was measured in duplicate runs, each with triplicate wells. When the duplicate T/S values disagreed by more than 7%, the sample was run in triplicate and the two closest values were used. The Dixon Q test was used to remove outliers from the triplicates. The average of the T or S concentrations from the remaining wells was used to calculate the T/S ratio for each sample. This is repeated to get the run 2 T/S ratios. If the difference between run 1 and run 2 larger than 7%, a third run was performed and the average of the 2 closest values was used as the final data. Potential batch difference was adjusted by running combined plates with a small set of samples from each plate. All samples used the same lot of reagents for LTL assay. The average inter-assay coefficient of variation (CV) for this study was 2.2%. The PCR efficiencies were 96.2 ± 1.6% and 98.0 ± 2.9% for the telomere reactions (T) and S reactions (S) respectively. All samples were processed in the Blackburn Telomere Lab at UCSF. We did not calculate the interclass correlation coefficient (ICC) on repeat DNA extractions for this study because they were assayed before this recommendation was made by the Telomere Research Network. | PMC10070244 | ||
Data analysis | NAFLD, necrosis, hepatic injury, q-norm, inflammation, lipogranulomas, cirrhosis, SD, fibrosis, NASH, steatosis microvesicular steatosis, lobular inflammation, steatosis | LIPOGRANULOMA, INFLAMMATION, CIRRHOSIS, FIBROSIS, NECROSIS, REGRESSION, STEATOSIS | Data were checked for normality using graphical indicators as well as statistical tests such as Shapiro–Wilk. Baseline descriptive data were calculated including means ± SD and percentages of categorical data for patient demographics including age at DNA collection, ethnicity, sex, specifics regarding liver histology at baseline including steatosis, fibrosis, and components of NASH [ballooning, inflammation (lobular and portal)) as well as the NAFLD activity score (NAS) which incorporates lobular inflammation, ballooning, and steatosis]We subsequently assessed what were potential predictive factors for NASH improvement, also defined as resolution of NASH, at 96 weeks, defining improvement as changing from definite or borderline NASH to not NASH based on biopsy alone. Other analyses included factors associated with LTL based at time of collection as an outcome. In most cases, the baseline data collection timepoint was most closely related to the LTL measurement including baseline biopsy, liver and fasting labs and anthropometric measurements. However, as not all patients had the DNA blood draw collected at the same time point in the study, in some cases biopsy or blood collection at the 96-week time point was used instead. As LTL data were not normally distributed, Mann Whitney U test was used for continuous predictors and chi-squared tests for categorical ones. Residuals of linear models were checked for normality using graphical tests and q-norm and p-norm plots. As the departures from normality were not severe, linear regression was used in multivariable models with LTL as the dependent variable.Multivariable models were constructed to assess independent predictors for NASH improvement at 96 weeks (logistic regression) including variables that were significant at p < 0.10 in bivariate analysis (defined as moving from indeterminate NASH or definite NASH to not NASH), treatment group assignment (placebo versus metformin versus vitamin E) as well as LTL given our initial hypotheses and other variables with previously demonstrated biological plausibility for association with NASH improvement. We did not include collinear variables in multivariable models such as waist circumference and body mass index (BMI) simultaneously. We also constructed linear regression models to assess factors associated with longer leukocyte telomere at baseline (or at closest timepoint to when DNA was collected) including variables that were significant at p < 0.10 in bivariate analysis as well as those with biological plausibility based on previously determined biological plausibility with LTL.Additional multivariable models were constructed to assess independent predictors for worsening of lobular inflammation using ordinal models (with lobular inflammation defined as 0 foci, less than 2 foci with 20 times magnification, 2–4 foci with 20 times magnification and greater than 4 foci with 20 times