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Standard of Care (SOC) | All participants in the SOC clusters are able to access the nurse-led HIV prevention and treatment services at PHCs in the surveillance area. Standard services include HIV counselling and POCT, with immediate initiation of ART if positive, or PrEP if negative and eligible according to South African National PrEP guidelines [ | PMC10428543 | ||
Thetha Nami ngithethe nawe | adolescent- | The intervention is a tailored psychosocial support and social mobilisation into community-based SRH and differentiated HIV prevention, including PrEP and UTT. The intervention is provided by 90 (17 men, 73 women aged 18–30) area-based peer navigators and adolescent- and youth-friendly nurse-led SRH mobile clinics that visit fixed sites across the clusters every 2 weeks.Peer navigators are overseen by a team of 8 peer navigator supervisors, and a committee that includes a professional nurse, a social worker, and team leads. They undergo weekly team debriefings and ongoing supervision and training facilitated by supervisors and team leads. Peer navigators deliver the following services to 15–30-year-olds in their area: providing safe spaces and community advocacy to create an enabling environment; youth groups to mobilize young people; structured psychosocial and health needs assessment using a secure electronic clinical management tool programmed into a tablet or mobile phone using REDCap software [ | PMC10428543 | |
SRH mobile clinic procedures | syphilis, adolescent-, gonorrhoea, chlamydia | HEPATITIS B, STIS, SYPHILIS, GONORRHOEA, ADVERSE EFFECTS | The SRH mobile clinics visit the intervention clusters every 2 weeks. The clinics deliver nurse-led HIV testing, prevention and care including adolescent- and youth-friendly, gender neutral, HIV status neutral, individualized risk assessments for HIV care and PrEP, integrated with SRH services (one stop shops). During the SRH clinic appointment, participants will receive counselling around sexual health, fertility intentions, contraception and HIV. This is part of sexual health counselling with PrEP to stay negative or ART to stay well and virally suppressed (undetectable = uninfectious). All clinic attendees are offered pregnancy testing (if female), family planning support, choice of contraception, and syndromic management for STIs, and, if male, referral to voluntary medical male circumcision. Everyone is offered HIV counselling and POCT, and immediate initiation of ART if positive. All those who are HIV negative undergo screening for PrEP eligibility according to South African National guidelines. Those who are sexually active are also offered testing for STIs, including POCT for syphilis and hepatitis B (and vaccine if negative), self-taken vaginal swabs or urine tests for gonorrhoea and chlamydia, and treatment and partner notification if positive.If the participant agrees to immediate PrEP/ART initiation, s/he is issued with a month’s supply of tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) or ART. Participants receive a phone call seven days after initiating PrEP/ART to complete a standard symptom screen for adverse effects and be referred to a fixed PHC for care if necessary. Participants have a mobile clinic appointment scheduled one month after PrEP/ART initiation. As per national guidelines, mobile clinic appointments for refills and monitoring are every 3 months thereafter; we provide community refills aiming for continuous PrEP supplies. If they agree, participants are referred back to peer navigators for adherence support and to ensure clinical follow-up. The electronic clinical management tool facilitates secure bidirectional communication of case-based action plans between the mobile clinic, the oversight committee and the peer navigator teams in the cluster. | PMC10428543 |
Primary outcomes | HIV infection | HIV INFECTION | There are 3 co-primary outcomes: 1) effectiveness of the intervention in reducing the prevalence of sexually transmissible HIV; 2) uptake of universal risk informed HIV prevention intervention, in particular PrEP; 3) cost of transmissible HIV infection averted.We will measure transmissible HIV as the proportion of participants aged 16–30 years providing a blood sample at endline who are living with HIV and have a detectable HIV viral load of ≥ 400 copies/mL. This composite outcome captures the effect of the intervention on both incident HIV and untreated HIV. Success of our intervention implies that there will be fewer cases of young people who acquire HIV, and those who do acquire HIV will be identified and started on treatment, both of which will reduce the number of individuals with unsuppressed (transmissible) HIV.We will measure the uptake of universal risk informed HIV prevention intervention as the proportion of participants who are aware of their HIV status and are either on treatment if living with HIV or have taken up PrEP if HIV negative and eligible. We will measure the costs to the provider or healthcare system for each participant screened, enrolled and retained on PrEP per covered month. We will compare the costs of care in the intervention and control periods to determine the cost-effectiveness of the intervention in achieving the endpoints, i.e., the cost per transmissible HIV case averted, the cost per case linked to risk differentiated biosocial HIV prevention, cost per case linked to PrEP. | PMC10428543 |
Secondary outcomes | HIV; mental health as measured by PHQ9, alcohol | Secondary outcomes of the trial include: access to sexual and reproductive health services; STI prevalence; HIV incidence (measured using recency assays); proportion of men and women aged 15–30 at risk of acquiring HIV or transmitting HIV; mental health as measured by PHQ9, alcohol and drug use; and socioeconomic outcomes (educational, employment and food security). Secondary process and economic outcomes include evaluation of fidelity, acceptability, practicability, cost, uptake, and reach of the different intervention components. | PMC10428543 | |
Randomisation restriction | The 40 administrative areas were randomly allocated in a 1:1 ratio to early or delayed roll-out of the intervention. Randomisation was restricted to ensure that the trial sequences were reasonably balanced with respect to several key covariates that were thought to be associated with the outcome: the population size of young people aged 15–30 years; location in the northern or southern part of the study area; proximity to a major road. The tolerance thresholds for balance were defined through an iterative process in which different thresholds were tried and the number and the validity of the acceptable allocations were examined. With unrestricted randomisation, every pair of clusters has the same probability of being allocated to the same sequence. When evaluating our restricted randomisation scheme, we aimed to obtain a sufficient number of acceptable allocations and a reasonably uniform distribution of joint allocation probabilities.The mean population size of young people in the 40 clusters was 606. Just over half (21, 52.5%) of the clusters were in the northern surveillance area, and 9 clusters (22.5%) were along the major road. We restricted to allocation options that had absolute differences in the mean cluster size between the two sequences of ≤ 100, the proportion of northern clusters in each sequence was 40.5–64.5%, and the proportion along the main road was 12.4–32.6% (mean ± 1.5 standard deviations). Without restrictions, there were 13.8 × 10 | PMC10428543 | ||
Randomisation and assignment of intervention | Peer navigators and other key stakeholders were invited to a public randomisation ceremony. The public ceremony ensured transparency and fairness in the randomisation and increased buy-in and engagement of the community. A random subset of 10,000 acceptable allocations was taken from those previously generated to use for the ceremony. Each allocation was given a unique running number, 1 through 10,000. Four sacks containing 10 balls each, numbered 0–9 was prepared. For each cluster, the peer navigators chose their own leader to represent their cluster. First, each leader was asked to draw a piece of paper from a box. All the papers were blank except for four. Next, the four leaders with the non-blank papers were each invited to draw a ball from one of the four sacks. The 4-digit number that was generated by this process corresponded to the allocation running number (with 0000 representing 10,000). | PMC10428543 | ||
Blinding | BLIND | Investigators, statisticians, research assistants enrolling to the surveys, and laboratory staff will be blind to intervention assignment throughout. Participants, peer navigators and clinical teams cannot be blinded or masked. | PMC10428543 | |
Criteria for discontinuing or modifying allocated interventions | ADVERSE EFFECTS | In the intervention clusters, nurses and/or peer navigators will engage participants throughout the trial, and tailor their HIV prevention to their risk, including stopping and starting PrEP. Participants who experience adverse effects will be referred to a fixed PHC for care if necessary. If anyone seroconverts on PrEP (new positive ELISA test), we will support them to start ART immediately, check for HIV resistance, and switch to monitoring HIV viral loads. In the control clusters, care will be provided by the department of health nurses in PHCs according to the current South African National guidelines. All study participants will continue to receive ART/PrEP and contraception through the PHCs after the trial end. | PMC10428543 | |
Strategies to improve adherence in the intervention clusters | All those who start PrEP, ART or contraception in the intervention clusters are offered peer navigator support as part of their individualized adherence plan and to support the refills and/or appointment scheduling and reminders. Neutral text message reminders are provided for participants who have access to private messaging and phone calls. A telephone hotline managed by a nurse is provided which participants can contact at any time for clinical guidance and psychosocial support. | PMC10428543 | ||
Outcome ascertainment | Data for outcome ascertainment are/will be collected from four sources: i) cross-sectional surveys of random samples of 15–30-year-olds who are resident in the 40 clusters; ii) programme, process, and clinical data; iii) qualitative data collected during the process evaluation; iv) records of resource utilisation (such as consumables, medicines, diagnostics) and cost data including financial reports for staff and overhead costs. | PMC10428543 | ||
Cross-sectional surveys | For each cross-sectional survey, we will use the surveillance area as a sampling frame to randomly select a sample of young people stratified by sex. Our initial sample size calculations were based on sampling At each survey, the study team will visit the sampled individuals at their homes to give them information about the study and invite them to participate. Those who are interested in participating will be asked to provide written informed consent if aged ≥ 18 years, or written assent and parental consent if aged < 18. Researchers will make up to four attempts at different times of the day to enrol the sampled individuals at home or a place of their choice. Based on our experience this will enable us to enrol 3200 (~ 80 per cluster) and reach our target sample size.After informed consent, participants will be asked to provide a blood sample for HIV testing (and viral load if positive), and to complete a 20–30-min interviewer-administered questionnaire. Sensitive questions will be self-completed. Questions will include awareness of HIV status; awareness and uptake of PrEP, voluntary medical male circumcision, ART and contraception; and exposure to youth groups, peer navigators, and SRH mobile clinics. We will also collect data on sociodemographics, sexual risk (e.g., number of partners, condom use, and transactional sex), reproductive health (e.g., contraception, pregnancy, fatherhood); and mental health (PHQ9, alcohol and drug use). Participants will also be asked for their consent to link their survey data with programmatic data collected from peer navigators, SRH mobile clinics, and PHCs in the surveillance area (Table Schedule of enrolment, interventions, and assessments for Thetha Nami ngithethe nawe stepped wedge cRCT | PMC10428543 | ||
Programme and process data | We will collect aggregate data on uptake and retention in the different components of the intervention in all young people aged 15–30 years who are resident in the 40 clusters (around 26,000). We will collect the programme data from the peer navigators’ participants-support management tools. Peer navigators use these tools to record psychosocial and health needs assessments, and the health promotion, service and/or referral provided. For those attending the clinics, we will collect aggregate clinical data from the clinical management tool, including HIV testing, ART uptake, PrEP eligibility screening, PrEP uptake and other services received. We will also measure retention, adherence, and reasons for stopping and/or restarting PrEP. Within the 11 PHCs in the surveillance area, we will also use the ClinicLink system to identify 15–30 year-old individuals by cluster who attend the clinics for HIV testing, PrEP or ART (Table | PMC10428543 | ||
Qualitative data | Qualitative data will be conducted by a team of research assistants and include in-depth interviews (IDI) with peer navigators ( | PMC10428543 | ||
Costing data | We will work closely with the Health Economics and Epidemiology Research Office to establish the costs of implementing the intervention. We will adapt data collection tools that we have used in previous peer-led trials to measure the costs of the peer navigator intervention to collect bottom-up ingredient-based costs [ | PMC10428543 | ||
Theory of change | It is envisaged that the intervention would reduce the burden of transmissible HIV amongst young people aged 15–30 through a reduced incidence of new cases of HIV and an increase in those with HIV who are virologically suppressed on ART. The Theory of Change (Fig. | PMC10428543 | ||
Sample size | HIV and 0.4 | DECAY | Data from our previous studies and the demographic surveillance suggested 8% of young people aged 15–30 have a transmissible HIV viral load (primary outcome 1), and around 35% are aware of their HIV status and either on PrEP or on ART with undetectable viral load (primary outcome 2). Our original design specified 2000 young people aged 15–30 (50 per cluster) interviewed in each of the three cross-sectional survey waves. Assuming an intracluster correlation coefficient (ICC) within wave of 0.1 for transmissible HIV and 0.4 for intervention uptake, and a decay (autocorrelation) between waves of 0.9 for both outcomes, this design provided 90% power to detect an increase from 35 to 47% in primary outcome 2 and 80% power to show a reduction in primary outcome 1 from 8 to 4% when comparing the intervention to standard of care [ | PMC10428543 |
Data management | Data collected by the peer navigators and clinic staff will be captured electronically on tablets using REDCap software. Automatic checks for invalid values, internal inconsistency and implausible responses will be programmed into REDCap, and additional data validation checks will be run after data collection. Data from REDCap will be uploaded to a MySQL database server within a secure server cluster at AHRI. | PMC10428543 | ||
Statistical analysis | REGRESSION | To quantify the effect of the intervention on sexually transmissible HIV, we will fit a logistic regression model to data from all three survey waves to estimate the odds ratio (OR) and 95% confidence interval (CI), adjusting for design factors and survey wave, acknowledging the clustering of the data through generalized estimating equations. To increase power and also handle any chance imbalance in the distribution of HIV risk factors between exposures, we will also adjust for pre-specified predictors known to be associated with HIV transmission risk in this population at cluster and individual level.To measure the uptake of the universal risk-informed HIV prevention intervention we will use the survey data collected at the end of intervention exposure periods, among survey participants who consent to linkage of their survey data with our programmatic and clinical data. We will calculate the proportion and 95% CI (acknowledging clustering) of participants who are aware of their HIV status and are either on treatment if living with HIV or have taken up PrEP if HIV negative and eligible. As a sensitivity analysis, we will also compare uptake of PrEP based on our programmatic data, AHRI’s Clinic Link system, and routine electronic health records (e.g. TIER.net), and compare this with what we find in the cross-sectional surveys.To examine the cost of transmissible HIV averted, we will measure the costs in the intervention and SOC periods including HIV screening, risk assessment, PrEP initiation and adherence on PrEP. This analysis will take the cost perspective of the provider (i.e., Department of Health, implementing partners and other agencies) and include the cost of any resources used to provide services to the client irrespective of the payer. We will use different costing methods to estimate the costs of: a) services provided prior to PrEP initiation, b) PrEP provision and c) ancillary services provided alongside PrEP provision. A top down costing approach will be used to fully capture the costs which occur prior to PrEP initiation and at an above-site level, as provision of these services is not always recorded at the level of the participant. A bottom-up micro-costing of the resources used to provide PrEP and ancilliary services that are captured in the routine medical records of the participants (e.g., PrEP and other drugs dispensed, clinic visits, pharmacy, laboratory tests performed, counselling visits) will be conducted. The total and average costs of achieving each endpoint (i.e. the cost per transmissible HIV case averted, the cost per case linked to risk differentiated biosocial HIV prevention and the cost per case linked to PrEP) for each period will be calculated and an incremental cost-effectiveness ratio determined.We will use mixed methods to explore acceptability and equity of reach; fidelity and facets of the packages that are valued and by whom (including key groups that are harder to reach e.g. mobile youth, young women who sell sex and men who have sex with men); and any unintended social harm [A significance level of 0.05 will be used for all inferential analyses unless otherwise stated; a correction for multiplicity will not be applied because the three outcomes reflect different trial domains (effectiveness, process and cost). A detailed statistical analysis plan will be completed before the end of data collection. | PMC10428543 | |