magnification) and the ordinal sequence being worsening, staying the same and improving from baseline to follow-up biopsy using the criteria as described above. Other multivariable models that we evaluated included changes in portal inflammation (none, mild, more than mild), fibrosis (none, mild Z3 perisinusoidal, moderate Z3 perisinusoidal, portal/periportal, Z3 periportal, bridging, cirrhosis) and ballooning (none, few, many) to try to test the hypothesis that LTL may be a biomarker to predict potential changes in hepatic health. These areas of hepatic histology were chosen given their importance in diagnosis of NASH and due to univariate findings suggesting associations between LTL and lobular and portal inflammation. Our criteria for constructing these models were similar in that we included predictors that were significant in bivariate analysis at p < 0.10 and others that were associated with biological plausibility as well as treatment assignment group for the TONIC trial.Lastly, we evaluated other specific hepatic histology characteristics in relation to worsening in lobular inflammation including location of steatosis [Zone 3 (central), Zone 1 (periportal), Azonal, Panacinar] and type of steatosis microvesicular steatosis; markers of hepatic injury or necrosis such as acidophil bodies, Mallory bodies, microgranulomas and pigmented macrophages; and metabolic associated characteristics such as megamitochondria, glycogen nuclei and large lipogranulomas. Components of the NAS score including fibrosis stage (mild Z3 perisinusoidal, moderate Z3 perisinusoidal, portal/periportal, Z3 periportal or bridging) and ballooning were also assessed in relation to overall changing patterns of lobular inflammation. | PMC10070244 |
Results | PMC10070244 | |||
Population characteristics | In the TONIC trial, there were 149 children that had DNA samples collected with sufficient DNA to assess for child’s LTL. LTL measured 1.33 + /0.23 T/S units for the group as a whole (Table TONIC patients with leukocyte telomere length data (n = 149). | PMC10070244 | ||
Factors associated with NASH improvement over 96 weeks | NASH | There were 47 (35.1%) children who improved during the follow-up period and 87 who did not (64.0%) (Table NASH improvement* from baseline to 96 weeks.*Based on biopsy alone.Metabolic correlates at baseline were also compared between those that improved and those that did not. Markers of glucose metabolism tended to be lower in those that improved including fasting glucose levels (86.8 ± 9.7 versus 90.2 ± 9.3 ml/dL; p = 0.04) and the 2-h glucose tolerance test (114.5 ± 3.3 versus 123.0 ± 26.7 ml/dL; p = 0.06). | PMC10070244 | |
Characteristics associated with LTL at baseline | inflammation | INFLAMMATION | Demographic factors associated with LTL at baseline included an inverse association with age (rho = − 0.24; p < 0.001; Table Leukocyte telomere length in relation to baseline characteristics.Histologic-specific factors that were associated with LTL included lobular and portal inflammation which positively associated with LTL although results only trended towards statistical significance (rho = 0.15, p = 0.08) and (rho = 0.16, p = 0.09; Table | PMC10070244 |
Multivariable models | microvesicular steatosis, NASH, lobular inflammation | INFLAMMATION, INFLAMMATION | In a multivariable model evaluating independent risk factors for NASH improvement at 96 weeks of follow-up, based on biopsy results, including treatment assignment group, sex, LTL, age of enrollment, waist circumference, fasting glucose and alkaline phosphate baseline levels, the only variable that neared statistical significance was fasting glucose level (Odds Ratio (OR), 0.96, 95% CI 0.92–1.01, p = 0.09) in addition to treatment assignment group (vitamin E) (Table Predictors of NASH improvement* at 96 weeks.*Based on biopsy.Predictors of leukocyte telomere length at baseline.Leukocyte telomere length association with lobular inflammation multivariable analysis.Predictors of Lobular Inflammation Worsening at 96 Weeks (n = 131).Predictors of lobular worsening at 96 weeks.Lastly, we ran a final model of lobular inflammation worsening at 96 weeks but included specifics from the biopsy report that were predictive of lobular improvement in biariate analysis. Specifically, we included presence of acidophil bodies and microvesicular steatosis at baseline (both which were significantly associated with lobular inflammation in univariate analysis). In a multivariable model adjusting for all the previous covariates mentioned in the previous lobular inflammation model, neither were associated with lobular inflammation worsening (results not shown). | PMC10070244 |