In-depth interviews | Interviews will be based on a topic guide focusing on the experience and perceptions of the intervention. Interviews will be recorded and transcribed verbatim, with the permission of participants. Data from the IDIs will be managed for analysis using NVIVO software. The software will be used to manage categorization and coding of identified themes from the interview transcripts. Identified themes (including participants’ quotes) and interview transcripts will be reviewed and compared by the research team for inconsistencies and adequate representation of participants’ comments. A thematic analysis of all interview data will be conducted, drawing on the theory of change to categorise themes and organise the findings. | PMC10428543 | ||
Adverse event reporting and harms | ADVERSE EVENTS, ADVERSE EVENT | This is an implementation study and all tests and drugs used are approved for clinical use in South Africa. All clinical care follows South African clinical guideline. The risk of harm is anticipated to be low. Adverse events (AEs) and serious adverse events (SAE) will be captured through the process evaluation, community engagement units and community advisory boards, the hotline, as well as the peer navigators and clinic staff and logged using our incident reporting form for up to up to 12 months after the start of the intervention. Reported AEs and SAEs will be monitored, categorized based on an established grading system, and followed-up accordingly by AHRI. All AEs and SAEs will be reported to the principal investigator, Trial Steering Committee, UKZN and UCL Biomedical Research Ethics Committee. | PMC10428543 | |
Ethics and trial oversight | We assert that all procedures contributing to this study comply with the ethical guidelines and standards of the relevant national and institutional committees on human experimentation and with the Declaration of Helsinki. Ethical approval has been obtained from the University of KwaZulu-Natal Biomedical Research Ethics Committee (BREC/00003735/2021) and UCL Research Ethics Committee (5672/006). All staff (including peer navigators) will be provided with training on research ethics including confidentiality, voluntary participation and good clinical practice. We will ensure confidentiality at all levels of the research process, and none of our reports, presentations or articles will contain study participants identifying information. Pseudo names will be used when reporting the data particularly qualitative data. Each participant will be assigned a unique non-identifying participant identification number. Prior to their involvement in the study, participants will be provided with adequate information about the study and they will be allowed to ask questions for clarifications. Voluntary informed consent will be ensured once participants have the full understanding of the study procedures. Written informed consent will be obtained from all participants aged 18–30 years; written assent from participants aged 15–17 years, with written informed consent from their parents or guardian. All participants will have the right to withdraw from the study at any time. it will be stated clearly to participants that their refusal to participate in the study or desire to withdraw from the study will not affect them or any other health related services they are currently accessing, including peer navigator support and clinical services provided in the study mobile clinics and DoH clinics. We have established a Trial Advisory Group with clinical trials, PrEP, statistical and social science expertise to oversee the trial. This is an effectiveness trial of different models of service delivery and all tests and drugs used are approved for clinical use in South Africa. All clinical care follows South African clinical guidelines. The risk of harm is anticipated to be low and detailed in the study protocol. For the costing, additional ethical approval has been obtained from the University of Witwatersrand Human Research Ethics Committee (Medical) (HREC 220708) and Boston University IRB (H43001). All deviations from protocol, protocol modifications will be communicated to Trial Steering Committee, Biomedical Research Ethics Committees (UCL and KZN), trial registry and in the trial publications. | PMC10428543 | ||
Discussion | ’ | The findings of this trial will inform the scale up of peer-led social mobilization into community-based sexual and reproductive health interventions optimized to support the uptake and retention of adolescents and young adults in long term HIV treatment, HIV pre-exposure prophylaxis and other prevention, and contraception.During the planning phase we liaised with the National and Provincial Department of Health to ensure that the interventions are designed to generate the data needed to scale-up the interventions. We established a working group of health officials that lead HIV testing, prevention and SRH in the district and a nascent technical advisory group in the KZN province. These groups helped us optimize and integrate our existing community-based PrEP delivery with the primary health care; agree the location and distribution of spokes, and the evaluation framework. The main goal of this trial is a scalable ‘decentralised hub and spoke model’ that is aligned with re-engineering of primary care, supports effective (risk-informed) use of biosocial HIV prevention (including PrEP and UTT), and provides the infrastructure to market, test, and rapidly evaluate the implementation of new products. The model is designed to improve sexual health and reduce transmissible HIV amongst young people aged 15–30 in rural KZN, South Africa. We therefore anticipate that if effective the intervention will be scaled up within the district and allow us to test the real-world implementation of newer products such as long-acting PrEP as they emerge. This will potentially harness the full potential of antiretroviral therapy to reduce HIV incidence. | PMC10428543 | |
Trial registration | NCT05405582 | PMC10428543 | ||
Acknowledgements | Sibonelo, Zethu, Mbali, Mfekayi, Nombuso Mtshali, Nompumelelo | The authors acknowledge the Thetha Nami ngithethe nawe implementation and research team including the research assistants (Mthobisi Zikhali, Sibongseni Xulu, Xolani Ngwenya, Zakhele Zikhali), clinical team (Funanai Shange, Hlengiwe Ncanana, Lethiwe Mlambo, Monsley Myeni, Ndumiso Vilane, Nokwazi Ntombela, Nolwazi Ngcobo, Sinegugu Majozi, Sithembiso Luthuli), research administrator (Zama Nkalane), peer supervisors (Buyisile Kunene, Happy Matsebo, Mabali Mtshali, Sibonelo Mhlongo, Sithabiso Masango, Sphamandla Ngwenya, Thembisile Mthembu, Zanini Khumalo), and peer navigators (Anathi Olwethu Ntombela, Azande Myeni, Bongokuhle Sangweni, Busisiwe Gumede, Busisiwe Mthabela, Buyisile Kunene, Cabangile Wendy Mafu, Fanelesibonge Mathenjwa, Hlengiwe Dorcas Ncanana, Hlengiwe Mpanza, Khanyisile Mdluli, Kwanele Mbatha, Kwanele Msweli, Kwanele Nqobile Jobe, Lindelwa Bongekile Nkosi, Londeka Mlungwana, Londeka Myeni, Lungile Ncube, Luyanda Ncube, Mbali Mtshali, Menzi Manqele, Motsebo Happy Mthethwa, Mpendulo Mkhwanazi, Mpendulo Sibiya, Msawenkosi Shabalala, Mthobisi Mkhwanazi, Nduduzo Zuma, Nhlakanipho Mkhwanazi, Nhlonipho Khumalo, Njabulo Zulu, Nkululelo Mantengu, Nobuhle Mthembu, Nodumo Ncube, Nokubekezela Mkhwanazi, Nokubonga Gumede, Nokubonga Mfekayi, Nokuthula Fezile Nsele, Nokwanda Dube, Nokwazi Mkhwanazi , Nombuso Mtshali, Nomfundo Ndlovu, Nomfundo Ntshangase, Nompilo Mkhwanazi, Nompumelelo Hlabisa, Nompumelelo Zikhali, Nonhlanhla Mncwango, Nonhlanhla Mthethwa, Nonjabulo Mashaya, Nontando Mkhasibe, Nontando Sibiya, Nontethelelo Myeni, Nosipho Mpanza, Nosipho Nyawo, Nothile Kunene, Nqobile Masisi Mahlangu, Ntombiziningi Khumalo, Ntombizonke Masuku, Philasande Mfekayi, Sanele Zungu, Sanelisiwe Xulu, Senamile Mathunjwa, Sibekezelo Gina, Sibonelo Mhlongo, Sibusiso Mazibuko, Sibusiso Nkosi, Sifundo Sibiya, Sikhulile Mbuyazi , Silindile Mbatha, Simphiwe Thembisile Nkosi, Sinqobile Gumede, Sinqobile Mngomezulu, Siphamandla Ngwenya, Siphamandla Nsele, Sithabiso Masango, Sithembile Sangweni, Sithembile Thethwayo, Sithokozile Gugu Sithole, Siyabonga Ngubane, Sthobile Thethwayo, Thembisile Mthembu, Thobeka Manqele, Thobile Mfekayi, Thobile Ngcobo, Tholakele Madini, Thulani Mfekayi, Xolile Ncube, Xolile Sinenhlanhla Nyawo, Zamokwakhe Gumede, Zandile Nxumalo, Zandile Ximba, Zanini Khumalo, Zethu Thabethe), for their commitment to the study. We also extend our appreciation to our research community including the community advisory boards in uMkhanyakude district. | PMC10428543 | |
Authors’ contributions | JJ | MS conceived the study. MS, AC, KB, NC, TZ, JD, CH, NO, JB, and JS designed the study. JB and MS wrote the first draft of the manuscript. JB, MS, AC, KB, LS, JS, SH, GH, JM, CH, NC, TZ, TS, and JJ read and critically revised the manuscript. All authors read and approved the final manuscript. | PMC10428543 | |