Acknowledgements | Digestive, NASH, Nonalcoholic Steatohepatitis, Diabetes, Cancer | CANCER, KIDNEY DISEASES, NONALCOHOLIC STEATOHEPATITIS, DIABETES | We thank the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) investigators and the Ancillary Studies Committee for providing clinical samples and relevant data from the TONIC trial, and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) for its support of the NASH CRN and this research. This ancillary study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants U01DK061713, U01DK061718, U01DK061728, U01DK061732, U01DK061734, U01DK061737, U01DK061738, U01DK061730, U24DK061730). The TONIC trial was conducted by the NASH CRN and supported in part by the Intramural Research Program of the National Cancer Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The vitamin E and matching placebo were provided by Pharmavite through a Clinical Trial Agreement with the NIH. Trial protocol and more details about the trial can be accessed by contacting Laura Wilson (author on this paper). | PMC10070244 |
Author contributions | J.W. and P.R. wrote the main manuscript text; J.W., P.R., L.W. and R.G. conducted all analyses; J.L. and J.W. interpreted telomere findings; all authors reviewed the manuscript. | PMC10070244 | ||
Data availability | NASH | Access to data will be provided based on request to the corresponding author and the NASH CRN. | PMC10070244 | |
Competing interests | The authors declare no competing interests. | PMC10070244 | ||
References | PMC10070244 | |||
Background | denture, denture adhesives, dry mouth | DRY MOUTH, CAVITY | A denture adhesive for dry mouth with good cleaning properties has recently been developed. While previous studies on models have shown the effectiveness of denture adhesives in terms of retention and cleanability, no reports have evaluated their effectiveness in the oral cavity. The aim of this study was to compare and investigate the retention and usability of an experimental palatal plate in the dentulous jaw using a denture adhesive for dry mouth, a conventional cream-type denture adhesive, an oral moisturizer, and a denture moisturizer. | PMC10230757 |
Methods | denture, dry mouth | DRY MOUTH | Ten healthy dentulous participants (mean age 27.2 ± 1.6 years) were included in the study. Palatal plates were fabricated. Four test samples were used: denture adhesive for dry mouth, conventional denture adhesive (cream type), oral moisturizer, and denture moisturizer. The sample was applied to the inner surface of the palatal plates, and the retentive force of the palatal plate was measured every 10 min for 30 min. After the measurements, the study participants were asked to rinse the palatal plate with water and subjectively evaluate the samples used. | PMC10230757 |
Results | denture, dry mouth | DRY MOUTH | The conventional denture adhesive (cream type) showed increased retentive force over time, with the maximum retentive force obtained after 10 min of application. However, its washability was rated second lowest. The denture adhesive for dry mouth showed the highest retentive force immediately after application. Its washability was also good. | PMC10230757 |
Conclusions | denture, dry mouth | DRY MOUTH, CAVITY | The results suggest that the denture adhesive for dry mouth has reasonable retentive force in the oral cavity and cleaning properties compared to the conventional cream-type denture adhesive. | PMC10230757 |
Keywords | PMC10230757 | |||
Background | stroke, edentulous, Parkinson’s disease, neurological diseases, denture adhesives, denture, dentulous, dry mouth | NEUROLOGICAL DISEASE, STROKE, CAVITY, DRY MOUTH, CREST | The proportion of older individuals in Japan has been increasing. According to the Statistics Bureau of the Ministry of Internal Affairs and Communications in 2022, the ageing rate was 29.3% and is expected to increase in the future [With the ageing of patients who require removable dentures, the oral cavity becomes more prone to oral motility disorders due to neurological diseases such as stroke and Parkinson’s disease [However, denture adhesives tend to adhere and remain on the oral mucosa and denture base. The American College of Prosthodontists’ guidelines on denture adhesives have also mentioned its problems regarding cleanability [Furthermore, denture adhesives are water absorbent and may contribute to dry mouth. For this reason, oral moisturizers with good cleaning properties may be used as a substitute for denture adhesives in patients with dry mouth [A gel-type denture adhesive for dry mouth with good cleaning properties has been recently developed for denture wearers with dry mouth [However, there have been no reports comparing the retentive force of dentures in the actual oral cavity with the use of denture adhesives, including those for dry mouth. This may be because denture wearers, especially edentulous patients, have various oral conditions in terms of the shape of the jaw crest, degree of oral dryness, etc. Moreover, measuring retentive force under the same conditions is difficult. Therefore, prior to measuring the maintenance force of dentures in the oral cavity, basic data must be collected first by performing measurements using an experimental palatal base in dentulous individuals with stable conditions. In a previous study [ | PMC10230757 |
Methods | PMC10230757 | |||
Test samples (Table | denture moisturizer, denture, Denture, dry mouth | DRY MOUTH |
Principal components of the test sampleAntiseptic,Bacteriostatic actionSweetening materials,Moisturizer, Thickening agentAlternative sweetener,MoisturizerThis study was a pilot controlled clinical trial of a novel denture adhesive for dry mouth (PK) with a water-soluble main ingredient. In this trial, PK was compared to other three active experimental conditions, including a traditional denture adhesive and two types of oral moisturizers. A negative control condition (fifth condition) was also added to the study. In this study, the following test samples were prepared: denture adhesive for dry mouth (PK; Pitatto Kaiteki Gel®: NISIKA, Yamaguchi, Japan), cream-type denture adhesive (NP; New Poligrip® Sa: Glaxo Smith Kline, Tokyo, Japan), gel-type oral moisturizer (BT; Biotene Oral balance Jell®: T&K, Tokyo, Japan), denture moisturizer (DW; Denture Wet®: DENTCARE, Osaka, Japan). The amount of each coating was 1.5 g for PK, 0.6 g for NP, 1.8 g for BT, and 1.2 g for DW. | PMC10230757 |
Participants | vomiting reflex, dentulous | ORAL MUCOSITIS | The study participants included 10 healthy adult dentulous individuals (5 males and 5 females, mean age 27.2 ± 1.6 years) who fully understood the purpose of the experiment and provided written consent. The exclusion criteria of this study were as follows: those with intraoral findings that would interfere with measurements (e.g., torus palatinus or oral mucositis), those with a vomiting reflex, and those undergoing medication therapy. However, none of the 10 participants met the above exclusion criteria; thus, all were included in the final study cohort. First, impressions of the maxillae of the 10 participants were taken. A palatal plate was fabricated on a plaster cast made from an impression, and the retentive force was measured under five conditions, including the use of four test substances and a control without any application. In addition, a subjective evaluation of the usability of the four test substances was conducted using a questionnaire. Each of the five conditions was evaluated on a different day. | PMC10230757 |
Fabrication of the palatal plates | Impressions of the maxillary dentition of the 10 study participants were taken using alginate impression material (AROMA FINE PLUS®; GC, Tokyo, Japan). Models for fabrication of the palatal plates were made from improved dental stone (NEW FUJIROCK®; GC, Tokyo, Japan). The design of the palatal plates was similar to the model used in a previous study [ | PMC10230757 | ||
Retentive force measuring device | With reference to previous studies [ | PMC10230757 | ||
Fabrication of the devices for pressure welding | Previous studies have shown that the load on the palatal plate during pressure contact influences the retentive force. For this reason, a device was needed to define the loads. We fabricated palatal plates that were seated under standardized pressures using custom-made devices for pressure welding. In turn, the retentive force was measured using a digital force gauge at specific periods. The devices were made to maintain a constant pressure load with the placement of the palatal plate in the mouth and application of pressure. These devices for pressure welding were fabricated for each of the 10 palatal plate surfaces by moulding room temperature-cured resin (TrayResin®, Shofu, Kyoto, Japan). The pressure sensor (compact pressure contact load cell LMA-A®, Kyowa, Tokyo, Japan) was incorporated into the pressure welding device (Fig. | PMC10230757 | ||