Funding | This trial was made possible through funding from Bill and Melinda Gates Foundation (INV-033650); US National Institute of Health (NIH) R01 (5R01MH114560-03); Africa Health Research Institute is the trial sponsor and is supported by core funding from the Wellcome Trust (Core grant number (082384/Z/07/Z). MS is an NIHR Research Professor (NIHR 301634). GH. is supported by a fellowship from the Wellcome Trust and Royal Society [grant number 210479/Z/18/Z]. NC is supported by a Wellcome Trust Early career fellowship (grant number 224309/Z/21/Z). The open access publication was made possible via the Bill and Melinda Gates Foundation (OPP1136774 and OPP1171600). For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The funders and sponsor have played no role in the study design, writing of the manuscript and in the decision to submit the manuscript for publication. | PMC10428543 | ||
Availability of data and materials | Data sharing is not applicable to this article as no datasets are reported. However, following completion of the study all the datasets generated and/or analysed during the current trial will be made available in the AHRI repository at the time of publication of the primary outcome paper. Access to the datasets generated in the study will be included in all papers reporting study outcomes. Access to the full protocol and model consent forms may be available from the author. | PMC10428543 | ||
Declarations | PMC10428543 | |||
Ethics approval and consent to participate | We assert that all procedures contributing to this study comply with the ethical guidelines and standards of the relevant national and institutional committees on human experimentation and with the Declaration of Helsinki. Ethical approval has been obtained from the University of KwaZulu-Natal Biomedical Research Ethics Committee (BREC/00003735/2021) and UCL Research Ethics Committee (5672/006). All staff (including peer navigators) will be provided with training on research ethics including confidentiality, voluntary participation and good clinical practice. We will ensure confidentiality at all levels of the research process, and none of our reports, presentations or articles will contain study participants identifying information. Pseudo names will be used when reporting the data particularly qualitative data. Each participant will be assigned a unique non-identifying participant identification number. Prior to their involvement in the study, participants will be provided with adequate information about the study and they will be allowed to ask questions for clarifications. Voluntary informed consent will be ensured once participants have the full understanding of the study procedures. Written informed consent will be obtained from all participants aged 18–30 years; written assent from participants aged 15–17 years, with written informed consent from their parents or guardian. All participants will have the right to withdraw from the study at any time. it will be stated clearly to participants that their refusal to participate in the study or desire to withdraw from the study will not affect them or any other health related services they are currently accessing, including peer navigator support and clinical services provided in the study mobile clinics and DoH clinics. We have established a Trial Advisory Group with clinical trials, PrEP, statistical and social science expertise to oversee the trial. This is an effectiveness trial of different models of service delivery and all tests and drugs used are approved for clinical use in South Africa. All clinical care follows South African clinical guidelines. The risk of harm is anticipated to be low and detailed in the study protocol. For the costing, additional ethical approval has been obtained from the University of Witwatersrand Human Research Ethics Committee (Medical) (HREC 220708) and Boston University IRB (H43001). All deviations from protocol, protocol modifications will be communicated to Trial Steering Committee, Biomedical Research Ethics Committees (UCL and KZN), trial registry and in the trial publications. | PMC10428543 | ||
Consent for publication | Not applicable. | PMC10428543 | ||
Competing interests | The authors declare no competing interests. | PMC10428543 | ||
References | PMC10428543 | |||
Introduction | dysphagia, palate, mastication and deglutition | DYSPHAGIA, POSTERIOR | The tongue heavily interacts with the hard and soft palate during speech production as well as mastication and deglutition, cooperating with the lips, mandible, pharynx, and larynx. Therefore, tongue function impairment negatively influences speech production, masticatory, and swallowing movements, leading to dysphagia. Quantitative evaluation of the tongue function is essential for dysphagia rehabilitation, and tongue pressure (TP) is used as a quantitative and convenient index of tongue strength. However, decreased TP is associated with reduced swallowing and masticatory functionThe tongue right positioner (TRP) (Fig. Views of the tongue right positioner. Left: Occlusal view; Right: Posterior view. | PMC9968309 |
Methods | PMC9968309 | |||
Ethical considerations | This single-arm study was conducted per the Declaration of Helsinki of 1975, revised in 2013, and was approved by the Ethics Committee of the Tokyo Medical and Dental University (D2020-023). Written informed consent was obtained from all participants. | PMC9968309 | ||
Participants | dysphagia | DYSPHAGIA | Patients who visited a university dental hospital between September 2020 and September 2021 and had dysphagia were enrolled in this study. The inclusion criteria were as follows: (1) at least three of the six anterior teeth in the upper jaw remained, (2) at least two of the five molars on both the right and left sides of the upper jaw remained, (3) the lingual frenulum was not short, (4) those who could handle the use of the TRP, and (5) those who agreed to join this study. The exclusion criteria were the following: (1) inability to follow instructions, (2) altered consciousness, and (3) tracheostomy. Eight male patients with an average age of 58.8 ± 12.3 years received TRP intervention. | PMC9968309 |
Intervention | PMC9968309 | |||
Tongue right positioner | TONGUE | The TRP (Tongue Lab Japan, Kyoto, Japan), patented by Tongue Lab., Paris, France, was provided to all participants. It is a custom-made removable oral device consisting of a resin button and a transverse arch (Fig. | PMC9968309 | |
Outcome | SECONDARY | The outcome variables were assessed at the beginning of the study and at the 2-month follow-up visit. In this study, TP was the primary outcome, and the secondary outcomes were tongue and lip movement speed, peak nasal inspiratory flow (PNIF), and ultrasound assessment of swallowing-related muscles. | PMC9968309 | |
Measurement | dysphagia | DYSPHAGIA | The measurements were performed by dentists who belong to the department of dysphagia rehabilitation in a university hospital and are accustomed to using the measurement devices. Before the measurements, the dentists calibrated the usage of all measurement devices employed in this study. | PMC9968309 |
Tongue pressure | incisors, palate | TP was evaluated using a JMS tongue pressure measurement device (JMS Co. Ltd., Hiroshima, Japan). Participants in the sitting position were asked to place the balloon in their mouth and hold the plastic pipe with their upper and lower central incisors with their lips closed. A dentist held the probe in the correct position while recording the measurements. The participants were then asked to push the balloon with their tongue against their hard palate for 7 s with maximum pressure. The TP was measured three times, and the average value was recorded as described previously | PMC9968309 | |
Tongue and lip movement speed | The tongue and lip movements were evaluated using oral diadochokinesis (ODK). ODK was measured using the KENKO-KUN Handy, an oral function-measuring device (Takei Scientific Co., Ltd., Niigata, Japan). Participants were asked to pronounce a monosyllable as quickly as possible for 5 s. The device recorded the number of repetitions for each syllable and calculated the number of syllables produced per second. The monosyllables ‘‘pa,’’ ‘‘ta,’’ and ‘‘ka’’ were used to evaluate the ability of the lips, the tip of the tongue, and the posterior region of the tongue, respectively | PMC9968309 | ||
Ultrasonographic assessment of swallowing-related muscles | The cross-sectional area of the geniohyoid muscle (CSA of the GH) and the thickness of the tongue were evaluated using an ultrasonic measuring device (SonoSite M-turbo, Fujifilm, Tokyo, Japan) in B modeThe intraclass correlation coefficients (ICC) (1,1) and (2,1) were calculated to evaluate the reliability of the examiner. ICC (1,1) 0.925 and (2,1) 0.966 is used for measuring the CSA of the GH, and ICC (1,1) 0.936 and (2,1) 0.925 for the thickness of the tongue, which revealed high reliability. ImageJ software (National Institutes of Health, Bethesda, MD, USA) was used for image processing. The CSA of the GH and tongue thickness were measured thrice and twice, respectively, and the mean values were recorded. During the analysis, the examiner was blinded to the information, including the names of the participants and whether the image was taken at baseline or at follow-up. | PMC9968309 | ||
Peak nasal inspiratory flow | A previous report | PMC9968309 | ||