Measuring conditions | moistness, dry mouth | DRY MOUTH | The five measurement conditions were: (1) control, storage in water only and no test sample applied; (2) NP coating; (3) PK coating; (4) BT coating; and (5) DW coating. The order by which the five conditions were measured was determined using the Latin square design. The study participants were instructed to rinse before the start of the measurements and sit during the measurements. The measurements started at 16:00. In all cases, oral moistness was measured with an oral moisture meter (Mucus®; LIFE, Saitama, Japan) prior to the measurements to ensure that there was no dry mouth. | PMC10230757 |
Measurement of retentive force | The palatal plate was placed in the mouth after applying the substance to its inner surface. Then, a constant load of 25 N was applied for 10 s in the direction of the occlusal plane using the device for pressure welding. The palatal plate was then towed at an angle of 60° to Camper’s plane at a rate of 1 N/s to measure the retentive force. The maximum retentive force until the palatal plate detached from the palatal mucosa was measured. After measurement, the palatal plate was again fitted, and 25 N pressure was applied using the device for pressure welding. The measurements started when the palatal plate was fitted and were taken every 10 min for 30 min. They were repeated four times at each 10-min time point, with the first time being excluded and the average of the second to fourth times taken as the measured retentive force at that time point. In addition, averages were calculated for each time point for the 10 study participants (Fig. | PMC10230757 | ||
Subjective evaluation of the usability of the test sample | After the measurement of retentive force, the study participants were asked to rinse the palatal plate with water and evaluate five parameters—taste, unstickiness, stability, wettability, and washability—on a 100-mm visual analogue scale after each test sample was used (Fig. | PMC10230757 | ||
Statistical analysis | Statistical analysis was performed using IBM SPSS Statistics for Windows, version 27 (IBM Corp., Armonk, N.Y., USA). A one-way analysis of variance was performed for each test substance at each time and for each substance at each time point. Tukey’s method was then used to analyse whether each test substance changed over time and whether there was a difference in retentive force between substances at each time point. A one-way analysis of variance was performed on the results of the subjective evaluation of usability. Tukey’s method was used to analyse whether there was a difference in usability among the substances for each question item. All significance levels were set at 5%. The null hypotheses were that the retentive force does not change with time, that the retentive force changes with the type of substance, and that the usability does not change with the type of substance. | PMC10230757 | ||
Results | PMC10230757 | |||
Retentive force | PMC10230757 | |||
Comparison of the retentive force for test samples at each time point (Figs. | PK, NP, and BT showed significantly higher retentive force than the control immediately after application (p < 0.05). No significant difference was observed between DW and the control (p < 0.05). After 10 min of application, PK showed higher retentive force than the control (p < 0.05). NP showed the highest retentive force among the control and test substances (p < 0.05). BT and DW were comparable to the control (p < 0.05). After 20 min of application, PK showed higher retention than the control (p < 0.05). Similar with the 10-min duration, NP showed the highest retentive force among the control and test substances (p < 0.05). BT and DW were also comparable to the control (p < 0.05). After 30 min of application, only NP showed a higher retentive force than the control, PK, and BT. DW showed the highest retentive force among the test substances (p < 0.05). BT and DW were comparable to the control (p < 0.05).
Measuring retentive force (N) | PMC10230757 | ||
Changes in retentive force in each test substance over time (Figs. | There was no significant difference in the retentive force of the control and DW immediately after application and after 10, 20, and 30 min (p < 0.05). PK showed significantly lower retentive force after 30 min than immediately after application (p < 0.05). Moreover, no significant differences were found among the retentive forces immediately after application and at any time point, except at 30 min (p < 0.05). NP has significantly lower retentive force immediately after application than after 10, 20, and 30 min; however, there were no significant differences among the other time points (p < 0.05). BT has significantly higher retentive force immediately after application than after 10, 20, and 30 min; however, there were no significant differences among the other time points (p < 0.05). | PMC10230757 | ||
Subjective evaluation of the usability of the test substance (Table | In the ‘taste’ parameter, BT showed significantly higher values than the other three test samples, and there were no significant differences among the other test samples (p < 0.05). NP was lower than PK, BT, and DW in the ‘unstickiness’ parameter (p < 0.05). Meanwhile, DW showed lower values than BT (p < 0.05). PK was higher than DW in the ‘stability’ parameter (p < 0.05). Meanwhile, NP was higher than BT and DW (p < 0.05). No significant difference was observed between DW and BT (p < 0.05). In the ‘wettability’ parameter, PK was higher than NP but lower than BT (p < 0.05). BT was the highest among the test samples (p < 0.05). Finally, PK was higher than NP and DW in the ‘washability’ parameter (p < 0.05). Meanwhile, no significant difference was observed between PK and BT (p < 0.05). NP showed lower values than PK and BT (p < 0.05). DW was the lowest among the test samples (p < 0.05).
Subjective evaluation of the usability of the test samples (mm) | PMC10230757 | ||
Discussion | ’, moisture retention, denture adhesives, denture, dry mouth | DRY MOUTH, CAVITY | In this pilot trial, we compared a novel denture adhesive for dry mouth (PK) to an array of other conditions. The other four tested conditions were conventional cream-type denture adhesive, oral moisturizer, denture moisturizer with an oil-based ingredient, and a negative control. In general, PK showed promising results in terms of achieved retentive strength over time and subjective outcomes.In this study, BT, which has a high viscosity, was selected among the oral moisturizers. Yamagaki et al. [Regarding the testing procedures, used devices followed standards set by a previous study, starting by the retentive force measuring device. To define the direction of traction, the angle gauge used in this study (Digital angle gage WR300 Type 2®, Wixey, US) can be set with reference to any plane. First, the arm at the end of the maintenance force measuring device was used to align the reference to the Frankfort plane of the participant, from which the device was tilted to 60° for traction. The use of the Camper’s plane as the reference plane in setting the virtual occlusal plane seems reasonable since it is used in daily clinical practice. In a study by Bandai et al. [This study also standardized the time for experimental procedures. Considering the diurnal variation of salivary secretion and body temperature [The two null hypotheses, that retentive force does not change with time and that the retentive force does not change with the type of substance, were rejected by one-way ANOVA. PK, NP, and BT showed higher retentive force than the control immediately after fitting. On the other hand, no significant difference was observed between DW and controls. Therefore, DW may not be able to increase retentive force. After 10 min, the retentive force of BT decreased to the same level as that of the control, suggesting that the duration of the effect of BT on the palatal plate was approximately 10 min only. BT contains more water-soluble components such as glycerol, which may have been washed out from the mucosal surface by saliva, resulting in a shorter duration than that of NP. After 20 min of application, NP showed the highest retentive force. PK showed higher retentive force than the control, but lower than NP. Since NP binds to water and exhibits adhesive properties, it became compatible with the water in the oral cavity in approximately 20 min, which generated a strong retentive force. A significant difference was observed after 30 min, suggesting that its effect lasts from 20 to 30 min, compared with the control. However, the retentive force decreased over time, so it could be necessary to apply again after 30 min of use. NP remained to have high retentive force, suggesting that it is effective in increasing