Other measurements | dysphagia, DSS | DYSPHAGIA | The Barthel index (BI), the functional oral intake scale (FOIS) scores, and the dysphagia severity scale (DSS) of the participants were recorded. The BI is an index of daily living activities consisting of 10 questions, with scores between 0 and 100. A higher score was associated with a higher physical function | PMC9968309 |
Statistical analysis | The Shapiro–Wilk test was used to test the normality of all data, after which the paired | PMC9968309 | ||
Ethics approval | This single-arm study was conducted per the Declaration of Helsinki of 1964, revised in 2013, and was approved by the Ethics Committee of the Tokyo Medical and Dental University (D2020-023). | PMC9968309 | ||
Consent to participate | Written informed consent was obtained from all participants. | PMC9968309 | ||
Discussion | dysphagia, DSS | DYSPHAGIA, DISEASE, NEUROMUSCULAR DISEASES, DISEASES, CEREBRAL INFARCTION | The TRP was employed for patients with dysphagia for the first time, showing that TP increased after 2-month use. Interestingly, although three participants had progressive disease, TP increased. Therefore, the device can serve as a valuable tool for functional rehabilitation of the tongue in patients with such diseases.A decrease in TP was observed in only one of the eight participants. However, the TP of this participant at baseline was 40.8 kPa, which was not significantly low despite the presence of dysphagia, with a decrease of only 0.8 kPa. Therefore, TRP may not have been very useful in this case. However, TRP could be suitable for dysphagia caused by low TP.Although a few mechanisms associated with TRP and improvement in TP have been reported, a possible explanation might be the lingual–hypoglossal reflex. When filiform papillae on the tongue are mechanically stimulated, the tongue’s tip curves upward, the tongue hollows from side to side with the upward curvature of the lateral edges, and the posterior part is depressedThe ultrasonographic evaluation revealed that the CSA of the GH did not improve in this study (The ODK and PNIF were also measured. The ‘Pa’ of ODK (r = 0.45) and PNIF (r = 0.48) during the follow-up visit tended to increase, but when compared with that of baseline, no significant differences were found. There may be a significant difference between baseline and follow-up values in future studies with a larger sample size. In this study, cases of some patients with progressive disease should have been adjusted or homogenized. Although the improvement was not significant, the PNIF scores increased. This finding is consistent with a previous studyIn contrast, the ‘ta’ and ‘ka’ of ODK decreased slightly. In the ‘ta’ of the ODK, the score of four participants, including the three participants with progressive neuromuscular diseases, increased whereas that of the other two decreased. The ‘ka’ scores of the two participants decreased, while no change was observed in that of the remaining participants. The improvement in the ‘ta’ could be explained by enhanced genioglossal muscle strength, similar to the improvement in TP. However, the ‘ka’ did not change or decrease. Of the two participants whose ‘ka’ decreased, one had progressive disease, and the other had a history of cerebral infarction. The ‘ta’ and ‘ka’ of ODK reflect the anterior and posterior movements of the tongue, respectively. TRP could maintain the movement of the anterior tongue despite the presence of progressive diseases.This study had some limitations. First, only eight participants were included. Further, as we conducted this pilot study before conducting a randomized controlled trial with both TRP and placebo groups, we did not include a control group. Furthermore, confounding factors were not considered in this study. In the subsequent randomized controlled trial, the sample size will be set using the effect size calculated from the result of this study. Additionally, the participants were heterogeneous: the BIs, the FOIS scores, and the DSS ranged from 25 to 100, 2 to 7, and 2 to 4, respectively. Therefore, more studies are required with a larger number of male and female participants to clarify the effectiveness of TRP use in improving oral function. Second, although TP increased, the ultrasound assessment showed no improvement, suggesting that the muscle characteristics did not change after wearing TRP. Third, the increase in TP may be due to the lingual–hypoglossal reflex. However, it was difficult to prove that the reflex had actually occurred. Fourth, we only verbally confirmed the participants’ usage of TRP at 1- and 2-month follow-up visits. Although the compliance of the participants in this study was adequate that all of them wore TRP every night for the 2-month period, a checklist should be distributed to confirm the achievement rate in a future study. Fifth, we did not find any changes in DSS scores, evaluated by videoendoscope, between the initial and 2-month follow-up visits. The range of each DSS score is wide, and the DSS score does not reflect the movement of swallowing-related organs. Moreover, we could not evaluate the tongue’s position. Since the previous study indicated that TRP could improve the tongue’s position, leading to the increase of PNIF, we should have evaluated its position using videofluorography. Lastly, since the period of TRP usage was 2 months, TP possibly decreases after patients stop TRP usage. However, it remains unclear whether the effect of TRP continues even after the interventional period. Therefore, the long-term effect of TRP usage should also be evaluated in the future.This is the first study to consider the oral or swallowing function of TRP users. Therefore, a randomized controlled trial should be conducted in future studies to emphasize the effectiveness of TRP in oral function. Considering that the ES of TP is 0.84 in this study, 48 participants, including 24 with TRP and placebo oral device (α = 0.05, power = 0.8), are required. Furthermore, since we did not observe any changes via the videoendoscope, swallowing evaluations with videofluorography should be conducted to observe the changes in swallowing kinematics and anatomical characteristics in future studies.Numerous exercises have been suggested to improve TP | PMC9968309 |
Author contributions | All authors contributed to the study’s conception and design. Material preparation, data collection, and analysis were performed by R.Y., K.H., C.N., T.O., and A.S. The first draft of the manuscript was written by R.Y., and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. All participants signed informed consent for the publication of their data. | PMC9968309 | ||
Funding | TONGUE | Fifty percent of the cost for proofreading by Editage and article publishing charges were paid for by Tongue Lab Japan, Kyoto, Japan. In addition, eight tongue right positioner devices and one peak nasal inspiratory flow meter were provided by Tongue Lab Japan for this study. | PMC9968309 | |
Data availability | The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request. | PMC9968309 | ||
Competing interests | The authors declare no competing interests. | PMC9968309 | ||
References | PMC9968309 | |||
Background | Aphthous stomatitis | MUCOSAL DISEASE, DISEASE, MINOR, RECURRENT APHTHOUS STOMATITIS, APHTHOUS STOMATITIS | Aphthous stomatitis is one of the most common oral mucosal diseases. Due to the commonness of recurrent aphthous stomatitis and considering the anti-inflammatory, analgesic, and tissue regenerative properties of atorvastatin and the lack of a study on the effect of statins on minor recurrent aphthous stomatitis, this study investigates the effect of atorvastatin mucoadhesive tablets as a topical treatment on reduction of symptoms and duration of this disease. | PMC10182658 |
Methods | pain | This study is a randomized, double-blinded clinical trial. Patients were divided into two groups, atorvastatin and, placebo; each of the patients received three mucoadhesive tablets daily in the morning, noon, and night. Finally, the patients were examined on days 0 (baseline), 3, 5, and 7 to determine the diameter of the inflammatory halo. The VAS scale was used to evaluate pain intensity for up to 7 days after each meal. The data was entered into SPSS 24 software and analyzed. | PMC10182658 | |
Results | pain | The halo diameter did not significantly differ between the two groups on baseline (P > 0.05). However, on the study’s third, fifth, and seventh days, the difference between the two groups was remarkable, so in the atorvastatin group, the size of the lesions decreased in shorter healing time (P < 0.05). In addition, the patient’s pain intensity (VAS) also showed a significant decrease in the atorvastatin group except on the first, second, and seventh days of the study (P < 0.05). | PMC10182658 | |
Conclusion | pain | MINOR, RECURRENT APHTHOUS STOMATITIS | Atorvastatin mucoadhesive tablets effectively reduce the pain of patients with minor recurrent aphthous stomatitis and reduce the size and healing time of the lesions, so their application should be considered in treating minor recurrent aphthous stomatitis. The present study was approved by the Medical Ethics Committee of Mazandaran University of Medical Sciences with the ethics code IR.MAZUMS.REC.1400.8346. Also, this study received code IRCT20170430033722N4. | PMC10182658 |
Keywords | PMC10182658 | |||
Background | itching, burning, herpetic, inflammation, ulcerative, aphthous stomatitis, necrotic, pain, palate, cardiovascular problems, ulcer | RECURRENT APHTHOUS STOMATITIS, ULCER, HYPERLIPIDEMIA, INFLAMMATION, MINOR, ULCERATIVE, APHTHOUS STOMATITIS, ULCERS, NECROTIC, DISEASE, ADVERSE EFFECTS, ADHESION, RECURRENT APHTHOUS STOMATITIS, HYPERTENSION, APHTHOUS STOMATITIS, TYPE 2 DIABETES | Recurrent aphthous stomatitis (RAS) is an ulcerative and painful lesion with a prevalence of 5–60%, which can interfere with an individual’s nutrition, speech, and oral hygiene due to its painful nature, which in turn can affect the patient’s quality of life [Aphthous stomatitis is clinically divided into minor, major, and herpetic forms. The most common form of RAS is minor, with a prevalence of more than 80%. Clinically, minor aphthous stomatitis is in the form of shallow ulcers with a size smaller than 5 mm, single or multiple, round or oval with a necrotic base and erythematous border with a burning pain that appears 2 to 48 h before the formation of the ulcer. The lesions specifically involve the non-keratinized and moveable mucosa of the mouth, including the mucosa of the lips, cheeks, lateral and ventral surface of the tongue, soft palate, and oropharynx [Significant treatment protocols have been introduced for this condition, but the etiology of this disease is still idiopathic, and these treatments are primarily symptomatic rather than preventive [Statins are inhibitors of the enzyme 3-hydroxyl-3methylglutaryl coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the first step of cholesterol biosynthesis, so the primary role of statins is to reduce the risk of cardiovascular problems in patients with hyperlipidemia, hypertension, and type 2 diabetes [The beneficial effects of statins are related to their anti-inflammatory properties. They reduce the release of C-reactive peptides, cytokines, chemokines, and adhesion molecules; they also affect T-cell activity modulation. Statins inhibit the migration of leukocytes by decreasing the expression of adhesion molecules. Furthermore, prevent inflammation by suppressing chemokine release and Th1-type chemokine receptors of T-cells [The topical use of these drugs can put a higher dose of the medicine in contact with the ulcer for a more extentended period and simultaneously reduce the side effects caused by systemic drug use. Studies have shown that the topical use of this substance may cause mild adverse effects such as itching, burning, and irritation. However, it is well tolerated and highly compatible with many patients [Given the anti-inflammatory, analgesic, and tissue regenerative properties of atorvastatin and the lack of a study on the effect of statins on minor recurrent intraoral ulcers, we decided to evaluate the efficacy of atorvastatin mucoadhesive tablets as a topical treatment on reducing the symptoms and duration of minor recurrent aphthous stomatitis. | PMC10182658 |
Methods | COMPLICATIONS | This randomized, double-blinded clinical trial was approved by the Medical Ethics Committee of Mazandaran University of Medical Sciences (Moral Code: IR.MAZUMS.REC.1400.8346).All patients received a sufficient explanation about the treatment process and possible complications; then signed a consent form before entering the study. | PMC10182658 | |
Participants and inclusion criteria | aphthous lesions, Behcet’s syndrome, stomatitis, urticaria, myopathy | MUSCULAR DISORDERS, STOMATITIS, LIVER FAILURE, MINOR, URTICARIA, SYNDROMES, RECURRENT APHTHOUS STOMATITIS, APHTHOUS ULCERS, MYOPATHY, SKIN AUTOIMMUNE DISEASE | According to the study conducted by Babaei et al. with the mean and standard deviation of the lesion diameter on the seventh day in the control group of 0.60 ± 0.69 and the intervention group of 1.29 ± 0.66 with a confidence level of 95%, a test power of 90%, and for the two-way test, by using the formula for comparing the two averages in the G-power software. The sample size of the current study was calculated 44 patients (22 patients in each group) [The patient selection was based on the inclusion criteria from those referred to Mazandaran dental school with recurrent aphthous stomatitis in the age range 20–40, reporting a history of minor aphthous ulcers in areas such as the lips and buccal mucosa. The patients were randomly divided into two groups: 22 patients in the intervention group and 22 patients in the control group. The head nurse of the dental clinic (who was not from analyzers or evaluators) registered the patients and gave the medication to participants (atorvastatin mucoadhesive tablets or placebo). This intervention took 7 days.The inclusion criteria of this study include patients with minor recurrent stomatitis, patients with aphthous lesions in lips and buccal mucosa (due to greater access and less movement that allows mucoadhesive tablets to remain on the lesion), systemically healthy, not taking immunosuppressive drugs within the past month, not using dentures, not taking antibiotics. Also, pregnant patients, people who were not able to use mucoadhesive tablets, people with syndromes manifesting aphthous-like lesions (Behcet’s syndrome), smokers, people with mucosal skin autoimmune diseases, patients with liver failure, myopathy, and muscular disorders, patients experiencing urticaria and skin and mucosal itchiness, and those who were not able to study due to personal or social reasons, were excluded from the study [ | PMC10182658 |
Developing mucoadhesive tablets | Mucoadhesive tablets were produced in the laboratory of Mazandaran medical university (Faculty of pharmacy). 10-mg atorvastatin mucoadhesive tablets were prepared with different proportions of the medicine and bioadhesive polymers such as HPMC or CMC. Tablets were prepared by direct compression method after weighing and complete mixing of medicine, polymer, and other excipients such as Avicel as a filler, Colloidal silicon dioxide as a glidant, and Magnesium stearate as a lubricant.In the present study, atorvastatin was manufactured by Tehran Chemical Company, Avicel was produced by Saba Chemical Company, Magnesium stearate was developed by Axin Chemical Company in Iran, and Aerosol was manufactured by Avonic Company in Germany. | PMC10182658 | ||
Study protocol | aphthous, pain | In this study, the evaluator and all patients in both groups were blinded. The patients were informed to visit the dental clinic during the first 24 h after the occurrence of aphthous lesions, and their first visit was regarded as the baseline (day 0). During the initial visit, patients were firstly assured about the safety of the project; then they were asked to read and sign the consent form and also complete the questionnaire containing the medical and dental history of patients. In the same session, the first mucoadhesive tablet was placed on the patient’s aphthous lesion by the examiner; notably, that the evaluator in this study was blinded and not conscious of the medicine which was given to each patient. Patients were informed to use the tablets 3 times daily in the morning, noon, and night. They were instructed how to use mucoadhesive tablets and advised to avoid eating and drinking for 30 min after usage and remove the tablet after 30 min. In the control group, the same procedure was performed with a placebo which contains all materials used in atorvastatin mucoadhesive tablets, except the primary substance, which is atorvastatin. All patients were advised not to use other anti-inflammatory medicines.To evaluate the amount of pain and healing of the lesions, the patients were clinically examined 0 (baseline), 3, 5, and 7 days later using a metal caliper to determine the diameter of the lesions and the inflammatory area around them [ | PMC10182658 | |
Data analysis | pain | After completing the data and information collection, the acquired data was entered into SPSS 24 software. Then, quantitative variables were reported using the mean ± standard deviation. A Chi-square test was used to compare gender distribution between the two groups. The normal distribution of quantitative variables was evaluated using the Kolmogorov-Smirnov test. The comparison of quantitative variables between the two groups was performed by independent T-test or Mann-Whitney test. Friedman’s test was performed to assess the changes in the erythematous aura and pain score over time, separating the intervention and control groups. The Generalized Estimated Equations (GEE) test was used to examine changes in the diameter of the inflammatory aura and pain intensity between the two groups over 7 days. A significance level of 0.05 was considered for all tests. | PMC10182658 | |
Results | pain | This study was conducted as a double-blinded clinical trial. Somehow, 44 patients who met the inclusion criteria of the study were selected from those who were referred to the dental clinic of Mazandaran University of Medical Sciences (18 men and 26 women) and completed the treatment and study period. At the same time, they were divided into two groups: intervention (Atorvastatin) and control (Placebo) groups. 22 patients were included in each study group and all patients were studied and examined for 7 days. To evaluate the diameter of the inflammatory halo, patients were clinically examined on the baseline (day zero), 3rd, 5th, and 7th days. The patients were also taught to determine the intensity of pain based on the VAS scale. Participants in this study reported no side effects or complaints from the mucoadhesive tablets (Fig.