the retentive force for more than 30 min. PK showed a gradual decrease in retentive force over time. Meanwhile, NP showed a rapid increase in retentive force from immediately after the application to 10 min afterwards. Compared with the other test substances, 10 min is necessary for it to take effect and for the retentive force to stabilise. When using BT, the retention force was stronger immediately after application than at other time points, and decreased after 10 min. Therefore, its duration of effect was within 10 min, and its effectiveness as a substitute for denture adhesives was limited. Finally, DW did not show significant differences over time, suggesting that it is unlikely to be effective in increasing retentive force.In terms of subjective properties, the null hypothesis that the usability does not change when the sample is changed was rejected by one-way ANOVA. PK performed relatively well for wettability and washability, which can be explained by its moisturizing ingredients (e.g., sodium polyacrylate and sodium hyaluronate). Due to its higher moisture retention, its ‘wettability’ is higher in the subjective evaluation. Its ‘washability’ is also higher due to its high content of water-soluble components. A report by Ohno et al. [The limitations of the present study include taking measurements from healthy study participants without dry mouth and subjects having stable oral environmental conditions. Furthermore, this measurement time was 30 min, which was assumed to be the duration of one meal, but the effect of a longer using was not clear. A study by Ohno et al. [ | PMC10230757 |
Acknowledgements | Not applicable. | PMC10230757 | ||
Author contributions | K.Y. contributed to Conceptualization, Date curation, Formal analysis, Original draft, and Writing-review and editing. Y.S. contributed to Conceptualization, Supervision and Writing-review and editing. J.F. contributed to Conceptualization, Date curation, Formal analysis, Original draft, and Writing-review and editing. O.S. contributed Conceptualization, Supervision, and Writing-review and editing. All authors have read and agreed to the published version of the manuscript. | PMC10230757 | ||
Funding | Not applicable. | PMC10230757 | ||
Data Availability | The datasets generated and/or analysed during the current study are not publicly available due to protect the privacy of study participants but are available from the corresponding author on reasonable request. | PMC10230757 | ||
Competing interests | The authors declare no competing interests. | PMC10230757 | ||
Ethics approval and consent to participate | This study was conducted under the approval of Showa University Dental Hospital Clinical Trial Review Committee (approval number: SUDH0065). Written informed consent from all participants were obtained from all participants before initiating the study, and all methods were performed in accordance with the Declaration of Helsinki and the relevant guidelines and regulations. | PMC10230757 | ||
Consent for publication | Not applicable. | PMC10230757 | ||
Abbreviations | denture | cream-type denture adhesivegel-type denture adhesive for dry mouthgel-type oral moisturizerdenture moisturizer | PMC10230757 | |
References | PMC10230757 | |||
Purpose | The aim of this randomized controlled clinical trial was to evaluate peri-implant marginal bone levels (MBLs) and soft tissue dimension changes 1 year after loading. Patients in the control group received bone-level implants, whereas in the test group, tissue-level implants with a convergent transmucosal neck were used. | PMC10264266 | ||
Material and methods | MBLs were calculated by measuring the distance from the implant shoulder to the first visible bone-to-implant contact using standardized periapical digital radiographs. Baseline (day of loading) and follow-up digital models obtained with an intraoral scanner were used to quantify the changes in the peri-implant soft tissue dimensions with a best-fit algorithm. | PMC10264266 | ||
Results | bone loss | BONE LOSS | The difference between final and baseline MBLs showed a mean bone loss of 0.16 ± 0.01 mm in the test group ( | PMC10264266 |
Conclusions | peri-implant | The present study demonstrated peri-implant hard and soft tissues stability at both implant designs with no significant differences 12 months after loading. | PMC10264266 | |
Clinical relevance | There is still insufficient scientific evidence to demonstrate the role and advantages of the convergent transmucosal neck on the behavior of the peri-implant soft and hard tissues stability compared to a straight neck in bone-level implants 12 months after loading. | PMC10264266 | ||
Keywords | Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. | PMC10264266 |
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