CONSORT flowchartThe comparison of gender in the two groups showed that the distribution of gender in control (female: 59.1%, male: 40.9%), and atorvastatin (female: 59.1%, male: 40.9%) groups were not significantly different from each other and they were homogeneously distributed (P = 0.999). Also, the mean and standard deviation of the age in control (14.27 ± 39.09) and atorvastatin (13.64 ± 34.81) groups were examined, and according to the results of the Mann-Whitney test, the mean age in the two groups did not show a statistically significant difference (P = 0.372). | PMC10182658 | |
Inflammatory halo diameter | pain | STILL | Based on Friedman’s test, an intra-group comparison of the results showed that halo diameter decreased significantly during the study period in both the intervention and control groups. Still, the intensity of the decrease was faster and more noticeable in the atorvastatin group (P = 0.000) (Table
comparison of halo diameter and pain intensity during study in both groups
Halo diameter of treatment groups in time intervals | PMC10182658 |
Pain intensity | Pain, pain | Based on Friedman’s test results, intragroup comparison of patient pain intensity (VAS) showed a significant decrease from day one to seven in both intervention and control groups (P = 0.000) (Table In the inter-group comparison of pain intensity, no significant difference was found between the two groups on the first, second, and seventh days (P > 0.05). However, from the third day to the sixth day, the pain significantly decreased in the intervention group and the difference between the two groups was statistically significant (P < 0.05) (Table
Pain intensity by treatment group in time intervals | PMC10182658 | |
Discussion | aphthous lesions, granuloma, bone loss, Tahamtan, trauma, inflammation, cancer, blood lipid disorders, periodontitis, arthritis, pain, aphthous, aphthous ulcers, ulcer, orthodontic, Alzheimer | GRANULOMA, BONE LOSS, ULCER, SECONDARY INFECTION, INFLAMMATION, DISEASES, CANCER, PERIODONTITIS, ARTHRITIS, EPITHELIALIZATION, CHRONIC PERIODONTITIS, PROLIFERATIVE, APHTHOUS ULCERS, CHRONIC INFLAMMATION, OXIDATIVE STRESS, ACUTE AND CHRONIC INFLAMMATION, PATHOGENESIS, ALZHEIMER | This study examined the effect of atorvastatin mucoadhesive tablets on the diameter of the inflammatory halo and the pain intensity of aphthous ulcers in patients. This study was conducted as a double-blinded clinical trial on 44 patients participating in the study (22 patients in the atorvastatin group and 22 patients in the placebo group), and the findings of this study were compared inter-groups and intra-groups. The results of this study show that the halo diameter in the atorvastatin group had significantly reduced compared to the placebo group, so that on the seventh day of the study, the aphthous lesions in the atorvastatin group had improved significantly. However, in the placebo group, the average diameter of the inflammatory halo was more than one millimeter. The pain intensity of participants (VAS) showed a notable decrease in the atorvastatin group except on days one, two, and seven of the study. In addition, the pain reduction process was faster in the atorvastatin group than in the control group.Many studies have investigated the anti-inflammatory, analgesic, and antioxidant effects of atorvastatin [Statins are among the least complicated and most effective drugs used to treat blood lipid disorders. This category of drugs effectively reduces low-density lipoprotein in the blood; in addition, they have a beneficial outcomes in reducing oxidative stress, anti-inflammatory effects, immune modulation, analgesia, Etc. [Most of the side effects mentioned for atorvastatin are related to anti-inflammatory properties because inflammation plays a significant role in the pathogenesis of various diseases such as cancer, arthritis, and Alzheimer’s. The anti-inflammatory function of these drugs is mainly related to the reduction of C-reactive protein, which is one of the most prominent factors in inflammation. However, in various studies, many other processes have been described for this function [The analgesic effect of atorvastatin is caused by processes such as inhibiting cytokines, MMP-2, and NGF in the sciatic nerves and spinal cord, as well as increasing the level of antioxidants and reducing the production of prostaglandins, all of which act in peripheral sensory receptors [Masoumi et al. investigated the effect of oral atorvastatin and local injection of this drug on treating periodontitis in rats. This study states that both forms of atorvastatin reduce inflammation and the cascade of oxidant production and subsequent tissue destruction, as well as bone loss caused by collagen destruction in periodontitis. The results obtained from systemic use are not significantly different from topical use, but the topical form of this drug is preferable due to fewer side effects [In a study, Tahamtan et al. systemically reviewed articles related to the effects of Statins on oral and dental health. In their research, due to the positive impact of Statins on bone metabolism, inflammation, and antioxidant properties, also strong effects on epithelialization and wound healing, and antibacterial, antiviral and, antifungal properties, the effect of this drug on oral health was investigated. The study’s results demonstrated that Statins have a significant impact on chronic periodontitis, implant osseointegration, orthodontic dental movements, soft and hard tissue repair, anticancer effects, Etc. [Ghasias et al. investigated the antioxidant, analgesic, and anti-inflammatory function of atorvastatin and rosuvastatin in different animal models, the findings showed that these two medicines have no effect on central pain receptors, but their analgesic property is due to their role in peripheral analgesic processes so that they observed a remarkable inhibition of pain caused by acetic acid, which leads to pain sensation by increasing the levels of PGE2 and PGF2a. It was also observed that atorvastatin reduces pain sensitivity by reducing bradykinin and cytokines; as a result, the analgesic effect observed in atorvastatin is similar to the effect of anti-inflammatory agents. Examining the anti-inflammatory effect of these two medicines on acute and chronic inflammation showed that atorvastatin reduces acute inflammation by inhibiting the release of bradykinin, prostaglandin, and substance P. In chronic inflammation, these medicines reduce the mass of granuloma by inhibiting the proliferative phase of inflammation. The oxidative stress reduction action of these two drugs is also due to the increase in cellular antioxidants, the decrease in NADPH oxidase expression, and the regulation of catalase overexpression [Nowadays, the use of mucoadhesive tablets made with herbals and chemicals is a common method in the treatment of aphthous lesions, and many studies have been conducted in this field, which includes the efficacy of mucoadhesive tablets containing propolis, licorice, and zinc sulfate on aphthous lesions. The results of these studies were favorable and promising because the combination of the medicines with mucoadhesive tablets has anti-inflammatory properties; on the other hand, the tablets last longer at the lesion site and increase the treatment effectiveness [In general, the use of topical mucoadhesive tablets is a new and efficient method against mechanical trauma and inflammation of the lesion. In fact, in this method, a protective layer is created on the lesion as an auxiliary method and decreases the pain and discomfort caused by aphthous lesions and eliminates the lesion faster. Among the other advantages of this method, we can indicate the prevention of secondary infection of the ulcer, and as a result, no antibiotic or antifungal prescription will be needed [According to the previous studies and considering the findings of the present study, it seems that the significant reduction in the size of the aphthous lesion and the pain intensity of patients in the atorvastatin group compared with a control group is related to the anti-inflammatory, analgesic or antioxidant properties of atorvastatin. However, due to the lack of similar articles in this field, we cannot only rely on this study and judge atorvastatin mucoadhesive tablets efficacy, and more studies are needed on this subject. In addition, the lack of direct access to patients during the seven days of study can be considered another limitation of this study. | PMC10182658 |
Conclusion | aphthous, pain | RECURRENCE, RECURRENT APHTHOUS STOMATITIS | The results of this study show that the atorvastatin mucoadhesive tablets effectively reduce the pain and discomfort of patients and cause the healing and size reduction of aphthous lesions. So these tablets may be effective in the treatment of patients with recurrent aphthous stomatitis due to their anti-inflammatory and wound-healing properties. However, further studies with larger sample sizes should be conducted. Furthermore, the effect of these tablets on the recurrence of RAS and the application of these tablets in treating other oral lesions can be considered in future studies. | PMC10182658 |
Acknowledgements | We would like to thank all participants who contributed to this study, the research center of Mazandaran University of Medical Sciences, and all who helped in the completion of this study. | PMC10182658 | ||
Funding | No funding resources were used in this research. | PMC10182658 | ||
Data availability | All data generated or analyzed during this study are included in this published article. | PMC10182658 | ||
Declarations | PMC10182658 | |||
Ethics approval and consent to participate | All methods were carried out in accordance with relevant guidelines and regulations. Informed consent was obtained from all subjects and/or their legal guardian(s).The present study was approved by the Medical Ethics Committee of Mazandaran University of Medical Sciences with the ethics code IR.MAZUMS.REC.1400.8346. Also, this study received code IRCT20170430033722N4. | PMC10182658 | ||
Consent for publication | Not applicable. | PMC10182658 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10182658 | ||
Abbreviations | Aphthous | Visual Analogue ScaleRecurrent Aphthous StomatitisGeneralized Estimated Equations | PMC10182658 | |
References | PMC10182658 | |||
Introduction | fractures, Cut-out | Cut-out is the most frequently reported mechanical failure of internal fixation of pertrochanteric fractures. The purpose of this study was to examine if hydroxyapatite-coated screw thread on a sliding hip screw (SHS) could reduce screw migration within the femoral head in patients with stable pertrochanteric fractures. | PMC10503211 | |
Materials and methods | fracture, pertrochanteric fracture | EVANS | In a double-blinded randomized controlled study, 37 patients at mean age 78 (range 56–96), with pertrochanteric fracture (Evans I, II, IV) received surgery with a SHS with a hydroxyapatite-coated or a non-coated lag screw thread. Radiostereometry and standard radiographs were obtained 1 day, 6 weeks, 3- and 6 months post-operatively to evaluate screw and fracture migration and fracture reposition. The two groups were combined to describe fracture migration. | PMC10503211 |
Results | There was similar and small screw migration in the femoral head between the two groups at 6 weeks, 3- and 6 months ( | PMC10503211 | ||
Conclusion | fracture, fractures | There was no clinical benefit of hydroxyapatite coating on lag screw migration in this patient cohort. Migration of the pertrochanteric fractures was higher with poor fracture reposition but fractures generally stabilized after 6 weeks follow-up. The study was registered at ClinicalTrials.gov (NCT05677061). | PMC10503211 | |
Highlights | fracture, fractures | FRACTURE COMPRESSION |
Hydroxyapatite coating on the screw thread did not improve screw fixation in the femoral head of a sliding hip screw in pertrochanteric fractures.Displacement of pertrochanteric fractures operated with a sliding hip screw was primarily a fracture compression across the screw axis.Pertrochanteric fractures operated with a sliding hip screw stabilized after 6 weeks indicating fracture healing. | PMC10503211 |
Keywords | PMC10503211 | |||
Introduction | femoral neck fractures, fracture, fractures | Hip fractures come at a high cost for the patient, the healthcare system, and for society [The failure rate of pertrochanteric fracture fixation has been reported from 2% and up to 20% [Radiostereometric analysis (RSA) have proven useful, accurate and precise for three-dimensional measurement of the displacement of femoral neck fractures after osteosynthesis and for migration of orthopaedic implants in the bones [ | PMC10503211 | |
Patients and methods | fracture | EVANS, WEST, MINOR, DETACHMENT | The study was designed as a double-blinded randomized clinical trial, with blinding for patients and outcome assessors but not to the surgeons. Between December 2008 and January 2013, 37 patients were enrolled having sustained a stable pertrochanteric fracture with an intact greater trochanter and lateral femoral wall, regardless of detachment of the minor trochanter (Evans type I, II and IV). Patients were operated at two centers: Copenhagen University Hospital, Hvidovre, and Holstebro Regional Hospital, Hospital Unit West, Holstebro. Patients were randomly assigned to a lag screw with either a HA-coated screw thread or a NON-coated screw thread (Fig. CONSORT flow chart showing the inclusion/exclusion process until 6-month final follow-up | PMC10503211 |
Criteria | fracture, fractures | The inclusion criteria were: patients > 50 years of age admitted with a stabile pertrochanteric fracture, able to speak Danish and sign the written consent, and expected to be able to complete the postoperative controls. The exclusion criteria were: patients who were unable to follow the standard hip fracture regime, were breastfeeding, pregnant, terminal ill, in need of an open fracture reduction, in need of a SHS lateral plate with an angle different from 135° or longer than 4 holes, fractures where fewer than 3 tantalum beads were inserted in the femoral head, Tip Apex Distance (TAD) > 20 mm in two dimensions on the first post-operative X-ray, fracture displacement > 20 mm in two dimensions on the first post-operative X-ray. | PMC10503211 | |
Sample size | A power analysis was performed using the y-translation screw migration measure of the first 4 patients (pilot group) after 6 months follow-up. Expecting a 40% loss of fixation with NON-coated screws [ | PMC10503211 | ||
Implants | All patients received a 4-hole 135° SHS plate (HipLOC™, Biomet, Warsaw, IN, USA). All lag screws were marked preoperatively with 4 tantalum beads in a specific predetermined pattern (Fig. Sliding hip screw marked with 4 tantalum markers. | PMC10503211 | ||
Surgery | thrombosis, femoral head position | THROMBOSIS, BLOOD, AIDS | All surgeries were performed by or under direct supervision of an orthopedic surgeon. The procedure was performed under general anesthesia with the leg under traction using an approximately 10 cm lateral thigh incision and with the vastus lateralis muscle held anteriorly. A k-wire was placed using a 135° guide and fluoroscopy to aim for a central femoral head position in both the anterior–posterior (AP) and lateral (LAT) plane. After reaming the implant canal, 6 1-mm tantalum beads were inserted in the femoral head/neck fragment, and 7 tantalum beads were inserted into the greater and lesser trochanter with an 18 cm long bead gun (Wennbergs Finmek, Gunilse, Sweden). Randomization was done after tantalum bead placement. Subsequently, the screw length was measured and the screw and a 4-hole plate was inserted. The wound was closed using resorbable 2–0 suture in the fascia and subcutaneous tissue and nylon 4–0 skin suture. Post-surgery, patients were mobilized with full weight bearing and walking aids as needed. Cefuroxime (Braun, Frederiksberg, Denmark) 1500 mg intra-venous (IV) administration was used as preoperative antimicrobial prophylaxis. Low molecular weight heparin (Dalteparin, Pfizer, Ballerup, Denmark) 5000 international units (IU) was used for thrombosis prophylaxis preoperative as needed and 12 h post-operative for 7 days. Blood transfusion was given postoperative upon anemic symptoms and low hemoglobin level (< 6.0 mmol/L). | PMC10503211 |
Radiostereometric analysis | The first RSA recording was performed within 24 h after surgery and after the patient had been weight-bearing. A standard RSA system with 2 synchronized ceiling fixed roentgen tubes angled 40° towards each other and a uniplanar calibration box (Carbon Box 19, RSAcore, Leiden, The Netherlands) was used [RSA analysis was done marker-based with an EGS cylinder model referenced to the lag screw to align the coordinate system in the screw y-axis (yellow). The x-axis (red) was aligned with the horizontal image plane and the z-axis (green was directed out of plane. The screw markers (red), the head/neck markers (pink), and trochanter markers (blue) were combined in marker-models for each model. The direction of the displayed axes (x, y and z) corresponds to positive values | PMC10503211 | ||
RSA precision | The condition number (CN), describing the dispersion of the marker model, was mean 298 (SD 346) in the greater/lesser trochanter, mean 126 (SD 16) for the screw, and mean 120 (SD 61) for the head/neck segment. The rigid body error for marker stability was set at 0.35 mm. When accepting CN higher than 150, the verification of precision is essential [ | PMC10503211 | ||
Radiographic evaluation | fracture | EVANS | An experienced surgeon classified the pertrochanteric fracture according to Evans classification [ | PMC10503211 |
Patient reported and clinical outcomes | fracture, NMS | NMS | Patient evaluation was performed pre-operatively asking patients to recall their status before the fracture self-reported mobility level with new mobility score (NMS) (0–9 points) [ | PMC10503211 |
Statistics | fracture | IMPACTION | Normality of the data distribution was assessed by probability plots. Data following a normal distribution was reported with 95% confidence intervals (CI 95%) and data with non-normal distribution was reported as median values with interquartile range (IQR). Hypotheses of no difference for clinical, patient reported, and radiographic variables comparing the HA-coated group with the NON-coated group was tested statistically using Student’s t-test for normally distributed data Wilcoxon signed-rank test for data with a non-normal distribution. Chi-squared test was used to test categorical data, i.e., screw placement in the femoral head.RSA measured migration during the follow-up was evaluated as 1) screw migration – with reference to the femoral head/neck segment, and as 2) fracture migration (femoral head/neck segment) – with reference to the trochanter region. Further, fracture migration from baseline to 6 weeks (impaction phase) and from 6 weeks to 6 months (stabilization phase) was compared for all patients. Hypotheses of no difference in screw migration between the HA-coated and the NON-coated group was analyzed using univariate repeated measurement analysis (mixed model) on follow-up time with group HA-coated/NON-coated as fixed effects, and patient as random effect. We used pairwise group comparisons for each follow-up time to describe differences. Unequal standard deviations and correlations of the groups were considered in the analyses. Normal distribution of the mixed-model residuals was tested by Q–Q plots. As no statistically significant or clinically important differences were found between the groups regarding screw migration, the groups were combined for the further statistical analysis (mixed model) of fracture migration during the impaction phase and stabilization phase. Repeatability of RSA double examinations were estimated and reported as absolute mean differences and prediction intervals (1.96 × SD). We used Stata 16 (StataCorp, College Station, TX, USA) for statistical analysis. The statistical significance was set at | PMC10503211 |
Ethics, registration and funding | MAY | The study was approved by the Danish National Scientific Committee on Research Ethics (H-KF-298036, issue date May 3rd, 2006) and Data Protection Agency (2008-41-2757, issue date March 3rd, 2006) and was performed in agreement with the Helsinki ll declaration. The study was registered at ClinicalTrials.gov (NCT05677061) | PMC10503211 | |
Results | PMC10503211 | |||
Demographics | The consort study flowchart and the baseline patient demographics are shown in Fig. Demographics at baselineASA score: American Society of Anesthesiology physical classification score system, | PMC10503211 |
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